R G

d V
ti e
U n
-
9 9
i r
a h
t
 Any screen.
Any time.
Anywhere.
Activate the eBook version
e.
of this title at no additional charge.

Expert Consult eBooks give you the power to browse and find content,
view enhanced images, share notes and highlights—both online and offline.

Unlock your eBook today.

1 Visit expertconsult.inkling.com/redeem
Scan this QR code to redeem your
2 Scratch off your code eBook through your mobile device:

3 Type code into “Enter Code” box

4 Click “Redeem”
5 Log in or Sign Up
6 Go to “My Library”
It’s that easy!

For technical assistance:

email expertconsult.help@elsevier.com
call 1-800-401-9962 (inside the US)
call +1-314-447-8200 (outside the US)
Use of the current edition of the electronic version of this book (eBook) is subject to the terms of the nontransferable, limited license granted on expertconsult.inkling.com.
Access to the eBook is limited to the first individual who redeems the PIN, located on the inside cover of this book, at expertconsult.inkling.com and may not be
transferred to another party by resale, lending or other means.
 G
VIDEO CONTENTS

R
Videos available at expertconsult.inkling.com
37-1 Shave biopsy
37-2 Punch biopsy
37-3 Narrow hole lipoma excision

d V
ti e
37-4 Excision
37-5 Fusiform excision

n
37-6 Transposition flap
37-7 Split thickness skin graft
37-8 Mohs surgery

-
38-1 Full face ablative resurfacing
39-1 Filler, lips
U
9
39-2 Botulinum toxin, glabella

ri 9
39-3 Botulinum toxin, frontalis
39-4 Starch iodine test for hyperhidrosis

h
39-5 Botulinum toxin, hyperhidrosis axilla

a
39-6 Sclerotherapy

t
39-7 Foam sclerotherapy
This page intentionally left blank
 Diseases
Andrews’

of
the
Skin
G
R
CLINICAL DERMATOLOGY

V
d
ti e
U n
-
9
ri 9
a h
t
Executive Content Strategist: Russell Gabbedy
Senior Content Development Specialist: Ailsa Laing
Publishing Services Manager: Patricia Tannian
Senior Project Manager: John Casey
Designer: Christian Bilbow
Original cover images: Upper left: Dr. Donald Adler (deceased);
Upper right: Dr. Shyam Verma; Center: Dr. Debabrata Bandyopadhyay;
Lower right: Dr. William D. James.
 Diseases
Andrews’
G
V R
Skin
n
ti e
d of
the

U
CLINICAL DERMATOLOGY

-
9
Twelfth Edition

ri 9
William D. James, MD Timothy G. Berger, MD
Paul R Gross Professor of Dermatology Professor of Clinical Dermatology
Department of Dermatology Executive Vice Chair and Residency

h
University of Pennsylvania School of Medicine Program Director

a
Philadelphia, Pennsylvania Chair in Dermatology Medical Student

t
Education
Dirk M. Elston, MD University of California, San Francisco
San Francisco, California
Professor and Chairman
Department of Dermatology
and Dermatologic Surgery tahir99 (blink99)
Medical University of South Carolina UnitedVRG, Original Release.
Charleston, South Carolina; https://kat.cr/user/Blink99/
Former Director
Ackerman Academy of Dermatopathology
New York, New York
 John . ennedy Bl d.
Ste.
Philadelphia PA

ANDREWS’ DISEASES OF THE SKIN: CLINICAL DERMATOLOGY,

TWELFTH EDITION ISBN: 978-0-323-31967-6
International Edition ISBN: 978-0-323-31968-3
Copyright © 2016 by Elsevier, Inc. All rights reserved.
th
edition by lse ier nc.

o part o this publication may be reproduced or transmitted in any orm or by any means
electronic or mechanical including photocopying recording or any in ormation storage
and retrie al system without permission in writing rom the publisher. Details on how to
see permission urther in ormation about the Publisher s permissions policies and our
arrangements with organi ations such as the Copyright Clearance Center and the
Copyright Licensing Agency can be ound at our website www.else ier.com permissions.

This boo and the indi idual contributions contained in it are protected under copyright by
the Publisher (other than as may be noted herein).

Notices
nowledge and best practice in this eld are constantly changing. As new research and
e perience broaden our understanding changes in research methods pro essional practices
or medical treatment may become necessary.
Practitioners and researchers must always rely on their own e perience and nowledge
in e aluating and using any in ormation methods compounds or e periments described
herein. n using such in ormation or methods they should be mind ul o their own sa ety
and the sa ety o others including parties or whom they ha e a pro essional responsibility.
With respect to any drug or pharmaceutical products identi ed readers are ad ised to
chec the most current in ormation pro ided (i) on procedures eatured or (ii) by the
manu acturer o each product to be administered to eri y the recommended dose or
ormula the method and duration o administration and contraindications. t is the
responsibility o practitioners relying on their own e perience and nowledge o their
patients to ma e diagnoses to determine dosages and the best treatment or each
indi idual patient and to ta e all appropriate sa ety precautions.
To the ullest e tent o the law neither the Publisher nor the authors contributors or
editors assume any liability or any in ury and or damage to persons or property as a
matter o products liability negligence or otherwise or rom any use or operation o any
methods products instructions or ideas contained in the material herein.

International Standard Book Number: ISBN: 978-0-323-31967-6

Printed in China
Last digit is the print number
 CONTENTS

1 Skin: Basic Structure and Function 1 20 Parasitic Infestations, Stings, and Bites 418
2 Cutaneous Signs and Diagnosis 11 21 Chronic Blistering Dermatoses 451
3 Dermatoses Resulting from 22 Nutritional Diseases 471
Physical Factors 18
23 Diseases of Subcutaneous Fat 480
4 Pruritus and Neurocutaneous Dermatoses 45

G
24 Endocrine Diseases 491
5 Atopic Dermatitis, Eczema, and

R
25 Abnormalities of Dermal Fibrous
Noninfectious Immunodeficiency Disorders 62
and Elastic Tissue 500
6 Contact Dermatitis and Drug Eruptions
7 Erythema and Urticaria
90
136
d V
26 Errors in Metabolism 509

ti e
27 Genodermatoses and
8 Connective Tissue Diseases 153 Congenital Anomalies 542
9 Mucinoses
10 Seborrheic Dermatitis, Psoriasis,
179

U n
28 Dermal and Subcutaneous Tumors
29 Epidermal Nevi, Neoplasms, and Cysts
579
625

-
Recalcitrant Palmoplantar Eruptions,
30 Melanocytic Nevi and Neoplasms 680
Pustular Dermatitis, and Erythroderma 185

9
31 Macrophage/Monocyte Disorders 699
11 Pityriasis Rosea, Pityriasis Rubra

ri 9
Pilaris, and Other Papulosquamous 32 Cutaneous Lymphoid Hyperplasia,
and Hyperkeratotic Diseases 199 Cutaneous T-Cell Lymphoma,

h
Other Malignant Lymphomas, and
12 Lichen Planus and Related Conditions 209

a
Allied Diseases 726

t
13 Acne 225
33 Diseases of the Skin Appendages 747
14 Bacterial Infections 245
34 Disorders of the Mucous Membranes 789
15 Diseases Resulting from Fungi
35 Cutaneous Vascular Diseases 807
and Yeasts 285
36 Disturbances of Pigmentation 856
16 Mycobacterial Diseases 319
37 Dermatologic Surgery 874
17 Hansen’s Disease 331
38 Cutaneous Laser Surgery 901
18 Syphilis, Yaws, Bejel, and Pinta 343
39 Cosmetic Dermatology 913
19 Viral Diseases 359

v
This page intentionally left blank
 PREFACE AND ACKNOWLEDGMENTS
n rews remains as it was rom the beginning an authored
te t whose one olume is lled with clinical signs symptoms
diagnostic tests and therapeutic pearls. The authors ha e
remained general clinical dermatologists in an era o subspe
cialists in academia. They are committed to eeping n rews
as an e cellent tool or anyone who needs help in diagnosing
a patient with a clinical conundrum or treating a patient with
a therapeutically challenging disease.
n rews is primarily intended or the practicing dermatolo
gist. t is meant to be used on the des top at his or her clinic
gi ing consistent concise ad ice on the whole spectrum o
clinical situations aced in the course o a busy wor day. While
we ha e been true to our commitment to a single olume
wor we pro ide our te t in a con enient online ormat as
well. Because o its relati e bre ity but complete co erage o
our eld many nd the te t ideal or learning dermatology
or the rst time. t has been a mainstay o the resident yearly
curriculum or many programs. We are hope ul that trainees
will learn clinical dermatology by studying the clinical descrip
tions disease classi cations and treatment insights that de ne
n rews . We belie e that students interns internists or other
medical specialists amily practitioners and other health pro
essionals who desire a comprehensi e dermatology te tboo
will nd that ours meets their needs. Long time dermatolo
gists will hope ully disco er n rews to be the needed update
that satis es their li elong learning desires. n our collecti e
trips around the world we ha e been grati ed to see our
international colleagues studying n rews . Thousands o
boo s ha e been purchased by Chinese and Bra ilian derma
tologists alone.
any ma or changes ha e been made to this edition. Bill
James Tim Berger and Dir lston three great riends o o er
three decades ha e wor ed closely to continue to impro e the
uality o our te t. The surgical chapters ha e been updated
and e panded by saac euhaus. e has added ideos o some
o the most common procedures which are a ailable online.
We than him or his continued wor to impro e this portion
o our te tboo . Robert icheletti e pertly updated Chapters
and . e is an internist dermatologist with superior
writing s ills whose contributions are most appreciated. We
ha e tried to ensure that each entity is discussed only once in
a complete yet concise manner. n order to do this we ha e
had to ma e decisions regarding the placement o disease
processes in only one site. Clearly neutrophilic eccrine hidrad
enitis or e ample could be presented under drug eruptions
neutrophilic reacti e conditions in ection or cancer associated
disease or with eccrine disorders. The nal decisions are a
team e ort and made in the interest o eliminating redun
dancy. This allows us to present our uni ed philosophy in
treating patients in one dense olume.
edical science continues to progress at brea nec speed.
ur understanding o the etiology o certain conditions has
now led us to recategori e well recogni ed disease states and
dictated the addition o many newly described entities. olec
ular in estigati e techni ues technologic brea throughs and
designer therapeutics lead the way in pro iding ad ances in
our specialty. We co er the new understanding ollowing
rom such inno ations by discussing the mechanisms at wor
in genetic diseases co ering the latest in dermatopathologic
staining and analysis and enlarging the therapeutic recom
mendations to include our e panded therapeutic options such
as biologic response modi ers and biologically engineered tar
geted medications. We ha e attempted to de ne therapeutics
in a ashion that emphasi es those inter entions with the
highest le el o e idence but also present less critically in es
tigated therapeutic options. To care or our patients we need
a large array o options. ot all are ully supported by ormal
e idence yet are help ul to indi idual patients.
tensi e re isions were necessary to add this wealth o new
in ormation. We selecti ely discarded older concepts. By elimi
nating older not currently use ul in ormation we maintain the
brie but complete one olume presentation that we and all
pre ious authors ha e emphasi ed. Additionally older re er
ences ha e been updated. The classic early wor s are not cited;
instead we ha e chosen to include only new citations and let
the bibliographies o the current wor pro ide the older re er
ences as you need them. A ma or e ort in this edition was to
reillustrate the te t with hundreds o new color images. any
ha e been added to the printed te t; you will also nd a
number only in the online ersion. n oy We ha e loo ed to
our own collections to accomplish this. These are the result o
many hours o personal e ort the generosity o our patients
and a large number o residents and aculty o the programs
in which we currently wor or ha e wor ed in the past. Addi
tionally riends and colleagues rom all parts o the globe ha e
allowed us to use their photographs. They ha e gi en their
permission or use o these wonder ul educational photos to
enhance your understanding o dermatology and how s in
diseases a ect our patients. We cannot than them enough.
All o the authors recogni e the importance o our mentors
teachers colleagues residents and patients in orming our
collecti e e pertise in dermatology. Dir Tim and Bill were
all trained in military programs and our indebtedness to this
ellowship o clinicians is unbounded. The many institutions
we ha e called home rom the ast Coast o Walter Reed the
ni ersity o Pennsyl ania and Geisinger edical Center to
the West Coast o the ni ersity o Cali ornia at San rancisco
and many in between such as Broo e in San Antonio and the
Cle eland Clinic nurtured us and e panded our hori ons.
ur riendship goes well beyond the limits o our pro ession;
it is wonder ul to wor with people you not only respect as
colleagues but also en oy as closely as amily. Barbara Lang
and Laura Bec erman pro ided e pert assistance throughout
the re ision process to Bill and Tim respecti ely. We are
indebted to their hard wor . inally we are proud to be a part
o the lse ier team and ha e such pro essionals as Ailsa
Laing John Casey and Russell Gabbedy supporting us e ery
step o the way.
vii
 DEDICATION

The authors left to right : Tim Berger Bill James Dir lston

or m famil whose love an support sustain me an ma e me happ

WDJ

M wife essica an m chil ren Olivia an Mateo who give me the jo an

strength to un erta e such a tas
TGB

o m wife an best frien ath an our won erful chil ren Carl an ate
D

viii
 CONTRIBUTORS

Isaac M. Neuhaus, MD
Associate Pro essor
Dermatologic Surgery and Laser Center
ni ersity o Cali ornia San rancisco
San rancisco Cali ornia

Robert G. Micheletti, MD
Assistant Pro essor o Dermatology and edicine
ni ersity o Pennsyl ania
Perelman School o edicine
Philadelphia Pennsyl ania

ix
This page intentionally left blank
 Bonus images for this chapter can be found online at
Skin: Basic Structure and Function
S in is composed o three layers the epidermis dermis and
subcutaneous at (panniculus) ( ig. ). The outermost layer
the epidermis is composed o iable eratinocytes co ered by
a layer o eratin the stratum corneum. The principal compo
nent o the dermis is the brillar structural protein collagen.
The dermis lies on the panniculus which is composed o
lobules o lipocytes separated by collagenous septa that contain
the neuro ascular bundles.
There is considerable regional ariation in the relati e thic
ness o these layers. The epidermis is thic est on the palms
and soles measuring appro imately . mm. t is ery thin on
the eyelid where it measures less than . mm. The dermis is
thic est on the bac where it is times as thic as the
o erlying epidermis. The amount o subcutaneous at is gener
ous on the abdomen and buttoc s compared with the nose and
sternum where it is meager.
EPIDERMIS AND ADNEXA
During the rst wee s o li e the etus is co ered by a layer
o non eratini ing cuboidal cells called the periderm ( ig. ).
Later the periderm is replaced by a multilayered epidermis.
Adne al structures particularly ollicles and eccrine sweat
units originate during the third month o etal li e as down
growths rom the de eloping epidermis. Later apocrine sweat
units de elop rom the upper portion o the ollicular epithe
lium and sebaceous glands rom the midregion o the ollicle.
Adne al structures appear rst in the cephalic portion o the
etus and later in the caudal portions.
The adult epidermis is composed o three basic cell types
eratinocytes melanocytes and Langerhans cells. An addi
tional cell the er el cell can be ound in the basal layer o
the palms and soles oral and genital mucosa nail bed and
ollicular in undibula. Located directly abo e the basement
membrane one er el cells contain intracytoplasmic dense
core neurosecretory li e granules and through their associa
tion with neurites act as slow adapting touch receptors. They
ha e direct connections with ad acent eratinocytes by desmo
somes and contain a paranuclear whorl o intermediate eratin
laments. Both polyclonal eratin immunostains and mono
clonal immunostaining or eratin stain this whorl o
eratin laments in a characteristic paranuclear dot pattern.
er el cells also label or neuroendocrine mar ers such as
chromogranin and synaptophysin.
Keratinocytes
eratinocytes or s uamous cells are the principal cells o the
epidermis. They are o ectodermal origin and ha e the special
i ed unction o producing eratin a comple lamentous
protein that not only orms the sur ace coat (stratum corneum)
o the epidermis but also is the structural protein o hair and
nails. ultiple distinct eratin genes ha e been identi ed and
expertconsult.inkling.com
1
consist o two sub amilies acidic and basic. The product o one
basic and one acidic eratin gene combines to orm the mul
tiple eratins that occur in many tissues. The presence o
arious eratin types is used as a mar er or the type and
degree o di erentiation o a population o eratinocytes. er
atins are critical or normal unctioning o the epidermis and
eratin mutations are recogni ed causes o s in disease. uta
tions in the genes or eratins and are associated with
epidermolysis bullosa simple . eratin and mutations are
associated with epidermolytic hyper eratosis. ild orms o
this disorder may represent locali ed or widespread e pres
sions o mosaicism or these gene mutations.
The epidermis can be di ided into the innermost basal layer
(stratum germinati um) the malpighian or pric le layer
(stratum spinosum) the granular layer (stratum granulosum)
and the horny layer (stratum corneum). n the palms and
soles a pale clear to pin layer the stratum lucidum is noted
ust abo e the granular layer. When the s in in other sites is
scratched or rubbed the malpighian and granular layers
thic en a stratum lucidum orms and the stratum corneum
becomes thic and compact. istones appear to regulate epi
dermal di erentiation and histone deacetylation suppresses
e pression o pro laggrin. Slow cycling stem cells pro ide a
reser oir or regeneration o the epidermis. Sites rich in stem
cells include the deepest portions o the rete especially on
palmoplantar s in as well as the hair bulge. Stem cells di ide
in re uently in normal s in but in cell culture they orm
acti e growing colonies. They can be identi ed by their high
e pression o β integrins and lac o terminal di erentiation
mar ers. Stem cells can also be identi ed by their low le els
o desmosomal proteins such as desmoglein . The basal cells
di ide and as their progeny mo e upward they atten and
their nucleus disappears. Abnormal eratini ation can mani
est as para eratosis (retained nuclei) as corps ronds (round
clear to pin abnormally eratini ed cells) or as grains (elon
gated basophilic abnormally eratini ed cells).
During eratini ation the eratinocyte rst passes through
a synthetic and then a degradati e phase on its way to becom
ing a horn cell. n the synthetic phase within its cytoplasm the
eratinocyte accumulates intermediate laments composed
o a brous protein eratin arranged in an α helical coiled
pattern. These tono laments are ashioned into bundles which
con erge on and terminate at the plasma membrane where
they end in speciali ed attachment plates called desmosomes.
The degradati e phase o eratini ation is characteri ed by the
disappearance o cell organelles and the consolidation o all
contents into a mi ture o laments and amorphous cell en e
lopes. This programmed process o maturation resulting in
death o the cell is called terminal di erentiation. Terminal
di erentiation is also seen in the in oluting stage o eratoac
anthomas where the initial phase o proli eration gi es way
to terminal eratini ation and in olution.
Premature programmed cell death or apoptosis appears in
hemato ylin and eosin ( ) stained sections as scattered
bright red cells some o which may contain small blac
1
1 Apocrine
Skin: Basic Structure and Function
Epidermis
Meissner nerve
ending
papillary
Dermis
reticular
Sebaceous gland
Arrector pili muscle
Hair shaft
Pacini nerve ending
Subcutaneous tissue
Fig. 1-1 Diagrammatic cross section of the skin and panniculus.
Fig. 1-2 Fetal periderm covering fetal mesenchyme.
py notic nuclei. These cells are present at arious le els o the
epidermis because this orm o cell death does not represent
part o the normal process o maturation. Widespread apop
tosis is noted in the errucous phase o incontinentia pigmenti.
t is also a prominent nding in catagen hairs where apoptosis
results in the in olution o the in erior segment o the hair
ollicle.
n normal s in the plasma membranes o ad acent cells are
separated by an intercellular space. lectron microscopic his
tochemical studies ha e shown that this interspace contains
glycoproteins and lipids. Lamellar granules ( dland bodies or
membrane coating granules) appear in this space primarily at
the inter ace between the granular and corni ed cell layers.
Lamellar granules contribute to s in cohesion and imperme
ability. Conditions such as lamellar ichthyosis and legel s
hyper eratosis demonstrate abnormal lamellar granules.
Glycolipids such as ceramides contribute a water barrier
unction to s in and are typically ound in topical products
meant to restore the epidermal barrier. Lamellar bodies orm
2
unit
Straight duct
Coiled gland
Eccrine
sweat unit
Spiraled duct
Straight duct
Coiled duct
Eccrine gland
Dermal
vasculature
Superficial plexus
Deep plexus
abnormally in the absence o critical ceramides such as gluco
sylceramide or there is disproportion o critical lipids. Des
mosomal adhesion depends on cadherins including the
calcium dependent desmogleins and desmocollins. Antibod
ies to these molecules result in immunobullous diseases but
desmogleins unction not only in adhesion but also in di er
entiation. The binding o the desmoglein cytoplasmic tail to
the sca olding protein rbin downregulates the Ras Ra
pathway to promote strati cation and di erentiation o era
tinocytes in the epidermis.
eratinocytes o the granular one contain in addition to
the eratin lament system eratohyaline granules com
posed o amorphous particulate material o high sul ur
protein content. This material pro laggrin is a precursor to
laggrin so named because it is thought to be responsible or
eratin lament aggregation. Con ersion to laggrin ta es
place in the granular layer and this orms the electron dense
inter lamentous protein matri o mature epidermal eratin.
alli rein related peptidase a serine protease secreted
rom lamellar granules appears to unction in pro llagrin
clea age.
eratohyalin is hygroscopic and repeated cycles o hydra
tion and dehydration contribute to normal des uamation o
the stratum corneum. chthyosis ulgaris is characteri ed by
a diminished or absent granular layer contributing to the
retention hyper eratosis noted in this disorder. eratohyalin
results in the ormation o so t e ible eratin. eratin that
orms in the absence o eratohyaline granules is typically
hard and rigid. air bers and nails are composed o hard
eratin.
eratinocytes play an acti e role in the immune unction o
the s in. n conditions such as allergic contact dermatitis these
cells participate in the induction o the immune response
rather than acting as passi e casualties. eratinocytes secrete
a wide array o cyto ines and in ammatory mediators includ
ing tumor necrosis actor (T ) α. They also can e press mol
ecules on their sur ace such as intercellular adhesion molecule
( CA ) and ma or histocompatibility comple ( C)
class molecules suggesting that eratinocytes acti ely
respond to immune e ector signals.
Melanocytes
elanocytes are deri ed rom the neural crest and by the
eighth wee o de elopment can be ound within the etal
epidermis. n normal sun protected trun epidermis melano
cytes reside in the basal layer at a re uency o about in e ery
basal eratinocytes. Areas such as the ace shins and geni
talia ha e a greater density o melanocytes and in hea ily
sun damaged acial s in art immunostaining can demon
strate ratios o melanocytes to basal eratinocytes that
approach . Recognition o the ariation in melanocyte
eratinocyte ratio is critical in the interpretation o biopsies o
suspected lentigo maligna (malignant melanoma in situ) on
sun damaged s in.
Racial di erences in s in color are not caused by di erences
in the number o melanocytes. t is the number si e and dis
tribution o the melanosomes or pigment granules within
eratinocytes that determine di erences in s in color. Pale
s in has ewer melanosomes and these are smaller and pac
aged within membrane bound comple es. Dar s in has more
melanosomes and these tend to be larger and singly dis
persed. Chronic sun e posure can stimulate melanocytes to
produce larger melanosomes thereby ma ing the distribution
o melanosomes within eratinocytes resemble the pattern
seen in dar s inned indi iduals.
n histologic sections o s in routinely stained by the
melanocyte appears as a cell with ample amphophilic cyto
plasm or as a clear cell in the basal layer o the epidermis.
The apparent halo is an arti act ormed during ation o the
specimen. This occurs because the melanocyte lac ing tono
laments cannot orm desmosomal attachments with erati
nocytes. eratinocytes also re uently demonstrate clear
spaces but can be di erentiated rom melanocytes because
they demonstrate cell cell unctions and a layer o cytoplasm
peripheral to the clear space.
The melanocyte is a dendritic cell. ts dendrites e tend or
long distances within the epidermis and any one melanocyte
is there ore in contact with a great number o eratinocytes;
together they orm the so called epidermal melanin unit. era
tinocytes acti ely ingest the tips o the melanocytic dendrites
thus imbibing the melanosomes.
elanosomes are synthesi ed in the Golgi one o the cell
and pass through a series o stages in which the en yme tyrosi
nase acts on melanin precursors to produce the densely pig
mented granules. elanocytes in red haired indi iduals tend
to be rounder and to produce more pheomelanin. The mela
nocortin receptor ( C R) is important in the regulation o
melanin production. Loss o unction mutations in the MC
gene bring about a change rom eumelanin to pheomelanin
production whereas acti ating gene mutations can enhance
eumelanin synthesis. ost redheads are compound hetero y
gotes or homo ygotes or a ariety o loss o unction muta
tions in this gene.
Antimicrobial peptides including cathelicidin and β
de ensins are ey components o the innate immune system.
They protect against in ection are implicated in the pathogen
esis o atopic dermatitis and play a role in control o pigmen
tation. The β de ensins encompass a class o small cationic
proteins important to both the innate and the adapti e immune
system. β De ensin also unctions as a melanocortin receptor
ligand.
umelanin production is optimal at p . and changes in
cellular p also result in alterations o melanin production
and the eumelanin pheomelanin ratio. Within eratinocytes
melanin typically orms a cap o er the nucleus where it
presumably unctions principally in a photoprotecti e
role. idence o eratinocyte photodamage in the orm o
thymidine dimer ormation can be assessed using gas
chromatography mass spectrometry or en yme lin ed immu
nosorbent assays. Pigment within melanocytes also ser es to
protect the melanocytes themsel es against photodamage
such as ultra iolet A ( VA) induced membrane damage.
Areas o leu oderma or whitening o s in can be caused
Epidermis and adnexa
by ery di erent phenomena. n itiligo the a ected s in
becomes white because o destruction o melanocytes. n albi
nism the number o melanocytes is normal but they are
unable to synthesi e ully pigmented melanosomes because o
de ects in the en ymatic ormation o melanin. Local areas o
increased pigmentation can result rom a ariety o causes.
The typical rec le results rom a locali ed increase in produc
tion o pigment by a near normal number o melanocytes.
Blac sunburn or in spot lentigines demonstrate basilar
hyperpigmentation and prominent melanin within the stratum
corneum. e i are benign proli erations o melanocytes. ela
nomas are their malignant counterpart. elanocytes and era
tinocytes e press neurotrophins (ectodermal ner e growth
actors). elanocytes release neurotrophin but the release is
downregulated by ultra iolet B ( VB) irradiation suggesting
neurotrophins as possible targets or therapy o disorders o
pigmentation. elanocytes e press toll li e receptors (TLRs)
and stimulation by bacterial lipopolysaccharides increases
pigmentation.
Langerhans cells
Langerhans cells are normally ound scattered among erati
nocytes o the stratum spinosum. They constitute o the
cells in this layer. As with melanocytes Langerhans cells are
not connected to ad acent eratinocytes by the desmosomes.
The highest density o Langerhans cells in the oral mucosa
occurs in the estibular region and the lowest density is in the
sublingual region suggesting the latter is a relati ely immu
nologically pri ileged site.
At the light microscopic le el Langerhans cells are di cult
to detect in routinely stained sections. owe er they appear
as dendritic cells in sections impregnated with gold chloride
a stain speci c or Langerhans cells. They can also be stained
with CD α or S immunostains. ltrastructurally they are
characteri ed by a olded nucleus and distinct intracytoplas
mic organelles called Birbec granules. n their ully de el
oped orm the organelles are rod shaped with a acuole at
one end resembling a tennis rac uet. The acuole is an arti act
o processing.
unctionally Langerhans cells are o the monocyte
macrophage lineage and originate in bone marrow. They unc
tion primarily in the a erent limb o the immune response by
pro iding or the recognition upta e processing and presen
tation o antigens to sensiti ed T lymphocytes and are impor
tant in the induction o delayed type sensiti ity. nce an
antigen is presented Langerhans cells migrate to the lymph
nodes. yaluronan (hyaluronic acid) plays a critical role
in Langerhans cell maturation and migration. Langerhans
cells e press langerin membrane adenosine triphosphatase
(ATPase CD ) and CCR whereas CD α+ dermal dendritic
cells e press macrophage mannose receptor CD actor
a and chemo ine receptor suggesting di erent unc
tions or these two CD α+ populations. s in is depleted o
Langerhans cells by e posure to V radiation it loses the
ability to be sensiti ed until its population o Langerhans cell
is replenished. acrophages that present antigen in Langer
hans cell depleted s in can induce immune tolerance. n con
trast to Langerhans cells which ma e interleu in (L )
the macrophages ound in the epidermis h a ter VB irra
diation produce L resulting in downregulation o the
immune response. At least in mice iral immunity appears to
3
 re uire priming by CD α+ dendritic cells rather than Langer
1 hans cells suggesting a comple pattern o antigen presenta
tion in cutaneous immunity.
Vaccine studies suggest the importance o arious cutane
ous dendritic cells. icroneedle deli ery o accine into s in
Skin: Basic Structure and Function
can pro o e CD + T cell e pansion mediated by CD c(+)
CD b(+) langerin negati e dendritic cells.
Afshar M, et al: Innate immune defense system of the skin. Vet
Dermatol 2013; 24(1):32–38.e8–e9.
Chen J, et al: Skin permeation behavior of elastic liposomes: role of
formulation ingredients. Expert Opin Drug Deliv 2013; 10(6):845–856.
Chen Y, et al: Biomaterials as novel penetration enhancers for
transdermal and dermal drug delivery systems. Drug Deliv 2013;
20(5):199–209.
Ernfors P: Cellular origin and developmental mechanisms during the
formation of skin melanocytes. Exp Cell Res 2010; 316(8):1397–1407.
Hammers CM, et al: Desmoglein-1, differentiation, and disease. J Clin
Invest 2013; 123(4):1419–1422.
Homberg M, et al: Beyond expectations: novel insights into epidermal
keratin function and regulation. Int Rev Cell Mol Biol 2014;
311:265–306.
Iglesias-Bartolome R, et al: Control of the epithelial stem cell
epigenome: the shaping of epithelial stem cell identity. Curr Opin Cell
Biol 2013; 25(2):162–169.
Lee HJ, et al: Epidermal permeability barrier defects and barrier repair
therapy in atopic dermatitis. Allergy Asthma Immunol Res 2014;
6:276–287.
Ortonne JP, et al: Latest insights into skin hyperpigmentation. J Investig
Dermatol Symp Proc 2008; 13(1):10–14.
Roberts N, et al: Developing stratified epithelia: lessons from the
epidermis and thymus. Wiley Interdiscip Rev Dev Biol 2014; 3:389–402.
Sakabe J, et al: Kallikrein-related peptidase 5 functions in proteolytic
processing of profilaggrin in cultured human keratinocytes. J Biol
Chem 2013; 288(24):17179–17189.
DERMOEPIDERMAL JUNCTION
The unction o the epidermis and dermis is ormed by the
basement membrane one (B ). ltrastructurally this one
is composed o our components the plasma membranes o
the basal cells with the speciali ed attachment plates (hemides
mosomes); an electron lucent one called the lamina lucida;
the lamina densa (basal lamina); and the brous components
associated with the basal lamina including anchoring brils
dermal micro brils and collagen bers. At the light micro
scopic le el the periodic acid Schi (PAS) positi e basement
membrane is composed o the brous components. The basal
lamina is synthesi ed by the basal cells o the epidermis. Type
V collagen is the ma or component o the basal lamina. Type
V collagen is the ma or component o anchoring brils. The
two ma or hemidesmosomal proteins are BP (bullous pem
phigoid antigen ) and BP (bullous pemphigoid antigen
type V collagen).
n the upper permanent portion o the anagen ollicle
plectin BP BP α β integrin laminin and type V
collagen show essentially the same e pression as that ound
in the inter ollicular epidermis. Staining in the lower transient
portion o the hair ollicle howe er is di erent. All B
components diminish and may become discontinuous in the
in erior segment o the ollicle. emidesmosomes are also not
apparent in the B o the hair bulb. The lac o hemidesmo
somes in the deep portions o the ollicle may relate to the
transient nature o the in erior segment whereas abundant
hemidesmosomes stabili e the upper portion o the ollicle.
The B is considered to be a porous semipermeable
lter which permits e change o cells and uid between
the epidermis and dermis. t urther ser es as a structural
support or the epidermis and holds the epidermis and dermis
together. The B also helps to regulate growth adhesion
4
and mo ement o eratinocytes and broblasts as well as
apoptosis. uch o this regulation ta es place through acti a
tion o integrins and syndecans. tracellular matri protein
demonstrates loss o unction mutations in lipoid proteinosis
resulting in reduplication o the basement membrane.
Breitkreutz D, et al: Skin basement membrane: the foundation of
epidermal integrity: BM functions and diverse roles of bridging
molecules nidogen and perlecan. Biomed Res Int 2013; 2013:179784.
Masunaga T: Epidermal basement membrane: its molecular
organization and blistering disorders. Connect Tissue Res 2006;
47(2):55–66.
EPIDERMAL APPENDAGES: ADNEXA
ccrine and apocrine glands ducts and pilosebaceous units
constitute the s in adne a. mbryologically they originate as
downgrowths rom the epidermis and are there ore ectoder
mal in origin. edgehog signaling by the transducer nown
as smoothene appears critical or hair de elopment. Abnor
malities in this pathway contribute to the ormation o pilar
tumors and basal cell carcinoma. n the absence o hedgehog
signaling embryonic hair germs may de elop instead into
modi ed sweat gland or mammary epithelium.
Although the arious adne al structures ser e speci c unc
tions all can unction as reser e epidermis in that reepitheli
ali ation occurs a ter in ury to the sur ace epidermis principally
because o the migration o eratinocytes rom the adne al
epithelium to the s in sur ace. t is not surprising there ore
that s in sites such as the ace or scalp which contain pilose
baceous units in abundance reepitheliali e more rapidly than
s in sites such as the bac where adne a o all types are com
parati ely scarce. nce a wound has reepitheliali ed granula
tion tissue is no longer produced. Deep sauceri ed biopsies
in an area with ew adne a will slowly ll with granulation
tissue until they are ush with the surrounding s in. n con
trast areas rich in adne a will uic ly be co ered with epithe
lium. o more granulation tissue will orm and the contour
de ect created by the sauceri ation will persist.
The pseudoepitheliomatous hyperplasia noted in in ections
and in ammatory conditions consists almost e clusi ely o
adne al epithelium. Areas o thin inter ening epidermis are
generally e ident between areas o massi ely hypertrophic
adne al epithelium.
Eccrine sweat units
The intraepidermal spiral duct which opens directly onto the
s in sur ace is called the acros ringium t is deri ed rom
dermal duct cells through mitosis and upward migration. The
acrosyringium is composed o small polygonal cells with a
central round nucleus surrounded by ample pin cytoplasm.
n the stratum corneum o erlying an actinic eratosis the
lamellar spiral acrosyringeal eratin o ten stands out promi
nently against the compact red para eratotic eratin produced
by the actinic eratosis.
The straight dermal portion o the duct is composed o a
double layer o cuboidal epithelial cells and is lined by an
eosinophilic cuticle on its luminal side. The coiled secretory
acinar portion o the eccrine sweat gland may be ound within
the super cial panniculus. n areas o s in such as the bac
that possess a thic dermis the eccrine coil is ound in the deep
dermis surrounded by an e tension o at rom the underlying
panniculus. An inner layer o epithelial cells the secretory
portion o the gland is surrounded by a layer o attened
myoepithelial cells. The secretory cells are o two types large
pale glycogen rich cells and smaller dar er staining cells. The
pale glycogen rich cells are thought to initiate the ormation
o sweat. The dar er cells may unction similar to cells o the
dermal duct which acti ely reabsorb sodium thereby modi y
ing sweat rom a basically isotonic to a hypotonic solution by
the time it reaches the s in sur ace. Sweat is similar in compo
sition to plasma containing the same electrolytes but in a
more dilute concentration. Physical conditioning in a hot en i
ronment results in production o larger amounts o e tremely
hypotonic sweat in response to a thermal stimulus. This adap
ti e response allows greater cooling with conser ation o
sodium.
n humans eccrine sweat units are ound at irtually all s in
sites. n most other mammals the apocrine gland is the ma or
sweat gland.
Physiologic secretion o sweat occurs as a result o many
actors and is mediated by cholinergic inner ation. eat is a
prime stimulus to increased sweating but other physiologic
stimuli including emotional stress are important as well.
During early de elopment there is a switch between adrener
gic and cholinergic inner ation o sweat glands. Some respon
si eness to both cholinergic and adrenergic stimuli persists.
Cholinergic sweating in ol es a biphasic response with initial
hyperpolari ation and secondary depolari ation mediated by
the acti ation o calcium and chloride ion conductance. Adren
ergic secretion in ol es monophasic depolari ation and is
dependent on cystic brosis transmembrane conductance reg
ulator GCl. Cells rom patients with cystic brosis demon
strate no adrenergic secretion. Vasoacti e intestinal polypeptide
may also play a role in stimulating eccrine secretion.
Apocrine units
Apocrine units de elop as outgrowths not o the sur ace epi
dermis but o the in undibular or upper portion o the hair
ollicle. Although immature apocrine units are ound co ering
the entire s in sur ace o the human etus these regress and
are absent by the time the etus reaches term. The straight
e cretory portion o the duct which opens into the in undibu
lar portion o the hair ollicle is composed o a double layer
o cuboidal epithelial cells.
The coiled secretory gland is located at the unction o the
dermis and subcutaneous at. t is lined by a single layer o
cells which ary in appearance rom columnar to cuboidal.
This layer o cells is surrounded by a layer o myoepithelial
cells. Apocrine coils appear more widely dilated than eccrine
coils and apocrine sweat stains more deeply red in sec
tions contrasting with the pale pin o eccrine sweat.
The apices o the columnar cells pro ect into the lumen o
the gland and in histologic cross section appear as i they are
being e truded (decapitation secretion). Contro ersy sur
rounds the mode o secretion in apocrine secretory cells
whether merocrine apocrine holocrine or all three. The com
position o the product o secretion is only partially under
stood. Protein carbohydrate ammonia lipid and iron are all
ound in apocrine secretion. t appears mil y white although
lipo uscin pigment may rarely produce dar shades o brown
and gray blue (apocrine chromhidrosis). Apocrine sweat is
odorless until it reaches the s in sur ace where it is altered by
bacteria which ma es it odori erous. Apocrine secretion is
mediated by adrenergic inner ation and by circulating cate
cholamines o adrenomedullary origin. Vasoacti e intestinal
polypeptide may also play a role in stimulating apocrine secre
tion. Apocrine e cretion is episodic although the actual secre
tion o the gland is continuous. Apocrine gland secretion in
humans ser es no nown unction. n other species it has a
protecti e as well as a se ual unction and in some species it
is important in thermoregulation as well.
Although occasionally ound in an ectopic location apocrine
units o the human body are generally con ned to the ollow
ing sites a illae areolae anogenital region e ternal auditory
canal (ceruminous glands) and eyelids (glands o oll). They
are also generally prominent in stroma o the sebaceous ne us
Epidermal appendages: adnexa
o Jadassohn. Apocrine glands do not begin to unction until
puberty.
Hair follicles
During embryogenesis mesenchymal cells in the etal dermis
collect immediately below the basal layer o the epidermis.
pidermal buds grow down into the dermis at these sites. The
de eloping ollicle orms at an angle to the s in sur ace and
continues its downward growth. At this base the column o
cells widens orming the bulb and surrounds small collec
tions o mesenchymal cells. These papillary mesenchymal
bodies contain mesenchymal stem cells with broad unctional
ity. At least in mice they demonstrate e tramedullary hema
topoietic stem cell acti ity representing a potential therapeutic
source o hematopoietic stem cells and a possible source o
e tramedullary hematopoiesis in i o.
Along one side o the etal ollicle two buds are ormed; an
upper bud de elops into the sebaceous gland and a lower bud
becomes the attachment or the arrector pili muscle. A third
epithelial bud de elops rom the opposite side o the ollicle
abo e the le el o the sebaceous gland anlage and gi es rise
to the apocrine gland. The uppermost portion o the ollicle
which e tends rom its sur ace opening to the entrance o the
sebaceous duct is called the in undibular segment. t resem
bles the sur ace epidermis and its eratinocytes may be o
epidermal origin. The portion o the ollicle between the seba
ceous duct and the insertion o the arrector pili muscle is the
isthmus. The inner root sheath ully eratini es and sheds
within this isthmic portion. The in erior portion includes the
lowermost part o the ollicle and the hair bulb. Throughout
li e the in erior portion undergoes cycles o in olution and
regeneration.
air ollicles de elop se uentially in rows o three. Primary
ollicles are surrounded by the appearance o two secondary
ollicles; other secondary ollicles subse uently de elop
around the principal units. The density o pilosebaceous units
decreases throughout li e possibly because o dropout o the
secondary ollicles. n mouse models signaling by molecules
designated as ectodysplasin A and noggin is essential or the
de elopment o primary hair ollicles and induction o second
ary ollicles. Arrector pili muscles contained within the ollicu
lar unit interconnect at the le el o the isthmus.
The actual hair sha t as well as an inner and an outer root
sheath is produced by the matri portion o the hair bulb
( ig. ). The sheaths and contained hair orm concentric
cylindrical layers. The hair sha t and inner root sheath mo e
together as the hair grows upward until the ully eratini ed
inner root sheath sheds at the le el o the isthmus. The epi
dermis o the upper part o the ollicular canal is contiguous
with the outer root sheath. The upper two portions o the ol
licle (in undibulum and isthmus) are permanent; the in erior
segment is completely replaced with each new cycle o hair
growth. n the scalp anagen the acti e growth phase lasts
about years. ormally about o all scalp hairs
are in the anagen phase a gure that decreases with age and
decreases aster in indi iduals with male pattern baldness (as
length o anagen decreases dramatically). Scalp anagen hairs
grow at a rate o about . mm day. Catagen or in olution
lasts about wee s. Telogen the resting phase lasts about
months. ost sites on the body ha e a much shorter
anagen and much longer telogen resulting in short hairs that
5

1
Skin: Basic Structure and Function
Outer root sheath
Inner root sheath
Hair shaft
Hair cuticle
Cortex
Medulla
Bulb with matrix cells
Dermal papilla
stay in place or long periods without growing longer.
Prolongation o the anagen phase results in long eyelashes
in patients with ac uired immunode ciency syndrome
(A DS).
uman hair growth is cyclic but each ollicle unctions as
an independent unit ( ig. ). There ore humans do not shed
hair synchronously as most animals do. ach hair ollicle
undergoes intermittent stages o acti ity and uiescence. Syn
chronous termination o anagen or telogen results in telogen
e u ium. ost commonly telogen e u ium is the result o
early release rom anagen such as that induced by a ebrile
illness surgery or weight loss.
Pregnancy is typically accompanied by retention o an
increased number o scalp hairs in anagen as well as a pro
longation o telogen. Soon a ter deli ery telogen loss can be
detected as abnormally prolonged telogen hairs are released.
At the same time abnormally prolonged anagen hairs are
con erted synchronously to telogen. Between and months
later a more pro ound e u ium is noted. Patients recei ing
chemotherapy o ten ha e hair loss because the drugs inter ere
with the mitotic acti ity o the hair matri leading to the or
mation o a tapered racture. nly anagen hairs are a ected
lea ing a sparse coat o telogen hairs on the scalp. As the
matri reco ers anagen hairs resume growth without ha ing
to cycle through catagen and telogen.
The growing anagen hair is characteri ed by a pigmented
bulb ( ig. ) and an inner root sheath ( ig. ). istologi
cally catagen hairs are best identi ed by the presence o many
apoptotic cells in the outer root sheath ( ig. ). Telogen club
6
Fig. 1-3 Anatomy of the hair follicle.
Cross-
section
hairs ha e a nonpigmented bulb with a shaggy lower border.
The presence o bright red trichilemmal eratin bordering the
club hair results in a ame thrower li e appearance in ertical
sections ( ig. ). As the new anagen hair grows the old
telogen hair is shed.
The scalp hair o white people is round; pubic hair beard
hair and eyelashes are o al. The scalp hair o blac people is
also o al and this along with cur ature o the ollicle ust
abo e the bulb causes blac hair to be curly. ncombable hair
is triangular with a central canal. air shape is at least partially
controlled by the trichohyalin gene.
air color depends on the degree o melani ation and dis
tribution o melanosomes within the hair sha t. elanocytes
o the hair bulb synthesi e melanosomes and trans er them to
the eratinocytes o the bulb matri . Larger melanosomes are
ound in the hair o blac persons; smaller melanosomes
which are aggregated within membrane bound comple es
are ound in the hair o white persons. Red hair is character
i ed by spherical melanosomes. Graying o hair results rom
a decreased number o melanocytes which produces ewer
melanosomes. Repetiti e o idati e stress causes apoptosis o
hair ollicle melanocytes resulting in normal hair graying.
Premature graying is related to e haustion o the melanocyte
stem cell pool.
Although the genetics o balding is comple it is nown that
polymorphisms in the androgen receptor gene are carried on
the chromosome inherited rom the mother. The genetics o
emale pattern hair loss is less clear because polymorphisms
in the androgen receptor do not appear to be associated with
 Epidermal appendages: adnexa
Growing
hair

Sebaceous Club hair

gland

Dermal Growing
papilla hair

Anagen Catagen Telogen Anagen

Fig. 1-4 Phases of the growth cycle of a hair.

Fig. 1-6 Cross section of isthmus of anagen follicle

demonstrating glycogenated outer root sheath and keratinized
inner root sheath.

lipid lled pale cells which are continuously being e truded

Fig. 1-5 Cross section of anagen bulb demonstrating pigment within
matrix.
emale pattern hair loss and adrenal androgens may play a
larger role.
Sebaceous glands
Sebaceous glands are ormed embryologically as an outgrowth
rom the upper portion o the hair ollicle. They are composed
o lobules o pale staining cells with abundant lipid droplets
in their cytoplasm. At the periphery o the lobules basaloid
germinati e cells are noted. These cells gi e rise to the
through the short sebaceous duct into the in undibular portion
o the hair ollicle. The sebaceous duct is lined by a red cuticle
that undulates sharply in a pattern resembling shar s teeth.
This same undulating cuticle is seen in steatocystoma and
some dermoid cysts.
Sebaceous glands are ound in greatest abundance on the
ace and scalp although they are distributed throughout all
s in sites e cept the palms and soles. They are always associ
ated with hair ollicles e cept at the ollowing sites tarsal
plate o the eyelids (meibomian glands) buccal mucosa and
ermilion border o the lip ( ordyce spots) prepuce and
mucosa lateral to the penile renulum (Tyson glands) labia
minora and emale areola ( ontgomery tubercles).
Although sebaceous glands are independent miniorgans
in their own right they are anatomically and unctionally
7
 Fig. 1-7 Catagen hair
1 with many apoptotic
keratinocytes within
the outer root
sheath.
Skin: Basic Structure and Function
Fig. 1-8 Vertical
section of telogen
hair demonstrating
“flame thrower”
appearance of
club hair.
related to the hair ollicle. Cutaneous disorders attributed to
sebaceous glands such as acne ulgaris are really disorders
o the entire pilosebaceous unit. The clinical mani estations o
acne including the comedo papule pustule and cyst would
not orm regardless o increased sebaceous gland acti ity as
long as the sebaceous duct and in undibular portion o the hair
ollicle remained patent and lipid and cell debris (sebum)
were able to reach the s in sur ace.
ost lipids produced by the sebaceous gland are also pro
duced elsewhere in the body. Wa esters and s ualene are
uni ue secretory products o sebaceous glands. Sebocytes
e press histamine receptors and antihistamines can reduce
8
s ualene le els suggesting that antihistamines could play a
role in modulating sebum production. S in lipids contribute
to the barrier unction and some ha e antimicrobial proper
ties. Antimicrobial lipids include ree sphingoid bases deri ed
rom epidermal ceramides and atty acids (e.g. sapienic acid)
deri ed rom sebaceous triglycerides.
Novotný J, et al: Synthesis and structure-activity relationships of skin
ceramides. Curr Med Chem 2010; 17(21):2301–2324.
Patzelt A, et al: Drug delivery to hair follicles. Expert Opin Drug Deliv
2013; 10(6):787–797.
Westgate GE, et al: The biology of hair diversity. Int J Cosmet Sci 2013;
35(4):329–336.
Xu X, et al: Co-factors of LIM domains (Clims/Ldb/Nli) regulate corneal
homeostasis and maintenance of hair follicle stem cells. Dev Biol
2007; 312(2):484–500.
NAILS
ails act to assist in grasping small ob ects and in protecting
the ngertip rom trauma. atri eratini ation leads to the
ormation o the nail plate. ingernails grow an a erage o
. mm day re uiring about months to replace a com
plete nail plate. The growth rate is much slower or toenails
with months re uired to replace the great toenail.
Abnormalities o the nail may ser e as important clues to
cutaneous and systemic disease and may pro ide the astute
clinician with in ormation about disease or to ic e posures
that occurred se eral months earlier.
The eratin types ound in the nail are a mi ture o epider
mal and hair types with the hair types predominating. ail
isthmus eratini ation di ers rom that o the nail bed in that
eratin is only present in nail isthmus. Brittle nails demon
strate widening o the intercellular space between nail erati
nocytes on electron microscopy.
Whereas most o the s in is characteri ed by rete pegs that
resemble an egg crate the nail bed has true parallel rete ridges.
These ridges result in the ormation o splinter hemorrhages
when small uantities o e tra asated red blood cells mar
their path. The nail cuticle is ormed by eratinocytes o the
pro imal nail old whereas the nail plate is ormed by matri
eratinocytes. ndogenous pigments tend to ollow the
contour o the lunula (distal portion o matri ) whereas e og
enous pigments tend to ollow the contour o the cuticle. The
dorsal nail plate is ormed by the pro imal matri and the
entral nail plate is ormed by the distal matri with some
contribution rom the nail bed. The location o a melanocytic
lesion within the matri can be assessed by the presence o
pigment within the dorsal or entral nail plate.
Fleckman P, et al: Comparative anatomy of mouse and human nail
units. Anat Rec (Hoboken) 2013; 296(3):521–532.
DERMIS
The constituents o the dermis are mesodermal in origin e cept
or ner es which as with melanocytes deri e rom the neural
crest. ntil the si th wee o etal li e the dermis is merely a
pool o scattered dendritic shaped cells containing acid muco
polysaccharide which are the precursors o broblasts. By the
th wee broblasts are acti ely synthesi ing reticulum
bers elastic bers and collagen. A ascular networ de el
ops and by the th wee at cells ha e appeared beneath the
dermis. During etal de elopment Wnt β catenin signaling is
critical or di erentiation o entral ersus dorsal dermis and
the dermis then ser es as a sca old or the adne al structures
identi ed with entral or dorsal sites.
 n ant dermis is composed o small collagen bundles that
stain deeply red. any broblasts are present. n adult dermis
ew broblasts persist; collagen bundles are thic and stain
pale red.
Two populations o dermal dendritic cells are noted in the
adult dermis. actor a positi e dermal dendrocytes appear
to gi e rise to dermato bromas angio bromas ac uired digital
bro eratomas pleomorphic bromas and brous papules.
CD + dermal dendroctyes are accentuated around hair olli
cles but e ist throughout the dermis. They disappear rom the
dermis early in the course o morphea. Their loss can be diag
nostic in subtle cases. CD + dermal dendrocytes reappear in
the dermis when morphea responds to VA light treatment.
The principal component o the dermis is collagen a amily
o brous proteins comprising at least genetically distinct
types in human s in. Collagen ser es as the ma or structural
protein or the entire body; it is ound in tendons ligaments
and the lining o bones as well as in the dermis. Collagen
represents o the dry weight o s in. The broblast syn
thesi es the procollagen molecule a helical arrangement o
speci c polypeptide chains that are subse uently secreted by
the cell and assembled into collagen brils. Collagen is rich in
the amino acids hydro yproline hydro ylysine and glycine.
The brillar collagens are the ma or group ound in the s in.
Type collagen is the ma or component o the dermis. The
structure o type collagen is uni orm in width and each ber
displays characteristic cross striations with a periodicity o
nm. Collagen bers are loosely arranged in the papillary
and ad entitial (periadne al) dermis. Large collagen bundles
are noted in the reticular dermis (dermis below le el o post
capillary enule). Collagen messenger R A and collagen
mR A are both e pressed in the reticular and papillary dermis
and are downregulated by V light as is the collagen regula
tory proteoglycan decorin. This downregulation may play a
role in photoaging.
Type V collagen is ound in the B . Type V collagen is
the ma or structural component o anchoring brils and is
produced predominately by eratinocytes. Abnormalities
in type V collagen are seen in dystrophic epidermolysis
bullosa and autoantibodies to this collagen type characteri e
ac uired epidermolysis bullosa. Collagen bers are continu
ously being degraded by proteolytic en ymes called spare
collagenases and replaced by newly synthesi ed bers. Addi
tional in ormation on collagen types and diseases can be ound
in Chapter .
The broblast also synthesi es elastic bers and the ground
substance o the dermis which is composed o glycosamino
glycans or acid mucopolysaccharides. lastic bers di er both
structurally and chemically rom collagen. They consist o
aggregates o two components protein laments and elastin
an amorphous protein. The amino acids desmosine and isodes
mosine are uni ue to elastic bers. lastic bers in the papil
lary dermis are ne whereas those in the reticular dermis are
coarse. The e tracellular matri or ground substance o the
dermis is composed o sul ated acid mucopolysaccharide
principally chondroitin sul ate and dermatan sul ate neutral
mucopolysaccharides and electrolytes. Sul ated acid muco
polysaccharides stain with colloidal iron and with alcian blue
at both p . and p . . They stain metachromatically with
toluidine blue at both p . and p . . yaluronan (hyal
uronic acid) is a minor component o normal dermis but is the
ma or mucopolysaccharide that accumulates in pathologic
states. t stains with colloidal iron and with both alcian blue
and toluidine blue (metachromatically) but only at the higher
p or each stain.
Collagen is the ma or stress resistant material o the s in.
lastic bers contribute little to resisting de ormation and
tearing o s in but ha e a role in maintaining elasticity.
Connective tissue isease is a term generally used to re er to a
clinically heterogeneous group o autoimmune diseases
including lupus erythematosus scleroderma and dermato
myositis. Scleroderma in ol es the most isible collagen
abnormalities as collagen bundles become hyalini ed and the
Dermis
space between collagen bundles diminishes. Both lupus and
dermatomyositis produce increased dermal mucin mostly
hyaluronic acid. Bullous lupus has autoantibodies directed
against type V collagen.
De ects in collagen synthesis ha e been described in a
number o inheritable diseases including hlers Danlos syn
drome lin ed cutis la a and osteogenesis imper ecta.
De ects in elastic tissue are seen in ar an syndrome and
pseudo anthoma elasticum.
Vasculature
The dermal asculature consists principally o two intercom
municating ple uses. The subpapillary ple us or upper hori
ontal networ contains the postcapillary enules and courses
at the unction o the papillary and reticular dermis. This
ple us urnishes a rich supply o capillaries end arterioles
and enules to the dermal papillae. The deeper lower hori
ontal ple us is ound at the dermal subcutaneous inter ace
and is composed o larger blood essels than those o the
super cial ple us. odular lymphoid in ltrates surrounding
this lower ple us are typical o early in ammatory morphea.
The asculature o the dermis is particularly well de eloped
at sites o adne al structures. Associated with the ascular
ple us are dermal lymphatics and ner es.
Muscles
Smooth muscle occurs in the s in as arrectores pilorum (erec
tors o the hairs) as the tunica dartos (or dartos) o the scrotum
and in the areolas around the nipples. The arrectores pilorum
are attached to the hair ollicles below the sebaceous glands
and in contracting pull the hair ollicle upward producing
goose esh. The presence o scattered smooth muscle through
out the dermis is typical o anogenital s in.
Smooth muscle also comprises the muscularis o dermal and
subcutaneous blood essels. The muscularis o eins is com
posed o small bundles o smooth muscle that crisscross at
right angles. Arterial smooth muscle orms a concentric
wreathli e ring. Speciali ed aggregates o smooth muscle cells
(glomus bodies) are ound between arterioles and enules
and are especially prominent on the digits and at the lateral
margins o the palms and soles. Glomus bodies ser e to
shunt blood and regulate temperature. ost smooth muscle
e presses desmin intermediate laments but ascular smooth
muscle instead e presses imentin. Smooth muscle actin is
consistently e pressed by all types o smooth muscle.
Striated ( oluntary) muscle occurs in the s in o the nec as
the platysma muscle and in the s in o the ace as the muscles
o e pression. This comple networ o striated muscle ascia
and aponeuroses is nown as the super cial muscular aponeu
rotic system (S AS).
Nerves
n the dermis ner e bundles are ound together with arterioles
and enules as part o the neuro ascular bundle. n the deep
dermis ner es tra el parallel to the sur ace and the presence
o long sausageli e granulomas ollowing this path is an
important clue to the diagnosis o ansen s disease.
9
 Touch and pressure are mediated by eissner corpuscles
1 ound in the dermal papillae particularly on the digits palms
and soles and by Vater Pacini corpuscles located in the deeper
portion o the dermis o weight bearing sur aces and genitalia.
ucocutaneous end organs are ound in the papillary dermis
Skin: Basic Structure and Function
o modi ed hairless s in at the mucocutaneous unctions the
glans prepuce clitoris labia minora perianal region and
ermilion border o the lips. Temperature pain and itch sen
sation are transmitted by unmyelinated ner e bers that ter
minate in the papillary dermis and around hair ollicles.
mpulses pass to the central ner ous system by way o the
dorsal root ganglia. istamine e o ed itch is transmitted by
slow conducting unmyelinated C polymodal neurons. Signal
transduction di ers or sensations o heat and cold and in
peripheral ner e a ons.
Postganglionic adrenergic bers o the autonomic ner ous
system regulate asoconstriction apocrine gland secretions
and contraction o arrector pili muscles o hair ollicles. Cho
linergic bers mediate eccrine sweat secretion.
Mast cells
ast cells play an important role in the normal immune
response as well as immediate type sensiti ity contact allergy
and brosis. easuring microns in diameter with ample
amphophilic cytoplasm and a small round central nucleus
normal mast cells resemble ried eggs in histologic sections. n
telangiectasia macularis erupti a perstans (T P mastocyto
sis) they are spindle shaped and hyperchromatic resembling
large dar broblasts. ast cells are distinguished by contain
ing up to granules each measuring . . micron in
diameter. Coarse particulate granules crystalline granules
and granules containing scrolls may be seen. n the cell s
sur ace are glycoprotein receptor sites or
immunoglobulin ( g ). There is heterogeneity to mast cells
with type or connecti e tissue mast cells ound in the dermis
and submucosa and type or mucosal mast cells ound in
the bowel and respiratory tract mucosa.
ast cell granules stain metachromatically with toluidine
blue and methylene blue (in Giemsa stain) because o their
high content o heparin. They also contain histamine neutro
phil chemotactic actor eosinophil chemotactic actor o ana
phyla is tryptase ininogenase and β glucosaminidase.
Slow reacting substance o anaphyla is (leu otrienes C and
D ) leu otriene B platelet acti ating actor and prostaglan
din D are ormed only a ter g mediated release o granules.
ast cells stain reliably with the Leder ASD chloracetase
esterase stain. Because this stain does not rely on the presence
o mast cell granules it is particularly use ul in situations
when mast cells ha e degranulated. n orensic medicine uo
rescent labeling o mast cells with antibodies to the mast cell
en ymes chymase and tryptase is use ul in determining the
10
timing o s in lesions in regard to death. Lesions sustained
while li ing show an initial increase and then a decline in mast
cells. Lesions sustained postmortem demonstrate ew mast
cells.
Cutaneous mast cells respond to en ironmental changes.
Dry en ironments result in an increase in mast cell number
and cutaneous histamine content. n mastocytosis mast cells
accumulate in s in because o abnormal proli eration migra
tion and ailure o apoptosis. The terminal deo ynucleotidyl
trans erase mediated deo yuridine triphosphate biotin nic
end labeling (T L) method is used to assess apoptosis and
demonstrates decreased staining in mastocytomas. Proli era
tion usually is only moderately enhanced.
Abraham SN, et al: Mast cell-orchestrated immunity to pathogens. Nat
Rev Immunol 2010; 10(6):440–452.
Metz M, et al: Mast cell functions in the innate skin immune system.
Immunobiology 2008;213(3–4):251–260.
Mikesh LM, et al: Proteomic anatomy of human skin. J Proteomics
2013; 84:190–200.
SUBCUTANEOUS TISSUE (FAT)
Beneath the dermis lies the panniculus with lobules o at cells
or lipocytes separated by brous septa composed o collagen
and large blood essels. The collagen in the septa is continuous
with the collagen in the dermis. Just as the epidermis and
dermis ary in thic ness according to s in site so does the
subcutaneous tissue. The panniculus pro ides buoyancy and
unctions as a repository o energy and an endocrine organ. t
is an important site o hormone con ersion such as that o
androstenedione into estrone by aromatase. Leptin a hormone
produced in lipocytes regulates body weight through the
hypothalamus and in uences how we react to a ors in ood.
Various substances can a ect lipid accumulation within lipo
cytes. bestatin is a polypeptide that reduces eed inta e and
weight gain in rodents. ( )Ternatin a highly methylated
cyclic heptapeptide that inhibits at accumulation produced
by the mushroom Coriolus versicolor has similar e ects in mice.
Study o these molecules pro ides insight into the molecular
basis o weight gain and obesity. Abnormal at distribution
and insulin resistance are seen in Cushing syndrome and as a
result o antiretro iral therapy. n obese children and adoles
cents de eloping diabetes se ere peripheral insulin resistance
is associated with intramyocellular and intra abdominal lipo
cyte lipid accumulation.
Certain in ammatory dermatoses nown as the panniculi
tides principally a ect this le el o the s in producing sub
cutaneous nodules. The pattern o the in ammation speci cally
whether it primarily a ects the septa or the at lobules ser es
to distinguish arious conditions that may be clinically similar.
Khan MH et al: Treatment of cellulite. Part I. Pathophysiology. J Am
Acad Dermatol 2010; 62(3):361–370.
 Bonus images for this chapter can be found online at
Cutaneous Signs and Diagnosis
n some patients the appearance o s in lesions may be so
distincti e that the diagnosis is clear at a glance. n others
sub ecti e symptoms and clinical signs alone are inade uate
and a complete history and laboratory e amination including
a biopsy are essential to arri e at a diagnosis.
The same disease may show ariations under di erent con
ditions and in di erent indi iduals. The appearance o the
lesions may ha e been modi ed by pre ious treatment or
obscured by e traneous in uences such as scratching or sec
ondary in ection. Sub ecti e symptoms may be the only e i
dence o a disease as in pruritus and the s in appearance may
be generally unremar able. Although history is important the
diagnosis in dermatology is most re uently made based on
the ob ecti e physical characteristics and location or distribu
tion o one or more lesions that can be seen or elt. There ore
care ul physical e amination o the s in is paramount in der
matologic diagnosis.
CUTANEOUS SIGNS
Typically most s in diseases produce or present with lesions
that ha e more or less distinct characteristics. They may be
uni orm or di erse in si e shape and color and may be in
di erent stages o e olution or in olution. The original lesions
are nown as the primary lesions and identi cation o such
lesions is the most important aspect o the dermatologic physi
cal e amination. They may continue to ull de elopment or be
modi ed by regression trauma or other e traneous actors
producing secondary lesions.
Primary lesions
Primary lesions are o the ollowing orms macules (or
patches) papules (or pla ues) nodules tumors wheals esi
cles bullae and pustules.
Macules (maculae, spots)
acules are ariously si ed circumscribed changes in s in
color without ele ation or depression (nonpalpable) ( ig. ).
They may be circular o al or irregular and may be distinct in
outline or may ade into the surrounding s in. acules may
constitute the whole lesion or part o the eruption or may be
merely an early phase. the lesions become slightly raised
they are then designated papules or in some cases morbilli
orm eruptions.
Patches
A patch is a large macule cm or greater in diameter as may
be seen in ne us ammeus or itiligo.
expertconsult.inkling.com
2
Papules
Papules are circumscribed solid ele ations with no isible
uid arying in si e rom a pinhead to cm. They may be
acuminate rounded conical at topped or umbilicated and
may appear white (as in milium) red (ec ema) yellowish
( anthoma) or blac (melanoma).
Papules are generally centered in the dermis and may be
concentrated at the ori ces o the sweat ducts or at the
hair ollicles. They may be o so t or rm consistency. The
sur ace may be smooth or rough. capped by scales they are
nown as s uamous papules and the eruption is called
papulos uamous.
Some papules are discrete and irregularly distributed as in
papular urticaria whereas others are grouped as in lichen
nitidus ( ig. ). Some persist as papules whereas those o
the in ammatory type may progress to esicles and e en to
pustules or they may erode or ulcerate be ore regression ta es
place.
The term maculopapular should not be used. There is no
such thing as a maculopapule although there may be both
macules and papules in an eruption. Typically such eruptions
are morbilli orm.
Plaques
A pla ue is a broad papule (or con uence o papules)
cm or more in diameter ( ig. ). t is generally at but
may be centrally depressed. The center o a pla ue may be
normal s in.
Nodules
odules are morphologically similar to papules but are larger
than cm in diameter. odules most re uently are centered
in the dermis or subcutaneous at.
Tumors
Tumors are so t or rm reely mo able or ed masses o
arious si es and shapes but generally greater than cm in
diameter. General usage dictates that the word tumor means
a neoplasm. They may be ele ated or deep seated and in some
cases are pedunculated (neuro bromas). Tumors ha e a ten
dency to be rounded. Their consistency depends on the con
stituents o the lesion. Some tumors remain stationary
inde nitely whereas others increase in si e or brea down.
Wheals (hives)
Wheals are e anescent edematous plateauli e ele ations o
arious si es ( ig. ). They are usually o al or o arcuate
contours pin to red and surrounded by a are o macular
11
2
Cutaneous Signs and Diagnosis

Fig. 2-1 Macular depigmentation, vitiligo.

Fig. 2-4 Acute urticaria.

Fig. 2-2 Whitish grouped papules of lichen nitidus. Fig. 2-5 Vesicles, bullae, and erosions; bullous pemphigoid.

Fig. 2-3 Moist plaques erythema. Whorls may be discrete or may coalesce. These
of condyloma lata. lesions o ten de elop uic ly (minutes to hours). Because the
wheal is the prototypic lesion o urticaria diseases in which
wheals are prominent are re uently described as urticarial
(e.g. urticarial asculitis). Dermatographism or pressure
induced whealing may be e ident.

Vesicles (blisters)
Vesicles are circumscribed uid containing ele ations
mm in si e. They may be pale or yellow rom serous
e udate or red rom serum mi ed with blood. The ape may
be rounded acuminate or umbilicated as in ec ema herpeti
cum. Vesicles may be discrete irregularly scattered grouped
(e.g. herpes oster) or linear as in allergic contact dermatitis
rom urushiol (poison i y oa ). Vesicles may arise directly or
rom a macule or papule and generally lose their identity in a
short time brea ing spontaneously or de eloping into bullae
through coalescence or enlargement or de eloping into pus
tules ( ig. ). When the contents are o a seropurulent char
acter the lesions are nown as esicopustules. Vesicles ha e
either a single ca ity (unilocular) or se eral compartments
(multilocular).

Bullae
Bullae are rounded or irregularly shaped blisters containing
serous or seropurulent uid. They di er rom esicles only in
si e being larger than cm. They are usually unilocular but
12

Fig. 2-6 Erythematous plaques studded with sheets of pustules,
pustular psoriasis.
may be multilocular. Bullae may be located super cially in the
epidermis so their walls are accid and thin and sub ect to
rupture spontaneously or rom slight in ury. A ter rupture
remnants o the thin walls may persist and together with the
e udate may dry to orm a thin crust; or the bro en bleb may
lea e a raw and moist base which may be co ered with sero
purulent or purulent e udate. Less re uently irregular eg
etations may appear on the base (as in pemphigus egetans).
When subepidermal the bullae are tense do not rupture
easily and are o ten present when the patient is e amined.
i ols y s sign re ers to the diagnostic maneu er o putting
lateral pressure on unblistered s in in a bullous eruption and
ha ing the epithelium shear o . Asboe ansen s sign re ers to
the e tension o a blister to ad acent unblistered s in when
pressure is put on the top o the blister. Both these signs dem
onstrate the principle that in some diseases the e tent o
microscopic esiculation is more than what is e ident by
simple inspection. These ndings are use ul in e aluating the
se erity o pemphigus ulgaris and se ere bullous drug reac
tions. emorrhagic bullae are common in pemphigus herpes
oster se ere bullous drug reactions and lichen sclerosus. The
cellular contents o bullae may be use ul in cytologically con
rming the diagnosis o pemphigus herpes oster and herpes
simple .
Pustules
Pustules are small ele ations o the s in containing purulent
material usually necrotic in ammatory cells ( ig. ). They
are similar to esicles in shape and usually ha e an in amma
tory areola. Pustules are usually white or yellow centrally but
may be red i they also contain blood. They may originate as
pustules or may de elop rom papules or esicles passing
through transitory early stages during which they are nown
as papulopustules or esicopustules.
Secondary lesions
Secondary lesions are o many types; the most important are
scales crusts erosions ulcers ssures and scars.
Scales (exfoliation)
Scales are dry or greasy laminated masses o eratin. The
body ordinarily is constantly shedding imperceptible tiny
thin ragments o stratum corneum. When the ormation o
epidermal cells is rapid or the process o normal eratini ation
is disturbed pathologic e oliation results producing scales.
These scales ary in si e; some are ne delicate and branny
as in tinea ersicolor whereas others are coarser as in ec ema
and ichthyosis and still others are strati ed as in psoriasis.
Large sheets o des uamated epidermis are seen in to ic epi
dermal necrolysis staphylococcal scalded s in syndrome and
Cutaneous signs
in ection associated (to in mediated) des uamations such as
scarlet e er. Scales ary in color rom white gray to yellow
or brown rom the admi ture o dirt or melanin. ccasionally
they ha e a sil ery sheen rom trapping o air between
their layers; these are micaceous scales characteristic o pso
riasis. When scaling occurs it usually suggests a pathologic
process in the epidermis and para eratosis is o ten present
histologically.
Crusts (scabs)
Crusts are dried serum pus or blood usually mi ed with
epithelial and sometimes bacterial debris. When crusts become
detached the base may be dry or red and moist.
Excoriations and abrasions (scratch marks)
An e coriation is a punctate or linear abrasion produced by
mechanical means usually in ol ing only the epidermis but
sometimes reaching the papillary layer o the dermis. coria
tions are caused by scratching with the ngernails in an e ort
to relie e itching. the s in damage is the result o mechanical
trauma or constant riction the term abrasion may be used.
re uently there is an in ammatory areola around the e co
riation or a co ering o yellowish dried serum or red dried
blood. coriations may pro ide access or pyogenic microor
ganisms and the ormation o crusts pustules or cellulitis
occasionally associated with enlargement o the neighboring
lymphatic glands. n general the longer and deeper the e co
riations the more se ere is the pruritus that pro o ed them.
Lichen planus is an e ception howe er in which pruritus is
se ere but e coriations are rare.
Fissures (cracks, clefts)
A ssure is a linear cle t through the epidermis or into the
dermis. These lesions may be single or multiple and ary rom
microscopic to se eral centimeters in length with sharply
de ned margins. issures may be dry or moist red straight
cur ed irregular or branching. They occur most o ten when
the s in is thic ened and inelastic rom in ammation and
dryness especially in regions sub ected to re uent mo ement.
Such areas are the tips and e ural creases o the thumbs
ngers and palms; the edges o the heels; the cle ts between
the ngers and toes; at the angles o the mouth; the lips; and
around the nares auricles and anus. When the s in is dry
e posure to cold wind water and cleaning products (soap
detergents) may produce a stinging burning sensation indi
cating microscopic ssuring is present. This may be re erred
to as chapping as in chapped lips. When ssuring is present
pain is o ten produced by mo ement o the parts which opens
or deepens the ssures or orms new ones.
Erosions
Loss o all or portions o the epidermis alone as in impetigo
produces an erosion. t may or may not become crusted but
it heals without a scar.
Ulcers
lcers are rounded or irregularly shaped e ca ations that
result rom complete loss o the epidermis plus some portion
13
 Fig. 2-7 Ulceration
2 secondary to
squamous cell
carcinoma.
Cutaneous Signs and Diagnosis
o the dermis. They ary in diameter rom a ew millimeters
to se eral centimeters ( ig. ). lcers may be shallow in ol
ing little beyond the epidermis as in dystrophic epidermolysis
bullosa the base being ormed by the papillary layer or they
may e tend deeply into the dermis subcutaneous tissues or
deeper as with leg ulcers. lcers heal with scarring.
Scars
Scars are composed o new connecti e tissue that has replaced
lost substance in the dermis or deeper parts resulting rom
in ury or disease as part o the normal reparati e process.
Their si e and shape are determined by the orm o the pre i
ous destruction. Scarring is characteristic o certain in amma
tory processes and is there ore o diagnostic alue. The pattern
o scarring may be characteristic o a particular disease. Lichen
planus and discoid lupus erythematosus or e ample ha e
in ammation that is in relati ely the same area anatomically
yet discoid lupus characteristically causes scarring as it
resol es whereas lichen planus rarely results in scarring o the
s in. Both processes howe er cause scarring o the hair ol
licles when occurring on the scalp. Scars may be thin and
atrophic or the brous elements may de elop into neoplastic
o ergrowths as in hypertrophic scars or eloids. Some indi
iduals and some areas o the body especially the anterior
chest and upper bac are especially prone to hypertrophic
scarring. Scars rst tend to be pin or iolaceous later becom
ing white glistening and rarely hyperpigmented. Scars are
persistent but usually become so ter less ele ated and less
noticeable o er years.
GENERAL DIAGNOSIS
nterpretation o the clinical picture may be di cult because
identical clinical lesions may ha e many di erent causes.
oreo er the same s in disease may gi e rise to di erse erup
tions. Thus or each speci c type or primary morphologic
lesion there is a di erential diagnosis o the conditions that
could produce that lesion. Also there is a parallel list o all the
ariations that a single s in disease can cause; or e ample
lichen planus may ha e hyperpigmented patches iolaceous
14
pla ues hypertrophic papules and rarely minute papules or
e en cysts.
Being super cial s in lesions can be easily obser ed and
palpated. agni cation may be easily applied enhancing
isuali ation o the ne details o the lesions. Smears and
cultures may be readily obtained or bacteria and ungi. Biopsy
and histologic e amination o s in lesions are usually minor
procedures ma ing histopathology an important component
o many dermatologic e aluations. The threshold or biopsy
should be low. This is especially true o in ammatory derma
toses potentially in ectious conditions and s in disorders in
immunosuppressed and hospitali ed patients in whom clini
cal morphology may be atypical. nce therapy is begun
empirically histologic eatures may be altered by the treat
ment ma ing pathologic diagnosis more di cult.
History
nowledge o the patient s age health occupation hobbies
diet and li ing conditions is important as well as the onset
duration and course o the disease and the response to pre i
ous treatment. The amily history o similar disorders and
other related diseases may be use ul.
A complete drug history is one o the most important aspects
o a thorough history. This includes prescription and o er the
counter medications supplements herbal products eyedrops
and suppositories. Drug reactions are re uent and may simu
late many di erent s in diseases clinically and histologically.
t is e ually important to in uire about topical agents that
ha e been applied to the s in and mucous membranes or
medicinal or cosmetic purposes because these agents may
cause cutaneous or systemic reactions.
A complete medical history that includes other medical
diagnoses o the patient is essential. Certain s in diseases are
speci c to or associated with other conditions such as cutane
ous Crohn s disease and pyoderma gangrenosum in Crohn s
disease. Tra el abroad the patient s en ironment at home and
at wor seasonal occurrences and recurrences o the disease
and the temperature humidity and weather e posure o the
patient are all important actors in a dermatologic history.
abitation in certain parts o the world predisposes to distinc
ti e diseases or that particular geographic locale including
San Joa uin Valley e er (coccidioidomycosis) ansen s
disease leishmaniasis and histoplasmosis. Se ual orientation
and practices may be rele ant as in genital ulcer diseases and
human immunode ciency irus ( V) in ection.
Examination
amination should be conducted in a well lit room. atural
sunlight is the ideal illumination. Abnormalities o melanin
pigmentation (e.g. itiligo melasma) are more clearly isible
under ultra iolet ( V) light. A Wood s light ( nm) is most
o ten used and is also aluable or the diagnosis o some types
o tinea capitis tinea ersicolor and erythrasma.
A magni ying lens is o inestimable alue in e amining
small lesions. t may be necessary to palpate the lesion or
rmness and uctuation; rubbing will elucidate the nature o
scales and scraping will re eal the nature o the lesion s base.
Pigmented lesions especially in in ants should be rubbed in
an attempt to elicit Darier s sign (whealing) as seen in urti
caria pigmentosa. Dermoscopy is an essential part o the e am
ination o pigmented lesions.
The entire eruption must be seen to e aluate distribution
and con guration. This is optimally done by ha ing the patient
completely undress and iewing rom a distance to ta e in the

Fig. 2-8 Grouped vesicles along a dermatome, herpes zoster.
whole eruption at once. Pee a boo e amination by ha ing
the patient e pose one anatomic area a ter another while
remaining clothed is not optimal because the e amination o
the s in will be incomplete and the o erall distribution is di
cult to determine. A ter the patient is iewed at a distance
indi idual lesions are e amined to identi y primary lesions
and to determine the e olution o the eruption and the pres
ence o secondary lesions.
Diagnostic details of lesions
Distribution
Lesions may be ew or numerous and in arrangement they
may be discrete or may coalesce to orm patches o peculiar
con guration. Lesions may appear o er the entire body or
may ollow the lines o clea age (pityriasis rosea) dermatomes
(herpes oster) ( ig. ) or lines o Blasch o (epidermal ne i).
Lesions may orm groups rings crescents or unusual linear
patterns. A remar able degree o bilateral symmetry is char
acteristic o certain diseases such as dermatitis herpeti ormis
itiligo and psoriasis.
Evolution
Some lesions appear ully e ol ed. thers de elop rom
smaller lesions then remain the same during their entire e is
tence (e.g. warts). When lesions succeed one another in a
series o crops as in aricella and dermatitis herpeti ormis a
polymorphous eruption results with lesions in arious stages
o de elopment or in olution all present at the same time.
Involution
Certain lesions disappear completely whereas others lea e
characteristic residual pigmentation or scarring. Residual dys
pigmentation although a signi cant cosmetic issue is not con
sidered a scar. The pattern in which lesions in olute may be
use ul in diagnosis as with the typical eratotic papule o
pityriasis lichenoides arioli ormis acuta.
Grouping
Grouping is a characteristic o dermatitis herpeti ormis herpes
simple and herpes oster (see ig. ). Small lesions arranged
around a large one are said to be in a corymbose (corymbi
orm) arrangement. Concentric annular lesions are typical o
borderline ansen s disease and erythema multi orme. These
General diagnosis
Fig. 2-9 Papules in an annular configuration, granuloma annulare.
are sometimes said to be in a coc ade pattern re erring to
the tricolor coc ade hats worn by rench re olutionists. lea
and other arthropod bites are usually grouped and linear
(brea ast lunch and dinner sign). Grouped lesions o arious
si es may be called agminated.
Configuration
Certain terms are used to describe the con guration that an
eruption assumes either primarily or by enlargement or coales
cence. Lesions in a line are called linear and they may be con u
ent or discrete. Lesions may orm a complete circle (annular)
( ig. ) or a portion o a circle (arcuate or gyrate) or may be
composed o se eral intersecting portions o circles (polycyclic).
the eruption is not straight but does not orm parts o circles
it may be serpiginous. Round lesions may be small li e drops
called guttate; or larger li e a coin called nummular. nusual
con gurations that do not correspond to these patterns or to
normal anatomic or embryonic patterns should raise the pos
sibility o an e ogenous dermatosis or actitia.
Color
The color o the s in is determined by melanin o yhemoglo
bin reduced hemoglobin lipid and carotene. ot only do the
proportions o these components a ect the color but their
depth within the s in the thic ness o the epidermis and
hydration also play a role. The Tyndall e ect modi es the
color o s in and o lesions by the selecti e scattering o light
wa es o di erent wa elengths. The blue ne us and mongo
lian spots are e amples o this light dispersion e ect in which
brown melanin in the dermis appears blue gray.
The color o lesions may be aluable as a diagnostic actor.
Dermatologists should be aware that there are many shades o
pin red and purple each o which tends to suggest a diagno
sis or disease group. nter ace reactions such as lichen planus
or lupus erythematosus are described as iolaceous. Lipid
containing lesions are yellow as in anthomas ( ig. ) or
steatocystoma multiple . The orange red (salmon) color o pity
riasis rubra pilaris is characteristic. The constituti e color o the
s in determines the uality o the color one obser es with a
speci c disorder. n dar s inned persons erythema is di cult
to percei e. Pruritic lesions in A rican Americans may e ol e
to be small shiny at topped papules with a iolaceous hue
rom the combination o erythema and pigment incontinence.
These licheni ed lesions would be suspected o being lichenoid
by the untrained eye but are in act ec ematous.
15
2
Cutaneous Signs and Diagnosis
B paresthetica the patient may percei e both pruritus and
Fig. 2-10 Eruptive xanthoma. A, Yellow color easily discerned on
white skin. B, Yellow color subtler in brown or black skin.
Patches lighter in color than the normal s in may be com
pletely depigmented or may ha e lost only part o their
pigment (hypopigmented). This is an important distinction
because certain conditions are or may be hypopigmented
such as tinea ersicolor ne us anemicus ansen s disease
hypomelanotic macules o tuberous sclerosis hypomelanosis
o to seborrheic dermatitis and idiopathic guttate hypomela
nosis. True depigmentation should be distinguished rom this;
it suggests itiligo ne us depigmentosus halo ne us sclero
derma morphea or lichen sclerosus.
yperpigmentation may result rom epidermal or dermal
causes. t may be related to either increased melanin or deposi
tion o other substances. pidermal hyperpigmentation occurs
in ne i melanoma ca au lait spots melasma and lentigines.
These lesions are accentuated when e amined with a Wood s
light. Dermal pigmentation occurs subse uent to many in am
matory conditions (postin ammatory hyperpigmentation) or
rom deposition o metals medications medication melanin
comple es or degenerated dermal material (ochronosis).
These conditions are not enhanced when e amined by a
Wood s light. The hyperpigmentation ollowing in ammation
is most re uently the result o dermal melanin deposition but
in some conditions such as lichen aureus is caused by iron.
Dermal iron deposition appears more yellow brown or golden
than dermal melanin.
Texture/consistency
Palpation is an essential part o the physical e amination o
lesions. Does the lesion blanch on pressure not it may be
16 purpuric. s it uctuant so it may ha e ree uid in it. s it
Fig. 2-11 Scalp plaque with scarring alopecia hyperpigmentation and
depigmentation, discoid lupus erythematosus.
cold or hot there is a nodule or tumor does it sin through
a ring into the panniculus li e a neuro broma s it hard
enough or calci cation to be suspected merely ery rm li e
a eloid or dermato broma or branny li e scleredema
Hyperesthesia/anesthesia
Certain conditions may be associated with increased or
decreased sensation. or e ample the s in lesions o border
line and tuberculoid ansen s disease typically are anesthetic
in their centers. n neuropathic conditions such as notalgia
hyperesthesia. eurally mediated itch may be accompanied
by other neural sensations such as heat or burning. The com
bination o pruritus with other neural symptoms suggests the
in ol ement o ner es in the pathologic process.
Hair, nails, and oral mucosa
n ol ement o hair bearing areas by certain s in disorders
causes characteristic lesions. Discoid lupus or e ample
causes scarring alopecia with characteristic dyspigmentation
( ig. ). n the s in the lesions may be much less charac
teristic. Di use hair loss may be seen in certain conditions
such as acrodermatitis enteropathica and may be a clue to the
diagnosis. n addition loss o hair within a s in lesion may
suggest the diagnosis such as the alopecia seen in the tumid
pla ues o ollicular mucinosis.
Some s in disorders cause characteristic changes o the
nails e en when the periungual tissue is not in ol ed. The
pitting seen in psoriasis and alopecia areata may be use ul in
con rming these diagnoses when other ndings are not char
acteristic. n addition the nails and ad acent structures may
be the sole site o pathology as in candidal paronychia.
The complete s in e amination includes e amination o the
oral mucosa. ral lesions are characteristically ound in iral
syndromes (e anthems) lichen planus V associated aposi
sarcoma ( ig. ) and autoimmune bullous diseases (pem
phigus ulgaris).
Self-examination
Patients at ris or the de elopment o s in cancer should be
taught the correct method o s in sel e amination speci
cally the ABCD s o melanoma detection and the types o
lesions that might represent basal cell carcinoma or s uamous
cell carcinoma.
 http://www.siumed.edu/medicine/dermatology/student_information/
skinphysicalexam.pdf
http://www.aad.org/education/medical-student-core-curriculum
http://www.aad.org/spot-skin-cancer/understanding-skin-cancer/
how-do-i-check-my-skin/how-to-perform-a-self-exam

General diagnosis
http://missinglink.ucsf.edu/lm/DermatologyGlossary/index.html

Bonus images for this chapter can be found online at

expertconsult.inkling.com
eFig. 2-1 Macular depigmentation, vitiligo.
eFig. 2-2 Ulcer of the lip, chancre of primary syphilis.
eFig. 2-3 Annular, arcuate, and polycyclic configurations; granuloma
annulare.
eFig. 2-4 Acral small blue papule, blue nevus.
eFig. 2-5 Scalp plaque with scarring alopecia hyperpigmentation and
Fig. 2-12 Oral Kaposi sarcoma. depigmentation, discoid lupus erythematosus.

R G
d V
ti e
U n
-
9
ri 9
a h
t

17
 General diagnosis
eFig. 2-4 Acral small blue papule, blue nevus.

eFig. 2-1 Macular depigmentation, vitiligo.

eFig. 2-2 Ulcer of the lip, chancre of primary syphilis.

eFig. 2-3 Annular,

arcuate, and
polycyclic
configurations;
granuloma annulare.

eFig. 2-5 Scalp plaque with scarring alopecia hyperpigmentation and

depigmentation, discoid lupus erythematosus.

17.e1
 Bonus images for this chapter can be found online at
expertconsult.inkling.com
3 Dermatoses Resulting from Physical Factors
The body re uires a certain amount o heat but beyond de
nite limits insu cient or e cessi e amounts are in urious. The
local action o e cessi e heat causes burns or scalds; undue
cold causes chilblains rostbite and congelation. Thresholds
o tolerance e ist in all body structures sensiti e to electromag
netic wa e radiation o arying re uencies such as rays and
ultra iolet ( V) rays. The s in which is e posed to so many
e ternal physical orces is more sub ect to in uries caused by
this radiation than any other organ.
HEAT INJURIES
Thermal burns
n ury o arying intensity may be caused by the action o
e cessi e heat on the s in. this heat is e treme the s in and
n
underlying tissue may be destroyed. The changes in the s in
resulting rom dry heat or scalding are classi ed in our
U
degrees as ollows
irst egree burns o the s in result merely in an acti e
-
congestion o the super cial blood essels causing
erythema that may be ollowed by epidermal
des uamation (peeling). rdinary sunburn is the most
9
common e ample o a rst degree burn. The pain and
increased sur ace heat may be se ere and some
ri 9
constitutional reaction can occur i the in ol ed area is
large.
Secon egree burns are subdi ided into super cial and
h
deep orms.
n the super cial second degree burn there is a
a
transudation o serum rom the capillaries which
t
causes edema o the super cial tissues. Vesicles and
blebs are ormed by the serum gathering beneath the
outer layers o the epidermis. Complete reco ery
without scarring is usual in patients with super cial
burns.
The deep second degree burn is pale and anesthetic.
n ury to the reticular dermis compromises blood ow
and destroys appendages so healing ta es more than
month and results in scarring.
hir egree burns in ol e loss o the ull thic ness o the
dermis and o ten some o the subcutaneous tissues.
Because the s in appendages are destroyed there is no
epithelium a ailable or regeneration o the s in. An
ulcerating wound is produced which on healing lea es a
scar.
ourth egree burns in ol e the destruction o the entire
s in including the subcutaneous at and any underlying
tendons.
Both third degree and ourth degree burns re uire gra ting
or closure. All third and ourth degree burns are ollowed by
18
constitutional symptoms o arying se erity depending on
the si e o the in ol ed sur ace the depth o the burn and
particularly the location o the burned sur ace. The more as
cular the in ol ed area the more se ere are the symptoms.
The prognosis is poor or any patient in whom a large area
G
o s in sur ace is in ol ed particularly i more than two thirds
o the body sur ace has been burned. Women in ants and
R
toddlers all ha e a greater ris o death rom burns than men.
cessi e scarring with either eloidli e scars or at scars
V
with contractures may produce de ormities and dys unction
o the oints as well as chronic ulcerations rom impairment
d
o local circulation. Delayed postburn blistering may occur in
partial thic ness wounds and s in gra t donor sites. t is most
ti e
common on the lower e tremities and is sel limited. Although
burn scars may be the site o de elopment o carcinoma e i
dence supports only the possibility o a modest e cess o s ua
mous cell carcinomas in burn scars. With modern reconstructi e
surgery this un ortunate end result can be minimi ed.
Treatment
mmediate rst aid or minor thermal burns consists o prompt
cold applications (ice water or cold tap water i no ice is a ail
able) which are continued until pain does not return on stop
ping them.
The esicles or blebs o second degree burns should not be
opened but should be protected rom in ury because they orm
a natural barrier against contamination by microorganisms.
they become tense and unduly pain ul the uid may be e acu
ated under strictly aseptic conditions by puncturing the wall
with a sterile needle allowing the blister to collapse onto the
underlying wound. cision o ull thic ness and deep dermal
wounds that will not reepitheliali e within wee s (as
soon as hemodynamic stability is achie ed normally
days) reduces wound in ections shortens hospital stays and
impro es sur i al. Additionally contractures and unctional
impairment may be mitigated by such inter ention and gra t
ing. The role o early ablati e laser treatments to pre ent dis
abling scars and its use in impro ing ully ormed scars is an
area o acti e in estigation. The most super cial wounds may
be dressed with greasy gau e whereas sil er containing
dressings are used or their antiobiotic properties in intermedi
ate wounds.
luid resuscitation treatment o inhalation in ury and hyper
catabolism monitoring and early inter ention o sepsis pain
control en ironmental control and nutritional support are
ey components o the critical care o burns. ntensi e care
management in a burn center is recommended or patients
with partial thic ness wounds co ering more than o the
body sur ace i in ol ing the ace hands eet genitalia
perineum or oints; i secondary to electrical chemical or
inhalation in ury; in patients with special needs; and or any
ull thic ness burn.

Fig. 3-1 Electrical burn from biting on a cord.
Fig. 3-2 Lightning
strike.
Electrical burns
lectrical burns may occur rom contact or as a ash e posure.
A contact burn is small but deep causing some necrosis o the
underlying tissues. Low oltage in uries usually occur in the
home are treated conser ati ely and generally heal well. ral
commissure burns may re uire reconstructi e procedures
( ig. ). igh oltage burns are o ten occupational; internal
damage may be mas ed by minimal sur ace s in change and
may be complicated by subtle and slowly de eloping se uelae.
arly surgical inter ention to impro e circulation and repair
ital tissues is help ul in limiting loss o the e tremity.
lash burns usually co er a large area and being similar to
any sur ace burn are treated as such. Lightning may cause
burns a ter a direct stri e where an entrance and an e it
wound are isible ( ig. ). This is the most lethal type o
stri e and cardiac arrest or other internal in uries may occur.
ther types o lightning stri e are indirect and result in the
ollowing burns
Linear burns in areas on which sweat was present
Burns in a eathery or arborescent pattern which is
belie ed to be pathognomonic
Punctate burns with multiple deep circular lesions
Thermal burns rom ignited clothing or heated metal
which may occur i the patient was spea ing on a cell
phone or listening to an iPod or similar de ice when
struc
Heat injuries
Hot tar burns
Polyo yethylene sorbitan in bacitracin inc neomycin
polymy in B (e.g. eosporin) ointment itamin ointment
(e.g. Webber) and sun ower oil are e cellent dispersing
agents that acilitate the remo al o hot tar rom burns.
Cancio LC, et al: Evolving changes in the management of burns and
environmental injuries. Surg Clin North Am 2012; 92:959.
Chetty BV, et al: Blisters in patients with burns. Arch Dermatol 1992;
128:181.
Compton CC: The delayed postburn blister. Arch Dermatol 1992; 128:24.
Dega S, et al: Electrical burn injuries. Burns 2007; 33:653.
Glatstein MM, et al: Pediatric electrical burn injuries. Pediatr Emerg Care
2013; 29:737.
Heffernan EJ, et al: Thunderstorms and iPods. N Engl J Med 2007;
357:198.
Kerby JD, et al: Sex differences in mortality after burn injury. Burn Care
Res 2006; 27:452.
Ng K, et al: Management of hot tar burn using vitamin E ointment
containing petroleum and polyoxyethylene sorbitan. CJEM 2013; 15:1.
Pham TN, Gibran NS: Thermal and electrical injuries. Surg Clin North Am
2007; 87:185.
Russell KW, et al: Lightning burns. J Burn Care Res 2013; Jun 24.
[Epub ahead of print.]
Shumaker PR, et al: Functional improvements in traumatic scars and
scar contractures using an ablative fractional laser protocol. J Trauma
Acute Care Surg 2012; 73(2 Suppl 1):S116.
Wallingford SC, et al: Skin cancer arising in scars: a systematic review.
Dermatol Surg 2011; 37(9):1239.
Wasaik J, et al: Minor thermal burns. Clin Evid 2005; 14:2388.
Miliaria
iliaria the retention o sweat as a result o occlusion o
eccrine sweat ducts produces an eruption that is common in
hot humid climates such as in the tropics and during the hot
summer months in temperate climates. Staph lococcus epi er
mi is which produces an e tracellular polysaccharide sub
stance induces miliaria in an e perimental setting. This
polysaccharide substance may obstruct the deli ery o sweat
to the s in sur ace. The occlusion pre ents normal secretion
rom the sweat glands and e entually pressure causes rupture
o the sweat gland or duct at di erent le els. The escape o
sweat into the ad acent tissue produces miliaria. Depending
on the le el o the in ury to the sweat gland or duct se eral
di erent orms are recogni ed.
Miliaria crystallina (sudamina)
iliaria crystallina is characteri ed by small clear super cial
esicles with no in ammatory reaction ( ig. ). t appears in
bedridden patients whose e er produces increased perspira
tion or when clothing pre ents dissipation o heat and
moisture as in bundled children. The lesions are generally
asymptomatic and their duration is short li ed because they
tend to rupture at the slightest trauma. Drugs such as isotreti
noin bethanechol and do orubicin may induce sudamina.
The lesions are sel limited; no treatment is re uired.
Miliaria rubra (prickly heat)
The lesions o miliaria rubra appear as discrete e tremely
pruritic erythematous papulo esicles accompanied by a
19

3 pustulosa or rubra with resolution a ter stabili ation.
Dermatoses Resulting from Physical Factors
Fig. 3-3 Miliaria crystallina.
Fig. 3-4 Miliaria
pustulosa. (Courtesy
of Curt Samlaska,
MD.)
U n Treatment
-
9
ri 9
h
sensation o pric ling burning or tingling. They later may
become con uent on a bed o erythema. The sites most re
a
t
uently a ected are the antecubital and popliteal ossae trun
in ramammary areas (especially under pendulous breasts)
abdomen (especially at the waistline) and inguinal regions;
these sites re uently become macerated because e aporation
o moisture has been impeded. ercise induced itching or
that o atopic dermatitis may also be caused by miliaria rubra.
The site o in ury and sweat escape is in the pric le cell layer
where spongiosis is produced.
Miliaria pustulosa
iliaria pustulosa is preceded by another dermatitis that has
produced in ury destruction or bloc ing o the sweat duct
( ig. ). The pustules are distinct super cial and indepen
dent o the hair ollicle. The pruritic pustules occur most
re uently on the intertriginous areas e ure sur aces o the
e tremities scrotum and bac o bedridden patients. Contact
dermatitis lichen simple chronicus and intertrigo are some
o the associated diseases although pustular miliaria may
occur se eral wee s a ter these diseases ha e subsided. Recur
rent episodes may be a sign o type pseudohypoaldosteron
20
ism because salt losing crises may precipitate miliaria
Miliaria profunda
onpruritic esh colored deep seated whitish papules char
acteri e miliaria pro unda. t is asymptomatic usually lasts
only h a ter o erheating has ended and is concentrated on
the trun and e tremities. cept or the ace a illae hands
and eet where there may be compensatory hyperhidrosis all
the sweat glands are non unctional. The occlusion is in the
upper dermis. iliaria pro unda is obser ed only in the tropics
and usually ollows a se ere bout o miliaria rubra.
Postmiliarial hypohidrosis
Postmiliarial hypohidrosis results rom occlusion o sweat
ducts and pores and it may be se ere enough to impair an
indi idual s ability to per orm sustained wor in a hot en i
ronment. A ected persons may show decreasing e ciency
G
irritability anore ia drowsiness ertigo and headache; they
may wander in a da e.
R
t has been shown that hypohidrosis in ariably ollows mili
aria and that the duration and se erity o the hypohidrosis
V
are related to the se erity o the miliaria. Sweating may be
depressed to hal the normal amount or as long as wee s.
d
Tropical anhidrotic asthenia
ti e
Tropical anhidrotic asthenia is a rare orm o miliaria with
long lasting poral occlusion which produces anhidrosis and
heat retention.
The most e ecti e treatment or miliaria is to place the patient
in a cool en ironment. en a single night in an air conditioned
room helps to alle iate the discom ort. Circulating air ans can
also be used to cool the s in. Anhydrous lanolin resol es the
occlusion o pores and may help to restore normal sweat secre
tions. ydrophilic ointment also helps to dissol e eratinous
plugs and acilitates the normal ow o sweat. Soothing
cooling baths containing colloidal oatmeal or cornstarch are
bene cial i used in moderation. Patients with mild cases may
respond to dusting powders such as cornstarch or baby
talcum powder.
Dimon NS, et al: Goosefleshlike lesions and hypohidrosis. Arch
Dermatol 2007; 143:1323.
Godkar D, et al: Rare skin disorder complicating doxorubicin therapy:
miliaria crystallina. Am J Ther 2005; 12:275.
Haas N, et al: Congenital miliaria crystallina. J Am Acad Dermatol 2002;
47:S270.
Haque MS, et al: The oldest new finding in atopic dermatitis: subclinical
miliaria as an origin. JAMA Dermatol 2013; 149:436.
La Shell MS, et al: Pruritus, papules, and perspiration. Ann Allergy
Immunol 2007; 98:299.
Mowad CM, et al: The role of extracellular polysaccharide substance
produced by Staphylococcus epidermidis in miliaria. J Am Acad
Dermatol 1995; 20:713.
Onal H, et al: Miliaria rubra and thrombocytosis in
pseudohypoaldosteronism. Platelets 2012; 23:645.
Erythema ab igne
rythema ab igne is a persistent erythema or the coarsely
reticulated residual pigmentation resulting rom it that is
usually produced by long e posure to e cessi e heat without
the production o a burn ( ig. ). t begins as a mottling

Fig. 3-5 Erythema ab igne from transcutaneous electrical nerve
stimulation (TENS) unit, with device wire at lower right.
caused by local hemostasis and becomes a reticulated ery
thema lea ing pigmentation. ultiple colors are simultane
ously present in an acti e patch arying rom pale pin to old
rose or dar purplish brown. A ter the cause is remo ed the
a ection tends to disappear gradually but sometimes the pig
mentation is permanent.
istologically an increased amount o elastic tissue in the
dermis is noted. The changes in erythema ab igne are similar
to those o actinic elastosis. nter ace dermatitis and epithelial
atypia may be noted.
rythema ab igne on the legs results rom habitually
warming them in ront o open replaces space heaters or car
heaters. Similar changes may be produced on the lower bac
or at other sites o an electric heating pad application on the
upper thighs with laptop computers or on the posterior thighs
rom heated car seats. The condition occurs also in coo s sil
ersmiths and others e posed o er long periods to direct
moderate heat.
pithelial atypia which may lead to Bowen s disease and
s uamous cell carcinoma has rarely been reported to occur
o erlying erythema ab igne. n remote areas o ashmir
angri re pots can induce erythema ab igne and cancer
within the a ected area. Treatment with uorouracil ( )
imi uimod or photodynamic therapy may be e ecti e in
re ersing this epidermal alteration.
The use o emollients containing α hydro y acids or a cream
containing uocinolone acetonide . hydro uinone
and tretinoin . may help reduce the unsightly pigmenta
tion as may treatment with the switched neodymium
doped yttrium aluminum garnet ( d AG) laser.
Brodell D, et al: Automobile seat heater-induced erythema ab igne. Arch
Dermatol 2012; 148(2):264–265.
Cho S, et al: Erythema ab igne successfully treated using 1,064-nm
Q-switched neodymium-doped yttrium aluminum garnet laser with low
fluence. Dermatol Surg 2011; 37(4):551–553.
Huynh N, et al: Erythema ab igne. Cutis 2011; 88(6):290–292.
Riahi RR, et al: Practical solutions to prevent laptop-induced erythema
ab igne. Int J Dermatol 2014; 53:e395–396.
Wani I: Kangri cancer. Surgery 2010; 147:586–588.
Wharton JB, et al: Squamous cell carcinoma in situ arising in the setting
of erythema ab igne. J Drugs Dermatol 2008; 7(5):488–489.
COLD INJURIES
posure to cold damages the s in by at least three mecha
nisms as ollows
Cold injuries
Fig. 3-6 Acrocyanosis.
Reduced temperature directly damages the tissue as in
rostbite and cold immersion oot.
Vasospasm o essels per using the s in pre ents
ade uate per usion o the tissue and causes ascular
in ury and conse uent tissue in ury (pernio acrocyanosis
and rostbite).
n unusual circumstances adipose tissue is predisposed
to damage by cold temperatures because o at
composition or location (cold panniculitis; see
Chapter ).
utdoor wor ers and recreationalists military ser ice
members alcoholic persons and homeless people are particu
larly li ely to sustain cold in uries. aneu ers to treat ortho
pedic in uries or heatstro e and cooling de ices or other
therapeutic use may result in cold in uries ranging rom acro
cyanosis to rostbite.
Jurkovich GJ: Environmental cold-induced injury. Surg Clin North Am
2007; 87:247.
Acrocyanosis
Acrocyanosis is a persistent blue discoloration o the entire
hand or oot worsened by cold e posure. The hands and eet
may be hyperhidrotic ( ig. ). t occurs chie y in young
women. Cyanosis increases as the temperature decreases and
changes to erythema with ele ation o the dependent part. The
cause is un nown. Smo ing should be a oided. Acrocyanosis
is distinguished rom Raynaud syndrome by its persistent
(rather than episodic) nature and lac o tissue damage (ulcer
ation distal ngertip resorption).
Acrocyanosis with swelling o the nose ears and dorsal
hands may occur a ter inhalation o butyl nitrite. nter eron
alpha a may induce it. Repeated in ection o the dorsal hand
with narcotic drugs may produce lymphedema and an appear
ance similar to the edematous phase o scleroderma. This
so called pu y hand syndrome may include erythema or a
bluish discoloration o the digits. Patients with anore ia
ner osa re uently mani est acrocyanosis as well as perniosis
li edo reticularis and acral coldness. t may impro e with
weight gain. Appro imately one third o patients with s in
ndings o P S syndrome (polyneuropathy organomeg
aly endocrinopathy component s in changes) ha e acro
cyanosis. Also in patients with a homo ygous mutation in
S MD and cerebro ascular occlusi e disease acrocyanosis
was re uent.
21
 Acral ascular syndromes such as gangrene Raynaud phe
3 nomenon and acrocyanosis may be a sign o malignancy. n
o reported cases the diagnosis o cancer coincided
with the onset o the acral disease. such changes appear or
worsen in an elderly patient especially a man without e po
Dermatoses Resulting from Physical Factors

sure to asoconstricti e drugs or prior autoimmune or ascu

lar disorders a paraneoplastic origin should be suspected.
Brown PJ, et al: The purple digit. Am J Clin Derm 2010; 11:103.
Del Giudice P, et al: Hand edema and acrocyanosis: puffy hand
syndrome. Arch Dermatol 2006; 142:1084.
Kurklinsky AK, et al: Acrocyanosis. Vasc Med 2011; 16(4):288–301.
Miest RY, et al: Cutaneous manifestations in patients with POEMS
syndrome. Int J Dermatol 2013; 52(11):1349–1356.
Poszepczynska-Guigné E, et al: Paraneoplastic acral vascular syndrome.
J Am Acad Dermatol 2002; 47(1):47–52.
Strumia R: Eating disorders and the skin. Clin Dermatol 2013; A
31(1):80–85.
Xin B, et al: Homozygous mutation in SAMHD1 gene causes cerebral
vasculopathy and early onset stroke. Proc Natl Acad Sci USA 2011;
108(13):5372–5377.

Chilblains (pernio, perniosis)

Chilblains constitute a locali ed erythema and swelling caused

R G
V
by e posure to cold. Blistering and ulcerations may de elop
in se ere cases. n people predisposed by poor peripheral

d
circulation e en moderate e posure to cold may produce chil
blain. Cryoglobulins cryo brinogens antiphospholipid anti

ti e
bodies or cold agglutinins may be present and pathogenic.
Chilblain li e lesions may occur in discoid and systemic lupus
erythematosus (chilblain lupus) as a presenting sign o leu e
mia cutis or i occurring in in ancy may herald the a a o

n
ishimura syndrome. Chilblain may also be a diagnostic sign B
o Aicardi Gouti res syndrome. The chronic use o crac

U
cocaine and its attendant peripheral asoconstriction will lead Fig. 3-7 Chilblains (pernio) in adult (A) and child (B).
to perniosis with cold numb hands and atrophy o the digital

-
at pads especially o the thumbs and inde ngers as well
as nail cur ature. Because patients are o ten not conscious o the cold e posure
Chilblains occur chie y on the hands eet ears and ace that triggers the lesions appropriate dress must be stressed

9
especially in children; onset is enhanced by dampness ( ig. e en i patients say they do not sense being cold. Since central
). n ohs surgery technicians the hands are a ected i an cooling triggers peripheral asoconstriction eeping the

ri 9
orthopedic cold therapy system is used; the s in under the
de ice de elops the lesions. The lateral thighs are in ol ed in
women e uestrians who ride on cold damp days and the hips
in those wearing tight tting eans with a low waistband.
whole body (not ust the a ected e tremity) warm is critical.
eating pads may be used udiciously to warm the parts.
Smo ing is strongly discouraged.
i edipine mg three times a day has been e ecti e.

h
Wading across cold streams may produce similar lesions. Vasodilators such as nicotinamide mg three times a day
ondigital lesions o cold in ury can be nodular. or dipyridamole mg three times a day or the phosphodi

t a
Patients with chilblain are o ten unaware o the cold in ury
when it is occurring but later burning itching and redness
call it to their attention. The a ected areas are bluish red with
the color partially or totally disappearing on pressure and are
cool to the touch. Sometimes the e tremities are clammy
because o e cessi e sweating. As long as the dampness and
cold e posure continues new lesions will continue to appear.
n estigation into an underlying cause should be underta en
in patients with chilblains that are recurrent chronic e tend
ing into warm seasons or poorly responsi e to treatment.
Pernio histologically demonstrates a lymphocytic asculitis.
There is dermal edema and a super cial and deep peri ascu
lar tightly cu ed lymphocytic in ltrate. The in ltrate in ol es
the essel walls and is accompanied by characteristic u y
edema o the essel walls.
Treatment
The a ected parts should be protected against urther e po
sure to cold or dampness. the eet are in ol ed woolen
soc s should be worn at all times during the cold months.
22
esterase inhibitor sildena l mg twice daily may be used to
impro e circulation. Pento i ylline and hydro ychloro uine
may be e ecti e. Spontaneous resolution occurs without treat
ment in wee s. Systemic corticoid therapy is use ul in
chilblain lupus.
Abdel-Salam GM, et al: Chilblains as a diagnostic sign of Aicardi-
Goutières syndrome. Neuropediatrics 2010; 41:18.
Boada A, et al: Perniosis. Am J Dermatolpathol 2010; 32:19.
Kanazawa N: Nakajo-Nishimura syndrome: an antiinflammatory disorder
showing pernio-like rashes and progressive partial lipodystrophy.
Allergol Int 2012; 61:197.
King JM, et al: Perniosis induced by a cold-therapy system. Arch
Dermatol 2012; 148(9):1101.
Lutz V, et al: Chilblains and antiphospholipid antibodies. Br J Dermatol
2010; 163:641.
Mireku KA, et al: Tender macules and papules on the toes. JAMA
Dermatol 2014; 150:329–330.
Payne-James JJ, et al: Pseudosclerodermatous triad of perniosis, pulp
atrophy and parrot-beaked clawing of the nails: newly recognized
syndrome of chronic crack cocaine use. J Forensic Leg Med 2007; 14:65.
Stewart CL, et al: Equestrian perniosis. Am J Dermatopathol 2013;
35(2):237.
 Viguier M, et al: Clinical and histopathologic features and immunologic
variables in patients with severe chilblains: a study of the relationship
to lupus erythematosus. Medicine (Baltimore) 2001; 80:180.
Weismann K, et al: Pernio of the hips in young girls wearing tight-fitting
jeans with a low waistband. Acta Derm Venereol 2006; 86:558.
Yang X, et al: Adult perniosis and cryoglobulinemia. J Am Acad
Dermatol 2010; 62(6):e21.
Yang X, et al: Successful treatment of perniosis with
hydroxychloroquine. J Drugs Dermatol 2010; 9(10):1242.
Frostbite
When so t tissue is ro en and locally depri ed o blood
supply the damage is called rostbite. The ears nose chee s
ngers and toes are most o ten a ected. The ro en part pain
lessly becomes pale and wa y. Various degrees o tissue
destruction similar to that caused by burns are encountered.
These are erythema and edema esicles and bullae super cial
gangrene deep gangrene and in ury to muscles tendons
periosteum and ner es ( ig. ). The degree o in ury is
directly related to the temperature and duration o ree ing.
A rican Americans are at increased ris o rostbite.
Treatment
arly treatment o rostbite be ore swelling de elops should
consist o co ering the part with clothing or with a warm
hand or other body sur ace to maintain a slightly warm tem
perature so that ade uate blood circulation can be main
tained. Rapid rewarming in a water bath between and
C ( ) is the treatment o choice or all orms o
rostbite. Rewarming should be delayed until the patient has
been remo ed to an area where there is no ris o re ree ing.
Slow thawing results in more e tensi e tissue damage. Anal
gesics should be administered because o the considerable
pain e perienced with rapid thawing. When the s in ushes
and is pliable thawing is complete. The use o tissue plas
minogen acti ator to lyse thrombi decreases the need or
amputation i gi en within h o in ury. Supporti e mea
sures such as bed rest a high protein high calorie diet
wound care and a oidance o trauma are imperati e. Any
rubbing o the a ected part should be a oided but gentle
massage o pro imal portions o the e tremity that are not
numb may be help ul.
The use o anticoagulants to pre ent thrombosis and gan
grene during the reco ery period has been ad ocated. Pent
o i ylline ibupro en and aspirin may be use ul ad uncts.
Antibiotics should be gi en as a prophylactic measure against
Fig. 3-8 Frostbite in a homeless person.
in ection and tetanus immuni ation should be updated.
Reco ery may ta e many months. n uries that a ect the pro i
mal phalan or the carpal or tarsal area especially when
accompanied by a lac o radiotracer upta e on bone scan
ha e a high li elihood o re uiring amputation. Whereas prior
Cold injuries
cold in ury is a ma or ris actor or recurrent disease sympa
thectomy may be pre enti e against repeated episodes.
Arthritis may be a late complication.
Hallam M-J, et al: Managing frostbite. BMJ 2010; 341:1151.
Kahn JE, et al: Frostbite arthritis. Ann Rheum Dis 2005; 64:966.
McIntosh SE, et al: Wilderness Medical Society Practice Guidelines for
the prevention and treatment of frostbite. Wilderness Environ Med
2011; 22:156.
Tropy JM, et al: Frostbite. JAMA 2011; 306:2633.
Immersion foot syndromes
Trench foot
Trench oot results rom prolonged e posure to cold wet con
ditions without immersion or actual ree ing. The term is
deri ed rom trench war are in World War when soldiers
stood sometimes or hours in trenches with a ew inches o
cold water in them. ishermen sailors and shipwrec sur i
ors may be seen with this condition. The lac o circulation
produces edema paresthesias and damage to the blood
essels. Similar ndings may complicate the o eruse o ice
cold water and ans by patients trying to relie e the pain
associated with erythromelalgia. Gangrene may occur in
se ere cases. Treatment consists o remo al rom the causal
en ironment bed rest and restoration o the circulation. ther
measures such as those used in the treatment o rostbite
should be employed.
Warm water immersion foot
posure o the eet to warm wet conditions or h or more
may produce a syndrome characteri ed by maceration blanch
ing and wrin ling o the soles and sides o the eet ( ig. ).
tching and burning with swelling may persist or a ew days
a ter remo al o the cause but disability is temporary. This
condition was o ten seen in military ser ice members in
Vietnam but has also been seen in persons wearing insulated
boots.
Fig. 3-9 Warm water
immersion foot.
(Courtesy of James
WD (ed): Textbook
of Military Medicine,
Office of the Surgeon
General, United States
Army, 1994.)
23
 Fig. 3-10 Tropical
3 immersion foot.
(Courtesy of James
WD (ed): Textbook of
Military Medicine,
Dermatoses Resulting from Physical Factors

Office of the Surgeon

General, United States
Army, 1994.)

Fig. 3-11 Acute sunburn. (Courtesy of Dr. L. Lieblich.)

G
The amount o V e posure increases at higher altitudes is
substantially larger in temperate climates in the summer

R
months and is greater in tropical regions. VA may be
re ected somewhat more than VB rom sand snow and ice.

V
Warm water immersion oot should be di erentiated rom Whereas sand and snow re ect as much as o the VB
tropical immersion oot seen a ter continuous immersion o water allows o the V to penetrate up to eet. Cloud

d
the eet in water or mud at temperatures abo e C( . ) co er although bloc ing substantial amounts o isible light
or days. This was nown as paddy oot in Vietnam. t is a poor V absorber. During the middle h o the day the

ti e
in ol es erythema edema and pain o the dorsal eet as well intensity o VB is two to our times greater than in the early
as e er and adenopathy ( ig. ). Resolution occurs morning and late a ternoon.
days a ter the eet ha e been dried.
Warm water immersion oot can be pre ented by allowing Clinical signs and symptoms

n
the eet to dry or a ew hours in e ery or by greasing the
soles with a silicone grease once a day. Reco ery is usually Sunburn is the normal cutaneous reaction to sunlight in e cess

U
rapid i the eet are thoroughly dry or a ew hours. o an erythema dose. VB erythema becomes e ident at around
Adnot J, et al: Immersion foot syndromes. In: James WD (ed): Military h a ter e posure and pea s at h but the onset is sooner

-
Dermatology. Washington, DC: Office of the Surgeon General, 1994. and the se erity greater with increased e posure. The ery
Davis MD: Immersion foot associated with the overuse of ice, cold thema is ollowed by tenderness and in se ere cases blistering
water, and fans. J Am Acad Dermatol 2013; 69:169. which may become con uent ( ig. ). Discom ort may be

9
Wrenn K: Immersion foot. Arch Intern Med 1991; 151:785. se ere; edema typically occurs in the e tremities and ace;
chills e er nausea tachycardia and hypotension may be

ri 9
present. n se ere cases such symptoms may last or as long
ACTINIC INJURY as a wee . Des uamation is common about wee a ter
sunburn e en in areas that ha e not blistered.
Sunburn and solar erythema A ter V e posure s in pigment undergoes two changes

h
immediate pigment dar ening ( PD eirows y phenome
The solar spectrum has been di ided into di erent regions by non) and delayed melanogenesis. PD is ma imal within

t a
wa elength. The parts o the solar spectrum important in pho hours a ter sun e posure and results rom metabolic changes
tomedicine include V radiation (below nm) isible light and redistribution o the melanin already in the s in. t
( nm) and in rared radiation (beyond nm). Visible occurs a ter e posure to long wa e VB VA and isible
light has limited biologic acti ity e cept or stimulating the light. With large doses o VA the initial dar ening is pro
retina. n rared radiation is e perienced as radiant heat. Below longed and may blend into the delayed melanogenesis. PD
nm is the V spectrum di ided into three bands VA is not photoprotecti e. Delayed tanning is induced by the
nm; VB nm; and VC nm. VA same wa elengths o VB that induce erythema begins
is di ided into two subcategories VA ( nm) and days a ter e posure and lasts days. Delayed melano
VA ( nm). Virtually no VC reaches the arth s genesis by VB is mediated through the production o D A
sur ace because it is absorbed by the o one layer abo e the damage and the ormation o cyclobutane pyrimidine dimers
arth. (CPD). There ore although VB induced delayed tanning
The minimal amount o a particular wa elength o light does pro ide some protection rom urther solar in ury it is
capable o inducing erythema on an indi idual s s in is called at the e pense o damage to the epidermis and dermis.
the minimal erythema dose ( D). Although the amount o Tanning is not recommended or sun protection. Commercial
VA radiation is times greater than VB radiation during tanning bed induced tanning while increasing s in pigment
midday hours VB is up to times more erythemogenic does not increase VB D and is there ore not protecti e
than VA and so essentially all solar erythema is caused by or VB damage. Such tanning de ices ha e been shown to
VB. The most biologically e ecti e wa elength o radiation cause melanoma and their use or tanning purposes should
rom the sun or sunburn is nm. Although it does not play be banned. An indi idual s inherent baseline pigmentation
a signi cant role in solar erythema VA is o ma or impor ability to tan and susceptibility to burns are described as the
tance in patients with drug induced photosensiti ity. person s s in type. S in type is used to determine starting
24

Table 3-1 Skin types (phototypes)
Skin type Baseline skin color
V e posure. This is the time when the angle o the sun is
less than degrees or when a person s shadow is shorter
than his or her height. n temperate latitudes it is almost
Sunburn and tanning
history impossible to burn i these hours o sun e posure are a oided.
Trees and arti cial shade pro ide substantial protection rom

I White Always burns, never tans
II White Always burns, tans
minimally
III White Burns moderately, tans
gradually
IV Olive Minimal burning, tans well
V Brown Rarely burns, tans darkly
VI Dark brown Never burns, tans darkly
black
doses o phototherapy and sunscreen recommendations and
re ects the ris o de elopment o s in cancer and photoag
ing (Table ).
posure to VB and VA causes an increase in the thic
ness o the epidermis especially the stratum corneum. This
increased epidermal thic ness leads to increased tolerance to
urther solar radiation. Patients with itiligo may increase
their V e posure without burning by this mechanism.
Treatment
nce redness and other symptoms are present treatment o
sunburn has limited e cacy. The damage is done and the
in ammatory cascades are triggered. Prostaglandins espe
cially o the series are important mediators. Aspirin (acetyl
salicylic acid ASA) and nonsteroidal anti in ammatory drugs
( SA Ds) including indomethacin ha e been studied as well
as topical and systemic steroids. edium potency (class )
topical steroids applied h a ter the e posure (when erythema
rst appears) pro ide a small reduction in signs and symp
toms. ral SA Ds and systemic steroids ha e been tested
primarily be ore or immediately a ter sun e posure so there
is insu cient e idence to recommend their routine use e cept
immediately a ter solar o ere posure. There ore treatment o
sunburn should be supporti e with pain management (using
acetaminophen ASA or SA Ds) plus soothing topical emol
lients or corticosteroid lotions. n general a sunburn ictim
e periences at least or days o discom ort and e en pain
be ore much relie occurs.
Prophylaxis
Sunburn is best pre ented. se o the V inde acilitates
ta ing ade uate precautions to pre ent solar in ury. umer
ous educational programs ha e been de eloped to ma e the
public aware o the ha ards o sun e posure. Despite this
sunburn and e cessi e sun e posure continue to occur in the
nited States and Western urope especially in white persons
under age more than o whom report at least one
sunburn per year. Sun protection programs ha e the ollowing
our main messages
A oid midday sun.
See shade.
Wear sun protecti e clothing.
Apply a sunscreen.
The period o highest VB intensity between A and
P accounts or the ast ma ority o potentially ha ardous
Actinic injury
VB. oliage in trees pro ides the e ui alent o sun protec
tion actor (SP ) depending on the density o the green
ery. Clothing can be rated by its ability to bloc VB
radiation. The scale o measure is the V protection actor
( P ) analogous to SP in sunscreens. Although it is an in
itro measurement as with SP P correlates well with the
actual protection the product pro ides in i o. n general
denser wea es washed older clothing and loose tting
clothes screen VB more e ecti ely. Wetting a abric may
substantially reduce its P . Laundering a abric in a
Tinosorb containing material (SunGuard) will add substan
tially to the P o the abric. ats with at least a inch brim
all around are recommended.
A sunscreen s e cacy in bloc ing the VB (sunburn
inducing) radiation is e pressed as an SP . This is the ratio
o the number o Ds o radiation re uired to induce ery
thema through a lm o sunscreen ( mg cm ) compared with
unprotected s in. ost persons apply sunscreens in too thin
a lm so the actual applied SP is about hal that on
the label. Sunscreen agents include V absorbing chemicals
(chemical sunscreens) and V scattering or bloc ing agents
(physical sunscreens). A ailable sunscreens especially those
o high SP s (> ) usually contain both chemical sunscreens
(e.g. p aminoben oic acid PABA PABA esters cinnamates
salicylates anthranilates ben ophenones ben ylidene cam
phors such as ecamsule e oryl diben oylmethanes
Parsol in some products present as multicompound
technology eliople and Tinosorb S ) and physical
agents ( inc o ide or titanium dio ide). Sunscreens are a ail
able in numerous ormulations including sprays gels emol
lient creams and wa stic s. Sunscreens may be water resistant
with some maintaining their SP a ter min o water immer
sion and others maintaining their SP a ter min o water
immersion.
or s in types (see Table ) daily application o a
broad spectrum sunscreen with an SP o in a acial mois
turi er oundation or a tersha e is recommended. or
outdoor e posure a sunscreen o SP or higher is recom
mended or regular use. n persons with se ere photosensiti
ity and at times o high sun e posure high intensity sunscreens
o SP + with inorganic bloc ing agents may be re uired.
Application o the sunscreen at least min be ore and min
a ter sun e posure has begun is recommended. This dual
application approach will reduce the amount o s in e posure
by two old to three old o er a single application. Sunscreen
should be reapplied a ter swimming or igorous acti ity or
toweling. Sunscreen ailure occurs mostly in men rom ailure
to apply it to all the sun e posed s in or ailure to reapply
sunscreen a ter swimming. Sunscreens may be applied to
babies (under months) on limited areas. Vitamin D supple
mentation is recommended with the most stringent sun pro
tection practices. The dose is daily or those and
younger and or older patients.
Photoaging and cutaneous immunosuppression are medi
ated by VA as well as VB. or this reason sunscreens with
impro ed VA co erage ha e been de eloped. Those contain
ing e cellent protection or both VB and VA are identi ed
on the label by the words broad spectrum and these sun
screens should be sought by patients.
Bens G: Sunscreens. Adv Exp Med Biol 2014; 810:429–463.
Butler DB, et al: Prevalence of sunburn, sun protection, and indoor
tanning behaviors among Americans. J Am Acad Dermatol 2011;
65:S114.e1–e11.
25
 Diffey B: Sunscreens. Photodermatol Photoimmunol Photomed 2009;
3 25:233–236.
Faurschaou A, et al: Topical corticosteroids in the treatment of acute
sunburn. Arch Dermatol 2008; 144:620.
Fisher DE, et al: Indoor tanning: science, behavior, and policy. N Engl J
Dermatoses Resulting from Physical Factors
Med 2010; 363(10):901–903.
Gonzalez S, et al: Photoprotection. G Ital Dermatol Venereol 2010;
145:515–523.
Lim HW, et al: Adverse effects of ultraviolet radiation from the use of
indoor tanning equipment: time to ban the tan. J Am Acad Dermatol
2011; 64(5):893–902.
Medeiras VL, et al: Sunscreens in the management of
photodermatoses. Skin Therapy Lett 2010; 15:1.
Malbasa C, et al: Photoprotection with clothing and sunscreens. G Ital
Dermatol Venereol 2010; 145:509–514.
Polefka PG, et al: Effects of solar radiation on the skin. J Cosmet
Dermatol 2012; 11:134–143.
Vanchinathan V, et al: A dermatologist’s perspective on vitamin D. Mayo
Clin Proc 2012; 87:372–380.
Ephelis (freckle) and lentigo
rec les are small (< . cm) brown macules that occur in pro
usion on the sun e posed s in o the ace nec shoulders
and bac s o the hands. They become prominent during the
summer when e posed to sunlight and subside sometimes
completely during the winter when there is no e posure.
Blonds and redheads with blue eyes and o Celtic origin (s in
types or ) are especially susceptible. phelides may be
genetically determined and may recur in successi e genera
tions in similar locations and patterns. They usually appear at
about age years.
phelis must be di erentiated rom lentigo simple . The
lentigo is a benign discrete hyperpigmented macule appear
ing at any age and on any part o the body including the
mucosa. The intensity o the color is not dependent on sun
e posure. The solar lentigo appears at a later age mostly in
persons with long term sun e posure. The bac s o the hands
and ace (especially the orehead) are a ored sites ( ig. ).
istologically the ephelis shows increased production o
melanin pigment by a normal number o melanocytes. ther
wise the epidermis is normal whereas the lentigo has elon
gated rete ridges that appear to be club shaped.
rec les and solar lentigines are best pre ented by appropri
ate sun protection. Cryotherapy topical retinoids hydro ui
none intense pulse light undecylenoyl phenylalanine and
lasers are e ecti e in the treatment o solar lentigines.
Fig. 3-12 Solar lentigines.
26
Hafner C, et al: The absence of BRAF, FGFR3, and PIK3CA mutations
differentiates lentigo simplex from melanocytic nevus and solar lentigo.
J Invest Dermatol 2009; 129(11):2730–2735.
Katoulis AC, et al: A randomized, double-blind, vehicle-controlled study
of a preparation containing undecylenoyl phenylalanine 2% in the
treatment of solar lentigines. Clin Exp Dermatol 2010; 35(5):473–476.
Photoaging (dermatoheliosis)
The characteristic changes induced by chronic sun e posure
are called photoaging or dermatoheliosis. An indi idual s ris
or de eloping these changes correlates with the person s s in
type (see Table ). Ris or melanoma and nonmelanoma
s in cancer is also related to s in type. The persons most sus
ceptible to the deleterious e ects o sunlight are those o s in
type blue eyed air comple ioned persons who do not tan.
They are re uently o rish or other Celtic or Anglo Sa on
descent. ndi iduals who de elop photoaging ha e the genetic
susceptibility and ha e had su cient actinic damage to
de elop s in cancer and they there ore re uire more re uent
and care ul cutaneous e aminations.
Chronic sun e posure and chronologic aging are additi e.
Cigarette smo ing is also important in the de elopment o
wrin les resulting in the inability o obser ers to distinguish
solar induced rom smo ing induced s in aging accurately.
The areas primarily a ected by photoaging are those regularly
e posed to the sun the V area o the nec and chest bac and
sides o the nec ace bac s o the hands and e tensor arms
and in women the s in between the nees and an les. The s in
becomes atrophic scaly wrin led inelastic or leathery with
a yellow hue (milian citrine s in). n some persons o Celtic
ancestry dermatoheliosis produces pro ound epidermal
atrophy without wrin ling resulting in an almost translucent
appearance o the s in through which hyperplastic sebaceous
glands and prominent telangiectasias are seen ( ig. ).
These persons are at high ris or nonmelanoma s in cancer.
Pigmentation is une en with a mi ture o poorly demarcated
hyperpigmented and white atrophic macules obser ed. The
photodamaged s in appears generally dar er because o these
irregularities o pigmentation; in addition dermal hemosid
erosis occurs rom actinic purpura. Solar lentigines occur on
the ace and dorsa o the hands.
any o the te tural and tinctorial changes in sun damaged
s in are caused by alterations in the upper dermal elastic
tissue and collagen. This process is called solar (actinic) elas
tosis which imparts a yellow color to the s in. any clinical
ariants o solar elastosis ha e been described and an a ected
indi idual may simultaneously ha e many o these changes.
Fig. 3-13 Dermatoheliosis.

Fig. 3-14 Poikiloderma of Civatte.
Fig. 3-15 Cutis rhomboidalis nuchae.
Small yellowish papules and pla ues may de elop along the
sides o the nec . They ha e been ariably named striated
beaded lines (the result o sebaceous hyperplasia) or bro
elastolytic papulosis o the nec which is caused by solar
elastosis. At times usually on the ace or chest this elastosis
may orm a macroscopic translucent papule with a pearly
color that may closely resemble a basal cell carcinoma (actinic
elastotic pla ue). Similar pla ues may occur on the heli or
antiheli o the ear (elastotic nodules o the ear). Poi iloderma
o Ci atte re ers to reticulate hyperpigmentation with telangi
ectasia and slight atrophy o the sides o the nec lower
anterior nec and V o the chest. The submental area shaded
by the chin is spared ( ig. ). Poi iloderma o Ci atte re
uently presents in air s inned men and women in their mid
to late thirties or early orties. Cutis rhomboidalis nuchae
(sailor s or armer s nec ) is characteristic o long term chronic
sun e posure ( ig. ). The s in on the bac o the nec
becomes thic ened tough and leathery and the normal s in
mar ings are e aggerated. odular elastoidosis with cysts
and comedones occurs on the in erior periorbital and malar
s in ( a re Racouchot syndrome) ( ig. ) on the orearms
(actinic comedonal pla ue) or heli o the ear. These lesions
appear as thic ened yellow pla ues studded with comedones
and eratinous cysts. The ears may e hibit one or more rm
nodules on the heli nown as weathering nodules. Biopsy
re eals brosis and cartilage metaplasia.
Telangiectasias o er the chee s ears and sides o the nec
may de elop. Because o the damage to the connecti e tissue
o the dermis s in ragility is prominent and patients
note s in tearing rom tri ial in uries. This is nown as
Actinic injury
Fig. 3-16 Favre-Racouchot syndrome (nodular elastoidosis with cysts
and comedones).
dermatoporosis. ost re uently patients complain that e en
minimal trauma to their e tensor arms leads to an ecchymosis
a phenomenon called actinic purpura. As the ecchymoses
resol e dus y brown macules remain or months increasing
the mottled appearance o the s in. Deep dissecting hemato
mas may result as well causing large areas o necrosis. Again
minor trauma may lead to a pain ul deep bruise or simply
erythema without e er. This se ere complication o derma
toporosis occurs primarily on the legs o elderly women many
o whom are ta ing anticoagulants or systemic steroids. White
stellate pseudoscars on the orearms are a re uent complica
tion o this enhanced s in ragility. n some patients so t
esh colored to yellow papules and nodules coalesce on the
orearms to orm a cordli e band e tending rom the dorsal to
the e ural sur aces (solar elastotic bands).
Both VB and VA radiation induce reacti e o ygen species
(R S) and hydrogen pero ide. Acting through acti ator
protein (AP ) transcription o arious matri degrading
en ymes is upregulated speci cally matri metalloproteinase
( P ; collagenase) P (stromelysin ) and P
(gelatinase). n dar ly pigmented persons V e posure does
not acti ate P in part e plaining the protecti e e ect o
s in pigmentation against photoaging. n chronologically
aged s in P le els are also increased through AP .
Thus chronologic aging and photoaging may be mediated
through an identical biochemical mechanism.
istologically chronically sun e posed s in demonstrates
homogeni ation and a aint blue color o the connecti e tissue
o the upper reticular dermis so called solar elastosis. This
elastotic material is deri ed largely rom elastic bers stains
with histochemical stains or elastic bers and demonstrates
mar ed increased deposition o bulin and its brea down
products. Types and collagen are decreased. Characteristi
cally there is a one o normal connecti e tissue immediately
below the epidermis and abo e the elastotic material.
Colloid milium
There are two orms o colloid milium adult and u enile. n
both the adult and the u enile orm o colloid milium the
primary s in lesion is a translucent esh colored or slightly
yellow mm papule. inimal trauma may lead to purpura
rom ascular ragility. istologically the colloid consists o
intradermal amorphous ssured eosinophilic material. n
adult colloid milium lesions appear in the sun e posed areas
o the hands ace nec orearms and ears in middle age and
older adults usually men. Lesions o ten coalesce into pla ues
and may rarely be errucous. Petrochemical e posures ha e
27
 been associated with adult colloid milium. Pigmented orms
3 o colloid milium are associated with hydro uinone use.
Lesions ha e been induced by tanning bed e posure and they
can be unilateral usually in commercial dri ers. Adult colloid
milium may be considered a papular ariant o solar elastosis.
Dermatoses Resulting from Physical Factors
The colloid material is deri ed rom elastic bers and solar
elastosis is ound ad acent to the areas o colloid degeneration
histologically.
Ju enile colloid milium is much rarer. t de elops be ore
puberty and there may be a amily history. The lesions are
similar to the adult orm but appear initially on the ace later
e tending to the nec and hands. Sun e posure also appears
to be important in inducing lesions o u enile colloid milium.
Ju enile colloid milium ligneous con uncti itis and ligneous
periodontitis may appear in the same patient and are probably
o similar pathogenesis. istologically u enile colloid milium
can be distinguished rom adult colloid milium by the nding
o eratinocyte apoptosis in the o erlying epidermis. The
colloid material in u enile colloid milium is deri ed rom the
apoptotic eratinocytes and stains or cyto eratin.
Treatment with ractional photothermolysis or AL
photodynamic therapy may be e ecti e or colloid milium.
Prevention and treatment
Because both VB and VA are capable o inducing the
tissue destructi e biochemical pathways implicated in photo
aging sun protection against both portions o the V spec
trum is the primary pre ention re uired against photoaging.
Because photoaging as with other orms o radiation damage
appears to be cumulati e reducing the total li etime V e po
sure is the goal. The guidelines pre iously outlined or sunburn
prophyla is should be ollowed.
The regular use o emollients or moisturi ing creams on the
areas o sun damage will reduce scaling and may impro e
ragility by ma ing the s in more pliable. α ydro y acids
may impro e s in te ture when used in lower nonirritating
concentrations. Topical tretinoin adapalene and ta arotene
can impro e the changes o photoaging. Changes are slow and
irritation may occur. Chemical peels resur acing techni ues
laser and other light technologies ( or ascular alterations
pigmented lesions and dermal alterations) botulinum to ins
and so t tissue augmentation are all used to treat the conse
uences o photoaging. The surgical and laser treatments o
photoaging are discussed in Chapter .
Antoniou C, et al: Photoaging. Am J Clin Dermatol 2010; 11:95–102.
Balus L, et al: Fibroelastolytic papulosis of the neck: a report of 20
cases. Br J Dermatol 1997; 137:461.
Calderone DC, Fenske NA: The clinical spectrum of actinic elastosis.
J Am Acad Dermatol 1995; 32:1016.
Chung HT, et al: Firm papules on the auricular helix. JAMA Dermatol
2013; 149(4):475-480.
Desai C, et al: Colloid milium. Arch Dermatol 2006; 142:784.
Gambichler T, et al: Cerebriform elastoma: an unusual presentation of
actinic elastosis. J Am Acad Dermatol 2005; 52:1106.
Hughes MC, et al: Sunscreen and prevention of skin aging. Ann Intern
Med 2013; 158(11):781–790.
Katoulis AC, et al: Poikiloderma of Civatte. Dermatology 2007; 214:177.
Kaya G, et al: Deep dissecting hematoma: an emerging severe
complication of dermatoporosis. Arch Dermatol 2008;
144(10):1303–1308.
Kwittken J: Papular elastosis. Cutis 2000; 66:81.
Marra DE, et al: Fractional photothermolysis for the treatment of adult
colloid milium. Arch Dermatol 2007; 143:572.
Martorell-Calatayud A, et al: Familial juvenile colloid milium. J Am Acad
Dermatol 2011; 64(1):203–206.
Mehregan D, et al: Adult colloid milium. Int J Dermatol 2011;
50:1531–1534.
Mukherjee S, et al: Retinoids in the treatment of skin aging. Clin Interv
Aging 2006; 1:327.
28
Rabe JH, et al: Photoaging: mechanisms and repair. J Am Acad
Dermatol 2006; 55:1.
Tierney E, et al: Photodynamic therapy for the treatment of cutaneous
neoplasia, inflammatory disorders, and photoaging. Dermatol Surg
2009; 35(5):725–746.
Tierney E, et al: Treatment of poikiloderma of Civatte with ablative
fractional laser resurfacing. J Drugs Dermatol 2009; 8(6):527–534.
Tierney E, et al: Recent advances in combination treatments for
photoaging. Dermatol Surg 2010; 36:829–840.
Tierney EP, et al: Fractionated carbon dioxide laser treatment of
photoaging. Dermatol Surg 2011; 37(9): 1279–90.
Wang B: Photoaging. J Cutan Med Surg 2012; 15(1):374–377.
PHOTOSENSITIVITY
Photosensiti ity disorders include cutaneous reactions that
are chemically induced ( rom an e ogenous source) metabolic
(inborn errors such as the porphyrias resulting in production
o endogenous photosensiti ers) idiopathic and light e acer
bated (genetic and ac uired). Phototo icity and the idiopathic
disorders are discussed here; the other conditions are co ered
in later chapters.
Chemically induced photosensitivity
A number o substances nown as photosensiti ers may
induce an abnormal reaction in s in e posed to sunlight or its
e ui alent. The result may be a greatly increased sunburn
response without allergic sensiti ation called phototo icity.
Phototo icity may occur rom both e ternally applied (phyto
photodermatitis and berlo ue dermatitis) and internally
administered chemicals (phototo ic drug reaction). n con
trast photoallergic reactions are true allergic sensiti ations
triggered by sunlight produced either by internal administra
tion (photoallergic drug reaction) or by e ternal contact
(photoallergic contact dermatitis). Chemicals capable o induc
ing phototo ic reactions may also produce photoallergic
reactions.
n the case o e ternal contactants the distinction between
phototo icity and photoallergy is usually straight orward.
Phototo icity occurs on initial e posure has an onset o less
than h occurs in the ast ma ority o persons e posed to
the phototo ic substance and sunlight and shows a histologic
pattern similar to sunburn. By contrast photoallergy occurs
only in sensiti ed persons may ha e a delayed onset (up to
days the period o initial sensiti ation) and shows histo
logic eatures o allergic contact dermatitis.
Action spectrum
Chemicals nown to cause photosensiti ity (photosensiti ers)
are usually resonating compounds with a molecular weight o
less than daltons. Absorption o radiant energy (sunlight)
by the photosensiti er produces an e cited state; returning to
a lower energy state gi es o energy through uorescence
phosphorescence charge trans er heat or ormation o ree
radicals. ach photosensiti ing substance absorbs only speci c
wa elengths o light called its absorption spectrum. The spe
ci c wa elengths o light that e o e a photosensiti e reaction
are called the action spectrum. The action spectrum is included
in the absorption spectrum o the photosensiti ing chemical.
The action spectrum that produces phototo icity is mostly in
the long ultra iolet ( VA) region and may e tend into the
isible light region ( nm).
Photosensiti ity reactions occur only when there is su cient
concentration o the photosensiti er in the s in and when the
s in is e posed to a su cient intensity and duration o light
in the action spectrum o that photosensiti er. The intensity o
the photosensiti ity reaction is generally dose dependent and
is worse with a greater dose o photosensiti er and greater
light e posure.
Phototoxic reactions
A phototo ic reaction is a nonimmunologic reaction that
de elops a ter e posure to a speci c wa elength and intensity
o light in the presence o a photosensiti ing substance. t is a
sunburn type reaction with erythema tenderness and e en
blistering occurring only on the sun e posed parts. This type
o reaction can be elicited in many persons who ha e no pre i
ous history o e posure or sensiti ity to that particular sub
stance but indi idual susceptibility aries widely. n general
to elicit a phototo ic reaction a considerably greater amount
o the photosensiti ing substance is necessary than that needed
to induce a photoallergic reaction. The erythema begins as
with any sunburn within h but worsens or h be ore
beginning to subside. posure o the nail bed may lead to
onycholysis called photo onycholysis ( ig. ). Phototo ic
reactions especially rom topically applied photosensiti ers
may cause mar ed hyperpigmentation e en without signi
cant preceding erythema.
Phototoxic tar dermatitis
Coal tar creosote crude coal tar or pitch in con unction with
sunlight e posure may induce a sunburn reaction associated
with a se ere burning sensation. These olatile hydrocarbons
may be airborne so the patient may gi e no history o
touching tar products. The burning and erythema may con
tinue or days. Although up to o white persons
e posed to such a combination de elop this reaction persons
with type V or V s in are protected by their constituti e s in
pigmentation. A ter the acute reaction hyperpigmentation
occurs which may persist or years. Coal tar or its deri ati es
may be ound in cosmetics drugs dyes insecticides and
disin ectants.
Phytophotodermatitis
urocoumarins in many plants may cause a phototo ic reac
tion when they come in contact with s in that is e posed to
VA light. This is called phytophotodermatitis. Se eral hours
a ter e posure a burning erythema occurs ollowed by edema
and the de elopment o esicles or bullae. An intense residual
hyperpigmentation results that may persist or wee s or
months. The intensity o the initial phototo ic reaction may be
mild and may not be recalled by the patient despite signi cant
Fig. 3-17 Photo-
onycholysis from
minocycline.
hyperpigmentation. ragrance products containing bergapten
a component o oil o bergamot will produce this reaction.
a ragrance containing this metho ypsoralen or other uro
coumarin is applied to the s in be ore e posure to the sun or
tanning lights berlo ue dermatitis may result. This hyperpig
Photosensitivity
mentation which may be preceded by redness and edema
occurs primarily on the nec and ace. Arti cial bergapten ree
bergamot oil and laws limiting the use o urocoumarins in
urope and the nited States ha e made this a rare condition.
owe er lorida Water and ananga Water colognes
ormerly popular in the ispanic A rican American and
Caribbean communities contain this potent photosensiti er
and can still be ordered online as can other aromatherapy
products containing urocoumarins.
ost phototo ic plants are in the amilies mbelli erae
Rutaceae (rue) Compositae and oraceae. ncriminated
plants include agrimony angelica atrillal ba achi buttercup
common rice cowslip dill ennel g garden and wild carrot
garden and wild parsnip gas plant goose oot abon lime and
Persian lime lime bergamot masterwort mustard parsley St.
John s wort and yarrow. n awaii the anise scented mo i
hana berry Pelea anisata was nown to nati es or its photo
to ic properties (mo ihana burn). t is a member o the rue
amily. posure through limes used to a or gin and tonics
and e ican beer may result in phototo ic reactions in outdoor
bartenders and their customers ( ig. ). ome tanning solu
tions containing g lea es can produce phytophotodermatitis.
These conditions may be widespread and se ere enough to
re uire burn unit management ( ig. ).
ccupational disability rom e posure to the pin rot ungus
Sclerotinia sclerotiorum present on celery roots occurs in
celery armers. n addition disease resistant celery contains
urocoumarins and may produce phytophotodermatitis in
grocery wor ers. sually insu cient sensiti ing urocouma
rin is absorbed rom dietary e posure; howe er ingested
herbal remedies may cause systemic phototo icity.
Dermatitis bullosa striata pratensis (grass or meadow der
matitis) is a phytophotodermatitis caused by contact not with
grass but with yellow owered meadow parsnip or a wild
yellow owered herb o the rose amily. The eruption consists
o strea s and bi arre con gurations with esicles and bullae
that heal with residual hyperpigmentation. The usual cause is
sunbathing in elds containing the phototo ic plants. Simi
larly tourists in the tropics may rinse their hair with lime uice
outdoors and strea y hyperpigmentation o the arms and
bac will result where the lime uice runs down ( ig. ).
Blistering phytophotodermatitis must be di erentiated rom
rhus dermatitis. The esicles and bullae o rhus are not
Fig. 3-18
Phytodermatitis to
lime in a bartender.
29
 Fig. 3-19 Severe
3 phytophototoxicity.
Dermatoses Resulting from Physical Factors
Fig. 3-20
Phytophotodermatitis;
the patient had rinsed
her hair with lime juice
in Mexico.
necessarily limited to the sun e posed areas and itching is the
most prominent symptom. Lesions continue to occur in rhus
dermatitis or a wee or more. n phytophotodermatitis the
reaction is limited to sun e posed sites a burning pain appears
within h and mar ed hyperpigmentation results. The
asymmetry atypical shapes and strea ing o the lesions are
help ul in establishing the diagnosis. These eatures may lead
to a misdiagnosis o child abuse.
Treatment o a se ere acute reaction is similar to the man
agement o a sunburn with cool compresses mild analgesics
i re uired and topical emollients. se o topical steroids and
strict sun a oidance immediately a ter the in ury may protect
against the hyperpigmentation. The hyperpigmentation is best
managed by tincture o time.
Abali AE, et al: Burns or phytophotodermatitis, abuse or neglect. J Burn
Care Res 2012; 33(6):e309.
Carlsen K, et al: Phytophotodermatitis in 19 children admitted to
hospital and their differential diagnosis. J Am Acad Dermatol 2007;
57:S88.
30
Fig. 3-21 Polymorphous light eruption, papulovesicular variant.
Eickhorst K, et al: Rue the herb: Ruta graveolens–associated
phytophotodermatitis. Dermatitis 2007; 18:52.
Flugman SL: Mexican beer dermatitis. Arch Dermatol 2010; 146:1194.
Maloney FJ, et al: Iatrogenic phytophotodermatitis resulting from herbal
treatment of an allergic contact dermatitis. Clin Exp Dermatol 2006;
31:39.
Pomeranz MK, et al: Phytophotodermatitis and limes. N Engl J Med
2007; 357:e1.
Rademaker M, et al: Phytophotodermatitis caused by Ficus pumila.
Contact Dermatitis 2012; 67:53.
Sasseville D: Clinical patterns of phytodermatitis. Dermatol Clin 2009;
27:299.
Zink A, et al: Images in clinical medicine. Phototoxic dermatitis. N Engl
J Med 2014; 371:559.
Idiopathic photosensitivity disorders
This idiopathic group includes the photosensiti ity diseases
or which no cause is nown. These disorders are not associ
ated with e ternal photosensiti ers (e cept or some cases o
chronic actinic dermatitis) or inborn errors o metabolism.
Polymorphous light eruption
Polymorphous light eruption (PL P L ) is the most common
orm o photosensiti ity. n arious studies o orthern uro
pean white persons a history o PL can be elicited in between
and o the adult population. t represents about one
uarter o all photosensiti e patients in re erral centers. All
races and s in types can be a ected. The onset is typically in
the rst our decades o li e and emales outnumber males by
or . The pathogenesis is un nown but a amily history
may be elicited in o patients. Some in estigators
report that o patients with PL may ha e positi e
antinuclear antigens (A As) and a amily history o lupus
erythematosus. Photosensiti e systemic lupus erythematosus
(SL ) patients may gi e a history o PL li e eruptions or
years be ore the diagnosis o SL is made. PL patients should
be ollowed or the de elopment o symptoms o SL .
Clinically the eruption may ha e se eral di erent morphol
ogies although in the indi idual patient the morphology is
usually constant. The papular (or erythematopapular) ariant
is the most common but papulo esicular ec ematous ery
thematous and pla ueli e lesions also occur ( ig. ).
Pla ueli e lesions are more common in elderly patients and
may closely simulate lupus erythematosus with indurated
erythematous ed lesions. n A rican Americans a pinpoint
papular ariant has been obser ed closely simulating lichen

Fig. 3-22 Polymorphous light eruption, micropapular variant
resembling lichen nitidus.
nitidus but showing spongiotic dermatitis histologically ( ig.
). Scarring and atrophy do not occur; in dar ly pigmented
races howe er mar ed postin ammatory hyperpigmentation
or hypopigmentation may be present. n some patients pruri
tus only without an eruption may be reported (PL sine
eruptione). Some o these patients will de elop typical PL
later in li e.
The lesions o PL appear most o ten days a ter e po
sure to sunlight although patients may report itching and
erythema during sun e posure and de elopment o lesions
within the rst h. A change in the amount o sun e posure
appears to be more critical than the absolute amount o radia
tion. Patients li ing in tropical climates may be ree o erup
tion only to de elop disease when they mo e to temperate
ones where there is more mar ed seasonal ariation in V
intensity. Areas o in ol ement include the ace the V area o
the chest nec and arms. n general or each indi idual
certain areas are predisposed. Typically howe er areas pro
tected during the winter such as the e tensor orearms are
particularly a ected whereas areas e posed all year ( ace and
dorsa o hands) may be relati ely spared. The eruption appears
most re uently in the spring. The eruption o ten impro es
with continued sun e posure (hardening) so patients may be
clear o the condition in the summer or autumn.
An unusual ariant o PL is u enile spring eruption o the
ears (see ig. ). This occurs most re uently in boys age
years but may also be ound in young adult males. t
presents in the spring o ten a ter sun e posure on cold but
sunny days. The typical lesions are grouped small papules or
papulo esicles on the helices. Lesions may orm isible esi
cles and crusting. Ju enile spring eruption o the ears is sel
limited and does not scar. VA is the inducing spectrum and
some patients also ha e lesions o PL elsewhere. The histo
logic picture is identical to that o PL . Another locali ed
ariant o PL is spring and summer eruption o the elbows
but this occurs in adults e ually in men and women.
istologically a peri ascular predominantly T cell in l
trate is present in the upper and middle dermis. There is o ten
edema and endothelial swelling with occasional neutrophils.
pidermal changes are ariable with spongiosis and e ocyto
sis most o ten obser ed. ccasionally a irtual absence o
ndings microscopically may parado ically be reported and
has been re erred to as pauci in ammatory photodermatitis.
The reported action spectrum o PL aries possibly depend
ing on the di erent ethnic bac grounds o reported popula
tions. VA is most o ten responsible; howe er VB and both
wa elengths in combination are also re uently necessary.
Patients o ten report eruptions ollowing sun e posure through
window glass. Although rare isible light sensiti ity can also
occur. Typically women are more sensiti e than men to VA
only and men are more sensiti e to isible light. en although
the minority o PL patients tend to ha e more se ere PL and
broader wa elengths o sensiti ity. ost patients react more
Photosensitivity
in a ected sites and in some lesions can only be induced in
a ected areas. Phototesting produces ariable results. ne
protocol produced positi e results in o tested patients
using our e posures o VB VA or a combination in pre i
ously a ected sites. owe er the light sources are not readily
a ailable and reported protocols ary widely. n clinical prac
tice the diagnosis is usually made clinically.
The di erential diagnosis o PL includes lupus erythema
tosus photosensiti e drug eruption prurigo nodularis and
photoallergic contact dermatitis. istopathologic e amina
tion A A testing and direct immuno uorescence (D ) are
help ul in distinguishing these diseases. Serologic testing
alone may not distinguish PL rom SL because o the pos
sibility o positi e A A tests in PL patients. Lupus erythe
matosus may present initially with photosensiti ity be ore
other eatures o lupus occur. A newly described condition
sebaceous neutrophilic adenitis is characteri ed by erythema
tous circinate pla ues on the head nec and upper chest and
has been reported in the rst to second month o spring. is
tologically neutrophilic in ltration o the sebaceous glands
occurs sometimes orming microabscesses.
Therapeutically most patients with mild PL can be
managed by a oiding the sun and using barrier protection and
high SP broad spectrum sunscreens. t is critical that the
sunbloc s contain speci c absorbers or bloc ers (ecamsule
a oben one titanium dio ide inc o ide) o long wa e VA
because this is the most common triggering wa elength. Sun
bloc s containing more than one o these agents are more
e ecti e. DermaGard lm can be applied to windows at home
and in the car to bloc the transmission o almost all BV and
VA rays while allowing isible light to be transmitted. Deg
radation does occur so the lm should be replaced e ery
years. These measures o photoprotection are critical or all
patients since they are ree o to icity and reduce the amount
and duration o other therapies re uired. Patient education is
important in the management o PL . Phototesting may be
re uired to con ince patients that they are V sensiti e and
will also determine the action spectrum.
The use o topical tacrolimus ointment at night or twice
daily combined with the pre ious measures or sun a oidance
and the use o sunscreens controls PL in many patients. At
times topical steroids re uently o super or high potency and
in se eral daily to wee ly pulses are necessary to control the
pruritus and clear the eruption. Antihistamines (hydro y ine
diphenhydramine do epin) may be used or pruritus. Sys
temic corticosteroids in short courses may be necessary espe
cially in the spring. n patients whose condition is not
controlled by these measures hardening in the spring with
VB narrow band ( B) VB or psoralen plus VA (P VA)
can dramatically decrease the sun sensiti ity o patients with
PL and up to can be controlled with phototherapy. n
the most sensiti e patients systemic steroids may be needed
at the inception o the phototherapy. Systemic hydro ychloro
uine sul ate mg day may be used. t has a delayed
onset and is best instituted in the late winter to pre ent spring
outbrea s. Chloro uine or uinacrine may be e ecti e i
hydro ychloro uine is not but in general antimalarials are
in erior to phototherapy. n the most se ere cases manage
ment with a athioprine cyclosporine (cyclosporin A) thalido
mide or mycophenolate mo etil may be considered. these
agents are used in a patient considered to ha e PL an e alu
ation or chronic actinic dermatitis should be per ormed
because patients with PL rarely re uire these agents.
31

3 photobiologic, and follow-up study of 110 patients. J Am Acad
Dermatoses Resulting from Physical Factors
Fig. 3-23 Actinic prurigo, prurigo nodularis–like lesions.
Actinic prurigo
Actinic prurigo probably represents a ariant o PL ; it is most
o ten seen in ati e Americans o orth and Central America
and Colombia. The incidence in e ico has been reported at
between . and . . t has been reported in urope Aus
tralia and Japan as well. The emale male ratio is between
and . Actinic prurigo in ati e Americans in the nited
States begins be ore age in o cases and be ore age
in . p to o patients ha e a positi e amily history
(hereditary PL o ati e Americans). n urope o cases
occur be ore age . n the nuit Canadian population onset is
later and re uently in adulthood.
n childhood lesions begin as small papules or papulo esi
cles that crust and become impetigini ed. They are intensely
pruritic and re uently e coriated. n children the chee s
distal nose ears and lower lip are typically in ol ed. Cheilitis
may be the initial and only eature or years. Con uncti itis is
seen in o patients (limbal type ernal catarrh). Lesions
o the arms and legs are also common and usually e hibit a
prurigo nodule li e con guration ( ig. ). The eruption
may e tend to in ol e sun protected areas especially the but
toc s but lesions in these areas are always less se ere. n
adults chronic dry papules and pla ues are most typical and
cheilitis and crusting occur less re uently. S in lesions tend
to persist throughout the year in the tropics but are clearly
worse during periods o increased sun e posure. n temperate
and high latitude regions lesions occur rom arch through
the summer and substantially remit in the winter. ardening
as seen with PL does not occur. n up to o patients with
actinic prurigo that present be ore age the condition
impro es or resol es within years whereas adults usually
ha e the disease throughout li e.
nitial therapy is identical to that or PL . Thalidomide has
been used e ecti ely and sa ely o er many years or this con
dition. n patients re ractory to or intolerant o thalidomide
cyclosporin A can be e ecti e. Topical cyclosporin A may
be e ecti e in controlling limbal lesions o actinic prurigo
associated con uncti itis.
Akaraphanth R, et al: Adult-onset actinic prurigo in Thailand.
Photodermatol Photoimmunol Photomed 2007; 23:234.
32
Boonstra HE, et al: Polymorphous light eruption: a clinical,
Dermatol 2000; 42:199.
Chantorn R, et al: Photosensitivity disorders in children. Part 1. J Am
Acad Dermatol 2012; 67:1093.e1–e18.
Chiam LY, et al: Pinpoint popular polymorphous light eruption in Asian
skin. Photodermatol Photoimmunol Photomed 2009; 25:71.
Gruber-Wackernagel A, et al: Polymorphous light eruption. Dermatol Clin
2014; 32:315.
Hasan T, et al: Disease associations in PMLE. Arch Dermatol 1998;
134:1081.
Hatch KL, et al: Garments as solar ultraviolet radiation screening
materials. Dermatol Clin 2006; 24:85.
Honigsmann H: Polymorphous light eruption. Photodermatol
Photoimmunol Photomed 2008; 24:155.
Kerr AC: Actinic prurigo deterioration due to degradation of DermaGard
window film. Br J Dermatol 2007; 157:609.
Kerr HA, et al: Photodermatoses in African Americans. J Am Acad
Dermatol 2007; 57:638.
Millard TP, et al: Familial clustering of PLE in relatives of patients with
lupus erythematosus. Br J Dermatol 2001; 144:334.
Molina-Riuz AM, et al: Spring and summer eruption of the elbows. J Am
Acad Dermatol 2013; 68: 306-312.
Patel DC, et al: Efficacy of short-course oral prednisolone in PLE:
a randomized controlled trial. Br J Dermatol 2000; 143:828.
Roelandts R: The diagnosis of photosensitivity. Arch Dermatol 2000;
136:1152.
Ross G, et al: Actinic prurigo. Photodermatol Photoimmunol Photomed
2008; 24:272.
Schornagel IJ, et al: Diagnostic phototesting in PLE. Br J Dermatol
2005; 153:1220.
Stratigos AJ, et al: Juvenile spring eruption. J Am Acad Dermatol 2004;
50:57.
Su W, et al: Photodermatitis with minimal inflammatory infiltrate. Am J
Dermatopathol 2006; 28:482.
Trelles AS, et al: A new case of sebaceous neutrophilic adenitis. J Am
Acad Dermatol 2009; 60:887.
Van de Pas CB, et al: An optimal method of photoprovocation of PLE.
Arch Dermatol 2004; 140:286.
Wiseman MC, et al: Actinic prurigo. J Am Acad Dermatol 2001;
44:952.
Yong Gee SA, et al: Long-term thalidomide for actinic prurigo. Australas
J Dermatol 2001; 42:281.
Brachioradial pruritus
Polymorphous light eruption may present initially and only
on the brachioradial area. This type o brachioradial eruption
was the initial pattern o brachioradial pruritus described and
was termed solar pruritus ( ig. ). The ma ority o cases o
brachioradial pruritus especially those characteri ed by
se ere re ractory intractable pruritus and secondary se ere
licheni cation are now thought to represent a orm o neuro
pathic pruritus sometimes related to cer ical spine disease
(see Chapter ). Sunlight may be an eliciting actor and cer ical
spine disease a predisposing actor in patients with brachiora
dial pruritus. To identi y those patients in whom photosensi
ti ity plays a prominent role a high SP ( VA VB)
sunscreen should be applied to one arm only or se eral
wee s. n patients with PL this usually leads to impro e
ment o that one arm compared with the contralateral unpro
tected arm. n patients with primarily neuropathic disease
sunscreen application leads to minimal impro ement.
Solar urticaria
Solar urticaria is most common in women age . Within
seconds to minutes a ter light e posure typical urticarial
lesions appear and resol e in h rarely lasting more than
h ( ig. ). Delayed reactions rarely occur. Chronically
e posed sites may ha e some reduced sensiti ity. n se ere
attac s syncope bronchospasm and anaphyla is may occur.
 Fig. 3-24
Polymorphous light
eruption, brachioradial
distribution.
Fig. 3-25 Solar
urticaria.
Patients with solar urticaria may be sensiti e to wa elengths
o er a broad spectrum. The wa elengths o sensiti ity and
the minimal urticarial doses ( Ds) may ary with anatomic
site and o er time within the same patient. VA sensiti ity is
the most common but isible light sensiti ity is also re uently
reported. The photosensiti ity can be passi ely trans erred
and irradiation o the patient s serum with the acti ating
wa elength ollowed by rein ection will create a wheal in
the patient but not in an una ected patient. This suggests the
presence o a circulating photoinducible allergen to which the
indi idual patient with solar urticaria is sensiti e. n some
patients an inhibition spectrum may be identi ed that inhibits
the binding o the endogenous photoallergen to mast cells.
Solar urticaria is irtually always idiopathic. Rarely medica
tions such as tetracycline (but not minocycline) chlorproma
Photosensitivity
ine progestational agents and repirinast ha e been reported
to induce solar urticaria. rythropoietic protoporphyria and
more rarely porphyria cutanea tarda may present with lesions
simulating solar urticaria. There are rare reports o solar urti
caria in patients with lupus erythematosus.
The diagnosis o solar urticaria is usually straight orward
rom the history. Phototesting is use ul to determine the wa e
lengths o sensiti ity and to ascertain the D i VA desen
siti ation is being considered.
Because many patients ha e sensiti ity in the VA or e en
isible range broad spectrum sunscreens should be insti
tuted. Antihistamines especially the nonsedating agents
loratadine cetiri ine Cl and e o enadine may increase
the D old or more. igher doses twice or more the
standard recommendation may be re uired (e.g. mg o
e o enadine twice daily). These drugs plus sun a oidance
and broad spectrum sunscreens are the rst line therapy.
P VA or increasing VA e posures are e ecti e in more
di cult cases with P VA ha ing greater e cacy. Rush
hardening may induce VA tolerance allowing patients to
begin P VA therapy. P VA is e ecti e e en i the patient is
not sensiti e to VA. Cyclosporin A ( . mg g day) and
intra enous immune globulin ( V G; g g day or days)
ha e been anecdotally reported as e ecti e. or the most di
cult cases plasmapheresis may be used to remo e the circu
lating photoallergen allowing P VA to be gi en and leading
to remission.
Aubin F, et al: Severe and refractory solar urticaria treated with
intravenous immunoglobulins. J Am Acad Dermatol 2014; 71:948.
Beattie PE, et al: Characteristics and prognosis of idiopathic solar
urticaria: a cohort of 87 cases. Arch Dermatol 2003; 139:1149.
Botto NC, et al: Solar urticarial. J Am Acad Dermatol 2008; 59:909.
Fukunaga A, et al: The inhibition spectrum of solar urticaria suppresses
the wheal-flare response following intradermal injection with
photoactivated autologous serum but not with compound 48/80.
Photodermatol Photoimmunol Photomed 2006; 22:129.
Masuoka E, et al: Successful and long-lasting treatment of solar
urticarial with UVA rush hardening therapy. Br J Dermatol 2012;
167:198.
Ng JCH, et al: Changes of photosensitivity and action spectrum with
time in solar urticaria. Photodermatol Photoimmunol Photomed 2002;
18:191.
Rose RF, et al: Solar angioedema. Photodermatol Photoimmunol
Photomed 2005; 21:226.
Veien NK, et al: Brachioradial pruritus: a follow-up of 76 patients. Acta
Derm Venereol 2011; 91:183
Wessendorf U, et al: Fixed solar urticarial with delayed onset. J Am
Acad Dermatol 2009; 60:695-697.
Yap LM, et al: Drug-induced solar urticaria due to tetracycline. Australas
J Dermatol 2000; 41:181.
Hydroa vacciniforme
ydroa accini orme is a rare chronic photodermatosis with
onset in childhood. Boys and girls are e ually represented but
boys present earlier and on a erage ha e longer lasting
disease. There is a bimodal onset between ages and and
between and . The natural history o the typical disorder
is spontaneous remission be ore age but rare cases in young
adults do occur. Within h o e posure stinging begins. At
h or sooner erythema and edema appear ollowed by
the characteristic mm esicles. er the ne t ew days
these lesions rupture become centrally necrotic and heal with
a smallpo li e scar. Lesions tend to appear in crops with
disease ree inter als. The ears nose chee s and e tensor
33
 arms and hands are a ected. Subungual hemorrhage ocular Fig. 3-26 Chronic
3 in ol ement or oral ulcerations may occur.
istologically early lesions show intraepidermal esicula
actinic dermatitis.

tion and dermal edema that e ol e into a subepidermal blister.

ecrotic lesions show reticular degeneration o eratinocytes
Dermatoses Resulting from Physical Factors

with epidermal necrosis an ed by spongiosis with a dense

peri ascular in ltrate o neutrophils and lymphocytes. Dermal
essels may be thrombosed simulating asculitis. Lesions
may be reproduced by repetiti e VA with the action spec
trum in the nm range.
The di erential diagnosis includes PL actinic prurigo and
erythropoietic protoporphyria. Porphyrin le els are normal in
hydroa accini orme. n erythropoietic protoporphyria the
burning typically begins within minutes o sun e posure and
o er time patients de elop di use thic ened wa li e scar
ring rather than the smallpo li e scars o hydroa accin
i orme. istologic e aluation is use ul in distinguishing these
two conditions. Treatment is principally to a oid sunlight
e posure and to use broad spectrum sunscreens that bloc in
the VA range. Prophylactic B VB phototherapy in the
early spring may be e ecti e.
A subset o children and less o ten adults with photosensi
ti e hydroa accini orme li e s in lesions mani est acial
swelling indurated nodules or progressi e ulcers e er and
li er damage. ral esophageal or colonic ulcerations may
occur. ypersensiti ity to mos uito bites may also be seen.
These patients may de elop pstein Barr irus ( BV) associ
ated natural iller ( ) cell T cell lymphomas and die rom
this or a hemophagocytic syndrome. The hydroa accini orme
li e s in lesions may precede the diagnosis o the lymphoma
by up to a decade and initially the patient may appear to ha e
typical hydroa accini orme o the sel limited type. This is
there ore a disease spectrum with both typical and se ere
hydroa accini orme being BV associated. Treatment o the
lymphoma may lead to clearing o these lesions.
Chantorn R, et al: Photosensitivity disorders in children. Part 1. J Am
Acad Dermatol 2012; 67:1093.e1–e18.
Chen HH, et al: Hydroa vacciniforme–like primary cutaneous CD8-
positive T-cell lymphoma. Br J Dermatol 2002; 147:587.
Cho KH, et al: Epstein-Barr virus–associated peripheral T-cell lymphoma
in adults with hydroa vacciniforme–like lesions. Clin Exp Dermatol
2001; 26:242.
Gupta G, et al: Hydroa vacciniforme: a clinical and follow-up study of 17
cases. J Am Acad Dermatol 2000; 42:208.
Miyake T, et al: Survival rates and prognostic factors of Epstein-Barr
virus-associated hydroa vacciniforme and hypersensitivity to mosquito
bites. Br J Dermatol 2014; Sep 18.
Yammamoto T, et al: Oculomucosal and gastrointestinal involvement in
Epstein-Barr virus–associated hydroa vacciniforme. Eur J Dermatol
2012; 23:380.
Zeng Y, et al: Hydroa vacciniforme–like Epstein-Barr virus–associated
lymphoproliferative disease. Pediatr Dermatol 2012; 29:96.
Chronic actinic dermatitis
Chronic actinic dermatitis represents the end stage o progres
si e photosensiti ity in some patients. t has replaced the
terms persistent light reacti ity actinic reticuloid photosensi
ti e ec ema and chronic photosensiti ity dermatitis. The basic
components o this disease are as ollows
Persistent chronic ec ematous eruption in the absence o
e posure to nown photosensiti ers
sually broad spectrum photosensiti ity with decreased
D to VA and or VB and at times isible light
istology consistent with a chronic dermatitis with or
without eatures o lymphoma
Clinically chronic actinic dermatitis predominantly a ects
middle age or elderly men. n the nited States patients
34
with s in types V and V may be disproportionately a ected
( ig. ). S in lesions consist o edematous scaling thic
ened patches and pla ues that tend to be con uent. Lesions
occur primarily or most se erely on the e posed s in and may
spare the upper eyelids behind the ears and the bottom o
wrin les. n ol ement o une posed sites o ten occurs pro
gressing to erythroderma in the most se ere cases. ar ed
depigmentation resembling itiligo may result. Patients may
not reali e their condition is e acerbated by e posure to light.
t may persist in all seasons.
The pathogenesis o this syndrome is un nown. n some
patients a preceding topical or oral photosensiti er may be
implicated but chronic actinic dermatitis ails to impro e with
discontinuation o the inciting agent. n about one third o
patients photopatch testing yields a positi e response to pre
iously applied agents especially mus ambrette sunscreen
ingredients p phenylenediamine and he achlorophene. Patch
testing to standard agents may ha e a positi e result in about
o patients but no particular rele ance is ound. owe er
in appro imately o uropean patients ses uiterpene
lactone contact sensiti ity rom Compositae has been identi
ed. n addition more than o men o er age with
ses uiterpene lactone sensiti ity ha e abnormal phototesting
results. CD (suppressor cytoto ic) T cells are disproportion
ately represented in the cutaneous in ltrates in the ma ority o
patients and less re uently in the peripheral blood. g le els
may be ele ated.
n this clinical setting diagnosis o chronic actinic dermatitis
is established by histologic e aluation and phototesting. Pho
totesting o ten reproduces the lesions. About o patients
are sensiti e to VA VB and isible light; to VA and
VB; and to VB or VA only. The nding o photosen
siti ity to VA and VB helps to di erentiate chronic actinic
dermatitis rom drug induced photosensiti ity in which
patients usually e hibit only VA photosensiti ity. PL pho
toallergic contact dermatitis airborne contact dermatitis and
mycosis ungoides or S ary syndrome must be e cluded. PL
is e cluded by the broad spectrum reduced D in chronic
actinic dermatitis although some patients may begin with
a PL li e disease that later meets the criteria or chronic
actinic dermatitis. Contact dermatitis is e cluded by patch
and photopatch testing. ycosis ungoides may be di cult to
di erentiate rom chronic actinic dermatitis in cases with atyp
ical histology. Phototesting is critical in these patients. ycosis
ungoides will mani est a T cell receptor rearrangement in
lesional s in or peripheral blood and usually shows a CD
(helper) T cell predominance.
Therapy or chronic actinic dermatitis includes identi ying
possible topical photosensiti ers by photopatch testing and
scrupulously a oiding them. a imum sun a oidance and
broad spectrum sunscreens are essential. Topical tacrolimus is
use ul in many patients. Topical and systemic steroids are
e ecti e in some patients but chronic to icity o systemic
steroids limits chronic use. A athioprine mg day is
the most reproducibly e ecti e treatment and may be re uired
annually during periods o increased sun intensity. Low dose
P VA or B VB can be e ecti e when used with topical and
systemic steroids but patients may also be intolerant o this
approach. ydro yurea mg twice daily cyclosporin A
thalidomide and mycophenolate mo etil may also be used.
mmunosuppressi e agents may allow patients to tolerate
P VA therapy. With care ul management about in
patients will lose their photosensiti ity within years in
by years and hal o patients by years.
Beach RA, et al: Chronic actinic dermatitis. J Cutan Med Surg 2009;
13:121.
Chew AL, et al: Contact and photocontact sensitization in chronic
actinic dermatitis. Contact Dermatitis 2010; 62:42.
Dawe RS, et al: The natural history of chronic actinic dermatitis. Arch
Dermatol 2000; 136:1215.
Khaled A, et al: Chronic actinic dermatitis: two patients with successful
management using narrow band ultraviolet B phototherapy with
systemic steroids. Therapie 2011; 66:453.
Ma Y, et al: Treatment with topical tacrolimus favors chronic actinic
dermatitis. J Dermatol Treat 2010; 21:171.
Que SK, et al: Chronic actinic dermatitis. Dermatitis 2011;
22:147.
Safa G, et al: Recalcitrant chronic actinic dermatitis treated with
low-dose thalidomide. J Am Acad Dermatol 2005; 52:E6.
Thomson MA, et al: Chronic actinic dermatitis treated with
mycophenolate mofetil. Br J Dermatol 2005; 152:784.
Photosensitivity and HIV infection
Photosensiti ity resembling PL actinic prurigo or chronic
actinic dermatitis is seen in about o patients with human
immunode ciency irus ( V) in ection. n general photosen
siti ity is seen when the CD count is below (o ten < )
e cept in persons with a genetic predisposition ( ati e Ameri
cans). Photosensiti ity may be the initial mani estation o V will be hypopigmented or depigmented. Cutaneous necrosis
disease. A rican American patients are disproportionately rep
resented among patients with V photosensiti ity. Photosen
siti ity may be associated with ingestion o a photosensiti ing
medication especially SA Ds e a iren (used in AART
therapy) or trimethoprim sul ametho a ole but the s in erup
tion o ten does not impro e e en when the medication is dis
continued. istologically the lesions may show subacute or
chronic dermatitis o ten with a dense dermal in ltrate with
many eosinophils. istology identical to PL lichen planus
or lichen nitidus may also occur. When the CD count is below
especially in blac patients chronic actinic dermatitis with
eatures o actinic prurigo is typical. Widespread itiliginous
lesions may de elop. Therapy is di cult but thalidomide may
be bene cial.
Bilu D, et al: Clinical and epidemiological characterization of
photosensitivity in HIV-positive individuals. Photodermatol
Photoimmunol Photomed 2004; 20:175.
Isaacs T, et al: Annular erythema and photosensitivity as manifestations
of efavirenz-induced cutaneous reactions. J Antimicrob Chemother
2013; 68:2871.
Maurer TA, et al: Thalidomide treatment for prurigo nodularis in
HIV-infected subjects: efficacy and risk of neuropathy. Arch Dermatol
2004; 140:845.
Philips RC, et al: HIV photodermatitis presenting with widespread
vitiligo-like depigmentation. Dermatol Online J 2012; 18:6.
Radiodermatitis
RADIODERMATITIS
The ma or target within the cell by which radiation damage
occurs is the D A. The e ects o ioni ing radiation on the cells
depend on the amount o radiation its intensity (e posure
rate) and the characteristics o the indi idual cell. Rapidly
di iding cells and anaplastic cells in general ha e increased
radiosensiti ity compared with normal tissue. When radiation
therapy is deli ered it is re uently ractionated (i.e. di ided
into small doses). This allows the normal cells to reco er
between doses.
When the dose is large cell death results. n small amounts
the e ect is insidious and cumulati e. itosis is arrested tem
porarily with conse uent retardation o growth. The e posure
rate a ects the number o chromosome brea s. The more rapid
the deli ery o a certain amount o radiation the greater is the
number o chromosome brea s. The number o brea s is also
increased by the presence o o ygen.
Acute radiodermatitis
When an erythema dose o ioni ing radiation is gi en to
the s in there is a latent period o up to h be ore isible
erythema appears. This initial erythema lasts days but
may be ollowed by a second phase beginning up to wee
a ter the e posure and lasting up to month. When the s in
is e posed to a large amount o ioni ing radiation an acute
reaction de elops the e tent o which will depend on the
amount uality and duration o e posure. Such radiation
reaction occurs in the treatment o malignancy and in acci
dental o ere posure. The reaction is mani ested by initial
erythema ollowed by a second phase o erythema at
days ( ig. ). Vesiculation edema and erosion or ulcer
ation may occur accompanied by pain. The s in de elops a
dar color that may be mista en or hyperpigmentation but
that des uamates. This type o radiation in ury may subside
in se eral wee s to se eral months again depending on the
amount o radiation e posure. S in that recei es a large
amount o radiation will ne er return to normal. t will lac
adne al structures will be dry atrophic and smooth and
may complicate yttrium syno ectomy a treatment gi en
or chronic syno itis.
Fig. 3-27 Acute radiation burn during treatment of epithelioid
sarcoma.
35

3 Eosinophilic, polymorphic, and pruritic eruption
associated with radiotherapy
The polymorphic pruritic eruption arising se eral days to
Dermatoses Resulting from Physical Factors
se eral months a ter radiotherapy or cancer tends to a or the
e tremities. Acral e coriations erythematous papules esi
cles and bullae occur. t is not necessarily limited to the areas
o radiation treatment. istologically a super cial and deep
peri ascular lymphohistiocytic in ltrate with eosinophils is
present. Topical steroids antihistamines and VB are all
e ecti e and spontaneous resolution also occurs.
Chronic radiodermatitis
Chronic e posure to suberythema doses o ioni ing radia
tion o er a prolonged period will produce arying degrees o
damage to the s in and its underlying parts a ter a ariable
latent period ranging rom se eral months to se eral decades.
Radiodermatitis may also occur on the bac or an a ter
uoroscopy and roentgenography or diagnostic purposes
( ig. ).
Telangiectasia atrophy and hypopigmentation with resid
ual ocal increased pigment ( rec ling) may appear ( ig. ).
The s in becomes dry thin smooth and shiny. The nails may
become striated brittle and ragmented. The capacity to repair
in ury is substantially reduced resulting in ulceration rom
minor trauma. The hair becomes brittle and sparse. n more
se ere cases these chronic changes may be ollowed by radia
Fig. 3-28 Chronic radiodermatitis after fluoroscopy.
36 Fig. 3-29 Chronic radiodermatitis.
tion eratoses and carcinoma. Additionally subcutaneous
brosis thic ening and binding o the sur ace layers to deep
tissues may present as tender erythematous pla ues
months a ter radiation therapy ( ig. ). t may resemble
erysipelas or in ammatory metastases.
Radiation cancer
A ter a latent period a eraging years arious malignan
cies may de elop most re uently basal cell carcinoma (BCC)
ollowed by s uamous cell carcinoma (SCC). These may
appear in sites o prior radiation e en i there is no e idence
o chronic radiation damage. Sun damage may be additi e to
radiation therapy increasing the appearance o nonmelanoma
s in cancers. SCCs arising in sites o radiation therapy metas
tasi e more re uently than purely sun induced SCCs. n some
patients either type o tumor may predominate. Location
plays some role; SCCs are more common on the arms and
hands whereas BCCs are seen on the head and nec and
lumbosacral area. ther radiation induced cancers include
angiosarcoma ( ig. ) aposi sarcoma malignant brous
histiocytoma sarcomas and thyroid carcinoma. The incidence
o malignant neoplasms increases with the passage o time.
Treatment
Acute radiodermatitis may be reduced with a topical cortico
steroid ointment combined with an emollient cream applied
twice a day and instituted at the onset o therapeutic radio
therapy. Chronic radiodermatitis without carcinoma re uires
little or no attention e cept protection rom sunlight and the
e tremes o heat and cold. Care ul cleansing with mild soap
and water the use o emollients and occasionally hydrocorti
sone ointment are the only re uirements or good care.
The early remo al o precancerous eratoses and ulcerations
is help ul in pre enting the de elopment o cancers. or radia
tion eratoses treatment with cryosurgery imi uimod
cream ingenol or topical aminole ulinic acid (ALA) photo
dynamic therapy may be su cient. the eratosis eels in l
trated a biopsy is indicated. Radiation ulcerations should be
studied by e cisional or incisional biopsy i they ha e been
present or months or longer. Complete remo al by e cision
is re uently re uired to obtain healing and e clude ocal car
cinoma in the ulceration. Radiation induced nonmelanoma
s in cancers are managed by standard methods. The higher
ris o metastasis rom radiation induced SCCs mandates
care ul ollow up and regular regional lymph node e aluation.
Fig. 3-30 Delayed
radiation reaction 8
months after therapy.
 Balter S, et al: Patient skin reactions from interventional fluoroscopy
procedures. Am J Roentgenol 2014; 202:335.
Bolderston A, et al: The prevention and management of acute skin
reactions related to radiation therapy: a systematic review and practice
guideline. Support Care Cancer 2006; 14:802.
Cota C, et al: Localized post-radiation Kaposi sarcoma in a renal
transplant immunosuppressed patient. Am J Dermatopathol 2014;
36:270-273.
Davis MM, et al: Skin cancer in patients with chronic radiation
dermatitis. J Am Acad Dermatol 1989; 20:608.
James WD, et al: Late subcutaneous fibrosis following megavoltage
radiotherapy. J Am Acad Dermatol 1980; 3:616.
Lee DJ, et al: A pustular form of eosinophilic, polymorphous, and
pruritic eruption associated with radiotherapy. J Am Acad Dermatol
2011; 65:e51–e53.
Oztürk H, et al: Treatment of skin necrosis after radiation
synovectomy with yttrium-90: a case report. Rheumatol Int 2008;
28:1067–1068.
Ulff E, et al: A potent steroid cream is superior to emollients in reducing
acute radiation dermatitis in breast cancer patients treated with
adjuvant radiotherapy. Radiother Oncol 2013; 108:287–292.
Fig. 3-31
Angiosarcoma years
after radiation therapy.
A B
Fig. 3-33 A and B, Calluses from sitting in yoga position. (Courtesy of Dr. Shyam Verma.)
Watt TC, et al: Radiation-related risk of basal cell carcinoma: a report
from the Childhood Cancer Survivor Study. J Natl Cancer Inst 2012;
104:1240–1250.
Mechanical injuries
MECHANICAL INJURIES
echanical actors may induce distincti e s in changes. Pres
sure riction and the introduction o oreign substances (as by
in ection) are some o the means by which s in in uries may
occur.
Callus
Callus is a nonpenetrating circumscribed hyper eratosis pro
duced by pressure. t occurs on parts o the body sub ect to
intermittent pressure particularly the palms and soles and
especially the bony prominences o the oints. Those engaged
in arious sports certain occupations or other repetiti e acti
ity de elop callosities o distincti e si e and location as stig
mata. amples are sur er s nodules bo er s nuc le pads
ogger s toe rower s rump mil er s callus tennis toe ( ig.
) ogger s nipple prayer callus the yoga sign ( ig. )
nec callosities o iolinists pillar noc er s nuc les bowl
er s hand and Russell s sign. The latter are calluses small
lacerations or abrasions on the dorsum o the hand o erlying
the metacarpophalangeal and interphalangeal oints and are
seen as a clue to the diagnosis o bulimia ner osa.
Fig. 3-32 Tennis toe.
37
 The callus di ers rom the cla us in that it has no penetrat Fig. 3-34 Coral cuts.
3 ing central core and is a more di use thic ening. Callus tends
to disappear spontaneously when the pressure is remo ed.
(Courtesy of Curt
Samlaska, MD.)
ost problems are encountered with calluses on the soles.
Poorly tting shoes orthopedic problems o the oot caused
Dermatoses Resulting from Physical Factors

by aging or a de ormity o the oot e erting abnormal pressure

and high acti ity le el are some o the etiologic actors to be
considered in pain ul callosities o the eet.
Padding to relie e the pressure paring o the thic ened
callus and use o eratolytics such as salicylic acid plas
ters are e ecti e means o relie ing pain ul callosities. se o
ammonium lactate lotion or a urea containing cream is
o ten help ul.

Clavus (corns)
Corns are circumscribed horny conical thic enings with the
base on the sur ace and the ape pointing inward and pressing
on sub acent structures. There are two arieties the hard
corns which occur on the dorsa o the toes or on the soles and
the so t corns which occur between the toes and are so tened
by the macerating action o sweat. n a hard corn the sur ace
is shiny and polished and when the upper layers are sha ed
o a core is noted in the densest part o the lesion. t is this
core that causes a dull boring or sharp lancinating pain by
pressing on the underlying sensory ner es. Corns arise at sites
o riction or pressure and when these causati e actors are
remo ed they spontaneously disappear. re uently a bony
spur or e ostosis is present beneath both hard and so t corns
o long duration and unless this e ostosis is remo ed cure is
unli ely. The so t interdigital corn usually occurs in the ourth
interdigital space o the oot. re uently there is an e ostosis
at the metatarsophalangeal oint that causes pressure on the
ad acent toe. These are so t soggy and macerated so that they
appear white. Treatment by simple e cision may be e ecti e.
Plantar corns must be di erentiated rom plantar warts
and in most cases this can be done with con dence only by
paring o the sur ace eratin until either the pathognomonic
elongated dermal papillae o the wart with its blood essels
or the clear horny core o the corn can be clearly seen. Poro
eratosis plantaris discreta is a sharply marginated cone
shaped rubbery lesion that commonly occurs beneath the
metatarsal heads. ultiple lesions may occur. t has a
emale predominance is pain ul and is re uently con used
with a plantar wart or corn. eratosis punctata o the creases
may be seen in the creases o the toes where it may be mis
ta en or a corn.
The relie o pressure or riction by correcti e ootwear or
the application o a ring o so t elt wadding around the region
o the corn will o ten bring a good result. Soa ing the eet in
hot water and paring the sur ace by means o a scalpel blade
or pumice stone leads to symptomatic impro ement. Salicylic
acid is success ul when care ully and diligently used. A ter
care ul paring o the corn with emphasis on remo ing the
center core salicylic acid plaster is applied. Soa ing
the oot or 1 2 h be ore reapplying the medication enhances
the e ect. A ter h the plaster is remo ed the white macer
ated s in is rubbed o and a new plaster is reapplied. This is
continued until the corn is gone. t should be stressed that
remo al o any underlying bony abnormality i present is
o ten necessary to e ect a cure.
Pseudoverrucous papules and nodules
These stri ing mm shiny smooth red moist at topped
round lesions in the perianal area o children are considered
38
to be a result o encopresis or urinary incontinence. There is a
similarity to lesions a ecting urostomy or elderly incontinent
patients. Protection o the s in will help eliminate them.
Similar lesions ha e been described in women who repeatedly
apply an anti ungal (Vagisil) to the groin area.
Coral cuts
A se ere type o s in in ury may occur rom the cuts o coral
s eletons ( ig. ). The abrasions and cuts are pain ul and
local therapy may pro ide little or no relie . ealing may ta e
months. As a rule i secondary in ection is guarded against
such cuts heal as well as any others. The possibility o M co
bacterium marinum in ection must be considered in persistent
lesions.
Pressure ulcers (decubitus)
The bedsore or decubitus is a pressure ulcer produced any
where on the body by prolonged pressure. The pressure sore
is caused by ischemia o the underlying structures o the s in
at and muscles as a result o sustained and constant pressure.
sually it occurs in chronically debilitated persons who are
unable to change position in bed. The bony prominences o
the body are the most re uently a ected sites. About o
all pressure ulcers de elop on the lower body with in the
pel ic area and on the legs. The ulcer usually begins with
erythema at the pressure point; in a short time a punched
out ulcer de elops. ecrosis with a grayish pseudomem
brane is seen especially in the untreated ulcer. Potential
complications o pressure ulcers include sepsis local in ection
osteomyelitis stulas and SCC.
ore than ris actors ha e been identi ed with diabe
tes mellitus peripheral ascular disease cerebro ascular
disease sepsis and hypotension being prominent. Pressure
ulcers are graded according to a our stage system with the
earliest being recogni ed by changes in s in temperature
tissue consistency and sensation. The lesion rst appears as
an area o persistent redness. Stage is a super cial ulcer
in ol ing the epidermis and or dermis. The deeper stage
ulcers damage the subcutaneous at and stage V the muscle Fig. 3-35 Sclerosing
bone tendon or oint capsule. lymphangitis of penis.
Pre ention relies on redistributing pressure at a minimum
inter al o h. Treatment consists o relie o the pressure on
the a ected parts by re uent change o position meticulous

Mechanical injuries
nursing care and use o air lled products li uid lled ota
tion de ices or oam products. ther measures include ulcer
care management o bacterial coloni ation and in ection sur
gical repair i necessary continual education ade uate nutri
tion management o pain and pro ision o psychosocial
support.
lcer care is critical. Debridement may be accomplished by
sharp mechanical en ymatic and autolytic measures at least
once wee ly. n some patients operati e care will be re uired.
Stable heel ulcers are an e ception; debridement is unneces
sary i only a dry eschar is present. Wounds should be cleaned
initially and each dressing changed by a nontraumatic tech
ni ue. ormal saline rather than pero ide or po idone iodine
is best. Selection o a dressing should ensure that the ulcer Fig. 3-36 Black heel.
tissue remains moist and the surrounding s in dry.
cclusi e dressings include more than products gener
ally classi ed as lms alginates oams hydrogels hydro
bers and hydrocolloid dressings. Transparent lms are used
only or stage ulcers because they pro ide light drainage
whereas hydro bers are used only or ull thic ness stage
and V ulcers. Surgical debridement with reconstructi e
procedures may be necessary. Ad u ant therapies such as
ultrasound laser V radiation hyperbaric o ygen electrical
stimulation radiant heat application o growth actors cul
tured eratinocyte gra ts s in substitutes and miscellaneous
topical and oral agents are being in estigated to determine
their place in the treatment o these ulcers.
At times anaerobic organisms coloni e these ulcers and
cause a putrid odor. The topical application o metronida ole
eliminates this odor within h.

Friction blisters Sclerosing lymphangiitis

The ormation o esicles or bullae may occur at sites o com
bined pressure and riction and may be enhanced by heat and
moisture. The eet o military recruits in training the palms o
oarsmen who ha e not yet de eloped protecti e calluses and
the ngers o drummers (drummer s digits) are e amples o
those at ris . The si e o the bulla depends on the site o the
trauma. the s in is tense and uncom ortable the blister
should be drained but the roo should not be completely
remo ed because it may act as its own dressing.
n studies ocusing on the pre ention o riction blister o the
eet in long distance runners and soldiers acrylic ber soc s
with drying action ha e been ound to be e ecti e. Addition
ally pretreatment with a solution o aluminum chloride
he ahydrate or at least days has been shown to reduce oot
blisters signi cantly a ter prolonged hi ing but at the e pense
o s in irritation. mollients decrease the irritation but reduce
the o erall e ecti eness o the treatment.
Fracture blisters
racture blisters o erlie sites o closed ractures especially
the an le and lower leg. The blisters appear a ew days to
wee s a ter the in ury and are thought to be caused by ascu
lar compromise. racture blisters may create complications
such as in ection and scarring especially i blood lled or in
diabetic patients. The blisters generally heal spontaneously in
days but may cause delay o surgical reduction o the
racture.
This lesion is a cordli e structure encircling the coronal sulcus
o the penis or running the length o the sha t and has been
attributed to trauma during igorous se ual play ( ig. ).
ost i not all cases result rom a super cial thrombophlebitis
and thus has been renamed ondor s disease o the penis.
Some early reports a or a lymphatic origin o some cases;
CD and D stains will allow di erentiation o uture
cases. Treatment is not necessary; sclerosing lymphangiitis
ollows a benign sel limiting course.
Black heel
Synonyms or blac heel include talon noir and calcaneal pete
chiae. A sudden shower o minute blac punctate macules
occurs most o ten on the posterior edge o the plantar sur ace
o one or both heels ( ig. ) but sometimes distally on one
or more toes. Blac heel is o ten seen in bas etball olleyball
tennis or lacrosse players. Seeming con uence may lead to
mimicry o melanoma. The bleeding is caused by shearing
stress o sports acti ities. Paring with a o. blade and per
orming a guaiac test will con rm the diagnosis. Treatment is
unnecessary.
Subcutaneous emphysema
ree air occurring in the subcutaneous tissues is detected
by the presence o cutaneous crepitations. Gas producing
39
 Fig. 3-37
3 Subcutaneous
emphysema.
(Courtesy of Curt
Samlaska, MD.).
Dermatoses Resulting from Physical Factors
organisms especially Clostri ia and lea age o ree air rom
the lungs or gastrointestinal tract are the most common causes
( ig. ). Samlas a et al. re iewed the wide ariety o causes
o subcutaneous emphysema including penetrating and
nonpenetrating in uries iatrogenic causes occurring during
arious procedures in hospitali ed patients spontaneous
pneumomediastinum such as may occur with a iolent cough
childbirth asthma Boerhaa e syndrome (esophageal rupture
a ter omiting or the eimlich maneu er) intra abdominal
causes such as in ammatory bowel disease cancer perirectal
abscess pancreatitis or cystitis dental procedures when using
air pressure instruments and high speed drills and actitial
disease.
Traumatic asphyxia
Cer ico acial cyanosis and edema; multiple petechiae o the
ace nec and upper chest; and bilateral subcon uncti al hem
orrhage may occur a ter prolonged crushing in uries o the
thora or upper abdomen. Such trauma re erses blood ow in
the superior ena ca a or its tributaries.
Painful fat herniation
Also called pain ul pie ogenic pedal papules this rare cause
o pain ul eet represents at herniations through thin ascial
layers o the weight bearing parts o the heel ( ig. ). These
dermatoceles become apparent when weight is placed on the
heel and disappear as soon as the pressure is remo ed. These
at herniations are present in many people but the ma ority
e perience no symptoms. owe er e trusion o the at tissue
together with its blood essels and ner es may initiate pain on
prolonged standing. A oidance o prolonged standing will
relie e this pain. ther options include taping o the oot use
o compression stoc ings or use o plastic heel cups or padded
orthotic de ices to restrict the herniations. Laing et al. ound
o patients had pedal papules and interestingly by
placing pressure on the wrists ound to ha e pie ogenic
wrist papules.
40
Fig. 3-38 Piezogenic papules.
Fig. 3-39 Ulceration secondary to “skin popping.”
Narcotic dermopathy
eroin (diacetylmorphine) is a narcotic prepared or in ection
by dissol ing the heroin powder in boiling water and then
in ecting it. The a ored route o administration is intra enous.
This results in thrombosed cordli e thic ened eins at the
sites o in ection. Subcutaneous in ection ( s in popping ) can
result in multiple scattered ulcerations which heal with dis
crete atrophic scars ( ig. ). n addition amphetamines
cocaine and other drugs may be in ected. Subcutaneous in ec
tion may result in in ections complications o bacterial abscess
and cellulitis or sterile nodules apparently acute oreign body
reactions to the in ected drug or the adulterants mi ed with it.
Cocaine associated asculitis caused by le amisole is dis
cussed in Chapter . These lesions may ulcerate. Chronic
persistent rm nodules a combination o scar and oreign
body reaction may result. cocaine is being in ected it may
cause ulcers because o its direct asospastic e ect. Addicts
will continue to in ect heroin and cocaine into the chronic
ulcer bed.
The cutaneous mani estations o in ection o heroin and
other drugs also include camptodactylia edema o the eyelids
persistent nonpitting edema o the hands urticaria abscesses
atrophic scars and hyperpigmentation. Penta ocine abuse
leads to a typical clinical picture o tense woody brosis irreg
ular punched out ulcerations and a rim o hyperpigmentation
at in ection sites. tensi e calci cation may occur within the
thic ened sites.
 Alverez-Garrido H, et al: Immunohistochemical clues to the diagnosis of
Mondor’s disease of the penis. Clin Exp Dermatol 2009;
34:e663–e665.
Bae JM, et al: Differential diagnosis of plantar wart from corn, callus
and healed wart with the aid of dermoscopy. Br J Dermatol 2009;
160:220–222.
Berkeley RP, et al: Rare but serious: recognizing the signs and
symptoms of traumatic asphyxia. JEMS 2010; 35:30–34.
Brennan FH Jr, et al: Blisters on the battlefield. Mil Med 2012;
177:157–162.
Del Giudice P: Cutaneous complications of intravenous drug abuse.
Br J Dermatol 2004; 150:1.
Fleming JD, et al: Pentazocine-induced cutaneous scarring. Clin Exp
Dermatol 2013; 39:115–116. .
Garrido-Ruiz MC, et al: Vulvar pseudoverrucous papules and nodules
secondary to a urethral-vaginal fistula. Am J Dermatopathol 2011;
33:410–412.
Grover S: Pillar knocker’s callosities. Int J Dermatol 2012;
51:743–744.
Haitz KA, et al: Periorbital subcutaneous emphysema mistaken by
unilateral angioedema during dental crown preparation. JAMA
Dermatol 2014; 150:907.
Hennings C, et al: Illicit drugs. J Am Acad Dermatol 2013;
69:135–142.
Herring KM, et al: Friction blisters and sock fiber composition. J Am
Podiatr Med Assoc 1990; 80:63.
Knapik JJ, et al: Influence of an antiperspirant on foot blister
incidence during cross-country hiking. J Am Acad Dermatol 1998;
39:202.
Laing VB, et al: Piezogenic wrist papules. J Am Acad Dermatol 1991;
24:415.
Levine SM, et al: An evidence-based approach to the surgical
management of pressure ulcers. Ann Plast Surg 2012;
69:482–484.
Ma DL, et al: Piezogenic pedal papules. CMAJ 2013; 185:e847.
Mailler-Savage EA, et al: Skin manifestations of running. J Am Acad
Dermatol 2006; 55:290.
Moore ZE, et al: Risk assessment tools for the prevention of pressure
ulcers. Cochrane Database Syst Rev 2008; CDC006471.
Niederhauser A, et al: Comprehensive programs for preventing pressure
ulcers. Adv Skin Wound Care 2012; 25:167–188.
Reddy M, et al: Treatment of pressure ulcers: a systematic review.
JAMA 2008; 300:2647–2662.
Rudolph RI: Skin manifestations of cocaine use. J Am Acad Dermatol
2009; 60;346–347.
Samlaska CP, et al: Subcutaneous emphysema. Adv Dermatol 1996;
11:117.
Strumia R: Skin signs of anorexia nervosa. Dermatoendocrinology
2009; 1:268–270.
Uebbing CM, et al: Fracture blisters. West J Emerg Med 2011;
12:131–132.
Urbina F, et al: Black heel, talon noir or calcaneal petechiae? Australas
J Dermatol 2008; 49:148–151.
Verma SB, et al: Callosities of cross legged sitting. Int J Dermatol 2008;
47:1212–1214.
Wilcox JR, et al: Frequency of debridements and time to heal. JAMA
Dermatol 2013; 149:1050–1058.
FOREIGN BODY REACTIONS
Tattoo
Tattoos result rom the introduction o insoluble pigments into
the s in. They may be traumatic cosmetic or medicinal in
nature and may be applied by a pro essional or an amateur.
Pigment is applied to the s in and then needles pierce the
s in to orce the material into the dermis. Pigments used
include carmine indigo ermilion ndia in chrome green
magnesium (lilac color) Venetian red aluminum gold tita
nium (white color) or inc o ide lead carbonate copper
iron logwood cobalt blue cinnabar (mercuric sul de) and
cadmium sul de. Cadmium cobalt mercury and lead are not
Fig. 3-40 Red tattoo
reaction. (Courtesy of
Curt Samlaska, MD.).
Foreign body reactions
o ten used; howe er occasional photosensiti e reactions to
cadmium which was used or yellow color or to brighten the
cinnabar red are still seen. n isible tattoos seen only under
V light ha e ingredients such as polymethylmethacrylate
and melamine that may cause granulomatous reactions.
Tattoo associated dermopathies may be reacti e (allergic
lichenoid granulomatous or photosensiti e) ( ig. ) or
in ecti e (inoculation o syphilis in ectious hepatitis tubercu
losis V warts molluscum ansen s disease) or may induce
a oebner response in patients with acti e lichen planus or
psoriasis. Discoid lupus erythematosus has been reported to
occur in the red pigmented portion o tattoos. Tattoos o er
ne i may delay the diagnosis o melanoma. ccasionally the
tattoo mar s may become eloidal. Se ere allergic reactions to
temporary tattoos (painting o pigments such as henna on
sur ace o s in) occur when the allergen p phenylenediamine
is added to ma e the color more dramatic.
Red tattoos are the most common cause o delayed reactions
with the histologic ndings typically showing a lichenoid
process. ccasionally a pseudolymphomatous reaction may
occur in red tattoos. Dermatitis in areas o red (mercury) green
(chromium) or blue (cobalt) ha e been described in patients
who are patch test positi e to these metals. Sarcoidal oreign
body and allergic granulomatous reactions may also occur
within tattoos; aluminum may induce such reactions.
Treatment o such reactions is with topical or intralesional
steroids. cision is also satis actory when the lesions are
small enough and situated so that ellipsoid e cisions are
easible. Reactions may also be success ully treated with
switched lasers at times combined with ablati e ractional
resur acing Generali ed allergic reactions occasionally occur;
pre ention by treatment with oral steroids and antihistamines
has been suggested. Tattoo dar ening can occur as well as no
response to laser treatment. Caution must be used when treat
ing esh colored and pin red tattoos because they may
dar en a ter treatment li ely caused by the reduction o erric
o ide to errous o ide. White in composed mostly o tita
nium dio ide is o ten used to brighten green blue yellow
and purple tattoos. Laser irradiation reduces titanium to a
blue colored pigment. Test areas are recommended when
treating light colored acial tattoos. C resur acing lasers
used conser ati ely are an alternati e to the switched lasers
in such patients (see Chapter ).
41
 Paraffinoma (sclerosing lipogranuloma)
3 n ection o oils into the s in or cosmetic purposes such as
the smoothing o wrin les and the augmentation o breasts
was popular in the past. Para n camphorated oil cottonseed
Dermatoses Resulting from Physical Factors
or sesame oil mineral oil and beeswa may produce pla ue
li e indurations with ulcerations within months and up to
years. Se eral reports document penile para nomas caused
by sel in ection. When petroleum elly (Vaseline) gau e or a
topical ointment is used to dress unsutured wounds lipo
granulomas or in ammatory mild erysipelas li e lesions with
mar ed tenderness may occur. Present treatment methods or
sclerosing lipogranuloma are unsatis actory. Surgical remo al
must be wide and complete.
Granulomas
Silicone granuloma
Li uid silicones composed o long chains o dimethyl silo y
groups are biologically inert. Silicones ha e been used or
correcting wrin les reducing scars and building up atrophic
depressed areas o the s in. any case reports detail granulo
matous reactions to silicone some with migration and reacti e
nodules at points distant rom the in ection site ( igs. and
). Acupuncture needles are coated with silicone and gran
ulomas may occur at the entry points. The incidence o the
Fig. 3-41 Silicone reaction.
Fig. 3-42 Silicone granuloma.
42
nodular swellings which may be uite destructi e and treat
ment resistant remains un nown. t is clear that i used o
label medical grade silicone in ected in small olume should
be the rule and it should not be in ected into the penis or the
glandular tissue o the breast.
or breast augmentation silicone may be used as Silastic
implants. trauma causes rupture o the bag subcutaneous
brotic nodules o ten de elop. uman ad u ant disease
and sclerodermatous reactions a ter such e ents ha e been
reported; howe er large re iews ha e ailed to establish an
etiologic lin to silicone and connecti e tissue disease.
Treatment o silicone granulomas is o ten not success ul.
Surgical remo al may lead to stulas abscesses and mar ed
de ormity. Both minocycline mg twice daily or se eral
months and imi uimod cream ha e been anecdotally use ul.
Bioplasti ue consists o polymeri ed silicone particles dis
persed in a gel carrier. When used or lip augmentation
nodules may de elop. istologically these are oreign body
granulomas.
Mercury granuloma
ercury may cause oreign body giant cell or sarcoidal type
granulomas ( ig. ) pseudolymphoma or membranous at
necrosis. t is usually identi able as egg shaped e tracellular
dar gray to blac irregular globules. The gold lysis test is
positi e in tissues. nergy dispersi e radiographic spectros
copy may be done and will identi y mercury by the character
istic emission spi e. Such testing may be help ul in identi ying
any oreign substance suspected to ha e been implanted acci
dentally or intentionally by the patient. Systemic to icity or
embolus may de elop rom mercury and may result in death.
There ore e cision is necessary and can be accomplished
under ray guidance.
Beryllium granuloma
Beryllium granuloma is seen as a chronic persistent granulo
matous in ammation o the s in with ulceration that may
ollow accidental laceration usually in an occupational
setting.
Zirconium granuloma
A papular eruption in ol ing the a illae is sometimes seen
as an allergic reaction in those sha ing their armpits and
using a deodorant containing irconium ( ig. ). Although
irconium was eliminated rom aerosol type deodorants in
aluminum irconium comple is present in some anti
perspirants. Additionally arious poison i y lotions contain
Fig. 3-43 Mercury
granuloma.

Fig. 3-44 Aluminum-zirconium granuloma A B
secondary to antiperspirant use.
Fig. 3-45 A and B, Silica granuloma years after motorcycle crash.
irconium compounds. The lesions are brownish red dome
shaped shiny papules. This is an ac uired delayed type
allergic reaction resulting in a granuloma o the sarcoidal type.
A ter many months the lesions in olute spontaneously.
Silica granuloma
Automobile crashes and other types o trauma may produce
tattooing o dirt (silicon dio ide) into the s in which induces
silica granulomas ( ig. ). These typically present as blac
or blue papules or macules arranged in a linear ashion. At
times the granulomatous reaction to silica may be delayed or
many years with the ensuing reaction being both chronic and
dis guring. The granulomas may be caused by amorphous or
crystalline silicon dio ide ( uart ) magnesium silicate
(talcum) or comple polysilicates (asbestos). Talc granulomas
o the s in and peritoneum may de elop a ter surgery rom
the talcum powder used on surgical glo es. Silica granulomas
ha e a statistical association with systemic sarcoidosis and
silica may act as a stimulus or granuloma ormation in patients
with latent sarcoidosis.
Remo al o these granulomas is raught with di culties.
The best method o care is immediate and complete remo al
to pre ent these reactions. cision and systemic steroids ha e
been used but recurrences are common. Some reactions may
subside spontaneously a ter months. Dermabrasion is a
satis actory method or the remo al o dirt accidentally embed
ded into the s in o the ace or scalp.
Carbon stain
Discoloration o the s in rom embedded carbon usually
occurs in children rom improper use o rearms or rewor s
or rom a puncture wound by a pencil which may lea e a
permanent blac mar o embedded graphite easily mista en
or a metastatic melanoma ( ig. ). arcotic addicts who
attempt to clean needles by aming them with a lighted match
may tattoo the carbon ormed on the needle as it is inserted
Foreign body reactions
Fig. 3-46 Graphite
granuloma.
into the s in. The carbon is deposited at arious depths which
produces a connecti e tissue reaction and sometimes e en
eloids.
Carbon particles may be remo ed immediately a ter their
deposition using a toothbrush and orceps. This e peditious
and meticulous early care results in the best possible cosmetic
result. the particles are le t in place long enough they are
best remo ed using the switched d AG laser at nm.
n one series success was reported in o treated tattoos
with an a erage o . treatments. owe er microe plosions
producing po li e scars ha e occurred with each laser pulse.
Alternati ely dermabrasion may be used.
Injected filler substances
n ected or implanted ller substances used or acial
re u enation may produce oreign body or sarcoidal granulo
mas. Palpable thic ening and nodules ( ig. ) which are
occasionally pain ul ha e been reported with collagen hyal
uronic acid and acrylic hydrogels and polylactic acid polyal
ylimide and polymethylmethacrylate microspheres. The
reaction may be delayed or years; at times patients are reluc
tant to admit to these prior cosmetic inter entions and re
uently cannot name the ller used. Topical intralesional or
systemic steroids sometimes augmented by tacrolimus and
minocycline or do ycycline ha e been reported to be help ul
medical inter entions.
43

3 J Am Acad Dermatol 2007; 57:S54.
Dermatoses Resulting from Physical Factors
Fig. 3-47 Injected filler reaction.
Alani RM, et al: Acupuncture granulomas. J Am Acad Dermatol 2001;
45:S225.
Alijotas-Reig J, et al: Delayed immune-mediated adverse effects of
polyalkylimide dermal fillers. Arch Dermatol 2008; 144:637.
Almeida PJ, et al: Quantification of p-phenylenediamine and 2-hydroxy-
1,4-naphthaoqunione in henna tattoos. Contact Dermatitis 2012;
66:33–37.
Altemyer MD, et al: Cutaneous mercury granuloma. Cutis 2011;
88:189–193.
Angus JE, et al: Two cases of delayed granulomatous reactions to the
cosmetic filler Dermalive. Br J Dermatol 2006; 154:1074.
Antonovitch DD, et al: Development of sarcoidosis in cosmetic tattoos.
Arch Dermatol 2005; 141:869.
Bachmeyer C, et al: Penile paraffinoma developing during treatment with
pegylated interferon alfa-2a for chronic hepatitis C virus infection. Arch
Dermatol 2011; 147:1232–1233.
Bigata X, et al: Adverse granulomatous reaction after cosmetic dermal
silicone injection. Dermatol Surg 2001; 27:198.
Boztepe G, et al: Cutaneous silica granuloma. Eur J Dermatol 2005;
15:194.
Choudhary S, et al: Lasers for tattoo removal. Lasers Med Sci 2010;
25:619–627.
Dadzie OE, et al: Adverse cutaneous reactions to soft tissue filers: a
review of the histological features. J Cutan Pathol 2008; 35:536–548.
England RW, et al: Immediate cutaneous hypersensitivity after treatment
of tattoo with Nd:YAG laser. Ann Allergy Asthma Immunol 2002;
89:215.
Fusade T, et al: Treatment of gunpowder traumatic tattoo by Q-switched
Nd:YAG laser. Dermatol Surg 2000; 26:1057.
Garcovich S, et al: Lichenoid red tattoo reaction. Eur J Dermatol 2010;
22:93–96.
Gormley RH, et al: Role for trauma in introducing pencil “lead”
granuloma in the skin. J Am Acad Dermatol 2010; 62:1074.
Hou M, et al: Cutaneous silica granuloma with generalized involvement
of lymph nodes. J Dermatol 2011; 38:697–701.
Kazandjieva J, et al: Tattoos: dermatological complications. Clin
Dermatol 2007; 25:375.
44
Kenmochi A, et al: Silica granuloma induced by indwelling catheter.
Klontz KL, et al: Adverse effects of cosmetic tattooing. Arch Dermatol
2005; 141:918.
Lowe NJ, et al: Adverse reactions to dermal fillers. Dermatol Surg 2005;
31:1616.
Mafong EA, et al: Removal of cosmetic tattooing with the pulsed carbon
dioxide laser. J Am Acad Dermatol 2003; 48:271.
Montemarano AD, et al: Cutaneous granulomas caused by an
aluminum-zirconium complex. J Am Acad Dermatol 1997; 37:496.
Mortimer NJ, et al: Red tattoo reactions. Clin Exp Dermatol 2003;
28:508.
Ortiz AE, et al: Rising concern over cosmetic tattoos. Dermatol Surg
2012; 38:424–429.
Ross EV, et al: Tattoo darkening and nonresponse after laser treatment.
Arch Dermatol 2001; 137:33.
Rossman MD: Chronic beryllium disease. Appl Occup Environ Hyg
2001; 16:615.
Sclafarni AP, et al: Treatment of injectable soft tissue filler complications.
Dermatol Surg 2009; 35(Suppl 2):1672.
Senet P, et al: Minocycline for the treatment of cutaneous silicone
granulomas. Br J Dermatol 1999; 140:963.
Shimizu I, et al: Metal-induced granule deposition with
pseudoochronosis. J Am Acad Dermatol 2010; 63:357–359.
Suvanasuthi S, et al: Mycobacterium fortuitum cutaneous infection from
amateur tattoo. J Med Assoc Thai 2012; 95:834–847.
Tammaro A, et al: Contact allergic dermatitis to gold in a tattoo. Int J
Immunopathol Pharmacol 2011; 24:1111–1113.
Timko AL, et al: In vitro quantitative chemical analysis of tattoo
pigments. Arch Dermatol 2001; 137:143.
Tsang M, et al: A visible response to an invisible tattoo. J Cutan Pathol
2012; 39:877–880.
Uchida Y, et al: Facial paraffinoma after cosmetic paraffin injection.
J Dermatol 2007; 34:798.
Vagefi MR, et al: Adverse reactions to eyeliner tattoo. Ophthal Plast
Reconstr Surg 2006; 22:48.
Vargas-Machuca I, et al: Facial granulomas secondary to Dermalive
microimplants. Am J Dermatopathol 2006; 28:173.
Wolfram D, et al: Surgery for foreign body reactions to injectable fillers.
Dermatology 2006; 213:300.
Bonus images for this chapter can be found online at
expertconsult.inkling.com
eFig. 3-1 Pernio (chilblain).
eFig. 3-2 Stellate pseudoscars.
eFig. 3-3 Colloid milium.
eFig. 3-4 Berloque dermatitis.
eFig. 3-5 Chronic actinic dermatitis.
eFig. 3-6 Acute radiation burn during treatment of epithelioid
sarcoma.
eFig. 3-7 Prayer calluses.
eFig. 3-8 Scars caused by “skin popping”
eFig. 3-9 Red tattoo reaction. (Courtesy of Curt Samlaska, MD.)
 Foreign body reactions
eFig. 3-1 Pernio (chilblain).
eFig. 3-4 Berloque dermatitis.

eFig. 3-2 Stellate eFig. 3-5 Chronic

pseudoscars. actinic dermatitis.

eFig. 3-6 Acute

radiation burn during
treatment of
epithelioid sarcoma.

eFig. 3-3 Colloid milium.

44.e1
 eFig. 3-9 Red tattoo
3 reaction. (Courtesy of
Curt Samlaska, MD.)
Dermatoses Resulting from Physical Factors

eFig. 3-7 Prayer calluses.

eFig. 3-8 Scars caused

by “skin popping”

44.e2
 Bonus images for this chapter can be found online at
Pruritus and Neurocutaneous Dermatoses
PRURITUS
Pruritus commonly nown as itching is a sensation e clusi e
to the s in. t may be de ned as the sensation that produces
the desire to scratch. Pruritogenic stimuli are rst responded
to by eratinocytes which release a ariety o mediators and
ne intraepidermal C neuron laments. Appro imately o olliculitis uremic pruritus prurigo simple paraneoplastic
the a erent unmyelinated C neurons respond to pruritogenic
stimuli. tch sensations in these ner e bers are transmitted
ia the lateral spinothalamic tract to the brain where a ariety
o oci generate both stimulatory and inhibitory responses. The
sum o this complicated set o interactions appears to deter
mine the uality and intensity o itch.
tching may be elicited by many normally occurring stimuli
such as light touch temperature change and emotional stress.
Chemical mechanical and electrical stimuli may also elicit
itching. The brain may reinterpret such sensations as being
pain ul or causati e o burning or stinging sensations. A large
group o neuromediators and their receptors ha e been identi
ed. Some o the most important mediators are histamine and
the receptor tryptase and its proteinase acti ated receptor
type opioid peptides and the mu (μ) and appa (κ) opioid
receptors leu otriene B prostaglandins such as PG acetyl
choline cyto ines such as interleu in ( L ) and a ariety
o neuropeptides and asoacti e peptides (e.g. ner e growth
actor) and their receptors (e.g. anilloid). n estigation is
ongoing to disco er the relati e importance o each o these
mediators and to determine the clinical circumstances under
which therapeutic targeting o these molecules will lead to
relie o symptoms.
tch has been classi ed into our primary categories as
ollows
Pruritocepti e itch initiated by s in disorders
eurogenic itch generated in the central ner ous system
and caused by systemic disorders
europathic itch caused by anatomic lesions o the
central or peripheral ner ous system
Psychogenic itch the type obser ed in parasitophobia
An o erlap or mi ture o these types may be causati e in
any indi idual patient.
Patterns of itching
There are wide ariations in itching rom person to person
and a person may ha e a ariation in reactions to the same
stimulus. eat will usually aggra ate pree isting pruritus.
Stress absence o distractions an iety and ear may all
enhance itching. tching tends to be most se ere during
undressing or bed.
Se ere pruritus with or without prior s in lesions may be
paro ysmal in character with a sudden onset o ten se ere
enough to awa en the patient. t may stop instantly and
expertconsult.inkling.com
4
completely as soon as pain is induced by scratching. owe er
the pleasure o scratching is so intense that the patient despite
the reali ation o damaging the s in is o ten unable to stop
short o in icting such damage ( ig. ). tching o this dis
tincti e type is characteristic o a select group o dermatoses
lichen simple chronicus atopic dermatitis nummular ec ema
dermatitis herpeti ormis neurotic e coriations eosinophilic
itch (usually secondary to lymphoma) and prurigo nodularis.
n general only these disorders produce such intense pruritus
and scratching as to induce bleeding. n indi idual cases other
diseases may mani est such se ere symptoms.
Treatment
General guidelines or therapy o the itchy patient include
eeping cool and a oiding hot baths or showers and wool
clothing which is a nonspeci c irritant as is erosis. any
patients note itching increases a ter showers when they wash
with soap and then dry roughly. sing soap only in the a illa
and inguinal area patting dry and applying a moisturi er can
o ten help pre ent such e acerbations. Patients o ten use an
ice bag or hot water to ease pruritus; howe er hot water can
irritate the s in is e ecti e only or short periods and o er
time e acerbates the condition.
Relie o pruritus with topical remedies may be achie ed
with topical anesthetic preparations. any contain ben o
caine which may produce contact sensiti ation. Pramo ine in
a ariety o ehicles lidocaine ointment eutectic mi ture
o lidocaine and prilocaine ( LA) ointment and lidocaine
gel are pre erred anesthetics that may be bene cial in locali ed
conditions. LA and lidocaine may be to ic i applied to
large areas. Topical antihistamines are generally not recom
mended although do epin cream may be e ecti e or mild
pruritus when used alone. Do epin cream may cause contact
allergy or a burning sensation and somnolence may occur
when do epin is used o er large areas. Topical lotions that
contain menthol or camphor eel cool and impro e pruritus
and may be ept in the re rigerator to enhance this soothing
e ect. ther lotions ha e speci c ceramide content designed
to mimic that o the normal epidermal barrier. Capsaicin by
depleting substance P can be e ecti e but the burning sensa
tion present during initial use re uently causes patients to
discontinue its use. Topical steroids and calcineurin inhibitors
e ect a decrease in itching through their anti in ammatory
action and there ore are o limited e cacy in neurogenic psy
chogenic or systemic disease related pruritus.
Phototherapy with ultra iolet B ( VB) VA and psoralen
plus VA (P VA) may be use ul in a ariety o dermatoses
and pruritic disorders. any oral agents are a ailable to treat
pruritus. Those most re uently used by nondermatologists
are the antihistamines. irst generation antihistamines
such as hydro y ine and diphenhydramine may be help ul
in nocturnal itching but their e cacy as antipruritics
45

4 Vernereol 2012; 92:563–581.
Pruritus and Neurocutaneous Dermatoses
Fig. 4-1 Severe pruritus with excoriations.
is disappointing in many disorders e cept or urticaria and
mastocytosis. Do epin is an e ception in that it can reduce
an iety and depression and is use ul in se eral pruritic disor
ders. Sedating antihistamines should be prescribed cautiously
especially in elderly patients because o their impaired cogni
ti e ability. The nonsedating antihistamines and bloc ers
are only e ecti e in urticaria and mast cell disease. pioids
are in ol ed in itch induction. n general acti ation o μ opioid
receptors stimulates itch whereas κ opioid receptor sti
mulation inhibits itch perception; howe er the interaction is
comple . Additionally opioid altering agents such as naltre
one nalo one nal ura ne and butorphanol ha e signi cant
side e ects and arying modes o deli ery (intra enous intra
nasal oral). nitial reports o bene t in one condition are o ten
ollowed by con icting reports on urther study. Speci c rec
ommendations in select pruritic conditions are detailed in
those sections. These agents appear most use ul or cholestatic
pruritus. Central reduction o itch perception may be e ected
by anticon ulsants such as gabapentin and pregabalin and
antidepressants such as mirta apine and the selecti e
serotonin reupta e inhibitors (SSR s). Thalidomide through a
ariety o direct neural e ects immunomodulatory actions
and hypnosedati e e ects is also use ul in select patients.
Elmariah SB, et al: Topical therapies for pruritus. Semin Cutan Med Surg
2011; 30:118–126.
Feramisco JD, et al: Innovative management of pruritus. Dermatol Clin
2010; 28:467–478.
Greaves MW: Pathogenesis and treatment of pruritus. Curr Allergy
Asthma Rep 2010; 10:236–242.
Ikoma A, et al: Anatomy and neurophysiology of pruritus. Semin Cutan
Med Surg 2011; 30:64–70.
Matterne U, et al: Prevalence, correlates and characteristics of chronic
pruritus. Acta Derm Verereol 2011; 91:674–697.
Metz M, et al: Chronic pruritus: pathogenesis, clinical aspects and
treatment. J Eur Acad Dermatol Venereol 2010; 24:1249–1260.
Patel T, et al: Therapy of pruritus. Expert Open Pharmacother 2010;
11:1673.
Siepmann D, et al: Evaluation of the German guideline for chronic
pruritus. Dermatology 2011; 223:374–480.
Steinhoff M, et al: Pruritus. Semin Cutan Med Surg 2011; 30:127–137/
Tey HL, et al: Targeted treatment of pruritus. Br J Dermatol 2011;
165:5–17.
46
Weisshaar I, et al: European guideline on chronic pruritus. Acta Derm
Yosipovitch G, et al: Chronic pruritus. N Engl J Med 2013;
368:1625-1634.
Internal causes of pruritus
tching may be present as a symptom in a number o internal
disorders. The intensity and duration o itching ary rom one
disease to another. The most important internal causes o
itching include li er disease especially obstructi e and hepa
titis C (with or without e idence o aundice or li er ailure)
renal ailure diabetes mellitus hypothyroidism and hyperthy
roidism hematopoietic diseases (e.g. iron de ciency anemia
polycythemia era) neoplastic diseases (e.g. lymphoma
especially odg in disease leu emia myeloma) internal
solid tissue malignancies intestinal parasites carcinoid mul
tiple sclerosis ac uired immunode ciency syndrome (A DS)
and neuropsychiatric diseases especially anore ia ner osa.
The pruritus o odg in disease is usually continuous and
at times is accompanied by se ere burning. The incidence o
pruritus is and is the rst symptom o this disease in
o patients. ts cause is un nown. The pruritus o leu emia
e cept or chronic lymphocytic leu emia has a tendency to be
less se ere than in odg in disease.
nternal organ cancer may be ound in patients with general
i ed pruritus that is une plained by s in lesions. owe er no
signi cant o erall increase o malignant neoplasms can be
ound in patients with idiopathic pruritus. A suggested wor up
or chronic generali ed pruritus includes a complete history
thorough physical e amination and laboratory tests including
complete blood count (CBC) and di erential; thyroid li er
and renal panels; hepatitis C serology; human immunode
ciency irus ( V) antibody (i ris actors are present); uri
nalysis; stool or occult blood; serum protein electrophoresis;
and chest ray e aluation. Presence o eosinophilia on the
CBC is a good screen or parasitic diseases but i the patient
has been recei ing systemic corticosteroids blood eosinophilia
may not be a reliable screen or parasitic diseases and stool
samples or o a and parasites should be submitted. Additional
radiologic studies or speciali ed tests are per ormed as indi
cated by the patient s age history and physical ndings. A
biopsy or direct immuno uorescence is occasionally help ul
to detect dermatitis herpeti ormis or pemphigoid.
Cassano N, et al: Chronic pruritus in the absence of specific skin
disease. Am J Clin Dermatol 2010; 11:399–411.
Greaves MW: Pathogenesis and treatment of pruritus. Curr Allergy
Asthma Rep 2010; 10:236–242.
Ko MJ, et al: Postprandial blood glucose is associated with generalized
pruritus in patients with type 2 diabetes. Eur J Dermatol 2013;
23:688–693.
Yosipovitch G: Chronic pruritus: a paraneoplastic sign. Dermatol Ther
2010; 23:590–598.
Weisshaar I, et al: European guideline on chronic pruritus. Acta Derm
Vernereol 2012; 92:563–581.
Chronic kidney disease
Chronic idney disease (C D) is the most common systemic
cause o pruritus; o patients with chronic renal ailure
ha e itching. The pruritus is o ten generali ed intractable and
se ere; howe er dialysis associated pruritus may be episodic
mild or locali ed to the dialysis catheter site ace or legs.
The mechanism o pruritus associated with C D is multi
actorial. erosis secondary hyperparathyroidism increased
serum histamine le els hyper itaminosis A iron de ciency
anemia and neuropathy ha e been implicated. Complications
 Fig. 4-2 A, Acquired
perforating dermatosis
of uremia. B, Close-up
view of A.
A appears that lysophosphatidic acid ormed by the action o
B and pro ides dramatic relie rom the se ere pruritus.
such as ac uired per orating disease lichen simple chroni
cus and prurigo nodularis may de elop and contribute to the
degree and se erity o pruritus ( ig. ).
any patients ha e concomitant erosis and aggressi e use
o emollients including soa ing and smearing may help. A
trial o γ linolenic acid cream twice daily was e ecti e as was
one using baby oil. Gabapentin gi en three times wee ly at
the end o hemodialysis sessions can be e ecti e but its renal
e cretion is decreased in C D so a low initial dose o mg
a ter each session with slow upward titration is recommended.
A mainstay o C D associated pruritus has been narrow band
( B) VB phototherapy but a randomi ed controlled trial
(RCT) ailed to con rm its e cacy. Broad band VB may be
best in the C D patient. altre one topical tacrolimus and
ondansetron also were reported to be use ul in initial trials
but subse uent studies indicated these agents are ine ecti e.
al ura ne μg once daily a ter supper has demonstrated
impro ement and was relati ely well tolerated o er a year
study. Thalidomide intranasal butorphanol and intra enous
lidocaine are less practical options. Renal transplantation will
eliminate pruritus.
Berger TG, et al: Pruritus and renal failure. Semin Cutan Med Surg
2011; 30:99–100.
Ko MJ, et al: Narrowband ultraviolet B phototherapy for patients with
refractory uraemic pruritus. Br J Dermatol 2011; 165:633–639.
Kfoury LW, et al: Uremic pruritus. J Nephrol 2012; 25:644–652.
Kumagai H, et al: Efficacy and safety of a novel κ-agonist for managing
intractable pruritus in dialysis patients. Am J Nephrol 2012; 36:
175–183.
Lin T-C, et al: Baby oil therapy for uremic pruritus in haemodialysis
Pruritus
patients. J Clin Nurs 2011; 21:139–148.
Yue J, et al: Comparison of pregabalin with ondansetron in
treatment of uraemic pruritus in dialysis patients. Int Urol Nephrol
2014; Aug 7.
Biliary pruritus
Chronic li er disease with obstructi e aundice may cause
se ere generali ed pruritus and o patients with aun
dice ha e pruritus. ntrahepatic cholestasis o pregnancy
primary sclerosing cholangitis and hereditary cholestatic dis
eases such as Alagille syndrome all ha e pruritus in common.
Another disease primary biliary cirrhosis is discussed sepa
rately ne t because o its many other cutaneous mani esta
tions. epatitis C may be associated with pruritus as well.
tching o biliary disease is probably caused by central mech
anisms. The pathophysiology is not well understood but it
the en yme autota in on lysophosphatidylcholine is central.
The serum con ugated bile acid le els do not correlate with the
se erity o pruritus and the theory in o ing endogenous
opioids as the main cause has not been upheld by recent
studies.
Pruritus o chronic cholestatic li er disease is impro ed with
cholestyramine g daily. Ri ampin mg day
may be e ecti e but should be used with caution because it
may cause hepatitis. altre one up to mg day is use ul
but has signi cant side e ects. used naltre one should be
started at 1 4 tablet ( . mg) and increased by 1 4 tablet e ery
to days until pruritus impro es. Sertraline mg
day is another option. VB phototherapy was e ecti e in a
small case series. rsodeo ycholic acid is e ecti e or the pru
ritus in intrahepatic cholestasis o pregnancy but not or the
itching o primary biliary cirrhosis rom other causes. Li er
transplantation is the de niti e treatment or end stage disease
Primary biliary cirrhosis
Primary biliary cirrhosis occurs almost e clusi ely in women
older than . tching may begin insidiously and may be the
presenting symptom in a uarter to hal o patients. With time
e treme pruritus de elops in almost o patients. This
almost intolerable itching is accompanied by aundice and a
stri ing melanotic hyperpigmentation o the entire s in; the
patient may turn almost blac e cept or a hypopigmented
butter y area in the upper bac . rupti e anthomas planar
anthomas o the palms ( ig. ) anthelasma and tuberous
anthomas o er the oints may be seen.
Dar urine steatorrhea and osteoporosis occur re uently.
Serum bilirubin al aline phosphatase serum ceruloplasmin
serum hyaluronate and cholesterol alues are increased. The
antimitochondrial antibody test is positi e. The disease is
usually relentlessly progressi e with the de elopment o
hepatic ailure. Se eral cases ha e been accompanied by
scleroderma.
Beuers U, et al: Pruritus in cholestasis: facts and fiction. Hepatology
2014; 1:399–407.
Bunchornatavakul C, et al: Pruritus in chronic cholestatic lever disease.
Clin Liver Dis 2012; 16:331–346.
Decock S, et al: Cholestasis-induced pruritus treated with ultraviolet B
phototherapy. J Hepatol 2012; 57:637–641.
Imam MH, et al: Pathogenesis and management of pruritus in
cholestatic liver disease. J Gastroenterol Hepatol 2012; 27:1150–1158.
47

4 leg.
Pruritus and Neurocutaneous Dermatoses
Fig. 4-3 Primary biliary cirrhosis with plane xanthomas.
Uibo R, et al: Primary biliary cirrhosis: a multi-faced interactive disease
involving genetics, environment and the immune response. APMIS
2012; 120:857–871.
Polycythemia vera
ore than one third o patients with polycythemia era report
pruritus; it is usually induced by temperature changes or
se eral minutes a ter bathing. The cause is un nown.
Aspirin has been shown to pro ide immediate relie rom
itching; howe er there is a ris o hemorrhagic complications.
P VA and B VB are also e ecti e. A mar ed impro ement
is noted a ter an a erage o si treatments with complete
remission o ten occurring in wee s. Paro etine mg
day produced clearing or near complete clearing in a series
o nine patients. nter eron ( ) alpha has been shown
to be e ecti e or treating the underlying disease and associ
ated pruritus. Two new options are being tested based on
the nowledge that polycythemia era results rom a a
acti ating mutation. a inhibitors and m O inhibitors ha e
shown dramatic results in the relie o pruritus in limited early
trials.
Saini KS, et al: Polycythemia vera–associated pruritus and its
management. Eur J Clin Invest 2010; 40:828–834.
PRURITIC DERMATOSES
Winter itch
Asteatotic ec ema ec ema cra uel and erotic ec ema are
other names or this pruritic condition. Winter itch is charac
teri ed by pruritus that usually rst mani ests and is most
se ere on the legs and arms. tension to the body is common;
howe er the ace scalp groin a illae palms and soles are
spared. The s in is dry with ne a es ( ig. ). The pretibial
regions are particularly susceptible and may de elop ec ema
cra uel e hibiting ne crac s in the ec ematous area that
resemble the crac s in old porcelain dishes.
re uent and lengthy bathing with plenty o soap during
the winter is the most re uent cause. This is especially pre a
lent in elderly persons whose s in has a decreased rate o
repair o the epidermal water barrier and whose sebaceous
glands are less producti e. Low humidity in o erheated rooms
during cold weather contributes to this condition. n a study
o elderly indi iduals the pre alence o asteatosis ( . )
was second only to seborrheic dermatitis as the most common
nding.
48
Fig. 4-4 Dry skin of the
Treatment consists o educating the patient on using soap
only in the a illae and inguinal area and lubricating the s in
with emollients immediately a ter showering. Preparations
containing lactic acid or urea applied a ter bathing are help ul
in some patients but may cause irritation and may worsen
itching in patients with erythema and ec ema.
or those with more se ere symptoms long standing
disease or a signi cant in ammatory component a regimen
re erred to as soa ing and smearing is dramatically e ec
ti e. The patient soa s in a tub o plain water at a com ortable
temperature or min be ore bedtime. mmediately on
e iting the tub without drying triamcinolone . .
ointment is applied to the wet s in. This will trap the mois
ture lubricate the s in and allow or e cellent penetration o
the steroid component. An old pair o pa amas is then donned
and the patient will note relie e en on the rst night. The
nighttime soa s are repeated or se eral nights a ter which
the ointment alone su ces with the maintenance therapy o
limiting soap use to the a illae and groin and moisturi ation
a ter showering. Plain petrolatum may be used as the lubricant
a ter the soa ing i simple dryness without in ammation is
present.
Gutman A, et al: Soak and smear therapy. Arch Dermatol 2005;
141:1556.
Kimura N, et al: Prevalence of asteatosis and asteatotic eczema
among elderly residents in facilities covered by long-term care
insurance. J Dermatol 2013; 40:770.
Pruritus ani
Pruritus is o ten centered on the anal or genital area (less re
uently in both) with minimal or no pruritus elsewhere. Anal
neurodermatitis is characteri ed by paro ysms o iolent
itching when the patient may tear at the a ected area until
bleeding is induced. ani estations are identical to lichen
simple chronicus elsewhere on the body. Speci c etiologic
 actors should always be sought and generally can be classi
ed as dermatologic disease local irritants (which may coe ist
with colorectal and anal causes) and in ectious agents.
Allergic contact dermatitis is a common dermatologic cause
or secondary complication o pruritus ani. t occurs rom
arious medicaments ragrance in toilet tissue or preser a
ti es in moist toilet tissue with one study reporting o Nasseri YY, et al: Pruritus ani: diagnosis and treatment.
consecuti e patients being patch test positi e. Seborrheic der
matitis psoriasis lichen planus lichen sclerosis and atopic
dermatitis all may cause perianal itching and an e amination
o other classic sites o in ol ement with these conditions
should be care ully underta en. tramammary Paget s
disease and Bowen s disease although not o ten itchy may be
present and will not impro e with therapy. Biopsy o resistant
dermatitic appearing s in should be done in nonresponsi e
pruritus ani.
rritant contact dermatitis rom gastrointestinal contents
such as hot spices or cathartics or ailure to cleanse the area
ade uately a ter bowel mo ements may be causal. Anatomic
actors may lead to lea age o rectal mucus on to perianal s in
and thus promote irritation. Physical changes such as hemor
rhoids anal tags ssures and stulas may aggra ate or
produce pruritus.
ycotic pruritus ani is characteri ed by ssures and a white
sodden epidermis. Scrapings are e amined directly with
potassium hydro ide mounts and cultures will usually re eal
Can i a albicans Epi ermoph ton occosum or richoph ton
rubrum. ther sites o ungal in ection such as the groin toes
and nails should also be in estigated. rythrasma in the groin
and perianal regions may also occasionally produce pruritus.
The diagnosis is established by coral red uorescence under
the Wood s light. β emolytic streptococcal in ections ha e
also been implicated especially in young children. The use o
tetracyclines may cause pruritus ani most o ten in women by
inducing candidiasis. Diabetic patients are susceptible to peri
anal candidiasis.
Pinworm in estations may cause pruritus ani especially in
children and sometimes in their parents. octurnal pruritus is
most pre alent. ther intestinal parasites such as aenia
solium saginata amebiasis and Strong loi es stercoralis may
produce pruritus. Pediculosis pubis may cause anal itching;
howe er attention is ocused by the patient on the pubic area
where itching is most se ere. Scabies may be causati e but
o ten will also in ol e the nger webs wrists a illae areolae
and genitalia.
Lumbosacral radiculopathy also may be present with pruri
tus ani as assessed by radiographs and ner e conduction
studies; para ertebral bloc ade may help these patients.
Treatment
eticulous toilet care should be ollowed no matter what the
cause o the itching. A ter de ecation the anal area should be
cleansed whene er possible washed with mild soap and
water. Cleansing with wet toilet tissue is ad isable in all cases.
edicated cleansing pads (Tuc s) should be used regularly.
A ariety o moist toilet tissue products are now a ailable.
Contact allergy to preser ati es in these products is occasion
ally a problem. An emollient lotion (Balneol) is help ul or
cleansing without producing irritation.
nce the etiologic agent has been identi ed a rational and
e ecti e treatment regimen may be started. Topical corticoste
roids are e ecti e or most nonin ectious types o pruritus ani;
howe er use o topical tacrolimus ointment will re uently
su ce and is sa er. Pramo ine a nonsteroidal topical anes
thetic is also o ten e ecti e especially in a lotion orm com
bined with hydrocortisone. n pruritus ani as well as in
pruritus scroti and ul ae it is sometimes best to discontinue
all topical medications and treat with plain water sit baths at
night ollowed immediately by plain petrolatum applied o er
wet s in. This soothes the area pro ides a barrier and elimi
nates contact with potential allergens and irritants.
Pruritic dermatoses
Markell KW, et al: Pruritus ani. Surg Clin North Am 2010;
90:125–135.
Gastroenterol Clin North Am 2013; 42:801–813.
Silvestri DL, et al: Pruritus ani as a manifestation of systemic contact
dermatitis. Dermatitis 2011; 22:50–55.
Stermer E, et al: Pruritus ani. J Pediatr Gastroenterol Nutr 2009;
48:513–516.
Suys E, et al: Randomized study of topical tacrolimus ointment as
possible treatment for resistant idiopathic pruritus ani. J Am Acad
Dermatol 2012; 66:327–328.
Pruritus scroti
The scrotum o an adult is relati ely immune to dermatophyte
in ection but it is a susceptible site or circumscribed neuro
dermatitis (lichen simple chronicus) ( ig. ). Psychogenic
pruritus is probably the most re uent type o itching seen.
Why it pre erentially a ects the scrotum or in women the
ul a (see Pruritus ul ae) is unclear. Licheni cation may
result can be e treme and may persist or many years despite
intensi e therapy.
n ectious conditions may complicate or cause pruritus on
the scrotum but are less common than idiopathic scrotal pru
ritus. ungal in ections e cept candidiasis usually spare the
scrotum. When candidal in ection a ects the scrotum burning
rather than pruritus is re uently the primary symptom. The
scrotum is eroded weepy or crusted. The scrotum may be
a ected to a lesser degree in cases o pruritus ani but this
pruritus usually a ects the midline e tending rom the anus
along the midline to the base o the scrotum rather than the
dependent sur aces o the scrotum where pruritus scroti
usually occurs. Scrotal pruritus may be associated with aller
gic contact dermatitis rom topical medications including ste
roidal agents.
Topical corticosteroids are the mainstay o treatment but
caution should be e ercised. The addicted scrotum syn
drome may be caused by the use o high potency topical
steroidal agents. As with acial s in a ter attempts to wean
patients o the steroid se ere burning and redness may occur.
Fig. 4-5 Pruritus scroti.
49
 Although usually seen a ter chronic use this may occur e en
4 with short term high potency steroids. The scrotum is re
uently in contact with inner thigh s in producing areas o
occlusion which increases the penetration o topical steroid
agents. Topical tacrolimus ointment is use ul in o ercoming
Pruritus and Neurocutaneous Dermatoses
the e ects o o eruse o potent topical steroids. Another alter
nati e is gradual tapering to less potent corticosteroids. ther
use ul nonsteroidal alternati es include topical pramo ine
do epin and simple petrolatum which is applied a ter a sit
bath as described or pruritus ani.
Cohen AD, et al: Neuropathic scrotal pruritus. J Am Acad Dermatol
2005; 52:61.
Pruritus vulvae
The ul a is a common site or pruritus o di erent causes.
Pruritus ul ae is the counterpart o pruritus scroti. n a pro
specti e series o women with chronic ul ar symptoms
the most common causes were unspeci ed dermatitis ( ) who ha e polycythemia era hypereosinophilic syndrome or
lichen sclerosus ( ) chronic ul o aginal candidiasis ( ) myelodysplastic syndrome and two thirds are younger
dysesthetic ul odynia ( ) and psoriasis ( ). n prepuber
tal children such itching is most re uently irritant in nature
and girls generally bene t rom education about impro ed
hygienic measures.
Vaginal candidiasis is a re uent cause o pruritus ul ae.
This is true especially during pregnancy and when oral anti
biotics are ta en. The inguinal perineal and perianal areas
may be a ected. icroscopic e amination or Can i a albicans
and cultures or ungus should be per ormed. richomonas
vaginalis in ection may cause ul ar pruritus. or the detection
o vaginalis e amination o aginal secretions is o ten diag
nostic. The organism is recogni ed by its motility si e (some
what larger than a leu ocyte) and piri orm shape.
Contact dermatitis rom sanitary pads contracepti es
douche solutions ragrance preser ati es colophony ben o
caine corticosteroids and a partner s condoms may account
or ul ar pruritus. rinary incontinence should also be con
sidered. Lichen sclerosus is another re uent cause o pruritus
in the genital area in middle age and elderly women. Lichen
planus may in ol e the ul a resulting in pruritus and
mucosal changes including erosions and ulcerations resorp
tion o the labia minora and atrophy.
When burning rather than itching predominates the patient
should be e aluated or signs o sensory neuropathy.
Treatment
Candidiasis and richomonas treatments are discussed in
Chapters and respecti ely. Lichen sclerosus responds
best to pulsed dosing o high potency topical steroids or to
topical tacrolimus or pimecrolimus. Topical steroidal agents
and topical tacrolimus may be used to treat psychogenic pru
ritus or irritant or allergic reactions. Patch testing will assist in
identi ying the inciting allergen. igh potency topical steroids
are e ecti e in treating lichen planus but other options are
also a ailable (see Chapter ). Topical lidocaine topical
pramo ine or an oral tricyclic antidepressant may be help ul
in select cases. Any chronic s in disease that does not appear
to be responding to therapy should prompt a biopsy.
Bohl TG, et al: Overview of vulvar pruritus through the life cycle. Clin
Obstet Gynecol 2005; 48:786.
Caro-Bruce E, et al: Vulvar pruritus in a postmenopausal woman. CMAJ
2014; 186:688–689.
Haverhock E, et al: Prospective study of patch testing in patients with
vulvar pruritus. Australas J Dermatol 2008; 49:80–85.
Utas S, et al: Patients with vulvar pruritus. Contact Dermatitis 2008;
58:296–298.
50
Puncta pruritica (itchy points)
tchy points consists o one or two intensely itchy spots in
clinically normal s in sometimes ollowed by the appearance
o seborrheic eratoses at e actly the same site. Curettage
cryosurgery punch biopsy or li ely botulinum to in A in ec
tion o the itchy points may cure the condition.
Boyd AS, et al: Puncta pruritica. Int J Dermatol 1992; 31:370.
Salardini A, et al: Relief of intractable pruritus after administration of
botulinum toxin A. Clin Neuropharmacol 2008; 31:303–306.
Aquagenic pruritus and aquadynia
A uagenic pruritus is itching e o ed by contact with water o
any temperature. ost patients e perience se ere pric ling
discom ort within minutes o e posure to water or on cessa
tion o e posure to water There are two groups o patients
about one third consist o an older primarily male population
women who de elop a uagenic pruritus as young adults and
who ha e no nown underlying disease and may ha e a
amily history o similar symptoms.
A uagenic pruritus must be distinguished rom erosis or
asteatosis and an initial trial o soa ing and smearing as
pre iously described or winter itch is recommended. Treat
ment options or a uagenic pruritus include the use o anti
histamines sodium bicarbonate dissol ed in bath water
propranolol SSR s acetylsalicylic acid (ASA aspirin) prega
balin montelu ast and B VB or P VA phototherapy. ne
patient ound tight tting clothing settled the symptoms a ter
only min.
Shelley et al. reported two patients with widespread burning
pain that lasted min a ter water e posure calling this
reaction a uadynia and considering the disorder a ariant
o a uagenic pruritus. Clonidine and propranolol seemed to
pro ide some relie .
Heitkemper T, et al: Aquagenic pruritus. J Dtsch Dermatol Ges 2010;
8:797–804.
Herman-Kideckel SM et al: Successful treatment of aquagenic pruritus
with montelukast. J Cut Med Surg 2012; 16:151–152.
Koh MJA, et al: Aquagenic pruritus responding to combine ultraviolet
A/narrowband ultraviolet B therapy. Photodermatol Photoimmunol
Photomed 2009; 25:169–170.
Nosbaum A, et al: Treatment with propranolol of 6 patients with
idiopathic aquagenic pruritus. J Allergy Clin Immunol 2011;
128:1113.
Shelley WB, et al: Aquadynia. J Am Acad Dermatol 1998; 38:357.
Scalp pruritus
Pruritus o the scalp especially in elderly persons is rather
common. Lac o e coriations scaling or erythema e cludes
in ammatory causes o scalp pruritus such as seborrheic der
matitis psoriasis dermatomyositis or lichen simple chroni
cus. ost such cases remain idiopathic but some represent
chronic olliculitis. Treatment with topical tar shampoos sali
cylic acid shampoos corticosteroid topical gels mousse sham
poos and li uids can be help ul. n patients who ha e se ere
scalp pruritus with locali ed itch an intralesional in ection o
corticosteroid suspension may pro ide relie . inocycline or
oral antihistamines may be help ul. n other patients low
doses o antidepressants such as do epin are use ul.
Bin Saif GA, et al: The itchy scalp—searching for an explanation. Exp
Dermatol 2011; 20:959–968.
Drug-induced pruritus
edications should be considered a possible cause o pruritus
with or without a s in eruption. or e ample pruritus is re
uently present a ter opioid use. Also chloro uine and to a
lesser degree other antimalarials produce pruritus in many
patients especially A rican Americans treated or malaria.
SSR s and drugs causing cholestatic li er disease are other
re uent causes.
ydro yethyl starch ( S) is used as a olume e pander a
substitute or human plasma. ne third o all patients treated
will de elop se ere pruritus with long latency o onset (
wee s) and persistence. p to o patients ha e locali ed
symptoms. Antihistamines are ine ecti e.
Reich A, et al: Drug-induced pruritus. Acta Derm Venereol 2009;
89:236–244.
Chronic pruritic dermatoses of unknown cause
Prurigo simple is the pre erred term or the chronic itchy
idiopathic dermatosis described here. Papular dermatitis sub
acute prurigo itchy red bump disease and Rosen papular
eruption in blac men most li ely represent ariations o
prurigo simple . The term prurigo continues to lac nosologic
precision.
Prurigo simple is characteri ed by the lesion nown as the
prurigo papule which is dome shaped and topped with a
small esicle. The esicle is usually present only transiently
because o its immediate remo al by scratching so that a
crusted papule is more re uently seen. Prurigo papules are
present in arious stages o de elopment and are seen mostly
in middle age or elderly persons o both genders. The trun
and e tensor sur aces o the e tremities are common sites
symmetrically distributed. ther areas include the ace nec
lower trun and buttoc s. The lesions usually appear in crops
so that papulo esicles and the late stages o scarring may be
seen at the same time.
The histopathology o prurigo simple is nonspeci c but
o ten suggests an arthropod reaction. Spongiosis accompanied
by a peri ascular mononuclear in ltrate with some eosino
phils is o ten ound.
any conditions may cause pruritic erythematous papules.
Scabies atopic dermatitis insect bite reactions papular urti
caria dermatitis herpeti ormis contact dermatitis pityriasis
lichenoides et arioli ormis acuta (PL VA) transient acantho
lytic dermatosis (TAD) papuloerythroderma o u i derma
tographism and physical urticarias should be considered.
Biopsy may be help ul in di erentiating dermatitis herpeti or
mis PL VA TAD and on occasion unsuspected scabies.
Treatment
The medications or initial treatment o prurigo simple and
its ariants should be topical corticosteroids and oral anti
histamines. arly in the disease process moderate strength
steroids should be used; i the condition is ound to be unre
sponsi e a change to high potency orms is indicated.
Rebound may occur. ntralesional in ection o triamcinolone
will eradicate indi idual lesions. or more recalcitrant disease
VB or P VA therapy may be bene cial.
Bakker CV, et al: Bullous pemphigoid as pruritus in the elderly. JAMA
Dermatol 2013; 149:750–753.
Clark AR, et al: Papular dermatitis (subacute prurigo, “itchy red bump”
disease). J Am Acad Dermatol 1998; 38:929.
Gambichler T, et al: Immunophenotyping of inflammatory cells in
subacute prurigo. J Eur Acad Dermatol Venereol 2011;
25:1221–1226.
Fig. 4-6 Prurigo
pigmentosa.
Pruritic dermatoses
Prurigo pigmentosa
Prurigo pigmentosa is a rare dermatosis o un nown cause
characteri ed by the sudden onset o erythematous papules
or esicles that lea e reticulated hyperpigmentation when
they heal ( ig. ). The condition mainly a ects Japanese
although numerous cases ha e been reported in Caucasians.
Women outnumber men . The mean age o onset is . t
is associated with weight loss dieting anore ia diabetes
and etonuria. t is e acerbated by heat sweating and ric
tion and thus occurs most o ten in the winter and spring. The
areas most re uently in ol ed are the upper bac nape cla
icular region and chest. ucous membranes are spared.
istology o early lesions shows neutrophils in the dermal
papillae and epidermis. ollowing this a lichenoid dermatitis
with ariable psoriasi orm hyperplasia occurs. Direct immu
no uorescence yields negati e ndings. The cause is
un nown. inocycline mg day is the treatment o
choice. Dapsone and alteration o the diet are also e ecti e;
topical steroids are not e ecti e. Recurrence and e acerba
tions are common.
Hijazi M, et al: Prurigo pigmentosa. Am J Dermatopathol 2014;
36:800–806.
Marín PR, et al: Pruritic reticular eruption on the chest of a 24-year-old
woman—quiz case. Diagnosis: prurigo pigmentosa (PP). Arch
Dermatol. 2010; 146:81–86.
Oh YJ, et al: Prurigo pigmentosa. J Eur Acad Dermatol Venereol 2012;
26:1149–1153.
Papuloerythroderma of Ofuji
A rare disorder most o ten ound in Japan papuloerythro
derma o u i (P ) is characteri ed by at topped red to
brown pruritic papules that spare the s in olds producing
bands o unin ol ed cutis the so called dec chair sign.
Almost all patients are o er age with clear male predomi
nance. re uently there is associated blood eosinophilia. S in
biopsies re eal a dense lymphohistiocytic in ltrate eosino
phils in the papillary dermis and increased Langerhans cells.
alignancies ha e occurred in o reported cases but the
timing and course do not always o ten correlate with P .
Reported malignancies include T cell lymphomas B cell lym
phomas S ary syndrome and isceral carcinomas. Drugs
(e.g. aspirin ranitidine urosemide) and in ections (e.g. V
hepatitis C) may induce the condition. Se ere atopic dermatitis
and cutaneous T cell lymphoma may present with identical
morphologic nding o P . istory will assist in ma ing the
diagnosis o atropic dermatitis whereas biopsy may re eal
ndings diagnostic o eruptions.
51
 Systemic steroids are the treatment o choice and may result
4 in long term remission. Topical or systemic steroids tar deri
ati es emollients systemic retinoids cyclosporine VB and
P VA may also be therapeutic. V therapy with or without
steroids is a ored.
Pruritus and Neurocutaneous Dermatoses
Teraki Y, et al: High incidence of internal malignancy in
papuloerythroderma of Ofuji. Dermatology 2013; 224:5–9.
Torchia D, et al: Papuloerythroderma 2009. Dermatology 2010;
220:311–320.
Lichen simplex chronicus
Also nown as circumscribed neurodermatitis lichen simple
chronicus results rom long term chronic rubbing and scratch
ing more igorously than a normal pain threshold would
permit with the s in becoming thic ened and leathery. The
normal mar ings o the s in become e aggerated ( ig. ) so
that the striae orm a crisscross pattern producing a mosaic in
between composed o at topped shiny smooth uadrilateral
acets. This change nown as licheni cation may originate on
seemingly normal s in or may de elop on s in that is the site
o another disease such as atopic or allergic contact dermatitis
or ringworm. Such underlying etiologies should be sought
and i ound treated speci cally. Paro ysmal pruritus is the
main symptom.
Circumscribed licheni ed pruritic patches may de elop on
any part o the body; howe er lichen simple chronicus has
a predilection or the bac and sides o the nec the scalp the
upper eyelid the ori ce o one or both ears the palm soles
or o ten the wrist and an le e ures. The ul a scrotum and
anal areas are common sites although the genital and anal
areas are seldom in ol ed at the same time. The eruption may
be papular resembling lichen planus; and in other cases the
patches are e coriated slightly scaly or moist and rarely
nodular. Persistent rubbing o the shins or upper bac may
result in dermal deposits o amyloid and the subse uent
de elopment o lichen or macular amyloidosis respecti ely.
The onset o this dermatosis is usually gradual and insidi
ous. Chronic scratching o a locali ed area may be a response
to an inciting dermatitis; howe er scratching o the locali ed
site continues long a ter the original insult and becomes a
habit.
Fig. 4-7 Lichen
simplex chronicus.
52
Treatment
Cessation o pruritus is the goal with lichen simple chronicus.
t is important to stress the need or the patient to a oid
scratching the areas in ol ed i the sensation o itch is amelio
rated. Recurrences are re uent e en a ter the most thorough
treatment and in some cases the clearance o one lesion will
see the onset o another elsewhere.
A high potency steroid cream or ointment should be used
initially but not inde nitely because o the potential or steroid
induced atrophy. cclusion o medium potency steroids may
be bene cial. se o a steroid containing tape to pro ide both
occlusion and anti in ammatory e ects may ha e bene t.
Treatment can be shi ted to the use o medium to lower
strength topical steroid creams as the lesions resol e. Topical
do epin capsaicin or pimecrolimus cream or tacrolimus oint
ment pro ides signi cant antipruritic e ects and is a good
ad uncti e therapy.
ntralesional in ections o triamcinolone suspension using a
concentration o . mg mL may be re uired. Too super
cial an in ection in ites the twin ris s o epidermal and dermal
atrophy and depigmentation which may last or many months.
The suspension should not be in ected into in ected lesions
because it may cause abscess. Botulinum to in A in ection may
be curati e. n the most se ere cases complete occlusion with
an nna boot may brea the cycle.
Aschoff R, et al: Topical tacrolimus for the treatment of lichen simplex
chronicus. J Dermatol Treat 2007; 18:15.
Feily A, et al: A succinct review of botulinum toxin in dermatology.
J Cosmet Dermatol 2011; 10:58–67.
Rajalakshmi R, et al: Lichen simplex chronicus of the anogenital region.
Indian J Dermatol Venereol Leprol 2011; 77:28–36.
Stewart KMA: Clinical care of vulvar pruritus, with emphasis on one
common cause, lichen simplex chronicus. Dermatol Clin 2010;
28:669–680.
Prurigo nodularis
Prurigo nodularis is a disease with multiple itchy nodules
mainly on the e tremities ( ig. ) especially on the anterior
sur aces o the thighs and legs. A linear arrangement is
common. The indi idual lesions are pea si ed or larger rm
and erythematous or brownish. When ully de eloped they
become errucous or ssured. The course o the disease is
chronic and the lesions e ol e slowly. tching is se ere but
usually con ned to the lesions themsel es. Bouts o e treme
pruritus o ten occur when these patients are under stress.
Prurigo nodularis is one o the disorders in which the pruritus
is characteristically paro ysmal intermittent unbearably
se ere and relie ed only by scratching to the point o damag
ing the s in usually inducing bleeding and o ten scarring.
The cause o prurigo nodularis is un nown; multiple actors
may contribute including atopic dermatitis hepatic diseases
(including hepatitis C) V disease pregnancy renal ailure
lymphoproli erati e disease stress and insect bites. Pem
phigoid nodularis may be con used with prurigo nodularis
clinically.
The histologic ndings are those o compact hyper eratosis
irregular acanthosis and a peri ascular mononuclear cell in l
trate in the dermis. Dermal collagen may be increased espe
cially in the dermal papillae and subepidermal brin may be
seen both e idence o e coriation. n cases associated with
renal ailure transepidermal elimination o degenerated col
lagen may be ound.
Treatment
The initial treatment o choice or prurigo nodularis is
intralesional or topical administration o steroids. sually
superpotent topical products are re uired but at times lower
strength preparations used with occlusion may be bene cial
as when administered as the soa and smear regimen. The
use o steroids in tape (Cordran) and prolonged occlusion with
semipermeable dressings such as used or treating nonhealing
wounds can be use ul in limited areas. ntralesional steroids
will usually eradicate indi idual lesions but un ortunately
many patients ha e too e tensi e disease or these local mea
sures. P VA B VB and VA alone ha e been shown to be
e ecti e in some patients. Vitamin D ointment calcipotriene
ointment or tacrolimus ointment applied topically twice daily
may be therapeutic and steroid sparing. sotretinoin mg
g day or months may bene t some patients. anaging
dry s in with emollients and a oidance o soap with admin
istration o antihistamines antidepressants or an iolytics is o
moderate bene t in allaying symptoms.
Good results ha e been obtained with thalidomide lenalid
omide pregabalin and cyclosporine. With thalidomide onset
may be rapid or slow and sedation may occur; initial dose is
mg day titered to the lowest dose re uired. Patients
treated with thalidomide are at ris o de eloping a dose
dependent neuropathy at cumulati e doses o g.
Lenalidomide an analogue o thalidomide has less problems
with neuropathy but may cause myelosuppression enous
thrombosis and Ste ens Johnson syndrome. Pregabalin
mg day or months impro ed o patients in one
study. Cyclosporine at doses o . mg g day has also
been shown to be e ecti e in treating recalcitrant disease.
Cryotherapy may be used ad uncti ely.
Andersen TP, et al: Thalidomide in 42 patients with prurigo nodularis
Hyde. Dermatology 2011; 223:107–112.
Bruni E, et al: Phototherapy of generalized prurigo nodularis. Clin Exp
Dermatol 2009; 35:549–550.
Kanavy H, et al: Treatment of refractory prurigo nodularis with
lenalidomide. Arch Dermatol 2012; 148:794–796.
Mazza M, et al: Treatment of prurigo nodularis with pregabalin. J Clin
Pharm Ther 2013; 38:16–18.
Fig. 4-8 Prurigo nodularis. (Courtesy of Debabrata Bandyopadhyay,
MD.)
PSYCHODERMATOLOGY
Some purely cutaneous disorders are psychiatric in nature
their cause being directly related to psychopathologic causes
Psychodermatology
in the absence o primary dermatologic or other organic
causes. Delusions o parasitosis psychogenic (neurotic) e co
riations actitial dermatitis and trichotillomania compose the
ma or categories o psychodermatology. The di erential diag
nosis or these our disorders is two old re uiring the e clu
sion o organic causes and the de nition o a potential
underlying psychological disorder. Bromidrosiphobia is
another delusional disorder. Body dysmorphic disorder is a
spectrum o disease; some se erely a ected patients are delu
sional whereas others ha e more insight and are less unction
ally impaired.
Psychosis is characteri ed by the presence o delusional ide
ation which is de ned as a ed misbelie that is not shared
by the patient s subculture. onosymptomatic hypochondria
cal disorder is a orm o psychosis characteri ed by delusions
regarding a particular hypochondriacal concern. n contrast to
schi ophrenia there are no other mental de cits such as audi
tory hallucination loss o interpersonal s ills or presence o
other inappropriate actions. Patients with monosymptomatic
hypochondriacal psychosis o ten unction appropriately in
social settings e cept or a single ated belie that there is a
serious problem with their s in or with other parts o their
body.
Butler DC, et al: Psychotropic medications in dermatology. Semin Cutan
Med Surg 2013; 32:126–129.
Fried RG: Nonpharmacologic treatments of psychodermatologic
conditions. Semin Cutan Med Surg 2013; 32:119–125.
Leon A, et al: Psychodermatology. Semin Cutan Med Surg 2013;
32:64–67.
Locala JA: Current concepts in psychodermatology. Curr Psychiatry
Rep 2009; 11:211–218.
Skin signs of psychiatric illness
The s in is a re uent target or the release o emotional
tension. Some o the signs described here may become repeti
ti e compulsions that impair normal li e unctions and may be
mani estations o an obsessi e compulsi e disorder. Sel
in ury by prolonged compulsi e repetitious acts may produce
arious mutilations depending on the act and site o in ury.
Sel biting may be mani ested by biting the nails (onycho
phagia) ( ig. ) s in (most re uently the orearms hands
Fig. 4-9 Onychophagia. (Courtesy of Curt Samlaska, MD.)
53

4 Delusions o parasitosis (e.g. delusional parasitosis
Pruritus and Neurocutaneous Dermatoses
Fig. 4-10 Irritant dermatitis from chronic handwashing.
n
U
-
9
Fig. 4-11 Dermatitis caused by lip licking.
ri 9
and ngers) and lip. Dermatophagia is a habit or compulsion
conscious or subconscious. Bumping o the head produces
lacerations and contusions which may be so se ere as to
h
produce cranial de ects and li e threatening complications.
Compulsi e repetiti e handwashing may produce an irritant
t a
dermatitis o the hands ( ig. ).
Bulimia with its sel induced omiting results in Russell s
sign crusted papules on the dorsum o the dominant hand
rom cuts by the teeth. Clenching o the hand produces swell
ing and ecchymosis o the ngertips and subungual hemor
rhage. Sel in icted lacerations may be o suicidal intent. Lip
lic ing produces increased sali ation and thic ening o the
lips. entually the perioral area becomes red and produces
a distincti e picture resembling the e aggerated mouth
ma eup o a clown ( ig. ). Pressure produced by binding
the waistline tightly with a cord will e entually lead to atrophy
o the subcutaneous tissue.
Psychopharmacologic agents especially the newer atypical
antipsychotic agents and beha ioral therapy alone or in com
bination with these agents are the treatments o choice.
Kestenbaum T: Obsessive-compulsive disorder in dermatology. Semin
Cutan Med Surg 2013; 32:83–87.
Shukla R, et al: Psychopharmacology in psychodermatology. J Cutan
Med Surg 2008; 12:255–267.
Strumia R: Eating disorders and the skin. Clin Dermatol 2013;
31:80–85.
54
Delusions of parasitosis
bom
syndrome acarophobia dermatophobia parasitophobia
entomophobia pseudoparasitic dysesthesia) are rm ations
in a person s mind that he or she su ers rom a parasitic in es
tation o the s in. At times close contacts may share the delu
sion. The belie is so ed that the patient may pic small
pieces o epithelial debris rom the s in and bring them to be
e amined always insisting that the o ending parasite is con
tained in such material. Samples o alleged parasites enclosed
in assorted containers paper tissue or sandwiched between
adhesi e tape are so characteristic that it is re erred to as the
matchbo or iploc sign. sually the only symptom is
pruritus or a stinging biting or crawling sensation. ntranasal
ormication or a crawling sensation o the nasal mucosa is
common in this condition. Cutaneous ndings may range
rom none to e coriations prurigo nodularis and ran
ulcerations.
re uently these patients ha e paranoid tendencies. Women
G
are a ected o er men o ten during middle or old age. The
condition has been reported to be associated with schi ophre
R
nia bipolar disorders depression an iety disorders and
obsessional states but is usually a monosymptomatic hypo
V
chondriacal disorder. A ariety o organic conditions may be
causati e and should be considered. They include cocaine
d
alcohol and amphetamine abuse; dementia and other neuro
logic conditions (e.g. multiple sclerosis central ner ous
ti e
system tumors epilepsy Par inson s disease); malignancies
particularly lymphoma and leu emia; cerebro ascular disease;
endocrine disorders; in ectious diseases; pellagra; and itamin
B de ciency. A ariety o medications including gabapentin
antipar insonian and antihistaminic drugs and corticoste
roids may also produce this condition. Some o these agents
may produce cutaneous symptoms particularly pruritus
which may contribute to the delusion.
The di erential diagnosis is in uenced by the cutaneous
ndings and history. nitial steps should be directed at e clud
ing a true in estation such as scabies or an organic cause. A
thorough history particularly in re erence to therapeutic and
recreational drug use (e.g. amphetamines alcohol cocaine)
re iew o systems and physical e amination should be per
ormed. any consider orgellons disease simply to be
another name or delusions o parasitosis. Patients complain
o crawling biting burning or other sensations that cause
them to be intensely an ious. ten granules or bers are
pro ided by the patient or analysis. any patients ha e asso
ciated psychiatric conditions.
A s in biopsy is re uently per ormed more to reassure the
patient than to unco er occult s in disease. Screening labora
tory tests to e clude systemic disorders should be obtained
CBC; urinalysis; li er renal and thyroid unction tests; iron
studies; serum glucose and serum B ; olate; and electrolyte
le els. nce organic causes ha e been eliminated the patient
should be e aluated to determine the cause o the delusions.
Schi ophrenia monosymptomatic hypochondriacal psycho
sis psychotic depression dementia and depression with
somati ation are considerations in the di erential diagnosis.
anagement o this di cult problem aries. Although re er
ral to a psychiatrist may seem best most re uently the patient
will re ect suggestions to see psychiatric help. The dermatolo
gist is cautioned against con ronting the patient with the psy
chogenic nature o the disease. t is pre erable to de elop trust
which will usually re uire se eral isits. pharmacologic
treatment is underta en the patient may accept it i the medi
cation is presented as one that will alter the perception o this
bothersome sensation. Pimo ide was the long standing treat
ment o choice but is associated with a ariety o side e ects
including sti ness restlessness prolongation o T inter al
and e trapyramidal signs. Patients o ten respond to relati ely
low dosages in the mg range which limits these problems.
Pimo ide is appro ed or the treatment o Tourette syndrome
and patients should understand the labeling be ore obtaining
the drug. ewer atypical antipsychotic agents such as risperi
done and olan apine ha e ewer side e ects and are now
considered the appropriate rst line agents or the treatment
o delusions o parasitosis although the e perience with them
is more limited. With appropriate pharmacologic inter ention
at least o patients will li ely remit.
Accordino RE, et al: Morgellons disease? Dermatol Ther 2008; 21:8.
Elliott A, et al: Cocaine bugs. Am J Addict 2012; 21:180–181.
Friedman AC, et al: Delusional parasitosis presenting as folie à trois.
Br J Dermatol 2006; 155:841.
Huber M, et al: Delusional infestation. Gen Hosp Psychiatry 2011;
33:604–611.
Hylwa SA, et al: Delusional infestation, including delusions of
parasitosis. Arch Dermatol 2011; 147:1041–1045.
Lepping P, et al: Antipsychotic treatment of primary delusional
parasitosis: systematic review. Br J Psychiatry 2007;191:198.
Lewis EC et al: Delusions of parasitosis. Semin Cutan Med Surg 2013;
32:73–77.
Lopez PR, et al: Gabapentin-induced delusions of parasitosis. South
Med J 2010; 103:711–712.
Reichenberg JS, et al: Patients labeled with delusions of parasitosis
compose a heterogenous group. J Am Acad Dermatol 2013;
68:41–46.
Robles DT, et al: Morgellons disease and delusions of parasitosis. Am J
Clin Dermatol 2011; 12:1–6.
Sandoz A, et al: A clinical paradigm of delusions of parasitosis. J Am
Acad Dermatol 2008; 59:698–704.
Schairer D, et al: Psychology and psychiatry in the dermatologist’s
office. J Drug Dermatol 2012; 11:543-545.
Walling HW, et al: Intranasal formication correlates with diagnosis of
delusions of parasitosis. J Am Acad Dermatol 2008; 58:S35.
Psychogenic (neurotic) excoriations
any persons ha e unconscious compulsi e habits o pic ing
at themsel es and at times the tendency is so persistent and
pronounced that e coriations o the s in result. The lesions are
caused by pic ing digging or scraping and usually occur on
parts readily accessible to the hands. These patients admit
their actions induce the lesions but cannot control their
beha ior.
The e ca ations may be super cial or deep and are o ten
linear. The bases o the ulcers are clean or co ered with a scab.
Right handed persons tend to produce lesions on their le t side
and le t handed persons on their right side. There is e idence
o past healed lesions usually with linear scars or rounded
hyperpigmented or hypopigmented lesions in the area o the
acti e e coriations. The ace upper arms and upper bac are
common sites or these e coriations ( ig. ). Sometimes the
ocus is on acne lesions producing acne e cori e.
ost o these patients are otherwise healthy adults. They
usually lead normal li es. The organic di erential diagnosis is
ast and includes any condition that may mani est with e co
riations. The most common psychopathologies associated with
neurotic e coriations are depression obsessi e compulsi e
disorder and an iety.
The treatment o choice is do epin because o its antidepres
sant and antipruritic e ects; doses are slowly increased to
mg or higher i tolerated. any alternati es to do epin
may be indicated especially in those a ected by an obsessi e
compulsi e component including clomipramine paro etine
uo etine and sertraline. ther use ul drugs are desipramine
buspirone and rapid acting ben odia epines. Treatment is
di cult o ten re uiring a combined psychiatric and pharma
Psychodermatology
Fig. 4-12 Neurotic excoriations. (Courtesy of Lawrence Lieblich, MD.)
cologic inter ention. t is important to establish a constructi e
patient therapist alliance. Training in di ersion strategies
during scratching episodes may be help ul. An attempt
should be made to identi y speci c con icts or stressors pre
ceding onset. The therapist should concentrate on systematic
training directed at the beha ioral reaction pattern. There
should be support and ad ice gi en with regard to the patient s
social situation and interpersonal relations.
Kestenbaum T: Obsessive-compulsive disorder in dermatology. Semin
Cutan Med Surg 2013; 32:83–87.
Koblenzer CS, et al: Neurotic excoriations and dermatitis artefacta.
Semin Cutan Med Surg 2013; 32:95–100.
Misery L, et al: Psychogenic skin excoriations. Acta Derm Venereol
2012, 92:416–418.
Mustasim DF, et al: The psychiatric profile of patients with psychogenic
excoriation. J Am Acad Dermatol 2009; 61:611.
Factitious dermatitis and dermatitis artefacta
actitious dermatitis is the term applied to sel in icted s in
lesions with the intent to elicit sympathy escape responsibil
ity or collect disability insurance. alingering applies to the
latter two cases where material gain is the ob ecti e. This
contrasts with the usual dermatitis arte acta patient who has
an unconscious goal o gaining attention and assuming the
sic patient role. ost patients are adults in midli e with
women a ected three times more o ten than men. The ast
ma ority ha e multiple lesions and are unemployed or on sic
lea e. These s in lesions are pro o ed by mechanical means
or by the application or in ection o chemical irritants and
caustics. These patients o ten ha e a hollow history unable
to detail how the lesions appeared or e ol ed. The lesions may
simulate other dermatoses but usually ha e a distincti e geo
metric bi arre appearance ( ig. ) o ten with a shape and
arrangement not encountered in other disorders. The lesions
are generally distributed on parts easily reached by the hands
tend to be linear and arranged regularly and symmetrically
and are rarely seen on the right hand right wrist or right arm
unless the patient is le t handed.
When chemicals are used red strea s or guttate mar s are
o ten seen beneath the principal patch where drops o the
chemical ha e accidentally run or allen on the s in. According
to the manner o production the lesions may be erythematous
esicular bullous ulcerati e or gangrenous. The more
common agents o destruction used are the ngernails pointed
instruments hot metal chemicals (e.g. carbolic nitric or
acetic acid) caustic potash or soda turpentine table salt
urine and eces. The lesions are li ely to appear in crops. At
times the only sign may be the inde nitely delayed healing o
an operati e wound which is purposely ept open by the
55
 Fig. 4-13 Factitial
4 ulcers.
Pruritus and Neurocutaneous Dermatoses
patient. Tight cords or clothing tied around an arm or leg may
produce actitious lymphedema which may be mista en or
postphlebitic syndrome or ner e in ury as well as other orms
o chronic lymphedema.
Subcutaneous emphysema mani esting as cutaneous crepi
tations may be actitial in origin. Recurrent migratory subcu
taneous emphysema in ol ing the e tremities nec chest or
ace can be induced through in ections o air into tissue with
a needle and syringe. Circular poc ets and bilateral in ol e
U
ment without physical ndings indicating contiguous spread
rom a single source suggest a actitial origin. Puncturing the
-
buccal mucosa through to acial s in with a needle and pu ng
out the chee s can produce alarming results. ec and shoul
der crepitation is also a complication in manic patients that
9
results rom hyper entilation and breath holding.
The organic di erential diagnosis depends on the cutaneous
ri 9
signs mani ested such as gas gangrene or patients with acti
tious subcutaneous emphysema and the arious orms o
lymphedema or actitious lymphedema. A subset o these
patients ha e unchausen syndrome. They tend to cause
h
lesions that closely simulate nown conditions and they create
an intricate o ten antastic story surrounding the problem.
t a
Admissions to the hospital with e tensi e wor up o ten result.
Parents may induce lesions on their child to gain attention
so called unchausen by pro y which is really child abuse.
Considerations or psychopathology in dermatitis arte acta
include borderline personality disorders and psychosis.
Proo o diagnosis is sometimes di cult. cclusi e dress
ings may be necessary to protect the lesions rom ready access
by the patient. t is usually best not to re eal any suspicion o
the cause to the patient and to establish the diagnosis de ni
ti ely without the patient s nowledge. the patient is hospi
tali ed a resource ul cooperati e nurse may be use ul in
helping to establish the diagnosis. When in ection o oreign
material is suspected e amination o biopsy material by spec
troscopy may re eal talc or other oreign material.
Treatment should ideally in ol e psychotherapy but typi
cally the patient promptly re ects the suggestion and goes to
another physician to see a new round o treatment. t is best
or the dermatologist to maintain a close relationship with the
patient and pro ide symptomatic therapy and non udgmental
support. SSR s may address associated depression and an iety.
Very low dose atypical antipsychotics may also be added i
56
Fig. 4-14 Trichotillomania.
R G
V
needed. Consultation with an e perienced psychiatrist is
d
prudent.
Koblenzer CS, et al: Neurotic excoriations and dermatitis artefacta.
ti e
Semin Cutan Med Surg 2013; 32:95–100.
Shah KN, et al: Factitial dermatoses in children. Curr Opin Pediatr 2006;
18:403.
Ucmak D, et al: Dermatitis artefacta. Cutan Ocul Toxicol 2014; 33:22–27.
n
Trichotillomania
Trichotillomania (trichotillosis or neuromechanical alopecia) is
a neurosis characteri ed by an abnormal urge to pull out the
hair. The sites in ol ed are generally the rontal region o the
scalp eyebrows eyelashes and the beard. The classic presen
tation is the riar Tuc orm o erte and crown alopecia.
There are irregular areas o hair loss which may be linear or
bi arrely shaped. n re uently adults may pull out pubic hair.
airs are bro en and show di erences in length ( ig. ).
The pulled hair may be ingested and occasionally the tricho
be oar will cause obstruction. When the tail e tends rom the
main mass in the stomach to the small or large intestine
Rapun el syndrome is the diagnosis. The nails may show e i
dence o onychophagy (nail biting) but no pits are present.
The disease is se en times more common in children than in
adults and girls are a ected . times more o ten than boys.
Trichotillomania o ten de elops in the setting o psychoso
cial stress in the amily which may in ol e school problems
sibling ri alry mo ing to a new house hospitali ation o a
parent or a disturbed parent child relationship.
Di erentiation rom alopecia areata is possible because
o the arying lengths o bro en hairs present the absence o
nail pitting and the microscopic appearance o the twisted or
bro en hairs in contrast to the tapered ractures o alopecia
areata. ther organic disorders to consider are androgenic
alopecia tinea capitis monilethri pili torti pseudopelade o
Broc traction alopecia syphilis nutritional de ciencies and
systemic disorders such as lupus and lymphoma. Trichoscopy
re eals bro en hairs o arying lengths; some may be rayed
longitudinally split or coiled. necessary a biopsy can be
per ormed and is usually uite help ul. t re eals traumati ed
hair ollicles with peri ollicular hemorrhage ragmented
hair in the dermis empty ollicles and de ormed hair sha ts
(trichomalacia). ultiple catagen hairs are typically seen. An
alternati e techni ue to biopsy particularly or children is to
sha e a part o the in ol ed area and obser e or regrowth o
normal hairs. The di erential diagnosis or this impulse
control disorder should include underlying comorbid psycho
pathology such as an obsessi e compulsi e disorder (most
common) depression or an iety.
n children the diagnosis should be addressed openly and
re erral to a child psychiatrist or cogniti e beha ioral therapy
(CBT) should be encouraged. abit re ersal training is o ten
part o the treatment. n adults with the problem psychiatric
impairment may be se ere. Pharmacotherapy with clomip
ramine is the most e ecti e o the studied medications but
SSR s are most o ten prescribed and may help any associated
depression or an iety. acetylcysteine also shows promise; it
is a ailable in health ood stores and is relati ely ine pensi e
and well tolerated. Trichobe oars re uire surgical remo al.
Franklin ME, et al: Trichotillomania and its treatment. Expert Rev
Neurother 2011; 11:1165–1174.
Grant JE, et al: N-acetylcysteine, a glutamine inhibitor, in the treatment
of trichotillomania. Arch Gen Psychiatry 2009, 66:756–763.
Harrison JP, et al: Pediatric trichotillomania. Curr Psychiatry Rep 2012;
14:188–196.
Huynh M, et al: Trichotillomania. Semin Cutan Med Surg 2013;
32:88–94.
Morales-Fuentes B, et al: Trichotillomania, recurrent trichobezoar and
Rapunzel syndrome. Cir Cir 2010; 78:265–266.
Ravindran AV, et al: Obsessive-compulsive spectrum disorders. Can J
Psychiatry 2009; 54:331–343.
Woods DW, et al: Diagnosis, evaluation, and management of
trichotillomania. Psychiatr Clin North Am 2014; 37:301–317.
Dermatothlasia
Dermatothlasia is a cutaneous neurosis characteri ed by a
patient s uncontrollable desire to rub or pinch themsel es to
orm bruised areas on the s in sometimes as a de ense against
pain elsewhere.
Bromidrosiphobia
Bromidrosiphobia (delusions o bromhidrosis) is a mono
symptomatic delusional state in which a person is con inced
that his or her sweat has a repugnant odor that eeps other
people away. The patient is unable to accept any e idence to
the contrary. Three uarters o patients with bromidrosipho
bia are male with an a erage age o . Atypical antipsychotic
agents or pimo ide may be bene cial. t may be an early
symptom o schi ophrenia.
Body dysmorphic disorder (dysmorphic
syndrome, dysmorphophobia)
Body dysmorphic disorder is the e cessi e preoccupation o
ha ing an ugly body part. t is most common in young adults
o either gender. The concern is re uently centered about the
nose mouth genitalia breasts or hair. b ecti e e aluation
will re eal a normal appearance or slight de ect. These patients
are usually seen in dermatologic practice especially among
those presenting or cosmetic surgery e aluation. Patients may
mani est obsessional eatures spending long periods inspect
ing the area. Associated depression and social isolation along
with other comorbidities present a high ris o suicide. The
SSR s accompanied by CBT gi e the best results or those with
this somato orm disorder. ore se erely a ected patients
ha e delusions that may lead to re uests or repeated surger
ies o the site and re uire antipsychotic medications.
Buhlmann U, et al: Perceived ugliness. Curr Psychiatry Rep 2011;
13:283–288.
Cutaneous Dysesthesia Syndromes
Conrado LA, et al: Body dysmorphic disorder among dermatologic
patients. J Am Acad Dermatol 2010; 63:235–243.
Gupta R, et al: Body dysmorphic disorder. Semin Cutan Med Surg
2013; 32:78–82.
Ipser JC, et al: Pharmacotherapy and psychotherapy for body
dysmorphic disorder. Cochrane Database Syst Rev 2009;
(1):CD005332.
Sarwer DB, et al: Body image dysmorphic disorder in persons who
undergo aesthetic medical treatments. Aesthet Surg J 2012;
32:999–1009.
CUTANEOUS DYSESTHESIA SYNDROMES
Scalp dysesthesia
Cutaneous dysesthesia syndromes are characteri ed by pain
and burning sensations without ob ecti e ndings. any
patients report coe isting pruritus or transient pruritus associ
ated with the dysesthesia. Scalp dysesthesia occurs primarily
in middle age to elderly women. Cer ical spine degenerati e
dis disease was ound in o patients. The hypothesis is
that chronic tension is placed on the occipito rontalis muscle
and scalp aponeurosis. n one series gabapentin helped our
o the se en patients seen in ollow up. A psychiatric o erlay
is re uently associated and treatment with low dose antide
pressants may also be help ul.
Thornsberry LA, et al: Scalp dysesthesia related to cervical spine
disease. JAMA Dermatol 2013; 149:200–203.
Burning mouth syndrome (glossodynia,
burning tongue)
Burning mouth syndrome (B S) is di ided into two orms a
primary type characteri ed by a burning sensation o the oral
mucosa with no dental or medical cause and secondary B S
caused by a number o conditions including lichen planus
candidiasis itamin or nutritional de ciencies (e.g. low B
iron or olate) hypoestrogenism para unctional habits dia
betes dry mouth contact allergies cranial ner e in uries and
medication side e ects. denti cation o the underlying condi
tion and its treatment will result in relie o secondary B S.
Primary B S occurs most re uently in postmenopausal
women. They are particularly prone to a eeling o burning o
the tongue mouth and lips with no ob ecti e ndings. Symp
toms ary in se erity but are more or less constant. Patients
with B S o ten complain that multiple oral sites are in ol ed.
anagement with topical applications o clona epam capsa
icin do epin or lidocaine can help. ral administration o
α lipoic acid SSR s or tricyclic antidepressants (TCAs) gaba
pentin and ben odia epines has been reported to be e ecti e.
The most common best studied and most success ul therapy
is pro ided by the antidepressant medications because many
patients are depressed as well.
Burning lips syndrome may be a separate entity; it appears
to a ect both men and women e ually and occurs in indi idu
als between ages and . The labial mucosa may be smooth
and pale and the minor sali ary glands o the lips are re
uently dys unctional. Treatment with α lipoic acid showed
impro ement in months in a double blind controlled
study.
Crow HC, et al: Burning mouth syndrome. Oral Maxillofac Surg Clin
North Am 2013; 25:67–76.
57
 De Moraes M, et al: Randomized trials for the treatment of burning
4 mouth syndrome. J Oral Pathol Med 2012; 41:281–287.
Lopez-Jornet P, et al: Burning mouth syndrome. Med Oral Patol Oral Cir
Bucal 2010; 15:e562–e568.
Minguez-Sanz M-P, et al: Etiology of burning mouth syndrome. Med Oral
Pruritus and Neurocutaneous Dermatoses
Patol Oral Cir Bucal 2011; 16:e144–e148.
Spanemberg JC, et al: Aetiology and therapeutics of burning mouth
syndrome. Gerodontology 2012; 29:84–89.
Zakrzewska JM, et al: Interventions for the treatment of burning mouth
syndrome. Cochrane Database Syst Rev 2005; 25:CD002779.
Vulvodynia
Vul odynia is de ned as ul ar discom ort usually described
as burning pain occurring without medical ndings. t is
chronic de ned as lasting months or longer. Two subtypes
are seen the locali ed and generali ed subsets. Both may
occur only when pro o ed by physical contact as a spontane
ous pain or mi ed in type. Vul ar pain may be secondary to
many speci c underlying disorders but when caused by in ec
tions (most o ten candidal or herpetic) in ammatory condi
tions (e.g. lichen planus autoimmune blistering disease)
neoplastic disorders (e.g. e tramammary Paget s disease
s uamous cell carcinoma) neurologic etiologies (e.g. spinal
ner e compression herpetic neuralgia) or pre ious radiother
apy these conditions are treated appropriately and the
patient s condition is not categori ed as ul odynia. Thus the
diagnosis o ul odynia is a diagnosis o e clusion.
The pain e perienced may be debilitating. t may be accom
panied by pel ic oor abnormalities headaches bromyalgia
irritable bowel syndrome and interstitial cystitis. Psychosocial
problems result and may be e acerbated by stress depression
n
or an iety or may lead to such conditions o er time. A male
counterpart may be seen and has been called burning genital
U
s in syndrome and dysesthetic penodynia or scrotodynia.
Treatment should always include patient and partner educa
-
tion and psychological support including se therapy and
counseling as appropriate. Topical anesthetics and lubricants
such as petrolatum applied be ore intercourse may be tried
9
initially. limination o irritants treatment o atopy with
topical tacrolimus (allowing or the discontinuance o topical
ri 9
steroids which ha e usually been tried without success) and
the use o antihistamines or dermatographism may be help ul.
Pel ic oor physical therapy and at times CBT may be use ul.
Vul odynia is considered among the chronic pain syndromes
h
that can ha e a psychological impact. Treatment then centers
on the use o TCAs SSR s and neuroleptics chie y gabapen
a
t
tin or pregabalin. ther inter entions such as botulinum to in
A and surgery may be considered in indi idual patients but
the e idence or any o these therapies is limited.
Andrews JC: Vulvodynia interventions. Obstet Gynecol Surv 2011;
66:299–315.
Clare CA, et al: Vulvodynia in adolescence. J Pediatr Adolesc Gynecol
2011; 24:110–115.
Markos AR: The male genital skin burning syndrome (dysaesthetic
peno/scroto-dynia). Int J STD AIDS 2002; 13:271–272.
Nunns D, et al: Guidelines for the management of vulvodynia. Br J
Dermatol 2010; 162:1180–1185.
Shah M, et al: Vulvodynia. Obstet Gynecol Clin North Am 2014;
41:453–464.
Notalgia paresthetica
otalgia paresthetica is a unilateral sensory neuropathy char
acteri ed by in rascapular pruritus burning pain hyperalge
sia and tenderness o ten in the distribution o the second to
si th thoracic spinal ner es. A pigmented patch locali ed to
the area o pruritus is o ten ound caused by postin amma
58
tory change. acular amyloidosis may be produced by chronic
scratching. n most patients degenerati e changes in the
corresponding ertebrae are seen leading to spinal ner e
impingement. When this is present physical therapy nonste
roidal anti in ammatory drugs ( SA Ds) gabapentin o ycar
ba epine and muscle rela ants may be help ul as may
para ertebral bloc s.
Topical capsaicin or lidocaine patch has been e ecti e but
relapse occurs in most patients a ter discontinuing use. Botu
linum to in A in ections were reported to be success ul
although an RCT ailed to show e cacy. cellent long term
results may occur and in ections may be repeated as neces
sary. B VB is also an option.
Fleischer AB, et al: Notalgia paresthetica. Acta Derm Venereol 2011;
91:356–357.
Maari C, et al: Treatment of nostalgia paresthetica with botulinum toxin
A. J Am Acad Dermatol 2014; 70:1139–1141.
Perez-Perez L, et al: Notalgia paresthesica successfully treated with
narrow-band UVB. J Eur Acad Dermatol Venereol 2010; 24:730–732.
Savk E, et al: Investigation of spinal pathology in notalgia paresthetica.
G
J Am Acad Dermatol 2005; 52:1085.
Weinfeld PK, et al: Successful treatment of notalgia paresthetica with
botulinum toxin type A. Arch Dermatol 2007; 143:980.
R
Brachioradial pruritus
V
d
This condition is characteri ed by itching locali ed to the bra
chioradial area o the arm. To relie e the burning stinging or
ti e
e en pain ul uality o the itch patients will re uently use ice
pac s. The ma ority will ha e the sun induced ariety a ariant
o polymorphous light syndrome that usually responds well
to broad spectrum sunscreens (see Chapter ). n the remain
ing patients cer ical spine pathology is re uently ound on
radiographic e aluation. Searching or causes o the abnormal
ity should include discussion o spinal in ury such as trauma
arthritis or chronic repetiti e microtrauma whiplash in ury
or assessment or a tumor in the cer ical spinal column.
Gabapentin botulinum A to in topical amitriptyline
etamine or capsaicin aprepitant carbama epine cer ical
spine manipulation nec traction anti in ammatory medica
tions physical therapy and surgical resection o a cer ical rib
ha e all been success ul in indi idual patients with brachiora
dial pruritus.
Ally MS, et al: The use of aprepitant in brachioradial pruritus. JAMA
Dermatol 2013; 149:627–628.
Kavanagh GM, et al: Botulinum A toxin and brachioradial pruritus. Br J
Dermatol 2012; 166:1147.
Marziniak M, et al: Brachioradial pruritus as a result of cervical spine
pathology. J Am Acad Dermatol 2011; 65:756–762.
Poterucha TJ, et al: Topical amitriptyline-ketamine for the treatment of
brachioradial pruritus. JAMA Dermatol 2013; 149:148–150.
Veien NK, et al: Brachioradial pruritus. Acta Derm Venereol 2011;
91:183–185.
Meralgia paresthetica (Roth-Bernhardt disease)
Persistent numbness and periodic transient episodes o
burning or lancinating pain on the anterolateral sur ace o the
thigh characteri e Roth Bernhardt disease. The lateral emoral
cutaneous ner e inner ates this area and is sub ect to entrap
ment and compression along its course. Sensory mono
neuropathies besides notalgia paresthetica and meralgia
paresthetica include mental and intercostal neuropathy and
cheiralgia gonyalgia and digitalgia paresthetica.
eralgia paresthetica occurs most re uently in middle age
obese men. Additionally diabetes mellitus is se en times more
common in these patients than in the general population. Alo
pecia locali ed to the area inner ated by the lateral emoral
ner e may be a s in sign o this disease. ternal compression
may occur rom tight tting clothing cell phones or other
hea y ob ects in the poc ets or worn on belts or seat belt
in uries rom automobile crashes. nternal compression rom
arthritis o the lumbar ertebrae a herniated dis pregnancy
intra abdominal disease that increases intrapel ic pressure
iliac crest bone gra t har esting diabetes neuroma and rarely
a lumbar spine or pel ic tumor ha e been reported causes in
indi idual patients.
The diagnostic test o choice is somatosensory e o ed
potentials o the lateral emoral cutaneous ner e. Local anes
thetics (e.g. lidocaine patch) SA Ds rest a oidance o
aggra ating actors and weight reduction may lead to
impro ement; indeed o patients ha e spontaneous
impro ement aided by conser ati e measures. Gabapentin is
use ul in arious neuropathic pain disorders. such inter en
tions ail and a ner e bloc rapidly relie es symptoms local
in ltration with corticosteroids is indicated. Surgical decom
pression o the lateral emoral cutaneous ner e can produce
good to e cellent outcomes but should be reser ed or patients
with intractable symptoms who responded to ner e bloc s but
not corticosteroids. the ner e bloc does not result in
symptom relie computed tomography (CT) scan o the
lumbar spine as well as pel ic and lower abdominal ultra
sound e aminations to assess or tumors are indicated.
Khalil N, et al: Treatment for meralgia paresthetica. Cochrane Database
Syst Rev 2012; 12:CD004159.
Parisi TJ, et al: Meralgia paresthetica. Neurology 2011; 77:1538–1542.
Patijn J, et al: Meralgia paresthetica. Pain Prac 2011; 11:302–308.
Complex regional pain syndrome
ncompassing the descriptors re e sympathetic dystrophy
causalgia neuropathic pain and Sude syndrome comple
regional pain syndrome (CRPS) is characteri ed by burning
pain hyperesthesia and trophic disturbances resulting rom
in ury to a peripheral ner e. The continuing pain is dispropor
tionate to the in ury which may ha e been a crush in ury
laceration racture hypothermia sprain burn or surgery. t
usually occurs in one o the upper e tremities although leg
in ol ement is also common. The characteristic symptom is
burning pain aggra ated by mo ement or riction. The s in o
the in ol ed e tremity becomes shiny cold and atrophic and
may perspire pro usely. Additional cutaneous mani estations
include bullae erosions edema telangiectases hyperpigmen
tation ulcerations and brownish red patches with linear s
sures ( ig. ).
Fig. 4-15 Complex regional pain syndrome.
The intensity o the pain in CRPS patients aries rom tri ial
burning to a state o torture accompanied by e treme hyper
esthesia and re uently hyperhidrosis. ot only is the part
sub ect to an intense burning sensation but a touch o the
nger also causes e uisite pain. posure to the air is a oided
Cutaneous Dysesthesia Syndromes
with scrupulous care and the patient wal s care ully carrying
the limb tenderly with the sound hand. Patients are tremulous
and apprehensi e and they eep the hand constantly wet
nding relie in the moisture rather than in the temperature o
the application. A condition resembling permanent chilblains
or e en trophic ulcers may be present.
The syndrome usually begins with se ere locali ed burning
pain. ocal edema muscle spasm sti ness or restricted mobil
ity and asospasm a ecting s in color and temperature.
These may be ollowed by a di usion o the pain and edema
diminished hair growth brittle nails oint thic ening and
onset o muscle atrophy. inally irre ersible trophic changes
intractable pain in ol ing the entire limb e or contractures
mar ed atrophy o the muscles se ere limitation in oint and
limb mobility and se ere osteoporosis result.
ot all patients will ha e all the eatures o CRPS and
an early diagnosis impro es the chance o cure. The our
ma or components are categori ed as sensory asomotor
sudomotor edema and motor trophic. Signs pertaining to at
least two o these categories and symptoms relating to three
are necessary to meet the Budapest diagnostic criteria. A three
phase technetium bone scan is help ul in con rming the diag
nosis o CRPS.
Consultation with a neurologist or an anesthesiologist spe
ciali ing in pain is ad isable. steoporosis is a re uent com
plication and studies using pamidronate a power ul inhibitor
o bone absorption ha e been shown to impro e symptoms
o pain tenderness and swelling signi cantly. Pain relie
physical and ocational rehabilitation and psychological
inter ention are pillars o an integrated interdisciplinary
approach to patient care. These patients their amilies and
caregi ers re uire ongoing support education and counseling.
Drummond PD, et al: Sensory disturbances in complex regional pain
syndrome. Pain Med 2010; 22:1257–1266.
Goebel A: Complex regional pain syndrome in adults. Rheumatology
2011; 50:1739–1750.
Marinus J, et al: Clinical features and pathophysiology of complex
regional pain syndrome. Lancet Neurol 2011; 10:637–648.
Slobodin G, et al: Pamidronate treatment in rheumatology practice. Clin
Rheumatol 2009, 28:1359–1364.
Tran DQH, et al: Treatment of complex regional pain syndrome. Can J
Anesth 2010; 57:149–166.
Turner-Stokes L, et al: Complex regional pain syndrome in adults. Clin
Med 2011; 11:596–600.
Wasner G: Vasomotor disturbances in complex regional pain syndrome.
Pain Med 2010; 11:1267–1273.
Wertli M et al: Prognostic factors in complex regional pain syndrome.
J Rehabil Med 2013; 45:225–231.
Trigeminal trophic syndrome
nterruption o the peripheral or central sensory pathways o
the trigeminal ner e may result in a slowly enlarging unilat
eral unin amed ulcer on ala nasi or ad acent chee s in ( ig.
). The nasal tip is spared. t may in re uently occur else
where on the ace scalp ear or palate. The nec has been
reported to be a ected in the so called cer ical trophic syn
drome secondary to herpes oster associated ner e in ury.
nset o ulceration aries rom wee s to se eral years a ter
ner e in ury. Biopsy to e clude tumor or a ariety o granulo
matous or in ectious etiologies is usually indicated. The cause
is sel in icted trauma to the anesthetic s in; the appropriate
treatment is to pre ent this by occlusion or with psychotropic
59
 Fig. 4-16 Trigeminal becomes so t moist and malodorous and later e udes a thin
4 trophic syndrome. purulent discharge. A slough slowly de elops and an indo
lent necrotic ulcer is le t that lasts inde nitely. Whereas the
neuropathy renders the ulceration painless and wal ing con
tinues plantar ulcers in this condition ha e a surrounding
Pruritus and Neurocutaneous Dermatoses

thic callus. Deeper per oration and secondary in ection o ten

lead to osteomyelitis o the metatarsal or tarsal bones.
Treatment consists o relie o pressure on the ulcer through
use o a total contact cast and debridement o the surrounding
callosity. Remo able o loading de ices were ound to be sig
ni cantly less e ecti e in a systematic re iew and meta
analysis. Administration o local and systemic antibiotics is
sometimes help ul.
Morona JK, et al: Comparison of the clinical effectiveness of
different off-loading devices for the treatment of neuropathic
foot ulcers in patients with diabetes. Diabetes Metab Res Rev
2013; 29:183–193.

Fig. 4-17 Mal

perforans ulcer.

G
Sciatic nerve injury

R
Serious sciatic ner e in ury can result rom improperly per
ormed in ections into the buttoc s. lder patients are more

V
susceptible to in ection induced sciatic ner e in ury because o
their decreased muscle mass or the presence o debilitating

d
disease. The most common scenario or ner e damage is
improper needle placement. ther common causes o sciatic

ti e
neuropathy are hip surgery complications hip racture and
dislocation and compression by benign and malignant tumors.
A paralytic ootdrop is the most common nding. There is
sensory loss and absence o sweating o er the distribution o

n
the sciatic ner e branches. The s in o the a ected e tremity
becomes thin shiny and o ten edematous.

U
Surgical e ploration guided by ner e action potentials with
repair o the sciatic ner e is worthwhile and is most success ul

-
i done soon a ter in ury.
Topuz K, et al: Early surgical treatment protocol for sciatic nerve injury
due to injection: a retrospective study. Br J Neurosurg 2011;

9
25:509–515.

ri 9 Syringomyelia

h
Syringomyelia results rom cystic ca ities inside the cer ical
spinal cord caused by alterations o cerebrospinal uid ow.

t a
medication which is usually success ul. Scarring may be
se ere.
Collyer S, et al: Trigeminal trophic syndrome. Pract Neurol 2012;
12:341–342.
Franklin J, et al: Cervical neuropathic ulceration. J Otolaryngol Head
Neck Surg 2012; 41:E20–E22.
Samarin FM, et al: Cervical trophic syndrome. J Am Acad Dermatol
2010; 63:724–725.
Mal perforans pedis
Also nown as neuropathic ulceration or per orating ulcer o
the oot mal per orans is a chronic ulcerati e disease seen on
the sole in conditions that result in loss o pain sensation at a
site o constant trauma ( ig. ). The primary cause lies in
the posterolateral tracts o the cord (in arteriosclerosis and
tabes dorsalis) lateral tracts (in syringomyelia) or peripheral
ner es (in diabetes or ansen s disease).
n most patients mal per orans begins as a circumscribed
hyper eratosis usually on the ball o the oot. This lesion
60
Compression o the lateral spinal tracts produces sensory and
trophic changes on the upper e tremities particularly in the
ngers. The disease begins insidiously and gradually causes
muscular wea ness hyperhidrosis and sensory disturbances
especially in the thumb and inde and middle ngers. The s in
changes are characteri ed by dissociated anesthesia with loss
o pain and temperature sense but retention o tactile sense.
Burns are the most re uent lesions noted. Bullae warts and
trophic ulcerations occur on the ngers and hands and e en
tually contractures and gangrene occur. ther unusual ea
tures include hypertrophy o the limbs hands or eet and
asymmetric scalp hair growth with a sharp midline demarca
tion. The disease must be di erentiated chie y rom ansen s
disease. nli e ansen s disease syringomyelia does not
inter ere with sweating or bloc the are around a histamine
wheal.
arly surgical treatment allows or impro ement o symp
toms and pre ents progression o neurologic de cits.
Stienen MN, et al: Adult syringomyelia. Praxis (Bern 1994) 2011;
100:715–725.
Hereditary sensory and autonomic neuropathies Bonus images for this chapter can be found online at
A number o inherited conditions are characteri ed by ari expertconsult.inkling.com
able degrees o motor and sensory dys unctions combined eFig. 4-1 Eczema craquelé.
with autonomic alterations. rom a dermatologic standpoint

Cutaneous Dysesthesia Syndromes

eFig. 4-2 Lichen sclerosis in patient with vitiligo.
altered pain and temperature sensation trophic changes
eFig. 4-3 Lichen simplex chronicus.
sweating abnormalities ulcers o the hands and eet and in
eFig. 4-4 Prurigo nodularis. (Courtesy of Lawrence Lieblich, MD.)
some patients sel mutilating beha ior may be present. These
eFig. 4-5 Samples brought in by patient with delusions of parasitosis.
e syndromes and their ariants are now nown to be sec
eFig. 4-6 Factitial ulcer.
ondary to disease producing mutations in genes.
eFig. 4-7 Complex regional pain syndrome.
Rotthier A, et al: Mechanisms of disease in hereditary sensory and
eFig. 4-8 Diabetic foot ulcer.
autonomic neuropathies. Nat Rev Neurol 2012; 8:73–85.

61
 eFig. 4-1 Eczema eFig. 4-4 Prurigo
craquelé. nodularis. (Courtesy
of Lawrence Lieblich,
MD.)

Cutaneous Dysesthesia Syndromes

R G
d V
ti e
U n
-
9
ri 9
a h
t
eFig. 4-2 Lichen sclerosis in patient with vitiligo.

eFig. 4-5 Samples brought in by patient with delusions of

parasitosis.

eFig. 4-3 Lichen simplex chronicus.

61.e1
4
Pruritus and Neurocutaneous Dermatoses

eFig. 4-6 Factitial ulcer.

eFig. 4-7 Complex eFig. 4-8 Diabetic foot ulcer.

regional pain
syndrome.

61.e2
 Bonus images for this chapter can be found online at
expertconsult.inkling.com
5 Atopic Dermatitis, Eczema, and Noninfectious
Immunodeficiency Disorders
ATOPIC DERMATITIS
Atopic dermatitis (AD) is a chronic in ammatory s in disease
characteri ed by pruritus and a chronic course o e acerba
tions and remissions. t is associated with other allergic
conditions including ood allergies asthma and allergic rhi
nocon uncti itis. Because AD precedes the appearance o these
other atopic conditions it has been proposed that AD is
the rst step in an atopic march. Although this se uence o
atopic conditions does occur in many children whether the
AD is causal in the de elopment o the other mani estations
o atopy is unpro ed but plausible. or this reason early and
e ecti e treatment o AD is encouraged in an e ort to pre ent
other atopic conditions. The genetic de ect(s) predisposing
at ris indi iduals to the de elopment o AD is the same or
asthma and allergic rhinocon uncti itis and thus it has been
di cult to pro e that AD is causal in the de elopment o other
atopic conditions.
Epidemiology
The pre alence o AD asthma and allergic rhinocon uncti itis
increased dramatically in the last hal o the th century
becoming a ma or health problem in many countries. The
increase began rst in the most de eloped nations and as the
standard o li ing has increased worldwide so has the pre a
lence o AD. Rates o AD are about in the most de eloped
nations and e ceed in many countries resulting in a
worldwide cumulati e pre alence o . n the most de el
oped nations the rates o AD plateaued in the s whereas
de eloping nations ha e rates that continue to increase. ther
actors associated with high rates o AD are high latitude
(perhaps associated with low le els o annual sun e posure)
and lower mean annual temperature. A role or e posure to
allergens thought to trigger AD is not supported by epide
miologic studies. celand has a ery high rate o AD ( ) yet
has no dust mites ew trees and low pet ownership. owe er
children in celand o ten ha e positi e s in pric tests to en i
ronmental allergens ( ). This uestions the alue o such
tests in predicting causal en ironmental allergens in AD. Girls
are slightly more li ely to de elop AD. n the nited States
an increased ris o AD during the rst months o li e is
noted in in ants with A rican and Asian race ethnicity male
gender greater gestational age at birth and a amily history
o atopy particularly a maternal history o ec ema. ther
actors that increase the ris or the de elopment o AD early
in childhood include consumption o a Western diet birth
order ( rst children at greater ris ) and deli ery by cesarean
section all o which alter the intestinal microbiome. Speci
cally gut coloni ation with Clostri ium cluster is associated
with de elopment o AD. Dog ownership be ore age year
decreases the ris o de eloping AD by age but cat owner
ship has no e ect.
62
About o cases o AD appear in the rst year o li e the
ast ma ority within the rst years o li e and the remaining
cases o adult AD usually be ore age . Atopy is now so
common in the population that most indi iduals ha e a amily
history o atopy. le ated g le els are not diagnostic o
atopic disease in the adult. There ore ele ated g and a
amily history o atopy in an adult with new onset derma
titis should not be used to con rm the diagnosis o adult AD.
Rather a dermatologist should in re uently ma e the diagno
sis o adult atopic dermatitis or a dermatitis appearing or
the rst time a ter age . Adult AD should only be considered
when the dermatitis has a characteristic distribution and when
other signi cant diagnoses such as allergic contact dermatitis
photodermatitis and cutaneous T cell lymphoma ha e been
e cluded.
Genetic basis and pathogenesis
ighty percent o identical twins show concordance or AD. A
child is at increased ris o de eloping AD i either parent is
a ected. ore than one uarter o o spring o atopic mothers
de elop AD in the rst months o li e. one parent is atopic
more than hal the children will de elop allergic symptoms by
age . This rate rises to i both parents are atopic. All these
ndings strongly suggested a genetic cause or AD. ilaggrin
is a protein encoded by the gene L which resides in the
epidermal di erentiation comple ( DC) on chromosome
. chthyosis ulgaris is caused by mutations in the L
gene and is re uently associated with AD. our L muta
tions (R del S and R ) ha e an esti
mated combined allelic re uency o in indi iduals o
uropean descent. Di erent L gene mutations are associ
ated with AD in Asians. ilaggrin ( L ) also in the
DC and with similar unction to L is associated with per
sistent AD in A rican Americans (but not with asthma ood
allergies or seasonal allergies). n persons o uropean descent
inheriting one null L mutation slightly increases one s ris
o de eloping AD and inheriting two mutations either as
a homo ygote or a compound hetero ygote dramatically
increases one s ris . Between and o persons with one
or more L null mutations will de elop AD. L mutations
account or o AD cases in urope. owe er o
carriers with L null mutations ne er ha e AD. L muta
tions are associated with AD that presents early in li e tends
to persist into childhood and adulthood and is associated with
whee ing in in ancy and with asthma. L mutations are also
associated with allergic rhinitis and eratosis pilaris indepen
dent o AD. yperlinear palms are strongly associated with
L mutations with a positi e predicti e alue (PPV) or
mar ed palmar hyperlinearity. L M gene mutations encod
ing the alpha chain o laminin may also predispose to AD.
ot all cases o AD are associated with L mutations.
AD patients o ten demonstrate immunologic eatures
consistent with a T helper (Th ) phenotype with ele ated
g eosinophils on s in biopsy and positi e s in tests and
radioallergosorbent test (RAST). Thymic stromal lymphopoi
etin (TSLP) is an important interleu in ( L ) li e cyto ine
that through its interaction with mast cells and dendritic cells
promotes the secretion and production o Th cyto ines and
the de elopment o in ammatory Th CD + T cells (through
production o L L). TSLP is produced by eratinocytes and
is ound in high le els in AD s in lesions. Th innate lymphoid
cells are also increased in AD s in as are Th cells. n addi
tion L is produced by Th and Th cells is associated
with itching and downregulates eratinocyte e pression o
laggrin. Thus AD appears to represent a disorder character
i ed by a barrier de ect that engages the production o a spe
ci c Th immunophenotype through speci c cell types and
e ected by speci c cyto ines. The cyto ines produced worsen
the already de ecti e barrier. This leads to a icious cycle o
barrier ailure and progressi e in ammation producing a
chronic relapsing pruritic disorder.
Prevention in high-risk children
tensi e studies ha e been underta en to determine whether
it is possible to pre ent the de elopment o AD in children at
high ris those with parents or siblings with atopy. Soy or
mulas do not appear to reduce the ris o de eloping AD.
Prolonged e clusi e breast eeding beyond months o age
is not protecti e or the de elopment o AD. tensi ely
hydroly ed casein ormulas may be used as a supplement or
substitute or breast mil during the rst months o li e.
aternal allergen a oidance during pregnancy does not
reduce the ris o AD in the o spring. The use o probiotics
and prebiotics is not currently recommended although some
studies suggest these may be e ecti e in reducing AD. ouse
dust mite ( D ) a oidance does not reduce AD e en in
sensiti ed indi iduals and high le els o D in the en iron
ment in early li e reduces AD ris . Aggressi e emollient
therapy early in li e is recommended to repair any genetic or
ac uired epidermal barrier de ect.
Food allergy
The role o ood allergy in AD is complicated and the pur
ported role o oods in AD has changed in recent years. Parents
may be misin ormed about ood allergy by outdated nternet
resources. Appro imately o children with moderate to
se ere AD ha e ood allergy. owe er o children with
AD will ha e ele ated g to ood or inhalant allergens
ma ing a diagnosis o ood allergy with serum or pric tests
alone inad isable. Be ore ood allergy testing is underta en
treatment o the AD should be optimi ed. Parents are o ten
see ing a cause or the child s AD when in act it could be
controlled with appropriate topical measures. ood restriction
diets can be di cult and could put the child at ris or mal
nourishment and thus ood allergy should be pursued only
in children under age years with more se ere AD in whom
standard treatments ha e ailed. These children should also
ha e a history o possible triggering o AD by speci c ood
e posures. Testing i per ormed should only include oods to
which the child is li ely to be e posed. Double blind placebo
controlled ood challenges are the gold standard or diag
nosing ood allergy. S in pric tests ha e a high negati e
predicti e alue ( PV > ) but PPV o only . or
e ample more than o the .S. population has a positi e
pric test to peanut but only . are actually clinically aller
gic. Possible ood allergy detected by testing should be con
rmed by clinical history. A positi e RAST or s in pric test
or a ood that the child rarely or ne er ingests is probably not
causally rele ant to their AD. igher serum g le els and
larger wheal si es (> mm) are associated with greater li e
lihood o reacting to these oods when challenged. About
o ood allergy is caused by a limited number o oods as
ollows
Atopic dermatitis
n ants cow s mil egg soybean wheat
Children ( years) cow s mil egg peanut tree nuts
sh crustacean shell sh sesame iwi ruit
lder children peanut tree nuts sh shell sh sesame
pollen associated oods
Breast eeding mothers must a oid the incriminated oods i
their in ant has been diagnosed with a ood allergy.
Clinical manifestations
Atopic dermatitis can be di ided into three stages in antile
AD occurring rom months to years o age; childhood AD
rom years; and adolescent adult AD. n all stages pru
ritus is the hallmar . tching o ten precedes the appearance o
lesions; thus the concept that AD is the itch that rashes.
se ul diagnostic criteria include those o anni n and Ra a
the Wor ing Party and the American Academy o Derma
tology s Consensus Con erence on Pediatric Atopic Dermatitis
(Bo es and ). These criteria ha e speci city at or abo e
but ha e much lower sensiti ities ( ). There ore
these criteria are use ul or enrolling patients in studies and
ensuring that they ha e AD but not so use ul in diagnosing a
speci c patient with AD.
Infantile atopic dermatitis
i ty percent or more o AD cases present in the rst year o
li e but usually not until a ter months. c ema in in ancy
usually begins as erythema and scaling o the chee s ( ig. ).
The eruption may e tend to the scalp nec orehead wrists
e tensor e tremities and buttoc s. Children with AD who are
L gene mutants speci cally ha e more chee and e tensor
arm hand in ol ement. There may be signi cant e udate;
secondary e ects rom scratching rubbing and in ection
include crusts in ltration and pustules respecti ely. The
in ltrated pla ues e entually ta e on a characteristic licheni
ed appearance. The in antile pattern o AD usually disap
pears by the end o the second year o li e.
Fig. 5-1 Involvement of
the cheeks in infantile
atopic dermatitis.
63
5 Box 5-1 Criteria for atopic dermatitis Box 5-2 Modified criteria for children with atopic dermatitis

Major criteria Essential features

Must have three of the following: 1. Pruritus
Atopic Dermatitis, Eczema, and Noninfectious Immunodeficiency Disorders

1. Pruritus 2. Eczema
2. Typical morphology and distribution • Typical morphology and age-specific pattern
• Flexural lichenification in adults • Chronic or relapsing history
• Facial and extensor involvement in infancy
Important features
3. Chronic or chronically relapsing dermatitis
4. Personal or family history of atopic disease (e.g., asthma, 1. Early age at onset
allergic rhinitis, atopic dermatitis) 2. Atopy
3. Personal and/or family history
Minor criteria
4. IgE reactivity
Must also have three of the following:
5. Xerosis
1. Xerosis
2. Ichthyosis/hyperlinear palms/keratosis pilaris Associated features
3. IgE reactivity (immediate skin test reactivity, RAST test 1. Atypical vascular responses (e.g., facial pallor, white
positive) dermatographism)
4. Elevated serum IgE 2. Keratosis pilaris/ichthyosis/hyperlinear palms
5. Early age of onset 3. Orbital/periorbital changes
6. Tendency for cutaneous infections (especially 4. Other regional findings (e.g., perioral changes/periauricular
Staphylococcus aureus and HSV) lesions)
7. Tendency to nonspecific hand/foot dermatitis 5. Perifollicular accentuation/lichenification/prurigo lesions
8. Nipple eczema
9. Cheilitis
10. Recurrent conjunctivitis
11. Dennie-Morgan infraorbital fold
12. Keratoconus
13. Anterior subcapsular cataracts
14. Orbital darkening
15. Facial pallor/facial erythema
16. Pityriasis alba
17. Itch when sweating
18. Intolerance to wool and lipid solvents
19. Perifollicular accentuation
20. Food hypersensitivity
21. Course influenced by environmental and/or emotional factors
22. White dermatographism or delayed blanch to cholinergic
agents

RAST, Radioallergosorbent assay; HSV, herpes simplex virus.

Worsening o AD is o ten obser ed in in ants a ter immuni

ations and iral in ections. Partial remission may occur
during the summer with relapse in winter. This may relate to
the therapeutic e ects o ultra iolet ( V) B light and humidity
in many atopic patients as well as the aggra ation by wool
Fig. 5-2 Flexural involvement in childhood atopic dermatitis.
and dry air in the winter.

Childhood atopic dermatitis
During childhood lesions tend to be less e udati e. The classic
locations are the antecubital and popliteal ossae ( ig.
e or wrists eyelids ace and around the nec . Lesions are
o ten licheni ed indurated pla ues and in A rican American
patients may ha e a lichenoid appearance and a or the e ten
sor sur aces. These are intermingled with isolated e coriated
mm papules that are scattered more widely o er the
unco ered parts. ummular morphology and in ol ement o
the eet are more common in childhood AD.
Pruritus is a constant eature and most o the cutaneous
changes are secondary to it. tching is paro ysmal. Scratching
induces licheni cation and may lead to secondary in ection. A
icious cycle may be established the itch scratch cycle as
pruritus leads to scratching and scratching causes secondary
64
changes that in themsel es cause itching. nstead o scratching
causing pain in the atopic patient the pain induced by
scratching is percei ed as itch and induces more scratching.
) The scratching impulse is beyond the control o the patient.
Se ere bouts o scratching occur during sleep leading to poor
rest and chronic tiredness in atopic children. This can a ect
school per ormance.
Se ere AD in ol ing a large percentage o the body sur ace
area can be associated with growth retardation ( ig. ).
Restriction diets and steroid use may e acerbate growth
impairment. Aggressi e management o such children with
phototherapy or systemic immunosuppressi e agents may
allow or rebound growth. Children with se ere AD may
also ha e substantial psychological disturbances. Parents
should be uestioned with regard to school per ormance and
sociali ation.

Fig. 5-3 Severe, widespread atopic dermatitis.
Fig. 5-4 Prurigolike papules in adult atopic dermatitis.
Atopic dermatitis in adolescents and adults
ost adolescents and adults with AD will gi e a history o
childhood disease. AD will begin a ter age years in only
o patients diagnosed with AD. ne e ception is the
patient who mo es rom a humid tropical region to a more
temperate area o higher latitude. This climatic change is o ten
associated with the appearance o AD. n older patients AD
may occur as locali ed erythematous scaly papular e uda
ti e or licheni ed pla ues. n adolescents the eruption o ten
in ol es the classic antecubital and popliteal ossae ront and
sides o the nec orehead and area around the eyes. n older
adults the distribution is generally less characteristic and
locali ed dermatitis may be the predominant eature espe
cially hand nipple or eyelid ec ema. At times the eruption
may generali e with accentuation in the e ures. The s in
generally is dry and somewhat erythematous. Licheni cation
and prurigoli e papules are common ( ig. ). Papular lesions
tend to be dry slightly ele ated and at topped. They are
almost always e coriated and o ten coalesce to orm pla ues.
Staphylococcal coloni ation is almost uni ersal. n dar er
s inned patients the lesions are o ten dramatically hyperpig
mented re uently with ocal hypopigmented areas related to
healed e coriations.
Atopic dermatitis
Fig. 5-5 Atopic hand dermatitis.
tching usually occurs in crises or paro ysms o ten during
the e ening when the patient is trying to rela or during the
night. Adults re uently complain that ares o AD are trig
gered by acute emotional upsets. Stress an iety and depres
sion reduce the threshold at which itch is percei ed and result
in damage to the epidermal permeability barrier urther e ac
erbating AD. Atopic persons may sweat poorly and may com
plain o se ere pruritus related to heat or e ercise. Physical
conditioning and liberal use o emollients impro e this com
ponent and atopic patients can participate in competiti e
sports.
en in patients with AD in adolescence or early adulthood
impro ement usually occurs o er time and dermatitis is
uncommon a ter middle li e. n general these patients retain
mild stigmata o the disease such as dry s in easy s in irrita
tion and itching in response to heat and perspiration. They
remain susceptible to a are o their disease when e posed
to the speci c allergen or en ironmental situation. Some
will are in response to aeroallergens and a ew patients
will de elop e ural dermatitis in response to niacin induced
ushing. Photosensiti ity de elops in appro imately o
AD patients and may mani est as either a polymorphous light
eruption type reaction or simply e acerbation o the AD by
V e posure. ost patients ( ) are sensiti e to VA and
VB light but about are sensiti e to only VA or VB.
The a erage age or photosensiti e AD is the middle to late
thirties. uman immunode ciency irus ( V) in ection can
also ser e as a trigger and new onset AD in an at ris adult
should lead to counseling and testing or V i warranted.
The hands including the wrists are re uently in ol ed in
adults and hand dermatitis is a common problem or adults
with a history o AD. t is e tremely common or atopic hand
dermatitis to appear in young women a ter the birth o a child
when increased e posure to soaps and water triggers their
disease. Wet wor is a ma or actor in hand ec ema in general
including those patients with AD. Atopic hand dermatitis can
a ect both the dorsal and the palmar sur ace ( ig. ). era
tosis punctata o the creases a disorder seen almost e clu
si ely in blac persons is also more common in atopic patients.
Patients with AD ha e re uent e posure to preser ati es and
other potential allergens in the creams and lotions that are
continually applied to their s in. Contact allergy may mani est
as chronic hand ec ema. Patch testing with clinical correlation
is the only certain way to e clude contact allergy in an atopic
patient with chronic hand dermatitis.
yelids are o ten in ol ed ( ig. ). n general the in ol e
ment is bilateral and the condition ares with cold weather.
As in hand dermatitis irritants and allergic contact allergens
must be e cluded by a care ul history and patch testing.
65

5 ance are also common in AD patients.
Atopic Dermatitis, Eczema, and Noninfectious Immunodeficiency Disorders
Fig. 5-6 Periocular atopic dermatitis.
Associated features and complications
Cutaneous stigmata
A linear trans erse old ust below the edge o the lower
eyelids nown as the Dennie organ old is widely belie ed
to be indicati e o the atopic diathesis although it may be seen
with any chronic dermatitis o the lower lids. n atopic patients
with eyelid dermatitis increased olds and dar ening under
the eyes is common. When ta en together with other clinical
ndings these remain help ul clinical signs. A prominent
nasal crease may also be noted.
The less in ol ed s in o atopic patients is re uently dry
and slightly erythematous and may be scaly. istologically
the apparently normal s in o atopic patients is re uently
in amed subclinically. The dry scaling s in o AD may rep
resent low grade dermatitis. ilaggrin is processed by caspase
during terminal eratinocyte di erentiation into highly
hydroscopic pyrrolidone carbo ylic acid and urocanic acid
collecti ely nown as the natural moisturi ing actor ( ).
ull mutations in L lead to reduction in which prob
ably contributes to the erosis that is almost uni ersal in AD.
Transepidermal water loss (T WL) is increased. This may be
caused by subclinical dermatitis but also by abnormal deli
ery o lamellar body epidermal lipids (especially ceramide) to
the interstices o the terminally di erentiated eratinocytes.
The resulting de ecti e lipid bilayers retain water poorly
leading to increased T WL and clinical erosis. Pityriasis alba
is a orm o subclinical dermatitis re uently atopic in origin.
t presents as poorly marginated hypopigmented slightly
scaly patches on the chee s upper arms and trun typically
in children and young adults. t usually responds to emollients
and mild topical steroids pre erably in an ointment base.
eratosis pilaris ( P) consists o horny ollicular lesions o
the outer aspects o the upper arms legs chee s and buttoc s
and is o ten associated with AD. The eratotic papules on the
ace may be on a red bac ground a ariant o P called era
tosis pilaris rubra aceii. P is o ten re ractory to treatment.
oisturi ers alone are only partially bene cial. Some patients
will respond to topical lactic acid urea or retinoids. Retinoids
can easily irritate the s in o atopic patients and treatment
should begin with applications only once or twice a wee . P
must be distinguished rom ollicular ec ema because AD and
other ec emas are typically olliculocentric especially in blac
patients.
Thinning o the lateral eyebrows ( ertoghe s sign) is some
times present. This apparently occurs rom chronic rubbing
caused by pruritus and subclinical dermatitis. yper eratosis
66
and hyperpigmentation which produce a dirty nec appear
Vascular stigmata
Atopic indi iduals o ten e hibit perioral perinasal and peri
orbital pallor ( headlight sign ). White dermatographism is
blanching o the s in at the site o stro ing with a blunt instru
ment. This reaction di ers rom the triple response o Lewis
in that it typically lac s a wheal and the third response
( aring) is replaced by blanching to produce a white line.
Atopic patients are at increased ris o de eloping arious
orms o urticaria including contact urticaria. pisodes o
contact urticaria may be ollowed by typical ec ematous
lesions at the a ected site.
Ophthalmologic abnormalities
p to o patients with AD de elop cataracts either ante
rior or posterior subcapsular. Posterior subcapsular cataracts
in atopic indi iduals are indistinguishable rom corticosteroid
induced cataracts. De elopment o cataracts is more common
in patients with se ere dermatitis. eratoconus is an uncom
mon nding occurring in appro imately o atopic patients.
Contact lenses eratoplasty and intraocular lenses may be
re uired to treat this condition.
Susceptibility to infection
ore than o chronic ec ematous lesions contain Staph
lococcus aureus o ten in large numbers. n addition the
apparently normal nonlesional s in o atopic patients is also
re uently coloni ed by S aureus. The nding o increasing
numbers o pathogenic staphylococci on the s in o a patient
with AD is re uently associated with weeping and crusting
o s in lesions retro and in ra auricular and perinasal s
sures olliculitis and adenopathy. n any aring atopic patient
the possibility o secondary in ection must be considered. g
antibodies directed against Staph lococcus and its to ins ha e
been documented in some atopic indi iduals. Staphylococcal
production o superantigens is another possible mechanism
or staphylococcal ares o disease. Treatment o lesions o AD
with topical steroids is associated with reduced numbers o
pathogenic bacteria on the sur ace e en i antibiotics are not
used. Despite the re uent obser ation that the presence o
staphylococcal in ection o lesions o AD is associated with
worsening o disease it has been impossible to pro e that oral
antibiotic therapy ma es a long term di erence in the course
o the AD. onetheless treatment o the in ected AD patient
with oral antibiotics is a community standard o dermatolo
gists worldwide.
With the widespread presence o antibiotic resistant S
aureus dermatologists ha e shi ted rom the chronic use o
oral antibiotics in managing patients with re uent ares o
AD associated with staphylococcal in ection. Rather bleach
baths and reduction o nasal carriage ha e become the basis
or controlling in ection triggered AD. n an occasional patient
with AD and re uent in ections chronic suppressi e oral
antibiotic therapy may stabili e the disease. ptions include
cephalosporins trimethoprim sul ametho a ole (T P S )
clindamycin and (in older patients) do ycycline. denti ying
and treating S aureus carriers in the amily and pets may also
be o bene t. An unusual complication o S aureus in ection
in patients with AD is subungual in ection with osteomyelitis
o the distal phalan . n atopic patients with e er who appear
ery to ic the possibility o streptococcal in ection must be
considered. These children may re uire hospital admission
and intra enous antibiotics.
 Fig. 5-7 Recurrent
herpes simplex in
atopic dermatitis.
Patients with AD ha e increased susceptibility to general
i ed herpes simple in ection (ec ema herpeticum) as well as
widespread accinia in ection (ec ema accinatum) and com
plicated aricella. c ema herpeticum is seen most re uently
in young children and is usually associated with herpes simple
irus ( SV) type transmitted rom a parent or sibling. nce
in ected the atopic may ha e recurrences o SV and repeated
episodes o ec ema herpeticum. c ema herpeticum presents
as the sudden appearance o esicular pustular crusted or
eroded lesions concentrated in the areas o dermatitis ( ig. ).
The lesions may continue to spread and most o the s in
sur ace may become in ol ed. Secondary staphylococcal in ec
tion is common and local edema and regional adenopathy
re uently occur. lesions o ec ema herpeticum occur on
or around the eyelids ophthalmologic e aluation is recom
mended. The se erity o ec ema herpeticum is uite ariable
but most cases re uire systemic anti iral therapy and an anti
staphylococcal antibiotic. Delayed administration o acyclo ir
in hospitali ed patients is associated with prolonged hospital
stay. Genetic ariants in TSLP and inter eron regulatory actor
( R ) are associated with AD and ec ema herpeticum.
Vaccination against smallpo is contraindicated in persons
with AD e en when the dermatitis is in remission. Wide
spread and e en atal accinia can occur in patients with an
atopic diathesis.
Atopic indi iduals may also de elop e tensi e at warts or
molluscum contagiosum. Because the s in is easily irritated
chemical treatments such as salicylic acid and cantharidin are
poorly tolerated. Destruction with curettage ( or molluscum)
cryosurgery or electrosurgery may be re uired to clear the
lesions.
Differential diagnosis
Typical AD in in ancy and childhood is not di cult to diag
nose because o its characteristic morphology; predilection or
symmetric in ol ement o the ace nec and antecubital and
popliteal ossae; and association with ood allergy asthma
and allergic rhinocon uncti itis. Dermatoses that may resem
ble AD include seborrheic dermatitis (especially in in ants)
irritant or allergic contact dermatitis nummular dermatitis
photodermatitis scabies and cases o psoriasis with an ec em
Atopic dermatitis
atous morphology. Certain immunode ciency syndromes (see
later discussion) may e hibit a dermatitis remar ably similar
or identical to AD.
Histopathology
The histology o AD aries with the stage o the lesion
with many o the changes induced by scratching. yper era
tosis acanthosis and e coriation are common. Staphylococcal
coloni ation may be noted histologically. Although eosino
phils may not be seen in the dermal in ltrate staining or
eosinophil ma or basic protein ( BP) re eals deposition in
many cases.
General management
Education and support
Parental and patient education is o critical importance in
the management o AD. n the busy clinic setting derma
tologists re uently ha e insu cient time to educate patients
ade uately regarding the multiple actors that are important
in managing AD. ducational ormats that ha e pro ed
e ecti e ha e been immediate nursing education on the
correct use o medications wee ly e ening educational ses
sions and multidisciplinary day treatment enues. n all
cases written action plans outlining a stepwise approach
ha e been important or parent patient education. n addi
tion patients with chronic disease o ten become disen
chanted with medical therapies or simply burn out rom
ha ing to spend signi cant amounts o time managing their
s in disease. The psychological support that can be incorpo
rated into educational sessions can help moti ate parents
patients and eep them engaged in the treatment plan.
a ing a child with AD is e tremely stress ul and generates
signi cant stress within the amily. Sleep is lost by both the
patient and the parents. Supporti e educational techni ues
can help the amily cope with this burden. n addition the
dermatologist must consider the comple ity and time com
mitment o any prescribed regimen and ensure that the
parents patient understand and are committed to underta
ing the treatments proposed.
Barrier repair
Virtually all patients with AD ha e erosis and an impaired
epidermal barrier. The cornerstone o treatment and pre
ention o AD lies in addressing this problem. Patients
should moisturi e daily especially a ter bathing. This may be
with petrolatum or a petrolatum based product an oil based
product egetable shortening or a barrier repair moistur
i er that contains the essential lipids o the epidermal barrier.
These special barrier repair moisturi ers ha e similar bene ts
in AD to low potency topical steroids. They are easier to
apply and i a ailable to the patient may enhance compli
ance. Petrolatum and petrolatum based moisturi ers are most
o ten recommended and are the least e pensi e and most
e ecti e or most patients. owe er men with signi cant
body hair AD patients triggered by heat and the rare patient
with true allergic contact dermatitis to petrolatum may be
unable to tolerate petrolatum based agents. Patients should
67
 be instructed on the barrier damaging properties o soaps hot
5 water and scrubbing. Synthetic detergents that ha e a more
acidic p are pre erred to harsh soaps. Detergent use should
be restricted to the a illa groin ace soles and scalp. il
based cleansers can be used to wash the s in without water.
Atopic Dermatitis, Eczema, and Noninfectious Immunodeficiency Disorders
or ares o AD the soa and smear techni ue (soa in tub
then seal in water with a hea y moisturi er or medicated
ointments) or wet dressings (wet wraps) with topical steroids
can be ery e ecti e. n dry climates AD patients may note
some bene t with humidi ers. α ydro y acid containing
products (lactic acid glycolic acid) can be irritating and can
e acerbate in amed AD. These products should only be used
or the erosis o AD when there is absolutely no in amma
tion or pruritus.
Antimicrobial therapy
When the AD patient has e idence o in ection treatment with
topical or systemic antibiotics may be appropriate. Rather than
treating once an in ection occurs it appears that the ey in AD
is to reduce nasal staphylococcal carriage preempti ely and to
eep the s in decoloni ed rom Staph lococcus. Bleach bathes
ha e rapidly become a mainstay in AD patients. Twice wee ly
bathing in a tepid bath with 1 4 cup o standard household
bleach ( ) diluted in gallons o water dramatically
impro es AD on the trun and e tremities but less so on the
ace. This treatment combines decoloni ation o the s in with
hydration addressing two o the ma or actors in worsening
o AD. Ade uate moisturi ing a ter bathing is critical. ntra
nasal application o mupirocin is bene cial in reducing nasal
carriage. n o amilies at least one parent is carrying the
same staphylococcal strain as a coloni ed AD child. the AD
patient has recurrent in ections other carriers in the amily
and their pets are sought and treated aggressi ely. Recurrent
in ections especially urunculosis are a cardinal eature o
children and adults with AD who ha e systemic immunologic
abnormalities especially hyper g syndrome.
Environmental factors
Stress heat sweating and e ternal irritants may precipitate
an attac o itching and are in the AD patient. Wool garments
should be a oided. Addressing these triggers may impro e
the AD. tch ner es are more acti e at higher temperatures so
o erheating should be a oided. rritants and allergens in the
numerous products that AD patients may use can lead to ares
o AD. Patients should a oid products that contain common
allergens and should be e aluated or allergic contact derma
titis i a topical agent is associated with worsening o their AD.
Antipruritics
The primary treatment or the pruritus o AD is to reduce
the se erity o the AD. Antihistamines are re uently used
or the pruritus o AD but are only bene cial or their seda
ti e properties. prescribed sedating antihistamines are
optimally used nightly (not as needed ). Diphenhydramine
hydro y ine and do epin can all be e cacious. onsedating
antihistamines do not appear to bene t the pruritus o AD in
standard doses. n some patients gabapentin selecti e sero
tonin reupta e inhibitors (SSR s) mirta apine and e en
opiate antagonists may reduce pruritus. Applying ice during
intense bouts o itch may help to brea an itch paro ysm.
oisturi ing lotions containing menthol phenol or pramo
ine can be used between steroid applications to moisturi e
and reduce local areas o se ere itch. ore widespread use o
topical do epin (Sine uan) is limited by systemic absorption
and sedation.
68
Specific treatment modalities
Topical corticosteroid therapy
Topical corticosteroids are the most common class o medica
tions along with moisturi ers used or the treatment o AD.
They are e ecti e and economical. n in ants low potency
steroid ointments such as hydrocortisone or . are
pre erred. Regular application o emollients must be empha
si ed. nce corticosteroid receptors are saturated additional
applications o a steroid preparation contribute nothing more
than an emollient e ect. n most body sites once daily appli
cation o a corticosteroid is almost as e ecti e as more
re uent applications at lower cost and with less systemic
absorption. n some areas twice daily applications may be
bene cial but more re uent applications are almost ne er o
bene t. Steroid phobia is common in parents and patients with
AD. Less re uent applications o lower concentration agents
with emphasis on moisturi ing address these concerns. Appli
cation o topical corticosteroids under wet wraps or inyl
suit occlusion (soa and smear) can increase e ciency. or
re ractory areas a stronger corticosteroid such as desonide
alclometasone or triamcinolone may be used. A more potent
molecule is more appropriate than escalating concentrations
o a wea er molecule because the e ect o the latter plateaus
rapidly as receptors become saturated. Do not undertreat This
leads to loss o aith on the part o the patient parents and
prolongs the su ering o the patient. or se ere disease use
more potent topical steroids in short bursts o a ew days to a
wee to gain control o the disease. n re ractory and relapsing
AD twice wee ly steroid application may reduce ares.
n older children and adults medium potency steroids such
as triamcinolone are o ten used e cept on the ace where
milder steroids or calcineurin inhibitors are pre erred. or
thic pla ues and lichen simple chronicus li e lesions
e tremely potent steroids may be necessary. intments are
more e ecti e because o their moisturi ing properties and
re uire no preser ati es reducing the li elihood o allergic
contact dermatitis. an atopic patient worsens or ails to
impro e a ter the use o topical steroids and moisturi ers the
possibility o allergic contact dermatitis to a preser ati e or
the corticosteroids must be considered. Contact allergy to the
corticosteroid itsel can occur. Corticosteroid allergy seldom
mani ests as acute worsening o the ec ema. nstead it mani
ests as a are o ec ema whene er the corticosteroid is dis
continued e en or a day. This may be di cult to di erentiate
rom stubborn AD.
Although the potential or local and e en systemic to icity
rom corticosteroids is real the steroid must be strong enough
to control the pruritus and remo e the in ammation. en in
small children strong topical steroids may be necessary in
wee ly pulses to control se ere ares. onitoring o growth
parameters should be carried out in in ants and young
children.
Topical calcineurin inhibitors
Topical calcineurin inhibitors (TC s) such as tacrolimus or
pimecrolimus o er an alternati e to topical steroids. Systemic
absorption is generally not signi cant with either o these
agents. Although a . tacrolimus ointment is mar eted or
use in children it is unclear whether it really o ers any sa ety
ad antage o er the . ormulation. Tolerability is impro ed
i the ointment is applied to bone dry s in. Patients e peri
ence less burning i ec ematous patches are treated initially
with a corticosteroid with transition to a TC a ter partial
clearing. mpro ement tends to be steady with progressi ely
smaller areas re uiring treatment. TC s are particularly use ul
on the eyelids and ace in areas prone to steroid atrophy
when steroid allergy is a consideration or when systemic
steroid absorption is a concern. Tacrolimus is more e ecti e
than pimecrolimus with tacrolimus . ointment e ui alent
to triamcinolone acetonide . and pimecrolimus e ui alent
to a class V or V topical corticosteroid.
Tar
Crude coal tar in white petrolatum or hydrophilic
ointment SP or li uor carbonis detergens (LCD) in
hydrophilic ointment SP is sometimes help ul or an area o
re ractory AD. Tar preparations are especially bene cial when
used or intensi e treatment or adults in an inpatient or day
care setting especially in combination with V phototherapy.
Phototherapy
topical modalities ail to control AD phototherapy is the
ne t option on the therapeutic ladder. arrow band ( B) VB
is highly e ecti e and has replaced broadband V or treating
AD. When acutely in amed AD patients may tolerate V
poorly. nitial treatment with a systemic immunosuppressi e
can cool o the s in enough to institute V treatments. Patients
with signi cant erythema must be introduced to V at ery
low doses to a oid nonspeci c irritancy and aring o the AD.
ten the initial dose is much lower and the dose escalation
much slower than in patients with psoriasis. n acute ares o
AD VA can be used. or patients unresponsi e to B VB
photochemotherapy with psoralen plus VA (P VA) can be
e ecti e. t re uires less re uent treatments and can be gi en
either topically (soa bath P VA) or systemically (oral
P VA). Goec erman therapy with tar and VB in a day treat
ment setting will lead to impro ement in more than o considered in re ractory cases but only
patients with re ractory AD and prolonged remission can be
induced.
Systemic therapy
Systemic corticosteroids
n general systemic corticosteroids should be used only to
control acute e acerbations. n patients re uiring systemic
steroid therapy short courses (≤ wee s) are pre erred.
repeated or prolonged courses o systemic corticosteroids are
re uired to control the AD phototherapy or a steroid sparing
agent should be considered. Chronic corticosteroid therapy or
AD re uently results in signi cant steroid induced side
e ects. steoporosis in women re uires special consideration
and should be addressed with a bisphosphonate early in the
course o therapy when bone loss is greatest. Pre enti e strate
gies such as calcium supplements itamin D supplementa
tion bisphosphonates regular e ercise and smo ing cessation
should be strongly encouraged. Dual energy ray absorpti
ometry (D A) scans are recommended.
Cyclosporine
Cyclosporine (cyclosporin A) is highly e ecti e in the treat
ment o se ere AD but the response is rarely sustained a ter
the drug is discontinued. t is ery use ul to gain rapid control
o se ere AD. Cyclosporine has been shown to be sa e and
e ecti e in both children and adults although probably toler
ated better in children. Potential long term side e ects espe
cially renal disease re uire care ul monitoring with attempts
to transition the patient to a potentially less to ic agent i pos
sible. The dose range is mg g in children and mg
in adults with a better and more rapid response at the higher
end o the dose range. Rebound aring o AD is possible and
can be signi cant a ter stopping cyclosporin A and a plan
should be in place or this e entuality.
Atopic dermatitis
Other immunosuppressive agents
Se eral immunosuppressi e agents ha e demonstrated e
cacy in patients with AD. These agents do not appear to be
as e ecti e or uic to wor as cyclosporine. owe er o er
time they may ha e a better sa ety pro le so patients re uir
ing long term immunosuppression may bene t rom one o
these agents. They include a athioprine ( muran) mycophe
nolate mo etil (CellCept) and methotre ate (Rheumatre ).
The dosing o a athioprine is guided by the serum thiopu
rine methyltrans erase le el. ycophenolate mo etil ( )
is generally well tolerated and as with a athioprine ta es
about wee s to begin to reduce the AD. n ortunately the
response o AD patients to is ariable with not
responding. Low dose wee ly methotre ate is well tolerated
and has demonstrated e cacy in AD in children and adults
e ui alent to a athioprine. cyclosporin A is not to be used
the choice o steroid sparing agent is personali ed to the
patient s ris actors and tolerance o the medication.
ydro yurea as used or psoriasis in the past can be e ec
ti e in AD i other steroid sparing agents ail as well as in
the patient with li er disease.
ntra enous immune globulin ( V G) has had some limited
success in managing AD but its high cost precludes it use
e cept when other reasonable therapeutic options ha e been
e hausted. nter eron ( ) γ gi en by daily in ection has
demonstrated e cacy in both children and adults with se ere
AD. The onset o response can be delayed. γ is well toler
ated but can cause uli e symptoms. mali umab can be
o patients achie e
a or greater reduction o their AD. n i imab has not been
bene cial in AD. ste inumab has been e ecti e in a ew
reports since the in ammatory cascade triggering and main
taining AD does in ol e Th cells.
Traditional Chinese herb mi tures ha e shown e cacy in
children and in animal models or AD. The acti e herbs appear
to be ophiopogon tuber and Schisandra ruit. Chinese herbs
are usually deli ered as a brewed tea to be drun daily. Their
bitter taste ma es them unpalatable to most Western patients.
owe er this option should be considered in patients who
might accept this treatment approach.
Management of acute flare
nitially the precipitating cause o the are should be sought.
Recent stress ul e ents may be associated with ares. Second
ary in ection with S aureus should be assumed in most cases.
Less re uently SV or co sac ie irus may be in ol ed. Pity
riasis rosea may also cause AD to are. The de elopment o
contact sensiti ity to an applied medication or photosensiti
ity must be considered.
n the patient with an acute are treating triggers may lead
to impro ement (see earlier discussion). A short course o
systemic corticosteroids may be o bene t but patients should
be counseled that prolonged systemic corticosteroid therapy
must be a oided. ome hospitali ation may be use ul. The
patient goes home to bed isolated rom wor and other
stressors; large doses o a sedating antihistamine are gi en at
bedtime; and the patient soa s in the tub twice daily then
applies a topical steroid ointment under wet pa amas and a
sauna suit (soa and smear). ten days o such intensi e
home therapy will brea a se ere are.
69

5
Agusti-Mejias AM, et al: Severe refractory atopic dermatitis in an
adolescent patient successfully treated with ustekinumab. Ann
Dermatol 2013; 25:3.
Allen HB, et al: Lichenoid and other clinical presentations of atopic
dermatitis in an inner city practice. J Am Acad Dermatol 2008; 58:503.
Atopic Dermatitis, Eczema, and Noninfectious Immunodeficiency Disorders
Andreae DA, Wang J: Immunologic effects of omalizumab in children
with severe refractory atopic dermatitis: a randomized, placebo-
controlled clinical trial. Pediatrics 2014; 134: S160.
Annesi-Maesano I, et al: Time trends in prevalence and severity of
childhood asthma and allergies from 1995 to 2002 in France. Allergy
2009; 64:798.
Aronson AC, et al: Delayed acyclovir and outcomes of children
hospitalized with eczema herpeticum. Pediatrics 2011; 128:6.
Ashcroft DM, et al: Efficacy and tolerability of topical pimecrolimus and
tacrolimus in the treatment of atopic dermatitis: meta-analysis of
randomised controlled trials. BMJ 2005; 330:516.
Boguniewicz M, et al: A multidisciplinary approach to evaluation and
treatment of atopic dermatitis. Semin Cutan Med Surg 2008; 27:115.
Bonness S, et al: Pulsed-field gel electrophoresis of Staphylococcus
aureus isolates from atopic patients revealing presence of similar
strains in isolates from children and their parents. J Clin Microbiol
2008; 46:456.
Brown SJ, et al: Atopic eczema and the filaggrin story. Semin Cutan
Med Surg 2008; 27:128.
Carson CG, et al: Clinical presentation of atopic dermatitis by filaggrin
gene mutation status during the first 7 years of life in a prospective
cohort study. PLoS One 2012; 7:e48678.
Chisolm SS, et al: Written action plans: potential for improving
outcomes in children with atopic dermatitis. J Am Acad Dermatol
2008; 59:677.
Clausen M, et al: High prevalence of allergic diseases and sensitization
in a low allergen country. Acta Paediatr 2008; 97:1216.
Clayton TH, et al: The treatment of severe atopic dermatitis in childhood
with narrowband ultraviolet B phototherapy. Clin Exp Dermatol 2007;
32:28.
Fleischer DM, et al: Primary prevention of allergic disease through
nutritional interventions. J Allergy Clin Immunol 2013; 1:29.
Flohr C, Mann J: New approaches to the prevention of childhood atopic
dermatitis. Allergy 2014; 69:56.
Flohr C, Mann J: New insights into the epidemiology of childhood atopic
dermatitis. Allergy 2014; 69:3.
Eichenfeld LF, et al: Guidelines of care for the management of atopic
dermatitis. Section 1. Diagnosis and assessment of atopic dermatitis.
J Am Acad Dermatol 2014; 70:2.
Eichenfeld LF, et al: Guidelines of care for the management of atopic
dermatitis. Section 2. Management and treatment of atopic dermatitis
with topical therapies. J Am Acad Dermatol 2014; 71:116.
Epstein TG, et al: Opposing effects of cat and dog ownership and
allergic sensitization on eczema in an atopic birth cohort. J Pediatr
2011; 158:2.
Gao PS, et al: Genetic variants in interferon regulatory factor 2 (IRF2)
are associated with atopic dermatitis and eczema herpeticum. J Invest
Dermatol 2012; 132:3(Pt 1).
Gao PS, et al: Genetic variants in thymic stromal lymphopoietin are
associated with atopic dermatitis and eczema herpeticum. J Allergy
Clin Immunol 2010; 125:6.
Gittlem JK, et al: Progressive activation Th2/Th22 cytokines and
selective epidermal proteins characterizes acute and chronic atopic
dermatitis. J Allergy Clin Immunol 2012; 130:6.
Haeck IM, et al: Enteric-coated mycophenolate sodium versus
cyclosporine as a long-term treatment in adult patients with severe
atopic dermatitis: a randomized controlled trial. J Am Acad Dermatol
2011; 64:6.
Hotze M, et al: Increased efficacy of omalizumab in atopic dermatitis
patients with wild-type filaggrin status and higher serum levels of
phosphatidylcholines. Allergy 2014; 69:132.
Huang JT, et al: Treatment of Staphylococcus aureus colonization in
atopic dermatitis decreases disease severity. Pediatrics 2009;
123:e808.
Isaksson M, et al: Children with atopic dermatitis should always be
patch-tested if they have hand or foot dermatitis. Acta Derm Venereol
2014 [Epub ahead of print].
Jolles S, et al: Use of IGIV in the treatment of atopic dermatitis,
urticaria, scleromyxedema, pyoderma gangrenosum, psoriasis, and
pretibial myxedema. Int Immunopharmacol 2006; 6:579.
70
Julián-Gónzalez RE, et al: Less common clinical manifestations of atopic
dermatitis: prevalence by age. Pediatr Dermatol 2012; 29:580.
Luca NJ, et al: Eczema herpeticum in children: clinical features and
factors predictive of hospitalization. J Pediatr 2012; 161:4.
Makino T, et al: Effect of bakumijiogan, an herbal formula in traditional
Chinese medicine, on atopic dermatitis–like skin lesions induced by
mite antigen in NC/Jic mice. Biol Pharm Bull 2008; 31:2108.
Margolis DJ, et al: Filaggrin-2 variation is associated with more
persistent atopic dermatitis in African American subjects. J Allergy Clin
Immunol 2014; 133:784.
Margolis DJ, et al: Thymic stromal lymphopoietin variation, filaggrin loss
of function, and the persistence of atopic dermatitis. JAMA Dermatol
2014; 150:254.
Meduri NB, et al: Phototherapy in the management of atopic dermatitis:
a systematic review. Photodermatol Photoimmunol Photomed 2007;
23:106.
Moore E, et al: Nurse-led clinics reduce severity of childhood atopic
eczema: a review of the literature. Br J Dermatol 2006; 155:1242.
Osawa R, et al: Filaggrin gene defects and the risk of developing
allergic disorders. Allergol Int 2011; 60:1.
Ozkaya E: Adult-onset atopic dermatitis. J Am Acad Dermatol 2005; 52:579.
Paller AS, et al: Tacrolimus ointment is more effective than
pimecrolimus cream with a similar safety profile in the treatment of
atopic dermatitis: results from 3 randomized, comparative studies.
J Am Acad Dermatol 2005; 52:810.
Penders J, et al: Establishment of the intestinal microbiota and its role
for atopic dermatitis in early childhood. J Allergy Clin Immunol 2013;
132:601.
Puya R, et al: Treatment of severe refractory adult atopic dermatitis with
ustekinumab. Int J Dermatol 2012; 51:1.
Rahman SI, et al: The methotrexate polyglutamate assay supports the
efficacy of methotrexate for severe inflammatory skin disease in
children. J Am Acad Dermatol 2013; 70:252.
Ricci G, et al: Three years of Italian experience of an educational
program for parents of young children affected by atopic dermatitis:
improving knowledge produces lower anxiety levels in parents of
children with atopic dermatitis. Pediatr Dermatol 2009; 26:1.
Ring J, et al: Guidelines for treatment of atopic eczema (atopic
dermatitis). Part I. J Eur Acad Dermatol Venereol 2012; 26:1176.
Rupnik H, et al: Filaggrin loss-of-function mutations are not associated
with atopic dermatitis that develops in late childhood or adulthood. Br
J Dermatol 2014 [Epub ahead of print].
Salimi M, et al: A role for IL-25 and IL-33-driven type-2 innate lymphoid
cells in atopic dermatitis. J Exp Med 2013; 210:13.
Selnes A, et al: Diverging prevalence trends of atopic disorders in
Norwegian children: results from three cross-sectional studies. Allergy
2005; 60:894.
Sidbury R, et al: Guidelines of care for the management of atopic
dermatitis. Section 3. Management and treatment with phototherapy
and systemic agents. J Am Acad Dermatol 2014; 71:327.
Sidbury R, et al: Guidelines of care for the management of atopic
dermatitis: Section 4. Prevention of disease flares and use of
adjunctive therapies and approaches. J Am Acad Dermatol 2014;
[Epub ahead of print].
Stott B, et al: Human IL-31 is induced by IL-4 and promotes Th2-driven
inflammation. J Allergy Clin Immunol 2013; 132:2.
Stemmler S, et al: Association of variation in the LAMA3 gene, encoding
the alpha-chain of laminin 5, with atopic dermatitis in a German
case-control cohort. BMC Dermatol 2014; 14: 17.
Ten Berge O, et al: Throwing a light on photosensitivity in atopic
dermatitis: a retrospective study. Am J Clin Dermatol 2009; 10:119.
Thomsen SF, et al: Outcome of treatment with azathioprine in severe
atopic dermatitis: a five-year retrospective study of adult outpatients.
Br J Dermatol 2014 [Epub ahead of print].
Van Drongelen V, et al: Reduced filaggrin expression is accompanied by
increased Staphylococcus aureus colonization of epidermal skin
models. Clin Exp Allergy 2014 [Epub ahead of print].
Van Os-Medendorp H, et al: Costs and cost-effectiveness of the nursing
program “Coping with itch” for patients with chronic pruritic skin
disease. Br J Dermatol 2008; 158:1013.
Wang WL, et al: Thymic stromal lymphopoietin: a promising therapeutic
target for allergic disease. Int Arch Allergy Immunol 2013; 160:18.
Waxweiler WT, et al: Systemic treatment of pediatric atopic dermatitis
with azathioprine and mycophenolate mofetil. Pediatr Dermatol 2011;
28:6.

ECZEMA
The word ec ema seems to ha e originated in AD and is
deri ed rom the Gree wor e ein meaning to to boil orth
or to e er esce. The term encompasses such disorders as
dyshidrotic ec ema and nummular ec ema ( ) but at times
is used synonymously or atopic dermatitis (as in in antile
ec ema ). The acute stage generally presents as a red edema
tous pla ue that may ha e grossly isible small grouped
esicles. Subacute lesions present as erythematous pla ues
with scale or crusting. Later lesions may be co ered by a drier
scale or may become licheni ed. n most ec ematous reactions
se ere pruritus is a prominent symptom. The degree o irrita
tion at which itching begins (the itch threshold) is lowered by
stress. tching is o ten prominent at bedtime and usually
results in insomnia. eat and sweating may also pro o e epi
sodes o itching.
istologically the hallmar o all ec ematous eruptions is
a serous e udate between cells o the epidermis (spongiosis)
with an underlying dermal peri ascular lymphoid in ltrate
and e ocytosis (lymphocytes present in o erlying epidermis
singly or in groups). Spongiosis is generally out o propor
tion to the lymphoid cells in the epidermis. This is in contrast
to mycosis ungoides which demonstrates minimal spon
giosis con ned to the area immediately surrounding the
lymphocytes.
n most ec ematous processes spongiosis is ery prominent
in the acute stage where it is accompanied by minimal
acanthosis or hyper eratosis. Subacute spongiotic dermatitis
demonstrates epidermal spongiosis with acanthosis and
hyper eratosis. Chronic lesions may ha e minimal accompa
nying spongiosis but acute and chronic stages may o erlap
because episodes o ec ematous dermatitis ollow one another.
Scale corresponds to oci o para eratosis produced by the
in amed epidermis. A crust is composed o serous e udate
acute in ammatory cells and eratin. c ema regardless
o cause will mani est similar histologic changes i allowed
to persist chronically. These eatures are related to chronic
rubbing or scratching and correspond clinically to lichen
simple chronicus or prurigo nodularis. istologic eatures at
this stage include compact hyper eratosis irregular acantho
sis and thic ening o the collagen bundles in the papillary
portion o the dermis. The dermal in ltrate at all stages is
predominantly lymphoid but an admi ture o eosinophils
may be noted. eutrophils generally appear in secondarily
in ected lesions. Spongiosis with many intraepidermal eosino
phils may be seen in the early spongiotic phase o pemphigoid
pemphigus and incontinentia pigmenti as well as some cases
o allergic contact dermatitis.
Regional eczemas
Ear eczema
c ema o the ears or otitis e terna may in ol e the heli
postauricular old and e ternal auditory canal. By ar the most
re uently a ected site is the e ternal canal where ec ema
is o ten a mani estation o seborrheic dermatitis or allergic
contact dermatitis caused by topical medications especially
neomycin ( ig. ). Secretions o the ear canal deri e rom
the speciali ed apocrine and sebaceous glands which orm
cerumen. Rubbing wiping scratching and pic ing e acerbate
the condition. Secondary bacterial coloni ation or in ection is
common. n ection is usually caused by staphylococci strep
tococci or Pseu omonas. Contact dermatitis rom neomycin
ben ocaine and preser ati es may be caused by topical
Fig. 5-8 Ear eczema
secondary to allergic
contact dermatitis.
Eczema
remedies. Pseu omonas aeruginosa can result in malignant
e ternal otitis with ulceration and sepsis. arlobe dermatitis is
irtually pathognomonic o metal contact dermatitis (espe
cially nic el) and occurs most re uently in women who ha e
pierced ears.
Treatment should be directed at remo al o causati e agents
such as topically applied allergens. irst e amine the ear with
an otoscope and be sure there is not a per orated tympanic
membrane. there is drainage rom a per orated tympanic
membrane management should be in consultation with an
otolaryngologist. This purulent uid can be the cause o an ear
ec ema in ectious ec ematoid dermatitis. the tympanic
membrane is intact scales and cerumen should be remo ed
by gentle la age with an ear syringe. A combination o cipro
o acin plus a topical steroid (e.g. Ciprode ) is pre erred to
neomycin containing products. Corticosteroids alone can be
e ecti e or nonin ected dermatitis. or ery weepy lesions
aluminum acetate optic solution (e.g. Domeboro) may be
drying and bene cial.
Eyelid dermatitis
yelid dermatitis is most o ten related to atopic dermatitis or
allergic contact dermatitis or both (see Chapter ). Allergic
con uncti itis in an atopic patient may lead to rubbing and
scratching o the eyelid and result in secondary eyelid derma
titis. Seborrheic dermatitis psoriasis and airborne dermatitis
are other possible causes. inety percent o patients with
eyelid dermatitis are emale. When an ocular medication con
tains an allergen the allergen passes through the nasolacrimal
duct and dermatitis may also be noted below the nares in
addition to the eyelids. Some cases o eyelid contact dermatitis
are caused by substances trans erred by the hands to the
eyelids. eyelid dermatitis occurs without associated AD an
allergen is detected in more than o cases. ore than
o patients with AD and eyelid dermatitis will also ha e aller
gic contact dermatitis contributing to the condition. ragrances
and balsam o Peru metals (nic el and gold) parapheny
lenediamine uaternium oleamidopropyl dimethylamine
thiuram (in rubber pads used to apply eyelid cosmetics) and
tosylamide ormaldehyde (in nail polish) are common en i
ronmental allergens causing eyelid dermatitis. n medications
preser ati es such as cocamidopropyl betaine and acti e
71
 agents such as phenylephrine hydrochloride sodium cromo
5 glycate papain and ido uridine ha e all been implicated.
yelid dermatitis re uires care ul management o ten in col
laboration with an ophthalmologist. The most important aspect
is to identi y and eliminate any possible triggering allergens as
Atopic Dermatitis, Eczema, and Noninfectious Immunodeficiency Disorders
noted abo e. Patch testing or standard allergens as well as the
patient s ocular medications is re uired. Preser ati e ree eye
medications should be used. The ophthalmologist should
monitor the patient or con uncti al complications measure
the intraocular pressure and monitor or the de elopment
o cataracts especially in patients with AD who ha e an
increased ris or cataracts. nitially topical corticosteroids and
petrolatum based emollients are recommended. the derma
titis is persistent the patient may be transitioned to TC s to
reduce the long term ris o ocular steroid complications. The
TC s are o ten not initially tolerated on in amed eyelids due
to the burning. there is an associated allergic con uncti itis
or in patients who ail treatment with topical medications
applied to the eyelid ocular instillation o cyclosporine
ophthalmic emulsion (Restasis) can be bene cial. Cromolyn
sodium ophthalmic drops may be used to stabili e mast cells
in the eyelid and reduce pruritus. n balsam o Peru allergic
patients a balsam elimination diet may bene t.
Breast eczema (nipple eczema)
c ema o the breasts usually a ects the areolae and may
e tend on to the surrounding s in ( ig. ). The area around
the base o the nipple is usually spared and the nipple itsel
is less re uently a ected. The condition is rarely seen in men.
sually ec ema o the nipples is o the moist type with oo ing
and crusting. Pain ul ssuring is re uently seen especially in
nursing mothers. Atopic dermatitis is a re uent cause and
nipple ec ema may be the sole mani estation o AD in adult
women. t re uently presents during breast eeding. The role
o secondary in ection with bacteria and Can i a should be
considered in breast eeding women. ther causes o nipple
ec ema are allergic contact dermatitis and irritant dermatitis.
rritant dermatitis occurs rom riction ( ogger s nipples) or
rom poorly tting brassieres with seams in women with
asymmetric and large breasts. n patients in whom ec ema o
the nipple or areola has persisted or more than months
especially i it is unilateral a biopsy is mandatory to rule out
the possibility o Paget s disease o the breast. Topical
Fig. 5-9 Nummular
eczema of the breast.
72
corticosteroids or TC s are o ten e ecti e in the treatment o
non Paget ec ema o the breast. e oid hyper eratosis o the
nipples is a chronic condition that may mimic nipple ec ema
but it is not responsi e to corticosteroids.
ipple ec ema in the breast eeding woman is a therapeutic
challenge. The dermatitis may appear in an atopic woman
when her child begins to ingest solid oods. This may signal
contact dermatitis to a ood. Allergic contact dermatitis may
de elop to topical protecti e creams (containing itamin A
and aloe chamomile or preser ati es). Staphylococcal
superin ection may de elop and can be identi ed by culture.
ral antibiotics are the pre erred treatment or bacterial sec
ondary in ection. Candidal in ection o the areola may present
as normal s in erythema or an acute or chronic ec ema. The
area o the areola immediately ad acent to the nipple tends to
be in ol ed sometimes with ne hairline crac s. Patients re
uently complain o se ere pain especially with nursing.
Analgesia may be re uired and breast eeding may need to be
suspended or a period. Pumping and the use o a silicone
nipple shield may be help ul. Associated conditions include
oral thrush in the in ant antibiotic use and a personal history
o aginal candidiasis. Cultures may or may not be positi e
rom the a ected areola nipple. The child s mouth should also
be cultured e en i the e amination is completely normal
because candidal coloni ation o the breast eeding in ant s
mouth may be asymptomatic with no ndings on clinical
e amination. A positi e culture rom the in ant in the setting
o nipple ec ema in the mother would warrant therapy o the
mother and in ant. Therapy with topical or systemic anti un
gal agents may be re uired to determine whether Can i a is
pathogenic. ral ucona ole can be dramatically e ecti e in
these patients. Topical gentian iolet . applied once daily
to the nipple or up to wee or all purpose nipple ointment
(mupirocin g; nystatin units mL ointment
g; clotrima ole aginal cream g; and betametha
sone . ointment g) is an e ecti e topical agent. Guaia
ulene (A ulon) is a dar blue hydrocarbon used in urope
or nipple crac s with breast eeding.
The child s thrush should also be treated. A lactation con
sultant or nurse may be help ul in managing these patients
since poor positioning during breast eeding is a common
co actor in the de elopment o nipple ec ema.
Hand eczema
and ec ema is a common and important s in condition.
ery year about o the population has at least one
episode o hand dermatitis and at any time about o the
population is a ected. The genetic ris actors or the de elop
ment o hand dermatitis are un nown. Adult emale patients
with AD may de elop hand dermatitis. Atopic patients with
the L null mutation may ha e a speci c orm o hand der
matitis characteri ed by dorsal hand and nger dermatitis
olar wrist in ol ement and hyperlinear palms but limited
palmar dermatitis. and ec ema is the most common occupa
tional s in condition accounting or more than o all
occupational dermatitides. About per wor ers are
a ected annually. Tobacco smo ing and alcohol consumption
do not appear to be ris actors or the de elopment o hand
ec ema. Women are at increased ris most o which is
accounted or by a spi e in the rate o hand ec ema in the
age group when increased en ironmental e posures
increase women s ris (e.g. child care housecleaning).
Chronic hand ec ema especially i se ere signi cantly
reduces the patient s uality o li e and is associated with
symptoms o depression. A signi cant portion o patients with
hand ec ema will still be a ected years later. The ris or
persistence o the hand ec ema is doubled i there is associated
ec ema at other sites at presentation i there is a childhood
history o AD and i the onset o the hand ec ema was be ore
age . Pre enti e inter entions ha e been success ul on the
ollowing two ronts
. Persons at high ris or hand ec ema can be identi ed
and counseled to a oid high ris occupations.
. nce occupational hand ec ema de elops some
occupation speci c strategies can lead to impro ement
and pre ent recurrence.
The e aluation and management o hand ec ema ha e been
hampered by the lac o a uni orm classi cation system and a
dearth o controlled therapeutic trials. The diagnostic dilemma
in hand dermatitis is in part related to two actors. The clinical
appearance o the s in eruption on the palms and soles may
be ery similar independent o the etiology. n addition irtu
ally all chronic hand dermatitis demonstrates a chronic der
matitis histologically again independent o pathogenic cause.
Psoriasis speci cally on the palms and soles may show spon
giosis and closely resemble a dermatitis ( ig. ). As a result
the proposed classi cation schemes rely on a combination o
morphologic eatures history o coe istent illnesses occupa
tional e posure and results o patch testing. The di erent
types o hand ec ema are as ollows
. Allergic contact dermatitis (with or without an
additional irritant component)
. rritant hand dermatitis
. Atopic hand ec ema (with or without an additional
irritant component)
. Recurrent esicular (or esiculobullous) hand ec ema
. yper eratotic hand ec ema
. Pulpitis (chronic ngertip dermatitis)
. ummular dermatitis
A complete history care ul e amination o the rest o the
body sur ace and re uently patch testing are essential in
establishing a diagnosis. Patch testing is recommended in all
patients with chronic hand ec ema. Allergens in the en iron
ment especially shower gels and shampoos in the wor place
and in topical medications may be important in any gi en
patient. Patch testing must include broad screens o common
allergens or cases o allergic contact dermatitis will be missed.
The role o ingested nic el in the de elopment o hand
ec ema in nic el allergic patients is contro ersial. Some prac
titioners treat such patients with low nic el diets and e en
disul ram chelation with reported bene t. owe er the ris
o de elopment o hand ec ema in adulthood is independent
o nic el allergy. Similarly the role o low balsam diets in the
management o balsam o Peru allergic patients with hand
ec ema is unclear.
Fig. 5-10 Hand
eczema.
Wet wor de ned as s in in li uids or glo es or more than
hours per day or handwashing more than times per
day is a strong ris actor or hand ec ema. igh ris occupa
tions include those that entail wet wor and those with
e posure to potential allergens. These nine high ris occu
Eczema
pations include ba ers hairdressers dental surgery assistants
itchen wor ers coo s butchers health care wor ers clean
ers physicians dentists eterinarians and laboratory techni
cians. n about o patients with hand ec ema especially i
se ere it is associated with prolonged missed wor ob
change and ob loss. n health care wor ers the impaired
barrier poses a ris or in ection by blood borne pathogens.
Almost one third o ba er s apprentices de elop hand
dermatitis within months o entering the pro ession. Among
hairdressers the incidence approaches a ter se eral
years. Both irritant dermatitis and allergic contact dermatitis
are important actors with glyceryl monothioglycolate and
ammonium persul ate being the most common allergens
among hairdressers. Cement wor ers ha e a high rate o hand
dermatitis related to contact allergy al alinity and hygro
scopic e ects o cement. Dorsal hand dermatitis in a cement
wor er suggests contact allergy to chromate or cobalt. The
addition o errous sul ate to cement has no e ect on irritant
dermatitis but reduces the incidence o allergic chromate der
matitis by two thirds.
Among patients with occupational hand dermatitis atopic
patients are disproportionately represented. and dermatitis
is re uently the initial or only adult mani estation o an atopic
diathesis. The li elihood o de eloping hand ec ema is great
est in patients with AD more common i the AD was se ere
but is still increased in incidence in patients with only respira
tory atopy. ne third to hal o patients with hand ec ema
ha e atopy. Atopic patients should recei e career counseling
in adolescence to a oid occupations that are li ely to induce
hand dermatitis.
Contact urticaria syndrome may present as immediate
burning itching or swelling o the hands but a chronic ec em
atous phase may also occur. Late is an important cause o the
syndrome but raw meat lettuce garlic onion carrot tomato
spinach grape ruit orange radish g parsnip cheese or any
number o other oods may be implicated.
Vesiculobullous hand eczema (pompholyx, dyshidrosis)
diopathic acute esicular hand dermatitis is not related
to bloc age o sweat ducts although palmoplantar hyper
hidrosis is common in these patients and control o hyper
hidrosis impro es the ec ema. Acute pompholy also nown
as cheiropompholy i it a ects the hands presents with
se ere sudden outbrea s o intensely pruritic esicles. Primary
lesions are macroscopic deep seated multilocular esicles
resembling tapioca on the sides o the ngers ( ig. )
palms and soles. The eruption is symmetric and pruritic with
pruritus o ten preceding the eruption. Coalescence o smaller
lesions may lead to bulla ormation se ere enough to pre ent
Fig. 5-11 Acute vesiculobullous hand eczema. 73
 Fig. 5-12
5 Hyperkeratotic hand
dermatitis.
Atopic Dermatitis, Eczema, and Noninfectious Immunodeficiency Disorders
ambulation. ndi idual outbrea s resol e spontaneously o er
se eral wee s. Bullous tinea or an id reaction rom a derma
tophyte should be e cluded and patch testing should be con
sidered to rule out allergic contact dermatitis.
Chronic vesiculobullous hand eczema
n chronic cases the lesions may be hyper eratotic scaling
and ssured and the dyshidrosi orm pattern may be recog
ni ed only during e acerbations. The pruritic mm esicles
tend to be most pronounced at the sides o the ngers. n long
standing cases the nails may become dystrophic. The distri
bution o the lesions is as a rule bilateral and roughly
symmetric.
Hyperkeratotic hand dermatitis
ales outnumber emales by and the patients are usually
older adults. The eruption presents as hyper eratotic ssure
prone erythematous areas o the middle or pro imal palm.
Vesicles are not seen. The olar sur aces o the ngers may
also be in ol ed ( ig. ). Plantar lesions occur in about
o patients. istologically the lesions show chronic spongiotic
dermatitis. The most important di erential diagnosis is psoria
sis and some o the patients with chronic hyper eratotic hand
dermatitis will ultimately pro e to be psoriatic. The presence
o sharply demarcated pla ues nail pitting or occasional
crops o pustules is an important clue to psoriatic hand
in ol ement.
Pulpitis (fingertip hand dermatitis)
This hyper eratotic and ssuring ec ema a ects primarily the
ngertips and may e tend to merge with ec ema o the palm.
Vesicles can occur. n ol ement o the three ngers o the
dominant hand suggests a contact dermatitis (irritant or aller
gic) whereas similar in ol ement o the nondominant hand
suggests egetables and other items related to ood prepara
tion that are held in this hand or cutting (e.g. garlic).
Treatment
The hands are essential or wor both in and out o the home.
Treatment regimens must be practical and must allow patients
to unction as normally as possible. The e cacy o some o the
treatments depends on the morphology o the eruption and
the diagnostic classi cation (see pre ious discussion).
74
Protection
Vinyl glo es may be worn during wet wor especially when
detergents are used. Although inyl glo es protect against
chemicals they do not pre ent e posure to heat through the
glo e or the macerating e ect o sweat which accumulates
under the glo es. They are also much less durable than rubber
glo es. Rubber glo es may be used at home i patients do not
e hibit allergy to rubber chemicals or late . Wearing white
cotton glo es under the inyl glo es is bene cial. or rough
wor such as gardening wearing protecti e cloth or leather
glo es is essential.
Barrier repair
oisturi ing is a critical component o the management o
hand dermatitis. Application o a protecti e moisturi ing
cream or ointment a ter each handwashing or water e posure
is recommended. Creams re uire a preser ati e and ha e a
higher ris o contact sensiti ity. intments tend to ha e ew
ingredients and do not generally re uire a preser ati e. At
night e en during periods o remission a hea y moisturi ing
ointment should be applied to the hands a ter soa ing in
water. palmar dryness is present occlusion o the moistur
i er with a plastic bag or inyl glo es is recommended. White
petrolatum is ine pensi e and nonsensiti ing and remains a
aluable agent in the treatment o hand dermatitis. Jars o
cream used by patients with hand dermatitis were contami
nated with Staph lococcus aureus in o cases in one study.
Topical agents
Superpotent and potent topical corticosteroids are rst line
pharmacologic therapy. Their e cacy is enhanced by presoa
ing and occlusion (soa and smear techni ue or wet dress
ings). A single application with occlusion at night is o ten
more e ecti e than multiple daytime applications. The treat
ment is continued until the hands are clear and then either
emollients are substituted or maintenance treatment two or
three times wee ly is continued to pre ent recurrence. n
re ractory cases superpotent corticosteroids may be used or
wee s then on wee ends with a milder corticosteroid
applied during the wee .
The TC s may be o bene t in some mildly a ected patients.
Soa s with a tar bath oil or applications o LCD or
crude coal tar in an ointment base may be o bene t especially
in patients with hyper eratotic hand ec ema. Be arotene gel
can be bene cial in up to o patients with re ractory hand
ec ema.
Phototherapy
Phototherapy in the orm o high dose VA soa or cream
P VA and oral P VA can be e ecti e. Gi en the thic ness
o the palms VA irradiation should be deli ered min a ter
soa ing as opposed to bath P VA which can be done imme
diately a ter bathing. Relati ely ew phototo ic reactions are
seen with regimens that use a min soa in a mg L
solution o metho ypsoralen starting with . . J cm
and increasing by . . J cm three times a wee .
Super cial Gren ray radiotherapy remains a iable modal
ity but well maintained machines are ew in number. The
depth o penetration o these ery so t rays is limited so it
is best used a ter acute crusting and esiculation ha e been
cleared with other treatment.
Botulinum toxin A
n patients with palmoplantar hyperhidrosis and associated
hand ec ema treatment o the hyperhidrosis with intradermal
in ections o botulinum to in A leads to both dramatic resolu
tion o the sweating and clearing o the hand ec ema. The
hand ec ema returns when the sweating returns.
 ontophoresis which also reduces sweating can similarly
impro e hand dermatitis. This illustrates the importance o
wetness in the e acerbation o hand ec ema.
Systemic agents
The systemic agents used to treat se ere chronic hand derma
titis are identical to those used or AD. The use o systemic
corticosteroids usually results in dramatic impro ement.
n ortunately relapse re uently occurs almost as rapidly so
systemic steroids are recommended only to control acute e ac
erbations. or e ample patients with in re uent but se ere
outbrea s o pompholy may bene t rom a ew wee s o
systemic steroids starting at about mg g day. Patients
with persistent se ere hand dermatitis should be considered
or alternati e steroid sparing therapy.
ethotre ate (in psoriatic doses) a athioprine and
(adult dose o . g twice daily) can be considered.
Cyclosporine can be e ecti e but gi en the chronicity o
hand ec ema its use is best reser ed or se ere outbrea s. ral
retinoids may ha e a place in the management o hand der
matitis. Alitretinoin mg day will lead to complete or near
complete clearance o chronic re ractory hand ec ema in about
o patients especially those with hyper eratotic hand
ec ema. The onset o response is delayed with some patients
achie ing optimal bene t only a ter more than months o
treatment. Acitretin mg day may ha e similar bene t.
Workplace modifications
The incidence o hand dermatitis in the wor place can be
reduced by identi ying ma or irritants and allergens pre ent
ing e posure through engineering controls substituting less
irritating chemicals when possible en orcing personal protec
tion and glo e use and instituting organi ed wor er educa
tion. and ec ema classes ha e been documented to reduce
the burden o occupational dermatitis. t is important to note
that pre ention o e posure to a wea but re uent irritant can
ha e more pro ound e ects than remo al o a strong but in re
uently contacted irritant.
Proper glo es are essential in industrial settings. itrile
glo es are generally less permeable than late glo es. Glo es
o ethylene inyl alcohol copolymer sandwiched with polyeth
ylene are e ecti e against epo y resin methyl methacrylate
and many other organic compounds. Late and inyl glo es
o er little protection against acrylates. The ( h) glo e and
nitrile are best in this setting. As hospitals transition to nonla
te glo es it is important to note that e en low protein
powder ree late glo es reduce sel reported s in problems
among health wor ers.
Diaper (napkin) dermatitis
Diaper dermatitis has dramatically decreased as a result o
highly absorbable disposable diapers. onetheless dermatitis
o the diaper area in in ants remains a common cutaneous
disorder. The highest pre alence occurs between and
months o age. Diaper dermatitis is also seen in adults with
urinary or ecal incontinence who wear diapers.
rritant diaper dermatitis is an erythematous dermatitis
limited to e posed sur aces. The olds remain una ected in
contrast to intertrigo in erse psoriasis and candidiasis where
the olds are re uently in ol ed. n se ere cases o irritant
dermatitis there may be super cial erosion or e en ulceration
(Jac uet erosi e diaper dermatitis) iolaceous pla ues and
nodules (granuloma gluteal in antum) or pseudo errucous
papules and nodules; these three entities are part o a disease
spectrum. The tip o the penis may become irritated and
crusted with the baby urinating re uently and spots o blood
appearing on the diaper.
Eczema
Fig. 5-13 Napkin psoriasis.
cessi e hydration with maceration o the s in is the
primary causal actor in diaper dermatitis. The absence o
diaper dermatitis in societies where children do not wear
diapers clearly implicates the diaper en ironment as the cause
o the eruption. oist s in is more easily abraded by riction
o the diaper as the child mo es. Wet s in is more permeable
to irritants. S in wetness also allows the growth o bacteria
and yeast. Bacteria raise the local p increasing the acti ity
o ecal lipases and proteases. Can i a albicans is re uently a
secondary in ader and when present produces typical satel
lite erythematous lesions or pustules at the periphery as
the dermatitis spreads. Staph lococcus aureus and group A
β hemolytic streptococci can in ect diaper dermatitis. Breast
eeding is associated with less re uent diaper dermatitis and
diarrhea is a ris actor.
The di erential diagnosis o diaper dermatitis should include
nap in psoriasis ( ig. ) seborrheic dermatitis AD Langer
hans cell histiocytosis tinea cruris acrodermatitis enteropath
ica aminoacidurias biotin de ciency and congenital syphilis.
Allergic contact dermatitis is becoming more re uently recog
ni ed as a cause o dermatitis in the diaper area. Allergens
include sorbitan ese uoleate ragrances disperse dye cyclo
he ylthiopthalimide and mercaptoben othia ole (in rubber
diaper co ers). Gi en the s ill o most pediatricians in the man
agement o diaper dermatitis dermatologists should thin
about these conditions in in ants who ha e ailed the standard
inter entions used by pediatricians. Re ractory diaper dermati
tis may re uire a biopsy to e clude some o these conditions.
Pre ention is the best treatment. Diapers that contain super
absorbent gel ha e been pro ed e ecti e in pre enting diaper
dermatitis in both neonates and in ants. They wor by absorb
ing the wetness away rom the s in and by bu ering the p .
Cloth diapers and regular disposable diapers are e ual in their
propensity to cause diaper dermatitis and are in erior to the
superabsorbent gel diapers. The re uent changing o diapers
is also critical e ery hours or newborns and e ery hours
or older in ants. The renewed popularity o cloth and bamboo
diapers as more natural and ecologic has led to a reemergence
o se ere diaper dermatitis in some uropean countries.
Protecting the s in o the diaper area is the most important
treatment or diaper dermatitis. inc o ide paste and petrola
tum are both e ecti e barriers pre enting the urine and stool
rom contacting the dermatitis. inc o ide paste with .
micona ole may be considered i Can i a may be present.
simple impro ed hygiene and barrier therapy are not e ecti e
the application o a mi ture o e ual parts nystatin ointment
and hydrocortisone ointment at each diaper change o ers
both anticandidal acti ity and an occlusi e protecti e barrier
rom urine and stool and can be ery e ecti e.
75
 Circumostomy eczema
5 c emati ation o the surrounding s in re uently occurs a ter
an ileostomy or colostomy. t is estimated that o ileos
tomy patients ha e some postoperati e sensiti ity as a result
Atopic Dermatitis, Eczema, and Noninfectious Immunodeficiency Disorders
o the lea age o intestinal uid onto unprotected s in. As
the consistency o the intestinal secretion becomes iscous
the sensiti ation subsides. Proprietary medications containing
araya powder ha e been help ul; cholestyramine (an
ion e change resin) in A uaphor and topical sucral ate as a
powder or emollient at g concentration are e ecti e treat
ments. Psoriasis may also appear at ostomy sites especially in
patients with in ammatory bowel disease ( BD) being treated
with tumor necrosis actor (T ) inhibitors and de eloping
psoriasis as a complication. Topical treatment may be di cult
because the appliance adheres poorly a ter the topical agents
are applied. A topical corticosteroid spray may be used and
will not inter ere with appliance adherence. Contact dermatitis
to the ostomy bag adhesi e can be problematic and e en sup
posedly hypoallergenic ostomy bags may still trigger derma
titis in these patients.
Autosensitization and conditioned irritability
The presence o a locali ed chronic and usually se ere ocus
o dermatitis may a ect distant s in in two ways. Patients
with a chronic locali ed dermatitis may de elop dermatitis
at distant sites rom scratching or irritating the s in. This is
called conditioned irritability. The most common scenario
is distant dermatitis in a patient with a chronic ec ematous
leg ulcer. Autoec emati ation re ers to the spontaneous
de elopment o widespread dermatitis or dermatitis distant
rom a local in ammatory ocus. The agent causing the local
in ammatory ocus is not the direct cause o the dermatitis at
the distant sites. Autoec emati ation most re uently pres
ents as a generali ed acute esicular eruption with a promi
nent dyshidrosi orm component on the hands. The most
common associated condition is a chronic ec ema o the legs
with or without ulceration. The angry bac or e cited
s in syndrome obser ed with strongly positi e patch tests
and the local dermatitis seen around in ectious oci (in ectious
ec ematoid dermatitis) may represent a limited orm o this
reaction.
Id reactions
Patients with a ariety o in ectious disorders may present
with ec ematous dermatitis. The classic e ample is the esicu
lar id reactions o the hands in response to an in ammatory
tinea o the eet. Similarly in ammatory tinea capitis is o ten
associated with a ocal or di use dermatitis primarily o the
upper hal o the body. ummular ec ematous lesions or pity
riasis rosea li e lesions may occur in patients with head or
pubic louse in estation. d reactions clear when the ocus
o in ection or in estation is treated but topical or systemic
anti in ammatory agents may be re uired until the triggering
in ection is eradicated.
Juvenile plantar dermatosis
Ju enile plantar dermatosis is an ec ematous disorder o chil
dren rom age years to puberty. t usually begins as a patchy
symmetric smooth red gla ed macule on the base or medial
sur ace o the great toes sometimes with ssuring and des
uamation. Lesions e ol e into red scaling patches in ol ing
the weight bearing and rictional areas o the eet usually
symmetrically. The ore oot is usually much more in ol ed
than the heel. Toe webs and arches are spared. The eruption
76
is disproportionately more common in atopic children. n
some patients a similar eruption occurs on the ngers.
The disease is caused by the repeated maceration o the eet
by occlusi e shoes especially athletic shoes or by the abrasi e
e ects o pool sur aces or di ing boards. The a ected soles
remain wet in the rubber bottoms o the shoes or are macer
ated by pool water. Thin nonabsorbent synthetic soc s con
tribute to the problem.
istologically there is psoriasi orm acanthosis and a sparse
largely lymphocytic in ltrate in the upper dermis most dense
around sweat ducts at their point o entry into the epidermis.
Spongiosis is o ten present and the stratum corneum is thin
but compact.
The diagnosis o plantar dermatosis is apparent on inspec
tion especially i there is a amily or personal history o atopy
and the toe webs are spared. Treatment in ol es a oidance o
maceration. oot powders thic absorbent soc s absorbent
insoles and ha ing alternate pairs o shoes to wear to allow
the shoes to dry out are all bene cial. Topical corticosteroid
medications are o limited alue and o ten are no more
e ecti e than occlusi e barrier protection. Petrolatum or urea
preparations can sometimes be o bene t. ost cases clear
within years o diagnosis.
Allergic contact dermatitis may play a signi cant role in
plantar dermatoses in childhood. n one study rom Scotland
o children with in ammatory dermatitis o the soles
had rele ant positi e patch tests and o children with
typical u enile plantar dermatitis also had a rele ant contact
allergen. Re ractory plantar dermatitis in childhood should
suggest allergic contact dermatitis.
Xerotic eczema
erotic ec ema is also nown as winter itch ec ema cra uel
and asteatotic ec ema. These i idly descripti e terms are all
applied to dehydrated s in showing redness dry scaling and
ne crac ling that may resemble crac led porcelain or the s
sures in the bed o a dried la e. The primary lesion is an
erythematous patch co ered with an adherent scale. As the
lesion enlarges ne crac s in the epidermis occur ( ig. ).
ummular lesions may occur. erotic nummular ec ema is
less weepy than classic nummular dermatitis. a ored sites
are the anterior shins e tensor arms and an . lderly
persons are particularly predisposed and erosis is the most
Fig. 5-14 Eczema
craquelé.
common cause o pruritus in older indi iduals. erotic ec ema
is seen most re uently during the winter when there is low
relati e humidity. Bathing with hot water and harsh soaps
contributes. The epidermal water barrier is impaired and
T WL is increased. pidermal barrier repair begins to decrease
a ter age correlated with an increase in epidermal p . This
is why older patients complain that they ha e not changed
their bathing routine or soaps yet ha e de eloped erotic
dermatitis. The loss o barrier repair ability is impro ed by
acidi ying the epidermis showing the bene t o mild acids in
treating erosis. etero ygous null mutation o the L gene
is associated with erosis in young ( ) and older ( ) sion may be necessary. secondary staphylococcal in ection
adults.
Ta ing short tepid showers limiting use o soap to soiled
and apocrine bearing areas a oiding harsh soaps and using
acid p synthetic detergents and promptly applying an emol
lient a ter bathing are usually e ecti e. White petrolatum and
emollients containing urea or lactic acid are e ecti e.
Topical corticosteroids in ointment ehicles are use ul or
in amed areas.
Nummular eczema (discoid eczema)
ummular ec ema ( ) usually begins on the lower legs
dorsa o the hands or e tensor sur aces o the arms. n younger
adults emales predominate but most patients older than
are male. Alcohol consumption has been associated with
in adult males. A single lesion o ten precedes the eruption and
may be present or some time be ore other lesions appear. The
primary lesions are discrete coin shaped erythematous
edematous esicular and crusted patches ( ig. ). ost
lesions are cm in diameter. Lesions may orm a ter trauma
(conditioned hyperirritability). As new lesions appear the old
lesions e pand as tiny papulo esicular satellite lesions appear
at the periphery and use with the main pla ue. n se ere
cases the condition may spread into palm si ed or larger
patches. Pruritus is usually se ere and o the same paro ys
mal compulsi e uality and nocturnal timing seen in AD and
prurigo nodularis.
Atopic dermatitis re uently has nummular morphology in
adolescents but in atopy the lesions tend to be more chronic
and licheni ed. istologically is characteri ed by acute or
Fig. 5-15 Nummular
eczema.
subacute spongiotic dermatitis. The s in lesions o nummular
dermatitis are re uently coloni ed with Staph lococcus aureus
in re uency similar to that seen in AD. Rele ant positi e
patch tests are ound in one uarter to one third o patients
with . This may represent the primary cause o the derma
Eczema
titis or a secondary allergy that de eloped rom products used
to treat the .
nitial treatment consists o simple soa ing and greasing
with an occlusi e ointment and once daily or twice daily
application o a potent or superpotent topical corticosteroid
cream or ointment. intments are more e ecti e and occlu
is present an antibiotic with appropriate co erage can be
used. Stopping alcohol consumption may impro e response.
A sedating antihistamine do epin or gabapentin at bedtime
can help with sleep and reduce nighttime scratching. n some
cases re ractory to topical agents intralesional or systemic cor
ticosteroid therapy may be re uired. n patients unresponsi e
to topical steroids phototherapy with B VB bath (soa ) or
oral P VA can be e ecti e. or re ractory pla ues the addi
tion o topical tar as crude coal tar or LCD may be
bene cial.
Pruritic dermatitis in elderly persons
Pruritic s in conditions are common in elderly patients
appearing about age and increasing in se erity with age.
ales are more o ten a ected and Asians and Caucasians
more re uently ha e pruritus as seniors than A rican Ameri
cans or ispanics.
The dermatoses seen in this age group are typically ec ema
tous or papular. The ec ematous pla ues may resemble num
mular dermatitis a eature recogni ed by arion Sul berger
when he coined the phrase e udati e discoid and lichenoid
chronic dermatitis or oid oid disease. The pathogenic basis
o this component o dermatitis in elderly persons may be
related to barrier ailure due to loss o acidi cation o the
epidermis. n addition patients o ten ha e urticarial papules
on the trun and pro imal e tremities that resemble insect
bites. These lesions are termed subacute prurigo and histo
logically demonstrate eatures o an arthropod assault with
super cial and deep peri ascular lymphohistiocytic in ltrates
dermal edema and at times interstitial eosinophils. Lesions
may also show eatures o transient acantholytic dermatitis or
eosinophilic olliculitis. This component o the eruption may
be related to the tendency o elderly indi iduals to ha e an
immune system that s ews toward Th because o loss o Th
unction. At times patients will ha e both types o eruption
either simultaneously or se uentially. The combination o
barrier ailure and an immune system s ewed toward Th is
parallel to what occurs in the setting o AD. or this reason
some practitioners consider this adult atopic dermatitis.
owe er it is un nown whether these conditions ha e a
genetic basis or more li ely gi en the time o onset
are caused by ac uired barrier and immune system abnormali
ties. n these patients allergic contact dermatitis and photo
dermatitis may be present or de elop. Patch testing may
identi y important allergens a oidance o which leads to
impro ement.
Calcium channel bloc ers may be associated with pruritic
dermatitis but stopping them will clear only about one uarter
o patients ta ing that class o medication. ydrochlorothia
ide is also more re uently used by itchy elderly patients.
Treatment or these patients is similar to that o AD patients
with oral antipruritics emollients and topical corticosteroids
(soa and smear) as rst line therapy. n re ractory cases pho
totherapy ( VB or P VA) Goec erman therapy ( VB plus
77
 crude coal tar) in a day treatment setting and immunosup
5 pressi e agents can be e ecti e. nad ertent use o photo
therapy in the patient with coe istent photosensiti ity will
lead to an e acerbation o pruritic dermatitis.
Atopic Dermatitis, Eczema, and Noninfectious Immunodeficiency Disorders
HORMONE-INDUCED DERMATOSES
Autoimmune progesterone dermatitis may appear as urticar
ial papules deep gyrate lesions papulo esicular lesions an
ec ematous eruption or targetoid lesions. rticarial and ery
thema multi orme li e lesions are most characteristic. Lesions
typically appear days be ore menses and impro e or
resol e a ew days ollowing menses. Pruritus is common.
nset is typically in the third and ourth decades o li e. amil
ial cases ha e been reported. When urticaria is the predomi
nant s in lesion there is a generali ed distribution and it may
be accompanied by laryngospasm. Anaphylactoid reactions
may occur. ral erosions may be present. any o the reported
patients had recei ed arti cial progestational agents be ore the
onset o the eruption. n some it appeared during a normal
pregnancy. The eruption may worsen or clear during preg
nancy. Rarely it can occur in males gi en progesterone and
adolescent emales. Progesterone luteal phase support during
in itro ertili ation has e acerbated the disease.
n most cases diagnosis has been con rmed by intradermal
testing with progesterone. A positi e test may be immediate
( min) or delayed ( h). lares may be induced by
intramuscular intra aginal or oral progesterone. The most
common treatment is an oral contracepti e to suppress o ula
tion thereby reducing progesterone le els. Topical corticoste
roids or mild ec ematous cases and antihistamines in urticarial
cases can be bene cial. or more re ractory cases or in patients
with erythema multi orme ed drug or anaphyla is as the
cause suppression o progesterone production with con u
gated estrogen and gonadotropin releasing antagonists such
as leuprolide acetate dana ol and tamo i en has been suc
cess ul. Desensiti ation protocols may allow or use o proges
terone during in itro ertili ation and pregnancy. enopause
and oophorectomy (e cept in one reported patient) ha e been
curati e.
Autoimmune estrogen dermatitis also presents as a cyclic
s in disorder that may appear ec ematous papular bullous
or urticarial. Pruritus is typically present. S in eruptions may
be chronic but are e acerbated premenstrually or occur only
immediately be ore the menses. Characteristically the derma
tosis clears during pregnancy and at menopause. ntracutane
ous s in testing with estrone produces a papule lasting longer
than h or an immediate urticarial wheal (in patients with
urticaria). n ections o progesterone yield negati e results
ruling out autoimmune progesterone dermatitis. Tamo i en is
e ecti e in some cases.
Agner T, et al: Hand eczema severity and quality of life: a cross-
sectional, multicentre study of hand eczema patients. Contact
Dermatitis 2008; 59:43.
Alonso C, et al: Efficacy of petrolatum jelly for the prevention of diaper
rash: a randomized clinical trial. J Spec Pediatr Nurs 2013; 18:123.
Asai J, et al: Case of autoimmune progesterone dermatitis presenting
as fixed drug eruption. J Dermatol 2009; 36:643.
Barrett ME, et al: Dermatoses of the breast in lactation. Dermatol Ther
2013; 26:331.
Bernstein I, et al: A case of progesterone-induced anaphylaxis, cyclic
urticaria/angioedema, and autoimmune dermatitis. J Womens Health
2011; 20:643.
Bonamonte D, et al: Nummular eczema and contact allergy: a
retrospective study. Dermatitis 2012; 23:153.
Chawla SV, et al: Autoimmune progesterone dermatitis. Arch Dermatol
2009; 145:341.
Coenraads PJ: Hand eczema. N Engl J Med 2012; 367:1829.
78
Cvetkovski RS, et al: Prognosis of occupational hand eczema: a
follow-up study. Arch Dermatol 2006; 142:305.
Darling MI, et al: Sole dermatitis in children: patch testing revisited.
Pediatr Dermatol 2012; 29:254.
Delle Sedie A, et al: Psoriasis, erythema nodosum, and nummular
eczema onset in an ankylosing spondylitis patient treated with
infliximab. Scand J Rhematol 2007; 36:403.
Guillet MH, et al: A 3-year causative study of pompholyx in 120
patients. Arch Dermatol 2007; 143:1504.
Gunes T, et al: Guaiazulene: a new treatment option for recalcitrant
diaper dermatitis in NICU patients. J Matern Fetal Neonatal Med 2013;
26:197.
Heimall LM, et al: Beginning at the bottom: evidence-based care of
diaper dermatitis. MCN Am J Matern Child Nurs 2012; 37:10.
Isaksson M, et al: Children with atopic dermatitis should always be
patch-tested if they have hand or foot dermatitis. Acta Derm Venereol
2014 [Epub ahead of print].
Jacob SE: Ciclosporin ophthalmic emulsion: a novel therapy for
benzyl alcohol–associated eyelid dermatitis. Contact Dermatitis 2008;
58:169.
Jenkins J, et al: Autoimmune progesterone dermatitis associated with
infertility treatment. J Am Acad Dermatol 2008; 58:353.
Kim WJ, et al: Features of Staphylococcus aureus colonization in
patients with nummular eczema. Br J Dermatol 2013; 168:656.
Kontochristopoulos G, et al: Letter: regression of relapsing dyshidrotic
eczema after treatment of concomitant hyperhidrosis with botulinum
toxin-A. Dermatol Surg 2007; 33:1289.
Krupa Shankar DS, Shrestha S: Relevance of patch testing in patients
with nummular dermatitis. Indian J Dermatol Venereol Leprol 2005;
71:406.
Lakshmi C, Srinivas CR: Hand eczema: an update. Indian J Dermatol
Venereol Leprol 2013; 78:569.
Le K, Wood G: A case of autoimmune progesterone dermatitis
diagnosed by progesterone pessary. Australas J Dermatol 2011;
52:139.
Lee M, et al: A case of autoimmune progesterone dermatitis
misdiagnosed as allergic contact dermatitis. Allergy Asthma Immunol
Res 2011; 3:141.
Lerbaek A, et al: Incidence of hand eczema in a population-based twin
cohort: genetic and environmental risk factors. Br J Dermatol 2007;
157:552.
Li CH, et al: Diaper dermatitis: a survey of risk factors for children aged
1-24 months in China. J Int Med Res 2012; 40:1752.
Lundov MD, et al: Creams used by hand eczema patients are often
contaminated with Staphylococcus aureus. Acta Derm Venereol 2012;
92:441.
Lynde C, et al: Extended treatment with oral alitretinoin for patients with
chronic hand eczema not fully responding to initial treatment. Clin Exp
Dermatol 2012; 37:712.
Mauruani A, et al: Re-emergence of papulonodular napkin dermatitis
with use of reusable diapers: report of 5 cases. Eur J Dermatol 2013;
23:246.
Mutasim DF, et al: Bullous autoimmune estrogen dermatitis. J Am Acad
Dermatol 2003; 49:130.
Nivenius E, et al: Tacrolimus ointment vs steroid ointment for eyelid
dermatitis in patients with atopic keratoconjunctivitis. Eye 2007;
21:968.
Petering H, et al: Comparison of localized high-dose UVA1 irradiation
versus topical cream psoralen-UVA for treatment of chronic vesicular
dyshidrotic eczema. J Am Acad Dermatol 2004; 50:68.
Poffet F, et al: Autoimmune progesterone dermatitis: potential role of
cutaneous angiogenin expression? Dermatol 2011; 223:32.
Prieto-Garcoa A, et al: Autoimmune progesterone dermatitis: clinical
presentation and management with progesterone desensitization for
successful in vitro fertilization. Fertil Steril 2011; 95:1121.e9.
Ravanfar P, et al: Diaper dermatitis: a review and update. Curr Opin
Pediatr 2012; 24:472.
Sergeant A, et al: Heterozygous null alleles in filaggrin contribute to
clinical dry skin in young adults and the elderly. J Invest Dermatol
2009; 129:1042.
Stamatas GN, Tierney NK: Diaper dermatitis: etiology, manifestations,
prevention and management. Pediatr Dermatol 2014; 31:1.
Thyssen JP, et al: Filaggrin null-mutations may be associated with a
distinct subtype of atopic hand eczema. Acta Derm Venereol 2010;
90:528.
 Thyssen JP, et al: Xerosis is associated with atopic dermatitis, hand
eczema and contact sensitization independent of filaggrin gene
mutations. Acta Derm Venereol 2013; 93:406.
Toms-Whittle LM, et al: Autoimmune progesterone dermatitis: a
diagnosis easily missed. Clin Dermatol 2010; 36:378.
Wollina U: Pompholyx: a review of clinical features, differential
diagnosis, and management. Am J Clin Dermatol 2010; 11:305.
IMMUNODEFICIENCY SYNDROMES
Primary immunode ciency diseases (P Ds) are important to
the dermatologist. P Ds may present with s in mani estations
and the dermatologist may be instrumental in re erring appro
priate patients or immunode ciency e aluation. These condi
tions ha e also gi en us tremendous insight into the genetic
ma eup and unctioning o the immune system. The P Ds
can be classi ed as those with predominantly antibody de
ciency impaired cell mediated immunity (cellular immunode
ciencies T cells natural iller cells) combined B cell
and T cell de ciencies de ects o phagocytic unction com
plement de ciencies and well characteri ed syndromes with
immunode ciency. ore than P Ds ha e been identi ed
as o the classi cation. any o the original paradigms
o P Ds ha e been re uted. P Ds are not rare can be sporadic
(not amilial) can ha e adult onset can be autosomal domi
nant ha e incomplete penetrance and may e en spontane
ously impro e o er time.
The dermatologist should suspect a P D in certain situations
and the type o immunode ciency can at times be suggested
by the clinical situation. S in in ections especially chronic and
recurrent bacterial s in in ections can be the initial mani esta
tion o a P D with neutropenia ele ated g or T helper cell
immunode ciency. ungal (especially Can i a) and iral in ec
tions (warts molluscum) suggest a P D o helper T cells or a
speci c monogenetic de ect (STAT L ). ot all immuno
de ciencies present with in ections but rather an in amma
tory phenotype. c ematous dermatitis and erythroderma at
times closely resembling se ere atopic or seborrheic dermati
tis may a ect the s in o P D patients. They may be re ractory
to standard therapies. Granuloma ormation autoimmune dis
orders and asculitis are other cutaneous mani estations seen
in some orms o primary immunode ciency. The P Ds in
which a speci c in ection or nding is the more common pre
sentation are discussed in other chapters including chronic
mucocutaneous candidiasis (Chapter ); ermans y Pudla
Ch dia igashi and Griscelli syndromes with pigmentary
anomalies (Chapter ); and cartilage hair hypoplasia syn
drome with disorders o hair (Chapter ). The conditions
described ne t are the most important P D conditions with
which dermatologists should be amiliar.
Abrams M, et al: Genetic immunodeficiency diseases. Adv Dermatol
2007; 23:197.
Mohiuddin MS, et al: Diagnosis and evaluation of primary
panhypogammaglobulinemia: a molecular and genetic challenge.
J Allergy Clin Immunol 2013; 131:1717.
Notarangelo L, et al: Primary immunodeficiency diseases: an update
from the International Union of Immunological Societies Primary
Immunodeficiency Diseases Classification Committee Meeting in
Budapest, 2005. J Allergy Clin Immunol 2006; 117:883.
Ozcan E, et al: Primary immune deficiencies with aberrant IgE
production. J Allergy Clin Immunol 2008; 122:1054.
Rezaei N, et al: Primary immunodeficiency diseases associated with
increased susceptibility to viral infections and malignancies. J Allergy
Clin Immunol 2011; 127:1329.
Schwartzfarb EM, et al: Pyoderma gangrenosum in a patient with
Bruton’s X-linked agammaglobulinemia: shared pathogenesis of
altered tumor necrosis factor alpha? J Clin Aesthet Dermatol 2008;
1:26.
Sillevis Smitt JH, et al: The skin in primary immunodeficiency disorders.
Eur J Dermatol 2005; 15:425.
Uzzaman A, Fuleihan RL: Approach to primary immunodeficiency. Allergy
Asthma Proc 2012; 33:S91.
Immunodeficiency syndromes
Disorders of antibody deficiency
X-linked agammaglobulinemia
Also nown as Bruton syndrome lin ed agammaglobulin
emia ( LA) is caused by mutations in the gene (Bruton
tyrosine inase) which is essential or the de elopment o B
lymphocytes. LA typically presents between and
months o li e because the neonate obtains ade uate immu
noglobulin rom the mother to protect it rom in ection in
young in ancy. The a ected boys present with in ections o
the upper and lower respiratory tracts gastrointestinal (G )
tract s in oints and central ner ous system (C S). The
in ections are usually caused by Streptococcus pneumoniae
Staph lococcus aureus aemophilus in uen ae elicobacter and
Pseu omonas. Recurrent s in staphylococcal in ection may be
a prominent component o this condition. Atopic li e derma
titis and pyoderma gangrenosum ha e been described. epa
titis B entero irus and rota irus in ections are common in
LA patients and one third de elop a rheumatoid li e arthri
tis. ntero irus in ection may result in a dermatomyositis
meningoencephalitis syndrome. An absence o palpable
lymph nodes is characteristic.
mmunoglobulin A g gD and g are irtually absent
rom the serum although gG may be present in small amounts.
The spleen and lymph nodes lac germinal centers and plasma
cells are absent rom the lymph nodes spleen bone marrow
and connecti e tissues. n LA B cells usually only ma e up
. o circulating peripheral blood lymphocytes (normal
). ore than di erent mutations ha e been identi
ed in the gene in LA patients. Some o these mutations
only partially compromise the gene so some patients may ha e
milder phenotype and up to circulating B cells ma ing
di erentiation rom common ariable immunode ciency di
cult. n addition to mutations in the gene mutations in
other genes re uired or immunoglobin production such as
M CD CD LLa L and L C can be
responsible or panhypogammaglobulinemia.
Treatment with gamma globulin has enabled many patients
to li e into adulthood. The maintenance dose re uired can
ary considerably rom patient to patient. igh dose V G
may also lead to impro ement o pyoderma gangrenosum
li e lower e tremity ulcerations. Chronic sinusitis and pulmo
nary in ection remain problematic because o the lac o gA
and chronic sinopulmonary in ections re uire repeated pul
monary unction monitoring.
Dua J, et al: Pyoderma gangrenosum–like ulcer caused by Helicobacter
cinaedi in a patient with X-linked agammaglobulinaemia. Clin Exp
Dermatol 2012; 37:642.
Hunter HL, et al: Eczema and X-linked agammaglobulinaemia. Clin Exp
Dermatol 2008; 33:148.
Lin MT, et al: De novo mutation in the BTK gene of atypical X-linked
agammaglobulinemia in a patient with recurrent pyoderma. Ann Allergy
Asthma Immunol 2006; 96:744.
Isolated IgA deficiency (OMIM 137100)
An absence or mar ed reduction o serum gA (< mg dL) is
the most common immunode ciency state. The incidence
aries greatly based on ethnic bac ground about in the
Arab Peninsula and Spain in the nited States
and in Japan. Certain medications appear
79
 to induce selecti e gA de ciency including phenytoin
5 sul asala ine cyclosporine nonsteroidal anti in ammatory
drugs ( SA Ds) and hydro ychloro uine. The genetic cause
in most cases is un nown.
rom to o all symptomatic immunode ciency
Atopic Dermatitis, Eczema, and Noninfectious Immunodeficiency Disorders
patients ha e gA de ciency. ost gA de cient patients
howe er are completely well. those with symptoms hal
ha e repeated in ections o the G and respiratory tracts and
one uarter ha e autoimmune disease. Allergies such as ana
phylactic reactions to trans usion or V G asthma and atopic
dermatitis are common in the symptomatic group. There is
an increased association o celiac disease dermatitis herpeti
ormis and BD. Vitiligo alopecia areata and other autoim
mune diseases (e.g. systemic lupus erythematosus SL
dermatomyositis scleroderma thyroiditis rheumatoid arthri
tis polyarteritis li e asculitis S gren syndrome) ha e all
been reported to occur in these patients. alignancy is
increased in adults with gA de ciency.
Mellemkjaer L, et al: Cancer risk among patients with IgA deficiency
or common variable immunodeficiency and their relatives: a
combined Danish and Swedish study. Clin Exp Immunol 2002;
130:495.
Paradela S, et al: Necrotizing vasculitis with a polyarteritis nodosa–like
pattern and selective immunoglobulin A deficiency: case report and
review of the literature. J Cutan Pathol 2008; 35:871.
Samolitis NJ, et al: Dermatitis herpetiformis and partial IgA deficiency.
J Am Acad Dermatol 2006; 54:S206.
Yel L: Selective IgA Deficiency. J Clin Immunol 2010; 30:10.
Common variable immunodeficiency
Common ariable immunode ciency (CV D) is a heteroge
neous disorder and is the most common immunode ciency
syndrome a ter gA de ciency. Patients ha e low le els o gG
and gA and also ha e low le els o g . Lymphocyte
counts may be normal or low. ultiple genetic de ects ha e
been ound in CV D including mutations in COS (CV D type
) S (type ) CD (type ) S C (type )
MS (type ) CD (type ) C (type ) L (type )
P CD (type ) and (CV D ). These patients do not
orm antibodies to bacterial antigens and ha e recurrent
sinopulmonary in ections. They ha e a predisposition to
autoimmune disorders such as itiligo and alopecia areata G
abnormalities lymphoreticular malignancy ( old increase
o lymphoma) and gastric carcinoma. onin ectious granulo
mas ha e been reported in as many as o CV D patients.
Se en percent o CV D patients with granulomas ha e cutane
ous granulomas and irtually all patients with cutaneous
granulomas also ha e isceral granulomas. These patients are
more o ten emale and ha e higher ris or lymphoma than
other CV D patients. The granulomas can show multiple his
tologic patterns granuloma annulare li e sarcoidal and e en
caseating. They show a CD CD ratio o less than distin
guishing these granulomas rom sarcoidosis. CV D patients
who de elop granulomas ha e more se ere depletion o
isotype switched memory B cells and na e T cells an immu
nologic pro le also seen in ata ia telangiectasia patients with
cutaneous granulomas.
Replacement o the reduced immunoglobulins with V G
may help reduce in ections. Topical systemic and intrale
sional corticosteroids may be used or the granulomas depend
ing on their e tent. n i imab and etanercept ha e been
e ecti e in steroid re ractory cases.
Artac H, et al: Sarcoid-like granulomas in common variable
immunodeficiency. Rheumatol Int 2009; 30:109.
DeJager M, et al: Immunohistochemical features of cutaneous
granulomas in primary immunodeficiency disorders: comparison with
cutaneous sarcoidosis. J Cutan Pathol 2008; 35:467.
80
Fernandez-Ruiz M, et al: Fever of unknown origin in a patient with
common variable immunodeficiency associated with multisystemic
granulomatous disease. Intern Med 2007; 46:1197.
Lin JH, et al: Etanercept treatment of cutaneous granulomas in common
variable immunodeficiency. J Allergy Clin Immunol 2006; 117:878.
Lun KR, et al: Granulomas in common variable immunodeficiency: a
diagnostic dilemma. Australas J Dermatol 2004; 45:51.
Mazzatenta C, et al: Granulomatous dermatitis in common variable
immunodeficiency with functional T-cell defect. Arch Dermatol 2006;
142:783.
Mitra A, et al: Cutaneous granulomas associated with primary
immunodeficiency disorders. Br J Dermatol 2005; 153:194.
Class-switch recombination defects (formerly
immunodeficiency with hyper-IgM)
This group o diseases includes de ects that are combined
T cell and B cell abnormalities such as CD de ciency CD
and CD ligand de ciency CD L and disorders o
primary B cells such as cytidine deaminase CD and
uracil D A glycosylase U de ciencies. Class switch
recombination de ects are rare and the di erent genetic dis
eases included in this group appear to ha e di erent clinical
mani estations. These patients e perience recurrent sino
pulmonary in ections diarrhea and oral and anogenital
ulcers. eutropenia may be associated with the ulcers. Recal
citrant human papilloma irus in ections (typically at warts)
may occur.
ypomorphic mutations in EMO or are associated
with hypogammaglobulinemia and ele ated g and may be
associated with anhidrotic ectodermal dysplasia with immu
node ciency. EMO mutations cause lin ed recessi e dis
orders with lymphocytosis and ele ated CD and CD cells
and low le els o cells. The mother may ha e mild stig
mata o incontinentia pigmenti. These male in ants present
within the rst ew months o li e with hypohidrosis delayed
tooth eruption and immunode ciency. air may be absent.
re uent in ections o the s in and respiratory tract are
common. The eruption has been characteri ed as an atopic
dermatitis li e eruption although some patients may ha e
prominent intertriginous lesions resembling seborrheic der
matitis. Treatment is bone marrow transplantation.
Chang MW, et al: Mucocutaneous manifestations of the hyper-IgM
immunodeficiency syndrome. J Am Acad Dermatol 1998; 38:191.
Mancini AJ, et al: X-linked ectodermal dysplasia with immunodeficiency
caused by NEMO mutation: early recognition and diagnosis. Arch
Dermatol 2008; 144:342.
Thymoma with immunodeficiency
Thymoma with immunode ciency also nown as Good syn
drome occurs in adults in whom pro ound hypogammaglob
ulinemia and benign thymoma appear almost simultaneously.
t is now classi ed predominantly as an antibody de ciency
disorder. There is a stri ing de ciency o B and pre B cells.
ne patient de eloped ul o aginal gingi al lichen planus.
yelodysplasia and pure red blood cell aplasia may occur.
Patients are at ris or atal opportunistic pulmonary in ec
tions with ungi and Pneumoc stis. Thymectomy does not
pre ent the de elopment o the in ectious or lymphoreticular
complications. Supporti e therapy with V G granulocyte
macrophage colony stimulating actor (G CS ) and trans u
sions may be re uired.
Moutasim KA, et al: A case of vulvovaginal gingival lichen planus in
association with Good’s syndrome. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 2008; 105:e57.
Ohuchi M, et al: Good syndrome coexisting with leukopenia. Ann
Thorac Surg 2007; 84:2095.
Disorders with T-cell deficiency
T cell de ciency states can result rom lac o thymic tissue
en yme de ects to ic to T lymphocytes (purine nucleoside
phosphorylase de ciency) ailure to e press sur ace mole
cules re uired or immune interactions (CD ma or histocom
patibility comple C class and ) or de ects in signaling
molecules ( AP ).
DiGeorge syndrome
DiGeorge syndrome is an autosomal dominant disorder that
in o cases is caused by hemi ygous deletion o pter
and rarely by deletions in p. any cases are sporadic. ost
DiGeorge syndrome patients ha e the congenital anomalies
and only minor thymic anomalies. They present with hypocal
cemia or congenital heart disease. The syndrome includes con
genital absence o the parathyroids and an abnormal aorta.
Aortic and cardiac de ects are the most common cause o
death. DiGeorge syndrome is characteri ed by a distincti e
acies notched low set ears micrognathia shortened phil
trum and hypertelorism. Patients with these DiGeorge
congenital mal ormations and complete lac o thymus
are deemed to ha e complete DiGeorge syndrome. Cell
mediated immunity is absent or depressed and ew T cells
with the phenotype o recent thymus emigrants are ound in
the peripheral blood or tissues. pportunistic in ections are
common despite normal immunoglobulin le els. aternally
deri ed gra t ersus host disease (GV D) may occur in these
patients. A small subset o patients with complete DiGeorge
syndrome de elop an ec ematous dermatitis lymphadenopa
thy and an oligoclonal T cell proli eration. The condition may
present as an atopic li e dermatitis se ere and e tensi e seb
orrheic dermatitis or an erythroderma. This is called atypical
complete DiGeorge syndrome. Biopsies show eatures o a
spongiotic dermatitis with eosinophils necrotic eratinocytes
with satellite necrosis and characteristically perieccrine and
intraeccrine in ammation. This resembles the histology o
grade or GV D lichen striatus and some cases o mycosis
ungoides. ne A rican American patient with DiGeorge syn
drome de eloped a granulomatous dermatitis. The treatment
or complete DiGeorge syndrome is thymic transplantation.
Davies EG: Immunodeficiency in DiGeorge syndrome and options for
treating cases with complete athymia. Front Immunol 2013; 4:322.
Jyonouchi H, et al: SAPHO osteomyelitis and sarcoid dermatitis in a
patient with DiGeorge syndrome. Eur J Pediatr 2006; 165:370.
Selim MA, et al: The cutaneous manifestations of atypical complete
DiGeorge syndrome: a histopathologic and immunohistochemical
study. J Cutan Pathol 2008; 35:380.
Miscellaneous T-cell deficiencies and severe
combined immunodeficiency
IPEX syndrome
The immune dysregulation polyendocrinopathy enteropa
thy lin ed ( P ) syndrome is a rare disorder presenting
neonatally with the classic triad o autoimmune enteropathy
endocrinopathy (diabetes thyroiditis) and ec ematous der
matitis. le ated g le els eosinophilia and ood allergies
plus the ec ematous dermatitis all are mani estations o Th
s ewing o the immune system. Patients present with di use
and se ere erythematous e udati e pla ues resembling AD.
Secondary in ection is common and staphylococcal septice
mia can occur. The s in eruption may be ollicularly based or
may lead to prurigo nodularis. The scalp de elops hyper era
totic psoriasi orm pla ues. Cheilitis and onychodystrophy
can occur. Alopecia areata chronic urticaria and bullous
tahir99 - UnitedVRG
pemphigoid are cutaneous autoimmune mani estations o
P syndrome.
The P syndrome is caused by mutations in O P ( or
head bo P protein) the master control gene or regulatory
T cell (Treg) de elopment. P li e disease may also be
Immunodeficiency syndromes
caused by loss o unction mutations in CD S b and
C and gain o unction mutations in S (signal trans
ducer and acti ator o transcription ) O P is necessary or
the de elopment o Tregs which are re uired to maintain
immune homeostasis and mediate peripheral tolerance to
sel and nonsel antigens. The enteropathy may be dri en
by autoantibodies to illin and these autoantibodies can be
used diagnostically. Treatment is immunomodulator therapy
or bone marrow transplantation.
Severe combined immunodeficiency
Se ere combined immunode ciency (SC D) is a heteroge
neous group o genetic disorders characteri ed by se erely
impaired cellular and humoral immunity. Se ere T cell de
ciency and low lymphocyte count are ound in irtually all
SC D patients. Candidiasis (moniliasis) o the oropharyn and
s in intractable diarrhea and pneumonia are the triad o nd
ings that usually lead to the diagnosis o SC D. n addition
se ere recurrent in ections may occur caused by Pseu omonas
Staph lococcus nterobacteriaceae or Can i a erwhelming
iral in ections are the usual cause o death. ngra tment o
maternally transmitted or trans usion deri ed lymphocytes
can lead to GV D. The initial seborrheic dermatitis li e erup
tion may represent maternal engra tment GV D. This cutane
ous eruption may be asymptomatic but tends to generali e.
ore se ere ec ematous dermatitis and erythroderma may
de elop with alopecia. Cutaneous granulomas ha e been
reported.
De ciency or total absence o circulating T lymphocytes
characteri es SC D. mmunoglobulin le els are consistently
ery low but B cell numbers may be reduced normal or
increased. The thymus is ery small; its mal ormed architec
ture at autopsy is pathognomonic.
The inheritance is either autosomal recessi e or lin ed.
orty percent o SC D cases are lin ed and caused by de
ciency o a common γ chain that is an essential component o
the L receptor. Twenty percent are caused by adenosine
deaminase (ADA) de ciency and rom a mutations.
Prenatal diagnosis and carrier detection are possible or
many orms o SC D. The de niti e treatment is hematopoietic
stem cell transplantation ( SCT bone marrow transplanta
tion). This should ideally be carried out be ore age 3 1 2 months
or optimal outcome. The success rate approaches . n
utero SCT has been success ul in lin ed SC D. SC D
patients rarely li e longer than years without transplanta
tion. n a erage years a ter success ul SCT SC D patients
may de elop se ere human papilloma irus ( PV) in ection
with common warts at warts or e en epidermodysplasia
erruci ormis. The de elopment o PV in ections in SC D
patients ollowing SCT is only seen in patients with either
a or γ chain (gamma c) de ciency but more than o
these patients may de elop this complication.
Miscellaneous Genetic Disorders
of Cellular Immunity
The P and P gene de ciencies are e tremely rare auto
somal recessi e disorders that result in se ere reduction o
C class e pression on the sur ace o cells. CD cells are
decreased but CD cells are normal as are B cell numbers and
81
 serum immunoglobulins. Three orms o disease occur. The
5 patient with the rst phenotype de elops se ere bacterial
ungal and parasitic in ection and dies by age . The patient
with the second phenotype is completely asymptomatic. The
third group is the most common. Group patients present in
Atopic Dermatitis, Eczema, and Noninfectious Immunodeficiency Disorders
childhood with recurrent and chronic bacterial respiratory
in ections. These lead to bronchiectasis and e entually atal
respiratory ailure in adulthood. The s in abnormalities appear
in late childhood or more re uently in young adulthood (a ter
age ). ecroti ing granulomatous lesions appear as pla ues
or ulcerations on the lower legs and on the mid ace around
the nose. The perinasal lesions are uite destructi e and
resemble lethal midline granuloma or Wegener s granulo
matosis. asal polyps with necroti ing granulomatous histol
ogy also occur. ne patient also de eloped leu ocytoclastic
asculitis.
The AP (ζ chain TCR associated protein inase o
D) de ciency is an autosomal recessi e disorder o con
siderable heterogeneity. This en yme is re uired or T cell
receptor (TCR) intracellular signaling. Patients present be ore
age years with recurrent bacterial iral and opportunistic
in ections diarrhea and ailure to thri e. They ha e a lympho
cytosis with normal CD and B cells and decreased CD
cells. Some patients de elop an e oliati e erythroderma
eosinophilia and ele ated g le els.
menn syndrome ( ; histiocytic medullary
reticulosis) is a rare disorder that presents at birth or in the
neonatal period. Classic menn was caused by de ects in mol
ecules in ol ed in the ariable di ersity and oining V(D)J
process. t is also caused by hypomorphic mutations in some
o the genes that cause SC D. Both antibody production and
cell mediated immune unction are impaired. Genetic muta
tions causing menn syndrome occur in and
o cases classic menn) DCL E C (encoding ART S)
D lig L α L γ C D D and P These
mutations all result in de ecti e T cell de elopment and oligo
clonal abnormally acti ated T cells. Clinical eatures include
se ere e oliati e erythroderma eosinophilia alopecia Pneu
moc stis jiroveci and iral pneumonias colitis hepatospleno
megaly lymphadenopathy hypogammaglobulinemia and
ele ated g .
De la Morena MT, Nelson RP Jr: Recent advances in transplantation for
primary immune deficiency diseases: a comprehensive review. Clin
Rev Allergy Immunol 2014; 46:131.
D’Hennezel E, et al: The immunogenetics of immune dysregulation,
polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. J Med
Genet 2012; 49:291.
Dvorak CC, et al: The natural history of children with severe combined
immunodeficiency: baseline features of the first fifty patients of the
Primary Immune Deficiency Treatment Consortium prospective study
6901. J Clin Immunol 2013; 33:1156.
Gadola SD, et al: TAP deficiency syndrome. Clin Exp Immunol 2000;
121:173.
Halabi-Tawil M, et al: Cutaneous manifestations of immune
dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)
syndrome. Br J Dermatol 2009; 160:645.
Horino S, et al: Selective expansion of donor-derived regulatory T cells
after allogeneic bone marrow transplantation in a patient with IPEX
syndrome. Pediatr Transplant 2014; 18:e25.
Kelly BT, et al: Screening for severe combined immunodeficiency in
neonates. Clin Epidemiol 2013; 5:363.
Kim VH, et al: Emergency treatment for ζ chain–associated protein of
70 kDa (ZAP70) deficiency. J Allergy Clin Immunol 2013; 131:1233.
Laffort C, et al: Severe cutaneous papillomavirus disease after
haemopoietic stem-cell transplantation in patients with severe
combined immune deficiency caused by common gamma c cytokine
receptor subunit or JAK-3 deficiency. Lancet 2004; 363:2051.
Lampasona V, et al: Autoantibodies to harmonin and villin are
diagnostic markers in children with IPEX syndrome. PLoS One
2013; 8:e78664.
82
Lee PP, et al: The many faces of ARTEMIS-deficient combined
immunodeficiency: two patients with DCLRE1C mutations and a
systematic literature review of genotype-phenotype correlation. Clin
Immunol 2013; 149:464.
Marrella V, et al: Omenn syndrome does not live by V(D)J
recombination alone. Curr Opin Allergy Clin Immunol 2011; 11:525.
Moins-Teisserenc HT, et al: Association of a syndrome resembling
Wegener’s granulomatosis with low surface expression of HLA class-I
molecules. Lancet 1999; 354:1598.
Plebani A, et al: Defective expression of HLA class I and CD1a
molecules in boy with Marfan-like phenotype and deep skin ulcers.
J Am Acad Dermatol 1996; 35:814.
Shearer WT, et al: Establishing diagnostic criteria for severe combined
immunodeficiency disease (SCID), leaky SCID, and Omenn
syndrome: the Primary Immune Deficiency Treatment Consortium
experience. J Allergy Clin Immunol 2013; 133:1092.
Uzel G, et al: Dominant gain-of-function STAT1 mutations in FOXp3
wild-type immune dysregulation–polyendocrinopathy–enteropathy–X-
linked–like syndrome. J Allergy Clin Immunol 2013; 131:161.
Verbsky JW, Chatila TA: Immune dysregulation, polyendocrinopathy,
enteropathy, X-linked (IPEX) and IPEX-related disorders: an evolving
web of heritable autoimmune diseases. Curr Opin Pediatr 2013;
25:708.
Wiskott-Aldrich syndrome
Wis ott Aldrich syndrome an lin ed recessi e syndrome
consists o a triad o chronic ec ematous dermatitis resembling
AD ( ig. ); increased susceptibility to bacterial in ections
such as pyoderma or otitis media; and thrombocytopenic
purpura with small platelets. Le els o g are ariable gA
is normal to high and g is ele ated as is gG. T cells (espe
cially na e T cells) are low in in ancy and progressi ely
decline in number and acti ity o er time. ntreated sur i al
is about years with death rom in ection bleeding or lym
phoma ( o patients).
The genetic cause o Wis ott Aldrich syndrome is a muta
tion in the SP gene. This gene codes or a protein called
WASP which is uni ersally e pressed in hematopoietic cells
and is critical in the reorgani ation o the actin cytos eleton in
hematopoietic cells in response to e ternal stimuli. The hema
topoietic cells o a ected patients cannot polari e or migrate
in response to physiologic stimuli accounting or the protean
clinical eatures o the syndrome. Wis ott Aldrich syndrome
occurs when mutations in SP lead to absence or truncation
o the WASP protein (WASP mutations). utations that
result in normal length but some loss o unction in the WASP
protein (WASP + mutations) result in two di erent syndromes
lin ed thrombocytopenia ( LT) and intermittent lin ed
Fig. 5-16 Eczematous eruption with purpura in Wiskott-Aldrich
syndrome.
thrombocytopenia. Gain o unction mutations in WASP
cause lin ed neutropenia. Patients with LT may also ha e
an atopic li e dermatitis but this is usually milder than the
se ere and di cult to control ec ema a ecting patients with
the ull Wis ott Aldrich syndrome. WASP LT patients may
also de elop autoimmune disease especially autoimmune
hemolytic anemia asculitis enoch Sch nlein li e purpura
and BD. igh g is associated with the de elopment o
autoimmune disease.
Treatment is with platelet trans usions antibiotics and
V G i re uired. ten splenectomy is per ormed to help
control bleeding but this leads to increased ris o sepsis and
is not routinely recommended. mmunosuppressi e therapy
or ritu imab may be used to control autoimmune complica
tions. Bone marrow transplantation rom a human leu ocyte
antigen ( LA) identical sibling as early as possible in the
disease course pro ides complete re ersal o the platelet and
immune dys unction as well as impro ement or clearing o
the ec ematous dermatitis. Sur i al at years with a matched
sibling donor transplant approaches . gG de ciency is present and in ections are re uent V G may
Massaad MJ, et al: Wiskott-Aldrich syndrome: a comprehensive review.
Ann NY Acad Sci 2013; 1285:26.
Ataxia telangiectasia
Ata ia telangiectasia is an autosomal recessi e condition
caused by mutations in a single gene on chromosome
M which encodes a protein called AT . This protein is
critical in cell cycle control. When AT is absent the cell
cycle does not stop to repair D A damage particularly
double stranded brea s or or B(D)J recombination o immu
noglobulin and TCR genes. This results in immunode ciency
and an increased ris or malignancy. The initial prominent
s in eature is progressi e ocular and cutaneous telangiecta
sias starting at age . These begin on the bulbar con unc
ti a but later de elop on the eyelids ( ig. ) ears and
e ors o the arms and legs. Premature aging (with loss o
subcutaneous at and graying o hair) and progressi e neuro
degeneration also occur. The AT protein seems to be
important in maintaining mitochondrial homeostasis and
this de ect may be responsible or the premature aging and
neurodegeneration.
Cutaneous nonin ectious granulomas may occur and can be
ulcerati e and pain ul. ther cutaneous eatures include large
irregular segmental ca au lait spots itiligo seborrheic der
matitis AD recurrent impetigo and acanthosis nigricans. Late
tightening o the s in can occur and resembles acral sclerosis.
Fig. 5-17 Ataxia telangiectasia.
tahir99 - UnitedVRG
Sinopulmonary in ections are common especially otitis
media sinusitis bronchitis and pneumonia. Varicella (at
times se ere) herpes simple molluscum contagiosum and
herpes oster can occur. Re ractory warts occur in more than
o patients. Aside rom candidal esophagitis unusual
Immunodeficiency syndromes
opportunistic in ections are rare. Childhood immuni ations
including li e iral accines are well tolerated.
Lymphopenia is common with reduction o both B and T
cells occurring in the ma ority o patients. Th cell counts can
be below . gA gG gG and g de ciencies can all be
present. Parado ically g gA and gG can be ele ated in
some patients including the presence o monoclonal gam
mopathy in more than . The immunologic abnormalities
are not progressi e. Lymphoma ris is increased more than
old (especially B cell lymphoma) and leu emia (espe
cially T cell chronic lymphocytic leu emia) is increased
old. Treatment includes high igilance or in ection and
malignancy. n patients with low CD counts prophyla is to
pre ent Pneumoc stis pneumonia can be considered. When
be bene cial. V G and intralesional corticosteroids may be
used or the cutaneous granulomas. Carriers o ata ia telangi
ectasia ha e an increased ris or breast cancer. Because o the
accumulation o chromosomal brea s a ter radiation e posure
both the ata ia telangiectasia patients and the carriers should
minimi e radiation e posure.
Ambrose M, Gatti RA: Pathogenesis of ataxia-telangiectasia: the next
generation of ATM functions. Blood 2013; 121:4036.
Primary immunodeficiency diseases
associated with warts
Depressed T cell unction either iatrogenic or genetic is asso
ciated with an increased ris o PV in ection. owe er a ew
P Ds are associated with a particular burden o PV in ection
and PV in ection may be an initial or prominent component
o the syndrome.
WHIM syndrome
The warts hypogammaglobulinemia in ections and myelo
athe is (W ) syndrome is an autosomal dominant disor
der with hypogammaglobulinemia reduced B cell numbers
and neutropenia. The most common genetic cause is a trunca
tion mutation o C C which leads to gain o unction in
that gene. Additional mutations that are not in the C C
gene can also cause W but all o them lead to unctional
hyperacti ity o C C . C C causes retention o neutro
phils in the bone marrow and is the basis o the neutropenia
and myelo athe is (increased apoptotic neutrophils in bone
marrow). There is pro ound loss o circulating CD + memory
B cells resulting in hypogammaglobulinemia with the obser
ation that W patients ha e normal antibody response to
certain antigens but ail to maintain this antibody production.
owe er normal immunoglobulin le els do not e clude the
diagnosis o W . Almost o W patients ha e
warts at the time o their diagnosis ( ig. ). These include
common and genital wart types. A signi cant number o
emale W patients ha e cer ical and ul al dysplasia
which can progress to carcinoma. W patients ha e dispro
portionately more PV in ections than SC D patients but ha e
little problem resol ing other iral in ections. owe er they
may de elop pstein Barr irus ( BV) induced lymphomas.
The ast ma ority o patients in early childhood ha e recurrent
sinopulmonary in ections s in in ections osteomyelitis and
urinary tract in ections. Recurrent pneumonias lead to bron
chiectasis. Treatment is G CS V G prophylactic antibiotics
83
 Fig. 5-18 Warts in
5 WHIM syndrome.
Atopic Dermatitis, Eczema, and Noninfectious Immunodeficiency Disorders
and aggressi e treatment o in ections. The PV in ections can
progress to atal carcinomas and there ore male patients must
be regularly e amined by dermatologists and emale patients
by gynecologists; a low threshold or biopsy o genital lesions
is re uired.
DOCK8 deficiency
De ciency in D C (dedicator o cyto inesis ) are associ
ated with hyper g syndrome. owe er unli e other genetic
causes o hyper g D C de ciency is uni uely associated
with a susceptibility to cutaneous iral in ections including
SV molluscum contagiosum and PV. Warts can be at or
errucous and a ect about two thirds o patients.
GATA2 deficiency
GATA is an important transcription actor in ol ed in hema
topoiesis maintenance o the stem cell compartment. GATA
de ciency leads to a constellation o syndromes characteri ed
by myelodysplasia opportunistic in ections and leu emia.
Patients ha e pro ound monocytopenia o ten neutropenia
and B and dendritic cell lymphocytopenia. T cell counts
are ariable. ore than o patients ha e se ere or dis
seminated PV in ection usually erruca plana or erruca
ulgaris and it is the rst mani estation in the ma ority o
patients usually in adolescence or early adulthood. Se ere
cer ical PV in ection can also occur and may lead to cancer.
Thirty percent o patients de elop a corticosteroid responsi e
panniculitis. Venous thrombosis occurs in and lymph
edema in o patients. Allogeneic hematopoietic stem cell
transplantation seems to be curati e.
WILD syndrome
The warts immunode ciency lymphedema and dysplasia
(W LD) syndrome is rare and presents at age months with
84 lower e tremity lymphedema that is progressi e and later
may in ol e the upper e tremities and groin. Warts begin in
adolescence and result in anogenital dysplasia and cancer.
Patients also ha e T cell and B cell lymphopenia. This may
represent a mutation syndrome.
Dotta L, et al: Clinical and genetic features of warts,
hypogammaglobulinemia, infections and myelokathexis (WHIM)
syndrome. Curr Mol Med 2011; 11:317.
Kreuter A, et al: A human papillomavirus–associated disease with
disseminated warts, depressed cell-mediated immunity, primary
lymphedema, and anogenital dysplasia. Arch Dermatol 2008;
144:366.
Leiding JW, et al: Warts and all: HPV in primary immunodeficiencies.
J Allergy Clin Immunol 2012; 130:1030.
Mansour S, et al: Emberger syndrome: primary lymphedema with
myelodysplasia—report of seven new cases. Am J Med Genet 2010;
152A:2287.
Minegishi Y, Saito M: Cutaneous manifestations of hyper-IgE syndrome.
Allergol Int 2012; 61:191.
Pasquete M, et al: High frequency of GATA2 mutations in patients with
mild chronic neutropenia, evolving tomonomac syndrome,
myelodysplasia, and acute myeloid leukemia. Blood 2013; 121:822.
Sanal O, et al: Additional diverse findings expand the clinical
presentation of DOCK8 deficiency. J Clin Immunol 2012; 32:698.
Spinner MA, et al: GATA2 deficiency: a protean disorder of
hematopoiesis, lymphatics and immunity. Blood 2014; 123:809.
Defects of phagocyte number, function, or both
Chronic granulomatous disease
Chronic granulomatous disease (CGD) is a rare disorder
caused by mutations in one o the genes that encode the sub
units o the supero ide generating phagocyte ADP o idase
system responsible or the respiratory burst in ol ed in organ
ism illing. CGD is characteri ed by repeated and recurrent
bacterial and ungal in ections o the lungs s in lymph nodes
and bones. Gingi ostomatitis (aphthousli e ulcerations) and
a seborrheic dermatitis o the periauricular perinasal and
perianal area are characteristic. The dermatitis is re uently
in ected with Staph lococcus aureus and regional adenopathy
and abscesses may complicate the in ections. The term sup
purati e dermatitis is used in the immunology literature to
describe this seborrheic li e dermatitis with secondary in ec
tion analogous to the in ecti e dermatitis seen in human
T cell lymphotropic irus ( TLV) in ection. n addition to
S aureus Serratia species are o ten isolated rom s in abscesses
and osteomyelitis. spergillus is the most common agent
causing pneumonia in CGD patients. n tuberculosis endemic
areas CGD patients re uently de elop acti e tuberculosis or
prolonged scarring abscesses or disseminated in ection ol
lowing bacille Calmette Gu rin (BCG) immuni ation.
There are our types o CGD one lin ed and three auto
somal recessi e. The lin ed orm is the most common
( o CGD patients) and is caused by a mutation in the
C gene which leads to absence o the high molecular
weight subunit o cytochrome b (gp pho ) and a total
absence o ADP o idase acti ity. n autosomal recessi e
orms mutations in the genes encoding or the remaining
three o idase components ha e been described p pho
C p pho C and p pho C ne patient
with a mutation in p pho C has been described. The
lin ed ariant has the most se ere phenotype. Compared
with the autosomal recessi e CGD patients the lin ed
patients present at an earlier age ( s. months) and are
diagnosed at an earlier age ( s. years). The lac o
supero ide generation apparently causes disease not because
the bacteria are not being illed by the supero ide but because
the supero ide is re uired to acti ate proteases in phagocytic
acuoles that are needed to ill in ectious organisms.
 Granuloma ormation is characteristic o CGD and can occur
in the G tract li er bladder bone and lymph nodes. p to
o biopsies rom these organs will demonstrate granulo
mas at times with identi able ungal or mycobacterial organ
isms. These patients are o ten recei ing prophylactic antibiotics
howe er so organisms are re uently not ound. Subcorneal
pustular eruptions can also be seen in CGD patients. n the
intestinal tract an BD li e process occurs with granulomas
in the colon. This can cause signi cant G symptoms.
The diagnosis o CGD is made by demonstrating low reduc
tion o yellow nitroblue tetra olium ( BT) to blue orma an
in the BT test. Dihydrorhodamine ow cytometry
(D R) chemiluminescence production and the erricyto
chrome c reduction assay are also con rmatory. Western blot
analysis or ADP o idase e pression and D A se uencing
can pinpoint the genetic mutation.
emale carriers o the lin ed orm o CGD ha e a mi ed
population o normal and abnormal phagocytes and there ore
show intermediate BT reduction and two discrete popula
tions with D R testing. The ma ority o carriers ha e s in
complaints. Raynaud phenomenon can occur. ore than hal
will report a photosensiti e dermatitis ha e oral ulcer
ations and a third ha e oint complaints. S in lesions in car
riers ha e been described as discoid lupus erythematosus
(DL ) li e but histologically the inter ace component is o ten
absent and the lesions resemble tumid lupus. Direct immuno
uorescence e amination is usually negati e as is common
in tumid lupus erythematosus (L ). Less re uently CGD
patients themsel es ha e been described as ha ing similar L
li e lesions or arcuate dermal erythema. Despite these nd
ings the ast ma ority o patients with L li e s in lesions
both carriers and CGD patients are antinuclear antibody
(A A) negati e.
Treatment o in ections should be early and aggressi e.
There should be a low threshold to biopsy s in lesions as they
may re eal important and potentially li e threatening in ec
tions. Patients usually recei e chronic T P S prophyla is
chronic oral itracona ole or another anti spergillus agent and
γ in ections. Bone marrow or stem cell transplantation has
been success ul in restoring en yme unction reducing in ec
tions and impro ing the associated bowel disease. owe er
sur i al is not increased with bone marrow transplantation so
this is not routinely underta en.
Cale CM, et al: Cutaneous and other lupus-like symptoms in carriers of
X-linked chronic granulomatous disease: incidence and autoimmune
serology. Clin Exp Immunol 2007; 148:79.
Gallin JI, et al: Itraconazole to prevent fungal infections in chronic
granulomatous disease. N Engl J Med 2003; 348:2416.
Lee PP, et al: Susceptibility to mycobacterial infections in children with
X-linked chronic granulomatous disease: a review of 17 patients
living in a region endemic for tuberculosis. Pediatr Infect Dis J 2008;
27:224.
Leiding JW, Holland SM: Chronic granulomatous disease. In Pagon RA,
et al (eds): GeneReviews 2012 [Internet].
Levine S, et al: Histopathological features of chronic granulomatous
disease (CGD) in childhood. Histopathology 2005; 47:508.
Luis-Montoya P, et al: Chronic granulomatous disease: two members of
a single family with different dermatologic manifestations. Skinmed
2005; 4:320.
Raptaki M, et al: Chronic granulomatous disease: a 25-year patient
registry based on a multistep diagnostic procedure, from the referral
center for primary immunodeficiencies in Greece. J Clin Immunol 2013;
33:1302.
Leukocyte adhesion deficiency
This rare autosomal recessi e disorder has three types. Leu o
cyte adhesion de ciency (LAD) type is caused by a mutation
in the common chain (CD ) o the β integrin amily ( . The initial eruption is noted rst on the ace or scalp but
t is characteri ed by recurrent bacterial in ections o the s in
tahir99 - UnitedVRG
and mucosal sur aces especially gingi itis and periodontitis.
S in ulcerations rom in ection may continue to e pand. Cel
lulitis and necrotic abscesses especially in the perirectal area
can occur. inor in uries may lead to pyoderma gangrenosum
li e ulcerations that heal slowly. n ections begin at birth and
Immunodeficiency syndromes
omphalitis with delayed separation o the cord is characteris
tic. eutrophilia is mar ed usually times normal and
the count may reach up to during in ections. Despite
this there is an absence o neutrophils at the sites o in ection
demonstrating the de ecti e migration o neutrophils in these
patients. LAD type patients are a ected either se erely (<
o normal CD e pression) or moderately ( . o normal
e pression.) Patients with moderate disease ha e less se ere
in ections and sur i e into adulthood whereas patients with
se ere disease o ten die in in ancy.
LAD type is caused by a mutation in SLC C which
results in a general de ect in ucose metabolism which results
in decreased ucosylation o selectin ligands on leu ocytes.
This leads to impaired tethering and rolling on acti ated
endothelial cells. Se ere mental retardation short stature a
distincti e acies and the rare hh blood phenotype are the
eatures. nitially these patients ha e recurrent cellulitis with
mar ed neutrophilia but the in ections are not li e threaten
ing. A ter age years in ections become less o a problem and
patients de elop chronic periodontitis.
LAD type is caused by a mutation in the gene E M
and is characteri ed by se ere recurrent in ections bleeding
tendency ( rom impaired platelet unction) and mar ed
neutrophilia.
Bone marrow transplantation is re uired or patients with
se ere LAD type and LAD type .
Dababneh R, et al: Periodontal manifestation of leukocyte adhesion
deficiency type I. J Periodontol 2008; 79:764.
Etzioni A: Leukocyte adhesion deficiencies: molecular basis, clinical
findings, and therapeutic options. Adv Exp Med Biol 2007; 601:51.
Harris ES et al: Lessons from rare maladies: leukocyte adhesion
deficiency syndromes. Curr Opin Hematol 2013; 20:16.
Mellouli F, et al: Successful treatment of Fusarium solani ecthyma
gangrenosum in a patient affected by leukocyte adhesion deficiency
type 1 with granulocytes transfusions. BMC Dermatology 2010;
10:10.
Parvaneh N, et al: Characterization of 11 new cases of leukocyte
adhesion deficiency type 1 with seven novel mutations in the ITGB2
gene. J Clin Immunol 2010; 30:756.
Qasim W, et al: Allogeneic hematopoietic stem-cell transplantation for
leukocyte adhesion deficiency. Pediatrics 2009; 123:836.
Simpson BN, et al: A new leukocyte hyperadhesion syndrome of
delayed cord separation, skin infection, and nephrosis. Pediatrics
2014; 133:e257.
Svensson L, et al: Leukocyte adhesion deficiency-III is caused by
mutations in KINDLIN3 affecting integrin activation. Nat Med 2009;
15:306.
Hyperimmunoglobulinemia E syndrome
There are at least three de ned mutations that cause hyperim
munoglobulinemia syndrome ( S; also called hyper g
syndrome). The autosomal dominant orm is caused by a
mutation in S and the autosomal recessi e orm by
mutations in DOC and rarely in tyrosine inase
The two autosomal orms o S are clinically somewhat
di erent and are described separately.
Autosomal dominant S was rst called Job s syndrome
or Buc ley s syndrome. The classic triad is an AD li e ec ema
tous dermatitis recurrent s in and lung in ections and high
serum g . The s in disease is the rst mani estation o STAT
de ciency and begins at birth in o cases within the rst
wee o li e in more than and in the rst month in .
uic ly generali es to a ect the ace scalp and body. The rash 85
 a ors the shoulder arms chest and buttoc s. The newborn
5 rash begins as pin papules that may initially be diagnosed as
neonatal acne. The papules de elop uic ly into pustules
then coalesce into crusted pla ues. istologically these
papules are intraepidermal eosinophilic pustules. The derma
Atopic Dermatitis, Eczema, and Noninfectious Immunodeficiency Disorders
titis e ol es to bear a close resemblance to AD o ten ery
se ere and occurs in o autosomal dominant
patients. Staphylococcal in ection o the dermatitis is common
and treatment o the staphylococcal in ection with antibiotics
and bleach baths leads to impro ement. g le els are abo e
in o patients with autosomal dominant S but
since only about o children with g le els abo e
actually ha e S other eatures must be used to con rm the
diagnosis. Abscesses sometimes cold are characteristic. Recur
rent pyogenic pneumonia is the rule starting in childhood.
Because o the lac o neutrophilic in ammation in the pneu
monia symptoms may be lac ing and lead to a delay in diag
nosis. Although antibiotic treatment clears the pneumonia
healing is abnormal with the ormation o bronchiectasis and
pneumatoceles a characteristic eature o S. ucocutane
ous candidiasis is common typically thrush aginal candidia
sis and candida onychomycosis. usculos eletal abnormalities
are common including scoliosis osteopenia minimal trauma
ractures ( ) and hypere tensibility leading to premature
degenerati e oint disease. Retention o some or all o the
primary teeth is a characteristic eature. ther oral mani esta
tions include median rhomboid glossitis high arch palate and
abnormally prominent wrin les on the oral mucosa. Arterial
aneurysms are common including Chiari mal ormation
( ) and coronary ascular abnormalities ( ). The latter
can cause myocardial in arction. Autosomal dominant
patients ha e a characteristic acies de eloping during child
hood and adolescence. eatures include acial asymmetry
broad nose deep set eyes and a prominent orehead. The
acial s in is rough with large pores. There is an increased ris
o malignancy predominantly B cell non odg in lymphoma.
Laboratory abnormalities are limited to eosinophilia and an
ele ated g . n adults g le els may become normal. Th
cells are lac ing rom the peripheral blood o S mutation
patients. A scoring system de eloped at the ational nstitutes
o ealth ( ) can accurately identi y patients with S recessi e traits. De ciencies o all
selecting those in whom genetic testing could be considered.
Autosomal recessi e S is much less common. These
patients also ha e se ere ec ema and recurrent s in and
lung in ections although the lung in ections resol e without
pneumatoceles. ood allergies are o ten present in autosomal
recessi e S caused by DOC mutation as is decreased
g . These patients are predisposed to cutaneous iral
in ections especially warts molluscum contagiosum herpes
simple and aricella oster. They also de elop mucocutane
ous candidiasis. eurologic disease is much more common
in autosomal recessi e S ranging rom acial paralysis to
hemiplegia. Autosomal recessi e S patients ha e normal
acies no ractures and normal shedding o primary denti
tion but a dramatic increase in malignancy especially
leu emia.
Treatment or S is currently traditional. n ections are
suppressed with bleach baths and chronic antibiotic prophy
la is (usually with T P S ); anti ungal agents may be used
or candidal in ections o the s in and nails. Topical anti
in ammatories are used to manage the ec ema and in se ere
cases cyclosporine can be considered. Bisphosphonates are
used or osteopenia. The role o V G antihistamines and
omali umab (antibody against g ) is un nown. n patients
with autosomal recessi e S hematopoietic cell transplan
tation ( CT) is recommended because o the high ris o
malignancy and C S in arction. Autosomal dominant
patients with malignancy should be considered or CT since
86
it can re erse the S reducing the in ectious complications
ollowing CT.
Eberting CL, et al: Dermatitis and the newborn rash of hyper-IgE
syndrome. Arch Dermatol 2004; 140:1119.
Freeman AF, et al: Hyper IgE (Job’s) syndrome: a primary immune
deficiency with oral manifestations. Oral Dis 2009; 15:2.
S Ling JC, et al: Coronary artery aneurysms in patients with hyper IgE
recurrent infection syndrome. Clin Immunol 2007; 122:255.
Mogensen TH, et al: STAT3 and the hyper-lgE syndrome: clinical
presentation, genetic origin, pathogenesis, novel findings and
remaining uncertainties. JAK-STAT 2013; 2e23435.
Rael EL, et al: The hyper-lgE syndromes: lessons in nature, from bench
to bedside. World Allergy Organ J 2012; 5:79.
Woellner C, et al: Mutations in STAT3 and diagnostic guidelines for
hyper-IgE syndrome. J Allergy Clin Immunol 2010;125:424.
Yong PF, et al: An update on the hyper-lgE syndromes. Arthritis Res
Ther 2012; 14:228.
Complement deficiency
The complement system is an e ector pathway o proteins that
results in membrane damage and chemotactic acti ity. our
ma or unctions result rom complement acti ation cell
lysis opsoni ation phagocytosis in ammation and immune
comple remo al. n the classical complement pathway
complement is acti ated by an antigen antibody reaction
in ol ing gG or g . Some complement components are
directly acti ated by binding to the sur ace o in ectious organ
isms; this is called the alternate pathway. The central com
ponent common to both pathways is C . n the classical
S pathway antigen antibody comple es se uentially bind and
acti ate three complement proteins C C and C leading
to the ormation o C con ertase an acti ator o C . The
alternate pathway starts with direct acti ation o C . rom
acti ated C C C are se uentially acti ated. Cytolysis is
induced mainly through the membrane attac comple ( AC)
which is made up o the terminal components o complement.
psoni ation is mainly mediated by a subunit o C b and
in ammation by subunits o C C and C .
nherited de ciencies o complement are usually autosomal
components o the clas
sical pathway as well as inhibitors o this pathway ha e been
described. Genetic de ciency o the C inhibitor is the only
autosomal dominant orm o complement de ciency and
results in hereditary angioedema (see Chapter ). n general
de ciencies o the early components o the classical pathway
result in connecti e tissue disease states whereas de ciencies
o the late components o complement lead to recurrent neis
serial sepsis or meningitis. erlap e ists and patients with
late component de ciencies may e hibit connecti e tissue
disease and patients with de ciencies o early components
such as C may mani est in ections. De ciency o C results
in recurrent in ections with encapsulated bacteria such as
Pneumococcus aemophilus in uen ae and Streptococcus p o
genes. C inacti ator de ciency as with C de ciency results
in recurrent pyogenic in ections. Properdin (component o
alternate pathway) dys unction is inherited as an lin ed trait
and predisposes to ulminant meningococcemia. De ciency o
C is the most common complement de ciency in Japan but
is uncommon in other countries. ost patients appear healthy.
ASP de ciency resulting in absent hemolytic acti ity by
the lectin pathway is considered a complement de ciency and
results in a syndrome resembling SL and increased pyogenic
in ection. actor de ciency results in recurrent in ections
including eisseria meningiti es. Partially de cient amily
members may also ha e increased in ections.
S C de ciency is the most common complement de ciency
in the nited States and urope. ost patients are healthy but
 Fig. 5-19 Annular
subacute cutaneous
lupus erythematosus
(SCLE) lesions that
characterize C2
deficiency.
SL li e syndromes de elop in re uent in ections
anaphylactoid purpura dermatomyositis asculitis and cold
urticaria may be seen. C C and C de cient patients
ha e SL at rates o and respecti ely. Comple
ment de ciency associated SL typically has early onset pho
tosensiti ity less renal disease and Ro La autoantibodies in
two thirds o patients. C and C de cient patients with L
typically ha e subacute annular morphology ( ig. ) Third the recipient must be unable to re ect the transplanted
S gren syndrome arthralgias and oral ulcerations. Renal
disease anti dsD A antibodies and anticardiolipin antibod
ies are uncommon. Patients with C de ciency may ha e
lupus and in ol ement o the palms and soles.
any o the complement component de ciencies can be
ac uired as an autoimmune phenomenon or a paraneoplastic
nding. amples include ac uired angioedema as when C
inhibitor is the target or lipodystrophy and nephritis when
C con ertase is the target.
When complement de ciency is suspected a use ul screen
ing test is a C (total hemolytic complement) determina
tion because de ciency o any o the complement components
will usually result in C le els that are dramatically reduced
or ero.
Kosaka S, et al: Cutaneous vasculitic and glomerulonephritis associated
with C4 deficiency. Clin Exp Dermatol 2013; 38:492.
Lipsker D, Hauptmann G: Cutaneous manifestations of complement
deficiencies. Lupus 2010; 19:1096.
Sozeri B, et al: Complement-4 deficiency in a child with systemic lupus
erythematosus presenting with standard treatment-resistant severe skin
lesion. ISRN Rhematol 2011; 2011:917673.
Tichaczek-Goska D: Deficiencies and excessive human complement
system activation in disorders of multifarious etiology. Adv Clin Exp
Med 2012; 21:105.
Graft-versus-host disease
Gra t ersus host disease (GV D) occurs most re uently in
the setting o SCT but may also occur ollowing organ trans
plantation or in the rare situation o trans usion o acti e lym
phoid cells into an immunode cient child postpartum or e en
in utero. Blood trans usions with acti e lymphocytes (nonradi
ated whole blood) rom amily members or in populations
with minimal genetic ariability gi en to an immunode cient
tahir99 - UnitedVRG
Fig. 5-20 Acute
graft-versus-host
disease.
Immunodeficiency syndromes
patient can result in GV D. SCT rom a mono ygotic twin
(syngeneic) or e en rom the patient s own stem cells (autolo
gous) can induce a mild orm o GV D.
De elopment o GV D re uires three elements. irst the
transplanted cells must be immunologically competent.
Second the recipient must e press tissue antigens that are not
present in the donor and there ore are recogni ed as oreign.
cells. mmunologic competence o the transplanted cells is
important because ablating them too much may lead to ailure
o engra tment or more o ten incomplete eradication o
the recipient s malignancy (gra t s. tumor e ect). There ore
some degree o immunologic competence o the transplanted
cells is desired. or this reason the pre alence o GV D still
remains about a ter SCT. Another important actor in
determining the de elopment and se erity o the GV D is the
preconditioning regimen. Chemotherapy and radiation cause
acti ation o dendritic cells (antigen presenting cells APCs) in
tissues with high cell turno er the s in gut and li er. These
APCs increase their e pression o LA and other minor cell
sur ace antigens priming them to interact with transplanted
lymphoid cells. ost APCs are important in presenting these
antigens to the acti e lymphoid donor cells. Cyto ines espe
cially L T α and γ are important in enhancing this
host donor immunologic interaction. Reducing this early
in ammatory component in GV D can delay the onset o the
GV D but may not reduce the pre alence. The indications or
SCT age limits and allowable degree o LA incompatibil
ity ha e resulted in greater use o SCT increasing the number
o persons at ris or GV D.
nitially only reactions that occurred within the rst
days a ter transplantation were considered acute GV D but
it is now recogni ed that classic acute GV D can occur up to
year or more a ter SCT especially with tapering o anti
GV D immunosuppressi es. Acute GV D is based on the
clinical presentation not the duration ollowing transplanta
tion. n acute GV D the cutaneous eruption typically begins
between the th and nd days a ter transplantation with a
pea at day ( ig. ). Acute GV D is characteri ed by an
erythematous morbilli orm eruption o the ace and trun
which may become con uent and result in e oliati e eryth
roderma. t o ten begins with punctate lesions corresponding
87
 to hair ollicles and eccrine ducts resembling eratosis pilaris.
5 en when morbilli orm dar er punctate areas are a help ul
clinical sign. n children the diaper area is o ten in ol ed. The
eruption may appear papular and ec ematous in ol ing web
spaces periumbilical s in and ears. The appearance bears
Atopic Dermatitis, Eczema, and Noninfectious Immunodeficiency Disorders
some resemblance to scabies.
The di erential diagnosis or the eruption o acute GV D
includes the eruption o lymphocyte reco ery engra tment
syndrome iral e anthem and drug eruption. The cutaneous
histology in the early phases o acute GV D may not be able
to distinguish these entities. Grade V GV D is characteri ed
by ull thic ness slough and may resemble to ic epidermal
necrolysis. The mucous membranes and the con uncti ae can
be in ol ed as well which can be di cult to distinguish rom
chemotherapy induced and in ectious mucositis. ten about
the same time the patient de elops the other characteristic
eatures o acute GV D cholestatic hepatitis with ele ated
bilirubin and high olume diarrhea. Syngeneic autologous
GV D usually in ol es only the s in and is sel limited. The
preconditioning regimens are thought to result in loss o
sel tolerance.
ngra tment syndrome is a combination o symptoms that
occur about the time o engra tment and neutrophil reco ery.
Patients de elop e er (without in ectious source) diarrhea
pulmonary in ltrates with hypo ia and capillary lea syn
drome with edema and weight gain. t occurs as soon as days
a ter autologous SCT and days a ter allogeneic trans
plants. The associated s in eruption is clinically and histologi
cally identical to acute GV D but at presentation it is usually
diagnosed as a drug eruption and antibiotic therapy is re
uently changed. cular in ol ement with eratitis can occur.
This syndrome occurs in o post SCT patients and is
a signi cant cause o morbidity and mortality in autologous
peripheral blood progenitor cell transplant patients. n one
series engra tment syndrome accounted or o all
transplant related mortality. t is mediated by cyto ine pro
duction and neutrophil in ltration o the organs damaged by
the conditioning chemotherapy especially the lungs. Admin
istration o G CS and autologous transplantation are ris
actors or its de elopment. The relationship o engra tment
syndrome to eruption o lymphocyte reco ery is unclear.
Treatment is high dose systemic corticosteroids.
With impro ed support or GV D patients a ter SCT
more are sur i ing and de elop chronic disease
(cGV D). t is the second most common cause o death in
SCT patients. t is unclear whether cGV D is mediated by
the same pathologic mechanisms as acute GV D. Chronic
disease has eatures more typical o an autoimmune disease.
Diagnostic criteria ha e been adopted with diagnostic and
distincti e cutaneous mani estations. The most common
diagnostic eature occurring in o patients who de elop
cGV D is a lichen planus li e eruption. t typically occurs
months a ter gra ting usually beginning on the hands and eet
but becoming generali ed. t may present with a malar rash
resembling L . The chronic inter ace dermatitis can lea e the
s in with a poi ilodermatous appearance. Similar lichen
planus li e lesions may occur on the oral mucosa and can
result in pain and poor nutrition. Lichen sclerosus li e lesions
can also occur. n ol ement o the aginal or esophageal
mucosa can result in se ere scarring and strictures. About
o men with cGV D ha e genital s in changes and ha e
cGV D o the penis. cGV D o the s in and oral mucosa is
associated with genital in ol ement. LS li e lesions phimosis
and in ammatory balanitis are most common; o men
with penile cGV D report erectile dys unction.
Sclerosis is the other diagnostic amily o s in lesions. This
can include lesions resembling super cial morphea which can
ha e o erlying lichen sclerosus li e changes. The morpheali e
88
Fig. 5-21 Chronic graft-versus-host disease.
lesions demonstrate an isomorphic response a oring areas o
pressure especially the waistband and brassiere band areas.
Deeper sclerotic lesions resembling eosinophilic asciitis
(resulting in oint contractures ig. ) and restriction o the
oral commissure due to sclerosis can occur. These sclerotic
pla ues may ulcerate especially during P VA therapy. The
e tent o in ol ement o the deep tissues such as muscle and
ascia cannot be easily de ned by clinical e amination and
may be aided by magnetic resonance imaging ( R ). Rarely
the myositis o cGV D may be accompanied by a s in erup
tion similar to dermatomyositis.
The distincti e eatures o GV D include depigmentation
resembling itiligo; scarring or nonscarring alopecia; nail
dystrophy (e.g. longitudinal ridging brittle thin nails pte
rygium nail loss); and erostomia and other S gren li e
mucosal symptoms.
istologically acute GV D demonstrates acuolar inter
ace dermatitis. ndi idual eratinocyte necrosis with ad acent
lymphocytes (satellite necrosis) is typically present suggest
ing cell mediated cytoto icity. The e tent o necrosis bulla
ormation and slough is used in grading schemes. n early
acute GV D the ndings may be ocal and restricted to hair
ollicles and sweat ducts. The histologic ndings in early
disease may be nonspeci c and many treatment protocols do
not depend on histologic eatures to initiate therapy. A bac
ground o epidermal disorder and atypia resembling bowenoid
actinic eratosis is almost uni ersally present in later lesions
o acute GV D and is a help ul diagnostic eature. Similar
epidermal changes may be seen with cancer chemotherapy
especially in acral erythema or a ter busul an. Chronic GV D
demonstrates lichenoid dermatitis or dermal sclerosis with
hyalini ation o collagen bundles and narrowing o the space
between bundles.
Pre ention o posttrans usion GV D is most sa ely achie ed
by irradiating the blood be ore trans usion in high ris indi
iduals. Acute GV D is managed on the s in with topical
corticosteroids TC s and V phototherapy. When systemic
symptoms appear a glucocorticoid cyclosporine or tacroli
mus is instituted. tracorporeal photopheresis can be consid
ered in patients with acute or chronic GV D unresponsi e to
these rst line therapies. Bath P VA with or without isotreti
noin can impro e sclerotic cGV D. Bloc ing the cyto ine
storm with monoclonal antibodies such as etanercept or in i
imab was initially promising but since has been associated
with in asi e ungal in ections. Ritu imab by targeting B
cells has shown some bene t in steroid re ractory cGV D.
Sirolimus and e erolimus appear to ha e acti ity against
brosis and may be use ul in brotic cGV D. matinib may
also be use ul in cGV D with brosis by inhibiting platelet
deri ed growth actor receptor (PDG R). esenchymal stem
cells ha e been reported to be e ecti e in patients with re rac
tory acute or chronic GV D without discernible ad erse
e ects.
GVHD in solid-organ transplantation
Transplantation o a solid organ into a partially immunosup
pressed host may result in GV D because the organ may
contain immune cells. The pre alence o GV D a ter solid
organ transplantation is e tremely low about at one center
o er years with more than transplants. The ris or
de eloping GV D a ter solid organ transplantation is related
to the type o organ transplanted and depends on the amount
o lymphoid tissue that the organ contains. The ris pro le is
small intestine > li er pancreas > idney > heart. n li er and
small intestine transplants the ris is but when it occurs
mortality is . Close matching increases the ris o GV D
in organ transplantation because the immunocompetent
recipient cells are less li ely to recogni e the donor lympho
cytes as nonsel and destroy them. Also A rican American
race and cytomegalo irus (C V) in ection increase the ris .
The onset is usually wee s ollowing transplantation but
can be delayed or years. e er rash and pancytopenia are
the cardinal eatures. The s in is the rst site o in ol ement
and only cutaneous disease occurs in o cases. Both acute
and chronic GV D s in ndings can occur. S in biopsies tend
to show more in ammation than in SCT associated GV D.
n GV D accompanying li er transplantation the li er is
una ected because it is syngeneic with the donor lympho
cytes. n these patients pancytopenia can occur and is a re
uent cause o mortality. The diagnosis o GV D in patients
recei ing organ transplantation can be aided by documenting
tahir99 - UnitedVRG
macrochimerism in the peripheral blood and s in a ter the rst
month o transplantation.
Byun HJ, et al: Clinical differentiation of acute cutaneous graft-versus-
host disease from drug hypersensitivity reactions. J Am Acad Dermatol
Immunodeficiency syndromes
2011; 65:726.
Hymes SR, et al: Graft-versus-host disease. Part I. Pathogenesis and
clinical manifestations of graft-versus-host disease. J Am Acad
Dermatol 2012; 66:515e1.
Hymes SR, et al: Graft-versus-host disease. Part II. Management of
cutaneous graft-versus-host disease. J Am Acad Dermatol 2012;
66:535e1.
Mueller SM, et al: Genital chronic GVHD in men after hematopoietic
stem cell transplantation: a single-center cross-sectional analysis of
155 patients. Biol Blood Marrow Transplant 2013; 19:1574.
Sharma A, et al: Graft-versus-host disease after solid organ
transplantation: a single center experience and review of literature. Ann
Transplant 2012; 17:133.
Ziemer M, et al: Histopathological diagnosis of graft-versus-host
disease of the skin: an interobserver comparison. J Eur Acad Dermatol
Venereol 2014; 28:915.
Bonus images for this chapter can be found online at
expertconsult.inkling.com
eFig. 5-1 Dennie-Morgan folds (or Morgan folds).
eFig. 5-2 Nasal crease.
eFig. 5-3 Pityriasis alba.
eFig. 5-4 Hyperkeratotic hand dermatitis.
eFig. 5-5 Napkin psoriasis.
eFig. 5-6 Juvenile plantar dermatosis.
eFig. 5-7 Nummular eczema.
eFig. 5-8 Eczematous eruption with purpura in Wiskott-Aldrich
syndrome.
89
 Immunodeficiency syndromes
eFig. 5-1 Dennie-Morgan folds (or Morgan folds).
eFig. 5-4 Hyperkeratotic hand dermatitis.

eFig. 5-2 Nasal crease. eFig. 5-5 Napkin psoriasis.

eFig. 5-3 Pityriasis eFig. 5-6 Juvenile

alba. plantar dermatosis.

89.e1
 eFig. 5-7 Nummular eFig. 5-8 Eczematous
5 eczema. eruption with purpura
in Wiskott-Aldrich
syndrome.
Atopic Dermatitis, Eczema, and Noninfectious Immunodeficiency Disorders

89.e2

tahir99 - UnitedVRG
 Bonus images for this chapter can be found online at
expertconsult.inkling.com
6 Contact Dermatitis and Drug Eruptions
CONTACT DERMATITIS
There are two types o dermatitis caused by substances coming
in contact with the s in irritant dermatitis and allergic contact
dermatitis. rritant dermatitis is an in ammatory reaction in
the s in resulting rom e posure to a substance that causes an
eruption in most people who come in contact with it. Allergic
contact dermatitis is an ac uired sensiti ity to arious
substances that produce in ammatory reactions only in those
persons who ha e been pre iously sensiti ed to the allergen.
Irritant contact dermatitis
any substances act as irritants that produce a nonspeci c
in ammatory reaction o the s in. This type o dermatitis may
be induced in any person i there is contact with a su ciently
high concentration. o pre ious e posure is necessary and
n
the e ect is e ident within minutes or a ew hours at most.
The concentration and type o to ic agent duration o e po
U
sure and condition o the s in at the time o e posure produce
the ariation in se erity o the dermatitis rom person to
-
person or rom time to time in the same person. The s in may
be more ulnerable because o maceration rom e cessi e
humidity or e posure to water heat cold pressure or riction.
9
Dry s in as opposed to wet s in is less li ely to react to con
tactants although in chronic erosis as seen in elderly patients
ri 9
increased sensiti ity to irritants results. Thic s in is less reac
ti e than thin s in. Atopic patients are predisposed to irritant
hand dermatitis. Repeated e posure to some o the milder
irritants may produce a hardening e ect o er time. This
h
process ma es the s in more resistant to the irritant e ects o
a gi en substance. Symptomatically pain and burning are
t a
more common in irritant dermatitis contrasting with the usual
itch o allergic reactions. A oidance substitution o nonirritat
ing agents when possible and protection most o ten by
wearing glo es are the mainstays o treatment.
Alkalis
rritant dermatitis is o ten produced by al alis such as soaps
detergents bleaches ammonia preparations lye drain pipe
cleaners and toilet bowl and o en cleansers. Al alis penetrate
and destroy deeply because they dissol e eratin. Strong solu
tions are corrosi e and immediate application o a wea acid
such as inegar lemon uice or . hydrochloric acid solu
tion will lessen their e ects.
The principal compounds are sodium potassium ammo
nium and calcium hydro ides. ccupational e posure is re
uent among wor ers in soap manu acturing. Sodium silicate
(water glass) is a caustic used in soap manu acture and paper
si ing and or the preser ation o eggs. Al alis in the orm o
soaps bleaching agents detergents and most household
cleansing agents gure prominently in the causes o hand
90
ec ema. Al aline sul des are used as depilatories ( ig. ).
Calcium o ide ( uic lime) orms sla ed lime when water is
added. Se ere burns may be caused in plasterers.
Acids
G
The power ul acids are corrosi e whereas the wea er acids
are astringent. ydrochloric acid produces burns that are less
R
deep and more liable to orm blisters than in uries rom sul u
ric and nitric acids ( ig. ). ydrochloric acid burns are
V
encountered in those who handle or transport the product and
in plumbers and those who wor in gal ani ing or tin plate
d
actories. Sul uric acid produces a brownish charring o the
s in beneath which is an ulceration that heals slowly. Sul uric
ti e
acid is used more widely than any other acid in industry; it is
handled principally by brass and iron wor ers and by those
who wor with copper or bron e. itric acid is a power ul
o idi ing substance that causes deep burns; the tissue is
stained yellow. Such in uries are obser ed in those who manu
acture or handle the acid or use it in the ma ing o e plosi es
in laboratories. At times nitric acid or ormic acid is used in
assaults secondary to interpersonal con icts resulting in scar
ring most prominently o the ace with the complication o
renal ailure present in a small number o cases.
ydro uoric acid is used widely in rust remo er in the
semiconductor industry and in germicides dyes plastics and
glass etching. t may act insidiously at rst starting with ery
thema and ending with esiculation ulceration and nally
necrosis o the tissue. ydro uoric acid is one o the strongest
inorganic acids capable o dissol ing glass. ypocalcemia
hypomagnesemia hyper alemia and cardiac dysrhythmias
may complicate hydro uoric acid burns. luorine is best neu
trali ed with he a uorine solution ollowed by calcium
gluconate solution or magnesium o ide.
alic acid may produce paresthesia o the ngertips with
cyanosis and gangrene. The nails become discolored yellow.
alic acid is best neutrali ed with limewater or mil o mag
nesia to produce precipitation. Titanium hydrochloride is used
in the manu acture o pigments. Application o water to the
e posed part will produce se ere burns. There ore treatment
consists only o wiping away the no ious substance.
Phenol (carbolic acid) is a protoplasmic poison that pro
duces a white eschar on the sur ace o the s in. t can penetrate
deep into the tissue. a large sur ace o the s in is treated with
phenol or cosmetic peeling e ects the absorbed phenol may
produce glomerulonephritis and arrhythmias. Locally tempo
rary anesthesia may also occur. Phenol is readily neutrali ed
with ethyl or isopropyl alcohol.
Chromic acid burns which may be seen in electroplating
and dye production occupations may result in e tensi e
tissue necrosis and acute renal damage. cision o a ected
s in down to the ascia should be accomplished rapidly
and hemodialysis to remo e circulating chromium should
start in the rst h. ther strong acids that are irritants

Fig. 6-1 Alkali burn caused by depilatory.
Fig. 6-2 Acid burn.
include acetic trichloracetic arsenious chlorosul onic uoro
boric hydriodic hydrobromic iodic perchloric phosphoric
salicylic silico uoric sul onic sul urous tannic and tungstic
acids.
Treatment o acid burns consists o immediate rinsing with
copious amounts o water and al ali ation with sodium bicar
bonate calcium hydro ide (limewater) or soap solutions.
Phosphorus burns should be rinsed o with water ollowed
by application o copper sul ate to produce a precipitate.
Airbag dermatitis
Airbags are deployed as a sa ety eature on cars when
rapid deceleration occurs. Acti ation o a sodium a ide and
cupric o ide propellant cartridge releases nitrogen gas which
e pands the bag at speeds e ceeding m h ( miles h).
Talcum powder sodium hydro ide and sodium carbonate are
released into the bag. Abrasions thermal riction and chemi
cal burns and an irritant contact dermatitis may result. Super
cial erythema may respond well to topical steroids but
ull thic ness burns may occur and re uire debridement and
gra ting.
Other irritants
etal salts that act as irritants include the cyanides o calcium
copper mercury nic el sil er and inc and the chlorides o
calcium and inc. Bromine chlorine uorine and iodine are
also irritants. ccupational e posure to methyl bromide may
produce erythema and esicles in the a illary and inguinal
areas. nsecticides including dichloro inyl dimethyl phos
phate used in roach powder and y repellents and illers can
act as irritants.
tahir99 - UnitedVRG
Fiberglass dermatitis
iberglass dermatitis is seen a ter occupational or inad ertent
e posure. The small spicules o glass penetrate the s in and
cause se ere irritation with tiny erythematous papules scratch
Contact dermatitis
mar s and intense pruritus. sually there is no delayed
hypersensiti ity reaction. Wearing clothes that ha e been
washed together with berglass curtains handling air condi
tioner lters or wor ing in the manu acture o berglass mate
rial may produce se ere olliculitis pruritus and eruptions
that may simulate scabies or insect bites. iberglass is also
used in thermal and acoustic installation the wind industry
padding ibration isolation curtains draperies insulation or
automobile bodies urniture gasoline tan s and spacecra t.
Talcum powder dusted on the e ure sur aces o the arms
be ore e posure ma es the bers slide o the s in. A thorough
washing o the s in a ter handling berglass is help ul. Patch
testing to epo y resins should be done when e aluating
wor ers in berglass and rein orced plastics operations
because an allergic contact dermatitis may be di cult to
discern rom berglass dermatitis.
Dusts
Some dusts and gases may irritate the s in in the presence o
heat and moisture such as perspiration. The dusts o lime inc
and arsenic may produce olliculitis. Dusts rom arious woods
such as tea may incite itching and dermatitis. Dusts rom
cinchona bar uinine and pyrethrum produce widespread
dermatitis. Tobacco dust in cigar actories powdered orris
root lycopodium and dusts o arious nutshells may cause
swelling o the eyelids and dermatitis o the ace nec and
upper e tremities the distribution o an airborne contact der
matitis. Dusts ormed during the manu acture o high e plo
si es may cause erythematous esicular and ec ematous
dermatitis that may lead to generali ed e oliati e dermatitis.
Capsaicin
and irritation produced by capsaicin in hot peppers used in
orean and orth Chinese cuisine ( unan hand) may be
se ere and prolonged sometimes necessitating stellate gan
glion bloc ade and gabapentin. Pepper spray used by police
in high concentrations and by ci ilians in less concentrated
ormulas contains capsaicin and may produce se ere burns.
Cold water is not much help; capsaicin is insoluble in water.
Acetic acid (white inegar) or antacids ( aalo ) may com
pletely relie e the burning e en i applied an hour or more
a ter the contact. Application should be continued until the
area can be dried without return o the discom ort.
Tear gas dermatitis
Lacrimators such as chloroacetophenone in concentrated orm
may cause dermatitis with a delayed appearance about
h a ter e posure. rritation or sensiti ation with ery
thema and se ere esiculation may result. Treatment consists
o la age o the a ected s in with sodium bicarbonate solution
and instillation o boric acid solution into the eyes. Contami
nated clothing should be remo ed.
Sul ur mustard gas also nown as yperite (dichlorodiethyl
sul de) has been used in chemical war are (e.g. ra ran war
in the s). rythema esicles and bullae result rom mild
to moderate e posure ( ig. ). To ic epidermal necrolysis
(T ) li e appearance may ollow more concentrated contact.
The earliest and most re uently a ected sites are areas
co ered by clothing and humidi ed by sweat such as the
groin a illae and genitalia.
91
 Fig. 6-3 Mustard gas
6 burn. (Courtesy of
James WD [ed]:
Textbook of Military
Medicine. Office of the
Contact Dermatitis and Drug Eruptions
Surgeon General,
United States Army,
1994.)
Fig. 6-4 Mace-induced
reaction.
n
U
-
ace is a mi ture o tear gas (chloroacetophenone) in tri
9
chloroethane and arious hydrocarbons resembling erosene.
t is a ailable in a ariety o sel de ense sprays. ace is a
ri 9
potent irritant and may cause allergic sensiti ation ( ig. ).
Treatment consists o changing clothes then washing with oil
or mil ollowed by washing with copious amounts o water.
h
Chloracne
t a
Wor ers in the manu acture o chlorinated compounds may
de elop chloracne with small straw colored ollicular plugs
and papules chie y on the malar crescent retroauricular
areas earlobes nec shoulders and scrotum. istologically
there is a loss o sebaceous glands and the ormation o cystic
structures. The synthetic wa es chloronaphthalene and chlo
rodiphenyl used in the manu acture o electric insulators and
in paints arnishes and lac uers predispose wor ers engaged
in the manu acture o these synthetic wa es to chloracne.
posure to dichloroben onitrile during the manu acture
o a herbicide and to ′ ′ tetrachloroa oo yben ene
which is an unwanted intermediate byproduct in the manu
acture o a pesticide may also produce chloracne.
A contaminant in the synthesis o herbicides and he achlo
rophene tetracholorodiben o p dio in produces a
chemical burn in the acute stage but chloracne hyperpigmen
tation hirsutism and s in ragility (with or without criteria
or porphyria cutanea tarda) are mani estations o chronic
to icity. Gastrointestinal tract cancer and malignancies
o the lymphatic and hematopoietic systems are suspected to
result. While direct contact is the usual method o e posure
92
inhalation ingestion or contact with contaminated clothing
may also result in chloracne. Chloracne may persist or long
periods because dio in is stored in the li er and released
slowly into the circulation. Treatment is with medications
used in acne ulgaris including isotretinoin.
Hydrocarbons
any hydrocarbons produce s in eruptions. Crude petroleum
causes generali ed itching olliculitis or acnei orm eruptions.
The irritant properties o petroleum deri ati es are directly
proportional to their at sol ent properties and in ersely pro
portional to their iscosity. ils o the naphthalene series are
more irritating than those o the para n series. Re ned rac
tions rom petroleum are less irritating than the unre ned
products although ben ene naphtha and carbon disul de
may cause a mild dermatitis.
Lubricating and cutting oils are causes o similar cutaneous
lesions. They represent a re uent cause o occupational der
matoses in machine tool operators machinists layout men
G
instrument ma ers and setup men. nsoluble (neat) cutting
oils are responsible or a ollicular acnei orm eruption on the
R
dorsa o the hands the orearms ace thighs and bac o the
nec . yperpigmentation eratoses and scrotal cancer ha e
V
been ound in those e posed to insoluble cutting oils. Soluble
oils and synthetic uids used in metalwor ing do not result
d
in acne but rather an ec ematous dermatitis usually o the
dorsal orearms and hands. Appro imately o the time it
ti e
is irritant and in the remainder it is allergic. Allergic contact
dermatitis arises rom arious additi es such as biocides col
oring agents and deodori ers.
Coal bri uette ma ers de elop dermatitis as a result o a
tarry residue rom petroleum used in their trade. Para n
e posure leads to pustules eratoses and ulcerations. Shale
oil wor ers de elop an erythematous ollicular eruption that
e entually leads to eratoses which may become the sites o
carcinoma. t is estimated that o shale oil wor ers ha e
s in problems.
mpure and low grade para ns and mineral oils cause
similar s in eruptions. nitially the s in changes are similar to
those in chloracne. er time a di use erythema with dappled
pigmentation de elops. Gradually eratoses appear and a ter
many years some o these are the sites o carcinoma. elano
derma may occur rom e posure to mineral oils and lower
grade petroleum rom creosote asphalt and other tar products.
Photosensiti ation may play a role. Creosote is a contact irri
tant sensiti er and photosensiti er. Allergy is demonstrated
by patch testing with creosote in oil.
Petrolatum dermatitis may appear as a errucous thic ening
o the s in caused by prolonged contact with impure petro
leum elly or occasionally lubricating oil. A ollicular centered
process may occur in which erythematous horny nodules are
present usually on the anterior and inner aspects o the thighs.
There are no comedones and the lesions are separated by
apparently normal s in.
Acne corne consists o ollicular eratosis and pigmentation
resulting rom crude petroleum tar oils and para n. The
dorsal aspects o the ngers and hands the arms legs ace
and thora are the areas usually in ol ed. The lesions are ol
licular horny papules o ten blac and are associated at rst
with a ollicular erythema and later with a dirty brownish or
purplish spotty pigmentation which in se ere cases becomes
widespread and is especially mar ed around the genitals. This
syndrome may simulate pityriasis rubra pilaris or lichen
spinulosus.
Coal tar and pitch and many o their deri ati es produce
photosensiti ation and an acnei orm olliculitis o the ore
arms legs ace and scrotum. ollicular eratoses (pitch warts)
may de elop and later turn into carcinoma. Soot lamp blac
and the ash rom peat res produce dermatitis o a dry
scaly character which o er time orms warty outgrowths and
cancer. Chimney sweep s cancer occurs under a soot wart and
is usually located on the scrotum where soot sebum and dirt
collect in the olds o the s in. This orm o cancer has irtually
disappeared.
Ac uired per orating disease may occur in oil eld wor ers
who use drilling uid containing calcium chloride. Patients
de elop tender umbilicated papules o the orearms that
microscopically show transepidermal elimination o calcium.
Solvents
The sol ents cause appro imately o occupational derma
titis. When sol ents are applied to the hands to cleanse them
the sur ace oil is dissol ed and a chronic ssured dermatitis
results. Additionally peripheral neuropathy and chemical
lymphangitis may occur a ter the sol ents are absorbed
through the ssured s in. Sol ent sni ers may de elop an
ec ematous eruption around the mouth and nose; erythema
and edema occur. This is a direct irritant dermatitis caused by
the inhalation o the sol ent placed on a hand erchie .
Trichloroethylene is a chlorinated hydrocarbon sol ent
and degreasing agent also used in the dry cleaning and
re rigeration industry. nhalation may produce e oliati e
erythroderma mucous membrane erosions eosinophilia and
hepatitis.
Allergic contact dermatitis caused by alcohol is rarely
encountered with lower aliphatic alcohols. A se ere case o
bullous and hemorrhagic dermatitis on the ngertips and
deltoid region was caused by isopropyl alcohol. Although
rare ethyl alcohol dermatitis may also be encountered. Cetyl
and stearyl alcohols may pro o e contact urticaria.n secreRe
Ale IS, et al: Irritant contact dermatitis. Rev Environ Health 2014;
29:195–206.
Bordel-Gomez MT, et al: Fiberglass dermatitis. Contact Dermatitis 2008;
59:120.
Bourke J, et al: Guidelines for the management of contact dermatitis.
Br J Dermatol 2009; 160:946.
Edlich RF, et al: Modern concepts of treatment and prevention of
chemical injuries. J Long Term Eff Med Implants 2005; 15:303.
Flammiger A, et al: Sulfuric acid burns. Cutan Ocul Toxicol 2006;
25:55.
Goon AT, et al: A case of trichloroethylene hypersensitivity syndrome.
Arch Dermatol 2001; 137:274.
Herzemans-Boer M, et al: Skin lesions due to methyl bromide. Arch
Dermatol 1988; 124:917.
Jia X, et al: Adverse effects of gasoline on the skin of gasoline workers.
Contact Dermatitis 2002; 46:44.
Karunadasa KP, et al: Burns due to acid assaults in Sri Lanka. J Burn
Care Res 2010; 31:781.
Landeck L, et al: Clinical course of occupational irritant contact
dermatitis of the hands in relation to filaggrin genotype status and
atopy. Br J Dermatol 2012; 167:1302.
Momeni AZ, et al: Skin manifestations of mustard gas. Arch Dermatol
1992; 128:775.
Passarini B, et al: Chloracne. Dermatology 2010; 221:63.
Salzman M, et al: Updates on the evaluation and management of
caustic exposures. Emerg Med Clin North Am 2007; 25:459.
Saurat JH, et al: The cutaneous lesions of dioxin exposure: lessons
from the poisoning of Victor Yushchenko. Toxicol Sci 2012; 125:310.
Saxena AK, et al: Multimodal approach for the management of Hunan
hand syndrome. Pain Prac 2013; 13:227.
Seyfarth F, et al: Dry skin, barrier function, and irritant contact dermatitis
in the elderly. Clin Dermatol 2011; 29:31.
Stuke LE, et al: Hydrofluoric acid burns. J Burn Care Res 2008; 29:893.
Wu JJ, et al: A case of air bag dermatitis. Arch Dermatol 2002;
138:1383.
Yoshirmura CA, et al: Seventy per cent hydrofluoric acid burns. J Burn
Care Res 2011; 32:e149.
tahir99 - UnitedVRG
Allergic contact dermatitis
Allergic contact dermatitis results when an allergen comes into
contact with pre iously sensiti ed s in. t is caused by a spe
ci c ac uired hypersensiti ity o the delayed type also nown
Contact dermatitis
as cell mediated (type V) hypersensiti ity. These sensiti ers
do not cause demonstrable s in changes on initial contact.
Persons may be e posed to allergens or years be ore nally
de eloping hypersensiti ity. Genetic ariability in the immu
nologic processes leading to sensiti ation and other actors
such as concentration o the allergen applied its ehicle
timing and site o the e posure presence o occlusion age
gender and race o the patient and presence o other s in
or systemic disorders li ely determine whether any gi en
e posure will result in sensiti ation. nce sensiti ed
howe er subse uent outbrea s may result rom e tremely
slight e posure.
Childhood e posures do result in allergy and the re uency
o allergy in this age group is increasing. The most common
rele ant allergens are nic el cobalt and ragrance. Sensiti ity
is rarely lost o er the years; older patients ha e similar rates
o allergy as adults.
ccasionally dermatitis may be induced when the allergen
is ta en internally by a patient rst sensiti ed by topical appli
cation as with substances such as cinnamon oil or arious
medications. The anamnestic response is termed systemic
contact dermatitis. t may appear rst at the site o the prior
sensiti ation or past positi e patch test but may spread to a
generali ed morbilli orm or ec ematous eruption. Additional
morphologic patterns include esicular hand ec ema urti
caria erythema multi orme asculitis or symmetric drug
related intertriginous and e ural e anthema (SDR ).
ormerly called baboon syndrome SDR is a deep red io
let eruption on the buttoc s genital area inner thighs and
sometimes the a illae.
The most common causes o contact dermatitis in the
nited States are to icodendrons (poison i y oa or sumac)
nic el balsam o Peru M rox lon pereirae neomycin ra
grance ormaldehyde and the ormaldehyde releasing pre
ser ati es bacitracin and rubber compounds. re uent
positi e reactions to gold and thimerosal do not o ten corre
late with the clinical e posure history. Gold reactions which
may be prolonged can be correlated in some cases with oral
gold e posure or occupational dermatitis but in most cases
the rele ance is uestionable. Thimerosal reactions are prob
ably related to its use as a preser ati e in common accines
and s in testing material. t also ser es as a mar er or
piro icam photosensiti ity.
c ematous delayed type hypersensiti ity reaction as
e empli ed by allergic contact dermatitis and the patch test
must be distinguished rom immediate type hypersensiti ity
reaction. The latter presents within minutes o e posure with
urticaria and is pro ed with a scratch test. t should be ept in
mind howe er that persons who de elop contact urticaria to
a substance may concomitantly ha e a type V delayed type
sensiti ation and ec ema rom the same allergen.
n some patients impetigo pustular olliculitis and
irritation or allergic reactions rom applied medications are
superimposed on the original dermatitis. A particularly e ing
situation is when allergy to topical corticosteroids complicates
an ec ema in which case the pree isting dermatitis usually
does not are but simply does not heal as e pected. The cuta
neous reaction may also pro o e a hypersusceptibility to
arious other pre iously innocuous substances which contin
ues the ec ematous in ammatory response inde nitely.
These eruptions resol e when the cause is identi ed and
a oided. or acute generali ed allergic contact dermatitis
treatment with systemic steroidal agents is e ecti e beginning
93
 with mg day o prednisone in a single oral dose and Fig. 6-5 Positive patch
6 tapering slowly to topical steroids. When the eruption is
limited in e tent and se erity local application o topical cor
test reaction.

ticosteroid creams lotions or aerosol sprays is pre erred.

Contact Dermatitis and Drug Eruptions

Testing for sensitivity

Patch test
The patch test is used to detect hypersensiti ity to a substance
that is in contact with the s in so that the allergen may be
determined and correcti e measures ta en. So many allergens
can cause allergic contact dermatitis that it is impossible to test
a person or all o them. n addition a good history and obser
ation o the pattern o the dermatitis its locali ation on the
body and its state o acti ity are help ul in determining the
cause. The patch test is con rmatory and diagnostic but only
within the ramewor o the history and physical ndings; it
is rarely help ul i it must stand alone. nterpretation o the
rele ance o positi e tests and the subse uent education o

G
patients are challenging in some cases. The Contact Allergen
anagement Program (CA P) pro ides names o alternati e

R
products that may be used by patients when an allergen is
identi ed. This is a ailable through the American Contact

V
Dermatitis Society.
The patch test consists o application o substances sus

d
pected to be the cause o the dermatitis to intact unin amed inter ere with the number and unction o ey immunologic
s in. Patch testing may be administered by the thin layer processes leading to sensiti ation and reacti ity to testing.

rapid use epicutaneous (TR ) test or by indi idually pre
pared patches. The TR test has resulted in more screening
or allergic contact dermatitis than in the past but i it does
not re eal the allergen or a highly suspect dermatitis testing
ti e
alse negati e reactions may result; the alue o testing in
such circumstances is that i a positi e reaction occurs a diag
nosis may be made. Vitiliginous s in is less reacti e than nor
mally pigmented ad acent s in.

n
with an e panded series will on a erage yield rele ant aller
gens in more than hal o these patients. Dermatitis originating Provocative use test

U
in the wor place will almost always re uire indi iduali ed The pro ocati e use test will con rm a positi e closed patch
testing. test reaction to ingredients o a substance such as a cosmetic;

-
Test substances are applied usually to the upper bac it is used to test products that are made to stay on the s in
although i only one or two are applied the upper outer arm once applied. The material is rubbed on to normal s in o the
may be used. ach patch should be numbered to a oid con u inner aspect o the orearm se eral times a day or days.

9
sion. The patches are remo ed a ter h (or sooner i se ere
itching or burning occurs at the site) and read. The patch sites Photopatch test

ri 9
need to be e aluated again at day or because positi e reac
tions may not appear earlier. Some allergens may ta e up to
day to show a reaction and the patient should be ad ised to
return i such a delayed reaction occurs. rythematous papules
The photopatch test is used to e aluate or contact photoal
lergy to such substances as sul onamides phenothia ines
p aminoben oic acid o yben one methyl coumarin mus
ambrette and tetrachlorosalicylanilide. A standard patch test

h
and esicles with edema are indicati e o allergy ( ig. ). is applied or h; this is then e posed to J m o VA
ccasionally patch tests or potassium iodide nic el or and read a ter another h. To test or methyl coumarin

t a
mercury will produce pustules at the site o the test applica
tion. sually no erythema is produced; there ore the reaction
has no clinical signi cance.
Strong patch test reactions may induce a state o hyperirri
tability ( e cited s in syndrome ) in which ad acent tests
that would otherwise be negati e appear as wea ly positi e.
Wea ly positi e tests in the presence o strong tests do not
pro e sensiti ity. The s in and mucous membranes ary
widely in the ability to react to antigens. The oral mucosa is
more resistant to primary irritants and is less liable to be
in ol ed in allergic reactions. This may be because the eratin
layer o the s in more readily combines with haptens to orm
allergens. Also the oral mucosa is bathed in sali a which
cleanses and bu ers the area and dilutes irritants. owe er
patch testing or arious types o oral signs and symptoms
such as swelling tingling and burning perioral dermatitis
and the appearance o oral lichen planus is use ul in determin
ing a cause in many cases.
Potent topical corticosteroids ultra iolet ( V) light arious
immunosuppressants (e.g. oral prednisone) and the ac uired
immunode ciency syndrome (A DS) ha e been reported to
94
sensiti ity the patch is applied in the same manner but or
only min be ore light e posure rather than or h. A
duplicate set o nonirradiated patches is used in testing or the
presence o routine delayed hypersensiti ity reactions. Also a
site o normal s in is gi en an identical dose o VA to test
or increased sensiti ity to light without prior e posure to
chemicals. There is a steady increase in incidence o photoal
lergy to sunscreening agents and a decreasing incidence o
such reactions to ragrance.
Regional predilection
amiliarity with certain contactants and the typical dermatitis
they elicit on speci c parts o the body will assist in diagnosis
o the etiologic agent.
Head and neck
The scalp is relati ely resistant to the de elopment o contact
allergies; howe er in ol ement may be caused by hair dye
hair spray shampoo or permanent wa e solutions. The sur
rounding glabrous s in including the ear rims and bac s o

Fig. 6-6 Eyelid dermatitis.
the ears may be much more in amed and suggesti e o the
cause. Persistent otitis o the ear canal may be caused by sen
siti ity to neomycin an ingredient o most aural medications.
The eyelids are the most re uent site or nail polish dermati
tis. Volatile gases alse eyelash adhesi e ragrances preser
ati es mascara rubber in sponges used to apply cosmetics
and eyeshadow are also re uently implicated ( ig. ). Peri
oral dermatitis and cheilitis may be caused by a oring agents
in denti rices and gum as well as ragrances shellac medica
ments and sunscreens in lipstic and lip balms. Per ume der
matitis may cause redness ust under the ears or on the nec .
arlobe dermatitis is indicati e o nic el sensiti ity. Photocon
tact dermatitis may in ol e the entire ace and may be sharply
cut o at the collar line or e tend down on to the sternum in
a V shape. There is a typical clear area under the chin where
there is little or no e posure to sunlight. The le t chee and le t
side o the nec ( rom sun e posure while dri ing) may be the
rst areas in ol ed.
Trunk
The trun is an in re uent site; howe er the dye or nish o
clothing may cause dermatitis. The a illa may be the site
o deodorant dermatitis and clothing dye dermatitis; in ol e
ment o the a illary ault suggests the ormer; o the
a illary olds the latter. n women brassieres cause dermatitis
rom the material itsel the elastic or the metal snaps or
underwires.
Arms
The wrists may be in ol ed because o ewelry or the bac s o
watches and clasps all o which may contain nic el. Wrist
bands made o leather are a source o chrome dermatitis.
Hands
nnumerable substances may cause allergic contact dermatitis
o the hands which typically occurs on the bac s o the hands
and spares the palms. lorists will o ten de elop ngertip or
palmar lesions (see ig. ). A hand dermatitis that changes
rom web spaces to ngertips or rom palms to dorsal hands
should trigger patch testing. Poison i y and other plant der
matitides re uently occur on the hands and arms. Rubber
glo e sensiti ity must be ept constantly in mind. sually
irritancy is superimposed on allergic contact dermatitis o the
hands altering both the morphologic and histologic clues to
the diagnosis.
Abdomen
The abdomen especially the waistline may be the site o
rubber dermatitis rom the elastic in pants and undergar
tahir99 - UnitedVRG
ments. The metallic ri ets in blue eans may lead to periumbili
cal dermatitis in nic el sensiti e patients as may piercings o
the umbilicus.
Groin
Contact dermatitis
The groin is usually spared but the buttoc s and upper thighs
may be sites o dermatitis caused by dyes. The penis is re
uently in ol ed in poison i y dermatitis. Condom dermatitis
may also occur. The perianal region may be in ol ed rom the
caine medications in suppositories as well as preser ati es
and ragrances in cleansing materials. Almost hal o women
with pruritus ul ae ha e one or more rele ant allergens;
o ten these are medicaments ragrances or preser ati es.
Lower extremities
The shins may be the site o rubber dermatitis rom elastic
stoc ings. eet are sites or shoe dermatitis most o ten attrib
utable to rubber sensiti ity chrome tanned leather dyes or
adhesi es. Application o topical antibiotics to stasis ulcers
re uently leads to sensiti ity and allergic contact dermatitis.
Bonitsis NG, et al: Allergens responsible for allergic contact dermatitis
among children. Contact Dermatitis 2011; 64:245.
Bourke I, et al: Guidelines for the management of contact dermatitis.
Br J Dermatol 2009; 160:946.
Bryden AM, et al: Photopatch testing of 1155 patients. Br J Dermatol
2006; 155:737.
Diepgen TL, et al: Management of chronic hand eczema. Contact
Dermatitis 2007; 57:203.
Feser A, et al: Periorbital dermatitis. Br J Dermatol 2008; 159:858.
Jean SE, et al: Contact dermatitis in leg ulcer patients. J Cutan Med
Surg 2009; 13(suppl 1):S38.
Fonacier LS, et al: Allergic contact dermatitis. Ann Allergy Asthma
Immunol 2014; 113:9–12.
Kockentiet B, et al: Contact dermatitis in athletes. J Am Acad Dermatol
2007; 56:1048.
Mowad CM: Patch testing. Curr Opin Allergy Clin Immunol 2006; 6:340.
Prakash AV, et al: Contact dermatitis in older adults. Am J Clin Dermatol
2010; 11:373.
Rietschel RL, Fowler JF Jr: Fisher’s Contact Dermatitis, 6th edn.
Hamilton: BC Decker, 2008.
Schena D, et al: Contact allergy in chronic eczematous lip dermatitis.
Eur J Dermatol 2008; 18:688.
Schlosser BJ: Contact dermatitis of the vulva. Dermatol Clin 2010;
28:697.
Sheman A, et al: Contact allergy alternatives. Dis Mon 2008; 54:7.
Simonsen AB, et al: Contact allergy and allergic contact dermatitis in
children. Contact Dermatitis 2011; 65:254.
Spring S, et al: Contact dermatitis to topical medicaments. Dermatitis
2012; 23:210.
Tan CH, et al: Contact dermatitis. Clin Dermatol 2014; 32:116–124.
Thyssen JP, et al: The epidemiology of contact allergy in the general
population. Contact Dermatitis 2007; 57:287.
Torgerson RR, et al: Contact allergy in oral disease. J Am Acad
Dermatol 2007; 57:315.
Uter W, et al: Patch test results with patients’ own perfumes,
deodorants and shaving lotions. J Eur Acad Dermatol Venereol 2007;
21:374.
Veien NK: Systemic contact dermatitis. Int J Dermatol 2011; 50:1445.
Warshaw EM, et al: Positive patch test reactions in older individuals. J
Am Acad Dermatol 2012; 66:229.
Winnicki M, et al: A systematic approach to systemic contact dermatitis
and symmetric drug-related intertriginous and flexural exanthema
(SDRIFE). Am J Clin Dermatol 2011; 12:171.
Dermatitis resulting from plants
A large number o plants including trees grasses owers
egetables ruits and weeds are potential causes o dermati
tis. ruptions rom them ary considerably in appearance
but are usually esicular and accompanied by mar ed
edema. A ter pre ious e posure and sensiti ation to the acti e
95
 substance in the plant the typical dermatitis results rom ree
6 posure. The onset is usually a ew hours or days a ter contact.
The characteristic linearly grouped lesions are probably
produced by brushing the s in with a lea edge or a bro en
twig or by carriage o the allergen under the nails. Contrary
Contact Dermatitis and Drug Eruptions
to general belie the contents o esicles are not capable o
producing new lesions.
Toxicodendron (poison ivy)
oxico en ron dermatitis includes dermatitis rom members o
the Anacardiaceae amily o plants poison i y ( ra icans or
hus ra icans) poison oa iversilobum iversaloba
poison sumac vernix vernix Japanese lac uer tree
cashew nut tree (allergen in nutshell) mango (allergen in rind
lea es or sap) Rengas tree and ndian mar ing nut tree. The
gin go (allergen in ruit pulp) spider ower or sil er oa
luta species o trees and shrubs in Southeast Asia Bra ilian
pepper tree also nown as lorida holly and poisonwood tree
contain almost identical antigens.
oxico en ron dermatitis appears within h o e posure o
a person pre iously sensiti ed to the plant. t usually begins
on the bac s o the ngers interdigital spaces wrists and
eyelids although it may begin on the an les or other parts that
ha e been e posed. ar ed pruritus is the rst symptom;
in ammation esicles and bullae may then appear. The es
icles are usually grouped and o ten linear ( ig. ). Large
bullae may be present especially on the orearms and hands.
The eyelids are pu y and worst in the morning impro ing as
the day progresses ( ig. ). Pruritus ani and in ol ement o
the genital areas occur re uently. A blac lac uer deposit may
occur in which the sap o the plant has been o idi ed a ter
being bound to the stratum corneum ( ig. ). ntreated oxi
n
co en ron dermatitis usually lasts wee s.
The ngers trans er the allergen to other parts especially the
U
orearms and the male prepuce which become greatly swollen.
owe er once the causati e oil has been washed o there is
-
no spreading o the allergen and no urther spread o the der
matitis. Some persons are so susceptible that direct contact is
9
Fig. 6-7 Acute poison
ri 9
ivy reaction.
a h
t
96
not necessary the allergen apparently being carried by the ur
o their pets or by the wind. t can also be ac uired rom gol
clubs or shing rods or e en rom urniture that a dog or cat
might ha e occupied a ter e posure to the catechol. ccasion
ally eating the allergen as occurred in a patient who ingested
raw cashew nuts in an imported pesto sauce may result
in SDR (see earlier) or a systemati ed allergic contact der
matitis with the morphology o a generali ed erythematous
papular eruption.
The cause is an oleoresin nown as urushiol o which the
acti e agent is a mi ture o catechols. This and related resor
cinol allergens are present in many plants and also in Philo en
ron species wood rom Persoonia elliptica wheat bran and
marine brown algae.
The most stri ing diagnostic eature is the linearity o the
lesions. t is rare to see esicles arranged linearly e cept in
plant induced dermatitis. A history o e posure in the country
or par to plants that ha e shiny lea es in groups o three
ollowed by the appearance o esicular lesions within days
usually establishes the diagnosis.
G
radication o plants ha ing grouped lea es o three
growing in re uented places is one easy pre enti e measure
R
as is recognition o the plants to a oid. An e cellent resource
is a pamphlet a ailable rom the American Academy o Der
V
matology. the indi idual is e posed washing with soap and
water within min may pre ent an eruption. Protecti e
d
barrier creams are a ailable that are somewhat bene cial.
uaternium bentonite has been shown to pre ent or dimin
ti e
ish e perimentally produced poison i y dermatitis.
Fig. 6-8 Acute poison ivy reaction.
Fig. 6-9 Black dot sign in poison ivy reaction.
 nnumerable attempts ha e been made to immuni e
against poison i y dermatitis by oral administration o the
allergen or subcutaneous in ections o oily e tracts. To date
no accepted method o immuni ation is a ailable. Repeated
attac s do not con er immunity although a single se ere
attac may achie e this by what has been called massi e
dose desensiti ation.
When the diagnosis is clear and the eruption se ere or e ten
si e systemic steroidal agents are e ecti e beginning with
mg o prednisone in a single oral dose daily tapered o
o er a wee period. When the eruption is limited in e tent
and se erity local application o topical corticosteroid creams
lotions or aerosol sprays is pre erred. Time honored calamine
lotion without phenol is help ul and does no harm. Antihista
minic ointments should be a oided because o their sensiti a
tion potential. This also applies to the local application o the
caine topical anesthetics.
Other Toxicodendron-related dermatitides
Lac uer dermatitis is caused by a urniture lac uer made rom
the Japanese lac uer tree used on urniture ewelry or bric
a brac. Anti ue lac uer is harmless but lac uer less than or
years old is highly antigenic. Cashew nutshell oil is e tracted
rom the nutshells o the cashew tree nacar ium occi entale
This esicant oil contains cardol a phenol similar to urushiol
in poison i y. The li uid has many commercial applications
such as the manu acture o bra e linings arnish synthetic
glue paint and sealer or concrete.
ango dermatitis is uncommon in nati es o mango
growing countries (e.g. Philippines Guam awaii Cuba)
who ha e ne er been e posed to contact with oxico en ron
species. any persons who ha e been so e posed howe er
whether or not they had dermatitis rom it are sensiti ed by
one or a ew episodes o contact with the peel o the mango
ruit. The palms carry the allergen so the eyelids and the male
prepuce are o ten early sites o in ol ement.
Gin go tree dermatitis simulates oxico en ron dermatitis
with its se ere esiculation erythematous papules and edema.
The causati e substances are gin golic acids rom the ruit
pulp o the gin go tree. ngestion o the gin go ruit may
result in perianal dermatitis. Gin go biloba gi en orally or
cerebral disturbances is made rom a lea e tract so it does not
elicit a systemic contact allergy when ingested.
Flowers and houseplants
Among the more common houseplants the el ety lea ed
philodendron Philo en ron cr stallinum (and its se eral ari
ants) nown in ndia as the money plant is a re uent cause
o contact dermatitis. The eruption is o ten seen on the ace
especially the eyelids carried there by hands that ha e watered
or cared or the plant. nglish i y ollows philodendron in
re uency o cases o occult contact dermatitis. Primrose der
matitis a ects the ngers eyelids and nec with a punctate or
di use erythema and edema. ormerly ound most re uently
in urope the primrose is now a common .S. houseplant.
Primin a uinone is the causati e oleoresin abounding in the
glandular hairs o the plant Primula obconica.
The popular cut ower the Peru ian lily is the most
common cause o allergic contact dermatitis in orists. When
handling owers o the genus lstroemeria the orist uses the
thumb and second and third digits o the dominant hand.
Because it is chronic ssured hyper eratotic dermatitis results
identical to the tulip ngers seen among sensiti ed tulip
wor ers ( ig. ). Testing is done with the allergen tulipo
side A. t does not penetrate nitrile glo es.
Chrysanthemums re uently cause dermatitis with the
hands and eyelids o orists most o ten a ected. The
α methylene portion o the ses uiterpene lactone molecule is
tahir99 - UnitedVRG
Contact dermatitis
Fig. 6-10 Chronic fissured fingertip dermatitis in a florist.
the antigenic site as it is in the other genera o the Compositae
amily.
A se ere in ammatory reaction with bulla ormation may
be caused by the prairie crocus ( nemone patens L.) the oral
emblem o the pro ince o anitoba. Se eral species o
ornamental bottle brush rom ueensland revillea ban sii
ob n or on robusta may cause allergic contact der
matitis. t is e ported to the nited States and other Western
countries. The allergen is a long chain al yl resorcinol. Cross
sensiti ity to oxico en ron has been demonstrated.
Contact dermatitis may be caused by handling many other
owers such as the geranium scorpion ower (Phacelia crenu
lata or P campanularia) hydrangea creosote bush Larvia
tri entata eracula da odil o glo e lilac lady slipper mag
nolia and tulip and narcissus bulbs. The poinsettia and olean
der almost ne er cause dermatitis despite their reputation or
it although they are to ic i ingested. Treatment o all these
plant dermatitides is the same as that recommended or to i
codendron dermatitis.
Parthenium h sterophorus a photosensiti ing weed was acci
dentally introduced into ndia in and has spread o er
most o the country; it is also spreading in Australia parts o
A rica China and Argentina. The well deser ed reputation
or harm ulness o die enbachia a common glossy lea ed
house plant rests on the high content o calcium o alate crys
tals in its sap which burn the mouth and throat se erely i any
part o the plant is chewed or swallowed. Se ere edema o the
oral tissues may result in complete loss o oice thus its
common nic name dumb cane. t does not appear to sensi
ti e. The castor bean the seed o icinus communis contains
ricin a poisonous substance (phytoto in). ts sap contains an
antigen that may cause anaphylactic hypersensiti ity and also
dermatitis.
Fruit and vegetables
any egetables may cause contact dermatitis including
asparagus carrot celery cow parsnip cucumber garlic
ndian bean mushroom onion parsley tomato and turnip.
nion and celery among other egetables ha e been incrimi
nated in the production o contact urticaria and e en anaphy
la is. Se eral plants including celery g lime and parsley
can cause a phototo ic dermatitis because o the presence o
psoralens.
Trees
Trees with timber and sawdust that may produce contact der
matitis include ash birch cedar cocobolo elm entuc y
co ee tree oa mahogany mango maple mes uite milo
myrtle pine and tea . The late o g and rubber trees may
97
 also cause dermatitis usually o the phototo ic type. elaleuca
6 oil (tea tree oil) which may be applied to the s in to treat a
ariety o maladies can cause allergic contact dermatitis pri
marily through the allergen D limonene. The e otic woods
especially cocobolo and rosewood and tea tree oil are promi
Contact Dermatitis and Drug Eruptions
nent among allergens that may produce erythema multi orme
a ter cutaneous e posure. oxico en ron arious medicaments
and a ariety o other allergens may induce this reaction.
Tree-associated plants
oresters and lumber wor ers can be e posed to allergenic
plants other than trees. Lichens are a group o plants com
posed o symbiotic algae and ungi. oresters and wood chop
pers e posed to these lichens growing on trees may de elop
se ere allergic contact dermatitis. posure to the lichens may
also occur rom rewood uneral wreaths and also ragrances
added to a tersha e lotions (oa moss and tree moss). Sensiti
ation is produced by D usnic acid and other lichen acids con
tained in lichens. The lea y li erwort rullania nis uallensis a
orest epiphyte growing on tree trun s has produced allergic
dermatitis in orest wor ers. The eruption is commonly called
cedar poisoning. t resembles oxico en ron dermatitis; its
attac s are more se ere during wet weather. The allergen is
ses uiterpene lactone.
Pollens and seeds
The pollens in ragweed are composed o two antigens. The
protein raction causes the respiratory symptoms o asthma
and hay e er and the oil soluble portion causes contact der
matitis. Ragweed oil dermatitis is a seasonal disturbance seen
mainly during the ragweed growing season rom spring to
all. Contact with the plant or with wind blown ragments o
n
the dried plant produces the typical dermatitis. The oil causes
swelling and redness o the lids and entire ace and a red
U
blotchy eruption on the orearms that a ter se eral attac s
may become generali ed with licheni cation. t closely resem
-
bles chronic atopic dermatitis with licheni cation o the ace
nec and ma or e ures and se ere pruritus. The distribution
also mimics that o photodermatitis with ragweed dermatitis
9
di erentiated by its in ol ement o the upper eyelids and the
retroauricular and submental areas. Chronic cases may con
ri 9
tinue into the winter although signs and symptoms are most
se ere at the height o the season. Ses uiterpene lactones are
the cause. Coe istent sensiti ation to pyrethrum may account
or prolongation o ragweed dermatitis. en outnumber
h
women in hypersensiti ity reactions; armers outnumber
patients o all other occupations.
t a
Marine plants
umerous a uatic plants are to ic or produce contact derma
titis. Algae are the worse o enders. reshwater plants are
rarely o concern. Seaweed dermatitis is a type o swimmer s
eruption produced by contact with a marine blue green alga
which has been identi ed as L ngb a majuscula omont The
onset is within a ew minutes o lea ing the ocean with se ere
itching and burning ollowed by dermatitis blisters and
deep pain ul des uamation that a ects the areas co ered by
the bathing suit especially the scrotum perineum and peri
anal areas and occasionally the breasts in women). Patch tests
with the alga are neither necessary nor help ul because it is a
potent irritant. Bathing in resh water within or min o
lea ing the ocean may pre ent the dermatitis. The Bermuda
re sponge may produce contact erythema multi orme.
Trawler shermen in the Dogger Ban area o the orth Sea
de elop allergic dermatitis a ter contact with lc oni ium hir
sutum This seaweedli e animal colony becomes caught in nets
and produces erythema edema and licheni cation on the
shermen s hands and wrists.
98
Plant-associated dermatitis
Phototo ic contact dermatitis rom plants is discussed in
Chapter .
The residua o arious insecticides on plants may also
produce dermatitis. This is especially true o sprays containing
arsenic and malathion. Rando ( chloro diallyl acet
amide) has been reported as the cause o hemorrhagic bullae
on the eet o armers. Lawn care companies spray herbicides
and ungicides throughout the spring summer and all.
Dryene thiuram carbamates and chlorothalonil are potential
sensiti ers in these wor ers whose clothing re uently
becomes wetted while spraying.
Barbs bristles spines thorns spicules and cactus needles
are some o the mechanical accessories o plants that may
produce dermatitis. Sabra dermatitis is an occupational der
matitis resembling scabies. t is seen among pic ers o the
pric ly pear cactus plant. t also occurs in persons handling
ndian gs in srael where the condition is seen rom July to
o ember. The penetration o minute in isible thorns into the
G
s in is the cause. gave americana is a low growing plant used
or ornamental purposes in many southwestern .S. commu
R
nities. Trimming during landscaping can induce an irritant
dermatitis caused by calcium o alate crystals. The stinging
V
nettle is a common weed that bears tiny spines with biologi
cally acti e substances such as histamine that produce itching
d
and urticaria within minutes o contact.
Plant derivatives
ti e
Sensiti ing substances deri ed rom plants are ound in the
oleoresin ractions that contain camphors essential oils
phenols resins and terpenes. The chie sensiti ers are the
essential oils. These may be locali ed in certain parts o the
plant such as in the peel o citrus ruits lea es o the eucalyp
tus tree and bar o the cinnamon tree. Aromatherapy an
increasingly popular treatment or relie o stress in ol es
either inhaling or massaging with essential oils; this may cause
allergic contact dermatitis in therapists or clients. posure to
botanical e tracts through many cosmetics and homeopathic
remedies has resulted in an increasing number o reports o
allergic contact sensiti ity to indi idual ingredients especially
tea tree oil.
Cinnamon oil (Cassia oil) is a common a oring agent espe
cially in pastries. and dermatitis in pastry ba ers is o ten
caused by cinnamon. t is also used as a a or or lipstic
bitters alcoholic and nonalcoholic be erages toothpaste and
chewing gum. Perioral dermatitis may be caused by cinnamon
in chewing gum. A cinnamon solution in oli e oil is used
or patch testing. ugenol clo e oil and eucalyptus oil are
used by dentists who may ac uire contact dermatitis
rom them. Anise peppermint and spearmint oils may cause
sensiti ation.
utmeg papri a and clo es are causes o spice allergy.
ragrance mi is a use ul indicator allergen. Lemon oil rom
lemon peel or lemon wood may cause sensiti ation in the
arious handlers o these substances. Citric acid may cause
dermatitis in ba ers. Lime oil in lime scented sha ing cream
or lotion may cause photoallergy. M rox lon pereirae contains
numerous substances including essential oils similar to the oil
o lemon peel. t is nown to cross react with anilla cinna
mon and many other substances. Vanillin is deri ed rom the
anilla plant and re uently produces contact dermatitis
anillism in those connected with its production and use.
Turpentine re uently acts as an irritant and as an allergic
sensiti er (carene). t is contained in paints paint thinners
arnishes and wa es.
Arberer W: Contact allergy and medicinal plants. J Dtsch Dermatol Ges
2008; 6:15.
 Crawford GH, et al: Use of aromatherapy products and increased risk of
hand dermatitis in massage therapists. Arch Dermatol 2004; 140:991.
Dos Reis VM: Dermatosis due to plants (phytodermatosis). An Bras
Dermatol 2010; 85:479.
Ferreira O, et al: Erythema multiforme–like lesions revealing allergic
contact dermatitis to exotic woods. Cutan Ocul Toxicol 2012; 31:61.
Ghorpade A: Tense bullae after Toxicodendron treatment for a twisted
ankle. Clin Exp Dermatol 2010; 35:e24.
Ghorpade A: Contact dermatitis caused by Indian marking nut juice
used to relieve ankle pain. Int J Dermatol 2014; 53:117.
Gladman AC: Toxicodendron dermatitis. Wilderness Environ Med 2006;
17:120.
Goon AT, et al: Plant dermatitis. Indian J Dermatol 2011; 56:707.
Hershko K, et al: Exploring the mango–poison ivy connection. Contact
Dermatitis 2005; 52:3.
Jack AR, et al: Allergic contact dermatitis to plant extracts in cosmetics.
Semin Cutan Med Surg 2013; 32:140.
Koo B, et al: Five-year-old boy with a diffuse erythematous rash with
black crusts. Pediatr Dermatol 2010; 27:395.
Linares T, et al: Phytodermatitis caused by Agave americana. Allergol
Immunopathol (Madr) 2011; 39:184.
McGovern TW, et al: Is it, or isn’t it? Poison ivy look-a-likes. Am J
Contact Dermat 2000; 11:104.
Modi GM, et al: Irritant contact dermatitis from plants. Dermatitis 2009;
20:63.
Paulsen E, et al: Systemic allergic dermatitis caused by Apiaceae root
vegetables. Contact Dermatitis 2014; 70:98.
Rutherford T, et al: Allergy to tea tree oil. Australas J Dermatol 2007;
48:83.
Sharma VK, et al: Parthenium dermatitis. Photochem Photobiol Sci
2013; 12:85.
Swinnen I, et al: An update on airborne contact dermatitis: 2007–2011.
Contact Dermatitis 2013; 68:232.
Trehan I, et al: Mango contact allergy. J Travel Med 2010; 17:284.
Veien NK: Systemic contact dermatitis. Int J Dermatol 2011; 50:1445.
Verma P, et al: Severe marking-nut dermatitis. Dermatitis 2012; 23:293.
Dermatitis from clothing
A predisposition to contact dermatitis rom clothing occurs in
persons who perspire reely or who are obese and wear cloth
ing that tends to be tight. Depending on the o ending sub
stance arious regions o the body will be a ected. Regional
location is help ul in identi ying the sensiti ing substance. The
a illary olds are o ten in ol ed; the aults o the a illae are
usually spared. Sites o increased perspiration and sites where
e aporation is impeded such as the intertriginous areas will
tend to leach dyes rom abrics to produce dermatitis. Areas
where the material is tight against the s in such as the waist
band or nec are re uently in ol ed ( ig. ). The thighs
are a ected when pants contain the o ending allergen. The
hands ace and undergarment sites are usually spared but
otherwise these reactions may be scattered and generali ed.
Secondary changes o licheni cation and in ection occur re
uently because o the chronicity o e posure.
Cotton wool linen and sil abrics were used e clusi ely
be ore the ad ent o synthetic abrics. ost materials are now
blended in de nite proportions with synthetics to produce
superior lasting and esthetic properties. Dermatitis rom
cotton is irtually none istent. n most cases there is no true
sensiti ation to wool. Wool acts as an irritant because o the
barbs on its bers. These barbs may produce se ere pruritus
at points o contact with the s in especially in the intertrigi
nous areas. n persons with sensiti e s in such as those with
atopic dermatitis the wearing o wool is not ad isable because
o its mechanical irritati e properties. Sil is a sensiti er but
rarely; the nature o the allergen is not nown. any patients
belie e their detergent is the source o a dermatitis but this is
rarely the case.
umerous synthetic bers are a ailable or clothing and
accessory manu acture all o which again are remar ably ree
tahir99 - UnitedVRG
Contact dermatitis
Fig. 6-11 Waistband clothing dermatitis.
o sensiti ing properties. Poly inyl resins are the plastics
used in such apparel as raincoats rainhoods wristbands
suspenders plastic mittens and glo es. These also are only
in re uently ound to be causes o contact dermatitis.
The most common causes o clothing dermatitis are the
abric nishers dyes and rubber additi es. abric nishers are
used to impro e the durability appearance and eel o a mate
rial. Antiwrin ling and crease holding chemicals are mostly
resins which are incorporated into the bers as they are being
manu actured or applied to the nished abric. abrics are
treated to ma e them less ulnerable to the e ects o perspira
tion and ironing. Clothing may be treated with these sub
stances to ma e it dry rapidly a ter washing. They are used to
ma e clothing abrics shrin resistant and water and stain
repellent. When all these uses are ta en into consideration the
low incidence o dermatitis rom these ormaldehyde resin
materials is remar able.
thylene urea melamine ormaldehyde resin and dimethylol
dihydro yethylene urea ormaldehyde resin are the best
screening agents. any persons also react to ormaldehyde
and the ormaldehyde releasing preser ati es such as uater
nium . A oidance o e posure o the s in to ormaldehyde
resin is most di cult. ew clothes should be thoroughly
washed twice be ore wearing the rst time. en with this
precaution howe er allergens may still be present in su
cient uantities to continue the dermatitis. Jeans Spande
sil linen nylon and cotton that is not
wrin le resistant or color ast are best tolerated. T shirts sweat
shirts and pants white underclothes suitable or bleaching
and garments o mi ed synthetic bers with cotton bers
added to ma e them drip dry are most li ely to cause prob
lems in these patients.
An increasing number o patients allergic to clothing dye are
being reported. Synthetic abrics such as polyester and acetate
liners in women s clothing are prime causes and women
are more a ected than men. en in ants may be a ected
howe er with dyes in diapers accounting or some cases.
any patients do not react to paraphenylene diamine but
only to the disperse dye allergens. The best screening agents
are disperse blue and . Suspected abrics may be soa ed
in water or min and applied under a patch or h.
Lymphomatoid contact allergy may result rom clothing dye
reacti ity.
Spande is a nonrubber (but elastic) polyurethane ber. t is
widely used or garments such as girdles brassieres and
99
 soc s but is generally sa e in the nited States because it is
6 ree o rubber additi es.
Carlson RM, et al: Diagnosis and treatment of dermatitis due to
formaldehyde resin in clothing. Dermatitis 2004; 15:169.
Contact Dermatitis and Drug Eruptions
Donovan J, et al: Allergic contact dermatitis from formaldehyde textile
resins in surgical uniforms and nonwoven textile masks. Dermatitis
2007; 18:40.
Malinauskiene L, et al: Contact allergy from disperse dyes in textiles: a
review. Contact Dermatitis 2013; 68:65.
Narganes LM, et al: Lymphomatoid dermatitis caused by contact with
textile dyes. Contact Dermatitis 2013; 68:62.
Nedorost S, et al: Allergens retained in clothing. Dermatitis 2007;
18:212.
Reich HC, et al: Allergic contact dermatitis from formaldehyde textile
resins. Dermatitis 2010; 21:65.
Slodownik D, et al: Textile allergy. Contact Dermatitis 2011; 65:38.
Wentworth AB, et al: Patch testing with textile allergens. Dermatitis 2012;
23:269.
Zug KA, et al: The value of patch testing patients with a scattered
generalized distribution of dermatitis. J Am Acad Dermatol 2008;
59:426.
Shoe dermatitis
ootwear dermatitis may begin on the dorsal sur aces o the
toes and may remain locali ed to that area inde nitely ( ig.
). There is erythema licheni cation and in se ere cases
weeping and crusting. Secondary in ection is re uent. n
se ere cases an id reaction may be produced on the hands
similar to the reaction rom ungal in ection o the eet. A
diagnostic point is the normal appearance o the s in between
the toes which has no contact with the o ending substance.
n ungal in ections the toe webs are usually in ol ed. Another
n
pattern seen is in ol ement o the sole with sparing o the
instep and e ural creases o the toes. Also purpuric reactions
- U
9
ri 9
h
t a
Fig. 6-12 Shoe dermatitis.
100
may occur to components o blac rubber mi . yperhidrosis
and atopy predispose to de elopment o shoe allergy.
Shoe dermatitis is most re uently caused by the rubber
accelerators mercaptoben othia ole carbamates and tetra
methylthiuram disul de. Potassium dichromate in leather and
the adhesi es used in synthetic materials (especially p tert
butylphenol ormaldehyde resin) are also common shoe aller
gens. Diisocyanates are used in ma ing oam rubber padding
or athletic shoes and may cause allergy. Dimethyl umarate
is a preser ati e used in antihumidity sachets. t is a olatile
substance and may deposit on shoes during its transport.
Dimethyl umarate is highly allergenic and se eral outbrea s
o shoe dermatitis in urope ha e occurred secondary to this
allergen. ther causati e agents are elt cor liners ormalde
hyde dyes asphalt and tar. Patch testing with pieces o
arious shoe parts may be done by soa ing them or min
in water and applying them to the bac or h. nce the
allergen has been identi ed selection o shoes without the
o ending substance will lead to resolution. n ortunately this
is a di cult process because most shoes are made in areas
G
without mandatory labeling re uirements and plastic
wooden or abric shoes that contain ewer allergens are o ten
R
impractical.
Castando-Tardan MP, et al: Allergic contact dermatitis to Crocs. Contact
V
Dermatitis 2008; 58:248.
Matthys E, et al: Shoe allergic contact dermatitis. Dermatitis 2014;
d
25:163–171.
Munk R, et al: Thiurams in shoe contact dermatitis. Contact Dermatitis
ti e
2013; 68:185.
Švecová D, et al: Footwear contact dermatitis from dimethyl fumarate.
Int J Dermatol 2013; 52:803.
Washaw EM, et al: Shoe allergens. Dermatitis 2007; 18:191.
Dermatitis from metals and metal salts
etal dermatitis is most re uently caused by nic el and chro
mates. sually with the e ception o nic el the pure metals
generally do not cause hypersensiti ity; only when they are
incorporated into salts do they cause reactions. ost ob ects
containing metal or metal salts are combinations o se eral
metals some o which may ha e been used to plate the sur ace
thereby enhancing its attracti eness durability or tensile
strength. or this reason suspected metal caused dermatitis
should be in estigated by doing patch tests to se eral o the
metal salts.
Patients ha e de eloped a ariety o dermatoses most o ten
ec ematous in type a ter placement o an orthopedic gyneco
logic or dental implant or a pacema er de brillator or
endo ascular de ice. n general patch testing in patients with
nown metal hypersensiti ity be ore placement may help
guide the speci c type o de ice to be used. When patients are
symptomatic with an ec ematous process a ter implantation
patch testing will allow e aluation o allergy by testing with
an e tended tray metals a test dis o the metal used in the
implant and bone cement. A positi e diagnosis o allergy at a
minimum re uires the appearance o a chronic dermatitis a ter
placement no other cause a positi e patch test or the sus
pected metal (or with drug eluting stents the drug) and
healing a ter remo al. This scenario is e ceedingly uncom
mon; the remo al o the oreign material needs to be udged
as necessary reasonable and sa e and no ob ecti e criteria
e ist to determine the necessity. Dental and gynecologic
implants are more re uently replaced; some patients do
impro e.
Black dermatographism
Blac or greenish staining under rings metal wristbands
bracelets and clasps is caused by the abrasi e e ect o

Fig. 6-13 Nickel dermatitis caused by earring.
Fig. 6-14 Jeans button nickel-induced dermatitis.
cosmetics or other powders containing inc or titanium o ide
on gold ewelry. This s in discoloration is blac because o the
deposit o metal particles on s in that has been powdered and
that has metal such as gold sil er or platinum rubbing on it.
Abrasion o the metal results because some powders are hard
( inc o ide) and can abrade the metal.
Nickel
Because we are all constantly e posed to nic el nic el derma
titis is a re uent occurrence. Although still most common
among women sensiti ation is increasing among men. A
direct relationship between pre alence o nic el allergy and
number o pierced sites has been documented. ic el pro
duces more cases o allergic contact dermatitis than all other
metals combined. rythematous and ec ematous eruptions
sometimes with licheni cation appear beneath earrings ( ig.
) bracelets rings wrist watches clasps and eans buttons
( ig. ). The snaps on clothing ha e been implicated in
producing allergy in children; nic el is the most common
cause o allergic contact dermatitis in children as well as
adults. Patients with dermatitis on one ear or the preauricular
area were reported to be allergic to their cell phone. The metal
tahir99 - UnitedVRG
portion o ten contains nic el the implicated allergen. ic el
ran s highly on lists o occupationally induced allergic contact
dermatitis.
ic el dermatitis is seen most re uently on the earlobes.
Piercing the earlobes with nic el plated instruments or
Contact dermatitis
wearing nic el plated ewelry readily induces nic el sensiti
ity. arlobes should be pierced only with stainless steel instru
ments and only stainless steel earrings should be worn until
the ears ha e healed. posure to the metal may not be readily
apparent most o the time. en with gold ewelry the clasps
and solder may contain nic el. ic el ob ects may be plated
with chrome but may still cause nic el dermatitis through the
leaching o some o the nic el through the small pores o the
chromium plating.
ic el o ides in green paints may produce nic el dermatitis.
omeopathic and complementary medicaments may also
contain enough nic el to produce a contact allergy. Sweat
containing sodium chloride may combine with nic el to orm
nic el chloride. This a ects the degree o nic el dermatitis
being more se ere in persons who perspire pro usely.
The diagnosis is established by a positi e patch test reaction
to nic el sul ate. ic el may be detected by applying a reshly
prepared alcohol solution o dimethylglyo ime and a
a ueous solution o ammonia separately in e ual amounts to
the test ob ect. n the presence o nic el the cotton swab used
to apply the solution will turn orange pin . A positi e test
always means that nic el is present but a negati e test does
not rule out its presence. Sweat blood or saline may leach
nic el rom stainless steel.
Prophylactic measures should include the reduction o per
spiration in those sensiti e to nic el. Topical corticosteroids
applied be ore e posure to nic el such as be ore putting on a
wristband may be success ul. Clasps and other ob ects are
a ailable in plastic material so that some o the e posure to
nic el may be decreased. Polyurethane arathane ( lecto)
applied in three coats will gi e protection or se eral months.
Treatment o nic el dermatitis consists o the application o
topical corticosteroids. n urope laws regulating the
ma imum content o nic el in ewelry ha e led to a mar ed
decrease in sensiti ation.
and ec ema and pompholy in nic el sensiti e or cobalt
sensiti e patients ha e rarely been aggra ated by ingested
metals in the diet. n se ere treatment resistant dermatitis a
speci c diet low in nic el and cobalt may be tried.
Chromium
The chromates are strongly corrosi e and irritating to the s in
and may act as primary irritants or as sensiti ers to produce
allergic contact dermatitis. Besides a ecting employees in
chromate wor s chrome dermatitis is encountered among
tanners painters dyers photographers polishers welders
aircra t wor ers diesel engine wor ers and those in ol ed
with the bleaching o crude oils tallows and ats. Traces o
dichromates in shoe leather and glo es may cause ec ema o
the eet and hands. any ippers are chromium plated and
the nic el underneath may be the causati e agent. Chromium
metal and stainless steel do not produce contact dermatitis.
inc chromate paint is a source o dermatitis. atches hide
glues chrome alloys cigarette lighters and leather hatbands
sandals or camera cases may cause chrome dermatitis. Anti
corrosion solutions used or re rigeration and other recircula
tion systems o ten contain chromates that produce dermatitis.
ost wor ers in the cement industry who ha e cement ec ema
show positi e patch tests to dichromates. Cement ec ema is
o ten a primary irritant dermatitis complicated by allergic
contact dermatitis to the he a alent chromates. The incidence
o cement dermatitis has decreased signi cantly o er the
years belie ed to be the result o the addition o errous
101
 sul ate deli ery o premi ed cement to the ob site and
6 impro ed education.
The s in changes are multi orm ranging rom a mild ollicu
lar dermatitis to widespread nodular and crusted eruptions
all being worse on e posed parts. ten the eruptions are slow
Contact Dermatitis and Drug Eruptions
to clear up lasting rom a ew wee s to months a ter contact
has ceased. ea y e posure o industrial wor ers to chro
mates may produce chrome ulcers on the bac s o the hands
and orearms usually beginning around a hair ollicle or in
the creases o the nuc les or nger webs. The hole begins
as a small abrasion that deepens and widens as its edges
grow thic e entually orming a conical indolent ulceration.
Chrome ulcers may also arise on and per orate the nasal
septum. Arsenic e posure may result in similar ulcers.
Diagnosis o chrome sensiti ity is made by a positi e patch
test to potassium dichromate in petrolatum. The he a alent
chrome compounds are the most re uent cause o chrome
dermatitis because these penetrate the s in more easily than
the tri alent orm. Both orms are sensiti ers. en with a oid
ance o chromate containing materials chromate induced der
matitis is o ten persistent.
Mercury
The mercurials may act not only as irritants but also as sensi
ti ers. Thimerosal is a mercuric containing preser ati e; it is
an allergen that is rarely rele ant. Allergy to this compound
is li ely to ha e been caused by e posure during childhood
accinations and to tincture o merthiolate antiseptic. n
general these patients tolerate repeated accinations well.
ost indi iduals are sensiti ed to the ethyl mercuric compo
nent o thimerosal; howe er those who react to the thiosali
cylic acid portion de elop photodermatitis to piro icam.
ercury in amalgam dental llings has been shown in mul
tiple large studies to cause oral lichenoid eruptions. The rela
tionship is especially strong when the oral lesion o ten with a
pain ul erosion present is apposed to a gold or amalgam
lling. n many cases when sensiti ity is pro ed by patch
testing and llings are replaced in olution o the oral ndings
occurs.
Cobalt
Cobalt is re uently combined with nic el as a contaminant
and patients allergic to cobalt typically are also allergic to
nic el. The metals ha e similar properties but do not produce
cross reactions. Cobalt dermatitis may occur in those in ol ed
in the manu acture o polyester resins and paints hard metals
used or cutting and drilling tools and cement. Cobalt
dermatitis may also occur in producers o pottery ceramics
metal alloys glass carbides and pigments. ndi iduals may
be e posed to cobalt in hair dye ypaper and itamin B .
Blue tattoo pigment contains cobalt o ide. Rarely cobalt chlo
ride may cause nonimmunologic local release o asoreacti e
materials with a local urticarial response.
Gold
Gold dermatitis may rarely occur rom the wearing o gold
ewelry. A predisposing actor in such patients is the presence
o dental gold. ral lichenoid eruptions ha e also been
reported with gold similar to the situation with mercury
containing amalgams. t is not uncommon to see positi e reac
tions to gold when patch testing patients with acial eyelid
or widespread dermatitis o un nown cause. Although it is
di cult to ma e a direct clinical correlation with any one piece
o ewelry occasionally patients will clear i they stop wearing
all gold ewelry. n most patients howe er there is a lac o
rele ance.
A number o cases o dermatitis resulting rom gold ewelry
especially gold rings contaminated with radon and its decay
102
products ha e been reported. This may result in radiation
dermatitis and s uamous cell carcinoma o the nger. Appar
ently the source o contaminated gold or the rings had been
reclaimed decayed radon gold seeds.
Other metals
ost other common metals are not important in causing
contact dermatitis. Platinum dermatitis may occur rom e po
sure to platinum salts and sprays in industry. Platinum rings
earrings white gold spectacles clasps and other ewelry cause
eruptions resembling those caused by nic el. inc aluminum
copper sul ate titanium and antimony dermatitis rarely occur
although these metals may act as irritants.
Atanaskova Mesinkovska N, et al: The effect of patch testing on surgical
practices and outcomes in orthopedic patients with metal implants.
Arch Dermatol 2012; 148:687.
De Medeiros LM, et al: Complementary and alternative remedies: an
additional source of potential systemic nickel exposure. Contact
Dermatitis 2008; 58:97.
Giorgini S, et al: Occupational airborne allergic contact dermatitis
caused by gold. Dermatitis 2010; 21:284.
Heim KE, et al: Children’s clothing fasteners as a potential source of
exposure to releasable nickel ions. Contact Dermatitis 2009; 60:100.
Honari G, et al: Hypersensitivity reactions associated with endovascular
devices. Contact Dermatitis 2008; 59:7.
Kornick R, et al: Nickel. Dermatitis 2008; 19:3.
Mahta V, et al: Persistent nodular contact dermatitis to gold. Indian J
Dermatol Vernereol Leprol 2010; 76:397.
Malinauskiene L, et al: Systemic contact dermatitis in a gold-allergic
patient after treatment with an oral homeopathic drug. J Am Acad
Dermatol 2013; 68:e58.
Mislankar M, et al: Low nickel diet scoring system for systemic nickel
allergy. Dermatitis 2013; 24:190.
Reed KB, et al: Retrospective evaluation of patch testing before or after
metal device implantation. Arch Dermatol 2008; 144:999.
Roberts H, et al: Nickel allergy presenting as mobile phone contact
dermatitis. Australas J Dermatol 2010; 51:23.
Schalock PC, et al: Hypersensitivity reactions to metallic implants:
diagnostic algorithm and suggested patch test series for clinical use.
Contact Dermatitis 2012; 66:4.
Stuckert J, et al: Low cobalt diet for dyshidrotic eczema. Contact
Dermatitis 2008; 59:361.
Suneja T, et al: Blue-jean button nickel. Dermatitis 2007; 18:208.
Thyssen JP: Cobalt sensitization and dermatitis. Dermatitis 2012;
23:203.
Thyssen JP, et al: Patch test reactivity to metal allergens following
regulatory intervention. Contact Dermatitis 2010; 63:102.
Torgerson RR, et al: Contact allergy in oral disease. J Am Acad
Dermatol 2007; 57:315.
Contact stomatitis
The role o contact allergy in oral symptomatology is signi
cant. Appro imately o patients with oral symptoms will
ha e rele ant allergens most re uently metals used in dental
llings ood additi es ( a orings and antio idants) and
dental products (acrylic monomers epo y resins hardeners
used in prosthodontics and dental impression materials).
Chewing gums and denti rices may also produce contact sto
matitis. ngredients responsible or this are he ylresorcinol
thymol dichlorophen oil o cinnamon and mint.
Clinical signs may be bright erythema o the tongue and
buccal mucosa with scattered erosions. Angular cheilitis may
also de elop. ral lichenoid lesions may be caused by sensiti
ation to metals in dental llings and gold caps or crowns.
Batchelor JM, et al: Allergic contact stomatitis caused by a polyether
dental impression material. Contact Dermatitis 2010; 63:296.
Biron JF, et al: Cinnamon-induced oral contact stomatitis. Dent Today
2013; 82:82.
Krishen C, et al: Dental allergic contact dermatitis. Dermatitis 2012;
23:222.

Fig. 6-15 Occupational dermatitis from rubber glove allergy.
Torgerson RR, et al: Contact allergy in oral disease. J Am Acad
Dermatol 2007; 57:315.
Zug KA, et al: Patch-testing North American lip dermatitis patients.
Dermatitis 2008; 19:202.
Rubber dermatitis
Rubber dermatitis generally occurs on the hands rom wearing
rubber glo es as by surgeons nurses and homema ers ( ig.
). The eruption is usually sharply limited to the glo ed
area but may spread up the orearms. Rubber dermatitis
also de elops rom e posure to condoms diaphragms swim
goggles caps and scuba mas s wet suits bandages or chronic
leg ulcers respirators gas mas s rubber sheets and cosmetic
sponges. Shoe dermatitis may be caused by rubber allergy to
insoles or snea ers (see earlier).
atural and synthetic rubbers are used separately or in com
bination to ma e the nal rubber product. The chemicals
added in the rubber manu acturing process most importantly
the accelerators and antio idants are the common causes o
allergic contact dermatitis. A similar list o additi es is present
in neoprene a synthetic rubber. ne particular class o addi
ti e in neoprene is causing an increasing number o reactions
the dial yl thioureas. These are not in the standard patch trays
and thus may escape detection unless applied as a supplemen
tal allergen. lastic in underwear is chemically trans ormed by
laundry bleach into a potent sensiti ing substance. The aller
gen is permanent and cannot be remo ed by washing. The
o ending garments must be thrown out and the use o bleaches
interdicted.
Accelerators
During the manu acturing process chemicals are used to
hasten the ulcani ation o rubber. Among the numerous
chemicals a ailable tetramethylthiuram disul de mercapto
ben othia ole and diphenylguanidine are re uently used.
tahir99 - UnitedVRG
Tetramethylthiuram disul de and its analogs nown as disul
ram and thiuram may produce contact dermatitis when
moist s in is e posed to the nished rubber product. n a
year study o cases o allergy to rubber additi es
thiuram mi was by ar the most common sensiti er. ercap
Contact dermatitis
toben othia ole is most o ten the cause in shoe allergy and
thiuram in glo e allergy.
Antioxidants
Antio idants are used to preser e rubber. Amine antio idants
such as phenyl α naphthylamine are most e ecti e. ydro
uinone antio idants may cause depigmentation o the s in
as well as allergic contact dermatitis. A re uent antio idant
sensiti er propyl p phenylenediamine is used in tires hea y
duty rubber goods boots and elastic underwear.
Bendewald MJ, et al: An 8-year retrospective review of patch testing with
rubber allergens. Dermatitis 2010; 21:33.
Cao LY, et al: Allergic contact dermatitis to synthetic rubber gloves. Arch
Dermatol 2010; 146:1001.
Cravo M, et al: Allergic contact dermatitis to rubber-containing
bandages in patients with leg ulcers. Contact Dermatitis 2008; 58:371.
Dall AB-H, et al: Targeted testing with dietheythliourea often reveals
clinically relevant allergic contact dermatitis caused by neoprene
rubber. Contact Dermatitis 2012; 67:89.
Nedorost S: Clinical patterns of hand and foot dermatitis. Dermatol Clin
2009; 27:281.
Warshaw EM, et al: Positive patch-test reactions to mixed dialkyl
thioureas. Dermatitis 2008; 19:190.
Adhesive dermatitis
Cements glues and gums may cause adhesi e dermatitis.
ormaldehyde resin adhesi es contain ree ormaldehyde
naphtha glue and disin ectants. Synthetic resin adhesi es
contain plastici ers; hide glues may contain chromates rom
the tanned leather and other glues incorporate preser ati es
such as ormaldehyde. Dental bonding adhesi es may contain
acrylic monomers and epo y resins and hardeners. Pressure
sensiti e adhesi es contain rubber and acrylates and anaero
bic adhesi es ha e primarily acrylates.
Vegetable gums such as gum tragacanth gum arabic and
araya may be used in denture adhesi es hair wa e lotions
topical medications toothpastes and depilatories and many
cause contact dermatitis. Resins are used in adhesi e tapes and
in arious adhesi es such as tincture o ben oin. Turpentine
is re uently ound in rosin; abietic acid in the rosin is the
causati e sensiti er.
Adhesi e tape reactions are re uently irritant in nature.
Allergic reactions to adhesi e tape itsel are caused by the
rubber components accelerators antio idants and arious
resins or turpentine. Some adhesi e tapes contain acrylate
polymers rather than rubber adhesi es. These acrylates may
cause allergic contact dermatitis. Pressure sensiti e adhesi es
are in widespread use in the tape and label industries. Aller
gens present in these adhesi es include rosin rubber accelera
tors antio idants acrylates hydro uinones lanolin thiourea
compounds and dodecylmaleamic compounds.
Bhargava K, et al: Eyelid allergic contact dermatitis caused by ethyl
cyanoacrylate–containing eyelash adhesive. Contact Dermatitis 2012;
67:306.
Corazza M, et al: Allergic contact dermatitis in a volleyball player due to
protective adhesive taping. Eur J Dermatol 2011; 21:430.
Howard BK, et al: Contact dermatitis from Dermabond. Contact
Dermatitis 2010; 62:314.
Meikle A, et al: Allergic contact dermatitis at the epidural catheter site
due to Mastisol liquid skin adhesive. Can J Anaesth 2012; 59:515.
Ruhlemann D, et al: Contact dermatitis to self-adhesive ECG electrodes.
Contact Dermatitis 2010; 62:314.
103
 Synthetic resin dermatitis
6 The many arieties o synthetic resins preclude ade uate dis
cussion o each. The reactions during the manu acture o these
substances are more common than those in their nished state.
Contact Dermatitis and Drug Eruptions
Epoxy resins
The epo y resins in their li uid (noncured monomer) orm
may produce se ere dermatitis especially during the manu
acturing process. The ully polymeri ed or cured product is
nonsensiti ing. onindustrial e posure is usually to epo y
resin glues nail lac uers and arti cial nails. po y resins are
used in the home as glues and paints (bathtub and re rigera
tor). Artists and sculptors re uently use epo y resins.
po y resins consist o two or more components the resin
and the curing agent. Appro imately o allergic reactions
are to the resin and to the hardener. The numerous curing
agents include the amines phenolic compounds pero ides
and polyamides. These may be irritants and or allergens. The
resin based on an acetone and phenol compound nown as
bisphenol A in its raw state may cause allergic contact derma
titis. B S G A a combination o bisphenol A and glycidyl
methacrylate is the main allergen in dental bonding agents.
po y resins are used also as stabili ers and plastici ers. Their
use in the manu acture o poly inyl chloride (plastic) lm has
caused dermatitis rom plastic handbags beads glo es and
panties.
Polyester resins
rdinarily completely cured or polymeri ed resins are not
sensiti ers. The unsaturated polyester resins are dissol ed
and later copolymeri ed with inyl monomers. Such polyester
resins are used or polyester plastici ers polyester bers
(Dacron) and polyester lm ( ylar). The unsaturated polyes
ter resins on the other hand will produce primary irritation
in their abrication or among sculptors. The dermatitis occurs
typically as an ec ematous eruption on the bac o the hands
wrists and orearms. Polyester resins are incorporated into
other plastic material as laminates to gi e them strength;
applications include boat hulls automobile body putty sa ety
helmets uel tan s lampshades and s ylights.
Acrylic monomers
Cyanoacrylates are used widely as adhesi es in a ariety o
home and commercial products. They are generally a rare
cause o contact dermatitis. With the ad ent o s in bonding
agents reports o allergy may increase. ulti unctional acrylic
monomers may produce allergic or irritant contact dermatitis.
Pentaerythritol triacrylate trimethylolpropane triacrylate and
he anediol diacrylate are widely used acrylic monomers.
Printers handling multi unctional acrylic monomers in print
ing in s and acrylic printing plates may present with an ery
thematous pruritic eruption mainly o the hands and arms
swelling o the ace and in ol ement o the eyelids.
rthopedic surgeons e perience contact dermatitis rom the
use o acrylic bone cement (methyl methacrylate monomer)
used in mending hip oints. Dentists and dental technicians are
e posed when applying this to teeth. The sensiti er passes
through rubber and poly inyl glo es and may additionally
cause paresthesias. n patients who are allergic to their acrylate
dental prosthesis coating this with V light cured acrylate
lac uer may allow it to be worn without ad erse e ects.
Ben oyl pero ide is a popular acne remedy. t is also used
or bleaching our and edible oils and or curing plastics such
as acrylic dentures. n re uently an allergic contact dermatitis
may result.
Aalto-Korte K, et al: Methacrylate and acrylate allergy in dental
personnel. Contact Dermatitis 2007; 57:324.
104
Bangsgaard N, et al: Contact allergy to epoxy resin. Contact Dermatitis
2012; 67:73.
Ozkaya E: Neighborial allergy: a hidden cause of nonoccupational
airborne contact dermatitis in a housewife from epoxy resin. Dermatitis
2012; 23:124.
Shmidt E, et al: Patch-testing with plastics and glues series allergens.
Dermatitis 2010; 21:269.
Strazzula L, et al: Fingertip purpura in a dental student. JAMA Dermatol
2014; 150:784–785.
Cosmetic dermatitis
Cutaneous reactions to cosmetics may be di ided into irritant
allergic hypersensiti ity and photosensiti ity reactions. ore
than hal the reactions occur on the ace and are caused pri
marily by s in care products nail cosmetics sha ing
preparations and deodorants. The leading cause o allergic
contact dermatitis associated with cosmetics is rom ragrance.
A close second is preser ati es such as Bronopol ( bromo
nitropropane diol) athon CG uaternium u yl
and imida olidinyl urea. The third leading cause is
p phenylenediamine in hair dye. t is recommended that patch
testing with the patient s own product as long as it is applied
to the s in as a lea e on product be part o the e aluation.
Fragrances
Almost all cosmetic preparations s in care products and
many medications contain ragrance; e en those labeled non
scented o ten contain a mas ing ragrance that may be a
sensiti er. en ragrance ree products ha e been docu
mented to contain the raw ragrance ingredients such as rose
oil in all natural products. Again ragrances are the most
common cosmetic ingredient causing allergic contact derma
titis. Photodermatitis irritation contact urticaria and dyspig
mentation are other types o reactions that ragrances may
produce.
The most common indi idual allergens identi ed are cin
namic alcohol oa moss cinnamic aldehyde hydro y citro
nellal mus ambrette isoeugenol geraniol coumarin lyral
( ig. ) and eugenol. re uently unspeci ed allergens are
the cause because they are not listed on labels and ragrances
are combinations o many di erent ingredients. M rox lon
pereirae (balsam o Peru) will identi y appro imately hal o
those o ten unsuspected cases o allergic dermatitis and addi
tional testing with the ragrance mi es will identi y o er .
Additionally a natural ragrance mi ture o asmine absolute
ylang ylang oil narcissus absolute spearmint oil and sandal
wood oil is recommended. ew products should be tested or
tolerance in patients with a history o ragrance sensiti ity.
Fig. 6-16 Fragrance allergy, lyral.
 About o the population ha e ragrance sensiti ity.
Women still outnumber men but as the re uency o ragrance
contact reactions has increased o er the years men ha e
shown a steeper increase in sensiti ity. ragrance is one aller
gen that may be trans erred by s in to s in contact to a sensi
ti e person causing connubial contact dermatitis. ngestion
o balsam related oods such as tomatoes citrus ruits and
spices may cause a are in some sensiti e patients. n particu
larly di cult to treat patients balsam restricted diets may be
bene cial but are not easy to ollow.
Hair dyes
Permanent hair dyes incorporate p phenylenediamine (PPDA)
a popular but potent sensiti er that may cross react with many
chemicals. n rinses and tints the a o dyes acid iolet B
water soluble nigrosine and ammonium carbonate may sen
siti e and cross react with PPDA. Wor ers in the manu acture
o PPDA urriers hairdressers and those in the photographic
and rubber ulcani ation industries de elop eruptions rst on
the bac o the hands wrists orearms eyelids and nose
consisting o an ec ematous erythematous oo ing dermatitis.
Licheni cation and scaling are seen in the chronic type. n
those with dyed hair sensiti ity is mani ested by itching
redness and pu ness o the upper eyelids tops o the ears
temples and bac o the nec ( ig. ). Beard dermatitis may
be caused by coloring o the acial hair and eyelid dermatitis
by dying eyelashes. PPDA added to temporary henna tattoos
to ma e them dar er has resulted in acute esicular allergic
reactions some with scarring and hyperpigmentation.
um um is a common cosmetic in ndia primarily smeared
on the orehead o women to denote their marital status; one
o many reported allergens in the product is PPDA.
or those sensiti e to this type o hair dye use o semiper
manent or temporary dyes might be the solution. n the case
o sensiti ity to the latter egetable dyes such as henna may
be tried. etallic dyes are usually not a ored by women but
are re uently used by men as hair color restorers. The
metallic hair dyes may contain nic el cobalt chromium or
lead. air dyes containing D C and D C dyes o ten do not
cross react with PPDA.
Other hair products
air bleach products incorporate pero ides persul ates and
ammonia which may act as primary irritants. air bleaches
Fig. 6-17 Hair dye allergy.
tahir99 - UnitedVRG
that contain ammonium persul ate a primary irritant may
produce a local urticarial and a generali ed histamine
reaction.
Se eral types o permanent wa e preparations e ist. The
al aline permanent wa e preparations which use ammonium
Contact dermatitis
thioglycolate are rarely i e er sensiti ers and usually cause
only hair brea age and irritant reactions. The hot type or acid
perm is a common sensiti er the allergen being glyceryl
monothioglycolate. Cosmetologists are at ris or de elop
ment o hand dermatitis. The glyceryl monothioglycolate per
sists in the hair or at least months a ter application and may
cause a long lasting dermatitis. t readily penetrates rubber
and inyl glo es. A more neutral p permanent wa e solution
is less allergenic than the acid perms; howe er allergy to
cysteamine hydrochloride ound in neutral permanent
wa e products may occur. This allergen does not penetrate
household weight late glo es and hair wa ed with it does
not produce allergic reactions in sensiti ed indi iduals. Also
it is an amine salt not a thioglycolate so cross reacti ity is
unli ely.
air straighteners using greases and gums are not sensiti
ers; howe er the per ume incorporated in these preparations
can be sensiti ing. Thioglycolates are also used and hair
brea age may occur with these products.
air sprays may contain shellac gum arabic sunscreens
and synthetic resins as sensiti ers and allergic reactions occur
in re uently. Lanolin is re uently incorporated into aerosol
sprays.
Chemical depilatories containing calcium thioglycolate and
the sul des and sul hydrates may cause primary irritant der
matitis. echanical hair remo ers include the mercaptans
wa es and resins; resins may produce allergic dermatitis.
air tonics and lotions with tincture o cinchona produce
allergic sensiti ation; tincture o cantharidin and salicylic acid
cause primary irritation. Resorcin uinine sul ate and per
umes such as bay rum are also sensiti ers.
Nail products
ail lac uers may contain tosylamide ormaldehyde resin
and are a re uent cause o eyelid and nec dermatitis. Pol
ishes ree o this resin are a ailable. ail polish remo ers
are sol ents such as acetone which can cause nail brittleness.
The acrylic monomers in arti cial nails as well as the ethyl
cyanoacrylate glue re uired to attach the prosthetic nail may
produce allergic sensiti ity. Photoinitiating agents such as
ben ophenone used in photobonded acrylic sculptured nails
are other potential allergens.
Lipsticks
Various R and C dyes sunscreens shellac a oring agents
preser ati e and lipstic per umes may cause sensiti ation
reactions. Lipstic s are tested as is. Lip plumpers may cause
contact urticaria in those being issed. Propolis is ound in
many so called natural products including lip balms tooth
pastes lotions shampoos and other cosmetics. ts main aller
gens are two types o ca eates.
Eye makeup
n mascara eye shadow and eyeliners the preser ati e
shellac metals base wa and per umes are the components
that may produce sensiti ation but this occurs rarely. alse
positi e reactions to some mascaras occur when a closed patch
test is used. This is caused by the irritati e ualities o the
sol ents. An open or nonocclusi e patch test is recommended.
A pro ocati e use test in the antecubital ossae may ultimately
be necessary. The rubber sponges used to apply eye ma eup
or cocamidopropylbetaine in eye ma eup remo er also cause
eyelid dermatitis.
105

6 Sunscreens
p Aminoben oic acid (PABA) and its deri ati es (e.g. padi
mate padimate A glycerol PABA) diben oylmethanes
salicylates cinnamates and ben ophenones are photosensiti
Contact Dermatitis and Drug Eruptions
ers as well as sensiti ers. allergy to PABA e ists its deri a
ti es should be a oided and the patient should be aware
that thia ides sul onylurea antidiabetic medication a o dyes
p aminosalicylic acid ben ocaine and PPDA all may cause
dermatitis rom cross reactions. yben one is the most
common sunscreen allergen.
Bleaching creams
ydro uinones are occasional sensiti ers. Ammoniated
mercury is a sensiti ing agent ormerly used in bleaching
creams.
Lanolin
The atty alcohol lanolin is rarely a sensiti er on normal s in
and most cosmetic and s in care products do not cause der
matitis. t pro o es allergic reactions more re uently in thera
peutic agents used by atopic patients and in emollient products
that may be used postsurgically.
Dentifrices and mouthwashes
Denti rices and mouthwashes contain sensiti ers such as the
essential oils used as a oring agents preser ati es ormalin
antibiotics and antiseptics. Circumoral dermatitis and cheilitis
may be caused by tartar control types o denti rice.
Axillary antiperspirants
Aluminum salts such as aluminum chloride and chlorhydro
ide and inc salts such as inc chloride act as primary irritants
and may rarely produce a olliculitis. Aluminum chlorhydrate
is considered to be the least irritating antiperspirant. irco
nium salt preparations now remo ed rom all antiperspirants
produced a granulomatous reaction. irconium aluminum
comple es howe er are o ten used as the acti e ingredient in
topical antiperspirants and may produce granulomas. uater
nary ammonium compounds in some roll on deodorants may
produce allergic contact dermatitis.
Axillary deodorants and feminine hygiene sprays
ragrances bacteriostats and propellants cause the ma ority
o the reactions seen with these products. Deodorants that
contain cinnamic aldehyde can induce irritation on a illary
s in e en when tolerated on healthy s in in other sites.
Cosmetic intolerance syndrome
ccasionally a patient will complain o intense burning or
stinging a ter applying any cosmetic. The patient usually has
only sub ecti e symptoms but ob ecti e in ammation may
also be present. The underlying cause may be di cult to docu
ment e en a ter thorough patch photopatch and contact
urticaria testing. ndogenous disease such as seborrheic der
matitis rosacea or atopic dermatitis may complicate the
assessment. A oidance o all cosmetics with only glycerin
being allowed or months is o ten necessary to calm the
reacti e state. Adding bac cosmetics one at a time no more
re uently than one a wee may then be tolerated.
Alani JI, et al: Allergy to cosmetics. Dermatitis 2013; 24:283–290.
Alrowaishdi F, et al: Allergic contact cheilitis caused by carnauba wax in
a lip balm. Contact Dermatitis 2013; 69:318–319.
Broides A, et al: Contact dermatitis with severe scalp swelling and
upper airway compromise due to black henna hair dye. Pediatr Emerg
Care 2011; 27:745–746.
Das S, et al: Shellac. Dermatitis 2011; 22:220–222.
De Groot AC: Propolis. Dermatitis 2013; 24:263–282.
106
Esdaile B, et al: Allergic contact dermatitis caused by polyester-8 in a
sunscreen moisturizer. Contact Dermatitis 2012; 67:105–106.
Firoz EF, et al: Lip plumper contact urticaria. J Am Acad Dermatol 2009;
60:861–863.
Ghazavi MK, et al: Photo-allergic contact dermatitis caused by isoamyl
P-methoxycinnamate in an “organic” sunscreen. Contact Dermatitis
2011; 64:115–116.
Hamilton T, et al: Allergic contact dermatitis to preservatives and
fragrances in cosmetics. Skin Therapy Lett 2011; 16:1–4.
Handa S, et al: Contact dermatitis to hair dye. Indian J Dermatol
Venereol Leprol 2012; 78:683–690.
Heisterberg M, et al: Deodorants are the leading cause of allergic
contact dermatitis to fragrance ingredients. Contact Dermatitis 2011;
64:258–264.
Jacob SE, et al: Benzyl alcohol: a covert fragrance. Dermatitis 2007;
18:232–233.
Jefferson J, et al: Update on nail cosmetics. Dermatol Ther 2012;
25:481–490.
Jensen, P, et al: Connubial allergic contact dermatitis caused by
fragrance ingredients. Dermatitis Dermatol Ther 2012; 25:481–490.
Kind F, et al: Contact dermatitis to para-phenylenediamine in hair dye
following sensitization to black henna tattoos. J Dtsch Dermatol Ges
2012; 10:572–578.
Kumar P, et al: Patch testing in suspected allergic contact dermatitis to
cosmetics. Dermatol Res Pract 2014; 2014:695387.
Landers MC, et al: Permanent wave dermatitis. Am J Contact Dermat
2003; 14:157–160.
Lee SS, et al: Multicenter study of preservative sensitivity in patients
with suspected cosmetic contact dermatitis in Korea. J Dermatol 2012;
39:677–681.
Leventhal JS, et al: Crystal deodorant-induced axillary granulomatous
dermatitis. Int J Dermatol 2014; 53:e59–e60.
Lev-Tov H, et al: The sensitive skin syndrome. Indian J Dermatol 2012;
57:419–423.
Miest RY, et al: Diagnosis and prevalence of lanolin allergy. Dermatitis
2013; 24:119–123.
Nardelli A, et al: Results of patch testing with fragrance mix 1, fragrance
mix 2, and their ingredients, and Myroxylon pereirae and colophonium,
over a 21-year period. Contact Dermatitis 2013; 68:307–313.
Nguyen JC, et al: Allergic contact dermatitis caused by lanolin (wool)
alcohol contained in an emollient in three postsurgical patients. J Am
Acad Dermatol 2010; 62:1064–1065.
Scheman A, et al: Balsam of Peru. Dermatitis 2013; 24:153–160.
Warshaw EM, et al: Positive patch test reactions to lanolin. Dermatitis
2009; 20:79–88.
Washaw EM, et al: Patch test reactions associated with sunscreen
products and the importance of testing to an expanded series.
Dermatitis 2013; 24:176–182.
Waters AJ, et al: Photocontact allergy to PABA in sunscreens: the need
for continued vigilance. Contact Dermatitis 2009; 60:172–173.
Wetter DA, et al: Results of patch testing to personal care product
allergens in a standard series and a supplemental cosmetic series. J
Am Acad Dermatol 2010; 63:789–798.
Preservatives
Preser ati es are added to any preparation that contains water
to ill microorganisms and pre ent spoilage. Such products
include moist materials such as baby wipes which when used
in either in ants or adults can produce reactions caused by
preser ati es. The most important class is ormaldehyde and
the ormaldehyde releasing compounds including uater
nium (the leading preser ati e sensiti er in the nited
States) imida olidinyl urea dia olidinyl urea D D hydan
toin and bromo nitropropane diol.
athon CG or methylchloroisothia olinone methylisothia
olinone ( C ) and u yl (methyldibromoglutaro
nitrile and pheno yethanol in ratio) are other important
preser ati e allergens. n u yl the methyldibromoglu
taronitrile component produces the allergic response. This
preser ati e may produce alse negati e results on testing so
repeat open testing is indicated i a speci c lea e on product
is suspected o causing allergy. uropean regulations limit
e posure to methyldibromoglutaronitrile. As with similar
laws regulating nic el in urope allergy to this preser ati e
is also lowering in incidence o er time.
Tea tree oil is an additi e to some natural products that may
ser e as an antimicrobial. t is becoming a more re uent sen
siti er as more products include this oil as a natural antimi
crobial agent. Sorbic acid is a rare sensiti er among the
preser ati es; howe er it is a cause o acial ushing and
stinging through its action as an inducer o nonimmunologic
contact urticaria. Ben al onium chloride is widely used but a
rare sensiti er. Triclosan and ben yl alcohol are wea sensiti
ers. Thimerosal is discussed earlier.
Formaldehyde and formaldehyde-releasing agents
ormaldehyde is used rarely primarily in shampoos. Because
it is uic ly diluted and washed away sensiti ation through
this e posure is rare. ormaldehyde releasers are polymers o
ormaldehyde that may release small amounts o ormalde
hyde under certain conditions. Allergy may be to the
ormaldehyde releasing preser ati es (which act as antibacte
rial and anti ungal agents in their own right) or to the released
ormaldehyde. Cross reacti ity among them is common so
when allergy is pro ed to one compound and a oidance does
not clear the eruption screening or clinically rele ant reac
tions to the others is indicated. This may be done by repetiti e
open application testing to the lea e on product or by e tended
patch testing.
Parabens
Allergic contact dermatitis may de elop rom parabens
which are used in cosmetics oods drugs denti rices and
suppositories. The paraben esters (methyl ethyl propyl and
butyl p hydro yben oates) are used in low concentrations in
cosmetics and rarely cause dermatitis. They are ound in
higher concentration in topical medicaments and may be the
cause o allergic reactions. Perpetuation o a dermatitis
despite e ecti e topical medication suggests the possibility
o paraben or corticosteroid sensiti ity or the presence o
another sensiti er. Parabens which are re uently used as
bacteriostatic agents are capable o producing immunologi
cally mediated immediate systemic hypersensiti ity reac
tions. Cross reacti ity to p phenylenediamine and ben ocaine
occurs in some indi iduals.
p-Chloro-metaxylenol (PCMX)
This chlorinated phenol antiseptic is used in many o er the
counter products with the disin ectant properties o p chloro
metacresol. Sensiti ation occurs primarily through e posure
to betamethasone containing cream. PC is cross reacti e
with p chloro metacresol.
Aakhus AE, et al: Allergy to methyldibromoglutaronitrile/phenoxyethanol
(Euxyl K 400): regulatory issues, epidemiology, clinical characteristics,
and management. Dermatitis 2011; 22:127–140.
Boyapati A, et al: Allergic contact dermatitis to methylisothiazolinone:
exposure from baby wipes causing hand dermatitis. Australas J
Dermatol 2013; 54:264–267.
Chow ET, et al: Frequency of positive patch test reactions to
preservatives. Australas J Dermatol 2013; 54:31–35.
Curry EJ, et al: Benzyl alcohol allergy. Dermatitis 2005; 16:203.
Maier LE, et al: Hand dermatitis. Dermatol Clin 2001; 27:251–264.
Maio P, et al: Contact allergy to methylchloroisothiazolinone/
methylisothiazolinone (MCI/MI). Cutan Ocul Toxicol 2012;
31:151–153.
Schnuch A, et al: Risk of sensitization to preservatives estimated on the
basis of patch test data and exposure, according to a sample of 3541
leave-on products. Contact Dermatitis 2011; 65:167–174.
Wilson M, et al: Chloroxylenol. Dermatitis 2007; 18:120.
Yim E, et al: Contact dermatitis caused by preservatives. Dermatitis
2014; 25:215–231.
tahir99 - UnitedVRG
Vehicles
ormulation o topically applied products is comple and
additi es are blended to ma e a pleasant base or carriage o
the acti e ingredient to the s in. Various emulsi ers humec
Contact dermatitis
tants stabili ers sur actants and sur ace acti e agents are
used to ma e esthetically pleasing preparations. These may
cause irritation erythema and allergy. The sur actant cocami
dopropyl betaine produces dermatitis o the head and nec in
consumers and the hands in hairdressers o ten rom its pres
ence in shampoos. Propolis and lanolin are discussed pre i
ously under Cosmetic dermatitis.
Propylene glycol
Propylene glycol is widely used as a ehicle or topical medi
cations cosmetics (especially antiperspirants) and arious
emollient lotions. t is used in the manu acture o automobile
bra e uid and al yd resins as a lubricant or ood machinery
and as an additi e or ood colors and a oring agents.
Propylene glycol must be considered as a sensiti er able to
produce contact dermatitis and it can cause a are o the
contact dermatitis when ingested. t is tested as a a ueous
solution but irritant reactions or alse negati e results are
common. A use test o the implicated propylene glycol
containing products may be re uired.
Ethylenediamine
thylenediamine is used as a stabili er in medicated creams.
t may cause contact dermatitis and cross react with internally
ta en aminophylline which consists o theophylline and eth
ylenediamine. ydro y ine is a pipera ine deri ati e that is
structurally based on a dimer o ethylenediamine to which
patients sensiti e to the stabili er may de elop a generali ed
itchy red eruption that recurs each time hydro y ine is ta en
orally.
Al Jasser M, et al: Propylene glycol. Skin Therapy Lett 2011; 16:5–7.
Jacob SE, et al: Cocamidopropyl betaine. Dermatitis 2008; 19:157–160.
Lowther A, et al: Systemic contact dermatitis from propylene glycol.
Dermatitis 2008; 19:105–108.
Reid N, et al: Worsening of contact dermatitis by oral hydroxyzine: a
case report. Dermatol Online J 2013; 19:4.
Suuronen K, et al: Occupational contact allergy to cocamidopropyl
betaine and its impurities. Contact Dermatitis 2012; 66:286–292.
Warshaw EM, et al: Positive patch-test reactions to propylene glycol.
Dermatitis 2009; 20:14–20.
Topical drug contact dermatitis
Drugs in addition to their pharmacologic and possible to ic
action also possess sensiti ing properties. Sensiti ation may
occur not only rom topical application but also rom inges
tion in ection or inhalation. Some drugs such as the antihis
tamines including topical do epin sensiti e much more
re uently when applied topically than when ta en orally.
With the ad ent o transdermal patches or deli ery o medi
cations such as nitroglycerin hormones nicotine clonidine
entanyl lidocaine and scopolamine reports o sensiti ation
ha e been increasing ( ig. ). Clonidine induces the highest
rate o allergic reactions. At times erythema multi orme li e
reactions may occur with transdermally applied drugs.
Some drugs may produce sensiti ation o the s in when
applied topically; i the medication is ta en later internally an
acute are at the site o the contact dermatitis may result. This
anamnestic (recalled) eruption or systemic contact dermatitis
can occur with antihistamines sul onamides and penicillin.
The same is true o the local anesthetic ointments containing
caine medications. sually i sensiti ation occurs when
using transdermal patches the drugs do not cause systemic
107

6 use a ter minor surgical procedures. A ter clean surgical pro
Contact Dermatitis and Drug Eruptions
Fig. 6-18 Nitroglycerin patch allergy.
contact dermatitis when ta en orally. The important topical
medications that cause irritation or allergic contact dermatitis
are discussed ne t.
Local anesthetics
Physicians and dentists may de elop allergic contact dermati
tis rom local anesthetics. n addition the continued use o
these local anesthetics as antipruritic ointments and lotions
causes sensiti ation o the s in. Ben ocaine is a re uently
used topical antipruritic and is the most common topical sen
siti er o this group. tchy dermatitis o the anogenital area
may be caused by a topical anesthetic.
Local anesthetics may be di ided into two groups. The rst
group includes the p aminoben oic acid esters such as ben o
caine butethamine chloroprocaine procaine ( o acaine)
and tetracaine. The second group which sensiti es much less
re uently includes the amides such as dibucaine ( uper
cainal) lidocaine (Lido antle LA Lidoderm patch L
ylocaine) mepi acaine (Carbocaine) and prilocaine. n addi
tion the preser ati e methylparaben re uently ound in
these prepared solutions may cause hypersensiti ity reactions
that can easily be misattributed to the local anesthetics. t
should be ept in mind that numerous cross reactions are
seen in ben ocaine sensiti e indi iduals. These are discussed
earlier in the sections on sunscreens and preser ati es. Lido
caine can induce contact urticaria as well.
Antimicrobials
Physicians dentists nurses and other medical personnel as
well as patients especially those with chronic leg ulcers may
de elop contact dermatitis rom arious antibiotics. eomycin
and bacitracin are only behind nic el ragrances (and the
related M rox lon pereirae) and uaternium as the most
common sensiti ers in the nited States. As a topical antibi
otic neomycin sul ate has been incorporated into innumerable
ointments creams and lotions. t is present in such prepara
tions as underarm deodorants otic and ophthalmologic prepa
rations and antibiotic creams and ointments a ailable without
prescription. The signs o neomycin sensiti ity may be those
o a typical contact dermatitis but are o ten signs o a recalci
trant s in eruption that has become licheni ed and e en
hyper eratotic. This may result because many topical agents
contain se eral types o antibiotic but also o ten ha e cortico
steroids present. This picture may be seen in persistent
e ternal otitis lichen simple chronicus o the nuchal area or
dermatophytosis between the toes. A late appearing reaction
on patch testing can occur so an assessment at day is
recommended.
108
Allergy to bacitracin increased dramatically because o its
cedures white petrolatum is as e ecti e in wound healing as
antibiotic ointment and it pre ents more in ection and does
not carry the allergenic potential. Petrolatum should be used
a ter clean cutaneous surgery; antibiotic ointments are not nec
essary. With e idence indicating that use o topical antibiotics
a ter clean cutaneous surgery is waning the re uency o baci
tracin allergy should decrease as well. There is a high rate o
co reaction (not cross reaction) with neomycin because o
simultaneous e posures. Contact urticaria and anaphyla is
are reported more o ten with bacitracin than with other
antibiotics.
a enide acetate the topical antimicrobial ound in Sul a
mylon a burn remedy may cause allergic contact dermatitis
as can metronida ole.
Antifungal agents
Allergic contact dermatitis to imida ole and other anti ungal
agents may occur. There is a high cross reacti ity rate among
micona ole isocona ole clotrima ole and o icona ole
because o their common chemical structure.
Phenothiazine drugs
andling in ectable solutions and tablets may produce derma
titis in patients sensiti ed to chlorproma ine and other pheno
thia ine deri ati es. The reactions may be photoallergic or
nonphotoallergic.
Corticosteroids
umerous reports o large series o patients who ha e de el
oped allergy to common corticosteroid preparations empha
si e the need or a high inde o suspicion when treating
patients with chronic dermatitis who ail to impro e or who
worsen when topical steroidal agents are used. nce sensi
ti ed to one type o corticosteroid cross sensiti ation may
occur. The corticosteroids ha e been separated into the ollow
ing our structural classes
Class A is the hydrocortisone ti ocortol pi alate group.
Class B is the triamcinolone acetonide budesonide
group.
Class C is the betamethasone group.
Class D is the hydrocortisone butyrate group.
There are re uent cross reactions between classes B and D.
Ti ocortol pi alate and budesonide ha e been ound to be the
best screening agents nding o steroid allergies. Patch
testing to the implicated lea e on product may be use ul. An
empiric trial o deso imetasone (Topicort) or mometasone
( locon) in the absence o patch testing will gi e the best
chance o selecting a topical steroid with an e tremely low ris
o sensiti ation.
Cronin H, et al: Anaphylactic reaction to bacitracin ointment. Cutis 2009;
83:127.
Isaksson M: Systemic contact allergy to corticosteroids revisited.
Contact Dermatitis 2007; 57:368.
Javanovic M, et al: Contact urticaria and allergic contact dermatitis to
lidocaine in a patient sensitive to benzocaine and propolis. Contact
Dermatitis 2006; 54:124.
Jean SE, et al: Contact dermatitis in leg ulcer patients. J Cutan Med
Surg 2009; 13:S38.
Musel AL, et al: Cutaneous reactions to transdermal therapeutic
systems. Dermatitis 2006; 17:109.
Nihawan RI, et al: Systemic contact dermatitis. Dermatol Clin 2009;
27:355.
Ramirez P, et al: Allergic contact dermatitis from antihemorrhoidal
ointments. Dermatitis 2010; 21:176.
Sasseville K: Contact dermatitis from topical antibiotics. Eur J Dermatol
2011; 3:311.
 Timmermans MW, et al: Allergic contact dermatitis from EMLA cream. J
Dtsch Dermatol Ges 2009; 7:237.
Torres MJ, et al: Hypersensitivity reactions to corticosteroids. Curr Opin
Allergy Clin Immunol 2010; 10:273.
Veien NK: Systemic contact dermatitis. Int J Dermatol 2011; 50:1445.
Warshaw EM, et al: Patch-test reactions to topical anesthetics.
Dermatitis 2008; 19:81.
Wu PA, et al: Topical antibiotic use following dermatologic procedures.
J Am Acad Dermatol 2013; 68:516.
Occupational contact dermatitis
Wor ers in arious occupations are prone to contact dermati
tis rom primary irritants and allergic contactants. n certain
occupations it is a common occurrence. rritant contact der
matitis occurs more re uently in the wor place but it tends
to be less se ere and less chronic than allergic contact derma
titis (see ig. ). ccupational s in disease has declined
o er the past years but still constitutes appro imately
o all occupational disease cases. Agriculture orestry and
shing ha e the highest incidence o occupational s in disease
with the manu acturing and health care sectors contributing
many cases as well.
rritant contact dermatitis is o ten present in wet wor obs
and allergy occurs in hairdressers machinists and many
others with uni ue e posures to multiple sensiti ing chemi
cals. The hands are the parts most a ected and are in ol ed
in o allergic reactions and o irritant dermatitis.
po y resin is an allergen o errepresented when e aluating
occupational patients. The allergens most re uently encoun
tered in occupational cases are carba mi thiuram mi epo y
resin ormaldehyde and nic el.
Management
ccupational contact dermatitis is managed by eliminating
contact o the s in with irritating and sensiti ing substances.
The wor en ironment should be care ully controlled with
use o all a ailable protecti e de ices to pre ent accidental
and e en planned e posures. Personal protecti e measures
such as re uent clothing changes cleansing showers protec
ti e clothing and protecti e barrier creams should be used as
appropriate. and cleansing procedures should be thoroughly
sur eyed with particular attention to the soaps a ailable and
the sol ents used.
Treatment o the dermatitis ollows closely that recom
mended or oxico en ron dermatitis. Topical corticosteroid
preparations are especially help ul in the acute phase. or dry
ssured hands soa ing them in water or min at night ol
lowed immediately on remo ing (without drying them) with
triamcinolone . ointment will help hydrate and heal.
Topical tacrolimus ointment and pimecrolimus cream may
assist in maintenance therapy along with high lipid content
moisturi ing creams. When rubber and poly inyl glo es
cannot be used against irritant and allergenic substances pro
tecti e s in creams may o er a solution but are o ten impracti
cal. A wide ariety is a ailable but two main types are used
or wet wor to protect against acids al alis water based
paints coolants and cutting oils with water and or dry
wor to protect against oils greases cutting oils adhesi e
resins glues and wood preser ati es.
n ortunately despite the best e orts at treatment and pre
ention the prognosis or occupational s in disease is guarded.
ne third to one uarter heal and another one third to one
hal impro e with the remainder the same or worse. A change
or discontinuance o the ob does not guarantee relie ; many
indi iduals continue to ha e persistent postoccupational der
matitis. The importance o thorough patient education cannot
tahir99 - UnitedVRG
be o eremphasi ed. Atopic patients males with chromate
allergy emales with nic el allergy those with a delay in
diagnosis be ore institution o treatment and construction
industry wor ers are the worst whereas irritation rom met
alwor ing uids reactions to urushiols in oresters and aller
Contact dermatitis
gic contact dermatitis to acrylic monomers or amine curing
agents is usually short li ed.
Bauer A, et al: Intervention for preventing occupational irritant hand
dermatitis. Cochrane Database Syst Rev 2010; 6:CD004414.
Bourrain JL: Occupational contact urticaria. Clin Rev Allergy Immunol
2006; 30:39.
Diepgen TL, et al: Management of chronic hand eczema. Contact
Dermatitis 2007; 57:203.
Friis UF, et al: Occupational irritant contact dermatitis diagnosed by
analysis of contact irritants and allergens in the work environment.
Contact Dermatitis 2014; Oct 10.
Holness DL, et al: Workers with occupational contact dermatitis. Occup
Med 2012; 62:455.
Keegel T, et al: The epidemiology of occupational contact dermatitis
(1997–2007). Int J Dermatol 2009; 48:571.
Mai Konen T, et al: Long-term follow-up study of occupational hand
eczema. Br J Dermatol 2010 [Epub].
Nicholson PJ: Occupational contact dermatitis. Clin Dermatol 2011;
29:325.
Nicholson PJ, et al: Evidence-based guidelines for the prevention,
identification and management of occupational contact dermatitis and
urticaria. Contact Dermatitis 2010; 63:177.
Patruno C, et al: Occupational allergic contact dermatitis to acrylic nails
in beauticians. Occup Environ Med 2012; 69:772.
Ponten A, et al: Occupational allergic contact dermatitis caused by
sterile non-latex protective gloves. Contact Dermatitis 2012; 68:103.
Rietschel RL, Fowler JF Jr: Fisher’s Contact Dermatitis, 6th edn.
Hamilton: Lippincott, BC Decker, 2008.
Shalock PC, et al: Protection from occupational allergens. Curr Probl
Dermatol 2007; 34:58.
Slodownik D, et al: Occupational factors in skin diseases. Curr Probl
Dermatol 2007; 35:173.
Smedley J: Concise guidance: diagnosis, management and prevention
of occupational contact dermatitis. Clin Med 2010; 10:487.
Sohrabian S, et al: Contact dermatitis in agriculture. J Agromed 2007;
12:3.
Suneja T, et al: Occupational dermatoses in health care workers
evaluated for suspected allergic contact dermatitis. Contact Dermatitis
2008; 58:285.
Warshaw EM, et al: Occupational contact dermatitis in hairdressers/
cosmetologists. Dermatitis 2012; 23:258.
Zhai H, et al: Protection from irritants. Curr Probl Dermatol 2007; 34:47.
Contact urticaria
Contact urticaria may be de ned as a wheal and are reaction
occurring when a substance is applied to the intact s in. rti
caria is only one o a broad spectrum o immediate reactions
including pruritus dermatitis local or general urticaria bron
chial asthma orolaryngeal edema rhinocon uncti itis gastro
intestinal distress headache or anaphylactic reaction. Any
combination o these is subsumed under the e pression syn
drome o immediate reactions.
Contact urticaria may be nonimmunologic (no prior sensiti
ation) immunologic or o un nown mechanism. The nonim
munologic type is the most common and may be caused by
direct release o asoacti e substances rom mast cells. The
allergic type tends to be the most se ere because anaphyla is
is possible. The third type has eatures o both other types.
Nonimmunologic mechanism
The nonimmunologic type o reaction occurs most re uently
and may produce contact urticaria in almost all e posed indi
iduals. amples o this type o reaction are seen with nettle
rash (plants) dimethyl sul o ide (D S ) sorbic acid ben oic
acid cinnamic aldehyde cobalt chloride and Tra uril.
109

6 Immunologic mechanism
Contact Dermatitis and Drug Eruptions
110
The immunologic reaction is o the immediate ( g mediated)
type o hypersensiti ity. Late potatoes phenylmercuric pro
pionate and many other allergens ha e been reported to cause
this type.
Uncertain mechanism
The uncertain type o reaction occurs with agents that produce
contact urticaria and a generali ed histamine type o reaction
but lac a direct or immunologic basis or the reaction.
Substances causing contact urticaria
any di erent substances can elicit such a reaction. Contact
urticaria is seen in homema ers and ood wor ers who handle
raw egetables raw meats and sh shell sh and other oods.
Raw potatoes ha e been shown to cause not only contact urti
caria but also asthma at the same time. t has been seen in
hairdressers who handle bleaches and hair dyes containing
ammonium persul ate in whom the contact urticaria is accom
panied by swelling and erythema o the ace ollowed by
unconsciousness. Caterpillars moths and hedgehogs may
cause contact urticaria ust by touching the s in.
Additional substances inducing this reaction are oatmeal
our meat tur ey s in cal li er banana lemon monoamyla
mine ben ophenone nail polish tetanus antito in streptomy
cin cetyl alcohol stearyl alcohol estrogenic cream cinnamic
aldehyde sorbic acid ben oic acid castor bean lindane
carrots spices wool sil dog and cat sali a dog hairs horse
serum ammonia sul ur dio ide ormaldehyde acrylic mono
mers e otic woods wheat cod li er oil and aspirin.
Bacitracin ointment may cause anaphylactic reactions when
applied topically especially to chronic leg ulcers; howe er it
may rarely occur a ter application to acute wounds ( ig. ).
ni ersal precautions not only led to a mar ed increase in
delayed type hypersensiti ity reaction to rubber additi es
but also to many reports o contact urticaria and anaphyla is
to late . ost o these reactions occur in health pro essionals.
Reactions are characteri ed by itching and swelling o the
hands within a ew minutes o donning the glo es usually
resol ing within an hour a ter remo ing them. n patients with
continued e posure the eruption may e entually appear as
chronic ec ema. Glo e powder may aerosoli e the allergen
and produce more generali ed reactions. Although these reac
tions may occur on the ob many cases present as death or
near death e ents when sensiti ed indi iduals undergo
surgery or other procedures especially when there is mucosal
e posure (e.g. dental care rectal e amination childbirth).
Fig. 6-19 Contact urticaria caused by bacitracin applied to punch
biopsy site.
n addition to health care wor ers who ha e a reported
incidence o atopic persons and spina bi da patients
are other ris groups or the de elopment o type allergy to
late protein. The sensiti ed indi idual should also be aware
that up to o patients ha e a concomitant ruit allergy to
oods such as banana a ocado iwi chestnut and passion
ruit.
Testing
The usual closed patch tests do not show sensiti ity reactions.
nstead open patch tests are per ormed or eliciting immediate
type hypersensiti ity. The substance is applied to a cm area
on the orearm and obser ed or min or erythema that
e ol es into a wheal and are response. When oods are
tested a small piece o the actual ood is placed on the s in.
Rubber glo e testing can be done by applying one nger o a
late glo e to a moistened hand or min. no reaction is
obser ed the entire glo e is worn or another min. The
radioallergosorbent test (RAST) detects o late allergic
indi iduals. There is no standard allergen a ailable or pric
testing. Pric scratch or intradermal testing is underta en
only when there are problems o interpretation o the open
patch tests. These tests ha e produced anaphylactic reactions
and should only be attempted when support or this complica
tion is a ailable.
Management
A oidance o the o ending substance is best but i this is not
possible antihistamines are o bene t. generali ed urticaria
or asthmatic reactions occur systemic glucocorticoids are best.
or anaphyla is epinephrine and supporti e measures are
needed.
Alikhan A, et al: Produce-induced contact urticarial and dermatitis.
Contact Dermatitis 2009; 60:174.
Bourrain JL: Occupational contact urticaria. Clin Rev Allergy Immunol
2006; 30:39.
Bousquet J, et al: Natural rubber latex allergy among health care
workers. J Allergy Clin Immunol 2006; 118:447.
Cronin H, et al: Anaphylactic reaction to bacitracin ointment. Cutis 2009;
83:127.
Doutre MS: Occupational contact urticaria and protein contact
dermatitis. Eur J Dermatol 2005; 15:419.
Firoz EF, et al: Lip plumper contact urticaria. J Am Acad Dermatol 2009;
60:861.
Gimenez-Arnau A, et al: Immediate contact skin reactions, an update of
contact urticaria, contact urticarial syndrome and protein contact
dermatitis. Eur J Dermatol 2010; 20:552.
Konstantinou GN, et al: Food contact hypersensitivity syndrome. Clin Exp
Dermatol 2008; 33:383.
Stutz N, et al: Anaphylaxis caused by contact urticaria because of
epoxy resins. Contact Dermatitis 2008; 58:307.
Williams JD, et al: Occupational contact urticaria. Br J Dermatol 2008;
159:125.
DRUG REACTIONS
Epidemiology
Ad erse drug reactions (ADRs) are a common cause o der
matologic consultation. n a large rench study about in
inpatients on medical ser ices de eloped a drug eruption
compared with in on surgical ser ices. n the nited
States similar studies ha e shown a reaction rate o in
or medical inpatients. n only about o patients who were
care ully e aluated was it possible to attribute a speci c
medication de nitely as the cause o the eruption. Simple
e anthems ( ) and urticaria ( ) account or the ast
ma ority o drug eruptions. emales are . . times more
li ely to de elop drug eruptions e cept in children under age
 years with boys more li ely to be a ected than girls. Ami
nopenicillins cause drug eruptions in . o e posures
and trimethoprim sul ametho a ole (T P S ) in . . .
About o emergency department isits or ad erse e ents
caused by medications are related to antibiotics mainly peni
cillins and cephalosporins. onsteroidal anti in ammatory
drugs ( SA Ds) ha e a reaction rate o about in . n con
trast reaction rates or digo in lidocaine prednisone codeine
and acetaminophen are less than in .
Patients with human immunode ciency irus ( V) or
pstein Barr irus ( BV) in ection ha e dramatically increased
rates o e anthematous reactions to certain antibiotics. yper
sensiti ity syndromes rom multiple drug classes ha e been
associated with reacti ation o latent iral in ections primarily
human herpes irus ( V) and V but also BV and
cytomegalo irus (C V). uman leu ocyte antigen ( LA)
type in a race speci c manner may increase ris or drug
reactions or speci c medications.
Evaluation
our basic rules should always be applied in e aluating the
patient with a suspected ADR as ollows
. The patient is probably on unnecessary medications and
all o these should be stopped. Pare down the medication
list to the bare essentials.
. The patient must be as ed about nonprescription
medications and pharmaceuticals deli ered by other
means (e.g. eyedrops suppositories implants in ections
patches recreational drugs).
. Regardless o how atypical the patient s cutaneous
reaction always consider medication as a possible cause.
n patients with unusual reactions searching the medical
literature and calling the manu acturer or prior reports
may be use ul.
. The timing o drug administration must correlate
with the appearance o the eruption. A drug chart
lists all the drugs gi en to the patient in the le t column
with the dates along the lower a is and the course o the
drug eruption at the top. Lines e tend rom le t to right
or the dates o administration o each medication. These
are directly below the course o the eruption. This
graphic representation o the timing o medication
administration and eruption is a ery handy tool in
assigning plausibility to a certain medication causing an
eruption. The nurses notes and patient history are most
use ul in determining e actly when the eruption rst
appeared.
An important step in e aluating a patient with a potential
ADR is to diagnose the cutaneous eruption by clinical pattern
(e.g. urticaria e anthem asculitis hypersensiti ity syn
drome). Regularly updated manuals (e.g. Litt) or similar nter
net databases are strongly recommended as ready re erence
sources or this in ormation. The ollowing uestions pro ide
a ramewor or e aluation
as the suspected medication been reported to cause the
reaction the patient is e periencing ow re uently
as the patient had a pre ious reaction to any
medications
What are other possible causes o the patient s eruption
or e ample an e anthem could be related to an
associated iral illness not the medication.
When did the eruption appear relati e to the
administration o the suspected medication
Certain reactions are nown to be related to rate o
administration ( ancomycin red man syndrome) or
tahir99 - UnitedVRG
cumulati e dose (lichenoid reactions to gold). Could the
rate or dose be causing this patient s reaction
Does the eruption clear when the suspected medication is
stopped Because certain eruptions may clear with
continuation o the drug howe er this is a use ul but
Drug reactions
not irre utable criterion to ascribe a speci c reaction to a
medication.
Does the reaction recur with rechallenge
S in testing may be use ul in e aluating type (immediate)
hypersensiti ity reactions. t is most re uently used in e alu
ating ad erse reactions to penicillin local anesthetics insulin
and accines. RAST has demonstrated a alse negati e
rate in penicillin type allergy; thus in their current orm
RASTs cannot replace s in testing. ntradermal s in pric
and patch testing are also reported to be bene cial in some
patients with morbilli orm reactions or ed drug reaction.
Lymphocytoto icity assays which are a ailable commercially
may be predicti e o an ad erse reaction and ha e been used
in patients with anticon ulsant or sul onamide hypersensiti
ity reaction.
The patient should be gi en concrete ad ice about the reac
tion. What was the probability that the patient s reaction was
caused by the medication Can the patient ta e the medication
again and i so what may occur What cross reactions are
nown What other medications must the patient a oid
nusual reactions should be reported to regulatory agencies
and the manu acturer whereas routine reporting o e an
thems is strongly discouraged because this practice dilutes
important sa ety signals related to unusual reactions.
Pathogenesis
T cells speci cally T helper (Th ) cells are thought to be
important inducers o ADRs. T cells in the dermis in
acute generali ed e anthematous pustulosis (AG P) secrete
interleu in ( L ) a neutrophil attracting chemo ine. n
drug rash (reaction) with eosinophilia and systemic symptoms
(DR SS) they secrete L and eota in recruiting eosinophils.
As a conse uence o T helper cell acti ation memory T cells
are produced resulting in recurrence o the eruption on rechal
lenge. Since Th cells are mediators o these eruptions
inter eron ( ) γ release assays using peripheral blood lym
phocytes are being e aluated or con rming the inciting medi
cation in ADRs. The sensiti ity appears to be drug class
dependent with low sensiti ity or ADRs induced by anticon
ulsants antibiotics and cardio ascular medications.
Large molecules such as rat or mouse deri ed antibodies
can be immunogenic. ost medications howe er are too
small to be recogni ed as antigens by immunologically acti e
cells. They must bind to a larger molecule usually a protein
to orm an immunogenic product. The medication is the
hapten and the immunologically acti e molecule is a
medication protein comple or hapten carrier comple . Some
medications such as penicillin are acti e enough to bind
directly to proteins. ost howe er need to be metaboli ed to
more acti e or more immunogenic orms to bind to proteins
and cause an immunologic reaction. The drug metabolites can
also be to ic to cells causing direct cell damage. Drug metabo
lism o ten occurs in the cytochrome P system in the li er.
There has also been a proposed model or ADRs in which
the drug or a metabolite binds directly to T cells or Langerhans
cells in close opposition to sentinel T cells in the s in. This
direct binding could acti ate the T cell Langerhans cell inter
acti e unit resulting in the production o biologically acti e
molecules. This would e plain how some drug eruptions
occur soon a ter e posure or with the rst e posure to a medi
cation. t could also e plain a dose dependent e ect in drug 111
 eruptions. Also a systemic iral in ection may ha e already
6 acti ated the immune cells in the s in reducing their thresh
old or acti ation by drug binding. nce the T cell is acti ated
it may produce a ariety o reactions as ollows
Contact Dermatitis and Drug Eruptions
antithymocyte globulin is associated with circulating immune
comple es. edications notably ce aclor induce a serum
sic ness li e illness not associated with circulating immune
comple es. Both calcium channel bloc ers and inter eron are
strongly associated with ec ematous eruptions.

. T cells stimulate γ production and a Th response

simulating contact dermatitis. This type o reaction could
be bullous but without e tensi e epidermal necrosis.
. T cells could be acti ated to unction in a Th manner
and stimulate eosinophil ingress through Th cyto ines
(morbilli orm and urticarial drug eruptions).
. T cells could acti ate cytoto ic (CD +) T cells which
would secrete per orin gran yme B and as ligand
resulting in eratinocyte apoptosis. This could e plain
bullous reaction the obser ation that occasional necrotic
eratinocytes are seen in patients with e anthems and
the rare eruption that begins as an e anthem and
progresses to a bullous eruption. Drug eruptions
containing acti ated CD + T cells are more dangerous
since CD + cells attac all ma or histocompatibility
comple ( C) class e pressing cells (including
eratinocytes) resulting in more se ere reactions.
. T cells through cyto ine production recruit neutrophils
resulting in pustular e anthems and AG P.
Th cells are implicated in many drug eruptions and sul
ametho a ole induces a T cell switch mechanism based on
the TCRVβ domain altering peptide LA recognition.
Dermal CD + CD + o p regulatory T cells (Tregs) are
reduced in se ere bullous drug eruptions such as to ic
epidermal necrolysis (T ). Circulating Tregs e pressing
s in homing molecules are increased in early drug induced
hypersensiti ity syndrome (D S D S). The cells are immu
nologically acti e early in the course o the eruption enter the
s in and can e ecti ely suppress the immune response.
owe er they become unctionally de cient later perhaps
e plaining the occasional de elopment o autoimmune phe
nomena months a ter D S as well as the tendency o D S
reactions to relapse recur or ail to resol e. Peripheral blood
mononuclear cells are stimulated by the incriminated drug in
a lymphocyte trans ormation test (LTT) or only the rst wee
in T and e anthems. n D S howe er the LTT test is
negati e until wee s ollowing the eruption and remains
positi e or year or more. This supports the obser ation that
D S reactions are long li ed. n addition the LTT is essen
tially only use ul in diagnosing D S because it is rarely
per ormed during the rst wee o an ADR. n se ere drug
reactions micro R A a p downregulates the e pression o
the antiapoptotic B cell lymphoma leu emia li e protein
(BCL L ) promoting apoptosis.
Exanthems (morbilliform or
maculopapular reactions)
anthems are the most common orm o ad erse cutaneous
drug eruption. They are characteri ed by erythema o ten with
small papules throughout. anthems tend to occur within the
rst wee s o treatment but may appear later or e en up to
days a ter the medication has been stopped. Lesions tend
to appear rst pro imally especially in the groin and a illa
generali ing within or days. The ace may be spared. Pru
ritus is usually prominent helping to distinguish a drug erup
tion rom a iral e anthem. Antibiotics especially semisynthetic
penicillins and T P S are the most common causes o this
reaction pattern ( ig. ). Ampicillin amo icillin gi en
during BV in ection causes an e anthem in o adults
and o children. T P S gi en to A DS patients causes
e anthems in about . Certain uinolones (e.g. gemi o a
cin) cause e anthems at a high rate o erall and in
young women.
orbilli orm eruptions may rarely be restricted to a pre i
ously sunburned site the so called V recall li e phenom
enon. t occurs with arious antibiotics. The sunburn may ha e
occurred months be ore the drug eruption. This pattern o
eruption must be distinguished rom a true V recall caused
by antimetabolites (see later section Ad erse reactions to
chemotherapeutic agents ).
n the case o simple e anthems treatment is supporti e.
The eruption will clear within wee s o stopping the o end
ing medication and it may clear e en i the drug is continued.
Topical corticosteroids and antipruritics may be o bene t and
allow the course o therapy to be completed. Rechallenge
usually results in the reappearance o the eruption e cept in
the setting o V. n many V in ected patients with simple
reactions to T P S ree posure by slow introduction or
ull dose ree posure may be tolerated. n re uently in V
patients howe er and rarely in persons with normal immune
unction rechallenge may result in a more se ere blistering
reaction. The use o patch and intradermal testing or the con
rmation o the incriminated drug in morbilli orm e anthems
is not standardi ed. nly o patients who e perience

Clinical morphology
Cutaneous drug reactions are initially discussed here by mor
phologic pattern. n addition to the cutaneous eruption some
reactions may be associated with other systemic symptoms or
ndings. The modi er simple is used to describe reactions
without systemic symptoms or internal organ in ol ement.
Comple reactions are those with systemic ndings.
Comple reactions are also called D S because the ancillary
eatures o comple reactions are o ten a characteristic syn
drome o ndings (e.g. in ectious mononucleosis li e picture
with anticon ulsant hypersensiti ity reactions). D S or
comple reaction is synonymous with DR SS.
Drug reactions may cause cutaneous lesions and ndings
identical to a nown disease or disorder. These may be o
similar or disparate pathogenesis. or e ample true serum Fig. 6-20 Morbilliform (exanthematous) drug eruption caused by
sic ness caused by the in ection o oreign proteins such as exposure to an antibiotic.
112
the eruption on rechallenge will ha e a positi e patch or intra
dermal test.
Cutaneous ndings identical to simple e anthems may
occur as part o D S or DR SS. n contrast to simple e an
thems in comple e anthems the inciting agent must be
stopped immediately and rechallenge should rarely be under
ta en. en outside the setting o D S DR SS higher eosin
ophil counts correlate with more se ere ADRs.
Aquino MR, et al: Patch testing for drugs. Dermatitis 2013; 24:205–214.
Chen CJ, et al: A comprehensive 4-year survey of adverse drug
reactions using a network-based hospital system. J Clin Pharm Ther
2012; 37:647–651.
De la Torre C, et al: Advances in the diagnosis of drug eruptions. Actas
Dermosifiliogr 2013; 104:782–788.
Dodiuk-Gad RP, et al: Epidemiology of severe drug hypersensitivity.
Semin Cutan Med Surg 2014; 33:2–9.
Harp JL, et al: Severe cutaneous adverse reactions: impact of
immunology, genetics, and pharmacology. Semin Cutan Med Surg
2014; 33:17–27.
Heelan K, et al: Cutaneous drug reactions in children: an update.
Paediatr Drugs 2013; 15:493–503.
Raison-Peyron N: “Cutaneous adverse drug reactions” are not always
drug-induced. Eur J Dermatol 2013; 23:439–442.
Seitz CS, et al: Drug-induced exanthems: correlation of allergy testing
with histologic diagnosis. J Am Acad Dermatol 2013; 69:721–728.
Summers EM, et al: Chronic eczematous eruptions in the aging: further
support for an association with exposure to calcium channel blockers.
JAMA Dermatol 2013; 149:814–818.
Turk BG, et al: Adverse cutaneous drug reactions among hospitalized
patients: five year surveillance. Cutan Ocul Toxicol 2013; 32:41–45.
Walsh S, et al: Drug reaction with eosinophilia and systemic symptoms:
is cutaneous phenotype a prognostic marker for outcome? A review of
clinicopathological features of 27 cases. Br J Dermatol 2013;
168:391–401.
Yang J, et al: Peripheral blood eosinophil counts predict the prognosis
of drug eruptions. J Investig Allergol Clin Immunol 2013;23:248–255.
Drug-induced hypersensitivity syndrome or drug
reaction with eosinophilia and systemic symptoms
All patients with D S share the characteristic eatures o
e er rash and internal organ in ol ement. Characteristic
eatures include the ollowing
Rash de eloping late (> wee s) a ter the inciting
medication is started; o ten occurs with the rst e posure
to the medication
Long lasting symptoms (> wee s) a ter discontinuation
o the causati e drug
e er (> C)
ultiorgan in ol ement
osinophilia (> absolute eosinophilia); less common
with dapsone (criteria ary with some groups citing
counts greater than μl and others more than
μl or abo e i the leu ocyte count is lower than
μl)
Lymphocyte acti ation (lymphocytosis atypical
lymphocytosis lymphadenopathy)
re uent reacti ation o V V BV and C V
Se en ma or medications classes o medication are impli
cated as ollows
. Anticon ulsants phenobarbital lamotrigine and
phenytoin
. Long acting sul onamides sul ametho a ole
sul adia ine and sul asala ine (but not related
medications sul onylureas thia ine diuretics
urosemide and aceta olamide)
tahir99 - UnitedVRG
. Allopurinol
. e irapine
. Abaca ir
. Dapsone
Drug reactions
. inocycline
Vancomycin has also recently been recogni ed as a cause as
has trichloroethylene an industrial sol ent that causes DR SS
with reacti ation o latent V .
The s in eruption accompanying DR SS D S is typically
morbilli orm o ten with ollicular accentuation and can ary
rom aint and mild to se ere with e oliati e erythroderma.
acial edema o ten accompanies the s in eruption and the
eruption may e ol e to demonstrate super cial pustules
especially on the ace. Some patients with Ste ens Johnson
syndrome or to ic epidermal necrolysis may ha e some o the
eatures o DR SS speci cally e er eosinophilia and internal
organ in ol ement but these patients di er in that they may
re uire corticosteroids. Ad erse prognostic indicators include
tachycardia leu ocytosis tachypnea coagulopathy thrombo
cytopenia and gastrointestinal bleeding. Dysphagia can be
se ere. The internal organ in ol ement described in DR SS
can be di ided into two types ( ) organ dys unction occurring
during or immediately associated with the acute episode and
( ) late se uelae possibly with an autoimmune basis. The rst
category includes colitis intestinal bleeding encephalitis
aseptic meningitis hepatitis interstitial nephritis interstitial
pneumonitis respiratory distress syndrome sialadenitis and
myocarditis. Late se uelae include syndrome o inappropriate
secretion o antidiuretic hormone (S AD ) thyroiditis
Gra es disease and diabetes mellitus. Systemic lupus erythe
matosus (SL ) can rarely occur. n one series o patients
with DR SS died usually rom complications o li er or
renal in ol ement. t is important to note that the mani esta
tions o the syndrome ary by drug; dapsone hypersensiti ity
has a wea er association with eosinophilia and allopurinol
hypersensiti ity has more renal in ol ement. A erythema
multi orme li e eruption in patients with D S DR SS may
be predicti e o more se ere hepatic in ol ement.
n patients with se ere DR SS V can be ound in the
li er and cerebrospinal uid associated with hepatitis and
encephalitis and in one series all atal cases o DR SS were
associated with V reacti ation.
Anticonvulsant hypersensitivity syndrome
Anticon ulsant hypersensiti ity syndrome can be seen
with phenytoin phenobarbital carbama epine lamotrigine
onisamide and other anticon ulsants. The estimated inci
dence o this condition is to patients treated
with these medications but is times that rate or lamotrig
ine. Carbama epine is currently the most common anticon
ulsant causing DR SS because it is also used to treat
neuropathic pain bipolar disorder and schi ophrenia. edi
cation dosage does not determine ris or anticon ulsant
hypersensiti ity syndrome. V and V reacti ation
are obser ed in about o these patients and much more
o ten in carbama epine induced cases.
The DR SS begins on a erage days a ter starting the
anticon ulsant. Low grade e er and pharyngitis may precede
the eruption by a ew days. The s in eruption is typically
morbilli orm initially associated with mar ed acial and nec
edema ( ig. ). The eruption begins on the trun and ace
spreading centri ugally. As the eruption becomes more se ere
it may e ol e to con uent pla ues with purpura. The associ
ated intense dermal edema may lead to bulla ormation. ther
common ndings include e er (> or patients) adenopa
thy ( ) and ele ated li er unction tests ( ). Atypical
113
 Fig. 6-21
6 Erythroderma with
papulopustules and
lymphadenopathy,
phenytoin (Dilantin)–
Contact Dermatitis and Drug Eruptions
induced
hypersensitivity
syndrome. (Courtesy
of Dr. L. Lieblich.)
lymphocytosis can occur completing a mononucleosis
li e picture. Lung and renal in ol ement is uncommon.
Lamotrigine induced DR SS demonstrates eosinophilia in
only o patients lymphadenopathy in only and mul
tiorgan in ol ement in . The syndrome occurs within
wee s o starting the drug in most patients although a delay
o up to months has been noted in o cases. Coadmin
istration o alproate increases the ris o lamotrigine DR SS
whereas slow introduction reduces the ris .
n anticon ulsant hypersensiti ity syndrome as the erup
tion e ol es widespread pinpoint pustules typically appear
on the ace trun and e tremities especially in dar s inned
patients. The syndrome may continue to progress e en a ter
the inciting medication has been stopped. The associated hep
atitis can be li e threatening.
Because many o the anticon ulsants are metaboli ed
through the same pathway cross reactions are re uent
ma ing selection o an alternati e agent uite di cult. The
rate o cross reacti ity among phenytoin phenobarbital and
carbama epine is . n itro tests are commercially a ail
able and may aid in selecting an agent to which the patient
will not cross react. Valproate is generally considered a sa e
alternati e or patients sensiti e to aromatic anticon ulsants.
The management o anticon ulsant hypersensiti ity syn
drome re uires immediate discontinuation o the o ending
medication. Because cross reacti ity among these drugs is
high the therapeutic bene t o a medication rom this class
must be care ully reconsidered. the treatment is or depres
sion prophyla is a ter closed head in ury or atypical pain
syndromes medication rom another class can o ten be substi
tuted. Treatment is initially supporti e until the e tent and
se erity o the syndrome are assessed. Some patients clear i
the medication is simply discontinued. ndications or sys
temic corticosteroid treatment include se ere systemic to ic
ity with pulmonary cardiac li er or renal in ol ement. The
usually starting dose is . . mg g day. acetylcysteine
may be added i hepatitis is present. Steroid therapy is contin
ued at whate er dose is re uired or control then gradually
tapered. t may re uire wee s to wean the patient o cortico
steroids success ully. ntra enous immune globulin ( V G)
and other immunosuppressi es (e.g. a athioprine cyclospo
rine) ha e been success ully used in steroid re ractory cases.
114
Fig. 6-22 Allopurinol hypersensitivity syndrome.
Allopurinol hypersensitivity syndrome
Allopurinol hypersensiti ity syndrome typically occurs in
patients with pree isting renal ailure. ten a ected patients
are treated unnecessarily or asymptomatic hyperuricemia
with clear indications or therapy present in only about one
third o these patients. They are o ten gi en a dose not ad usted
or their coe isting renal disease and are re uently ta ing a
thia ide diuretic. Wee s to many months (a erage wee s)
a ter the allopurinol is begun the patient de elops a morbil
li orm eruption ( o cases) that o ten e ol es to an e olia
ti e erythroderma ( ) ( ig. ). Bullae may occur
especially on the palms and soles and oral ulcers may be
present. Associated with the dermatitis are e er eosinophilia
sometimes hepatitis ( o cases) and typically worsening o
renal unction ( the higher percentage in those with
pree isting renal disease). Lung in ol ement and adenopathy
occur in re uently. About o patients die as a result o this
syndrome o ten rom cardio ascular complications. Pancre
atitis and subse uent insulin dependent diabetes may occur
as a complication. Dialysis does not appear to accelerate the
resolution o the eruption suggesting that i a drug metabolite
is responsible it is not dialy able. There is a strong association
between LA B and the de elopment o allopurinol
hypersensiti ity syndrome in the an Chinese but not in
other races. V reacti ation may be associated. This syn
drome may be steroid responsi e but is e tremely slow to
resol e re uently lasting or months a ter allopurinol has
been stopped. Very gradual tapering o systemic corticoste
roids with monitoring o eosinophil count and renal unction
is essential. Too rapid tapering may lead to relapse o the
syndrome.
Sulfonamide hypersensitivity syndrome
ewer than . o treatment courses with sul onamides are
complicated by a hypersensiti ity syndrome. Sul onamide
hypersensiti ity syndrome is similar to that seen with
the anticon ulsants including the characteristic acial and
periorbital edema. t typically begins wee s a ter starting the
medication but may occur as soon as wee . The s in eruption
is usually morbilli orm or an erythroderma. Patients are
o ten slow acetylators unable to deto i y the to ic and
immunogenic metabolites generated during the metabolism o
the sul onamides. Patients with sul onamide hypersensiti ity
syndrome may de elop antibodies that recogni e microsomal
proteins to which the reacti e metabolite o the sul onamides
binds. epatitis nephropathy pneumonitis pericarditis
myocarditis pancreatitis and pleural e usion can all occur as
a part o the syndrome. The hepatitis can be li e threatening.
Treatment is with topical agents appropriate or the s in erup
tion and systemic corticosteroids or systemic complications.
onisamide a sul onamide anticon ulsant cross reacts with
sul onamides but not other anticon ulsants.
Minocycline hypersensitivity syndrome
inocycline hypersensiti ity syndrome occurs in young
adults usually in the conte t o acne therapy. De ciency o
glutathione S trans erases is common in a ected indi iduals
and is more common in persons o A rican Caribbean descent.
emales are more o ten a ected. inocycline may be detected
in the blood o these patients up to months a ter its discon
tinuation suggesting that slow metabolism and persistent
le els o medication may play a role. inocycline hypersensi
ti ity syndrome usually begins wee s a ter starting the
minocycline. e er a s in eruption and adenopathy occur in
more than o patients. eadache and cough are common
complaints. The eruption can be morbilli orm erythrodermic
or pustular. acial edema is common. Li er in ol ement
occurs in o patients and renal disease in . inocy
cline hypersensiti ity is particularly associated with intersti
tial pneumonia with eosinophilia. This may progress to
respiratory distress syndrome. t can be li e threatening but
most patients sur i e. yocarditis has also been reported.
Dapsone hypersensitivity syndrome
Dapsone hypersensiti ity syndrome occurs in less than o Both SJS and T
patients gi en this medication. t usually begins wee s or
more a ter starting dapsone. emolytic anemia and methemo
globinemia may be present. A morbilli orm eruption that heals
with des uamation is most characteristic. cterus and lymph
adenopathy occur in o patients. osinophilia is typically
not present. Li er in ol ement is a mi ture o hepatocellular
and cholestatic. The bilirubin is ele ated in partly attrib
utable to the hemolysis and hypoalbuminemia is characteris
tic. Li er in ol ement is o ten se ere and may be atal. As with
the hypersensiti ity syndromes pre iously discussed cortico
steroids are the mainstay o treatment.
Atzori L, et al: Cutaneous adverse drug reactions to allopurinol: 10-year
observational survey of the Dermatology Department–Cagliari
University (Italy). J Eur Acad Dermatol Venereol 2012; 26:1424–1430.
Bansal S, et al: Eosinophilia in pre-anesthetic assessment: a guide to
diagnosis of DRESS syndrome. J Anaesthesiol Clin Pharmacol 2013;
29:270–271.
Gill S, et al: Nevirapine-induced rash with eosinophilia and systemic
symptoms (DRESS). Indian J Pharmacol 2013; 45:401–402.
Husain Z, et al: DRESS syndrome. Part I. Clinical perspectives. J Am
Acad Dermatol 2013; 68:693.e1–e14.
Husain Z, et al: DRESS syndrome. Part II. Management and
therapeutics. J Am Acad Dermatol 2013; 68:709.e1–e9.
Kamijima M, et al: Occupational trichloroethylene hypersensitivity
syndrome: human herpesvirus 6 reactivation and rash phenotypes. J
Dermatol Sci 2013; 72:218–224.
Lee T, et al: Characteristics of liver injury in drug-induced systemic
hypersensitivity reactions. J Am Acad Dermatol 2013; 69:407–415.
tahir99 - UnitedVRG
Karlin E, et al: Genotyping for severe drug hypersensitivity. Curr Allergy
Asthma Rep 2014; 14:418.
Perkins JR, et al: The study of severe cutaneous drug hypersensitivity
reactions from a systems biology perspective. Curr Opin Allergy Clin
Immunol 2014; 14:301–306.
Drug reactions
Wei CH, et al: Identifying prognostic factors for drug rash with
eosinophilia and systemic symptoms (DRESS). Eur J Dermatol 2011;
21:930–937.
Yang MS, et al: Clinical features and prognostic factors in severe
cutaneous drug reactions. Int Arch Allergy Immunol 2013; 162:346–354.
Bullous drug reactions: Stevens-Johnson syndrome
and toxic epidermal necrolysis
S in blistering may complicate drug reactions in many ways.
edications may induce nown autoimmune bullous diseases
such as pemphigus (penicillamine) or linear gA disease ( an
comycin). AG P may be so e tensi e as to cause a positi e
i ols y s sign and ha e a bac ground o purpura and tar
getoid lesions simulating Ste ens Johnson syndrome (SJS
erythema multi orme ma us ma or) and to ic epidermal
necrolysis (T Lyell syndrome nonstaphylococcal scalded
s in syndrome). Pseudoporphyria and other photodermatoses
rom drugs may orm bullae. Cyto ines may produce wide
spread bullous eruptions perhaps through physiologic mech
anisms. The term bullous drug reaction howe er usually
re ers to a drug reaction in the erythema multi orme ( )
group ( ig. ). ( or a complete discussion o other orms o
erythema multi orme see Chapter .)
ortunately these are uncommon reactions to medications
with an incidence o . . per million person years or T
and . . per million person years or SJS. These drug
induced orms o are usually more e tensi e than herpes
associated or mycoplasma associated ma or but at
times the distinction may be di cult. The more se ere the
reaction the more li ely it is to be drug induced ( o cases
o SJS and o T ). The e act de nitions o SJS and T
remain arbitrary and some consider these syndromes to be
parts o a disease spectrum based on the ollowing
are most re uently induced by the
same medications.
Patients initially presenting with SJS may progress to
e tensi e s in loss resembling T .
The histologic ndings o T and SJS are
indistinguishable.
Both are increased by the same magnitude in V
in ection.
Fig. 6-23 Bullous drug reaction.
115
 owe er genetic e aluations o Caucasians with SJS and T
6 showed distinct genetic predispositions or these conditions.
n Taiwan carbama epine causes up to one third o cases
but only in urope. n an Chinese the LA haplotype
LA B is present in the ast ma ority o carbama epine
Contact Dermatitis and Drug Eruptions
induced SJS T patients and is present in about o anagement o SJS T
the an Chinese population in general. This LA association
is not usually ound in patients o other ethnicities with
carbama epine induced SJS T . LA typing should be per
ormed in all Asians be ore starting carbama epine since the
pre alence o LA B is in Asians in the nited
States and Asia. V reacti ation may also be seen in SJS
T patients.
ore than medications ha e been reported to cause SJS
and T . n adults common inciting medications are
T PS ( ) sul ado ine plus pyrimethamine
( ansidar R) ( ) ne irapine lamotrigine (
adults and children) and carbama epine ( ).
Antibiotics (especially long acting sul a drugs and penicillins)
other anticon ulsants anti in ammatories ( SA Ds) and
allopurinol are also re uent causes. Currently in urope
allopurinol is the most common cause o SJS and T . n
children SJS T is most o ten caused by sul onamides and
other antibiotics antiepileptics and acetaminophen. SJS T
rom T P S is signi cantly more common in the spring.
the inciting drug has a short hal li e and it is promptly
stopped mortality is reduced rom to . stablishing
causality o a drug can sometimes be di cult. Rechallenge can
be dangerous so in itro methods ha e been de eloped. Lym
phocyte granulysin e pression Gran yme B L Spot and
γ production assays together pro ided a sensiti ity o
and speci city o . importance o each o these mechanisms in SJS and T
e er and in uen a li e symptoms o ten precede the erup
tion by a ew days. S in lesions appear on the ace and trun
and rapidly spread usually within days to their ma imum
e tent. nitial lesions are macular and may remain so ollowed
by des uamation or may orm atypical targets with purpuric
centers that coalesce orm bullae then slough. Patients with
purpuric atypical targets may e ol e more slowly and usually
the s in lesions are clinically in ammatory. n SJS irtually
always two or more mucosal sur aces are also eroded with
the oral mucosa and con uncti a most re uently a ected. The
patient may ha e photophobia di culty with swallowing
rectal erosions pain ul urination and cough indicati e o
ocular alimentary urinary and respiratory tract in ol ement
respecti ely. er time more than o the s in sur ace may
be sloughed leading to SJS T o erlap; i more than o e pression by eratinocytes and as ligand production by
the s in is lost a case is classi ed as T . n other patients
macular erythema is present in a local or widespread distribu
tion o er the trun . ucosal in ol ement may not be ound.
The epidermis in the areas o macular erythema rapidly
becomes detached rom the dermis leading to e tensi e s in
loss o ten much more rapidly than occurs in the patients with
atypical targets and e tensi e mucosal in ol ement. Pure
T is a conceptual way o thin ing o such patients. Rarely
SJS T patients may present with lesions predominantly in
sun e posed areas with a clear history o a recent signi cant
sun e posure. This suggests that in rare cases SJS T may
be photo induced or photo e acerbated. Patients with SJS
T may ha e internal in ol ement similar to patients
with DR SS D S caused by the same medication. These
most re uently include eosinophilia hepatitis and worsening
renal unction.
A s in biopsy is usually per ormed. ro en section analysis
may lead to a rapid diagnosis. The histology o T and SJS
is similar. There is a lymphocytic in ltrate at the dermoepider
mal unction (D J) with necrosis o eratinocytes that at times
may be ull thic ness. There is typically cellular necrosis out
116
o proportion to the in ltrate. Paraneoplastic pemphigus also
shows changes o and may be e cluded with direct immu
no uorescence (D ). Patients with gra t ersus host disease
(GV D) may also demonstrate a T li e picture with identi
cal histology.
patients is similar to those with an
e tensi e burn. They ha e uid and electrolyte imbalances
bacteremia rom loss o the protecti e s in barrier hyperca
tabolism and sometimes acute respiratory distress syndrome
(ARDS). Their metabolic and uid re uirements are less than
in burn ictims but nutritional support and monitoring or
sepsis are critical. Burn units are typically s illed in managing
SJS T patients. n addition to e tent o s in loss age
nown malignancy tachycardia renal ailure hyperglycemia
and low bicarbonate are all ris actors or ha ing a higher
mortality with SJS T . SC RT the most common model
used to predict mortality gi es point or each o these nd
ings with a . mortality or points and a mortality
or or more points. owe er respiratory tract in ol ement
not included in the SC RT is also a poor prognostic sign.
About one uarter o T patients ha e bronchial in ol e
ment. n T epithelial detachment o the respiratory mucosae
and associated ARDS are associated with a mortality o .
Pree isting diabetes mellitus and concurrent tuberculosis may
also increase mortality.
The use o systemic agents to treat SJS T is contro ersial
because o the increased ris o septic death. V G has been
used at a dose o g g day or the rst days ollowing
admission but data supporting its e cacy are mi ed.
eratinocyte death in SJS and T is proposed to occur
through more than one potential mechanism and the relati e
is not
nown. Acti ated cytoto ic T cells and natural iller ( ) cells
produce granulysin per orin and gran yme B all o which
can induce eratinocyte necrosis. Th cells appear to play a
role in mediating the disease. n addition eratinocyte necro
sis can be induced by the binding o soluble as ligand (s asL)
to as (also nown as the death receptor or CD ). Soluble as
ligand is ele ated in the blood o patients with T and its
le el correlates with body sur ace area (BSA) in ol ement. n
addition the peripheral blood mononuclear cells o patients
with T secrete as ligand on e posure to the incriminated
drug. The sera o patients with T induce necrosis o cul
tured eratinocytes and a monoclonal antibody to as ligand
in a dose dependent manner inhibits eratinocyte necrosis
e posed to T patient sera. This strongly supports as
immune cells as the mechanisms by which T is mediated.
The proposed mechanism o action o V G in T is by V G
bloc ing the binding o s asL to as stopping eratinocyte
apoptosis.
The presence o cytoto ic T lymphocytes and cells
within the dermis sub acent to the necrotic epidermis suggests
that immunosuppressi e agents that bloc immune unction
could also be e ecti e in SJS or T . Cyclosporine is the most
promising agent with some in itro and in i o data support
ing its use whereas in itro data suggest that sirolimus could
promote eratinocyte necrosis. considered immunosup
pressi e treatment should be used as soon as possible gi en
as a short trial to see i the process may be arrested and then
tapered rapidly to a oid the ris o continued immunosup
pression in a patient with substantial loss o s in. Anecdotally
both etanercept mg twice and in i imab mg g intra
enously once ha e led to rapid termination o s in slough
ing but a prospecti e trial o thalidomide (another anti T
agent) was discontinued because o e cessi e mortality in the
acti e treatment arm. Data are mi ed regarding systemic cor
ticosteroid therapy or s in disease and there is a clear ris o
sepsis. Systemic and topical steroid therapy or ocular in ol e Fig. 6-24 Radiation-
ment may impro e outcomes as may topical cyclosporine. n induced reaction.
patients with SJS T who also ha e systemic in ol ement
as seen in D S (considered by some as SJS T representing
the cutaneous eruption o D S) systemic corticosteroids

Drug reactions
should be gi en early and tapered as rapidly as possible.
or patients who sur i e the a erage time or epidermal
regrowth is wee s. The most common se uelae are ocular
scarring and ision loss. The only predictor o e entual isual
complications is the se erity o ocular in ol ement during the
acute phase. A siccali e syndrome with dry eyes may also
result e en in patients who ne er had clinical ocular in ol e
ment during the acute episode. ther complications include
cutaneous scarring erupti e melanocytic lesions and nail
abnormalities. Transient widespread errucous hyperplasia
resembling con uent seborrheic eratoses has also been
reported.
Bouvresse S, et al: Toxic epidermal necrolysis, DRESS, AGEP: do
overlap cases exist? Orphanet J Rare Dis 2012; 7:72.
Butt TF, et al: Internet accounts of serious adverse drug reactions: a
study of experiences of Stevens-Johnson syndrome and toxic
epidermal necrolysis. Drug Saf 2012; 35:1159–1170.
Castelain F, et al: Toxic epidermal necrolysis. Curr Drug Saf 2012;
7:332–338.
Ellender RP, et al: Clinical considerations for epidermal necrolysis.
Ochsner J 2014; 14:413–417.
Ferrandiz-Pulido C, et al: A review of causes of Stevens-Johnson
syndrome and toxic epidermal necrolysis in children. Arch Dis Child Radiation-induced erythema multiforme
2013; 98:998–1003.
Fu M, et al: Recovered patients with Stevens-Johnson syndrome and phenytoin is gi en prophylactically in neurosurgical patients
toxic epidermal necrolysis maintain long-lived IFN-γ and sFasL who are recei ing whole brain radiation therapy and systemic
memory response. PLoS One 2012; 7:e45516. steroids an unusual reaction occurs. As the dose o steroids is
Jalilian C, Jevtic A: The management of toxic epidermal necrolysis. being reduced erythema and edema initially appear on the
Australas J Dermatol 2013; 54:75–76. head in the radiation ports. This e ol es o er or days to
Kapoor S: Emerging new markers of toxic epidermal necrolysis. J lesions with the clinical appearance and histology o SJS or
Intensive Care Med 2013; 28:72.
e en T . The eruption spreads caudad and mucosal in ol e
Kirchhof MG, et al: Retrospective review of Stevens-Johnson syndrome/
toxic epidermal necrolysis treatment comparing intravenous ment may occur ( ig. ). A similar syndrome has been
immunoglobulin with cyclosporine. J Am Acad Dermatol 2014 Jul 30 reported with the use o ami ostine phenobarbital or le eti
[Epub ahead of print]. racetam during radiation or head and nec cancers. This
Mockenhaupt M: Stevens-Johnson syndrome and toxic epidermal syndrome can rarely be seen with radiation therapy alone.
necrolysis: clinical patterns, diagnostic considerations, etiology, and ami ostine is used to reduce acute and chronic radiation
therapeutic management. Semin Cutan Med Surg 2014; 33:10–16. associated head and nec erostomia there is a signi cant ris
Porebski G, et al: In vitro drug causality assessment in Stevens-Johnson o SJS T .
syndrome: alternatives for lymphocyte transformation test. Clin Exp
Allergy 2013; 43:1027–1037. Barbosa LA, Teixeira CB: Erythema multiforme associated with
Schwartz RA, et al: Toxic epidermal necrolysis. Part I. Introduction, prophylactic use of phenytoin during cranial radiation therapy. Am J
history, classification, clinical features, systemic manifestations, Health-Syst Pharm 2008; 65:1048.
etiology, and immunopathogenesis. J Am Acad Dermatol 2013; Chodkiewicz HM, et al: Radiation port erythema multiforme: erythema
69:173.e1–e13. multiforme localized to the radiation port in a patient with non–small
Schwartz RA, et al: Toxic epidermal necrolysis. Part II. Prognosis, cell lung cancer. Skinmed 2012; 10:390.
sequelae, diagnosis, differential diagnosis, prevention, and treatment. Elazzazy S, et al: Toxic epidermal necrolysis associated with antiepileptic
J Am Acad Dermatol 2013; 69:187.e1–e16. drugs and cranial radiation therapy. Case Rep Oncol Med 2013;
Sekula P, et al: Comprehensive survival analysis of a cohort of patients 2013:415031.
with Stevens-Johnson syndrome and toxic epidermal necrolysis. J Vern Gross TZ, et al: Erythema multiforme, Stevens Johnson syndrome,
Invest Dermatol 2013; 133:1197–1204. and toxic epidermal necrolysis syndrome in patients undergoing
Teraki Y, et al: Possible role of TH17 cells in the pathogenesis of radiation therapy: a literature review. Am J Clin Oncol 2012; Aug 13.
Stevens-Johnson syndrome and toxic epidermal necrolysis. J Allergy PMID: 22892429.
Clin Immunol 2013; 131:907–909.
Thammakumpee J, et al: Characteristics of toxic epidermal necrolysis
and Stevens-Johnson syndrome: a 5-year retrospective study. J Med
Assoc Thai 2013; 96:399–406. Human immunodeficiency virus disease and
Weinand C, et al: 27 years of a single burn centre experience with drug reactions
Stevens-Johnson syndrome and toxic epidermal necrolysis:
analysis of mortality risk for causative agents. Burns 2013; Patients in ected with V especially those with Th cell
39:1449–1455. counts between and are at increased ris or the
Yip VL, et al: HLA genotype and carbamazepine-induced cutaneous
de elopment o ad erse reactions to medications. orbilli
adverse drug reactions: a systematic review. Clin Pharmacol Ther
2012; 92:757–765.
orm reactions to T P S occur in or more o A DS
Zhu QY, et al: Toxic epidermal necrolysis: performance of SCORTEN patients being treated or Pneumoc stis jiroveci ( ormerly P
and the score-based comparison of the efficacy of corticosteroid carinii) pneumonia. n two thirds o patients without li e
therapy and intravenous immunoglobulin combined therapy in China. threatening reactions T P S treatment can be continued
J Burn Care Res 2012; 33:e295–e308. with simple conser ati e support and the eruption may
117

tahir99 - UnitedVRG
 resol e. Associated hepatitis or neutropenia may re uire dis
6 continuation o the drug. A similar increased rate o reaction
to amo icillin cla ulanate is also seen and patients ha e
been described with sensiti ity to multiple antituberculosis
agents especially streptomycin and o o acin. the dermati
Contact Dermatitis and Drug Eruptions
tis is treatment limiting but the eruption is not li e threaten
ing low dose rechallenge desensiti ation may be attempted.
t is success ul in o patients in the short term and in
more than in the long term. n act initial introduction
o T PS or prophyla is by dose escalation reduces the
rate o ad erse reactions as well. owe er rechallenge at ull
dose may ha e the same rate o recurrent eruptions as does
introduction by dose escalation. Low dose rechallenge is
usually sa e but se ere acute reactions may occur including
mar ed hypotension. Although most ADRs occur in the rst
ew days o rechallenge reactions may appear months a ter
restarting T P S and may be atypical in appearance. The
mechanism o this increased ad erse reaction to T P S is
un nown.
Se ere bullous reactions SJS and T are times
more common per drug e posure in patients with A DS.
These reactions are usually caused by sul a drugs especially
long acting ones but may be caused by many agents. e i
rapine a nonnucleoside re erse transcriptase inhibitor has
been associated with a high rate o se ere drug eruptions
including SJS T . ost o these ADRs are cutaneous and
occur in the rst wee s o treatment. This high rate o reac
tion can be reduced by starting with a lower lead in dose and
by concomitant treatment with prednisone during the induc
tion period. e irapine hypersensiti ity syndrome presents
with e er hepatitis or rash. ore than o patients will
de elop SJS T . LA DRB patients are at increased
ris or cutaneous reactions to ne irapine i not associated
with hepatoto icity. epatitis but not cutaneous reactions is
seen more o ten in patients with CD counts abo e . ther unusual ariants o D include ec ematous urticarial
i ed drug eruptions ( D s) are also re uently seen in
patients with V in ection. Abaca ir is associated with a
potentially li e threatening ADR in o patients. The syn
drome includes e er rash and gastrointestinal or respira
tory symptoms. t usually occurs in the rst wee s o
treatment but can occur within hours o the rst dose. Rechal
lenge in these patients may lead to li e threatening hypoten
sion and death. Abaca ir hypersensiti ity is increased in
patients who are LA B positi e and screening o
patients or this LA type and not e posing patients with
this LA type to abaca ir ha e decreased the number o
cases o abaca ir hypersensiti ity syndrome. ADRs to abaca
ir can also occur in LA B negati e patients.
Aciclo ir nucleoside and nonnucleoside re erse transcrip
tase inhibitors (e cept ne irapine) and protease inhibitors
are uncommon causes o ADRs. any reactions attributed to
these agents may actually be coe istent V associated pru
ritic disorders especially olliculitis which are common in
patients with A DS.
Isaacs T, et al: Annular erythema and photosensitivity as
manifestations of efavirenz-induced cutaneous reactions: a review
of five consecutive cases. J Antimicrob Chemother 2013;
68:2871–2874.
Lehloenya RJ, et al: Multiple drug hypersensitivity reactions to anti-
tuberculosis drugs: five cases in HIV-infected patients. Int J Tuberc
Lung Dis 2012; 16:1260–1264.
Mittmann N, et al: Incidence of toxic epidermal necrolysis and Stevens-
Johnson syndrome in an HIV cohort: an observational, retrospective
case series study. Am J Clin Dermatol 2012; 13:49–54.
Punyaratabandhu P, et al: Skin manifestation of Thai HIV infected patients
in HAART era. J Med Assoc Thai 2012; 95:497–504.
Scherer K, et al: Desensitization in delayed drug hypersensitivity
reactions: an EAACI position paper of the Drug Allergy Interest Group.
Allergy 2013; 68:844–852.
118
Fig. 6-25 Fixed drug reactions caused by aspirin.
Fixed drug reactions (eruptions)
i ed drug reactions are common. i ed drug eruptions
( D s) are so named because they recur at the same site with
each e posure to the medication. The time rom ingestion o
the o ending agent to the appearance o symptoms is between
min and hours a eraging hours. n most patients si
or ewer lesions occur and o ten only one. n re uently D s
may be multi ocal with numerous lesions ( ig. ). They
may present anywhere on the body but hal occur on the oral
and genital mucosa. D s represent o all genital ulcers
e aluated at clinics or se ually transmitted diseases and can
occur in young boys. n males lesions are usually uni ocal and
can a ect the glans or sha t o the penis. D o the ul a is
o ten symmetric presenting as an erosi e ul itis with lesions
on the labia minora and ma ora and e tending to the perineum.
papular purpuric linear giant and psoriasi orm. At times
some lesions o D will not reacti ate with e posure because
o a presumed re ractory period that may last rom wee s
to months.
Clinically an D begins as a red patch that soon e ol es
to an iris or target lesion similar to erythema multi orme and
that may e entually blister and erode. Lesions o the genital
and oral mucosae usually present as erosions. ost lesions are
to se eral cm in diameter but larger pla ues may occur
resembling cellulitis. Characteristically prolonged or perma
nent postin ammatory hyperpigmentation results although a
nonpigmenting ariant o an D is recogni ed. With repeated
or continued ingestion o the o ending medication new
lesions may be added sometimes e entuating in a clinical
picture similar to SJS with similar morbidity and mortality.
istologically an inter ace dermatitis occurs with subepider
mal esicle ormation necrosis o eratinocytes and a mi ed
super cial and deep in ltrate o neutrophils eosinophils and
mononuclear cells. Pigment incontinence is usually mar ed
correlating with the pigmentation resulting rom D s.
Because biopsies are generally per ormed during the acute
stage o a recurrence the stratum corneum is normal. Papillary
dermal brosis and deep peri ascular pigment incontinence
are o ten present rom prior episodes. This contrast between a
normal stratum corneum (suggesting an acute process) and
chronic dermal changes is irtually pathognomonic o D .
edications inducing D s are usually those ta en intermit
tently. any o the SA Ds especially pyra olone deri ati es
paracetamol napro en o icams and me enamic acid cause
D with a special predilection or the lips. Sul onamides
trimethoprim and T P S are now responsible or the
ma ority o genital D s. Barbiturates tetracyclines ucon
a ole uoro uinolones phenolphthalein acetaminophen
cetiri ine celeco ib de tromethorphan hydro y ine uinine
lamotrigine phenylpropanolamine erythromycin and Chinese
and Japanese herbs are also among the long list o possible
causes. The ris o de eloping a D has been lin ed to LA
B . Patch tests with arious concentrations o the o ending
medication can reproduce the lesion on a ected but not una
ected s in. Tape stripping the s in be ore applying the sus
pected medication in arious ehicles may increase the
li elihood o a positi e patch test. This techni ue appears to be
most use ul in pyra olone deri ati e related reactions that are
reproduced in or more o cases.
ccasionally D s do not result in long lasting hyperpig
mentation. The so called nonpigmenting D is distincti e
and has two ariants. The pseudocellulitis or scarlatini orm
type is characteri ed by large tender erythematous pla ues
that resol e completely within wee s only to recur on reinges
tion o the o ending drug. Pseudoephedrine hydrochloride is
by ar the most common culprit. The second ariant is sym
metric drug related intertriginous and e ural e anthema
(SDR ormerly baboon syndrome; see Allergic contact
dermatitis earlier). SDR pre erentially a ects the but
toc s groin and a illae with erythematous ed pla ues.
istologically a giant cell lichenoid dermatitis can be seen in
this setting.
The diagnosis o D is o ten straight orward and is eluci
dated by the history. Antibiotics manu actured o erseas are
readily a ailable in many ethnic mar ets and the ormulations
may not be care ully regulated. n some patients the reaction
may be to a dye in a medication rather than the acti e ingredi
ent. i ed drug reaction may rarely be related to oods includ
ing residual antibiotics in meat products and uinine contained
in tonic water. Con rmation with pro ocation tests can be
per ormed. Because o the re ractory period pro ocation
tests need to be delayed at least wee s rom the last eruption.
an oral pro ocation test is considered the initial challenge
should be o the standard dose and patients with wide
spread lesions (SJS T li e) should not be challenged. Patch
testing using a drug concentration o in petrolatum or
water applied to a pre iously reacted site is the recommended
approach. n most patients the treatment is simply to stop the
medication. Desensiti ation can be success ul.
Lesions o an D contain intraepidermal CD + T cells with
the phenotypic mar ers o e ector memory T cells. These epi
dermal resident T cells produce γ. Such cells are ound in
resol ed lesions o herpes simple irus ( SV) suggesting
they are a de ense mechanism pre enting iral reacti ation in
the epidermis. nce the medication is stopped the abundant
CD + o P T cells (Tregs) in lesions o D are belie ed to
downregulate the eruption. n SJS T patients such Tregs
are ound in much ewer numbers than in D e plaining the
progression o SJS T despite stopping o the medication.
Resident mast cells in lesions o D may be the cells initially
acti ated with drug e posure e plaining the rapid onset o
the lesion.
Centers for Disease Control and Prevention: Fixed drug eruption
associated with sulfonamides sold in Latino grocery stores—Greater
Washington, DC, Area, 2012–2013. MMWR 2013; 62(46):914–916.
Hiware S, et al: Evaluation of cutaneous drug reactions in patients
visiting outpatient departments of Indira Gandhi Government Medical
College and Hospital (IGGMC and H), Nagpur. Indian J Dermatol
2013; 58:18–21.
Leleu C, et al: Quinoline yellow dye–induced fixed food-and-drug
eruption. Contact Dermatitis 2013; 68:187–188.
Lim WS, et al: A case of fixed drug eruption due to doxycycline and
erythromycin present in food. Allergy Asthma Immunol Res 2013;
5:337–339.
Lipowicz S, et al: Prognosis of generalized bullous fixed drug eruption:
comparison with Stevens-Johnson syndrome and toxic epidermal
necrolysis. Br J Dermatol 2013; 168:726–732.
tahir99 - UnitedVRG
Ognongo-Ibiaho AN, et al: Epidemiological study of fixed drug eruption in
Pointe-Noire. Int J Dermatol 2012; 51(Suppl 1):30–31, 33–35.
Ohira A, et al: Fixed eruption due to quinine in tonic water: a case
report with high-performance liquid chromatography and ultraviolet A
analyses. J Dermatol 2013; 40:629–631.
Drug reactions
Özkaya E: Oral mucosal fixed drug eruption: characteristics and
differential diagnosis. J Am Acad Dermatol 2013; 69:e51–e58.
Acute generalized exanthematous pustulosis
Also nown as to ic pustuloderma and pustular drug erup
tion AG P is an uncommon reaction with an incidence o
cases per million per year. The a erage age in urope is in the
ties and about one decade younger in srael and Taiwan.
Children can be a ected. Women ha e been a ected slightly
more than men until recently when a strong emale predomi
nance has been identi ed. Drugs are the most common cause
o this reaction pattern although AG P has also been reported
a ter mercury e posure. AG P ollowing iral and bacterial
in ections has been reported but a causal association has not
been alidated. Similarly Loxosceles spider (e.g. brown recluse)
bites ha e been ollowed by AG P but some o these patients
ha e also recei ed antibiotics. Recent reports o acute local
i ed e anthematous pustulosis (AL P) appear to be acne
i orm eruptions that occur acutely a ter antibiotic e posure.
The relationship to AG P is unclear.
The eruption is o sudden onset within day in many cases
associated with antibiotics and a eraging days in other
cases. The rash is accompanied by e er in most patients.
acial edema may be present. nitially there is a scarlatini orm
erythema. The eruption e ol es and disseminates rapidly
consisting usually o more than non ollicular pustules less
than mm in diameter ( ig. ). i ols y s sign may be
positi e. ucous membrane in ol ement is common but
usually a ects only one sur ace and is nonerosi e. Laboratory
abnormalities typically include a leu ocytosis with neutro
philia ( ) and at times an eosinophilia ( ). Typically the
entire sel limited episode lasts up to days. Characteristi
cally widespread super cial des uamation occurs as the
eruption clears. AG P can recur with a second e posure to the
medication.
n more than o patients drugs are the cause o AG P.
re uently implicated medications include ampicillin
amo icillin pristinamycin uinolones hydro ychloro uine
sul onamide antibiotics terbina ne imatinib and diltia em.
Corticosteroids macrolides o icam SA Ds pseudoephed
rine tera osin omepra ole sennoside and antiepileptics ha e
also caused AG P. n some patients contact sensiti ity has
been implicated as a cause with a ariety o triggering agents.
Fig. 6-26 Acute generalized exanthematous pustulosis.
119
 Recently radiocontrast material has been shown to cause
6 AG P. n o patients no trigger can be identi ed.
n the classic case the diagnosis is straight orward with the
characteristic sudden and rapid onset widespread pustula
tion and sel limited course. The acial edema and pustulation
Contact Dermatitis and Drug Eruptions
can simulate DR SS D S rom anticon ulsants. n anticon
ulsant hypersensiti ity syndrome eosinophilia lymphade
nopathy atypical lymphocytosis and li er dys unction are
o ten ound. Recently cases o AG P ha e been reported with
a prolonged course widespread erosi e mucosal lesions and
systemic in ol ement identical to DR SS D S suggesting
that AG P may coe ist with the anticon ulsant hypersen
siti ity syndrome. About o patients with AG P ha e
systemic in ol ement with respiratory in ol ement most
common and in about or less s in lesions similar to SJS
T are seen. These include purpuric atypical targets and
widespread s in loss. Pustular psoriasis especially pustular
psoriasis o pregnancy can be di cult to di erentiate rom
AG P. there are no characteristic lesions o psoriasis else
where and no prior personal or amily history o psoriasis
distinguishing these two entities may be impossible and the
patient may need to be ollowed or a nal diagnosis to be
made. A microbial pustulosis in the setting o a connecti e
tissue disease can also resemble AG P but lesions are usually
locali ed to the e ors and the course is more chronic.
istologically early lesions show mar ed papillary edema
neutrophil clusters in the dermal papillae and peri ascular
eosinophils. There may be an associated leu ocytoclastic
asculitis. Well de eloped lesions show intraepidermal or
subcorneal spongi orm pustules. there is a bac ground o
erythema multi orme clinically the histologic eatures o
may be superimposed. The presence o eosinophils and the
mar ed papillary edema help to distinguish this eruption rom
pustular psoriasis. owe er pustular psoriasis o pregnancy
is o ten associated with tissue eosinophilia.
Patch testing with the suspected agent may reproduce a
pustular eruption on an erythematous base at h in about
o patients. Patch testing rarely will result in a recrudes
cence o AG P. AG P is mediated by T cells which produce
high le els o L γ L L and granulocyte
macrophage colony stimulating actor (G CS ). L is also
produced by eratinocytes in lesions o AG P.
ost patients with AG P can be managed with topical cor
ticosteroids and antihistamines. n many cases systemic cor
ticosteroids are also gi en. n se ere cases in i imab and
etanercept ha e rapidly stopped the pustulation and appeared
to ha e hastened the resolution o the eruption. This approach
has also been used in AG P T patients with success.
Cyclosporine as used or pustular psoriasis has been used
e ecti ely in an AG P patient who relapsed as systemic cor
ticosteroids were tapered.
Bailey K, et al: Acute generalized exanthematous pustulosis induced by
hydroxychloroquine: first case report in Canada and review of the
literature. J Cutan Med Surg 2013; 17:414–418.
Bommarito L, et al: A case of acute generalized exanthematous
pustulosis due to amoxicillin-clavulanate with multiple positivity to
beta-lactam patch testing. Eur Ann Allergy Clin Immunol 2013;
45:178–180.
Eyler JT, et al: Two cases of acute generalized exanthematous
pustulosis related to oral terbinafine and an analysis of the clinical
reaction pattern. Dermatol Online J 2012; 18(11):5.
Hotz C, et al: Systemic involvement of acute generalized exanthematous
pustulosis: a retrospective study on 58 patients. Br J Dermatol 2013;
169:1223–1232.
Mohyuddin GR, et al: Acute generalized exanthematous pustulosis with
multiple organ dysfunction syndrome. Am J Crit Care 2013;
22:270–273.
Otero Rivas MM, et al: Acute generalized exanthematous pustulosis due
to dextromethorphan. Dermatol Online J 2013; 19(10):20030.
120
Drug-induced pseudolymphoma
At times e posure to medication may result in cutaneous
in ammatory patterns that resemble lymphoma. These pseu
dolymphomatous drug eruptions may resemble either T cell
or B cell lymphomas. The most common drug induced pseu
dolymphoma is one resembling cutaneous T cell lymphoma
(CTCL) clinically and histologically. The most common setting
in which these pseudolymphomas occur is a drug induced
hypersensiti ity syndrome (DR SS D S) as described
earlier in which in re uently the histology may resemble
CTCL. ore rarely medications may induce pla ues or
nodules usually in elderly white men a ter many months o
treatment. Lymphadenopathy and circulating S ary cells
may also be present. CD + cells may be present in the
in ltrate. sually other eatures (e.g. eratinocyte necrosis
dermal edema) help to distinguish these reactions rom true
lymphoma. mportantly T cell receptor gene rearrangements
in the s in and blood may be positi e (or show pseudoclones)
in these drug induced cases representing a potential pit all
or the unwary physician. Pseudolymphoma resol es with
discontinuation o the medication. The medication groups
primarily responsible are anticon ulsants sul a drugs
(including thia ide diuretics) dapsone and antidepressants.
Vaccinations and herbal supplements can also induce
pseudolymphoma.
Kerl K: Histopathological patterns indicative of distinct adverse drug
reactions. Chem Immunol Allergy 2012; 97:61–78.
Macisaac JL, et al: Cutaneous T-cell lymphoma–like drug eruption in an
HIV-positive patient taking vancomycin and rifampin. J Cutan Med
Surg 2013; 17:433–436.
Pulitzer MP, et al: CD30+ lymphomatoid drug reactions. Am J
Dermatopathol 2013; 35:343–350.
Urticaria/angioedema
edications may induce urticaria by immunologic and non
immunologic mechanisms. n either case clinically the lesions
are pruritic wheals or angioedema ( ig. ). rticaria may
be part o a more se ere anaphylactic reaction with broncho
spasm laryngospasm or hypotension. mmediate hypersensi
ti ity s in testing and sometimes RAST is use ul in e aluating
ris or these patterns o reaction.
Aspirin and SA Ds are the most common causes o nonim
munologic urticarial reactions. They alter prostaglandin metab
olism enhancing degranulation o mast cells. They may
there ore also e acerbate chronic urticaria o other causes. The
nonacetylated salicylates (trilisate and salsalate) do not cross
react with aspirin in patients e periencing bronchospasm and
may be sa e alternati es. Some patients ha e urticaria to only
one medication in this amily without cross reaction with other
SA Ds suggesting that speci c g mediated mechanisms
may also be possible in SA D induced urticaria. ther agents
causing nonimmunologic urticaria include radiocontrast mate
rial opiates tubocurarine and polymy in B. Pretesting does
not e clude the possibility o anaphylactoid reaction to radio
contrast material. The use o low osmolarity radiocontrast
material and pretreatment with antihistamines systemic ste
roids and in those with a history o asthma theophylline may
reduce the li elihood o reaction to radiocontrast material.
mmunologic urticaria is most o ten associated with penicil
lin and related β lactam antibiotics and relates to the minor
determinants rather than the β lactam ring. t is associated
with g antibodies to penicillin or its metabolites. S in testing
with ma or and minor determinants is use ul in e aluating
patients with a history o urticaria associated with penicillin
e posure. Patients with penicillin allergy ha e an increased

Fig. 6-27 Angioedema and urticaria.
rate o reaction to cephalosporins. n the case o ce aclor hal
o anaphylactic reactions occur in patients with a history o
penicillin allergy. Third generation cephalosporins especially
ce dinir are much less li ely to induce a reaction in a penicillin
allergic patient than are rst or second generation agents.
Bupropion is o ten used or depression and smo ing cessa
tion. t can induce urticaria which may be associated with
hepatitis and a serum sic ness li e syndrome. Two antihista
mines cetiri ine and hydro y ine may induce urticaria an
apparent parado which may lead to con usion in the clinical
setting.
Angioedema is a nown complication o the use o
angiotensin con erting en yme (AC ) inhibitors and angio
tensin antagonists. Blac s are at almost e times greater
ris than whites. Lisinopril and enalapril produce angioedema
more re uently than captopril. Angioedema typically occurs
within a wee o starting therapy but may begin a ter months
o treatment. The episodes may be se ere re uiring hospital
i ation in up to o patients intensi e care in up to
and intubation in up to . ne uarter o patients a ected
gi e a history o pre ious angioedema. Captopril enhances the
are reaction around wheals. The angioedema appears to be
dose dependent because it may resol e with decreased dose.
All these actors suggest that the angioedema may represent
a conse uence o a normal pharmacologic e ect o the AC
inhibitors. The bloc ing o ininase by AC inhibitors may
increase tissue inin le els enhancing urticarial reactions and
angioedema. Although this is dose dependent AC inhibitor
users with one episode o angioedema ha e a old ris o a
second episode and the recurrent episodes may be more
se ere. The treatment o urticaria is discussed in Chapter .
Red man syndrome
The intra enous in usion o ancomycin especially i rapid is
re uently complicated by a characteristic reaction called red
tahir99 - UnitedVRG
man syndrome. At any time during the in usion a macular
eruption appears initially on the bac o the nec sometimes
spreading to the upper trun ace and arms. Angioedema
has been described. There is associated pruritus and heat as
well as hypotension that may be se ere enough to cause
Drug reactions
cardiac arrest. ral ancomycin has caused a similar reaction
in a child. Children with systemic u enile idiopathic arthritis
(J A) may ha e potentially atal macrophage acti ation syn
drome during or a ter a red man reaction rom ancomycin.
The red man reaction is caused by ele ated blood histamine.
Red man syndrome can be pre ented in most patients by
reducing the rate o in usion o the antibiotic or by pretreat
ment with and antihistamines. Although typically
reported with ancomycin similar anaphylactoid reactions
ha e been seen with cipro o acin ce epime amphotericin B
ri ampin in i imab and teicoplanin.
Bauters T, et al: Vancomycin-induced red man syndrome in pediatric
oncology: still an issue? Int J Clin Pharm 2012; 34:13–16.
Myers AL, et al: Defining risk factors for red man syndrome in children
and adults. Pediatr Infect Dis J 2012; 31:464–468.
Panos G, et al: Red man syndrome adverse reaction following
intravenous infusion of cefepime. Antimicrob Agents Chemother 2012;
56:6387–6388.
Photosensitivity reactions (photosensitive
drug reactions)
edications may cause phototo ic photoallergic and lichen
oid reactions and photodistributed telangiectasias as well as
pseudoporphyria. The mechanisms o photosensiti ity are dis
cussed in Chapter . n many cases the mechanism or drug
induced photosensiti ity is un nown. ost medication related
photosensiti ity is triggered by radiation in the VA range
partly because ( ) most photosensiti ing drugs ha e absorp
tion spectra in the VA and short isible range ( nm)
and ( ) VA penetrates into the dermis where the photosen
siti ing drug is present. The most common causes o photo
sensiti ity are SA Ds T P S thia ide diuretics and
related sul onylureas uinine and uinidine phenothia ines
and certain tetracyclines; numerous other medications in
many classes induce photosensiti ity less re uently.
Phototo ic reactions are related to the dose o both the medi
cation and the V irradiation. Reactions can occur in anyone
i su cient thresholds are reached and do not re uire prior
e posure or participation by the immune system. Persons o
higher s in types are at lower ris o de eloping phototo ic
eruptions in some studies. There is indi idual ariation in the
amount o photosensiti ity created by a standard dose o med
ication independent o serum concentration. This remains
une plained but re ects the clinical setting where interindi
idual ariability in de elopment o phototo ic eruptions
is seen. Reactions can appear rom hours to days a ter e po
sure. Tetracyclines amiodarone and SA Ds are common
culprits. The reaction may present as immediate burning with
sun e posure (amiodarone chlorproma ine) or e aggerated
sunburn ( uoro uinolone antibiotics chlorproma ine amio
darone thia ide diuretics uinine tetracyclines). yperpig
mentation may complicate phototo ic reactions and may last
or many months. Treatment may include dose reduction and
photoprotection by a sunbloc with strong co erage through
the whole VA spectrum.
Photoallergic reactions are typically ec ematous and pru
ritic may rst appear wee s to months a ter drug e posure
and in ol e the immune system. n ortunately in the patient
with photoallergy to systemic medications photopatch testing
is in re uently positi e and o limited clinical alue. n general
photoallergic reactions are not as dependent on drug dose as
121
 Fig. 6-28 Amiodarone-
6 induced pigmentation.
Contact Dermatitis and Drug Eruptions
Fig. 6-29 Piroxicam photosensitivity.
phototo ic reactions. Photosensiti ity o both the phototo ic
and the photoallergic type may persist or months to years
a ter the medication has been stopped. Photosensiti ity reac
tions to arious drugs are discussed indi idually ne t empha
si ing the characteristic patterns seen with each medication
group.
Amiodarone photosensiti ity de elops in up to o aggressi e and potentially atal s uamous cell carcinomas in
treated patients and occurs a ter a cumulati e dose o g. A
reduced minimal erythema dose ( D) to VA but not VB
occurs and gradually returns to normal between and
months a ter stopping the medication. Stinging and burning
may occur as soon as min a ter sun e posure. Less re
uently a dus y blue red erythema o the ace and dorsa o
the hands occurs ( ig. ). At times papular reactions
are also seen. Des uamation as seen a ter sunburn is not
obser ed ollowing amiodarone photosensiti ity reactions.
This reaction may be dose dependent and acute burning may
be relie ed by dose reduction. arrow band VB may desen
siti e patients with persistent phototo icity a ter stopping
amiodarone.
The SA Ds especially piro icam are re uently associated
with photosensiti ity ( ig. ). The characteristic reaction is
a esicular eruption o the dorsa o the hands sometimes asso
ciated with a dyshidrosi orm pattern on the lateral aspects o
the hands and ngers. n se ere cases e en the palms may be
122
in ol ed. istologically this reaction pattern shows intraepi
dermal spongiosis e ocytosis and peri ascular in ammatory
cells a pattern typical o photoallergy. owe er this reaction
may occur on the initial e posure to the medication but pho
toto icity tests in animals and humans ha e been negati e.
Patients with photosensiti ity to piro icam may also react to
thiosalicylic acid a common sensiti er in thimerosal. al o
patients ha ing a positi e patch test to thimerosal with no prior
e posure to piro icam test positi e to piro icam. This suggests
that piro icam reactions seen on initial e posure to the medica
tion may be related to sensiti ation during prior thimerosal
e posure.
Sul onamide antibiotics related hypoglycemic agents and
the sul onylurea diuretics may all be associated with photo
sensiti ity reactions. n addition patients may tolerate one o
the medications rom this group but when additional members
o the group are added clinical photosensiti ity occurs. The
typical pattern is erythema scale and in chronic cases licheni
cation and hyperpigmentation.
luoro uinolone antibiotics are re uently associated with
photosensiti ity reactions. Spar o acin is highly photosensi
ti ing; eno acin cipro o acin and sita o acin are mildly
photosensiti ing; and le o o acin rarely i e er causes
photosensiti ity.
Photodistributed lichenoid reactions ha e been reported
most o ten rom thia ide diuretics uinidine and SA Ds
but also occur rom diltia em and clopidogrel bisul ate.
They present as erythematous patches and pla ues. Some
times typical Wic ham s striae are obser ed in the lesions.
istologically photodistributed lichenoid reactions are o ten
indistinguishable rom idiopathic lichen planus. ar ed
hyperpigmentation may occur especially in persons o higher
s in types ( V V ) and diltia em induced cases. The lichenoid
nature o the eruption may not be clinically ob ious and his
tology is re uired to con rm the diagnosis. This hyperpigmen
tation may persist or months. VA associated phototo icity
is also common with emura enib with reduced VA D
in o those tested.
Voricona ole a second generation tria ole has been associ
ated with an unusual combination o photosensiti e phenom
ena. Photosensiti ity occurs in or more o patients ta ing
oricona ole or more than wee s. t appears to be VA
induced and is not dose dependent. sually the photosensi
ti ity is mild and with the use o sun protection and topical
treatment oricona ole can be continued. Cheilitis and acial
erythema are typical initial mani estations. n a ew patients
howe er signi cant complications occur. Pseudoporphyria
(with oot erosions as well) erupti e lentigines and atypical
ne i premature aging and e en the de elopment o highly
sun e posed sites ha e been reported. A ected patients can
closely resemble patients with eroderma pigmentosa. Photo
distributed granuloma annulare has also been seen. This
se ere orm o photosensiti ity rapidly resol es on stopping
oricona ole. Posacona ole can be an e ecti e alternati e.
Photodistributed telangiectasia is a rare complication o
calcium channel bloc ers (ni edipine elodipine amlodipine).
VA appears to be the action spectrum. Ce ota ime has also
been reported to produce this reaction. Corticosteroids oral
contracepti es isotretinoin s lithium thiothi ene lithium
methotre ate and other medications may induce telangiecta
sia but not through photosensiti ity.
Pseudoporphyria is a photodistributed bullous reaction clin
ically and histologically resembling porphyria cutanea tarda
( ig. ). Patients present with blistering on sun e posed s in
o the ace and hands and s in ragility. Varioli orm scarring
occurs in o patients. acial scarring is especially common
in children with pseudoporphyria. ypertrichosis is rarely

Fig. 6-30 Sixteen-year-old with scarring from pseudo–porphyria
cutanea tarda reaction to tetracycline.
ound; dyspigmentation and sclerodermoid changes are not
reported. Porphyrin studies are normal. The blistering usually
resol es gradually once the o ending medication is stopped.
owe er s in ragility may persist or years. apro en is the
most re uently reported cause. p to o children with J A
treated with SA Ds may de elop pseudoporphyria. Pseudo
porphyria has also been reported to other SA Ds (o apro in
nabumetone etopro en me enamic acid; but not piro icam)
tetracycline urosemide nalidi ic acid isotretinoin acitretin
uorouracil bumetanide dapsone oral contracepti es ro e
co ib celeco ib cyclosporine oricona ole and pyrido ine.
Tanning booth (sunbed) e posure and e en e cessi e sun
e posure can produce pseudoporphyria. Cases in women out
number men by . Some women with sunbed induced
pseudoporphyria are ta ing oral contracepti es. Patients on
dialysis may de elop pseudoporphyria and acetylcysteine
in doses up to mg twice daily may lead to impro ement in
these cases. istologically a pauci in ammatory subepider
mal esicle is seen. D may show immunoglobulin and com
plement deposition at the D J and peri ascularly as seen in
porphyria cutanea tarda.
Boussemart L, et al: Prospective study of cutaneous side-effects
associated with the BRAF inhibitor vemurafenib: a study of 42 patients.
Ann Oncol 2013; 24:1691–1697.
Elkeeb D, et al: Photosensitivity: a current biological overview. Cutan
Ocul Toxicol 2012; 31:263–272.
Gelot P, et al: Vemurafenib: an unusual UVA-induced photosensitivity.
Exp Dermatol 2013; 22:297–298.
Hansford JR, et al: Idiosyncratic nature of voriconazole photosensitivity
in children undergoing cancer therapy. J Antimicrob Chemother 2012;
67:1807–1809.
Haylett AK, et al: Voriconazole-induced photosensitivity: photobiological
assessment of a case series of 12 patients. Br J Dermatol 2013;
168:179–185.
Lacouture ME, et al: Analysis of dermatologic events in vemurafenib-
treated patients with melanoma. Oncologist 2013; 18:314–322.
Srinivas CR, et al: Photodermatoses in India. Indian J Dermatol
Venereol Leprol 2012; 78(Suppl 1):1–8.
Anticoagulant-induced skin necrosis
Both war arin and heparin induce lesions o cutaneous necro
sis although by di erent mechanisms. bese postmenopausal
women are predisposed and lesions tend to occur in areas
with abundant subcutaneous at such as the breast abdomen
thigh or buttoc s. The clinical appearance o erlaps with
tahir99 - UnitedVRG
Drug reactions
Fig. 6-31 Warfarin-induced necrosis.
calciphyla is and patients with war arin induced calciphy
la is ha e been described.
War arin induced s in necrosis (W S ) usually occurs
days a ter therapy is begun and a high initial dose increases
the ris . Patients with a much more delayed onset (up to
years) are ascribed to noncompliance drug drug interactions
or li er dys unction. W S occurs in to
patients treated with war arin. Lesions begin as red pain ul
pla ues that de elop petechiae then orm a large bulla. ecro
sis ollows ( ig. ). Priapism can complicate war arin
necrosis. ereditary or ac uired de ciency o protein C and
less o ten protein S antithrombin or actor V Leiden and
lupus anticoagulant syndrome are associated with war arin
necrosis. A less common ariant seen in patients with a deep
enous thrombosis (DVT) o an e tremity is necrosis o a distal
e tremity usually the one with the DVT. War arin induced
enous limb necrosis is most o ten seen in cancer patients but
also in the setting o heparin induced thrombocytopenia and
antiphospholipid syndrome.
arly in war arin treatment the serum le els o the itamin
dependent antithrombotic protein C all. Since the hal li e
o antithrombotic protein C is shorter than that o the itamin
dependent prothrombotic actors and an ac uired
state o reduced protein C le el occurs be ore the clotting
actors are reduced. This creates a temporary prothrombotic
state. This is more li ely to occur i the le els o protein C are
already low i other antithrombotic proteins are de cient or
i the patient has an associated hypercoagulable state. This
e plains why the syndrome does not always recur with
gradual reinstitution o war arin and why it has been reported
to resol e with continued war arin treatment. istologically
nonin ammatory thrombosis with brin in the subcutaneous
and dermal essels is seen. Treatment is to stop the war arin
administer itamin to re erse the war arin and begin
heparin or low molecular weight (L W) heparin. Adminis
tration o puri ed protein C can rapidly re erse the syndrome
as well as associated priapism. Ri aro aban a direct inhibitor
o acti ated actor that does not inhibit other itamin
dependent proteins may be considered an alternati e antico
agulant. Dabigatran ete ilate has been suggested or pre ention
o war arin induced s in necrosis in the patient with protein
C de ciency.
eparin induces necrosis both at the sites o local in ections
and in a widespread pattern when in used intra enously or
gi en by local in ection. Local reactions are the most common.
eparin can also induce local allergic reactions at in ection
sites which are distinct rom the necrosis syndrome. ndepen
dent o its method o deli ery heparin induced s in necrosis
lesions present as tender red pla ues that undergo necrosis
usually days a ter the heparin treatments are started.
ntraepidermal hemorrhagic bullae ha e also been described.
n ractionated heparin is more li ely to cause this complica
tion than ractionated L W heparin and postsurgical patients
are at greater ris than medical patients. en the heparin
123
 used or dialysis or to ush arterial catheters may be associ
6 ated with cutaneous necrosis simulating calciphyla is.
Some necrotic reactions to local in ections and most dis
seminated reactions occurring with intra enous heparin are
associated with heparin induced thrombocytopenia ( T).
Contact Dermatitis and Drug Eruptions
Patients with underlying prothrombotic conditions such as
actor V Leiden and prothrombin mutations or ele ated le els
o actor V may de elop se ere s in lesions i they de elop
T and heparin necrosis. A heparin dependent antiplatelet
antibody is the pathogenic basis o T and apparently o
heparin induced s in necrosis. This antibody causes both the
thrombocytopenia and the aggregation o platelets in essels
leading to thrombosis (white clot syndrome). The antibody
may appear up to wee s a ter the heparin has been discon
tinued so the onset o the syndrome may be delayed. isto
logically brin thrombi are less reproducibly ound in a ected
tissues because the ascular thrombosis is the result o platelet
aggregation not protein deposition. The process may not only
produce in arcts in the s in but also cause arterial thrombosis
o the limbs heart lung and brain resulting in signi cant
morbidity or mortality. Bilateral adrenal necrosis caused by
hemorrhagic in arction can occur and i not detected early
may lead to death rom acute addisonian crisis. The syndrome
must be recogni ed immediately in any patient recei ing
heparin with late de eloping thrombocytopenia. The treat
ment is to stop the heparin and gi e a direct thrombin inhibitor
and itamin . A ter the platelet count has returned to normal
war arin therapy is typically gi en or months. Patients
with T cannot be treated with war arin immediately as the
war arin would be ine ecti e in stopping the thrombosis
(it is not antithrombotic) and may worsen the thrombosis by
enhancing coagulation. The diagnosis o T can be delayed
because the antiplatelet antibody may not be present while the
platelet count is alling. Adding war arin at this time can lead
to disastrous widespread acral thrombosis resembling dis
seminated intra ascular coagulation (D C).
S in necrosis has also been associated with eno aparin.
Patients with cancer an ac uired prothrombotic state are at
increased ris or DVT. they are treated with heparin and
de elop T patients are at e treme ris or de elopment o
a prothrombotic state i treated with war arin. n this setting
digital and limb gangrene has occurred in the ace o normal
peripheral pulses and supertherapeutic anticoagulation by
standard measures (international normali ed ratio R). The
consumpti e coagulopathy induced by the cancer is the under
lying trigger.
Choudhry S, et al: Heparin-induced bullous hemorrhagic dermatosis.
Cutis 2013; 91:93–98.
Gucalp A, et al: Skin necrosis induced by generic enoxaparin. Am J
Hematol 2013; 88:339.
Hafiji J, et al: Warfarin-induced calciphylaxis successfully treated with
sodium thiosulphate. Australas J Dermatol 2013; 54:133–135.
Hermans C, et al: Dabigatran etexilate (Pradaxa) for preventing
warfarin-induced skin necrosis in a patient with severe protein C
deficiency. Thromb Haemost 2012; 107:1189–1191.
Martinelli I, et al: Anticoagulant treatment with rivaroxaban in severe
protein S deficiency. Pediatrics 2013; 132:e1435–e1439.
Mungalsingh CR, et al: Warfarin-induced skin necrosis. Clin Med 2012;
12:90–91.
Saifan C, et al: Warfarin-induced calciphylaxis: a case report and review
of literature. Int J Gen Med 2013; 6:665–669.
Stelfox HT, et al: Skin necrosis in patients with arterial catheters flushed
with a solution containing heparin. Intensive Care Med 2012;
38:918–919.
Vitamin K reactions
Se eral days to wee s a ter in ection o itamin an allergic
reaction at the in ection site may occur ( ig. ). ost a ected
124
Fig. 6-32 Vitamin K allergy.
patients ha e li er disease and are being treated or ele ated
prothrombin time. The lesions are pruritic red patches or
pla ues that can be deep seated in ol ing the dermis and
subcutaneous tissue. There may be super cial esiculation.
Lesions occur most o ten on the posterior arm and o er the
hip or buttoc s. Pla ues on the hip tend to progress around
the waist and down the thigh orming a cowboy gunbelt and
holster pattern. Small generali ed ec ematous papules may
occur on other s in sites in se ere reactions. These reactions
usually persist or wee s but may persist much longer or
resol e only to recur spontaneously. n testing patients with
this pattern o reaction are positi e on intradermal testing to
the pure itamin .
n urope a second pattern o itamin reaction has been
reported. Subcutaneous sclerosis with or without asciitis
appears at the in ection site many months a ter itamin
treatment. There may ha e been a preceding acute reaction as
pre iously described. Peripheral eosinophilia may be ound.
These pseudosclerodermatous reactions ha e been termed
Te ier s disease and last se eral years.
The addition o itamin to cosmetics has led to allergic
contact dermatitis rom the itamin con rmed by patch
testing.
Injection site reactions
n addition to allergic reactions as described with itamin
cutaneous necrosis may occur at sites o medication in ections.
These are o two typical orms those associated with intra e
nous ( V) in usions and those related to intramuscular ( )
in ections. Pharmacologic agents that e tra asate into tissue
during V in usion may cause local tissue necrosis resulting
rom inherent tissue to ic properties. These include chemo
therapeutic agents calcium salts radiocontrast material and
na cillin. in ections may produce a syndrome called embolia
cutis medicamentosa li edoid dermatitis or icolau syn
drome. mmediately a ter in ection local intense pain occurs
and the o erlying s in blanches (ischemic pallor). Within
minutes to hours the site de elops an erythematous macule
that e ol es into a li edoid iolaceous patch with dendrites.
This becomes hemorrhagic then ulcerates o ten orming a
deep ulcer many centimeters in diameter. entually o er
wee s to months the ulcer heals with an atrophic scar. uscle
and li er en ymes may be ele ated and neurologic symptoms
and se uelae occur in one third o patients. The circulation o
the limb may be a ected rarely leading to amputation. icolau
syndrome has been seen with in ection o many unrelated
agents including SA Ds local anesthetics corticosteroids
antibiotics alpha sedati es accines and medro ypro
gesterone acetate (Depo Pro era). t appears to be caused by
periarterial in ection leading to arterial thrombosis.
in ections into subcutaneous tissue o the abdomen buttoc s
or thighs o patients with multiple sclerosis has resulted in
subcutaneous at. Stains or iron may be negati e in some
cases. Calcium stains may also be positi e because minocycline
β binds calcium. n unusual cases electron microscopy or sophis
ticated chemical analysis can con rm the presence o minocy
cline in the granules. The least common type (type ) is

similar lesions. Patient education and auto in ectors can
pre ent this complication. Biopsy o the inter eron in ection
site reactions resembles lupus panniculitis. Vitamin B also
produces locali ed sclerodermoid reactions. Treatment o
icolau syndrome is conser ati e dressing changes debride
ment bed rest and pain control. Surgical inter ention is rarely
re uired.
Pereira SP, et al: Adverse events associated with vitamin K1: results of a
worldwide postmarketing surveillance programme. Pharmacoepidemiol
Drug Saf 1998; 7:173–182.
Sousa T, et al: Localized cutaneous reaction to intramuscular vitamin K
in a patient with acute fatty liver of pregnancy. Dermatol Online J 2010;
16(12):16.
Drug-induced pigmentation
Pigmentation o the s in may result rom drug administration.
The mechanism may be postin ammatory hyperpigmentation
in some patients but re uently is related to actual deposition
o the drug in the s in.
inocycline induces many types o hyperpigmentation
which may occur in arious combinations in the a ected
patient. Classically three types o pigmentation are described.
Type is a blue blac discoloration appearing in areas o prior
in ammation o ten acne or surgical scars ( ig. ). This may
be the most common type seen by dermatologists. t does not
appear to be related to the total or daily dose o e posure. n
all other types o pigmentation resulting rom minocycline the
incidence increases with total dose with up to o treated
patients e periencing hyperpigmentation with more than
year o therapy. The second type (type ) is the appearance o
a similar colored pigmentation on the normal s in o the ante
rior shins analogous to that seen in antimalarial induced
hyperpigmentation. t is initially mista en or ecchymoses but
does not ade uic ly. n most cases types and minocycline
pigmentation occur a ter months to se eral years o treat
ment. Generali ed blac hyperpigmentation has occurred a ter
se eral days or a ew wee s o treatment in Japanese patients.
n type and type minocycline hyperpigmentation histo
logic e aluation re eals pigment granules within macrophages
in the dermis and at times in the at resembling a tattoo. These
granules usually stain positi ely or both iron and melanin
the usual method or con rming the diagnosis. At times the
macrophages containing minocycline are ound only in the
Fig. 6-33 Minocycline-induced hyperpigmentation.
Drug reactions
generali ed muddy brown hyperpigmentation accentuated
in sun e posed areas. Tigecycline may produce similar hyper
pigmentation. istologic e amination re eals only increased
epidermal and dermal melanin. This may represent the conse
uence o a low grade photosensiti ity reaction.
n addition to the s in minocycline types and pigmenta
tion may also in ol e the sclera con uncti a bone thyroid
ear cartilage (simulating al aptonuria) nail bed oral mucosa
and permanent teeth. Tetracycline staining o the teeth is
usually related to childhood or etal e posure is brown and
is accentuated on the gingi al third o the teeth. Dental hyper
pigmentation caused by minocycline in contrast occurs in
adults is gray or gray green and is most mar ed in the mid
portion o the tooth. Some patients with a ected teeth do not
ha e hyperpigmentation elsewhere. Cutaneous hyperpigmen
tation rom minocycline ades slowly and the teeth may
remain pigmented or years. The blue gray pigmentation o
the s in may be impro ed with the switched ruby laser or
ractional photothermolysis.
Chloro uine hydro ychloro uine and uinacrine all may
cause a blue blac pigmentation o the ace e tremities ear
cartilage oral mucosa and nails. Pretibial hyperpigmentation
is the most common pattern and is similar to that induced by
minocycline. The gingi a or hard palate may also be discol
ored. uinidine may also rarely cause such a pattern o hyper
pigmentation. uinacrine is yellow and concentrated in the
epidermis. Generali ed yellow discoloration o the s in and
sclera (mimic ing aundice) occurs reproducibly in patients
but ades within months o stopping the drug. n dar
s inned patients this color is mas ed and less signi cant
cosmetically. istologically in both orms o pigmentation
pigment granules are present within macrophages in the
dermis.
Amiodarone a ter months causes photosensiti ity in
o treated patients. n o patients a slate gray
hyperpigmentation de elops in the areas o photosensiti ity.
The pigmentation gradually ades a ter the medication is
discontinued. istologically periodic acid Schi (PAS)
positi e yellow brown granules are seen within the cytoplasm
o macrophages in the dermis. lectron microscopy re eals
membrane bound structures resembling lipid containing lyso
somes. t responds to treatment with the switched ruby
laser.
Clo a imine treatment is reproducibly complicated by the
appearance o a pin discoloration that gradually becomes
reddish blue or brown and is concentrated in the lesions o
patients with ansen s disease. This pigmentation may be
dis guring and is a ma or cause o noncompliance with this
drug in the treatment o ansen s disease. istologically a
PAS positi e brown granular pigment is ariably seen within
oamy macrophages in the dermis. This has been called drug
induced lipo uscinosis.
ido udine causes a blue or brown hyperpigmentation that
is most re uently obser ed in the nails. The lunula may be
blue or the whole nail plate may become dar brown. Di use
hyperpigmentation o the s in pigmentation o the lateral
tongue and increased tanning are less common. t occurs in
dar ly pigmented persons is dose dependent and clears a ter
ido udine is discontinued. ydro yurea causes a similar
pattern o hyperpigmentation ( ig. ).
Chlorproma ine thiorida ine imipramine and clomip
ramine may cause a slate gray hyperpigmentation in sun
e posed areas a ter long periods o ingestion. re uently
125

tahir99 - UnitedVRG

6 induced reaction.
Contact Dermatitis and Drug Eruptions
Fig. 6-34 Hydroxyurea-induced pigmentation, tongue.
corneal and lens opacities are also present so all patients with
hyperpigmentation rom these medications should ha e an
ophthalmologic e aluation. The pigmentation rom the phe
nothia ines ades gradually o er years e en i the patient is
treated with another phenothia ine. The corneal but not the
lenticular changes also resol e. mipramine hyperpigmenta
tion has been reported to disappear within year. istologi
cally in sun e posed but not sun protected s in numerous
re ractile golden brown granules are present within macro
phages in the dermis along with increased dermal melanin.
The slate gray color comes rom a mi ture o the golden
brown pigment o the drug and the blac color o the melanin
iewed in the dermis.
The hea y metals gold sil er and bismuth produce blue to
slate gray hyperpigmentation. Pigmentation occurs a ter years
o e posure predominantly in sun e posed areas and is per
manent. Sil er is by ar the most common orm o hea y
metal induced pigmentation seen by dermatologists. t occurs
in two orms local or systemic. Local argyria typically ollows
the topical use o sil er sul adia ine or sil er containing dress
ings (Acticoat). Blue gray pigmentation occurs at the site o
application. mplantation into the s in by needles or pierced
ewelry may lead to ocal areas o argyria. Systemic argyria
can also arise rom topical application to the s in (in burn and
epidermolysis bullosa patients) by inhalation by mucosal
application (nose drops or eyedrops) or by ingestion. Patients
may purchase or build de ices that allow them to ma e col
loidal sil er solutions which they then ingest in the belie that
it will impro e their health. A ter se eral months o such e po
sure the s in becomes slate gray or blue gray primarily in
areas o sun e posure. istologically granules o sil er are
ound in basement membranes around adne al (especially
eccrine) and ascular structures. Sun e posure leads to the
sil er binding to either sul ur or selenium in the s in increas
ing deposition. The deposited sil er acti ates tyrosinase
increasing pigmentation. ost patients with argyria ha e no
systemic symptoms or conse uences o the increased sil er in
their body. n one patient the use o a switched nm
neodymium doped yttrium aluminum garnet ( d AG)
laser impro ed the condition. Gold deposition was more
common when gold was used as a treatment or rheumatoid
arthritis. Cutaneous chrysiasis also presents as blue gray pig
mentation usually a ter a cumulati e dose o g. Chrysiasis
is also more prominent in sun e posed sites. Dermatologists
should remain aware o this condition since patients treated
with gold e en decades earlier may de elop dis guring
hyperpigmentation a ter switched laser therapy or hair
remo al or lentigines lightening. Chrysiasis has been treated
126
Fig. 6-35 Cefaclor-
e ecti ely in one patient using repeated nm pulsed dye
laser therapy. Bismuth also pigments the gingi al margin. is
tologically granules o the metals are seen in the dermis and
around blood essels. Arsenical melanosis is characteri ed by
blac generali ed pigmentation or by a pronounced truncal
hyperpigmentation that spares the ace with scattered depig
mented macules that resemble raindrops.
The calcium channel bloc er (CCB) diltia em can cause a
se ere photodistributed hyperpigmentation. This is most
common in A rican American or ispanic women and occurs
about year a ter starting therapy. The lesions are slate gray
or gray blue macules and patches on the ace nec and ore
arms. Peri ollicular accentuation is noted. istology shows a
sparse lichenoid dermatitis with prominent dermal melano
phages. The action spectrum o the drug appears to be in
the VB range but hyperpigmentation is induced by VA
irradiation. The mechanism appears to be postin ammatory
hyperpigmentation rom a photosensiti e lichenoid eruption
rather than drug or drug metabolite deposition. Treatment is
broad spectrum sunscreens stopping the diltia em and
bleaching creams i needed. ther CCBs can be substituted
without the reappearance o the hyperpigmentation.
Periocular hyperpigmentation occurs in patients treated
with prostaglandin analogs or glaucoma. These agents also
cause pigmentation o the iris. yelash length increases. The
periocular hyperpigmentation may gradually resol e when
the medications are discontinued.
Vasculitis and serum sickness–like reactions
True leu ocytoclastic asculitis can be induced by many medi
cations but these e ents are rare e cept in the case o propyl
thiouracil. True serum sic ness is caused by oreign proteins
such as antithymocyte globulin with resulting circulating
immune comple es. n the patient with true serum sic ness
purpuric lesions tend to be accentuated along the unction
between palmoplantar and glabrous s in (Wallace line).
Serum sic ness li e reactions re er to ad erse reactions that
ha e similar symptoms to serum sic ness but in which
immune comple es are not ound. This reaction was particu
larly common with ce aclor. Patients present with e er an
urticarial rash and arthralgias wee s a ter starting the
medication ( ig. ). inocycline bupropion and ritu imab
ha e been reported to cause serum sic ness li e reactions.
Lichenoid reactions
Lichenoid reactions can be seen with many medications
including gold hydrochlorothia ide urosemide SA Ds
aspirin antihypertensi es (AC inhibitors β bloc ers CCBs)
tera osin uinidine proton pump inhibitors pra astatin
phenothia ines anticon ulsants antituberculous drugs eto
cona ole sildena l imatinib and antimalarials. epatitis B
immuni ation may trigger a lichenoid eruption. Reactions
may be photodistributed (lichenoid photoeruption) or gener
ali ed and drugs causing lichenoid photoeruptions may also
induce more generali ed ones. n either case the lesions may
be pla ues (occasionally with Wic ham striae) small papules
or e oliati e erythema. Photolichenoid reactions a or the
e tensor e tremities including the dorsa o the hands. ral
in ol ement is less common in lichenoid drug reactions than
in idiopathic lichen planus but can occur (and with imatinib
may be se ere). t appears as either pla ues or erosions. The
lower lip is re uently in ol ed in photolichenoid reactions.
The nails may also be a ected and can be the only site o
in ol ement. Lichenoid drug eruptions can occur within
months to years o starting the o ending medication and may
ta e months to years to resol e once the medication has been
stopped. istologically in ammation occurs along the D J
with necrosis o eratinocytes and a dermal in ltrate com
posed primarily o lymphocytes. osinophils are use ul i
present but are not common in photolichenoid reactions. The
histology is o ten similar to idiopathic lichen planus and a
clinical correlation is re uired to determine i the lichenoid
eruption is drug induced. the drug is essential the course o
treatment may be tolerated with corticosteroid therapy.
Lichenoid reactions may be restricted to the oral mucosa
especially i induced by dental amalgam. n these patients the
lesions are topographically related to the dental llings or to
metal prostheses. Patients may be patch test positi e to
mercury or less o ten gold cobalt or nic el in up to two
thirds o cases. Amalgam replacement will result in resolution
o the oral lesions in these cases. Patients with cutaneous
lesions o lichen planus and oral lesions do not impro e with
amalgam remo al. An unusual orm o eruption is the drug
induced ulceration o the lower lip. Patients present with a
persistent erosion o the lower lip that is tender but not indu
rated. t is induced by diuretics and resol es slowly once they
are discontinued.
Fessa C, et al: Lichen planus–like drug eruptions due to β -blockers: a
case report and literature review. Am J Clin Dermatol 2012;
13:417–421.
Ghosh SK: Generalized lichenoid drug eruption associated with imatinib
mesylate therapy. Indian J Dermatol 2013; 58:388–392.
Lage D, et al: Lichen planus and lichenoid drug-induced eruption: a
histological and immunohistochemical study. Int J Dermatol 2012;
51:1199–1205.
Lehloenya RJ, et al: Lichenoid drug reaction to antituberculosis drugs
treated through with topical steroids and phototherapy. J Antimicrob
Chemother 2012; 67:2535–2537.
Adverse reactions to chemotherapeutic agents
Chemotherapeutic agents can cause ad erse reactions by mul
tiple potential mechanisms. Ad erse reactions may be related
to to icity either directly to the mucocutaneous sur aces (sto
matitis alopecia) or to some other organ system and re ected
in the s in such as purpura resulting rom thrombocytopenia.
As organic molecules or monoclonal antibodies chemothera
peutic agents can act as antigens inducing classic immunologic
reactions. n addition since they are inherently immunosup
pressi e they can cause s in reactions associated with altera
tions o immune unction. Some o these patterns may be
tahir99 - UnitedVRG
o erlapping and clinically di cult to distinguish. or e ample
oral erosions may occur as a to ic e ect o chemotherapy and
also by immunosuppression associated acti ation o SV.
Dermatologists are rarely con ronted with the relati ely
common acute hypersensiti ity reactions seen during in usion
Drug reactions
o chemotherapeutic agents. These reactions resemble type
allergic reactions with urticaria and hypotension and can be
pre ented by premedication with systemic corticosteroids and
antihistamines in most cases.
umerous macular and papular eruptions ha e been
described with chemotherapeutic agents as well. any occur
at the earliest reco ery o the bone marrow as lymphocytes
return to the peripheral circulation. They are associated with
e er. This phenomenon has been called cutaneous eruptions
o lymphocyte reco ery. istologically these reactions dem
onstrate a nonspeci c super cial peri ascular mononuclear
cell in ltrate composed primarily o T lymphocytes. Treat
ment is not re uired and the eruption spontaneously resol es.
Radiation enhancement and recall reactions
Radiation dermatitis in the orm o intense erythema and
esiculation o the s in may be obser ed in radiation ports.
Administration o many chemotherapeutic agents during or
about the time o radiation therapy may induce an enhanced
radiation reaction. n some patients howe er months to years
a ter radiation treatment the administration o a chemothera
peutic agent may induce a reaction within the prior radiation
port with eatures o radiation dermatitis. This phenomenon
has been termed radiation recall reported with numerous
chemotherapeutic agents high dose α and sim astatin.
Besides the s in internal structures such as the gut may also
be a ected. A similar reaction o reacti ation o a sunburn
a ter methotre ate therapy also occurs. anthems restricted
to prior areas o sunburn are not true radiation recall.
Chemotherapy-induced acral erythema
(palmoplantar erythrodysesthesia syndrome,
hand-foot syndrome)
Chemotherapy induced acral erythema is a relati ely common
syndrome most re uently caused by uorouracil ( )
do orubicin and cytosine arabinoside but also seen with
doceta el capecitabine and high dose liposomal do orubicin
and daunorubicin. A locali ed pla ue o ed erythrodyses
thesia has been described pro imal to the in usion site o
doceta el. The reaction may occur in as many as or more
o treated patients. The reaction is dose dependent and may
appear with bolus short term in usions or low dose long term
in usions. t may present days to months a ter the treatments
are started. t is probably a direct to ic e ect o the chemo
therapeutic agents on the s in. The large number o sweat
glands on the palms and soles that may concentrate the che
motherapeutic agents may e plain the locali ation o the to ic
ity. n the case o pegylated liposomal do orubicin locali ation
o the chemotherapeutic agent to the sweat glands has been
demonstrated and the sweat glands appear to be the organ
by which the chemotherapy is deli ered onto the sur ace o
normal s in. A e ural eruption in the groin and a illa may
accompany acral erythema again rom sweat gland accumula
tion o the drug in these regions. Cases o neutrophilic eccrine
hidradenitis and syringometaplasia all induced by the same
agents suggest that the eccrine glands are uni ue targets or
ad erse reactions to antineoplastic agents.
The initial mani estation is o ten dysesthesia or tingling o
the palms and soles. This is ollowed in a ew days by pain ul
symmetric erythema and edema most pronounced o er the
127
 Fig. 6-36 Hand-foot
6 syndrome.
Contact Dermatitis and Drug Eruptions
distal pads o the digits. The reaction may spread to the dorsal
hands and eet and may be accompanied by a morbilli orm
eruption o the trun nec scalp and e tremities. er the
ne t se eral days the erythema becomes dus y de elops
areas o pallor blisters des uamates and then reepithelial
i es. The des uamation is o ten the most prominent part o
the syndrome. Blisters de eloping o er pressure areas o the
hands elbows and eet are a ariant o hand oot syndrome
( ig. ). The patient usually reco ers without complication
although rarely ull thic ness ischemic necrosis occurs in the
areas o blistering.
The histopathology is nonspeci c with necrotic eratino
cytes and acuolar changes along the basal cell layer. Acute
GV D is in the di erential diagnosis. istologic e aluation
may not be use ul in the acute setting to distinguish these
syndromes. ost help ul are gastrointestinal or li er ndings
o GV D.
ost patients re uire only local supporti e care. Cold com
presses and ele ation are help ul and cooling the hands
during treatment may reduce the se erity o the reaction.
odi cation o the dose schedule can be bene cial. Pyrido
ine mg daily decreases the pain o induced
acral erythema. V G has been reported to be bene cial in a
methotre ate induced case o acral erythema. Cyclosporine
has been reported to result in worsening o the condition.
Sora enib and sunitinib are small multi inase inhibiting
molecules with bloc ing acti ity or numerous tyrosine
inases including ascular endothelial growth actor (V G )
platelet deri ed growth actor (PDG Rβ ) and c it ligand
(stem cell actor). Both agents induce a condition similar to
acral erythema also re erred to as hand oot s in reaction
( SR). Patients also present with acral pain and dysesthesia
but usually less se ere and with less edema than with classic
chemotherapeutic agents. n contrast to classic acral erythema
multi inase inhibitor induced SR causes mar ed patchy
hyper eratotic pla ues o er areas o riction. The SR is dose
dependent high grade in o cases (with blisters ulceration
and unctional loss) and results in the sora enib being stopped
in about o patients. The addition o another V G inhibi
tor be aci umab leads to worse SR. Pain ul distal subun
gual splinter hemorrhages can also occur wee s a ter onset
o treatment. t has been suggested that the bloc ing o V G
128
Fig. 6-37 Bleomycin-
induced flagellate
hyperpigmentation.
may be pathogenically important in causing SR splinter
hemorrhages. The de elopment o hand oot syndrome in
patients recei ing sora enib or metastatic renal cell carcinoma
is associated with better tumor response and impro ed
progression ree sur i al.
istologically there are hori ontal layers o necrotic erati
nocytes within the epidermis (i biopsy is ta en in rst
days) or in the stratum corneum (later biopsies). Topical ta
arotene urea heparin ointment and uorouracil cream
ha e been used to treat SR rom multi inase inhibitors.
eutrophilic eccrine hidradenitis is discussed in Chapter .
Chemotherapy-induced dyspigmentation
any chemotherapeutic agents (especially the antibiotics bleo
mycin do orubicin and daunorubicin) and the al ylating
agents (cyclophosphamide and busul an) cause arious pat
terns o cutaneous hyperpigmentation. Adriamycin (do orubi
cin) causes mar ed hyperpigmentation o the nails s in and
tongue. This is most common in blac patients and appears in
locations where constitutional hyperpigmentation is sometimes
seen. ydro yurea can also cause this pattern o hyperpigmen
tation. t is similar to ido udine associated pigmentation seen
in pigmented persons. Cyclophosphamide causes trans erse
banding o the nails or di use nail hyperpigmentation begin
ning pro imally. Bleomycin and cause similar trans erse
bands. Busul an and induce di use hyperpigmentation
that may be photoaccentuated. Parado ic hyperpigmentation o
the s in nails and hair caused by imatinib has been reported.
rupti e melanocytic ne i and lentigines with an acral predis
position ha e been seen with sora enib therapy.
Bleomycin induces characteristic agellate erythematous
urticarial wheals associated with pruritus within hours or
days o in usion ( ig. ). Lesions continue to appear or
days to wee s. Although in estigators ha e not always been
able to induce lesions the pattern strongly suggests scratching
is the cause o the erythematous lesions. A similar character
istic pattern o agellate hyperpigmentation occurs a ter bleo
mycin treatment possibly preceded by the erythematous
reaction or simply pruritus. Bleomycin hyperpigmentation
may be accentuated at areas o pressure strongly supporting
trauma as the cause o the peculiar pattern.
 Fig. 6-38 Shiitake
mushroom–induced
dermatitis. (Courtesy
of Don Adler, DO.)
Fig. 6-39 5-Fluorouracil
(5-FU)–induced
serpentine
hyperpigmentation.
Patients may present with linear erythematous wheals
days a ter eating raw or coo ed shiita e mushrooms ( ig.
). This so called to icodermia or shiita e agellate derma
titis is thought to be caused by a to ic reaction to lentinan a
polysaccharide component o the mushrooms. t is sel limited
and resol es within days to wee s o its appearance but can
be treated with topical corticosteroids to relie e the associated
pruritus some patients e perience. ther associations with
agellate eruptions include adult onset Still s disease derma
tomyositis and doceta el therapy.
luorouracil and less re uently other chemotherapeutic
agents may produce a serpentine hyperpigmentation o erly
ing the eins pro imal to an in usion site ( ig. ). This
represents postin ammatory hyperpigmentation rom a direct
cytoto ic e ect o the chemotherapeutic agent.
matinib in doses o mg daily leads to generali ed
or locali ed depigmentation in or more o pigmented
persons. t starts an a erage o wee s a ter treatment and
progresses o er time i treatment with imatinib is continued.
Patients also complain o an inability to tan and photosensi
ti ity. ne patient with itiligo had signi cant progression
with imatinib therapy. The proposed mechanism is inhibition
o stem cell actor which is implicated in melanogenesis. By
a similar mechanism sunitinib leads to depigmentation o the
hair a ter wee s o treatment. Sunitinib may lead to yellow
tahir99 - UnitedVRG
pigmentation o the s in rom the drug or its metabolites being
deposited.
Exudative hyponychial dermatitis
Drug reactions
ail to icity is common ( ) during chemotherapy or
breast cancer especially i doceta el is in the chemotherapeu
tic regimen. Subungual hemorrhage subungual abscesses
paronychia subungual hyper eratosis and onychomadesis all
occur. n its most se ere orm se ere e udation and onycholy
sis may result. All these reactions probably represent arious
degrees o to icity to the nail bed. Capecitabine has caused a
similar reaction.
Palifermin-associated papular eruption
Pali ermin is a recombinant human eratinocyte growth actor
used to reduce the se erity and duration o mucositis in
patients undergoing preparati e regimens or hematopoietic
stem cell transplantation. An intertriginous erythema accom
panied by oral white con uent pla ues and small lichenoid
papules de eloped in one patient recei ing pali ermin therapy.
The papules resembled at warts clinically and histologically
but were human papilloma irus ( PV) negati e by in situ
hybridi ation studies. A direct hyperproli erati e e ect o the
eratinocyte growth actor is the proposed mechanism.
Scleroderma-like reactions to taxanes
Patients treated with doceta el or paclita el may de elop an
acute di use in ltrated edema o the e tremities and head.
This occurs a ter one to se eral courses o the ta ane. The
a ected areas speci cally the lower e tremities e ol e o er
months to become sclerotic and at times pain ul. le ion con
tractures o the palm digits and large oints may occur. Biop
sies o the initial lesion show lymphangiectasia and a di use
in ltration with mononuclear cells in the super cial dermis.
Late brotic lesions demonstrate mar ed dermal brosis.
Discontinuation o the ta ane therapy leads to resolution in
most cases. Lupusli e reactions including subacute cutaneous
lupus ha e also been reported with the ta anes.
Adverse reactions to immunosuppressants
used in dermatology
A athioprine is used as a steroid sparing agent or dermato
logic conditions and can cause a hypersensiti ity syndrome.
n addition neutrophilic dermatoses resembling Sweet
syndrome appear with a athioprine therapy and resol e
with its discontinuation. Patients with in ammatory bowel
disease appear to be at particular ris . Photosensiti ity can
also occur with a athioprine despite its re uent use in se ere
photodermatoses.
ethotre ate can cause erosi e s in lesions in two patterns.
lceration or erosion o psoriatic pla ues may be a sign that
the patient is ta ing a midwee dose o methotre ate. This
can be associated with se ere methotre ate marrow to icity.
renal ailure is present or occurs during low dose methotre
ate therapy a se ere bullous eruption resembling T can
occur. This apparently represents se ere cutaneous to icity
rom the prolonged blood and s in le els o methotre ate that
result rom reduced e cretion because o coe istent renal
disease and drug drug interactions. this scenario is recog
ni ed leuco orin rescue should be gi en immediately.
Baldo BA, et al: Adverse reactions to targeted and non-targeted
chemotherapeutic drugs with emphasis on hypersensitivity responses and
the invasive metastatic switch. Cancer Metastasis Rev 2013; 32:723–761.
129
 Boussemart L, et al: Prospective study of cutaneous side-effects
6 associated with the BRAF inhibitor vemurafenib: a study of 42 patients.
Ann Oncol 2013; 24:1691–1697.
Chan MP, et al: Subcutaneous Sweet syndrome in the setting of myeloid
disorders: a case series and review of the literature. J Am Acad
Contact Dermatitis and Drug Eruptions

Dermatol 2013; 68:1006–1015.

Maldonado Cid P, et al: Acral erythema worsened by intravenous
infusions of cyclosporin. Dermatol Online J 2013; 19(3):16.
Nakano K, et al: Hand-foot skin reaction is associated with the clinical
outcome in patients with metastatic renal cell carcinoma treated with
sorafenib. Jpn J Clin Oncol 2013; 43:1023–1029.
Nardone B, et al: The effect of hand-foot skin reaction associated with
the multikinase inhibitors sorafenib and sunitinib on health-related
quality of life. J Drugs Dermatol 2012; 11:e61–e65.
Rehan HS, et al: Adverse drug reactions: trends in a tertiary care
hospital. Curr Drug Saf 2012; 7:384–388.
Reyes-Habito CM, et al: Cutaneous reactions to chemotherapeutic drugs
and targeted therapy for cancer. Part II. Targeted therapy. J Am Acad
Dermatol 2014; 71:217.e1–217.e11.
Rinderknecht JD, et al: RASopathic skin eruptions during vemurafenib
therapy. PLoS One 2013; 8(3):e58721.
Shabaruddin FH, et al: A systematic review of utility values for
chemotherapy-related adverse events. Pharmacoeconomics 2013;
31:277–288.
Zhu SY, et al: Radiation recall reaction: two case studies illustrating an
uncommon phenomenon secondary to anti-cancer agents. Cancer Biol
Med 2012; 9:202–204.

Cutaneous side effects of epidermal growth factor

receptor inhibitors
pidermal growth actor receptor ( G R) is e pressed by
basal eratinocytes sebocytes and the outer root sheath
e plaining why up to o patients treated with G R inhib Fig. 6-40 Epidermal growth factor receptor (EGFR) inhibitor–induced
itors may de elop cutaneous side e ects. erosis is o ten seen. paronychia.
Pain ul periungual or nger pulp ssures and paronychia
(with or without periungual pyogenic granulomas) may
de elop ( ig. ). The most common and characteristic
ad erse s in reaction is a dose dependent papulopustular
eruption. The eruption begins days a ter initiation o
therapy attaining ma imum se erity in the second wee . The
seborrheic areas o the scalp central ace upper bac and
retroauricular regions are mainly a ected. The primary lesion
is a ollicular papule or pustule with ew or no comedones.
emorrhagic crusting and con uence can occur resembling
rosacea ulminans (pyoderma aciale) in the most se erely
a ected patients. Cultures should be per ormed to rule out
secondary in ection in patients with se ere or unusual mani
estations. Telangiectasia may be prominent and long eye
lashes and curlier scalp hair may also be seen.
The eruption may itch. The presence and se erity o this s in
eruption are correlated with sur i al so some oncologists will
increase the dose to induce the eruption. Radiation therapy
during G R inhibitor therapy will enhance the s in to icity
but pre iously radiated s in is o ten spared rom inhibitor
to icity. ecti e topical therapies ha e included metronida Fig. 6-41 Bevacizumab-induced ulceration of striae.
ole clindamycin hydrocortisone pimecrolimus and treti
noin. ral tetracyclines can treat or pre ent the eruption. n
the most se ere cases isotretinoin or acitretin can be used. predilection. ncreased ascular permeability caused by
Tumor necrosis actor (T ) α and L are in ol ed in the PDG R inhibition has been the proposed mechanism. Dasat
pathogenesis o G R inhibitor to icity. tanercept and inib has caused a lobular panniculitis. Be aci umab a V G
ana inra there ore can also be therapeutically use ul. inhibitor causes bleeding and wound healing complications.
tensi e cutaneous surgery should probably be delayed or
Cutaneous side effects of multikinase inhibitors days a ter be aci umab therapy and days should elapse
a ter surgery be ore initiation o be aci umab therapy. Be a
n addition to the reactions pre iously listed multi inase ci umab has also been associated with ulceration o striae
inhibitors may cause other s in reactions. Psoriasis e acer distensae ( ig. ). Sora enib has been associated with the
bation acral psoriasi orm hyper eratosis and pityriasis rapid de elopment o multiple s uamoproli erati e lesions
rosea li e eruptions ha e been described with imatinib. Both called eratoacanthomas or s uamous cell carcinomas as well
imatinib and sunitinib cause acial edema with a periocular as erupti e melanocytic lesions. Be arotene was reported as
130
therapeutic in a patient with sora enib induced s uamoproli
erati e lesions. ultiple monomorphous ollicular eratotic
s in colored papules resembling eratosis pilaris can de elop
during sora enib treatment. istologically these papules
show hyperplasia o the ollicular isthmus or ollicular hyper
Wiznia LE, et al: Unique presentations of epidermal growth factor
receptor inhibitor–induced papulopustular eruption related to bacterial
superinfection. Dermatol Online J 2013; 19(3):8.

Drug reactions
eratosis with plugging. acial and scalp erythema and dys Adverse reactions to biologic agents
esthesia occur in about o sora enib treated patients.
Tumor necrosis factor inhibitors
Adverse reactions to cytokines The T inhibitors are associated with palmoplantar pustulo
sis pustular olliculitis worsening o psoriasis inter ace der
Cyto ines which are normal mediators o in ammation or cell matitis neutrophilic eccrine hidradenitis Sweet syndrome
growth are increasingly used in the management o malignan systemic lupus and asculitis. n ection site reactions ( SRs)
cies and to ameliorate the hematologic complications o disease are common with etanercept therapy or rheumatologic
or its treatment. S in to icity is a common complication o the disease with o patients de eloping SR. SRs present
use o these agents. any cause local in ammation and ulcer as erythematous mildly swollen pla ues appearing days
ation at the in ection site in a large number o the patients a ter the in ection. Pruritus occurs in o patients. SR is
treated. ore widespread papular eruptions are also re most common early in the treatment course (median number
uently reported but these ha e been poorly studied in most o in ections our) and stops appearing with continued treat
cases and are o unclear pathogenesis. ment. ndi idual lesions resol e o er days. Recall SR
Granulocyte colony stimulating actor (G CS ) has been (reappearance o eruption at pre ious SR site) occurs in
associated with the induction o se eral neutrophil mediated o patients. This ad erse reaction appears to be mediated by
disorders most o ten Sweet syndrome or bullous pyoderma CD + T cells. Cyto ine therapy with T and α β
gangrenosum. These occur about wee a ter cyto ine therapy and γ also causes SRs.
is initiated and are present despite persistent neutropenia in The parado ic appearance o psoriasis or a psoriasi orm der
peripheral blood. A rare complication o G CS is a thrombotic matitis is now a well recogni ed complication o T inhibitor
and necroti ing panniculitis. Both G CS and G CS therapy. t occurs with all three o the common T inhibitors
may e acerbate leu ocytoclastic asculitis. α γ and in i imab etanercept and adalimumab. The ris may be
G CS ha e been associated with the e acerbation o psoriasis. slightly higher or adalimumab. The psoriasis can appear rom
G CS can also cause cutaneous eruptions containing histio days to years a ter anti T therapy. There is no age or gender
cytes. Ana inra and rarely erythropoietin can cause similar predisposition. Se eral clinical patterns ha e been described.
granulomatous s in reactions. Palmoplantar pustulosis represents about o cases. Gen
L re uently causes di use erythema ollowed by des erali ed pustular disease may accompany the palmoplantar
uamation pruritus mucositis (resembling aphthosis) glos lesions. Pla ue type psoriasis occurs in about one third o T
sitis and ushing. The ma ority o erythema reactions with inhibitor induced psoriasis ( ig. ). ew onset guttate pso
L treatment are mild to moderate but some may be se ere. riasis occurs in o cases. Stopping the T inhibitor led
rythroderma with blistering or T li e reactions can occur to impro ement or resolution in the ast ma ority o patients.
and may be dose limiting. Administration o iodinated con n some cases therapy was continued and the eruption
trast material within wee s o L therapy is associated with resol ed. perts disagree as to whether switching to a di er
a hypersensiti ity reaction in o patients. e er chills ent anti T agent may be tolerated in these patients. any
angioedema urticaria and hypotension may occur. Subcuta patients ha e been rechallenged with other T inhibitors. n
neous in ections o L can lead to in ection site nodules or se ere cases this is probably not prudent but in milder or
necrosis. istologically a di use panniculitis with nonin am locali ed cases this could be considered. The psoriasis caused
matory necrosis o the in ol ed tissue is present. Rarely linear by anti T agents can be treated with topical corticosteroids
gA disease can be induced by α. V phototherapy topical itamin D analogs methotre ate
Dosal J, et al: Ulceration of abdominal striae distensae (stretch marks) acitretin or cyclosporine. The proposed mechanism or the
in a cancer patient. Arch Dermatol 2012; 148:385–390. appearance with psoriasis with anti T therapy is either
Giacchero D, et al: A new spectrum of skin toxic effects associated with o eracti ity o Th cells or increased α production by
the multikinase inhibitor vandetanib. Arch Dermatol 2012; s in resident plasmacytoid dendritic cells. Systemic α
148:1418–1420.
Habl G, et al: Differentiation of irradiation and cetuximab induced skin
reactions in patients with locally advanced head and neck cancer
undergoing radioimmunotherapy: the HICARE protocol (head and
neck cancer: immunochemo and radiotherapy with Erbitux)—a
multicenter Phase IV trial. BMC Cancer 2013; 13:345.
Li JR, et al: Efficacy of a protocol including heparin ointment for
treatment of multikinase inhibitor-induced hand-foot skin reactions.
Support Care Cancer 2013; 21:907–911.
Liu HB, et al: Skin rash could predict the response to EGFR tyrosine
kinase inhibitor and the prognosis for patients with non–small cell lung
cancer: a systematic review and meta-analysis. PLoS One 2013;
8:e55128.
Moreno Garcia V, et al: Association of creatine kinase and skin toxicity
in Phase I trials of anticancer agents. Br J Cancer 2012;
107:1797–1800.
Peters KB, et al: Ulceration of striae distensae in high-grade glioma
patients on concurrent systemic corticosteroid and bevacizumab
therapy. J Neurooncol 2011; 101:155–159.
Uhlenhake EE, et al: Sorafenib induced eruptive melanocytic lesions.
Dermatol Online J 2013; 19(5):18184. Fig. 6-42 Plaque-type psoriasis.
131

tahir99 - UnitedVRG
 and topical imi uimod (an inter eron inducer) ha e been
6 reported to e acerbate psoriasis supporting this hypothesis.
Sarcoidosis induced by anti T agents could also be related
to increased Th unction.
About o patients treated or rheumatoid arthritis
Contact Dermatitis and Drug Eruptions
with etanercept de elop new antinuclear antibodies (A As)
and anti double stranded D A (dsD A) antibodies.
Anti Sm antibodies can also occur. Similarly patients treated
with in i imab may de elop new A As anti dsD A ( ) considerable itching o these parts. The hands and eet are also
and anticardiolipin antibodies. All three common T inhib
itors ha e caused drug induced lupus (D L) with eatures o
SL . t begins on a erage a ter wee s o treatment. Com
pared with D L rom other medications the T inhibitors
cause more s in disease with malar rash discoid lesions and
photosensiti ity. any o the patients ul ll the American
Rheumatology Association (ARA) criteria or SL and sig
ni cant internal organ in ol ement can occur including
renal and central ner ous system (C S) in ol ement. taner
cept speci cally seems to cause s in lesions more re uently.
tanercept patients also de eloped asculitis more o ten.
The ast ma ority o patients impro e about months a ter
therapy has been discontinued. Switching rom one T
inhibitor to another has been reported to be success ul.
Dermatomyositis has also been caused by T inhibitor
treatment.
Vasculitis is also a well recogni ed complication o treat
ment with T inhibitors. tanercept is the most common
agent to induce asculitis. The lesions o asculitis may begin
around the in ection sites in some etanercept induced asculi
tis cases. ore than o patients present with s in lesions
usually a leu ocytoclastic asculitis. lcerations nodules
digital lesions chilblains li edo and other morphologies ha e
also been described. Visceral asculitis occurs in about one
uarter o patients. They may be A A positi e or antineutro
phil cytoplasmic antibody (A CA) positi e (usually p A CA)
or may ha e cryoglobulins. Drug induced antiphospholipid
syndrome with T inhibitors can be associated with D L or
asculitis and presents with thrombosis as well as cutaneous
lesions. Some patients with T inhibitor induced asculitis
ha e died. Stopping the T inhibitor leads to resolution o
the asculitis in more than o cases. Rechallenge leads to
new asculitic lesions in o cases. ther neutrophilic dis
orders induced by T inhibitors include Sweet syndrome
li e reactions and neutrophilic eccrine hidradenitis.
Lichenoid drug eruptions ha e been reported rom all three
commonly used anti T agents. They are typically pruritic
and a ect areas typically in ol ed by lichen planus the e or
wrists. owe er gluteal cle t lesions are also common. n
some cases the lichenoid eruption superimposes itsel on pso
riatic lesions presenting as an e acerbation o the psoriasis.
Biopsies show eatures o both lichen planus and psoriasis
and stopping the anti T therapy leads to impro ement
o the psoriasis. Despite these agents immunosuppressi e
properties patients can still de elop allergic contact dermatitis
while ta ing them and patch testing during anti T treat
ment may identi y rele ant allergens. t appears that patients
recei ing anti T agents are at slightly increased ris or
de elopment o nonmelanoma s in cancers especially i they
also ha e used methotre ate.
Hawryluk EB, et al: Broad range of adverse cutaneous eruptions
in patients on TNF-α antagonists. J Cutan Pathol 2012;
39:481–492.
Peluso R, et al: Side effects of TNF-α blockers in patients with psoriatic
arthritis: evidences from literature studies. Clin Rheumatol 2013;
32:743–753.
Wright LN, et al: Modeling the transcriptional consequences of
epidermal growth factor receptor ablation in Ras-initiated squamous
cancer. Clin Cancer Res 2012; 18:170–183.
132
Mercury
ercury may induce multiple cutaneous syndromes. The
classic syndrome is acrodynia also nown as calomel disease
pin disease and erythrodermic polyneuropathy. Acrodynia
is caused by mercury poisoning usually in in ancy. The s in
changes are characteristic and almost pathognomonic pain ul
swelling o the hands and eet sometimes associated with
cold clammy and pin or dus y red. The erythema is usually
blotchy but may be di use. emorrhagic puncta are re
uently e ident. er the trun a blotchy macular or papular
erythema is usually present. Stomatitis and loss o teeth may
occur. Constitutional symptoms consist o moderate e er irri
tability mar ed photophobia increased perspiration and a
tendency to cry most o the time. There is always moderate
upper respiratory in ammation with throat soreness. The
in ant may ha e hypertension hypotonia muscle wea ness
anore ia and insomnia. Albuminuria and hematuria are
usually present. The diagnosis is made by nding mercury in
the urine.
An e anthem may occur rom inhalation o mercury apors
or absorption by direct contact. A di use symmetric ery
thematous morbilli orm eruption in the e ors and pro imal
e tremities begins within a ew days o e posure. Accentua
tion in the groin and medial thighs produces a baboon syn
drome appearance. The eruption burns or itches and small
ollicular pustules appear. tensi e des uamation occurs
with resolution. ld bro en thermometers or the application
o mercury containing s in lightening creams and herbal
medications are potential sources. n aiti elemental mercury
is applied to sur aces or religious purposes and may result in
contamination o those coming in contact.
ercury is also a possible cause o oreign body granulomas
and hyperpigmentation at sites o application. An eruption o
mm minimally pruritic papules and papulo esicles on the
palms (all patients) and soles arms and trun has also been
ascribed to le els o mercury in the blood at near the upper
limits considered to be sa e. Treatment with a sea ood ree diet
and chelation with succimer led to resolution o the eruption
in some patients. ummular dermatitis impro ed in
two mercury patch test positi e patients when their dental
amalgam was remo ed.
Adawe A, et al: Skin-lightening practices and mercury exposure in the
Somali community. Minn Med 2013; 96:48–49.
Centers for Disease Control and Prevention: Mercury exposure among
household users and nonusers of skin-lightening creams produced in
Mexico, California and Virginia, 2010. MMWR 2012; 61:33–36.
Cristaudo A, et al: Use of potentially harmful skin-lightening products
among immigrant women in Rome, Italy: a pilot study. Dermatology
2013; 226:200–206.
Park JD, et al: Human exposure and health effects of inorganic and
elemental mercury. J Prev Med Public Health 2012; 45:344–352.
Halogenoderma
Bromoderma and fluoroderma
Bromides and uorides produce distincti e ollicular erup
tions acnei orm papular or pustular. Vegetati e e udati e
pla ues studded with pustules may de elop resembling
Sweet syndrome pyoderma gangrenosum or an orthopo i
rus in ection. Any area o s in may be a ected but bromo
derma and especially uoroderma tend to a ect the lower
e tremities more than iododerma. istologically the lesions
show epidermal hyperplasia with intraepidermal and dermal
neutrophilic abscesses. There is rapid in olution o the lesions
on cessation o bromide ingestion. cessi e cola or so t drin
 Fig. 6-43 Iododerma.
consumption or ingestion o bromine containing medications
(ipratropium bromide de tromethorphan hydrobromide
potassium bromide pipobroman edecitral) may be the
cause o a bromoderma. Serum bromide le el is ele ated and
con rms the diagnosis. luoroderma has been associated with
intensi e use o dental uoride treatments.
Iododerma
odides may cause a wide ariety o s in eruptions. The most
common sources o e posure are oral and V contrast materials
and when iodides are used to treat thyroid disease. Application
o po idone iodine to the s in mucosa or as a tub soa has
produced iododerma. The most common type is the acnei orm
eruption with numerous acutely in amed ollicular pustules
each surrounded by a ring o hyperemia ( ig. ). Dermal
bullous lesions are also common and may become ulcerated
and crusted resembling pyoderma gangrenosum or Sweet
syndrome. The eruption may in ol e the ace upper e tremi
ties trun and e en the buccal mucosa. Acne ulgaris and
rosacea are un a orably a ected by iodides. Acute iododerma
may ollow V radiocontrast studies in patients with renal
ailure. The lesions may be associated with se ere leu ocyto
clastic asculitis intraepidermal spongi orm pustules and
suppurati e olliculitis. The lesions respond to prednisone.
Aliagaoglu C, et al: Iododerma following topical povidone-iodine
application. Cutan Ocul Toxicol 2013; 32:339–4340.
Guerrero AF, et al: Thyroid protection gone awry: iododerma following
potassium iodide administration prior to metaiodobenzylguanidine
scintigraphy. Thyroid 2011; 21:93–94.
Ogretmen Z, et al: Use of topical povidone-iodine resulting in
iododerma. Indian J Dermatol 2011; 56:346–347.
Rothman LR, et al: Iododerma following serial computed tomography
scans in a lung cancer patient. J Drugs Dermatol 2013; 12:574–576.
Saurat JH, et al: The cutaneous lesions of dioxin exposure: lessons
from the poisoning of Victor Yushchenko. Toxicol Sci 2012;
125:310–317.
Vandergriff TW, et al: Iododerma following radioactive iodine ablation of
the thyroid for Graves disease. J Drugs Dermatol 2011; 10:1070–1071.
Drug-induced autoimmune diseases
Lupus erythematosus
Drug induced SL is rarely associated with s in lesions. t
occurs in older patients and a ects men as re uently as
tahir99 - UnitedVRG
women. The symptoms are generally mild and include e er
myalgias arthralgias and serositis. This orm o D L is associ
ated with a positi e A A homogeneous pattern and antihis
tone antibodies but a negati e anti dsD A antibody and
normal complement le els. Procainamide hydrala ine uini
Drug reactions
dine captopril isonia id minocycline carbama epine pro
pylthiouracil sul asala ine and the statins are among the
reported agents triggering this orm o D L. The T inhibi
tors especially etanercept may also cause an SL li e syn
drome but with prominent s in lesions. Women are a ored
and nephropathy and C S in ol ement can occur. Again the
a ected patients are A A positi e but also anti dsD A anti
body positi e and more than hal are hypocomplementemic.
ethima ole has been implicated in bullous SL .
umerous medications ha e been reported to produce cuta
neous lesions characteristic o subacute cutaneous lupus ery
thematosus (SCL ). The eruption begins days to years a ter
starting the medications. ydrochlorothia ide diltia em (and
other calcium channel bloc ers) and terbina ne are the most
common causati e agents but AC inhibitors proton pump
inhibitors statins T inhibitors anticon ulsants SA Ds
paclita el do ycycline and e en agents used to treat lupus
(e.g. hydro ychloro uine le unomide) can induce SCL .
These patients may also be A A positi e and may ha e
antihistone antibodies but in addition ha e positi e anti SSA
antibodies. Cutaneous lesions are photosensiti e but not pho
todistributed annular or papulos uamous pla ues. Chilblain
li e lesions are rarely seen. Treatment is as or SCL with
sun a oidance and topical and systemic corticosteroids as
re uired. Drug withdrawal results in resolution o er wee s to
months. The positi e serologies may decrease as the eruption
impro es. The pathogenesis o drug induced SCL is
un nown but most causati e agents also cause both photo
sensiti e and lichenoid drug eruptions. tanercept can produce
both classic drug induced SL and drug induced SCL .
Hydroxyurea dermopathy
Chronic use o hydro yurea or chronic myelogenous leu e
mia thrombocythemia or psoriasis may be associated with
the de elopment o cutaneous lesions characteristic o derma
tomyositis. Scaly linear erythema o the dorsal hands accen
tuated o er the nuc les is noted. There may be mar ed acral
atrophy and telangiectasia. lbow and eyelid in ol ement
characteristic o dermatomyositis may also be seen. Biopsy
shows acuolar degeneration o the basal cells and an inter ace
lymphocytic in ltrate. The s in lesions tend to impro e o er
months although the atrophy may not impro e.
Grönhagen CM, et al: Subacute cutaneous lupus erythematosus and its
association with drugs: a population-based matched case-control
study of 234 patients in Sweden. Br J Dermatol 2012; 167:296–305.
Lamond NW, et al: Drug-induced subacute cutaneous lupus
erythematosus associated with nab-paclitaxel therapy. Curr Oncol
2013; 20:e484–e487.
Miller KK, et al: Drug-induced subacute cutaneous lupus
erythematosus related to doxycycline. Dermatol Online J 2011;
17(10):3.
Seo JY, et al: Methimazole-induced bullous systemic lupus
erythematosus: a case report. J Korean Med Sci 2012; 27:818–821.
Linear IgA bullous dermatosis
Linear gA disease is re uently associated with medication
e posure especially ancomycin. en and women are e ually
a ected and the eruption usually begins within wee s o
ancomycin therapy. Clinical morphology is ariable and can
include accid or tense bullae esicles erythematous papules
or pla ues e anthematous morbilli orm eruptions typical o
133
 a drug e anthem and targetoid papules. T or se ere SJS
6 may be simulated but mucosal in ol ement is only
and con uncti al in ol ement . istology will show sub
epidermal blistering with neutrophils and eosinophils in biop
sies ta en rom bullous lesions. n nonbullous and T SJS
Contact Dermatitis and Drug Eruptions
li e lesions there is a acuolar lichenoid dermatitis with
eosinophils. nless D is per ormed this would be inter
preted as erythema multi orme or a drug eruption and the
diagnosis o linear gA disease would be missed. Treatment is
to stop the o ending drug and to gi e dapsone at mg
daily i needed.
Leukotriene receptor antagonist–associated Churg-
Strauss syndrome
Asthma patients being treated with leu otriene receptor
antagonists may de elop a syndrome resembling Churg
Strauss asculitis. t occurs days to months a ter the
leu otriene receptor antagonist has been started. nhaled uti
casone has also been reported to produce this syndrome.
n ol ement may be limited to the s in. eatures o the syn
drome include peripheral eosinophilia pulmonary in ltrates
and less o ten neuropathy sinusitis pericardial e usion and
cardiomyopathy. S in lesions occur in about hal the patients
and are usually purpuric and a or the lower legs. istologi
cally the s in lesions show leu ocytoclastic asculitis with
signi cant tissue eosinophilia. n one patient cutaneous peri
ascular granulomas with eosinophils were ound in the s in
with surrounding necrobiotic collagen. Perinuclear A CA
(p A CA) may be positi e. Withdrawal o leu otriene recep
tor antagonist therapy may lead to impro ement but systemic
therapy with prednisone and cyclophosphamide may be
re uired. The neuropathy may be permanent. The pathogen
esis o this drug induced syndrome is un nown. Some cases
occur as corticosteroids are tapered but others ha e occurred
in steroid na e asthmatic patients. nopposed leu otriene B
acti ity a potent chemoattractant or eosinophils and neutro
phils may e plain the clinical ndings.
Carlesimo M, et al: Churg-Strauss and montelukast. Int J Immunopathol
Pharmacol 2011; 24:1079–1082.
Man MA, et al: Churg-Strauss syndrome associated with montelukast:
case report. Pneumologia 2012; 61:113–116.
Adverse reactions to corticosteroids
Cutaneous reactions may result rom topical intralesional
subcutaneous or systemic deli ery o corticosteroids.
Topical application
The prolonged topical use o corticosteroid preparations may
produce distincti e changes in the s in. The appearance o
these side e ects depends on our actors strength o the
steroid area to which it is applied amount o coe istent sun
damage at the site o application and patient s predisposition
to certain side e ects. Atrophy striae telangiectasia s in ra
gility and purpura are the changes most re uently seen
( ig. ). The most stri ing changes o telangiectasia are seen
in air s inned indi iduals who use uorinated corticosteroids
on the ace. The changes in the s in are enhanced by occlusion.
When these side e ects occur the strength o the steroid
should be reduced or substituted with pimecrolimus or tacro
limus. Wee ly pulse dosing o a potent topical corticosteroid
can also reduce the incidence o side e ects. Ad uncti e mea
sures to reduce steroid re uirement could include addition o
topical do epin pramo ine or menthol and camphor to the
134
Fig. 6-44 Steroid-induced
striae.
B
regimen. sually the telangiectases disappear a ew months
a ter corticosteroid applications are stopped.
When corticosteroid preparations are applied to the ace
o er wee s or months persistent erythema with telangiecta
ses and o ten small pustules may occur. Perioral dermatitis
and rosacea may be caused by topical corticosteroids. Steroid
rosacea has been reported rom long term use o hydrocor
tisone cream. or this reason the authors do not recommend
chronic topical corticosteroid preparations o any strength
in the ad uncti e treatment o rosacea. A topical calcineurin
inhibitor may be used instead as an anti in ammatory
although it can also induce a rosacea li e eruption. When a
rosacea li e eruption appears in the setting o a topical anti
in ammatory a pustule should be opened and the contents
e amined or o ergrowth o Demo ex mites.
Repeated application o corticosteroids to the ace scrotum
or ul a may lead to mar ed atrophy o these tissues includ
ing the red scrotum syndrome. The tissues become addicted
to the topical steroid so that withdrawing treatment results in
se ere itching or burning and intense erythema. Topical appli
cation o corticosteroids can produce epidermal atrophy
with hypopigmentation. used o er large areas su cient
topical steroids may be absorbed to suppress the hypothalamic
pituitary a is. This may a ect the growth o children with
atopic dermatitis and has led to addisonian steroid depen
dency and also Cushing syndrome. Atopic children with more
than BSA in ol ement ha e short stature. This may be
related to their increased use o potent topical corticosteroids.
n addition bone mineral density is reduced in adults with
chronic atopic dermatitis se ere enough to re uire corticoste
roid preparations stronger than hydrocortisone.
Injected corticosteroids
ntralesional in ection o corticosteroids is aluable in the man
agement o many dermatoses. The in ection o corticosteroids
may produce subcutaneous atrophy at the site o in ection. The
in ected corticosteroid may also migrate along lymphatic
channels causing not only local side e ects but also linear
atrophic hypopigmented hairless strea s. These may ta e
years to resol e. These complications are best a oided by
in ecting directly into the lesion not into the at and using
only the minimal concentration and olume re uired. Triam
cinolone acetonide not he acetonide should be used or
in ecting cutaneous lesions.
ntramuscular steroid in ections should always be gi en into
the buttoc s with a long needle (at least 1 1 2 inches in adults).
n ection o corticosteroids into the deltoid muscle sometimes
causes subcutaneous atrophy. The patient becomes aware o
the reaction by noticing depression and depigmentation at the
site o in ection. There is no pain but it is bothersome cosmeti
cally. The patient may be assured that this will ll in e entu
ally but may ta e se eral years.
Systemic corticosteroids
Prolonged use o corticosteroids may produce numerous
changes o the s in. n addition steroids ha e a pro ound
e ect on the metabolism o many tissues leading to predict
able and sometimes pre entable complications. in ections
are not a sa er deli ery method than oral administration.
Purpura and ecchymosis
The s in may become thin and ragile. Spontaneous tearing
may occur rom tri ial trauma. Purpura and ecchymoses are
especially seen o er the dorsal orearms in many patients o er
age caused by aggra ation o actinic purpura.
Cushingoid changes
The most common change is probably the alteration in at
distribution. Bu alo hump acial and nec ullness increased
supracla icular and suprasternal at gynecomastia protuber
ant or pendulous abdomen and attening o the buttoc s may
occur. Aggressi e dietary management with reduction in car
bohydrate and caloric inta e may ameliorate these changes.
Steroid acne
Small rm ollicular papules on the orehead chee s and
chest may occur. en inhaled corticosteroids or pulmonary
disease can cause acne. Steroid acne can persist as long as the
corticosteroids are continued. The management is similar to
acne ulgaris with topical preparations and oral antibiotics.
Acne rom androgen use closely resembles steroid acne.
Striae
Striae may be widely distributed especially o er the abdomen
buttoc s and thighs.
Other skin changes
There may be generali ed s in dryness ( erosis). The s in may
become thin and ragile; eratosis pilaris may de elop; persis
tent erythema o the s in in sun e posed areas may occur and
erythromelanosis may rarely occur.
tahir99 - UnitedVRG
Hair changes
air loss occurs in about hal o patients recei ing long term
corticosteroids in large doses. There may be thinning and
brittle racturing along the hair sha t. air growth may be
Drug reactions
increased on the bearded area and on the arms and bac with
ne ellus hairs.
Systemic complications
ypertension cataracts aseptic necrosis o the hip and osteo
porosis are potential conse uences o prolonged therapy with
systemic steroids. Bone loss can occur early in the course o
corticosteroid therapy so it should be managed preempti ely.
ecti e management can reduce steroid induced osteoporo
sis. All patients with anticipated treatment courses longer than
month should be supplemented with calcium and itamin D
( . . g calcium and cholecalci erol daily) and a
bisphosphonate such as alendronate or risedronate. Smo ing
should be stopped and alcohol consumption minimi ed. Bone
mineral density can be accurately measured at baseline with
dual energy ray absorptiometry (D A) scan and ollowed
during corticosteroid therapy. ypogonadism which contrib
utes to osteoporosis can be treated in men and women with
testosterone or estrogen respecti ely. mplementation o bone
loss pre ention strategies by dermatologists is unacceptably
low.
Torres MJ, et al: Hypersensitivity reactions to corticosteroids. Curr Opin
Allergy Clin Immunol 2010; 10:273–279.
Bonus images for this chapter can be found online at
expertconsult.inkling.com
eFig. 6-1 Toxicodendron radicans subspecies radicans, a common
poison ivy species found in the eastern United States. (Courtesy of
James WD [ed]: Textbook of Military Medicine. Office of the
Surgeon General, United States Army, 1994.)
eFig. 6-2 Acute poison ivy reaction.
eFig. 6-3 Shoe dermatitis.
eFig. 6-4 Fixed drug reactions. (Courtesy of Dr. L. Lieblich.)
eFig. 6-5 Nonpigmenting fixed dry eruption caused by
pseudoephedrine.
eFig. 6-6 Argyria.
eFig. 6-7 Lichenoid drug eruption caused by gold.
eFig. 6-8 Acneiform eruption caused by epidermal growth factor
receptor (EGFR) inhibitor therapy.
eFig. 6-9 Topical steroid atrophy.
eFig. 6-10 Fat atrophy caused by superficial steroid injection.
135
 eFig. 6-4 Fixed drug
reactions. (Courtesy
of Dr. L. Lieblich.)

Drug reactions
eFig. 6-1 Toxicodendron radicans subspecies radicans, a common
poison ivy species found in the eastern United States. (Courtesy of
James WD [ed]: Textbook of Military Medicine. Office of the
Surgeon General, United States Army, 1994.)

eFig. 6-2 Acute poison

ivy reaction.

eFig. 6-5 Nonpigmenting fixed dry eruption caused by

pseudoephedrine.

eFig. 6-3 Shoe dermatitis. eFig. 6-6 Argyria.

135.e1
 eFig. 6-9 Topical
6 steroid atrophy.
Contact Dermatitis and Drug Eruptions

eFig. 6-7 Lichenoid drug eruption caused by gold.

eFig. 6-8 Acneiform eruption caused by epidermal growth factor eFig. 6-10 Fat atrophy caused by superficial steroid injection.
receptor (EGFR) inhibitor therapy.

135.e2

tahir99 - UnitedVRG
 Bonus images for this chapter can be found online at
expertconsult.inkling.com
7 Erythema and Urticaria
FLUSHING
lushing presents with transient erythema usually locali ed
to the ace nec and upper trun . enopausal ushing may
be associated with perspiration as is ushing induced by high
ambient temperature e er or consumption o hot or spicy
oods and be erages. lushing associated with medications
histamine or serotonin is generally dry.
enopausal ushing may be age related may be induced
by oophorectomy or medication (tamo i en leuprolide
acetate) and may begin long be ore menses cease. en may
also e perience climacteric ushing a ter surgery or antiandro
gen therapy ( utamide).
Blushing or emotional ushing may be either emotionally
or physiologically induced. Simple acial redness may occur
in indi iduals with translucent s in and is called anatomically
predisposed blushing. ntense ushing may be associated with
rosacea. n patients with rosacea e ercise ambient heat or
cold spicy oods alcohol and hot be erages are common
triggers or ushing. Drugs associated with ushing include
niacin calcium channel bloc ers cyclosporine chemothera
peutic agents ancomycin bromocriptine intra enous con
trast material sildena l and related drugs or erectile
dys unction and high dose methylprednisolone. Se ere sero
tonin to icity with ushing can be precipitated by the combi
nation o a monoamine o idase inhibitor and a selecti e
serotonin reupta e inhibitor (SSR ). Reduced or absent
methylnicotinate induced ushing has been noted in patients
with schi ophrenia. This lac o ushing in response to meth
ylnicotinate has been used or diagnostic psychiatric testing.
lushing a ter induction o general anesthesia with agents
such as thiopental and muscle rela ants is more common in
patients prone to blushing. t appears to be neuronally medi
ated rather than related to histamine release. ndogenous
asoacti e substances are associated with ushing in carcinoid
syndrome mastocytosis medullary thyroid carcinoma and
pheochromocytoma.
ood associated ushing may be caused by capsaicin (red
pepper) sodium nitrate or alcohol. Alcohol may produce
ushing in patients using topical calcineurin inhibitors. Sul
tes are ound in wine dried ruit prepared oods and resh
grapes and potatoes. Ciguatera or scombroid sh poisoning is
a orm o histamine related ood poisoning caused by hista
mine within the esh o the sh. Dietary histamine is normally
deto i ed by amine o idases and those with low amine
o idase acti ity are at greater ris or histamine to icity. ndi
iduals who ush without an identi able cause should be
in estigated or dietary triggers and subtle mani estations o
rosacea. rinary catecholamines and serotonin and histamine
metabolites should be measured i an endogenous cause is
suspected. any cases o ushing remain idiopathic. These
patients may be managed with a oidance o dietary triggers
and by sipping iced water to brea the ush. enopausal
ushing responds to low dose oral or transdermal estrogen.
136
The Women s ealth nitiati e studies concerning hormone
replacement therapy ( RT) suggested that breast cancer ris
is increased by combinations o estrogen and progestogen
ta en or longer than years. nopposed estrogen can increase
the ris o endometrial carcinoma in premenopausal women.
RT does not appear to lower the ris o cardiac e ents and
the ris s o long term therapy o ten outweigh the bene ts.
Short term RT may still be ery help ul in the management
o perimenopausal ushing because alternati es including
SSR s adrenergic agents gabapentin and phytoestrogens
ha e generally been disappointing. lushing can be reduced
by a oidance o alcohol ca eine and spicy oods. iacin
induced ushing is mediated by prostaglandin D . PGD
shows some response to aspirin as well as the PGD( )
receptor antagonist laropiprant.
Demoncheaux JP, et al: A large outbreak of scombroid fish poisoning
associated with eating yellowfin tuna (Thunnus albacares) at a military
mass catering in Dakar, Senegal. Epidemiol Infect 2012;
140:1008–1012.
Hsu CC, et al: Pronounced facial flushing and persistent erythema of
rosacea effectively treated by carvedilol, a nonselective β-adrenergic
blocker. J Am Acad Dermatol 2012; 67:491–493.
Maintz L, et al: Histamine and histamine intolerance. Am J Clin Nutr
2007; 85:1185–1196.
Ogunleye T, et al: Ethanol-induced flushing with topical pimecrolimus
use. Dermatitis 2008; 19:E1–E2.
Paolini JF, et al: Effects of laropiprant on nicotinic acid–induced flushing
in patients with dyslipidemia. Am J Cardiol 2008; 101:625–630.
Sassarini J, et al: Hot flushes: are there effective alternatives to
estrogen? Menopause Int 2010; 16:81–88.
ERYTHEMAS
The term erythema means blanchable redness (hyperemia) o
the s in. A number o reacti e s in conditions are re erred
to as erythema. These include to ic erythemas related to
iral and bacterial in ections erythema multi orme erythema
nodosum and the gyrate ( gurate) erythemas.
Erythema palmare
rythema palmare or persistent palmar erythema is usually
most mar ed on the hypothenar areas and is associated with
an ele ated le el o circulating estrogen. Cirrhosis hepatic
metastases and pregnancy are common causes.
Serrao R, et al: Palmar erythema. Am J Clin Dermatol 2007; 8:347–356.
Generalized erythema
Generali ed erythema may be caused by medications bacte
rial to ins or iral in ection. t is o ten une en in distribution
being most noticeable on the chest pro imal e tremities and
ace. n general these reactions are sel limited and resol e
 Fig. 7-1 Erythema
toxicum neonatorum.

Erythemas
when the o ending medication is stopped or the associated Fig. 7-2 Erythema multiforme, target lesions.
in ection is treated or resol es. Speci c e anthems associated
with bacterial or iral in ections are discussed in Chapters
and .

Erythema toxicum neonatorum

rythema to icum neonatorum occurs in ust under hal o
healthy ull term newborns usually on the second or third day
o li e ( ig. ). Because it is so common dermatologists are
usually consulted only or the most orid or atypical cases.
Characteristically the broad erythematous are is much more
prominent than the small ollicular papule or pustule it sur
rounds. Lesions in ol e the ace trun and pro imal e tremi
ties and appear rarely on the soles or palms. There may be
con uent erythema on the ace. e er is absent and the erup
tion generally disappears by the th day. rythema to icum
must be distinguished rom miliaria bacterial olliculitis neo
natal herpes and scabies. When the rash is atypical smears
o the pustules demonstrating eosinophils are ade uate to
con rm the diagnosis. Rarely a biopsy is re uired and dem
onstrates olliculitis containing eosinophils and neutrophils.
Monteagudo B, et al: Prospective study of erythema toxicum
neonatorum. Pediatr Dermatol 2012; 29:166–168.
Morgan AJ, et al: Erythema toxicum neonatorum revisited. Cutis 2009;
83:13–16.
Erythema multiforme
n on ebra rst described erythema e udati um mul
ti orme. The original disease described by on ebra is now
called erythema multi orme minor (minus) or herpes simple
associated erythema multi orme. t is strongly associated with
a preceding herpetic in ection. When multiple mucous mem
branes are in ol ed the lesions are more intense and e er or
arthralgias accompany the eruption erythema multi orme
ma or (ma us) is diagnosed. This is most o ten caused by
M coplasma in ection. n contrast Ste ens Johnson syndrome
(SJS) and to ic epidermal necrolysis (T ) usually represent
ad erse reactions to medications (see Chapter ). As treatment
and prognosis are related in part to the inciting agent it is
use ul to classi y erythema multi orme ( ) as ollows
erpes simple associated ( A ) lesions may appear as indurated pla ues target lesions or
rythema multi orme ma or (most o ten caused by
M coplasma)
Chronic oral
Contact dermatitis induced (see Chapter )
Radiation induced (see Chapter )
diopathic
Fig. 7-3 Erythema multiforme involving dorsal hands and penis.
Clinical features
rythema multi orme minor ( A ) is a recurrent sel
limited disease usually o young adults occurring seasonally
in the spring and all with each episode lasting wee s. The
indi idual clinical lesions begin as sharply marginated ery
thematous macules which become raised edematous papules
o er h. The lesions may reach se eral centimeters in
diameter. Typically a ring o erythema orms around the
periphery and centrally the lesions become atter more pur
puric and dus y. This lesion is the classic target or iris
lesion with three ones central dus y purpura; an ele ated
edematous pale ring; and surrounding macular erythema
( igs. and ). The central area may be bullous. Typical
targets are best obser ed on the palms and soles. Lesions gen
erally appear symmetrically and acrally with initial in ol e
ment most re uently on the dorsal hands. The dorsal eet
e tensor limbs elbows nees palms and soles typically
become in ol ed. n about o patients more widespread
lesions occur on the trun . The oebner phenomenon or pho
toaccentuation may be obser ed. ucosal in ol ement occurs
in o cases and is usually limited to the oral mucosa. ral
erosions ( ig. ).
An atypical ariant o A has been described in women.
t consists o outbrea s o unilateral or segmental papules
and pla ues that may be ew in number or solitary. Lesions
may be up to cm in diameter. The pla ues are erythematous
and e ol e to ha e a dus y center which des uamates.
Subcutaneous nodules resembling erythema nodosum may be
137

tahir99 - UnitedVRG
7
Erythema and Urticaria
Fig. 7-4 Mucosal lesions of erythema multiforme.
Fig. 7-5 Ocular erythema multiforme.
simultaneously present. istologic e amination shows ea
tures o and herpes simple irus ( SV) D A is
identi ed in the lesions by polymerase chain reaction (PCR).
Acyclo ir suppression pre ents the lesions and prednisone
therapy seems to increase the re uency o attac s.
rythema multi orme ma or is re uently accompanied by a
ebrile prodrome and sometimes arthralgias. t occurs in all
ages is centered on the e tremities and ace but more o ten
than minor may include truncal lesions which are papular
and erythematous to dus y in color. ucous membrane
disease is prominent and o ten in ol es not only the oral
mucosa and lips but the genital and ocular mucosa as well
( ig. ). SJS is distinguished morphologically by the presence
o purpura or bullae in macular lesions o the trun ( ig. ).
n children polycyclic urticarial lesions o ten become dus y
centrally and are re uently misdiagnosed as . This presen
tation o urticaria has been dubbed urticaria multi orme. t
represents urticaria and histologic changes o are ne er
present.
Etiologic factors
Typical minor is usually associated with a preceding oro
labial SV in ection. A lesions appear wee s (a erage
days) a ter the herpes outbrea . pisodes o minor may
not ollow e ery episode o herpes and some outbrea s
will not be preceded by a clinically recogni able herpetic
lesion. sing PCR and in situ hybridi ation techni ues SV
D A and antigens ha e been ound in the lesions o
minor. The ma ority o idiopathic cases o minor are
138
Fig. 7-6 Atypical target lesion in Stevens-Johnson syndrome.
associated with recurrent SV in ection and patients may be
success ully treated with suppressi e anti iral regimens.
ma or is associated with M coplasma in ections although a
minority may result rom herpes simple and a reaction to
medications.
Histopathology
The histologic eatures are similar in A and ma or
and are not predicti e o etiology. The e tent o epidermal
in ol ement depends on the duration o the lesion and where
in the lesion the biopsy is ta en. All lesions are characteri ed
by cellular necrosis. Biopsies o demonstrate a normal
bas et wea e stratum corneum and a acuolar inter ace reac
tion. Vacuoles and oci o indi idual cell necrosis are present
and out o proportion to the number o lymphocytes. The
dermal in ltrate is largely mononuclear and tends to be pri
marily around the upper dermal essels and along the dermo
epidermal unction. Acti ated T lymphocytes are present in
lesions o with cytoto ic or suppressor cells more promi
nent in the epidermis and helper T cells in the dermis. Leu o
cytoclastic asculitis is not obser ed. osinophils may be
present but are rarely prominent. The presence o eosinophils
is not predicti e o the etiology. istologically must be
distinguished rom the ollowing
i ed drug eruption which o ten has a deeper in ltrate
eosinophils and neutrophils papillary dermal brosis
and melanophages around postcapillary enules
Gra t ersus host disease (GV D) which typically has a
more compact stratum corneum and epithelial disorder
resembling Bowen s disease
Pityriasis lichenoides which characteristically has a
lymphocyte in e ery acuole erythrocyte e tra asation
and neutrophil margination within dermal essels
Lupus erythematosus which has compact hyper eratosis
a deeper periadne al in ltrate dermal mucin and
basement membrane one thic ening
Differential diagnosis
When characteristic target lesions are present the diagnosis
o is established clinically. When bullae are present
ma or must be distinguished rom bullous arthropod reac
tions and autoimmune bullous diseases pemphigus i mucous
membrane in ol ement is prominent and bullous pemphi
goid i lesions are small and erythema is prominent at the
periphery o the bulla. Paraneoplastic pemphigus may produce
atypical target lesions mucosal in ol ement and a acuolar
inter ace dermatitis and may appear similar to M coplasma
induced ma or. se o direct immuno uorescence may be
necessary to e clude this possibility.
Treatment
Treatment o is determined by its cause and e tent.
minor is generally related to SV and pre ention o herpetic
outbrea s is central to control o the subse uent episodes o
. A sunscreen lotion and sunscreen containing lip balm
should be used daily on the ace and lips to pre ent ultra iolet
B ( VB) induced outbrea s o SV. this does not pre ent
recurrence or i genital SV is the cause chronic suppressi e
doses o an oral anti iral drug ( alacyclo ir g day or am
ciclo ir mg day) may be used. this dose is ine ecti e
it may be doubled. This will pre ent recurrences in up to
o SV related cases. ntermittent treatment with systemic
anti irals or the use o topical anti irals is o minimal bene t
in pre enting A . n patients whose condition ails to
respond ade uately to anti iral suppression dapsone cyclo
sporine or thalidomide may occasionally be help ul. t should
be noted that most cases o minor ( A ) are sel limited
and symptomatic treatment may be all that is re uired. Symp
toms related to oral lesions o ten respond to topical swish and
spit mi tures containing lidocaine diphenhydramine (Bena
dryl) and aolin. n e tensi e cases o minor systemic
corticosteroids ha e been used but because these theoretically
may reacti ate SV steroids are best gi en concurrently with
an anti iral drug. or patients with widespread unrespon
si e to the pre ious therapies management is as or se ere
drug induced SJS (see Chapter ).
Bakis S, et al: Intermittent oral cyclosporin for recurrent herpes
simplex–associated erythema multiforme. Australas J Dermatol 2005;
14:18.
Chen CW, et al: Persistent erythema multiforme treated with thalidomide.
Am J Clin Dermatol 2008; 9:123–127.
Emer JJ, et al: Urticaria multiforme. J Clin Aesth Dermatol 2013;
6:34-39.
Majorana A, et al: Oral mucosal lesions in children from 0 to 12 years
old: ten years’ experience. Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 2010; 110:e13–e18.
Samim F, et al: Erythema multiforme. Dent Clin North Am 2013;
57:583–596.
Sokumbi O, et al: Clinical features, diagnosis, and treatment of erythema
multiforme. Int J Dermatol 2012; 51:889–902.
Wetler DA, et al: Recurrent erythema multiforme. J Am Acad Dermatol
2010; 62:45.
Oral erythema multiforme
A uni ue subset o is limited to or most prominent in the
oral ca ity. Clinically patients are otherwise well; are
emale with a mean age o years. The minority about
ha e recurrent sel limited cyclic disease. The oral ca ity is
the only site o in ol ement in in there is oral and
lip in ol ement and in the s in is also in ol ed. All
portions o the oral ca ity may be in ol ed but the tongue
gingi a and buccal mucosa are usually most se erely a ected.
Lesions are almost uni ersally eroded with or without a pseu
domembrane. There are no well designed trials o treatment
or oral but the treatments pre iously listed or minor
are typically used. Swish and spit mi tures containing lido
caine diphenhydramine and aolin are help ul or symptom
atic relie . Patients should be warned to chew care ully because
the anesthetic e ect may dampen their gag re e .
Joseph TI, et al: Drug-induced oral erythema multiforme. J Oral
Maxillofac Pathol 2012; 16:145–148.
Scully C, Bagan J: Oral mucosal diseases: erythema multiforme. Br J
Oral Maxillofac Surg 2008; 46:90–95.
tahir99 - UnitedVRG
Erythemas
Fig. 7-7 Erythema annulare centrifugum.
Gyrate erythemas (figurate erythemas)
The gyrate erythemas are characteri ed by clinical lesions that
are round (circinate) ringli e (annular) polycyclic ( gurate)
or arcuate. The primary lesions are erythematous and slightly
ele ated. There may be a trailing scale as in erythema annu
lare centri ugum. n some o these diseases the lesions are
transient and migratory and in some they are ed. Gyrate
erythemas o ten represent the cutaneous mani estations o
an in ection malignancy or drug reaction. Certain diseases
in this group ha e speci c causes (erythema marginatum o
rheumatic e er carrier state o chronic granulomatous
disease erythema migrans o Lyme borreliosis) and are dis
cussed in the rele ant chapters.
Erythema annulare centrifugum
rythema annulare centri ugum ( AC) is the most common
gyrate erythema. t is characteri ed by asymptomatic annular
or polycyclic lesions that grow slowly ( mm day) rarely
reaching more than cm in diameter. Characteristically
there is a trailing scale at the inner border o the annular
erythema ( ig. ). The sur ace is typically de oid o crusts
or esicles although atypical cases with telangiectasia and
purpura ha e been described. Lesions usually occur on the
trun and pro imal e tremities. ucosal lesions are absent.
istologically the epidermis will show mild ocal spongio
sis and para eratosis. Within the super cial dermis and at
times the deep dermis lymphocytes are organi ed tightly
around the blood essels in a pattern described as a coat
slee e arrangement. The gyrate erythemas are di ided into
the super cial and deep types but these histologic types do
not correlate with etiology.
Wa ing and waning in se erity AC tends to be recurrent
o er months to years. ost cases e entually subside spontane
ously. While acti e the eruption is o ten responsi e to topical
steroids. Topical calcipotriol has also been reported to be
success ul.
The ma ority o AC cases are idiopathic. Some cases are
clearly associated with dermatophytosis or the ingestion o
molds such as those in blue cheese. ther oods such as
tomatoes are sometimes implicated and a dietary ournal may
be help ul. edications are implicated in some cases and
internal cancer has been ound. Laboratory tests should be
dictated by the physical e amination and associated signs and
symptoms. n one study o patients had an associated
cutaneous ungal in ection such as tinea pedis and had
internal malignancies.
139
 Fig. 7-8 Erythematous
7 gyratum repens.
Erythema and Urticaria
The di erential diagnosis o AC includes conditions that
can ha e annular con guration including granuloma annulare
secondary syphilis tinea subacute cutaneous lupus erythema
tosus sarcoidosis ansen s disease erythema marginatum
erythema migrans annular urticaria and mycosis ungoides.
istologic e amination clinical eatures and basic laboratory
e aminations will usually allow these diseases to be e cluded.
Erythema gyratum repens
rythema gyratum repens ( GR) is a rare disease that is stri
ing and uni ue in appearance. Lesions consist o undulating
wa y bands o slightly ele ated erythema with trailing scale
o er the entire body. Lesions migrate rapidly (up to cm day)
and are characteristically concentric gi ing the s in a wood
grain appearance ( ig. ).
Pruritus may be se ere and blood eosinophilia is o ten
ound. n more than o patients an underlying malig
nancy is ound. Lung cancer is the most common associated
malignancy although a wide range o neoplasms has been
described. The s in eruption precedes the detection o the
malignancy by an a erage o months. Gi en the high re
uency o malignant disease patients with GR should ha e
e tensi e e aluations to e clude internal malignancy. the
carcinoma is remo ed the lesions clear. therwise the erup
tion is generally resistant to treatment although cetiri ine and
topical corticosteroids ha e been reported to impro e indi
idual cases. GR may be a drug induced eruption or rarely
secondary to pulmonary tuberculosis. These patients respond
to discontinuation o the implicated medication or to treat
ment o the underlying condition.
Eosmophilic annular erythema
Adults or children may de elop bilateral annular erythema
usually presenting on the trun and o ten symmetrical. emales
are the a ored se . istologically a dense peri ascular and
interstitial lymphocytic in ltrate with many eosinophils is seen
but without ame gures. Spontaneous resolution may occur.
ydro ychloro uine and or prednisone are a ored treat
ments when needed. o associated conditions are present.
eutrophilic gurate erythema o in ancy is a ariant with a
dermal neutrophilic in ltrate and aryorrhe is on biopsy.
140
Fig. 7-9 Wells syndrome (eosinophilic cellulitis).
Campbell L, et al: Erythema gyratum repens without associated
malignancy. J Am Acad Dermatol 2011; 65:e22–e23.
Chodkiewicz HM, et al: Paraneoplastic erythema annulare centrifugum
eruption. Am J Clin Dermatol 2012; 13:239–246.
De La Torre-Lugo EM, et al: Erythema gyratum repens. J Am Acad
Dermatol 2011; 64:e89–e90.
El-Khalawany M, et al: Eosinophilic annular erythema is a peculiar
subtype in the spectrum of Wells syndrome. J Eur Acad Dermatol
Venereo 2013; 27:973–979.
Honma M, et al: Erythema annulare centrifugum simulating erythema
gyratum repens. J Dermatol 2011; 38:192–193.
Kim KJ, et al: Clinicopathologic analysis of 66 cases of erythema
annulare centrifugum. J Dermatol 2002; 29:61.
Patrizi A, et al: Neutrophilic figurate erythema of infancy. Pediatr
Dermatol 2008; 25:255–260.
Rao NG, et al: Annular erythema responding to tacrolimus ointment.
J Drugs Dermatol 2003; 2:421.
Rongioletti F, et al: Erythema gyratum repens is not an obligate
paraneoplastic disease. J Eur Acad Dermatol Venereol 2014;
28:112–115.
EOSINOPHILIC CELLULITIS (WELLS SYNDROME)
n Wells described our patients with acute onset o
pla ues resembling cellulitis that persisted or many wee s
( ig. ). Wells syndrome occurs at all ages and pruritus is
common. The condition is typically recurrent and indi idual
episodes may be prolonged. Degranulation o dermal eosino
phils produces the ame gures seen in histologic sections.
These consist o dermal collagen with adherent eosinophil
granules. osinophilic panniculitis may also be present.
t is unclear whether Wells syndrome is a distinct disorder
sui generis or a reaction pattern to many possible allergic
stimuli. any (perhaps most) cases represent arthropod reac
tions. t has also been associated with onchocerciasis intestinal
parasites aricella mumps immuni ation drug reactions that
include the anti tumor necrosis actor (T ) α biologic agents
myeloproli erati e diseases angioimmunoblastic lymphade
nopathy atopic diathesis in ammatory bowel disease ( BD)
hypereosinophilic syndrome Churg Strauss syndrome and
ungal in ection. Treatment includes topical and intralesional
corticosteroids oral antihistamines tacrolimus ointment
minocycline VB psoralen plus ultra iolet A (P VA)
dapsone and low dose prednisone. Despite that some cases
may be caused by e posure to T inhibitors one patient
whose condition responded well to adalimumab has been
documented. Any triggering actor such as arthropod bites
should be eliminated.
Boura P, et al: Eosinophilic cellulitis (Wells’ syndrome) as a cutaneous
reaction to the administration of adalimumab. Ann Rheum Dis 2006;
65:839–840.
 Powell JG, et al: Eosinophilic cellulitis (Wells syndrome) in a pediatric Fig. 7-10 Sweet
patient: a case report and review of the literature. Cutis 2012; syndrome,
89:191–194. erythematous lesions.
Sarin KY, et al: Treatment of recalcitrant eosinophilic cellulitis with
adalimumab. Arch Dermatol 2012; 148:990–992.

Reactive neutrophilic dermatoses

Tugnet N, et al: Wells syndrome (eosinophilic cellulitis) secondary to
infliximab. Rheumatology 2012; 51:195–196.
Verma P, et al: Idiopathic bullous eosinophilic cellulitis (Wells syndrome)
responsive to topical tacrolimus and antihistamine combination. Indian
J Dermatol Venereol Leprol 2012; 78:378–380.
Winfield H, et al: Eosinophilic cellulitis–like reaction to subcutaneous
etanercept injection. Arch Dermatol 2006; 142:218–220.

REACTIVE NEUTROPHILIC DERMATOSES

As with the gyrate erythemas the reacti e neutrophilic der
matoses tend to ollow certain stimuli such as acute upper
respiratory tract in ections ( R s) or are associated with
underlying diseases such as BD and hematologic malig
nancy. Some o the neutrophilic dermatoses share common
triggers and clinical eatures may o erlap. Patients may
e hibit the simultaneous or se uential appearance o two or
more o the conditions. ost o ten is the combination o typical
lesions o Sweet syndrome on the upper body and erythema
nodosum ( ) li e lesions on the legs. n these patients his
tology o ten enables the diagnosis o subcutaneous Sweet syn
drome or the type lesions allowing one diagnosis to be
made. n occasional cases howe er it may be di cult to
establish the diagnosis rmly as one o the neutrophilic reac
ti e dermatoses. or these reasons it is clinically use ul to
thin o these diseases as orming a spectrum o conditions
e pressed in certain indi iduals by a group o stimuli with
arious o erlapping morphologies.

Erythema nodosum
rythema nodosum is discussed in Chapter .

Sweet syndrome (acute febrile neutrophilic

dermatosis)
Since its rst description in by Dr. Robert Sweet as a
recurrent ebrile dermatosis in women the spectrum o this
syndrome has e panded. Sweet syndrome primarily a ects
adults and emales outnumber males by about . n younger
adults emale predominance is mar ed but in persons older
than the gender ratio is more e ual and cases associated
with malignancy ha e a ratio. n children boys and girls
are e ually a ected. n urope cases are more common in the
spring and all. our subtypes o Sweet syndrome ha e been
described based on their pathogenesis the classic type ( ) in re uently.
cases associated with neoplasia ( ) cases associated with
in ammatory disease ( ) and cases associated with preg
nancy ( ).
The clinical eatures o all our subtypes are similar although
dus y bullous and necrotic lesions that o erlap with pyo
derma gangrenosum are more common in patients with
associated leu emia. The primary s in lesion is a sharply mar
ginated rapidly e tending tender erythematous or iola
ceous pain ul ele ated pla ue cm in diameter. Lesions
may appear intensely edematous or merely indurated ( ig.
). They typically in ol e the ace nec upper trun and
e tremities. Some patients ha e lesions locali ed to the chee s.
Lesions may burn but do not itch. The sur ace o the pla ues
may de elop esiculation or postulation as a result o an
intense dermal in ammatory in ltrate and accompanying
Fig. 7-11 Sweet syndrome; note superficial pustules.
dermal edema ( ig. ). Clinical morphologic ariants
recently described include three immunocompromised
patients with deep necrosis simulating necroti ing asciitis
and a second report o three patients whose lesions were
e tremely large and described as giant cellulitis li e in appear
ance. Pathergy and oebneri ation a ter trauma or VB occur
ore than three uarters o Sweet syndrome patients ha e
systemic ndings. The most common is e er present in
o patients. Arthritis arthralgias or myalgias occur
in one third to two thirds o cases. About o patients
ha e con uncti itis or episcleritis. ther ocular mani esta
tions include periorbital in ammation dacryoadenitis limbal
nodules peripheral ulcerati e eratitis glaucoma iritis and
choroiditis. ral lesions resembling aphthae occur in or
o classic cases but in or more o those associated with
hematologic malignancy. Cough dyspnea and pleuritis may
represent pulmonary in ol ement. Pulmonary in ltrates and
e usions are o ten seen on chest radiographs o such patients.
Rarely there may be cardiac renal hepatic intestinal and
neurologic in ol ement. ulti ocal sterile osteomyelitis may
occur.
141

tahir99 - UnitedVRG
 Laboratory ndings include an ele ated sedimentation rate
7 ( ) neutrophilia (
(increased bands;
) leu ocytosis ( ) and a le t shi t
). Antineutrophilic cytoplasmic antibod
ies (A CAs) ha e been reported. n most cases an attac lasts
wee s and then resol es. Recurrences may be seen with
Erythema and Urticaria
the same precipitating cause such as R . Persistent cases
with new lesions erupting be ore the old lesions resol e may
continue or many years.
The histologic hallmar o Sweet syndrome is a nodular and
di use dermal in ltrate o neutrophils with aryorrhe is and
massi e papillary dermal edema. Leu ocytoclastic asculitis
may be present ocally and this does not e clude a diagnosis
o Sweet syndrome. pper dermal edema may be so intense
as to orm subepidermal bullae. Leu emic cells may be present
in the in ltrate and clonal restriction o neutrophils has
e en been seen in Sweet syndrome not associated with
malignancy.
istologic ariants described as histiocytic or lymphocytic
Sweet syndrome ha e been reported. ccasionally the main
in ltrating cell resembles these cell types but on immunohis
tochemical stains they are ound to be o myelogenous origin.
Special in estigations such as myelopero idase stains are posi
ti e and con rm Sweet syndrome as the diagnosis. sually
myelodysplasia or ran leu emia is present or will mani est
in the not so distant uture.
The ma ority o cases o Sweet syndrome ollow a R
and are there ore acute and sel limited. ther associated
conditions include in ections with ersinia to oplasmosis his
toplasmosis salmonellosis tuberculosis tonsillitis and ul o
aginal in ections. Sweet syndrome has been reported in
association with BD and o erlaps with the bowel bypass or
blind loop syndrome. Cases ha e also been associated with
peripheral ulcerati e eratitis and Beh et syndrome.
ematologic malignancies or solid tumors are present in
about o reported cases. Sweet syndrome o ten presents
early in the course o the cancer when therapy is more e ca
cious. Associated malignancies are usually hemoproli erati e
and include leu emias (usually acute myelogenous) lympho
mas anemias myelodysplastic syndrome and polycythemia
era. Solid tumors are o any type but are most o ten genito
urinary breast (in women) or gastrointestinal (in men).
Anemia is ound in o men and o women with
malignancy associated Sweet syndrome. Thrombocytopenia is
seen in hal . Solitary bullous or ulcerati e lesions are more
re uently associated with malignancy.
Pregnancy associated Sweet syndrome typically presents in
the rst or second trimester with lesions on the head nec
trun and less o ten on the upper e tremities. Lower e tremity
lesions resembling may occur. The condition may resol e
spontaneously or clear with topical or systemic corticoste
roids. t may recur with subse uent pregnancies but there
seems to be no ris to the etus.
any drug therapies ha e been associated with Sweet li e
reactions in the s in although the strongest association e ists
or granulocyte colony stimulating actor and all trans retinoic
acid. ral contracepti es radiation therapy elds accines
borte omib gemcitabine trimethoprim sul ametho a ole
and minocycline ha e been implicated. All trans retinoic acid
causes terminal di erentiation o some leu emic clones and is
used to treat promyelocytic leu emia. A ter about wee s o
treatment Sweet li e lesions may appear. nitially these s in
lesions may contain immature blasts ma ing it di cult to
distinguish them rom leu emia cutis. Later the lesions
contain more mature neutrophils. nduction o the s in lesions
appears to be related to the desired pharmacologic e ect o
the medication.
The two ma or criteria or the diagnosis o Sweet syndrome
are the presence o red edematous pla ues and a biopsy dem
142
Box 7-1 Revised diagnostic criteria for diagnosis of Sweet
syndrome*
Major criteria
1. Abrupt onset of erythematous plaques or nodules,
occasionally with vesicles, pustules, or bullae
2. Nodular and diffuse neutrophilic infiltration in the dermis with
karyorrhexis and massive papillary dermal edema
Minor criteria
1. Preceded by a respiratory infection, gastrointestinal tract
infection or vaccination, or associated with:
• Inflammatory disease or infection
• Myeloproliferative disorders or other malignancy
• Pregnancy
2. Malaise and fever (>38°C [100.4°F])
3. Abnormal laboratory findings ≥3 of the following:
• Erythrocyte sedimentation rate >20 mm/hr
• C-reactive protein elevated
• Leukocytosis >8000/mm3
• Left shift with >70% neutrophils
4. Excellent response to treatment with systemic corticosteroids
*Both major criteria and two minor criteria are needed for diagnosis.
onstrating neutrophils aryorrhe is and mar ed papillary
dermal edema. inor criteria include associated symptoms or
conditions laboratory ndings and response to therapy.
Patients should ha e both ma or criteria and two o the our
minor criteria or diagnosis (Bo ). can be distinguished
by its typical morphology and histologic eatures. Clinically
both diseases can ha e red pla ues and central esiculation
can occur. True target lesions are not seen in Sweet syndrome.
Bowel bypass syndrome has s in lesions that on histologic
e amination are identical to those o Sweet syndrome; e er
and arthritis also accompany bowel bypass syndrome.
Although it is easy to distinguish classic rom Sweet syn
drome these two conditions share many eatures. Both occur
most o ten in young adult women and re uently ollow R s.
Both may be associated with pregnancy underlying malig
nancy and BD. n both e er and arthritis may occur along
with leu ocytosis with neutrophilia. There are many reports
o simultaneous or se uential and Sweet syndrome in
the same patient. Leu emia associated Sweet syndrome may
o erlap with pyoderma gangrenosum. A search or an under
lying cause should be underta en especially in persons o er
age and those with anemia thrombocytopenia or lesions
that are bullous or necrotic. The standard treatment is systemic
corticosteroids with appro imately mg g day o oral
prednisone. This will result in resolution o e er and s in
lesions within days. Sul apyridine potassium iodide colchi
cine dapsone do ycycline clo a imine cyclosporine and
nonsteroidal anti in ammatory drugs ( SA Ds) may be
help ul in chronic or re ractory disease. edication should be
continued or se eral wee s to pre ent relapse.
Neutrophilic dermatosis of the dorsal hands
Lesions o neutrophilic dermatosis o the dorsal hands present
as edematous pustular or ulcerati e nodules or pla ues local
i ed to the dorsal hands ( ig. ). istologically papillary
dermal edema and a nodular and di use neutrophilic in ltrate
with aryorrhe is are noted. As in Sweet syndrome leu ocy
toclastic asculitis may be present ocally. ndi idual ares

Fig. 7-12 Neutrophilic dermatosis of the dorsal hands.
respond to prednisone and dapsone but recurrences are
common. As the clinical appearance tendency to relapse
response to treatment and histologic eatures o erlap with
those o Sweet syndrome and pyoderma gangrenosum this
condition illustrates the close relationship o the arious
neutrophilic dermatoses. eutrophilic dermatosis o the
dorsal hands is best considered a locali ed ariant o Sweet
syndrome.
Neutrophilic eccrine hidradenitis
eutrophilic eccrine hidradenitis is discussed in Chapter
Marshall syndrome
The rare arshall syndrome is characteri ed by s in lesions
resembling Sweet syndrome which are ollowed by ac uired
cutis la a. Cases occur primarily in children. Small red papules
e pand to urticarial targetoid pla ues with hypopigmented
centers. istologic e aluation o the s in lesions usually shows
a neutrophilic dermatosis irtually identical to Sweet syn
drome. ccasionally an eosinophilic in ltrate will be ound.
The lesions resol e with destruction o the elastic tissue at
the site producing so t wrin led s in colored protuberant
pla ues that can be pushed into the dermis. lastic tissue in
other organs may also be a ected especially the heart and
lungs. Some cases may be associated with α antitrypsin
de ciency.
Chan MP, et al: Subcutaneous Sweet syndrome in the setting of myeloid
disorders. J Am Acad Dermatol 2013; 68:1006–1015.
Cohen PR: Sweet’s syndrome—a comprehensive review of an acute
febrile neutrophilic dermatosis. Orphanet J Rare Dis 2007; 2:34.
Cook-Norris RH, et al: Neutrophilic dermatosis of the hands: an
under-recognized hematological condition that may result in
unnecessary surgery. Am J Hematol 2009; 84:60.
Del Pozo J, et al: Neutrophilic dermatosis of the hands: presentation of
eight cases and review of the literature. J Dermatol 2007; 34:243–247.
Gottlieb CC, et al: Ocular involvement in acute febrile neutrophilic
dermatosis (Sweet syndrome): new cases and review of the literature.
Surv Ophthalmol 2008; 53:219–226.
Gray PEA, et al: Neonatal Sweet syndrome. Pediatrics 2012;
129:e1353–e1359.
Haider M, et al: Acquired cutis laxa type II (Marshall syndrome) in and
18-month-old child. Pediatr Dermatol 2010; 27:89–91.
Kaminska EC, et al: Giant cellulitis-like Sweet syndrome in the setting of
autoimmune disease. J Am Acad Dermatol 2014; 71:e94–95.
Kroshinsky D, et al: Necrotizing Sweet syndrome. J Am Acad Dermatol
2012; 67:945–954.
Neoh CY, et al: Sweet’s syndrome: a spectrum of unusual clinical
presentations and associations. Br J Dermatol 2007; 156:480–485.
tahir99 - UnitedVRG
Reactive neutrophilic dermatoses
Fig. 7-13 Enlarging ulcer of pyoderma gangrenosum.
Ratzinger G, et al: Acute febrile neutrophilic dermatosis: a
histopathologic study of 31 cases with review of literature. Am J
Dermatopathol 2007; 29:125–133.
Requena L, et al: Histiocytoid Sweet syndrome: a dermal infiltration of
immature neutrophilic granulocytes. Arch Dermatol 2005; 141:837.
Surovy AM, et al: Giant cellulitis-like Sweet syndrome. JAMA Dermatol
2013; 149:79–83.
Tabanlioğlu D, et al: Sweet’s syndrome and erythema nodosum: a
companionship or a spectrum? A case report with review of the
literature. Int J Dermatol 2010; 49:62–66.
Thompson DF, et al: Drug-induced Sweet’s syndrome. Ann
Pharmacother 2007; 41:802–811.
. Uihlein LC, et al: Sweet’s syndrome in children. Pediatr Dermatol 2012;
29:38–44.
Vignon-Pennamen MD, et al: Chronic recurrent lymphocytic Sweet
syndrome as a predictive marker of myelodysplasia. Arch Dermatol
2006; 142:1170–1176.
Wallach D, et al: From acute febrile neutrophilic dermatosis to
neutrophilic disease: forty years of clinical research. J Am Acad
Dermatol 2006; 55:1066–1071.
Pyoderma gangrenosum
Brunsting is credited with the initial clinical description o
pyoderma gangrenosum (PG) in . Classic PG begins as an
in ammatory pustule with a surrounding halo that enlarges
and begins to ulcerate. A primary lesion may not always be
seen and a substantial proportion o lesions appear at sites o
trauma (pathergy). Satellite iolaceous papules may appear
ust peripheral to the border o the ulcer and brea down to
use with the central ulcer. ully de eloped lesions are pain ul
ulcers with sharply marginated undermined blue to purple
borders ( ig. ). PG most typically occurs in adults age
and presents on the lower e tremities and trun . Lesions
heal with characteristic thin atrophic scars. Pustular PG con
sists o pustules that generally do not progress to ulcerati e
lesions. This orme ruste o PG is most o ten seen in BD
patients. Pyostomatitis egetans and subcorneal pustular
dermatosis are two other pustular neutrophilic diseases
reported in association with PG sometimes in patients with
gA gammopathy.
Bullous PG is more super cial and less destructi e than the
ulcerati e type. These lesions ha e considerable o erlap
with what has been called bullous Sweet syndrome and are
usually seen in patients with leu emia or polycythemia era.
These red pla ues become dus y and de elop super cial ero
sions. They are not deep usually are not undermined and are
less pain ul than ulcerati e PG.
Vegetati e PG is the least aggressi e orm o PG. Lesions
present as chronic super cial cribri orm ulcerations usually
o the trun that enlarge slowly and ha e ele ated borders
143
 and clean bases. The lesions are rarely pain ul generally
7 respond to relati ely conser ati e treatments and are usually
not associated with underlying systemic disease. PG is rare in
children. ore than o these patients ha e underlying
BD and another ha e leu emia. An association o child
Erythema and Urticaria
hood ac uired immunode ciency syndrome (A DS) and PG
has been documented. About one uarter o children with PG
ha e no underlying disease. Genital and head nec lesions
can occur in children.
erall appro imately o patients with PG ha e an
associated disease most o ten BD both Crohn s disease and
ulcerati e colitis. Between . and o patients with BD
de elop PG. The two diseases may are together or run an
independent course. Surgical remo al o the diseased intestine
may lead to complete remission o PG or lesions may persist
or rst appear a ter remo al o the a ected bowel. ost
patients with PG and BD ha e colon in ol ement. The ulcer
ati e and pustular types o PG are most re uently seen in
patients with associated BD. A peristomal ariant occurs near
such sites as pain ul erosions with iolaceous undermined
borders.
any other associated conditions ha e been reported. Leu
emia (chie y acute or chronic myelogenous leu emia)
myeloma monoclonal gammopathy (chie y gA) polycythe
mia era myeloid metaplasia chronic acti e hepatitis
hepatitis C human immunode ciency irus ( V) in ection
systemic lupus erythematosus pregnancy PAPA syndrome
(see Autoin ammatory syndromes ne t) and Ta ayasu arte
ritis are among the many diseases seen in con unction with PG.
ore than one third o PG patients ha e arthritis usually an
asymmetric seronegati e monoarticular arthritis o the large
oints. onoclonal gammopathy usually gA is ound in
o PG patients. Children with congenital de ciency o leu o
cyte adhesion glycoproteins (LAD) de elop PG li e lesions.
There are increasing reports o PG occurring in hidradenitis
suppurati a patients.
arly biopsies o PG show a suppurati e olliculitis. The
a ected ollicle is o ten ruptured. As the lesions e ol e they
demonstrate suppurati e in ammation in the dermis and sub
cutaneous at. assi e dermal edema and epidermal neutro
philic abscesses are present at the iolaceous undermined
border. These eatures are not diagnostic and in ectious causes
must be e cluded.
The clinical picture o PG in the classic ulcerati e orm is
characteristic. Because no diagnostic serologic or histologic
eatures e ist howe er PG remains a diagnosis o e clusion.
ultiple in ections including mycobacteria deep ungi gum
matous syphilis synergistic gangrene and amebiasis must be
e cluded with cultures and special studies. ther disorders
re uently misdiagnosed as PG include ascular occlusi e or
chronic enous disease asculitis cancer and e ogenous
tissue in ury including actitial disease.
Pyoderma gangrenosum may be misdiagnosed as a spider
bite i there is only a solitary lesion on an e tremity. Spider
bites tend to e ol e more rapidly and may be associated with
other systemic symptoms or ndings such as disseminated
intra ascular coagulation. Various orms o cutaneous large
essel asculitis may produce similar clinical lesions and are
e cluded by histologic e aluation and ancillary studies such
as A CA and antiphospholipid antibody tests. Thus the
initial wor up o the patient includes studies necessary to
ensure that the proper diagnosis is made as well as to in es
tigate possible associated diseases.
The most di cult diagnosis to e clude is actitial disease.
The clinical lesions may be stri ingly similar e ol ing rom
small papulopustules to orm ulcerations that do not heal.
istologic e aluation will o ten simply show suppurati e der
matitis since the in ected or applied caustic substance may not
144
be identi able (urine disin ectants drain cleaner). en the
most e perienced clinician may misdiagnose actitial disease
as PG.
anagement o PG is challenging. The initial step is to clas
si y the lesion by type. nderlying conditions should be
sought e en i no symptoms are ound. Treatment o underly
ing BD may lead to impro ement. n general the egetati e
type will respond to topical or local measures. The treatment
is determined by the se erity o disease and rate o progres
sion. n rapidly progressi e cases aggressi e early manage
ment may reduce morbidity.
Local treatment includes both proper wound care and medi
cation to reduce in ammation; compresses or whirlpool baths
are ollowed by the use o ointment or hydrophilic occlusi e
dressings. n solitary lesions or slowly progressi e cases appli
cation o potent topical corticosteroids intralesional steroid
in ections or tacrolimus may be bene cial although pathergy
may be seen at sites o in ection. The absorption o tacrolimus
in large or multiple wounds may lead to systemic blood le els.
Systemic corticosteroids can be e tremely e ecti e with initial
doses in the range o mg g. control is achie ed the dose
may be rapidly tapered. corticosteroid reduction is not
possible a steroid sparing agent may be added. Patients
unresponsi e to oral corticosteroids may bene t rom pulse
methylprednisolone mg g or days ollowed by
mg o prednisone tapering as the lesions heal.
n general when the disease is aggressi e and corticosteroid
therapy does not lead to rapid resolution an immunosuppres
si e agent is added. Cyclosporine and in i imab result in a
rapid response and are the immunosuppressi es o choice or
PG in such situations. The lesions o ten respond dramatically
to these agents including many that ha e not responded
ade uately to corticosteroids. nitial doses o cyclosporine o
appro imately mg g day are e ecti e in most cases. n
treatment ailures the dose can be raised to mg g day.
The response is independent o any underlying cause. n i
imab is gi en as intra enous in usions in doses o about mg
g at wee s and and then e ery wee s. n ery aggres
si e rapidly progressi e cases consideration should be gi en
to starting cyclosporine or in i imab treatment early to gain
control o the disease. ther use ul systemic agents include
etanercept adalimumab ale acept uste inumab mycopheno
late mo etil ( ) granulocyte apheresis intra enous
immune globulin ( V G) al ylating agents and thalidomide.
Sul apyridine sul asala ine salicyla osul apyridine dapsone
methotre ate a athioprine and minocycline generally are less
help ul and may be use ul ad uncts.
nce the in ammatory component is controlled the
ulceration(s) will need to heal so proper wound care is essen
tial. pidermal allogra ts or autogra ts may be applied soon
a ter PG is controlled. Pathergy is rarely noted at the donor
site when patients are recei ing ade uate immunosuppressi e
therapy.
Ahronowitz I, et al: Etiology and management of pyoderma
gangrenosus. Am J Clin Dermatol 2012; 13:191–211.
Binus AM, et al: Pyoderma gangrenosum. Br J Dermatol 2011;
165:1244–1250.
Cozzani E, et al: Pyoderma gangrenosum. G Ital Dermatol Venereol
2014; 149:587–600.
Callen JP, et al: Pyoderma gangrenosum: an update. Rheum Dis Clin
North Am 2007; 33:787–802.
Hsaio JL, et al: Hidradenitis suppurativa and concomitant pyoderma
gangrenosum. Arch Dermatol 2010; 146:1265–1270.
Li J, et al: Treatment of pyoderma gangrenosum with mycophenolate
mofetil as a steroid-sparing agent. J Am Acad Dermatol 2013; 69:565–569.
Kikuchi N, et al: Pyoderma gangrenosum following surgical procedures.
Int J Dermatol 2010; 49:346–348.
Miller J, et al: Pyoderma gangrenosum: a review and update on new
therapies. J Am Acad Dermatol 2010; 62:646–654.
 Rudocco E, et al: Pyoderma gangrenosum. J Eur Acad Dermatol
Venereol 2009; 23:1008–1017.
Turner RB, et al: Rapid resolution of pyoderma gangrenosum after
treatment with intravenous cyclosporine. J Am Acad Dermatol 2010;
63:e72–e74.
AUTOINFLAMMATORY SYNDROMES
The autoin ammatory syndromes are a group o disorders
characteri ed by bouts o systemic in ammation related to
dysregulation o the innate immune system. These conditions
present most o ten in children with episodes that o ten
include e er and symptoms related to the s in gastrointesti
nal (G ) tract eyes chest musculos eletal system and central
ner ous system (C S). n ammatory s in lesions are o ten
prominent mani estations especially acne PG and erysipelas
li e and urticaria li e lesions. Although more than hal o
these are autosomal dominant disorders inherited in patients
with a amily history o these syndromes or o dea ness
amyloidosis or renal ailure should be sought. n addition
many ac uired syndromes ha e eatures o autoin amma
tory disease such as Schnit ler syndrome (see under rti
caria later) as well as Beh et syndrome and periodic e er
aphthous stomatitis pharyngitis and adenitis (P APA) syn
drome (see Chapter ).
amilial editerranean e er ( ) is the most common
inherited autoin ammatory syndrome and was the rst rec
ogni ed. is an autosomal recessi e syndrome character
i ed by recurrent attac s o h o e er and a monoarthritis
with o erlying erysipelas li e erythema. Peritonitis pleuritis
and asculitis including enoch Sch nlein purpura may also
occur in these patients who usually present be ore the teenage
years. is caused by mutation in the ME gene which
produces pyrin but appro imately o patients with a
similar phenotype lac a detectable gene de ect. Colchicine is
the mainstay o treatment or patients and can reduce the
ris o associated amyloidosis. Rilonacept an interleu in
( L ) soluble usion protein receptor may help those resis
tant to colchicine.
The PAPA syndrome is an autosomal dominant disorder
characteri ed by pyogenic sterile arthritis PG and acne and
is caused by proline serine threonine phosphatase interacting
protein PS P P or CD binding protein CD P
gene mutations. PSTP P CD BP a tyrosine phosphorylated
protein in ol ed in cytos eletal organi ation interacts with
pyrin the gene product important in the pathogenesis o . in ammatory disease spectrum. This disease was dubbed
The T receptor associated periodic syndrome (TRAPS) is
similar to but shows autosomal dominant inheritance
longer attac s and a lac o response to colchicine. TRAPS is
associated with mutations in the S gene resulting
in decreased serum soluble T receptor. TRAPS and de
ciency o the L receptor antagonist (D TRA) are the most
common autoin ammatory syndromes with onset in adult
hood. ebrile episodes o wee s are accompanied by peri
orbital edema and a pain ul distally migrating erythematous
or urticarial li e pla ues. SA Ds or prednisone can treat the
acute episodes; anti T receptor antagonists or ana inra
may pre ent bouts. An autosomal recessi e D TRA leads to
episodes o generali ed pustular psoriasis nail dystrophy and
geographic tongue. Treatment is as or pustular psoriasis.
De ciency o the L receptor antagonist (D RA) also mani
ests as a pustular eruption although onset is in the neonatal
period. Bone lesions oral ulcers and other ndings are all
re ersed dramatically by ana inra.
The recessi ely inherited hyper gD syndrome ( DS)
associated with mutations in the me alonate inase M
gene leading to V de ciency also presents with hereditary
periodic e er. Two thirds o patients mani est arious
tahir99 - UnitedVRG
morbilli orm urticarial eruptions. ral and genital ulcerations
may occur.
There are three autosomal dominant cryopyrin associated
periodic syndromes. amilial cold autoin ammatory syn
drome is characteri ed by e er cold urticaria con uncti itis
Autoinflammatory syndromes
and arthralgia elicited by generali ed e posure to cold. Patients
with uc le Wells syndrome mani est most o ten in adoles
cence with acute ebrile in ammatory episodes comprising
abdominal pain arthritis urticaria hearing loss and multior
gan amyloidosis. eonatal onset multisystem in ammatory
disease is characteri ed by e er chronic meningitis u eitis
sensorineural hearing loss urticarial rash and a de orming
arthritis. Patients may also ha e dysmorphic acial appear
ance clubbing o the ngers mild mental retardation and
papilledema. All three o these conditions ha e mutations in
the L P gene. A second amilial cold autoin ammatory
syndrome is similar in its clinical ndings but is related to
mutations in the LP gene.
A newly described autoin ammatory disease CA DL is
characteri ed by chronic atypical neutrophilic dermatosis
with lipodystrophy and ele ated temperature. Patients present
in the newborn period with e er swollen purplish red eyelids
red and purplish papules and pla ues o the trun nec and
e tremities and lipodystrophy o the ace along with other
systemic ndings. The s in biopsy re eals atypical cells o the
myelocytic lineage in the dermis. t is caused by a mutation in
the PSM gene.
Blau syndrome is an autosomal dominant disease with
arthritis u eitis granulomatous in ammation and campto
dactyly. t is associated with mutations in the OD gene
which also predisposes to Crohn s disease and early onset
sarcoidosis. Another ac uired syndrome consisting o derma
titis e er arthritis and serositis without autoantibody or
mation and with the occurrence o a OD mutation has been
described in patients. The dermatitis was polymorphic but
many patients had papules and pla ues on the ace trun and
e tremities. Biopsies were also ariable. The authors named it
A D; the only e ecti e therapy was prednisone or topical
corticosteroids. Lastly two patients with urticarial lesions that
burned rather than itched had accompanying e er or arthral
gias and or laboratory mar ers o systemic in ammation
such as a high erythrocyte sedimentation rate ( SR) or
C reacti e protein (CRP). They did not respond to antihista
mines but did respond to ana inra suggesting their urticarial
lesions were mediated by L and t into this ac uired auto
neutrophilic urticaria with systemic in ammation which is
di erentiated rom prior reports o neutrophilic urticaria.
Belani H, et al: Neutrophilic urticaria with systemic inflammation. JAMA
Dermatol 2013; 149:453-458.
Braun-Falco M, et al: Skin manifestations in autoinflammatory
syndromes. J Dtsch Dermatol Ges 2011; 9:232–245.
Farasat S, et al: Autoinflammatory diseases: clinical and genetic
advances. Arch Dermatol 2008; 144:392–402.
Gattorno M et al: Treatment of autoinflammatory syndromes. Curr Opin
Pediatr 2010; 22:771–778.
Hashkes PH, et al: Autoinflammatory syndromes. Pediatr Clin North Am
2012; 59:447–470.
Kluk J, et al: Chronic atypical neutrophilic dermatosis with lipodystrophy
and elevated temperature syndrome. Br J Dermatol 2014;
170:215–217.
Rigant D, et al: Monogenic autoinflammatory syndromes
at a dermatological level. Arch Dermatol Res 2011;
303:375–380.
Ross JB, et al: Use of anakinra (Kineret) in the treatment of familial cold
autoinflammatory syndrome with a 16-month follow-up. J Cutan Med
Surg 2008; 12:8–16.
Shinkai K, et al: Cryopyrin-associated periodic syndromes and
autoinflammation. Clin Exp Dermatol 2008; 33:1–9.
145

7 secondary to
Erythema and Urticaria
Fig. 7-14 Acute urticaria.
Tufekci O, et al: CANDLE syndrome. J Pediatr Hematol Oncol 2014; July
17.
Yao Q, et al: Dermatitis as a characteristic phenotype of a new
autoinflammatory disease associated with NOD2 mutations. J Am
Acad Dermatol 2013; 68:624–631.
URTICARIA (HIVES)
rticaria is a ascular reaction o the s in characteri ed by
the appearance o wheals ( ig. ) generally surrounded
by a red halo or are and associated with se ere itching
stinging or pric ing sensations. These wheals are caused by
locali ed edema. Clearing o the central region may occur
and lesions may coalesce producing an annular or polycy
clic pattern. Subcutaneous swellings (angioedema) may or
may not accompany the wheals. When angioedema is not
present and e er malaise and oint bone pain coe ist
diagnostic consideration o an autoin ammatory condition is
necessary including many inherited syndromes as pre i
ously described.
Schnit ler syndrome is another diagnosis to consider. This
rare ac uired disorder is a combination o chronic nonpruritic
urticaria e er o un nown origin disabling bone pain hyper
ostosis increased SR and monoclonal g gammopathy.
Pruritus is not generally a eature. The age o onset ranges
rom years without gender predilection. The s in biopsy
most o ten re eals a predominant neutrophilic peri ascular
and interstitial in ltrate although about one third o cases are
mononuclear. n some patients the g gammopathy pro
gresses to neoplasia especially Waldenstr m macroglobulin
emia. ecti e therapy or patients with Schnit ler syndrome
has included ana inra ritu imab tocili umab rilonacept and
cana inumab.
Classification
Acute urticaria e ol es o er days to wee s producing e anes
cent wheals that indi idually rarely last more than hours
with complete resolution o the urticaria within wee s o
onset. Daily episodes o urticaria and or angioedema lasting
more than wee s are designated chronic urticaria. Chronic
urticaria predominantly a ects adults and is twice as common
in women as in men.
ore than o cases o chronic urticaria are o un nown
causation and are called chronic spontaneous urticaria. Phys
ical stimuli may produce urticarial reactions and represent
up to o cases o chronic urticaria. The physical
146
Fig. 7-15 Urticaria
hepatitis B.
urticarias include dermatographic cold heat cholinergic
a uagenic solar ibratory gal anic and e ercise induced
cases. Physical urticaria usually coe ists with chronic sponta
neous urticaria.
Etiologic factors
n general in ections ingestants inhalants and in ections
should be considered as possible underlying causes o urti
caria. n acute spontaneous cases R s and iral in ections are
the most common etiologies in children. Drugs (e.g. SA Ds
antibiotics) and oods are other common causes in both adults
and children. Clues suggesting physical urticaria as both a
primary cause and as a coe istent second etiology should be
sought historically.
n addition to streptococcal and iral R s the possibility o
locali ed in ection in the tonsils a tooth sinuses gallbladder
prostate bladder or idney should be considered. Treatment
with antibiotics or elicobacter p lori has led to resolution o
the urticaria. Chronic iral in ections such as hepatitis B and
C may cause urticaria ( ig. ). Acute in ectious mononu
cleosis and psittacosis may also be triggering conditions. el
minths may cause urticaria and include scaris n lostoma
Strong loi es ilaria Echinococcus Schistosoma richinella ox
ocara and li er u e.
The most allergenic oods are chocolate shell sh nuts
peanuts tomatoes strawberries melons por cheese garlic
onions eggs mil and spices. ood allergens that may cross
react with late include chestnuts bananas passion ruit
a ocado and iwi. ood additi es and preser ati es are also
implicated in some cases. atural ood additi es that may be
implicated in urticaria include yeasts salicylates citric acid
egg and sh albumin. Synthetic additi es include a o dyes
ben oic acid deri ati es sul te and penicillin.
nhalants that ha e caused urticaria include grass pollens
house dust mites eathers ormaldehyde acrolein (produced
when rying with lard or by smo ing cigarettes containing glyc
erin) castor bean or soybean dust coo ed lentils cottonseed
animal dander cosmetics aerosols pyrethrum and molds.
n ections o both prescribed and recreational drugs as well
as accinations should be considered in the historical data
obtained.

Fig. 7-16 Dermatographism.
onimmunologic mechanisms can produce mast cell
degranulation. Common triggers include opiates polymy in
B tubocurarine radiocontrast dye aspirin other SA Ds tar
tra ine and ben oate.
Physical (inducible) urticarias
Speci c physical stimuli cause up to o all urticarias and
occur most re uently in persons age . The most common
orm is dermatographism ollowed by cholinergic urticaria
and cold urticaria. Se eral orms o physical urticaria may
occur in the same patient. Physical urticarias particularly der
matographic delayed pressure cholinergic and cold urticar
ias are re uently ound in patients with chronic idiopathic
urticaria. Pro ocati e testing o o all treatment at sites not
recently a ected by urticaria is a use ul diagnostic maneu er
and repeated testing with treatment may help gauge therapeu
tic response. Treatment may be a oidance o the pro ocati e
stimulus and o ten antihistamines as discussed later or
chronic urticaria.
Dermatographism
Dermatographism is a sharply locali ed edema or wheal with
a surrounding erythematous are occurring in seconds to
minutes a ter the s in has been stro ed ( ig. ). t a ects
o the population. Dermatographism may arise sponta
neously a ter drug induced urticaria and persist or months.
t has also been reported to be associated with the use o the
bloc er amotidine. t may occur in hypothyroidism and
hyperthyroidism in ectious diseases diabetes mellitus and
during onset o menopause. t may be a cause o locali ed or
generali ed pruritus. Antihistamines suppress this reaction.
The addition o an antihistamine may be o bene t.
Cholinergic urticaria
Cholinergic urticaria produced by the action o acetylcholine
on the mast cell is characteri ed by minute highly pruritic
punctate wheals or papules mm in diameter and sur
rounded by a distinct erythematous are ( ig. ). These
lesions occur primarily on the trun and ace. The condition
spares the palms and soles. Lesions persist or min and
are ollowed by a re ractory period o up to h. Broncho
spasm may occur. amilial cases ha e been reported.
The lesions may be induced in the susceptible patient by
increasing the core body temperature with either e ercise or a
warm bath to raise core temperature by . . C( . . ).
n some cases an attac may be aborted by rapid cooling o
the body as by ta ing a cold shower. Cholinergic dermatog
raphism is noted in some patients.
tahir99 - UnitedVRG
Urticaria (hives)
Fig. 7-17 Cholinergic urticaria, small papules with surrounding large,
erythematous flare.
Antihistamines suppress this reaction. The addition o an
antihistamine may be o bene t. Antihistamines ha e been
combined with other agents such as montelu ast and pro
pranolol. Attenuated androgens such as dana ol may be o
bene t in patients with re ractory cholinergic urticaria.
Adrenergic urticaria
Adrenergic urticaria may occur alone or may coe ist with
cholinergic urticaria. Bouts o urticaria are mediated by
norepinephrine. The eruption consists o small ( mm) red
macules and papules with a pale halo appearing within
min o emotional upset co ee or chocolate. Serum cat
echolamines norepinephrine dopamine and epinephrine
may rise greatly during attac s whereas histamine and sero
tonin le els remain normal. Propranolol mg our times
daily is e ecti e; atenolol has been ine ecti e. A pro ocati e
test consists o intradermal administration o ng o
norepinephrine.
Cold urticaria
posure to cold may result in edema and whealing on the
e posed areas usually the ace and hands. The urticaria does
not de elop during chilling but on rewarming. This heteroge
neous group o disorders is classi ed into primary (essential)
secondary and amilial cold urticaria.
Primary (essential) cold urticaria is not associated with
underlying systemic diseases or cold reacti e proteins. Symp
toms are usually locali ed to the areas o cold e posure
although respiratory and cardio ascular compromise may
de elop. atal shoc may occur when these persons go swim
ming in cold water or ta e cold showers. This type o cold
urticaria usually begins in adulthood. t usually yields a posi
ti e ice cube test result. Antihistamines suppress this reaction.
The addition o an antihistamine may be o bene t. Desen
siti ation by repeated increased e posures to cold has been
e ecti e in some cases. n many patients cold urticaria will
resol e a ter months although about o patients ha e
symptomatic disease or years. As a pro ocati e test a plastic
wrapped ice cube is applied to the s in or min. no
wheal de elops the area should be anned or an additional
min. The use o a combination o cold and mo ing air is in
some cases more e ecti e in reproducing lesions than cold
alone. The pro ocati e test is not per ormed i secondary cold
urticaria is being considered.
Secondary cold urticaria is associated with an underlying
systemic disease such as cryoglobulinemia. ther associations
include cryo brinogenemia multiple myeloma secondary
147
 syphilis hepatitis and in ectious mononucleosis. Patients may
7 ha e headache hypotension laryngeal edema and syncope.
An ice cube test is not recommended because it can precipitate
ascular occlusion and tissue ischemia.
amilial cold autoin ammatory syndrome is grouped with
Erythema and Urticaria
the other autoin ammatory syndromes discussed earlier. The
lesions produce a burning sensation rather than itching. They
may ha e cyanotic centers and surrounding white halos and
last or h. They may be accompanied by e er chills
headache arthralgia myalgia and abdominal pain. A promi
nent eature is leu ocytosis which is the rst obser able
response to cold. amilial cold urticaria will yield a negati e
ice cube test result.
Heat urticaria
Within min o the s in being e posed to heat abo e C
( . ) the e posed area begins to burn and sting then
becomes red swollen and indurated. This rare type o urti
caria may also be generali ed and is accompanied by cramps
wea ness ushing sali ation and collapse. eat desensiti a
tion may be e ecti e. As a pro ocati e test apply a heated
cylinder C ( ) to a small area o s in on the upper
body or min.
Solar urticaria
Solar urticaria appears soon a ter unshielded s in is e posed
to sunlight. t is classi ed by the wa elengths o light that
precipitate the reaction. Visible light can trigger solar urticaria
and sunscreens may not pre ent it. Angioedema may occa
sionally occur. Solar urticaria may be a mani estation o
porphyria leu ocytoclastic asculitis and Churg Strauss syn
drome. Treatment is sun a oidance sunscreens antihista
mines repetiti e phototherapy and P VA. (Solar urticaria is
re iewed more e tensi ely in Chapter .)
Pressure urticaria (delayed pressure urticaria)
Pressure urticaria is characteri ed by the de elopment o
swelling with pain that usually occurs h a ter local pres
sure has been applied. t occurs most re uently on the eet
a ter wal ing and on the buttoc s a ter sitting. t is uni ue in
that there may be a latent period o as long as h be ore
lesions de elop. Arthralgias e er chills and leu ocytosis can
occur. The pain and swelling last or h. Pressure urticaria
may be seen in combination with other physical urticarias. As
a pro ocati e test a lb weight is suspended rom the shoul
der by a cm strap or min and the area inspected a ter
h. Antihistamines may suppress this reaction. The addi
tion o an antihistamine or montelu ast may be o bene t.
Systemic corticosteroids are o ten therapeutic but are gener
ally unsuitable or long term use. Trane amic acid high dose
V G or an anti T biologic may be e ecti e in patients
re ractory to other treatment.
Exercise-induced urticaria
Although both cholinergic urticaria and e ercise urticaria are
precipitated by e ercise they are distinct entities. Raising the
body temperature passi ely will not induce e ercise urticaria
and the lesions o e ercise urticaria are larger than the tiny
wheals o cholinergic urticaria ( ig. ). rticarial lesions
appear min a ter the start o e ercise. Anaphyla is may
be associated. Atopy is common in these patients and some
ha e documented ood allergy. Some patients only ha e such
a reaction a ter eating celery be ore e ercise. A oiding these
allergens may impro e symptoms.
Antihistamines suppress the e ercise induced reaction. The
addition o an antihistamine may be o bene t. Sel
in ectable epinephrine its are recommended or rare patients
with episodes o anaphyla is mani esting with respiratory
148
Fig. 7-18 Exercise-induced urticaria.
symptoms. ercise is a pro ocati e test but may re uire
priming with the identi ed ood allergens.
Vibratory angioedema
Vibratory angioedema a orm o physical urticaria may be an
inherited autosomal dominant trait or may be ac uired a ter
prolonged occupational ibration e posure. Dermatographism
pressure urticaria and cholinergic urticaria may occur in
a ected patients. Plasma histamine le els are ele ated during
attac s. The appearance o the angioedema is usually not
delayed. The treatment is antihistamines. As a pro ocati e test
laboratory orte ibration is applied to the orearm or min.
Aquagenic urticaria
The rare a uagenic urticaria is elicited by water or seawater
at any temperature. Pruritic wheals de elop immediately or
within minutes at the sites o contact o the s in with
water irrespecti e o temperature or source and clear within
min. Sweat sali a and e en tears can precipitate a reac
tion. A uagenic urticaria may be amilial in some cases or
associated with atopy or cholinergic urticaria. Systemic symp
toms ha e been reported including whee ing dysphagia and
respiratory distress. The pathogenesis is un nown but may be
associated with water soluble antigens that di use into the
dermis and cause histamine release rom sensiti ed mast cells.
Whealing may be pre ented by pretreatment o the s in
with petrolatum. Antihistamines suppress this reaction. The
addition o an antihistamine may be o bene t. P VA
appears to pre ent s in lesions but may not pre ent the symp
toms o pruritus. The pro ocati e test is to apply water com
presses C( ) to the s in o the upper body or min.
Galvanic urticaria
Gal anic urticaria has been described a ter e posure to a gal
anic de ice used to treat hyperhidrosis. The relationship o
this condition to other orms o physical urticaria remains to
be established.
Pathogenesis/histopathology
Capillary permeability results rom the increased release o
histamine rom the mast cells situated around the capillaries.
The mast cell is the primary e ector cell in urticarial reactions.
ther mediators include L in the autoin ammatory condi
tions discussed earlier and brady inin in angioedema associ
ated with angiotensin con erting en yme (AC ) inhibitors
and in the hereditary and ac uired angioedema syndromes
discussed shortly.
 About one third o patients with chronic idiopathic urticaria
ha e circulating unctional histamine releasing gG autoanti
bodies that bind to the high a nity g receptor. Some patients
ha e gG that does not bind the g receptor but rather causes
mast cell degranulation. Thyroid autoantibodies are o ten
present in women with chronic idiopathic urticaria but clini
cally rele ant thyroid disease is seldom present. en in those
with thyroid disease treatment o the thyroid disorder gener
ally does not a ect the course o the urticaria.
The histopathologic changes in acute urticaria include mild
dermal edema and margination o neutrophils within postcap
illary enules. Later neutrophils migrate through the essel
wall into the interstitium and eosinophils and lymphocytes
are also noted in the in ltrate. aryorrhe is and brin deposi
tion within essel walls are absent helping to di erentiate
urticaria rom asculitis.
A subset o patients ha e urticarial lesions with biopsies that
show a preponderance o neutrophils; this has been called
neutrophilic urticaria. Patients with such histology may
present with acute urticaria chronic urticaria or physical urti
caria. Because neutrophils are typically present in urticaria in
general it is li ely that cases o neutrophilic urticaria simply
represent urticaria with upregulation o some mast cell
deri ed cyto ines.
Diagnosis
Diagnosis o urticaria and angioedema is usually made on
clinical grounds. Lesions in a ed location or more than h Treatment
suggest urticarial asculitis the urticarial phase o an immu
nobullous eruption granuloma annulare sarcoidosis or
cutaneous T cell lymphoma. indi idual wheals last or
longer than h a s in biopsy should be per ormed.
Clinical evaluation
Laboratory e aluation should be dri en by associated signs
and symptoms. Random tests in the absence o a suggesti e
history or physical ndings are rarely cost e ecti e and are not
recommended. A practical e aluation is limited to a detailed
history and a thorough physical e amination. uestions to as
include a history o the timing duration and re uency o
wheals and any associated angioedema; possible association
with oods drugs ebrile illness occupation tra el or hobbies;
and a amily or personal history o atopy or potential physical
causes. A history o aspirin or SA D ingestion should trigger
their a oidance because these drugs may not only cause urti
caria but also aggra ate pree isting disease.
the urticaria is acute and recurrent ood allergy may be
suggested by a ood diary. Serum radioallergosorbent tests
(RASTs) can be used to detect speci c g and elimination
diets can occasionally be bene cial in some patients. ne such
diet permits inclusion o lamb bee rice potatoes carrots
string beans peas s uash applesauce tapioca preser es
(pear peach cherry) rye crac ers butter sugar tea without
mil or lemon and co ee without cream. This diet is ollowed
or wee s. urticaria does not occur suspected oods are
added one by one and reactions obser ed. This diet is best
tried only a ter a care ul history.
Angioedema in the absence o urticaria may be related to
hereditary angioedema or an AC inhibitor. C esterase de
ciency does not cause hi es only angioedema and measure
ment o C is indicated. C is low an e aluation o C
esterase inhibitor is appropriate.
n patients with chronic spontaneous urticaria a directed
history and physical e amination should elicit signs or
tahir99 - UnitedVRG
symptoms o thyroid disease connecti e tissue disease
changes in bowel or bladder habits aginal or urethral dis
charge other locali ed in ection aundice or ris actors or
hepatitis or Lyme disease. Positi e ndings should prompt
appropriate screening tests. Although sinus ray lms a pan
Urticaria (hives)
oramic dental lm streptococcal throat culture abdominal
ultrasonography and urinalysis with urine culture (with pros
tate massage in men) may re eal the most common occult
in ections triggering urticaria positi e cases are almost always
associated with some signs or symptoms suggesti e o the
diagnosis. or e ample i the patient has a history o sinus
di culties particularly i there is palpable tenderness o er the
ma illary or ethmoid sinuses radiologic sinus e aluation is
recommended. Lastly a routine complete blood count (CBC)
with di erential li er unction testing and SR or CRP le el
may be done to help decide i in ection may be an causal
actor. n areas where parasitic disease is common eosino
philia is an ine pensi e screening test with a air yield.
the history suggests a physical urticaria the appropriate
challenge test should be used to con rm the diagnosis. Lesions
that burn rather than itch resol e with purpura or last longer
than h should prompt a biopsy to e clude urticarial
asculitis. lesions burn rather than itch and i patients ha e
associated e er arthralgias or other e idence o systemic
in ammation and antihistamines are not e ecti e an ac uired
autoin ammatory syndrome should be considered and a trial
o ana inra may be use ul.
Acute urticaria
The mainstay o treatment o acute urticaria is administration
o antihistamines. n adults nonsedating antihistamines pose
a lower ris o psychomotor impairment. the cause o the
acute episode can be identi ed a oiding that trigger should
be stressed. n patients with acute urticaria that does not
respond to antihistamines systemic corticosteroids are gener
ally e ecti e. Less rebound is seen with a wee tapered
course o systemic corticosteroid therapy than with shorter
courses.
or se ere reactions including anaphyla is respiratory and
cardio ascular support is essential. A . mL dose o a
dilution o epinephrine is administered e ery min as
needed. n young children a hal strength dilution is used. n
rapidly progressi e cases intubation or tracheotomy may be
re uired. Ad uncti e therapy includes intramuscular antihis
tamines ( mg hydro y ine or diphenhydramine e ery
h as needed) and systemic corticosteroids ( mg hydrocor
tisone or mg methylprednisolone intra enously e ery h
or doses).
Chronic urticaria
n chronic spontaneous urticaria the goal o therapy is to
alle iate symptoms. The mainstay o treatment is administra
tion o antihistamines. These should be ta en on a daily basis;
antihistamines should not be prescribed to be ta en only as
needed. Second generation antihistamines (cetiri ine des
loratadine e o enadine acri astine ebastine mi olastine)
are large lipophilic molecules with charged side chains that
bind e tensi ely to proteins pre enting the drugs rom cross
ing the blood brain barrier; thus they produce less sedation in
most patients than the third generation antihistamine le oce
tiri ine. Long acting orms are a ailable and the long hal li e
o these antihistamines and reduced sedation result in
impro ed compliance and e cacy. irst line treatment is the
149
 use o a second or third generation nonsedating antihista
7 mine such as cetiri ine in standard dosage. a ter wee s
the symptoms persist the dosage should be increased up to
our times the standard dosage usually adding a second pill
in the e ening then a third in the A and a ourth in the A
Erythema and Urticaria
to a ma imum o pills per day two in the morning and two
in the e ening. this is ine ecti e another nonsedating anti
histamine may be tried. Some e perience indicates that e o
enadine is less li ely to wor at higher than standard dosages
so this is not escalated i there is no response at standard
dosage. Cetiri ine and some o the other second generation
antihistamines can cause drowsiness in some indi iduals
particularly in higher doses or when combined with other
antihistamines.
Although some add an bloc er such as ranitidine as well
e idence is con icting on whether this is an e ecti e strategy.
Ranitidine should not be used alone or treatment o urticaria
because it may inter ere with eedbac inhibition o histamine
release. Also do epin a tricyclic antidepressant with potent
antihistaminic acti ity may be use ul but e idence is
wea . Do epin is re uently dosed at bedtime so much o the
drowsiness and dry mouth are gone by morning. The same is
true or rst generation antihistamines; i any is added to the
pre ious second generation strategy it should only be used
at night.
it is necessary to consider other therapies the ollowing
guidance is o ered. Cyclosporine and prednisone are o ten
e ecti e but the potential or side e ects limit their clinical
utility. Also because the prognosis is that at least
patients and up to in some studies will continue to ha e
chronic spontaneous urticaria a ter years the role o these
two agents is limited. Dapsone colchicine and sul asala ine
may be most use ul i the biopsy shows a preponderance o
neutrophils and they may be added to antihistamine treat
ment i some response to the latter has been obtained. ydro y
chloro uine leu otriene receptor antagonists such as
montelu ast and e en phototherapy may ha e some bene t
in indi idual patients. Also their more satis actory sa ety
pro le ma es these therapies worth considering as alterna
ti es to medications such as omali umab and metho
tre ate which show more e idence o e cacy. Data are
accumulating that omali umab a recombinant humani ed
monoclonal antibody that binds to ree g is e ecti e in
many patients with chronic spontaneous urticaria in doses o
mg e ery wee s.
Topical corticosteroids topical antihistamines and topical
anesthetics ha e no role in the management o chronic urti
caria. or local treatment tepid or cold tub baths or showers
may be reely ad ocated i cold is not a trigger. Topical
camphor and menthol can pro ide symptomatic relie . Sarna
lotion contains menthol phenol and camphor.
n about one third o patients with chronic idiopathic urti
caria autoantibodies bind to high a nity g receptors.
n ortunately testing or this condition is not well standard
i ed has alse positi e results and is impractical. chronic
spontaneous urticaria is nonresponsi e to the pre ious
approach patients may re uire more aggressi e management
including chronic immunosuppressi e therapy plasmapher
esis or V G.
Angioedema
Angioedema is an acute e anescent circumscribed edema
that usually a ects the most distensible tissues such as the
eyelids lips ( ig. ) earlobes and e ternal genitalia or
the mucous membranes o the mouth tongue or laryn . The
swelling occurs in the deep dermis or in the subcutaneous
150
Fig. 7-19 Angioedema of the lips.
tissues and as a rule is only slightly tender with the o erlying
s in unaltered edematous or rarely ecchymotic. There may
be a di use swelling on the hands orearms eet and an les.
re uently the condition begins during the night and is ound
o on awa ening. Angioedema may target the G and respiratory
tracts resulting in abdominal pain cory a asthma and respi
ratory problems. Respiratory tract in ol ement can produce
airway obstruction. Anaphyla is and hypotension may also
occur.
There are two distinct subsets o angioedema. The rst is
considered a deep orm o urticaria and may be obser ed as
solitary or multiple sites o angioedema alone or in combina
tion with urticaria. The action o histamine creates asomotor
lability and pruritus may be a signi cant eature. The second
subgroup angioedema associated with C esterase inhibitor
de ciency or that related to AC inhibitors is not associated
with hi es or pruritus. Symptoms o pain predominate and
this de ciency is mediated by brady inin.
Hereditary angioedema
Also nown as uinc e edema hereditary angioedema ( A )
was originally described and named by sler in . A
characteristically appears be ore age . Sudden attac s o
angioedema occur as re uently as e ery wee s throughout
the patient s li e lasting or days. Swelling is typically
asymmetric and urticaria or itching does not occur. The pre
sentation may o erlap with that o the autoin ammatory
syndromes.
Patients may e perience local swelling in subcutaneous
tissues ( ace hands arms legs genitals buttoc s); abdominal
organs (stomach intestines bladder) mimic ing surgical
emergencies; and the upper airway (laryn ) which can be li e
threatening. There is minimal response to antihistamines epi
nephrine or corticosteroids. ortality is high o ten caused by
laryngeal edema. G edema is mani ested by nausea omiting
and se ere colic and it may simulate appendicitis so closely
that appendectomy is mista enly per ormed. The actors that
trigger attac s are minor trauma surgery sudden changes o
temperature or sudden emotional stress.
nherited in an autosomal dominant ashion A is esti
mated to occur in in persons. There are three
phenotypic orms o the disease. Type is characteri ed by low
antigenic and unctional plasma le els o a normal C esterase
inhibitor protein (C ). Type is characteri ed by the pres
ence o normal or ele ated antigenic le els o a dys unctional
protein. Type demonstrates normal C unction and
normal complement. The ma ority o patients are women. Cri
teria or type include a long history o recurrent attac s o
s in swelling abdominal pain or upper airway obstruction;
absence o urticaria; amilial occurrence; normal C and C
concentrations; and ailure o treatment with antihistamines
corticosteroids and C concentrate.
The screening test o choice or types and is a C le el.
C will be low (< o normal) as a result o continuous
acti ation and consumption. n addition to depressed C
le els patients with types and also ha e low C C and
C le els. the clinical picture and screening tests are positi e
a titer o C should be ordered. C is a labile protein and
sample decay is common. A low C in the presence o
normal C le els should raise the suspicion o sample decay
rather than true A .
The treatment o choice or acute A types and is
plasma deri ed or recombinant C inhibitor or contact system
modulators such as ecallantide or icatibant. Short term pro
phyla is (e.g. or patients undergoing dental care endoscopy
or intubation or surgery) can be obtained rom C inhibitors
or dana ol an attenuated androgen. strogens in oral con
tracepti es in contrast may precipitate attac s. Attenuated
androgens C inhibitors and in some cases anti brinolytics
are use ul or long term prophyla is. Patients with type do
not respond to C replacement but may respond to dana ol.
Acquired C1 esterase inhibitor deficiency
Some patients present with symptoms indistinguishable rom
A but with onset a ter the ourth decade o li e and lac ing
a amily history. As in A there is no associated pruritus
or urticaria. This condition is subdi ided into ac uired angio
edema and and an idiopathic orm. Ac uired angioedema
is a rare disorder associated with lymphoproli erati e
disease. These associations include lymphomas (usually B
cell) chronic lymphocytic leu emia monoclonal gammopa
thy myeloma myelo brosis Waldenstr m macroglobulin
emia and breast carcinoma. Some patients ha e detectable
autoantibodies to C . Worsening o stable A has been
the presenting sign o lymphoma. Part o the management o
this condition is to treat the causati e associated condition.
Ac uired angioedema is an e tremely rare disease de ned
by the presence o autoantibodies to C . t is important to
reali e that autoantibodies directed against C may also be
ound in ac uired angioedema particularly in patients with
B cell lymphomas so the diagnosis o ac uired angioedema
is made only when no such underlying condition e ists.
The pathophysiology o ac uired angioedema is un nown
but may be related to increased catabolism o C ; many
patients with the disorder ha e been shown to produce normal
amounts o C . n ac uired angioedema hepatocytes and
monocytes are able to synthesi e normal C ; howe er a
subpopulation o B cells secretes autoantibodies to the unc
tional region o the C molecule.
anagement o acute attac s in ac uired angioedema is
directed toward replacement o C with plasma deri ed or
recombinant C inhibitor. Some patients de elop progressi e
resistance to the in usions. Anti brinolytic agents such as
aminocaproic acid or trane amic acid may be bene cial
and are more e ecti e than antiandrogen therapy. Synthetic
androgens such as dana ol may be help ul in angioedema .
owe er androgens are ine ecti e in treating patients with
ac uired angioedema stressing the importance o identi y
ing these patients. mmunosuppressi e therapy has been
shown to be e ecti e in the treatment o ac uired angioedema
tahir99 - UnitedVRG
by decreasing autoantibody production. Systemic corticoste
roids may be temporarily e ecti e.
Episodic angioedema with eosinophilia
Urticaria (hives)
pisodic angioedema or isolated acial edema may occur with
e er weight gain eosinophilia and ele ated eosinophil ma or
basic protein (Gleich syndrome). The disorder is not uncom
mon and there is no underlying disease. ncreased le els o
L ha e been documented during periods o attac . Treat
ment options include administration o systemic steroidal
medications imatinib antihistamines and V G.
Anaphylaxis
Anaphyla is is an acute and o ten li e threatening immuno
logic reaction re uently heralded by scalp pruritus di use
erythema urticaria or angioedema. Bronchospasm laryngeal
edema hyperperistalsis hypotension and cardiac arrhythmia
may occur. Antibiotics (especially penicillins) other drugs
and radiographic contrast agents are the most common causes
o serious anaphylactic reactions. ymenoptera stings are the
ne t most re uent cause ollowed by ingestion o crustaceans
and other ood allergens. Atopic dermatitis is re uently
associated with anaphyla is regardless o origin. Causati e
agents can be identi ed in up to two thirds o cases and recur
rent attac s are the rule. ercise induced anaphyla is o ten
depends on priming by prior ingestion o a speci c ood or
ood in general and aspirin may be an additional e acerbating
actor.
Bernstein JA, et al: The diagnosis and management of acute and
chronic urticaria. J Allergy Clin Immunol 2014; 133:1270–1277.
Bianca-Lopez N, et al: Value of the clinical history in the diagnosis of
urticaria/angioedema induced by NSAIDs with cross-intolerance. Clin
Exp Allergy 2012; 43:85–91.
Hogan SR, et al: Adrenergic urticaria. J Am Acad Dermatol 2014;
70:763–766.
Kaplan AP: Biologic agents in the treatment of urticaria. Curr Allergy
Asthma Rep 2012; 12:288–291.
Khakoo G, et al: Clinical features and natural history of physical urticaria
in children. Pediatr Allergy Immunol 2008; 19:363–366.
Konstantinou GN, et al: EAACI taskforce position paper: evidence for
autoimmune urticaria and proposal for defining diagnostic criteria.
Allergy 2013; 68:27–36.
Lacy KE, et al: Galvanic urticaria. Clin Exp Dermatol 2006;
31:739–740.
Magerl M, et al: The definition and diagnostic testing of physical and
cholinergic urticarias: EAACI/GA2/EDF/UNEV consensus panel
recommendations. Allergy 2009; 64:1715–1721.
Marrouche N, et al: Childhood urticaria. Curr Opin Allergy Clin Immunol
2012; 12:485–490.
Maurer M, et al: Revisions to the international guideline on the
diagnosis and therapy of chronic urticaria. J Dtsch Dermatol Ges
2013; Aug 19. [Epub ahead of print.]
Metz M, et al: Omalizumab in chronic urticaria. Curr Opin Allergy Clin
Immunol 2012; 12:406–411.
Morita E, et al: Food-dependent exercise-induced anaphylaxis. J
Dermatol Sci 2007; 47:109–117.
Parish LC: Hereditary angioedema. J Am Acad Dermatol 2011;
65:843–850.
Patruno C, et al: Vibratory angioedema in a saxophonist. Dermatitis
2009; 20:346–347.
Pressler A, et al: Failure of omalizumab and successful control with
ketotifen in a patient with vibratory angio-oedema. Clin Exp Dermatol
2013; 38:151–153.
Sanchez-Borges M, et al: Diagnosis and treatment of urticaria and
angioedema. WAO J 2012; 5:125–147.
Scranton SE, et al: Episodic angioedema with eosinophilia: successful
treatment with imatinib. Ann Allergy Asthma Immunol 2008;
100:172–174.
151
 Sokumbi O, et al: Clinical and histopathologic review of Schnitzler
7 syndrome. J Am Acad Dermatol 2012; 67:1289–1295.
Tarbox JA, et al: Utility of routine laboratory testing in management of
Bonus images for this chapter can be found online at
expertconsult.inkling.com
chronic urticaria/angioedema. Ann Allergy Asthma Immunol 2011;
107:239–243. eFig. 7-1 Erythema multiforme, target lesions.
Erythema and Urticaria

Tinazzi E, et al: Schnitzler syndrome, and autoimmune autoinflammatory
syndrome. Autoimmunity Rev 2011; 10:404–409.
Trojan TD, et al: Calcineurin inhibitors in chronic urticaria. Curr Opin
Allergy Clin Immunol 2012; 12:412–420.
Vanderschueren S, et al: Canakinumab in Schnitzler syndrome. Semin
Arthritis Rheum 2013; 42:413–416.
Xu Y-Y, et al: Update on treatment of hereditary angioedema. Clin Exp
All 2013; 43:395–406.
Yao Q, et al: Dermatitis as a characteristic phenotype of a new
autoinflammatory disease associated with NOD2 mutations. J Am
Acad Dermatol 2013; 68:624–631.
Zuberbier T, et al: EAACI/GA2LEN/EDF/WAQ guideline: definition,
classification and diagnosis of urticaria. Allergy 2009;
64:1417–1426.
Zuberbier T, et al: EAACI/GA2LEN/EDF/WAQ guideline: management of
urticaria. Allergy 2009; 64:1427–1443.
eFig. 7-2 Erythema multiforme, target lesions.
eFig. 7-3 Erythema multiforme involving the lips.
eFig. 7-4 Mucosal lesions of erythema multiforme.
eFig. 7-5 Erythema annulare centrifugum.
eFig. 7-6 Sweet syndrome, intensely edematous lesion.
eFig. 7-7 Sweet syndrome, erythema lesions.
eFig. 7-8 Enlarging ulcer of pyoderma gangrenosum.
eFig. 7-9 Cold urticaria after ice cube applied to site for 3 min.
eFig. 7-10 Annular and polycyclic urticaria.
eFig. 7-11 Dermatographism.
eFig. 7-12 Cholinergic urticaria, small papules with surrounding large,
erythematous flare.
eFig. 7-13 Cold urticaria after ice cube applied to site for 3 min.

152
 Urticaria (hives)
eFig. 7-1 Erythema multiforme, target lesions. eFig. 7-4 Mucosal lesions of erythema multiforme.

eFig. 7-2 Erythema

multiforme, target
lesions.

eFig. 7-5 Erythema annulare centrifugum.

eFig. 7-6 Sweet

syndrome, intensely
edematous lesion.

eFig. 7-3 Erythema multiforme involving the lips.

152.e1

tahir99 - UnitedVRG
 eFig. 7-10 Annular and
7 polycyclic urticaria.
Erythema and Urticaria

eFig. 7-7 Sweet syndrome, erythema lesions.

eFig. 7-8 Enlarging

ulcer of pyoderma
gangrenosum.

eFig. 7-11
Dermatographism.

eFig. 7-9 Cold urticaria

after ice cube applied
to site for 3 min.

152.e2
 Urticaria (hives)
eFig. 7-12 Cholinergic urticaria, small papules with surrounding eFig. 7-13 Cold urticaria after ice cube applied to site for 3 min.
large, erythematous flare.

152.e3

tahir99 - UnitedVRG
 Bonus images for this chapter can be found online at
Connective Tissue Diseases
Lupus erythematosus (L ) dermatomyositis scleroderma
rheumatoid arthritis S gren syndrome eosinophilic asciitis
relapsing polychondritis and related disorders are classi ed
as connecti e tissue diseases. Basic to all these is a comple
array o autoimmune responses that target or a ect collagen
or ground substance.
LUPUS ERYTHEMATOSUS
Lupus may mani est as a systemic disease or in purely cutane
ous orms. Cutaneous mani estations o L are classi ed as in
Bo . The course o DL is ariable but
Chronic cutaneous lupus erythematosus
Discoid lupus erythematosus
Discoid lupus erythematosus (DL ) generally occurs in young
adults with women outnumbering men . Lesions begin as
dull red macules or indurated pla ues that de elop an adher
ent scale then e ol e with atrophy scarring and pigment
changes ( ig. ). n dar er s inned indi iduals lesions typi
cally demonstrate areas o both hyperpigmentation and depig
mentation. n lighter s inned patients the pla ues may appear
gray or ha e minimal pigment alteration. The hyper eratosis
characteristically e tends into patulous ollicles producing
carpet tac li e spines on the undersur ace o the scale.
Very small lesions o DL may be mista en or actinic era
toses. Some early discoid lesions are super cial resembling
seborrheic dermatitis. thers may be brightly erythematous or
e en urticarial.
Localized discoid lupus erythematosus
Discoid lesions are usually locali ed abo e the nec . a ored
sites are the scalp bridge o the nose malar areas lower lip
and ears ( ig. ). The concha o the ear and e ternal canal
are re uently in ol ed. Some patients present with perior
bital edema and erythema. n the scalp most lesions begin as
erythematous patches or pla ues that e ol e into white o ten
depressed hairless patches. Peri ollicular erythema and the
presence o easily e tractable anagen hairs are signs o acti e
disease and are help ul in monitoring the response to therapy.
Scarred areas may appear completely smooth or may demon
strate dilated ollicular openings in the ew remaining ollicles.
tching and tenderness are common and may rarely be se ere.
n the lips lesions may be gray or red and hyper eratotic.
They may be eroded and are usually surrounded by a narrow
red in ammatory one ( ig. ). n one study o DL
patients had mucosal in ol ement o the mouth nose eye or
ul a. Rarely aggressi e s uamous cell carcinoma arises in
long standing lesions o DL .
expertconsult.inkling.com
8
Generalized discoid lupus erythematosus
Generali ed DL is less common than locali ed DL . All
degrees o se erity are encountered. ost o ten the thora
and upper e tremities are a ected as well as the head and
nec ( ig. ). The scalp may become uite bald with stri
ing patterns o hyperpigmentation and depigmentation.
Di use scarring may in ol e the ace and upper e tremities.
Laboratory abnormalities such as an ele ated erythrocyte
sedimentation rate ( SR) ele ated antinuclear antibodies
(A As) single stranded (ss) D A antibodies and leu ope
nia are more common with this orm o L than with local
i ed DL .
o cases con ned
to the s in at the outset will remain so. Progression rom
purely cutaneous DL to systemic lupus erythematosus
(SL ) occurs in re uently. owe er patients with SL re
uently ha e discoid lesions. These patients generally ha e
systemic in ol ement early in the course o their disease
rather than e ol ing rom chronic cutaneous L to SL .
e er and arthralgia are common in patients with SL and
discoid lesions. n patients with systemic symptoms abnor
mal laboratory tests such as ele ation o A As antibodies
to double stranded (ds) D A and C leu openia hematu
ria and proteinuria help to identi y patients with SL and
suggest a prognosis.
Childhood discoid lupus erythematosus
Among children with DL a low re uency o photosensiti
ity and a higher rate o association with SL ha e been noted.
n most other respects the clinical presentation and course are
similar to those in adults.
Histology
The epidermis may demonstrate e acement o the rete ridge
pattern or irregular acanthosis. Compact hyper eratosis
without para eratosis is characteristic and ollicular plugging
is typically prominent. ydropic degeneration o the basal
layer o the epidermis and ollicular epithelium results in pig
mentary incontinence. A patchy peri ascular and periadne al
lymphoid in ammatory in ltrate occurs in the super cial and
deep dermis. The in ltrate characteristically surrounds essels
ollicles and the eccrine coil. ncreased mucin is o ten present
and may be isible as deposition o a blue to amphophilic
substance between collagen bundles or merely as a widening
o the space between the bundles. Thic ening o the basement
membrane one (B ) may be prominent.
The histology aries with the stage o the lesion. Acute
lesions show only patchy lymphoid in ammation and acu
olar inter ace dermatitis. Lesions established or se eral
months begin to show hyper eratosis B thic ening and
dermal mucin. Chronic inacti e lesions show atrophy with
postin ammatory pigmentation and scarring throughout the
dermis. At this stage the in ammatory in ltrate is sparse to
153
8 Box 8-1 Classification of cutaneous manifestations of lupus
erythematosus (LE)
I. Chronic cutaneous LE
Connective Tissue Diseases

A. Discoid LE
1. Localized
2. Disseminated
B. Verrucous (hypertrophic) LE (Behçet): usually acral and
often lichenoid
C. Lupus erythematosus–lichen planus overlap
D. Chilblain LE
E. Tumid lupus
F. Lupus panniculitis (LE profundus)
1. With no other involvement
2. With overlying discoid LE
3. With systemic LE
Fig. 8-2 Discoid lupus erythematosus.
II. Subacute cutaneous LE
A. Papulosquamous
B. Annular
C. Syndromes commonly exhibiting similar morphology
1. Neonatal LE
2. Complement deficiency syndromes
3. Drug-induced
III. Acute cutaneous LE: localized or generalized erythema or
bullae, generally associated with SLE

Fig. 8-1 Extensive

scarring from discoid
lupus erythematosus.

Fig. 8-3 Lupus of the lip.

Fig. 8-4 Generalized

discoid lupus
erythematosus.

absent. Pilosebaceous units e cept or orphaned arrector

muscles are destroyed. At this stage the dermis appears
brotic but an elastic tissue stain can still distinguish the
di use dermal scar o lupus rom the ocal wedge shaped
super cial scars o lichen planopilaris (LPP) or olliculitis o immunoglobulin and complement located at the dermo
decal ans. Direct immuno uorescence (D ) testing o epidermal unction (D J). Transporting specimens in normal
lesional s in is positi e in more than o cases pro ided saline may result in a higher yield than ree ing or ichel s
the lesions ha e been acti e or at least se eral months and transport medium i the specimen can reach the laboratory
usually demonstrate strong continuous granular deposition within hours.
154

tahir99 - UnitedVRG

Differential diagnosis
Discoid L must o ten be di erentiated rom seborrheic der
matitis rosacea lupus ulgaris sarcoidosis drug eruptions
actinic eratosis Bowen s disease lichen planus (LP) tertiary
syphilis and polymorphous light eruption (P L ). Seborrheic
dermatitis does not show atrophy alopecia or dilated ollicles
and has greasy yellowish scale without ollicular plugs. Acral
lip and scalp lesions o chronic cutaneous L may demon
strate lichenoid dermatitis histologically. n these cases the
presence o continuous granular immunoglobulin in addition
to cytoid bodies is a help ul distinguishing eature.
n rosacea atrophy does not occur and pustules are almost
always ound. Apple elly nodules (granulomas) are seen with
diascopy in lupus ulgaris. Sunlight sensiti ing agents such
as sul onamides may produce lesions similar to L because
phototo ic reactions demonstrate acuolar inter ace dermati
tis. t may be necessary to di erentiate syphilis and sarcoid by
biopsy and serologic testing. P L is distinguished by the
absence o scarring and the presence o intensely edematous
pla ues and papules. D is generally negati e or nonspeci c
in P L .
Hypertrophic lupus erythematosus
onpruritic papulonodular lesions may occur on the arms and
hands resembling eratoacanthoma or hypertrophic LP ( ig.
). The lips and scalp may also demonstrate lesions that
resemble LP or LPP. istologic sections o these lesions typi
cally demonstrate lichenoid dermatitis and a care ul e amina
tion or other characteristic s in lesions o L or LP as well as
D testing may be critical in establishing a diagnosis. B
thic ening dermal mucin eccrine coil in ol ement and sub
cutaneous nodular lymphoid in ltrates are eatures o L that
are not ound in LP.
Lupus erythematosus–lichen planus
overlap syndrome
n addition to the cases o hypertrophic L with lichenoid
histology pre iously discussed there are patients with a true
Fig. 8-5 Hypertrophic
lupus erythematosus.
o erlap syndrome with eatures o both L and LP. The lesions
are usually large atrophic hypopigmented red or pin
patches and pla ues. Pigment abnormalities become promi
nent o er time and ne telangiectasia and scaling are usually
present. The e tensor aspects o the e tremities and midline
Lupus erythematosus
bac are typically a ected. Prominent palmoplantar in ol e
ment is characteristic and tends to be the most troublesome
eature or these patients. ail dystrophy and anonychia may
occur. Scarring alopecia and oral in ol ement ha e been noted
in some patients. The histology o indi idual lesions has ea
tures o LP and or L . D usually suggests the ormer but
immuno uorescence may demonstrate a continuous granular
deposition o immunoglobulin. Response to treatment is poor
although potent topical corticosteroids dapsone thalidomide
or isotretinoin may be e ecti e. Some patients re uire immu
nosuppressi e therapy with agents such as mycophenolate
mo etil ( ) or a athioprine. t should also be noted that
antimalarials can occasionally produce a lichenoid drug erup
tion in patients with L .
Chilblain lupus erythematosus
Chilblain L ( utchinson) is a chronic unremitting orm o
L a ecting the ngertips rims o ears cal es and heels
especially in women. t is usually preceded by DL on the ace.
Systemic in ol ement is sometimes seen. imicry o sarcoid
osis may be stri ing. Cryoglobulins and antiphospholipid
antibody (APLA) should also be sought.
Tumid lupus erythematosus
Tumid L is a rare but distincti e entity. Patients present with
edematous erythematous pla ues usually on the trun ( ig.
). istologically the lesions demonstrate a patchy super
cial and deep peri ascular and periadne al lymphoid in ltrate
that re uently a ects the eccrine coil. Dermal mucin deposi
tion is typical and may be stri ing. The lesions generally
respond readily to antimalarials. Tumid L shares many
Fig. 8-6 Tumid lupus.
155
 Fig. 8-7 Lupus
8 panniculitis with
overlying discoid
lupus erythematosus.
Connective Tissue Diseases
eatures with reticular erythematous mucinosis and some
authorities consider them to be closely related entities.
Lupus erythematosus panniculitis (lupus
erythematosus profundus)
Patients with the panniculitis type o L de elop subcutane
ous nodules that are usually rm sharply de ned and non
tender. The pro imal e tremities are typically in ol ed.
sually the o erlying s in is normal but o erlying discoid or
tumid lesions may occur ( ig. ). Some cases are disco ered
incidentally when an unrelated lesion is biopsied. The lesions
may heal with deep depressions rom loss o the panniculus.
L panniculitis is characteristically chronic and occurs most
o ten in women between ages and . any patients ha e
DL at other sites or less typically in the o erlying s in.
istologic sections demonstrate lymphoid nodules in the
subcutaneous septa necrosis o the at lobule and brinoid or
hyaline degeneration o the remaining lipocytes. Lipomembra
nous change resembling rost on a windowpane is more
typical o stasis panniculitis (lipodermatosclerosis) but it may
be noted ocally in L panniculitis. The o erlying epidermis
may show basal li ue action and ollicular plugging or may
be normal. Dermal lymphoid nodules or ertical columns o
lymphoid cells may be seen in brous tract remnants. Dermal
mucin may be prominent and dermal collagen hyalini ation
(resembling that seen in morphea) may be present. Continu
ous granular deposition o immunoglobulin and C may be
seen at the D J. n acti e cases abundant brin is usually
noted in the panniculus.
The most important entity to consider in the di erential
diagnosis is subcutaneous panniculitis li e lymphoma. mpor
tant clues include the presence o lipocytes rimmed by atypi
cal lymphocytes with nuclear molding and the presence o
constitutional symptoms. rythrophagocytosis may be present
ocally and T cell clonality can usually be demonstrated. The
in ltrate may be CD dominant or may label strongly or
CD as in natural iller cell lymphoma or CD as in ana
plastic lymphoma. CD and CD e pression may be reduced
(aberrant loss o pan T mar ers). n ortunately T cell clonal
ity erythrophagocytosis CD predominance and loss o
CD or CD may also be seen in patients with L panniculitis
who respond to antimalarials or corticosteroids and do not
156
tahir99 - UnitedVRG
Fig. 8-8 Subacute cutaneous lupus erythematosus.
progress to clinical lymphoma. Ta en together these data
suggest that some cases o lymphoma may be irtually indis
tinguishable rom L panniculitis or that some cases o L
panniculitis represent an aborti e lymphoid dyscrasia.
Subacute cutaneous lupus erythematosus
n Sontheimer Thomas and Gilliam described a clini
cally distinct subset o cases o L to which they ga e the name
subacute cutaneous lupus erythematosus (SCL ). Patients are
most o ten white women age . SCL patients ma e up
appro imately o the L population. Lesions are scaly
and e ol e as polycyclic annular lesions or psoriasi orm
pla ues. The lesions ary rom red to pin with aint iolet
tones. The scale is thin and easily detached and telangiectasia
or dyspigmentation may be present. ollicles are not in ol ed;
the lesions tend to be transient or migratory and there is no
scarring. Lesions tend to occur on sun e posed sur aces o the
ace and nec the V portion o the chest and bac ( ig. )
and the sun e posed areas o the arms. Photosensiti ity is
prominent in about hal o patients. Concomitant DL is
present in o cases.
About three uarters o patients ha e arthralgia or arthritis
ha e leu openia and ha e a positi e A A test
(usually in a particulate pattern). About one third o patients
meet the American Rheumatology Association (ARA) criteria
or a diagnosis o SL . The ma ority o cases ha e antibodies
to Ro SSA antigen and most are positi e or human leu ocyte
antigen ( LA) DR . La SSB may also be present and many
patients ha e o erlap eatures with S gren syndrome. The
disease generally runs a mild course and renal central ner ous
system (C S) or ascular complications are unusual. An asso
ciation with autoimmune thyroid disease has been noted.
ost patients respond to sun protection and antimalarial
agents. Drug induced SCL is most o ten related to hydro
chlorothia ide but may also be seen with angiotensin
con erting en yme (AC ) inhibitors calcium channel bloc ers
(CCBs) inter erons ( s) anticon ulsants griseo ul in gly
buride piro icam penicillamine spironolactone terbina ne
and statins.
Histopathology
Vacuolar inter ace dermatitis is a uni ersal nding in acti e
SCL lesions. ild hyper eratosis and para eratosis may be
present. Chronic changes o DL such as ollicular plugging
B thic ening and hea y lymphoid aggregates are usually

Fig. 8-9 Neonatal lupus erythematosus.
lac ing. Dermal mucin is ariable. D is positi e in lesional
s in in only about one third o cases. A dustli e particulate
deposition o gG in epidermal nuclei o Ro positi e patients
may be present and is a help ul diagnostic nding.
Neonatal lupus erythematosus
ost in ants with neonatal lupus are girls born to mothers
who carry the Ro SSA antibody. These in ants ha e no s in
lesions at birth but de elop them during the rst ew wee s
o li e. Annular erythematous macules and pla ues may
appear on the head and e tremities ( ig. ). Periocular
in ol ement (raccoon eyes) may be prominent. With time the
lesions ade and become atrophic. Telangiectasia or dermal
mucinosis in an acral papular pattern may be the predominant
ndings in some cases. Telangiectatic macules or angiomatous
papules may be ound in sun protected sites such as the diaper
area may occur independently o acti e lupus s in lesions
and may be persistent. The s in lesions usually resol e spon
taneously by months o age and usually heal without
signi cant scarring although atrophy and telangiectatic mats
may persist. Dyspigmentation and persistent telangiectasias
may remain or months to years. al the mothers are
asymptomatic at deli ery although many will subse uently
de elop arthralgia S gren syndrome or other mild systemic
ndings.
Although the s in lesions are transient hal the patients
ha e an associated isolated congenital heart bloc usually
third degree which is permanent. Some in ants ha e only this
mani estation o L and or cardiac lesions alone there is no
emale predominance. n children with cutaneous in ol e
ment thrombocytopenia and hepatic disease may occur as
re uently as cardiac disease.
There is a strong association with Ro SSA autoantibody.
Almost all mothers and thus almost all in ants are positi e
or this antibody although some mothers are also positi e or
La SSB and some with only R P antibodies ha e been
described. n ants with only R P antibodies ha e not
de eloped heart bloc . There is lin age to LA DR in the
mother. The ris that a second child will ha e neonatal L is
appro imately . Japanese in ants apparently di er in that
they may e press anti dsD A antibodies and progress to
SL . n unselected women with anti Ro antibodies only
will ha e an in ant with neonatal L .
Complement deficiency syndromes
Although de ciency o many complement components may
be associated with L li e conditions de ciencies o the early
components especially C and C are most characteristic.
any such cases are ound to ha e photosensiti e annular
SCL lesions and Ro SSA antibody ormation. Patients with
C de ciency o ten ha e hyper eratosis o the palms and
soles. etero ygous de ciency o either complement com
Lupus erythematosus
ponent C A or C B has a re uency o appro imately
in white populations. omo ygous de ciency o both is
rare and a ected patients may present with SL with mesan
gial glomerulonephritis membranous nephropathy and
se ere s in lesions. Although re uently asymptomatic homo
ygous C de ciency can cause se ere in ections SL and
atherosclerosis.
Systemic lupus erythematosus
oung to middle aged women are predominantly a ected by
SL mani esting a wide range o symptoms and signs. S in
in ol ement occurs in o cases and is o ten help ul in
arri ing at a diagnosis. ts importance is suggested by the act
that o the American College o Rheumatology (ACR)
criteria or the diagnosis o SL are mucocutaneous ndings.
The diagnostic criteria are as ollows
. alar rash
. Discoid rash
. Photosensiti ity
. ral ulcers ( )
. Arthritis
. Proteinuria > . g day or casts
. eurologic disorders (sei ures or psychosis in the
absence o other nown causes)
. Pleuritis pericarditis
. Blood abnormalities (e.g. hemolytic anemia
leu openia thrombocytopenia)
. mmunologic disorders including anti dsD A
antibody anti Sm APLAs (based on gG or g
anticardiolipin antibodies lupus anticoagulant (LA)
or alse positi e serologic test or syphilis nown or
at least months)
. Positi e A A blood test
or identi cation o patients in clinical studies a patient
may be said to ha e SL i our or more o these criteria are
satis ed serially or simultaneously. t is important to note that
many patients present with autoantibodies arthralgia and
constitutional signs but do not meet ACR criteria or SL .
With time patients may e ol e to meet all criteria. The Sys
temic Lupus nternational Collaborating Clinics (SL CC)
group re ision o the ACR criteria results in greater sensiti ity
with e ual speci city. According to the SL CC rule the patient
must mani est at least our criteria (including at least one clini
cal criterion and one immunologic criterion) or must ha e
biopsy pro en lupus nephritis in the presence o either A As
or anti dsD A antibodies.
Cutaneous manifestations
The characteristic butter y acial erythema seen in patients
with SL is a common mani estation o acute cutaneous L .
The eruption usually begins on the malar area and the bridge
o the nose. There may be associated edema. The ears and
chest may also be the sites o early lesions. Biopsies at all sites
show inter ace dermatitis and a scant peri ascular lymphoid
in ltrate. The eruption may last a day to se eral wee s and
resol es without scarring. There may be more widespread
erythema in some cases.
157
8
Connective Tissue Diseases

Fig. 8-10 Bullous lupus erythematosus. Fig. 8-11 Oral lesions of systemic lupus erythematosus.

Bullous lesions o lupus erythematosus (BL ) occur as

single or grouped esicles or bullae o ten widespread with
a predilection or sun e posed areas ( ig. ). Rarely the
lesions may itch. ost sets o published criteria re uire that
patients with BL meet ACR criteria or SL but some
patients ha e identical bullous lesions and less than our
ACR criteria. ACR criteria are critical to ensure that patients
with similar se erity are enrolled in clinical trials but these
sometimes all short in the e aluation o a gi en patient. is
tologically neutrophils accumulate at the D J and within
dermal papillae. n bullous lesions there is a subepidermal
bulla or super cial dermal edema containing neutrophils.
luorescence with gG g gA or C is typically present in
a continuous granular pattern at the B on D testing.
eutrophils are ound in or below the lamina densa on
immuno uorescent electron microscopy. ost o these
patients are LA DR positi e. The recognition o this subset
as distinct is made clear by its o ten dramatic therapeutic
response to dapsone. pidermolysis bullosa ac uisita is his
topathologically and immunopathologically identical since
both diseases are mediated by circulating antibodies against
type V collagen. Dapsone is usually ine ecti e in epider Fig. 8-12 Papulonodular mucinosis.
molysis bullosa ac uisita. Bullous lesions also occasionally
arise as a result o li ue acti e degeneration o the basal cell
layer or ull thic ness epidermal necrosis resembling to ic orrhages erosions shallow angular ulcerations with sur
epidermal necrolysis (T ). rounding erythema and gingi itis are common ( ig. ).
A ariety o ascular lesions occur in o SL patients. rythema petechiae and ulcerations may occur on the hard
ten ngertips or toes show edema erythema or telangiec palate.
tasia. ail old capillary loops in L are more li ely to show ultiple erupti e dermato bromas ha e been described in
wandering glomeruloid loops whereas dermatomyositis and SL . Leg ulcers typically deeply punched out and with ery
scleroderma capillary loops demonstrate symmetric dilation little in ammation may be seen on the pretibial or malleolar
and dropout o essels. Capillary loops in the sler Weber areas. any o these patients present with a li edoid pattern
Rendu syndrome demonstrate ectasia o hal the capillary and many ha e an antiphospholipid antibody. Sneddon syn
loop. rythema multi orme ( ) li e lesions may predomi drome is composed o li edo reticularis and stro es related to
nate termed Rowell syndrome. Rarely T may be associ a hyalini ing asculopathy. Both li e and T li e pre
ated with lupus. sentations ha e been described.
n addition to periungual telangiectasia red or spotted Calcinosis cutis is uncommon but may be dramatic. Also
lunulae may be present in patients with SL as in RA. The seen in re uently are pla ueli e or papulonodular depositions
palms soles elbows nees or buttoc s may become persis o mucin. These reddish purple to s in colored lesions are
tently erythematous or purplish sometimes with o erlying o ten present on the trun and arms or head and nec ( ig.
scale. Di use nonscarring hair loss is common. Short hairs in ). Lastly a symmetric papular eruption o the e tremities
the rontal region are called lupus hairs. These hairs result may occur ( ig. ). These s in colored to erythematous
rom a combination o chronic telogen e u ium and increased lesions with a smooth ulcerated or umbilicated sur ace may
hair ragility. show asculitis or in older lesions a palisaded granulomatous
ucous membrane lesions are seen in o SL in ammation. These occur in patients with SL RA or other
patients and chronic cutaneous lupus may be locali ed to immune comple mediated disease. This eruption has been
the eyelid or oral mucosa. Con uncti itis episcleritis and re erred to as palisaded neutrophilic and granulomatous der
nasal and aginal ulcerations may occur. ral mucosal hem matitis o immune comple disease.

158

tahir99 - UnitedVRG

Fig. 8-13 Palisaded neutrophilic granulomatous dermatitis.
Fig. 8-14 Cutaneous
thrombosis in
antiphospholipid
antibody syndrome.
Systemic manifestations
ost organs can be in ol ed in SL ; the symptoms and nd
ings are o ten caused by immune comple disease especially
asculitis. The earliest changes noted may be transitory or
migratory arthralgia o ten with periarticular in ammation.
e er weight loss pleuritis adenopathy or acute abdominal
pain may occur. Arthralgia is o ten the earliest abnormality
and may remain the sole symptom or some time. About
o SL patients will mani est this symptom. Arthralgia
de orming arthropathy and acute migratory polyarthritis
resembling RA may all occur as mani estations o SL . A as
cular necrosis o the emoral head has been obser ed. Although
this is a nown complication o systemic corticosteroid therapy
it has also occurred in patients with SL who ha e ne er ta en
corticosteroids.
Patients with SL ha e a higher rate o peripheral arterial
disease compared with controls. Thrombosis in essels o
arious si es and thromboembolism may be a recurring e ent
( ig. ). t may be attributed to a plasma constituent para
do ically called lupus anticoagulant (LA) because it causes
prolonged coagulation studies in itro but thrombosis in
i o. The nding o an LA is usually associated with APLAs.
These may be anticardiolipin antibodies but other APLA
types antiphosphatidylserine antiphosphatidylinositol and
antiphosphatidylethanolamine may occur. APLAs and ele
Lupus erythematosus
ated homocysteine may each increase the ris o thrombosis.
APLAs are associated with early onset organ damage. any
but not all patients ha e a alse positi e blood test or syphilis.
n one study in ammatory lesions o SL and in ections were
the most common causes o death during the initial years o
disease while thromboses were the most common cause o
death a ter the rst years.
Renal in ol ement may be o either nephritic or nephrotic
type leading in either case to chronic renal insu ciency with
proteinuria and a otemia. Acti e nephritis is unli ely in the
absence o anti dsD A. Both anti dsD A antibody and anti
C antibody are o relati ely high speci city or acti e
nephritis. ypercholesterolemia and hypoalbuminemia may
occur. mmunoglobulin and complement components ha e
been ound locali ed to the B o glomeruli where asculitis
produces the characteristic wire loop lesion.
yocarditis is indicated by cardiomegaly and gallop rhythm
but the electrocardiographic ( CG) changes are usually not
speci c. Pericarditis the most re uent cardiac mani estation
and endocarditis also occur. Raynaud phenomenon occurs in
about o patients who ha e less renal disease and conse
uently lower mortality.
The C S may be in ol ed with asculitis mani ested by
hemiparesis con ulsions epilepsy diplopia retinitis choroi
ditis psychosis and other personality disorders. Li edo retic
ularis is a mar er or patients at ris or C S lesions (Sneddon
syndrome; see earlier).
diopathic thrombocytopenic purpura is occasionally the
orerunner o SL . Coombs positi e hemolytic anemia neu
tropenia and lymphopenia are other hematologic ndings.
Gastrointestinal (G ) in ol ement may produce symptoms o
nausea omiting and diarrhea. re uently the intestinal wall
and the mesenteric essels show asculitis. Pulmonary
in ol ement with pleural e usions interstitial lung disease
and acute lupus pneumonitis may be present. S gren syn
drome ( eratocon uncti itis sicca) and ashimoto thyroiditis
are associated with SL . erlap with any o the connecti e
tissue diseases may be seen occurring in appro imately
o patients. uscular atrophy may accompany e treme wea
ness so that dermatomyositis may be suspected. yopathy o
the acuolar type may produce muscular wea ness myocar
dial disease dysphagia and achalasia o the esophagus.
Steroid myopathy may also occur. The serum aldolase le el
may be ele ated with a normal creatine phospho inase. Type
B insulin resistance syndrome with insulin receptor antibodies
accompanied by pancytopenia has been reported in the setting
o chronic discoid L e ol ing to SL .
A history o e posure to e cessi e sunlight be ore the onset
o the disease or be ore an e acerbation is sometimes obtained.
Some patients may ha e only mild constitutional symptoms
or wee s or months but immediately a ter e posure to strong
sunlight they may de elop the acial eruption and se ere
disease complications.
ydrala ine procainamide sul onamides penicillin anti
con ulsants minocycline and isonia id ha e been implicated
as causes o drug induced L . ost drug induced lupus is
associated with a positi e A A test antihistone antibodies
and sometimes serositis. Penicillamine induces (or unmas s)
true SL and etanercept has produced a range o ndings
including SL . Anti tumor necrosis actor (T ) agents ha e
produced a shi t to a lupus pro le o autoantibodies in patients
with RA.
159
 Childhood systemic lupus erythematosus
8 The onset o childhood SL occurs between ages and with
girls outnumbering boys . The s in mani estations may be
the typical butter y eruption on the ace and photosensiti ity.
Connective Tissue Diseases
n addition there may be morbilli orm bullous purpuric
ulcerating or nodose lesions. The oral mucosa is re uently
in ol ed. S in eruptions may be associated with oint renal
neurologic and G disease. Weight loss atigue hepatospleno
megaly lymphadenopathy and e er are other mani esta
tions. Pediatric patients with SL and APLAs speci cally
lupus anticoagulants are at high ris o de eloping thrombo
embolic e ents.
Pregnancy
Women with L may ha e success ul pregnancies but they
might ha e di culty concei ing and miscarriages occur with
greater re uency especially among those with APLAs. The
course o pregnancy may be entirely normal with remission
o the L or the symptoms o L may become worse. Ris o
etal death is increased in women with a pre ious history o
etal loss and anticardiolipin or anti Ro antibodies. Low dose
aspirin is o ten used in the ormer situation. or the patient
with these antibodies but without a history o pre ious etal
loss the ris o etal loss or neonatal lupus is low. n most
cases the pregnancy itsel is well tolerated although a are o
SL may occur during the postpartum period. Se eral studies
ha e ailed to demonstrate a clinically signi cant association
between oral contracepti e ( C) use and ares o SL . There
is a high incidence o thromboses in women with APLAs and
Cs containing second or third generation progestogens may
induce a higher ris .
Etiology
A amily history o connecti e tissue disease is a strong ris
actor or all orms o L . LA and gene lin age studies
suggest a strongly heritable component and some s in lesions
o L ollow lines o Blasch o suggesting post ygotic muta
tion or loss o hetero ygosity or a genetic locus. The C reacti e
protein (CRP) response is de ecti e in patients with ares o
SL and the gene locus or CRP maps to . within an
inter al lin ed with SL . Gene polymorphisms in P L a
member o the T amily ha e also been lin ed with SL .
ncreased e pression o T α and inducible protein
my o irus protein A is noted in cutaneous L . Polymorphisms
o the C gene are associated with both systemic and cuta
neous L . Strong lin age has been ound with SL at p .
and as well as other candidate
sites. Lin age aries in di erent ethnic groups and di erent
clinical subsets o lupus. Ta en together these data suggest
polygenetic susceptibility to L .
Both ultra iolet ( V) B and VA can upregulate antigen
e pression and cyto ines causing release o se uestered anti
gens and ree radical damage. All these mechanisms may con
tribute to photosensiti ity and V induced ares o systemic
disease.
Se eral aspects o the altered immune response are worth
particular attention. T suppressor cell unction is reduced in
patients with L . erproduction o γ globulins by B cells and
reduced clearance o immune comple es by the reticuloendo
thelial system may contribute to complement mediated
damage. ternali ation o cellular antigens such as Ro SSA
in response to sunlight may lead to cell in ury by way o
antibody dependent cellular cytoto icity. Abnormal apoptosis
or reduced clearance o apoptotic cells may lead to increased
e posure o nucleosome antigens and antinucleosome anti
160
tahir99 - UnitedVRG
bodies. LA DR indi iduals who are slow acetylators are
predisposed to de elop hydrala ine induced L . Antibody to
the histone comple A B is closely associated with
disease. n most drug induced L antibodies are directed
against histones. ceptions include penicillamine and etaner
cept which may induce or unmas nati e disease with anti
dsD A antibodies. Pegylated α and riba irin ha e also
produced systemic L during treatment or chronic hepatitis
C. Drugs implicated in SCL are listed earlier in this chapter.
L Cana anine an amino acid ound in al al a sprouts and
tablets can also induce or worsen SL . inimal credible data
e ist regarding other possible aggra ating dietary actors but
some reports ha e implicated e cess calories e cess protein
high at (especially saturated and ω polyunsaturated atty
acids) e cess inc and e cess iron. Well designed studies are
needed. Cigarette smo ing is associated with increased disease
acti ity in SL and can inter ere with the e ects o antima
larial drugs.
Laboratory findings
There may be hemolytic anemia thrombocytopenia lympho
penia or leu openia; SR usually is greatly ele ated during
acti e disease Coombs test may be positi e there is a biologic
alse positi e test or syphilis and a rheumatoid actor (R )
may be present. gG le els may be high the albumin globulin
ratio is re ersed and serum globulin is increased especially
the γ globulin or α raction. Albumin red blood cells and
casts are the most re uent ndings in the urine.
Immunologic findings
. test. This is positi e in o cases o SL .
uman substrates such as ep or B tumor cell lines
are ar more sensiti e than mouse substrates. A A
pattern has some correlation with clinical subsets such
as a shrun en peripheral pattern in SL with renal
disease a ne particulate pattern in subacute cutaneous
L and a homogeneous pattern with antihistone
antibodies.
. Lupus er thematosus cell test. This is speci c but not ery
sensiti e and has been deleted rom the ACR criteria.
. Double stran e D . nti sD anti native D .
This is speci c but not ery sensiti e. t indicates a high
ris o renal disease and correlates with a shrun en
peripheral A A pattern and positi e D in sun
protected s in.
. nti Sm antibo . Sensiti ity is less than but
speci city is ery high.
. ntinuclear ribonucleic aci protein anti n P . Very high
titers are present in mi ed connecti e tissue disease
( CTD). Lower titers may be seen in SL .
. nti La antibo ies. These are common in SCL and
S gren syndrome and occasionally ound in SL .
. nti o antibo ies. These are ound in about o SL
and o S gren patients. They are more common in
patients with SCL ( ) neonatal L ( ) C and
C de cient L ( ) late onset L ( ) and
Asian patients with L ( ). Photosensiti ity may
be stri ing and e ternali ation o the antigen is seen
a ter V e posure.
. Serum complement. Low le els indicate acti e disease
o ten with renal in ol ement.
. Lupus ban test. Direct cutaneous immuno uorescence.
Continuous granular deposits o immunoglobulins and
complement along the D J occur in more than o
well established lesions o DL . n SL it usually is
 positi e in sun e posed s in. A positi e test in normal
protected s in correlates with the presence o anti
dsD A antibodies and renal disease. The lupus band
test is seldom per ormed because the same population
o patients can be detected with anti dsD A antibodies.
. nti ssD antibo . This test is sensiti e but not
speci c. any patients are photosensiti e. An g
isotope seen in DL may identi y a subset o patients at
ris or de eloping systemic symptoms.
. ntiphospholipi antibo ies. Both the anticardiolipin
antibody and the lupus anticoagulant are subtypes o
APLAs. These are associated with a syndrome that
includes enous thrombosis arterial thrombosis
spontaneous abortions and thrombocytopenia. Li edo
reticularis is a re uent s in nding and non ading
acral microli edo with small pin cyanotic lesions on
the hands and eet is a subtle clue to the presence o
APLAs. These antibodies may occur in association with
lupus and other connecti e tissue disease or as a
solitary e ent. n the latter case it is re erred to as the
primary antiphospholipid syndrome.
Differential diagnosis
Diagnostically SL must be di erentiated rom dermatomyo
sitis polyarteritis nodosa acute rheumatic e er RA pel
lagra pemphigus erythematosus (Senear sher syndrome)
drug eruptions hyperglobulinemic purpura S gren syn
drome necroti ing angiitis and myasthenia gra is. The SL
patient may ha e e er arthralgia wea ness lassitude diag
nostic s in lesions increased SR cytopenias proteinuria
immunoglobulin deposition at D J and positi e A A test.
Biopsies o s in lesions and in ol ed idney may also be
diagnostic.
Treatment
Some general measures are important or all patients with L .
posure to sunlight must be a oided and a high sun protec
tion actor (SP ) sunscreen should be used daily. Photosensi
ti ity is re uently present e en i the patient denies it and all
patients must be educated about sun a oidance and sunscreen
use. The patient should also a oid e posure to e cessi e cold
to heat and to locali ed trauma. Biopsies and scar re ision will
o ten pro o e a are o the disease. Women with SL ha e an
increased ris o osteoporosis independent o corticosteroid
use and ritu imab may increase the ris . Bone density should
be monitored and calcium and itamin D supplementation
considered. Some women will bene t rom bisphosphonate
therapy especially i corticosteroids are used. The most rapid
bone loss with corticosteroid therapy occurs at the onset o
treatment so bisphosphonate therapy should not be delayed.
Patients who will be treated with immunosuppressi e agents
should recei e a tuberculin s in test as well as a thorough
physical e amination. Aggressi e treatment is o ten necessary
or discoid lesions and scarring alopecia. The slowly progres
si e nature o these lesions and the lac o systemic in ol e
ment may lead to inappropriate therapeutic complacency.
The result is slow progressi e dis gurement.
Local treatment
The application o potent or superpotent topical corticoste
roids is bene cial in L patients. cclusion may be necessary
and may be enhanced by customi ed inyl appliances (espe
cially or oral lesions) or surgical dressings. Tape containing
corticosteroid (Cordran) is sometimes help ul. The single most
e ecti e local treatment is the in ection o corticosteroids into
the lesions. Triamcinolone acetonide . mg mL is in l
trated into the lesion through a gauge needle at inter als o
wee s. o more than mg o triamcinolone should be
used at one time. Steroid atrophy is a alid concern but so are
the atrophy and scar produced by the disease. The minimal
Lupus erythematosus
intralesional dose needed to control the disease should be
used; when the response is poor howe er it is generally better
to err on the slightly more aggressi e side o treatment than
to undertreat. Topical calcineurin inhibitors (topical macrolac
tams) may also be use ul as second line topical therapy. Pho
todynamic therapy has been reported as e ecti e.
Systemic treatment
The sa est class o systemic agent or L is the antimalarials.
Retinoids are second line agents and are particularly help ul
in treating hypertrophic L . Systemic immunosuppressi e
agents are o ten re uired to manage the systemic mani esta
tions o L and these are third line systemic agents or cutane
ous L . Thalidomide can be e ecti e but its use is limited by
the ris o teratogenicity and neuropathy. Dapsone is the drug
o choice or bullous systemic L and may be e ecti e in some
cases o SCL and DL . ral prednisone is generally reser ed
or acute ares o disease. Biologic agents are now used or
re ractory disease as described later.
Antimalarials
ydro ychloro uine (Pla uenil) at a dose or . mg g day
or less has an e cellent sa ety pro le and is generally used as
rst line systemic therapy in most orms o cutaneous L .
no response occurs a ter months another agent should be
considered. Chloro uine (Aralen) is e ecti e at mg day
or an a erage adult but is di cult to procure. uinacrine
(Atabrine) mg day may be added to hydro ychloro
uine because it adds no increased ris o retinal to icity.
uinacrine is also di cult to procure and carries a higher ris
o dis guring pigmentation than the other antimalarials. Sys
temic treatment can sometimes be reduced or stopped during
the winter months. A Cochrane group re iew o randomi ed
controlled trials (RCTs) concluded that hydro ychloro uine
and acitretin appear to be o similar e cacy although ad erse
e ects are more se ere and occur more o ten with acitretin.
cular to icity is rare with doses o hydro ychloro uine o
. mg g day or less. phthalmologic consultation should
be obtained be ore and at month to month inter als
during treatment. Constriction o isual elds to a red ob ect
and paracentral scotomas are rare at the recommended dose
but e en a small ris o loss o ision must be ta en seriously.
The nding o any isual eld de ect or pigmentary abnormal
ity is an indication to stop antimalarial therapy.
ther reported side e ects with antimalarials include eryth
roderma purpura urticaria ner ousness tinnitus abdu
cens ner e paralysis to ic psychoses leu openia and
thrombocytopenia. Antimalarials e cept in ery small doses
will e acerbate s in disease or cause hepatic necrosis in
patients with porphyria cutanea tarda. They may also worsen
or induce psoriasis. uinacrine produces a yellow discolor
ation o the s in and con uncti ae. uinacrine has also been
nown to produce blue blac pigmentation o the hard palate
nail beds cartilage o the ears alae nasi and sclerae. ther
antimalarials may also rarely produce a blue blac pigmenta
tion o s in. Bullous lichenoid drug eruption nausea
omiting anore ia and diarrhea may de elop. Aplastic
anemia has rarely been noted in long term therapy. A patient s
brown or red hair may turn light blond.
Corticosteroids
Systemic corticosteroids are highly e ecti e or widespread
or dis guring lesions but disease acti ity o ten rebounds
161
 uic ly when the drug is discontinued. Because o long term
8 side e ects corticosteroid treatment should be limited to
short (generally ≤ wee s) courses to treat ares o disease or
to obtain initial control while antimalarial therapy is being
initiated. n patients with renal or neurologic in ol ement
Connective Tissue Diseases
corticosteroids should be administered in doses ade uate to
control the disease while treatment with a steroid sparing
regimen is initiated. Treatment with mg day intra e
nous methylprednisolone or days ollowed by oral pred
nisone . mg g day is e ecti e in uic ly re ersing
most clinical and serologic signs o acti ity o lupus nephri
tis. n general the corticosteroid dose should be optimi ed to
the lowest possible that controls symptoms and laboratory
abnormalities.
Immunosuppressive therapy
Aggressi e treatment protocols with agents such as pulse
cyclophosphamide (with hydration and mesna to pre ent
bladder to icity) ha e greatly impro ed the outcome o renal
L . ther immunosuppressi e agents (e.g. a athioprine
methotre ate ) are o ten employed as steroid sparing
agents or re ractory cutaneous disease. Some authorities ha e
suggested that a athioprine is in erior to in the treat
ment o cutaneous lesions. nterleu in ( L) receptor inhibi
tion with tocili umab appears promising but may cause
neutropenia.
Other therapy
sotretinoin therapy mg g day may be e ecti e espe
cially in patients with hypertrophic or lichenoid lesions o L .
Rapid relapse may be noted when the drug is discontinued.
Dapsone clo a imine acitretin alpha a aurano n (oral
gold) high dose intra enous gamma globulin ( V G) e ali
umab and thalidomide ha e all been reported as e ecti e in
anecdotal use or limited trials. Pulsed dye laser has been
shown to be e ecti e or some erythematous lesions o cutane
ous L but should be used cautiously because it may also
cause ares o disease. lares are also common with surgical
modalities used to impro e scarring or alopecia. Anti CD
monoclonal antibody (ritu imab) has been used success ully
to treat li e threatening re ractory SL with renal and C S
in ol ement as well as or hypocomplementemic urticarial
asculitis and re ractory cutaneous lesions. Although lupus is
a photosensiti e disorder VA therapy appears to be a
use ul ad u ant treatment modality in some patients and pho
todynamic therapy has been e ecti e in some patients. lu
astatin appears promising in patients with antiphospholipid
syndrome based on its ability to suppress prothrombotic
mar ers. Clinical alidation is needed along with no el
agents because aspirin resistance is common among patients
with the syndrome. Tolerogenic dendritic cells show some
promise or the treatment o autoimmune diseases including
lupus.
Akdogan A, et al: Aspirin resistance in systemic lupus erythematosus. a
pilot study. Lupus 2013; 22(8):835–838.
Albrecht J, et al: Dermatology position paper on the revision of the
1982 ACR criteria for systemic lupus erythematosus. Lupus 2004;
13:839.
Barsalou J, et al: An update on childhood-onset systemic lupus
erythematosus. Curr Opin Rheumatol 2013; 25(5):616–622.
Boackle SA: Advances in lupus genetics. Curr Opin Rheumatol 2013;
25(5):561–568.
Calvo-Alén J, et al: SER consensus statement on the use of biologic
therapy for systemic lupus erythematosus. Rheumatol Clin 2013;
9(5):281–296.
Cavazzana I, et al: Treatment of lupus skin involvement with quinacrine
and hydroxychloroquine. Lupus 2009; 18(8):735–739.
Condon MB, et al: Prospective observational single-centre cohort study
to evaluate the effectiveness of treating lupus nephritis with rituximab
162
tahir99 - UnitedVRG
and mycophenolate mofetil but no oral steroids. Ann Rheum Dis 2013;
72(8):1280–1286.
Erkan D, et al: A prospective open-label pilot study of fluvastatin on
proinflammatory and prothrombotic biomarkers in antiphospholipid
antibody positive patients. Ann Rheum Dis 2014; 73(6):1176–1180.
Grech P, et al: Targeted therapies in systemic lupus erythematosus.
Lupus 2013; 22(10):978–986.
Hassan AA, et al: Peripheral arterial disease in patients with systemic
lupus erythematosus: a prospective controlled study. Int J Rheum Dis
2013; 16(3):319–324.
Hofmann S, et al: Effects of rituximab-based B-cell depletion therapy on
skin manifestations of lupus erythematosus: report of 17 cases and
review of the literature. Lupus 2013; 22(9):932–939.
Jessop S, et al: Drugs for discoid lupus erythematosus. Cochrane
Database Syst Rev 2009; (4):CD002954.
Kuhn A, et al: Treatment of cutaneous lupus erythematosus. Lupus
2010; 19(9):1125–1136.
Liu CC, et al: Biomarkers in systemic lupus erythematosus: challenges
and prospects for the future. Ther Adv Musculoskelet Dis 2013;
5(4):210–233.
Llanos C, et al: Tolerogenic dendritic cells as a therapy for treating
lupus. Clin Immunol 2013; 148(2):237–245.
Luo YJ, et al: Correlation of cutaneous immunoreactants in lesional skin
with the serological disorders and disease activity of systemic lupus
erythematosus. PLoS One 2013; 8(8):e70983.
Marzano AV, et al: Drug-induced lupus: an update on its dermatologic
aspects. Lupus 2009; 18(11):935–940.
Md Yusof MY, et al: B-cell-targeted therapies in systemic lupus
erythematosus and ANCA-associated vasculitis: current progress.
Expert Rev Clin Immunol 2013; 9(8):761–772.
Ostensen M, et al: Pathogenesis of pregnancy complications in
systemic lupus erythematosus. Curr Opin Rheumatol 2013;
25(5):591–596.
Petri M, et al: Derivation and validation of the Systemic Lupus
International Collaborating Clinics classification criteria for systemic
lupus erythematosus. Arthritis Rheum 2012; 64(8):2677–2686.
Pinto CM, et al: Bone mineral density in systemic lupus erythematosus
women one year after rituximab therapy. Lupus 2013; Aug 29. [Epub
ahead of print.] PMID: 23989736.
Rao V, et al: Latest advances in connective tissue disorders. Ther Adv
Musculoskelet Dis 2013; 5(4):234–249.
Sticherling M, et al: Diagnostic approach and treatment of cutaneous
lupus erythematosus. J Dtsch Dermatol Ges 2008; 6(1):48–59.
Sui W, et al: Hematopoietic and mesenchymal stem cell transplantation
for severe and refractory systemic lupus erythematosus. Clin Immunol
2013; 148(2):186–197.
Van Vollenhoven RF: Challenges and opportunities in SLE clinical trials.
Curr Opin Rheumatol 2013; 25(5):606–615.
Walling HW, et al: Cutaneous lupus erythematosus: issues in diagnosis
and treatment. Am J Clin Dermatol 2009; 10(6):365–381.
Zattra E, et al: TNF blockade and cutaneous lupus erythematosus:
where do we stand and where are we going? Immunotherapy 2013;
5(8):791–794.
DERMATOMYOSITIS
Dermatomyositis (D ) is typically characteri ed by in am
matory myositis and s in disease although the hypomyop
athic type (D with subclinical or absent myopathy) also
occurs. uscle in ol ement without s in changes is called
polymyositis (P ). With or without s in lesions wea ness o
pro imal muscle groups is characteristic.
Skin findings
sually the disease begins with erythema and edema o the
ace and eyelids. yelid in ol ement may be characteri ed by
pruritic and scaly pin patches edema and pin ish iolet
(heliotrope) discoloration or bullae ( ig. ). Pruritic scaly
pin patches are o ten seen in amyopathic D . dema and
pin ish iolet discoloration are o ten signs o in ammation in
 Fig. 8-15 Heliotrope
rash in patient with
dermatomyositis.
Fig. 8-16 Chest erythema in dermatomyositis.
the underlying striated orbicularis oculi muscle rather than
the s in itsel ; the patient s eyelids may be tender to the touch.
Bullous D may portend a poor prognosis and patients o ten
ha e se ere in ammatory myopathy or lung disease.
ther s in changes include erythema scaling and swelling
o the upper ace o ten with in ol ement o the scalp and
eyebrows. er time the lesions tend to de elop a reticulated
pattern o white scarring. tensor sur aces o the e tremities
are o ten pin red or iolaceous with an atrophic appearance
or o erlying scale. The similarity to psoriasis can be stri ing
and patients may su er se ere ares o D i they are inap
propriately treated with phototherapy or presumed psoriasis.
Photosensiti ity to natural sunlight is common as well. irm
slightly pitting edema may be seen o er the shoulder girdle
arms and nec ( ig. ). Associated erythema and scale
(with or without poi iloderma) o er the shoulder regions is
nown as the shawl sign. Similar changes on the hip are
called the holster sign. Pruritus may be se ere especially on
the scalp and is much more common in D than in psoriasis
or L . ccasionally a agellate pattern mimic ing bleomycin
induced linear edematous strea s or erythroderma may be
seen.
n the hands telangiectatic essels o ten become prominent
in the pro imal nail olds. nlarged capillaries o the nail old
appear as dilated sausage shaped loops with ad acent a as
cular regions similar to those changes obser ed in sclero
derma but without the associated sclerodactyly. There may be
cuticular o ergrowth with an irregular rayed appearance
( ig. ). A pin to reddish purple atrophic or scaling erup
tion o ten occurs o er the nuc les nees and elbows (Got
tron s sign). lat topped polygonal iolaceous papules o er
the nuc les (Gottron s papules) are less common but highly
characteristic o D ( ig. ). yper eratosis scaling ssur
ing and hyperpigmentation o er the ngertips sides o the
thumb and ngers with occasional in ol ement o the palms
Dermatomyositis
Fig. 8-17 Cuticular fraying of proximal nailfold.
Fig. 8-18 Gottron’s
papules of
dermatomyositis
involving the knuckles.
is re erred to as mechanic s hands and has been reported in
o patients with antisynthetase antibodies ( ig. ).
ntermittent e er malaise anore ia arthralgia and mar ed
weight loss are typically present at this stage.
n some patients with disease remission the residual hyper
pigmentation simulates the bron e discoloration o Addison s
disease. Rarely large persistent ulcerations in e ural areas
or o er pressure points may de elop. lceration in the early
stages o D has been reported to be associated with a higher
incidence o cancer and a poor prognosis but the authors ha e
seen many patients with ulcerati e D without associated
cancer. n later stages ulceration may merely be a mani esta
tion o pressure or trauma to atrophic areas. Rarely D may
be associated with clinical ndings o pityriasis rubra pilaris
(Wong ariant o D ) or generali ed subcutaneous edema.
Calcium deposits in the s in and muscles occur in more than
hal o children with D and are ound in re uently in adults.
Calci cation is related to duration o disease acti ity and its
se erity. Calcinosis o the dermis subcutaneous tissue and
muscle occurs mostly on the upper hal o the body around
the shoulder girdle elbows and hands. lcerations and cel
lulitis are re uently associated with this debilitating and dis
abling complication o D .
163

8 myositis
Connective Tissue Diseases
Fig. 8-19 “Mechanic’s hands” in dermatomyositis.
Muscle changes
n patients with se ere D early and e tensi e muscular
wea ness occurs with acute swelling and pain. The muscle
wea ness is seen symmetrically most re uently in ol ing the
shoulder girdle and sometimes the pel ic region as well as
the hands. The patients may notice di culty in li ting e en the
lightest ob ects. They may be unable to raise their arms to
comb their hair and rising rom a chair may be impossible
without pushing o with the arms. Patients o ten complain
o pain in the legs when standing bare oot or o being unable
to climb stairs. Di culty in swallowing tal ing and breath
ing caused by wea ness o the in ol ed muscles may be
noted early in the disease. Some patients with se ere dia
phragmatic disease re uire mechanical entilation. Cardiac
ailure may be present in the terminal phase o the disease.
S in in ol ement re uently precedes muscle in ol ement
but some patients ha e typical s in ndings o D but ne er
de elop clinically apparent muscle in ol ement. These cases
ha e been termed amyopathic D or D sine myositis.
owe er muscle in ammation o ten is present but not symp
tomatic and the term hypomyopathic is pre erred. uscle
en ymes (to include both creatine inase C and aldolase)
electromyography ( G) and magnetic resonance imaging
( R ) may be re uired to detect subtle in ol ement.
Diagnostic criteria
The ollowing criteria are used to de ne D P odic rescreening may be o alue but the appropriate inter al
S in lesions
eliotrope rash (red purple edematous erythema on
upper palpebra)
Gottron s papules or sign (red purple at topped
papules atrophy or erythema on e tensor sur aces and
nger oints)
Pro imal muscle wea ness (upper or lower e tremity
and trun )
le ated serum C or aldolase le el
uscle pain on grasping or spontaneous pain
yogenic changes on G (short duration polyphasic
motor unit potentials with spontaneous brillation
potentials)
Positi e anti Jo (histadyl tR A synthetase) antibody
ondestructi e arthritis or arthralgias
Systemic in ammatory signs ( e er > C at a illa
ele ated serum CRP le el or accelerated SR o
> mm h by Westergren method)
164
tahir99 - UnitedVRG
Pathologic ndings compatible with in ammatory
Patients with the rst criterion s in lesions and our o the
remaining criteria ha e D . Patients lac ing the rst criterion
but with at least our o the remaining criteria ha e P . Some
patients with D ha e little e idence o myopathy and drug
eruptions may mimic the characteristic rash. n particular
hydro yurea has been associated with a D li e eruption.
Antisynthetase antibody syndrome presents with ariable sys
temic mani estations mainly P interstitial lung disease
cutaneous lesions and Raynaud phenomenon.
Associated diseases
Dermatomyositis may o erlap with other connecti e tissue
diseases. Sclerodermatous changes are the most re uently
obser ed; this is called sclerodermatomyositis. Antibodies
such as anti u and anti P scl may be present in this sub
group. i ed connecti e tissue disease associated with high
anti ribonucleoprotein (R P) RA L and S gren syndrome
may occur concomitantly. D may be associated with inter
stitial lung disease which is re uently the cause o death. The
presence o anti Jo antibody as well as other antisynthetase
antibodies such as anti PL anti PL anti DJ and anti J
correlates well with the de elopment o pulmonary disease.
en patients without anti Jo should routinely be screened
or interstitial lung disease ( LD) because up to o LD
patients are seronegati e or the anti Jo antibody in pub
lished reports.
Neoplasia with dermatomyositis
n adults malignancy is re uently associated with D . The
malignancy is disco ered be ore simultaneously or a ter the
D at near e ual rates. The highest probability o nding an
associated tumor occurs within years o the diagnosis.
actors associated with malignancy include age constitutional
symptoms rapid onset o D lac o Raynaud phenomenon
and a grossly ele ated SR or C le el. alignancy is most
re uently seen in patients in the th and si th decades o li e.
Routine age appropriate screening may be inade uate to
unco er a signi cant number o malignancies. n addition to
history and physical e amination a stool guaiac test or occult
blood ( emoccult) mammography pel ic e amination chest
radiography and computed tomography (CT) scans o the
abdominal pel ic and thoracic areas may be indicated. Peri
or screening has not been established. The presence o leu o
cytoclastic asculitis might indicate a higher potential or
malignancy.
Childhood dermatomyositis
Se eral eatures o childhood dermatomyositis di er rom
the adult orm. Two childhood ariants e ist. The more
common Brunsting type has a slow course progressi e
wea ness calcinosis and steroid responsi eness ( ig. ).
Calcinosis may in ol e intermuscular ascial planes or may
be subcutaneous. The second type the Ban er type is
characteri ed by a asculitis o the muscles and G tract
rapid onset o se ere wea ness steroid unresponsi eness
and high mortality. nternal malignancy is seldom seen in
children with either type but insulin resistance may be
present. Calcinosis cutis is more common in children with
se ere disease.

Fig. 8-20 Childhood dermatomyositis.
Etiology
idence indicates that muscle ndings in D are related to
humoral immunity a asculopathy mediated by complement
deposition lysis o endomysial capillaries and resulting
muscle ischemia. n contrast P and inclusion body myositis
are related to clonally e panded CD + cytoto ic T cells in ad
ing muscle bers and causing necrosis through the per orin
pathway. The initial immune response in D is an α β
induced cascade with secondary stimulation o γ. any
autoantibodies may be present in D some o which are
disease speci c and can identi y speci c subgroups. n addi
tion to the antisynthetase antibodies pre iously discussed the
anti i antibody is present in some patients with acute onset
o classic D and a good prognosis.
Both healthy indi iduals and children with u enile D
may demonstrate persistence o maternal microchimerism but
the incidence is higher in children with u enile D . This has
also been demonstrated in patients with other connecti e
tissue diseases such as scleroderma. The nding may be an
epiphenomenon or may be part o a pathogenic alloimmune
response. An inherited predisposition has been demonstrated
and studies o u enile D gene e pression ha e shown
D A in o patients.
Viral or bacterial in ections may produce an abnormal
immune response and human herpes irus reacti ation
has been reported. ulminant disease may be related to
an endotheliotropic iral in ection. pitopes o group A β
hemolytic streptococcal protein ha e se uence homology
with myosin and can elicit both cell mediated cytoto icity
and T α production when incubated with mononuclear
cells rom children with acti e u enile D . The T α Differential diagnosis
A allele is associated with increased T α synthesis
in u enile D patients and with increased thrombospondin
and small essel occlusion. nterestingly as with L D
can be induced by anti T biologic agents. n adults with
P and D endothelial damage occurs early. Pathogenic
actors in adults include L α trans orming growth actor
(TG ) β and myoblast production o L . Cases associated
with terbina ne may be related to apoptosis induced by
the drug.
Incidence
The disease is twice as pre alent in women as in men and our
times as common in blac as in white patients. There is a
bimodal pea the smaller one seen in children and the larger
pea in adults age . used as steroid sparing agents and should be started early in
Histopathology
The histologic changes in D are similar to those o L . The
two may be indistinguishable although lesions o D tend to
become atrophic more o ten. Lesions typically demonstrate
Dermatomyositis
thinning o the epidermis hydropic degeneration o the basal
layer B thic ening papillary dermal edema and a peri
ascular and periadne al lymphocytic in ltrate in the super
cial and deep dermis with increased dermal mucin. Scattered
melanophages are present in the super cial dermis. Com
pared with L D shows less eccrine coil in ol ement and
ewer ertical columns o lymphocytes in brous tract rem
nants. Subcutaneous lymphoid nodules and panniculitis are
rarely seen in D . Characteristic changes are ound in the
muscles. The deltoid trape ius and uadriceps muscles seem
to be almost always in ol ed and are good biopsy sites.
uscle bundles demonstrate lymphoid in ammation and
atrophy which pre erentially a ects the periphery o the
muscle bundle. uscle biopsy is directed to those areas ound
to be most tender or in which G demonstrates myopathy.
R is a use ul aid in identi ying acti e sites or muscle biopsy
and may ob iate the need or biopsy in some cases. The short
T in ersion reco ery (ST R) R images are best and can be
used to locali e disease and longitudinally assess results o
treatment.
Laboratory findings
The serum C le els are ele ated in most patients. Aldolase
lactic dehydrogenase (LD ) and transaminases (ALT AST)
are other indicators o acti e muscle disease. There may be
leu ocytosis anemia with low serum iron and an increased
SR. Positi e A A tests are seen in o patients i a
human diploid substrate is used; ha e myositis
speci c antibodies.
Cutaneous D is positi e in at least one third o cases with
a higher yield in well established lesion (at least months
old). Cytoid bodies are o ten seen although continuous granu
lar staining with gG g and gA may be seen.
ray studies with barium swallow may show wea pharyn
geal muscles and a collection o barium in the piri orm sinuses
and alleculae. R o the muscles is an e cellent way to
assess acti ity o disease nonin asi ely.
The G studies or diagnosis show spontaneous brilla
tion polyphasic potential with oluntary contraction short
duration potential with decreased amplitude and sal os o
muscle stimulation.
Dermatomyositis must be di erentiated rom erysipelas SL
angioedema drug eruptions trichinosis and . Aldosteron
ism with adenoma o adrenal glands and hypo alemia may
also cause pu y heliotrope eyelids and ace. ydro yurea
may produce an eruption resembling D .
Treatment
Prednisone is the mainstay o acute treatment or D patients
at doses beginning with mg g day until se erity decreases
and muscle en ymes are almost normal. The dosage is reduced
with clinical response. The aspartate transaminase (AST
SG T) alanine transaminase (ALA SG T) and C return to
normal le els as remission occurs. ethotre ate and are
165
 the course o treatment to reduce steroid side e ects. Because
8
o the increased ris o LD with methotre ate some a oid this
agent in patients with pulmonary disease or anti Jo antibod
ies. A athioprine is less e pensi e than but s in disease
may not respond as well. patients do not respond ade uately
Connective Tissue Diseases
to methotre ate or a athioprine a trial o V G ( g
g day or days each month) cyclosporine or tacrolimus
may be bene cial. V G has been associated with thromboem
bolic e ents including deep enous thrombosis pulmonary
embolism myocardial in arction and cerebro ascular acci
dent (stro e) and this ris must be weighed against the ben
e ts o the drug. Anti T α treatment with in i imab has
pro ed a rapidly e ecti e therapy or some patients with myo
sitis. tanercept has also been used but some studies ha e
ound little impro ement or ares o muscle disease. Because
anti T therapy has been shown to induce D in the setting
o RA patients should be monitored care ully. Cyclophospha
mide is generally reser ed or re ractory cases. Le unomide
an immunomodulatory drug used to treat RA has been e ec
ti e as ad u ant therapy.
n se ere u enile D pulse V methylprednisone ( mg
g day) or oral prednisone are e ecti e or acute manage
ment but some data suggest that corticosteroids may not be
necessary in many children treated with methotre ate or V G.
Ritu imab appears promising in the treatment o re ractory
disease. nset o calcinosis is associated with delays in diag
nosis and treatment as well as longer disease duration. Calci
nosis related to D has been treated with aluminum hydro ide
diphosphonates diltia em probenecid colchicine low doses
o war arin and surgery with ariable but usually poor
results. Autologous stem cell transplantation has been reported
as success ul and polymy in B immobili ed ber column
treatment has been reported as success ul or rapidly progres
si e LD.
The s in lesions may respond to systemic therapy; howe er
response is unpredictable and s in disease may persist
despite in olution o the myositis. Because D is photosensi
ti e sunscreens with high SP (> ) should be used daily
and patients should be counseled about sun a oidance.
Topical corticosteroids may be help ul in some patients. Anti
malarials such as hydro ychloro uine at mg day
( mg g day in children) ha e been shown to be use ul
in abating the eruption o D although ad erse cutaneous
reactions are common. on li e threatening cutaneous reac
tions occur in appro imately one third o patients and up to
one hal o those who react to hydro ychloro uine will also
react to chloro uine. n pregnant patients who re uire treat
ment e idence supports the use o topical corticosteroids and
topical calcineurin inhibitors. Published e idence also sug
gests that systemic corticosteroids hydro ychloro uine and
a athioprine may be used in pregnancy when necessary. i
dence supporting the use o ritu imab V G dapsone photo
therapy and plasmapheresis consists only o case reports or
clinical e perience.
Prognosis
a or causes o death in D patients are cancer ischemic
heart disease and lung disease. ndependent ris actors
include ailure to induce clinical remission white blood cell
count abo e mm temperature greater than C
( . ) at diagnosis older age shorter disease history and
dysphagia. arly aggressi e therapy in u enile cases is associ
ated with a lower incidence o disabling calcinosis cutis. Anti
Ro and anti melanoma di erentiation associated gene
antibody (anti DA ) are mar ers or LD. Anti Jo may cor
relate more strongly with pulmonary alterations in P .
166
tahir99 - UnitedVRG
Broccolo F, et al: Selective reactivation of human herpesvirus 6 in
patients with autoimmune connective tissue diseases. J Med Virol
2013; 85(11):1925–1934.
Callen JP: Cutaneous manifestations of dermatomyositis and their
management. Curr Rheumatol Rep 2010; 12(3):192–197.
Chen Z, et al: Utility of anti–melanoma differentiation–associated gene 5
antibody measurement in identifying patients with dermatomyositis and
a high risk for developing rapidly progressive interstitial lung disease: a
review of the literature and a meta-analysis. Arthritis Care Res
(Hoboken) 2013; 65(8):1316–1324.
Choy E, et al: Immunosuppressant and immunomodulatory treatment
for dermatomyositis and polymyositis. Cochrane Database Syst Rev
2005; (3):CD003643.
Femia AN, et al: Cutaneous dermatomyositis: an updated review of
treatment options and internal associations. Am J Clin Dermatol 2013;
14(4):291–313.
Ghirardello A, et al: Autoantibodies in polymyositis and
dermatomyositis. Curr Rheumatol Rep 2013; 15(6):335.
Holzer U, et al: Successful autologous stem cell transplantation in two
patients with juvenile dermatomyositis. Scand J Rheumatol 2010;
39(1):88–92.
Mira-Avendano IC, et al: A retrospective review of clinical features
and treatment outcomes in steroid-resistant interstitial lung disease
from polymyositis/dermatomyositis. Respir Med 2013;
107(6):890–896.
Nagappa M, et al: Efficacy and limitations of pulse cyclophosphamide
therapy in polymyositis and dermatomyositis. J Clin Neuromuscul Dis
2013; 14(4):161–168.
Nakashima R, et al: Anti-MDA5 (melanoma differentiation–associated
gene 5) antibody and dermatomyositis with rapidly progressive
interstitial pneumonia. Nihon Rinsho Meneki Gakkai Kaishi 2013;
36(2):71–76.
Nalotto L, et al: Rituximab in refractory idiopathic inflammatory
myopathies and antisynthetase syndrome: personal experience
and review of the literature. Immunol Res 2013;
56(2/3):362–370.
Sasaki O, et al: A case of polymyxin B–immobilized fiber column
treatment for rapidly progressive interstitial pneumonia associated with
clinically amyopathic dermatomyositis. Case Rep Med 2013;
2013:750275.
Shimizu M, et al: Cutaneous calcinosis in juvenile dermatomyositis.
J Pediatr 2013; 163(3):921.
Uribe L, et al: Antisynthetase antibody syndrome: case report
and review of the literature. Clin Rheumatol 2013;
32(5):715–719.
SCLERODERMA
Scleroderma is characteri ed by the appearance o circum
scribed or di use hard smooth i ory colored areas that are
immobile and gi e the appearance o hidebound s in. t occurs
in both locali ed and systemic orms. Cutaneous types may be
categori ed as morphea (locali ed generali ed pro unda
atrophic and pansclerotic types) or linear scleroderma (with
or without melorheostosis or hemiatrophy). Progressi e sys
temic sclerosis (PSS) and the Thibierge Weissenbach syndrome
(usually called CR ST syndrome) are the two types o sys
temic scleroderma.
Cutaneous types
Localized morphea
The morphea orm o scleroderma is twice as common in
women as men and occurs in childhood as well as adult li e.
t presents most o ten as macules or pla ues a ew centimeters
in diameter but also may occur as bands or in guttate lesions
or nodules. Rose or iolaceous macules may appear rst ol
lowed by smooth hard somewhat depressed yellowish white
or i ory lesions. The lesions are most common on the trun
but also occur on the e tremities.
The margins o the areas are generally surrounded by a
lilac border or by telangiectases. Within the patch s in elas
ticity is lost and when it is pic ed up between the thumb
and inde nger it eels rigid. The ollicular ori ces may be
unusually prominent leading to a condition that resembles
pigs in.
n guttate morphea multiple small chal white at or
slightly depressed macules occur o er the chest nec shoul
ders or upper bac . The lesions are not ery rm and may be
di cult to separate clinically rom guttate lichen sclerosus et
atrophicus (LSA).
Morphea–lichen sclerosus et atrophicus overlap
Some patients present with lesions o both morphea and LSA
typically women with widespread morphea who ha e LSA
lesions separated rom morphea or o erlying morphea. When
the changes are seen abo e dermal changes o morphea the
characteristic in ammatory lymphoid band o LSA is lac ing
suggesting that the super cial homogeni ation is actually a
mani estation o morphea rather than a separate disease
process.
Generalized morphea
Widespread in ol ement by indurated pla ues with pigmen
tary change characteri es generali ed morphea. uscle atrophy
may be present but no isceral in ol ement ( ig. ). Patients
may lose their wrin les as a result o the rmness and contrac
tion o s in. Spontaneous in olution is less common with gen
erali ed morphea than with locali ed lesions.
Atrophoderma of Pasini and Pierini
n Pasini described a peculiar orm o atrophoderma now
thought to be in the spectrum o morphea. The disease consists
o brownish gray o al round or irregular smooth atrophic
lesions depressed below the le el o the s in with a well
demarcated sharply sloping border. Some o the appearance
o depression is an optical illusion related to the color change.
Atrophoderma occurs mainly on the trun o young predomi
nantly emale patients ( ig. ). The lesions are usually
asymptomatic and may measure cm or more in diameter.
Linear atrophoderma o oulin is a related condition that
ollows lines o Blasch o.
Biopsies o atrophoderma demonstrate a reduction in the
thic ness o the dermal connecti e tissue. Some widening and
hyalini ation o collagen bundles may be noted. Because the
changes may be subtle a biopsy should include normal
appearing s in so that a comparison may be made.
Fig. 8-21 Generalized morphea.
Pansclerotic morphea
Pansclerotic morphea mani ests as sclerosis o the dermis pan
niculus ascia muscle and at times the bone. The patient has
disabling limitation o oint motion.
Scleroderma
Morphea profunda
orphea pro unda in ol es deep subcutaneous tissue includ
ing ascia. There is clinical o erlap with eosinophilic asciitis
eosinophilia myalgia syndrome and the Spanish to ic oil syn
drome. The latter two conditions were related to contaminants
ound in batches o tryptophan or coo ing oil. nli e eosino
philic asciitis morphea pro unda shows little response to cor
ticosteroids and tends to run a more chronic debilitating
course.
Linear scleroderma
These linear lesions may e tend the length o the arm or leg
and may ollow lines o Blasch o. The condition o ten begins
during the rst decade o li e. Lesions may also occur parasag
ittally on the rontal scalp and e tend partly down the
orehead (en coup de sabre; ig. ). The Parry Romberg
syndrome which mani ests as progressi e hemi acial atrophy
epilepsy e ophthalmos and alopecia may be a orm o linear
scleroderma. When the lower e tremity is in ol ed there may
be associated spina bi da aulty limb de elopment hemiat
rophy or e ion contractures. elorheostosis seen on radio
graphs as a dense linear cortical hyperostosis may occur. At
times linear lesions o the trun merge into more generali ed
in ol ement. Physical therapy o the in ol ed limb is o para
mount importance to pre ent contractures and ro en oints.
Systemic types
CREST syndrome
This ariant o systemic scleroderma has the most a orable
prognosis because o the usually limited systemic in ol e
ment. Patients with CR ST syndrome de elop calcinosis cutis
Fig. 8-22
Atrophoderma of
Pasini and Pierini.
167
 Fig. 8-23 En coup de
8 sabre.
Connective Tissue Diseases
Fig. 8-24 Calcinosis in CREST syndrome.
Raynaud phenomenon esophageal dysmotility sclerodactyly
and telangiectasia ( ig. ). Patients may present with sclero
dactyly se ere heartburn or telangiectatic mats. The mats
tend to ha e a smooth outline in contrast to the mats o the
sler Weber Rendu syndrome which tend to e hibit an irreg
ular outline with more radiating essels. This orm o sclero
derma generally lac s serious renal or pulmonary in ol ement.
Anticentromere antibodies are highly speci c or the CR ST
syndrome being positi e in o cases and only
o patients with progressi e sclerosis.
Progressive systemic sclerosis
Progressi e systemic sclerosis (PSS) is a generali ed disorder
o connecti e tissue in which there is thic ening o dermal
collagen bundles as well as brosis and ascular abnormali
ties in internal organs. Raynaud phenomenon is the rst mani
estation o PSS in more than hal the cases. ther patients
present with woody edema o the hands. The heart lungs
G tract idney and other organs are re uently in ol ed.
Women are a ected three times more o ten than men with
pea age o onset between the third and th decades.
Classic criteria include either pro imal sclerosis or two or all
o the ollowing
168
tahir99 - UnitedVRG
Fig. 8-25 Sclerodactyly.
. Sclerodactyly ( ig. )
. Digital pitting scars o the ngertips or loss o substance
o the distal nger pad
. Bilateral basilar pulmonary brosis
Locali ed orms o scleroderma must be e cluded. These
criteria ha e been shown to be sensiti e and speci c
or the diagnosis. The ACR has proposed an e panded list o
criteria or PSS as ollows
. S in changes tightness thic ening and nonpitting
induration sclerodactyly pro imal scleroderma; changes
pro imal to the metacarpophalangeal or
metatarsophalangeal oints and a ecting other parts o
the e tremities ace nec or trun (thora or abdomen)
digital pitting loss o substance rom the nger pad
bilateral rm but pitting nger or hand edema abnormal
s in pigmentation (o ten pepper and salt ). The changes
are usually bilateral and symmetric and almost always
include sclerodactyly.
. a nau phenomenon at least two phase color change in
ngers and o ten toes consisting o pallor cyanosis and
reacti e hyperemia
. isceral manifestations bibasilar pulmonary brosis not
attributable to primary lung disease lower (distal)
esophageal dysphagia lower (distal) esophageal
dysmotility colonic sacculations
Skin findings
n the earlier phases o scleroderma a ected areas are ery
thematous and swollen. Patients are re uently misdiagnosed
as ha ing carpal tunnel syndrome and may e en ha e positi e
G results. Raynaud phenomenon is o ten present and sug
gests the correct diagnosis. er time sclerosis super enes.
The s in becomes smooth yellowish and rm and shrin s so
that the underlying structures are bound down. The earliest
changes o ten occur insidiously on the ace and hands and in
more ad anced stages these parts become hidebound so
the ace is e pressionless the mouth is constricted ( ig. )
and the hands are clawli e. The acial s in appears drawn
stretched and taut with loss o lines o e pression. The lips
are thin contracted and radially urrowed; the nose appears
sharp and pinched; and the chin may be puc ered. The nec
sign is described as a ridging and tightening o the nec on
e tension occurring in o patients with scleroderma.
The disease may remain locali ed to the hands and eet or
long periods (acrosclerosis). The ngers become semi e ed
 Fig. 8-26 Facial
involvement in
scleroderma.
immobile and useless the o erlying s in hard inelastic
incompressible and pallid. The terminal phalanges are board
li e and indurated. n the round nger pad sign the ngers
lose their normal pea ed contour and appear as rounded
hemispheres when iewed rom the side. This process may
lead to loss o pulp on the distal digit. Trophic ulcerations and
gangrene may occur on the tips o the ngers and nuc les
which may be pain ul or insensiti e. n pterygium in ersum
unguis the distal part o the nail bed remains adherent to the
entral sur ace o the nail plate; it may be seen in scleroderma
and L or may be idiopathic. Dilated nail old capillary loops
are present in o systemic scleroderma patients. Sym
metrically dilated capillaries are seen ad acent to a ascular
areas. ail old capillary hemorrhage in two or more ngers is
highly speci c or scleroderma and correlates with the anti
centromere antibody.
eloidli e nodules may de elop on the e tremities or the
chest and there may be a widespread di use calci cation o
the s in as shown by radiographs. A di use in ol ement o
the chest may lead to a cuirassli e restraint o respiration. Late
in the course o the disorder hyperpigmented or depigmented
spots or a di use bron ing may be present. The most charac
teristic pigmentary change is a loss o pigment in a large patch
with peri ollicular pigment retention within it. Peri ollicular
pigmentation may appear in response to V light e posure.
Pigment may also be retained o er super cial blood essels.
The a ected areas become hairless and atrophy is o ten asso
ciated with telangiectasia. Bullae and ulcerations may de elop
especially on the distal parts o the e tremities.
Internal involvement
Sclerosis may in ol e most o the internal organs. sophageal
in ol ement is seen in more than o PSS patients; the
distal two thirds o the esophagus is a ected leading to dys
phagia and re u esophagitis. Small intestinal atonia may lead
to constipation malabsorption or diarrhea. Pulmonary bro
sis with arterial hypo ia dyspnea and producti e cough may
be present. Progressi e nonspeci c interstitial brosis with
bronchiectasis and cyst ormation is the most re uent patho
logic change. Pulmonary hypertension and right sided heart
ailure are ominous signs occurring in o patients. The
cardiac in ol ement produces dyspnea and other symptoms
o congesti e heart ailure. Sclerosis o the myocardium also
produces conduction changes and may result in arrhythmia.
Pericarditis hypertension and retinopathy may be present.
The s eletal mani estations include articular pain swelling
and in ammation. Polyarthritis may be the rst symptom in
PSS. There is limitation o motion as a result o s in tautness
Scleroderma
ollowed by an ylosis and se ere contractual de ormities.
The hand oints are in ol ed most re uently. There may be
resorption and shortening o the phalanges and narrowing o
the oint spaces. steoporosis and sclerosis o the bones o the
hands and eet may occur as well as decalci cation o the
ault o the s ull.
Childhood PSS has identical cutaneous mani estations.
Raynaud phenomenon occurs less o ten whereas cardiac wall
in ol ement is more common and is responsible or hal o
deaths. Renal disease is unusual. amilial scleroderma rarely
occurs.
Prognosis
The course o PSS is ariable. Renal disease accounts or some
early mortality but pulmonary disease remains the ma or
cause o death. The patient s age at disease onset is a signi
cant ris actor or pulmonary arterial hypertension. Cardiac
disease also correlates with a poor prognosis whereas G
in ol ement contributes mainly to morbidity. A A patterns
predict di erent subsets o disease with arying prognosis.
Anticentromere antibodies correlate with CR ST syndrome
and a good prognosis whereas Scl and A A correlate with
a poorer prognosis. alignancy may be associated with PSS
in up to o patients with lung and breast cancer the most
re uent associated malignancies. The presence o many telan
giectases is strongly associated with the presence o pulmo
nary ascular disease.
Laboratory findings
n PSS A A testing is positi e in more than o patients.
As noted se eral o these antibodies identi y speci c clinical
subsets o patients. The antinucleolar pattern is considered
most speci c or scleroderma and when present as the only
pattern it is highly speci c or scleroderma. When antibodies
to such nucleolar antigens as R A polymerase t and brillarin
are present di use sclerosis generali ed telangiectasia and
internal organ in ol ement are o ten seen. The homogeneous
A A pattern is seen in patients with P Scl antibodies the
mar er or P scleroderma o erlap. The true spec led or anti
centromere pattern is sensiti e and speci c or the CR ST
ariant. Patients with antibodies to Scl tend to ha e di use
truncal in ol ement pulmonary brosis and digital pitted
scars but a lower incidence o renal disease. Antibodies to
nuclear R P are ound in patients with Raynaud phenome
non polyarthralgia arthritis and swollen hands. Very high
R P titers de ne mi ed connecti e tissue disease. These
patients are airly homogeneous and the term is not synony
mous with connecti e tissue o erlap. Anti ssD A antibodies
are common in linear scleroderma. Anti Rpp chemilumines
cence and anti Th To by immunoprecipitation correlate with
limited cutaneous and internal in ol ement. Cryoglobulins
are only ound in about o patients with PSS but the pres
ence o cryoglobulinemic asculitis is associated with a poor
prognosis.
Radiographic findings
The G tract is usually in ol ed. The esophagus may ha e
decreased peristalsis and dilation. sophagography and
esophageal manometry may be help ul. n early esophageal
in ol ement a barium swallow in the usual upright position
may be reported as normal. the patient is supine howe er
barium will o ten be seen to pool in the accid esophagus. The
stomach may be dilated and atonic resulting in delayed
169
 emptying time. n ol ement o the small intestine may cause
8 e treme dilation o the duodenum and e unum producing a
characteristic radiographic picture o persistently dilated
intestinal loops long a ter the barium has passed through.
Colonic or small intestinal sacculations may be present.
Connective Tissue Diseases
Histology
Systemic and locali ed orms o scleroderma show similar
histologic changes although lymphoid in ltrates tend to be
hea ier in the acute phase o morphea. n the acute phase
there is a peri ascular lymphocytic in ltrate with plasma cells
that is hea iest at the unction o the dermis and subcutaneous
at. Collagen bundles become hyalini ed and the space
between ad acent bundles is lost. Loss o CD + dermal den
dritic cells is an early nding.
Dermal sclerosis typically results in a rectangular punch
biopsy specimen. As the dermis replaces the subcutaneous
tissue eccrine glands appear to be in the midportion o the
thic ened dermis. The subcutaneous at is uantitati ely
reduced and ad entitial at ( at that normally surrounds
adne al structures on trun ) is lost. Collagen abuts directly on
the adne al structures. lastic bers in the reticular dermis
may be prominent and stain bright red and the papillary
dermis may appear pale and edematous. n ad anced lesions
the in ammatory in ltrate may be minimal. Pilosebaceous
units are absent and eccrine glands and ducts are compressed
by surrounding collagen.
n D testing o s in the nucleolus may be stained in the
eratinocytes i antinucleolar circulating antibodies are
present. A pepper dot epidermal nuclear reaction pattern
may be seen in CR ST patients who ha e anticentromere anti
bodies in their serum.
Differential diagnosis
y edema is so ter and associated with other signs o hypo
thyroidism. Diabetic scleredema tends to be erythematous and
a ects the central bac in a pebbly pattern. Scleromy edema
begins with discrete papules but may assume an appearance
similar to PSS. A paraprotein is typically present. Sclerodac
tyly may be con used with digital changes o ansen s disease
and syringomyelia. osinophilic asciitis is more steroid
responsi e. The s in is thic ened edematous and erythema
tous and has a coarse peau d orange appearance unli e
its sclerotic taut appearance in scleroderma. The hands and
ace are usually spared in eosinophilic asciitis and when the
arms are in ol ed the blood essels draw inward when the
arms are raised producing a dry ri erbed appearance.
n itiligo the depigmentation is the sole change in the s in
and sclerosis is absent. Scleroderma in the atrophic stage
may closely resemble acrodermatitis chronica atrophicans
(ACA) but ACA shows more attenuation o collagen bers
and a di use lymphohistiocytic in ltrate. Lyme titers may be
positi e.
Dermal brosis is a ma or eature o chronic sclerodermoid
gra t ersus host disease (GV D) porphyria cutanea tarda
phenyl etonuria carcinoid syndrome u enile onset diabetes
progeria and the Werner urie and Crow u ase (P S)
syndromes. ccupational e posure to silica epo y resins
poly inyl chloride (PVC) and ibratory stimuli ( ac hammer
or chainsaw) may produce sclerodermoid conditions. Chemi
cals (e.g. PVC) bleomycin isonia id penta ocine alproate
sodium epo y resin apor itamin (a ter in ection)
contaminated Spanish rapeseed oil (to ic oil syndrome)
contaminated tryptophan (eosinophilia myalgia syndrome)
170
tahir99 - UnitedVRG
nitro urantoin and hydantoin may also induce arious pat
terns o brosis. The sti s in syndrome also nown as
congenital ascial dystrophy is characteri ed by stony hard
induration o the s in and deeper tissues o the buttoc s
thighs and legs with oint limitation and limb contractures.
The disease begins in in ancy. Scleroderma li e symptoms
may be the presenting eatures o multiple myeloma and amy
loidosis. gG related disease presents with so t tissue sclero
sis ele ated serum gG and increased gG positi e plasma
cells in a ariety o tissues.
Pathogenesis
The pathogenesis o scleroderma and morphea in ol es as
cular damage autoimmune mechanisms and possibly micro
chimerism resulting in alloimmune gra t ersus host reactions.
Both anticardiolipin and anti β glycoprotein antibodies
appear to play roles in pathogenesis. The plasma D dimer con
centration correlates with macro ascular complications. or
relia af elii and orrelia garinii are related to the de elopment
o morpheali e lesions in some cases. ther en ironmental
agents may be in ol ed. pidemiologic studies support the
role o organic sol ents and certain chemicals. n women there
is an association with teaching and wor ing in the te tile
industry.
The immune mechanisms in ol ed are comple . pregu
lated proteins and messenger R As include monocyte
chemoattractant protein ( CP ) pulmonary and acti ation
regulated chemo ine macrophage in ammatory protein
( P ) L L L CRP platelet deri ed growth actor
receptor β (PDG R β ) and TG β although TG β has not
correlated well in some studies. These actors may stimulate
e tracellular matri production TG β production and acti a
tion and chemoattraction o T cells. Various target antigens
ha e been proposed including a protein termed protein
highly e pressed in testis (P T) which is ectopically o er
e pressed in scleroderma dermal broblasts. Serum antibod
ies to a recombinant P T ragment ha e been detected in
( . ) o scleroderma patients but in none o SL
patients or healthy controls. The presence o anti P T
antibodies was associated with di use cutaneous scleroderma
and lung in ol ement.
The macrophage receptor protein CD is upregulated in
scleroderma and increased le els o soluble CD correlate
with disease progression. pression o CD is increased on
broblasts in lesional s in and ligation o CD by recombi
nant human CD results in increased production o L
L and CP in a dose dependent manner. These phenom
ena are not shown in normal broblasts with the addition o
CD . Lesion s in o early stage scleroderma contains T cells
pre erentially producing high le els o L . CD + T helper
(Th ) li e cells can inhibit collagen production by normal
broblasts and the inhibition is mediated by T α. The inhi
bition is dominant o er the enhancement induced by L and
TG β . To be inhibitory Th cells re uire acti ation by CD
ligation. Th cells are less potent than T helper (Th ) cells in
inhibiting collagen production by normal broblasts and
broblasts rom in ol ed s in are resistant to inhibition. tan
ercept has been shown to decrease serum TG β tissue
hydro yproline dermal brosis and the number o α S A
positi e cells. owe er because Th cells reduce type col
lagen synthesis through the e ect o T α T α bloc ade
by new biologics should be approached with caution. Drug
induced morphea has been related to the cathepsin inhibitor
balicatib used or osteoporosis. Capecitabine an oral prodrug
o uorouracil used in the treatment o metastatic colon
and breast carcinoma has been associated with a hand oot
syndrome with sclerodactyly. nset o systemic sclerosis with
digital ulcers has been reported during β therapy or mul
tiple sclerosis.
Treatment
Although e ecti e treatment is a ailable or many o the is
ceral complications o scleroderma treatment or the s in
disease remains unsatis actory. Spontaneous impro ement
may be seen in some children and in some cases o locali ed
scleroderma. Physical therapy emphasi ing range o motion
or all oints as well as the mouth is important. posure to
cold is to be a oided and smo ing is orbidden. Among
patients with scleroderma smo ers are three to our times
more li ely than ne er smo ers to incur digital ascular
complications.
Vasodilating drugs CCBs angiotensin receptor antago
nists topical nitrates and prostanoids remain the mainstay
o medical therapy or Raynaud phenomenon. Antio idants
such as itamin C ha e been used but data are mi ed. Both
sildena l (Viagra) and V or inhaled iloprost are use ul in
the treatment o both pulmonary hypertension and Raynaud
phenomenon. Gin go biloba has been shown to ha e
some e cacy in a double blind trial. ral L arginine has
re ersed digital necrosis in some patients with Raynaud phe
nomenon and impro ed symptoms in others. CCBs such as
ni edipine (Procardia L) mg day are o ten used
as rst line therapy. Some patients who e perience worsen
ing o esophageal re u with ni edipine do better with diltia
em (Cardi em CD) mg day. Botulinum to in
topical nitroglycerin and simple hand warming on a regular
basis may also be e ecti e. Bosentan an oral dual endothe
lin receptor antagonist has been e ecti e in pre enting
and treating scleroderma related ulcers and oral treprostinil
diethanolamine has been shown to impro e s in per usion in
an open label trial.
Systemic corticosteroids ha e been used but e idence o
bene t is limited and patients must be monitored closely or
scleroderma renal crisis. T bloc ade has shown some
bene t in reducing brosis but has also triggered onset o
disease. Ritu imab has resulted in resolution o limited disease
associated with anti T therapy. Cyclophosphamide has
shown some promising results in the treatment o cutaneous
disease impro ing s in scores ma imal oral opening e ion
inde orced ital capacity ( VC) and carbon mono ide di
using capacity (DLC ). Results with cyclophosphamide ha e
been superior to those obtained with D penicillamine. ral
methotre ate or cyclophosphamide has been used with pred
nisolone in some trials. ral cyclophosphamide must be gi en
in the morning with igorous hydration. any rheumatolo
gists pre er intra enous pulse cyclophosphamide with the
sul hydryl compound mesna and hydration to reduce bladder
to icity. Cyclophosphamide has been used together with anti
thymocyte globulin and hematopoietic stem cell in usion.
ther e ol ing therapies include agents that target TG β
signaling tyrosine inase inhibitors (e.g. imatinib) and inhib
itors o histone deacetylase.
Phototherapy and photochemotherapy especially with
VA ha e also shown some e cacy. Widespread morphea
has been treated with oral calcitriol and calcipotriene may
ha e some e cacy as a topical agent. alo uginone an inhibi
tor o collagen type synthesis can decrease collagen synthesis
in the tight s in mouse and murine GV D. Application
o halo uginone caused a reduction in s in scores in a pilot
study with scleroderma patients. Carbon dio ide (C ) laser
apori ation has produced remission o symptoms in cutane
ous calcinosis o CR ST syndrome. Some data suggest that
minocycline may be e ecti e in the control o calcinosis in
systemic sclerosis. ral type collagen has been disappointing
o erall but may be o some limited bene t or s in ndings
in late phase disease.
Although there is strong e idence that the AC inhibitors
Scleroderma
are disease modi ying or scleroderma renal crisis better ran
domi ed controlled trials are still needed. poprostenol is
used to treat pulmonary hypertension in scleroderma based
largely on e idence that it can be li e sa ing in the treatment
o primary pulmonary hypertension. ther promising drugs
or isceral in ol ement include bosentan ( or pulmonary
hypertension and ischemic ulcers) cyclophosphamide ( or
al eolitis) γ ( or interstitial pulmonary brosis) V pros
taglandins ( or ascular disease) and sildena l ( or pulmo
nary hypertension and Raynaud phenomenon).
The uture lies with early aggressi e inter ention be ore the
de elopment o brosis and organ damage. Bone marrow and
nonmyeloablati e allogeneic hematopoietic stem cell trans
plantation has shown dramatic and sustained bene ts in some
patients. t should be noted that increased renal and pulmo
nary to icity as well as parenchymal brosis has been
reported in some patients with scleroderma and this treat
ment should still be considered e perimental. b ecti e mea
sures o impro ement o s in sclerosis can be obtained by
means o durometer measurements and high resolution ultra
sound. The course o microangiopathic changes can be e alu
ated with serial nail old ideocapillaroscopy.
Arkachaisri T, et al: Development and initial validation of the localized
scleroderma skin damage index and physician global assessment of
disease damage: a proof-of-concept study. Rheumatology (Oxford)
2010; 49(2):373–381.
Bielecki M, et al: Increased release of soluble CD163 by the peripheral
blood mononuclear cells is associated with worse prognosis in
patients with systemic sclerosis. Adv Med Sci 2013; 58(1):126–133.
Brenner M, et al: Phototherapy and photochemotherapy of sclerosing
skin diseases. Photodermatol Photoimmunol Photomed 2005;
21:157.
Chimenti MS, et al: Resolution with rituximab of localized scleroderma
occurring during etanercept treatment in a patient with rheumatoid
arthritis. Eur J Dermatol 2013; 23(2):273–274.
Fett N: Scleroderma: nomenclature, etiology, pathogenesis, prognosis,
and treatments: facts and controversies. Clin Dermatol 2013;
31(4):432–437.
Giuggioli D, et al: Systemic sclerosis and cryoglobulinemia: our
experience with overlapping syndrome of scleroderma and severe
cryoglobulinemic vasculitis and review of the literature. Autoimmun Rev
2013; 12(11):1058–1063.
Ingegnoli F, et al: Nailfold capillaroscopy in systemic sclerosis: data
from the EULAR Scleroderma Trials and Research (EUSTAR) database.
Microvasc Res 2013; 89:122–128.
Iudici M, et al: Glucocorticoids in systemic sclerosis: weighing the
benefits and risks—a systematic review. Clin Exp Rheumatol 2013;
31(2 Suppl 76):157–165.
Markatseli TE, et al: Subcutaneous calcifications in a patient with diffuse
scleroderma. Clin Exp Rheumatol 2013; 31(2 Suppl 76):180.
Muangchant C, et al: The significance of interleukin-6 and C-reactive
protein in systemic sclerosis: a systematic literature review. Clin Exp
Rheumatol 2013; 31(2 Suppl 76):122–134.
Muro Y, et al: What autoantibody tests should become widely available
to help scleroderma diagnosis and management? Arthritis Res Ther
2013; 15(4):116.
Naert A, et al: Successful treatment with bosentan of lower extremity
ulcers in a scleroderma patient. Case Rep Med 2013; 2013:690591.
Reddi DM, et al: Scleroderma and IgG4-related disease. Am J
Dermatopathol 2013; 35(4):458–462.
Shah AA, et al: Telangiectases in scleroderma: a potential clinical
marker of pulmonary arterial hypertension. J Rheumatol 2010;
37(1):98–104.
Shah AA, et al: My approach to the treatment of scleroderma. Mayo
Clin Proc 2013; 88(4):377–393.
Shah AA, et al: Open label study of escalating doses of oral treprostinil
diethanolamine in patients with systemic sclerosis and digital ischemia:
171
 pharmacokinetics and correlation with digital perfusion. Arthritis Res
8 Ther 2013; 15(2):R54.
Yaqub A, et al: Localized cutaneous fibrosing disorders. Rheum Dis Clin
North Am 2013; 39(2):347–364.
Zulian F, et al: Scleroderma in children: an update. Curr Opin
Connective Tissue Diseases
Rheumatol. 2013; 25(5):643–650.
EOSINOPHILIC FASCIITIS
n Lawrence Shulman described a disorder that he
called di use eosinophilic asciitis. Classically patients had
engaged in strenuous muscular acti ity or a ew days or
wee s be ore the acute onset o wea ness atigability and
pain and swelling o the e tremities. The prodrome was ol
lowed by se ere induration o the s in and subcutaneous
tissues o the orearms and legs. A a orable response to cor
ticosteroids was noted. Since the initial description en iron
mental e posures ha e been reported as possible triggers or
the syndrome including L tryptophan contaminated with
′ ethylidenebis orrelia and e posure to trichloroethylene.
Alterations in L tryptophan metabolism ha e been described
with ele ated le els o L ynurenine and uinolinic acid. Some
consider this disease to be a ariant o scleroderma. Polycy
themia era metastatic colorectal carcinoma and multiple
myeloma ha e been associated in a limited number o patients
suggesting that some cases may represent a paraneoplastic
phenomenon.
The s in is usually edematous and erythematous with a
coarse peau d orange appearance most noticeable inside the
upper arms thighs or an s. The hands and ace are usually
spared. When the patient holds the arms laterally or ertically
linear depressions occur within the thic ened s in. This
groo e sign or dry ri erbed sign ollows the course o
underlying essels ( ig. ). This contrasts with scleroderma
in which the s in remains smooth and taut. Limitation o
e ion and e tension o the limbs and contracture may
de elop and patients are o ten unable to stand ully erect. n
contrast to scleroderma Raynaud phenomenon is usually
absent. Associated systemic abnormalities ha e included
carpal tunnel syndrome peripheral neuropathy sei ures pos
terior ischemic optic neuropathy pleuropericardial e usion
pancytopenia anemia antibody mediated hemolytic anemia
Fig. 8-27 Eosinophilic
fasciitis.
172
tahir99 - UnitedVRG
thrombocytopenia S gren syndrome lymphadenopathy
pernicious anemia and gA nephropathy. Detected cyto ine
abnormalities are similar to those in atopic patients but with
a stri ing ele ation o TG β . Considerable e idence sup
ports a Th mediated pathway. SR is generally increased
and hypergammaglobulinemia is common. ncreased produc
tion o L and clonal populations o circulating T cells ha e
been reported.
Biopsy shows a patchy lymphohistiocytic and plasma cell
in ltrate in the ascia and sub ascial muscle with massi e
thic ening o the ascia and deep subcutaneous septa. Periph
eral blood eosinophilia o is the rule but eosinophils
may or may not be present in the a ected ascia. The in am
matory in ltrate is mainly composed o macrophages and
lymphocytes o ten with a CD + T lymphocyte predominance.
ew eosinophils are typically present in tissue although they
may be numerous in some cases. Cytoto ic CD + T lympho
cytes may be demonstrated by gran yme B staining. a or
histocompatibility comple ( C) class antigens are upreg
ulated in muscle bers but C class antigens are not
usually e pressed by muscle bers. C b membrane attac
comple ( AC) deposits are generally not detected. CT and
R ha e both been used to demonstrate ascial thic ening
and may ob iate the need or biopsy in some cases.
The response to systemic corticosteroids is generally e cel
lent. n responders complete reco ery is usual within
years. Some patients ha e also demonstrated a response to
histamine bloc ers including hydro y ine and cimetidine.
Patients with a prolonged course unresponsi e to systemic
corticosteroids are being recogni ed with increasing re
uency. any o these poorly responsi e cases o erlap with
morphea pro unda. n re ractory cases Pla uenil cyclospo
rine methotre ate a athioprine psoralen plus VA (P VA)
bath P VA e tracorporeal photochemotherapy V G ritu
imab and other immunosuppressi e regimens ha e been used
with ariable success. The increased synthesis o L may be
bloc ed by α suggesting a possible role or in the
treatment o this disorder. Both in i imab and V cyclophos
phamide used with moderate to high dose prednisolone ha e
been reported as e ecti e in re ractory cases.
Khanna D, et al: Infliximab may be effective in the treatment of
steroid-resistant eosinophilic fasciitis: report of three cases.
Rheumatology (Oxford) 2010; 49(6):1184–1188.
Kissin EY, et al: Ultrasound assessment of subcutaneous
compressibility: a potential adjunctive diagnostic tool in eosinophilic
fasciitis. J Clin Rheumatol 2013; 19(7):382–385.
Lebeaux D, et al: Eosinophilic fasciitis (Shulman disease). Best Pract
Res Clin Rheumatol 2012; 26(4):449–458.
Tyndall A, et al: The differential diagnosis of systemic sclerosis. Curr
Opin Rheumatol 2013; 25(6):692–699.
MIXED CONNECTIVE TISSUE DISEASE
i ed connecti e tissue disease ( CTD) is de ned by the
presence o Raynaud phenomenon arthralgias swollen oints
esophageal dys unction muscle wea ness and sausageli e
appearance o the ngers together with the presence o high
titer anti R P antibodies in the absence o anti Sm antibodies.
The term is not synonymous with o erlap syndrome a com
bination o diseases in which each disease complies with the
diagnostic criteria or that disorder. Also CTD is not syn
onymous with undi erentiated connecti e tissue disease
( CTD) patients with connecti e tissue disease who ha e
not yet de eloped a de ned disease. nly about o patients
with CTD go on to de elop CTD.
The A A test typically demonstrates a particulate pattern
in CTD re ecting the high titers o nuclear R P antibodies
(anti R P antibodies). This A A pattern generally persists
through periods o remission and is a aluable diagnostic test.
n addition particulate epidermal nuclear gG deposition on
D study o s in is a distincti e nding in CTD. Anti TS
R A antibodies appear to de ne a subpopulation with pre
dominance o lupusli e clinical eatures. Patients with a
younger age o onset and those with pulmonary hypertension
Raynaud phenomenon and li edo reticularis ha e a higher
ris o mortality. Causes o death include pulmonary brosis
and pulmonary arterial hypertension cardio ascular e ents
renal disease C S disease thrombotic thrombocytopenic
purpura and in ection.
or acute treatment corticosteroids such as prednisone
( mg g day) are e ecti e or in ammatory eatures such as
arthritis and myositis. As with L CTD may be associated
with an independent ris o osteoporosis and the long term
morbidity associated with corticosteroid treatment can be sig
ni cant. Bisphosphonate therapy and therapy with a steroid
sparing agent should be considered early. n general the L
eatures o CTD are the most li ely to impro e with therapy
and the scleroderma eatures are the least li ely to impro e.
Generally the prognosis is better than that o scleroderma
largely related to the lower incidence o renal disease. Small
molecule tyrosine inase inhibitors such as imatinib dasatinib
and nilotinib target TG β and PDG signaling and are being
in estigated as therapeutic options. Li e threatening complica
tions re ractory to other treatment o ten respond to ritu imab.
n the setting o thrombocytopenia the response rate is . o elastic bers (tram trac sign) many new collagen bundles
Braun-Moscovici Y, et al: Rituximab: rescue therapy in life-threatening
complications or refractory autoimmune diseases: a single center
experience. Rheumatol Int 2013; 33(6):1495–1504.
Hajas A, et al: Clinical course, prognosis, and causes of death in mixed
connective tissue disease. J Rheumatol 2013; 40(7):1134–1142.
Jovancevic B, et al: Anti B-cell therapy against refractory
thrombocytopenia in SLE and MCTD patients: long-term follow-up and
review of the literature. Lupus 2013; 22(7):664–674.
Ortega-Hernandez OD, et al: Mixed connective tissue disease: an
overview of clinical manifestations, diagnosis and treatment. Best Pract
Res Clin Rheumatol 2012; 26(1):61–72.
Szodoray P, et al: Distinct phenotypes in mixed connective tissue
disease: subgroups and survival. Lupus 2012; 21(13):1412–1422.
NEPHROGENIC SYSTEMIC FIBROSIS
ephrogenic systemic brosis ( S ) is a recently recogni ed
brosing s in condition that resembles scleromy edema his
tologically. t usually de elops in patients with renal insu
ciency on hemodialysis although it has been noted in patients
with acute renal ailure who had ne er undergone dialysis.
pidemiologic and ray emission spectroscopic studies ha e
implicated gadolinium containing R contrast agents and
incidence o S has decreased since their use has been limited
in patients with renal ailure. Concurrent in ection increased
serum phosphate and calcium concentrations and acidosis
may play important roles in pathogenesis. Clinical ndings o
S include thic ened sclerotic or edematous papules and
pla ues in ol ing the e tremities and trun ( ig. ). ellow
scleral pla ues and scleral telangiectasia resembling con unc
ti itis ha e been described. So t tissue calci cation is rare but
may be e tensi e when it occurs. Clinically S di ers rom
scleromy edema by the lac o in ol ement o the ace
absence o plasma cells and lac o paraproteinemia. Systemic
in ol ement is generally absent but may occur with brosis
and calci cation o the diaphragm psoas muscle renal tubules
and rete testes.
Circulating antiphospholipid antibodies ha e been noted in
some patients. istologic sections demonstrate plump bipolar
Fig. 8-28
Hyperpigmented
sclerotic plaques of
nephrogenic fibrosing
dermopathy.
Nephrogenic systemic fibrosis
CD + spindle cells with dendrites e tending along both sides
and increased mucin. With time thic ened collagen bundles
become prominent in the reticular dermis. ssi cation with
trapped elastic bers appears to be airly speci c or gado
linium e posure. yo broblasts ha e been noted in lesional
s in. mmunohistochemical staining or CD and procolla
gen in the spindle cells o D suggests that many o the
dermal cells o D may represent circulating brocytes
recruited to the dermis. The CD positi ity in D contrasts
with the loss o CD + cells in morphea.
ecti e therapy remains elusi e. Topical retinoids ste
roids and itamin D analogs are not e ecti e. mmunosup
pressi e therapy appears to be o little bene t. n three cases
e ol ing a ter li er transplantation treatment with basili
imab calcineurin inhibitor and prednisone did not
stop the de elopment o woody s in induration o the
distal e tremities erythematous papules and contractures.
The most e ecti e treatment strategy appears to be optimi a
tion o renal unction through medical therapy or transplanta
tion. Some data support a bene cial e ect rom phototherapy
e tracorporeal photopheresis or V sodium thiosul ate
tyrosine inase inhibitors and rapamycin. The proli erating
brocytes o S e press phospho S inase a protein
downstream rom the mammalian target o rapamycin. All
patients should be re erred or physical therapy.
Bhawan J, et al: Sclerotic bodies beyond nephrogenic systemic fibrosis.
J Cutan Pathol 2013; 40(9):812–817.
Chen AY, et al: Nephrogenic systemic fibrosis: a review. J Drugs
Dermatol 2010; 9(7):829–834.
Elmholdt TR, et al: Antifibrotic effect after low-dose imatinib mesylate
treatment in patients with nephrogenic systemic fibrosis: an open-label
non-randomized, uncontrolled clinical trial. J Eur Acad Dermatol
Venereol 2013; 27(6):779–784.
Girardi M, et al: Nephrogenic systemic fibrosis: clinicopathological
definition and workup recommendations. J Am Acad Dermatol 2011;
65(6):1095–1106.
Martin DR, et al: Decreased incidence of NSF in patients on dialysis
after changing gadolinium contrast-enhanced MRI protocols. J Magn
Reson Imaging 2010; 31(2):440–446.
Swaminathan S, et al: Rapid improvement of nephrogenic systemic
fibrosis with rapamycin therapy: possible role of phospho-70-
ribosomal-S6 kinase. J Am Acad Dermatol 2010; 62(2):343–345.
173
 Swaminathan S, et al: Gadolinium contrast agent-induced CD163(+)
8 ferroportin(+) osteogenic cells in nephrogenic systemic fibrosis. Am J
Pathol 2013; 183(3):796–807.
Connective Tissue Diseases
SJÖGREN SYNDROME (SICCA SYNDROME)
S gren syndrome is a chronic autoimmune disorder charac
teri ed by lymphocytic in ltration o the e ocrine glands par
ticularly the sali ary and lacrimal glands. ne third o patients
present with e traglandular mani estations such as asculitis.
ost patients are age or older and more than are
women. Secondary S gren syndrome is de ned as erostomia
and eratocon uncti itis sicca in patients with other connec
ti e tissue diseases. The presence o arthritis leu openia pro
teinuria or low complement le els suggests secondary S gren
syndrome. These patients ha e lower incidences o erostomia
and LD compared with patients who ha e primary S gren
syndrome.
erostomia may produce di culty in speech and eating
increased tooth decay thrush and decreased taste (hypogeu
sia). Patients re uently suc on sour candies to stimulate what
little sali ary secretions remain and those un amiliar with the
condition may blame the habit o suc ing lemon drops or the
ensuing tooth decay. S gren syndrome alters the composition
o sali a producing a decrease in sali ary amylase and car
bonic anhydrase along with an increase in lacto errin β
microglobulin cystatin C sodium and lyso yme C.
Rhinitis sicca (dryness o nasal mucous membranes) may
induce nasal crusting and decreased ol actory acuity (hypos
mia). Vaginal dryness and dyspareunia may de elop. Dry
eyes are pain ul eel gritty or scratchy and produce discharge
and blurry ision. atigue is a prominent symptom. n addi
tion there may be laryngitis gastric achlorhydria thyroid
enlargement resembling ashimoto thyroiditis malignant
lymphoma thrombotic thrombocytopenic purpura pain ul
distal sensory a onal neuropathy and splenomegaly.
S in mani estations o S gren syndrome include asculitis
erosis pruritus and annular erythema. Decreased sweating
occurs. Asian patients ha e been described who de elop ery
thematous indurated annular dermal pla ues primarily on
the ace. This is di erent rom the annular lesions o SCL
which show epidermal change and histologic changes o
lupus. Patients may also present with an o erlap o S gren
syndrome and L . A common nding in these patients is Ro
SSA antibody positi ity. SCL patients with S gren syndrome
ha e a worse prognosis than patients with SCL not associ
ated with S gren syndrome.
Patients with S gren syndrome and cutaneous asculitis
also ha e a signi cant incidence o peripheral renal or C S
asculitis. Cutaneous asculitis may present as purpura o the
legs which may be palpable or nonpalpable. S gren asculitis
accounts or most patients with Waldenstr m benign hyper
gammaglobulinemic purpura; about o these patients will
ha e or will de elop S gren syndrome and a high percentage
ha e SSA and SSB antibodies. ther cutaneous ascular mani
estations are urticarial asculitis digital ulcers and petechiae.
istologically a leu ocytoclastic asculitis is ound at the
le el o the postcapillary enule with e pansion o the ascu
lar wall brin deposition and aryorrhe is but no necrosis
o the endothelium.
Labial sali ary gland biopsy rom inside the lower lip is
usually regarded as the most de niti e test or S gren syn
drome. Typically there is a dense lymphocytic in ltrate with
many plasma cells and ewer histiocytes in aggregates within
minor sali ary glands. ore than one ocus o or more
lymphocytes is typically present per mm o the tissue
biopsy. Lymphoepithelial islands predominate early whereas
174
tahir99 - UnitedVRG
glandular atrophy predominates in the late stages. At this
stage ew lymphoid aggregates are present. erostomia is
diagnosed by the Schirmer test and re ects diminished glan
dular secretion rom the lacrimal glands. maging studies are
also help ul.
Classically the diagnosis is made when there is ob ecti e
e idence or two o three ma or criteria ( ) erophthalmia ( )
erostomia and ( ) an associated autoimmune rheumatic or
lymphoproli erati e disorder. These criteria may be too restric
ti e howe er because patients are increasingly being identi
ed with predominantly e traglandular disease. The lac o
sicca symptoms or anti SSA or anti SSB antibodies does not
e clude S gren syndrome. umerous serologic abnormalities
are associated with S gren syndrome or its associated condi
tions. Antibodies to odrin a ma or component o the mem
brane cytos eleton o most eu aryotic cells are present in
some populations with primary and secondary S gren syn
drome. gA and gG antibodies against α odrin are detected
in and respecti ely in some studies. n other popula
tions odrin antibodies are less help ul. About o patients
ha e anti Ro SSA antibodies; hal as many ha e anti La SSB
antibodies. The rheumatoid actor is usually positi e and
ele ated SR serum globulin and CRP and high titers o gG
gA and g are common. Cryoglobulins may be demon
strated. Dendritic cells are increased in tissue during the early
phases o the disease.
The a uaporin amily o water channels (proteins reely per
meated by water but not protons) appears to be an important
target in the pathogenesis o S gren syndrome. Both duct and
secretory cells are targets or the acti ation o CD + T cells.
L and γ are upregulated. t appears that Th cyto ines
mediate the unctional interactions between antigen presenting
cells (APCs) and CD + T cells in early lesions.
Patients with S gren syndrome are predisposed to the
de elopment o lymphoreticular malignancies especially non
odg in B cell lymphoma. Both malignant and nonmalignant
e traglandular lymphoproli erati e processes occur. Cases o
pseudolymphoma ha e the potential or regression or or pro
gression to o ert B cell lymphoma. Patients with palpable
purpura low C and mi ed monoclonal cryoglobulinemia are
at higher ris or lymphoma.
The di erential diagnosis o S gren syndrome includes sar
coidosis lymphoma amyloidosis and human immunode
ciency irus ( V) disease. V produces di use in ltrati e
lymphocytosis syndrome (D LS) which is characteri ed by
massi e parotid enlargement; prominent renal lung and G
mani estations; and a low re uency o autoantibodies.
Treatment or S gren syndrome has largely been symptom
atic but disease modi ying therapy is also becoming a reality.
Arti cial lubricants are help ul or eye symptoms as well as
oral nasal and aginal dryness. Topical lubricants are use ul
or erosis. n hot climates patients with impaired sweating
must be counseled to a oid heatstro e. Pharmacologic agents
such as pilocarpine and ce imeline are help ul to stimulate
sali ation. These agents may also ha e a role in the treatment
o dry eyes. Topical cyclosporine loo s promising or local
treatment o S gren syndrome as does topical human
therapy or oral lesions. n all trials mechanical stimulation by
the lo enge may play a signi cant role in impro ement o
symptoms as re ected in a high placebo response. Acid
maltose lo enges are less e pensi e and remain use ul or
symptomatic relie . or patients with systemic disease bio
logic T inhibitors such as in i imab show some promise.
Pilocarpine in doses o mg day has been shown to ha e
a bene cial e ect on sub ecti e eye symptoms as well as
impro ement o rose bengal staining. An increase in tear pro
duction as measured by the Schirmer test was not substanti
ated. Gene therapy also loo s promising at least in animal
models. L genes can be trans erred by adeno irus ectors
and can ha e disease modi ying e ects in the sali ary glands
o a mouse model. Se ere systemic asculitis causing renal
disease has responded to corticosteroids with or without
cyclophosphamide. ycophenolate sodium and ritu imab
ha e both been used to treat se ere mani estations associated
with S gren syndrome. Ritu imab has pro ed e ecti e in
double blind RCTs and ritu imab plus cyclophosphamide
incristine and prednisone ha e been used to treat S gren
syndrome associated B cell non odg in lymphoma.
Dong L, et al: Possible mechanisms of lymphoma development in
Sjögren’s syndrome. Curr Immunol Rev 2013; 9(1):13–22.
Huang YF, et al: The immune factors involved in the pathogenesis,
diagnosis, and treatment of Sjogren’s syndrome. Clin Dev Immunol
2013; 2013:160491.
Lieberman SM: Childhood Sjögren syndrome: insights from adults and
animal models. Curr Opin Rheumatol 2013; 25(5):651–657.
Mavragani CP, et al: New advances in the classification, pathogenesis
and treatment of Sjögren’s syndrome. Curr Opin Rheumatol 2013;
25(5):623–629.
Nocturne G, et al: Advances in understanding the pathogenesis of
primary Sjögren’s syndrome. Nat Rev Rheumatol 2013; 9(9):544–556.
Yang Y, et al: The clinical and laboratory characteristics of Sjögren’s
syndrome that progresses to systemic lupus erythematosus: a
retrospective case-control study. Int J Rheum Dis 2013; 16(2):173–177.
RHEUMATOID ARTHRITIS
The ma ority o s in mani estations o rheumatoid arthritis are
the result o neutrophil mediated in ury. There may be annular
erythemas purpura bullae shallow ulcers and gangrene o
the e tremities. any diseases ha e been reported to occur in
association with RA such as erythema ele atum diutinum
pyoderma gangrenosum elty syndrome gA asculitis
linear gA disease S gren syndrome bullous pemphigoid
and yellow nail syndrome. Treatment o RA with disease
modi ying drugs has reduced the burden o destructi e disease
or patients. Biologic agents are being used with increasing
re uency although traditional drugs such as methotre ate
still ha e a role. n patients with RA tuberculin s in testing
and γ release assay testing are less sensiti e compared
with controls. Both may be ad isable be ore initiating therapy
with anti T agents.
ethotre ate treated RA patients ha e an increased inci
dence o melanoma as well as non odg in lymphoma and
lung cancer. The disease itsel predisposes to in ections (e.g.
papilloma irus) which should be ollowed or de elopment
o cutaneous lesions. interest to dermatologists e tracts
rom the hus amily o plants ha e shown some bene t in
limited studies. atumumab a new anti CD human mono
clonal antibody has shown promise in early clinical trials.
Rheumatoid nodules
Subcutaneous nodules are seen in o patients ( ig.
). They may arise anywhere on the body but most re
uently are ound o er the bony prominences especially on
the e tensor sur ace o the orearm ust below the elbow and
the dorsal hands. The lesions are nontender rm s in colored
round nodules which may or may not be attached to the
underlying tissue. re uently they are attached to the brous
portions o the periarticular capsule or they may be ree in the
subcutaneous tissue. Rheumatoid nodules can easily be mis
ta en or anthomas because o a yellow color (pseudo antho
matous ariant). They also occur in o patients with SL
especially around small oints o the hands. Rheumatoid actor
(R ) may or may not be present. istologic e amination o the
Rheumatoid arthritis
Fig. 8-29 Rheumatoid nodules.
rheumatoid nodule shows intensely staining oci o brin sur
rounded by histiocytes in palisade arrangement. eutrophils
and neutrophilic debris may be noted in association with the
brin and o er time the surrounding histiocytes are replaced
by brosis.
Rheumatoid nodules are di erentiated rom eberden
nodes which are tender hard bony e ostoses on the dorso
lateral aspects o the distal interphalangeal oints o patients
with degenerati e oint disease. odules or tophi o gout are
characteri ed by masses o eathery urate crystals surrounded
by a chronic in ammatory in ltrate o ten containing oreign
body giant cells.
Rarely RA patients present with multiple ulcerated nodules
and high R but no acti e oint disease. This ariant o rheu
matoid disease without destructi e oint disease is designated
rheumatoid nodulosis.
Rheumatoid vasculitis
Peripheral ascular lesions appear as typical eatures o RA.
These are locali ed purpura cutaneous ulceration and gan
grene o the distal parts o the e tremities. Additionally
papular lesions located primarily on the hands ha e been
described as rheumatoid papules. These show a combination
o asculitis and palisading granuloma ormation. An R is
typically present. Peripheral neuropathy is re uently associ
ated with the asculitis. The presence o rheumatoid nodules
may help to distinguish these lesions o asculitis rom SL
polyarteritis nodosa Buerger s disease (thromboangiitis oblit
erans) and the dysproteinemias. Prednisone and cytoto ic
agents are re uently used as in other orms o asculitis.
Ritu imab has also been used success ully.
Rheumatoid neutrophilic dermatosis
Chronic urticaria li e pla ues characteri ed histologically by
a dense neutrophilic in ltrate ha e been described in patients
with debilitating RA ( ig. ). The di erential diagnosis
includes erythema ele atum diutinum and Sweet syndrome.
Related palisading granulomas
nterstitial granulomatous dermatitis with arthritis is a condi
tion with a range o clinical presentations. t can present
with round to o al erythematous or iolaceous pla ues on the
an s a illae inner thighs and lower abdomen. Linear
175
 Fig. 8-30 Rheumatoid
8 neutrophilic
dermatosis presents
with urticarial plaques.
Connective Tissue Diseases
slightly red or s in colored cords e tending rom the upper
bac to the a illa may occur. The presence o these linear
bands has been called the rope sign. When the lesions
resol e they may lea e behind hyperpigmentation and a
slightly wrin led appearance. Arthritis may occur be ore
during or a ter the eruption and tends to a ect multiple oints
o the upper e tremities. Although patients do not ha e a well
de ned associated connecti e tissue disease some cases are
associated with L or other autoimmune diseases. Some pre
sentations are paraneoplastic associated with a range o solid
and hematopoietic tumors.
istologically a moderate to dense in ammatory in ltrate
is seen through the reticular dermis composed mostly o his
tiocytes distributed interstitially around discrete bundles o
sclerotic collagen. Variable numbers o neutrophils and eosin
ophils are seen. ucin necrobiosis asculitis and acuolar
change are usually absent or mild. The eruption is typically
asymptomatic and may spontaneously in olute a ter many
months or years. therapy is re uired intralesional cortico
steroids methotre ate etanercept uste inumab tocili umab
and cyclosporine ha e been used.
Palisaded neutrophilic and granulomatous dermatitis is
usually associated with a well de ned connecti e tissue
disease usually L or RA. t o ten presents with eroded or
ulcerated symmetrically distributed umbilicated papules or
nodules on the elbows nuc les and nees. The biopsy may
re eal leu ocytoclastic asculitis and collagen degeneration in
early lesions or palisaded granulomatous in ltrates with der
mato brosis and scant neutrophilic debris in older lesions.
ethotre ate induced papular eruption appears in patients
with rheumatic diseases during methotre ate therapy. They
present with erythematous indurated papules usually located
on the pro imal e tremities. istopathologic e amination
re eals an in ammatory in ltrate composed o histiocytes
interstitially arranged between collagen bundles o the dermis
intermingled with ew neutrophils. At times small rosettes
composed o clusters o histiocytes surrounding a thic central
collagen bundle are present in the deep reticular dermis.
Leloup P, et al: Ustekinumab therapy for severe interstitial
granulomatous dermatitis with arthritis. JAMA Dermatol 2013;
149(5):626–627.
Marmon S, et al: Lupus-erythematous-associated interstitial
granulomatous dermatitis. Dermatol Online J 2012; 18(12):31.
176
tahir99 - UnitedVRG
Fig. 8-31 Evanescent
eruption of Still’s
disease.
Martínez-Martínez M, et al: Cutaneous papillomavirus infection in
patients with rheumatoid arthritis or systemic lupus erythematosus: a
case-control study. Lupus 2013; 22(9):948–952.
Moyano Almagro B, et al: Interstitial granulomatous dermatitis and
arthritis revealing oesophageal carcinoma. Clin Exp Dermatol 2013;
38(5):501–503.
O’Shea JJ, et al: Janus kinase inhibitors in autoimmune diseases. Ann
Rheum Dis 2013; 72(Suppl 2):111–115.
Peroni A, et al: Interstitial granulomatous dermatitis: a distinct entity with
characteristic histological and clinical pattern. Br J Dermatol 2012;
166(4):775–783.
Schanz S, et al: Interstitial granulomatous dermatitis with arthritis
responding to tocilizumab. Arch Dermatol 2012; 148(1):17–20.
Song GG, et al: Interferon-gamma release assays versus tuberculin skin
testing in patients with rheumatoid arthritis. Int J Rheum Dis 2013;
16(3):279–283.
Walling HW: Interstitial granulomatous dermatitis associated with
chronic inflammatory demyelinating polyneuropathy. Cutis 2012;
90(1):30–32.
Juvenile rheumatoid arthritis
(juvenile idiopathic arthritis)
Ju enile rheumatoid arthritis (JRA) is not a single disease but
a group o disorders characteri ed by arthritis and young age
o onset. The subset called Still s disease accounts or only
o the patients. t shows s in mani estations in about o
young patients age years. An eruption consisting o e a
nescent nonpruritic salmon pin macular or papular lesions
on the trun and e tremities may precede the onset o oint
mani estations by many months ( ig. ). eutrophilic pan
niculitis has been described. The systemic symptoms o e er
and serositis usually recur o er wee s each a ternoon. ost
patients remit permanently by adulthood. L β L and
L are implicated in the pathogenesis o JRA as are
phagocyte speci c S proteins such as S A S A
and S A . Steroid sparing agents are use ul to decrease
steroid associated to icity. The dose response cur e or meth
otre ate plateaus with parenteral administration o mg
m wee . The ull therapeutic e ect may not be e ident or
months. Re ractory disease has been treated with pulse meth
ylprednisolone tocili umab and cyclophosphamide. Ana inra
has shown modest e cacy.
 Lequerré T, et al: Interleukin-1 receptor antagonist (anakinra) treatment
in patients with systemic-onset juvenile idiopathic arthritis or adult
onset Still disease: preliminary experience in France. Ann Rheum Dis
2008; 67(3):302–308.
Zhang X, et al: Clinical pharmacology of tocilizumab for the treatment of
systemic juvenile idiopathic arthritis. Expert Rev Clin Pharmacol
2013;6(2):123–137.
Fibroblastic rheumatism
ibroblastic rheumatism is characteri ed by bilateral distal
polyarthritis e ion contractures cutaneous nodules sclero
dactylitis thic ened palmar ascia and Raynaud phenome
non. Biopsy demonstrates a broblastic proli eration with a
collagenous stroma arying rom smooth muscle actin
positi e cellular ascicles to paucicellular areas with randomly
arranged spindle or stellate cells. lastic bers are typically
absent. Standard therapy includes immunosuppressi e agents
typically methotre ate and oral corticosteroids although some
patients ha e responded to physical therapy without immu
nosuppressi e treatment. nter eron has also been used.
Jurado SA, et al: Fibroblastic rheumatism: a report of 4 cases with
potential therapeutic implications. J Am Acad Dermatol 2012;
66(6):959–965.
Parida JR, et al: An unusual case of polyarthritis, skin nodules and
patchy skin thickening: fibroblastic rheumatism. Int J Rheum Dis 2012;
15(1):e12–e14.
Trotta F, et al: Multicentric reticulohistiocytosis and fibroblastic
rheumatism. Best Pract Res Clin Rheumatol 2012; 26(4):543–557.
Paraneoplastic rheumatism
Paraneoplastic syndromes resembling adult Still s disease
ha e been associated with a ariety o neoplasms including
gastric carcinoma lung carcinoma and lymphoma. Patients
with new onset o rheumatologic disease should be screened
or signs and symptoms suggesting neoplasm.
Symmetric synovitis
Symmetric seronegati e syno itis is an idiopathic orm o
arthritis sometimes associated with idiopathic edema. Sym
metric syno itis may also be a mani estation o Blau syndrome
an early onset granulomatous disease with symmetric arthritis
and recurrent u eitis related to the caspase recruitment
domain gene C D OD and considered by some to be a
orm o early onset sarcoidosis.
Alias A, et al: Rheumatology and oncology: an updated review of
rheumatic manifestations of malignancy and anti-neoplastic therapy.
Bull NYU Hosp Joint Dis 2012; 70(2):109–114.
Okamoto M, et al: A case of paraneoplastic syndrome mimicking adult
Still’s disease caused by rectal cancer. J Am Geriatr Soc 2013;
61(7):1243–1245.
Punzi L, et al: Miscellaneous non-inflammatory musculoskeletal
conditions: Blau syndrome. Best Pract Res Clin Rheumatol 2011;
25(5):703–714.
Serrano Ostoa B, et al: Remitting symmetric seronegative synovitis with
pitting edema (RS3PE). Rheumatol Clin 2012; 8(3):156–157.
RELAPSING POLYCHONDRITIS
Relapsing polychondritis is characteri ed by intermittent epi
sodes o in ammation o the articular and nonarticular carti
lage resulting in chondrolysis and collapse o the in ol ed
Fig. 8-32 Relapsing
polychondritis
characteristically
involves cartilaginous
portions of the ear but
Relapsing polychondritis
spares the lobe.
cartilage. The course o the disease is chronic and ariable
with episodic ares. Both genders are e ually a ected with
age at onset usually in the ourth to th decade. Dissolution
o the cartilage in ol es the ears nose and respiratory tract.
During bouts o in ammation the bright red in ol ement o
the ears is con ned to the cartilaginous portion while the ear
lobes remain conspicuously normal ( ig. ). The a ected
areas are swollen and tender. There may be conducti e dea
ness as a result o the obstruction produced by the swollen
cartilage. The nasal septal cartilage is similarly in ol ed to
produce rhinitis with crusting and bleeding and e entually
saddle nose. n ol ement o the bronchi laryn and epiglottis
produces hoarseness coughing and dyspnea. igratory
arthralgia and atypical chest pain are o ten present. Patients
e aluated or chest pain are o ten released without treatment
and with a diagnosis o costochondritis. cular disease most
o ten presents as con uncti itis scleritis or iritis. Per oration
o the globe may occur. Complete heart bloc has been reported
as a presenting sign. The AG C syndrome is a combination
o Beh et s disease and relapsing polychondritis (mouth and
genital ulcers with in amed cartilage).
Cell mediated immunity to cartilage has been demonstrated
in itro with a degree o response correlated with disease
acti ity. gG anti type collagen antibodies ha e been docu
mented again in titers corresponding with disease acti ity.
le ations in SR CRP le els and urinary type collagen
neoepitope le els correlate with disease acti ity. A second
connecti e tissue disease or other autoimmune disease is
present in about one third o patients with relapsing polychon
dritis and some cases appear to be paraneoplastic occurring
in association with hematopoietic malignancies. Limited data
suggest that serum le els o Th cyto ines ( γ L L )
may correlate better with disease acti ity than those o Th
cyto ines ( L L L L ).
istologically a predominantly neutrophilic in ltrate is
noted in the perichondrium. Varying degrees o chondrolysis
may be present. D o ten demonstrates a lupusli e continu
ous granular band o immunoglobulin and complement in the
perichondrium.
Dapsone mg once or twice daily or an adult reduces
the re uency o ares but is usually inade uate to control
relapsing polychondritis. Colchicine le unomide or hydro y
chloro uine may also be help ul. Systemic corticosteroids
177
 should be used to treat acute ares but most patients re uire
8
Arnaud L, et al: The Relapsing Polychondritis Disease Activity Index:
a steroid sparing immunosuppressi e drug. A athioprine development of a disease activity score for relapsing polychondritis.
methotre ate cyclophosphamide T α inhibitors Autoimmun Rev 2012; 12(2):204–209.
V G ana inra tocili umab and ritu imab ha e been used Chopra R, et al: Relapsing polychondritis. Rheum Dis Clin North Am
but only about hal o the patients e perienced a good response. 2013; 39(2):263–276.
Connective Tissue Diseases

Sustained response to etanercept has been reported e en a ter Kemta Lekpa F, et al: Biologics in relapsing polychondritis: a literature
ailure to respond to in i imab. ndobronchial ultrasonogra review. Semin Arthritis Rheum 2012; 41(5):712–719.
McCarthy EM, et al: Treatment of relapsing polychondritis in the era of
phy has been used to acilitate the diagnosis o relapsing poly
biological agents. Rheumatol Int 2010; 30(6):827–828.
chondritis and estimate the si e o the in ol ed airway or
placement o stents.

Bonus images for this chapter can be found online at expertconsult.inkling.com

eFig. 8-1 Discoid lupus erythematosus.
eFig. 8-2 Ear involvement with discoid lupus
erythematosus.
eFig. 8-3 Lower eyelid lesion of discoid lupus
erythematosus.
eFig. 8-4 Discoid lupus erythematosus.
eFig. 8-5 Dyspigmentation and scarring of
discoid lupus erythematosus.
eFig. 8-6 Hypertrophic lupus erythematosus of
the lip.
eFig. 8-7 Characteristic palmar involvement in
lupus–lichen planus overlap syndrome.
eFig. 8-8 Annular lesions of subacute
cutaneous lupus erythematosus.
eFig. 8-9 Psoriasiform subacute cutaneous
lupus erythematosus.
eFig. 8-10 Annular erythematous lesions of
neonatal lupus erythematosus.
eFig. 8-11 Periocular neonatal lupus
erythematosus.
eFig. 8-12 Palmar erythema in systemic lupus
erythematosus.
eFig. 8-13 Lupus hair; short, miniaturized hairs
affecting the anterior hairline.
eFig. 8-14 Bullous lupus erythematosus.
eFig. 8-15 Scalp erythema in
dermatomyositis.
eFig. 8-16 Poikiloderma on the trunk in
dermatomyositis.
eFig. 8-17 Dilated vessels and avascular
regions in dermatomyositis.
eFig. 8-18 Gottron’s sign.
eFig. 8-19 Calcinosis cutis in long-standing
dermatomyositis.
eFig. 8-20 Vasculitis in childhood
dermatomyositis.
eFig. 8-21 Atrophic lesions of dermatomyositis
involving the knuckles.
eFig. 8-22 Morphea.
eFig. 8-23 Linear scleroderma presents with
induration and pigmentary change.
eFig. 8-24 Scleroderma.
eFig. 8-25 Calcinosis in CREST syndrome.
eFig. 8-26 Scarring, loss of finger pad
substance, and pterygium inversum unguis.
eFig. 8-27 Pterygium inversum unguis in
progressive systemic sclerosis.
eFig. 8-28 Ulceration of the fingertip.
eFig. 8-29 Eosinophilic fasciitis, “dry riverbed
sign.”
eFig. 8-30 Mucosal ulcerations in mixed
connective tissue disease.
eFig. 8-31 Rheumatoid vasculitis, frequently
results in ulceration.
eFig. 8-32 Palisaded neutrophilic and
granulomatous dermatitis.
eFig. 8-33 Rheumatoid neutrophilic dermatosis
presents with urticarial plaques.

178

tahir99 - UnitedVRG
 Relapsing polychondritis
eFig. 8-4 Discoid lupus erythematosus.
eFig. 8-1 Discoid lupus erythematosus.

eFig. 8-2 Ear eFig. 8-5

involvement with Dyspigmentation and
discoid lupus scarring of discoid
erythematosus. lupus erythematosus.

eFig. 8-6 Hypertrophic lupus erythematosus of the lip.

178.e1
eFig. 8-3 Lower eyelid lesion of discoid lupus erythematosus.
 8
Connective Tissue Diseases

eFig. 8-7 Characteristic palmar involvement in lupus–lichen planus

overlap syndrome.

eFig. 8-8 Annular

lesions of subacute
eFig. 8-10 Annular erythematous lesions of neonatal lupus
cutaneous lupus
erythematosus.
erythematosus.

eFig. 8-9 Psoriasiform

subacute cutaneous
lupus erythematosus.

eFig. 8-11 Periocular neonatal lupus erythematosus.

eFig. 8-12 Palmar erythema in systemic lupus erythematosus.

178.e2

tahir99 - UnitedVRG
 Relapsing polychondritis
eFig. 8-13 Lupus hair; short, miniaturized hairs affecting the anterior
hairline.

eFig. 8-16 Poikiloderma on the trunk in dermatomyositis.

eFig. 8-17 Dilated

vessels and avascular
regions in
dermatomyositis.

eFig. 8-14 Bullous lupus erythematosus.

eFig. 8-15 Scalp erythema in dermatomyositis.

178.e3
eFig. 8-18 Gottron’s sign.
 eFig. 8-19 Calcinosis eFig. 8-21 Atrophic
8 cutis in long-standing
dermatomyositis.
lesions of
dermatomyositis
involving the knuckles.
Connective Tissue Diseases

eFig. 8-20 Vasculitis in eFig. 8-22 Morphea.

childhood
dermatomyositis.

178.e4

tahir99 - UnitedVRG
 eFig. 8-23 Linear eFig. 8-26 Scarring,
scleroderma presents loss of finger pad
with induration and substance, and
pigmentary change. pterygium inversum
unguis.

Relapsing polychondritis
eFig. 8-27 Pterygium
inversum unguis in
progressive systemic
sclerosis.

eFig. 8-24 Scleroderma.

eFig. 8-25 Calcinosis in CREST syndrome.

178.e5
 8
Connective Tissue Diseases

eFig. 8-28 Ulceration of the fingertip.

eFig. 8-29 Eosinophilic

fasciitis, “dry riverbed
eFig. 8-30 Mucosal ulcerations in mixed connective tissue disease.
sign.”

178.e6

tahir99 - UnitedVRG
 eFig. 8-32 Palisaded
neutrophilic and
granulomatous
dermatitis.

Relapsing polychondritis
eFig. 8-31 Rheumatoid vasculitis, frequently results in ulceration.

eFig. 8-33 Rheumatoid neutrophilic dermatosis presents with

urticarial plaques.

178.e7
 Bonus images for this chapter can be found online at
Within the dermis is a brillar matri termed ground sub
stance composed o proteoglycans and glycosaminoglycans.
These acid mucopolysaccharides produced by broblasts are
highly hygroscopic binding about times their own
olume in water. They are critical in holding water in the
dermis and are responsible or dermal olume and te ture.
ormally the sul ated acid mucopolysaccharide chondroitin
sul ate and heparin are the primary dermal mucins. n certain
diseases broblasts produce abnormally large amounts o
acid mucopolysaccharides usually hyaluronic acid. These
acid mucopolysaccharides (mucin) accumulate in large
amounts in the dermis and may be isible as pale blue granu
lar or amorphous material between collagen bundles. They are
o ten not isuali ed with hemato ylin and eosin stains because
the water they bind is remo ed in processing so the presence
o increased mucin is suspected by the presence o large
empty spaces between the collagen bundles. Acid mucopoly
saccharides can be detected by special stains such as colloidal
iron alcian blue and toluidine blue. ncubation o the tissue
with hyaluronidase eliminates the staining con rming the
presence o hyaluronic acid.
ncreased dermal mucin may result rom many diseases and
is a normal component o wound healing. The mucinoses are
diseases in which production o increased amounts o mucin
is the primary process. ucin may also accumulate in the s in
as a secondary phenomenon as when it is present in lupus
erythematosus dermatomyositis Degos disease granuloma
annulare and cutaneous tumors or a ter therapies such as
psoralen plus ultra iolet A (P VA) or retinoids. The genetic
diseases in which mucin accumulates as a result o inherited
metabolic abnormalities are termed the mucopolysaccharido
ses (see Chapter ). y edema and pretibial my edema are
re iewed in Chapter .
Rongioletti F, et al: Cutaneous mucinoses: microscopic criteria for
diagnosis. Am J Dermatopathol 2001; 23:257.
Yaqub A, et al: Localized cutaneous fibrosing disorders. Rheum Dis Clin
North Am 2013; 39:347–364.
LICHEN MYXEDEMATOSUS
The terminology used to describe disorders in the lichen
my edematosus group has aried widely o er the years; the
classi cation o Rongioletti and Rebora is used here. A
generali ed orm scleromy edema is accompanied by a
monoclonal gammopathy and may ha e systemic organ
in ol ement. i e locali ed orms are recogni ed character
i ed by a lac o a monoclonal antibody and systemic disease.
Also patients may ha e disease that does not t into these
subsets and their condition is termed atypical or intermedi
ate in type. Thyroid disease should not account or the nd
ings in any category.
tahir99 - UnitedVRG
expertconsult.inkling.com
Mucinoses
9
Generalized lichen myxedematosus
Scleromy edema a ects both men and women and generally
appears between ages and . t is chronic and progressi e.
The primary lesions are multiple wa y mm dome
shaped or at topped papules ( ig. ). They may coalesce
into pla ues ( ig. ) or may be arranged in linear arrays. Less
o ten urticarial nodular or e en annular lesions are seen. The
dorsal hands ace elbows and e tensor e tremities are most
re uently a ected ( ig. ). ucosal lesions are absent.
A di use in ltration de elops leading to woody sclerosis
o the s in. A reduced range o motion o the mouth hands
and e tremities may ollow ( ig. ). n the glabella and
orehead coalescence o lesions leads to the prominent ur
rowing o a leonine acies. At the pro imal interphalangeal
oint induration surrounding a centrally depressed area has
been called the doughnut sign. Pruritus may occur.
Scleromy edema is o ten associated with isceral disease.
Gastrointestinal ndings are most common. Dysphagia rom
esophageal in ol ement o ten occurs and the stomach or
intestine may also be a ected. Pulmonary complications with
dyspnea caused by restricti e or obstructi e disease are also
common. Pro imal muscle wea ness with an in ammatory
myopathy or a nonspeci c acuolar change may occur. Carpal
tunnel syndrome occurs in o patients. Arthralgia or
in ammatory arthritis re uently de elop. Disease speci c
adenopathy and renal impairment may be present.
The most serious systemic ndings are cardiac hematologic
and neurologic mani estations. Peripheral neuropathies and
central ner ous system (C S) disturbances can occur includ
ing con usion di iness dysarthria ascending paralysis sei
ures syncope and coma. The latter conditions ha e been
called dermatoneuro syndrome. iddle age men are most
re uently a ected and one third o these patients demon
strate recurrent symptoms. Plasmapheresis and intra enous
immune globulin ( V G) may result in dramatic reco ery rom
this li e threatening emergency. Visceral disease can be atal.
Criteria or inclusion in the scleromy edema category
include mucin deposition broblast proli eration and brosis
normal thyroid unction tests and presence o a monoclonal
gammopathy. Appro imately o patients do not ha e this
latter nding on initial e aluation. The gammopathy is usually
an gG λ type suggesting an underlying plasma cell dyscrasia.
Bone marrow e amination may be normal or may re eal
increased numbers o plasma cells or ran myeloma.
Clinical and histologic eatures are usually diagnostic. S in
biopsies o early papular lesions demonstrate a proli eration
o broblasts with mucin and many small collagen bers. The
papules generally appear more brotic than mucinous. er
time broblast nuclei become less numerous and collagen
bers become thic ened.
any clinical ndings in scleromy edema are also ound in
systemic scleroderma including cutaneous sclerosis Raynaud
179
9
Mucinoses

Fig. 9-1 Shiny papules of early scleromyxedema.

Fig. 9-4 Scleromyxedema, tightness of lower face and mouth.

thic ening in the setting o renal ailure. n its earliest orm it

includes mucin along with collagen deposition with a proli
eration o CD + cells in the dermis. The histologic ndings
are identical to those o scleromy edema and a rst report
re erred to a scleromy edema li e disease associated with
renal ailure. The clinical ndings are dominated by brosis
(see Chapter ).
Treatment o scleromy edema is di cult and usually
underta en in concert with an oncologist. any patients are
treated with immunosuppressi e agents especially melpha
lan borte omib or cyclophosphamide with or without plasma
e change and high dose prednisone. Temporary remission o
progressi e isceral disease may occur. These short term ben
e ts must be weighed against the increase in malignancies and
sepsis complicating such therapy. Chances o remission are
enhanced by the use o autologous stem cell transplantation
with high dose melphalan. V G is relati ely e ecti e and
sa e. aintenance in usions are necessary.
Fig. 9-2 Scleromyxedema.
S in directed therapy may also be used. Physical therapy is
indicated. Retinoids plasmapheresis e tracorporeal photo
Fig. 9-3
chemotherapy gren ray and electron beam therapy P VA
Scleromyxedema.
thalidomide inter eron ( ) α cyclosporine topical dimethyl
(Courtesy of Marshall
Guill, MD.)
sul o ide and topical and intralesional hyaluronidase and cor
ticosteroids ha e all produced impro ement in the s in o
select patients. any others howe er ha e not bene ted and
isceral disease is usually not a ected. ltra iolet B ( VB)
light and α ha e e acerbated scleromy edema.
ccasional patients are reported who spontaneously remit
e en a ter many years o disease; howe er scleromy edema
remains a therapeutic challenge and the o erall prognosis is
poor.

Localized lichen myxedematosus

phenomenon dysphagia and carpal tunnel syndrome. This
distinction in some cases may be di cult without a biopsy.
ther in ltrati e disorders such as amyloidosis must be
e cluded. Association with hepatitis C has been reported re
uently. ephrogenic systemic brosis presents with s in
180
The locali ed ariants o lichen my edematosus lac isceral
in ol ement or an associated gammopathy. As a group they
are benign but o ten persistent. o therapy is reliably e ecti e
in any o the locali ed orms o lichen my edematosus. Since
there is no gammopathy isceral in ol ement or associated
thyroid disease in any o the ariants o ten no treatment is
needed. Sha e e cision or carbon dio ide (C ) ablation are
other options or indi idual lesions. Spontaneous resolution
may occur in all arieties.
Discrete papular lichen myxedematosus
Discrete papular lichen my edematosus is characteri ed by
the occurrence o wa y mm rm esh colored papules

Fig. 9-5 Acral persistent papular mucinosis.
usually con ned to the limbs or trun . The papules may ha e
an erythematous or yellowish hue may coalesce into nodules
or pla ues and may number into the hundreds. odules may
occasionally be the predominant lesion present with ew or
absent papules. The underlying s in is not indurated and
there is no associated gammopathy or internal in ol ement.
Biopsy re eals the presence o mucin in the upper and middle
dermis. ibroblast proli eration is ariable but collagen depo
sition is minimal. The slow accumulation o papules is the
usual course without the de elopment o a gammopathy or
internal mani estations. ccasional cases may spontaneously
in olute.
any patients with ac uired immunode ciency syndrome
(A DS) ha e been reported to de elop mucinous papules
usually widespread unassociated with a paraprotein. t is
usually seen in ad anced human immunode ciency irus
( V) disease in patients with multiple in ectious complica
tions. These lesions may occur in association with an ec ema
tous dermatitis or on normal s in. associated with an
ec ematous dermatitis the lesions o ten clear i the ec ema is
controlled. Lesions on normal s in may respond to systemic
retinoid therapy. At times spontaneous remission occurs. The
authors ha e also seen a patient with A DS and true sclero
my edema with isceral in ol ement and two patients ha e
been reported with acral persistent papular mucinosis.
Acral persistent papular mucinosis
Patients with acral persistent papular mucinosis ha e a ew to
more than bilaterally symmetric mm esh colored
papules locali ed to the hands and wrists ( ig. ). The nees
cal es or elbows may also be in ol ed in a minority o
patients. The ace and trun are spared. Women outnumber
men by . The course is one o persistence and slow progres
sion. Two in ol ed sisters ha e been reported. istologically
there is a collection o upper dermal mucin with minimal or
no increase in broblasts. lectrocoagulation o these lesions
was reported to result in no recurrence in months.
Self-healing papular mucinosis
Sel healing papular mucinosis occurs in a u enile and an
adult orm. The u enile ariant also called sel healing u e
nile cutaneous mucinosis is a rare but distinct disorder char
acteri ed by the sudden onset o s in lesions and polyarthritis.
Children usually between ages and are a ected. amilial
cases are reported. S in lesions are i ory white papules o the
head nec trun and typically the periarticular regions; deep
nodules on the ace and periarticular sites; and hard edema o
the periorbital area and ace. An acute arthritis a ects the
nees elbows and hand oints. n the adult orm papular
lesions occur usually without the associated oint symptoms
( ig. ). istology o the s in lesions re eals dermal mucin
tahir99 - UnitedVRG
Lichen myxedematosus
Fig. 9-6 Self-healing papular mucinosis.
with minimal broblastic proli eration or collagen deposition.
Although the initial presentation is worrisome the prognosis
is e cellent. Spontaneous resolution without se uelae occurs
o er se eral months.
Papular mucinosis of infancy
Also re erred to as cutaneous mucinosis o in ancy this rare
syndrome occurs at birth or within the rst ew months o li e.
S in colored or translucent grouped or discrete mm
papules de elop on the trun or upper e tremities especially
the bac o the hands. Biopsies show ery super cial upper
dermal mucin without proli eration o broblasts. isting
lesions remain static; new lesions continue to accumulate
gradually. Similar lesions may sometimes be noted in associa
tion with neonatal lupus erythematosus.
Nodular lichen myxedematosus
Patients may ha e multiple nodules on the trun or
e tremities.
Atypical or intermediate lichen myxedematosus
The cutaneous mucinoses are all relati ely uncommon. n a
literature dominated by case reports indi idual patients ha e
been ound who do not t well into the abo e scheme. or
e ample some patients with acral persistent papular mucino
sis ha e a paraprotein with locali ed papular mucinosis and
gA nephropathy whereas others with apparently classic
scleromy edema with isceral lesions may not ha e a detect
able circulating paraprotein.
Abbot RA, et al: Widespread papules in a patient with HIV. Clin Exp
Dermatol 2010; 35:801–802.
Andre Jorge F, et al: Treatment of acral persistent popular mucinosis
with electrocoagulation. J Cutan Med Surg 2011; 15:227–229.
Blum M, et al: Scleromyxedema: a case series highlighting
long-term outcomes of treatment with IVIG. Medicine (Baltimore)
2008; 87:10.
Brunet-Possenti F, et al: Combination of intravenous immunoglobulins
and lenalidomide in the treatment of scleromyxedema. J Am Acad
Dermatol 2013; 69:319–320.
Canueto J, et al: The combination of bortezomib and dexamethasone is
an efficient therapy for relapsed/refractory scleromyxedema. Eur J
Haematol 2012; 88:450–454.
Concheiro J, et al: Discrete papular lichen myxedematosus. Clin Exp
Dermatol 2009; 34:e608–e610.
Donato ML, et al: Scleromyxedema: role of high-dose melphalan with
autologous stem cell transplantation. Blood 2006; 107:463.
181
 Feliciani C, et al: Adult self-healing popular mucinosis on genital skin.
9 Clin Exp Dermatol 2009; 34:e760–e762.
Fleming KE, et al: Scleromyxedema and the dermato-neuro syndrome.
J Cutan Pathol 2012; 39:508-517.
Hummers LK: Scleromyxedema. Curr Opin Rheumatol 2014; 26:658.
Mucinoses
Lee WS, et al: Cutaneous focal mucinosis arising from the chin. J
Craniofac Surg 2010; 21:1639–1641.
Luo DQ, et al: Acral persistent papular mucinosis. J Dtsch Dermatol
Ges 2011; 9:354–359.
Rampino M, et al: Scleromyxedema: treatment of widespread cutaneous
involvement by total skin electron beam therapy. Int J Dermatol 2007;
46:864.
Rongioletti F, et al: Scleromyxedema. J Am Acad Dermatol 2013;
69:66–72.
Rongioletti F, et al: Treatment of localized lichen myxedematosus of
discrete type with tacrolimus ointment. J Am Acad Dermatol 2008;
58:530.
Wang P, et al: Localized papular mucinosis with IgA nephropathy. Arch
Dermatol 2011; 147:599–602.
Yamamoto M, et al: Plaque-type focal mucinosis. Int J Dermatol 2011;
50:893–900.
Zeng R, et al: Nodular lichen myxedematosus during childhood: a case
report. Pediatr Dermatol 2014; Sep 22.
SCLEREDEMA
Scleredema is a s in disease characteri ed by a sti ening and
hardening o the subcutaneous tissues as i in ltrated with
para n. t occurs in two orms with and without diabetes mel
litus. n the more generali ed nondiabetic condition a sudden
onset a ter an in ection typically streptococcal may occur. This
reacti e ariant may also present as a drug eruption. n other
cases onset is insidious and chronic and has no preceding in ec
tion. n the more common diabetes associated disease a long
lasting induration o the upper bac is characteristic.
n cases not associated with diabetes emales outnumber
males by . The age at onset is rom childhood through adult
hood. S in tightness and induration begin on the nec and or
ace spreading symmetrically to in ol e the arms shoulders
bac and chest. The distal e tremities are spared. The patient
may ha e di culty opening the mouth or eyes and a mas li e
e pression as a result o the in ltration. The in ol ed s in
which is wa y and o woodli e consistency gradually transi
tions into normal s in with no clear demarcation. Associated
ndings occur in ariable numbers o patients and can include
dysphagia caused by tongue and upper esophageal in ol e
ment cardiac arrhythmias and an associated paraproteinemia
usually an gG type. yeloma may be present. There may be
pleural pericardial or peritoneal e usion.
n about hal the patients in whom scleredema ollows an
in ection spontaneous resolution will occur in months to a ew
years. n one patient whose disease had a sudden onset a ter
beginning in i imab treatment or rheumatoid arthritis the
condition resol ed uic ly a ter discontinuation o the medi
cine and did not recur a ter etanercept was initiated. The
remaining patients with nondiabetic scleredema ha e a pro
longed course. Therapy is generally o no bene t but patients
may li e with the disease or many years. Cyclosporine VA
pulsed de amethasone tamo i en V G and e tracorporeal
photopheresis ha e reportedly been bene cial in indi idual
patients. Borte omib induced remission in one patient with
myeloma associated scleredema.
n the second group which in most dermatologists e peri
ence is the more common type there is an association
with late onset insulin dependent diabetes. en outnumber
women by . A ected men tend to be obese. The lesions
are o insidious onset and long duration presenting as woody
induration and thic ening o the s in o the mid upper bac
182
Fig. 9-7 Scleredema.
nec and shoulders ( ig. ). There is a sharp step o rom
the in ol ed to the normal s in. Persistent erythema and
olliculitis may in ol e the a ected areas. The associated dia
betes is o long duration and is di cult to control. urther
patients o ten ha e complications o their diabetes such as
nephropathy atherosclerotic disease retinopathy and neu
ropathy. Control o the diabetes does not a ect the course o
the scleredema. o paraprotein is detected and no isceral
in ol ement is seen. Lesions are persistent and usually unre
sponsi e to treatment. ntra enous penicillin electron beam
alone or in combination with photon irradiation narrow band
VB and both bath and systemic P VA in one case combined
with colchicine ha e each been e ecti e in indi idual patients.
Although low dose methotre ate was success ul in one patient
it was ine ecti e in a case series o se en patients.
The histology o both orms is identical. The s in is dramati
cally thic ened with the dermis o ten e panded two old to
three old. There is no hyalini ation such as that seen in sclero
derma but rather the thic dermal collagen bundles are sepa
rated by clear spaces that may contain isible mucin (hyaluronic
acid). The amount o mucin is ariable and usually only prom
inent in early lesions. n late lesions slightly widened spaces
between thic collagen bundles are the sole nding because
the amount o mucin is scant.
Aichelburg MC, et al: Successful treatment of poststreptococcal
scleredema adultorum Buschke with intravenous immunoglobulins.
Arch Dermatol 2012; 148:1126–1128.
Alsaeedi SH, et al: Treatment of scleredema diabeticorum with
tamoxifen. J Rheumatol 2010; 37:2636–2637.
Beers WH, et al: Scleredema adultorum of Buschke: a case
report and review of the literature. Semin Arthritis Rheum 2006;
35:355.
Ioannidou DI, et al: Scleredema adultorum of Buschke presenting as
periorbital edema. J Am Acad Dermatol 2005; 52:41.
Kokpol C, et al: Successful treatment of scleredema diabeticorum by
combining local PUVA and colchicine. Case Rep Dermatol 2012;
4:265–268.
Kroft EB et al: Ultraviolet A phototherapy for sclerotic skin diseases.
J Am Acad Dermatol 2008; 59:1017–1030.
Kurihara Y, et al: Case of diabetic scleredema: diagnostic value of
magnetic resonance imaging. J Dermatol 2011; 38:693–696.
Morais P, et al: Scleredema of Buschke following Mycoplasma
pneumoniae respiratory infection. Int J Dermatol 2011; 50:454–457.
 Ranganathan P: Infliximab-induced scleredema in a patient with
rheumatoid arthritis. J Clin Rheumatol 2005; 11:319.
Szturz P, et al: Complete remission of multiple myeloma associated
scleredema after bortezomib-based treatment. Leuk Lymphoma 2013;
54:1324–1326.
Yachoui R, et al: Scleredema in a patient with AIDS-related
lipodystrophy syndrome. Case Rep Endocrinol 2013; Jan 10. [Epub
ahead of print.]
RETICULAR ERYTHEMATOUS MUCINOSIS
(REM SYNDROME, PLAQUELIKE
CUTANEOUS MUCINOSIS)
Reticular erythematous mucinosis (R ) a ors women in the
third and ourth decades o li e. The eruption re uently
appears a ter intense sun e posure. Clinical lesions are ery
thematous pla ues or reticulated patches that are se eral cen
timeters in diameter and usually in the midline o the chest
and bac ( ig. ). olution is gradual photosensiti ity may
be present and lesions induced with VB. nset or e acerba
tion with oral contracepti es menses and pregnancy is
another eature. Serologic tests or lupus erythematosus (L )
are negati e.
istologically there are arying degrees o lymphocytic
in ltration around dermal essels with deposits o mucin in
the dermis. Direct immuno uorescence is negati e but ocal
acuolar inter ace dermatitis is sometimes seen. Treatment
with antimalarials is success ul in most cases. The pulsed dye
laser has led to resolution in two patients.
Lesions o R ha e also been reported to occur on the ace
arms abdomen and groin. When e aluating patients with
mucinous smooth sur aced erythematous lesions it is important
to consider the possibility o connecti e tissue disease. Pla ue
li e or papulonodular lesions in sites away rom the central
chest and bac may in re uently herald the de elopment o
systemic L discoid L dermatomyositis or scleroderma.
Tumid lupus erythematosus is a subset o chronic cutaneous
lupus characteri ed by erythematous papules nodules and
pla ues that most o ten in ol e the ace e tensor aspects o
the arms shoulders V o the nec and upper bac . istology
more o ten has a deep peri ascular and pen ollicular location
and commonly re eals direct immuno uorescence acti ity
than R . Tumid L is photoinducible and responsi e to
Fig. 9-8 Reticulated erythematous mucinosis.
tahir99 - UnitedVRG
antimalarials. Although serologic abnormalities occur in a
small percentage o patients this is usually a s in limited
condition.
Cinotti E, et al: Reticular erythematous mucinosis. J Eur Acad Dermatol
Follicular mucinosis (alopecia mucinosa)
Venereol 2014; Aug 4.
Clarke JT: Recognizing and managing reticular erythematous
mucinosis. Arch Dermatol 2011; 147:715–716.
Kreuter A, et al: Clinical features and efficacy of antimalarial treatment
for reticulated erythematous mucinosis. Arch Dermatol 2011;
147:710–715.
Susok L, et al: Complete clearance of reticular erythematous mucinosis
with quinacrine monotherapy. Arch Dermatol 2012; 148:768–769.
Thareja S, et al: Reticulated erythematous mucinosis. Int J Dermatol
2012; 51:903–909.
Wristen CC, et al: Plaque-like cutaneous mucinosis. Am J Dermatopathol
2012; 34:e50–e54.
FOLLICULAR MUCINOSIS (ALOPECIA MUCINOSA)
n Pin us used the name alopecia mucinosa to describe
a series o patients who had in ammatory pla ues with alo
pecia characteri ed histologically by mucinous deposits in the
outer root sheaths o the hair ollicles. The pla ues may be
simply hypopigmented or erythematous and scaly ec ema
tous or composed o esh colored ollicular papules ( ig.
). There may be only one lesion especially on the head and
nec or multiple sites may be present. The pla ues are rm
and coarsely rough to the palpating nger. They are distrib
uted mostly on the ace nec and scalp but may appear on
any part o the body. tching may or may not be present. Alo
pecia occurs regularly in lesions on the scalp and re uently
in lesions located elsewhere. Some papules show a comedoli e
blac central dot that corresponds to a bro en hair or the
mucin itsel . These may cause the sur ace o a patch to resem
ble eratosis pilaris. Sensory dissociation with hot cold per
ception alterations or anesthesia to light touch has been
reported in some lesions with a resultant misdiagnosis o
ansen s disease.
The term alopecia mucinosa may be used to describe the
disease process and ollicular mucinosis to describe the histo
logic eatures. The disease may be limited to s in and benign
(primary ollicular mucinosis) or may be associated with ol
licular mycosis ungoides. When lesions are solitary or ew in
number and cluster on the head and nec o indi iduals
younger than the condition usually ollows a benign
chronic course e en when the in ltrate is ound to be clonal
in nature. Widespread lesions in an older patient howe er
will usually be ound to be cutaneous T cell lymphoma (CTCL)
Fig. 9-9 Alopecia
mucinosa.
183
 at initial presentation or will progress to lymphoma within
9 years. These two subsets are not e clusi e howe er and no
clinical or histologic criteria absolutely distinguish them in the
absence o diagnostic ndings o CTCL.
istologically ollicular mucinosis demonstrates large col
Mucinoses

lections o mucin within the sebaceous gland and outer root

sheath. The mucin typically stains as hyaluronic acid. A mi ed
dermal in ltrate is present. When the condition occurs in asso
ciation with CTCL the peri ollicular in ltrate is atypical but
not generally epidermotropic and considerable admi ture o
eosinophils and plasma cells is present. The additional nding
o the presence o syringolymphoid hyperplasia should raise
concern that lymphoma is or will become e ident. T cell recep
tor gene rearrangement studies that indicate clonality are also
supporti e but do not alone predict an aggressi e course.
Spontaneous in olution o primary ollicular mucinosis
may occur especially in young children. Topical corticoste
roids produce impro ement. ydro ychloro uine is an
e cellent rst line systemic therapy. Dapsone P VA radia
tion therapy alpha b minocycline isotretinoin photo
dynamic therapy and indomethacin ha e been e ecti e in
indi idual cases. ollicular mycosis ungoides with or without
associated mucin is more re ractory to treatment and has a
worse prognosis than classic CTCL.
Alikhan A, et al: Pediatric follicular mucinosis. Pediatr Dermatol 2013;
30:192–198.
Lehman JS, et al: Folliculotropic mycosis fungoides. Arch Dermatol
2010; 146:662.
Schneider SW, et al: Treatment of so-called idiopathic follicular
mucinosis with hydroxychloroquine. Br J Dermatol 2010; 163:420.
White FN, et al: Acneiform follicular mucinosis responding to
hydroxychloroquine. Arch Dermatol 2011; 147:130–131.
Zvulunov A, et al: Clinical and histopathologic spectrum of alopecia
mucinosa/follicular mucinosis and its natural history in children. J Am
Acad Dermatol 2012; 67:1174–1181.
CUTANEOUS FOCAL MUCINOSIS
ocal mucinosis is characteri ed by a solitary nodule or papule.
Lesions are asymptomatic and usually occur on the ace nec
trun or e tremities. They appear in adulthood. istologi
cally the lesion is characteri ed by a loose dermal stroma
containing large uantities o mucin together with numerous
dendritic shaped broblasts. The clinical appearance is not
distincti e and at times may suggest a cyst basal cell carci
noma or neuro broma. Treatment is surgical e cision.
Lee WS, et al: Cutaneous focal mucinosis arising from the chin. J
Craniofac Surg 2010; 21:1639.
Takemura N, et al: Cutaneous focal mucinosis. J Dermatol 2005;
32:1051.
Fig. 9-10 Distortion of nail distal to myxoid cyst.
tiple digital mucous cysts as the initial mani estation o u e
nile rheumatoid arthritis.
When a syno ial cyst is present beneath the pro imal nail
old a characteristic groo e may be ormed in the nail plate
by pressure o the lesion on the nail matri ( ig. ). Those
located beneath the nail cause a trans erse nail cur ature and
a red or blue discoloration o the lunula. ail integrity typi
cally is compromised leading to distal or longitudinal split
ting or onycholysis. The diagnosis can be con rmed by
magnetic resonance imaging ( R ) or surgical e ploration.
y oid cysts contain a clear iscous stic y uid that may
spontaneously drain. These cysts do not ha e an epithelial
lining but rather a compacted brous wall.
Treatment depends on the site o the my oid cyst. The
repeated puncture techni ue or cysts located beneath the
pro imal nail old may achie e a cure rate o up to but
multiple punctures (> ) may be re uired. This techni ue may
be complicated by local tissue or oint in ection. Steroids may
be in ected into the tissue a ter draining the cyst. ntralesional
in ection o sodium tetradecyl sul ate has an response
rate. Destruction by cryotherapy C laser ablation curettage
and ulguration are alternati es with similar cure rates but
these therapies result in scarring.
Surgical approaches that re ect the s in o erlying the cyst
and either e cise or tie o the communication to the oint
which may be isuali ed by in ecting the my oid cyst with
methylene blue ha e a cure rate greater than .
Li K, et al: Digital mucous cysts. Cutan Med Surg 2010; 14:199–206.
Park SE, et al: Treatment of digital mucous cysts with intralesional
sodium tetradecyl sulfate injection. Dermatol Surg 2014; 40:1249.

MYXOID CYSTS
y oid cysts also called syno ial and digital mucous cysts Bonus images for this chapter can be found online at
occur most re uently on the dorsal or lateral terminal digits expertconsult.inkling.com
o the hands but may also occur on the toes. These lesions
present as solitary mm opalescent or s in colored cysts. eFig. 9-1 Scleromyxedema. (Courtesy of Marshall Guill, MD.)
They may occur as asymptomatic swellings o the pro imal eFig. 9-2 Scleromyxedema. (Courtesy of Marshall Guill, MD.)
nail old as subungual growths or o er the distal interphalan eFig. 9-3 Scleromyxedema. (Courtesy of Marshall Guill, MD.)
geal oint. Women are more re uently a ected and osteoar eFig. 9-4 Nephrogenic systemic fibrosis.
thritis is o ten present in the ad acent distal interphalangeal eFig. 9-5 Scleredema.
oint. y oid cysts that can be reduced with pressure com eFig. 9-6 Reticulated erythematous mucinosis.
municate directly with the oint space. eFig. 9-7 Alopecia mucinosa.
ultiple my oid cysts are associated with connecti e tissue eFig. 9-8 Myxoid (digital mucous) cyst.
disease. oung children e en in ants may present with mul

184
 Myxoid cysts
eFig. 9-1 Scleromyxedema. (Courtesy of Marshall Guill, MD.)

eFig. 9-4 Nephrogenic systemic fibrosis.

eFig. 9-2 Scleromyxedema. (Courtesy of Marshall Guill, MD.)

eFig. 9-5 Scleredema.

eFig. 9-6 Reticulated

erythematous
mucinosis.

eFig. 9-3 Scleromyxedema. (Courtesy of Marshall Guill, MD.)

184.e1

tahir99 - UnitedVRG
 eFig. 9-8 Myxoid
9 (digital mucous) cyst.
Mucinoses

eFig. 9-7 Alopecia mucinosa.

184.e2
 Bonus images for this chapter can be found online at
Seborrheic Dermatitis, Psoriasis,
Recalcitrant Palmoplantar Eruptions,
Pustular Dermatitis, and Erythroderma
SEBORRHEIC DERMATITIS
Clinical features
Seborrheic dermatitis is common occurring in o the
population. t is a chronic super cial in ammatory disease
with a predilection or the scalp eyebrows eyelids nasolabial
creases lips ears ( ig. ) sternal area a illae submam
mary olds umbilicus groins and gluteal crease. The disease
is characteri ed by scaling on an erythematous base. The scale
o ten has a yellow greasy appearance. tching may be se ere.
Dandru (pityriasis sicca) represents a mild orm o seborrheic
dermatitis. An oily type pityriasis steatoides is accompanied
by erythema and an accumulation o thic crusts.
ther types o seborrheic dermatitis on the scalp include
arcuate polycyclic or petaloid patches and psoriasi orm e u
dati e or crusted pla ues. The disease re uently spreads
beyond the hairy scalp to the orehead ears postauricular
regions and nec . n these areas the patches ha e con e
borders and are reddish yellow or yellowish. n dar s inned
indi iduals arcuate and petaloid lesions typically in ol e the
hairline. n e treme cases the entire scalp is co ered by a
greasy dirty crust with an o ensi e odor. n in ants yellow
or brown scaling lesions on the scalp with accumulated adher
ent epithelial debris are called cradle cap.
rythema and scaling are o ten seen in the eyebrows. The
lids may show ne yellowish white scales and aint erythema.
The edges o the lids may be erythematous and granular (mar
ginal blepharitis) and the con uncti ae may be in ected. the
glabella is in ol ed ssures in the wrin les at the inner end
o the eyebrow may accompany the ne scaling. n the naso
labial creases and on the alae nasi there may be yellowish or
reddish yellow scaling macules sometimes with ssures. n
men olliculitis o the beard area is common.
n the ears seborrheic dermatitis may be mista en or an
in ectious otitis e terna. There is scaling in the aural canals
around the auditory meatus usually with mar ed pruritus.
The postauricular region and s in under the lobe may be
in ol ed. n these areas the s in o ten becomes red ssured
and swollen. n the a illae the eruption begins in the apices
bilaterally and later progresses to neighboring s in. This
pattern resembles that o allergic contact dermatitis to deodor
ant but di ers rom that o clothing dermatitis (which in ol es
periphery o a illae but spares the ault). The in ol ement
may ary rom simple erythema and scaling to more pro
nounced petaloid patches with ssures. The in ramammary
olds and the umbilicus may be in ol ed. The presternal area
is a a ored site on the trun .
Seborrheic dermatitis is common in the groin and gluteal
crease where its appearance may closely simulate tinea cruris
or candidiasis. n these areas the appearance o ten o erlaps
with that o in erse psoriasis. n act many o these patients
ha e an o erlap o the two conditions (sebopsoriasis or
tahir99 - UnitedVRG
expertconsult.inkling.com
10
seborrhiasis) in the groin as well as the scalp. The lesions may
also become generali ed and progress to an e oliati e eryth
roderma (erythroderma des uamati um) especially in in ants.
A minority o these in ants will ha e e idence o immunosup
pression. n adults generali ed eruptions may be accompa
nied by adenopathy and may simulate mycosis ungoides or
psoriatic erythroderma.
Seborrheic dermatitis may be associated with se eral inter
nal diseases. Par inson s disease is o ten accompanied by
se ere re ractory seborrheic dermatitis in ol ing the scalp
and ace with wa y pro use scaling. A unilateral in ury to
the inner ation o the ace or a stro e may lead to unilat
eral locali ed seborrheic dermatitis. Patients with ac uired
immunode ciency syndrome (A DS) ha e an increased inci
dence o seborrheic dermatitis. An increased incidence has
also been noted in patients who are seropositi e or human
immunode ciency irus ( V) but ha e not de eloped other
signs o clinical disease. Diabetes mellitus (especially in
obese persons) sprue malabsorption disorders epilepsy
neuroleptic drugs (e.g. haloperidol) and reactions to arsenic
and gold ha e all produced seborrheic dermatitis li e
eruptions.
Etiology and pathogenesis
The etiology o this common disorder is comple but may be
related to the presence o the lipophilic yeast Malasse ia ovalis
Pit rosporum ovale which produces bioacti e indoles oleic
acid malsse in and indole carbaldehyde. The density o
yeast has been correlated with the se erity o the disease and
reduction o the yeast occurs with response to therapy. M
ovalis may also be abundant on the scalps o patients who ha e
no clinical signs o the disease and the yeast may only be
pathogenic in predisposed indi iduals.
Patients with seborrheic dermatitis may show upregulation
o inter eron ( ) γ e pressed interleu in ( L ) e pressed
L β and L . pression o cytoto icity acti ating ligands
and recruitment o natural iller ( ) cells ha e also been
noted.
Histology
The epidermis demonstrates regular acanthosis with some
thinning o the suprapapillary plates. Varying degrees o
spongiosis and lymphocyte e ocytosis are noted. A character
istic nding is the presence o a ocal scale crust ad acent to
the ollicular ostia.
Differential diagnosis
Some cases o seborrheic dermatitis bear a close clinical resem
blance to psoriasis and the two conditions may o erlap.
185

10
Seborrheic Dermatitis, Psoriasis, Recalcitrant Palmoplantar Eruptions, Pustular Dermatitis, and Erythroderma
Fig. 10-1 Seborrheic dermatitis.
Patients with psoriasis tend to ha e more pronounced ery
thema and hea ier sil ery scales that peel in layers. Remo al
o scales in psoriasis may disclose bleeding points (Auspit
sign). This sign is common but lac s great speci city. Se ere
itching a ors seborrheic dermatitis. Characteristic psoriasis
elsewhere (nail pitting balanitis) may resol e the uestion.
mpetigo o the scalp especially when associated with pedicu
losis may cause di culty in di erentiation. Scalp impetigo
can be an indolent crusted dermatosis associated with ailure
to thri e. Langerhans cell histiocytosis may also resemble seb
orrheic dermatitis but typically demonstrates yellow brown
peri ollicular papules and groin ssuring. Crusted scabies o
the scalp can also be con used with seborrheic dermatitis and
richoph ton tonsurans o ten produces a subtle seborrheic
scale. n subtle cases o tinea a moist gau e pad rubbed igor
ously on the scalp will typically dislodge short bro en potas
sium hydro ide ( ) positi e hairs. This can be the astest
way to ma e the diagnosis.
Treatment
Agents suitable or use on glabrous s in include corticosteroid
creams gels sprays and oams. Corticosteroids tend to
produce a rapid e ect but on the ace e en midpotency
corticosteroids can produce steroid rosacea. or this reason
anti ungal agents and topical calcineurin inhibitors (C s)
are o ten pre erred. etocona ole ciclopiro sertacona ole
186
tacrolimus pimecrolimus inc pyrithione and uassia amara
e tract preparations are all e ecti e alone and in combination.
The anti ungals are now a ailable in a wide range o ehicles
to include oams gels and li uids. Bi ona ole shampoo has
been e ecti e in treating in ants and small children. Topical
C s may be associated with a burning sensation especially
on moist s in and may produce ushing i patients consume
alcohol. Patients generally tolerate these agents better a ter
initial treatment with a corticosteroid. An open randomi ed
prospecti e comparati e study o topical pimecrolimus
cream ersus topical etocona ole cream ound the two to
be e ually e ecti e but side e ects were somewhat more
common with pimecrolimus. Preliminary studies suggest oral
itracona ole and oral terbina ne may show some e cacy.
ral ucona ole showed marginal bene t. Study results with
topical metronida ole ha e been mi ed.
When secondary bacterial in ection is present a topical or
oral antibiotic may be re uired. n patients in ected with V
lithium succinate ointment ( alith) has been used or acial
disease. Lithium gluconate ointment has compared a or
ably with etocona ole emulsion in healthy adults and was
more e ecti e in terms o control o scaling and symptoms.
Sodium sul acetamide products with or without sul ur are
e ecti e in some re ractory patients.
or scalp disease selenium sul de etocona ole tar inc
pyrithione uocinolone and resorcin shampoos are e ecti e.
n many patients these agents may be used two to three
times a wee with a regular shampoo used in between as
re uired. White patients o ten pre er anti ungal oams and
gels as well as corticosteroid solutions oams gels and
sprays whereas some blac patients pre er ointment or oil
preparations.
tching o the e ternal ear canal usually responds to a
topical corticosteroid C s or anti ungals (e.g. etocona ole
ciclopiro ). Some patients re uire the use o a class cortico
steroid on wee ends to control re ractory pruritus. Cortisporin
otic suspension (neomycin polymy in B hydrocortisone) can
bring about prompt clearing but contact dermatitis to neomy
cin may complicate the use o some Cortisporin products.
Desonide otic lotion ( . desonide acetic acid) is also
e ecti e and may be better tolerated than Domeboro otic solu
tion (aluminum acetate).
Sodium sul acetamide drops or ointment may be e ecti e
or seborrheic blepharitis. ral tetracyclines can also be e ec
ti e and ha e been shown to decrease the density o microor
ganisms in the a ected ollicles. Steroid preparations are
suitable or short term use but may induce glaucoma and cata
racts. Daily gentle cleansing with a cotton tipped applicator
and baby shampoo in water can reduce symptoms. n se ere
cases oral antibiotics or oral anti ungals may be combined
with topical agents.
Alizadeh N, et al: Comparison the efficacy of fluconazole and
terbinafine in patients with moderate to severe seborrheic
dermatitis. Dermatol Res Pract 2014; 2014:705402.
Dessinioti C, et al: Seborrheic dermatitis: etiology, risk factors, and
treatments: facts and controversies. Clin Dermatol 2013;
31(4):343–351.
Diehl C, et al: Efficacy of topical 4% Quassia amara gel in facial
seborrheic dermatitis: a randomized, double-blind, comparative study.
J Drugs Dermatol 2013; 12(3):312–315.
Gary G: Optimizing treatment approaches in seborrheic dermatitis.
J Clin Aesthet Dermatol 2013; 6(2):44–49.
Kastarinen H, et al: Topical anti-inflammatory agents for seborrhoeic
dermatitis of the face or scalp. Cochrane Database Syst Rev 2014
May 19; 5:CD009446.
Kim TW, et al: Proactive treatment of adult facial seborrhoeic
dermatitis with 0.1% tacrolimus ointment: randomized, double-
blind, vehicle-controlled, multi-centre trial. Acta Derm Venereol
2013; 93(5):557–561.
 Fig. 10-3 Pustular
psoriasis of the hand.

Psoriasis
Fig. 10-2 Psoriasis.

Lee YW, et al: Evaluation of expression of lipases and phospholipases

of Malassezia restricta in patients with seborrheic dermatitis. Ann
Dermatol 2013; 25(3):310–314.

PSORIASIS
Clinical features
Psoriasis is a common chronic and recurrent in ammatory
disease o the s in characteri ed by circumscribed erythema
tous dry scaling pla ues o arious si es usually co ered by
sil ery white lamellar scales. The lesions are usually sym
metrically distributed and ha e a predilection or the scalp
nails e tensor sur aces o the limbs umbilical region and
sacrum. t usually de elops slowly but may be e anthematous
with the sudden onset o numerous guttate (dropli e) lesions
( ig. ). Sub ecti e symptoms such as itching or burning
may be present and may cause e treme discom ort.
The early lesions are small erythematous macules co ered
with dry sil ery scales rom the onset. The lesions increase in
si e by peripheral e tension and coalescence. The scales are Fig. 10-4 Nail with oil spot of psoriasis.
micaceous meaning they peel in layers and are looser toward
the periphery and adherent centrally. When remo ed bleed Fig. 10-5 Nail pitting
ing points appear (Auspit sign). Although pla ues typically and distal onycholysis
predominate lesions may be annular or polycyclic. ld in psoriasis.
patches may be thic and co ered with tough lamellar scales
li e the outside o an oyster shell (psoriasis ostracea). Descrip
ti e terms applied to the di erse appearance o the lesions
include psoriasis guttata in which the lesions are the si e o
water drops; psoriasis follicularis in which tiny scaly lesions
are located at the ori ces o hair ollicles; psoriasis gurata
annulata or g rata in which cur ed linear patterns are pro
duced by central in olution; psoriasis iscoi ea in which
central in olution does not occur and solid patches persist;
and psoriasis rupioi es in which crusted lesions occur resem
bling syphilitic rupia. The term chronic pla ue psoriasis is o ten
applied to stable lesions o the trun and e tremities. n erse
psoriasis predominates in intertriginous areas. Pustular ari
ants o psoriasis may be chronic on the palms and soles ( ig.
) or these may be erupti e and accompanied by se ere
to icity and hypocalcemia. Types
n ol ed nails can demonstrate distal onycholysis random
pitting caused by para eratosis rom the pro imal matri Seborrheic-like psoriasis
( ig. ) oil spots (yellow areas o subungual para eratosis
rom the distal matri ; ig. ) or salmon patches (nail bed Some cases o psoriasis o erlap with seborrheic dermatitis.
psoriasis). Thic subungual hyper eratosis may resemble Seborrheic lesions may predominate on the ace under the
onychomycosis. breasts and in the scalp e ures and a illae. Lesions in these
187

tahir99 - UnitedVRG
 areas are moist and erythematous with yellow greasy so t
10 scales rather than dry and micaceous scales. Terms such as
sebopsoriasis and seborrhiasis may be used to describe the
condition o such patients.
Seborrheic Dermatitis, Psoriasis, Recalcitrant Palmoplantar Eruptions, Pustular Dermatitis, and Erythroderma
Inverse psoriasis
n erse psoriasis selecti ely and o ten e clusi ely in ol es
olds recesses and e or sur aces such as the ears a illae
groin in ramammary olds na el intergluteal crease penis
lips and web spaces. ther areas such as the scalp and nails
may be in ol ed.
“Napkin” psoriasis
ap in psoriasis or psoriasis in the diaper area is character
istically seen in in ants between and months o age. Lesions
appear as brightly erythematous sharply demarcated patches
o s in in ol ing much o the diaper area. The lesions typically
clear with topical therapy but psoriasis may reappear in
adulthood.
Psoriatic arthritis
i e clinical patterns o psoriatic arthritis occur as ollows
. Asymmetric distal interphalangeal oint in ol ement
with nail damage ( ) carriage.
. Arthritis mutilans with osteolysis o phalanges and
metacarpals ( ) ( ig. )
. Symmetric polyarthritis li e rheumatoid arthritis (RA)
with clawhand ( ) (von Zumbusch psoriasis)
n
. ligoarthritis with swelling and tenosyno itis o one or a
ew hand oints ( )
. An ylosing spondylitis alone or with peripheral arthritis
U
( ).
-
ost radiographic ndings resemble those in RA but certain
ndings are highly suggesti e o psoriasis. These include
erosion o terminal phalangeal tu ts (acrosteolysis) tapering
9
or whittling o phalanges or metacarpals with cupping o
pro imal ends o phalanges ( pencil in a cup de ormity )
ri 9
bony an ylosis osteolysis o metatarsals predilection or
distal interphalangeal and pro imal interphalangeal oints
relati e sparing o metacarpophalangeal and metatarsopha
langeal oints para ertebral ossi cation asymmetric sacroili
h
itis and rarity o bamboo spine when the spine is in ol ed.
a
t
Fig. 10-6 Psoriatic arthritis.
188
Almost hal the patients with psoriatic arthritis ha e type
human leu ocyte antigen ( LA) B .
Rest splinting passi e motion and nonsteroidal anti
in ammatory drugs ( SA Ds) may pro ide symptomatic
relie but do not pre ent de ormity. ethotre ate cyclospo
rine tacrolimus and biologic agents are disease modi ying
drugs that pre ent de ormity.
Guttate psoriasis
n the distincti e guttate orm o psoriasis typical lesions are
the si e o water drops mm in diameter. Lesions typically
occur as an abrupt eruption a ter acute in ection such as a
streptococcal pharyngitis. Guttate psoriasis occurs mostly in
patients under age . This type o psoriasis usually responds
rapidly to broad band ultra iolet B ( VB) at erythemogenic
doses. Suberythemogenic doses o ten ha e little impact on the
lesions. This is one o the ew orms o psoriasis where broad
band VB may ha e an ad antage o er narrow band VB.
inimal erythemogenic (erythema) dose ( D) testing is rec
G
ommended to allow or appropriately aggressi e treatment.
Recurrent episodes may be related to pharyngeal carriage o
R
the responsible streptococcus by the patient or a close contact.
A course o a semisynthetic penicillin (e.g. diclo acillin
V
mg our times daily or days) with ri ampin ( mg
day or adult) may be re uired to clear chronic streptococcal
d
ti e
Generalized pustular psoriasis
Typical patients with generali ed pustular psoriasis ha e
pla ue psoriasis and o ten psoriatic arthritis. The onset is
sudden with ormation o la es o pus periungually on the
palms and at the edge o psoriatic pla ues. rythema occurs
in the e ures be ore the generali ed eruption appears. This
is ollowed by a generali ed erythema and more pustules ( ig.
). Pruritus and intense burning are o ten present. ucous
membrane lesions are common. The lips may be red and scaly
and super cial ulcerations o the tongue and mouth occur.
Geographic or ssured tongue re uently occurs ( ig. ).
Fig. 10-7 Fissured and
geographic tongue in
patient with
generalized pustular
psoriasis.
 Fig. 10-9 Generalized
pustular flare in a
patient with
acrodermatitis
continua.

Psoriasis
Fig. 10-8 Geographic tongue in pustular psoriasis.

The patient is re uently ill with e er erythroderma hypo

calcemia and cache ia. A number o cases o acute respiratory
distress syndrome associated with pustular and erythroder
mic psoriasis ha e been reported. ther systemic com
plications include pneumonia congesti e heart ailure and
hepatitis.
pisodes are o ten pro o ed by withdrawal o systemic cor
ticosteroids. The authors ha e also obser ed generali ed pus
tular psoriasis as the presenting sign o Cushing s disease.
ther implicated drugs include iodides coal tar terbina ne
minocycline hydro ychloro uine aceta olamide and salicy Fig. 10-10
lates. There is usually a strong amilial history o psoriasis. Erythrodermic
Generali ed pustular psoriasis may occur in in ants and chil psoriasis.
dren with no implicated drug. t may also occur as an episodic
e ent punctuating the course o locali ed acral pustular
psoriasis.
Acitretin is the drug o choice in this se ere disease. The
response is generally rapid. sotretinoin is also e ecti e. Cyclo
sporine methotre ate and biologic agents are alternati es. n
some cases dapsone is e ecti e in doses o mg day.

Acrodermatitis continua (of Hallopeau)

Typical patients de elop acral erythematous pla ues studded
with pustules. The nail beds are hea ily in ol ed and the
ngernails oat away on la es o pus resulting in anonychia.
yper eratosis o ten ensues and the ngertips become
increasingly pain ul tapering to long eratotic points. cca
sionally patients may de elop generali ed pustular ares
( ig. ). Acrodermatitis continua is discussed in more detail
later (see Dermatitis repens under Recalcitrant palmoplantar
eruptions).

Impetigo herpetiformis
eratotic lesions. Patients are o ten positi e or LA B and
The term impetigo herpeti ormis has been applied to pustular de elop reacti e arthritis and s in disease a ter a bout o ure
psoriasis o pregnancy. le ural erythema studded with pus thritis or enteritis.
tules o ten occurs initially ollowed by a generali ed pustular
are and increasing to icity. These patients are pregnant so Erythrodermic psoriasis
systemic retinoids are not appropriate. any patients only
respond to deli ery and early deli ery should be strongly Patients with psoriasis may de elop a generali ed erythro
considered as soon as it is sa e or the in ant. Alternati ely derma ( ig. ). rythrodermic psoriasis is co ered in
patients may respond to prednisone mg g day. The cor greater detail in Chapter under oliati e dermatitis.
ticosteroid can also contribute to neonatal lung maturity.

Keratoderma blennorrhagicum (Reiter syndrome) Course

eratoderma blennorrhagicum resembles psoriasis both histo The course o psoriasis is unpredictable. t usually begins on
logically and clinically e cept or its tendency or thic er the scalp or elbows and may remain locali ed in the original
189

tahir99 - UnitedVRG
 Fig. 10-11 Koebner
10 phenomenon in
psoriasis.
Seborrheic Dermatitis, Psoriasis, Recalcitrant Palmoplantar Eruptions, Pustular Dermatitis, and Erythroderma
region or years. Chronic disease may also be almost entirely
limited to the ngernails. n ol ement o er the sacrum may
easily be con used with candidiasis or tinea. nset may also
be sudden and widespread.
Two o the chie eatures o psoriasis are its tendency to
recur and its persistence. The isomorphic response ( oebner
n
phenomenon) is the appearance o typical lesions o psoriasis
at sites o e en tri ial in ury ( ig. ). Lesions may occur at
U
sites o scratches incisions and burns. Lesions may rst
appear a ter iral e anthema or pityriasis rosea. The isomor
-
phic response may occur i psoriatic lesions are se erely
burned during phototherapy. With a reduction in light dosage
the erythema and burning resol e and the pla ues begin to
9
clear. Worono s ring is concentric blanching o the erythema
tous s in at or near the periphery o a healing psoriatic pla ue.
ri 9
t is o ten the rst sign that the patient s psoriasis is respond
ing to phototherapy.
The palms and soles are sometimes e clusi ely a ected
showing discrete dry erythematous scaling patches circum
h
scribed errucous thic enings or pustules on an erythematous
base. The patches usually begin in the midportion o the palms
t a
or on the soles and gradually e pand. Psoriasis o the palms
and soles is typically chronic and e tremely resistant to
treatment.
any studies report an association between hepatitis C and
psoriasis and hepatitis C irus ( CV) has also been impli
cated in psoriatic arthritis. treatment o psoriasis is to include
a potentially hepatoto ic drug such as methotre ate CV
serology should be obtained. Also inter eron ( ) treatment
o the hepatitis can urther e acerbate or induce psoriasis.
Anti tumor necrosis actor (T ) α therapy shows promise in
the treatment o psoriasis e en in the setting o chronic CV
in ection.
Inheritance
n a large study o psoriasis in mono ygotic twins heritability
was high and en ironmental in uence low. Patients with
psoriasis o ten ha e relati es with the disease and the
incidence typically increases in successi e generations. ulti
actorial inheritance is li ely. Analysis o population speci c
190
LA haplotypes has pro ided e idence that susceptibility to
psoriasis is lin ed to ma or histocompatibility comple (
classes and on human chromosome . A number o genetic
C)
loci are lin ed to psoriasis including PSO S on chromosome
and within the C and PSO S on chromosome .
Also there are two subsets that di er in age o onset and re
uency o LA associations. arly onset is type psoriasis and
is associated mostly with Cw B and DR . Late onset is
type and predominantly eatures Cw . PSO S has also
been con rmed as a susceptibility locus or psoriasis.
A ariety o other LA associations ha e been reported. t
is belie ed that any indi idual who has B or B carries a
e old ris o de eloping psoriasis. n pustular psoriasis
LA B may be seen whereas B and B are increased in
guttate and erythrodermic psoriasis. n palmoplantar pustulo
sis there is an association with LA B Bw Cw and DR .
LA typing is a research tool or population based studies
but o limited alue in assessing an indi idual patient.
G
Epidemiology
R
Psoriasis occurs with e ual re uency in both genders. Between
and o the .S. population has psoriasis. t occurs less
V
re uently in the tropics. t is less common in orth American
and West A rican blac persons. ati e ( ndian) Americans
d
and nati e i ians rarely ha e psoriasis. The onset o psoriasis
is at a mean age o years but the range is wide rom the
ti e
neonatal period to the se enties. Se ere emotional stress tends
to aggra ate psoriasis in almost hal o those studied.
n pregnancy there is a distinct tendency or impro ement
or e en temporary disappearance o lesions in the ma ority o
women studied. A ter childbirth there is a tendency or e ac
erbation o lesions. Parado ically pregnancy is also the milieu
or impetigo herpeti ormis and psoriasis may beha e di er
ently rom one pregnancy to another in the same patient.
A high pre alence o celiac disease has been noted in patients
with psoriasis. Lymphoma also has an increased incidence in
these patients and psoriasis has been lin ed to the metabolic
syndrome and a higher ris o cardio ascular disease although
early age o onset does not appear to correlate with greater ris .
Pathogenesis
Psoriasis is a hyperproli erati e disorder but the proli eration
is dri en by a comple cascade o in ammatory mediators.
Psoriasis appears to represent a mi ed T helper (Th ) and
Th in ammatory disease. Th cells appear to be more pro
imal in the in ammatory cascade. T cells and cyto ines play
pi otal roles in the pathophysiology o psoriasis. ere pres
sion o type cyto ines such as L L L L γ
and T α has been demonstrated and o ere pression o
L leads to the accumulation o neutrophils. The main signal
or Th de elopment is L which promotes intracellular
γ production. n animal models shi ting rom Th to Th
responses impro es psoriasis. L is capable o inducing Th
responses and impro ing psoriasis. Reduced e pression o the
anti in ammatory cyto ines L RA and L has been ound
and polymorphisms or L genes correlate with psoriasis.
L is a type cyto ine with ma or in uence on immuno
regulation inhibiting type proin ammatory cyto ine pro
duction. Patients recei ing established traditional therapies
show rising le els o L messenger R A e pression sug
gesting that L may ha e antipsoriatic capacity.
The response to biologic agents has demonstrated that Th
T regulatory cells CD + lymphocytes CD a and T α are
important in the pathogenesis o psoriasis. L triggers
in ammatory cell recruitment angiogenesis and production
o in ammatory cyto ines including γ T α and L
all o which are upregulated in psoriatic lesions. The interplay
is comple but L appears to be proin ammatory while
L may ser e to retard eratinocyte di erentiation. L
stimulates sur i al as well as proli eration o Th cells. Cir
culating cells are reduced in psoriasis. ther cyto ines that
may play an important pathogenetic role in psoriasis include
L A and Th cells.
Streptococci
Streptococci play a role in some patients. Patients with psoria
sis report sore throat more o ten than controls. β emolytic
streptococci o Lance eld groups A C and G can cause e ac
erbation o chronic pla ue psoriasis. Th cells recogni e cell
wall e tract isolated rom group A streptococci. LA ariation
has a signi cant e ect on the immune response to group A
streptococci.
Stress
Various studies ha e shown a positi e correlation between
stress and se erity o disease. n almost hal o patients studied
stress appears to play a signi cant role.
Drug-induced psoriasis
Psoriasis may be induced by β bloc ers lithium antimalarials
terbina ne calcium channel bloc ers captopril glyburide
granulocyte colony stimulating actor interleu ins inter er
ons and lipid lowering drugs. Systemic steroids may cause
rebound or pustular ares. Antimalarials are associated with
erythrodermic ares but patients tra eling to malaria endemic
regions should ta e appropriate prophyla is. ten drugs
such as do ycycline or me o uine are appropriate or the
geographic area but when a uinine deri ati e o ers the best
protection it is generally better to ta e the prophylactic doses
o a uinine deri ati e than to ris disease and ull dose
treatment.
Pathology
istologically all psoriasis is pustular. The microscopic pus
tules include spongi orm intraepidermal pustules and unro
microabscesses within the stratum corneum. n early guttate
lesions ocal para eratosis is noted within the stratum
corneum. The para eratotic ocus typically has an outline
resembling a seagull. eutrophils are generally noted imme
diately abo e the ocus o para eratosis but in some sections
the neutrophils will not be isible as a result o sampling error.
n pla ue psoriasis neutrophilic oci are so numerous that
they are rarely missed. eutrophilic microabscesses are gener
ally present at multiple le els in the stratum corneum usually
on top o small oci o para eratosis. These oci generally alter
nate with areas o ortho eratotic stratum corneum suggesting
that the underlying spongi orm pustules arise in a rhythmic
ashion. The granular layer is absent ocally corresponding to
areas producing oci o para eratosis. n well de eloped
pla ues there is regular epidermal acanthosis with long
bulbous rete ridges thinning o er the dermal papillae and
dilated capillaries within the dermal papillae. The last two
ndings correlate with the Auspit sign. The stratum corneum
may be entirely para eratotic but still shows multiple small
neutrophilic microabscesses at arying le els. Spongiosis is
typically scant e cept in the area immediately surrounding
collections o neutrophils.
tahir99 - UnitedVRG
n pustular psoriasis geographic tongue and Reiter syn
drome intraepidermal spongi orm pustules tend to be much
larger. Grossly pustular lesions o ten ha e little associated
acanthosis. n Reiter syndrome the stratum corneum is o ten
massi ely thic ened with prominent oci o neutrophils abo e
Psoriasis
para eratosis alternating with ortho eratosis.
Acral lesions o ten demonstrate nondiagnostic eatures his
tologically. Spongiosis is typically prominent in these lesions
and o ten leads to a di erential diagnosis o psoriasis or
chronic psoriasi orm spongiotic dermatitis. oci o neutrophils
o ten contain serum and may be interpreted as impetigini ed
crusting.
n direct immuno uorescence testing the stratum corneum
demonstrates intense uorescence with all antibodies comple
ment and brin. This uorescence may be partially indepen
dent o the uorescent label as it has been noted in hemato ylin
and eosin stained sections and ro en unstained sections. The
same phenomenon o stratum corneum auto uorescence has
been noted in some cases o candidiasis that demonstrate a
psoriasi orm histology.
Psoriasis can generally be distinguished rom dermatitis by
the paucity o edema relati e absence o spongiosis tortuosity
o the capillary loops and presence o neutrophils abo e oci
o para eratosis. eutrophils in the stratum corneum are o ten
seen in tinea impetigo candidiasis and syphilis but they
rarely are ound atop para eratosis alternating with ortho
eratosis rhythmically. n psoriasi orm syphilis the rete ridges
are typically long and slender; a acuolar inter ace dermatitis
is usually present; dermal blood essels appear to ha e no
lumen because o endothelial swelling; and plasma cells are
present in the dermal in ltrate. About one third o biopsies o
syphilis lac plasma cells but the remaining characteristics
still suggest the correct diagnosis. Psoriasi orm lesions o
mycosis ungoides e hibit epidermotropism o large lympho
cytes with little spongiosis. The lymphocytes are typically
larger dar er and more angulated than the lymphocytes in
the dermis. There is associated papillary dermal brosis and
the super cial peri ascular in ltrate is asymmetrically distrib
uted around the postcapillary enules a oring the epidermal
side ( bare underbelly sign ).
Clinical differential diagnosis
Psoriasis must be di erentiated rom dermatomyositis (D )
lupus erythematosus (L ) seborrheic dermatitis pityriasis
rosea lichen planus ec ema and psoriasi orm syphilid. The
distribution in psoriasis is on the e tensor sur aces especially
o the elbows and nees and on the scalp; D shares this
distribution whereas L generally lac s in ol ement o the
e tensor sur aces. Patients with D may e hibit a heliotrope
sign atrophy poi iloderma and nail old changes. Ad anced
lesions o discoid L o ten demonstrate ollicular hyper era
tosis (carpet tac sign). Seborrheic dermatitis has a predilec
tion or the eyebrows nasolabial angle ears sternal region
and e ures. The scales in psoriasis are dry white and shiny
whereas those in seborrheic dermatitis are greasy and yellow
ish. n remo al o the scales in psoriasis blood oo es rom
the capillaries (Auspit sign) whereas this does not occur in
seborrheic dermatitis.
n pityriasis rosea the eruption is located on the upper arms
trun and thighs and the duration is o er wee s. Lesions are
typically o al and ollow s in tension lines. ndi idual lesions
show a crin ling o the epidermis and collarette scaling. A
herald patch is re uently noted. Lichen planus chie y a ects
the e or sur aces o the wrists and an les. ten the iola
ceous color is pronounced. n dar er s inned indi iduals the
lesions ha e a tendency to pronounced hyperpigmentation.
191
 The nails are not pitted as in psoriasis but longitudinally
10 ridged rough and thic ened. Pterygium ormation is charac
teristic o lichen planus.
and ec ema may resemble psoriasis. n general psoriatic
lesions tend to be more sharply marginated but at times the
Seborrheic Dermatitis, Psoriasis, Recalcitrant Palmoplantar Eruptions, Pustular Dermatitis, and Erythroderma
lesions are indistinguishable. Psoriasi orm syphilid has in l
trated copper colored papules o ten arranged in a gurate
pattern. Serologic tests or syphilis are generally positi e but
pro one reactions may occur and the serum may ha e to be
diluted to obtain a positi e test. Generali ed lymphadenopa
thy and mucous patches may be present.
Treatment
Topical therapy intralesional triamcinolone e cimer laser or
other orms o intense pulsed light may be suitable or limited
pla ues. Phototherapy remains highly cost e ecti e or wide
spread psoriasis. Cyclosporine has a rapid onset o action but
is generally not suitable or sustained therapy. ethotre ate
remains the systemic agent against which others are com
pared. Biologic agents can produce dramatic responses at dra
matic e pense.
Topical treatment
Corticosteroids
Topical application o corticosteroids in creams ointments
lotions oams and sprays is the most re uently prescribed
therapy or locali ed psoriasis. Class steroids are suitable or
wee courses o therapy on most body areas. Therapy can
n
be continued with pulse applications on wee ends to reduce
the incidence o local ad erse e ects. n the scalp corticoste
U
roids in propylene glycol gel oam and spray bases are pre
erred by most white patients. Blac patients may nd them
-
drying and may pre er oil and ointment preparations. Low to
mid strength creams are pre erred in the intertriginous areas
and on the ace. To augment e ecti eness o topical cortico
9
steroids in areas with thic eratotic scale the area should be
hydrated be ore application and co ered with an occlusi e
ri 9
dressing o polyethylene lm (plastic wrap) or a sauna suit.
Side e ects include epidermal atrophy steroid acne miliaria
and pyoderma.
ntralesional in ections o triamcinolone are help ul or
h
re ractory pla ues. Triamcinolone acetonide ( enalog) sus
pension mg mL may be diluted with sterile saline to ma e
t a
a concentration o . mg mL. Good results are also obtained
in the treatment o psoriatic nails by in ecting triamcinolone
into the region o the matri and the lateral nail old. A digital
bloc can be per ormed be ore in ection to pro ide anesthesia.
n ections are gi en once a month until the desired e ect is
achie ed.
Tars
Crude coal tar and tar e tracts such as li uor carbonis deter
gens (LCD) can be compounded into agents or topical use.
Tar bath oils and shampoos are readily a ailable. il o cade
(pine tar) or birch tar in concentrations o may also be
incorporated into ointments. The odor o all tars may be o en
si e and relapse is more rapid than with topical agents such
as calcipotriene.
Anthralin
Anthralin is e ecti e but is irritating and stains s in clothing
and bedding. To a oid these drawbac s short contact anthra
lin treatment (SCAT) can be help ul with anthralin washed o
a ter min. Anthralin e erts a direct e ect on eratino
192
cytes and leu ocytes by suppressing neutrophil supero ide
generation and inhibiting monocyte deri ed L
T α.
L and
Tazarotene
Ta arotene is a nonisomeri able retinoic acid receptor speci c
retinoid. t appears to treat psoriasis by modulating eratino
cyte di erentiation and hyperproli eration as well as by sup
pressing in ammation. Combining its use with a topical
corticosteroid and wee end pulse therapy can decrease
irritation.
Calcipotriene
Vitamin D a ects eratinocyte di erentiation partly through
its regulation o epidermal responsi eness to calcium. Treat
ment with the itamin D analog calcipotriene (Do one ) in
ointment cream or solution orm has been e ecti e in the
treatment o pla ue type and scalp psoriasis. Combination
therapy with calcipotriene and high potency steroids may
pro ide greater response rates ewer side e ects and steroid
G
sparing. Calcipotriene is unstable in the presence o many
other topical agents and degrades in the presence o V light.
R
onitoring o serum calcium le els in adults is not re uired.
Calcipotriene plus betamethasone dipropionate (Taclone ) is
V
more e ecti e than either agent alone.
Macrolactams (calcineurin inhibitors)
d
Topical macrolactams such as tacrolimus and pimecrolimus
ti e
are especially help ul or thin lesions in areas prone to atrophy
or steroid acne. The burning associated with these agents can
be problematic but may be a oided by prior corticosteroid
treatment and application to dry s in rather than a ter bathing.
Salicylic acid
Salicylic acid is used as a eratolytic agent in shampoos
creams and gels. t can promote the absorption o other topical
agents. Widespread application may lead to salicylate to icity
mani esting with tinnitus acute con usion and re ractory
hypoglycemia especially in patients with diabetes and those
with compromised renal unction.
Ultraviolet light
Phototherapy is a cost e ecti e and underused modality or
psoriasis. n most cases sunlight impro es psoriasis. owe er
se ere burning o the s in may cause the oebner phenome
non and an e acerbation. Arti cial VB light is produced by
uorescent bulbs in broad band or narrow band ( B) spec
trum. a imal e ect is usually achie ed at Ds. Although
suberythemogenic doses can be e ecti e the response is
slower than with erythemogenic regimens. With treatment a
tanning response occurs and the dose must be increased to
maintain e cacy. aintenance VB phototherapy a ter clear
ing contributes to the duration o remission and is usti ed or
many patients.
sing a monochromator it has been shown that wa e
lengths o and nm are ine ecti e; at
and nm howe er there is clearing. B VB (pea emis
sion about nm) has been more e ecti e in treating psoria
sis than broad band VB. rythemogenic doses are not
re uired to achie e a response. The response rates are better
than and close to those achie able with psoralen plus
ultra iolet A (P VA) therapy.
Goeckerman technique
Goec erman therapy remains an e ecti e and cost e ecti e
method o treatment e en in patients with poor responses to
biologic agents. n its modern orm a tar preparation is
applied to the s in and a tar bath is ta en at least once a day.
The e cess tar is remo ed with mineral or egetable oil and
V light is gi en. n psoriasis day care centers patients clear
in an a erage o days and remain ree o disease or
e tended periods. The addition o a topical corticosteroid to
the Goec erman regimen shortens the time re uired or remis
sion. Phototo ic reactions (tar smarts) may result rom VA
generated by the predominantly VB bulbs.
Ingram technique
ngram therapy consists o a daily coal tar bath in a solution
such as mL LCD to L o warm water. This is ollowed
by daily e posure to V light or increasing periods. An
anthralin paste is then applied to each psoriatic pla ue. Talcum
powder is sprin led o er the lesions and stoc inette dressings
are applied. odern ersions o the techni ue employ SCAT.
PUVA therapy
igh intensity longwa e V radiation ( VA) gi en h a ter
ingestion o metho ypsoralen ( soralen ltra) twice a
wee is highly e ecti e e en in se ere psoriasis. ost patients
clear in treatments but maintenance treatment is needed.
Although P VA therapy is highly e ecti e in patients with
less than o the s in sur ace a ected VB may be as
e ecti e. Polyethylene sheet bath P VA is another therapeu
tic alternati e to oral psoralen VA. The patient is immersed
in a psoralen solution contained in plastic sheeting that con
orms to the patient s body.
ral psoralen can produce cataracts and protecti e eyewear
must be used. P VA therapy is a ris actor or s in cancer
including s uamous cell carcinoma (SCC) and melanoma.
Arsenic e posure is a more signi cant co actor than prior
e posure to methotre ate VB or concomitant use o topical
tar. en treated without genital protection are at an increased
ris o de eloping SCC o the penis and scrotum. Although
the ris o cancer is dose related there is no de niti e thresh
old dose o cumulati e P VA e posure abo e which carcino
genicity can be predicted.
Surgical treatment
n patients with pharyngeal coloni ation by streptococci an
e cellent response has been reported a ter tonsillectomy. ore
e ecti e antibiotic regimens such as a day course o diclo
acillin combined with ri ampin ( mg day or adult) ha e
largely replaced tonsillectomy.
Hyperthermia
Local hyperthermia can clear psoriatic pla ues but relapse is
usually rapid. icrowa e hyperthermia may produce signi
cant complications such as pain o er bony prominences and
tissue destruction.
Occlusive treatment
cclusion with surgical tape or dressings can be e ecti e as
monotherapy or when combined with topical drugs.
Systemic treatment
Corticosteroids
The ha ards o the in udicious use o systemic corticosteroids
must be emphasi ed. There is great ris o rebound or
induction o pustular psoriasis when therapy is stopped. Cor
ticosteroid use is generally restricted to uni ue circumstances
such as impetigo herpeti ormis when e peditious deli ery is
not possible.
tahir99 - UnitedVRG
Methotrexate
This olic acid antagonist remains the standard against which
other systemic treatments are measured. ethotre ate has a
greater a nity or dihydro olic acid reductase than does olic
Psoriasis
acid. The indications or methotre ate include psoriatic eryth
roderma psoriatic arthritis acute pustular psoriasis ( on
umbusch type) or widespread body sur ace area (BSA)
in ol ement. Locali ed pustular psoriasis or palmoplantar
psoriasis that impairs normal unction and employment may
also re uire systemic treatment.
t is important to ensure the patient has no history o li er
or idney disease. ethotre ate can be to ic to the li er
and decreased renal clearance can enhance to icity. ther
important actors to consider are alcohol abuse cryptogenic
cirrhosis se ere illness debility pregnancy leu openia
thrombocytopenia acti e in ectious disease immunode
ciency anemia colitis and ability to comply with directions.
epatic en ymes bilirubin serum albumin creatinine al a
line phosphatase complete blood count platelet count hepa
titis serology (B and C) V antibody and urinalysis should
all be e aluated be ore starting treatment. Patients with hypo
albuminemia ha e a higher ris o de eloping pulmonary
complications.
The need or li er biopsy remains contro ersial. Biopsy is
not without ris s and is not usually per ormed in the setting
o methotre ate therapy or rheumatic disease. owe er
patients with psoriasis ha e a greater ris o li er disease than
other patient populations. n most patients with no ris actors
or li er disease the rst li er biopsy is obtained at appro i
mately . . g o cumulati e methotre ate and repeated
e ery subse uent . . g until a total o . g is reached. The
re uency then changes to e ery . . g cumulati e inter
als. These recommendations are li ely to change as more data
are e aluated. Wee ly blood counts and monthly li er en yme
assessment are recommended at the onset o therapy or when
the dosage is changed. onitoring o aminoterminal procol
lagen peptide may reduce the need or li er biopsy.
umerous treatment schedules ha e e ol ed. The authors
recommend either three di ided oral doses ( h apart) wee ly
wee ly single doses orally or single wee ly subcutaneous
in ections. The wee ly dose aries rom mg to more than
mg with most patients re uiring mg a wee . nce a
single dose e ceeds mg oral absorption is unpredictable
and subcutaneous in ections are recommended. idwee
doses can result in se ere to icity and must be a oided. ral
or cutaneous ulceration may be a sign that the patient has
ta en a midwee dose. ral olic acid has been reported to
decrease side e ects especially nausea and doses o mg
day are used. ral olic acid is not ade uate or the treatment
o o erdosage and leu o orin must be used in such cases.
Cyclosporine
The therapeutic bene t o cyclosporine in psoriatic disease
may be related to downmodulation o proin ammatory epi
dermal cyto ines. The microemulsion ormulation eoral has
greater bioa ailability and is now standard. Doses o mg
g day generally produce rapid clearing o psoriasis with
both e cacy and ris being dose related. n ortunately the
lesions recur rapidly as well and transition to another orm o
therapy is re uired. Treatment durations o up to months are
associated with a low incidence o renal complications but
blood pressure and serum creatinine must be monitored and
doses ad usted accordingly. sually the dose is reduced i the
baseline creatinine increases by one third. Some data support
the easibility o pulse dosing or a ew days each wee or
both the induction and the maintenance o response in psoria
sis patients.
193
 published trials suggests that o the agents studied at the end
10 Diet
The anti in ammatory e ects o sh oils rich in n polyun
o the induction phase (wee ) uste inumab has the great
est probability o achie ing at least impro ement rom
saturated atty acids (P As) ha e been demonstrated in baseline in the psoriasis area and se erity inde (PAS )
RA in ammatory bowel disease psoriasis and asthma. n ollowed by in i imab adalimumab and etanercept. ewer
Seborrheic Dermatitis, Psoriasis, Recalcitrant Palmoplantar Eruptions, Pustular Dermatitis, and Erythroderma

and n P As a ect a ariety o cyto ines including L anti L agents can achie e PAS a dramatic impro e
L and T . erbal remedies ha e also been used with ment o er pre ious biologic agents. The anti L agents
ariable e ects. any o these products are unpalatable and include secu inumab i e i umab and brodalumab. or
their e cacy does not compare a orably to pharmacologic comparison in controlled trials o in i imab the percentage
agents. o patients reaching PAS at wee is about with
in i imab at mg g and at mg g compared with
Oral antimicrobial therapy or placebo. About o patients recei ing etanercept
The association o streptococcal pharyngitis with guttate pso mg subcutaneously twice wee ly achie e PAS at
riasis is well established. Staph lococcus aureus and streptococci wee s and at wee s. With the mg induction
secrete e oto ins that act as superantigens producing massi e dose administered twice a wee about o patients
T cell acti ation and pharyngeal coloni ation should be achie e PAS at wee s and at wee s. The data
addressed as pre iously noted. ral bile acid supplementation a ailable suggest that about o patients ta ing mg
has been shown to impro e psoriasis presumably by a ecting o adalimumab e ery other wee achie e PAS by wee
the micro ora and endoto ins in the gut. ral etocona ole and about o those ta ing mg a wee achie e
itracona ole and other antibiotics ha e shown e cacy in a PAS .

G
limited number o patients with psoriasis.
Risks
Retinoids

R
The anti T agents may induce ares o psoriasis through
ral treatment with the aromatic retinoid ethylester etretinate upregulation o plasmacytoid dendritic cells. This may be a

V
has been e ecti e in many patients with psoriasis especially class e ect. The biologic agents all suppress the normal
in pustular disease. Because o its long hal li e etretinate has immune response. n i imab has been associated with reacti

d
been replaced by acitretin. Alcohol ingestion can con ert ation o tuberculosis demyelinating disease and serious sys
acitretin to etretinate and is discouraged. Cis retinoic acid temic opportunistic in ection. n i imab may also lose its

can also produce good results in some patients with pustular
psoriasis. All these drugs are potent teratogens and ele ated
triglyceride le els may complicate therapy. Combinations o
retinoic acids with photochemotherapy can be e ecti e in
ti e
e ect because o neutrali ing antibodies. ethotre ate or a a
thioprine may be needed as concomitant therapy to reduce the
incidence o neutrali ing antibodies and in usion reactions.
en though adalimumab is a ully human antibody it may

n
chronic pla ue psoriasis resulting in lowered cumulati e also induce an antibody response. Serious in ections ha e been
doses o light. reported in RA patients treated with this agent. tanercept has

U
been associated with in ection onset or e acerbation o mul
Dapsone tiple sclerosis asculitis and L li e mani estations. All these

-
Dapsone use is limited largely to palmoplantar pustulosis or e ects are rare and may not be statistically increased rom the
other ariants o pustular psoriasis. en in this setting it is a general population. any o the reported complications such
second line or third line agent with limited e cacy. as lymphoma demyelinating disease progressi e multi ocal

9
leu oencephalopathy and in ection are not uni ue to any one
Biologic agents immunosuppressi e agent.

ri 9
A number o biologic agents are a ailable that can produce
dramatic responses in some patients with psoriasis; all are
e pensi e. Retrospecti e analysis using BSA multiplied by
The ational Psoriasis oundation has endorsed a recom
mendation that all patients be screened or latent tuberculosis
in ection be ore any immunologic therapy. The oundation
recommends delaying immunologic therapy until prophyla is

h
physician s global assessment as an endpoint suggests that or latent tuberculosis in ection is completed although noting
outcomes with biologic agents are superior to those with other that patients with se ere disease may be treated a ter

a
γ assays ha e greater speci city

t
systemic agents despite the patients ta ing biologics ha ing a months o prophyla is.
higher baseline se erity and a greater number o pre ious than tuberculin s in tests and are being used along with
treatments. imaging studies to con rm tuberculosis in patients with posi
Se eral agents bloc T α. n i imab is a chimeric mono ti e s in tests.
clonal antibody (mAb) to T α and re uires intra enous
in usion; etanercept is a usion protein o human T type Combination therapy
receptor and the c region o gG ; and adalimumab is a
recombinant ully human gG mAb to T α. Ale acept is a n more se ere orms o psoriasis a combination o treatment
usion protein o the e ternal domain o L A and the c modalities may be employed. n treating patients with metho
region o gG ; it bloc s T cell acti ation and triggers apopto tre ate or e ample concomitant topical agents may be used
sis o pathogenic T cells. Golimumab is an anti T agent with to minimi e the dose. ethotre ate has been combined with
less re uent dosing used in patients with psoriatic arthritis in i imab to reduce the incidence o neutrali ing antibodies
and certoli umab has also demonstrated e cacy. ste inumab and also has been used with acitretin in managing patients
a human mAb against L and L is the rst o a new with se ere generali ed pustular psoriasis. The use o P VA
class o agents that appear highly e ecti e. They bloc the and retinoids is called Re P VA and has been studied e ten
in ammatory pathway at a more pro imal point than anti si ely. Acitretin has been combined with biologic agents to
T agents. treat re ractory psoriasis. Combination systemic therapy has
the potential to reduce o erall to icity i the to icities o each
Percentage of patients clearing with each drug agent are di erent. owe er new regimens should be used
Published data allow or some comparisons o biologic agents with caution because o the potential or cumulati e to icity
but the endpoints o some trials di er. A meta analysis o or drug interaction.
194
Evolving therapies
Alternati e therapies or psoriasis include mycophenolate
mo etil sul asala ine paclita el a athioprine umaric acid
esters climatotherapy and gren ray therapy. ail disease can
respond to systemic agents topical retinoids local triamcino
lone in ections and topical uorouracil. The latter agent can
cause onycholysis i applied to the ree edge o the nail. Apre
milast a small molecule speci c inhibitor o phosphodiester
ase has demonstrated e cacy in recalcitrant pla ue psoriasis.
Janus inase (JA ) inhibitors such as to acitinib ha e demon
strated e cacy in the treatment o psoriasis. The side e ect
pro le o to acitinib includes dose dependent decreases in red
blood cell counts along with transient or re ersible dose
dependent decreases in neutrophil counts. To acitinib has also
demonstrated transient increases in lymphocyte counts pri
marily attributable to increases in B cell counts.
Akaraphanth R, et al: Efficacy of a far erythemogenic dose of narrow-
band ultraviolet B phototherapy in chronic plaque-type psoriasis. J
Dermatol 2010; 37(2):140–145.
Au SC, et al: Comparison of the efficacy of biologics versus
conventional systemic therapies in the treatment of psoriasis at a
comprehensive psoriasis care center. J Drugs Dermatol 2013;
12(8):861–866.
Bhatia BK, et al: Diet and psoriasis. Part II. Celiac disease and role of a
gluten-free diet. J Am Acad Dermatol 2014; 71:350–358.
Berends MA, et al: Reliability of the Roenigk classification of liver
damage after methotrexate treatment for psoriasis: a clinicopathologic
study of 160 liver biopsy specimens. Arch Dermatol 2007;
143(12):1515–1519.
Chirch LM, et al: Proactive infectious disease approach to dermatologic
patients who are taking tumor necrosis factor-alfa antagonists. Part I.
Risks associated with tumor necrosis factor-alfa antagonists. J Am
Acad Dermatol 2014; 71:1.e1–8.
Chirch LM, et al: Proactive infectious disease approach to dermatologic
patients who are taking tumor necrosis factor-alfa antagonists. Part II.
Screening for patients on tumor necrosis factor-alfa antagonists. J Am
Acad Dermatol 2014; 71:11.e1–7.
Colombo MD, et al: Cyclosporine regimens in plaque psoriasis: an
overview with special emphasis on dose, duration, and old and new
treatment approaches. SciWorldJ 2013 Jul 25; 2013:805705.
Debbaneh M, et al: Diet and psoriasis. Part I. Impact of weight loss
interventions. J Am Acad Dermatol 2014; 71:133–140.
Demirsoy EO, et al: Effectiveness of systemic treatment agents on psoriatic
nails: a comparative study. J Drugs Dermatol 2013; 12(9):1039–1043.
Filkor K, et al: Genome wide transcriptome analysis of dendritic cells
identifies genes with altered expression in psoriasis. PLoS One 2013;
8(9):e73435.
Fitzmaurice S, et al: Goeckerman regimen for management of psoriasis
refractory to biologic therapy: the University of California San Francisco
experience. J Am Acad Dermatol 2013; 69(4):648–649.
Gan EY, et al: Therapeutic strategies in psoriasis patients with psoriatic
arthritis: focus on new agents. BioDrugs 2013; 27(4):359–373.
Gottlieb AB, et al: Efficacy, tolerability, and pharmacodynamics of
apremilast in recalcitrant plaque psoriasis: a Phase II open-label study.
J Drugs Dermatol 2013; 12(8):888–897.
Kwatra SG, et al: JAK inhibitors in psoriasis: a promising new treatment
modality. J Drugs Dermatol 2012; 11(8):913–918.
Millsop JW, et al: Diet and psoriasis. Part III. Role of nutritional
supplements. J Am Acad Dermatol 2014; 71:561-569.
Puig L, et al: Efficacy of biologics in the treatment of moderate-to-
severe plaque psoriasis: a systematic review and meta-analysis of
randomized controlled trials with different time points. J Eur Acad
Dermatol Venereol 2013; Aug 19. doi: 10.1111/jdv.12238. [Epub ahead
of print.] PMID: 24033851.
Punwani N, et al: Preliminary clinical activity of a topical JAK1/2 inhibitor
in the treatment of psoriasis. J Am Acad Dermatol 2012;
67(4):658–664.
Singh P, et al: Comparative evaluation of topical calcipotriol versus coal
tar and salicylic acid ointment in chronic plaque psoriasis. J Drugs
Dermatol 2013; 12(8):868–873.
Skroza N, et al: Correlations between psoriasis and inflammatory bowel
diseases. Biomed Res Int 2013; 2013:983902.
tahir99 - UnitedVRG
Villacorta R, et al: Cost-effectiveness of moderate to severe psoriasis
therapy with etanercept and ustekinumab in the United States.
Pharmacoeconomics 2013; 31(9):823–839.
Wu JJ, et al: Association of gender, tumor necrosis factor inhibitor
therapy, and myocardial infarction risk in patients with psoriasis. J Am
Reactive arthritis with conjunctivitis/urethritis/diarrhea (Reiter syndrome)
Acad Dermatol 2013; 69(4):650–651.
REACTIVE ARTHRITIS WITH CONJUNCTIVITIS/
URETHRITIS/DIARRHEA (REITER SYNDROME)
Reiter syndrome is a characteristic clinical triad o urethritis
con uncti itis and arthritis. The disease occurs chie y in
young men o LA B genotype generally ollowing a bout
o urethritis or diarrheal illness. Systemic in ol ement can
include the gastrointestinal tract idneys central ner ous
system and cardio ascular system. Because ew patients
present with the classic triad the American College o Rheu
matology recogni es criteria or limited mani estations o the
syndrome including peripheral arthritis o more than month
duration in association with urethritis cer icitis or bilateral
con uncti itis.
ans Reiter was a a i war criminal in ol ed with or
ha ing nowledge o in oluntary sterili ation as well as a
study o an e perimental typhus accine that resulted in hun
dreds o deaths o concentration camp internees. Some belie e
that he should no longer be a orded the name recognition to
designate the syndrome.
Clinical features
Any part o the triad may occur rst o ten accompanied by
e er wea ness and weight loss. Although the inciting ure
thritis may be bacterial later mani estations include a nonbac
terial urethritis with pain ul urination and pyuria. Cystitis
prostatitis and seminal esiculitis may be accompaniments.
Vul ar ulceration has been reported. About one third o
patients de elop con uncti itis which may be bulbar tarsal
or angular. eratitis is usually super cial and e tremely
pain ul. ritis is common especially in recurrent cases. n re
uently optic neuritis may occur. eitis correlates with a ial
oint disease and LA B positi ity. An asymmetric arthritis
may a ect peripheral oints especially weight bearing oints.
ts onset is usually sudden. Pain in one or both heels is a re
uent symptom. Sacroiliitis may de elop in up to two thirds
o patients most o whom are o LA B type.
The s in in ol ement usually begins with small guttate
hyper eratotic crusted or pustular lesions o the genitals ( ig.
) palms or soles. n ol ement o the glans penis (bala
nitis circinata) occurs in o patients. Lesions on the soles
and trun o ten become thic ly crusted or hyper eratotic. The
eruption on the soles is nown as eratoderma blennorrhagi
cum and occurs in o patients ( ig. ). The buccal
palatal and lingual mucosa may show painless shallow red
erosions. The nails become thic and brittle with hea y sub
ungual eratosis. Children are much more li ely to ha e the
postdysenteric orm o ten with con uncti itis and arthritis as
the most prominent complaints.
The syndrome generally ollows an in ectious urethritis or
diarrheal illness. mplicated organisms include Chlam ia Shi
gella Salmonella ersinia Camp lobacter Ureaplasma orrelia
Cr ptospori ium gonococci and bacille Calmette Gu rin
(BCG). Chlam ia trachomatis and Ureaplasma ureal ticum ha e
been isolated rom the syno ial uid o a ected oints and
some patients respond to antibiotic therapy. Chlamydial anti
gens demonstrate high homology with human se uences con
taining the binding moti o LA B . Reiter syndrome has
195

10
Seborrheic Dermatitis, Psoriasis, Recalcitrant Palmoplantar Eruptions, Pustular Dermatitis, and Erythroderma
Fig. 10-12 Genital involvement in reactive arthritis.
Fig. 10-13
Keratoderma
blennorrhagicum.
U
-
9
ri 9
h
t a
also been obser ed in V disease but may not be directly
related to the irus because it re uently occurs during treat
ment as the immune response impro es. The disease has also
been triggered by adalimumab and le unomide in the setting
o an ylosing spondyloarthropathy and Crohn s disease.
Peripheral leu ocytosis o mm and ele ated
erythrocyte sedimentation rate are the most consistent nd
ings. There is no speci c test or Reiter syndrome. The di er
ential diagnosis includes RA an ylosing spondylitis gout
psoriatic arthritis gonococcal arthritis acute rheumatic e er
chronic mucocutaneous candidiasis and serum sic ness. The
presence o associated mucocutaneous lesions establishes the
diagnosis. Some cases o Lyme disease o erlap with Reiter
syndrome. ndi idual s in lesions may be indistinguishable
rom those in psoriasis. yper eratotic lesions generally ha e
a thic er scale crust than most psoriatic pla ues but are
otherwise identical.
196
ucocutaneous lesions are generally sel limited and clear
with topical corticosteroids. Joint disease is managed with rest
and SA Ds. Antibiotics such as do ycycline ha e been
e ecti e in some cases. mmunosuppressi e agents such as
methotre ate are used or re ractory oint disease. n i imab
has been success ul in treating se ere disease. Re ractory s in
lesions are treated similar to re ractory psoriasis and se erely
a ected patients ha e responded to acitretin or cyclosporine.
Alvarez-Navarro C, et al: Novel HLA-B27-restricted epitopes from
Chlamydia trachomatis generated upon endogenous processing of
bacterial proteins suggest a role of molecular mimicry in reactive
arthritis. J Biol Chem 2013; 288(36):25810–25825.
Connor BA, et al: Post-infectious sequelae of travelers’ diarrhea. J Travel
Med 2013; 20(5):303–312.
Sampaio-Barros PD, et al: An analysis of 372 patients with anterior
uveitis in a large Ibero-American cohort of spondyloarthritis: the
RESPONDIA Group. Clin Exp Rheumatol 2013; 31(4):484–489.
Vasala M, et al: High frequency of reactive arthritis in adults after
Yersinia pseudotuberculosis O:1 outbreak caused by contaminated
grated carrots. Ann Rheum Dis 2014; 73(10):1793–1796.
SUBCORNEAL PUSTULAR DERMATOSIS
(SNEDDON-WILKINSON DISEASE)
R G
V
n Sneddon and Wil inson described a chronic pustular
d
disease that occurred chie y in middle age women. The pus
tules are super cial and arranged in annular and serpiginous
ti e
patterns especially on the abdomen a illae and groins. Cul
tures rom the pustules are sterile. ral lesions are rare. The
condition is chronic with remissions o ariable duration.
istologically the pustules orm below the stratum corneum
n
as in impetigo. Acantholysis is absent but spongi orm pus
tules may be noted in the upper epidermis. The histologic
di erential diagnosis includes pustular psoriasis and super
cial ungal and bacterial in ections.
gA pemphigus shows signi cant o erlap with subcorneal
pustular dermatosis. Presentations o gA pemphigus include
subcorneal pustular dermatosis and intraepidermal neutro
philic gA dermatosis types. mmunoblotting techni ues ha e
shown that human desmocollin is an autoantigen or the
subcorneal pustular dermatosis type o gA pemphigus.
Locali ed cases may respond well to topical corticosteroids.
Dapsone mg day (adult) is e ecti e or most o
the remaining cases. Some patients ha e responded better to
sul apyridine therapy. Acitretin B VB phototherapy col
chicine a ithromycin biologic agents and tetracycline
with niacinamide may also be e ecti e in subcorneal pustular
dermatosis.
Bedi MKL: Successful treatment of long-standing, recalcitrant
subcorneal pustular dermatosis with etanercept. Skinmed 2007;
6(5):245–247.
Bliziotis I, et al: Regression of subcorneal pustular dermatosis type of
IgA pemphigus lesions with azithromycin. J Infect 2005; 51:E31.
EOSINOPHILIC PUSTULAR FOLLICULITIS
osinophilic pustular olliculitis ( P ) was rst described in
by u i although it is also re erred to as sterile eosino
philic pustulosis. t occurs more o ten in males and is mostly
reported in Asia. The mean age o onset is . t is character
i ed by pruritic ollicular papulopustules that measure
mm. The lesions tend to be grouped and pla ues usually
orm. ew lesions may orm at the edges o the pla ues
leading to peripheral e tension while central clearing ta es
place. The most re uent site is the ace particularly o er the
chee s. The trun and upper e tremities re uently are
a ected and ha e palmoplantar pustules. The distribu
tion is usually asymmetric and the typical course is one o
spontaneous remissions and e acerbations lasting se eral
years. The condition must be distinguished rom V
associated eosinophilic olliculitis (see Chapter ). A similar

Recalcitrant palmoplantar eruptions

condition has occurred in association with CV in ection
with allopurinol and during pregnancy.
istologically there is spongiosis and esiculation o the
ollicular in undibulum and hea y in ltration with eosino
phils. ollicular mucinosis may be present. There is a periph
eral eosinophilia in hal the cases and pulmonary eosinophilia
has been described. The cause is un nown; but numerous
studies ha e implicated chemotactic substances intercellular
adhesion molecule ( CA ) and cycloo ygenase generated A
metabolites. Tryptase positi e and chymase negati e mast
cells ha e also been implicated.
ndomethacin is e ecti e in the ast ma ority o patients
with eosinophilic pustular olliculitis. Topical and intralesional
corticosteroids clo a imine minocycline isotretinoin VB
therapy dapsone colchicine cyclosporine topical tacrolimus
nicotine patches in i imab and cetiri ine ha e also been
reported as e ecti e.
Childhood cases ha e been described. This subset di ers
rom the typical cases in Asian males. Pediatric patients
de elop sterile pustules and papules pre erentially o er the
scalp although scattered clusters o pustules may occur o er
the trun and e tremities. Leu ocytosis and eosinophilia are
o ten present. Recurrent e acerbations and remissions usually
occur with e entual spontaneous resolution. igh potency
topical steroids are the treatment o choice in pediatric patients.
Hasegawa A, et al: A case of eosinophilic pustular folliculitis with B
response to infliximab. J Am Acad Dermatol 2012; 67(4):e136–e137.
Hernández-Martín Á, et al: Eosinophilic pustular folliculitis of infancy: Fig. 10-14 A, Plantar pustulosis. B, Pustules and hyperkeratosis are
a series of 15 cases and review of the literature. J Am Acad
typical.
Dermatol 2013; 68(1):150–155.
Lim HL, et al: Recalcitrant eosinophilic pustular folliculitis of Ofuji with
palmoplantar pustulosis: dramatic response to narrowband UVB
phototherapy. Photodermatol Photoimmunol Photomed 2012;
istologically intraepithelial spongi orm pustules identical
28(4):219–221.
Oka D, et al: Refractory eosinophilic pustular folliculitis resistant to oral
to those o psoriasis are seen in the acute stage. Later stages
indomethacin successfully treated with adjuvant topical indomethacin. show hyper eratosis with para eratosis or atrophy.
J Dermatol 2014; 41:860–861. umerous treatment options ha e been used including
Yoshifuku A, et al: Transdermal nicotine patches for eosinophilic pustular topical corticosteroids calcipotriene dapsone sul apyridine
folliculitis. J Dermatol 2013; 40(9):711–714. methotre ate P VA acitretin cyclosporine and topical
mechlorethamine anti T agents and ana inra. The choice
o agent to use should consider the se erity o disease and the
patient s age and unctional impairment.
RECALCITRANT PALMOPLANTAR ERUPTIONS
Dermatitis repens Palmoplantar pustulosis (pustular psoriasis
of extremities)
Dermatitis repens also nown as acrodermatitis continua (see
earlier) and acrodermatitis perstans is a chronic in ammatory Chronic palmoplantar pustulosis is essentially a bilateral and
disease o the hands and eet. t usually remains stable on the symmetric dermatosis ( ig. ). The a orite locations are
e tremities but in rare cases generali ed pustular ares may the thenar or hypothenar eminences or the central portion o
occur. The disease usually begins distally on a digit either as the palms and soles. The patches begin as erythematous areas
a pustule in the nail bed or as a paronychia. tension ta es in which minute intraepidermal pustules orm. At the begin
place by eruption o resh pustules with subse uent hyper ning these are pinhead si ed; then they may enlarge and
eratosis and crusting. The disease is usually unilateral at rst coalesce to orm small la es o pus. As the lesions resol e
and asymmetric throughout its entire course. As the disease denuded areas crusts or hyper eratosis may persist. Palmo
progresses one or more o the nails may become dystrophic plantar pustulosis is strongly associated with thyroid disor
or oat away on pus. Anonychia is common in chronic cases. ders and cigarette smo ing. edications such as lithium
Some ha e used the term dermatitis repens to re er to more which aggra ate psoriasis ha e also been reported to induce
indolent in ol ement o the distal ngers. palmoplantar pustular psoriasis.
n ol ement o the mucous membranes may occur e en n ato described the rst case o bilateral cla icular
when the eruption o the s in is locali ed. Pain ul circular osteomyelitis with palmar and plantar pustulosis. n
white pla ues surrounded by in ammatory areolae are ound Sono a i described persistent palmoplantar pustulosis and
on the tongue and may orm a brinous membrane. issured sternocla icular hyperostosis. These conditions belong to the
or geographic tongue may occur. spectrum o s in and oint in ol ement designated by ahn
197

tahir99 - UnitedVRG
 as the SAP syndrome (syno itis acne pustulosis hyper
10 ostosis and osteitis). Common eatures include palmoplantar
pustulosis acnei orm eruption and pain and swelling o a
sternocla icular oint or at sternomanubrial or costochondral
unctions. There is shoulder nec and bac pain and limita
Seborrheic Dermatitis, Psoriasis, Recalcitrant Palmoplantar Eruptions, Pustular Dermatitis, and Erythroderma

tion o motion o the shoulders and nec is common. Brachial

ple us neuropathy and subcla ian ein occlusion may occur.
The lumbar spine and sacroiliac oints are usually spared.
Chronic multi ocal osteomyelitis in children may be a pediat
ric ariant. thers ha e described an association between
palmoplantar pustulosis and arthritis or osteitis. SAP syn
drome may coe ist with eatures o Beh et s disease. The
nees spine and an les may be in ol ed. ory ertebrae
ha e been described.
The disease typically is resistant to treatment. Topical corti
costeroids retinoids calcipotriene and macrolactams are o
some bene t. Acitretin is generally e tremely e ecti e at
Fig. 10-15 Acropustulosis of infancy. (Courtesy of Curt Samlaska,
mg g day although rebound occurs more uic ly than
MD.).
with etretinate. Low dose cyclosporine . mg g day
has also been e ecti e but it is not suitable or long term treat
ment. Dapsone colchicine le unomide and mycophenolate
mo etil may be e ecti e. ral metho ypsoralen and high by months o age. Lesions o ten predominate at the edges
intensity VA irradiation or soa P VA can both be help ul o the palms and soles. ndi idual crops o lesions clear in a
and gren ray therapy can induce prolonged remissions in ew wee s but recurrences may continue or months or years.
some patients. Chronic osteomyelitis in SAP syndrome has ost cases are postscabetic and acti e scabies can produce
been reported to respond to bisphosphonates. similar lesions.
istologically a subcorneal pustule with neutrophils is
noted. osinophils may be numerous. The lesions are easily
Pustular bacterid punctured to produce smears o the in ammatory cells so
biopsies are seldom employed.
Pustular bacterid was rst described by George Andrews. t is Lesions o ten respond to topical corticosteroids. Re ractory
characteri ed by a symmetric grouped esicular or pustular lesions may respond to dapsone at doses o mg g day.
eruption on the palms and soles mar ed by e acerbations and Abbas O, et al: Acrodermatitis continua of Hallopeau is a clinical
remissions o er long periods. Andrews regarded the disco phenotype of DITRA: evidence that it is a variant of pustular psoriasis.
ery o a remote ocus o in ection and cure on its elimination Dermatology 2013; 226(1):28–31.
as crucial to the diagnosis. Lutz V, et al: Acitretin- and tumor necrosis factor inhibitor-resistant
The primary lesions are pustules. Tiny hemorrhagic puncta acrodermatitis continua of Hallopeau responsive to the interleukin
intermingled with the pustules are re uently seen. When 1 receptor antagonist anakinra. Arch Dermatol 2012;
lesions are so numerous as to coalesce they orm a honey 148(3):297–299.
Sehgal VN, et al: Acrodermatitis continua of Hallopeau: evolution of
combli e structure in the epidermis. The disease usually
treatment options. Int J Dermatol 2011; 50(10):1195–1211.
begins on the midportions o the palms or soles rom which
it spreads outwardly until it may e entually co er the entire
e or aspects o the hands and eet. There is no in ol ement
o the webs o the ngers or toes as in tinea pedis.
When the eruption is ully de eloped both palms and soles
are completely co ered and the symmetry is pronounced. Bonus images for this chapter can be found online at
During resh outbrea s the white blood count may show a expertconsult.inkling.com
leu ocytosis that ranges rom to cells mm with
neutrophils. As a rule scaling is present in ully eFig. 10-1 Seborrheic dermatitis.
e ol ed lesions and the scales are adherent tough and dry. eFig. 10-2 Seborrheic dermatitis involving the chest.
During e acerbations crops o pustules or esicles ma e their eFig. 10-3 Psoriasis.
appearance and there is o ten se ere itching o the areas. eFig. 10-4 Psoriasis plaque, red plaque with silver scale on the knee.
Tenderness may be present. any regard this condition as a eFig. 10-5 Inverse psoriasis.
ariant o psoriasis triggered by in ection. eFig. 10-6 Nail pitting.
eFig. 10-7 Nail bed involvement in acrodermatitis continua.
eFig. 10-8 Guttate psoriasis.
Infantile acropustulosis eFig. 10-9 Erythrodermic psoriasis.
eFig. 10-10 Plantar pustulosis.
n antile acropustulosis is an intensely itchy esicopustular eFig. 10-11 Psoriasis.
eruption o the hands and eet ( ig. ). ost cases begin

198
 Recalcitrant palmoplantar eruptions
eFig. 10-1 Seborrheic dermatitis.
eFig. 10-4 Psoriasis plaque, red plaque with silver scale on the knee.

eFig. 10-2 Seborrheic

dermatitis involving
the chest.

eFig. 10-5 Inverse psoriasis.

eFig. 10-6 Nail pitting.

eFig. 10-3 Psoriasis.

198.e1

tahir99 - UnitedVRG
 eFig. 10-7 Nail bed
10 involvement in
acrodermatitis
continua.
Seborrheic Dermatitis, Psoriasis, Recalcitrant Palmoplantar Eruptions, Pustular Dermatitis, and Erythroderma

eFig. 10-9 Erythrodermic psoriasis.

eFig. 10-8 Guttate

psoriasis.

eFig. 10-10 Plantar pustulosis.

198.e2
 Recalcitrant palmoplantar eruptions
eFig. 10-11 Psoriasis.

198.e3

tahir99 - UnitedVRG
 Bonus images for this chapter can be found online at
Pityriasis Rosea, Pityriasis Rubra Pilaris, and Other
Papulosquamous and Hyperkeratotic Diseases
SMALL PLAQUE PARAPSORIASIS
Small pla ue parapsoriasis (SPP) is characteri ed by hyperpig
mented or yellowish red scaling patches round to o al in
con guration with sharply de ned regular borders. ost
lesions occur on the trun and all are cm in diameter. n
the digitate ariant yellowish tan elongated ngerprintli e
lesions are oriented along the clea age lines predominantly
on the an ( ig. ). These lesions may at times be longer
than cm. There is an absence o the induration the large
erythematous to purplish red lesions and poi iloderma that
characteri e small patches o cutaneous T cell lymphoma in its
early stages. The eruption may be mildly itchy or asymptom
atic and has a de nite male preponderance. Typical SPP rarely
progresses to mycosis ungoides although the histologic
changes can o erlap and clonality may be demonstrated.
Debate continues on this issue. A hypopigmented ariant may
ha e a somewhat higher rate o progression to hypopigmented
mycosis ungoides. SPP has been reported in the setting o
liposarcoma with resolution o the eruption a ter resection o
the tumor.
The histologic ndings o SPP are characteri ed by an in l
trate in the super cial dermis composed predominantly o
lymphocytes. The o erlying epidermis demonstrates mild
acanthosis spongiosis and ocal o erlying para eratosis. SPP
is considered to be a type o chronic spongiotic dermatitis.
Lesional s in also demonstrates an increase in CD a(+) Lang
erhans cells CD a positi e dermal dendritic cells and CD (+)
macrophages.
Although SPP may be re ractory to topical steroids alone
patients usually respond to phototherapy. Treatment with
ultra iolet B ( VB) narrow band ( B) VB or natural sun
light alone or in combination with a low strength topical cor
ticosteroid or simple lubricant will usually clear SPP. Without
treatment the patches o SPP may persist or years to decades
but rarely progress to lymphoma.
Arai R, et al: Retrospective study of 24 patients with large or small
plaque parapsoriasis treated with ultraviolet B therapy. J Dermatol
2012; 39(7):674–676.
Duarte IA, et al: An evaluation of the treatment of parapsoriasis with
phototherapy. An Bras Dermatol 2013; 88(2):306–308.
El-Darouti MA, et al: Hypopigmented parapsoriasis en plaque, a new,
overlooked member of the parapsoriasis family: a report of 34 patients
and a 7-year experience. J Am Acad Dermatol 2012; 67(6):1182–1188.
Lewin J, et al: Digitate dermatosis (small-plaque parapsoriasis).
Dermatol Online J 2012; 18(12):3.
Takahashi H, et al: Digitate dermatosis successfully treated by
narrowband ultraviolet B irradiation. J Dermatol 2011; 38(9):923–924.
CONFLUENT AND RETICULATED PAPILLOMATOSIS
(GOUGEROT AND CARTEAUD)
The eruption o con uent and reticulated papillomatosis typi
cally begins on the intermammary and upper lateral trun as
expertconsult.inkling.com
11
slightly scaly macules that slowly spread to in ol e the
remainder o the trun ( ig. ). n white patients the lesions
ary rom s in colored or aintly erythematous to hyperpig
mented; in pigmented persons lesions usually show hyper
pigmentation although a nonpigmenting orm with ne
white scale has been described. There may be se ere itching
or the lesions may be entirely asymptomatic. amilial cases
ha e been reported. An actinomycete dubbed Diet ia papillo
matosis has been isolated rom lesional s in. solated cases
ha e been associated with hypothyroidism and tetrasomy
syndrome.
istologically hyper eratosis acanthosis and papillomato
sis are generally seen and Pit rosporum Malasse ia yeast are
re uently present. The histologic changes resemble those seen
in acanthosis nigricans and the two conditions may occur
together.
A ariety o antibiotics ha e been success ul in treating this
papillomatosis. inocycline mg twice daily or wee s
is used most o ten. Success ul treatment has also been reported
with oral usidic acid clarithromycin amo icillin erythromy
cin a ithromycin and topical mupirocin. Topical and oral
retinoids ha e also been used success ully either alone or in
combination with topical lactic acid urea or alcohol. Con u
ent and reticulated papillomatosis associated with polycystic
o arian syndrome has responded to contracepti e therapy.
Pseudo atrophoderma colli may be a related condition that
occurs on the nec . t mani ests as papillomatous pigmented
and atrophic glossy lesions with delicate wrin ling which
tend to ha e a ertical orientation and may respond to
minocycline.
Berk DR: Confluent and reticulated papillomatosis response to 70%
alcohol swabbing. Arch Dermatol 2011; 147(2):247–248.
Hudacek KD, et al: An unusual variant of confluent and reticulated
papillomatosis masquerading as tinea versicolor. Arch Dermatol 2012;
148(4):505–508.
Koguchi H, et al: Confluent and reticulated papillomatosis associated
with 15q tetrasomy syndrome. Acta Derm Venereol 2013; 93(2):
202–203.
Tamraz H, et al: Confluent and reticulated papillomatosis: clinical and
histopathological study of 10 cases from Lebanon. J Eur Acad
Dermatol Venereol 2013; 27(1):e119–e123.
PITYRIASIS ROSEA
Clinical features
Pityriasis rosea is a mild in ammatory e anthem character
i ed by salmon colored papular and macular lesions that are
at rst discrete but may become con uent ( ig. ). The
indi idual patches are o al or circinate and co ered with
nely crin led dry epidermis which o ten des uamates
lea ing a collarette o scaling. When stretched across the long
a is the scales tend to old across the lines o stretch the
so called hanging curtain sign. The disease most re uently
begins with a single herald or mother patch ( ig. ) usually
199
 Fig. 11-1 Digitate
11 parapsoriasis.
(Courtesy of Thomas
Nicotori, MD.)
Pityriasis Rosea, Pityriasis Rubra Pilaris, and Other Papulosquamous and Hyperkeratotic Diseases

Fig. 11-4 Herald patch of pityriasis rosea.

Fig. 11-5 Pityriasis rosea.

obser ed in re uently. The incidence is highest between ages

Fig. 11-2 Confluent and reticulated papillomatosis.
Fig. 11-3 Pityriasis rosea.
larger than succeeding lesions which may persist wee or
longer be ore others appear. By the time in olution o the
herald patch has begun the e orescence o new lesions
spreads rapidly ( ig. ) and a ter wee s they usually
disappear spontaneously. Relapses and recurrences are
200
and and the disease is most pre alent in the spring and
autumn. Women are more re uently a ected than men.
The ully de eloped eruption has a stri ing appearance
because o the distribution and de nite characteristics o the
indi idual lesions. These are arranged so that the long a is o
the macules runs parallel to the lines o clea age. The eruption
is usually generali ed a ecting chie y the trun and sparing
sun e posed sur aces. At times it is locali ed to a certain area
such as the nec thighs groins or a illae. n these regions
con uent circinate patches with gyrate borders may orm and
may strongly resemble tinea corporis. Rarely the eyelids
palms and soles scalp or penis may be in ol ed. nilateral
and segmental orms ha e been described. ral lesions are
relati ely uncommon; they are asymptomatic erythematous
macules with raised borders and clearing centers or aphthous
ulcer li e lesions. They in olute simultaneously with the s in
lesions. oderate pruritus may be present particularly during
the outbrea and mild constitutional symptoms may occur
be ore the onset.
Blac children are particularly predisposed to the papular
ariant and are also more prone to acial and scalp in ol e
ment. The lesions o ten heal lea ing hypopigmented macules.
An in erse distribution sparing co ered areas can occur and
is common in papular cases. A esicular ariant has also been
described and erythema multi orme li e lesions may occur.
Purpuric pityriasis rosea may mani est with petechiae and
ecchymoses along Langer lines o the nec trun and pro
imal e tremities and may occasionally be a sign o an

tahir99 - UnitedVRG
underlying acute myeloid leu emia. Pityriasis rosea occurring
during pregnancy may be associated with premature deli ery
neonatal hypotonia and etal loss especially i the eruption
occurs within the rst wee s o gestation.
Etiology
Watanabe et al. ha e pro ided e idence or the long held
belie that pityriasis rosea is a iral e anthem. They demon
strated acti e replication o human herpes irus ( V)
and V in mononuclear cells o lesional s in as well
as identi ying the iruses in serum samples o patients includ
ing women who e perienced miscarriage in association with
pityriasis rosea. Although these iruses are almost uni ersally
ac uired in early childhood and remain in a latent phase as
mononuclear cells the eruption is li ely secondary to reacti a
tion leading to iremia. V and hepatitis C irus ( CV)
ha e also been implicated in indi idual cases.
A pityriasis rosea li e eruption may occur as a reaction to
captopril imatinib mesylate inter eron etoti en arsenicals
gold bismuth clonidine metho yproma ine tripelennamine
hydrochloride ergotamine lisinopril acyclo ir lithium adali
mumab nortriptyline lamotrigine ritu imab imatinib ase
napine barbiturates or bacille Calmette Gu rin (BCG) accine.
Histology
The histologic eatures o pityriasis rosea include mild acan
thosis ocal para eratosis and e tra asation o erythrocytes
into the epidermis. Spongiosis may be present in acute cases.
A mild peri ascular in ltrate o lymphocytes is ound in
the dermis. istologic e aluation is especially help ul in
e cluding the conditions with which pityriasis rosea may be
con used.
Differential diagnosis
Pityriasis rosea may closely mimic seborrheic dermatitis tinea
corporis macular syphilid drug eruption other iral e an
thems and psoriasis. n seborrheic dermatitis the scalp and
eyebrows are usually scaly; there is a predilection or the sternal
and interscapular regions as well as the e or sur aces o the
articulations where the patches are co ered with greasy scales.
Tinea corporis is rarely so widespread. Tinea ersicolor may
also closely simulate pityriasis rosea. A positi e potassium
hydro ide ( ) e amination ser es well to di erentiate these
last two. n macular syphilid the lesions are o a uni orm si e
and assume a brownish tint. Scaling and itching are absent or
slight and there is generali ed adenopathy with mucous mem
brane lesions palmoplantar lesions positi e nontreponemal
and treponemal tests and o ten the remains o a chancre. Scabies
and lichen planus may be con used with the papular type.
Treatment
ost patients with pityriasis rosea re uire no therapy because
they are asymptomatic; howe er the duration o the eruption
may be notably reduced by se eral inter entions. A Cochrane
re iew cited inade uate e idence or e cacy or most pub
lished treatments; howe er lac o e idence does not e uate
to lac o e cacy. Some e idence indicated that oral erythro
mycin may be e ecti e or both the rash and the itch although
this is based on only one small randomi ed controlled trial
(RCT; see ne t).
se o VB light in erythema e posures e pedites the in o
lution o the lesions a ter the acute in ammatory stage has
passed. The erythema produced by V treatment is ollowed
by super cial e oliation. n a comparison study using a
placebo o J VA light on the untreated side compared
Pityriasis rubra pilaris
with the VB treated side there was signi cant impro ement
in disease se erity on the treated side. owe er there was no
di erence in itchiness or disease course. Corticosteroid lotions
or creams pro ide some relie rom itching. A randomi ed
controlled trial suggested that high dose acyclo ir may be
e ecti e. ne RCT ound that erythromycin mg our
times daily or adults and mg g in our di ided doses
daily or children o er wee s resulted in complete clearance
o all lesions. This response in o patients contrasted with
none o the placebo patients ha ing the same response.
ther studies ha e challenged the e ecti eness o erythromy
cin and more research is needed. or dryness and irritation
simple emollients are recommended.
Bangash HK, et al: Pityriasis rosea–like drug eruption due to nortriptyline
in a patient with vulvodynia. J Low Genit Tract Dis 2013;
17(2):226–229.
Drago F, et al: Recurrence of hepatitis C virus infection during pityriasis
rosea. Acta Derm Venereol 2013; 93(4):483.
Drago F, et al: Evidence of human herpesvirus-6 and -7 reactivation in
miscarrying women with pityriasis rosea. J Am Acad Dermatol 2014;
71:198–199.
Ganguly S: A Randomized, double-blind, placebo-controlled
study of efficacy of oral acyclovir in the treatment of pityriasis
rosea. J Clin Diagn Res 2014; 8:YC01–4.
Oh CW, et al: Pityriasis rosea–like rash secondary to intravesical bacillus
Calmette-Guérin immunotherapy. Ann Dermatol 2012; 24(3):360–362.
Relhan V, et al: Pityriasis rosea with erythema multiforme–like lesions:
an observational analysis. Indian J Dermatol 2013; 58(3):242.
Sezer E, et al: Pityriasis rosea–like drug eruption related to rituximab
treatment. J Dermatol 2013; 40(6):495–496.
PITYRIASIS RUBRA PILARIS
Clinical features
Pityriasis rubra pilaris (PRP) is a chronic s in disease charac
teri ed by small ollicular papules disseminated yellowish
pin scaling patches and o ten solid con uent palmoplantar
hyper eratosis. The papules are the most important diagnostic
eature being more or less acuminate reddish brown about
pinhead si ed and topped by a central horny plug ( ig. ).
A hair or part o one is usually embedded in the horny center.
The highest incidence o onset is during the rst years o li e
or between ages and . The classic disease generally
Fig. 11-6 Pityriasis rubra pilaris.
201

11
Pityriasis Rosea, Pityriasis Rubra Pilaris, and Other Papulosquamous and Hyperkeratotic Diseases
Fig. 11-7 Islands of sparing in pityriasis rubra pilaris.
Fig. 11-8 Palmar
hyperkeratosis in
pityriasis rubra pilaris.
mani ests rst by scaliness and erythema o the scalp. The
eruption is limited in the beginning ha ing a predilection or
the sides o the nec and trun and the e tensor sur aces o
the e tremities especially the bac s o the rst and second
phalanges. Then as new lesions occur e tensi e areas are
con erted into sharply marginated patches o arious si es
which loo li e e aggerated goose esh and eel li e a nutmeg
grater. Any part or the entire s in sur ace may be a ected.
The in ol ement is generally symmetric and di use with
characteristic small islands o normal s in within the a ected
areas ( ig. ). There is a hyper eratosis o the palms and
soles with a tendency to ssures ( ig. ). n the soles
especially the hyper eratosis typically e tends up the sides
the so called sandal. The nails may be dull rough thic ened
brittle and striated and are apt to crac and brea . They are
202
tahir99 - UnitedVRG
rarely i e er pitted. The e oliation may become generali ed
and the ollicular lesions less noticeable nally disappearing
and lea ing a widespread dry scaly erythroderma. The s in
becomes dull red gla ed atrophic sensiti e to slight changes
in temperature and o er the bony prominences sub ect to
ulcerations. n the classic u enile type limited pla ues occur
on e tensor sur aces with ad acent nutmeg grater papules.
There are no sub ecti e symptoms e cept itching in some
cases. The oebner phenomenon may be present. The general
health o most patients is not a ected although occasionally
arthritis may accompany the eruption. A number o cases o
associated malignancy ha e recently been reported. t remains
to be established whether these are true associations or chance
ndings. Protein losing enteropathy may occur. Both hypo
thyroidism and hypoparathyroidism ha e been reported
as has the combination o sacroiliitis and autoimmune
thyroiditis.
Pityriasis rubra pilaris may be classi ed according to amil
ial (typically autosomal dominant) or ac uired types and to
the onset o disease in childhood or adulthood. Gri th s clas
si cation is use ul in this regard. Type the classic adult type
is seen most o ten and carries a good prognosis with
in oluting o er a year period. Li ewise most patients with
the classic u enile type (type ) ha e clearing o the disease
in year although it may recur e en into adulthood. The
atypical adult and u enile ariants and the circumscribed
u enile onset orm account or up to o cases and carry
a poorer prognosis or spontaneous reco ery. uman immu
node ciency irus ( V) patients may de elop PRP and ha e
associated acne conglobata hidradenitis suppurati a or lichen
spinulosus.
Etiology
The etiology o PRP is un nown. amilial cases are uncom
mon. ither gender may be a ected with e ual re uency.
Both clinically and histologically the disease has many ea
tures that suggest it is a itamin de ciency disorder particu
larly o itamin A. Some reports o patients with low serum
le els o retinol binding protein ha e appeared but this is not
a reproducible nding. A similar eruption has been described
secondary to imatinib sora enib and telapre ir.
Histology
There is hyper eratosis ollicular plugging and ocal para
eratosis at the ollicular ori ce. Para eratosis may alternate
both ertically and hori ontally producing a chec erboard
pattern. Acantholysis may be present especially within
adne al structures. The in ammatory in ltrate in the dermis
is composed o mononuclear cells and is generally mild.
Although ma ing an une ui ocal histologic diagnosis o PRP
may be di cult the ndings o psoriasis which is the most
common clinical entity in the di erential diagnosis are not
present.
Diagnosis
The diagnosis o ully de eloped PRP is rarely di cult because
o its distincti e eatures such as the peculiar orange or
salmon yellow color o the ollicular papules containing a
horny center on the bac s o the ngers sides o the nec and
e tensor sur aces o the limbs; the thic ened rough and
slightly or moderately scaly harsh s in; the sandal li e pal
moplantar hyper eratosis; and the islands o normal s in in
the midst o the eruption. t is distinguished rom psoriasis by
the scales which in the latter are sil ery and light and o erlap
li e shingles and by the papules which e tend peripherally
to orm patches. Phrynoderma ( ollicular hyper eratosis)
caused by itamin A de ciency gi es a somewhat similar
appearance to the s in as may ec ematous eruptions caused
by itamin B de ciency. Rheumatologic disorders such as
subacute cutaneous lupus erythematosus and dermatomyosi
tis may present with similar cutaneous ndings.
Treatment
The management o PRP is generally with systemic retinoids
although topical ta arotene has also been reported to be
o bene t. sotretinoin in doses o . mg g day may
induce prolonged remissions or cures. t may ta e months
or ull in olution to occur and tapering o the drug may
pre ent recurrence. Acitretin in doses o mg is also
e ecti e o er se eral months. ethotre ate has been used
with good results in doses o . mg either alone or in
combination with oral retinoids. Resolution by way o an ery
thema gyratum repens li e pattern has been described during
methotre ate therapy. V light may are some patients but
in others psoralen plus ultra iolet A (P VA) VA or B
VB alone or in combination with retinoids may be e ec
ti e. Phototesting be ore initiating light therapy is recom
mended. tracorporeal photochemotherapy cyclosporine
anti tumor necrosis actor (T ) agents uste inumab and
a athioprine ha e been reported to be e ecti e in resistant
and se ere cases.
Topical applications o calcineurin inhibitors lactic acid or
urea containing preparations may be help ul. Responses to
topical corticosteroids are not ery e ecti e as a rule. Systemic
corticosteroids are bene cial only or acute short term man
agement but are not recommended or chronic use. n V (A P ) encoding a water channel protein.
related disease multiagent anti iral therapy may be use ul
alone or in combination with retinoids.
Adnot-Desanlis L, et al: Effectiveness of infliximab in pityriasis rubra
pilaris is associated with pro-inflammatory cytokine inhibition.
Dermatology 2013; 226(1):41–46.
Eastham AB, et al: Treatment options for pityriasis rubra pilaris including
biologic agents: a retrospective analysis from an academic medical
center. JAMA Dermatol 2014; 150:92–94.
Ko CJ, et al: Pityriasis rubra pilaris: the clinical context of acantholysis
and other histologic features. Int J Dermatol 2011; 50(12):1480–1485.
Marchetti MA, et al: Pityriasis rubra pilaris treated with methotrexate
evolving with an erythema gyratum repens–like appearance. J Am
Acad Dermatol 2013; 69(1):e32–e33.
Mercer JM, et al: Familial pityriasis rubra pilaris: case report and review.
J Cutan Med Surg 2013; 17(4):226–232.
Pampín A, et al: Successful treatment of atypical adult pityriasis
rubra pilaris with oral alitretinoin. J Am Acad Dermatol 2013;
69(2):e105–e106.
Paz C, et al: Sorafenib-induced eruption resembling pityriasis rubra
pilaris. J Am Acad Dermatol 2011; 65(2):452–453.
Petrof G, et al: A systematic review of the literature on the treatment of
pityriasis rubra pilaris type 1 with TNF-antagonists. J Eur Acad
Dermatol Venereol 2013; 27(1):e131–e135.
Plana A, et al: Pityriasis rubra pilaris–like reaction induced by imatinib.
Clin Exp Dermatol 2013; 38(5):520–522.
Stalling SS, et al: Telaprevir-induced pityriasis rubra pilaris–like drug
eruption. Arch Dermatol 2012; 148(10):1215–1217.
PALMOPLANTAR KERATODERMA
The term eratoderma is re uently used synonymously with
eratosis palmaris et plantaris ( PP) and tylosis. This group
o conditions is characteri ed by e cessi e ormation o eratin
on the palms and soles. Some arieties e ist as part o a syn
drome. Ac uired types include eratoderma climactericum
arsenical eratoses corns calluses poro eratosis plantaris
discreta poro eratotic eccrine ostial and dermal duct ne us
glucan induced eratoderma in ac uired immunode ciency
Palmoplantar keratoderma
syndrome (A DS) eratosis punctata o the palmar creases
and many s in disorders associated with palmoplantar era
toderma such as psoriasis paraneoplastic syndromes PRP
lichen planus and syphilis. A high incidence o melanoma has
been noted in Japanese patients with palmoplantar erato
derma. Palmoplantar eratoderma has been described with
sora enib an oral multi inase inhibitor used in the treatment
o renal cell carcinoma. Arsenical eratoses can occur rom
tainted water supplies intentional poisoning and medications
containing arsenic. Arsenical eratoses ha e been treated with
a combination o eratolytics and low dose acitretin.
The hereditary types include hereditary palmoplantar era
toderma ( nna Thost) punctate palmoplantar eratosis
Papillon Le re syndrome mal de eleda amilial erato
derma with carcinoma o the esophagus ( owell ans) auto
somal dominant hereditary punctate eratoderma associated
with malignancy (Busch e isher Brauer) PP o Sybert (pal
moplantar hyper eratosis with transgrediens autosomal
dominant inheritance and a lac o associated systemic ea
tures) acro eratoelastoidosis ocal acral hyper eratosis and
se eral inherited disorders that ha e palmoplantar erato
derma as an associated nding such as pachyonychia con
genita tyrosinemia (Richner anhart) Darier s disease
a os syndrome ( eratoderma wooly hair and cardiomy
opathy) and dys eratosis congenita. any disorders that
ha e palmoplantar eratoderma as a eature are discussed in
other chapters.
A number o mutations in eratin genes ha e been ound.
American patients with nonepidermolytic palmoplantar era
toderma associated with malignancy are lin ed to a uaporin
Pachyonychia congenita is associated with mutations in the
helical initiation peptide o a or . pidermolytic
palmoplantar eratoderma ( PP ) is an autosomal dominant
disease caused by mutations o the gene or eratin . The
mutations locali e to se uences encoding the highly conser ed
A rod domain. Acantholysis o epidermal eratinocytes
suggests the presence o desmoglein gene mutations. Punc
tate eratoderma has been lin ed to as well as
COL mutations. A uagenic wrin ling is associated with
cystic brosis.
Keratolysis exfoliativa (lamellar dyshidrosis,
recurrent palmar peeling)
eratolysis e oliati a is a super cial e oliati e dermatosis o
the palms and sometimes soles. Clinically in ammation is
minimal to absent although white spots appear and gradually
e tend peripherally. The lesions rupture to produce an annular
adherent collarette ( ig. ) but remain largely asymptom
atic. The eruption is o ten e acerbated by en ironmental
actors. any patients ha e an atopic bac ground and some
ha e lesions o dyshidrotic ec ema. Although some suggest it
is a cohesion disorder o the stratum corneum eratolysis
e oliati a more li ely represents subclinical ec ema. The con
dition must be di erentiated rom dermatophytosis and a
e amination is recommended.
Because eratolysis e oliati a is generally asymptomatic
no treatment may be necessary. n some patients spontaneous
in olution occurs in a ew wee s. or patients who re uire
treatment emollients corticosteroid preparations tar urea
and lactic acid or ammonium lactate may be e ecti e.
203
 Fig. 11-9 Keratolysis
11 exfoliativa.
Pityriasis Rosea, Pityriasis Rubra Pilaris, and Other Papulosquamous and Hyperkeratotic Diseases

Fig. 11-11 Punctate keratoderma.

Fig. 11-10 Keratosis punctata of the palmar creases.

Keratosis punctata of the palmar creases

eratosis punctata o the palmar creases has also been re erred
to as eratotic pits o the palmar creases punctate eratosis o
the palmar creases eratosis punctata eratodermia punctata
hyper eratosis penetrans lenticular atrophia o the palmar
creases and hyper eratosis punctata o the palmar creases.
This common disorder occurs most o ten in blac patients. The
primary lesion is a mm depression lled with a comedo
li e eratinous plug. The lesions locali e to the creases o the
palms or ngers ( ig. ). The soles may be in ol ed. An
autosomal dominant inheritance pattern has been suggested
but onset is o ten delayed until adulthood.
eratosis punctata o the palmar creases has been associated
with atopic dermatitis Dupuytren contractures pterygium
in ersum unguis dermatitis herpeti ormis nuc le pads
striate eratoderma and psoriasis. eratolytic agents and
topical retinoids ha e pro ided temporary relie . tremely
pain ul lesions respond to punch e cision.
Punctate keratoses of the palms and soles
Punctate eratoses o the palms and soles has also been
re erred to as punctate eratoderma eratodermia punctata
eratosis punctata palmaris et plantaris eratoma hereditar
ium dissipatum palmare et plantare eratoderma dissemina
204
Fig. 11-12 “Music box” spiny keratoderma.
tum palmaris et plantaris palmar eratoses and palmar and
plantar seed dermatoses. Spiny eratoderma o the palms
and soles nown as music bo spines is a distinct ariant
( ig. ).
There may be rom to o er papules with an a erage in
one series o . ( ig. ). The main symptom is pruritus.
The onset is between ages and . Blac indi iduals pre
dominate and it more re uently a ects men. There ha e been
reports o autosomal dominant inheritance. The histology
demonstrates hyper eratosis and para eratosis py notic
acuolated epithelium basal layer spongiosis and dilated
occluded sweat ducts blood essels and lymph essels. nly
mechanical debridement and e cision ha e achie ed any per
manent results.
Circumscribed palmar hypo eratosis is a delayed mani es
tation o riction and repetiti e use trauma that presents

tahir99 - UnitedVRG
as a sharply circumscribed erythematous patch on the palm.
istologically thic ness o the stratum corneum decreases
abruptly.
Porokeratosis plantaris discreta
Poro eratosis plantaris discreta occurs in adults with a
emale preponderance. t is characteri ed by a sharply margin
ated rubbery wide based papule that on blunt dissection
re eals an opa ue plug without bleeding on remo al. Lesions
are multiple pain ul and usually mm in diameter. They
are usually con ned to the weight bearing area o the sole
beneath the metatarsal heads. Treatment may begin with tted
oot pads to redistribute the weight. Surgical e cision blunt
dissection and cryotherapy ha e been success ul.
Keratoderma climactericum
eratoderma climactericum is characteri ed by hyper erato
sis o the palms and soles (especially the heels) beginning at
about the time o menopause. The discrete thic ened hyper
eratotic patches are most pronounced at sites o pressure
such as around the rim o the sole. issuring o the thic ened
patches may be present. There is a stri ing resemblance to
plantar psoriasis and indeed eratoderma climactericum may
represent a orm o psoriasis. Therapy consists o eratolytics
such as salicylic acid ointment lactic acid creams or
urea mi tures. The response to topical corticosteroids
is o ten disappointing. Acitretin is more e ecti e than
isotretinoin.
Hereditary palmoplantar keratoderma
ereditary palmoplantar eratoderma ( nna Thost) is charac
teri ed by a dominantly inherited mar ed congenital thic en
ing o the epidermal horny layer o the palms and soles
usually symmetrically and a ecting all parts e ually ( ig.
). At times the thic ening e tends to the lateral or dorsal
sur aces especially o er the nuc les. The arches o the eet
Fig. 11-13 Unna-Thost
keratoderma.
are generally spared. The epidermis is thic yellowish and
horny. The uni orm thic ening orms a rigid plate which ends
with characteristic abruptness at the periphery o the palm.
yperhidrosis may cause a sodden appearance.
ereditary palmoplantar eratoderma is poorly responsi e
Palmoplantar keratoderma
to therapy; salicylic acid ammonium lactate and
urea ha e been used. Systemic retinoid therapy is impractical
because o bone to icity and topical retinoids are generally
not e ecti e.
Palmoplantar keratodermas and malignancy
owell ans reported a di use wa y eratoderma o the
palms and soles occurring as an autosomal dominant trait
associated with esophageal carcinoma. ther related eatures
are oral leu opla ia esophageal strictures s uamous cell car
cinoma o tylotic s in and carcinoma o the laryn and
stomach. The tylosis esophageal cancer gene has been local
i ed to chromosome . Ac uired orms o palmoplantar
eratoderma ha e also been associated with cancers o the
esophagus lung breast urinary bladder and stomach.
Mutilating keratoderma of Vohwinkel
Vohwin el described honeycomb palmoplantar hyper erato
sis associated with star shli e eratoses on the bac s o the
hands and eet linear eratoses o the elbows and nees and
annular constriction (pseudo ainhum) o the digits ( ig. )
which may progress to autoamputation. nheritance is mostly
autosomal dominant although a recessi e type e ists. The
disease is more common in women and in whites with
onset in in ancy or early childhood. Reported associations
include dea ness dea mutism high tone acoustic impair
ment congenital alopecia uni ersalis pseudopelade type alo
pecia acanthosis nigricans ichthyosi orm dermatoses spastic
paraplegia myopathy nail changes mental retardation and
bullous lesions on the soles. Vohwin el eratoderma maps to
chromosome and represents a mutation o loricrin. There
ha e been some reports o a response to acitretin (or etretinate)
therapy. utations in the gene or conne in produce a
similar phenotype.
ther orms o mutilating eratoderma also occur. They lac
the constricting bands honeycomb palmoplantar hyper era
tosis and star shli e eratoses o Vohwin el syndrome.
The a ected digits are o ten shortened narrow rigid and
tapered.
Fig. 11-14 Vohwinkel keratoderma.
205
 Olmsted syndrome agashima type eratosis is a nonprogressi e autosomal
11 lmsted syndrome is characteri ed by mutilating palmoplan
recessi e palmoplantar eratoderma that resembles a mild
orm o mal de eleda.
tar eratoderma and periori cial eratotic pla ues. The dis
tincti e eatures o this syndrome include a congenital sharply
Pityriasis Rosea, Pityriasis Rubra Pilaris, and Other Papulosquamous and Hyperkeratotic Diseases

marginated palmoplantar eratoderma; constriction o the Papillon-Lefèvre syndrome

digits; linear eratotic strea s on the e ural aspects o the
wrists; onychodystrophy; and periori cial eratoses. Constric
tion o digits may result in spontaneous amputations. ten
si e gra ting has sometimes been necessary. ost cases o
lmsted syndrome are sporadic. Associated abnormalities
ha e included hyperhidrosis o the palms and soles and con
genital dea ness. istologically there is acanthosis papilloma
tosis and ortho eratotic hyper eratosis. The nding o i
staining o suprabasal eratinocytes suggests that lmsted
syndrome is a hyperproli erati e disorder o the epidermis.
Acrokeratoelastoidosis
Acro eratoelastoidosis presents with translucent to erythema
tous papules at the margins o the palms. Both sporadic and
autosomal dominant orms ha e been reported. Small round
rm papules occur o er the dorsal hands nuc les and lateral
margins o the palms and soles. The lesions appear in early
childhood or adolescence in the inherited orm and progress
slowly. They are most o ten asymptomatic. The characteristic
histologic eature is dermal elastorrhe is.
The di erential diagnosis includes ocal acral hyper erato
sis which occurs as a amilial trait in A rican American
patients. The lesions are marginal hyper eratotic papules
o ten with a central dell and usually on both the hands and
the ngers. o alteration o the collagen or elastin is present
on biopsy.
The Papillon Le re syndrome is inherited in an autosomal
recessi e ashion and presents with palmoplantar erato
derma and destructi e periodontitis usually beginning in
young childhood. Well demarcated erythematous hyper er
atotic lesions on the palms and soles may e tend to the dorsal
hands and eet. yper eratosis may also be present on the
elbows nees and Achilles tendon areas. Trans erse groo es
o the ngernails may occur. Se ere gingi al in ammation
with loss o al eolar bone is typical. istology re eals a pso
riasi orm pattern. utations in the gene or cathepsin C ha e
been detected. The condition usually has an early age o onset
although a late onset ariant has been reported. Some patients
with late onset disease ha e not shown mutations in the
cathepsin C gene.
The early onset o periodontal disease has been attributed to
alterations in polymorphonuclear leu ocyte unction caused
by ctinom ces actinom cetemcomitans although a ariety o
other bacteria ha e also been implicated. Acro osteolysis and
pyogenic li er abscesses may occur. There are asymptomatic
ectopic calci cations in the choroid ple us and tentorium.
Some patients ha e responded to acitretin etretinate or
isotretinoin.
The stoc ing glo e distribution o the hyper eratosis is
similar to that seen in mal de eleda. aim un syndrome
is autosomal recessi e with periodontal disease eratoderma
and onychogryphosis lin ed to cathepsin C gene mutations.

Striate keratodermas
Collagenous and elastotic marginal plaques The striate eratodermas are a group o autosomal dominant
of the hands palmoplantar eratodermas with strea ing hyper eratosis
in ol ing the ngers and e tending onto the palm ( ig. ).
Collagenous and elastotic marginal pla ues o the hands are n some patients a hetero ygous C to A trans ersion in ol ing
slowly progressi e lesions at the margins o the palms that
demonstrate thic ened collagen bundles admi ed with elastic
bers and amorphous basophilic elastotic material.
Fig. 11-15 Striate
keratoderma.
Focal acral hyperkeratosis
ocal acral hyper eratosis occurs in autosomal dominant and
sporadic orms. Clinically it is characteri ed by crateri orm
eratotic papules and pla ues along the borders o the hands
and eet. t di ers rom acro eratoelastoidosis and collage
nous and elastotic marginal bands by the lac o underlying
dermal changes.

Mal de Meleda
al de eleda is a rare autosomal recessi e orm o palmo
plantar eratoderma seen in indi iduals rom the island o
eleda. The hyper eratosis does not remain con ned to the
palms and the e tensor sur aces o the arms are re uently
a ected. The disease has been mapped to chromosome
and mutations in the S (component B) gene ha e been
identi ed in amilies with this disorder. utations in the gene
encoding secreted lymphocyte antigen uro inase type plas
minogen acti ator receptor related protein SLU P ha e
been ound.
206

tahir99 - UnitedVRG
 Fig. 11-16
Transient reactive
papulotranslucent
acrokeratoderma.
the gene or desmoglein has been ound. utations in the
gene or desmopla in ha e also been described. Brunauer ohs
Siemens syndrome is one orm with diminished desmosomes
clumping o eratin laments and enlarged eratohyalin gran
ules. utations in genes or desmoglein desmopla in and
eratin ha e been described in these patients. n other patients
desmosome numbers are normal but their inner pla ues are
attenuated. Striate eratoderma has also been reported in asso
ciation with Rubinstein Taybi syndrome.
Richner-Hanhart syndrome
Richner anhart syndrome (tyrosinemia type ) is character
i ed by corneal opacities and eratosis palmoplantaris. The s in
mani estations usually de elop a ter the rst year o li e and
relate to de ects in tyrosine aminotrans erase. ewborn screen
ing can allow early inter ention with dietary restriction.
Acquired aquagenic syringeal acrokeratoderma
(aquagenic wrinkling of the palms)
Patients with papulotranslucent acro eratoderma sometimes
re erred to as a uagenic wrin ling de elop white papules on
the palms a ter water e posure. The lesions are sharply demar
cated rom the surrounding s in and appear white. There may
be a central prominent pore within each white lesion ( ig.
). The lesions appear min a ter e posure to water and
resol e within a short time o drying. Sometimes the white
s in can be peeled o . t may be a mar er or cystic brosis
and has also been reported in patients ta ing aspirin or ro e
co ib. Autosomal dominant inheritance has been suggested in
some cases and abnormal A P has been described in sweat
glands.
Baquerizo K, et al: Atypical form of transient reactive papulotranslucent
acrokeratoderma in a cystic fibrosis carrier. J Cutan Pathol 2013;
40(4):413–418.
Chang YY, et al: Keratolysis exfoliativa (dyshidrosis lamellosa sicca):
a distinct peeling entity. Br J Dermatol 2012; 167(5):1076–1084.
Fuchs-Telem D, et al: Epidermolytic palmoplantar keratoderma caused
by activation of a cryptic splice site in KRT9 . Clin Exp Dermatol 2013;
38(2):189–192.
Fig. 11-17
Erythroderma.
Exfoliative dermatitis (erythroderma)
Giehl KA, et al: Nonsense mutations in AAGAB cause punctate
palmoplantar keratoderma type Buschke-Fischer-Brauer. Am J Hum
Genet 2012; 91(4):754–759.
Guo BR, et al: Exome sequencing identifies a COL14A1 mutation in
a large Chinese pedigree with punctate palmoplantar keratoderma.
J Med Genet 2012; 49(9):563–568.
Kosem R, et al: Cathepsin C gene 5′-untranslated region mutation in
Papillon-Lefèvre syndrome. Dermatology 2012; 225(3):193–203.
Pohler E, et al: Haploinsufficiency for AAGAB causes clinically
heterogeneous forms of punctate palmoplantar keratoderma. Nat
Genet 2012; 44(11):1272–1276.
Tieu KD, et al: Thickened plaques on the hands: collagenous and
elastotic marginal plaques of the hands (CEMPH). Arch Dermatol
2011; 147(4):499–504.
EXFOLIATIVE DERMATITIS (ERYTHRODERMA)
oliati e dermatitis is also nown as dermatitis e oliati a
pityriasis rubra ( ebra) and erythroderma (Wilson Broc ).
Patients present with e tensi e erythema and scaling ( ig.
). ltimately the entire body sur ace is dull scarlet and
co ered by small laminated scales that e oliate pro usely.
Vesiculation and pustulation are usually absent. An e tensi e
telogen e u ium is o ten noted. n both PRP and mycosis
ungoides distinctly spared islands o s in are re uently
noted. Patients with PRP also ha e thic ened orange palms
and nutmeg grater ollicular papules on the dorsa o the
ngers (see earlier).
tching o the erythrodermic s in may be se ere and the
onset is o ten accompanied by symptoms o general to icity
including e er and chills. Transepidermal water loss is high
and secondary in ections by pyogenic organisms o ten com
plicate the disease course in the absence o treatment. Se ere
complications include sepsis high output cardiac ailure
acute respiratory distress syndrome and capillary lea syn
drome. The mortality rate attributable to the erythroderma
approaches in some series.
Etiology
rythroderma is re uently the result o generali ation o a
pree isting chronic dermatosis such as psoriasis or atopic
207
 dermatitis. any other cases are related to a medication and
11 some occur as a mani estation o an internal malignancy
erythrodermic mycosis ungoides or the S ary syndrome.
nternal malignancies pemphigus oliaceus generali ed der
matophytosis and e en orwegian scabies may show the
Pityriasis Rosea, Pityriasis Rubra Pilaris, and Other Papulosquamous and Hyperkeratotic Diseases
picture o generali ed e oliati e dermatitis. nade uate inta e
o branched chain amino acids in in ants with maple syrup
urine disease reportedly produces e oliati e erythroderma.
n a signi cant number o patients howe er the cause remains
idiopathic e en a ter e tensi e e aluation.
n se eral reported series the largest group o patients had
pree isting dermatoses including atopic dermatitis chronic
actinic dermatitis psoriasis seborrheic dermatitis PRP and
allergic or irritant contact dermatitis. Drug eruptions are gen
erally the ne t most common group ollowed by idiopathic
cases cutaneous T cell lymphoma (CTCL) paraneoplastic
erythroderma and leu emia cutis. Common implicated drugs
include allopurinol sul a drugs gold phenytoin phenobarbi
tal isonia id carbama epine cisplatin dapsone me o uine
tobramycin minocycline ni edipine and iodine. Anti T
therapy has produced the combination o erythroderma and
eratoderma.
n a study o erythrodermic patients managed in the com
munity e acerbation o pree isting dermatoses accounted or
compared with o those e aluated at a uni ersity
medical center; idiopathic cases or and respecti ely;
and CTCL or and respecti ely. n a study o chil
dren with erythroderma immunode ciency was diagnosed in
ichthyosis in etherton syndrome in and
ec ematous or papulos uamous dermatitis in . i e o
the patients remained idiopathic. A biopsy established the
diagnosis in only ( ) o cases. ortality was
usually related to an immunode ciency disorder. eonatal
erythroderma is re uently a mani estation o a genodermato
sis or immunode ciency syndrome. ther causes include pso
riasis metabolic disease and in ection. Atopic dermatitis
presenting as erythroderma is usually obser ed later a ter the
neonatal period.
n a comparison o patients with and without V in ection
erythroderma in the V positi e group was most o ten
related to drug reactions ( . ) with ethambutol accounting
or . . n the non V group drug reactions accounted or
only . . V positi e patients did not ha e an o erall
increase in the number o episodes o erythroderma.
ycosis ungoides can be erythrodermic without meeting
the criteria or the S ary syndrome. S ary syndrome consists
o generali ed e oliati e dermatitis with intense pruritus
leonine acies alopecia palmoplantar hyper eratosis and
onychodystrophy. The criteria or a diagnosis o S ary syn
drome include an absolute S ary cell count o at least
cells mm ; a CD CD ratio o or higher by ow cytome
try caused by an increase in circulating T cells or loss o
e pression o pan T cell mar ers; increased lymphocyte counts
with e idence o a T cell clone by Southern blot or polymerase
chain reaction; or a chromosomally abnormal T cell clone.
Prognosis is poor and similar to that o patients with nodal
in ol ement.
208
tahir99 - UnitedVRG
odg in disease may show generali ed e oliati e derma
titis. e er lymphadenopathy splenomegaly and hepato
megaly are re uently present. The erythrocyte sedimentation
rate is ele ated in most o these patients.
Histopathology
oliati e dermatitis may retain the histologic eatures o the
original disease process. This is particularly true in patients
with psoriasis and mycosis ungoides. ten howe er the
histology is nonspeci c with hyper eratosis mild acanthosis
and ocal para eratosis.
Treatment
n drug induced erythroderma the o ending drug must be
stopped. Application o a midstrength corticosteroid a ter
soa ing and occlusion under a sauna suit are o ten help ul
regardless o the cause o the erythroderma. oist pa amas
can be added under the sauna suit. Acitretin cyclosporine
and methotre ate are use ul in psoriatic erythroderma. sotret
inoin acitretin and methotre ate are use ul in erythroderma
caused by PRP. mmunosuppressi e agents such as a athio
prine and methotre ate are occasionally necessary in idio
pathic erythroderma patients not responding to therapy.
Carter JB, et al: Case records of the Massachusetts General Hospital:
Case 24-2013—a 53-year-old woman with erythroderma, pruritus, and
lymphadenopathy. N Engl J Med 2013; 369(6):559–569.
Dhar S, et al: Neonatal erythroderma: diagnostic and therapeutic
challenges. Indian J Dermatol 2012; 57(6):475–478.
Dunst-Huemer KM, et al: Generalized erythroderma and palmoplantar
hyperkeratosis in a patient receiving TNF-α antagonist therapy. J Cutan
Pathol 2013; 40(9):855–856.
Hulmani M, et al: Clinico-etiological study of 30 erythroderma cases
from tertiary center in South India. Indian Dermatol Online J 2014;
5:25–29.
Mohd Noor N, et al: Transepidermal water loss in erythrodermic patients
of various aetiologies. Skin Res Technol 2013; 19(3):320–323.
Rice SA, et al: Erythroderma in the emergency department. BMJ 2013;
346:f3613.
Yang JH, et al: Paraneoplastic erythroderma: an unusual
manifestation of diffuse large B-cell lymphoma. Int J Dermatol 2013;
52(9):1149–1151.
Bonus images for this chapter can be found online at
expertconsult.inkling.com
eFig. 11-1 Confluent and reticulated papillomatosis.
eFig. 11-2 Pityriasis rubra pilaris.
eFig. 11-3 Palmar hyperkeratosis in pityriasis rubra pilaris.
eFig. 11-4 Keratolysis exfoliativa.
eFig. 11-5 Transient reactive papulotranslucent acrokeratoderma.
 Exfoliative dermatitis (erythroderma)
eFig. 11-1 Confluent and reticulated papillomatosis.
eFig. 11-4 Keratolysis exfoliativa.

eFig. 11-5 Transient reactive papulotranslucent acrokeratoderma.

eFig. 11-2 Pityriasis rubra pilaris.

eFig. 11-3 Palmar

hyperkeratosis in
pityriasis rubra pilaris.

208.e1
 Bonus images for this chapter can be found online at
Lichen Planus and Related Conditions
LICHEN PLANUS
Lichen planus (LP) is a common pruritic in ammatory
disease o the s in mucous membranes and hair ollicles. t
occurs throughout the world in all races. Cutaneous lichen
planus a ects . o men and . o women. ral LP a ects
. o men and . o women. t may be amilial in rare
cases. The pattern o LP detected and the age distribution ary
among arious genetic and geographic groups. n persons o
uropean descent it appears primarily a ter age and pea s
between and . Very ew cases appear a ter age . Child
hood LP typically accounts or or less o LP cases although
in some regions including the ndian subcontinent Arab
countries and e ico it represents . Race appears to
be the critical actor; in the nited ingdom or e ample
ndians account or o childhood LP.
The primary lesions o LP are characteristic almost pathog
nomonic small at topped polygonal papules ( ig. ). The
color o the lesions initially is erythematous. Well de eloped
lesions are iolaceous and resol ing lesions are o ten hyper
pigmented especially in persons o color. The sur ace is glis
tening and dry with scant adherent scales. n the sur ace
gray or white puncta or strea s (Wic ham striae) cross the
lesions a eature seen more easily with dermoscopy. Lesions
begin as pinpoint papules and e pand to . . cm pla ues.
n re uently larger lesions are seen. There is a predilection or
the e or wrists trun medial thighs shins dorsal hands and
glans penis ( ig. ). The ace is only rarely in ol ed with
lesions usually con ned to the eyelids and lips. The palms and
soles may be a ected with small papules or hyper eratotic
pla ues ( ig. ). Certain morphologic patterns a or certain
locations (e.g. annular lesions a oring penis; eratotic lesions
a oring anterior shins). The oebner phenomenon occurs in
LP ( ig. ).
Pruritus is o ten prominent in LP. The pruritus may precede
the appearance o the s in lesions and as with scabies the
intensity o the itch may seem out o proportion to the amount
o s in disease. t may be almost intolerable in acute cases.
ost patients react to the itching o LP by rubbing rather than
scratching and thus scratch mar s are usually not present.
The natural history o LP is highly ariable and dependent
on the site o in ol ement and the clinical pattern. Two thirds
o patients with s in lesions will ha e LP or less than year
and many patients spontaneously clear in the second year.
ucous membrane disease is much more chronic. Recurrences
are common.
ail changes are present in appro imately o patients.
n ol ement o the nail can occur as an initial mani estation
especially in children. Longitudinal ridging and splitting are
most common seen in o patients. nycholysis and sub
ungual debris may be present indicating in ol ement o the
nail bed. The lunulae are red in o patients with nail LP.
n ol ement o the entire matri may lead to obliteration o
the whole nail plate (anonychia). Pterygium ormation is
tahir99 - UnitedVRG
expertconsult.inkling.com
12
characteristic o LP o the nails ( ig. ) but seen in only
about o patients. The nail matri is destroyed by the
in ammation and replaced by brosis. The pro imal nail old
uses with the pro imal portion o the nail bed. LP may be a
cause o some cases o nail dystrophy o childhood. n the
absence o periungual lesions or pterygium ormation nail
dystrophy usually resol es spontaneously and re uently in
these children no other stigmata o cutaneous or mucosal LP
are ound. Rarely nail bed LP can result in onychopapilloma
a locali ed distal subungual hyper eratosis.
n ol ement o the genitalia with or without lesions at other
sites is common. n the glans or sha t o the penis the lesions
may consist o at polygonal papules or these may be annular.
rosi e LP can occur on the glans. Simultaneous in ol ement
o the gingi al and penile mucosa may occur. n the labia and
anus similar lesions are obser ed generally whitish because
o maceration. al o women with oral LP also ha e ul al
LP but in only hal o these patients is the genital LP symp
tomatic. Vul al LP occurs in three main orms. The classic type
presents with polygonal papules resembling cutaneous LP
and a ects the clitoral hood and labia minora. Pruritus is the
usual symptom. Although only about o women with
ul al LP ha e erosive or ulcerative LP this type represents the
ast ma ority o patients seen or ul al LP since it is usually
ery symptomatic. Soreness pain and dyspareunia are re
uent complaints. Vaginal in ol ement with a bloody dis
charge can occur. n ol ement is symmetric rom the ourchette
to the anterior estibule. The erosions ha e a lacy white
periphery a good area to biopsy to con rm the diagnosis o
ul al LP. The third and least common orm o ul al LP is
the h pertrophic type. t in ol es the perineum and perianal
s in (but not the agina) with warty pla ues with a iolaceous
edge. Pruritus is se ere. Vul al splitting aginal stenosis and
sealing o the clitoral hood may be caused by LP which should
not be con used with lichen sclerosus.
Con uncti al in ol ement is a rarely recogni ed complica
tion o LP but was seen in . o patients with ul al LP in
one series. t most re uently occurs in patients with in ol e
ment o other mucosal sur aces. Cicatri ation lacrimal cana
licular duct scarring and eratitis can occur. t may closely
simulate mucous membrane pemphigoid. Routine histology
and direct immuno uorescence (D ) may be re uired to
con rm the diagnosis.
tic in ol ement by LP is rarely reported. t a ects primar
ily emales ( o patients) and is associated with oral and
ul al LP in more than o cases. earing loss and e ternal
auditory canal stenosis are the most common otic complaints
and complications. our o ( ) patients with otic lP also
had esophageal in ol ement.
Lichen planus o the esophagus is increasingly being recog
ni ed but occurs in only o patients with LP. The diagnosis
is re uently delayed. Dysphagia odynophagia and weight
loss are typical mani estations. The midesophagus is primarily
a ected. Virtually all the patients ha e coe istent oral disease.
209
12
Lichen Planus and Related Conditions

Fig. 12-1 Lichen planus, violaceous, flat-topped papules with

minimal scale.

Fig. 12-2 Lichen

planus of the penis.
Fig. 12-4 Koebnerized lichen planus. (Courtesy of Dr. Debabrata
Bandyopadhyay.)

Fig. 12-5 Lichen planus, nail involvement with pterygium. (Courtesy

of Lawrence Lieblich, MD.)

sophageal in ol ement is much more common in women

with ul o aginal and oral disease in whom de elop
esophageal lesions. Stricture ormation occurs in o
esophageal LP and may re uire re uent dilations. sophageal
s uamous cell carcinoma may complicate esophageal LP sug
gesting that once this diagnosis is made routine gastrointes
tinal e aluation is re uired.
Whether the many clinical ariants o LP represent separate
diseases or part o the LP spectrum is un nown. They all
demonstrate typical LP histologically. The ariants are
described separately because their clinical eatures are distinct
rom classic LP. Some patients with these clinical ariants may
ha e typical cutaneous ollicular or mucosal LP. The more
common or better nown ariants are described here.

Fig. 12-3 Lichen planus of the palm and sole. Linear lichen planus
Small linear lesions caused by the oebner phenomenon o ten
occur in classic LP. Limitation o LP to one band or strea has
also been described in less than o patients o uropean
descent. n Japan howe er up to o cases are linear and
210
in ndia o childhood cases o LP are linear. Although
originally described as ollowing dermatomes ( osteri orm)
the lesions actually ollow lines o Blasch o. t is more common
in children but also occurs in adults. Papules with arying
degrees o o erlying hyper eratosis or simple hyperpigmenta
tion may be the presenting mani estations. There are o ten
s ip areas o normal s in between the indi idual lesions.
Annular and annular atrophic lichen planus
en represent o patients with annular LP. Lesions with
this con guration a or the a illa penis scrotum and groin.
LP lesions o the mucosa scalp and nails are rare in patients
with annular LP. Patients usually ha e ewer than lesions.
ost patients with annular LP are asymptomatic. The ringed
lesions are composed o small papules and measure about
cm in diameter. Central hyperpigmentation may be the dom
inant eature. They may coalesce to orm polycyclic gures.
Annular lesions may also result rom central in olution o at
papules or pla ues orming lesions with iolaceous ele ated
borders and central hyperpigmented macules.
Hypertrophic lichen planus
ypertrophic LP usually occurs on the shins but may occur
anywhere. The typical lesions are errucous pla ues with ari
able amounts o scale ( ig. ). At the edges o the pla ues
small at topped polygonal papules may at times be disco
ered. Super cial inspection o the lesion o ten suggests
psoriasis or a eratinocytic neoplasm rather than LP but the
typical appearance resembling rapidly cooled igneous roc
(igneous roc sign) may be use ul in suggesting LP o er era
tinocytic neoplasms. The lesions are o ariable si e but are
re uently se eral centimeters in diameter and larger than the
lesions o classic LP. The anterior lower leg below the nee is
the sole area o in ol ement in most patients. Clinical diagno
sis may be di cult and biopsy is o ten re uired. istologi
cally the pseudoepitheliomatous eratinocyte hyperplasia
may be mar ed leading to the erroneous diagnosis o s ua
mous cell carcinoma (SCC). osinophils are much more o ten
present in the dermal in ltrate o hypertrophic LP than classic
LP. True SCC may also e ol e rom long standing hypertro
phic LP and o er o cutaneous SCC arising in LP occurs
below the nee in lesions o hypertrophic LP. n addition
eratoacanthoma li e proli erations may occur in lesions o
hypertrophic LP. This has also been called hypertrophic
Fig. 12-6 Hypertrophic lichen planus.
tahir99 - UnitedVRG
lichen planus li e reactions combined with in undibulocystic
hyperplasia. ypertrophic LP is chronic and o ten re ractory
to topical therapy. ypertrophic lupus erythematosus (L )
resembles hypertrophic LP both clinically and histologically.
ypertrophic L tends to a ect the distal e tremities ace
Lichen planus
and scalp. The nding o continuous granular immunoglobu
lin on D strongly suggests a diagnosis o hypertrophic L
rather than LP.
Erosive/ulcerative/mucosal lichen planus
lcerati e LP is rare on the s in but common on the mucous
membranes. A rare ulcerati e ariant o cutaneous LP or L
LP o erlap syndrome a ects the eet and toes causing bullae
ulcerations and permanent loss o the toenails. These chronic
ulcerations on the eet are pain ul and disabling. Cicatricial
alopecia may be present on the scalp and the buccal mucosa
may also be a ected. These cases are a therapeutic challenge
and aggressi e oral retinoid or immunomodulatory treatment
is indicated i there is a poor response to standard topical and
systemic agents. S in gra ting o the soles has produced suc
cess ul results.
ral mucosal LP is the most common orm o mucosal LP
and it is usually chronic. Between and o patients
with oral LP will also ha e s in lesions. Women represent
o patients with oral LP. ral LP in women begins years
later than in men (age s. ). ral lesions may be reticulate
(reticular) ( ig. ) erythematous (atrophic) or ulcerati e
(erosi e). The most common pattern in oral LP is the ulcerati e
orm ( o patients). sually reticulate and erythematous
lesions are ound ad acent to the ulcerati e areas. The ery
thematous pattern is the predominant pattern in o
patients but almost always reticulate lesions are also seen in
these patients. n oral LP the classic reticulate lesions are
most prominent in o patients. Symptoms are least
common in patients with reticulate lesions; are symptom
atic and then only when the tongue is in ol ed. All patients
with erosi e lesions are symptomatic usually with burning or
pain. Patients may simultaneously ha e se eral patterns
so patients are characteri ed by the primary orm they
e hibit. Lesions appear on any portion o the mouth and
multisite in ol ement is common. The buccal mucosa is
in ol ed in the gingi a in more than and the tongue
in about .
Fig. 12-7 Lichen planus, reticulate white lesions of the buccal
mucosa.
211
12
Lichen Planus and Related Conditions
Fig. 12-8 Desquamative gingivitis secondary to lichen planus.
n the gingi a LP may produce des uamati e gingi itis
( ig. ). Gingi al in ol ement is particularly di cult to
diagnose and o ten re uires biopsy or both histology and D
to con rm the diagnosis and e clude other autoimmune
causes o des uamati e gingi itis. Gingi al in ol ement is
associated with accelerated gingi al recession. echanical
in ury rom dental procedures and poorly tting appliances
may trigger or e acerbate gingi al LP. n the tongue and
palate lesions are o ten mista en or leu opla ia. The lower
lip is in ol ed in o oral LP patients but the upper lip in
only . Lower lip LP is re uently mista en or actinic chei
litis. mi uimod treatment can lead to e acerbation o the
labial LP with e tensi e erosion and crusting. ral LP is stable
but chronic with less than o patients ha ing a spontane
ous remission in an a erage year ollow up. Periodontitis
appears to e acerbate oral LP especially gingi al disease.
Pla ue control either by the patient a ter training or by a dental
pro essional impro es the clinical appearance and pain.
ral lichenoid lesion ( LL) re ers to an oral lesion histologi
cally identical to oral LP ( LP) but rom a di erent cause such
as gra t ersus host disease (GV D) medications and local
or systemic e posures. Gold cobalt indium manganese
chrome nic el palladium cinnamate and spearmint sensiti
ity may induce LLs. The most common causes howe er are
the metals in dental amalgams including mercury copper
inc and tin. the lesions in the oral mucosa are physically
close to the amalgam remo al o the amalgam will lead to
resolution o the LL in . n patients patch test positi e to
a metal in the amalgam and o LLs healed with
remo al o the amalgam in two studies. n patients with the
LL in strict contact with the amalgam and there is a rele ant
positi e patch test to a component o the amalgam or
more o LLs will heal. Patch testing howe er may not iden
ti y all patients whose LLs impro e with remo al o the oral
metal. Rarely patients with metal sensiti ity will also ha e
s in and nail lesions that impro e with remo al o the oral
metal. n one study o patients with nail LP who were
patch test positi e to a metal in their amalgam impro ed with
remo al o the dental material or with oral disodium chromo
glycate treatment.
n ol ement o the ul a and agina with LP along with
the gingi a has been called the ul o aginal gingi al (VVG)
syndrome. Although all three o these mucous membranes
may be in ol ed only one or two sites may be in ol ed at any
one time. The pre alence o erosi e ul ar LP had been under
appreciated simply because many women with oral LP did not
olunteer their ul o aginal complaints and were not as ed
about them. The aginal lesions o VVG are erythematous
riable erosions that are ery pain ul. ntreated scarring is
212
Fig. 12-9 Scarring and erosions in the vulvovaginal-gingival
syndrome.
se ere and can lead to adhesions estibular bands and e en
aginal stenosis ( ig. ). n one third o patients typical
reticulate buccal LP is seen and in up to the oral mucosa
is also in ol ed. Cutaneous lesions occur in o VVG
patients. The course o the ul o aginal syndrome is pro
tracted and patients re uently ha e se uelae including
chronic pain dyspareunia and e en scarring o the con unc
ti a urethra and oral laryngeal pharyngeal and esophageal
mucosae. ails are in ol ed in about o patients with
VVG compared with only o patients with oral LP. The
VVG syndrome is now considered to be a separate subgroup
o mucosal LP that is particularly disabling scarring and
re ractory to therapy.
Although the pathogenesis o LP is un nown e idence
shows that erosi e LP o the ul a (and lichen sclerosus) may
ha e an autoimmune basis. A personal and amily history o
autoimmune disorders (usually thyroid disease) is present in
up to o patients with ul ar LP and up to ha e
circulating autoantibodies. The pre alence o autoimmune
phenomena is not increased in patients with classic cutaneous
LP. The autoantibodies do not appear to be pathogenic
because the disease seems to be caused by cytoto ic T cells.
rosi e LP has signi cant impact on uality o li e and patients
with erosi e LP ha e high le els o depression an iety and
stress.
Cancer risk and lichen planus
Rare cases o s uamous cell carcinoma o the s in occurring
on the lower leg in lesions o hypertrophic LP ha e been
reported. There is no statistical increase in cutaneous or is
ceral carcinoma in patients with cutaneous LP and cutaneous
LP alone is not considered to be a condition with increased
cancer ris . ral LP and ul o aginal LP howe er do appear
to increase the ris o de eloping SCC. About o patients
with oral LP will de elop oral SCC. SCC occurs only in patients
with erythematous or ulcerati e LP not in those with only the
reticulate pattern. the oral LP patients who de elop oral
SCC about ha e only one cancer. The ma ority de elop
multiple cancers and close igilance is recommended in these
patients. LP patients with erosi e penile and aginal disease
also ha e de eloped SCC. The number o penile cases is too
low to determine the re uency but in patients with ul ar
LP de elopment o SCC may be as high as . Clinicians
should ha e a low threshold to biopsy ed erosi e or leu o
eratotic lesions in patients with mucosal LP. The use o oral
and topical calcineurin inhibitors (C s) or LP has been
associated with the appearance o SCC on the genitalia. There
is no e idence that the medications caused the neoplasia but
i these agents are used regular ollow up and care ul e ami
nation are re uired.
Hepatitis-associated lichen planus
Three li er conditions ha e been associated with LP hepatitis
C irus ( CV) hepatitis B immuni ation and primary biliary
cirrhosis. CV in ection has been ound in proportionately
more patients with LP than in controls in numerous studies.
The pre alence o CV in ection in patients with LP aries
rom . to . There is an association with the human
leu ocyte antigen ( LA) DR allele. The association o CV
in ection and LP has been uestioned. n a large series o
patients with oral LP rom the nited States none o the
patients was in ected with CV whereas o patients with
oral LP rom taly had CV. n Scotland o patients
in ected with CV had oral LP compared with o serone
gati e patients. Although the data are con icting screening
or CV appears appropriate in persons rom a geographic
region where or a population in whom CV in ection is re
uently associated with LP. These areas include ast and
Southeast Asia South America the iddle ast and urope.
n orth America South Asia and A rica such screening may
not be cost e ecti e but can still be recommended. The clinical
eatures o LP in patients with hepatitis C are identical to
classic LP but LP patients with CV in ection are reported as
being more li ely to ha e erosi e mucous membrane disease.
The e istence o underlying hepatitis cannot be predicted by
clinical pattern or the results o li er unction tests. Treatment
o hepatitis C with inter eron ( ) alpha may be associated
with the initial appearance o LP or e acerbation o pree isting
LP. LP may occur at in ection sites and s in testing may
reproduce LP li e lesions. LP may impro e or may not change
with and riba irin treatment or hepatitis C. mpro ement
is usually seen toward the end o the treatment course. ost
patients do not completely clear their LP. The CV genome is
not ound in lesions o LP associated with CV in ection.
epatitis B irus ( BV) immuni ation may be associated
with the appearance o LP in both children and adults. Lesions
are typical o LP and the oral mucosa may be a ected. Typi
cally the rst lesions o LP appear about month a ter the
second dose o accine. Lesions usually resol e a ter some
time.
Primary biliary cirrhosis and LP may coe ist. Patients with
this li er abnormality also ha e a mar ed propensity to
de elop a lichenoid eruption while recei ing D penicillamine
therapy. anthomas in patients with primary biliary cirrhosis
may appear initially in lesions o LP and the in ltrate although
lichenoid may contain anthomatous cells. Primary sclerosing
cholangitis has been associated with oral LP.
Bullous lichen planus
Two orms o LP may be accompanied by bullae. n classic LP
usually on the lower e tremities indi idual lesions will esic
ulate centrally ( ig. . ). This represents macroscopic e ag
geration o the subepidermal space ormed by the lichenoid
inter ace reaction destroying the basal eratinocytes. These
lesions o ten spontaneously resol e.
Lichen planus pemphigoides describes a rare subset o
patients who usually ha e typical LP then an a erage o
months later de elop blistering on their LP lesions and on
normal s in. Less o ten the blister and the LP lesions occur
simultaneously. Clinically these patients appear to be a
tahir99 - UnitedVRG
Fig. 12-10 Generalized
lichen planus.
Lichen planus
combination o LP and bullous pemphigoid. ral disease may
occur and resemble either LP or mucous membrane pemphi
goid. Lichen planus pemphigoides has been triggered by medi
cations especially angiotensin con erting en yme (AC )
inhibitors as well as inter eron BV and psoralen plus ultra
iolet A (P VA). Pruritus may be se ere and lesions may
e ol e to resemble pemphigoid nodularis. Bullous pemphi
goid a ects an older age group than LP pemphigoides; typical
onset or lichen planus pemphigoides is . istologically
the LP lesions show LP and the bullous lesions show the ea
tures o bullous pemphigoid. D is positi e in a linear pattern
with gG and C along the basement membrane one (B )
at the roo o saline split s in. The antigen targeted by the
autoantibody in lichen planus pemphigoides is located in the
same region as the bullous pemphigoid antigen at the basal
hemidesmosome. Antibodies rom patients with lichen planus
pemphigoides typically bind the D bullous pemphigoid
antigen but in a di erent region rom bullous pemphigoid
sera. Lichen planus pemphigoides tends to ollow a benign and
chronic course e en compared with bullous pemphigoid.
Treatment o lichen planus pemphigoides is similar to bullous
pemphigoid with potent topical steroids systemic steroids
tetracycline nicotinamide intra enous immune globulin
( V G) and immunosuppressi es all being ariably e ecti e.
Pathogenesis and histology
Lichen planus is characteri ed by an immunologic reaction
mediated by CD + T cells. These cells induce eratinocytes to
undergo apoptosis. Although this in ammatory reaction is
thought to be autoimmune the antigen targeted by these e ec
tor T lymphocytes is un nown. Patients with LP and LP ha e
a high rate o dyslipidemia with ele ated triglycerides ele
ated low density lipoprotein (LDL) cholesterol and reduced
high density lipoprotein ( DL) cholesterol. n ammatory
mar ers also are ele ated in the blood o LP patients poten
tially contributing to this dyslipidemia. n addition both
insulin resistance and ran type diabetes mellitus are
increased in patients with LP compared with controls. Both
insulin resistance and dyslipidemia are cardio ascular ris
actors. Adult LP patients should be e aluated appropriately.
213
 Lichen planus pemphigoides is hypothesi ed to result rom
12 e posure to the immune system o epitopes in the BP
antigen as eratinocytes are destroyed by the lichenoid in am
mation. pitope spreading can occur and LP pemphigoides
patients may also ha e autoantibodies to the same epitopes as
Lichen Planus and Related Conditions
bullous pemphigoid patients.
The histologic eatures o LP are distincti e and ary with
the stage o the lesion. n early lesions there is an inter ace
dermatitis along the dermoepidermal unction. As the lesion
e ol es the epidermis ta es on a characteristic appearance.
There is destruction o the basal layer with a sawtooth
pattern o epidermal hyperplasia ortho eratosis and beaded
hypergranulosis. The basal cells are lost so the basal layer is
described as s uamati ed. n the super cial dermis there is
a dense bandli e in ltrate composed o lymphocytes and
melanophages. Ci atte bodies (cytoid bodies colloid bodies)
represent necrotic eratinocytes in the super cial dermis.
ypertrophic LP shows mar ed epidermal hyperplasia (pseu
doepitheliomatous hyperplasia). ld lesions o LP show
e acement o the rete ridge pattern melanophages in the
upper dermis and occasional Ci atte bodies. LP rarely dem
onstrates para eratosis or eosinophils e cept in hypertrophic
LP. The presence o either o these suggests a di erent cause
o lichenoid tissue reaction such as lichenoid drug eruption.
Lichen planopilaris rontal brosing alopecia and Graham
Little Piccardi Lasseur syndrome show the ndings o LP
centered on the super cial ollicular epithelium.
Lesions o LP o the s in or mucosae can demonstrate clumps
o g on D and less re uently gA gG and C subepi
dermally corresponding to the colloid bodies. Dense shaggy
staining or brinogen along the B is characteristic o LP. A
lichenoid drug eruption may be di cult to di erentiate rom
LP. The presence o eosinophils or para eratosis supports the
diagnosis o lichenoid drug eruption. GV D tends to ha e a
sparser in ltrate. ypertrophic L may be histologically iden
tical to LP and the diagnosis is best made by clinical correlation
and D . n most other orms o L there is a greater tendency
or epidermal atrophy with para eratosis dermal mucin is
ound and ollicular plugging is more prominent. The in l
trate in lupus tends to surround and in ol e deep portions o
the appendageal structures such as the ollicular isthmus and
eccrine coil. Deep nodular peri ascular lymphoplasmacytic
in ltrates and necrosis o the at lobule with brin or hyalin
rings are also ndings characteristic o L .
Differential diagnosis
Classic LP displays lesions that are so characteristic that clini
cal e amination is o ten ade uate to lead to suspicion o the
diagnosis. Lichenoid drug eruptions may be di cult to distin
guish. A lichenoid drug reaction should be suspected i the
eruption is photodistributed scaly but not hypertrophic and
con uent or widespread clinical eatures that are unusual or
idiopathic LP. The presence o oral mucosa in ol ement may
prompt suspicion o LP but oral lesions may occasionally
occur in lichenoid drug eruptions as well. Pityriasis rosea
guttate psoriasis the small papular or lichenoid syphilid and
pityriasis lichenoides et arioli ormis acuta are dermatoses
that may resemble generali ed LP. ucous membrane lesions
may be con used with leu opla ia L mucous patches o
syphilis candidiasis cancer and oral lesions o autoimmune
bullous diseases such as pemphigus or cicatricial pemphi
goid. n the scalp the atrophic lesions may be mista en or
other cicatricial alopecias such as L olliculitis decal ans
and pseudopelade o Broc . ypertrophic LP type may simu
late psoriasis and SCC in situ. solated patches o LP may
resemble lichen simple chronicus.
214
Treatment
There is irtually no high uality e idence or treatment o
lichen planus o the s in scalp or mucosae. Limited lesions
may be treated with superpotent topical corticosteroids or
intralesional steroid in ections. n patients with widespread
disease these treatments are usually unsatis actory. Wide
spread lesions respond well to systemic corticosteroids but
tend to relapse as the dose is reduced. onthly pulse dosing
has been championed by dermatologists in ndia. Photother
apy may be e ecti e or cutaneous LP including narrow band
( B) ultra iolet B ( VB) VA and P VA. B VB was
superior to systemic corticosteroids in one study. Topical
cream P VA has been used e ecti ely in genital LP. The oral
retinoids isotretinoin alitretinoin and acitretin in doses
similar to or slightly lower than those used or other s in
conditions may also be use ul and a oid the long term com
plications o systemic steroids. They are especially bene cial
in patients with hypertrophic LP and palmoplantar LP. Reti
noid therapy may be combined with phototherapy in re rac
tory cases. Photodynamic therapy with topical aminole ulinic
acid can be e ecti e in penile LP. Low molecular weight
heparin (eno aparin) mg in ected subcutaneously once a
wee led to remission o cutaneous and reticulate oral LP in
o patients and impro ement in . no aparin is less
e ecti e than systemic steroids; erosi e oral LP responded
ariably and lichen planopilaris not at all. or erosi e s in
lesions topical tacrolimus or pimecrolimus can be e ecti e.
ydro ychloro uine in standard doses can be e ecti e or
cutaneous oral genital and ollicular LP. Adding uinacrine
mg daily may be considered in patients with only a partial
response to hydro ychloro uine. Thalidomide mg
daily can impro e re ractory oral and cutaneous LP. Apremi
last a phosphodiesterase type V inhibitor at a dose o mg
twice daily showed modest e cacy in pooled data but pru
ritus was dramatically decreased and o treated patients
cleared completely. edication related headache occurred in
o patients.
n the most se ere cases immunosuppressi e agents may be
indicated. Cyclosporine methotre ate and mycophenolate
mo etil are all options and can induce remission in se ere
cases o cutaneous and oral LP. The tumor necrosis actor
(T ) inhibitors adalimumab and etanercept as well as ale
acept ha e been e ecti e in anecdotal cases. Similarly e tra
corporeal photophoresis ana inra ritu imab and V G ha e
been success ul in e tremely re ractory cases.
or oral lesions superpotent steroids in rabase or gel orm
are use ul. Vinyl dental trays may be used to apply steroid
ointments to the gingi a. Begin with min applications three
times a day and reduce to maintenance o min e ery
e ening. Addition o nystatin to clobetasol in rabase may be
especially e ecti e. erall more than o patients with
ul ar LP ha e relie o symptoms with topical clobetasol.
ntralesional in ections may be used or ocal unresponsi e
lesions. Topical tacrolimus . ointment has become stan
dard treatment in erosi e LP o the oral and genital mucosa.
Burning may occur initially but can be reduced by concomi
tant use o topical steroids or initial use o a lower strength o
tacrolimus ointment. igher concentrations up to . also
may be used. ost patients ha e a partial but signi cant
response with increased ability to eat with much less pain.
Blood le els can be detected independent o area o in ol e
ment but tend to decrease o er time as the oral erosions heal.
Pimecrolimus can be used success ully in patients intolerant
o topical tacrolimus. Sustained remissions are rare and
chronic use is usually re uired to maintain remission. Topical
cyclosporine is ine ecti e. P VA photodynamic therapy and
nm e cimer laser ha e been e ecti e in oral LP. The
systemic agents recommended earlier to treat cutaneous LP
may also impro e mucosal disease. or VVG syndrome cor
ticosteroids topically and systemically are bene cial. Topical
therapy with corticosteroids may be enhanced by mi ing the
steroid in aginal bioadhesi e moisturi er (Replens). onto
phoresis may impro e deli ery.
Ahlgren C, et al: Contact allergy to gold in patients with oral lichen
lesions. Acta Derm Venereol 2012; 92:138.
Al-Khenaizan S: Lichen planus occurring after hepatitis B vaccination: a
new case. J Am Acad Dermatol 2001; 45:614.
Al-Khenaizan S, et al: Ulcerative lichen planus of the sole: excellent
response to topical tacrolimus. Int J Dermatol 2008; 47:626.
Alomari A, McNiff JM: The significance of eosinophils in hypertrophic
lichen planus. J Cutan Pathol 2014; 41:347.
Arias-Santiago S, et al: Cardiovascular risk factors in patients with lichen
planus. Am J Med 2010; 124:543.
Atefi N, et al: Prevalence of diabetes mellitus and impaired fasting
blood glucose in patients with lichen planus. Med J Islam Repub Iran
2012; 26:22.
Balasubramaniam P, et al: Lichen planus in children: review of 26 cases.
Clin Exp Dermatol 2008; 33:457.
Belfiore P, et al: Prevalence of vulval lichen planus in a cohort of women
with oral lichen planus: an interdisciplinary study. Br J Dermatol 2006;
155:994.
Bermejo-Fenoll A, et al: Familiar oral lichen planus: presentation of six
families. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;
102:e12.
Brauns B, et al: Intralesional steroid injection alleviates nail lichen
planus. Int J Dermatol 2011; 50:626.
Brehmer F, et al: Response of recalcitrant lichen planus to alitretinoin in
3 patients. J Am Acad Dermatol 2011; 65:e58.
Camisa C, Popovsky JL: Effective treatment of oral erosive lichen planus
with thalidomide. Arch Dermatol 2000; 136:1442.
Chandan V, et al: Esophageal lichen planus. Arch Pathol Lab Med 2008;
132:1026.
Chave TA, Graham-Brown RAC: Keratoacanthoma developing in
hypertrophic lichen planus. Br J Dermatol 2003; 148:592.
Chryssostalis A, et al: Esophageal lichen planus: a series of eight cases
including a patient with esophageal verrucous carcinoma—a case
series. Endoscopy 2008; 40:764.
Cohen PR, Kurzrock R: Anakinra-responsive lichen planus in a women
with Erdheim-Chester disease: a therapeutic enigma. Dermatol Online
J 2014; 20:21241.
Cooper S, et al: The association of lichen sclerosus and erosive lichen
planus of the vulva with autoimmune disease. Arch Dermatol 2008;
144:1432.
Copper S, Wojnarowska F: Influence of treatment of erosive lichen planus
of the vulva on its prognosis. Arch Dermatol 2006; 142:289.
Di Fede O, et al: Unexpectedly high frequency of genital involvement in
women with clinical and histological features of oral lichen planus.
Acta Derm Venereol 2006; 86:433.
Domingues E, et al: Imiquimod reactivation of lichen planus. Cutis 2012;
89:276.
Dreijer J, et al: Lichen planus and dyslipidaemia: a case-control study.
Br J Dermatol 2009; 11:626.
Elewa R, et al: Recalcitrant severe erosive cutaneous lichen planus
treated with extracorporeal photopheresis monotherapy. Br J Dermatol
2011; 165:441.
Fiveson D, et al: Treatment of generalized lichen planus with alefacept.
Arch Dermatol 2006; 142:151.
Ganguly S, Jaykar KC: Twenty-nail dystrophy in association with
zosteriform lichen planus. Indian J Dermatol 2012; 57:329.
Goettmann S, et al: Nail lichen planus: epidemiological, clinical,
pathological, therapeutic and prognosis study of 67 cases. J Eur Acad
Dermatol Venereol 2012; 26:1304.
Goñi Esarte S, et al: Rituximab as rescue therapy in refractory
esophaegeal lichen planus. Gastroentereol Hepatol 2013; 36:264.
Gonzalez-Moles MA, et al: Treatment of severe erosive gingival
lesions by topical application of clobetasol propionate in custom
trays. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;
95:688.
Guyot AD, et al: Treatment of refractory erosive oral lichen planus with
extracorporeal photochemotherapy: 12 cases. Br J Dermatol 2007;
156:553.
tahir99 - UnitedVRG
Halawani M, et al: Hepatitis C virus genotypes among patients with
lichen planus in the Kingdom of Saudi Arabia. Int J Dermatol 2014;
53:171.
Hamada T, et al: Lichen planus pemphigoides and multiple
keratoacanthomas associated with colon adenocarcinoma. Br J
Lichen planus
Dermatol 2004; 151:232.
Harden D, et al: Lichen planus associated with hepatitis C virus: no viral
transcripts are found in the lichen planus, and effective therapy for
hepatitis C virus does not clear lichen planus. J Am Acad Dermatol
2003; 49:847.
Holló P, et al: Successful treatment of lichen planus with adalimumab.
Acta Derm Venereol 2012; 92:339.
Hoskyn J, Guin J: Contact allergy to cinnamyl in a patient with oral
lichen planus. Contact Dermatitis 2005; 52:161.
Hoshi A, et al: Penile carcinoma originating from lichen planus on glans
penis. J Urol 2008; 71:816.
Iorizzo M: Nail lichen planus—a possible new indication for oral
alitretinoin. J Eur Acad Dermatol Venereol 2014. [EPub ahead of
print.]
Iraji F, et al: Comparison the narrow band UVB versus systemic
corticosteroids in the treatment of lichen planus: a randomized clinical
trial. J Res Med Sci 2011; 16:1578.
Iraji F, et al: Comparison of the therapeutic effect of low-dose low-
molecular-weight heparin (enoxaparin) vs. oral prednisone in treatment
of patients with lichen planus: clinical trial. Adv Biomed Res 2013;
2:76.
Irla N, et al: Nail lichen planus: successful treatment with etanercept.
Case Rep Dermatol 2010; 2:173.
Ito Y, et al: Disseminated lichen planus due to a zinc allergy. J Dermatol
2012; 39:948.
Jang N, Fischer G: Treatment of erosive vulvovaginal lichen planus with
methotrexate. Australas J Dermatol 2008; 49:219.
Kanwar AJ, De D: Methotrexate for treatment of lichen planus: old
drug, new indication. J Eur Acad Dermatol Venereol 2013;
27:e410.
Keenan AV, Ferraiolo D: Insufficient evidence for effectiveness of any
treatment for oral lichen planus. Evid Based Dent 2011: 12:85.
Kirby B, et al: Treatment of lichen planus of the penis with
photodynamic therapy. Br J Dermatol 1999; 141:765.
Kirtschig G, et al: Successful treatment of erosive vulvovaginal lichen
planus with topical tacrolimus. Br J Dermatol 2002; 147:625.
Köksal AS, et al: Treatment of esophageal stricture due to lichen planus
with intralesional corticosteroid injection. Surg Laparosc Endosc
Percutan Tech 2014; 24:e32.
Kolios AG, et al: Oral, esophageal and cutaneous lichen ruber planus
controlled with alitretinoin: case report and review of the literature.
Dermatology 2013; 226:302.
Kollner K, et al: Treatment of oral lichen planus with the 308-nm UVB
excimer laser—early preliminary results in eight patients. Lasers Surg
Med 2003; 33:158.
Kortekangas-Savolainen O, Kiilholma P: Treatment of vulvovaginal erosive
and stenosing lichen planus by surgical dilatation and methotrexate.
Acta Obstet Gynecol Scand 2007; 86:339.
Kossard S, et al: Hypertrophic lichen planus–like reactions
combined with infundibulocystic hyperplasia. Arch Dermatol 2004;
140:1262.
Krasowska D, et al: Development of squamous cell carcinoma with
lesions of cutaneous lichen planus. Eur J Dermatol 2007; 17:447.
Kyriakis KP, et al: Sex and age distribution of patients with lichen
planus. Eur Acad Dermatol Venereol 2006; 18:625.
Lade NR, et al: Blaschkoid lichen planus: not a Koebner phenomenon.
Dermatol Online J 2013; 19:17.
Laeijendecker R, et al: Oral lichen planus and allergy to dental amalgam
restorations. Arch Dermatol 2004; 140:1434.
Laeijendecker R, et al: Oral lichen planus and hepatitis C virus infection.
Arch Dermatol 2005; 141:906.
Le Cleach L, Chosidow O: Lichen planus. N Engl J Med 2012;
366:723.
Level NJ: No evidence for therapeutic effect of topical cyclosporin in
oral lichen planus. Br J Dermatol 2006; 155:477.
Lewis FM, Bogliatto F: Erosive vulval lichen planus: a diagnosis not to
be missed—a clinical review. Eur J Obstet Gynecol Reprod Biol 2013;
171:214.
Limas C, Limas CJ: Lichen planus in children: a possible complication
of hepatitis B vaccines. Pediatr Dermatol 2002; 19:204.
215
 Lonsdale-Eccles AA, Velangi S: Topical pimecrolimus in the treatment of
12 genital lichen planus: a prospective case series. Br J Dermatol 2005;
153:390.
Lora V, et al: Zosteriform lichen planus after herpes zoster: report of a
new case of Wolf’s isotopic phenomenon and literature review.
Lichen Planus and Related Conditions
Dermatol Online J 2014;20.
Lospinoso DJ, et al: Lupus erythematosus/lichen planus overlap
syndrome: successful treatment with acitretin. Lupus 2013; 22:851.
Lozada-Nur F, Sroussi H: Tacrolimus powder in Orabase 0.1% for the
treatment of oral lichen planus and oral lichenoid lesions: an open
clinical trial. Oral Surg Oral Med Oral Pathol Oral Endod 2006;
102:744.
Luis-Montaya P, et al: Lichen planus in 24 children with review of the
literature. Pediatr Dermatol 2005; 22:295.
Lundqvist EN, et al: Psychological health in patients with genital and
oral erosive lichen planus. Eur Acad Dermatol Venereol 2006;
20:661.
Maender J, et al: Complete resolution of generalized lichen planus after
treatment with thalidomide. J Drugs Dermatol 2005; 4:86.
Maluf R, et al: Bilateral lower eyelid margin erosion associated with
lichen planus. Ophthal Plast Reconstr Surg 2006; 22:310.
Mansura A, et al: Ultraviolet A-1 as a treatment for ulcerative lichen
planus of the feet. Photodermatol Photoimmunol Photomed 2006;
22:164.
Montebugnoli L, et al: Clinical and histologic healing of lichenoid oral
lesions following amalgam removal: a prospective study. Oral Surg
Oral Med Oral Pathol Oral Radiol 2012; 113:766.
Morales-Callaghan A Jr, et al: Annular atrophic lichen planus. J Am Acad
Dermatol 2005; 52:906.
Muñoz ER, et al: Isolated conjunctival lichen planus: a diagnostic
challenge. Arch Dermatol 2011; 147:465.
Nagao Y, et al: Exacerbation of oral erosive lichen planus by
combination of interferon and ribavirin therapy for chronic hepatitis C.
Int J Mol Med 2005; 15:237.
Nakashima C, et al: Treatment of intractable oral lichen planus with
intravenous immunoglobulin therapy. Eur J Dermatol 2012; 22:693.
Nishizawa A, et al: Close association between metal allergy and nail
lichen planus: detection of causative metals in nail lesions. J Eur Acad
Dermatol 2013; 27:e231.
Noda S, et al: Lichen planus in a patient with long-term exposure to
chrome. Eur J Dermatol 2011; 21:417.
Okiyama N, et al: Squamous cell carcinoma arising from lichen planus
of nail matrix and nail bed. J Am Acad Dermatol 2005; 53:908.
Pandhi D et al: Lichen planus in childhood: a series of 316 patients.
Pediatr Dermatol 2014, 31:59.
Parodi A, et al: Prevalence of stratified epithelium-specific antinuclear
antibodies in 138 patients with lichen planus. J Am Acad Dermatol
2007; 56:974.
Passeron T, et al: Treatment of erosive oral lichen planus by the 308 nm
excimer laser. Lasers Surg Med 2004; 34:205.
Passeron T, et al: Treatment of oral erosive lichen planus with 1%
pimecrolimus cream. Arch Dermatol 2007; 143:472.
Paul J, et al: An open-label pilot study of apremilast for the treatment of
moderate to severe lichen planus: a case series. J Am Acad Dermatol
2013; 68:255.
Petropoulou H, et al: Effective treatment of erosive lichen planus
with thalidomide and topical tacrolimus. Int J Dermatol 2006;
45:1244.
Polderman MC, et al: Ultraviolet A1 in the treatment of generalized lichen
planus: a report of 4 cases. J Am Acad Dermatol 2004; 50:646.
Quispel R, et al: High prevalence of esophageal involvement in lichen
planus: a study using magnification chromoendoscopy. Endoscopy
2009; 41:187.
Radfar L, et al: A comparative treatment study of topical tacrolimus and
clobetasol in oral lichen planus. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 2008; 105:187.
Reich HL, et al: Annular lichen planus: a case series of 20 patients. J
Am Acad Dermatol 2004; 50:595.
Reichrath J, et al: Treatment of genito-anal lesions in inflammatory skin
diseases with PUVA cream photochemotherapy: an open pilot study in
12 patients. Dermatology 2002; 205:245.
Richert B, et al: Nail bed lichen planus associated with
onychopapilloma. Br J Dermatol 2007; 156:1071.
Rogers RS, Bruce AJ: Lichenoid contact stomatitis. Arch Dermatol 2004;
140:1524.
216
Sakuma-Oyama Y, et al: Lichen planus pemphigoides evolving into
pemphigoid nodularis. Clin Exp Dermatol 2003; 28:613.
Salem CB, et al: Captopril-induced lichen planus pemphigoides.
Pharmacoepidemiol Drug Safety 2008; 17:722.
Salgado DS, et al: Plaque control improves the painful symptoms of oral
lichen planus gingival lesions: a short-term study. J Oral Pathol Med
2013; 42:728.
Sanchez-Perez J, et al: Lichen planus with lesions on the palms and/or
soles: prevalence and clinicopathological study of 36 patients. Br J
Dermatol 2000; 142:310.
Saricaoglu H, et al: Narrowband UVB therapy in the treatment of
lichen planus. Photodermatol Photoimmunol Photomed 2003;
19:265.
Sartori-Valinotti JC, et al: A 10-year review of otic lichen planus: the
Mayo Clinic experience. JAMA Dermatol 2013; 149:1082.
Schwartz M, et al: Two siblings with lichen planus and squamous cell
carcinoma of the esophagus. Eur J Gastroenterol Hepatol 2006;
10:1111.
Setterfield JF, et al: The vulvovaginal gingival syndrome: a severe
subgroup of lichen planus with characteristic clinical features and a
novel association with the class II HLA DQb1* 0201 allele. J Am Acad
Dermatol 2006; 55:98.
Seyhan M, et al: High prevalence of glucose metabolism disturbance in
patients with lichen planus. Diabetes Research Clin Pract 2007;
77:198.
Shah KM, et al: Oral lichenoid reaction due to nickel alloy contact
hypersensitivity. BMJ Case Rep 2013; 2013.
Simpson RC, et al: Real-life experience of managing vulval erosive
lichen planus: a case-based review and UK multicenter case note
audit. Br J Dermatol 2012; 167:85.
Sing SK, et al: Squamous cell carcinoma arising from hypertrophic
lichen planus. Eur Acad Dermatol Venereol 2006; 20:745.
Singal A: Familial mucosal lichen planus in three successive
generations. Int J Dermatol 2005; 44:81.
Singh S, et al: Lichen planus causing severe vulval stenosis: rare
presentation of a common dermatosis. Int J Dermatol 2013; 52:1398.
Stone SJ, et al: Cost-effectiveness of personalized plaque control for
managing the gingival manifestations of oral lichen planus: a
randomized control study. J Clin Periodontol 2013; 40:859.
Thorne JE, et al: Lichen planus and cicatrizing conjunctivitis:
characterization of five cases. Am J Ophthalmol 2003; 136:239.
Thornhill M, et al: The role of histopathological characteristic in
distinguishing amalgam-associated oral lichenoid reactions and oral
lichen planus. J Oral Pathol Med 2006; 35:233.
Tong DC, Ferguson MM: Concurrent oral lichen planus and primary
sclerosing cholangitis. Br J Dermatol 2002; 147:356.
Torti D, et al: Oral lichen planus. Arch Dermatol 2007; 143:511.
Tosti A, et al: Nail changes in lichen planus may resemble those of
yellow nail syndrome. Br J Dermatol 2000; 142:848.
Tosti A, et al: Nail lichen planus in children: clinical features, response
to treatment, and long-term follow-up. Arch Dermatol 2001; 137:1027.
Turan H, et al: Methotrexate for the treatment of generalized lichen
planus. J Am Acad Dermatol 2009; 60:164.
Verma S: Lichen planus affecting eyelid alone: a rare entity. Indian J
Dermatol Venereol Leprol 2006; 72:398.
Walsh DS, et al: A vaginal prosthetic device as an aid in treating
ulcerative lichen planus of the mucous membrane. Arch Dermatol
1995; 131:265.
Webber NK, et al: Lacrimal canalicular duct scarring in patients with
lichen planus. Arch Dermatol 2012; 148:224.
Wee JS, et al: Efficacy of mycophenolate mofetil in severe
mucocutaneous lichen planus: a retrospective review of 10 patients. Br
J Dermatol 2012; 167:36.
Welsh JP, et al: A novel visual clue for the diagnosis of hypertrophic
lichen planus. Arch Dermatol 2006; 142:954.
Wong CS, et al: Isolated vulval splitting—is this normal or pathological?
J Obstet Gynaecol 2004; 24:899.
Xia J, et al: Short-term clinical evaluation of intralesional triamcinolone
acetonide injection for ulcerative oral lichen planus. J Oral Pathol Med
2006; 35:327.
Yokozeki H, et al: Twenty-nail dystrophy (trachyonychia) caused by
lichen planus in a patient with gold allergy. Br J Dermatol 2005;
152:1089.
Zaraa I, et al: Lichen planus pemphigoides: four new cases and a
review of the literature. Int J Dermatol 2013; 52:406.

Fig. 12-11 Cicatricial alopecia caused by lichen planus.
Adnexal lichen planus: follicular lichen
planus (lichen planopilaris) and acrosyringeal
lichen planus
Lichen planopilaris (LPP) is lichen planus in ol ing the ol
licular apparatus. ost cases in ol e the scalp and LPP is an
important cause o cicatricial alopecia ( ig. ; see Chapter
). rom o a ected patients are women usually
about age . The oral mucosa is in ol ed with reticulate
LP in o patients and o patients ha e cutane
ous in ol ement. Graham Little Piccardi Lasseur syndrome
describes patients with LPP o the scalp with coe istent era
tosis pilaris li e LPP lesions on the s in. n addition to this
classic ariant o lichen planopilaris a newly recogni ed
ariant o cutaneous LPP presents with numerous small
( mm) s in colored papules on the upper hal o the ace
o ten lateral to the eye. These are seen in association with
alopecia o the eyebrows and rontal brosing alopecia (LPP
ariant o scalp). The rarest ariant o LPP is lichen planus
ollicularis tumidus ormerly called agminate lichen ollicu
laris with cysts and comedones. This presents in the retroau
ricular area and on the chee s o middle age women where
the lesions appear as tumid red iolet pla ues co ered with
numerous small white yellow cysts and comedones. The
lesions resemble the pla ues seen in a re Racouchot syn
drome and some cases o phymatous and cystic rosacea. The
ears chin and scalp can be similarly in ol ed. ther ariants
o LP o the s in and nails can occur in the same patient and
these may appear at about the same time. istologically a
dense lichenoid in ltrate surrounds the ollicles and cysts o
the a ected s in. The cysts are considered secondary to the
lichenoid in ammation. Similar lesions ha e been seen in ol
licular mycosis ungoides probably orming by a similar
mechanism. a re Racouchot syndrome ollicular mucinosis
and L must be distinguished histologically rom LPP.
Lichen planus can in ol e the soles and at times the palms.
Lesions are typically scaly pla ues that loo ery psoriasi orm
and are usually only diagnosed by the coe istence o typical
LP elsewhere or by biopsy. Less o ten the lesions o LP o the
palms and soles may present as petechial li e lesions or
di use eratoderma. When palmoplantar LP a ects primarily
the acrosyringium the lesions appear as umbilicated papules
or punctate eratoses. A biopsy is usually re uired to con rm
the diagnosis unless typical LP is present elsewhere. Palmo
plantar LP can respond well to oral retinoids.
Andrews ID, et al: A papular eruption on the face: a distinct subtype of
lichen planopilaris. J Dermatol Case Rep 2013; 1:23.
tahir99 - UnitedVRG
Lichen planus
Fig. 12-12 Lichen planus pigmentosa. (Courtesy of Dr. Debabrata
Bandyopadhyay.)
Donati A, et al: Facial papules in frontal fibrosing alopecia. Arch
Dermatol 2011; 147:1424.
Guttee RM: Acrosyringeal lichen planus of palm. Indian J Dermatol
Venereol Leprol 2012; 78:521.
Guttee RM: Unilateral acrosyringeal lichen planus of palm. Indian
Dermatol Online J 2013; 4:350.
Jiménez-Gallo D, et al: Facial follicular cysts: a case of lichen planus
follicularis tumidus. J Cutan Pathol 2013; 40:818.
Kim MJ, et al: Two cases of palmoplantar lichen planus with various
clinical features. J Dermatol 2010; 37:985.
Zeng YP, et al: Lichen planus with palmoplantar involvement: rapid
therapeutic response to acitretin: Eur J Dermatol 2011; 21:632.
Lichen planus pigmentosus/actinicus
Lichen planus pigmentosus is seen primarily in Central
America the ndian subcontinent the iddle ast and Japan.
t appears to be a orm o LP restricted to certain racial groups.
The persons rom these genetic groups can de elop the condi
tion when they mo e to orth America and urope but Cau
casians rom urope and orth America do not de elop
lichen planus pigmentosus when they mo e to tropical areas
where the disease is common. Lichen planus pigmentosus
patients are young usually and men and women are
e ually a ected. en present a decade earlier (mean age
s. ). The ace and nec are primarily in ol ed ( ig. )
but the a illa in ramammary region and groin may also be
a ected. Lesions may be unilateral. The condition is usually
mild (< body sur ace area) and although patients may
ha e associated pruritus it is usually much milder than in
patients with classic LP. Sometimes classic LP papules occur
at other sites or at the periphery o the lesions. n the nited
States persons o color may demonstrate this pattern o LP.
ndi idual lesions are typically se eral millimeters to se eral
centimeters in si e are o al in shape and may ollow lines o
Blasch o.
Some patients with lichen planus pigmentosus may ha e
lesions predominantly in sun e posed areas and the diagnosis
o lichen planus actinicus can be used in these cases. Lichen
planus actinicus is reported most re uently in A rica the
iddle ast and the ndian subcontinent and represents a
substantial proportion o LP diagnosed in these geographic
areas ( o all LP patients in an gyptian series). ost cases
217
 reported as lichen planus actinicus occur in childhood through
12 young adulthood with the primary decade o presenta
tion. The disease presents in the spring or summer and is
re uently uiescent in winter. Lesions a or the sun e posed
parts o the body especially the ace which is almost always
Lichen Planus and Related Conditions
the most se erely a ected site. ost lesions occur on the ore
head chee s eyelids and lips. utside the ace the V area o
the chest the nec the bac s o the hands and the lower e ten
sor orearms are in ol ed. Associated pruritus the hallmar
o LP is usually described as mild or absent. Lesions are
usually annular but may be reticulate or di use. ndi idual
lesions are o ten macular but may be pla ues with peripheral
iolaceous papules. Characteristically lesions are hyperpig
mented sometimes with the blue gray tinge o dermal
melanin. They may resemble melasma.
Because cases o lichen planus pigmentosus and lichen
planus actinicus o erlap it is best to thin o these conditions
as a single disorder that may or may not be photoe acerbated.
t is important to recogni e the lichen planus actinicus ariant
o lichen planus pigmentosus because the actinicus patients do
respond to sun protection with gradual ading o their hyper
pigmentation. ucous membrane disease is signi cantly less
common in patients with lichen planus pigmentosus actinicus.
istologically any papular element will usually show eatures
o LP. en macular areas may show subtle e idence o an
inter ace dermatitis with prominent dermal melanophages.
Lichen planus pigmentosus in ersus is described in the lit
erature as a uni ue separate and rare disorder. Lesions can
be seen in patients with classic lichen planus pigmentosus;
howe er this in erse pattern has a di erent racial distribution
and has been reported in Caucasian patients as well as Asians
and ispanics. The a illae are the primary region o in ol e
ment in most patients ( ) although the groin in ramam
mary nec retroauricular and e ural areas can also be
in ol ed. As with other types o lichen planus pigmentosus
pruritus is uncommon in the in ersus type and oral nail and
hair in ol ement usually does not occur.
The treatment o lichen planus pigmentosus o all types is
similar to other orms o LP. Topical corticosteroids and C s
antimalarials and e en immunomodulators can be used. The
lesions may ade slowly because they are primarily caused by
melanin incontinence and e en i the acti e agent has stopped
the inter ace reaction the pigment will persist.
Erythema dyschromicum perstans
rythema dyschromicum perstans is also nown as ashy der
matosis or dermatosis cenicienta. The age o onset is irtually
always be ore but it is a chronic disease so patients o all
ages ha e been described. Prepubertal children ha e been
reported. Lesions are typically se eral centimeters in si e and
a ect primarily the trun . A characteristic ery ne (se eral
millimeters) erythematous palpable nonscaling border is
seen at the periphery o the lesions. This is described as eeling
li e a small cord. n ortunately this leading edge (and diag
nostic eature) o the disorder is only present early in the
disease course (a ew months). Pruritus is not reported and
typical lichenoid papules are said not to occur. ail and
mucosal in ol ement is not ound. An association with
LA DR has been suggested or e ican patients. n ortu
nately erythema dyschromicum perstans became a catchall
term or the panoply o dermatologic disorders that heal with
prominent postin ammatory change in pigmented persons. t
is now belie ed that most cases pre iously called erythema
dyschromicum perstans are actually cases o lichen planus
pigmentosus. Childhood cases may represent idiopathic erup
ti e macular pigmentation. True erythema dyschromicum
218
perstans i it e ists is uite rare and largely restricted to
certain geographic regions.
At the acti e border the characteristic histologic eatures o
erythema dyschromicum perstans are those o a lichenoid der
matitis. n the centers o the lesions the histologic changes are
those o postin ammatory pigmentation. Therapeutic agents
used or LP may bene t the acute in ammatory stage but ha e
limited e ect on the pigmented lesions. Spontaneous impro e
ment has occurred leading some to suggest that no treatment
is reasonable.
Idiopathic eruptive macular pigmentation
Although rarely reported idiopathic erupti e macular pig
mentation ( P) is not rare. oung persons (mean age
years in one study) presented with asymptomatic widespread
brown to gray macules o up to se eral centimeters in diam
eter on the nec trun and pro imal e tremities. Lesions are
not con uent and there is no history o preceding in amma
tion. At times there is slight papillomatosis histologically
identical to that seen in con uent and reticulate papillomatosis
(CARP). nli e CARP howe er P does not respond to
oral minocycline. Lesions may spontaneously in olute. Some
cases reported as erythema dyschromicum perstans in child
hood may actually represent P.
Anbar T, et al: A clinical and epidemiological study of lichen planus
among Egyptians of Al-Minya province. Dermatol Online 2005;
11:4.
Barros HR, et al: Lichen planus pigmentosus inversus. An Bras
Dermatol 2013; 88:146.
Chiu MW, et al: Multiple brown patches on the trunk: idiopathic eruptive
macular pigmentation with papillomatosis (IEMP). Arch Dermatol 2010,
146:1301.
Correa M, et al: HLA-DR association with the genetic susceptibility to
develop ashy dermatosis in Mexican mestizo patients. J Am Acad
Dermatol 2007; 56:617.
Gaertner E, Elstein W: Lichen planus pigmentosus-inversus: case report
and review of an unusual entity. Dermatol Online J 2012; 18:11.
Jang KA, et al: Idiopathic eruptive macular pigmentation: report of 10
cases. J Am Acad Dermatol 2001; 44:351.
Jansen T, et al: Lichen planus actinicus treated with acitretin and topical
corticosteroids. J Eur Acad Dermatol Venereol 2002; 16:171.
Kanwar AJ, et al: A study of 124 Indian patients with lichen planus
pigmentosus. Clin Exp Dermatol 2003; 28:481.
Kim G, Mikkilineni R: Lichen planus actinicus. Dermatol Online J 2007;
13:13.
Najhawan RI, et al: Lichen planus pigmentosus-inversus involving the
post-auricular sulci. Dermatol Online J 2013; 19: 18571.
Ohshima N, et al: Lichen planus pigmentosus-inversus occurring
extensively in multiple intertriginous areas. J Dermatol 2012;
39:412.
Ramírez P, et al: Childhood actinic lichen planus: successful treatment
with antimalarials. Australas J Dermatol 2012; 53:e10.
Rieder E et al: Lichen planus pigmentosus. Dermatol Online J 2013,
19:20713.
Shgal VN, et al: Lichen planus pigmentosus. Skinmed 2013; 11:96.
Verma S, Thakur BK: Idiopathic eruptive macular pigmentation with
papillomatosis. Indian Dermatol Online J 2011; 2:101.
Yokozeki H, et al: Multiple linear erythema dyschromicum perstans
(ashy dermatosis) in the lines of Blaschko. Dermatology 2005;
210:356.
KERATOSIS LICHENOIDES CHRONICA
eratosis lichenoides chronica is a rare dermatosis character
i ed by its chronicity. n adults the disease begins in the
late twenties. Typical lesions are papulonodular and hyper
eratotic and co ered with gray scales. These lesions a or
the e tremities and buttoc s. Although initially discrete
 Fig. 12-13 Keratosis
lichenoides chronica.

Lichen nitidus
Fig. 12-14 Lichen nitidus, linear lesion from trauma.

the lesions re uently coalesce to orm linear and reticulate

arrays o warty lichenoid lesions ( ig. ). Lesions are
in undibulocentric and acrosyringocentric. eratotic plugs
and prominent telangiectasia may be present. The palms and
soles ha e discrete hyper eratotic papules. There is an associ
ated sharply marginated erythema scaling and telangiectasia
o the ace super cially resembling seborrheic dermatitis or
rosacea. ail changes described include thic ening o the nail
plate yellowing longitudinal ridging onycholysis hyper er
atosis o the nail bed paronychia and warty lesions o the
periungual areas. n addition pain ul oral ulcerations occur in
o cases and oral or genital in ol ement occurs in o
adult patients. ther ndings include hoarseness rom ocal
cord edema and in ol ement o the eyelids (one third o
patients) con uncti a iris or anterior chamber.
Topical calcipotriol P VA retinoids with P VA bath Fig. 12-15 Lichen nitidus, characteristic lesions of the penile shaft.
P VA photodynamic therapy and oral retinoids (isotretinoin
and acitretin) may all pro e bene cial. eratosis lichenoides
chronica rarely responds to topical or systemic steroids. Child
hood cases are rare and di er rom adult cases. n ants are LICHEN NITIDUS
a ected in the rst year o li e and ha e prominent acial
purpura and erythema especially on the chee s. ore than Clinical features
hal o childhood cases are amilial suggesting autosomal
recessi e inheritance. Lichen nitidus (L ) is a chronic in ammatory disease charac
istologically there is irregular acanthosis or epidermal teri ed by minute shiny at topped pale e uisitely dis
atrophy with hyper eratosis and ones o para eratosis. A crete uni orm papules rarely larger than mm. Children
lichenoid in ltrate consisting primarily o lymphocytes and and young adults are primarily a ected. Pruritus is usually
acuolar alteration at the basal cell layer but concentrated minimal or absent but may be more prominent in more gen
around the in undibula or acrosyringia. ar ed ollicular erali ed cases. Linear arrays o papules ( oebner phenome
plugging and plugging o the acrosyringia are characteristic. non) are common especially on the penis orearms and
dorsal hands ( ig. ). nitially lesions are locali ed and
Boer A: Keratosis lichenoides chronica: proposal of a concept. Am J
Dermatopathol 2006; 28:260.
o ten remain limited to a ew areas chie y the penis and lower
Grammatikopoulou E, et al: Keratosis lichenoides chronica: a case abdomen the inner sur ace o the thighs and the e or aspects
report. Cutis 2010; 86:245. o the wrists and dorsal hands orearms ( ig. ). n other
Kunte C, et al: Keratosis lichenoides chronica: treatment with bath- cases the disease assumes a more widespread distribution
PUVA. Acta Derm Venereol 2007; 87:182. and the papules use into erythematous nely scaly pla ues.
Oyama N, et al: Juvenile-onset lichenoides chronica treated successfully The reddish color aries with tints o yellow brown or iolet.
with topical tacrolimus: a safe and favourable outcome. Eur J Dermatol nusual ariants o L include esicular hemorrhagic linear
2011; 21:595. purpuric (resembling a pigmented purpuric dermatosis) and
Ruis-Maldonaldo R, et al: Keratosis lichenoides chronica in spinous ollicular (resembling lichen spinulosus).
pediatric patients: a different disease. J Am Acad Dermatol 2007;
Palm and sole in ol ement may occur in L and the disease
56:S1.
Singh BE, et al: Pediatric onset keratosis lichenoides chronica: a case may be restricted to these areas. t presents with multiple tiny
report. Pediatr Dermatol 2012; 29:511. hyper eratotic papules. The papules may coalesce to orm
Zhou P, et al: Keratosis lichenoides chronica in association with primary di use hyper eratotic pla ues that ssure. The di erentiation
cutaneous anaplastic large cell lymphoma. Int J Dermatol 2014; o L rom hyper eratotic hand ec ema and LP o the palms
53:e80. is aided by the presence o a eratotic plug in the center o
219

tahir99 - UnitedVRG
 lesions o palmoplantar L . ail in ol ement with pitting
12 beaded longitudinal ridging and nail old in ammation has
been reported. ral in ol ement with gray yellow papules or
petechiae o the hard palate is rare.
A ariant o L termed actinic lichen nitidus has been
Lichen Planus and Related Conditions
reported in dar s inned patients rom the iddle ast and
ndian subcontinent. Cases seen in A rican Americans ha e
also been termed pinpoint papular polymorphous light
eruption (P L ) or nown by the older term summer
actinic lichenoid eruption. These cases all ha e lesions clini
cally and histologically identical to L which are limited to
the sun e posed areas o the dorsal hands brachioradial area
and posterior nec . The L histology may represent subacute
or chronic lesions o pinpoint P L . Actinic L pinpoint
papular P L usually responds to sun protection with or
without topical corticosteroids. ydro ychloro uine has been
used success ully in one oroccan case.
The cause o L is un nown. Rare amilial cases do occur.
The course o L is slowly progressi e with a tendency or
remission. The lesions may remain stationary or years but
o ten e entually disappear spontaneously and entirely. Treat
ment is not re uired because it is usually asymptomatic and
sel healing. owe er topical corticosteroids or C s can be
used or locali ed disease. B VB and P VA can be e ecti e
in generali ed cases but care must be ta en to be sure that the
L in not o the actinic ariety. Anecdotal reports suggest
therapeutic bene t rom oral retinoids (acitretin). As in LP
re ractory L cases re uiring aggressi e therapy may respond
to cyclosporin A.
Lichen nitidus is clinically and histologically distinct rom
lichen planus and immunohistochemical studies also suggest
they are distinct disorders. owe er patients ha e had both
disorders suggesting some common pathogenic basis. Both LP
and L ha e been reported secondary to hepatitis B immuni
ation and during treatment o hepatitis with alpha. There
are also reports o patients with both L and Crohn s disease
another condition with granulomatous in ammation.
Lichen nitidus has a characteristic histologic appearance.
Dermal papillae are widened and contain a dense in ltrate
composed o lymphocytes histiocytes and melanophages.
There is an accumulation o both CD + histiocytes and
S + CD a+ Langerhans cells in the dermal collections.
ultinucleate giant cells are o ten present imparting a granu
lomatous appearance to the in ltrate. The epidermal rete
ridges on either side o the papilla orm a clawli e collarette.
The o erlying epidermis is attenuated and there is usually
acuolar alteration o its basal layer. At times the in ltrate
may e tend down ad acent hair ollicles and eccrine ducts
ma ing distinction o L rom lichen scro ulosorum and
lichen striatus di cult.
Bilgili SG, et al: A case of generalized lichen nitidus successfully treated
with narrow-band ultraviolet B treatment. Photodermatol Photoimmunol
Photomed 2013: 29:215.
Bouras M, et al: Facial actinic lichen nitidus successfully treated with
hydroxychloroquine: a case report. Dermatol Online J 2013; 19:20406.
Çakmak SK, et al: Lichen nitidus with involvement of the palms. Pediatr
Dermatol 2013; 30:e100.
Dar NR, Rao SU: Facial lichen nitidus actinicus. Australas J Dermatol
2012; 53:e16.
Fetil E, et al: Lichen nitidus after hepatitis B vaccine. Int Soc Dermatol
2004; 43:956.
Ikenberg K, et al: Thirty-year history of palmar eruptions: a quiz. Acta
Derm Venereol 2011; 91:108.
Lee MW, et al: Penile lichen nitidus successfully treated with topical
pimecrolimus 1% cream. J Dermatol 2013; 40:499.
Lernia V, et al: Lichen planus appearing subsequent to generalized
lichen nitidus in a child. Pediatr Dermatol 2007; 24:453.
Leung AK, Ng J: Generalized lichen nitidus in identical twins. Case Rep
Dermatol Med 2012; 2012:982084.
220
MacDonald AJ, et al: Lichen nitidus and lichen spinulosus or spinous
follicular lichen nitidus. Clin Exp Dermatol 2005; 30:435.
Nakamizo S, et al: Accumulation of S-100+ CD1a+ Langerhans cells as
a characteristic of lichen nitidus. Clin Exp Dermatol 2011; 36:811.
Park J, et al: Persistent generalized lichen nitidus successfully treated
with 0.03% tacrolimus ointment. Eur J Dermatol 2013; 23:918.
Park JH, et al: Treatment of generalized lichen nitidus with narrowband
ultraviolet B. J Am Acad Dermatol 2006; 54:545.
Park JS: Lichen nitidus and lichen spinulosus or spinous follicular
lichen nitidus? A second case. Clin Exp Dermatol 2011; 36:557.
Park SH, et al: A case of palmar lichen nitidus presenting as a clinical
feature of pompholyx. Ann Dermatol 2010, 22:235.
Schelar M, et al: Generalized lichen nitidus with involvement of the
palms following interferon alpha treatment. Dermatol 2007; 215:236.
Solano-López G, et al: Actinic lichen nitidus in a Caucasian European
patient. J Eur Acad Dermatol Venereol 2014. [Epub ahead of print.]
Srivastava M, et al: Lasseur-Graham-Little-Piccardi syndrome. Dermatol
Online J 2007; 13:12.
Summe HS, et al: Generalized spinous follicular lichen nitidus with
perifollicular granulomas. Pediatr Dermatol 2013; 30:e20.
Tay EY, et al: Lichen nitidus presenting with nail changes: case report
and review of the literature. Pediatr Dermatol 2014. [Epub ahead of
print.]
Summey B, et al: Actinic lichen nitidus. Cutis 2008; 81:266.
Wanat KA, et al: Extensive lichen nitidus as a clue to underlying Crohn’s
disease. J Am Acad Dermatol 2012; 67:5.
Yanez S, Val-Bernal F: Purpuric generalized lichen nitidus: an unusual
eruption simulating pigmented purpuric dermatosis. Dermatology
2004; 208:167.
Yoon TY, et al: Two cases of perforating lichen nitidus. J Dermatol 2006;
33:278.
LICHEN STRIATUS
Lichen striatus is a airly common sel limited eruption seen
primarily in young children (mean age years). Girls are
a ected two to three times more re uently than boys. Lesions
begin as small papules that are erythematous and slightly scaly
( ig. ). n more dar ly pigmented persons hypopigmen
tation is prominent and may be purely macular. The mm
papules coalesce to orm a band cm wide either continuous
or interrupted which o er a ew wee s progresses down the
e tremity or around the trun ollowing lines o Blasch o. An
e tremity is more o ten in ol ed but trun lesions or lesions
e tending rom the trun onto an e tremity can also occur.
About o cases occur on the head. ultiple bands in re
uently occur. Lesions are usually asymptomatic but pruritus
may occur especially in patients who are also atopic.
ail in ol ement can occur i the process e tends down
the digit to the nail. Typically the lichen striatus appears rst
on the s in but the s in and nail abnormality may appear
Fig. 12-16 Lichen striatus.
simultaneously. n re uently only the nail may be in ol ed
or months with later appearance o the band on the s in or
the nail may remain the sole area o in ol ement throughout
the course o the disease. nilateral lichen striatus may be
associated with bilateral nail in ol ement. ail plate thin
ning longitudinal ridging splitting and nail bed hyper era
tosis may be seen. ten only a part o the nail is in ol ed.
The histology o in ol ed nails is identical to that o the s in
lesions.
The acti e lesions o lichen striatus last or an a erage o
year but may persist or up to years. entually all the
lesions including dystrophic nails spontaneously resol e
without scarring. ypopigmentation may persist or se eral
years. yperpigmentation is uncommon (< ) and should
suggest a diagnosis o linear LP instead. Relapses can occur in
up to o cases either in the same distribution or in a di
erent anatomic region.
The histologic eatures o lichen striatus ary partly re ect
ing the stage o e olution o the lesion. There may be a
spongiotic dermatitis but most re uently a lichenoid com
ponent is present. There is a bandli e in ltrate with necrotic
eratinocytes at the dermoepidermal unction. Granuloma
tous in ammation is occasionally present. Typically there is
a dense lymphoid in ltrate around the eccrine sweat glands
and ducts. This helps to distinguish lichen striatus rom
lichen planus.
ultiple reports e ist o simultaneous cases in siblings. There
is also a seasonal ariation with most cases occurring in the
spring and summer. pidemic outbrea s ha e been reported
suggesting a iral etiology or trigger. Trauma has also been
reported to precipitate an outbrea o lichen striatus.
Adult cases o lichen striatus di er rom those in childhood
and are rarer and more papulo esicular a ecting multiple
regions resol ing more rapidly (< months) and relapsing
more re uently (up to one third o patients). istologically
the lesions show more spongiotic and less lichenoid eatures
leading some authors to call these cases adult blasch itis or
Grosshans arot disease. This splitting o terms probably
has no clinical utility.
sually the diagnosis o lichen striatus is straight orward
in a young child with sudden onset o an eruption ollowing
the lines o Blasch o. The di erential diagnosis could include
linear LP linear psoriasis in ammatory linear errucous epi
dermal ne us epidermal ne us linear cutaneous L and
erruca plana. istologic e aluation will usually distinguish
these entities but this is rarely re uired.
Treatment is usually not necessary. Parents may be reas
sured o the uni ormly e cellent prognosis. Topical corticoste
roids and topical C s may accelerate the resolution o lesions.
The combination o ta arotene and topical steroid treatment
has led to rapid resolution in one series. n children with an
ac uired nail dystrophy o one or two digits lichen striatus
must be considered and watch ul waiting might be consid
ered be ore biopsying the nail.
Al-Niami FA, Cox NJ: Unilateral lichen striatus with bilateral
onychodystrophy. Eur J Dermatol 2009; 19:511.
Feely MA, Silverberg NB: Two cases of lichen striatus with prolonged
active phase. Pediatr Dermatol 2014; 31:e67.
Jo JH, et al: Early treatment of multiple and spreading lichen striatus
with topical tacrolimus. J Am Acad Dermatol 2007; 57:904.
Karakas M, et al: Lichen striatus following HBV vaccination. J Dermatol
2005; 32:506.
Karempelis PS, et al: Lichen striatus in a mother and son. Int J Dermatol
2014; 53:e366.
Lee DY, et al: Lichen striatus in an adult treated by a short
course of low-dose systemic corticosteroid. J Dermatol 2010;
38:298.
Litvinov IV, Jafarian F: Images in clinical medicine: lichen striatus and
lines of Blaschko. N Engl J Med 2012; 367:2427.
tahir99 - UnitedVRG
Lora V, et al: Lichen striatus associated with etanercept treatment of
rheumatoid arthritis. J Am Acad Dermatol 2014; 70:e90.
Mu EW, et al: Facial lichen striatus in children: retracting the lines of
Blaschko. Pediatr Dermatol 2013, 30:364.
Müller CS, et al: Lichen striatus and blaschkitis: reappraisal of the
Lichen sclerosus (lichen sclerosus et atrophicus)
concept of blaschkolinear dermatoses. Br J Dermatol 2011; 164:257.
Palleschi GM, et al: Lichen striatus and nail involvement: truly rare or
question of time? Int J Dermatol 2012 51:749.
Park JY, Kim YC: Lichen striatus successfully treated with photodynamic
therapy. Clin Exp Dermatol 2012; 37:562.
Patrizi A, et al: Lichen striatus: clinical and laboratory features of 115
children. Pediatr Dermatol 2004; 21:197.
Sato H, et al: Case of lichen striatus presenting with multiple lesions
along Blaschko’ s lines. J Dermatol 2012; 39:802.
Taniguchi K, et al: Lichen striatus: description of 89 cases in children.
Pediatr Dermatol 2004; 21:440.
Yousseff SM, Teng JM: Effective topical combination therapy for
treatment of lichen striatus in children: a case series and review.
J Drugs Dermatol 2002; 11:872.
LICHEN SCLEROSUS (LICHEN SCLEROSUS
ET ATROPHICUS)
Lichen sclerosus is a chronic disease o the s in and mucosa.
The terms lichen sclerosus et atrophicus raurosis ul ae and
balanitis erotica obliterans are synonymous but ha e been
replaced by the single term lichen sclerosus (LS). LS can
present rom childhood to old age. Although it occurs in all
races whites and ispanics are more re uently a ected and
it is rare in A rican Americans. Both genders de elop LS both
be ore and a ter puberty with emales predominating at all
ages. The pre alence is about . in the general adult emale
population and about one tenth as re uent in premenarchal
girls.
The pathogenesis o LS is poorly understood. Autoimmune
diseases (thyroid disease itiligo morphea alopecia areata
pernicious anemia) occur in one th to one third o women
with LS but are much less common in men. Psoriasis is
increased in women with LS reported to occur in . o
patients. Autoantibodies to e tracellular matri protein
( C ) are ound in o LS patients compared with
o controls and o patients with other autoimmune
diseases. The titer o the C autoantibody correlates with
the disease se erity. The importance o this humoral autoim
munity in the pathogenesis o LS is currently unclear.
n emales there is a bimodal age distribution prepubertal
and postmenopausal. The initial lesions o LS are white polyg
onal at topped papules pla ues or atrophic patches ( ig.
). Lesions may be surrounded by an erythematous to
Fig. 12-17 Lichen sclerosus of the glabrous skin.
221
12
Lichen Planus and Related Conditions
Fig. 12-18 Lichen sclerosus, white atrophic lesions with loss of
normal tissue markings.
iolaceous halo. n atrophic lesions the s in is smooth slightly
wrin led so t and white. Bullae o ten hemorrhagic telangi
ectasias and ed areas o purpura may occur on the patches.
About o women with LS are asymptomatic. owe er
when women re erred to specialists are uestioned irtually
are symptomatic. tching is re uently se ere especially
in the anogenital area. n the genital area ssuring and erosion
may occur. This may result in dysuria urethral and aginal
discharge dyspareunia and burning pain. ormal anatomic
structures may be obliterated with loss o the labia minora
clitoral hood and urethral meatus. n women this perineal
in ol ement typically a ects the ul ar and perianal areas
gi ing a gure or hourglass appearance. ntroital stenosis or
usion may occur. The aginal and cer ical mucosae are not
in ol ed by LS in contrast to LP. Prepubertal girls may
also be a ected and usually ha e ul ar and perianal lesions
( ig. ).
Vul ar disease is associated with similar s in changes to
those in adult women and pruritus may be a prominent
symptom. Perianal in ol ement may produce signi cant
symptomatology o constipation stool holding and rector
rhagia caused by rectal ssures. n antile perineal protrusion
re ers to a pyramidal so t tissue swelling co ered by red or
rose colored s in along the median perineal raphe (s in
between posterior ourchette and anus). This occurs only in
girls and appears to be a mani estation o LS in some prepu
bertal girls. Two thirds o girls with LS ha e been e aluated
or se ual abuse largely because o the ecchymoses that
accompany the lesions. ris o se ual abuse is suspected
appropriate in estigations must be per ormed.
There is clearly a relationship between the hormonal milieu
and LS. Postmenopausal women are pre erentially a ected.
Pregnancy leads to impro ement and o ten complete resolu
tion. ral contracepti e ( C) use is common in premeno
pausal women with LS. These Cs are o ten antiandrogenic.
Stopping Cs and treating with standard topical agents lead
to signi cant impro ement suggesting that the antiandrogen
Cs may ha e accelerated the appearance o the LS. owe er
treatment o postmenopausal women with estrogen supple
mentation does not alter the incidence or course o their LS.
n males lesions are atrophic and may be greatly hypopig
mented or depigmented resembling itiligo. Lesions usually
in ol e only the glans penis and the inner ores in o the
uncircumcised male. n re uently LS may e tend on to the
penile sha t and scrotum. the glans is in ol ed hemorrhage
is common and shallow erosions may occur. LS o the glans
222
Fig. 12-19 Lichen sclerosus, phimosis; note the hemorrhagic
macule.
does not usually lead to nonhealing erosions o the glans but
rather simply s in ragility. Phimosis and paraphimosis are
common complications o LS in men ( ig. ). Between
and o circumcision specimens rom prepubertal boys
show eatures o LS. Si ty percent o ac uired phimosis in
boys and at least in adult men are associated with LS.
ost men with LS are uncircumcised and e posure to urine
appears to be an important trigger or LS in males. Circumci
sion is e ecti e treatment or penile LS with cure rates o
. rethral meatal stenosis may occur and re uires
surgical correction. Perianal in ol ement by LS is rare in men
and boys with penile LS.
tragenital lesions are most re uent on the upper bac
chest and breasts and are usually asymptomatic. The tongue
and oral mucosa may also be in ol ed either alone or with
lesions elsewhere. Peristomal in ol ement around colostomy
sites may occur. Patients ha ing only e tragenital lesions with
histologic eatures o both LS and morphea ha e been reported.
About one uarter o these patients ha e LS li e changes o er
lying the morphea lesions (a recogni ed histopathologic
ariant o morphea) and in three uarters the e tragenital LS
lesions are distinct rom the morphea lesions. Genital LS is
much more common in patients (usually women) with local
i ed pla ue or generali ed morphea. n one study up to
o patients with morphea also had genital LS. The genital
area o patients with morphea should be e amined or the
presence o LS. Rarely in urope orrelia has been reported
to cause e tragenital LS and treatment with antibiotics has
arrested the progression o the lesions.
Lichen sclerosus and cancer
Although the ris is not as high as was proposed early in this
century LS o the genitalia is a condition with increased ris
or genital s uamous cell carcinoma in both women and men.
The li etime ris or women who are care ully ollowed
appears to be or less but is clearly higher than or the
general population. About one third o ul ar SCCs in women
arise on a bac ground o LS. uman papilloma irus ( PV)
appears to be associated with only about o SCCs arising
in women with LS. ypertrophic ul ar lesions and age
beyond are ris actors or the de elopment o SCC in
women with LS. Such lesions and patients should be e aluated
care ully. n men with LS the ris or genital SCC is less than
in women with LS. owe er about o cases o penile SCC
are associated with LS. ncogenic PV types do not appear
to be associated with LS related penile cancer.
Histopathology
arly lesions o LS are characteri ed by an inter ace dermatitis
with acuolar alteration o eratinocytes. With e olution the
epidermis is thinned and the rete ridges are e aced. Compact
ortho eratosis and ollicular and eccrine plugging are present.
The upper dermis is edematous with the upper dermal col
lagen homogeni ed. mmediately beneath the altered papil
lary dermis there is a sparse bandli e and peri ascular
lymphoid in ltrate. n pruritic lesions coe istent changes o
lichen simple chronicus may be seen with acanthosis rather
than atrophy o the epidermis.
Differential diagnosis
tragenital LS must be di erentiated rom guttate morphea
and LP especially o the atrophic type. Anogenital LS must be
distinguished rom genital LP lichen simple chronicus
ul ar intraepithelial neoplasia (SCC in situ) and e tramam
mary Paget s disease. The white color and atrophic sur ace are
characteristic and such areas are most ruit ul i biopsied to
con rm the diagnosis.
Treatment
The use o superpotent topical corticosteroids has dramatically
changed the management o anogenital LS. These are uni er
sally accepted as the treatment o choice or all orms o genital
LS. ost patients will respond to once daily application o
these agents and can subse uently be tapered to less re uent
applications (once or twice a wee ) or to lower strength corti
costeroids. ost women can achie e a symptom ree state
with g o clobetasol ointment used o er months and they
will re uire g or less per year to maintain control o the LS.
Generally the untreated lesions are atrophic and pulsed
wee end applications o a potent topical steroid are associated
with clinicohistologic re ersal o the epidermal atrophy as the
in ammatory process is controlled. Coe istent candidiasis
may be present or may appear with this treatment and can
be managed with topical or oral agents. Penile ul ar and
prepubertal LS in girls ha e all been documented to respond
to this orm o treatment. Phimosis in young boys should be
treated initially with potent topical steroids. The degree o
symptomatic impro ement ar e ceeds the ob ecti e impro e
ment. The ma ority o patients ha e dramatic reduction in
their itching and burning with topical clobetasol. owe er
the isible white atrophic scarred ul ar s in is o ten only
minimally impro ed. n one study o compliant patients
achie ed complete symptom control; none had disease pro
gression. n partially compliant patients only achie ed
complete symptom control and e perienced progression.
one o the ully compliant women de eloped ul ar SCC
but o ( ) o the partially compliant women did. This
adds limited e idence to the impression that good control o
LS is associated with better outcomes symptomatically unc
tionally and with respect to cancer de elopment. Vul ar pain
associated with LS may ha e a neuropathic component (as in
ul odynia) and treatment with tricyclic antidepressants
(e.g. amitriptyline) gabapentin and dulo etine hydrochlo
ride may be tried.
Topical tacrolimus . and . ointments and pimecro
limus cream ha e also been demonstrated to be e ecti e
in genital LS. owe er since superpotent corticosteroids ha e
pro en so e ecti e in genital LS topical C s should be
reser ed or patients in whom topical corticosteroids are
ine ecti e or not tolerated. Close clinical ollow up is
tahir99 - UnitedVRG
recommended because the long term ris o applying topical
C s to s in predisposed to malignant degeneration is not
nown. Topical calcipotriol may also be o bene t. Topical
testosterone was no more e ecti e than emollient and in one
trial was worse than emollients as maintenance therapy. t is
Lichen sclerosus (lichen sclerosus et atrophicus)
no longer recommended. ydro ychloro uine calcitriol
topical progesterone cream topical calcipotriol topical
tretinoin cyclosporine and hydro yurea can be considered in
re ractory cases. n one patient intralesional adalimumab
cleared LS o the glans penis. VA phototherapy led to mod
erate impro ement in some patients unresponsi e to topical
steroids. Patients who initially ailed topical steroid treatment
may respond to topical corticosteroids ollowing the V treat
ment. ntralesional steroid anesthetic in ections can be help ul
or persistently symptomatic areas. Surgical treatment can be
e ecti e starting with cryotherapy which has been reported
as help ul in three uarters o patients with se ere ul ar itch.
Photodynamic therapy has brought signi cant impro ement
in multiple reports and can be considered in re ractory cases.
tragenital LS is ery di cult to treat. superpotent topical
steroids are ine ecti e P VA VA B VB calcipotriol
or antimalarials may be tried. Gi en the appearance o LS li e
lesions in chronic GV D and the success o e tracorporeal
photophoresis ( CP) in cGV D CP has been tried in a ew
se ere cases o e tragenital LS with success.
Ayhan A, et al: Topical testosterone versus clobetasol for vulvar lichen
sclerosus. Int J Gynecol Obstet 2007; 96:117.
Barbara E, et al: High prevalence of concomitant anogenital lichen
sclerosus and extragenital psoriasis in adult women. Obstet Gynecol
2008; 111:1143.
Baskan EB, et al: Open label trial of cyclosporine for vulvar lichen
sclerosus. J Am Acad Dermatol 2007; 57:276.
Beattie PE, et al: UVA1 phototherapy for genital lichen sclerosus. Clin
Exp Dermatol 2006; 31:343.
Becker K, et al: Lichen sclerosus and atopy in boys: coincidence or
correlation? Br J Dermatol 2013; 168:362.
Bradford J, Fischer G: Long-term management of vulval lichen sclerosus
in adult women. Aus N Z J Obstet Gynaecol 2010; 50:148.
Brouillard C, et al: A case of cutaneous lichen sclerosus et atrophicus
effectively treated by extracorporeal photochemotherapy.
Photodermatol Photoimmunol Photomed 2013; 29:160.
Celis S, et al: Balanitis xerotica obliterans in children and
adolescents: a literature review and clinical series. J Pediatr Urol
2014; 10:34.
Chi CC, et al: Systematic review and meta-analysis of randomized
controlled trials on topical interventions of genital lichen sclerosus. J
Am Acad Dermatol 2012; 67:305.
Colbert R, et al: Progressive extragenital lichen sclerosus successfully
treated with narrowband UV-B phototherapy. Arch Dermatol 2007;
143:19.
Cusini M: Lichen sclerosus et atrophicus in males: how to diagnose,
how to manage. Acta Derm Venereol 2014; 94:499.
Dalmau J, et al: Psoralen UVA treatment for generalized prepubertal
extragenital lichen sclerosus et atrophicus. J Am Acad Dermatol 2006;
55:S56.
D’Hauwers KW, et al: Human papillomavirus, lichen sclerosus and penile
cancer: a study in Belgium. Vaccine 2012; 30:6573.
Doulaveri G, et al: Genital vulvar lichen sclerosus in monozygotic twin
women: a case report and review of the literature. Case Rep Dermatol
2013; 5:321.
Edmonds EV, et al: Extracellular matrix protein 1 autoantibodies in male
genital lichen sclerosus. Br J Dermatol 2011; 165:218.
Edmonds EV, et al: Clinical parameters in male genital lichen sclerosus:
a case series of 329 patients. J Eur Acad Dermatol Venereol 2012;
26:730.
Eisendle K, et al: Possible role of Borrelia burgdorferi sensu lato infection
in lichen sclerosus. Arch Dermatol 2008; 144:591.
Fistarol SK, Itin PH: Diagnosis and treatment of lichen sclerosus: an
update. Am J Clin Dermatol 2013; 14:27.
Gambichler T, et al: Differential expression of connective tissue growth
factor and extracellular matrix proteins in lichen sclerosus. J Eur Acad
Dermatol Venereol 2012; 26:207.
223
 Goldstein AT, et al: A double-blind, randomized controlled trial of
12 clobetasol versus pimecrolimus in patients with vulvar lichen sclerosus.
J Am Acad Dermatol 2011; 64:e99.
Gunthert A, et al: Early onset vulvar lichen sclerosus in premenopausal
women and oral contraceptives. Euro J Obstet Gynecol 2008; 137:56.
Lichen Planus and Related Conditions
Gupta S, et al: Treatment of genital lichen sclerosus with topical
calcipotriol. Int J STD AIDS 2005; 16:772.
Hernandez-Machin B, et al: Infantile pyramidal protrusion localized at the
vulva as a manifestation of lichen sclerosus et atrophicus. J Am Acad
Dermatol 2007; 56:S49.
Homer L, et al: Meatal stenosis in boys following circumcision for lichen
sclerosus (balanitis xerotica obliterans). J Urol 2014; 192:1784.
Kim GW, et al: Topical tacrolimus ointment for the treatment of lichen
sclerosus, comparing genital and extragenital involvement. J Dermatol
2012; 39:145.
Kreuter A, et al: Low-dose ultraviolet A1 phototherapy for extragenital
lichen sclerosus: results of a preliminary study. J Am Acad Dermatol
2002; 46:251.
Kreuter A, et al: Coexistence of lichen sclerosus and morphea: a
retrospective analysis of 472 patients with localized scleroderma
from a German tertiary referral center. J Am Acad Dermatol 2012;
67:1157.
Kreuter A, et al: Association of autoimmune diseases with lichen
sclerosus in 532 male and female patients. Acta Derm Venereol 2013;
93:238.
Kulkarni S, et al: Lichen sclerosus of the male genitalia and urethra:
Surgical options and results in a multicenter international experience
with 215 patients. Eur Urol 2009; 55:945.
Lansdorp CA, et al: Quality of life in Dutch women with lichen sclerosus.
Br J Dermatol 2013; 168:787.
LeFevre C, et al: Management of lichen sclerosus with triamcinolone
ointment: effectiveness in reduction of patient symptom scores. J Low
Genit Tract Dis 2011; 15:205.
Lowenstein EB, Zeichner JA: Intralesional adalimumab for the treatment
of refractory balanitis xerotica obliterans. JAMA Dermatol 2013; 149:23.
Lutz V, et al: High frequency of genital lichen sclerosus in a prospective
series of 76 patients with morphea: toward a better understanding of
the spectrum of morphea. Arch Dermatol 2012; 148:24.
Mannweiler S, et al: Penile carcinogenesis in a low-incidence area: a
clinicopathologic and molecular analysis of 115 invasive carcinomas
with special emphasis on chronic inflammatory skin disease. Am J
Surg Pathol 2011; 35:998.
Marchs-Braun N, et al: Acute urinary retention in an adolescent as the
presenting symptom of lichen sclerosus et atrophicus. J Pediatr
Adolesc Gynecol 2013; 26:e117.
Maronn M, et al: Constipation as a feature of anogenital lichen
sclerosus in children. Pediatr 2005; 115:e230.
Mentrikoski MJ, et al: Histologic and immunohistochemical assessment
of penile carcinomas in a North American population. Am J Surg
Pathol 2014; 38:1340.
Neill SM, et al: British Association of Dermatologists’ guidelines for the
management of lichen sclerosus 2010. Br J Dermatol 2010; 163:672.
Nelson DM, Peterson AC: Lichen sclerosus: epidemiological distribution
in an equal access health care system. J Urol 2011; 185:522.
Ozalp SS, et al: Vulval pruritus: the experience of gynaecologists
revealed by biopsy. J Obstet Gynaecol 2014; 10:1.
Philippou P, et al: Genital lichen sclerosus/balanitis xerotica obliterans in
men with penile carcinoma: a critical analysis. Br J Urol 2013; 111:970.
Poindexter G, Morrell D: Anogenital pruritus: lichen sclerosus in children.
Pediatr Ann 2007; 36:785.
Renaud Vilmer C: Effect of long term topical application of a potent
steroid on the course of the disease. Arch Dermatol 2004; 140:709.
Romero A, et al: Treatment of recalcitrant erosive vulvar lichen sclerosus
with photodynamic therapy. J Am Acad Dermatol 2007; 57:S46.
224
Schlosser BJ: Practice gaps. Missing genital lichen sclerosus in patients
with morphea: Don’t ask? Don’t tell? Comment on “High frequency of
genital lichen sclerosus in a prospective series of 76 patients with
morphea.” Arch Dermatol 2012; 148:28.
Simpkin S, et al: Clinical review of 202 patients with vulval lichen
sclerosus: a possible association with psoriasis. Aus J Dermatol 2007;
48:28.
Stucket M, et al: The outcome after cryosurgery and intralesional steroid
injection in vulvar lichen sclerosus corresponds to preoperative
histopathological findings. Dermatology 2005; 210:218.
Tausch TJ, Peterson AC: Early aggressive treatment of lichen sclerosus
may prevent disease progression. J Urol 2012; 187:2101.
Thami GP, Kaur S: Genital lichen sclerosus, squamous cell carcinoma
and circumcision. Br J Dermatol 2003; 148:1058.
Toberer F, Näher H: Lichen sclerosus et atrophicans leading to joint
contractures: restoring of joint mobility by extracorporeal
photopheresis. J Am Acad Dermatol 2012; 167:e269.
Ventolini G, et al: Lichen sclerosus: a 5-year follow-up after topical,
subdermal, or combined therapy. J Low Genit Tract Dis 2012; 16:271.
Vincent MV, Mackinnon E: The response of clinical balanitis xerotica
obliterans to the application of topical steroid-based creams. J Pediatr
Surg 2005; 40:709.
Wehbe-Alamah H, et al: Silent no more! The lived experiences of women
with lichen sclerosus. J Am Acad Nurs Pract 2012; 24:499.
West DS, et al: Dermatopathology of the foreskin: an institutional
experience of over 400 cases. J Cutan Pathol 2013; 40:11.
Weyers W: Hypertrophic lichen sclerosus sine sclerosis: clues to
histopathologic diagnosis when presenting as psoriasiform lichenoid
dermatitis. J Cutan Pathol 2014. [Epub ahead of print.]
Zavras N, et al: Infantile perianal pyramidal protrusion: a report of 8 new
cases and a review of the literature. Case Rep Dermatol 2012; 4:202.
Bonus images for this chapter can be found online at
expertconsult.inkling.com
eFig. 12-1 Lichen planus, violaceous, flat-topped papules with
minimal scale.
eFig. 12-2 Annular lichen planus.
eFig. 12-3 Lichen planus, penile papules.
eFig. 12-4 Lichen planus of the eyelids.
eFig. 12-5 Lichen planus of the lips.
eFig. 12-6 Lichen planus, hyperpigmented lesions.
eFig. 12-7 Lichen planus, annular type.
eFig. 12-8 Lichen planus of the sole.
eFig. 12-9 Lichen planus of the tongue.
eFig. 12-10 Lichen planus, nail involvement with pterygium.
eFig. 12-11 Koebnerization of lichen planus after Toxicodendron
dermatitis.
eFig. 12-12 Annular lichen planus.
eFig. 12-13 Follicular lichen planus.
eFig. 12-14 Lichen nitidus, pinhead-sized hypopigmented papules.
eFig. 12-15 Lichen nitidus.
eFig. 12-16 Lichen striatus.
eFig. 12-17 Lichen striatus, lesion following lines of Blaschko.
eFig. 12-18 Lichen sclerosus, early lesion of the glans penis.
eFig. 12-19 Lichen sclerosus of the vulva.
eFig. 12-20 Lichen sclerosus and phimosis.
 Lichen sclerosus (lichen sclerosus et atrophicus)
eFig. 12-1 Lichen planus, violaceous, flat-topped papules with eFig. 12-4 Lichen planus of the eyelids.
minimal scale.

eFig. 12-2 Annular lichen planus. eFig. 12-5 Lichen planus of the lips.

eFig. 12-3 Lichen eFig. 12-6

planus, penile Lichen planus,
papules. hyperpigmented
lesions.

224.e1

tahir99 - UnitedVRG
12
Lichen Planus and Related Conditions

eFig. 12-7 Lichen planus, annular type.

eFig. 12-10 Lichen planus, nail involvement with pterygium.

eFig. 12-8 Lichen planus of the sole.

eFig. 12-9 Lichen

planus of the tongue.

eFig. 12-11 Koebnerization of lichen planus after Toxicodendron

dermatitis.

224.e2
 eFig. 12-15 Lichen
nitidus.

Lichen sclerosus (lichen sclerosus et atrophicus)

eFig. 12-12 Annular lichen planus.

eFig. 12-13 Follicular

lichen planus.

eFig. 12-14 Lichen nitidus, pinhead-sized hypopigmented papules. eFig. 12-16 Lichen striatus.

224.e3

tahir99 - UnitedVRG
12
Lichen Planus and Related Conditions

eFig. 12-17 Lichen striatus, lesion following lines of Blaschko.

eFig. 12-19 Lichen sclerosus of the vulva.

eFig. 12-18 Lichen sclerosus, early lesion of the glans penis.

eFig. 12-20 Lichen sclerosus and phimosis.

224.e4
 Bonus images for this chapter can be found online at
ACNE VULGARIS
Clinical features
Acne ulgaris is a chronic in ammatory disease o the pilose
baceous ollicles characteri ed by comedones papules pus
tules nodules and o ten scars. The comedo is the primary
lesion o acne. t may be seen as a at or slightly ele ated
papule with a dilated central opening lled with blac ened
eratin (open comedo or blac head) ( ig. ). Closed com
edones (whiteheads) are usually mm yellowish papules that
may re uire stretching o the s in to isuali e. acrocomedo
nes which are uncommon may reach mm in si e. The
papules and pustules are mm in si e and are caused by
in ammation so erythema and edema occur ( ig. ). They
may enlarge become more nodular and coalesce into pla ues
o se eral centimeters that are indurated or uctuant contain
sinus tracts and discharge serosanguineous or yellowish pus
( ig. ).
Patients typically ha e a ariety o lesions in arious states
o ormation and resolution. n light s inned patients lesions
o ten resol e with a reddish purple macule that is short li ed.
n dar s inned indi iduals macular hyperpigmentation
results and may last se eral months ( ig. ). Acne scars are
heterogeneous in appearance. orphologies include deep
narrow ice pic scars seen most o ten on the temples and
chee s; canyon type atrophic lesions on the ace ( ig. );
whitish yellow papular scars on the trun and chin;
anetoderma type scars on the trun ; and hypertrophic and
eloidal ele ated scars on the nec and trun .
Acne a ects primarily the ace nec upper trun ( ig. ) such as se ual precocity irili ation or growth abnormality.
and upper arms. n the ace acne occurs most re uently on
the chee s and to a lesser degree on the nose orehead and
chin. The ears may be in ol ed with large comedones in the
concha cysts in the lobes and sometimes preauricular and
retroauricular comedones and cysts. n the nec especially in
the nuchal area large cystic lesions may predominate.
Acne typically begins at puberty and is o ten the rst sign
o increased se hormone production. When acne begins at age
years it is re uently comedonal in character a ecting
primarily the orehead and chee s. t may remain mild in its
e pression with only an occasional in ammatory papule.
owe er as hormone le els rise into the middle teenage
years more se ere in ammatory pustules and nodules occur
with spread to other sites. oung men tend to ha e an oilier
comple ion and more se ere widespread disease than young
women. Women may e perience a are o their papulopustu
lar lesions about wee be ore menstruation. Acne may also
begin in year old women who ha e not e perienced
teenage acne. This acne re uently mani ests as papules pus
tules and deep pain ul persistent nodules on the awline
chin and upper nec .
tahir99 - UnitedVRG
expertconsult.inkling.com
Acne
13
Acne is primarily a disease o the adolescent with o
all teenagers being a ected to some degree. t occurs with
greatest re uency between ages and in both genders.
Generally in olution o the disease occurs be ore age ;
howe er great ariability in age at onset and o resolution
occurs. About o women and o men will continue to
ha e clinical acne until age . A ew will ha e in ammatory
papules and nodules into late adulthood.
eonatal acne is a common condition that de elops a ew
days a ter birth has male preponderance and is characteri ed
by transient acial papules or pustules that usually clear spon
taneously in a ew days or wee s ( ig. ). n antile acne
includes cases that persist beyond the neonatal period or that
ha e an onset a ter the rst wee s o li e. ost neonatal acne
patients remit by age year although occasionally cases
e tend into childhood and through puberty. n prolonged
cases topical ben oyl pero ide erythromycin or the retinoids
may be e ecti e. With more in ammatory disease oral eryth
romycin mg twice daily or trimethoprim mg twice
daily may be added to topical medications. ral isotretinoin
has been used in the in antile period and is e ecti e. idchild
hood acne may e ol e rom persistent in antile acne or begin
a ter age year. t is uncommon and has a male predominance.
Grouped comedones papules pustules and nodules can
occur alone or in any combination usually limited to the ace
( ig. ). The duration is ariable rom a ew wee s to
se eral years and occasionally e tends into more se ere
pubertal acne. ten there is a strong amily history o mod
erately se ere acne. A pediatric endocrinology wor up is indi
cated or midchildhood acne and or earlier onset patients
with physical ndings suggesti e o a hormonal disorder
Acne onset rom age to is categori ed as preadolescent
acne. This is the time o adrenarche and unless there are signs
o androgen e cess no wor up is needed.
Pathogenesis
Acne ulgaris is e clusi ely a ollicular disease with the prin
cipal abnormality being comedo ormation. t is produced by
the impaction and distention o the ollicles with a eratinous
plug in the lower in undibulum. The eratinous plug is caused
by hyperproli eration and abnormal di erentiation o erati
nocytes o un nown causes. Androgens alterations in lipid
composition and an abnormal response to local cyto ines are
all hypothesi ed to be important. Androgen stimulation o
the sebaceous glands is critical. Acne begins a ter sebum secre
tion increases and women with hyperandrogenic states
o ten mani est acne along with hirsutism and menstrual
abnormalities. Treatment directed at reducing sebaceous
secretion such as isotretinoin estrogens or antiandrogens is
e ecti e in clearing acne.
225

13
Acne
Fig. 13-1 Acne vulgaris, with comedones, on the chin.
Fig. 13-2 Acne
vulgaris, with papules
and pustules, on the
cheek.
Fig. 13-3 Inflammatory acne with papules and nodules. (Courtesy of
Dr. Don Adler.)
As the retained cells bloc the ollicular opening the lower
portion o the ollicle is dilated by entrapped sebum. Disrup
tion o the ollicular epithelium permits discharge o the ol
licular contents into the dermis. The combination o eratin
sebum and microorganisms particularly Propionibacterium
acnes leads to the release o proin ammatory mediators and
the accumulation o lymphocytes neutrophils and oreign
body giant cells. This in turn causes the ormation o in am
matory papules pustules and nodulocystic lesions.
226
Fig. 13-4
Postinflammatory
hyperpigmentation at
sites of acne lesions.
Fig. 13-5 Acne scarring on the cheek.
Fig. 13-6 Upper chest involvement with acne. (Courtesy of Dr. Don
Adler.)
Additional actors may e acerbate acne or in a predisposed
patient cause the onset o acne. Comedogenic greasy or
occlusi e products such as hair pomades may induce closed
comedones and at times in ammatory lesions. ther types
o cosmetics may initiate or worsen acne but acne cosmetica
is uncommon because most cosmetics are tested or
comedogenicity.
any types o mechanical or rictional orces can aggra ate
e isting acne. A common problem is the o ere uberant

Fig. 13-7 Infantile acne.
Fig. 13-8 Childhood acne.
washing some patients thin may help rid them o their blac
heads or oiliness. A ey eature o mechanical or rictional acne
is an unusual distribution o the acne lesions. Pro ocati e
actors include chin straps iolins hats collars surgical tape
orthopedic casts chairs and seats. ne acne patient who had
laser hair remo al de eloped ares o in ammatory lesions
locali ed to the acne prone sites a ter each laser session; the
legs and abdomen were spared. All these actors are li ely to
irritate the ollicular epithelium and e acerbate the changes
that lead to comedogenesis and ollicular rupture. Prophylac
tic measures designed to interdict these arious mechanical
orces are bene cial.
n all women or children with acne the possibility o a
hyperandrogenic state should be considered. n women the
presence o irregular menses hirsutism seborrhea acanthosis
nigricans or androgenic alopecia increases the li elihood o
nding clinically signi cant hyperandrogenism. Additionally
gynecologic endocrine e aluation may be indicated in women
who ha e acne resistant to con entional therapy who relapse
uic ly a ter a course o isotretinoin or who e perience
sudden onset o se ere acne. Screening tests to e clude a iril
i ing tumor include serum dehydroepiandrosterone sul ate
(D AS) and testosterone obtained wee s be ore the onset
o menses. D AS le els may be ery high in adrenal tumors
(> μg dL) or less dramatic in congenital adrenal hyperpla
sia ( μg dL). arian tumor is suggested by testoster
one le els greater than ng dL. any patients with
late onset congenital adrenal hyperplasia will ha e normal
le els o D AS. Although hydro yprogesterone and
adrenocorticotropic hormone (ACT ) stimulation tests ha e
been used in this setting the baseline hydro yprogesterone
may be normal in some women with adult hydro ylase
de ciency and ACT stimulation may result in o erdiagnosis
o the syndrome. t is not clear that screening or adult onset
hydro ylase de ciency impro es patient outcome. Patients
with polycystic o arian syndrome (PC S) may ha e a high
serum testosterone le el ( ng dL) or an increase in the
luteini ing hormone ollicle stimulating hormone (L S )
tahir99 - UnitedVRG
ratio (> ) but American College o bstetricians and Gyne
cologists (AC G) guidelines suggest that laboratory and
imaging studies are best used to e clude a irili ing tumor.
The diagnosis o PC S may be made clinically by the presence
o ano ulation (< periods per year or periods > days apart)
Acne vulgaris
and signs o hyperandrogenism such as acne and hirsutism.
Acne neonatorum is e plained by in antile production o
androgens which wanes at to months. ccasional patients
ha e persistent acne although acne de eloping a ter age and
be ore age (with onset o adrenarche) may be a orm o acne
cosmetica acne enenata or drug induced acne or part o an
endocrinologic disorder. A wor up should be initiated i acne
de elops between ages and and no ob ious e ternal actor
is present. n the absence o any disco ered abnormalities the
ualitati e or uantitati e alteration o cutaneous androgen
metabolism and increased end organ sensiti ity could be pos
tulated as pathogenic mechanisms or preadolescent acne.
Pathology
Comedones re eal a thinned epithelium and a dilated ollicu
lar canal lled with lamellar lipid impregnated eratinous
material. n pustular cases there are olliculocentric abscesses
surrounded by a dense in ammatory e udate o lymphocytes
and polymorphonuclear leu ocytes. n addition to these nd
ings indolent nodular lesions re uently show plasma cells
oreign body giant cells and proli eration o broblasts.
pithelial lined sinus tracts may orm.
Treatment
General principles
t is important to ta e a complete historical record o prior
therapies including all o er the counter ( TC) products. The
dose timing combinations side e ects and response to inter
entions should be obtained. Corticosteroids anabolic ste
roids neuroleptics lithium and cyclosporine may worsen
acne. A amily history o acne and i present its tendency to
scarring should be noted. Women should be ueried regularly
about menstrual irregularities and hair growth in a male
pattern as well as use o cosmetics.
Treatment may ail because o drug interactions coe isting
conditions or antibiotic resistance but the most common and
important cause is lac o adherence to the treatment plan.
tili ing medications that are well tolerated ha e con enient
dosing regimens and are cosmetically acceptable will help.
owe er thorough patient education is essential e plaining
how lesions orm de ning the e pected response to and the
duration and side e ects o treatment and gi ing clear unam
biguous instructions. Patients should now the di erence
between acti e in ammatory lesions and the purplish red or
hyperpigmented macules o inacti e resol ed lesions. Topical
application should be to the entire a ected area rather than to
speci c lesions and oral and topical medications should be
used daily as pre enti e treatment.
A high glycemic diet may worsen acne although the
strength o its in uence is un nown. The authors in general
do not counsel patients to alter their diet unless large uanti
ties o s im mil are being ingested or obesity is present. A
trial lessening s im mil inta e is worthwhile with appropri
ate calcium and itamin D supplementation gi en. n obese
patients dietary counseling is recommended especially i
PC S o arian seborrhea acne hirsutism and androgenetic
alopecia syndrome or other syndromes nown to be associ
ated with insulin resistance and metabolic syndrome (e.g.
227

13 Box 13-1 Acne treatment
Mild
1. Comedonal
Acne
• Topical retinoid ± physical extraction (first line)
• Alternate retinoid, salicylic acid, azelaic acid (second line)
2. Papular/pustular
• Topical antimicrobial combination + topical retinoid, benzoyl
peroxide wash if mild truncal lesions (first line)
• Alternate antimicrobials + alternate topical retinoids, azelaic
acid, sodium sulfacetamide–sulfur, salicylic acid (second
line)
Moderate
1. Papular/pustular
• Oral antibiotic + topical retinoid + benzoyl peroxide (first
line)
• Alternate antibiotic, alternate topical retinoid, alternate
benzoyl peroxide (second line)
• In women, spironolactone + oral contraceptive + topical
retinoids ± topical antibiotic and/or benzoyl peroxide
• Isotretinoin if relapses quickly off oral antibiotics, does not
clear, or scars
Severe
1. Nodular/conglobate
• Isotretinoin
• Oral antibiotic + topical retinoid + benzoyl peroxide
• In women, spironolactone + oral contraceptive + topical
retinoid ± topical or oral antibiotics and/or benzoyl peroxide
A R A syndrome) are present. or some patients who
want a more natural approach to therapy and a change in
diet a low glycemic diet may be recommended. Scrubbing o
the ace increases irritation and may worsen acne. se o only
prescribed medications and a oidance o potentially drying
TC products such as astringents harsh cleansers and anti
bacterial soaps should be emphasi ed. oncomedogenic cos
metics are recommended and pressed powders and oil based
products should be a oided.
Medical therapy
Systemic and topical retinoids systemic and topical antimicro
bials and systemic hormonal therapy are the main therapeutic
classes o treatment a ailable. Treatment guidelines are out
lined in Bo . and are e ecti e in mild in ammatory acne. These topical
Topical treatment
All topical treatments are pre enti e and use or wee s is
re uired to udge their e cacy. The entire acne a ected area
is treated not ust the lesions and long term use is the rule. n
many patients topical therapy may be e ecti e as mainte
nance therapy a ter initial control is achie ed with a combina
tion o oral and topical treatment.
Topical retinoids
t has long been appreciated that topical retinoids are espe
cially e ecti e in promoting normal des uamation o the ol
licular epithelium reducing comedones and inhibiting the
de elopment o new lesions. Additionally they ha e a mar ed
anti in ammatory e ect inhibiting the acti ity o leu ocytes
the release o proin ammatory cyto ines and other mediators
and the e pression o transcription actors and toll li e recep
tors in ol ed in immunomodulation. These agents also help
228
penetration o other acti e agents. Thus the topical retinoids
should be used in most patients with acne and are the pre
erred agents in maintenance therapy.
Tretinoin was the rst o this group o agents to be used or
acne. Popular orms o tretinoin are . and . in a
cream base and the microni ed gels because these are less
irritating than standard gels and li uids. ts incorporation into
microspheres and a polyolprepolymer also helps to limit irrita
tion and ma e the product more stable in the presence o light
and o idi ers. Tretinoin treatment may ta e wee s be ore
impro ement occurs. When patients are tolerating the medica
tion and are slow to respond retinoic acid gel or solution may
be used. Tretinoin should be applied at night and is in preg
nancy category C.
Adapalene is a well tolerated retinoidli e compound that
has e cacy e ui alent to the lower concentrations o tretinoin.
Because it is light stable adapalene may be applied in either
the morning or the e ening. t is in pregnancy category C.
Ta arotene is comparati ely strong in its action but also
relati ely irritating. t should be applied once at night or e ery
other night and as it is in pregnancy category contracepti e
counseling should be pro ided.
nitially using retinoids e ery other night or adding a mois
turi er with their use may lessen their irritant e ects. They are
also particularly use ul in patients o color because retinoids
may lighten postin ammatory hyperpigmentation.
Benzoyl peroxide
Ben oyl pero ide has a potent antibacterial e ect. Propionibac
terium acnes resistance does not de elop during use. ts con
comitant use during treatment with antibiotics will limit the
de elopment o resistance e en i only gi en or short to
day pulses. Although ben oyl pero ide is most e ecti e in
in ammatory acne some studies ha e shown it to be comedo
lytic as well. The wash ormulations may be used or mild
truncal acne when systemic therapies are not re uired and
these need to be in place min to be e ecti e.
Treatment is usually once or twice daily. Ben oyl pero ide
may irritate the s in and produce peeling. Water based or
mulations o lowest strength are least irritating and do not
compromise e cacy. Application limited to once a day or
e ery other day will also help. Allergic contact dermatitis will
rarely de elop suggested by the complaint o itch rather than
stinging or burning. Ben oyl pero ide is in pregnancy cate
gory C.
Topical antibacterials
Topical clindamycin and erythromycin are a ailable in a
number o ormulations. n general they are well tolerated
products are in pregnancy category B. se o these topical
antibiotics alone howe er is not recommended because o
increasing antibiotic resistance. As mentioned concurrent
therapy with ben oyl pero ide will limit this problem. Con
comitant use with a topical retinoid will hasten the response
and allow or more rapid discontinuance o the antibiotic.
Dapsone is a ailable topically in a gel ormulation. emo
lytic anemia may occur and s in discoloration is possible
when ben oyl pero ide is applied a ter topical dapsone.
Additionally concomitant oral use o trimethoprim
sul ametho a ole will increase the systemic absorption o
topical dapsone. Dapsone is in pregnancy category C.
Sulfur, sodium sulfacetamide, resorcin, and salicylic acid
Although ben oyl pero ide retinoids and topical antibiotics
ha e largely supplanted these older medications sul ur res
orcin and salicylic acid preparations are still use ul and mod
erately help ul i the newer medications are not tolerated. They
are re uently ound in TC preparations. Sul acetamide
sul ur combination products are mildly e ecti e in both acne
and rosacea but should be a oided in patients with nown
hypersensiti ity to sul onamides.
Azelaic acid
This dicarbo ylic acid is usually well tolerated and has mild
e cacy in both in ammatory and comedonal acne. A elaic
acid may help to lighten postin ammatory hyperpigmenta
tion and is in pregnancy category B.
Combination topical therapy
Se eral products are a ailable that combine antibiotics such as
clindamycin and ben oyl pero ide or combine retinoids and
either antibiotics or ben oyl pero ide. n general these medi
cations increase adherence because they re uire less re uent
application and they may also limit irritation compared with
the cumulati e topical application o each product separately.
owe er combination topical therapy limits e ibility and
may cause more irritation than a single product used alone.
Oral antibiotics
ral antibiotics are indicated or moderate to se ere acne; in
patients with in ammatory disease who do not tolerate or
respond to topical combinations; or the treatment o chest
bac or shoulder acne; and in patients or whom absolute
control is deemed essential such as those who scar with each
lesion or who de elop in ammatory hyperpigmentation. t
generally ta es wee s to udge e cacy. Starting at a high
dose and reducing it a ter achie ing control is pre erred.
Wor ing to maintain control e entually with topical retinoids
or retinoid ben oyl pero ide combination therapy is ideal;
howe er eeping patients ree o disease or months
be ore each decrease in dosage is best to pre ent aring. ost
courses o oral therapy are o at least months duration.
There is concern that oral antibiotics may reduce the e ec
ti eness o oral contracepti es ( Cs). t is appropriate or this
as yet unpro ed (e cept with ri ampin which is not used or
acne) association to be discussed with patients and a second
orm o birth control o ered.
Tetracycline derivatives
Tetracycline s a ailability and utility are limited.
Doxycycline. The usual dose o do ycycline is mg
once or twice a day depending on the disease se erity. Pho
tosensiti ity reactions can occur with this orm o tetracycline
and can be dramatic. Vaginitis or perianal itching may result
rom tetracycline and its deri ati es (e.g. do ycycline) and
occurs in about o patients with Can i a albicans usually
present in the in ol ed site. The only other common side
e ects are gastrointestinal (G ) symptoms such as nausea. To
reduce the incidence o esophagitis tetracyclines should not
be ta en at bedtime. An enteric coated ormulation is a ailable
and limits the G side e ects. Staining o growing teeth occurs
precluding use o tetracyclines in pregnant women and in
children under age or . The tetracyclines should also be
a oided when renal unction is impaired.
Subantimicrobial dose do ycycline (do ycycline hyclate
mg) may be gi en twice daily. The ad antage o this is that
the anti in ammatory acti ity is being utili ed but no antibi
otic resistance results because o the low dose. A sustained
release mg ormulation is also a ailable. owe er these
low dose preparations appear to be o low e cacy.
Minocycline. inocycline is e ecti e in treating acne ul
garis. n patients whose P acnes in ection de elops tetracycline
resistance minocycline is an alternati e. The usual dose is
mg once or twice daily depending on the se erity o
disease. ts absorption is less a ected by mil and ood than
tahir99 - UnitedVRG
Acne vulgaris
Fig. 13-9 Minocycline-induced blue pigmentation of the teeth and
nails.
is tetracycline. Vertigo may occur and beginning minocycline
therapy with a single dose in the e ening may be prudent. An
e tended release preparation is also a ailable which limits the
estibular side e ects. Pigmentation in areas o in ammation
o oral tissues in postacne osteoma or scars in a photodistrib
uted pattern on the shins or in the sclera nail bed ear carti
lage or teeth or in a generali ed pattern may also be seen ( ig.
). Additionally lupusli e syndromes a hypersensiti ity
syndrome ( e er hepatitis and eosinophilia) serum sic ness
pneumonitis and hepatitis are uncommon but potentially
serious ad erse e ects o minocycline.
Amoxicillin
or those who cannot ta e tetracyclines because o side e ects
or in pregnant women re uiring oral antibiotic therapy amo
icillin may be use ul. Amo icillin and the much less e ecti e
erythromycin are in pregnancy category B. Amo icillin can be
gi en in doses ranging rom mg daily to mg three
times daily. Side e ects are allergic reactions which may be
serious and G upset. any patients o acne age ha e ta en
amo icillin in the past and are aware o their ability to tolerate
the medicine without allergic reactions.
Clindamycin
Past e perience has shown that clindamycin pro ides an e cel
lent response in the treatment o acne. owe er the potential
or the de elopment o pseudomembranous colitis and the
a ailability o isotretinoin ha e limited its use. The initial dose
o clindamycin is mg three times daily reduced gradually
as control is achie ed.
Other antibiotics
Sul onamides may be e ecti e in many cases unresponsi e
to other antibiotics; howe er the potential or se ere drug
eruptions limits their use by dermatologists. Trimethoprim
sul ametho a ole (T P S ; Bactrim Septra) in double
strength dose twice daily is recommended initially when
gi en to moderately to se erely a ected patients who ha e
ailed other oral medication. Trimethoprim alone mg
twice daily is also use ul. ral dapsone has been used in
se ere acne conglobata but is rarely used today. sotretinoin is
a ored.
Bacterial resistance
Propionibacterium acnes antimicrobial resistance has been a
clinically rele ant problem. owe er with the limited use o
erythromycin clindamycin and tetracycline this consider
ation is less problematic. Do ycycline resistance may occur
and minocycline is a suitable alternati e i this problem is
suspected. Although concomitant use o ben oyl pero ide will
229
 help limit cutaneous drug resistance problems it is now
13 appreciated that Staph lococcus aureus in the nares streptococci
in the oral ca ity and enterobacteria in the gut may also
become resistant. Also close contacts including treating der
matologists may harbor such drug resistant bacteria. Strate
Acne
gies to pre ent antibiotic resistance include limiting the
duration o treatment stressing the importance o adherence
to the treatment plan restricting the use o antibiotics to
in ammatory acne encouraging repeat treatment with the
same antibiotic unless it has lost its e cacy a oiding the use
o dissimilar oral and topical antibiotics at the same time and
using isotretinoin i unable to maintain clearance without oral
antibacterial therapy.
Hormonal therapy
ormonal inter entions in women may be bene cial e en in
the absence o abnormal laboratory tests. The wor up or the
woman with signs o hyperandrogenism such as acne men
strual irregularities hirsutism or androgenic alopecia is pre
sented earlier. Women with normal laboratory alues o ten
respond to hormonal therapy. Results ta e longer to be seen
with these agents with rst e idence o impro ement o ten
not apparent or months and continued impro ed response
seen or at least months. Good candidates or hormonal treat
ment include women with PC S late onset adrenal hyperpla
sia or another identi able endocrinologic condition and
women with late onset acne se ere acne acne unresponsi e
to other oral and topical therapies or acne that has relapsed
uic ly a ter isotretinoin treatment. Women with acne primar
ily located on the lower ace and nec and with deep seated
nodules that are pain ul and long lasting are o ten uite
responsi e to hormonal inter ention which may be consid
ered a rst line therapy in some women ( ig. ).
Oral contraceptives
The Cs bloc both adrenal and o arian androgens. rtho
Tri Cyclen strostep Alesse asmin and a are e amples
o Cs that ha e bene cial e ects on acne. The progestins that
these contain ha e either low androgenic acti ity or antiandro
genic acti ity. Both the physician and the patient should be
amiliar with the ad erse reactions associated with Cs such
as nausea omiting abnormal menses melasma weight gain
breast tenderness and rarely thrombophlebitis pulmonary
embolism and hypertension.
Spironolactone
Antiandrogen treatment during pregnancy will result in emi
ni ation o a male etus and thus spironolactone is usually
prescribed in combination with Cs. t may be e ecti e in
doses rom mg day. ost women will tolerate a start
ing dose o mg at night. ost also tolerate mg day (
in the A at night) but many will ha e side e ects at
Fig. 13-10 Jawline
lesions in adult
woman.
230
mg day ( twice daily). Side e ects include breast ten
derness headache di iness lightheadedness atigue irregu
lar menstrual periods and diuresis; the non central ner ous
system (C S) e ects are dose dependent. n a study o
women treated with spironolactone at mg day hyper
alemia was measurable but in the absence o renal or cardiac
disease was clinically insigni cant. ne third o patients
cleared one third had mar ed impro ement one uarter
showed partial impro ement and had no response. n the
author s e perience clearance or mar ed impro ement may
be e pected in a high percentage o women i doses up to
mg day are gi en. Spironolactone may be combined with
other topical or oral acne therapy. Se eral months o treatment
are usually re uired to see bene t.
Dexamethasone
De amethasone . . mg gi en once at night reduces
androgen e cess and may alle iate cystic acne. Corticosteroids
are e ecti e in the treatment o adult onset adrenal hyperpla
sia but antiandrogens are o ten used in this setting.
Prednisone
Although corticosteroids may produce steroid acne they are
also e ecti e anti in ammatory agents in se ere and intrac
table acne ulgaris. n se ere cystic acne and acne conglobata
corticosteroid treatment is e ecti e; howe er side e ects
restrict its use. Prednisone is generally only gi en to patients
with se ere in ammatory acne during the rst or months
o treatment with isotretinoin or initial reduction o in am
mation and to reduce isotretinoin induced ares.
Other hormonal agents
inasteride utamide estrogen gonadotropin releasing ago
nists and met ormin (by decreasing testosterone le els) ha e
all showed a bene cial e ect on acne. Because o side e ects
e pense and other considerations howe er these agents are
not typically used.
Oral retinoid therapy
Isotretinoin
sotretinoin is appro ed only or se ere cystic acne. owe er
it is use ul in less se ere orms o acne to pre ent the need or
continuous treatment and the repeated o ce isits o ten
re uired. A consensus o e perts ound that oral isotretinoin
is warranted or se ere acne poorly responsi e acne that
impro es by less than a ter months o therapy with
combined oral and topical antibiotics acne that relapses a ter
oral treatment scars and acne that induces psychological dis
tress. ther indications are gram negati e olliculitis in am
matory rosacea pyoderma aciale acne ulminans and acne
conglobata.
This retinoid is a reliable remedy in almost all acne patients
( ig. ). The dose o isotretinoin is . mg g day in
one or two daily doses. or se ere truncal acne in patients who
tolerate higher doses up to mg g day may be gi en. n
practice most patients are started at mg to a oid an
early are then increased to mg day to limit side
e ects which generally are dose related. Doses as low as
. mg g day are almost as e ecti e as the higher doses in
clearing acne; the disad antage is that lower doses are less
li ely to produce a prolonged remission e en a ter wee s
o treatment. To achie e potentially prolonged remission
patients should recei e mg g o er the treatment
course. An easy way to calculate the total isotretinoin dose
needed is to multiply the patient s weight in ilograms by .
The product is the total number o mg capsules needed to
reach the low end o the dosage spectrum. Two groups recently
 Fig. 13-11 A, Severe
back acne before
isotretinoin.
B, Response to
treatment.
A until stopping medication or at least month. sotretinoin is
B
reported treating patients with . mg g or a total dose o
appro imately mg g. These patients had a lower relapse
rate although side e ects may limit tolerance o such dosages.
The ma or ad antage o isotretinoin is that it is the only acne
therapy that is not open ended (i.e. leads to a remission that
may last many months or years). Appro imately o generally not serious. Dry lips s in eyes and oronasal mucosa
patients remain acne ree a ter a single course o isotretinoin.
Appro imately one third o the relapsing patients will need
only topical therapy with the others re uiring oral treatments.
any patients in the latter category pre er to be re treated
with isotretinoin because o its reliable e cacy and predictable
side e ects which will be similar to those e perienced in the
rst course. any treated patients will re uire at least a second
course o isotretinoin in years.
Some subsets o patients tend to relapse more o ten. n
patients under age years need a second course o
isotretinoin within year and within years. Adult
women and patients with mild acne tend to relapse more o ten
and more uic ly than se erely a ected year olds.
Although patients tolerance and response to repeated courses
are similar to their e perience with the rst course adult
women who relapse may be better managed with hormonal
therapies and mild acne treated with standard therapy.
n adult acne patients who re uently tolerate the side
e ects o isotretinoin less well lower doses and intermittent
tahir99 - UnitedVRG
therapy are possible. n adult acne patients treated with
. mg g day or wee in e ery wee s o er months
acne resol ed in and relapsed a ter year. n
nine patients age treated with . mg g day or
months all cleared and all e cept one remained clear
Acne vulgaris
months later.
Patient education is critical in isotretinoin therapy. ts most
serious ad erse e ect is the ris o se ere damage to the etus
i gi en during pregnancy. Retinoid embryopathy is a well
de ned syndrome characteri ed by cranio acial cardio ascu
lar C S and thymus abnormalities. t is crucial that a woman
o childbearing potential ollow closely the manu acturer s
recommendations. The use o consent orms contraception
education and une ui ocal documentation o the absence o
pregnancy through monthly laboratory testing are important
components o a .S. ood and Drug Administration ( DA)
mandated eri cation program designed to pre ent preg
nancy during treatment. Women should not become pregnant
not mutagenic and there is no ris to a etus while the male
partner is ta ing the drug.
A second ma or area o educational emphasis concerns the
psychological e ects o the medication. Reports o depression
psychosis suicidal ideation suicide and attempted suicide
ha e prompted numerous studies o the mental health o
patients ta ing isotretinoin. Although the usual outcome is
impro ed mood because the disease clears and only a raction
o the many large scale population based studies has ound
e idence o an ele ated incidence o depression a small
number o patients ha e de eloped depression and ha e posi
ti e dechallenge and rechallenge tests. Close monitoring or
depression ully educating the patient and enlisting the help
o a roommate or amily member to loo or changes in mood
are methods used to assess the psychological status o the
patient ta ing isotretinoin.
n ammatory bowel disease ( BD) is a third concern. Patients
with BD ha e been success ully treated with isotretinoin
without aring but new onset BD in patients e posed to
isotretinoin is a concern. The age o onset o BD o erlaps with
the age when acne will re uently be treated with isotretinoin
and antibiotics. A meta analysis o e studies concluded that
there was no increased ris o BD or the subtypes. n the
highest ris study one e tra case o BD would be predicted
i more than patients were treated. Long term use o
tetracycline medications and se ere acne itsel may be predis
posing actors or BD. Patients should be educated about this
potential problem and monitored appropriately.
ther side e ects o isotretinoin are dose dependent and
occur in up to o patients. These e ects can be treated with
moisturi ation. Dryness o the nasal mucosa leads to coloni a
tion by S aureus in o treated patients. S in abscesses
staphylococcal con uncti itis impetigo acial cellulitis and
olliculitis may result. Such coloni ation can be a oided by the
use o bacitracin ointment applied to the anterior nares twice
daily during isotretinoin therapy. Arthralgias may occur but
as with other side e ects do not re uire interruption o
therapy unless se ere. onitoring o serum lipids is done
because some patients will de elop hypertriglyceridemia. This
may be controlled by a oiding smo ing and alcohol and ol
lowing a low at diet. t should be emphasi ed that patients
who de elop this complication as well as their amily are at
ris or the de elopment o the metabolic syndrome.
Li er unction tests should be chec ed at regular inter als
depending on patient ris actors and the dose used. sotreti
noin should be ta en with a high at meal to ensure e cellent
absorption. A new ormulation not re uiring this type o meal
is a ailable.
231

13 Tumor necrosis factor inhibitors
Adalimumab etanercept and in i imab ha e been reported
in indi idual patients to impro e or clear se ere resistant acne.
Some cases ha e been part o an in ammatory syndrome (e.g.
Acne
SAP PAPA PASS) or ound in patients with BD. Para
do ically acne has also been reported as an ad erse reaction
to these medications.
Intralesional corticosteroids
ntralesional corticosteroids are especially e ecti e in reduc
ing in ammatory nodules. Triamcinolone acetonide at mg
mL ( enalog ) is best diluted with sterile normal saline solu
tion to . mg mL. n ecting less than . mL directly into the
center o the nodule will help sa eguard against atrophy and
hypopigmentation.
Physical modalities
Local surgical treatment is help ul in uic ly resol ing the
comedones although many clinicians wait until a ter or
more months o topical retinoid therapy to e tract the remain
ing comedones. The edge o the ollicle is nic ed with a o.
scalpel blade and the contents are e pressed with a comedo
e tractor. Scarring is not produced by this procedure. Light
electrode desiccation is an alternati e. n isotretinoin treated
patients macrocomedones present at wee s may be
e pressed since they tend to persist throughout therapy.
The use o photodynamic therapy and arious orms o
light laser or radio re uency energy is under in estigation.
Such inter entions clearly are capable o destroying sebaceous
glands and illing P acnes but the methods to deli er such
treatment in an e cient cost e ecti e sa e relati ely pain
ree and practical manner are still e ol ing. These treatments
will be a welcome addition with the potential to pro ide care
without the concerns associated with systemic drugs. ore
studies o larger patient populations with appropriate controls
are needed to e aluate the role o light and related energy in
the spectrum o acne therapy.
Complications
en with the e cellent treatment options a ailable scarring
may occur. This may be uite prominent and o ten results
rom the cystic type o acne although smaller lesions may
produce scarring in some indi iduals. Pitted scars wide
mouthed depressions and eloids primarily seen along the
awline and chest are common types o scarring ( ig. ).
Fig. 13-12 Keloid of the chest secondary to acne.
232
These may impro e spontaneously o er year or longer.
any treatment options are a ailable. Procedures reported to
be e ecti e in impro ing appearance include chemical peeling;
ablati e nonablati e and ascular laser therapy; s in nee
dling or rolling; dermabrasion; scar e cision; subcision; punch
gra ts alone or ollowed by dermabrasion or laser smoothing;
intralesional corticosteroids or uorouracil; ractionated laser
resur acing; at trans er; and use o ller substances.
ther complications rom acne are prominent residual
hyperpigmentation especially in dar er s inned patients;
pyogenic granuloma ormation which is more common in
acne ulminans and in patients treated with high dose isotreti
noin; osteoma cutis which consists o small rm papules
resulting rom long standing acne ulgaris; and solid acial
edema. The latter is a persistent rm acial swelling that is an
uncommon but distressing result o acne ulgaris or acne
rosacea. Both corticosteroids and isotretinoin ha e been
reported to be e ecti e treatments.
Arora MK, et al: Role of hormones in acne vulgaris. Clin Biochem 2011;
44:m1035–m1040.
Arowojolu AO, et al: Combined oral contraceptive pills for treatment of
acne. Cochrane Database Syst Rev 2007; 1:CD004425.
Arrington EA, et al: Combined oral contraceptives for the treatment of
acne. Cutis 2012; 90:83–90.
Azoulay L, et al: Isotretinoin therapy and the incidence of acne relapse.
Br J Dermatol 2007; 157:1240.
Berard A, et al: Isotretinoin, pregnancies, abortions and birth defects. Br
J Clin Pharmacol 2007; 63:196.
Blasiak RC, et al: High-dose isotretinoin treatment and the rate of retrial,
relapse, and adverse effects in patients with acne vulgaris. JAMA
Dermatol 2013; 149:1392–1398.
Bowe WP, et al: Diet and acne. J Am Acad Dermatol 2010; 63:124.
Brown RJ, et al: Minocycline-induced drug hypersensitivity syndrome
followed by multiple autoimmune sequelae. Arch Dermatol 2009;
145:63.
Bruzzese V: Pyoderma gangrenosum, acne conglobata, suppurative
hidradenitis, and axial spondyloarthritis. J Clin Rheumatol 2012;
18:413–415.
Chen W, et al: Acne-associated syndromes. J Eur Acad Dermatol
Venereol 2011; 25:637–646.
Costello M, et al: Insulin-sensitising drugs versus the combined oral
contraceptive pill for hirsutism, acne and risk of diabetes,
cardiovascular disease, and endometrial cancer in polycystic ovary
syndrome. Cochrane Database Syst Rev 2007; 1:CD005552.
Cyrulnik AA, et al: High-dose isotretinoin in acne vulgaris. Int J Dermatol
2012; 51:1123–1130.
Dalamaga M, et al: Ovarian SAHA syndrome is associated with a more
insulin-resistant profile and represents an independent risk factor for
glucose abnormalities in women with polycystic ovary syndrome. J Am
Acad Dermatol 2013; 69:922–930.
Dreno B, et al: Large-scale international study enhances understanding
of an emerging acne population. J Eur Acad Dermatol Venereol 2014;
Oct 8.
Eichenfiled LF, et al: Evidence-based recommendations for the diagnosis
and treatment of pediatric acne. Pediatrics 2013; 131:mS163.
Frangos JE, et al: Acne and oral contraceptives. J Am Acad Dermatol
2008; 58:781.
Gamble R, et al: Topical antimicrobial treatment of acne vulgaris. Am J
Clin Dermatol 2012; 13:141–152.
Garner SE, et al: Minocycline for acne vulgaris. Cochrane Database
Syst Rev 2012; 8:CD002086.
Goodman GJ, et al: The management of postacne scarring. Dermatol
Surg 2007; 33:1175.
Hahm BJ, et al: Changes of psychiatric parameters and their relationships
by oral isotretinoin in acne patients. J Dermatol 2009; 36:255.
Hu S, et al: Fractional resurfacing for the treatment of atopic facial acne
scars in Asian skin. Dermatol Surg 2009; 35:826.
Ismail NH, et al: High glycemic load diet, milk, and ice cream
consumption are related to acne vulgaris in Malaysian young adults.
BMC Dermatol 2012; 12:13.
Jacobls A, et al: Systemic review of the rapidity of the onset of action of
topical treatments in the therapy of mild-to-moderate acne vulgaris. Br J
Dermatol 2014; 170:557.
 James WD: Clinical practice: acne. N Engl J Med 2005; 352:1463. Fig. 13-13 Acne
Kwon HH, et al: Clinical and histological effect of a low glycaemic load conglobata with fistula
diet in treatment of acne vulgaris in Korean patients. Acta Derm formation.
Venereol 2012; 92:241–246.
Lee AT, et al: Dermatologic manifestations of polycystic ovary

Acne fulminans
syndrome. Am J Clin Dermatol 2007; 8:201.
Leyden JJ, et al: The use of isotretinoin in the treatment of acne
vulgaris. J Clin Aesthet Dermatol 2014; 7:S3–S21.
Manolache L, et al: A case of solid facial oedema successfully treated
with isotretinoin. J Eur Acad Dermatol Venereol 2009; 23:965.
Margolis D, et al: Potential association between the oral tetracycline
class of antimicrobials used to treat acne and inflammatory bowel
disease. Am J Gastroenterol 2010; 105:2610–2616.
Mays RM, et al: New antibiotic therapies for acne and rosacea.
Dermatol Ther 2012; 25:23–37.
Morrone A, et al: Clinical features of acne vulgaris in 444 patients with
ethnic skin. J Dermatol 2011; 38:405-408.
Nast A, et al: European evidence-based guidelines for the treatment of
acne. J Eur Acad Dermatol Venereol 2012; 26:S1–S29.
Perkins AC, et al: Acne vulgaris in women. J Womens Health (Larchmt)
2012; 21:223–230.
Rowe C, et al: Isotretinoin and mental health in adolescents. Australas J
Dermatol 2014; 55:162–167.
Sakamoto FH, et al: Photodynamic therapy for acne vulgaris. J Am Acad
Dermatol 2010; 63:183–193, 195–211.
Sand FL, et al: Adalimumab for the treatment of refractory acne Fig. 13-14 Acne
conglobata. JAMA Dermatol 2013; 149:1306–1307. conglobata of the
Strahan JE, et al: Cyclosporine-induced infantile nodulocystic acne. back. (Courtesy of
Arch Dermatol 2009; 145:797. Dr. Don Adler.)
Strauss JS, et al: Guidelines of care for acne vulgaris management.
J Am Acad Dermatol 2007; 56:651.
Taub AF: Procedural treatments for acne vulgaris. Dermatol Surg 2007;
33:1005.

ACNE CONGLOBATA
Cystic acne is the mildest orm o acne conglobata (conglobate
means shaped in a rounded mass) an unusually se ere type
o acne. This orm is characteri ed by numerous comedones
(many o which are double or triple) and large abscesses with
interconnecting sinuses cysts and grouped in ammatory
nodules ( ig. ). Suppuration is characteristic o acne con
globata. Pronounced scars remain a ter healing.
The cysts occur on the bac buttoc s chest orehead
chee s anterior nec and shoulders ( ig. ). They contain
a thic yellowish iscid stringy blood tinged uid. A ter
incision and drainage there is re uently a prompt re lling
with the same type o material. These cysts are suggesti e o
the type ound in hidradenitis suppurati a. idradenitis sup
purati a and dissecting cellulitis o the scalp may be seen with Bruzzese V: Pyoderma gangrenosum, acne conglobata, suppurative
hidradenitis, and axial spondyloarthritis. J Clin Rheumatol 2012;
acne conglobata an association nown as the ollicular occlu
18:413–415.
sion triad. Gerber PA, et al: The dire consequences of doping. Lancet 2008;
This se ere and pain ul disease occurs most re uently in 372:656.
young men about years old; it may e tend and persist into Hasegawa T, et al: Acne conglobata successfully treated by fractional
adulthood and e en into the th decade o li e especially o er laser after CO2 laser abrasion of cysts combined with topical tretinoin.
the posterior nec and bac . Women are less re uently J Dermatol 2009; 36:118.
a ected. Athletes and bodybuilders should be uestioned Myers JN, et al: Treatment of acne conglobata with modern external
about the use o anabolic steroids which may induce such beam radiation. J Am Acad Dermatol 2010; 62:861–863.
aggressi e acne.
The therapy o choice in all but the earliest lesions is isotreti
noin . mg g day to a total dose o mg g with a
second course i resolution does not occur a ter a rest period
ACNE FULMINANS
o months. Pretreatment with prednisone and low initial
doses o isotretinoin as described or acne ulminans are rec Acne ulminans is a rare orm o e tremely se ere cystic acne
ommended to a oid aring o disease. Carbon dio ide (C ) that occurs primarily in teenage boys. t is characteri ed
ractional laser abrasion o cysts e ternal beam radiation and by highly in ammatory nodules and pla ues that undergo
in i imab are other reported therapies. n i imab cleared a swi t suppurati e degeneration lea ing ragged ulcerations
patient in whom pyoderma gangrenosum acne conglobata mostly on the chest and bac . The ace is usually less se erely
suppurati e hidradenitis (PAS ) alone or with coe isting in ol ed. e er and leu ocytosis are common. Polyarthralgia
a ial spondyloarthritis (PASS syndrome). and polymyalgia destructi e arthritis and myopathy ha e
233

tahir99 - UnitedVRG
 been reported in association with acne ulminans. ocal lytic Soyfoo MS, et al: Successful treatment of SAPHO syndrome with
13 bone lesions may be seen. As in acne conglobata anabolic
steroids ta en by bodybuilders may induce this condition.
ibandronate. J Clin Rheumatol 2010; 16:253.

Prednisone mg is necessary during the initial

wee s to calm the dramatic in ammatory response o acne OTHER ACNE VARIANTS
Acne

ulminans. A ter wee s mg o isotretinoin is added.

This should be slowly increased to standard doses and contin
ued or a ull mg g cumulati e course. Large cysts
may be opened and the contents e pressed. ntralesional cor
ticosteroids will aid their resolution. n i imab and dapsone
are alternati es i isotretinoin is contraindicated.
Iqbal M, et al: Acne fulminans with SAPHO syndrome treated with
infliximab. J Am Acad Dermatol 2005; 52:S118.
Krause SL, et al: The dark side of beauty. Arch Dermatol 2012;
148:1210–1212.
Lages RB, et al: Acne fulminans successfully treated with prednisone
and dapsone. An Bras Dermatol 2012; 87:612–614.
Zaba R, et al: Acne fulminans. J Eur Acad Dermatol Venereol 2011;
25:501–507.
Tropical acne
Tropical acne is unusually se ere acne occurring in the tropics
during the seasons when the weather is hot and humid.
odular cystic and pustular lesions occur chie y on the bac
buttoc s and thighs ( ig. ). Characteristically the ace is
spared. Conglobate abscesses occur o ten especially on the
bac . Comedones are sparse. Acne tropicalis usually occurs in
young adults who may ha e had acne ulgaris at an earlier
age. This is especially true o those in the armed orces sta
tioned in the tropics and carrying bac pac s. Treatment is that
or cystic acne but acne tropicalis may persist until the patient
mo es to a cooler less humid climate.

SAPHO SYNDROME
The SAP syndrome is characteri ed by syno itis acne
pustulosis hyperostosis and osteitis. S in ndings may
include acne ulminans acne conglobata pustular psoriasis
hidradenitis suppurati a dissecting cellulitis o the scalp
Sweet syndrome Sneddon Wil inson disease and palmo
plantar pustulosis. These may be present at the outset o the
s eletal changes but most o ten precede bone ndings or in
o adult cases and o childhood cases do not occur
at all. The chest wall and mandible are the most common sites
or musculos eletal complaints in adults; the long bones par
ticularly the tibia predominate in children. Bone changes o
the anterior chest wall on nuclear scans are the most speci c
diagnostic ndings. Ac uired hyperostosis syndrome (A S)
and in a amilial setting o a dominantly inherited disorder
pyogenic sterile arthritis pyoderma gangrenosum and acne
(PAPA syndrome) both present with similar clinical scenarios.
PAPA syndrome is caused by mutations in the gene or
proline serine threonine phosphatase interacting protein .
Systemic retinoids and tumor necrosis actor (T ) antago
nists particularly in i imab ha e been success ul in treating
these patients. nterestingly Crohn s disease may be associ
ated with SAP syndrome or may occur during treatment
with T antagonists. isotretinoin is used it should be initi
ated at a low dosage such as mg day in combination with
prednisone or the rst month to pre ent aring o the disease.
Ana inra methotre ate sul asala ine and cyclosporine are
other less well documented but li ely e ecti e choices. Pami
dronate and other bisphosphonates such as ibandronate alen
dronate and oledronic acid are e ecti e in treating the
osteoarticular mani estations.
Acne estivalis
Also nown as allorca acne this rare orm o acne starts in
the spring progresses during the summer and resol es com
pletely in the all. Acne esti alis a ects almost e clusi ely
women age . Dull red dome shaped hard small papules
usually not larger than mm de elop on the chee s and
usually e tend on to the sides o the nec chest shoulders and
characteristically the upper arms. Comedones and pustules are
notably absent or sparse. Acne esti alis does not respond to
antibiotics but bene ts rom application o retinoic acid.
Excoriated acne
Also nown as pic er s acne and acne e cori e des eunes
lles e coriated acne is seen primarily in young women with
a super cial type o acne. The primary lesions are tri ial
or e en none istent but the compulsi e neurotic habit o
pic ing the ace and s uee ing minute comedones produces
secondary lesions that crust and may lea e scars. ten the
lesion that is e coriated is minute seen only in a magni ying
mirror.
coriated acne may be a sign o depression or an iety. t is
an obsessi e compulsi e symptom. the patient admits to
pic ing but being unable to stop this habit impro ement may
Fig. 13-15 Tropical
acne.

Chen W, et al: Acne-associated syndromes. J Eur Acad Dermatol

Venereol 2011; 25:637–646.
Colina M, et al: Clinical and radiologic evolution of synovitis, acne,
pustulosis, hyperostosis, and osteitis syndrome. Arthritis Rheum 2009;
61:813.
Firinu D, et al: Biological treatments for SAPHO syndrome. Inflamm
Allergy Drug Targets 2014; 13:199.
Galadari H, et al: Synovitis, acne, pustulosis, hyperostosis, and osteitis
syndrome treated with a combination of isotretinoin and pamidronate.
J Am Acad Dermatol 2009; 61:123.
Garcovich S, et al: Long-term treatment of severe SAPHO syndrome
with adalimumab. Am J Clin Dermatol 2012; 13:55–59.
Naves JE, et al: A systematic review of SAPHO syndrome and
inflammatory bowel disease association. Dig Dis Sci 2013;
58:2138–2147.
Nguyen MT, et al: The SAPHO syndrome. Semin Arthritis Rheum 2012;
42:254–265.
234
 ollow support and acne therapy. owe er most patients will
re uire inter entions with selecti e serotonin reupta e inhibi
tors beha ior modi cation or psychotherapy. ther pharma
cologic treatments that ha e been success ul in case reports
include do epin clomipramine naltre one pimo ide and
olan apine.
Gieler U, et al: Self-inflicted lesions in dermatology. Acta Derm Venereol
2013; 93:4–12.
Hjorth N, et al: Acne aestivalis: Mallorca acne. Acta Dermatol Venereol
1972; 2:61.
Wells JM: Tropical acne—one hundred cases. J R Army Med Corps
1981; 127:55.
ACNEIFORM ERUPTIONS
Acnei orm eruptions are ollicular eruptions characteri ed by
papules and pustules resembling acne. Brea s in the epithe
lium and spillage o ollicular contents into the dermis lead to
the lesions. ruptions are not necessarily con ned to the usual
sites o acne ulgaris o ten ha e a sudden onset are mono
morphous and usually appear in a patient well past adoles
cence. secondary to a drug an eruption begins within days
o initiation o the medication may be accompanied by e er
and malaise and resol es when the drug is stopped.
Acnei orm eruptions may originate rom s in e posure to
arious industrial chemicals such as umes generated in the
manu acture o chlorine and its byproducts. These chlorinated
hydrocarbons may cause chloracne consisting o cysts pus
tules olliculitis and comedones. The most potent acnei orm
inducing agents are the polyhalogenated hydrocarbons
notably dio in ( tetrachlorodiben o p dio in). Cutting
and lubricating oils pomades crude coal tar applied to the
s in or medicinal purposes hea y tar distillates coal tar
pitch and asbestos are nown to cause acnei orm eruptions.
Acne enenata or contact acne is another term applied to this
process.
Acnei orm eruptions are induced by medications such as
iodides rom radiopa ue contrast media or potassium iodide
bromides in drugs such as propantheline bromide testoster
one cyclosporine antiepileptic medications lithium and sys
temic corticosteroids. When medium or high doses o
corticosteroids are ta en or as brie y as days a distincti e
eruption may occur nown as steroid acne. t is a sudden
outcropping o in amed papules most numerous on the
upper trun and arms ( ig. ) but also seen on the ace.
The lesions typically present as papules rather than comedo
nes; howe er a histologic study con rmed they begin ollicu
larly with microcomedone ormation. Tretinoin (Retin A)
. cream applied once or twice daily may clear the lesions
within months despite the continuation o high doses o
corticosteroid. ral antibiotics and other typical acne medica
tions are also e ecti e. Topical steroids especially the uori
nated types or when applied under occlusion may also induce
an acnei orm eruption. Topical tacrolimus and pimecrolimus
may both induce a papulopustular eruption. pidermal
growth actor inhibitors including monoclonal antibodies and
tyrosine and multi inase inhibitors used in cancer therapy
produce a olliculitis in the ma ority o treated patients. ten
oral minocycline and topical ben oyl pero ide are gi en pro
phylactically at the outset o the cancer therapy to pre ent
what may be a dose limiting reaction. Radiation therapy or
malignancy also can induce acne in the radiation port.
Comedonal lesions may be limited to the nasal crease in the
e ural areas in children and on the temple and malar s in in
a re Racouchot syndrome.
Cho SB, et al: A new case of childhood flexural comedones. J Eur Acad
Dermatol Venereol 2009; 23:366–367.
tahir99 - UnitedVRG
Fig. 13-16 Steroid
acne. (Courtesy of
Curt Samlaska, MD.)
Gram-negative folliculitis
Dessinioti C, et al: Acneiform eruptions. Clin Dermatol 2014; 32:24–34.
Hameed AF: Steroid dermatitis resembling rosacea. ISRN Dermatol
2013; 49:1376.
Kraus SL, et al: The dark side of beauty: acne fulminans induced by
anabolic steroids in a male bodybuilder. Arch Dermatol 2012;
148:1210–1212.
Li JC, et al: Facial acne during topical pimecrolimus therapy for vitiligo.
Clin Exp Dermatol 2009; 34:e489–e490.
Li T, et al: Skin toxicities associated with epidermal growth factor
receptor inhibitors. Target Oncol 2009; 4:107.
Melnik B, et al: Abuse of anabolic-androgenic steroids and
bodybuilding acne. J Dtsch Dermatol Ges 2007; 5:110.
Momin SB, et al: A status report on drug-associated acne and
acneiform eruptions. J Drugs Dermatol 2010; 9:627–636.
Pelclova D, et al: Adverse health effects in humans exposed to
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Rev Environ Health 2006;
21:119.
Petukhova TA, et al: Acneiform eruptions associated with vemurafenib.
J Am Acad Dermatol 2013; 68:e97–e99.
Saurat JH, et al: The cutaneous lesions of dioxin exposure. Toxicol Sci
2012; 125:310–317.
Waller B, et al: Transverse nasal crease and transverse nasal milia.
Arch Dermatol 2012; 148:1037–1039.
GRAM-NEGATIVE FOLLICULITIS
Gram negati e olliculitis occurs in patients who ha e had
moderately in ammatory acne or long periods and ha e been
treated with long term antibiotics mainly tetracyclines.
During antibiotic treatment patients de elop either super cial
pustules mm in diameter aring out rom the anterior
nares or uctuant deep seated nodules ( ig. ). Culture
o these lesions usually re eals a species o lebsiella Esche
richia coli Enterobacter or rom the deep cystic lesions Proteus.
With long term broad spectrum antibiotic therapy the
anterior nares may become coloni ed with these gram negati e
organisms. As the use o long term antibiotic therapy declines
this disease has become less common.
sotretinoin is ery e ecti e and is the treatment o choice
in gram negati e olliculitis. This treatment not only clears
the acne component o the disease but also eliminates the
coloni ation o the anterior nares with gram negati e organ
isms. isotretinoin cannot be tolerated or is contraindicated
235
 amo icillin or T P S may be e ecti e in suppressing the
13 disease.
Boni R, et al: Treatment of gram-negative folliculitis in patients with
acne. Am J Clin Dermatol 2003; 4:273.
Acne
Lehrhoff S, et al: Serratia marcescens folliculitis and concomitant acne
vulgaris. Dermatol Online J 2012; 18:19.
ACNE KELOIDALIS
Acne eloidalis is most re uently encountered in young adult
blac ispanic or Asian men who otherwise are in e cellent
health. t is not associated with acne ulgaris and is a primary
cicatricial alopecia ariant. eloid acne is a persistent ollicu
litis and peri olliculitis o the bac o the nec that presents as
in ammatory papules and pustules. er time brosis ensues
with coalescence o rm papules into eloidal pla ues as on
the nec (acne eloidalis nuchae ig. ). At times sinus
tract ormation results.
istologically acne eloidalis is characteri ed by peri ol
licular chronic lymphocytic and plasmacytic in ammation
most intense at the le el o the isthmus and lower in undibu
lum o terminal hairs. There is lamellar broplasia most
mar ed at the le el o the isthmus and e entually in the
eloidal masses; the connecti e tissue becomes sclerotic
orming hypertrophic scars or eloids. Persistent ree hairs in
the dermis may be responsible or the prolonged in ammation
and e entual scarring.
Topical therapy with potent steroid ointments or oams
alone or ollowing twice daily tretinoin gel is use ul or the
ollicular papules. ral antibiotics o the tetracycline group
may be added and are help ul in suppressing the in amma
Fig. 13-17 Gram-negative folliculitis.
Fig. 13-18 Acne keloidalis nuchae.
236
tory response. Triamcinolone acetonide by intralesional in ec
tion using
and
mg mL into the in ammatory ollicular lesions
mg mL into the hypertrophic scars and eloids is
use ul in reducing in ammation and brosis. Smaller lesions
may be e cised to a le el below the hair ollicle and closed.
This may be ollowed by mg mL triamcinolone by intral
esional in ection e ery wee s. or larger lesions deep e ci
sion or C laser ablation le t to heal by primary intention may
be necessary. Laser hair remo al with the neodymium yttrium
aluminum garnet ( d AG) laser may be used as a pre en
ti e measure against acne eloidalis.
Bajaj V, et al: Surgical excision of acne keloidalis nuchae with
secondary intention healing. Clin Exp Dermatol 2008; 33:53.
Dragoni F, et al: Successful treatment of acne keloidalis nuchae
resistant to conventional therapy with 1064-nm ND:YAG laser. G Ital
Dermatol Venereol 2013; 148:231–232.
Esmat SM, et al: The efficacy of laser-assisted hair removal in the
treatment of acne keloidalis nuchae. Eur J Dermatol 2012; 22:645–650.
HIDRADENITIS SUPPURATIVA
Clinical features
idradenitis suppurati a is a chronic disease characteri ed by
recurrent abscess ormation primarily within the olded areas
o s in that contain both terminal hairs and apocrine glands.
The primary site o in ammation is not the gland but the ter
minal hair. Plewig uses the term dissecting terminal ollicu
litis to uni y diseases primarily a ecting the terminal hair
ollicle such as hidradenitis suppurati a acne eloidalis
nuchae pilonidal sinus and dissecting cellulitis o the scalp.
The a illa is the most re uently a ected site. The inguinal and
submammary areas are a ored in women ( igs. and
) with the buttoc perianal area and atypical areas (e.g.
retroauricular trun ) more o ten a ected in men although
any and all areas may be a ected in either gender. This post
pubertal process a ects women about our times more o ten
than men.
The disease is characteri ed by the de elopment o tender
red nodules which at rst are rm but soon become uctuant
and pain ul. Rupture o the lesion suppuration ormation o
sinus tracts and e tensi e scarring are distincti e. As one area
heals recurrent lesions orm so that the course o the disease
is protracted. t may e entually lead to the ormation o hon
eycombed stulous tracts with chronic in ection. The indi
idual lesions contain a thic iscous mucoid suppurati e
material. When a probe is used to e plore the suppurating
Fig. 13-19 Hidradenitis of the axilla.

Fig. 13-20 Hidradenitis of the groin.
nodule a burrowing sinus tract is usually detected that may
e tend or many centimeters running hori ontally ust under
neath the s in sur ace.
Disease se erity aries as does the impact on uality o
li e rom this chronic recurrent pain ul odi erous messy
condition. The ma ority o the appro imately o the
population a ected by hydradenitis suppurati a are mildly
a ected. Se ere debilitation occurs more o ten in men than
in women. en also more o ten ha e a history o acne
and pilonidal cysts. S uamous cell carcinoma (SCC a ter an
a erage years o acti e disease) interstitial eratitis spon
dyloarthropathy urethral esical and rectal stulas anemia
hypoproteinemia and amyloidosis ha e been reported to
complicate hidradenitis suppurati a but are rare. Pyoderma
gangrenosum lesions complicate this condition at times with
the diagnosis dependent on the clinical signs o a rapidly
e panding pain ul ulcer with undermined edges. These
lesions occur a median o years a ter the onset o hidrad
enitis and may be at sites distant rom or within the area o
the hidradenitis lesions. Some o these patients may ha e
associated conglobate acne (PAS ) or PASS syndrome. Sig
ni cant lymphedema o the penis and groin along with
alteration o the anatomy because o surgical inter ention
o ten ma es physical e amination o these sites di cult. The
ris o SCC occurring as an ulceration or thic ening in a s in
crease which can metastasi e and cause death re uires
attention to detail in this regard.
Etiology
Detailed histologic studies o hidradenitis suppurati a re eal
that terminal ollicle hyper eratosis is ollowed by rupture o
the ollicular epithelium and release o eratin sebum bacte
ria and hairs into the dermis. The resulting in ammatory
process engul s the apocrine gland and leads to rupture o the
o erlying s in brosis and sinus tract ormation. Secondary
bacterial in ection with Staph lococcus aureus Streptococcus p o
genes and arious gram negati e organisms may occur. The
initiating e ent is un nown. Comorbidities include obesity
metabolic syndrome in ammatory bowel disease and poly
cystic o arian syndrome. echanical riction o ten worsened
by obesity is an e acerbating actor as is bacterial in ection.
There is an autosomal dominant inherited orm o this disease.
utations in the gamma secretase genes CS PSE E
and PSE ha e been identi ed. utation positi e patients
ha e se ere and e tensi e disease and may ha e onset be ore
age .
tahir99 - UnitedVRG
Differential diagnosis
idradenitis is to be di erentiated rom common uruncles
which are typically unilateral. idradenitis must also be di
erentiated rom Bartholin abscess scro uloderma actinomyco
Hidradenitis suppurativa
sis granuloma inguinale and lymphogranuloma enereum.
Treatment
The earliest lesions o ten heal uic ly with intralesional steroid
therapy which may be used initially in combination with
topical Cleocin or oral do ycycline or minocycline. Topical
daily cleansing with chlorhe idine gluconate ( ibiclens) solu
tion or ben oyl pero ide wash is an important pre enti e
measure. Additionally laser hair remo al i per ormed
should be done in una ected sites as a pre enti e therapy.
ther general pre enti e strategies include reduction o ric
tion by wearing loose tting clothing and weight loss i
needed and a oidance o e cessi e sweating through the
use o topical aluminum chloride or botulinum to in A in ec
tions smo ing cessation and heat a oidance. The disease
itsel causes sterile abscesses but culture o the pus may re eal
S aureus or gram negati e organisms. The latter are usually
cultured in patients with chronic disease gi en long term anti
biotic therapy; antibiotics should be selected based on sensi
ti ities o the cultured organism. Antibiotics that may be
use ul in suppressing the disease long term include the tetra
cyclines amo icillin T P S DS or dapsone. The combina
tion o clindamycin and ri ampin both gi en in doses o
mg twice daily has been e tensi ely studied in urope
and ound to be uite e ecti e. n se erely a ected patients
admission and treatment with intra enous ertapenem was
reported to calm the disease so outpatient oral management
might be e ecti e. ncision and drainage is strongly
discouraged.
sotretinoin and acitretin are e ecti e in some cases but a
remission seldom ollows their use. Secondary in ection with
S aureus o ten occurs. The T antagonists ha e all been used;
in i imab is most e ecti e and may clear the condition during
use. n women spironolactone and Cs and nasteride in men
or postmenopausal women may be a help ul ad u ant. Cyclo
sporine or uste inumab may wor well in select cases.
Photodynamic therapy and lasers ha e also been in estigated
to arious degrees in hidradenitis. ethyl aminole ulinate or
aminole ulinic acid gi en be ore blue or red light acti ation
(photodynamic therapy) has had reports o success in some
cases but also anecdotal reports o lac o e cacy. t is incon
enient costly and o ten pain ul and does not produce remis
sion so urther studies are re uired be ore such treatment can
be recommended. d AG laser treatment has been reported
to be e ecti e in a prospecti e randomi ed controlled trial o
se erely a ected patients. A ter a series o three monthly
sessions signi cant impro ement was seen.
Chances o permanent cure are best when e cision o the
a ected areas is done. Wide surgical e cision using intraop
erati e color mar ing o sinus tracts is most e ecti e at limit
ing recurrence; howe er it has moderate morbidity especially
in the groin and perianal areas. The recurrence rate is low in
the a illary and perianal areas; howe er the inguinal olds
and especially the submammary sites more o ten recur so that
e cision o the latter site is uncommonly recommended. C
laser may also destroy lesions and sinus tracts. The open areas
may be closed or le t to heal secondarily.
ost patients with se ere recalcitrant hidradenitis suppura
ti a responded to the approach reported by an Rappard
combination clindamycin and ri ampin each mg twice
daily or to months. patients do not respond and a clear
237
 in ammatory component is present in i imab is added with Fig. 13-21 Dissecting
13 in usions gi en at wee s
wee s. A ter
and subse uently e ery
months any remaining sinuses and stulas
folliculitis. (Courtesy of
Curt Samlaska, MD.)
not responding to treatment are remo ed surgically.
Acne

Alhusayen R, et al: Pharmacologic interventions for hidradenitis

suppurativa. Am J Clin Dermatol 2012; 13:283–291.
Alikhan A, et al: Hidradenitis suppurativa. J Am Acad Dermatol 2009;
60:539.
Blok JL, et al: Systemic therapy with immunosuppressive agents
and retinoids in hidradenitis suppurativa. Br J Dermatol 2012;
168:243–252.
Bruzzese V: Pyoderma gangrenosum, acne conglobata, suppurative
hidradenitis, and axial spondyloarthritis. J Clin Rheumatol 2012;
18:413–415.
Deckers IE, et al: Correlation of early-onset hidradenitis suppurativa with
stronger genetic susceptibility and more widespread involvement. J
Am Acad Dermatol 2015; S0190-9622(14)02202-6.
Howland N, et al: Approach to the severe hidradenitis suppurativa
patient. Plast Reconstr Surg 2014: 134:148.
Hsiao JL, et al: Hidradenitis suppurativa and concomitant pyoderma
gangrenosum. Arch Dermatol 2010; 146:1265–1270.
Kimball AB, et al: Adalimumab for the treatment of moderate to
severe hidradenitis suppurativa. Ann Intern Med 2012;
157:846–855.
Kirby JS, et al: Health care utilization patterns and costs for patients
with hidradenitis suppurativa. JAMA Dermatol 2014; 150:937.
Kraft JN, et al: Hidradenitis suppurativa in 64 female patients: Scarring and alopecia ensue although seropurulent drainage
retrospective study comparing oral antibiotics and antiandrogen may last inde nitely. Adult blac men are most o ten a ected
therapy. J Cutan Med Surg 2007; 11:125. and the erte and occiput o the scalp are the a ored sites.
Levogiez C, et al: Clinicopathological study of 13 cases of squamous The primary lesions are ollicular and peri ollicular ery
cell carcinoma complicating hidradenitis suppurativa. Dermatology thematous papules that progress to abscesses. This disease is
2010; 220:147–153. a ariant o dissecting terminal hair olliculitis along with
Mendoca CO, et al: Clindamycin and rifampicin combination therapy for
hidradenitis suppurati a acne eloidalis nuchae and piloni
hidradenitis suppurativa. Br J Dermatol 2006; 154:977.
Micheletti RG: Natural history, presentation, and diagnosis of
dal sinus. Coagulase positi e S aureus may be ound in the
hidranenitis suppurativa. Semin Cutan Med Surg 2014; 33:S51. lesions.
Mikkelsen PR, et al: Hidradenitis suppurativa in children and Treatment with oral antibiotics such as the tetracyclines
adolescents. Paediatr Drugs 2014; Sep 19. T PS or the uinolones may produce good results. S
Miller IM, et al: Association of metabolic syndrome and hidradenitis aureus is cultured the combination o oral ri ampin and clinda
suppurativa. JAMA Dermatol 2014; 150:1273–1280. mycin has produced e cellent results. The combination o
Nassif A, et al: Complete remission of severe hidradenitis suppurativa intralesional steroid in ections and isotretinoin at a dose o
obtained in 4 patients using wide-spectrum antimicrobial treatment. . . mg g day or months may be success ul. Start
J Am Acad Dermatol 2012; 66 (poster abstract). ing at a lower dose such as mg day or the rst month or
Pink AE, et al: Gamma-secretase mutations in hidradenitis suppurativa.
two may pre ent a are o the condition. The length o remis
J Invest Dermatol 2013; 133:601–607.
Rambhatla PV, et al: A systematic review of treatments for hidradenitis sion with isotretinoin is ariable but treatment may be
suppurativa. Arch Dermatol 2012; 148:439–446. repeated with similar results e pected. The anti T medica
Randhawa HK, et al: Finasteride for the treatment of hidradenitis tions in i imab and adalimumab and the retinoid alitretinoin
suppurativa in children and adolescents. JAMA Dermatol 2013; ha e been help ul in indi idual cases.
149:732–735. A surgical approach is sometimes necessary. arsupiali a
Saraceno R, et al: Methyl aminolevulinate photodynamic therapy for the tion or e cision o sinus tracts may help limit in ammation.
treatment of hidradenitis suppurativa and pilonidal cysts. The d AG laser used to remo e hair has led to long term
Photodermatol Photoimmunol Photomed 2009; 25:164. impro ement. cision o the entire scalp has been necessary
Schrader AM, et al: Hidradenitis suppurativa. J Am Acad Dermatol
in select patients.
2014; 71:460.
Shlyankevich J, et al: Hidradenitis suppurativa is a systemic disease Georgala S, et al: Dissecting cellulitis of the scalp treated with rifampicin
with substantial comorbidity burden. J Am Acad Dermatol 2014; and isotretinoin. Cutis 2008; 82:195.
71:1144. Greenblatt DT, et al: Dissecting cellulitis of the scalp responding to oral
Tierney E, et al: Randomized control trial for the treatment of quinolones. Clin Exp Dermatol 2008; 33:99.
hidradenitis suppurativa with a neodymium-doped yttrium-aluminum- Housewright CD, et al: Excisional surgery (scalpectomy) for dissecting
garnet laser. Dermatol Surg 2009; 35:1. cellulitis of the scalp. Dermatol Surg 2011; 37:1189–1191.
Van Rappard DC, et al: Treatment of severe hidradenitis suppurativa with Krasner BD, et al: Dissecting cellulitis treated with the long-pulsed
infliximab in combination with surgical intervention. Br J Dermatol Nd:YAG laser. Dermatol Surg 2006; 32:1039.
2012; 167:202–208. Navarinni AA, et al: 3 cases of dissecting cellulitis of the scalp treated
with adalimumab. Arch Dermatol 2010; 146:517–520.
Prasad SC, et al: Successful treatment with alitretinoin of dissecting
cellulitis of the scalp in keratitis-ichthyosis-deafness syndrome. Acta
DISSECTING CELLULITIS OF THE SCALP Derm Venereol 2013; 93:473–474.

Also nown as peri olliculitis capitis abscedens et su odiens

this is an uncommon chronic suppurati e disease o the scalp
characteri ed by numerous ollicular and peri ollicular in am
matory nodules. These nodules suppurate and undermine to
orm intercommunicating sinuses as long as cm ( ig. ).
238
ACNE MILIARIS NECROTICA (ACNE VARIOLIFORMIS)
Acne miliaris necrotica consists o ollicular esicopustules
sometimes occurring as solitary lesions that usually are
e tremely itchy. They appear anywhere in the scalp or ad a
cent areas rupture early and dry up a ter a ew days. n some
patients especially those who manipulate the lesions S aureus
may be cultured. the lesions lea e large scars the term acne
arioli ormis is used; they are not separate diseases.
lushing is less common as is telangiectasia but persistent
edema may be problematic. Rhinophyma most o ten occurs in
this glandular subtype ( ig. ). Large hypertrophic
hyperemic nodular masses are centered o er the distal hal o
the nose. Di erentiation o this hypertrophic tissue rom a

Treatment is with culture directed antibiotics or i the
culture is negati e oral do ycycline. Do epin is help ul i
patients manipulate their lesions.
Fisher DA: Acne necroticans and Staphylococcus aureus. J Am Acad
Dermatol 1988; 18:1136.
Zirn JR, et al: Chronic acneiform eruption with crateriform scars. Arch
Dermatol 1996; 132:1365.
Rosacea
basal cell s in cancer or a cutaneous B cell lymphoma is at
times di cult. Rarely such so t tissue o ergrowth can a ect
the chin ears or orehead. ugely dilated ollicles contain
long ermicular plugs o sebum and eratin. The histologic
eatures are pilosebaceous gland hyperplasia with brosis
in ammation and telangiectasia.

Etiology
ROSACEA
The cause o rosacea remains un nown. ost patients ha e
Clinical features an abnormal asomotor response to thermal and other

Rosacea is characteri ed by a persistent erythema o the con e

Fig. 13-23
sur aces o the ace with the chee s and nose most re uently Papulopustular
a ected ollowed by in ol ement o the brow and chin. There rosacea. (Courtesy of
is a tendency to spare the periocular s in. Rosacea occurs most Curt Samlaska, MD.)
o ten in light s inned women age . owe er the se ere
type with phymatous changes occurs almost e clusi ely in
men. Additional common eatures include telangiectasia
ushing erythematous papules and pustules. These tend to
cluster in patterns allowing or the identi cation o se eral
subsets o patients; their recognition is important because the
therapeutic implications di er.
The erythrotelangiectatic type is characteri ed by a promi
nent history o a prolonged (> min) ushing reaction to
arious stimuli such as emotional stress hot drin s alcohol
spicy oods e ercise cold or hot weather or hot baths and
showers ( ig. ). ten a burning or stinging sensation
accompanies the ush but with no sweating lightheadedness
or palpitations. The s in is nely te tured may ha e a rough
ness and scaling o the a ected central acial sites and is easily
irritated. er time a purplish su usion and prominent tel
angiectasia may result.
The papulopustular subset o patients mani ests a stri ingly
red central ace accompanied by erythematous papules o ten
surmounted by a pinpoint pustule ( ig. ). The history o
ushing is also present in most patients but usually symp
toms o irritancy are not prominent. The s in is o normal or
at times slightly sebaceous uality and edema o the a ected Fig. 13-24 Glandular
sites may be present. Such edema may dominate the clinical rosacea.
presentation with the orehead eyelids and chee s ariably
a ected. This has been termed orbihan s disease and is most
li ely to complicate the papulopustular and glandular types.
n the glandular type o rosacea men with thic sebaceous
s in predominate. The papules are edematous the pustules
are o ten . . cm in si e and nodulocystic lesions may be
present ( ig. ). They tend to cluster in the central ace but
in a ected women the chin is a ored. There is re uently a
history o adolescent acne and typical scars may be seen.

Fig. 13-22
Erythrotelangiectatic
rosacea.

239

tahir99 - UnitedVRG
13
Acne
Fig. 13-25 Rhinophyma.
stimuli as pre iously described. arly in the process dys
regulation o the innate immune system and neuro ascular
control is documented. Additionally chronic solar damage is
an important contributor in producing damage to the dermal
matri and ground substance especially in the erythrotelan
giectatic subtype. Chronic asodilation edema and compro
mise o lymphatic drainage occur and lead to telangiectasia
and brosis. Pilosebaceous unit abnormalities are not typi
cally thought to be part o the pathogenesis o this condition;
howe er some e idence points to abnormalities being
present especially in the patient with the glandular type. As
e pected the pathogenic actors will ary among the subsets
o patients. Demo ex and elicobacter p lori ha e been e ten
si ely in estigated and do not appear to be central to the
etiology o rosacea.
Other clinical considerations
Ocular findings
Blepharitis recurrent chala ion and con uncti itis may be
seen in all subsets o rosacea ( ig. ). The eye itsel may
be a ected with eratitis iritis and episcleritis. An abnormal
Schirmer test occurs in o rosacea patients. Complaints
are o ten o a gritty stinging itchy or burning sensation in the
eye. Light sensiti ity and a oreign body sensation are also
present at times. cular rosacea occurs e ually in men and
women. Such eye ndings may occur be ore the s in disease.
These ndings ha e therapeutic implications and patients
will not always complain o them to their dermatologist so
these signs and symptoms should be acti ely sought when
e aluating rosacea patients.
Extrafacial lesions
lushing may in ol e the ears lateral acial contours nec
upper chest and scalp. Papules and pustules may be present
in persistent erythema o the scalp or the earlobes.
Topical corticosteroid use
Long term use o topical corticosteroids on the ace may result
in persistent erythema papules and pustules. The sites
in ol ed correspond to the areas o application and are not
necessarily limited to the central con e ities. Treatment is dis
continuance o the corticosteroid and institution o topical
tacrolimus in combination with short term minocycline.
Topical tacrolimus itsel has parado ically been reported to
induce a rosacea li e reaction so co erage with minocycline
240
Fig. 13-26 Ocular rosacea.
while discontinuing topical steroids is necessary. Addition
ally drin ing alcohol a ter application o tacrolimus or
pimecrolimus may induce ushing which may be con used
with new onset ushing related to rosacea.
Perioral dermatitis
Although perioral dermatitis has been classi ed with rosacea
ariants its distribution signs and symptoms ary such that
it is discussed separately later in this chapter.
Granulomatous lesions
Some patients with persistent acial erythema o the con e i
ties on biopsy o an erythematous papule show a granuloma
tous response closely resembling sarcoidosis or a necroti ing
granuloma. any e perienced clinicians will accurately
predict such ndings rom the clinical e amination. The most
important consideration in this case is that the patient s
response to treatment may be slower. When in ol ement o
granulomatous acial papules includes the eyelids and upper
lip and is not associated with ascular mani estations such as
ushing erythema or telangiectasia the term granulomatous
acial dermatitis is pre erred. This condition is discussed
separately.
Differential diagnosis
The persistent erythema o the central ace should be di er
entiated rom that seen in polycythemia era carcinoid mas
tocytosis and connecti e tissue disease (lupus erythematosus
dermatomyositis mi ed connecti e tissue disease). These
conditions do not ha e associated papules and pustules
and will mani est a ariety o systemic symptoms and e tra
acial signs and speci c laboratory mar ers are a ailable to
con rm clinical suspicions. aber syndrome is a genoderma
tosis characteri ed by a rosacea li e acial dermatosis and
multiple errucous lesions on non sun e posed s in. nset
o the acial lesions is in the rst two decades o li e in con
trast to the later onset o rosacea. Whereas rosacea may occur
in human immunode ciency irus ( V) disease a papulo
nodular eruption o the ace that may simulate acne rosacea
also occurs in patients with ac uired immunode ciency syn
drome (A DS). n e pressing the contents o hair ollicles
with a comedo e tractor numerous Demo ex mites are seen.
n such cases success with permethrin cream and lindane
has been reported. Lotions containing ben oyl pero ide
and precipitated sul ur (Sul o yl) are also reported to be
help ul.
Treatment
Treatments are directed at speci c ndings mani ested by
rosacea patients. Because erythema telangiectases papules
and pustules phymas ushing ocular symptoms and s in
sensiti ity are ariably present in the three subsets o disease
the speci c approach used will di er according to the actors
present. ther treatments are use ul in all patients.
General nonpharmacologic and
nonsurgical interventions
Sunscreens are an important component o therapy or all
rosacea patients and should be applied each morning. Sun
screens containing physical bloc ers in a dimethicone or cyclo
methicone ehicle generally are better tolerated especially by
the erythrotelangiectatic patients than those with chemical
agents. General a oidance o irritants such as astringents
peeling or acidic agents and abrasi e or e oliant preparations
is recommended. Cosmetic co erage o the erythema and tel
angiectases is best with a light green or yellow tinted ounda
tion set with powder.
ushing is induced by speci c trigger actors these should
be a oided as much as possible. The central ace may be pre
disposed to rosacea because the edema and lac o mo ement
o tissues with muscular mo ement may lead to lymphedema
and in ammation. Circular massage or se eral minutes a day
has led to impressi e impro ement. This benign inter ention
may be considered and should be studied. Arti cial tears and
cleansing the lids with warm water twice daily will help ocular
symptoms.
Topical therapy
etronida ole sodium sul acetamide sul ur cleansers and
creams i ermectin and a elaic acid are utili ed in rosacea.
These are the most commonly prescribed medications and are
especially use ul or the papulopustular patients and some
patients with the erythrotelangiectatic type. Ben oyl pero ide
and topical clindamycin alone or in combination are o ten
bene cial and well tolerated by the glandular subset o rosacea
patients. oral antibiotics are needed the topical products
may be used to maintain remission a ter discontinuance o oral
preparations.
Pimecrolimus or tacrolimus may also impro e select
patients erythema especially those with an accompanying
roughness or scaling o the s in sur ace. Both agents help the
irritated erythrotelangiectatic and at times the papulopustular
patients but are not e ecti e in the glandular type and tacro
limus in its ointment base may e acerbate the in ammatory
component in these patients. These drugs calm in ammation
and abate symptoms but re uire brie (no longer than wee )
pretreatment with a potent topical corticosteroid to be toler
ated initially. The role o topical retinoids re uires study.
any rosacea patients may tolerate a nighttime application o
tretinoin i Cetaphil lotion is used immediately be ore use.
Retinoids may help repair sun damaged s in and normali e
some o the abnormalities present. The α adrenergic receptor
agonist brimonidine is a ailable as a gel or the treatment o
acial redness. t is applied once in the morning which induces
asoconstriction or up to hours. rritation allergy is not
uncommon.
Oral therapy
ral antibiotics particularly do ycycline in a subantimicro
bial dose o mg e tended release ormulation or mg
tahir99 - UnitedVRG
once or twice daily usually controls more aggressi e papular
and pustular lesions and helps treat ocular lesions. ral anti
biotics should be discontinued once clearance o the in am
matory lesions is obtained; usually or months is necessary.
The topical appro ed preparations listed earlier should be
Rosacea
used as long term maintenance a ter clearance with the oral
medications because the disease will recur in most patients i
all therapy is stopped. signi cant ocular symptoms are
present oral antibiotics are an e ecti e and con enient method
o relie ing both the s in and the eye concerns. sotretinoin
gi en in lower doses than in acne ulgaris ( . mg g) and
at times as a long term suppressant may be necessary or
management o more resistant disease including patients with
a granulomatous histology. sotretinoin produces dramatic
impro ement e en in cases resistant to other orms o therapy
but relapse o ten occurs in a ew wee s or months. The authors
rarely use oral metronida ole (side e ects) or the macrolides
(lac o e cacy) despite their reported utility in rosacea.
ral medications or reduction o ushing are in re uently
help ul. ccasionally an escalating dose o propranolol car e
dilol or clonidine is help ul in reducing symptomatic ushing
but most a ected patients nd the side e ects occur be ore the
bene cial e ects are e ident. ne method is to start proprano
lol at mg three times daily and i no response is seen in
wee s to increase the dose by mg at one dose then again
e ery wee s until side e ects re uire discontinuation or
response occurs. Responses are mostly seen at a dose o
mg three times daily.
Surgical intervention
Surgical approaches to the reshaping o rhinophyma ha e
included the use o a heated scalpel electrocautery dermabra
sion laser ablation tangential e cision combined with scissors
sculpting and radio re uency electrosurgery. ten a combi
nation o these approaches is used to obtain the best esthetic
result. Lasers and light de ices are use ul or treating the ery
thema and telangiectases but the cost is not co ered by insur
ance which limits their a ailability. n a comparati e study the
pulsed dye laser and intense pulsed light de ice both signi
cantly reduced erythema telangiectasia and patient reported
symptoms and per ormed similarly well. Some ascular and
C ractionated lasers may also help in dermal collagen remod
eling and nonablati e re u enation such that the dermal matri
may be strengthened. or the patient incapacitated by ushing
burning and stinging endoscopic transthoracic sympathec
tomy may be considered but this e treme measure should only
rarely be considered because serious complications may result.
An approach to these patients should include only the medica
tions pre iously discussed but or those with signi cant dyses
thesia treatment with neuroleptics (e.g. gabapentin) tricyclic
antidepressants and pain modi ying antidepressants (e.g.
dulo etine) may be necessary.
An ad ocacy group that supports research and education in
rosacea the ational Rosacea Society is an e cellent resource
or patients.
Barzilai A, et al: Cutaneous B-cell neoplasms mimicking
granulomatous rosacea or rhinophyma. Arch Dermatol 2012;
148:824–831.
Craige H, et al: Symptomatic treatment of idiopathic and rosacea-
associated cutaneous flushing with propranolol. J Am Acad Dermatol
2005; 53:881.
Del Rosso JQ: Management of facial erythema of rosacea. J Am Acad
Dermatol 2013; 69:S44–S56.
Del Rosso JQ, et al: Consensus recommendations from the American
Acne and Rosacea Society on the management of rosacea. Part 1.
Cutis 2013; 92:234–240.
Elewski BE, et al: Rosacea. J Eur Acad Dermatol Venereol 2011;
25:188–200.
241
 Garg G, et al: Clinical efficacy of tacrolimus in rosacea. J Eur Acad Fig. 13-27 A and B,
13 Dermatol Venereol 2009; 23:239.
Hsu C-C, et al: Carvedilol for the treatment of refractory flushing and
Pyoderma faciale.
(Courtesy of Curt
persistent erythema of rosacea. Arch Dermatol 2011; 147:1258–1260. Samlaska, MD.)
Izikson L, et al: The flushing patient. J Am Acad Dermatol 2006; 55:193.
Acne

Kilty S, et al: Surgical treatment of rhinophyma. J Otolaryngol Head

Neck Surg 2008; 37:269.
Kim M-B et al: Pimecrolimus 1% cream for the treatment of rosacea.
J Dermatol 2011; 38:1135–1139.
Neuhaus IM, et al: Comparative efficacy of nonpurpuragenic pulsed dye
laser and intense pulsed light for erythematotelangiectatic rosacea.
Dermatol Surg 2009; 35:920.
Ogunleye T, et al: Ethanol-induced flushing with topical pimecrolimus
use. Dermatitis 2008; 19:E1.
Rallis E, Korfitis C: Isotretinoin for the treatment of granulomatous
rosacea: case report and review of the literature. J Cutan Med Surg
2012; 16:438–441.
Scharschmidt TC, et al: Neurogenic rosacea. Arch Dermatol 2011;
147:123–125.
Schram AM, et al: Neurogenic rosacea treated with endoscopic thoracic
sympathectomy. Arch Dermatol 2012; 148:270–271.
Steinhoff M, et al: New insights into rosacea pathophysiology. J Am A
Acad Dermatol 2013; 69:S15–S26.
Swanson LA, et al: Allergic contact dermatitis to topical brimonidine
tartrate gel 0.33% for treatment of rosacea. J Am Acad Dermatol 2014;
71:832.
Taieb A, et al: Superiority of ivermectin 1% cream over metronidazole
0.75% cream in treating inflammatory lesions of rosacea. Br J
Dermatol 2014; Sep 16.
Tan J, et al: Rosacea: current state of epidemiology. J Am Acad
Dermatol 2013; 69:S27–S35.
Tanghetti E, et al: Consensus recommendations from the American
Rosacea Society on the management of rosacea. Part 4. Cutis 2014;
93:71.
Teraki Y, et al: Tacrolimus-induced rosacea-like dermatitis. Dermatology
2012; 224:309–314.
Uslu M, et al: Rosacea treatment with intermediate-dose isotretinoin.
Acta Derm Venereol 2013; 92:73–77.
Van Zuuren E, et al: Interventions for rosacea. Cochrane Database Syst
Rev 2011; 3:CD003262.
Van Zuuren EJ, et al: Effective and evidence-based management
strategies for rosacea. Br J Dermatol 2011; 165:760–781.
Vieira AC, et al: Ocular rosacea. J Am Acad Dermatol 2013;
69:S36–S41.

PYODERMA FACIALE
Pyoderma aciale is an uncommon erupti e acial disorder
consisting o a dramatically ulminant onset o super cial and
deep abscesses cystic lesions ( ig. ) and sometimes sinus
tracts. dema and at times an intense reddish or cyanotic ery
thema accompany this pustular process. The lesions o ten
contain greenish or yellowish purulent material. lder cysts
contain an oily substance. The condition occurs mostly in post
adolescent women. t is distinguished rom acne by the absence
o comedones rapid onset ulminating course and absence o
acne on the bac and chest. Pyoderma aciale is di erentiated
rom rosacea by the inconsistent history o ushing the
absence o pree isting erythema or telangiectases o the con e
portions o the ace and the large abscesses and nodules. A ter
therapy a residual erythema o ten persists. This condition is
also nown as rosacea ulminans a designation many pre er
a ter Plewig categori ed it as such.
Treatment is similar to that o acne ulminans. ral steroids
are gi en or se eral wee s ollowed by the addition o
isotretinoin mg increasing to . mg g only a ter
the acute in ammatory component is well under control. Ste
roids may usually be discontinued a ter se eral wee s o
isotretinoin but the latter should be gi en or a ull mg
g total dose. Because patients are predominately women o
childbearing age pregnancy issues re uire ull discussion.
242
B
ndeed our o Plewig et al. s patients were pregnant and thus
could not use isotretinoin. n such patients amo icillin eryth
romycin a ithromycin or clindamycin all pregnancy cate
gory B drugs may be considered.
Crawford GH, et al: Pyoderma faciale. J Am Acad Dermatol 2005; 53:1106.
Fender AB, et al: Pyoderma faciale. Cutis 2008; 81:488.
Fuentelsaz V, et al: Rosacea fulminans in pregnancy: successful
treatment with azithromycin. Clin Exp Dermatol 2011; 36:674–676.
Plewig G, et al: Pyoderma faciale. Arch Dermatol 1992; 128:1611.
Ribeiro LB, et al: Rosacea fulminans. Cutis 2013; 92:29–32.
PERIORAL DERMATITIS
Perioral dermatitis is a common eruption consisting o discrete
papules and pustules on an erythematous and at times scaling
base. t is a distincti e dermatitis con ned symmetrically
around the mouth with a clear one o about mm between
the ermilion border and the a ected s in ( ig. ). There
is no itching although an uncom ortable burning sensation
may be present. t occurs almost e clusi ely in women age
. The use o uorinated topical corticosteroids is the most
re uently identi ed cause. posure may be in the orm o
creams ointments or inhalers.
 Granulomatous facial dermatitis
Fig. 13-28 Perioral dermatitis. Fig. 13-29 Lupus miliaris.

Treatment o perioral dermatitis includes discontinuing

topical corticosteroids or protecting the s in rom the inhaled
product. Additionally do ycycline will lead to control. Tacro
limus ointment . or pimecrolimus cream will pre ent
aring a ter stopping steroid use. n patients without steroid
e posure oral or topical antibiotics and topical adapalene
a elaic acid and metronida ole ha e all been success ul in
clearing the eruption.

Periorbital dermatitis
Periorbital (periocular) dermatitis is a ariant o perioral der
matitis occurring on the lower eyelids and s in ad acent to the
upper and lower eyelids. luorinated topical corticosteroids
ha e been implicated as the cause. intranasal inhaled corti
costeroids are used a perinasal distribution may be seen.
Prompt response to the same treatment employed in the peri
oral site is e pected.
Feser A, et al: Periorbital dermatitis. J Dtsch Dermatol Ges 2010;
8:159–165.
Hall CS, et al: Evidence based review of perioral dermatitis therapy.
G Ital Dermatol Venereol 2010; 145:433–444.
Peralta L, et al: Perioral dermatitis. Cutan Ocul Toxicol 2012;
31:160–163.
Poulos GA, et al: Perioral dermatitis associated with an inhaled
corticosteroid. Arch Dermatol 2007; 142:1460.
Schwarz T, et al: A randomized, double-blind, vehicle-controlled
study of 1% pimecrolimus cream in adult patients with perioral
dermatitis. J Am Acad Dermatol 2008; 59:34.
Tempark T, et al: Perioral dermatitis. Am J Clin Dermatol 2014;
15:101.
Wollenberg A, et al: Perioral dermatitis. J Dtsch Dermatol Ges 2011;
9:422–427.
GRANULOMATOUS FACIAL DERMATITIS
Se eral dermatoses o the ace characteri ed by granulomas
are included in this category. Patients with persistent acial
erythema in ol ing one or more con e sur aces o the
ace may ha e lesions that show a granulomatous reaction
histologically and they are included within rosacea. Some
patients ha e no other stigmata o rosacea and their nosol
ogy is unclear. These other entities which meet no other
criteria or rosacea other than ha ing pin papules on the
ace are included here. S owron et al. proposed the term
acial idiopathic granulomas with regressi e e olution
( G R ).
Fig. 13-30 Childhood granulomatous facial dermatitis.
Lupus miliaris disseminatus faciei
irm yellowish brown or red mm monomorphous
smooth sur aced papules are present not only on the butter y
areas but also on the lateral areas below the mandible and
periori cially ( ig. ). The eyelid s in is characteristically
in ol ed in patients with lupus miliaris disseminatus aciei
(L D ). The discrete papules appear as yellowish brown
lesions on diascopy and as caseating epithelioid cell granulo
mas histologically. Patients usually lac a history o ushing
do not ha e persistent erythema or telangiectasia ha e
in ol ement o the eyelids and heal with scarring as opposed
to rosacea patients. Long term therapy with minocycline or
isotretinoin may be used o ten with grati ying results. entu
ally sel in olution is e pected but may ta e se eral years.
Tranilast helped two patients with L D .
Granulomatous perioral dermatitis in children
n otherwise healthy prepubertal children a pro usion o
grouped papules may de elop on the perioral periocular and
perinasal areas ( ig. ). ight o the initial reported
patients also had generali ed lesions. Besides e tremity and
truncal lesions se eral girls had dramatic lesions o the labia
ma ora. Both genders are a ected e ually. Children with
s in o color (A ro Caribbean A rican American and
Asian) dominate the reports but white patients are also sus
ceptible. Because the histologic appearance is granulomatous
243

tahir99 - UnitedVRG
 sarcoidosis is o ten considered. Topical corticosteroids
13 howe er may worsen the condition and systemic in ol e
ment is not present. Topical metronida ole erythromycin
Bonus images for this chapter can be found online at
expertconsult.inkling.com
sul acetamide sul ur combinations and an oral macrolide or
tetracycline type antibiotic all are o ten e ecti e. n some eFig. 13-1 Upper chest involvement with acne.
Acne

patients the combination o prednisone and dapsone has eFig. 13-2 Minocycline-induced pigmentation at sites of inflammation
pro ed bene cial. in patient with acne.
eFig. 13-3 Staphylococcal infection in patient taking isotretinoin.
Al-Mutairi N: Nosology and therapeutic options for lupus miliaris (Courtesy of Curt Samlaska, MD.)
disseminatus faciei. J Dermatol 2011; 38:864–873.
eFig. 13-4 Acne conglobata.
Amiruddin D, et al: Clinical evaluation of 35 cases of lupus miliaris
disseminatus faciei. J Dermatol 2010; 37:618–620. eFig. 13-5 Rosacea.
Gutte R, et al: Childhood granulomatous periorificial dermatitis in eFig. 13-6 Steroid rosacea.
children with extrafacial involvement. Indian J Dermatol Venereol Leprol
2011; 77:703–706.
Koike Y, et al: Lupus miliaris disseminatus faciei successfully treated
with tranilast: report of two cases. J Dermatol 2011; 38:588–592.
Lucas CR, et al: Granulomatous periorificial dermatitis. J Cutan Med
Surg 2009; 13:115.
Skowron F, et al: FIGURE: facial idiopathic granulomas with regressive
evolution. Dermatology 2000; 201:289.

244
 Granulomatous facial dermatitis
eFig. 13-1 Upper chest involvement with acne. eFig. 13-4 Acne conglobata.

eFig. 13-5 Rosacea.

eFig. 13-2 Minocycline-induced pigmentation at sites of inflammation

in patient with acne.

eFig. 13-6 Steroid

rosacea.

eFig. 13-3 Staphylococcal infection in patient taking isotretinoin.

(Courtesy of Curt Samlaska, MD.)

244.e1

tahir99 - UnitedVRG
 Bonus images for this chapter can be found online at
Bacterial in ections in the s in o ten ha e distinct morphologic
characteristics that should alert the clinician that a potentially
treatable and re ersible condition e ists. These cutaneous
signs may be an indication o a generali ed systemic process
or simply an isolated super cial e ent. mmunode ciencies
with low immunoglobulin le els neutropenia reduced neu
trophil migration or illing and disease caused by the human
immunode ciency irus ( V) may be associated with se ere
or re ractory pyogenic in ections. Patients with atopic derma
titis and syndromes with atopic li e dermatitis are also
predisposed to bacterial in ections. The categori ation o
bacterial in ections in this chapter rst addresses diseases
caused by gram positi e bacteria ollowed by those caused by
gram negati e bacteria and then se eral miscellaneous dis
eases caused by the ric ettsiae mycoplasmas chlamydiae and
spirochetes.
Centers for Disease Control and Prevention: STD treatment guidelines
2010. MMWR 2010; 59(RR-12):1–110.
Chon SY, et al: Antibiotic overuse and resistance in dermatology.
Dermatol Ther 2012; 25:55–69.
Dawson AL, et al: Infectious skin diseases. Dermatol Clin 2012;
30:141–151.
Drucker CR: Update on topical antibiotics in dermatology. Dermatol
Ther 2012; 25:6–11.
Dumville JC, et al: Preoperative skin antiseptics for preventing surgical
wound infections after clean surgery. Cochrane Database Syst Rev
2013; 3:CD003949.
Grice EA, et al: Topographical and temporal diversity of the human skin
microbiome. Science 2009; 324:1190.
Mistry RD: Skin and soft tissue infections. Pediatr Clin North Am 2013;
60:1063–1082.
Petry V, et al: Bacterial skin colonization and infections in
patients with atopic dermatitis. An Bras Dermatol 2012;
87:729–734.
INFECTIONS CAUSED BY
GRAM-POSITIVE ORGANISMS
STAPHYLOCOCCAL INFECTIONS
The s in lesions induced by the gram positi e staphylococci
usually appear as pustules uruncles or erosions with honey
colored crusts. owe er bullae widespread erythema and
des uamation or egetating pyodermas may also be indica
tors o Staph lococcus aureus in ection. Purulent purpura may
indicate bacteremia or endocarditis caused by S aureus or in
immunocompromised patients S epi ermi is. Two distincti e
cutaneous lesions that occur with endocarditis are the sler
node and Janeway lesion or spot. The sler node is a pain ul
erythematous nodule with a pale center located on the nger
tips. The Janeway spot is a nontender angular hemorrhagic
lesion o the soles and palms ( ig. ). These lesions are
li ely caused by septic emboli.
expertconsult.inkling.com
Bacterial Infections
14
Staph lococcus aureus is a normal inhabitant o the anterior
nares in o adults and also resides on the hands and
perineum in smaller numbers o indi iduals. asal carriers are
particularly prone to in ections with S aureus because o its
continuous presence on the s in and nasal mucosa. Spread o
in ection in the hospital setting is re uently traced to the
hands o a health care wor er. Proper handwashing techni ue
is essential in pre enting this nosocomial complication. V
in ected patients are at least twice as o ten nasal carriers and
they tend to harbor S aureus in higher re uency and density
at other sites o the body thus predisposing them to s in and
systemic in ection.
Antibiotic resistance has become a clinically important con
sideration in many in ections. ethicillin resistant Staph lococ
cus aureus ( RSA) is an important pathogen in nosocomial
and community ac uired s in in ections. RSA in ection may
be suspected rom nowledge o local patterns o resistance
lac o response to initial methicillin sensiti e S aureus
( SSA) directed therapy (e.g. ce ale in) and actors predis
posing to coloni ation and in ection with this organism. Pre
disposing actors include age (> ) e posure to others with
RSA in ection prior antibiotic therapy trauma to the s in
rectal or nasal coloni ation crowded households child care
attendance contact sports chronic s in disease pets and
recent hospitali ation or chronic illness. n patients with ris
actors multidrug resistance is li ely and treatment with
intra enous ( V) ancomycin or line olid may be necessary.
n community ac uired in ection in patients without ris
actors clindamycin trimethoprim sul ametho a ole (T P
S alone or combined with ri ampin) do ycycline or oral
line olid o ten are e ecti e. T P S and do ycycline do not
co er group A streptococci; there ore i a mi ed in ection is
suspected adding cephale in or penicillin is necessary or
clindamycin alone will treat both pathogens. De niti e antibi
otic therapy may be tailored to the antibiotic susceptibility o
the cultured organism.
Superficial pustular folliculitis
(impetigo of Bockhart)
Boc hart impetigo is a super cial olliculitis with thin walled
pustules at the ollicle ori ces. Susceptible locations are the
e tremities and scalp although it is also seen on the ace
especially periorally. These ragile yellowish white domed
pustules de elop in crops and heal in a ew days. S aureus is
the most re uent cause. The in ection may secondarily arise
in scratches insect bites or other s in in uries.
.
Sycosis vulgaris (sycosis barbae)
Sycosis ulgaris also nown as barber s itch or sycosis
barbae is a peri ollicular chronic pustular staphylococcal
245
14
Bacterial Infections
Fig. 14-1 Janeway lesion in subacute bacterial endocarditis.
Fig. 14-2 Sycosis barbae.
in ection o the bearded region characteri ed by in ammatory
papules and pustules and a tendency to recurrence ( ig. ).
The disease begins with erythema and burning or itching
usually on the upper lip near the nose. n or days one or
more pinhead si ed pustules pierced by hairs de elop. These
rupture a ter sha ing or washing and lea e an erythematous
spot which is later the site o a resh crop o pustules. n this
manner the in ection persists and gradually spreads at times
e tending deep into the ollicles. A hairless atrophic scar bor
dered by pustules and crusts may result. arginal blepharitis
with con uncti itis is usually present in se ere cases o sycosis.
Sycosis ulgaris is to be distinguished rom tinea acne ul
garis pseudo olliculitis barbae and herpetic sycosis. Tinea
barbae rarely a ects the upper lip which is a common location
or sycosis. n tinea barbae in ol ement is usually in the sub
ma illary region or on the chin and spores and hyphae are
ound in the hairs. Pseudo olliculitis barbae mani ests torpid
papules at sites o ingrowing beard hairs in blac men. n
herpes simple irus ( SV) in ection duration is usually only
a ew days and e en in persistent cases there are esicles
which help to di erentiate SV rom sycosis ulgaris.
Folliculitis
Staphylococcal olliculitis may a ect areas such as the eye
lashes a illae pubis and thighs ( ig. ). n the pubis it
may be transmitted among se ual partners and mini epi
demics o olliculitis and urunculosis o the genital and gluteal
areas may be considered a se ually transmitted disease (STD).
Staphylococcal olliculitis has also been reported re uently in
246
tahir99 - UnitedVRG
Fig. 14-3 Staphylococcal folliculitis.
patients with ac uired immunode ciency syndrome (A DS)
and may be a cause o pruritus. An atypical pla ueli e orm
has been reported.
Treatment
Deep lesions o olliculitis represent small ollicular abscesses
and must be drained. Super cial pustules will rupture and
drain spontaneously. any patients will heal with drainage
and topical therapy. Bacitracin (Bactroban) or retapamulin
ointment and topical clindamycin (Cleocin) solution are e ec
ti e topical agents. S in sur ace staphylococcal carriage in
abrasions and ec ematous areas may be addressed with these
topical antibiotics topical chlorhe idine or bleach baths ( 1 2
cup bleach added to tub o bathwater). drainage and topical
therapy ail or i there is accompanying so t tissue in ection
a rst generation cephalosporin or penicillinase resistant pen
icillin (e.g. diclo acillin) is indicated unless RSA is sus
pected (see earlier). When the in ammation is acute hot wet
soa s with aluminum acetate (Burow) solution diluted
(Domeboro) are bene cial. An anhydrous ormulation o alu
minum chloride (Drysol erac AC) is e ecti e when used
once nightly or chronic olliculitis especially o the buttoc s.
Antibiotic ophthalmic ointments are used or blepharitis.
Furunculosis
A uruncle or boil is an acute round tender circumscribed
peri ollicular staphylococcal abscess that generally ends in
central suppuration ( ig. ). A carbuncle is merely two or
more con uent uruncles with separate heads.
The lesions begin in hair ollicles and o ten continue or a
prolonged period by autoinoculation. Some lesions disappear
be ore rupture but most undergo central necrosis and rupture
through the s in discharging purulent necrotic debris. Sites
o predilection are the nape a illae and buttoc s but boils
may occur anywhere.
The integrity o the s in sur ace may be impaired by irrita
tion pressure riction hyperhidrosis dermatitis dermato
phytosis sha ing and other actors. Local barrier compromise
predisposes to in ection by pro iding a portal o entry or the
ubi uitous S aureus The pro imate cause is either contagion
or autoinoculation rom a carrier ocus usually in the nose or
groin.
Certain systemic disorders may predispose to urunculosis
alcoholism; malnutrition; blood dyscrasias; disorders o
neutrophil unction; iatrogenic or other immunosuppression
(e.g. A DS); and diabetes ( ig. ). Patients with se eral o
these diseases as well as those recei ing renal dialysis or
 Fig. 14-4
Staphylococcal
abscess.
Fig. 14-5 Staphylococcal
abscess in a diabetic
patient.
isotretinoin or acitretin therapy are o ten nasal carriers o
S aureus. Additionally atopic dermatitis also predisposes to
the S aureus carrier state which helps e plain the obser ed
increases in the incidence o in ections in these diseases.
Hospital furunculosis
pidemics o staphylococcal in ections occur in hospitals.
ar ed resistance to antibacterial agents in these cases is
common. Attempts to control these outbrea s center on metic
ulous handwashing. n nurseries a all in neonatal coloni a
tion and in ections with S aureus and non group A streptococci
may be achie ed by using a solution o chlorhe idine or
s in and umbilical cord care.
Treatment
When the lesions are incipient and acutely in amed incision
should be strictly a oided and warm compresses and oral
antibiotics are administered. A penicillinase resistant penicil
lin or rst generation cephalosporin should be gi en orally in
a dose o g day according to the se erity o the case.
ethicillin resistant and e en ancomycin resistant strains
occur and i suspected are treated with trimethoprim
Staphylococcal Infections
sul ametho a ole double strength twice daily clindamycin
to mg three times daily or do ycycline or minocycline
mg two times daily. n patients with staphylococcal in ec
tions unresponsi e to these usual measures antibiotic resistant
strains should be suspected and sensiti ities chec ed. upi
rocin ointment applied to the anterior nares daily or days
and bleach baths may help pre ent recurrence.
When the uruncle has become locali ed and shows de nite
uctuation incision with drainage is indicated. The ca ity
should be pac ed with iodo orm or petrolatum gau e. n these
cases oral antibiotics are not usually necessary. ndications or
antibiotics in addition to drainage are high e er lesion larger
than cm or located in a critical location or di cult to drain
area multiple uruncles or signs and symptoms persisting
a ter drainage.
n boils o the e ternal auditory canal upper lip and nose
incision and drainage are generally only per ormed i antibi
otic therapy ails. n these patients antibiotic ointment should
be applied and antibiotics gi en internally. Warm saline
solution compresses should be applied liberally.
Chronic furunculosis
Despite treatment recurrences o some boils may be antici
pated. sually no underlying predisposing disease is present;
rather autoinoculation and intra amilial spread among colo
ni ed indi iduals are responsible.
ne o the most important actors in pre ention is to a oid
autoinoculation. t is important to emphasi e that the nasal
carrier state predisposes to chronic urunculosis. The s in
sur ace in the region o the uruncles may be a source o colo
ni ation especially i there are cuts e coriation or ec ematous
changes. n addition the ha ard o contamination rom the
perianal and intertriginous areas must be considered. n
general indications or elimination o the carriage state are
recurrent in ection e idence o spread to others and high ris
indi iduals in the household.
Routine precautions to ta e in attempting to brea the cycle
o recurrent urunculosis include a daily chlorhe idine wash
with special attention to the a illae groin and perianal area;
laundering o bedding and clothing on a daily basis initially;
use o bleach baths; and re uent handwashing. Additionally
the application o mupirocin ointment twice daily to the nares
o patients and amily members e ery ourth wee has been
ound to be e ecti e. Ri ampin ( mg day) or days
combined with diclo acillin or SSA or T P S or RSA
or low dose ( mg day) clindamycin or months is also
e ecti e in eradicating the nasal carriage state. The use o
bacitracin ointment inside the nares twice daily throughout
the course o isotretinoin therapy eliminates or greatly
reduces the ris o inducing nasal carriage o S aureus and
thus staphylococcal in ections.
Pyogenic paronychia
Paronychia is an in ammatory reaction in ol ing the olds o
the s in surrounding the ngernail. t is characteri ed by
acute or chronic purulent tender and pain ul swellings o
the tissues around the nail caused by an abscess in the nail
old. When the in ection becomes chronic hori ontal ridges
appear at the base o the nail. With recurrent bouts new
ridges appear.
247
 Fig. 14-6
14 Staphylococcal
paronychia.
Bacterial Infections
Fig. 14-7
Streptococcal
paronychia and
impetigo.
The primary predisposing actor that is identi able is sepa
ration o the eponychium rom the nail plate. The separation
is usually caused by trauma as a result o moisture induced
maceration o the nail olds rom re uent wetting o the hands.
The relationship is close enough to usti y treating chronic
paronychia as a wor related condition in bartenders ood
ser ers nurses and others who o ten wet their hands. The
moist groo es o the nail and nail old become secondarily
in aded by pyogenic cocci and yeasts. The causati e bacteria
are usually S aureus Streptococcus p ogenes Pseu omonas
species Proteus species or anaerobes. The pathogenic yeast is
most re uently Can i a albicans
The bacteria usually cause acute abscess ormation (Staph
lococcus ig. ) or erythema and swelling (Streptococcus ig.
) and C albicans most re uently causes a chronic swell
ing. an abscess is suspected applying light pressure with
the inde nger against the distal olar aspect o the a ected
digit will better demonstrate the e tent o the collected pus by
inducing a well demarcated blanching. Smears o purulent
material will help con rm the clinical impression. yrmecial
248
tahir99 - UnitedVRG
Fig. 14-8
Botryomycosis.
warts may mimic paronychia. Subungual blac macules ol
lowed by edema pain and swelling ha e been reported as a
sign o osteomyelitis caused by S aureus or Streptococcus viri
ans in children with atopic dermatitis.
Treatment o pyogenic paronychia consists mostly o protec
tion against trauma and concentrated e orts to eep the
a ected ngernails meticulously dry. Rubber or plastic glo es
o er cotton glo es should be used whene er the hand must
be placed in water. Acutely in amed pyogenic abscesses
should be incised and drained. The abscess may o ten be
opened by pushing the nail old away rom the nail plate. n
acute suppurati e paronychia especially i stains show pyo
genic cocci a semisynthetic penicillin or a cephalosporin with
e cellent staphylococcal acti ity should be gi en orally.
these are ine ecti e RSA or a mi ed anaerobic bacteria
in ection should be suspected. T P S or the latter or treat
ment dictated by the sensiti ity o the cultured organism will
impro e cure rates. Rarely long term antibiotic therapy may
be re uired.
While Can i a is the most re uently reco ered organism in
chronic paronychia topical or oral anti ungals lead to cure in
only about o cases. topical corticosteroids are used to
decrease in ammation and allow or tissue repair cure results
more reliably (almost in one study). ten an anti ungal
li uid such as micona ole is combined with a topical cortico
steroid cream or ointment.
Botryomycosis
Botryomycosis is an uncommon chronic indolent disorder
characteri ed by nodular crusted purulent lesions ( ig. ).
Sinuses that discharge sul ur granules are present. These heal
with atrophic scars. The granules most re uently yield S
aureus on culture although cases caused by Pseu omonas aeru
ginosa Escherichia coli Proteus acteroi es and Streptococcus
ha e been reported. Botryomycosis o ten occurs in patients
with altered immune unction such as those with neutrophilic
de ects. ther predisposing actors include diabetes V is noted. The e udate dries to orm loosely strati ed golden
in ection alcoholism and Job syndrome. Appropriate antibi
otics surgical drainage and surgical e cision are methods
used to treat botryomycosis.
Blastomycosis-like pyoderma
Large errucous pla ues with ele ated borders and multiple
pustules occur. ost patients with blastomycosis li e pyo
derma ha e some underlying systemic or local host compro
mise. Bacteria such as S aureus P aeruginosa Proteus E coli
or streptococci may be isolated. Antibiotics appropriate or the
organism isolated are curati e; howe er response may be
delayed and prolonged therapy re uired. Acitretin may also
be use ul.
Pyomyositis
Staph lococcus aureus abscess ormation within the deep large
striated muscles usually presents with e er and muscle pain.
t is typically hematogenous in origin. Pyomyositis is more
common in the tropics where it may a ect adults but most
re uently occurs in children. n temperate climates it occurs
in children and patients with A DS. The most re uent site in
tropical disease is the thigh whereas in V in ected patients
the deltoid muscle is most o ten in ol ed ollowed closely by
the uadriceps. Swelling and occasionally erythema or yellow
or purplish discoloration are isible signs o pyomyositis but
these are late ndings. on S aureus in ections may also cause
this same clinical picture. agnetic resonance imaging ( R )
with gadolinium in ection will help delineate the e tent o
disease. Drainage o the abscess and appropriate systemic
antibiotics are the recommended treatment.
Impetigo contagiosa
mpetigo contagiosa is a staphylococcal streptococcal or com
bined in ection characteri ed by discrete thin walled esicles
that rapidly become pustular and then rupture. mpetigo
occurs most re uently on the e posed parts o the body the
ace hands nec and e tremities ( ig. ). mpetigo on the
scalp is a re uent complication o pediculosis capitis.
The disease begins with mm erythematous macules which
may shortly de elop into esicles or bullae. As soon as these
lesions rupture a thin straw colored seropurulent discharge
Fig. 14-9 Impetigo.
yellow crusts which accumulate layer upon layer until they
are thic and riable. The crusts can usually be remo ed
readily lea ing a smooth red moist sur ace that soon collects
droplets o resh e udate again; these are spread to other parts
Staphylococcal Infections
o the body by ngers or towels. As the lesions spread periph
erally and the s in clears centrally large circles are ormed by
usion o the spreading lesions to produce gyrate patterns. n
streptococcal induced impetigo regional lymphadenopathy is
common but not serious.
ost studies nd o cases are caused by S aureus
with the remainder rom either S p ogenes or a combination
o these two organisms. Streptococci may represent an early
pathogen in the de elopment o impetigo with staphylococci
replacing streptococci as the lesion matures. Group B strepto
cocci are associated with newborn impetigo and groups C and
G are rarely isolated rom impetigo unli e the usual group A.
mpetigo occurs most re uently in early childhood ( ig.
) although all ages may be a ected. t occurs in the tem
perate one mostly during the summer in hot humid weather.
Common sources o in ection or children are pets dirty n
gernails and other children in schools day care centers or
crowded housing areas; sources or adults include in ected
children and sel inoculation rom nasal or perineal carriage.
mpetigo o ten complicates pediculosis capitis scabies SV
insect bites poison i y ec ema and other e udati e pustular
or itching s in diseases.
Group A β hemolytic streptococcal s in in ections are some
times ollowed by acute glomerulonephritis (AG ). ephrito
genic streptococci are generally associated with impetigo
rather than with upper respiratory tract in ections. There is no
e idence that AG occurs with staphylococcal impetigo. The
important actor predisposing to AG is the serotype o the
streptococcus producing the impetigo. Type and
strains and strain type are related to nephritis.
The incidence o AG with impetigo aries rom about
to ( with nephritogenic strains o streptococcus)
and occurs most re uently in childhood generally be ore age
. The prognosis in children is mostly e cellent but in adults
it is not as good. Treatment howe er early and appropriate
is not belie ed to reduce the ris o AG .
mpetigo may simulate se eral diseases. The circinate
patches are re uently mista en or ringworm but clinically
are uite di erent. mpetigo is characteri ed by super cial
ery weepy lesions co ered by thic bright yellow or orange
crusts with loose edges which do not resemble the scaling
patches with peripheral erythema seen in tinea. mpetigo may
be mista en or oxico en ron dermatitis but it is more crusted
and pustular and more li ely to in ol e the nostrils corners
o the mouth and ears. mpetigo is not associated with the
Fig. 14-10 Impetigo of
early childhood.
249
 eyelid pu ness the linear lesions or the itchiness typically Fig. 14-11 Bullous
14 present in dermatitis and caused by poison i y or oa . n
ecthyma the lesions are crusted ulcers not erosions.
impetigo.

Treatment
Bacterial Infections

Systemic antibiotics combined with topical therapy are recom

mended or patients with impetigo contagiosa. Because most
cases are caused by Staph lococcus a semisynthetic penicillin
or a rst generation cephalosporin is recommended unless
RSA is suspected as detailed earlier. All treatment should
be gi en or days. t is necessary to soa o the crusts re
uently a ter which an antibacterial ointment should be
applied. the lesions are locali ed especially i acial and are
present in an otherwise healthy child topical therapy may be
e ecti e as the sole treatment.
Applying antibiotic ointment as a prophylactic to sites o
s in trauma will pre ent impetigo in high ris children attend
ing day care centers. n one study in ections were reduced by
with antibiotic ointment ersus with placebo. Addi
tionally i recurrent staphylococcal impetigo de elops a
culture o the anterior nares may yield this organism. Such
carrier states may be treated by application o mupirocin oint
ment to the anterior nares twice daily or by a day course o
ri ampin mg day combined with diclo acillin ( or SSA)
or T P S ( or RSA).

Bullous impetigo
The bullous ariety o impetigo occurs characteristically in
newborns although it may occur at any age. The neonatal type
is highly contagious and is a threat in nurseries. n most cases
the disease begins between the ourth and tenth days o li e
with the appearance o bullae which may appear on any part
o the body. Common early sites are the ace and hands.
Constitutional symptoms are absent at rst but wea ness
and e er or a subnormal temperature may be present later.
Diarrhea with green stools re uently occurs. Bacteremia
pneumonia or meningitis may de elop rapidly with atal
termination.
n warm climates particularly adults may ha e bullous
impetigo ( ig. ) most o ten in the a illae or groins but
also on the hands. sually no scalp lesions are present. The
lesions are stri ingly large ragile bullae suggesti e o pem
phigus. When these rupture they lea e circinate weepy or
crusted lesions and in this stage it may be called impetigo
circinata. Children with bullous impetigo may gi e a history
o an insect bite at the site o onset o lesions. The ma ority are
caused by phage types or coagulase positi e S aureus or
a related group phage type. Bullous impetigo may be an
early mani estation o V in ection.
Staphylococcal scalded skin syndrome
Staphylococcal scalded s in syndrome (SSSS) is a generali ed
con uent super cially e oliati e disease occurring most
o ten in neonates and young children. t occurs rarely in
adults usually with renal compromise or immunosuppression
as a predisposing actor. SSSS is a ebrile rapidly e ol ing
des uamati e in ectious disease in which the s in e oliates
in sheets. S in does not separate at the dermoepidermal unc
tion as in to ic (drug induced) epidermal necrolysis (T )
but within the granular layer. The lesions are thus much more
super cial and less se ere than in T and healing is much
more rapid. They also e tend ar beyond areas o actual staph
ylococcal in ection by action o the e oliati e e oto ins types
250
Fig. 14-12 Staphylococcal scalded skin syndrome.
A and B elaborated by the staphylococcus in remote sites.
sually staphylococci are present at a distant ocus such as
the pharyn nose ear or con uncti a. Septicemia or a cutane
ous in ection may also be the causati e ocus.
Clinical mani estations o SSSS begin abruptly with e er
s in tenderness and erythema in ol ing the nec groins and
a illae ( ig. ). There is sparing o the palms soles and
mucous membranes. i ols y s sign is positi e. Generali ed
e oliation ollows within the ne t hours to days with large
sheets o epidermis separating. Group S aureus usually
phage types or is the causati e agent in most cases.
ta en cultures should be obtained rom the mucous mem
branes because the s in erythema and des uamation are
caused by the distant e ects o the e oliati e to ins unli e in
bullous impetigo where S aureus is present in the lesions.
Rapid diagnosis o SSSS can be made by e amining ro en
sections o a blister roo and obser ing that the ull thic ness
o the epidermis is not necrotic as in T but rather is clea ed
below the granular layer. The e oliati e to ins A B and D
speci cally clea e desmoglein the antigenic target o
autoantibodies in pemphigus oliaceus thus accounting
or the clinical and histologic similarity to pemphigus obser ed
in SSSS and bullous impetigo. Treatment o choice is a
penicillinase resistant penicillin such as diclo acillin com
bined with uid therapy and general supporti e measures.

tahir99 - UnitedVRG
 RSA is cultured and response is sluggish antibiotics directed
according to the susceptibility o the reco ered organism are
needed. The prognosis is good in children but mortality in
adults can reach .

Staphylococcal Infections
Gram-positive toxic shock syndromes
To ic shoc syndrome (TSS) is an acute ebrile multisystem
illness with one o its ma or diagnostic criteria being a wide
spread macular erythematous eruption. t is usually caused by
to in producing strains o S aureus most o which were ini
tially isolated rom the cer ical mucosa in menstruating young
women. Currently cases are most o ten caused by in ections
in wounds catheters contracepti e diaphragms or nasal
pac ing. ortality in these nonmenstrual cases is higher (up
to ) compared with menstrual related cases (< ) prob
ably as a result o delayed diagnoses. Also a similar syndrome
has been de ned in which the cause is group A or rarely
group B streptococci. This latter multiorgan disease has
systemic components similar to classic staphylococcal TSS;
howe er the in ection is usually a rapidly progressi e
destructi e so t tissue in ection such as necroti ing asciitis.
Women with an underlying chronic illness recently reco ered
rom aricella or using nonsteroidal anti in ammatory drugs
( SA Ds) are predisposed. t has a case atality rate o .
The streptococci are usually o types and with o
the isolates producing pyrogenic e oto in A.
The Centers or Disease Control and Pre ention (CDC) case
de nition o staphylococcal TSS includes a temperature o
. C( ) or higher an erythematous eruption des ua
mation o the palms and soles wee s a ter onset
( ig. ) hypotension and in ol ement o three or more Fig. 14-13 Desquamation of the palms and soles.
other systems gastrointestinal (G ; omiting diarrhea) mus
cular (myalgias increased creatinine inase le el) mucous
membrane (hyperemia) renal (pyuria without in ection or Treatment o TSS consists o systemic antibiotics such as
raised creatinine or blood urea nitrogen le els) hepatic ancomycin which may be combined with na cillin . g
(increased bilrubin serum glutamic o aloacetic transami intra enously e ery h in critically ill patients; igorous
nase serum glutamic pyru ic transaminase) hematologic uid therapy to treat shoc ; and drainage o the S aureus
(platelets < mm ) or central ner ous system (C S; dis in ected site.
orientation). n addition serologic tests or Roc y ountain
spotted e er leptospirosis and rubeola and cultures o Agarwal V, et al: Pyomyositis. Neuroimaging Clin North Am 2011;
blood urine and cerebrospinal uid should be negati e. Pro 21:975–983.
Al-Najar M, et al: Primary extensive pyomyositis in an
calcitonin an indicator o se ere bacterial in ection may be a
immunocompetent patient. Clin Rheumatol 2010; 29:1469–1472.
biologic mar er or the to ic shoc syndromes. Bulbar con Antoniou T, et al: Prevalence of community-associated methicillin-
uncti al hyperemia and palmar edema are two additional resistant Staphylococcus aureus colonization in men who have sex
clinical clues. Streptococcal TSS is de ned by isolation o with men. Int J STD AIDS 2009; 20:180.
group A β hemolytic streptococci hypotension and two or Atanaskova N, et al: Innovative management of recurrent furunculosis.
more o the ollowing renal impairment coagulopathy Dermatol Clin 2010; 28:479.
hepatic in ol ement acute respiratory distress syndrome a Bangert S, et al: Bacterial resistance and impetigo treatment trends.
generali ed erythematous macular eruption that may des ua Pediatr Dermatol 2012; 29:243–248.
mate and so t tissue necrosis myositis or gangrene. Berk DR, et al: MRSA, staphylococcal scalded skin syndrome, and
other cutaneous bacterial emergencies. Pediatr Ann 2010; 39:627–633.
About o the early cases o TSS occurred in young
Brewer JD, et al: Staphylococcal scalded skin syndrome and toxic
women between the rst and si th days o a menstrual period. shock syndrome after tooth extraction. J Am Acad Dermatol 2008;
During the initial outbrea the ma ority were using a super 59:342.
absorbent tampon. Cases now usually occur in women using Burdette SD, et al: Staphylococcus aureus pyomyositis compared with
contracepti e sponges in patients with nasal pac ing a ter non–Staphylococcus aureus pyomyositis. J Infect 2012; 64:507–512.
rhinoplasty and in patients with staphylococcal in ections o Caum RS, et al: Skin and soft-tissue infections caused by methicillin-
bone lung or so t tissue. The o ending S aureus strain pro resistant Staphylococcus aureus. N Engl J Med 2007; 357:380.
duces one or more e oto ins. Datta R, et al: Risk of infection and death due to methicillin-resistant
istologic ndings are spongiosis and neutrophils scattered Staphylococcus aureus in long-term carriers. Clin Infect Dis 2008;
throughout the epidermis indi idual necrotic eratinocytes 47:176.
Demos M, et al: Recurrent furunculosis. Br J Dermatol 2012;
peri ascular and interstitial in ltrates composed o lympho
167:725–735.
cytes and neutrophils and edema o the papillary dermis. TSS Durupt F, et al: Prevalence of Staphylococcus aureus toxins and nasal
must be di erentiated rom iral e anthems awasa i s carriage in furunculosis and impetigo. Br J Dermatol 2007; 157:43.
disease scarlet e er recurrent to in mediated perianal ery Elliott DJ, et al: Empiric antimicrobial therapy for pediatric skin and
thema drug eruptions Roc y ountain spotted e er sys soft-tissue infections in the era of methicillin-resistant Staphylococcus
temic lupus erythematosus (SL ) T and SSSS. aureus. Pediatrics 2009; 123:e959.
251
 Elston DM: How to handle a CA-MRSA outbreak. Dermatol Clin 2009; Fig. 14-14 Ecthyma.
14 27:43.
Forcade NA, et al: Antibacterials as adjuncts to incision and drainage for
adults with purulent methicillin-resistant Staphylococcus aureus
(MRSA) skin infections. Drugs 2012; 72:339–351
Bacterial Infections

Garcia C, et al: Staphylococcus aureus causing tropical pyomyositis,

Amazon Basin, Peru. Emerg Infect Dis 2013; 19:123–125.
Gutierrez K, et al: Staphylococcal infections in children, California, USA,
1985–2009. Emerg Infect Dis 2013; 19:10–20.
Jackson MA, et al: Staphylococcal infections in the era of MRSA. Pediatr
Rev 2011; 32:522–532.
Kato M, et al: Procalcitonin as a biomarker for toxic shock syndrome.
Acta Derm Venereol 2010; 90:441.
Kirkland EB, et al: Methicillin-resistant Staphylococcus aureus and
athletes. J Am Acad Dermatol 2008; 59:494.
Lappin E, et al: Gram-positive toxic shock syndromes. Lancet Infect Dis
2009; 9:281.
Low DE: Toxic shock syndrome: major advances in pathogenesis, but
not treatment. Crit Care Clin 2013; 29:651–675.
Mitsionis GI, et al: Pyomyositis in children. J Pediatr Surg 2009;
44:2173–2178.
Neylon O, et al: Neonatal staphylococcal scalded skin syndrome. Eur J
Pediatr 2010; 169:1503–1509.
Ouchi T, et al: A case of blastomycosis-like pyoderma caused by mixed
infection of Staphylococcus epidermidis and Trichophyton rubrum. Am
J Dermatopathol 2011: 33:397–399.
Patel GK, et al: Staphylococcal scalded skin syndrome. Am J Med
2010; 123:505–507.
Patrizi A, et al: Recurrent toxin-mediated perineal erythema. Arch
Dermatol 2008; 144:239. caused by S aureus and are seen in intra enous drug users and
Piechowicz L, et al: Outbreak of bullous impetigo caused by V in ected patients.
Staphylococcus aureus strains of phage type 3C/71 in a maternity The lesions tend to heal a ter a ew wee s lea ing scars but
ward linked to nasal carriage of a healthcare worker. Eur J Dermatol rarely may proceed to gangrene when resistance is low. Debili
2012; 22:252–255. tated patients o ten ha e a ocus o pyogenic in ection else
Rertveit S, et al: Impetigo in epidemic and nonepidemic phases. Br J where. Local adenopathy may be present. ncleanliness
Dermatol 2007; 157:100.
malnutrition and trauma are predisposing causes.
Ritting AW, et al: Acute paronychia. J Hand Surg Am 2012;
37:1068–1070.
Treatment is cleansing with soap and water a ter soa ing o
Rubenstein E, et al: Botryomycosis-like pyoderma in the genital region the crust with compresses ollowed by the application o
of a human immunodeficiency virus (HIV)–positive man successfully mupirocin retapamulin or bacitracin ointment twice daily.
treated with dapsone. Int J Dermatol 2010; 49:842. ral diclo acillin or a rst generation cephalosporin is also
Scheinpflug K, et al: Staphylococcal scalded skin syndrome in an adult indicated with ad ustments made according to the cultured
patient with T-lymphoblastic non-Hodgkin’s lymphoma. Oncologie organism s susceptibilities.
2008; 31:616.
Sica RS, et al: Prevalence of methicillin-resistant Staphylococcus
aureus in the setting of dermatologic surgery. Dermatol Surg 2009;
35:420.
Scarlet fever
Van Rijen M, et al: Mupirocin ointment for preventing Staphylococcus
aureus infections in nasal carriers. Cochrane Database Syst Rev 2008; Scarlet e er is a di use erythematous e anthem that occurs
4:CD006216. during the course o streptococcal pharyngitis. t a ects pri
marily children who de elop the eruption h a ter onset
o pharyngeal symptoms. The tonsils are red edematous and
co ered with e udate. The tongue has a white coating through
STREPTOCOCCAL SKIN INFECTIONS which reddened hypertrophied papillae pro ect gi ing the
so called white strawberry tongue appearance. By the ourth
Speci c diseases caused by direct in ection with Streptococcus or th day the coating disappears the tongue is bright red
p ogenes and its to ins as discussed in this chapter also ha e and the red strawberry tongue remains.
immune mediated conse uences including acute rheumatic The cutaneous eruption begins on the nec then spreads to
e er chronic rheumatic heart disease and acute poststrepto the trun and nally the e tremities ( ig. ). Within the
coccal glomerulonephritis. The last two only occur a ter phar widespread erythema are mm papules which gi e the
yngitis or tonsillitis. Although most o such complications s in a rough sandpaper uality. There is accentuation o er
occur in resource poor countries the global burden o these the s in olds and a linear petechial eruption called Pastia
se uelae is signi cant. lines is o ten present in the antecubital and a illary olds.
There is acial ushing and circumoral pallor. A branny des
uamation occurs as the eruption ades with peeling o the
Ecthyma palms and soles ta ing place about wee s a ter the acute
illness. The latter may be the only e idence that the disease
cthyma is an ulcerati e staphylococcal or streptococcal pyo has occurred.
derma almost always o the shins or dorsal eet. The disease The eruption is produced by erythrogenic e oto in
begins with a esicle or esicopustule which enlarges and in producing group A streptococci. Cultures o the pharyn will
a ew days becomes thic ly crusted. When the crust is remo ed reco er these organisms. Rarely scarlet e er may be related
there is a super cial saucer shaped ulcer with a raw base and to a surgical wound or burn in ection with streptococci. An
ele ated edges ( ig. ). n urban areas these lesions are ele ated antistreptolysin titer may pro ide e idence o
252

tahir99 - UnitedVRG

Fig. 14-15 Scarlet fever.
recent in ection i cultures are not ta en early. A condition
nown as staphylococcal scarlatina has been described that
mimics scarlet e er; howe er the strawberry tongue is
not seen.
Penicillin erythromycin or diclo acillin treatment is cura
ti e or scarlet e er and the prognosis is e cellent.
Recurrent toxin-mediated perianal erythema
This condition mani ests as a perineal erysipelas li e ery
thema that resol es with des uamation. Strawberry tongue
erythema o the hands with des uamation and a mild e er
or days be ore the eruption are other signs. n some patients
a staphylococcal or streptococcal pharyngitis impetigo or
perianal streptococcal dermatitis is present. There may be
recurrences in indi idual patients. Streptococcal pyrogenic
e oto ins A and B or TSS to in may be responsible or the
s in ndings.
Erysipelas
Also once nown as St. Anthony s re and ignis sacer erysip
elas is an acute β hemolytic group A streptococcal in ection o
the s in in ol ing the super cial dermal lymphatics. cca
sional cases caused by streptococci o group C or G are reported
in adults. Group B streptococcus is o ten responsible in the
newborn and may be the cause o abdominal or perineal ery
sipelas in postpartum women. t is characteri ed by local
redness heat swelling and a highly characteristic raised
indurated border ( ig. A). The onset is o ten preceded
by prodromal symptoms o malaise or se eral hours which
may be accompanied by a se ere constitutional reaction with
chills high e er headache omiting and oint pains. There
is usually a polymorphonuclear leu ocytosis o cells
mm or more. owe er many cases present solely as an ery
thematous lesion without associated systemic complaints.
The s in lesions may ary rom transient hyperemia ol
lowed by slight des uamation to intense in ammation with
esicles or bullae. The eruption begins at any one point as an
erythematous patch and spreads by peripheral e tension. n
the early stages a ected s in is scarlet hot to the touch
branny and swollen. A distincti e eature o the in ammation
is the ad ancing edge o the patch. This is raised and sharply
demarcated and eels li e a wall to the palpating nger. n
some cases esicles or bullae that contain seropurulent uid
occur and may result in local gangrene.
The legs and ace are the most common sites a ected. n
the ace the in ammation generally begins on the chee near
the nose or in ront o the lobe o the ear and spreads upward
Fig. 14-16 A and B,
Erysipelas.
Streptococcal skin infections
A
B
to the scalp with the hairline sometimes acting as a barrier
against urther e tension. n the legs edema and bullous
lesions are prominent eatures in many patients ( ig. B).
Septicemia deep cellulitis necroti ing asciitis and abscess
ormation may be complications especially in obese patients
and those with chronic alcohol abuse. Predisposing causes are
surgical wounds which may lead to gluteal and thigh in ol e
ment; ssures in the nares in the auditory meatus under the
earlobes on the anus or penis and between or under the toes
usually the little toe; abrasions or scratches; enous insu
ciency; obesity; lymphedema; and chronic leg ulcers.
Recognition o erysipelas generally is not di cult. t may be
con used with contact dermatitis rom plants drugs or dyes
and with angioneurotic edema but with each o these e er
pain and tenderness are absent and itching is se ere. A but
ter y pattern on the ace may mimic lupus erythematosus and
ear in ol ement may suggest relapsing polychondritis.
Systemic penicillin is rapidly e ecti e. mpro ement in the
general condition occurs in h but resolution o the cuta
neous lesion may re uire se eral days. Vigorous treatment
with antibiotics should be continued or at least days.
Locally ice bags and cold compresses may be used. Leg
in ol ement especially when bullae are present will more
li ely re uire hospitali ation with intra enous antibiotics.
lderly patients those with underlying immunocompromise
a longer duration o illness be ore presentation and patients
253
 with leg ulcers will re uire longer inpatient stays. A small
14 group will ha e recurrent disease in whom long term antibi
otic prophyla is may be bene cial.
Bacterial Infections
Cellulitis
Cellulitis is a suppurati e in ammation in ol ing the subcu
taneous tissue. sually but not always this ollows some
discernible wound. n the leg tinea pedis is the most common
portal o entry. ild local erythema and tenderness malaise
and chilly sensations or a sudden chill and e er may be present
at the onset. The erythema rapidly becomes intense and spreads
( ig. ). The area becomes in ltrated and pits on pressure.
The central part may become nodular and surmounted by a
esicle that ruptures and discharges pus and necrotic material.
Strea s o lymphangitis may spread rom the area to the
neighboring lymph glands ( ig. ). Gangrene metastatic
abscesses and se ere sepsis may ollow. These complications
are unusual in immunocompetent adults but children and
immunocompromised adults are at higher ris .
The diagnosis o cellulitis is usually made on clinical
grounds. t is uncommon or blood studies including cultures
and s in biopsies or aspirates to be positi e. howe er an
open wound is present there is a high probability o a culture
being positi e. Streptococci continue to cause appro imately
o cases and staphylococci the ma ority o the remainder.
Stasis dermatitis may mimic cellulitis. t does not hurt or cause
e er may be circum erential or centered o er the medial mal
leoli and is usually bilateral. Allergic contact dermatitis is
itchy but not pain ul.
Fig. 14-17 Cellulitis.
254
tahir99 - UnitedVRG
Patients with stasis dermatitis without systemic to icity
can be managed as outpatients. nitial empiric therapy with
diclo acillin or cephale in or days will usually su ce.
RSA is strongly suspected because o ris actors treatment
strategies are as outlined or staphylococcal in ections at the
start o this chapter.
Chronic recurrent erysipelas, chronic lymphangitis
rysipelas or cellulitis may be recurrent. Predisposing actors
include alcoholism diabetes immunode ciency tinea pedis
enous stasis lymphedema with or without lymphangie
ctasias prosthetic surgery o the nee a history o saphenous
phlebectomy lymphadenectomy or irradiation. Chronic
lymphedema is the end result o recurrent bouts o bacterial
lymphangitis and obstruction o the ma or lymphatic channels
o the s in. The nal result is a permanent hypertrophic bro
sis called elephantiasis nostras. t must be di erentiated rom
lymphangioma ac uired lymphangiectasia and other causes
such as neoplasms or lariasis.
During periods o acti e lymphangitis antibiotics in large
doses are bene cial and their use must be continued in smaller
maintenance doses such as mg o cephale in or penicillin
or long periods to achie e their ull bene ts. Compression
therapy to decrease lymphedema will aid in the pre ention o
recurrence.
Necrotizing fasciitis
ecroti ing asciitis is an acute necroti ing in ection in ol ing
the ascia. t may ollow surgery or per orating trauma or may
occur de no o. Within h redness pain and edema
uic ly progress to central patches o dus y blue discolor
ation with or without serosanguineous blisters ( ig. ).
Anesthesia o the in ol ed s in is characteristic. By the ourth
or th day these purple areas become gangrenous. any
orms o irulent bacteria ha e been cultured rom necroti ing
asciitis including microaerophilic β hemolytic streptococci
hemolytic staphylococcus coli orms enterococci Pseu omo
nas and acteroi es Both aerobic and anaerobic cultures
should always be ta en.
arly surgical debridement is an essential component o suc
cess ul therapy. Laboratory studies may help in assessing
the ris o a patient ha ing necroti ing asciitis. ne scoring
system gi es points or abnormalities in C reacti e protein
white blood cell count hemoglobin sodium creatinine and
glucose. Based on the total score patients are strati ed into
low ris medium ris and high ris categories. The most
de niti e con rmatory test is R . At the bedside the clini
cian may in ltrate the site with anesthetic ma e a cm
Fig. 14-18 Lymphangitis.
 Fig. 14-19 Necrotizing
fasciitis.
incision down to the ascia and probe with the nger. Lac o
bleeding a mur y discharge and lac o resistance to the
probing nger are ominous signs. done a biopsy should be
obtained rom normal appearing tissue near the necrotic one.
Treatment should include early surgical debridement appro
priate V antibiotics and supporti e care. ortality may be
e en in the best o circumstances. Poor prognostic actors
are age o er underlying diabetes or atherosclerosis delay
o more than days in diagnosis and surgical inter ention
and in ection on or near the trun rather than the more o ten
in ol ed e tremities. eonatal necroti ing asciitis most re
uently occurs on the abdominal wall and has a higher mortal
ity rate than in adults.
Blistering distal dactylitis
Blistering distal dactylitis is characteri ed by tense super cial
blisters occurring on a tender erythematous base o er the
olar at pad o the phalan o a nger or thumb or occasion
ally a toe ( ig. ). The typical patient is age years.
Group A β hemolytic streptococci or S aureus is the most
common cause. These organisms may be cultured rom blister
uid and occasionally rom clinically inapparent in ections o
the nasopharyn or con uncti a.
Perineal dermatitis
Clinically perineal dermatitis presents most o ten as a super
cial perianal well demarcated rim o erythema ( ig. );
ssuring may also be seen. Pain or tenderness especially
prominent on de ecation may lead to ecal retention in
a ected patients who are usually between ages and . t
may not resemble cellulitis but rather dermatitis. t may also
a ect the ul al and penile tissues. Group A streptococci are
most o ten the cause; howe er S aureus may be reco ered
rarely and when this occasionally occurs in adults the usual
cause is group B streptococci. The ast ma ority o in ections
are caused by streptococci so a systemic penicillin or eryth
romycin combined with a topical antiseptic or antibiotic is
the treatment o choice. The duration should be days
Streptococcal skin infections
Fig. 14-20 Blistering dactylitis.
Fig. 14-21 Perianal dermatitis.
depending on clinical response. Posttreatment swabs and uri
nalysis to monitor or poststreptococcal glomerulonephritis
are recommended.
Streptococcal intertrigo
n ants and young children may de elop a ery red ery
thema and maceration in the nec a illae or inguinal olds.
There are no satellite lesions. t may be pain ul and ha e a
oul odor. Group A β hemolytic streptococci are the cause
and topical antibiotics and oral penicillin combined with a
low potency topical corticosteroid is curati e in streptococcal
intertrigo.
Erythema marginatum
Delayed nonsuppurati e se uelae o streptococcal in ections
include erythema nodosum poststreptococcal glomerulone
phritis and rheumatic e er. The latter only ollows pharyn
gitis or tonsillitis but two s in signs are among the diagnostic
criteria o rheumatic e er erythema marginatum and subcu
taneous nodules. The remaining ma or signs ma ing up the
re ised Jones criteria are carditis polyarthritis and chorea.
rythema marginatum appears as a spreading patchy ery
thema that migrates peripherally and o ten orms polycyclic
con gurations ( ig. ). t is e anescent appearing or a
ew hours or days on the trun or pro imal e tremities. eat
may ma e it more isible and successi e crops may appear
o er se eral wee s. t is usually part o the early phase o the
255
 Fig. 14-22 Erythema
14 marginatum.
Bacterial Infections
disease coe isting with carditis but usually preceding the
arthritis. Children younger than years are more li ely to
mani est the eruption than older patients. A s in biopsy will
show a peri ascular and interstitial polymorphonuclear leu
ocyte predominance. n contrast the subcutaneous nodules
occur o er bony prominences and appear as a late mani esta
tion. The lesions o erythema marginatum usually are asymp
tomatic and resol e spontaneously.
Group B streptococcal infection
Streptococcus agalactiae is the ma or cause o bacterial sepsis and
meningitis in neonates. t may cause orbital cellulitis or acial
erysipelas in these patients. p to o healthy adults harbor
group B streptococci in their genital or G tract. A guideline
by oney et al. emphasi es pre ention o such disastrous
in ections in the newborn through culture identi cation o
mothers at ris and prophylactic antibiotics be ore deli ery
in culture positi e women. S agalactiae has been reported to
cause balanitis ul ar pain due to ne ssures with minimal
erythema to ic shoc li e syndrome cellulitis perianal der
matitis recurrent erysipelas or blistering dactylitis in adults.
Diabetes mellitus neurologic impairment cirrhosis and
peripheral ascular disease predispose patients to in ection
with S agalactiae n the postpartum period abdominal or
perineal erysipelas may be caused by this organism.
Streptococcus iniae infections
Cellulitis o the hands may be caused by the sh pathogen
Streptococcus iniae n Asian cuisine tilapia (also nown as St
Peter s sh or awaiian sun sh) is o ten purchased li e rom
a uariums in retail stores. n cleaning the reshly illed sh
be ore coo ing puncture wounds o the s in may be sustained
rom the dorsal n a sh bone or a ni e. Preparation o other
raw sea ood may also lead to S iniae in ection. Within h Sun JR, et al: Invasive infection with Streptococcus iniae in Taiwan. J
e er lymphangitis and cellulitis without s in necrosis or
bulla ormation occur. Treatment with penicillin is curati e.
A similar scenario occurred with a newly described species
Streptococcus hong ongensis sp no . Amo icillin cla ulanate
was e ecti e in the one reported case.
Bachmeyer C, et al: Relapsing erysipelas of the buttock due to
Streptococcus agalactiae in an immunocompetent woman. Clin Exp
Dermatol 2009; 34:267.
256
tahir99 - UnitedVRG
Baiano JC, et al: Toward control of Streptococcus iniae. Emerg Infect
Dis 2009; 15:1891–1896.
Bailey E, et al: Cellulitis. Dermatol Ther 2011; 24:229–239.
Buckland GT 3rd, et al: Persistent periorbital and facial lymphedema
associated with group A beta-hemolytic streptococcal infection.
Ophthalm Plast Reconstr Surg 2007; 23:161.
Carvalho SM, et al: Rheumatic fever: presentation and outcome. Rev
Bras Rheumatol 2012; 52:241–246.
Del Giudice P, et al: Severe relapsing erysipelas associated with chronic
Streptococcus agalactiae vaginal cononization. Clin Infect Dis 2006;
43:1141.
El Bouch R, et al: A case of recurrent toxin-mediated perineal erythema.
Arch Dis Child 2013; 98:776.
Fretzayas A, et al: MRSA blistering distal dactylitis and review of
reported cases. Pediatr Dermatol 2011; 28:433–435.
Glatz M, et al: Erysipelas of the thigh and gluteal region. Dermatology
2012; 225:277–283.
Gunderson CG, et al: A systematic review of bacteremias in cellulitis and
erysipelas. J Infect 2012; 64:148–155.
Hakkarainen TW, et al: Necrotizing soft tissue infections. Curr Probl Surg
2014; 51:344–362.
Hirschmann JV, et al: Lower limb cellulitis and its mimics. J Am Acad
Dermatol 2012; 67:163.e1-12, 177.e1-9.
Jamal N, et al: Necrotizing fasciitis. Pediatr Emerg Care 2011;
27:1195–1199.
Kahlke V, et al: Perianal streptococcal dermatitis in adults: its
association with pruritic anorectal diseases is mainly caused by group
B streptococci. Colorectal Dis 2013; 15:602–607.
Kilburn SA, et al: Interventions for cellulitis and erysipelas. Cochrane
Database Syst Rev 2010; 6:CD004299.
Koh TH, et al: Streptococcal cellulitis following preparation of fresh raw
seafood. Zoonoses Public Health 2009; 56:206.
Krasagakis K, et al: Local complications of erysipelas. Clin Exper
Dermatol 2010; 36:351–354.
Kutsuna S, et al: Scarlet fever in an adult. Intern Med 2014;
53:167–168.
Lamden KH: An outbreak of scarlet fever in a primary school. Arch Dis
Child 2011; 96:394–397.
Lau SK, et al: Streptococcus hongkongensis sp. nov., isolated from a
patient with an infected puncture wound and from a marine flatfish. Int
J Syst Evol Microbiol 2013; 63:2570–2576.
Laucerotto L, et al: Necrotizing fasciitis. J Trauma 2012;
72:560–566.
Mirowski GW, et al: Cutaneous vulvar streptococcal infection. J Low
Genit Tract Dis 2012; 16:281–284.
Mittal MK, et al: Group B streptococcal cellulitis in infancy. Pediatr
Emerg Care 2007; 23:324.
Money D, et al: The prevention of early-onset neonatal group B
streptococcal disease. J Obstet Gynaecol Can 2013;
35:939–951.
Patrizi A, et al: Recurrent toxin-mediated perineal erythema. Arch
Dermatol 2008; 144:239.
Phoenix G, et al: Diagnosis and management of cellulitis. BMJ 2012;
345:e4955.
Picard D, et al: Risk factors for abscess formation in patients with
superficial cellulitis (erysipelas) of the leg. Br J Dermatol 2012;
168:859–863.
Ralph AP, et al: Group A streptococcal diseases and their global
burden. Curr Top Microbiol Immunol 2013; 368:1–27.
Shimizu T, et al: Necrotizing fasciitis. Intern Med 2010; 49:1051.
Silverman RA, et al: Streptococcal intertrigo of the cervical folds in a
five-month-old infant. Pediatr Infect Dis J 2012; 31:872–873.
Singer AJ, et al: Management of skin abscesses in the era of
methicillin-resistant Staphylococcus aureus. N Engl J Med 2014;
370:1039–1047.
Med Microbiol 2007; 56:1246.
Thomas K, et al: Prophylactic antibiotics for the prevention of
cellulitis (erysipelas) of the leg. Br J Dermatol 2012;
166:169–178.
Thomas KS, et al: Penicillin to prevent recurrent leg cellulitis. N Engl J
Med 2013; 368:1695–1703.
Wasserzug O, et al: A cluster of ecthyma outbreaks caused by a single
clone of invasive and highly infective Streptococcus pyogenes. Clin
Infect Dis 2009; 48:1213.

MISCELLANEOUS GRAM-POSITIVE
SKIN INFECTIONS
Erysipeloid of Rosenbach
The most re uent orm o erysipeloid is a purplish margin
ated swelling on the hands. The rst symptom is pain at
the site o inoculation ollowed by swelling and erythema.
The most distincti e eature is the sharply marginated and
o ten polygonal patches o bluish erythema ( ig. ). The
erythema slowly spreads to produce a sharply de ned
slightly ele ated one that e tends peripherally as the
central portion ades away. the nger is in ol ed the
swelling and tenseness ma e mo ement di cult. Vesicles
re uently occur.
Another characteristic o the disease is its migratory nature;
new purplish red patches appear at nearby areas. the in ec
tion originally in ol ed one nger e entually all the ngers
and the dorsum o the hand the palm or both may become
in ected with the erythema appearing and disappearing; or
e tension may ta e place by continuity. The disease in olutes
without des uamation or suppuration. A di use or general
i ed eruption in regions remote rom the site o inoculation
may occur with e er and arthritic symptoms. Rarely septi
cemia may e entuate in endocarditis with prolonged e er
and constitutional symptoms.
The in ection is caused by Er sipelothrix rhusiopathiae. E rhu
siopathiae is present on dead matter o animal origin. Swine are
more re uently in ected than any other animal. A large per
centage o healthy swine are carriers o the organism. Tur eys
are also o ten in ected and the disease may arise rom han
dling contaminated dressed tur eys. t is also present in the
slime o saltwater sh on crabs and on other shell sh. The
disease is widespread along the entire Atlantic seacoast among
commercial shermen who handle li e sh crabs and shell
sh. The in ection also occurs among eterinarians and in the
meatpac ing industry principally rom handling por prod
ucts. E rhusiopathiae is a rod shaped nonmotile gram positi e
organism that tends to orm long branching laments. The
organism is cultured best on media orti ed with serum at
room temperature.
Treatment
The ma ority o the mild cases o erysipeloid run a sel limited
course o about wee s. n some patients a ter a short period
o apparent cure the eruption reappears either in the same area
or more li ely in an ad acent pre iously unin ol ed area.
Fig. 14-23 Erysipeloid.
Penicillin g day or days or ampicillin mg our
times daily is the best treatment or locali ed disease. peni
cillin cannot be used cipro o acin clindamycin or imipenem
may be used. or systemic orms million units day o
V penicillin or up to wee s may be necessary.
Miscellaneous gram-positive skin infections
Veraldi S, et al: Erysipeloid. Clin Exp Dermatol 2009; 34:859.
Werner K, et al: Erysipeloid (Erysipelothrix rhusiopathiae infection)
acquired from a dead kakapo. Arch Dermatol 2011; 147:1456–1458.
Pneumococcal cellulitis
Cellulitis may be caused by Streptococcus pneumoniae. Children
present with acial or periorbital cellulitis which may mani est
a iolaceous hue or bullae. ost patients under months o
age are pre iously healthy. e er leu ocytosis and septice
mia are almost uni ersal. Response to treatment with penicil
lin or in resistant cases ancomycin is e cellent. ost reported
disease was caused by the strains included in the pneumococ
cal accine so this condition has become rare as has occurred
with aemophilus in uen ae cellulitis. Chronically ill or immu
nosuppressed adults also may de elop pneumococcal cell
ulitis or other so t tissue in ections such as abscesses or
pyomyositis. n patients with diabetes or substance abuse
e tremity in ol ement is the rule whereas in those with SL
nephritic syndrome hematologic disorders or V disease
the head nec and upper torso are typically a ected. S in
in ol ement may also be seen as a surgical wound in ection.
Because septicemia tissue necrosis and suppurati e compli
cations are common aggressi e management is crucial with
surgical drainage and V antibiotics directed at the susceptibil
ity o the cultured organism.
Garcia-Lechuz JM, et al: Streptococcus pneumoniae skin and soft tissue
infections. Eur J Clin Microbiol Infect Dis 2007; 26:247.
Khan T, Martin DH: Streptococcus pneumoniae soft tissue infections in
human immunodeficiency virus. Am J Med Sci 2011; 342:235–238.
Anthrax
Cutaneous anthra is uncommon in much o the world; human
in ection generally results rom contact with in ected animals
or the handling o hides or other animal products rom stoc
that has died rom splenic e er. Cattlemen woolsorters
tanners butchers and wor ers in the goat hair industry are
most liable to in ection. uman to human transmission has
occurred rom contact with dressings rom lesions. The spores
o acillus anthracis persist and may be aerosoli ed so it is a
bioterrorism threat. n an outbrea o cutaneous disease
resulted rom powder containing en elopes sent through
the mail.
Anthra is an acute in ectious disease characteri ed by a
rapidly necrosing painless eschar with associated edema
and suppurati e regional adenitis. our orms o the disease
occur in humans cutaneous accounting or o cases
worldwide and almost all .S. cases; inhalational nown as
woolsorter s disease; gastrointestinal the rst case o which
occurred in the nited States in ; and injectional more
than cases o which occurred in the nited ingdom and
Germany. t is a complication o V drug use primarily in
heroin addicts.
The rst clinical mani estation o the cutaneous orm is an
in ammatory papule which begins about days a ter inoc
ulation usually on an e posed site. The in ammation de el
ops rapidly and a bulla surrounded by intense edema and
in ltration orms within another h. t then ruptures
spontaneously and a dar brown or blac eschar is isible
surrounded by esicles situated on a red hot swollen and
257
 indurated area. The lesion is neither tender nor pain ul. This
14 is o diagnostic importance. Pustules are almost ne er present.
The regional lymph glands become tender and enlarged and
re uently suppurate.
n patients with se ere disease the in ammatory signs
Bacterial Infections
increase; there is e tensi e edematous swelling and other
bullae and necrotic lesions de elop accompanied by a high
temperature and prostration terminating in death in a ew
days or wee s. This may occur in up to o untreated
patients. n mild cases the constitutional symptoms are some
times slight; the gangrenous s in sloughs and the resulting
ulcer heals.
nternally inhalational anthra is mani ested as a necroti
ing hemorrhagic mediastinal in ection. Anthra spores
in ol e the al eoli then the hilar and tracheobronchial nodes.
Bacteremia ollowed by hemorrhagic meningitis is the usual
se uence o e ents almost always ending in death. Gastroin
testinal anthra results when spores are ingested and multiply
in the intestinal submucosa. A necrotic ulcerati e lesion in the
terminal ileum or cecum may lead to hemorrhage. Patients
with in ectional disease present with e er and swelling o an
e tremity.
The disease is produced by acillus anthracis a large s uare
ended rod shaped gram positi e organism that occurs singly
or in pairs in smears rom the blood or in material rom the
local lesion or in long chains on arti cial media where it tends
to orm spores. The bacillus possesses three irulence actors
a polyglutamate acid capsule inhibiting phagocytosis; an
edema to in composed o edema actor and a transport
protein termed protecti e antigen; and lethal to in composed
o lethal actor plus protecti e antigen.
A biopsy should be obtained. This allows or immunohisto
chemical and polymerase chain reaction (PCR) studies as well
as routine histology and tissue Gram stain. icroscopically
there is loss o the epidermis at the site o the ulcer with sur
rounding spongiosis and intraepidermal esicles. Leu ocytes
are abundant in the epidermis. The dermis is edematous and
in ltrated with abundant erythrocytes and neutrophils. Vaso
dilation is mar ed. The causati e organisms are numerous and
are easily seen especially with Gram stain.
The diagnosis is made by demonstration o the causati e
agent in smears and cultures o the local material. The charac
teristic gangrenous lesion surrounded by esiculation intense
swelling and redness lac o pain and the patient s occupation
are accessory actors. PCR identi cation is readily a ailable due
to its bioterrorism threat. Staphylococcal carbuncle is the most
easily con used entity but here tenderness is prominent.
arly diagnosis and prompt treatment with cipro o acin
( mg) or do ycycline ( mg) twice daily or days are
curati e in the cutaneous orm when there are no systemic
symptoms lesions are not on the head or nec and are without
signi cant edema and the patient is not a child younger
than years. n these latter conditions more aggressi e V
therapy is re uired as outlined in the CDC management
guidelines a ailable at the CDC website. Asymptomatic
e posed indi iduals should be gi en prophylactic treatment
with a wee course o do ycycline or cipro o acin. A accine
is a ailable.
Aquino LL, et al: Cutaneous manifestations of category A bioweapons.
J Am Acad Dermatol 2011; 65:1213.
Doganay M, et al: A review of cutaneous anthrax and its outcome. J
Infect Public Health 2010; 3:98–105.
Hendricks KA, et al: Centers for Disease Control and Prevention expert
panel meetings on prevention and treatment of anthrax in adults.
Emerg Infect Dis 2014. Feb 20.
Hicks CW, et al: An overview of anthrax infection including the recently
identified form of disease in injection drug users. Intensive Care Med
2012; 38:1092–104.
258
tahir99 - UnitedVRG
Listeriosis
Listeria monoc togenes is a gram positi e bacillus with rounded
ends that may be isolated rom soil water animals and
asymptomatic indi iduals. uman in ection probably occurs
through the G tract; in the ma ority o patients howe er
the portal o entry is un nown. n ections in humans usually
produce meningitis or encephalitis with monocytosis. Ris
actors include alcoholism ad anced age pregnancy and
immunosuppression.
Cutaneous listeriosis is a rare disease. Veterinarians may
contract cutaneous listeriosis rom an aborting cow. The organ
ism in the s in lesions is identical to that isolated rom the
etus. The eruption consists o erythematous tender papules
and pustules scattered o er the hands and arms. There may
be a illary lymphadenopathy e er malaise and headache.
Treatment with sul onamides is e ecti e.
eonates are also at ris . The endocarditis meningitis and
encephalitis caused by Listeria may be accompanied by pete
chiae pustules and papules in the s in.
Cases o listeriosis may easily be missed on bacteriologic
e amination because the organism produces ew colonies
on original culture and may be dismissed as a streptococcus
or as a contaminant diphtheroid because o the similarity in
gram stained specimens. Serologic tests help to ma e the
diagnosis.
Listeria monoc togenes is sensiti e to most antibiotics.
Ampicillin is the antibiotic o choice and T P S is an
e ecti e alternate.
Gilchrist M: Cutaneous Listeria infection. Br J Hosp Med (Lond) 2009;
70:659.
Godshall CE, et al: Cutaneous listeriosis. J Clin Microbiol 2013;
51:3591–3596.
Zelenik K, et al: Cutaneous listeriosis in a veterinarian with evidence of
zoonotic transmission. Zoonoses Public Health 2014; 61:238–241.
Cutaneous diphtheria
Cutaneous diphtheria is common in tropical areas. ost o the
.S. cases are in nonimmuni ed migrant armwor er amilies
and in elderly alcoholics. Tra elers to de eloping countries
may also import disease.
S in lesions are caused by in ection with Cor nebacterium
iphtheriae usually in the orm o ulcerations. The ulcer is
punched out and has hard rolled ele ated edges with a pale
blue tinge ( ig. ). ten the lesion is co ered with a
leathery grayish membrane. Regional lymph nodes may be
a ected. ther types o s in in ol ement include ec ematous
impetiginous esicular and pustular lesions. Postdiphtherial
paralysis and potentially atal cardiac complications may
occur. These are mediated by a potent e oto in which stops
protein production at the ribosome le el.
Treatment consists o intramuscular ( ) in ections o diph
theria antito in a ter a con uncti al test has
been per ormed to rule out hypersensiti ity to horse serum.
ne drop o antito in diluted is placed in one eye and
drop o saline in the other eye. a ter min there is no reac
tion o antito in is gi en. rythromycin g
day is the drug o choice unless large proportions o resistant
organism are nown in the area. n se ere cases V penicillin
G day or days is indicated. Ri ampin mg
day or days will eliminate the carrier state.
Lowe CF, et al: Cutaneous diphtheria in the urban poor
populations of Vancouver, British Columbia. J Clin Microbiol
2011: 49:2664–2666.
Orouji A, et al: Cutaneous diphtheria in a German man with travel
history. Acta Derm Venereol 2012; 92:179–180.
 Fig. 14-24 Cutaneous
diphtheria.
Sears A, et al: Cases of cutaneous diphtheria in New Zealand. NZ
Med J 2012; 125:64–71.
Corynebacterium jeikeium sepsis
Cor nebacterium jei eium coloni es the s in o healthy indi
iduals with the highest concentration being in the a illary
and perineal areas. ospitali ed patients are more hea ily
coloni ed. Patients with granulocytopenia indwelling cathe
ters prosthetic de ices e posure to multiple antibiotics and
al ular de ects are at highest ris or the de elopment o
sepsis or endocarditis. A papular eruption cellulitis subcuta
neous abscesses tissue necrosis hemorrhagic pustules and
palpable purpura may be seen on the s in. Vancomycin is the
drug o choice. ortality is greater than in those with
leu openia but only i the marrow reco ers. ematopoi
etic growth actors should then be considered as ad uncti e
therapy in these patients.
Olson JM, et al: Cutaneous manifestations of Corynebacterium jeikeium
sepsis. Int J Dermatol 2009; 48:886.
Erythrasma
rythrasma is characteri ed by sharply delineated dry brown
slightly scaling patches occurring in the intertriginous areas
especially the a illae ( ig. ) the genitocrural crease and
the webs between the ourth and th toes and less o ten the
third and ourth toes. There may also be patches in the inter
gluteal cle t perianal s in and in ramammary area. The
ul ar mucosa can be a ected by thic des uamating yel
lowish hyper eratosis. Rarely widespread eruptions with
lamellated pla ues occur. The lesions are asymptomatic e cept
in the groins where there may be some itching and burning.
Patients with e tensi e erythrasma ha e been ound to ha e
diabetes mellitus or other debilitating diseases.
rythrasma is caused by the diphtheroid Cor nebacterium
minutissimum This non spore orming rod shaped gram
positi e organism may occasionally cause cutaneous granulo
mas or bacteremia in immunocompromised patients. Two
other diseases caused by Cor nebacterium pitted eratolysis
and trichomycosis a illaris may occur as a triad with
Fig. 14-25 Erythrasma.
Miscellaneous gram-positive skin infections
erythrasma. n the di erential diagnosis tinea cruris caused by
ungi intertrigo seborrheic dermatitis in erse psoriasis can
didiasis and lichen simple chronicus must be considered.
The Wood s light is the diagnostic medium or erythrasma.
The a ected areas show a coral red uorescence which results
rom the presence o a porphyrin. Washing o the a ected area
be ore e amination may eliminate the uorescence. Topical
erythromycin solution or topical clindamycin is easily applied
and rapidly e ecti e. ral erythromycin ( mg our times
daily or wee ) clarithromycin (single g dose) and topical
micona ole are e ually e ecti e.
Chodkiewicz HM, et al: Erythrasma. Int J Dermatol 2013;
52:516–518.
Keita S, et al: Dermatitis is the folds of black Africans in Bamako, Mali.
Int J Dermatol 2012; 51(Suppl 1):37–40, 41–44.
Rho N-K, et al: A corynebacterial triad. J Am Acad Dermatol 2008;
58:S57.
Wilson BB, et al: An atypical presentation of erythrasma. J Am Acad
Dermatol 2012; 67:e217–e218.
Arcanobacterium haemolyticum infection
This pleomorphic nonmotile non spore orming β hemolytic
gram positi e bacillus causes pharyngitis and an e anthem in
young adults. Acute pharyngitis in the year old age
group is only caused by group A streptococci in o
cases. A proportion o the remainder will be caused by rcano
bacterium haemol ticum.
The e anthem is an erythematous morbilli orm or scarlati
ni orm eruption in ol ing the trun and e tremities. Although
it usually spares the ace palms and soles atypical acral
in ol ement has been reported. The general clinical presenta
tion may include mild pharyngitis se ere diphtheria li e
illness or e en septicemia.
Cultures or haemol ticum should be done on blood
agar plates and obser ed or h. The diagnostic eatures are
enhanced by a C atmosphere during incubation at
C. Routine pharyngeal specimens are done on sheep blood
agar and will miss the growth o this organism because o its
slow hemolytic rate and growth o normal throat ora. Treat
ment o choice is erythromycin or in the case o se ere in ec
tion high dose penicillin G.
259
14
Gaston DA, Zurowski SM: Arcanobacterium haemolyticum pharyngitis
and exanthem. Arch Dermatol 1996; 132:61.
Mehta CL: Arcanobacterium haemolyticum. J Am Acad Dermatol 2003;
48:298.
Bacterial Infections
Intertrigo
ntertrigo is a super cial in ammatory dermatitis occurring
where two s in sur aces are in apposition. t is discussed
here because o its clinical association with se eral bacterial
diseases in this chapter. As a result o riction (s in rubbing
s in) heat and moisture the a ected old becomes erythem
atous macerated and secondarily in ected. There may be
erosions ssures and e udation with symptoms o burning
and itching. ntertrigo is most re uently seen during hot
and humid weather chie y in obese persons. Children and
elderly persons are also predisposed. This type o dermatitis
may in ol e the retroauricular areas; the olds o the upper
eyelids; the creases o the nec a illae and antecubital
areas; nger webs; in ramammary area; umbilicus; inguinal
perineal and intergluteal areas; popliteal spaces; and toe
webs.
As a result o the maceration a secondary in ection by bac
teria or ungi is induced. The in ramammary area in obese
women is most re uently the site o intertriginous candidia
sis. The groins are also re uently a ected by ungal (yeast or
dermatophyte) in ection. Bacterial in ection may be caused by
streptococci staphylococci Pseu omonas or Cor nebacterium
Pseu omonas is in ol ed it may stain the underwear bluish
green. Streptococcal intertrigo a ors the nec a illary and
inguinal olds o young children. There is a well demarcated
ery red moist shiny sur ace and a oul smell with an absence
o satellite lesions.
n the di erential diagnosis seborrheic dermatitis typically
in ol es the s in olds. ntertriginous psoriasis and erythrasma
are re uently o erloo ed especially when the inguinal and
intergluteal areas or ourth toe webs are in ol ed as in ery
thrasma. issured groin lesions may be a mani estation o
Langerhans cell histiocytosis.
Treatment o intertrigo is directed at elimination o the mac
eration. Appropriate antibiotics or ungicides are applied
locally. The apposing s in sur aces may be separated with
gau e or other appropriate dressings; or e ample nterDry
Ag te tile has an antimicrobial sil er comple impregnated
within the abric that when placed in the olded area not only
wic s away moisture but also retains the acti ity against ungi
and bacteria or up to days. Botulinum to in type A has
been used to dry out areas predisposed to recurrent disease.
Castellani paint is also use ul as is an antibacterial ointment.
Low potency topical corticosteroids and topical tacrolimus are
help ul to reduce in ammation but these should always be
used in con unction with a topical anti ungal or antimicrobial
agent.
Kaya TI, et al: Blue underpants sign. J Am Acad Dermatol 2005;
53:869–871.
Muller N: Intertrigo in the obese patient. Ostomy Wound Manage 2011;
57:16.
Santiago-et-Sanchez-Mateos JL, et al: Botulinum toxin type A for the
preventative treatment of intertrigo in a patient with Darier’s disease
and inguinal hyperhidrosis. Dermatol Surg 2008; 34:1733.
Silverman RA, et al: Streptococcal intertrigo of the cervical folds in a
five-month-old infant. Pediatr Infect Dis J 2012; 31:872–873.
Pitted keratolysis
n pitted eratolysis a bacterial in ection o the plantar stratum
corneum the thic weight bearing portions o the soles
260
tahir99 - UnitedVRG
Fig. 14-26 Pitted keratolysis. (Courtesy of Shyam Verma, MD.)
become gradually co ered with shallow asymptomatic dis
crete round pits mm in diameter some o which become
con uent orming urrows ( ig. ). en with ery sweaty
eet during hot humid weather are most susceptible. Rarely
palmar lesions may occur. o discom ort is produced
although the lesions are o ten malodorous.
ost disease is caused by tococcus se entarius. t produces
two serine proteases that can degrade eratin. Clinical diag
nosis is not di cult based on its uni ue appearance. isto
logic e amination generally demonstrates eratin pits lined by
small cocci as well as lamentous bacteria.
Topical erythromycin or clindamycin is curati e in pitted
eratolysis. icona ole or clotrima ole cream and Whit eld
ointment are e ecti e alternati es. Both ben oyl pero ide
gel and a solution o aluminum chloride may be used.
Botulinum to in helps i there is associated hyperhidrosis.
Blaise G, et al: Corynebacterium-associated skin infections. Int J
Dermatol 2008; 47:884.
Van der Snoek EM, et al: Pitted keratolysis. J Eur Acad Dermatol
Venereol 2013; 27:1120–1126.
Walling HW: Primary hyperhidrosis increases the risk of cutaneous
infection. J Am Acad Dermatol 2009; 61:242.
CLOSTRIDIAL INFECTIONS AND
GANGRENE OF THE SKIN
Gangrene o the s in results rom loss o the blood supply o
a particular area and in some cases rom bacterial in asion
that promotes necrosis and sloughing o the s in. The arious
orms o bacterial in ection causing gangrene are discussed
here. The in ectious causes are o ten se ere and acute and
may in ol e deep tissues; R may delineate the depth o
in ol ement. Vascular gangrene purpura ulminans and dia
betic gangrene are co ered in Chapter ; accinia gangrenosa
in Chapter ; and necroti ing asciitis earlier in this chapter.
Gas gangrene (clostridial myonecrosis)
Gas gangrene is the most se ere orm o in ectious gangrene;
it de elops in deep lacerations o muscle tissue ( ig. ).
The incubation period is only a ew hours. nset is usually
sudden and is characteri ed by a chill a rise in temperature
mar ed prostration and se ere local pain. Gas bubbles (chie y
hydrogen) produced by the in ection cause crepitation when
the area is palpated. A mousy odor is characteristic. A plain
radiograph will demonstrate the air. Gas gangrene is caused
by a ariety o Clostri ium species most re uently Clostri ium
 Fig. 14-27 Clostridial
gas gangrene.
perfringens C oe ematiens C septicum C if cile and C haemo
l ticum. These are thic gram positi e rods. Clostri ium spores
are resistant to s in sterili ation chemicals; i in ecting a site
that is being soiled by stool incontinence a mechanical wash
be ore the sterile procedure ollowed by an occlusi e sterile
dressing is recommended.
A subacute ariety o gas gangrene may be caused by an
anaerobic streptococcus (peptostreptococcus) acteroi es or
Prevotella This nonclostridial myositis may be clinically
similar but with delayed onset (se eral days). The purulent
e udate has a oul odor and gram positi e cocci in chains are
present. t is important to distinguish these two entities since
in ol ed muscle may reco er in nonclostridial myositis and
debridement may sa ely be limited to remo al o grossly
necrotic muscle. n ections with both clostridial and nonclos
tridial organisms such as Streptococcus faecalis S anginosus
Proteus Escherichia coli acteroi es and lebsiella species may
also cause crepitant cellulitis when the in ection is limited to
the subcutaneous tissue. Treatment o all clostridial in ections
is wide surgical debridement and intensi e antibiotic therapy
with V penicillin G and clindamycin. n occasional cases
o clindamycin resistant Clostri ium perfringens ancomycin
may be an e ecti e alternati e. yperbaric o ygen therapy
may be o alue i immediately a ailable. n ected patients
with cirrhosis and diabetes ha e a poorer prognosis.
Chronic undermining burrowing ulcers
(Meleney gangrene)
Chronic burrowing ulcer was rst described by eleney as
postoperati e progressi e bacterial synergetic gangrene. t
usually ollows drainage o peritoneal abscess lung abscess
or chronic empyema. A ter or wee s the wound mar ings
or retention suture holes assume a carbunculoid appearance
nally di erentiating into three s in ones outer bright red;
middle dus y purple; and inner gangrenous with a central
area o granulation tissue. The pain is e cruciating. n eleney
postoperati e progressi e gangrene the essential organism is
a microaerophilic nonhemolytic streptococcus (peptostrepto
coccus) in the spreading periphery o the lesion associated
with Staph lococcus aureus or nterobacteriaceae in the one o
gangrene.
This disease is di erentiated rom ecthyma gangrenosum
which begins as esicles rapidly progressing to pustulation
and gangrenous ulceration in debilitated patients and is
caused by Pseu omonas aeruginosa Amebic in ection with gan
grene usually ollows amebic abscess o the li er. The margins
o the ulcer are raised and e erted and the granulations ha e
the appearance o raw bee co ered with shreds o necrotic
material. Glairy pus can be e pressed rom the margins. Pyo
derma gangrenosum occurs in a di erent setting lac s the
bacterial ndings and does not respond to antibiotic therapy.
Clostridial infections and gangrene of the skin
usospirochetal gangrene occurs a ter a human bite.
Wide e cision and gra ting are primary therapy or eleney
gangrene. Antimicrobial agents penicillin and an aminogly
coside should be gi en as ad uncti e therapy.
Fournier gangrene of the penis or scrotum
ournier syndrome is a gangrenous in ection o the penis
scrotum or perineum that may be caused by in ection with
group A streptococci or with mi ed enteric bacilli and anaer
obes. This is usually considered a orm o necroti ing asciitis
because it spreads along ascial planes. Pea incidence is
between ages and although cases ha e been reported in
children. Diabetes mellitus obesity poor personal hygiene
long standing oral corticosteroid therapy and chronic alcohol
ism are predisposing actors. Culture or aerobic and anaero
bic organisms should be carried out and appropriate antibiotics
started; surgical debridement and general support should be
instituted.
Aridogan IA, et al: Epidemiological characteristics of Fournier’s
gangrene: a report of 71 patients. Urol Int 2012; 89:457–461.
Kaafarani HM, et al: Necrotizing skin and soft tissue infections. Surg
Clin North Am 2014; 94:155–163.
Khan F, et al: Fournier’s gangrene associated with intradermal injection
of cocaine. J Sex Med 2013; 10:1184–1186.
Khanna N: Clindamycin-resistant Clostridium perfringens cellulitis. J
Tissue Viability 2008; 17:95.
Ling I, et al: The crackling thigh. NZ Med J 2009; 122:81.
McHugh RC, et al: Clostridial sacroiliitis in a patient with fecal
incontinence. Pain Phys 2008; 11:249.
Oncel S, et al: Rapidly developing gas gangrene due to a simple
puncture wound. Pediatr Emerg Care 2010; 26:434–435.
Ullah S, et al: Fournier’s gangrene. Surgeon 2009; 7:138.
Actinomycosis
ctinom ces are anaerobic gram positi e lamentous bacteria
that coloni e the mouth colon and urogenital trac . n ections
are seen most o ten in the cer ico acial area but also on the
abdominal region thoracic area or pel is. iddle age men are
a ected most o ten. Diabetic and immunosuppressed patients
and alcoholics with poor dental hygiene are particularly at
ris . The lesions begin as rm nodules or pla ues and de elop
draining sinuses. Grains or sul ur granules may be present in
the e udate as in ungal mycetomas. n the cer ico acial
region the in ection is nown as lumpy aw. The underlying
bone may be in ol ed with periostitis or osteomyelitis. an
dibular in ection is seen our times as o ten as ma illary
in ol ement ( ig. ). The abdomen may be in ol ed a ter
a ruptured appendi or G surgical procedure. tension o
the in ection into the abdominal wall may produce draining
sinuses on the abdominal s in. n the thoracic region lung
in ection may spread to the thoracic wall.
ropharyngeal actinomycosis is usually caused by ctino
m ces israelii and gerencseriae The condition is o ten clini
cally misdiagnosed as a malignancy and the histologic
appearance o the characteristic granules allows diagnosis.
Sul ur granules consist o ne delicate branching laments.
osinophilic clubs composed o immunoglobulin are seen
at the periphery o the granule (Splendore oeppli phenom
enon). They resemble rays; hence the name ray ungus ( cti
nom ces). Gram stain demonstrates long gram positi e
laments.
261
14
Bacterial Infections
Fig. 14-28 Actinomycosis.
The crushed granule is used or inoculating cultures contain
ing brain heart in usion blood agar incubated under anaero
bic conditions at C. Culture is di cult; there ore direct
microscopy is important.
Penicillin G in large doses day or month ol
lowed by g day o oral penicillin or another months
may produce success ul and lasting results. ther e ecti e
medications ha e been ampicillin erythromycin tetracyclines
ce tria one and clindamycin. Surgical incision drainage and
e cision o de itali ed tissue are important.
Acevedo F, et al: Actinomycosis: a great pretender. Int J Infect Dis 2008;
12:358.
Briceño G, et al: Cutaneous fistula due to pulmonary actinomycosis in a
Mapuche girl. Pediatr Dermatol 2013; 30:504–505.
Garner JP, et al: Abdominal actinomycosis. Int J Surg 2007; 5:441.
Gupta V, et al: Primary cutaneous actinomycosis of upper extremity
masquerading as soft tissue neoplasm. Trop Doct 2012; 42:58–59.
Lancella A, et al: Two unusual presentations of cervicofacial
actinomycosis and a review of the literature. Acta Otorhinolaryngol Ital
2008; 28:89.
Wong VK, et al: Actinomycosis. BMJ 2011; 343:d6099.
Nocardiosis
ocardiosis usually begins as a pulmonary in ection rom
which dissemination occurs. Dissemination occurs most re
uently in association with debilitating conditions such as
odg in disease periarteritis nodosa leu emia A DS organ
transplants or SL . S in in ol ement is seen in o dis
seminated cases in the orm o abscesses erosions or esicu
lopustular lesions ( ig. ). Primary cutaneous disease also
occurs in healthy indi iduals in the orm o a draining abscess
or lymphangitic nodules ollowing a cutaneous in ury.
ocar ia asteroi es is usually responsible or the dissemi
nated orm o nocardiosis. ocar ia brasiliensis is the most
common cause o primary cutaneous disease. A pric by a
thorn or briar other penetrating in ury or an insect bite or
sting may be the inciting e ent.
ocardia are gram positi e partially acid ast aerobic la
mentous bacteria. Some are branched but laments tend to be
shorter and more ragmentary than those o ctinom ces The
surrounding red layer o immunoglobulin tends to be smooth
rather than club shaped. n Sabouraud de trose agar without
antibacterial additi es there are creamy or moist white colo
nies which later become chal y and orange colored.
The drug o rst choice or cutaneous nocardial in ection is
T PS tablets twice daily or wee s. inocycline
or asteroi es and amo icillin cla ulanate or brasiliensis
in ection are alternati es. Line olid is acti e but potential
ad erse e ects limit its use. Ami acin and imipenem are e ec
ti ely used in combination with a ariety o antibiotics or
disseminated in ection.
Bryant E, et al: Lymphocutaneous nocardiosis. Cutis 2010; 85:73–76
Dodiuk-Gad R, et al: Cutaneous nocardiosis. Int J Dermatol 2010;
49:1380–1385.
262
tahir99 - UnitedVRG
Fig. 14-29 Nocardiosis.
Hardak E, et al: Clinical spectrum and outcome of Nocardia infection:
experience of 15-year period from a single tertiary medical center. Am
J Med Sci 2012; 343:286–290.
Wilson JW: Nocardiosis. Mayo Clin Proc 2012; 87:403–407.
INFECTIONS CAUSED BY
GRAM-NEGATIVE ORGANISMS
PSEUDOMONAS INFECTIONS
Ecthyma gangrenosum
n the se erely ill patient with ecthyma gangrenosum opales
cent tense esicles or pustules are surrounded by narrow
pin to iolaceous halos. These lesions uic ly become hemor
rhagic and iolaceous and rupture to become round ulcers
with necrotic blac centers ( ig. ). They are usually on
the buttoc s and e tremities and are o ten grouped closely
together. cthyma gangrenosum occurs in debilitated persons
who may be su ering rom leu emia in the se erely burned
patient in pancytopenia or neutropenia or in patients with a
unctional neutrophilic de ect terminal carcinoma or other
se ere chronic disease. ealthy in ants may de elop lesions in
the perineal area a ter antibiotic therapy in con unction with
maceration o the diaper area.
The classic esicle suggests the diagnosis. The contents o
the esicles or hemorrhagic pustules will show gram negati e
bacilli on Gram staining and cultures will be positi e or Pseu
omonas aeruginosa Because this is usually a mani estation o
sepsis the blood culture will also show P aeruginosa. owe er
in healthy in ants with diaper area lesions in patients with
V in ection and in other occasional cases early lesions may
occur at a portal o entry allowing or diagnosis and treatment
be ore e olution into sepsis occurs. Although ecthyma gan
grenosum is classically associated with P aeruginosa in ection
similar hemorrhagic pustules may occur rom a ariety o
other gram negati e organisms (e.g. Serratia marcescens leb
siella pneumoniae eromonas h rophilia anthomonas malto
philia Morganella morganii Escherichia coli Citrobacter freun ii)
ungal in ections (e.g. Can i a albicans spergillus fumigatus
usarium solani Sc tali ium imi iatum) and at times Staph
lococcus aureus
Recommended treatment is the immediate institution o V
antipseudomonal penicillin. The addition o granulocyte
macrophage colony stimulating actor to stimulate both pro
li eration and di erentiation o myeloid precursors is an
ad unct in a patient with myelodysplasia or treatment induced
neutropenia. Patients ha e a poorer prognosis i there are
 Fig. 14-30 A and
B, Ecthyma
gangrenosum.

Pseudomonas infections
B

multiple lesions i there is a delay in diagnosis and institution

o appropriate therapy and i neutropenia does not resol e by
the end o a course o antibiotics. nstrumentation or catheter
i ation increases the ris o this in ection.
ther lesions also seen with Pseu omonas septicemia include
sharply demarcated areas o cellulitis macules papules
pla ues and nodules characteristically ound on the trun .
Pseu omonas mesophilica ur hol eria cepacia Citrobacter freun
ii and Stenotrophomonas maltophilia may also produce such
s in lesions in immunocompromised indi iduals.

Green nail syndrome

Green nail syndrome is characteri ed by onycholysis o the Fig. 14-31 Green nail syndrome complicating onycholysis.
distal portion o the nail and a stri ing greenish discoloration
in the separated areas ( ig. ). t is re uently associated
with paronychia in persons whose hands are o ten in water. Fig. 14-32 Gram-
negative toe web
ergrowth o P aeruginosa accounts or the pigment. Soa ing
infection.
the a ected nger in a acetic acid solution twice a day has
been ound to be help ul. Trimming the onycholytic nail plate
ollowed by application o eosporin solution twice a day is
also e ecti e.
Green oot syndrome results rom coloni ation o rubber
sports shoes with P aeruginosa. The organism produces
pyo erdin which stains the oot and toenails.

Gram-negative toe web infection

Toe web in ection o ten begins with dermatophytosis. With
increasing in ammation and maceration dermatophytosis
may progress to dermatophytosis comple in which many
types o gram negati e organism may be reco ered; howe er
it is more di cult to culture dermatophytes. entually
denudation with purulent or serous discharge and mar ed
edema and erythema o the surrounding tissue may be seen
( ig. ). Prolonged immersion may also cause hydration
and maceration o the interdigital spaces with o ergrowth o
gram negati e organisms. P aeruginosa is the most prominent
but re uently a mi ture o other gram negati e organisms
such as E coli and Proteus are present. Patients may ha e red
pain ul nodules o the cal that do not drain spontaneously
in olute then reappear wee s later. Culture o these once the scaling and peeling progress to white maceration
subcutaneous abscesses will re eal Pseu omonas or other soggy scaling bad odor edema and ssuring treatment must
gram negati e bacteria which li ely originate in the macer also include topical antibiotics or acetic acid compresses.
ated toe webs. Drying o the interdigital spaces with a an is a help ul ad unct.
arly dermatophytosis dermatophytosis simple may ull blown gram negati e toe web in ection with widespread
simply be treated with topical anti ungal agents. owe er denudation and erythema purulence and edema re uires sys
263
 temic antibiotics. A third generation cephalosporin or a uo
14 ro uinolone is recommended.
Blastomycosis-like pyoderma
Bacterial Infections
Large errucous pla ues with ele ated borders and multiple
pustules may occur as a chronic egetating in ection. ost
patients ha e an underlying systemic or local host compromise.
Bacteria such as P aeruginosa S aureus Proteus E coli and
streptococci may be isolated. Appropriate antibiotics or the
cultured organism may be augmented by acitretin.
Pseudomonas aeruginosa folliculitis
(hot tub folliculitis)
Pseudomonal olliculitis is characteri ed by pruritic ollicular
maculopapular esicular or pustular lesions occurring within
days a ter bathing in a hot tub whirlpool or public swim
ming pool ( ig. ). As the water temperature rises ree
chlorine le els all e en though total chlorine le els appear
ade uate. This allows the bacteria to proli erate. Di ing suits
may become coloni ed and wearing them may result in P
aeruginosa olliculitis. ne case occurred limited to the hand
and wrist occluded under coloni ed rubber glo es.
ost lesions occur on the sides o the trun a illae but
toc s and pro imal e tremities. The apocrine areas o the
breasts and a illae are o ten in ol ed. Associated complaints
may include earache sore throat headache e er and malaise.
Rarely systemic in ection may result; breast abscess and bac
teremia ha e been reported. Large community outbrea s ha e
occurred associated with public pools and employees o a
cardboard manu acturing acility who were e posed to wet
wor de eloped Pseu omonas olliculitis o the e tremities as
an occupational disorder. eromonas h rophilia was ound to
be responsible or a clinically similar olliculitis that a ected
two siblings playing in an in atable swimming pool.
The olliculitis in olutes usually within days without
therapy although multiple prolonged recurrent episodes ha e
occasionally been reported. n patients with e er constitu
tional symptoms or prolonged disease a third generation oral
cephalosporin or a uoro uinolone such as cipro o acin or
o o acin may be use ul. Pre enti e measures ha e been water
ltration automatic chlorination to maintain a ree chlorine
le el o ppm maintenance o water at p . . and re
uent changing o the water. Bromination o the water and
o one ioni ation are other options.
Pseu omonas hot oot syndrome was reported in a group o
children who de eloped pain ul erythematous plantar
Fig. 14-33 Pseudomonas hot
tub folliculitis.
264
tahir99 - UnitedVRG
nodules or pustules a ter wading in a community pool whose
oor was coated with abrasi e grit. ne biopsy showed neu
trophilic eccrine hidradenitis; another re ealed dermal micro
abscesses. ost were treated symptomatically and resolution
occurred within wee s. ther patients ha e been reported
a ter e posure to sauna and hot tubs.
External otitis
Swelling maceration and pain may be present. n up to
o cases P aeruginosa may be cultured. ternal otitis is espe
cially common in swimmers. Local application o antipseudo
monal and anti in ammatory Cortisporin otic solution or
suspension or acetic acid compresses with topical cortico
steroids will help clear this in ection. n patients with otorrhea
or pus emanating rom the canal i the symptoms ha e been
present or wee or more or i diabetes or an immunologic
de ect is present cleansing the canal isuali ing the tympanic
membrane or per oration and other precautions will be most
readily handled by an otolaryngology consultation. Applica
tion o otic Domeboro solution a ter swimming will help
pre ent recurrence. ungi such as Can i a and spergillus are
other causes. Anti ungal solutions (e.g. ciclopiro olamine)
combined with corticosteroid solutions are e ecti e in otomy
cosis. There is also a threat o e ternal otitis occurring a ter ear
surgery ( ig. ). the patient is a swimmer or has diabe
tes acetic acid compresses or or days be ore surgery may
pre ent this complication.
ternal otitis must be distinguished rom allergic contact
dermatitis due to neomycin in Cortisporin otic suspension.
Allergic contact dermatitis produces se ere pruritus although
tenderness may also be noted. Dermatitis may e tend down
the side o the chee in a pattern suggesting drainage o the
suspension.
A se ere type re erred to as malignant e ternal otitis occurs
in elderly patients with diabetes or in those immunocompro
mised with V in ection recei ing chemotherapy or li ing
with organ transplants. The swelling pain and erythema are
more pronounced with purulence and a oul odor. acial
ner e palsy de elops in o patients and cartilage necrosis
may occur. This is a li e threatening in ection in these older
compromised indi iduals and re uires swi t institution and
prolonged administration ( wee s) o oral uinolone
antibiotics.
Fig. 14-34
Pseudomonas
external otitis after
shave biopsy.
 Lastly commercial ear piercing o the upper ear cartilage
may lead to in ection with Pseu omonas with resulting cos
metic de ormity a reported complication.
Gram-negative folliculitis
Although gram negati e olliculitis is usually caused by
nterobacteriaceae lebsiella Escherichia Proteus or Serratia
occasional cases caused by Pseu omonas ha e been seen. They
di er rom gram negati e in ection in patients with acne in
that the site o Pseu omonas coloni ation is the e ternal ear
and topical therapy alone to the ace and ears is su cient or
cure. Also an outbrea o gram negati e pustular dermatitis
on the legs arms torso and buttoc s occurred in a group o
college students who hosted a mud wrestling social e ent.
Aygencel G, et al: Burkholderia cepacia as a cause of ecthyma
gangrenosum–like lesions. Infection 2008; 36:271.
Bae JM, et al: Green foot syndrome. J Am Acad Dermatol 2013;
69:e198–e199.
Carfrae MJ, et al: Malignant otitis externa. Otolaryngol Clin North Am
2008; 41:537.
Chang AY, et al: Nonpseudomonal ecthyma gangrenosum associated
with methicillin-resistant Staphylococcus aureus infection. Cutis 2012;
90:67–69.
Cho SB, et al: Green nail syndrome associated with military footwear.
Clin Exp Dermatol 2008; 33:791.
Goolamali SI, et al: Ecthyma gangrenosum. Clin Exp Dermatol 2009;
34:e180.
Handley RT: Otitis externa. JAAPA 2009; 22:44.
Hui CP et al: Acute otitis externa. Paediatr Child Health 2013;
18:96–101.
Kaitlin V, et al: Macerated foot dermatitis related to occlusive footwear.
WV Med J 2013; 109:8–9.
Keene WE, et al: Outbreak of Pseudomonas aeruginosa infections
caused by commercial piercing of the upper ear cartilage. JAMA 2004;
291:981.
Lambor DV, et al: Necrotising otitis externa. J Laryngol Otol 2013;
127:1071–1077.
Lu XL, et al: Good response of a combined treatment of acitretin and
antibiotics in blastomycosis-like pyoderma. Eur J Dermatol 2009;
19:261–262.
Manresa MJ, et al: Aeromonas hydrophilia folliculitis associated with an
inflatable swimming pool. Pediatr Dermatol 2009; 26:601–603.
Mazza J, et al: Pseudomonas folliculitis contracted from rubber gloves.
J Am Acad Dermatol 2013; 69:e93–e94.
Michl RK, et al: Outbreak of hot-foot syndrome caused by
Pseudomonas aeruginosa. Klin Paediatr 2012; 224:252–255.
Nieves D, et al: Smoldering gram-negative cellulitis. J Am Acad
Dermatol 1999; 41:319.
Patel JK, et al: Ecthyma gangrenosum caused by Escherichia coli
bacteremia. Cutis 2009; 84:261–267.
Prindaville B, et al: Chronic granulomatous disease presenting with
ecthyma gangrenosum in a neonate. J Am Acad Dermatol 2014;
71:e44–45.
Segna KG, et al: “Hot tub” folliculitis from a nonchlorinated children’s
pool. Pediatr Dermatol 2011; 28:590–591.
Tsychiyama K, et al: Ecthyma gangrenosum with Citrobacter freundii
infection. J Eur Acad Dermatol Venereol 2009; 23:709–710.
Yan W, et al: Ecthyma gangrenosum and multiple nodules. Pediatr
Dermatol 2011; 28:204–205.
MALACOPLAKIA (MALAKOPLAKIA)
This rare granuloma was originally reported only in the geni
tourinary tract o immunosuppressed renal transplant recipi
ents but malacopla ia may also occur in the s in and
subcutaneous tissues o other immunocompromised patients
as with V in ection. Patients are unable to resist in ections
with S aureus P aeruginosa and E coli. There is de ecti e
intracellular digestion o the bacteria once they ha e been
phagocytosed.
The granulomas may arise as massli e lesions or nodules
abscesses or ulcerations. They a or the perineum but also
a ect the abdominal wall thora e tremities and a illa. The
Chancroid
tongue is also a site o appearance usually presenting as a
mass lesion. istologically oamy eosinophilic ansemann
macrophages contain calci ed concentrically laminated intra
cytoplasmic bodies ( ichaelis Gutmann). Scattered immuno
blasts neutrophils and lymphocytes are ound in the dermis.
Success ul treatment o malacopla ia depends on the iso
lated organism; a uoro uinolone such as cipro o acin or
o o acin typically is use ul.
Alfonso JP, et al: Cutaneous malakoplakia. An Bras Dermatol 2013;
88:432–437.
Diapera MJ, et al: Malacoplakia of the tongue. Am J Otolaryngol 2009;
30:101.
Flann S, et al: Cutaneous malakoplakia in an abdominal skin fold. J Am
Acad Dermatol 2010; 62:896.
Rubinson R, et al: Malakoplakia. Pediatr Dermatol 2012; 29:541–543.
Verma SB: Cutaneous malakoplakia. Int J Dermatol 2011; 50:184–186.
HAEMOPHILUS INFLUENZAE CELLULITIS
aemophilus in uen ae type B causes a distincti e bluish or
purplish red cellulitis o the ace accompanied by e er in
children younger than years. The condition is rarely seen in
countries where the accination is a ailable. t is gi en at
and months o age. The importance o recogni ing in u
en ae cellulitis is related to the bacteremia that o ten accompa
nies the cellulitis. The bacteremia may lead to meningitis
orbital cellulitis osteomyelitis or pyarthrosis. Cultures o the
blood and needle aspirates o the cellulitis should yield the
organism. Ce ota ime or ce tria one is e ecti e. n a amily
with children under age the inde case both parents and
children at ris (un accinated) should be gi en ri ampin to
clear the nasal carriage state and pre ent secondary cases.
in uen a type A is not co ered by the accine and reports o
this organism causing in asi e in ection including cellulitis
are increasing.
Bruce MG, et al: Haemophilus influenzae serotype A invasive disease,
Alaska, USA, 1983–2011. Emerg Infect Dis 2013; 19:932–937.
Rimon A, et al: Periorbital cellulitis in the era of Haemophilus
influenzae type B vaccine. J Pediatr Ophthalmol Strabismus 2008;
45:300.
CHANCROID
Chancroid (so t chancre) is an in ectious ulcerati e STD
caused by the gram negati e bacillus aemophilus ucre i (the
Ducrey bacillus). ne or more deep or super cial tender
ulcers on the genitalia and pain ul inguinal adenitis in
which may suppurate are characteristic o the disease. en
outnumber women many old.
Chancroid begins as an in ammatory macule or pustule
days or rarely as long as wee s a ter intercourse. t gener
ally appears on the distal penis or perianal area in men or on
the ul a cer i or perianal area in women. owe er many
cases o e tragenital in ection on the hands eyelids lips
or breasts ha e been reported. Autoinoculation re uently
orms issing lesions on the genitalia and women are apt
to ha e more numerous lesions. The pustule ruptures early
with the ormation o a ragged ulcer that lac s the induration
o a chancre usually being so t with an inde nite in amma
tory thic ening. The ulcers appear punched out or ha e
undermined irregular edges surrounded by mild hyperemia
265

14
Bacterial Infections
Fig. 14-35 Chancroid.
( ig. ). The base is co ered with a purulent dirty e udate.
The ulcers bleed easily and are ery tender.
A number o clinical ariants ha e been described including
granuloma inguinale li e giant ulcers serpiginous ulcers
transient chancroid and ollicular and papular ariants.
nly about hal the cases o genital chancroid mani est
inguinal adenitis. Suppuration o the bubo (inguinal lymph
node) may occur despite early antibiotic therapy. The lymph
adenitis o chancroid mostly unilateral is tender and may
rupture spontaneously. Le t untreated the site o per oration
o the bro en down bubo may assume the eatures o a so t
chancre (chancrous bubo).
As a result o mi ed in ection phagedenic and gangrenous
eatures may de elop. Chronic pain ul destructi e ulcers
which begin on the prepuce or glans and spread by direct
e tension along the sha t o the penis are present. They may
sometimes attac the scrotum or pubes. The edges o the ulcer
are li ely to be ele ated rm and undermined. The granulat
ing base which bleeds easily is co ered with a thic purulent
e udate and dirty necrotic detritus. The neighboring s in may
be edematous and dus y red and the regional lymph glands
may be swollen although this is not necessarily a mar ed
eature. There is se ere mutilation as a result o sloughing
with no e idence o spontaneous healing.
This type o phagedena (spreading and sloughing ulcer
ation) is a rare complication o chancroidal in ections together
with another secondary bacterial in ection. Treatment is by
the use o antibiotics locally and internally directed against
secondary bacteria as well as the primary process. ultiple
in ections may be present such as chancroid syphilis or gran
uloma inguinale.
n histologic in estigation the ulcer may include a super
cial necrotic one with an in ltrate consisting o neutrophils
lymphocytes and red blood cells. Deep to this new essel
ormation is present with ascular proli eration. Deeper still
is an in ltrate o lymphocytes and plasma cells. Ducrey bacilli
may or may not be seen in the sections.
The de niti e diagnosis o chancroid re uires identi cation
by culture. Solid media culture techni ues ha e allowed
de niti e diagnosis and sensiti ity testing; howe er culture
is una ailable in many settings and reco ery is only about
success ul. Specimens or culture should be ta en rom
the purulent ulcer base and acti e border without e tensi e
cleaning. They should be inoculated in the clinic; transport
systems ha e not been e aluated. The selecti e medium con
tains ancomycin and cultures are done in a water saturated
en ironment with C at a temperature o C. cca
sional outbrea s are caused by ancomycin sensiti e strains.
266
tahir99 - UnitedVRG
n these cases culture will only be success ul using ancomycin
ree media.
Smears are only diagnostic in o cases in the best hands.
A probable diagnosis is made by a clinically compatible e ami
nation and negati e testing or conditions that may mimic
chancroid in presentation. Chancroid probably is most re
uently mista en or herpes progenitalis. A history o recur
rent grouped esicles at the same site should help eliminate
the chance o a misdiagnosis. Traumatic ulcerations should
also be ruled out; these occur mostly along the renulum or as
multiple erosions on the prepuce. Adenopathy is absent and
some degree o phimosis is present.
The clinical eatures that di erentiate chancroid rom syphi
litic chancre are described in Chapter . owe er the diag
nosis o chancroid does not rule out syphilis. ither the lesion
may already be a mi ed sore or the subse uent de elopment
o syphilis should be anticipated since the incubation period
o the chancre is much longer than that o chancroid. Repeated
dar eld e aminations or reponema palli um are necessary
e en in a sore where the diagnosis o chancroid has been
established. Serologic tests or syphilis should be obtained
initially then monthly or the ne t months and serologic
testing or V in ection should also be done. Chancroidal
genital ulcer disease acilitates the transmission o V
in ection. n V in ected patients chancroid may ha e a pro
longed incubation period the number o ulcers may be
increased e tragenital sites are more re uently a ected anti
biotic therapy ails more o ten and healing is slower when it
does occur. Complications such as penile amputation rom a
deep trans erse ulcer may result.
Treatment
The treatment o choice or chancroid is a ithromycin g
orally in a single dose. rythromycin mg our times a day
or days; ce tria one mg intramuscularly in a single
dose; and cipro o acin mg orally twice a day or days
are also recommended treatments. Cipro o acin should not
be used in pregnant or lactating women or in children younger
than years. Partners who ha e had se ual contact with the
patient within the days be ore the onset o symptoms
should be treated with a recommended regimen.
Phimosis that does not subside a ter irrigation o the prepu
tial ca ity may ha e to be relie ed by a dorsal slit. Circumci
sion should be de erred or at least or months. ran pus
is already present repeated aspirations (not incisions) may be
necessary.
Basta-Juzbasic A, et al: Chancroid, lymphogranuloma venereum,
granuloma inguinale, genital herpes simplex infection, and molluscum
contagiosum. Clin Dermatol 2014; 32:290–298.
Canhoto M, et al: Haemophilus ducreyi and Treponema pallidum
co-infection in and HIV-negative male presenting with anal ulcerations.
Colorectal Dis 2012; 14:e749–e750.
Kemp M, et al: European guidelines for the management of chancroid,
2011. Int J STD AIDS 2011; 22:241–244.
GRANULOMA INGUINALE (GRANULOMA
VENEREUM, DONOVANOSIS)
Granuloma inguinale is a mildly contagious chronic granu
lomatous locally destructi e disease characteri ed by progres
si e indolent serpiginous ulcerations o the groins pubes
genitalia and anus. The disease begins as single or multiple
subcutaneous nodules which erode through the s in to
produce clean sharply de ned lesions which are usually
painless ( ig. A). ore than o cases demonstrate
 Fig. 14-36 A and B,
Granuloma inguinale.
A inclusion bodies are ound. The parasiti ed histiocytes may
B
hypertrophic egetati e granulation tissue which is so t has
a bee y red appearance and bleeds readily. Appro imately
o cases ha e ulcerati e lesions with o erhanging edges
and a dry or moist oor ( ig. B). A membranous e udate
may co er the oor o ne granulations and the lesions are
moderately pain ul. ccasional cases are misdiagnosed as car
cinoma o the penis. The lesions enlarge by autoinoculation
and peripheral e tension with satellite lesions and by gradual
undermining o tissue at the ad ancing edge.
The genitalia are in ol ed in o cases inguinal region
in anal region in and distal sites in . Lesions
are limited to the genitalia in appro imately o patients
and to the inguinal region in less than . The lesions most
re uently occur on the prepuce or glans in men and on the
labia in women. The incubation period is un nown; it may
ary between and days with a to wee period being
most common.
Persisting sinuses and hypertrophic scars de oid o
pigment are airly characteristic o granuloma inguinale. The
regional lymph nodes are usually not enlarged. n later stages
as a result o cicatri ation the lymph channels are sometimes
bloc ed and pseudoelephantiasis o the genitals (esthiomene)
may occur. utilation o the genitals and destruction o deeper
tissues are obser ed in some patients. Dissemination rom the
inguinal region may be by hematogenous or lymphatic routes.
There may be in ol ement o li er other organs eyes ace
lips laryn chest and rarely bones. During childbearing the
cer ical lesions may e tend to the internal genital organs.
S uamous cell carcinoma may rarely super ene.
Granuloma inguinale is caused by the gram negati e bacte
rium lebsiella granulomatis t is se ually transmitted in the
ma ority o cases with con ugal in ection occurring in
o marital or steady se ual partners. Also it is speculated that
granulomatis is an intestinal inhabitant that leads to granu
loma inguinale through autoinoculation or se ually through
aginal intercourse i the agina is contaminated by enteric
bacteria or through rectal intercourse heterose ual or homo
se ual. granulomatis probably re uires direct inoculation
Gonococcal dermatitis
through a brea in the s in or mucosa to cause in ection. Those
a ected are generally young adults.
n histologic in estigation in the center o the lesion the
epidermis is replaced by serum brin and polymorphonu
clear leu ocytes. At the periphery the epidermis demonstrates
pseudoepitheliomatous hyperplasia. n the dermis there is a
dense granulomatous in ltration composed chie y o plasma
cells and histiocytes and scattered throughout are small
abscesses containing polymorphonuclear leu ocytes. Charac
teristic pale staining macrophages that ha e intracytoplasmic
measure μm or more in diameter. The o oid Dono an
bodies measure μm and may be isuali ed by using
Giemsa or sil er stains. The best method howe er is toluidine
blue staining o semithin plastic embedded sections. Crushed
smears o resh biopsy material stained with Wright or Giemsa
permit the demonstration o Dono an bodies and pro ide
rapid diagnosis.
Granuloma inguinale may be con used with ulcerations o
the groin caused by syphilis or carcinoma but it is di erenti
ated rom these diseases by its long duration and slow course
by the absence o lymphatic in ol ement and in the case o
syphilis by a negati e test or syphilis and ailure to respond
to antisyphilitic treatment. t should not be o erloo ed that
other enereal diseases especially syphilis o ten coe ist with
granuloma inguinale. Additionally all patients presenting
with STDs should be tested or V in ection and their se ual
partners e aluated. Lymphogranuloma enereum (LGV) at an
early stage would most li ely be accompanied by inguinal
adenitis. n later stages when stasis e coriations and enlarge
ment o the outer genitalia are common to granuloma ingui
nale and LGV the absence o a positi e LGV complement
ation test and the presence o Dono an bodies in the lesions
permit the diagnosis o granuloma inguinale.
Treatment
ral T P S ( double strength tablet) or do ycycline
( mg) twice daily or a minimum o wee s is the recom
mended regimen. Therapy should be continued until all
lesions ha e healed completely. Alternati e regimens are oral
cipro o acin mg twice daily; erythromycin base mg
our times daily; and a ithromycin g once wee ly all or at
least wee s. The addition o an V aminoglycoside such as
gentamicin mg g e ery h should be considered i lesions
do no respond within the rst ew days and in V in ected
patients.
Basta-Juzbasic A, et al: Chancroid, lympogranuloma venereum,
granuloma inguinale, genital herpes simplex infection, and molluscum
contagiosum. Clin Dermatol 2014; 32: 290–298.
Bezerra SM, et al: Granuloma inguinale. An Bras Dermatol 2011; 86:
585–586.
Narang T, et al: Genital elephantiasis due to donovanosis. Int J STD
AIDS 2013; 23:835–836.
GONOCOCCAL DERMATITIS
Primary gonococcal dermatitis is a rare in ection that occurs
a ter primary inoculation o the s in rom an in ected ocus. t
may present as grouped pustules on an erythematous base on
the nger simulating herpetic whitlow with or without an
ascending lymphangitis. Scalp abscesses in in ants may occur
267
 secondary to direct etal monitoring in mothers with gonor
14 rhea. t may also cause an in ammation o the median raphe
or a lymphangitis o the penis with or without accompanying
urethritis. Treatment is the same as that o gonorrheal urethri
tis. A single oral dose o ce ime mg is usually curati e.
Bacterial Infections
Ce tria one is also e ecti e as a mg single dose.
Gonococcemia
Gonococcemia is characteri ed by a hemorrhagic esiculopus
tular eruption bouts o e er and arthralgia or actual arthritis
o one or se eral oints. The s in lesions begin as tiny ery
thematous macules that e ol e into esicopustules on a deeply
erythematous or hemorrhagic base or into purpuric macules
that may be as much as cm in diameter ( ig. ). These
purpuric lesions occur acrally mostly on the palms and soles
and o er oints. They are accompanied by e er chills malaise
migratory polyarthralgia myalgia and tenosyno itis. The
esicopustules are usually tender and sparse and occur mainly
on the e tremities. n olution o the lesions ta es place in
about days.
any patients are women with asymptomatic anogenital
in ections in whom dissemination occurs during pregnancy or
menstruation. Li er unction abnormalities myocarditis peri
carditis endocarditis and meningitis may complicate this
in ection. n se ere or recurrent cases complement de ciency
especially o the late (C C C or C ) components should
be in estigated.
The causati e organism is eisseria gonorrhoeae These organ
isms can at times be demonstrated in the early s in lesion
histologically by smears and by cultures. Gonococci may be
ound in the blood genitourinary tract pharyn oints and
s in. The s in lesions o gonococcemia may be identical to
those seen in meningococcemia nongonococcal bacterial
endocarditis rheumatoid arthritis the ric ettsial diseases
SL periarteritis nodosa a erhill e er and typhoid e er.
Septic emboli with any gram negati e organism or Can i a
classically mani est as hemorrhagic pustules.
The treatment o choice or disseminated gonococcal in ec
tion is ce tria one g day intra enously or intramuscularly
or h a ter impro ement begins. Therapy then may be
switched to ce ime mg orally twice daily or at least
wee . Alternati e initial drugs include ce ota ime or ce ti o
ime g e ery h. Spectinomycin g intramuscularly e ery
h may be used or persons allergic to β lactam drugs.
a cephalosporin is used either do ycycline mg twice
daily or days or a ithromycin g as a single dose should
Fig. 14-37 Gonococcemia.
268
tahir99 - UnitedVRG
be gi en to treat coe isting chlamydial in ection. Serologic
testing or V in ection should also be done as well as screen
ing or syphilis. Se partners within days or symptomatic
in ection and days or asymptomatic in ection should be
re erred or treatment.
Dutertre M, et al: Gonococcemia mimicking a lupus flare in a young
woman. Lupus 2014; 23:81–83.
Mahendran SM: Disseminated gonococcal infection presenting as
cutaneous lesions in pregnancy. J Obstet Gynecol 2007; 27:617.
Suzaki A, et al: Disseminated gonococcal infection in Japan. Intern Med
2011; 50:2039–2043.
MENINGOCOCCEMIA
Acute meningococcemia presents with e er chills hypoten
sion and meningitis. al to two thirds o patients de elop a
petechial eruption most re uently on the trun and lower
e tremities which may progress to ecchymoses bullous
hemorrhagic lesions and ischemic necrosis ( ig. ). ten
acral petechiae are present and petechiae may be noted on the
eyelids. Angular in arcti e lesions with an erythematous rim
and gun metal gray interior are characteristic o meningococ
cal sepsis. ccasionally a transient blanchable morbilli orm
eruption is the only cutaneous nding. The oral and con unc
ti al mucous membranes may be a ected.
eningococcemia primarily a ects young children males
more re uently than emales. Patients with asplenia immu
noglobulin de ciencies or inherited or ac uired de ciencies
o the terminal components o complement or properdin are
predisposed to in ection.
A rare ariant is chronic meningococcemia. There are recur
rent episodes o e er arthralgias and erythematous macules
that may e ol e into lesions with central hemorrhage. Acral
hemorrhagic pustules similar to those ound in gonococcal
sepsis may be seen. Patients are generally young adults with
e ers lasting h interspersed with days o well being.
eningococcemia is caused by the astidious gram negati e
diplococcus eisseria meningiti is t has a polysaccharide
capsule that is important in its irulence and serotyping. The
human nasopharyn is the only nown reser oir with car
riage rates in the general population estimated to be .
Treatment is with V ce tria one g our times daily or
penicillin G g day up to day or days.
De amethasone ce ota ime chloramphenicol and T P S
are alternati es. ne dose o cipro o acin mg is gi en
a ter the initial course o antibiotics to clear nasal carriage.
ousehold members and day care and close school contacts
Fig. 14-38 Meningococcemia.
should recei e prophylactic therapy. Ri ampin mg g
e ery h or days is an alternati e prophylactic therapy
or children. A poly alent accine is e ecti e against groups
A C and W and is recommended or high ris groups.
Abbas A, Mujeeb AA: Purpura fulminans caused by meningococcemia in
an infant. BMJ Case Rep 2013; Aug 6.
Duggal S, et al: Recent outbreak of meningococcal meningitis: a
microbiological study with brief review of the literature. J Commun Dis
2007; 39:209.
Gunawardane ND, et al: Purpura fulminans from meningococcemia
mimicking Stevens-Johnson syndrome in an adult patient taking
etanercept. Arch Dermatol 2012; 148:1429–1431.
VIBRIO VULNIFICUS INFECTION
n ection with ibrio vulni cus a gram negati e rod o the
noncholera group o ibrios may produce either a rapidly
e panding cellulitis or a li e threatening septicemia in patients
e posed to the organism. This in ection mainly occurs along
the Atlantic seacoast. t may be ac uired through the G tract;
a ter being ingested with raw oysters or other sea ood the
bacterium enters the bloodstream at the le el o the duode
num. Pulmonary in ection by the aspiration o seawater has
been reported. Locali ed s in in ection may result a ter e po
sure o an open wound to seawater.
S in lesions characteristically begin within h o e po
sure with locali ed tenderness ollowed by erythema edema
and indurated pla ues. Lesions occur in almost o patients
and are most common on the lower e tremities. A purplish
discoloration de elops centrally and then undergoes necrosis
orming hemorrhagic bullae or ulcers ( ig. ). ther
reported lesions include hemorrhagic bullae pustules pete
chiae generali ed macules or papules and gangrene.
the s in is in aded primarily septicemia may not de elop
but the lesions may be progressi e and at times limb amputa
tion may be necessary. With septicemia cellulitic lesions are
the result o seeding o the subcutaneous tissue during bacte
remia. Patients with ad anced li er disease are at particular
ris or de eloping septicemia. ther predisposing disorders
are immunosuppression alcoholism adrenal insu ciency
diabetes renal ailure male gender and iron o erload states.
The irulence o the bacterium is related to the production o
e oto in and arious other actors. The mortality in patients
with septicemia is greater than . Aeromonas hydrophilia. Australas J Dermatol 2008; 49:39.
Treatment o this ulminant in ection which rapidly pro
duces septic shoc includes antibiotics surgical debridement
and appropriate resuscitati e therapy. Do ycycline together
with ce tria one is the treatment o choice. n patients with
pree isting hepatic dys unction or immunocompromise and
whose wounds are e posed to or ac uired in saltwater
Fig. 14-39 Vibrio vulnificus infection. (Courtesy of Curt Samlaska, MD.)
prophylactic antibiotic co erage with do ycycline mg
e ery h and cleansing with . sodium hypochlorite
solution may pre ent progressi e in ection.
Cazorla C, et al: Fatal Vibrio vulnificus infection associated with eating
Salmonellosis
raw oysters, New Caledonia. Emerg Infect Dis 2011; 17:136–137.
Kuo Chou TN, et al: Predictors of mortality in skin and soft-tissue
infections caused by Vibrio vulnificus. World J Surg 2010;
34:1669–1675.
Kuo YL, et al: Necrotizing fasciitis caused by Vibrio vulnificus. Eur J Clin
Microbiol Infect Dis 2007; 26:785.
Matsuoka Y, et al: Accurate diagnosis and treatment of Vibrio vulnificus
infection. Braz J Infect Dis 2013; 17:7–12.
Tsai YH, et al: Necrotizing soft-tissue infections and primary sepsis
caused by Vibrio vulnificus and Vibrio cholerae non-01. J Truama 2009;
66:899.
CHROMOBACTERIOSIS AND
AEROMONAS INFECTIONS
Chromobacterium is a genus o gram negati e rods that produce
arious discolorations on gelatin broth. Chromobacteria ha e
been shown to be common water and soil saprophytes o the
southeastern nited States and Australia. Se eral types o
cutaneous lesions are caused by chromobacteria ranging rom
uctuating abscesses and local cellulitis to anthra li e carbun
cular lesions with lymphangitis and atal septicemia. Chromo
bacterium violaceum the most common species produces a
iolet pigment. Patients with chronic granulomatous disease
may be at particular ris . A uoro uinolone in combination
with an aminoglycoside is best or treatment. A ter se eral
wee s o parenteral antimicrobial therapy an oral agent
(e.g. T P S tetracycline uoro uinolone) is gi en or
or months.
A gram negati e bacterium eromonas h rophilia another
typical soil and water saprophyte may cause similar s in
in ections as C violaceum mani esting as cellulitis pustules
uruncles gas gangrene or ecthyma gangrenosum li e
lesions a ter water related trauma and abrasions. olliculitis
caused by h rophilia may mimic Pseu omonas olliculitis.
The treatment o choice is cipro o acin.
Manresa MJ, et al: Aeromonas hydrophilia folliculitis associated with an
inflatable swimming pool. Pediatr Dermatol 2009; 26:601–603.
Mulholland A, et al: A possible new cause of spa bath folliculitis:
Tsai YH, et al: Necrotizing soft-tissue infections and sepsis caused by
Vibrio vulnificus compared with those caused by Aeromonas species.
J Bone Joint Surg Am 2007; 89:631.
Yang CH, et al: Chromobacterium violaceum infection. J Chin Med
Assoc 2011; 74:435–441.
SALMONELLOSIS
Salmonella is a genus o gram negati e rods that e ist in
humans either in a carrier state or as a cause o acti e enteric
or systemic in ection. ost cases o typhoid e er caused by
Salmonella t phi are ac uired by ingestion o contaminated
ood or water. Pets such as li ards sna es and turtles carry
salmonellae and ac uisition o the organism in petting oos
has also been reported. Poultry and poultry products are the
most important sources and are belie ed to be the cause in
about hal o common source epidemics. andwashing and
thorough coo ing o meats are recommended pre enti e
measures.
A ter an incubation period o wee s there is usually an
acute onset o e er chills headache constipation and bron
chitis. A ter days o e er and diarrhea s in lesions
269
 rose colored macules or papules ( rose spots ) mm in
14 diameter appear on the anterior trun between the umbilicus
and nipples. They occur in crops each group o lesions
lasting days the total duration o the e anthem being
wee s in untreated cases. Rose spots occur in o
Bacterial Infections
patients. A more e tensi e erythematous eruption occurring
early in the course erythema typhosum is rarely reported as
are erythema nodosum urticaria and ulcers or subcutaneous
abscesses.
The diagnosis is con rmed by culturing the organism
rom blood stool s in or bone marrow. the organism is
not grown on Shigella Salmonella medium or is not analy ed
correctly S t phi may be erroneously reported as a coli orm.
The pre erred antibiotic or therapy is cipro o acin or
ce tria one.
ccasionally S t phi may cause s in lesions without sys
temic in ection. Also in ection with nontyphoid Salmonella
such as S enterica may cause enteric e er with rose spots.
Coburn B, et al: Salmonella, the host and disease. Immunol Cell Biol
2007; 85:112.
Nishie H, et al: Non-typhoid Salmonella infection associated with rose
spots. Br J Dermatol 1999; 140:558.
Patel TA, et al: Imported enteric fever. Am J Trop Med Hyg 2010;
82:1121–1126.
SHIGELLOSIS
Shigellae are small gram negati e rods that cause bacillary
dysentery an acute diarrheal illness. ost cases are a result o
person to person transmission; howe er widespread epidem
ics ha e resulted rom contaminated ood and water. Small
blanchable erythematous macules on the e tremities as well
as petechial or morbilli orm eruptions may occur. en who
ha e se with men ( S ) may de elop a uruncle on the
penis caused by Shigella exneri Shigellosis may then occur as
a purely cutaneous orm o STD. Shigella and Salmonella are
among the organisms reported to induce the postdysenteric
orm o Reiter syndrome. Therapy with a uoro uinolone is
curati e.
Carter JD, et al: Reactive arthritis. Rheum Dis Clin North Am 2009;
35:21.
HELICOBACTER CELLULITIS
e er bacteremia cellulitis and arthritis may all be caused by
elicobacter cinae i or canis. Generally these mani estations
occur in V in ected patients; howe er malignancy diabe
tes and alcoholism are other predisposing conditions. cca
sionally elicobacter has been reported to cause postsurgical
wound in ections and sepsis in otherwise healthy indi iduals.
The cellulitis may be multi ocal and recurrent and may ha e
a distincti e red brown or copper color with minimal warmth.
Cipro o acin is generally e ecti e or treatment.
Itamura T, et al: Helicobacter cinaedi cellulitis and bacteremia in
immunocompetent hosts after orthopedic surgery. J Clin Microbiol
2007; 45:31.
Shimizu S, et al: Cutaneous manifestations of Helicobacter cinaedi
infection. Acta Derm Venereol 2013; 93:165–167.
RHINOSCLEROMA
Rhinoscleroma is a chronic in ammatory granulomatous
disease o the upper respiratory tract characteri ed by
sclerosis de ormity remission and e entual debility. Death
resulting rom obstructi e se uelae may occur. The in ection
270
tahir99 - UnitedVRG
Fig. 14-40
Rhinoscleroma.
(Courtesy of Jason
Robbins, MD.)
is limited to the nose pharyn and ad acent structures. The
disease begins insidiously with nasal catarrh increased nasal
secretion and subse uent crusting. Gradually there ensues a
nodular or rather di use sclerotic enlargement o the nose
upper lip palate or neighboring structures ( ig. ). The
nodules at rst are small hard subepidermal and reely
mo able but they gradually use to orm sclerotic pla ues that
adhere to the underlying parts. lceration is common. The
lesions ha e a distincti e stony hardness are insensiti e and
are o a dus y purple or i ory color. yperpigmentation can
be e pected in dar comple ioned indi iduals. n the more
ad anced stages o rhinoscleroma the reacti e growth pro
duces e tensi e mutilation o the ace and mar ed dis gure
ment. Complete obstruction o the nares super cial erosions
and seropurulent e udation may occur.
A microorganism lebsiella pneumoniae ssp. rhinoscleromatis
rst isolated by on risch is the causati e agent. The rhino
scleroma bacillus is a gram negati e rod short nonmotile
round at the ends always encapsulated in a gelatinous capsule
and measuring μm. t is ound in the throats o scleroma
patients only.
The disease occurs in both genders and is most common
during the third and ourth decades o li e. Although endemic
in tropical countries in A rica and Central America it is
occasionally ound in the nited States. Rare amilial cases
ha e been reported in which the condition may present in
childhood.
n the primary stage o nasal catarrh the histologic picture
is that o a mild nonspeci c in ammation. When proli eration
and tume action de elop the granulomatous tumor consists
largely o plasma cells i ulic cells an occasional hyaline
degenerated plasma cell (Russell body) a ew spindle cells
and brosis. The bacilli are ound within oamy macrophages
( i ulic cells) and are best isuali ed with the Warthin
Starry sil er stain.
Rhinoscleroma has such distincti e eatures that its diagno
sis should not be di cult. The diagnosis depends on bacterio
logic histopathologic and serologic tests. eat illed antigen
gi es a positi e complement ation reaction with scleroma
patients serum. Titers run as high as . Clinically rhino
scleroma can be con used with syphilitic gumma sarcoid
leishmaniasis rambesia (yaws) eloid lepra hypertrophic
orms o tuberculosis and rhinosporidiosis.
Treatment
Rhinoscleroma is usually progressi e and resistant to therapy.
owe er it may respond well to the uoro uinolones
although therapy should be prolonged lasting at least or
months to limit the chance o relapse. Corticosteroids are
use ul in the acute phase. Surgical inter ention or C laser
treatments may be needed to pre ent airway obstruction or to
correct de ormities.
Chou TC, et al: Emperipolesis is not pathognomonic for Rosai-Dorfman
disease. J Am Acad Dermatol 2013; 69:1066–1067.
De Pontual L, et al: Rhinoscleroma: a French national retrospective
study of epidemiological and clinical features. Clin Infect Dis 2008;
47:1396.
Suchanova PP, et al: Rhinoscleroma in an urban nonendemic setting.
Otolaryngol Head Neck Surg 2012; 147:173–174.
Tan SL, et al: Rhinoscleroma. Singapore Med J 2012; 53:e24–e27.
PASTEURELLOSIS
Primary cutaneous (ulceroglandular) Pasteurella haemol tica
Mannheimia haemol tica in ection may occur in patients with
s in in ury and e posure to this organism. P haemol tica is a
common pathogen o domestic animals associated with ship
ping e er in cattle and septicemia in lambs and newborn pigs.
The open sites become in amed lymphangitis and e er
de elop and a illary lymph nodes become enlarged. Diagno
sis is based on demonstration o the bacteria on culture o the
lesions.
Pasteurella multoci a is a small nonmotile gram negati e
bipolar staining bacterium. t is nown to be part o the normal
oral and nasal ora o cats and dogs but it may also be an
animal pathogen. The most common type o human in ection
ollows in uries rom animal bites principally cat and dog
bites but also cat scratches. A ter animal trauma erythema
swelling pain and tenderness de elop within a ew hours o
the bite with a gray colored serous or sanguinopurulent
drainage rom the puncture wounds ( ig. ). There may
or may not be regional lymphadenopathy or e idence o sys
temic to icity such as chills and e er. Septicemia may ollow
the local in ection in rare cases and tenosyno itis and osteo
myelitis appear with some re uency. Although P multoci a is
a gram negati e bacillus treatment is with systemic penicillin
G in addition to care ul cleansing and tetanus prophyla is.
Blasiak RC, et al: Pasturella multocida cellulitis in a 15-year-old male
with chronic lymphedema. J Am Acad Dermatol 2013; 68:e183–e184.
Wilkie IW, et al: Pasteurella multocida. Curr Top Microbiol Immunol
2012; 361:1–22.
DOG AND HUMAN BITE PATHOGENS
t is recommended that all cat bites and scratches all sutured
wounds o any animal source and any other animal in uries
o an unusual type or source be treated with antibiotics in
addition to care ul cleansing and tetanus prophyla is. While
Pasteurella species (P canis in dogs and P multoci a in cats) are
usually present in bite site cultures a comple mi o arious
other pathogens such as streptococci staphylococci Morax
ella eisseria usobacterium acteroi es and those indi idually
discussed ne t ma e the combination amo icillin cla ulanate
the best choice o initial therapy. Gati o acin and line olid are
other e ecti e medications.
Capnoc tophaga canimorsus is a gram negati e rod that is part
o the normal oral ora o dogs and cats. t is associated with
se ere septicemia a ter dog bites. Patients who ha e under
gone splenectomy are at particular ris . Alcoholism chronic
Fig. 14-41 Pasteurella
multocida infection.
Glanders
respiratory disease and other medical conditions also predis
pose to in ection; only one uarter o patients were healthy
be ore in ection with C canimorsus A characteristic nding is
a necroti ing eschar at the site o the bite. e er nausea and
omiting occur abruptly within days and the eschar
de elops soon therea ter. Disseminated intra ascular coagula
tion and e tensi e dry gangrene may complicate the course.
Sepsis a ter a dog bite is another ha ard aced by splenecto
mi ed patients in addition to their particular problems with
pneumococcus aemophilus in uen ae group B babesiosis
eisseria meningiti is and group A streptococcus. C canimor
sus is di cult to identi y by con entional cultures. Laboratory
personnel need to be aware o the clinical suspicion o in ec
tion with this organism. A alse positi e late agglutination
test or cryptococcal antigen in the CS may occur. Treatment
is with intensi e V antibiotics. n less se erely a ected
patients amo icillin cla ulanate may be e ecti e.
eisseria species and erge ella oohelcum are other oral and
nasal commensals in dogs; thus most reports o human disease
ollow animal bites. Ei enella corro ens a acultati e gram
negati e bacillus is a normal inhabitant o the human mouth.
ost in ections are caused by human bites or st ghts.
Amo icillin cla ulanate or penicillin G is e ecti e.
Babovic N, et al: Cat bite infections of the hand. J Hand Surg Am 2014;
39:286–290.
Brook I: Management of human and animal bite wound infection. Curr
Infect Dis Rep 2009; 11:389–395.
Christiansen CB, et al: Two cases of infectious purpura fulminans and
septic shock caused by Capnocytophaga canimorsus transmitted from
dogs. Scand J Infect Dis 2012; 44:635–639.
Gaastra W, Lipman LJ: Capnocytophaga canimorsus. Vet Microbiol 2010;
140:339–346.
Lohiya GS, et al: Human bites. J Natl Med Assoc 2013; 10:92–95.
Thomas N, Brook I: Animal bite–associated infections. Expert Rev Anti
Infect Ther 2011; 9:215–226.
GLANDERS
nce nown as e uinia arcy and malleus glanders is a rare
usually atal in ectious disease that occurs in humans by inoc
ulation with ur hol eria mallei t is encountered in those who
handle horses mules or don eys. The distincti e s in lesion
is an in ammatory papule or esicle that arises at the site o
271
 inoculation rapidly becomes nodular pustular and ulcer
14 ati e and orms an irregular e ca ation with undermined
edges and a base co ered with a purulent and sanguineous
INFECTIONS CAUSED BY BARTONELLA
e udate. n a ew days or wee s other nodules (called arcy Bartonellae are aerobic astidious gram negati e bacilli.
buds ) de elop along the lymphatics in the ad acent s in or Se eral species cause human diseases including artonella
Bacterial Infections

subcutaneous tissues and subse uently brea down. n the henselae (cat scratch disease and bacillary angiomatosis)
acute orm the s in in ol ement may be se ere and accom uintana (trench e er and bacillary angiomatosis) bacil
panied by e treme diarrhea. Patients with the chronic orm liformis ( erruga peruana and roya e er) grahamii (cat
ha e ew s in lesions and milder constitutional symptoms but scratch disease) and clarri geiae (possible cause o cat scratch
repeated cycles o healing and brea down o nodules may disease). These agents are transmitted by arthropod ectors in
occur or wee s. some cases. ni ue to this genus is the ability to cause ascu
The respiratory mucous membranes are especially suscep lar proli eration as seen in bacillary angiomatosis and erruga
tible to glanders. A ter accidental inhalation catarrhal symp peruana. The bartonellae in a ected tissue stain poorly with
toms are rst present and there may be epista is or a mucoid tissue Gram staining and are usually identi ed in tissue using
nasal discharge. The nasal discharge is a characteristic eature modi ed sil er stains such as Warthin Starry. They are di
o the disease. The diagnosis is established by nding the cult to culture ma ing tissue identi cation o characteristic
gram negati e organism in this discharge or in the s in ulcers bacilli an important diagnostic test. lectron microscopy and
and should be con rmed by serum agglutination. This organ PCR can be used i routine staining is negati e.
ism has been atal to many laboratory wor ers and e posure
in this setting is increasing with mallei considered a bioter
rorism threat. Cat-scratch disease
Treatment is chie y by immediate surgical e cision o the
inoculated lesions and antibiotics. Amo icillin cla ulanate Cat scratch disease is relati ely common. About cases
do ycycline or T P S or up to months may be e ecti e are reported annually in the nited States with occur
in disease limited to the s in whereas parenteral ce ta idime ring in children and young adults. Cat scratch disease is the
can be used or se ere or septic in ection. mipenem and do y most re uent cause o chronic lymphadenopathy in children
cycline in combination cured an in ected laboratory wor er. and young adults.
Bo ine arcy also occurs and is caused by M cobacterium artonella henselae causes the ast ma ority o cases o cat
farcinogenes and M senegalense t is present mostly in sub scratch disease. The in ectious agent is transmitted rom cat to
Saharan A rica and presents as a suppurati e granulomatous cat by eas and rom cats to humans by cat scratches or bites.
in ammation o the s in and lymphatics. Rarely dog bites may transmit this in ection. henselae can be
Anderson PD, et al: Bioterrorism. J Pharm Pract 2012; 25:521–529. ound in the primary s in and con uncti al lesions lymph
Dvorak GD, et al: Glanders. J Am Vet Med Assoc 2008; 233:570. nodes and other a ected tissues. n geographic areas where
Hamid ME: Epidemiology, pathology, immunology and diagnosis of cat eas are present about o cats are asymptomatically
bovine farcy. Prev Vet Med 2012; 105:1–9. bacteremic with this organism. An immunocompromised
Whitlock GC, et al: Glanders. FEMS Microbiol Lett 2007; 277:115. patient with typical cat scratch disease caused by artonella
grahamii has been reported. This organism in ects rodents and
is li ely ac uired by cats through hunting.
MELIOIDOSIS The primary s in lesion appears within days a ter the
cat scratch and may last or se eral wee s ( ig. ). t is
elioidosis (Whitmore s disease) is a speci c in ection caused present in o patients. The primary lesion is not
by a glandersli e bacillus ur hol eria pseu omallei The crusted and lymphangitis does not e tend rom it. The primary
disease has an acute pulmonary and septicemic orm in which
multiple miliary abscesses in the iscera occur resulting in
rapid death. Less o ten it runs a chronic course with subcu
taneous abscesses and multiple sinuses o the so t tissues. ts
clinical characteristics are similar to glanders disseminated
ungal in ections and tuberculosis. Se ere urticaria and nec
roti ing asciitis are uncommon complications.
elioidosis is endemic in ndia Southeast Asia and north
ern Australia and should be suspected in military personnel
and tra elers who ha e characteristic symptoms o a ebrile
illness and ha e been in that region. Recrudescence o disease
a ter a long latency period may occur. Diagnosis is made rom
the reco ery o the bacillus rom the s in lesions or sputum
and by serologic tests.
ecti e therapy is guided by the antibiotic sensiti ity o the
speci c strain. or the acute septicemic phase ce ta idime
meropenem or imipenem is indicated or wee s ollowed
by maintenance oral therapy with T P S . The ma ority o
chronic cutaneous in ections respond well to oral treatment
alone. aintenance oral therapy in both situations should con
tinue or to months.
Limmathurotsakul D, et al: Melioidosis. Br Med Bull 2011; 99:125–139.
Tzeng WT, et al: Recurrent cutaneous melioidosis treated with surgery
and antibiotics. J Plast Reconstr Aesthet Surg 2009; 62:280.
Wiersinga WJ, et al: Melioidosis. N Engl J Med 2012;
367:1035–1044. Fig. 14-42 Primary cat-scratch lesion with lymphadenopathy.
272

tahir99 - UnitedVRG
lesion may resemble an insect bite but is not pruritic. t heals
within a ew wee s usually with no scarring.
Lymphadenopathy the hallmar o the disease appears or
wee s a ter the primary lesions or days (a erage )
a ter inoculation. sually the lymphadenopathy is regional
and unilateral. Because most inoculations occur on the upper
e tremities epitrochlear and a illary lymphadenopathy is
most common ( ) ollowed by cer ical ( ) or inguinal
( ). Generali ed lymphadenopathy does not occur but sys
temic symptoms such as e er malaise and anore ia may be
present. Without treatment the adenopathy resol es o er a ew
wee s to months with spontaneous suppuration occurring in
o patients. the primary inoculation is in the con unc
ti a there is chronic granulomatous con uncti itis and preau
ricular adenopathy the so called oculoglandular syndrome
o Parinaud. n re uently acute encephalopathy osteolytic
lesions hepatic and splenic abscesses hypercalcemia and pul
monary mani estations ha e been reported. n addition ery
thema nodosum and a di use e anthem may accompany
cat scratch disease.
Diagnosis is made largely on clinical eatures. The primary
s in lesion or lymph node may be biopsied and the in ectious
agent identi ed. n ol ed lymph nodes and s in lesions dem
onstrate granulomatous in ammation with central stellate
necrosis. A serologic test is a ailable and although not repro
ducibly positi e early in the disease a titer o more than
is considered diagnostic o acute in ection. Cat scratch s in
testing ( anger and Rose test) can be used but is rarely done
i the history and clinical eatures are characteristic. ther
in ectious and neoplastic causes o locali ed lymphadenopa
thy such as tularemia sporotrichosis atypical mycobacterial
in ection and odg in disease may need to be e cluded.
The ast ma ority o cases o cat scratch disease resol e
spontaneously without antibiotic therapy. Such therapy has
not been demonstrated to shorten the duration o the disease
in most typical cases. luctuant lymph nodes should be aspi
rated not incised and drained. n patients with se ere disease
a ithromycin was ound to be more e ecti e than placebo in
one trial.
Trench fever
Trench e er is caused by artonella uintana which is spread
rom person to person by the body louse. rban cases o trench
e er caused by this agent are now most o ten seen in louse
in ested homeless persons. Patients present with e er that
initially lasts about wee and then recurs about e ery days.
ther symptoms are headache and nec shin and bac pain.
ndocarditis may occur. There are no s in lesions. Treatment
has not been studied systematically. Combination V gentami
cin and oral do ycycline is recommended.
Bacillary angiomatosis
Bacillary angiomatosis describes a clinical condition character
i ed by ascular s in lesions resembling pyogenic granulomas
( ig. ). nly two organisms ha e been pro en to cause
bacillary angiomatosis artonella henselae (cause o cat scratch
disease) and uintana (cause o trench e er). The s in
lesions caused by these two organisms are identical. the
bacillary angiomatosis is caused by henselae there is usually
a history o cat e posure and the same artonella can also be
isolated rom the blood o the source cat. Bacillary angioma
tosis caused by uintana is associated with homelessness
and louse in estation. The incubation period is un nown but
may be years.
Fig. 14-43 Bacillary
angiomatosis.
Infections caused by Bartonella
Bacillary angiomatosis occurs primarily in the setting o
immunosuppression especially A DS and may be the pre
senting sign o this condition. The helper T cell count is usually
less than cells mL. ther immunosuppressed patients
such as those with leu emia or transplant may ac uire the
condition. Rarely bacillary angiomatosis can occur in V
negati e patients with no apparent immune impairment. n
immunoincompetent hosts the bacteria proli erate locally and
are re uently blood borne. The local proli eration o bacteria
produces the angiogenic ascular endothelial growth actor
(V G ) leading to endothelial cell proli eration and the char
acteristic s in lesions. mmunocompetent hosts generally
resist this bacterial proli eration resulting in granulomatous
and necrotic rather than angiomatous lesions.
Se eral di erent orms o cutaneous lesions occur. The most
common orm resembles pyogenic granuloma which may
e hibit a surrounding collarete o scale. Less o ten subcutane
ous masses pla ues and ulcerations may occur. A single
patient may e hibit se eral o these morphologies. Lesions are
tender and bleed easily. Subcutaneous nodules are also tender
and may be poorly marginated. Lesions may number rom one
to thousands usually with the number gradually increasing
o er time i the patient is untreated.
n the setting o bacillary angiomatosis the in ection must be
considered disseminated. Bacteremia is detected in about
o a ected A DS patients leading to in ol ement o many
isceral sites most re uently the lymph node li er and spleen
and bone. Less re uently pulmonary G muscle oral and
brain lesions can occur. henselae is usually associated with
lymph node and li er and spleen in ol ement whereas
uintana more o ten causes bone disease and subcutaneous
masses. Visceral disease can be con rmed by appropriate
radiologic or imaging studies. Bone lesions are typically lytic
resembling osteomyelitis. n the li er and spleen peliosis
occurs. Li er unction tests characteristically demonstrate a
ery ele ated lactic dehydrogenase le el an ele ated al aline
phosphatase le el slight ele ation o the le els o hepatocel
lular en ymes and a normal bilirubin le el. Lesions on other
epithelial sur aces in muscle and in lymph nodes are usually
angiomatous.
Biopsies o bacillary angiomatosis s in lesions ha e the
same low power appearance as a pyogenic granuloma with
the proli eration o endothelial cells orming normal small
blood essels. Bacillary angiomatosis is distinguished rom
273
 pyogenic granuloma by the presence o neutrophils through
14 out the lesion not ust on the sur ace as seen in a pyogenic
granuloma. The neutrophils are sometimes aggregated around
granular material that stains slightly purple. This purple
material represents clusters o organisms which can at
Bacterial Infections
times be con rmed by modi ed sil er stain such as Steiner.
Tissue Gram stain does not routinely stain the bacteria in
bacillary angiomatosis lesions. lectron microscopy may iden
ti y bacteria in cases in which special stains are negati e. Bacil
lary angiomatosis is easily distinguished histologically rom
aposi sarcoma. n patch or pla ue lesions o aposi sarcoma
the new blood essels are abnormal in appearance being
angulated. ndothelial proli eration in aposi sarcoma is seen
in the dermis around the eccrine units ollicular structures
and e isting normal essels. odular aposi sarcoma is a
spindle cell tumor with slits rather than well ormed blood
essels. eutrophils and purple granular material are not
ound in aposi sarcoma but intracellular hyaline globules
are present.
The natural history o bacillary angiomatosis is e tremely
ariable. n most patients howe er lesions remain stable or
the si e or number o lesions gradually increases o er time.
The initial lesions are usually the largest and multiple satellite
or disseminated smaller lesions occur representing miliary
spread. ntreated bacillary angiomatosis can be atal with
patients dying o isceral disease or respiratory compromise
rom obstructing lesions.
The diagnosis o bacillary angiomatosis is irtually always
made by identi ying the in ectious agent in a ected tissue. The
organisms can also be cultured rom the lesions and the
patient s blood. owe er these organisms grow ery slowly
so cultures may not be positi e or more than month. Thus
tissue and blood cultures are usually con rmatory in nature.
Antibodies to artonella can be detected in most patients by an
indirect uorescence assay. Because o its limited a ailability
and bac ground positi ity in the general population o cat
owners howe er this test is not generally use ul in establish
ing the diagnosis o bacillary angiomatosis.
Treatment
Bacillary angiomatosis is dramatically responsi e to erythro
mycin mg our times daily or do ycycline mg twice
daily. inocycline tetracycline clarithromycin a ithromycin
ro ithromycin and chloramphenicol may also be e ecti e.
T PS cipro o acin penicillins and cephalosporins are
not e ecti e. Prophylactic regimens containing a macrolide
antibiotic or ri ampin pre ent the de elopment o bacillary
angiomatosis. Treatment duration depends on the e tent o
isceral in ol ement. Patients with only s in lesions or bacte
remia re uire at least wee s o treatment. or li er and
spleen in ol ement months o treatment is recommended
and or bone disease at least months o treatment should be
considered. nce treatment is begun symptoms begin to
resol e within hours to days. A Jarisch er heimer reaction
may occur with the rst dose o antibiotic. patients relapse
a ter an apparently ade uate course o treatment chronic sup
pressi e antibiotic therapy should be considered.
Oroya fever and verruga peruana
roya e ear and erruga peruana represent two stages o the
same in ection. roya e er (Carri n s disease) is the acute
ebrile stage and erruga peruana the chronic delayed stage.
These conditions are limited to and endemic in Peru and a ew
neighboring countries in the Andes and are restricted to
alleys m abo e sea le el. Both these conditions are
274
tahir99 - UnitedVRG
Fig. 14-44 Verruga peruana. (Courtesy of Francisco Bravo, MD.)
caused by artonella bacilliformis which is transmitted by a
sand y usually Lut om ia verrucarum A no el agent named
Candidatus artonella ancashi was the causati e organism in
one reported case o erruga peruana. umans represent the
only nown reser oir. en represent about three uarters o
cases and all ages may be a ected.
A ter an incubation period a eraging wee s the acute
in ection roya e er de elops. Symptomatology is highly
ariable. Some patients ha e ery mild symptoms. thers may
ha e high e er headache and arthralgias. Se ere hemolytic
anemia can de elop sometimes with leu openia and throm
bocytopenia. ntreated the atality rate is and with
antibiotic treatment is still . A ter the acute in ection
resol es a latency period ollows lasting rom wee s to
months. The erruga peruana eruptions then occur; these are
angiomatous pyogenic granuloma li e lesions irtually
identical clinically and histologically to the lesions o bacillary
angiomatosis ( ig. ). The lesions may be large and ew in
number (mular orm) small and disseminated (miliary orm)
or nodular and deep. Visceral disease has not been ound in
erruga peruana which is rarely atal. Lesions usually heal
spontaneously o er se eral wee s to months without scarring.
A lasting immunity results rom in ection.
The diagnosis o roya e er is made by identi ying the
bacteria within or attached to circulating erythrocytes using a
Giemsa stain. Verruga peruana can be diagnosed by s in
biopsy showing the same eatures as bacillary angiomatosis
but with the organisms staining with Giemsa.
The antibiotic treatment o choice or roya e er is chlor
amphenicol g day because Salmonella coin ection is the
most re uent cause o death. Protection rom sand y bites is
all important.
Al-Thunayan A, et al: Bacillary angiomatosis presenting as a pyogenic
granuloma of the hand in an otherwise apparently healthy patient. Ann
Plast Surg 2013; 70:652–653.
Blazes DL, et al: Novel Bartonella agent as a cause of verruga peruana.
Emerg Infect Dis 2013; 19:1111–1114.
Chen TC, et al: Cat scratch disease from a domestic dog. J Formos
Med Assoc 2007; 106:S65.
Chomel BB, et al: Bartonellosis, an increasingly recognized zoonosis. J
Appl Microbiol 2010; 109:743–760.
Maguina C, et al: Bartonellosis. Clin Dermatol 2009; 27:271.
Mejia F, et al: Bacillary angiomatosis. Am J Trop Med Hyg 2014;
91:439.
Oksi J, et al: Cat scratch disease caused by Bartonella grahamii in an
immunocompromised patient. J Clin Microbiol 2013; 51:2781–2784.
Pierad-Franhimont C, et al: Skin disease associated with Bartonella
infection. Clin Dermatol 2010; 28:483–488.
 Psarros G, et al: Bartonella henselae infections in solid organ transplant
recipients. Medicine 2012; 91:111–121.
Zangwill KM: Cat scratch disease and other Bartonella infections. Adv
Exp Med Biol 2013; 764:159–166.
Zarraga M, et al: Bacillary angiomatosis in an immunocompetent child.
Am J Dermatopathol 2011; 33:513.
PLAGUE
Plague normally in ol es an interaction among ersinia pestis
wild rodents and eas parasitic on the rodents. n ection in
humans with pestis is accidental and usually presents as
bubonic plague. ther clinical orms include pneumonic and
septicemic plague. n the milder orm the initial mani esta
tions are general malaise e er and pain or tenderness in
areas o regional lymph nodes most o ten in the inguinal or
a illary regions. n more se ere in ections ndings o to icity
prostration shoc and occasionally hemorrhagic phenomena
pre ail. Less common symptoms include abdominal pain
nausea omiting constipation ollowed by diarrhea general
i ed macular erythema and petechiae. Rarely esicular and
pustular s in lesions occur.
Plague is caused by pestis a pleomorphic gram negati e
bacillus. The principal animal hosts in ol ed ha e been roc
s uirrels prairie dogs chipmun s marmots s un s deer
mice wood rats rabbits and hares. Transmission occurs
through contact with in ected rodent eas or rodents pneu
monic spread or in ected e udates. enops lla cheopis ( rien
tal rat ea) has traditionally been considered the ector in
human outbrea s but Diamanus montanus hrassis bacchi and
Opisocrostis hirsutus are species o eas on wild animals
responsible or spreading syl atic plague in the nited States.
Rodents carried home by dogs or cats are a potential source
and an important one in eterinarians o in ection. The bites
scratches or contact with other in ectious material while han
dling in ected cats are an increasing ris actor as residential
de elopment continues in areas o plague oci in the western
nited States. Since o .S. cases ha e occurred in
the Roc y ountain states.
Blood bubo or parabubo aspirates e udates and sputum
should be e amined by smears stained with Gram stain or
speci c uorescent antibody techni ues culture and animal
inoculation. A retrospecti e diagnosis can be made by sero
logic analysis.
The most e ecti e drugs against pestis are gentamicin
and streptomycin which should be gi en intra enously.
ther e ecti e drugs include chloramphenicol the tetracy
clines and cipro o acin. Almost all cases are atal i not
treated promptly.
Anderson PD, et al: Bioterrorism. J Pharm Pract 2012; 25:521–529.
Eisen RJ, et al: Transmission of flea-borne zoonotic agents. Annu Rev
Entomol 2012; 57:61–82.
Lieberman JM: North American zoonoses. Pediatr Ann 2009; 38:193.
Prentice MB, et al: Plague. Lancet 2007; 369:1196.
RAT-BITE FEVER
Rat bite e er is a systemic illness usually ac uired by direct
contact with rats or other small rodents which carry the gram
negati e organisms Spirillum minor and Streptobacillus monili
formis among their oropharyngeal ora. S moniliformis is the
principal cause in the nited States whereas S minor is seen
mostly in Asia. Crowded li ing conditions homelessness
wor ing with rats in medical research or in pet shops or
ha ing one as a pet are predisposing actors in some in ected
patients. Although it usually ollows a rat bite in ection may
ollow the bites o s uirrels cats weasels pigs and a ariety
o other carni ores that eed on rats.
There are at least two distinct orms o rat bite e er
sodo u caused by Spirillum minor; and septicemia caused
by Streptobacillus moniliformis otherwise nown as epidemic
Tularemia
arthritic erythema or a erhill e er. The latter usually ollows
the bite o a rat but some cases ha e been caused by contami
nated mil . The clinical mani estations o these two in ections
are similar in that both produce a systemic illness character
i ed by e er rash and constitutional symptoms. owe er
clinical di erentiation is possible.
n the streptobacillary orm incubation is brie usually lasting
days a ter the bite when chills and e er occur. Within
more days the generali ed morbilli orm eruption appears and
spreads to include the palms and soles. t may become pete
chial. Arthralgia is prominent and pleural e usion may occur.
ndocarditis pneumonia and septic in arcts o ten ollow and
o untreated patients may die rom these causes.
Although in ection with S minor also begins abruptly with
chills and e er the incubation period is longer wee s.
The bite site is o ten in amed and may become ulcerated.
Lymphangitis may be present. The eruption begins with ery
thematous macules on the abdomen resembling rose spots
which enlarge become purplish red and orm e tensi e indu
rated pla ues. Arthritis may rarely occur. ndocarditis
nephritis meningitis and hepatitis are potential complica
tions. About o untreated patients die.
n both types o rat bite e er a leu ocytosis o
cells mm is present sometimes with eosinophilia. A
biologic alse positi e Venereal Disease Research Laboratories
(VDRL) test is ound in o patients. The course o S
minor in ection without treatment is generally rom to
wee s though relapses may occur or months.
The diagnosis is con rmed by culturing the causati e organ
ism rom the blood or oint aspirate or demonstration o an
antibody response in the streptobacillary orm. S minor is
demonstrable by animal inoculation with the patient s blood
usually in the guinea pig or mouse. Their blood will show
large numbers o organisms in Wright stained smears. Dem
onstration o S minor in a dar eld preparation o e udate
rom an in ected site establishes the diagnosis.
Rat bite e er must be di erentiated rom erysipelas pyo
genic cellulitis iral e anthems gonococcemia meningococ
cemia and Roc y ountain spotted e er.
Prompt cauteri ation o bites by nitric acid may pre ent the
disease. Cleansing o the wound tetanus prophyla is and
days o penicillin ( g day) are recommended or patients
seen shortly a ter a bite. Both types respond readily to penicil
lin tetracycline or streptomycin therapy.
Barnelee P, et al: Rat bite fever, a fatal case of Streptobacillus moniliformis
infection in a 14-year-old boy. J Forensic Sci 2011; 56:531–533.
Chean R, et al: Rat bite fever as a presenting illness in a patient with
AIDS. Infection 2012; 40:319–320.
Lewis BK, et al: Rat bite fever. Pediatr Dermatol 2012; 29:767–768.
McKee G, et al: Rat bite fever. CMAJ 2013; 185:1346.
TULAREMIA
Tularemia also nown as hara s disease or deer y e er is
a ebrile disease caused by rancisella tularensis a short non
motile non spore orming gram negati e coccobacillus. Tula
remia is characteri ed by sudden onset with chills headache
and leu ocytosis a ter an incubation period o days. ts
clinical course is di ided into se eral general types. The caus
ati e organism poses a bioterrorism threat.
The ast ma ority o tularemia cases are the ulceroglandu
lar type which begins with a primary papule or nodule that
275

14
Bacterial Infections
Fig. 14-45 Tularemia. (Courtesy of Steve Hess, MD.)
rapidly ulcerates at the site o in ection. This usually occurs
through contact with tissues or body uids o in ected
mammals rom an abrasion or scratch ( ig. ) usually on
the ngers nec or con uncti a. The bites o a tic Derma
centor an ersoni or mbl omma americanum and o a deer y
Chr sops iscalis also transmit this disease and in such cases
primary lesions are usually ound on the legs or the perineum.
The primary ulcer is tender rm indolent and punched out
with a necrotic base that heals with scar ormation in about
wee s. A lymphangitis spreads rom the primary lesion;
the regional lymph glands become swollen pain ul and
in amed and tend to brea down orming suppurati e sub
cutaneous nodules resembling those o sporotrichosis. The
ulcers e tend in a chain rom the ulcer to the enlarged lym
phatic glands.
The course o the ulceroglandular type is mar ed in the early
stages by headache anore ia and omiting as well as articu
lar and muscular pains. The e er is at rst continuous arying
between and ( . and C) and later shows
morning remissions then alls by lysis to normal. ther s in
lesions encountered in the disease course are not characteristic
and are probably o a to ic nature. A macular papular esicu
lar or petechial e anthem may occur. rythema multi orme
and erythema nodosum o ten occur. The clinical similarity o
the primary ulcer o tularemia to a chancre o sporotrichosis
is important in the di erential diagnosis.
n the typhoidal type the site o inoculation is not nown
and there is no local sore or adenopathy. This orm o tulare
mia is characteri ed by persistent e er malaise G symp
toms and the presence o speci c agglutinins in the blood
serum a ter the rst wee . ther uncommon types include an
oculoglandular orm in which primary con uncti itis is
accompanied by enlargement o the regional lymph nodes.
The pneumonic type occurs rarely in laboratory wor ers and
is most se ere. The oropharyngeal orm may occur a ter inges
tion o in ected and inade uately coo ed meat. n the glandu
lar type there is no primary lesion at the site o in ection but
there is enlargement o regional lymph glands ollowed by
generali ed in ol ement. Se eral cases mostly in children
ha e been ac uired rom cat bites the cats ha ing pre iously
bitten in ected rabbits.
The most re uent sources o human in ection are the han
dling o wild rabbits and the bite o deer ies or tic s. ut
brea s o tularemia occur chie y at times o the year when
contact with these sources o in ection is li ely. o instance
o the spread o the in ection rom person to person by
276
tahir99 - UnitedVRG
contact has been reported. The disease occurs most o ten in
the western and southern nited States although cases ha e
been reported in almost all states and in Japan. n Russia and
other countries in the orthern emisphere tularemia may
be contracted rom polluted water contaminated by in ected
rodent carcasses.
A de nite diagnosis is made by staining smears obtained
rom the e udate with speci c uorescent antibody. tular
ensis can be cultured only on special media containing cystine
glucose blood agar or other selecti e media. Routine culture
media do not support growth. The bacilli can be identi ed by
inoculating guinea pigs intraperitoneally with sputum or with
bronchial or gastric washings e udate rom draining lymph
nodes or blood. The agglutination titer becomes positi e in
the ma ority o patients a ter wee s o illness. A our old rise
in titer is diagnostic; a single con alescent titer o or
greater is diagnostic o past or current in ection. PCR is also
success ul in identi ying the in ectious agent.
The main histologic eature o tularemia is that o a granu
loma; the tissue reaction consists primarily o a massing o
endothelial cells and the ormation o giant cells. Central
necrosis and li ue action occur accompanied by polymorpho
nuclear leu ocyte in ltration. Surrounding this is a tubercu
loid granulomatous one and peripherally lymphocytes orm
a third one. Small secondary lesions may de elop. These pass
through the same stages and tend to use with the primary
lesion.
All butchers hunters coo s and others who dress rabbits
should wear protecti e glo es. Thorough coo ing destroys the
in ection in a rabbit thus rendering an in ected animal harm
less as ood. Tic s should be remo ed promptly and tic
repellents may be o alue or people with occupations that
re uire re uent e posure.
Streptomycin g intramuscularly e ery h or days is
the treatment o choice. b ious clinical impro ement occurs
a ter h although the e er may persist or as long as wee
a ter treatment is begun. Gentamicin is also e ecti e but the
tetracyclines are use ul only i gi en in high doses or days.
n itro testing and numerous case reports and small case
series are documenting the e cellent e ects o the uinolones
especially cipro o acin mg twice daily or days
or le o o acin mg day or wee s.
Carvalho CL, et al: Tularemia. Comp Immunol Microbiol Infect Dis 2014;
37:85–96.
Joseph B, et al: Current concepts in the management of biologic and
chemical warfare causalities. J Trauma Acute Care Surg 2013;
75:582–589.
Nigrovic LE, et al: Tularemia. Infect Dis Clin North Am 2008; 22:489.
Snowden J, et al: Tularemia. Clin Pediatr (Phila) 2011; 50:64–68.
Tularemia—Missouri: 2000–2007. MMWR 2009; 58:744.
BRUCELLOSIS
Brucellosis is also nown as undulant e er. Brucellae are
gram negati e rods that produce an acute ebrile illness with
headache or at times an indolent chronic disease characteri ed
by wea ness malaise and low grade e er. Brucellosis is
ac uired primarily by contact with in ected animals or animal
products. Wor ers in the meatpac ing industry are mainly at
ris ; howe er eterinarians pet owners and tra elers who
consume unpasteuri ed mil or cheese may also contract the
disease. Appro imately o patients de elop s in lesions.
The large ariety o cutaneous mani estations reported include
erythematous papules di use erythema abscesses erysipelas
li e lesions leu ocytoclastic asculitis thrombocytopenic
purpura Ste ens Johnson syndrome and erythema nodosum
li e lesions. Biopsy may re eal noncaseating granulomas.
Diagnosis is by culture o blood bone marrow or granulomas
and may be con rmed by a rising serum en yme lin ed
immunosorbent assay ( L SA) or agglutination titer. PCR is
a ailable as well. Treatment is with do ycycline and strepto
mycin in combination or wee s.
Buzgan T, et al: Clinical manifestations and complications in 1028 cases
of brucellosis. Int J Infect Dis 2010; 14:e469–e478.
Pappas G, et al: Brucellosis. N Engl J Med 2005; 352:2325.
Ulu-Kilic A, et al: Clinical presentations and diagnosis of brucellosis.
Recent Pat Antiinfect Drug Discov 2013; 8:34–41.
RICKETTSIAL DISEASES
Ric ettsiae are obligate intracellular gram negati e bacteria.
The natural reser oirs o these organisms are the blood
suc ing arthropods; when transmitted to humans through
insect inoculation the ric ettsiae may produce disease. ost
o the human diseases incurred are characteri ed by s in erup
tions e er headache malaise and prostration. Diagnosis is
usually made on a clinical basis and is con rmed by indirect
uorescence antibody testing which may be eri ed by
Western blot or PCR. Therapy is with do ycycline mg
twice daily or days. n addition to the diseases discussed in
the ollowing sections e er caused by Coxiella burnetii is
an acute ebrile illness rom this general class that in re uently
has s in mani estations but these are nonspeci c and nondi
agnostic in nature.
TYPHUS GROUP
Louse borne epidemic typhus caused by ic ettsia prowa e ii
mouse cat or rat ea borne endemic typhus caused by ic
ettsia t phi and scrub typhus a mite borne in ection caused by
ic ettsia tsutsugamushi constitute the typhus group.
Epidemic typhus
umans contract epidemic typhus rom an in estation by
body lice (Pe iculus humanus ar. corporis) which harbor the
ric ettsiae. prowa e ii is not transmitted transo arially
because it ills the louse wee s a ter in ection. or many
years humans were the only nown ector but se eral cases
o sporadic disease ha e been reported in ol ing direct or
indirect contact with the ying s uirrel and a reser oir e ists
in this animal. While the louse eeds on the person s s in it
de ecates. The organisms in the eces are scratched into the
s in. Some wee s a ter in ection the prodromal symptoms
o chills e er aches and pains appear. A ter days a pin
macular eruption appears on the trun and a illary olds and
rapidly spreads to the rest o the body but usually spares the
ace palms and soles. These macules may later become hem
orrhagic and gangrene o the ngers toes nose and ear
lobes may occur. ortality is in epidemics with the
highest death and complication rates occurring in patients
o er age .
Serologic testing using immuno uorescent antibody ( A)
and Western blot or speci city becomes positi e a ter the
th th day o illness. Do ycycline mg twice daily or
days is curati e. Prophyla is is by accination and delousing;
people who succumb are usually li ing under miserable sani
tary conditions as occur during war and a ter natural disas
ters. Vaccination is suggested only or special high ris groups.
Brill insser disease may occur as a recrudescence o pre i
ous in ection with a similar but milder course o illness that
more closely resembles endemic typhus.
Typhus group
Fig. 14-46 Endemic typhus. (Courtesy of Richard DeVillez, MD.)
Endemic typhus
ndemic (murine) typhus is a natural in ection o rats and
mice by t phi sporadically transmitted to humans by the
rat ea enops lla cheopis n south Te as the disease is
transmitted by the cat ea Ctenocephali es felis with opos
sums as the natural reser oir o disease. ndemic typhus has
the same s in mani estations as epidemic typhus ( ig. )
but these are less se ere and gangrene does not super ene.
Appro imately o patients with murine typhus ha e a
s in eruption. Serologic testing using A and Western blot
or speci city becomes positi e in o patients at wee
and almost all by wee s. e er and se ere headache are
suggesti e early symptoms. ndemic typhus occurs world
wide. n the nited States the southeastern states bordering
the Gul o e ico especially Te as and Cali ornia and
awaii ha e been the most common sites o incidence. t
most o ten occurs in urban settings with pea incidence in
the summer and all. Treatment is the same as that or louse
borne (epidemic) typhus.
Scrub typhus
Also nown as tsutsugamushi e er scrub typhus is character
i ed by e er chills intense headache s in lesions and pneu
monitis. The primary lesion is an erythematous papule at the
site o a mite bite most o ten on the scrotum groin or an le.
t becomes indurated and a multilocular esicle rests atop the
papule. entually a necrotic ulcer with eschar and surround
ing indurated erythema de elops and there is regional lymph
adenopathy. About days a ter a mite bite e er chills and
prostration de elop and within another days pneumonitis
and the s in eruption e ol e. The erythematous macular erup
tion begins on the trun e tends peripherally and ades in a
ew days. Dea ness and tinnitus occur in about one th o
untreated patients.
Scrub typhus is caused by tsutsugamushi. The ector is
the trombiculid red mite (chigger) which in ests wild rodents
in scrub or secondary egetation in transitional terrain
between orests and clearings in ar astern countries such
as Japan orea Southeast Asia and Australia. Serologic
diagnosis and treatment are as or other orms o ric ettsias;
howe er in areas o the world where there is reduced sus
ceptibility to tetracyclines such as Thailand ri ampin is more
reliable.
277

14 SPOTTED FEVER GROUP
The spotted e er group includes Roc y ountain spotted
e er caused by ic ettsia ric ettsii; editerranean (bouton
Bacterial Infections
neuse) e er which when seen in A rica has been called
enyan or South A rican tic bite e er caused by conorii;
orth Asian tic borne ric ettsiosis caused by sibirica;
ueensland tic typhus caused by australis; A rican tic
bite e er caused by africae; linders sland spotted e er
caused by honei; ucatan spotted e er caused by felis
carried by the cat ea ector Ctenocephali es felis Japanese
spotted e er caused by japonica; a spotted e er in the
nited States caused by par eri and one in Cali ornia caused
by ic ettsia D; Russian esicular ric ettsiosis caused by
a ari and a no el case in Bra il caused by ic ettsia sp in
the Atlantic rain orest. Additionally tic borne lymphade
nopathy (T B LA) and Dermacentor borne necrosis eschar
lymphadenopathy (D B L) are lin ed to a disease
transmitted by the Dermacentor tic ; they ha e distincti e ea
tures. The tic usually attaches to the scalp and will cause an
eschar and sometimes alopecia. Adenopathy e er and a
spotted eruption occur.
nly the rst two types o spotted e er listed Roc y oun
tain and editerranean are discussed here in detail. All
spotted e ers are characteri ed by headache e er and a
rash the latter most re uently being a pin papular eruption
which may ha e petechiae and in the case o A rican tic bite
e er eschars. All are treated with do ycycline mg twice
daily or days. ost patients respond well and complica
tions are minimal. Tic s are the ectors o all e cept ucatan
spotted e er. Tic pre ention strategies are outlined in
Chapter .
Rocky Mountain spotted fever
At wee s a ter the tic bite chills e er and wea ness
occur. An eruption appears but unli e typhus it begins on the
an les wrists and orehead rather than the trun . The initial
lesions are small red macules which blanch on pressure and
rapidly become papular in untreated patients. Spread to the
trun occurs o er h and the lesions become petechial and
hemorrhagic o er days ( ig. ).
A asculitis o the s in is the pathologic process and
ric ettsii can be ound in these initial macules by applying
a uorescent antibody techni ue to ro en sections. This is a
ery speci c but not ery sensiti e method. n the o
Fig. 14-47 Rocky Mountain spotted fever.
278
tahir99 - UnitedVRG
patients without a rash the ris o a delay in diagnosis and a
atal outcome is greatest with the case atality rate rising pre
cipitously i antibiotics are not initiated be ore the th day.
An eschar is occasionally present at the tic bite site and is a
subtle clue to the diagnosis. n untreated patients with se ere
disease a multisystem disorder appears with renal pulmo
nary C S and peripheral ner ous system abnormalities and
hepatomegaly most o ten ound. ortality in older patients
approaches but is much lower in younger patients.
Tic s spread the causati e organism ric ettsii Principal
o enders are the wood tic Dermacentor an ersoni the dog
tic (D variabilis and sanguineus in Ari ona) and the Lone
Star tic mbl omma americanum Antibodies become posi
ti e in the second or third wee o illness too late to be o help
when the decision to institute therapy is necessary. This deci
sion is made by clinical considerations. A clue may be the
recent illness o a pet dog because ric ettsii will cause symp
tomatic illness in in ected dogs. Treatment is with do ycycline
mg twice daily or days.
Mediterranean spotted fever
Boutonneuse e er or editerranean e er is an acute ebrile
disease endemic in southern urope and northern A rica; it is
the prototype o the spotted e er group o diseases. t a ects
primarily children and is characteri ed by a sudden onset
with chills high e er headache and lassitude. The tic bite
produces an indurated papule nown as tache noire which
becomes a necrotic ulcer ( ig. ). The erythematous
macular and papular eruption de elops on the trun palms
and soles ( ig. ).
The causati e organism is ic ettsia conorii transmitted by
the dog tic hipicephalus sanguineus As with all ric ettsial
diseases the diagnosis is con rmed with serology and treat
ment is with do ycycline. en without therapy the prognosis
is good and complications are rare with editerranean e er.
RICKETTSIALPOX
irst recogni ed in ew or in ric ettsialpo has been
ound in other .S. cities and in Russia. t is an acute ebrile
disease characteri ed by the appearance o an initial lesion at
the site o the mite bite about a wee be ore the onset o the
e er. This rm mm round or o al esicle persists or
wee s and heals with a small pigmented scar. Regional
Fig. 14-48 Tache noire
in boutonneuse fever.
 Fig. 14-49
Rickettsialpox.
lymphadenitis is present. The e er is remittent and lasts about
days. Chills sweats headache and bac ache accompany the
e er. A rash resembling aricella de elops or days a ter
onset o e er. This secondary eruption is papulo esicular
numbers about up to lesions and is generali ed in distri
bution. t ades in about wee .
The rodent mite llo erman ssus Lipon ssoi es sanguineus
transmits the causati e organism ic ettsia a ari The house
mouse Mus musculus is the reser oir. All cases ha e occurred
in neighborhoods in ested by mice on which the rodent mite
has been ound. Diagnosis is con rmed by serologic testing.
The disease is sel limited and complete in olution occurs in
at most wee s. Do ycycline is the agent o choice or treat
ment o ric ettsialpo .
Badiaga S, Brouqui P: Human louse-transmitted infectious diseases. Clin
Microbiol Infect 2012; 18:332–337.
Badiaga S, et al: Murine typhus in the homeless. Comp Immunol
Microbiol Infect Dis 2012; 35:39–43.
Bechah Y, et al: Epidemic typhus. Lancet Infect Dis 2008; 8:417.
Botelho-Nevers E, et al: Treatment of Rickettsia spp. infections. Expert
Rev Anti Infect Ther 2012: 10:1425–1437.
Channick RN, et al: A 60-year-old man with weakness, rash and renal
failure. N Engl J Med 2012; 366:1434–1443.
Cragun WC, et al: The expanding spectrum of eschar-associated
rickettsioses in the United States. Arch Dermatol 2010; 146:641.
Eisen RJ, et al: Transmission of flea-borne zoonotic agents. Annu Rev
Entomol 2012; 57:61–82.
Elston DM: Tick bites and skin rashes. Curr Opin Infect Dis 2010;
23:132.
Faucher JF, et al: Brill-Zinsser disease in a Moroccan man. Emerg Infect
Dis 2012; 18:171–172.
Gan SD, et al: Fever and a solitary papule on the foot. JAMA Dermatol
2014; 150:203–204.
Graham J, et al: Tick borne diseases. Pediatr Emerg Care 2011;
27:141–150.
Koh GC, et al: Diagnosis of scrub typhus. Am J Trop Med Hyg 2010;
82:368–370.
Liddell PW, et al: Murine typhus. Clin Lab Sci 2012; 25:81–87.
Maya RM, et al: Rocky Mountain spotted fever in a patient treated with
anti-TNF-α inhibitors. Dermatol Online J 2013; 19:7.
McQuiston JH, et al: Brill-Zinsser disease in a patient following infection
with sylvatic epidemic typhus associated with flying squirrels. Clin
Infect Dis 2010; 51:712–715.
Nachega JB, et al: Travel-acquired scrub typhus. J Travel Med 2007;
14:352.
Shapiro MR, et al: Rickettsia 364D. Clin Infect Dis 2010; 50:541–548.
Spolidorio MG, et al: Novel spotted fever group Rickettsiosis, Brazil.
Emerg Infect Dis 2010; 16:521–523.
Walter G, et al: Murine typhus in returned travelers. Am J Trop Med Hyg
2012; 86:1049–1053.
Woods CR: Rocky Mountain spotted fever in children. Pediatr Clin North
Am 2013; 60:455–470.
EHRLICHIOSIS
The tic borne ehrlichial organisms which a ect phagocytic
cells mani est as a ebrile illness accompanied by headache
and a rash. uman monocytic ehrlichiosis ( ) is caused
by Ehrlichia chaffeensis; human granulocytic anaplasmosis
( GA) by naplasma phagoc tophilia groups; Sennetsu e er a
mononucleosis type illness by Ehrlichia sennetsu; and Ehrlichia
ewingii all produce a similar symptomatic illness. is
Leptospirosis
transmitted by mbl omma americanum or Dermacentor variabi
lis. t is most common in men age . The predominant .S.
regions reporting ehrlichiosis are the south central southeast
ern and mid Atlantic states. The same xo es tic s that trans
mit Lyme disease and babesiosis transmit GA and the
in ection occurs in the same geographic areas the northeast
and Paci c northwestern nited States. Coin ection with these
agents occurs.
S in eruptions are present in only about one third o
patients and o GA patients. The lesions are usually
present on the trun and are nondiagnostic. A mottled or
di use erythema a ne petechial eruption lower e tremity
asculitis and a macular papular esicular or urticarial mor
phology ha e all been seen. Acral edema with des uamation
and petechiae o the palate may be present. n ol ement o the
idneys lungs and C S occurs in se ere cases.
the diagnosis is suspected a complete blood count will
usually show thrombocytopenia and leu openia. The leu o
cytes should be inspected microscopically or intracytoplasmic
microcolonies called morulae seen more re uently in GA
than . A testing and PCR analysis are positi e but
asymptomatic in ection is common and seropre alence rates
are high in endemic areas. Culture o the organism is diagnos
tic. Do ycycline is the treatment o choice mg twice daily
or days. Li e threatening disease is usually seen in the
immunosuppressed population.
Ismail N, et al: Human ehrlichiosis and anaplasmosis. Clin Lab Med
2010; 30:261.
Shah RG, et al: Clinical approach to known and emerging tick-borne
infections other than Lyme disease. Curr Opin Pediatr 2013;
25:407–418.
Thomas RJ, et al: Current management of human granulocytic
anaplasmosis, human monocytic ehrlichiosis and Ehrlichia ewingii
ehrlichiosis. Expert Rev Anti-Infect Ther 2009; 7:709–722.
LEPTOSPIROSIS
Leptospirosis is also nown as Weil s disease pretibial e er
and ort Bragg e er. t is a systemic disease caused by
many strains o the genus Leptospira A ter an incubation
period o days Weil s disease (icteric leptospirosis) starts
with an abrupt onset o chills ollowed by high e er intense
aundice petechiae and purpura on both s in and mucous
membranes and renal disease mani ested by proteinuria
hematuria and a otemia. Death may occur in o
patients as a result o renal ailure ascular collapse or hem
orrhage. Leu ocytosis o cells mm and lym
phocytosis in CS are usually present.
Pretibial e er ( ort Bragg e er anicteric leptospirosis) has
an associated acute e anthematous in ectious erythema gen
erally most mar ed on the shins. igh e er con uncti al
su usion nausea omiting and headache characteri e the
septicemic rst stage. This lasts days ollowed by a
day absence o e er. During the second stage when g
antibody de elops headache is intense e er returns and
ocular mani estations such as con uncti al hemorrhage and
su usion ocular pain and photophobia are prominent. At
this time the eruption occurs. t consists o cm erythema
tous patches or pla ues that histologically show only edema
and nonspeci c peri ascular in ltrate. The s in lesions resol e
spontaneously a ter days. There may be di erent clinical
mani estations rom identical strains o Leptospira
279
 Leptospira interrogans serotype icterohaemorrhagiae has been
14 the most common cause o Weil s disease whereas pretibial
e er is most o ten associated with serotype autumnalis
umans ac uire both types accidentally rom urine or tissues
o in ected animals or indirectly rom contaminated soil or
Bacterial Infections
rom drin ing or swimming in contaminated water. Tra elers
to the tropics who engage in water sports are at ris . n the
continental nited States dogs and cats are the most common
animal source; worldwide rats are more o ten responsible.
Leptospira enter the body through abraded or diseased s in
and the G or upper respiratory tract.
Leptospirosis may be diagnosed by nding the causati e
spirochetes in the blood by dar eld microscopy during the
rst wee o illness as well as by blood cultures guinea pig
inoculation and the demonstration o rising antibodies during
the second wee o the disease. The microagglutination sero
logic test is the test o choice but PCR and L SA testing are
also a ailable.
Treatment with tetracyclines and penicillin shortens the
disease duration i gi en early. Do ycycline mg day or
wee is e ecti e in mild disease; howe er V penicillin is
necessary in se erely a ected patients. A dose o mg once
wee ly may help pre ent in ection while isiting a hyperen
demic area.
Brett-Major DM, et al: Antibiotic prophylaxis for leptospirosis. Cochrane
Database Syst Rev 2009; CD007342.
Forbes AE, et al: Leptospirosis and Weil’s disease in the UK. Q J Med
2012; 105:1151–1162.
Guerra MA: Leptospirosis. J Am Vet Med Assoc 2009; 234:472.
Picardeau M: Diagnosis and epidemiology of leptospirosis. Med Mal
Infect 2013; 43:1–9.
BORRELIOSIS
Spirochetes o the genus orrelia are the cause o Lyme disease.
This multisystem in ection rst presents with s in ndings
and o er time multiple cutaneous signs may occur. These
microorganisms are also the cause o relapsing e er an acute
illness characteri ed by paro ysms o e er. The more common
type o relapsing e er is tic borne occasionally being
reported in the nited States. A louse borne type is endemic
only in thiopia. The nonspeci c macular or petechial erup
tion occurs near the end o the day ebrile crisis.
Lyme disease
orrelia burg orferi sensu lato species comple are responsible
or inducing Lyme disease. These spirochetes are transmitted
to humans by arious members o the amily o hard tic s
odidae. Thirteen genomic strains are recogni ed to be geo
graphically prominent and cause arying s in and systemic
disease mani estations. orrelia burg orferi sensu stricto causes
Lyme disease in the nited States. orrelia lonestari (a relapsing
e er type o orrelia not in the burg orferi sensu lato
comple ) causes disease in the southern states in which the
only s in nding is the diagnostic early mani estation ery
thema migrans. lonestari transmitted by the bite o the Lone
Star tic mbl omma americanum is the cause o southern
tic associated rash illness (STAR ) or asters disease a con
dition characteri ed by erythema migrans headache sti
nec myalgia and arthralgia. orrelia garinii and orrelia af elii
are two ma or strains present in urope with garinii the
principal agent o Lyme neuroborreliosis and af elii associ
ated with acrodermatitis chronica atrophicans lymphocy
toma and in some cases morphea and lichen sclerosis et
atrophicus. disease is not treated in the early stage chronic
280
tahir99 - UnitedVRG
arthritis and neurologic and cardiac complications re uently
de elop. ther strains are present in urope and Asia with a
ew reports implicating them in rare cases o Lyme disease.
Diagnosing early Lyme disease depends on recognition o
the s in eruption. Appro imately o patients recall a tic
bite which lea es a small red macule or papule at the site.
The areas most o ten in ol ed are the legs groins and a illa
with adults ha ing lower e tremity lesions most o ten and
children more li ely to mani est erythema migrans on the
trun . Between and days (median ) a ter the bite there
is gradual e pansion o the redness around the papule
( ig. A). The ad ancing border is usually slightly raised
warm red to bluish red and ree o any scale. Centrally the
site o the bite may clear lea ing only a ring o peripheral
erythema or it may remain red becoming indurated esicu
lar or necrotic. n urope the large annular ariety is most
common whereas in the nited States the lesions are usually
homogeneous or ha e a central redness. The annular erythema
usually grows to a median diameter o cm but may range
rom cm ( ig. B). t is accompanied by a burning
sensation in hal o patients; rarely is it pruritic or pain ul.
Locali ed alopecia may de elop at the site o erythema
migrans.
rom o patients will de elop multiple secondary
annular lesions similar in appearance to the primary lesion
but without indurated centers and generally o smaller si e
( ig. ). The lesions in number spare the palms and
soles. Without treatment erythema migrans and the second
ary lesions ade in a median o days although some may
be present or months. untreated patients e perience
recurrences o erythema migrans o er the ollowing months.
uropean cases o orrelia induced lymphocytoma occur early
in general rom the time o erythema migrans until months
later. These are B cell proli erations and present as red indu
rated papules and pla ues which occur most o ten on the
areola or earlobe.
Di use urticaria malar erythema and con uncti itis may be
present during this early period. alaise e er atigue head
aches sti nec arthralgia myalgia lymphadenopathy
anore ia and nausea and omiting may accompany early
signs and symptoms o in ection. sually the symptoms are
o mild se erity mimic ing a slight uli e illness e cept in
patients coin ected with babesiosis as in appro imately
o cases in southern ew ngland. Ehrlichia coin ections
may also occur because the latter two diseases are also tic
transmitted in ections.
About o untreated patients e entually de elop a
chronic arthritis o the nees which in hal o patients leads
to se ere disability. Cardiac in ol ement occurs most o ten in
young men with uctuating degrees o atrio entricular bloc
or complete heart bloc occurring o er a brie time days to
wee s early in the course o the illness. n uropean cases
a dilated cardiomyopathy may e entuate. eurologic ndings
include sti nec headache meningitis cogniti e de cits
paresthesias and radiculopathy Bell palsy optic neuritis es
tibular neuronitis oculomotor palsy and cranial and periph
eral neuropathies and are much more re uently mani ested
in uropean patients. onspeci c ndings include an ele ated
erythrocyte sedimentation rate in and an ele ated g
le el mild anemia and ele ated li er unction tests in o
patients.
ales and emales are e ually a ected and the age range
most o ten a ected is o bimodal type with an early pea at
and a later pea at years. nset o illness is gener
ally between ay and o ember with more than o cases
in the orthern emisphere identi ed in June July or August.
n the nited States tic transmission o Lyme disease is by
xo es scapularis in the ortheast and idwest and

B
Fig. 14-50 A and B, Erythema migrans.
Fig. 14-51 Secondary lesions of erythema migrans.
xo es paci cus is incriminated in the West. uropean cases are
transmitted by the tic s xo es ricinus and persulcatus and in
Asia by ovatus and persulcatus.
The di erent subtypes o orrelia present in urope account
or the clinical illness resulting rom in ection being somewhat
di erent rom that seen in the nited States. uropean ery
thema migrans occurs more o ten in emales and is less li ely
to ha e multiple lesions. ntreated lesions last longer; there
are more laboratory abnormalities in Lyme disease; the arthri
tis symptoms are prominent in the nited States but unusual
in urope; and the neurologic mani estations di er. n urope
in ection may lead to Bannwarth syndrome which is charac
teri ed by ocal se ere radicular pains; lymphocytic menin
gitis; and cranial ner e paralysis. Acrodermatitis chronica
atrophicans lymphocytoma cutis and some cases o morphea
atrophoderma o Pasini and Pierini anetoderma and lichen
Borreliosis
sclerosus et atrophicus are late cutaneous se uelae of orrelia
af elii or garinii in ection in urope. Some patients with
morphea type lesions may ha e histopathologic eatures o an
interstitial granulomatous dermatitis with histiocytic pseudo
rosettes present.
Se eral cases o transplacental transmission o orrelia
resulting in in ant death ha e been reported. owe er studies
o Lyme disease in pregnancy ha e generally ailed to impli
cate an association with etal mal ormations directly.
n histologic in estigation there is a super cial and deep
peri ascular and interstitial mi ed cell in ltrate. Lympho
cytes plasma cells and eosinophils may be seen the latter
especially prominent when the center o the lesion is biopsied.
Warthin Starry staining may re eal spirochetes in the upper
dermis.
The clinical nding o erythema migrans is the most sensi
ti e e idence o early in ection. Serologic con ersion in .S.
patients is as ollows when symptoms present or ewer
than days with symptoms or days and with
symptoms longer than wee s. or this reason the diagnosis
is made through recognition o erythema migrans. Although
culture with PCR analysis is speci c it is not sensiti e and is
not a ailable in most areas. Serologic testing is then the con
rmatory test. The screening e amination is L SA which is
sensiti e and speci c. Western blot is used to con rm
the result. There are three antigenic bands used in the g test
and in the gG test. Two o three in the g and o in
the gG must be positi e to diagnose Lyme disease. alse
positi e tests occur in syphilis pinta yaws leptospirosis
relapsing e er in ectious mononucleosis and disease associ
ated with autoantibody ormation. The VDRL is negati e in
burg orferi in ection. Patients with erythema migrans second
ary to STAR usually ha e negati e serology or Lyme disease.
Treatment
The treatment o choice in adults with Lyme disease is do y
cycline mg twice daily or wee s. Amo icillin mg
281
 twice daily or days or ce uro ime a etil mg twice
14 daily or days is also e ecti e. Do ycycline is also e ecti e
against Ehrlichia but the β lactams are not. Children under
age should be treated with amo icillin mg g day in
di ided doses. Pregnant women with locali ed early Lyme
Bacterial Infections
disease should ta e amo icillin; howe er i disseminated
disease is present parenteral penicillin G or ce tria one is
used. mmunode cient patients may also bene t rom V peni
cillin or ce tria one although the data are not robust or this
recommendation.
ore aggressi e regimens are necessary or carditis and
neurologic and arthritic in ol ement with parenteral dosing
regimens o ten indicated.
Tic control en ironmental measures and personal a oid
ance strategies are worthwhile when outdoor acti ities are
planned in tic in ested areas. nspecting or tic s a ter return
ing rom outdoor acti ity is a good pre enti e measure. The
tic needs to be attached or more than h to transmit disease
in the nited States. ymphs are small and may be di cult
to see; be aware o the rec le that mo es. Prophylactic antibi
otic therapy with one dose o mg do ycycline a ter a
nown tic bite with a partially engorged xo es scapularis in
high incidence areas is e ecti e. An e ecti e accine was
withdrawn rom the mar et because o poor sales.
Acrodermatitis chronica atrophicans
Also nown as primary di use atrophy acrodermatitis chron
ica atrophicans (ACA) is characteri ed by the appearance on
the e tremities o di use reddish or bluish red paper thin
s in. The underlying blood essels are easily seen through the
epidermis. t occurs almost e clusi ely in urope. The disease
begins on the bac s o the hands and eet then gradually
spreads to in ol e the orearms the arms and the lower
e tremities nees and shins. ccasionally e en the trun
may become in ol ed. n the beginning the areas may be
slightly edematous and scaly but generally they are le el with
the s in and smooth. A ter se eral wee s to months the s in
has a smooth so t thin el ety eel and may easily be li ted
into ne olds. t may ha e a peculiar pin ish gray color and
a crumpled cigarette paper appearance. Well de ned smooth
edematous bandli e thic enings de elop and may e tend
rom a nger to the elbow (ulnar bands) or may de elop in the
s in o er the shins. With progression o ACA mar ed atrophy
o the s in occurs.
Subcutaneous brous nodules may orm chie y o er the
elbows wrists and nees. odules may be single or multiple
and are rm and painless. Di use e tensi e calci cation o the
so t tissues may be re ealed by radiographic e amination.
anthomatous tumors may occur in the s in. ypertrophic
osteoarthritis o the hands is re uently obser ed. ccasion
ally atrophy o the bones o the in ol ed e tremities is
encountered. lcerations and carcinoma may super ene on
the atrophic patches. ACA is slowly progressi e but may
remain stationary or long periods. Patches may change
slightly rom time to time but complete in olution ne er
occurs.
A spirochetosis ACA is a late se uel o in ection with or
relia af elii transmitted by the tic xo es ricinus Almost all
patients with ACA ha e a positi e test or antibodies to the
spirochete and Warthin Starry stains demonstrate af elii in
tissue in some cases. The organism has been cultured rom
s in lesions o ACA.
istologically there is mar ed atrophy o the epidermis and
dermis without brosis. The elastic tissue is absent and the
cutaneous appendages are atrophic. n the dermis a bandli e
lymphocytic in ltration is seen which aries in abundance
282
tahir99 - UnitedVRG
according to the stage o the disease. The epidermis is slightly
hyper eratotic and attened and beneath it there is a distinc
ti e narrow one o connecti e tissue in which the elastic
tissue is intact.
Antibiotic therapy as or other orms o borreliosis cures
most patients with ACA.
Aberer E: What should one do in case of a tick bite? Curr Probl
Dermatol 2009; 37:155.
Bhate C, et al: Lyme disease. J Am Acad Dermatol 2011; 64:619–653.
Cutler SJ: Relapsing fever. J Appl Microbiol 2010; 108:1115–1122.
Eisendle K, et al: The expanding spectrum of cutaneous borreliosis. G
Ital Dermatol Venereol 2009; 144:157.
Esposito S, et al: Borrelia burgdorferi infection and Lyme disease in
children. Int J Infect Dis 2013; 17:e153–e158.
Feder HM Jr: Lyme disease in children. Infect Dis Clin North Am 2008;
22:315.
Feder HM Jr, et al: Southern tick-associated rash illness (STARI) in the
North: STARI following a tick bite in Long Island, New York. Clin Infect
Dis 2011; 53:e142–e146.
Masters EJ, et al: STARI, or Masters disease. Infect Dis Clin North Am
2008; 22:361.
Mullegger RR: Skin manifestations of Lyme borreliosis. Am J Clin
Dermatol 2008; 9:355.
Murray TS, et al: Lyme disease. Clin Lab Med 2010; 30:311.
Smetanick MT, et al: Acrodermatitis chronica atrophicans. Cutis 2010;
85:247.
Shapiro ED: Clinical practice. Lyme disease. N Engl J Med. 2014;
370:1724–1731.
Tiger JB, et al: Bullous Lyme disease. J Am Acad Dermatol 2014;
71:e133–134.
Stanek G, et al: Lyme borreliosis. Lancet 2012; 379:461–473.
Walsh CA, et al: Lyme disease in pregnancy. Obstet Gynecol Surv 2007;
62:41.
MYCOPLASMA
M coplasma organisms are distinct rom true bacteria in that
they lac a cell wall and di er rom iruses in that they grow
on cell ree media. M coplasma pneumoniae ( aton agent) is an
important cause o acute respiratory disease in children and
young adults. n the summer it may account or an estimated
o pneumonias. S in eruptions occur during the course
o in ection in appro imately o patients. The most
re uently reported is Ste ens Johnson syndrome. rythema
nodosum and Gianotti Crosti syndrome ha e been occasion
ally reported as well as isolated mucositis without s in lesions
( uchs syndrome or Ste ens Johnson syndrome without s in
lesions). ther e anthems include urticarial esicular esicu
lopustular maculopapular scarlatini orm petechial purpu
ric and morbilli orm lesions distributed primarily on the
trun arms and legs. lcerati e stomatitis and con uncti itis
may be present.
The diagnosis o M pneumoniae in ection is made in the
acute situation by clinical means but de niti e diagnosis is
made by en yme immunoassay PCR or complement ation
techni ues. Cold agglutinins with a titer o or more are
usually caused by M pneumoniae in ection. ccasionally acro
cyanosis may occur secondary to cold agglutinin disease
which clears with antibiotic therapy. Treatment is with either
a macrolide (erythromycin a ithromycin or clarithromycin)
or do ycycline or days.
Atkinson TP, et al: Epidemiology, clinical manifestations, pathogenesis
and laboratory detection of Mycoplasma pneumoniae infections. FEMS
Microbiol Rev 2008; 32:956.
Li K, et al: Stevens-Johnson syndrome without skin lesions (Fuchs
syndrome). Arch Dermatol 2012; 148:963–964.
Meyer Sauteur PM, et al: Fuchs syndrome associated with Mycoplasma
pneumonia (Stevens-Johnson syndrome without skin lesions). Pediatr
Dermatol 2011; 28:474–476.
 Schalock PC, et al: Mycoplasma pneumoniae–induced cutaneous
disease. Int J Dermatol 2009; 48:673.
CHLAMYDIAL INFECTIONS
Two species o chlamydiae Chlam ia trachomatis and Chla
m ia psittaci ha e been recogni ed. The two species share a
ma or common antigen and there are numerous serotypes
within each species. n humans Chlam ia causes trachoma
inclusion con uncti itis nongonococcal urethritis cer icitis
epididymitis proctitis endometritis salpingitis pneumonia
in the newborn psittacosis (ornithosis) and lymphogranu
loma enereum.
LYMPHOGRANULOMA VENEREUM
Lymphogranuloma enereum (LGV) is an STD caused by
microorganisms o the Chlam ia trachomatis group and char
acteri ed by suppurati e inguinal adenitis with matted lymph
nodes inguinal bubo with secondary ulceration and constitu
tional symptoms. A ter an incubation period o days a
primary lesion consisting o a mm herpeti orm esicle
or erosion de elops on the glans penis prepuce or coronal
sulcus or at the meatus. n S the lesion may be in the
rectum. n women it occurs on the ul a agina or cer i .
The lesion is painless and soon becomes a shallow ulceration.
The initial symptom may be urethritis or proctitis. tragenital
primary in ections o LGV are rare. An ulcerating lesion may
appear at the site o in ection on the ngers lips or tongue. n
patients with V in ection a pain ul perianal ulcer may
occur. Primary lesions heal in a ew days.
About wee s a ter the appearance o the primary lesion
enlargement o the regional lymph nodes occurs ( ig. ).
n one third o patients the lymphadenopathy is bilateral. n
the rather characteristic inguinal adenitis o LGV in men the
nodes in a chain use together into a large mass. The color o
the s in o erlying the mass usually becomes iolaceous the
swelling is tender and the bubo may brea down orming
multiple stulous openings. Adenopathy abo e and below
the Poupart ligament produces the characteristic but not
Fig. 14-52
Lymphogranuloma
venereum.
diagnostic groo e sign. Along with the local adenitis there
may be systemic symptoms o malaise oint pains con uncti
itis loss o appetite weight loss and e er which may persist
or se eral wee s. Patients with septic temperatures enlarged
li er and spleen and e en encephalitis ha e occasionally been
Lymphogranuloma venereum
obser ed.
Primary lesions o LGV are rarely obser ed in emale
patients; women also ha e a lower incidence o inguinal
buboes. Their bubo is typically pararectal in location. The
diagnosis is recogni ed only much later when the patient
presents with an increasingly pronounced in ammatory stric
ture which may be annular or tubular o the lower rectal wall.
Because most o the lymph channels running rom the ul a
drain into the nodes around the lower part o the rectum an
in ammatory reaction in these nodes results in secondary
in ol ement o the rectal wall. The iliac nodes may also be
in ol ed. LGV may start in the rectum as proctitis which may
then progress to the ormation o a stricture. The clinical hall
mar is bloody mucopurulent rectal discharge. The stricture
can usually be elt with the e amining nger cm abo e the
anus. ntreated rectal strictures in men and women may e en
tually re uire colostomy. With or without rectal strictures
women in later stages o the disease may show elephantiasis
o the genitals with chronic ulcerations and scarring o the
ul a (esthiomene). Such a reaction is rare in men.
Cutaneous eruptions ta e the orm o erythema nodosum
erythema multi orme photosensiti ity and scarlatini orm
eruptions. Arthritis associated with LGV in ol es the nger
wrist an le nee or shoulder oints. ar ed weight loss
pronounced secondary anemia wea ness and mental depres
sion are o ten encountered in the course o the anorectal syn
drome. Colitis resulting rom LGV is limited to the rectum and
rectosigmoid structures. Perianal stulas or sinuses are o ten
seen in cases o anorectal LGV. The arious e tragenital mani
estations include glossitis with regional adenitis unilateral
con uncti itis with edema o the lids caused by lymphatic
bloc age with lymphadenopathy acute meningitis meningo
encephalitis and pneumonia.
The diagnosis by nucleic acid ampli cation tests identi es
C trachomatis in a wide ariety o specimens including urine;
urethral rectal and ulcer swabs; bubo aspirates; and biopsy
specimens. The complement ation test is the most easible
and the simplest serologic test or detecting antibodies in
resource poor locales. These antibodies become detectable
about wee s a ter onset o illness; a titer o is highly
suggesti e. icrohemagglutination inhibition assays are also
a ailable and not only con rm the diagnosis but also identi y
the strain. Three serotypes designated L L and L are
nown or the LGV chlamydia. Characteristic sur ace antigens
allow separation o the LGV chlamydiae rom the agents that
cause trachoma inclusion con uncti itis urethritis and cer i
citis which also belong to the C trachomatis group.
Lymphogranuloma enereum occurs in all races and the
highest incidence is ound in the year old group.
Asymptomatic emale contacts who shed C trachomatis rom
the cer i are an important reser oir o in ection. The classic
disease in men is uncommon in the nited States whereas
anorectal LGV is increasing in S .
The characteristic changes in the lymph nodes consist o an
in ectious granuloma with the ormation o stellate abscesses.
There is an outer one o epithelioid cells with a central necrotic
core composed o debris o lymphocytes and leu ocytes. n
lesions o long duration plasma cells may be present. Stellate
abscess also occurs in cat scratch disease atypical mycobacte
rial in ection tularemia and sporotrichosis.
n contrast to LGV with chancroid a primary chancre
or multiple chancroidal ulcers are present and may permit
the demonstration o aemophilus ucre i The s in lesions
283
 are characteristic and usually much larger and more persistent Patel S, Hay P: Lymphogranuloma venereum and HIV infection:
14 than the primary lesion o LGV. Dono an bodies are demon
strable in granuloma inguinale; howe er inguinal adenitis is
misdiagnosed as Crohn’s disease. BMJ Case Rep 2010; Nov 26.
Singhrao T, et al: Lymphogranuloma venereum presenting as perianal
not characteristic. sthiomene may also be seen in both ulceration. Sex Transm Dis 2011; 87:123–124.
White JA: Manifestations and management of lymphogranuloma
diseases.
Bacterial Infections

venereum. Curr Opin Infect Dis 2009; 22:57.

the primary lesion o LGV is well de eloped it may be
con used with the primary lesion o syphilis. n any genital
lesion dar eld e amination or reponema palli um is indi
cated i a ailable. Syphilitic inguinal adenitis shows small Bonus images for this chapter can be found online at
hard nontender glands. t should be emphasi ed again that
all enereal in ections may be mi ed in ections and that obser expertconsult.inkling.com
ation or simultaneous or subse uent de elopment o another eFig. 14-1 Staphylococcal abscess.
enereal disease should be unrelenting. This includes sero eFig. 14-2 Impetigo.
logic testing or V disease. Late stages o LGV esthiomene eFig. 14-3 Sporotrichoid staphylococcal abscesses.
with ulcerating and cicatri ing lesions need to be di erenti eFig. 14-4 Staphylococcal scalded skin syndrome.
ated rom syphilis by a search or spirochetes the serologic eFig. 14-5 Ecthyma.
tests or syphilis and complement ation tests. eFig. 14-6 Erysipelas.
eFig. 14-7 Erysipelas.
Treatment eFig. 14-8 Necrotizing fasciitis.
eFig. 14-9 Erythrasma.
The recommended treatment o LGV is do ycycline mg
eFig. 14-10 Pitted keratolysis.
twice daily or wee s. An alternati e is erythromycin mg
eFig. 14-11 Nocardiosis.
our times daily or days. Se ual partners within the prior
eFig. 14-12 Gram-negative toe web infection.
days should also be treated. The uctuant nodules are aspi
eFig. 14-13 Pseudomonas folliculitis.
rated rom abo e through healthy ad acent normal s in to
pre ent rupture. eFig. 14-14 Chanchroid.
eFig. 14-15 Granuloma inguinale.
Basta-Juzbasic A, et al: Chancroid, lymphogranuloma venereum,
eFig. 14-16 Gonococcemia.
granuloma inguidale, genital herpes simplex nfection, and molluscum
contagiosum. Clin Dermatol 2014; 32:290–298. eFig. 14-17 Meningococcemia.
Bebear C, et al: Genital Chlamydia trachomatis infections. Clin Microbiol eFig. 14-18 Primary lesion of lymphogranuloma venereum.
Infect 2009; 15:4. eFig. 14-19 Tularemia.
Mistangelo M, et al: Rectal lymphogranuloma venereum. Colorectal Dis eFig. 14-20 Boutonneuse fever.
2012; 14:e792–e793.

284

tahir99 - UnitedVRG
eFig. 14-1 eFig. 14-4
Staphylococcal Staphylococcal
abscess. scalded skin
syndrome.

Lymphogranuloma venereum
eFig. 14-2 Impetigo.

eFig. 14-5 Ecthyma.

eFig. 14-3
Sporotrichoid
staphylococcal
abscesses.

eFig. 14-6 Erysipelas.

284.e1
 eFig. 14-7 Erysipelas. eFig. 14-10 Pitted
14 keratolysis.
Bacterial Infections

eFig. 14-8 Necrotizing fasciitis. eFig. 14-11 Nocardiosis.

eFig. 14-12 Gram-

negative toe web
infection.

eFig. 14-9 Erythrasma.

284.e2

tahir99 - UnitedVRG
 eFig. 14-16
Gonococcemia.

Lymphogranuloma venereum
eFig. 14-13 Pseudomonas folliculitis.

eFig. 14-17
Meningococcemia.

eFig. 14-14 Chanchroid.

eFig. 14-15 Granuloma

inguinale.

284.e3
14
Bacterial Infections

eFig. 14-18 Primary lesion of lymphogranuloma venereum.

eFig. 14-20 Boutonneuse fever.

eFig. 14-19 Tularemia.

284.e4

tahir99 - UnitedVRG
 Bonus images for this chapter can be found online at
Diseases Resulting from Fungi and Yeasts
SUPERFICIAL AND DEEP MYCOSES
An estimated o the world s population has some orm
o ungal in ection usually an anthropophilic richoph ton
in ection ma ing ungal in ections the most common type o
in ection worldwide. Cutaneous in ections are di ided into
super cial and deep mycoses. ost mycotic in ections are
super cial and are limited to the stratum corneum hair and
nails. n contrast most deep mycoses are e idence o dissemi
nated in ection typically with a primary pulmonary ocus.
Although blastomycosis histoplasmosis and coccidioidomy
cosis generally present as s in lesions they are almost always
e idence o a systemic in ection. A ew deep mycoses result
rom direct inoculation into the s in by a thorn or other oreign
body including cutaneous lymphangitic sporotrichosis
primary cutaneous phaeohyphomycosis and chromomycosis.
Phaeohyphomycosis generally begins as a s in in ection but
immunosuppressed patients are at great ris o dissemination
and death. en cutaneous sporotrichosis may occasionally
disseminate. Although most cutaneous aspergillosis repre
sents cutaneous emboli ation rom a systemic (o ten a pulmo
-
nary) ocus in burn ictims spergillus typically coloni es the
burn eschar. This coloni ation may o ten be treated with
debridement alone. Deep incisional biopsies are re uired to
9
determine i iable tissue has been in aded beneath the eschar.
idence o iable tissue in asion suggests a li elihood o
ri 9
systemic dissemination and is usually an indication or sys
temic anti ungal therapy.
The ma or ungi that cause only stratum corneum hair and
nail in ection are the dermatophytes. They are classi ed in
h
three genera Microsporum richoph ton and Epi ermoph ton
The identity o the pathogen may be important or determin
t a
ing a oonotic reser oir o in ection cat or dog or Microsporum
canis in ections cattle or richoph ton verrucosum and rats or
granular oophilic richoph ton mentagroph tes
Susceptibility and prevalence
Local immunosuppression rom a potent topical corticosteroid
or calcineurin inhibitor may promote widespread tinea in ec
tion. A de ecti e cutaneous barrier as in patients with ichthyo
sis can also predispose to widespread tinea in ection. Patients
with blood type A are somewhat more prone to chronic
disease and those with autosomal recessi e CARD de ciency
are susceptible to in asi e ungal in ection with dissemination
to lymph nodes and the central ner ous system (C S). any
indi iduals will carry richoph ton rubrum asymptomatically
which may be an autosomal dominant inherited tendency.
When they are e posed to a hot humid climate or occlusi e
ootwear these patients o ten become symptomatic. Reported
pre alence rates are there ore greatly a ected by climate oot
wear and li estyle.
expertconsult.inkling.com
15
Antifungal therapy
Topical agents pro ide sa e cost e ecti e therapy or limited
super cial ungal in ections. When considering the use o an
oral anti ungal agent actors include the type o in ection
G
organism spectrum pharmaco inetic pro le sa ety compli
ance and cost. Griseo ul in has a long sa ety record but
R
re uires much longer courses o therapy than newer agents.
Topical anti ungals remain ery cost e ecti e or limited cuta
V
neous disease.
Various classes o anti ungals are in use. The imida oles
d
include clotrima ole micona ole econa ole sulcona ole o i
cona ole oricona ole e nacona ole and etocona ole. They
ti e
wor by inhibition o cytochrome P α demethylase an
essential en yme in ergosterol synthesis. ystatin is a polyene
that wor s by irre ersibly binding to ergosterol an essential
component o ungal cell membranes. a ti ne terbina ne
n
and butena ne are allylamines and their mode o action is
inhibition o s ualene epo ydation. The tria oles include itra
U
cona ole and ucona ole which a ect the C P system.
or both itracona ole and griseo ul in ood increases
absorption. or itracona ole and etocona ole antacids
antagonists and proton pump inhibitors lower absorption.
Terbina ne is less acti e against Can i a and Microsporum
species (spp.) in itro. n i o ade uate doses can be e ecti e
against these organisms. Terbina ne has limited e cacy in the
oral treatment o tinea ersicolor but is e ecti e topically.
Although ew drug interactions ha e been reported with ter
bina ne and the bioa ailability is unchanged in ood hepato
to icity leu openia to ic epidermal necrolysis and taste
disturbances occur in re uently. etocona ole has a wide
spectrum o action against dermatophytes yeasts and some
systemic mycoses but has the potential or serious drug inter
actions and a higher incidence o hepatoto icity than other
a ailable agents.
lucona ole is mainly used to treat Can i a in ections but
has shown e cacy in the treatment o dermatophytoses both
in daily and in wee ly doses. Patients may ha e trouble
remembering intermittent dosing schedules.
Both terbina ne and itracona ole ha e been shown to be
e ecti e and well tolerated in se eral studies o the treatment
o tinea capitis and onychomycosis in children. owe er itra
cona ole has been associated with reports o heart ailure.
Voricona ole has e ceptional acti ity against a wide ariety
o yeasts as well as many other ungal pathogens but has
been associated with photosensiti ity premature photoaging
actinic eratoses s uamous cell carcinoma melanoma and
porphyria. Posacona ole has signi cant in itro acti ity
against Can i a spp. although some resistance has been
reported to this drug.
The echinocandins inhibit β ( ) glucan synthesis thus
damaging ungal cell walls. These drugs are acti e against
most Can i a spp. and ungistatic against spergillus spp. The
285
 echinocandins ha e limited acti ity against ygomycetes
15 Cr ptococcus neoformans or usarium spp. Caspo ungin was the
rst drug in this class to be mar eted in the nited States or
re ractory in asi e aspergillosis. ica ungin also belongs to
this anti ungal class. Ad erse e ents are uncommon but
Diseases Resulting from Fungi and Yeasts
include phlebitis e er ele ated li er en ymes and mild
hemolysis. The drugs must be gi en intra enously. etabo
lism is mainly hepatic. n the setting o Can i a sepsis results
are similar to those achie ed with amphotericin B with sub
stantially lower to icity. The echinocandins may be used
together with other anti ungal agents in the treatment o li e
threatening systemic ungal in ections such as disseminated
aspergillosis re ractory to other regimens.
THE SUPERFICIAL MYCOSES
TINEA CAPITIS
Tinea capitis also nown as scalp ringworm can be caused by
all the pathogenic dermatophytes e cept or Epi ermoph ton
occosum and richoph ton concentricum n the nited States
most cases are caused by richoph ton tonsurans which
replaced Microsporum au ouinii as the most common pathogen.
Pet e posure is associated with tinea capitis caused by Micros
porum canis.
Tinea capitis occurs mainly in children although it may be
seen at all ages. Boys ha e tinea capitis more re uently than
girls; howe er in epidemics caused by tonsurans both
genders are o ten a ected e ually. A rican American children
ha e a higher incidence o tonsurans in ections than Anglo
Americans. The in ection is also common among Latin Ameri
can children.
richoph ton tonsurans produces blac dot ringworm as well
as subtle seborrheic li e scaling and in ammatory erion.
Blac dot tinea may also be caused by richoph ton violaceum
an organism rarely seen in the nited States. Both o these
organisms produce chains o large spores within the hair sha t
(large spore endothri ) ( ig. ). They do not produce uo
rescence with Wood s light.
The Microsporum canis comple includes a group o organ
isms that produce small spores isible on the outside o the
hair sha t (small spore ectothri ). These ungi uoresce under
Wood s light e amination. The M canis comple includes
M canis M canis istortum Microsporum ferrugineum and
M au ouinii. M canis in ections begin as scaly erythematous
papular eruptions with loose and bro en o hairs. The lesions
typically become highly in ammatory although M au ouinii
Fig. 15-1 Black dot ringworm.
286
tahir99 - UnitedVRG
is less prone to produce in ammatory lesions. Deep tender
boggy pla ues e uding pus are nown as erion celsii ( ig.
). erion may be ollowed by scarring and permanent
alopecia in the areas o in ammation and suppuration. Sys
temic corticosteroids or a short period along with appropri
ate anti ungal therapy will greatly diminish the in ammatory
response and reduce the ris o scarring and this therapy
should be considered in the patient with highly in ammatory
lesions.
Asymptomatic carriers o tonsurans are common and
represent a source o in ection or classmates and siblings.
umerous studies ha e shown that o urban children
in Western countries ha e positi e scalp dermatophyte cul
tures. n one study o children with a positi e scalp
culture were asymptomatic. All these children were A rican
American.
The pre alence o dermatophytes aries throughout the
world. Where animal herding is an important part o the
economy oonotic ungi account or a signi cant proportion
o cases o tinea. n Asia organisms ary signi cantly by
region. n a study o ra i schoolchildren with tinea capitis
richoph ton verrucosum was the most common organism. Both
rubrum and mentagroph tes ar. mentagroph tes were more
common than tonsurans. n south central Asia violaceum
is the most common dermatophytic species isolated with M
au ouinii a close second. ther common organisms include
richoph ton schoenleinii tonsurans Microsporum g pseum
verrucosum and mentagroph tes n ast Asia violaceum
and M ferrugineum are important pathogens. n urope
A rican and Caribbean immigrants account or a large propor
tion o new patients with tinea capitis. mportant pathogens
include tonsurans M au ouinii ar. langeronii richoph ton
sou anense and violaceum richoph ton megninii is a rare
cause o tinea capitis largely restricted to southwestern urope.
n A rica large scale epidemics are associated with sou a
nense violaceum schoenleinii and Microsporum spp. n
Australia the predominantly white population e periences
in ections mostly with M canis but tonsurans is now e ual
in pre alence in some areas o the continent. Recent immi
grants ha e a high incidence o tinea capitis with organisms
common in their regions o origin. Among A rican and Arab
immigrants sou anense violaceum and M au ouinii are
particularly common.
Favus
a us which is e tremely rare in the nited States appears
chie y on the scalp but may a ect the glabrous s in and nails.
Fig. 15-2 Kerion.
 n the scalp conca e sul ur yellow crusts orm around loose
wiry hairs. Atrophic scarring ensues lea ing a smooth glossy
thin paper white patch. n the glabrous s in the lesions are
pinhead to cm in diameter with cup shaped crusts called
scutulae usually pierced by a hair as on the scalp. The scutulae
ha e a distincti e mousy odor. When the nails are a ected
they become brittle irregularly thic ened and crusted under
the ree margins.
a us among the Bantus in South A rica is called in A ri
aans wit op (whitehead). t is also pre alent in the iddle
ast southeastern urope and the countries bordering the
editerranean Sea.
Pathogenesis and natural history
The incubation period o anthropophilic tinea capitis lasts
days although the period is highly ariable and asymptom
atic carriers are common. The hyphae grow downward into
the ollicle on the hair s sur ace and the intra ollicular hyphae
brea up into chains o spores. There is a period o spread (
days to months) during which the lesions enlarge and new
lesions appear. At about wee s hairs brea o a ew milli
meters abo e the s in sur ace. Within the hair hyphae descend
to the upper limit o the eratogenous one and here orm
Adamson ringe on about the th day. o new lesions
de elop during the re ractory period ( months to se eral
years). The clinical appearance is constant with the host and
parasite at e uilibrium. This is ollowed by a period o in olu
tion in which the ormation o spores gradually diminishes.
oonotic ungal in ections o ten are more highly in ammatory
but undergo similar phases o e olution.
Diagnosis
-
Wood’s light
ltra iolet ( V) light o nm wa elength is obtained by
9
passing the beam through a Wood s lter composed o nic el
o ide containing glass. This apparatus commonly nown as
ri 9
the Wood s light is used to demonstrate ungal uorescence.
luorescent positi e in ections are caused by M au ouinii M
canis M ferrugineum M istortum and schoenleinii n a
dar room the s in under this light uoresces aintly blue and
h
dandru usually is bright blue white. n ected hair uoresces
bright green or yellow green. The uorescent substance is a
t a
pteridine. Large spore endothri organisms (e.g. tonsurans
violaceum) and verrucosum (a cause o large spore ecto
thri ) do not uoresce.
Laboratory examination
or demonstration o the ungus in a highly in ammatory
pla ue two or three loose hairs are care ully remo ed with
epilating orceps rom the suspected areas. uorescence
occurs it is important to choose these hairs. Bear in mind that
hairs in ected with tonsurans do not uoresce. n blac dot
ringworm or in patients with seborrheic scale small bro en
ragments o in ected hair will adhere to a moist gau e pad
rubbed across the scalp. The hairs are placed on a slide and
co ered with a drop o a potassium hydro ide ( ) mycelia that are distinctly striate at the periphery while
solution. A co erslip is then applied and the specimen is
warmed until the hairs are macerated. Dimethyl sul o ide
(D S ) can be added to the solution in concentrations
o up to . This additi e allows or rapid clearing o eratin
without heating. nce the hairs ha e so tened they are
compressed through the co erslip and e amined rst with a
low power ob ecti e and then with a high power ob ecti e or
detail. The patterns o endothri and ectothri in ol ement
described earlier together with local pre alence data allow
or identi cation o the organism.
act identi cation o the causati e ungus is generally
Tinea capitis
determined by culture although molecular se uencing o ers
a more rapid alternati e. or culture se eral in ected hairs are
planted on Sabouraud de trose agar Sabouraud agar with
chloramphenicol ycosel agar or dermatophyte test medium
(DT ). Cultures are best collected by rubbing the lesion igor
ously with a moistened cotton swab or gau e pad then strea
ing the cotton o er the agar sur ace. n the rst three media
a distincti e growth appears within wee s. ost re
uently the diagnosis is made by the gross appearance o the
culture growth together with the microscopic appearance.
With richoph ton spp. growth on di erent nutrient agars is
o ten re uired to identi y the organisms beyond genus. DT
not only contains antibiotics to reduce growth o contami
nants but also contains a colored p indicator to denote the
al ali producing dermatophytes. A ew nonpathogenic sapro
G
phytes will also produce al alini ation and in the occasional
case o onychomycosis o toenails caused by airborne molds
R
a culture medium containing an antibiotic may inhibit growth
o the true pathogen.
V
Trichophyton tonsurans
d
richoph ton tonsurans grows slowly in culture to produce a
granular or powdery yellow to red brown or bu colony.
ti e
Crater ormation with radial groo es may be produced.
Swollen microconidia may be seen regularly. Diagnosis is con
rmed by cultures growing poorly or not at all without
thiamine.
n
Trichophyton mentagrophytes
U
The mentagroph tes colony is el ety granular or u y. t
may be at or urrowed light bu white or sometimes pin .
The bac o the culture can ary rom bu to dar red. Round
microconidia borne laterally and in clusters con rm the
diagnosis within wee s. Spiral hyphae are sometimes
prominent.
Trichophyton verrucosum
Growth is slow and cannot be obser ed well or at least
wee s. The verrucosum colony is compact glassy el ety
heaped or urrowed and usually white but may be yellow or
gray. The colony may crac the agar. Chlamydospores (round
swellings along the hyphal structure) are present in early cul
tures and microconidia may be seen.
Microsporum audouinii
Culture o M au ouinii typically shows a slowly growing
matted el ety light brown colony the bac o which is
reddish brown to orange. The colony edge is generally striate
rather than smooth. icroscopically a ew large multisep
tate macroconidia may be seen. icroconidia in a lateral
position on the hyphae are cla ate. Rac uet mycelia termi
nal chlamydospores and pectinate hyphae are sometimes
seen.
Microsporum canis
The M canis culture grossly shows pro use cottony aerial
sometimes tending to become powdery in the center.
The color is bu to light brown. The bac o the colony is
lemon to orange yellow. There are numerous spindle shaped
thic walled echinulate macroconidia. Cla ate microconidia
may be ound along with chlamydospores and pectinate
bodies.
287
 Differential diagnosis
15 Tinea capitis must be di erentiated clinically rom chronic
staphylococcal olliculitis pediculosis capitis psoriasis sebor
rheic dermatitis secondary syphilis trichotillomania alopecia
Diseases Resulting from Fungi and Yeasts
areata lupus erythematosus (L ) lichen planus lichen simple
chronicus and arious in ammatory ollicular conditions. The
distincti e clinical eatures o tinea capitis are bro en o
stumps o hairs o ten in rounded patches in which there are
crusts or pustules and ew hairs. The bro en o hairs are loose
and when e amined are ound to be surrounded by or to
contain the ungus. Di use seborrheic scaling with hair loss
is a common presentation o tonsurans in ections.
n alopecia areata the a ected patches are bald and the s in
is smooth and shiny without signs o in ammation or scaling.
Stumps o bro en o hairs are in re uently ound and no
ungi are demonstrable. n seborrheic dermatitis the in ol ed
areas are co ered by ne dry or greasy scales. air may be
lost but the hairs are not bro en. Atopic dermatitis is rarely
associated with locali ed scalp in ol ement and clinical
e amination re uently re eals more typical generali ed nd
ings. n psoriasis well demarcated sometimes di use areas
o erythema and white or sil er scaling are noted. Lichen
simple chronicus is re uently locali ed to the in erior margin
o the occipital scalp. n trichotillomania as in alopecia areata
in ammation and scaling are absent. Circumscribed lesions
are ery rare. Serologic testing scalp biopsies and immuno
uorescent studies may be indicated i the alopecia o second
ary syphilis or lupus erythematosus is a serious consideration.
t should be noted that adult patients with L are susceptible
to tinea capitis which may be photosensiti e and di cult
to distinguish rom L pla ues without biopsy and
e aminations.
Treatment
umerous clinical trials ha e demonstrated the e ecti eness
o itracona ole terbina ne and ucona ole. Despite these
studies griseo ul in remains the most re uently used anti
ungal agent in children. t has a long sa ety record and pedia
tricians and amily practitioners are generally com ortable
with griseo ul in. A meta analysis o published studies shows
mean e cacy or griseo ul in treatment o about or
richoph ton spp. and or Microsporum or the ultrami
croni ed orm doses start at mg g day. The tablets can
be crushed and gi en with ice cream. Gri ul in V oral suspen
sion is less readily absorbed. The dose is mg g day.
Treatment should continue or months or or at least
wee s a ter negati e laboratory e aminations are obtained.
Doses much higher than those re ected in drug labeling are
o ten needed. or richoph ton in ections terbina ne is usually
e ecti e in doses o mg g day or wee s. Alternate
dosing schedules or terbina ne include one mg tablet or
patients o er g mg ( 1 2 tablet) or those g and
. mg ( 1 4 tablet) or those under g. Microsporum in ec
tions re uire higher doses and longer courses o therapy with
terbina ne. tracona ole has been shown to be e ecti e in
doses o mg g day or wee s and ucona ole at doses
o mg g day or wee s per orming almost as well as
griseo ul in. Reports o heart ailure with itracona ole ha e
limited its use.
Selenium sul de shampoo or etocona ole shampoo le t
on the scalp or min three times a wee can be used as
ad uncti e therapy to oral anti ungal agents to reduce the
shedding o ungal spores. Combs brushes and hats should
be cleaned care ully and natural bristle brushes must be
discarded.
288
tahir99 - UnitedVRG
Prognosis
Recurrence is uncommon when ade uate amounts o griseo
ul in ucona ole or terbina ne ha e been ta en although
e posure to in ected persons asymptomatic carriers or con
taminated omites will increase the relapse rate. Without med
ication there is spontaneous clearing at about age years
e cept with tonsurans which o ten persists into adult li e.
DERMATOPHYTIDS
n cases o in ammatory tinea capitis widespread id erup
tions may appear concomitantly on the trun and e tremities.
These are esicular lichenoid papulos uamous or pustular and
represent a systemic reaction to ungal antigens. Although the
eruptions are usually re ractory to topical corticosteroids they
typically clear rapidly a ter treatment o the ungal in ection.
The most common type o id reaction is seen on the hands
and sides o the ngers when there is an acute ungus in ection
o the eet. These lesions are mostly esicular and are e tremely
pruritic and e en tender. Secondary bacterial in ection may
occur; howe er ungus is not demonstrable in a true derma
tophytid. The onset can be accompanied by e er anore ia
generali ed adenopathy spleen enlargement and leu ocyto
sis. Dermatophytid reactions rom in ammatory tinea capitis
may occasionally present as widespread eruption usually ol
licular lichenoid or papulos uamous. Rarely the eruption
may be morbilli orm or scarlatini orm. The erysipelas li e der
matophytid is most re uently seen on the shin where it
appears as an ele ated sharply de ned erysipelas li e pla ue
about the si e o the hand usually with toe web tinea on the
same side. This orm o id reaction responds to systemic cor
ticosteroids and treatment o the tinea.
The histologic picture is characteri ed by spongiotic esicles
and a super cial peri ascular predominantly lymphohistio
cytic in ltrate. osinophils may be present. Diagnosis o a
dermatophytid reaction depends on the demonstration o a
ungus at some site remote rom the suspect lesions o the
dermatophytid the absence o ungus in the id lesion and
in olution o the lesion as the ungal in ection subsides.
TINEA BARBAE
Ringworm o the beard also nown as tinea sycosis and bar
ber s itch is not a common disease. t occurs chie y among
those in agricultural pursuits especially those in contact with
arm animals. The in ol ement is mostly one sided on the
nec or ace. Two clinical types are distinguished deep
nodular suppurati e lesions and super cial crusted partially
bald patches with olliculitis ( ig. ).
Fig. 15-3 Tinea
barbae.
 The deep type de elops slowly and produces nodular thic
enings and erionli e swellings usually caused by mentag
roph tes or verrucosum As a rule the swellings are con uent
and orm di use boggy in ltrations with abscesses. The o er
lying s in is in amed the hairs are loose or absent and pus
may be e pressed through the remaining ollicular openings.
Generally the lesions are limited to one part o the ace or
nec in men. The super cial crusted type is characteri ed by
a less in ammatory pustular olliculitis and may be associated
with violaceum or rubrum The a ected hairs can some
times be easily e tracted. Rarely Epi ermoph ton occosum
may cause widespread errucous lesions nown as errucous
epidermophytosis.
Diagnosis
The clinical diagnosis o tinea barbae is con rmed by the
microscopic mounts o e tracted hairs or a biopsy specimen.
Culture can be per ormed on e tracted hairs or tissue homog
enates o biopsy specimens.
Differential diagnosis
The di erential diagnosis includes staphylococcal olliculitis
(sycosis ulgaris) and herpetic in ections. Tinea barbae di ers
rom sycosis ulgaris by usually sparing the upper lip and by
o ten being unilateral. n sycosis ulgaris the lesions are pus
tules and papules pierced in the center by a hair which is
loose and easily e tracted a ter suppuration has occurred. er
petic in ections usually demonstrate umbilicated esicles.
T anc preparations ha e a low diagnostic yield but iral
culture or direct uorescent antibody is irtually always
positi e.
-
Treatment
9
As in tinea capitis oral anti ungal agents are re uired to cure
tinea barbae. Topical agents are only help ul as ad uncti e
ri 9
therapy. ral agents are used in the same doses and or the
same durations as in tinea capitis.
h
TINEA FACIEI
t a
ungal in ection o the ace is re uently misdiagnosed ( ig.
). Typical annular rings are usually lac ing and the lesions
Fig. 15-4 Tinea faciei.
are e uisitely photosensiti e. re uently a misdiagnosis
o L is made. Biopsies or direct immuno uorescence o ten
demonstrate some reactants on sun e posed s in adding
to the possible diagnostic con usion. rythematous slightly
scaling indistinct borders may be present at the periphery o
Tinea corporis (tinea circinata)
the lesions and are the best location or e amination.
topical corticosteroids ha e been used ungal olliculitis is a
re uent nding. A biopsy may be re uired to establish the
diagnosis. A high inde o suspicion is re uired because
ungal hyphae may be ew in number or con ned to hair ol
licles. The in ammatory pattern may be psoriasi orm spongi
otic or acuolar inter ace. The latter pattern has the potential
to perpetuate con usion with L .
sually the in ection is caused by rubrum mentagro
ph tes or M canis Tinea aciei caused by Microsporum nanum
has been described in hog armers. ungal olliculitis is
present oral medication is re uired. no olliculitis is present
the in ection generally responds well to topical therapy. ral
agents are appropriate or widespread in ections.
G
TINEA CORPORIS (TINEA CIRCINATA)
V R
Tinea corporis includes all super cial dermatophyte in ec
tions o the s in other than those in ol ing the scalp beard
ace hands eet and groin. This orm o ringworm is
d
characteri ed by one or more circular sharply circumscribed
slightly erythematous dry scaly usually hypopigmented
ti e
patches. An ad ancing scaling edge is usually prominent ( ig.
). Progressi e central clearing produces annular outlines
that gi e them the name ringworm. Lesions may widen to
orm rings many centimeters in diameter. n some cases con
n
centric circles or polycyclic lesions orm ma ing intricate pat
terns. Widespread tinea corporis may be the presenting sign
U
o ac uired immunode ciency syndrome (A DS) or may be
related to the use o a topical corticosteroid or calcineurin
inhibitor.
n the nited States rubrum M canis and mentagro
ph tes are common causes although in ection can be caused
by any o the dermatophytes. ultiple small lesions are
usually caused by e posure to a pet with M canis ther
oonotic ungi such as granular oophilic mentagroph tes
related to Southeast Asian bamboo rats can cause widespread
epidemics o highly in ammatory tinea corporis.
Tinea gladiatorum is a common problem or wrestlers. n
Pennsyl ania during the wrestling season about
o responding teams had at least one wrestler diagnosed
with ringworm despite that used pre enti e practices.
ne third o these teams reported that a wrestler missed a
Fig. 15-5 Tinea corporis.
289
 match because o the in ection. pponents e uipment and
15 mats represent potential sources o in ection.
Diagnosis
Diseases Resulting from Fungi and Yeasts
The diagnosis o tinea corporis is relati ely easy to ma e by
nding the ungus under the microscope in s in scrapings. n
addition s in scrapings can be cultured on a suitable medium.
Growth o the ungus on culture medium is apparent within
wee or wee s at most and in most cases is identi able to
the genus le el by the gross and microscopic appearance o
the culture. (Biopsy o a chronic re ractory dermatosis o ten
re eals tinea incognito.)
ther diseases that may closely resemble tinea corporis are
pityriasis rosea impetigo nummular dermatitis secondary
and tertiary syphilids seborrheic dermatitis and psoriasis.
These are distinguished by e amination and culture.
Treatment
Locali ed disease without ungal olliculitis may be treated
with topical therapy. Sulcona ole ( elderm) o icona ole
( istat) micona ole ( onistat cream or lotion or icatin
cream) clotrima ole (Lotrimin or ycele cream) econa ole
(Specta ole) na ti ne ( a tin) etocona ole ( i oral)
ciclopiro olamine (Lopro ) terbina ne (Lamisil) e nacon
a ole and butena ne ( enta ) are currently a ailable and
e ecti e. ost treatment times are between and wee s with
twice daily use. cona ole etocona ole o icona ole and ter
bina ne may be used once a day. With terbina ne the course
can be shortened to wee . Combination products with a
potent corticosteroid such as clotrima ole betamethasone re
uently produce widespread tinea and ungal olliculitis. Their
use should be discouraged.
tensi e disease or ungal olliculitis re uires systemic
anti ungal treatment. When tinea corporis is caused by ton
surans mentagroph tes or rubrum griseo ul in terbin
a ne itracona ole and ucona ole are all e ecti e. Shorter
courses are possible with newer anti ungals. Terbina ne
therapy or M canis typically re uires higher doses and longer
courses o therapy.
The ultramicroni ed orm o griseo ul in may be e ecti e
in doses o mg day or wee s. Appro imately
o patients will e perience nausea or headache with gris
eo ul in. These symptoms typically respond to a temporary
reduction in dosage. Absorption o griseo ul in is impro ed
when gi en with whole mil or ice cream. ecti e blood
le els in children occur at doses o mg g day although
higher doses are o ten needed. Terbina ne mg day or
wee s; itracona ole mg day or wee ; and ucon
a ole mg once wee ly or wee s ha e been e ecti e in
adults.
Other forms of tinea corporis
Fungal folliculitis (Majocchi granuloma)
and tinea incognito
ccasionally a deep pustular type o tinea circinata resem
bling a carbuncle or erion is obser ed on the glabrous s in
( ig. ). This type o lesion is a ungal olliculitis caused
most o ten by rubrum or mentagroph tes in ecting hairs at
the site o in ol ement. t presents as a circumscribed annular
raised crusty and boggy granuloma in which the ollicles are
290
tahir99 - UnitedVRG
Fig. 15-6 Majocchi granuloma.
distended with iscid purulent material. These occur most
re uently on the shins or wrists. The lesions are o ten seen in
areas o occlusion or sha ing or when a topical corticosteroid
has been used. n immunosuppressed patients the lesions
may be deep and nodular. ten patients ha e been treated
with a shotgun approach using both topical corticosteroids
and anti ungal agents. a topical anti ungal has been used
recently e amination and culture may be negati e. A
biopsy may be re uired to establish the diagnosis. ral therapy
is necessary to cure the lesions.
Tinea incognito is a term applied to atypical clinical lesions
o tinea usually produced by treatment with a topical cortico
steroid or occasionally a calcineurin inhibitor. The lesions are
o ten widespread and may lac an ad ancing raised scaly
border. The diagnosis may be established by e amina
tion or biopsy.
Tinea imbricata (Tokelau)
Tinea imbricata is a super cial ungal in ection limited to
southwest Polynesia elanesia Southeast Asia ndia and
Central America. t is characteri ed by concentric rings o
scales orming e tensi e patches with polycyclic borders. ry
thema is typically minimal. The eruption begins with one or
se eral small rounded macules on the trun and arms. The
small macular patch splits in the center and orms large a y
scales attached at the periphery. As the resultant ring spreads
peripherally another brownish macule appears in the center
and undergoes the process o splitting and peripheral e ten
sion. This cycle is repeated o er and o er again. When ully
de eloped the eruption is characteri ed by concentrically
arranged rings or parallel undulating lines o scales o erlap
ping each other li e shingles on a roo (imbrex means shingle ).
The causati e ungus is richoph ton concentricum although
a similar pattern may be produced by mentagroph tes and
tonsurans. icroscopically the scrapings show interlacing
septate mycelial laments that branch dichotomously. Poly
hedral spores are also present. Griseo ul in has been used but
the recurrence rate is high. n one study terbina ne mg
day or wee s was e ecti e in all o patients with tinea
imbricata. tracona ole at a dose o mg day ailed in o
patients but this may re ect the dose used in the study.
Tinea cruris
Tinea cruris also nown as oc itch and crotch itch occurs
most re uently in men on the upper and inner sur aces o the
thighs especially during the summer when the humidity is
high. t begins as a small erythematous and scaling or

Fig. 15-7 Tinea cruris.
esicular and crusted patch that spreads peripherally and
partly clears in the center so that the patch is characteri ed
chie y by its cur ed well de ned border particularly on its
lower edge ( ig. ). The border may ha e esicles pustules
or papules. t may e tend downward on the thighs and bac
ward on the perineum or about the anus. The scrotum is rarely
in ol ed.
Etiology and differential diagnosis
Ringworm o the groin is usually caused by rubrum
mentagroph tes or E occosum n ection with Can i a albicans
may closely mimic tinea cruris but is usually moister more
in ammatory and associated with satellite macules. Can i a
o ten produces collarette scales and satellite pustules.
The crural region is also a common site or erythrasma seb
orrheic dermatitis pemphigus egetans and intertriginous
psoriasis. rythrasma o ten has a copper color and is diag
-
nosed by Wood s light e amination which produces coral red
uorescence. Seborrheic dermatitis generally in ol es the
central chest and a illae in addition to the groin. Pemphigus
9
egetans produces macerated and eroded lesions. Diagnosis o
tinea cruris is established by biopsy and immuno uorescence.
ri 9
n erse psoriasis may be associated with collarette scales or
with serpiginous arrays o pustules at the border o in amma
tory lesions. When more typical lesions o psoriasis are lac ing
a biopsy may be re uired to establish the diagnosis.
h
Treatment
t a
The reduction o perspiration and enhancement o e apora
tion rom the crural area are important prophylactic measures.
The area should be ept as dry as possible by the wearing o
loose underclothing and trousers. Plain talcum powder or
anti ungal powders are help ul. Speci c topical and oral treat
ment or tinea cruris is the same as that described earlier or
tinea corporis.
TINEA OF HANDS AND FEET
Dermatophytosis o the eet long popularly called athlete s
oot is by ar the most common ungal disease. rubrum
causes the ma ority o in ections and there may be an autoso
mal dominant predisposition to this orm o in ection.
rubrum typically produces a relati ely nonin ammatory type
o dermatophytosis characteri ed by a dull erythema and pro
nounced sil ery scaling that may in ol e the entire sole and
sides o the oot gi ing a moccasin or sandal appearance. ne
hand may be in ol ed. The eruption may also be limited to a
small patch ad acent to a ungus in ected toenail or to a patch
Fig. 15-8 One hand of
“two foot, one hand”
fungal infection; both
feet were infected.
Tinea of hands and feet
G
R
V
d
ti e
n
U
Fig. 15-9 Bullous tinea.
between or under the toes. n some patients an e tensi e
patchy scaly eruption co ers most o the trun buttoc s and
e tremities. Rarely there is a patchy hyper eratosis resem
bling errucous epidermal ne us.
Generally tinea in ection o the hands is o the dry scaly
and erythematous type suggesti e o rubrum in ection.
ther areas are re uently a ected at the same time especially
the combination o both eet and one hand ( ig. ). Tinea
pedis caused by anthropophilic mentagroph tes inter igitale
presents with three distinct appearances ( ) multilocular
bullae in ol ing the thin s in o the plantar arch and along the
sides o the eet and heel ( ) erythema and des uamation
between the toes and ( ) white super cial onychomycosis. n
the human immunode ciency irus ( V) positi e popula
tion this latter syndrome is usually caused by rubrum nter
digital tinea must be distinguished rom simple maceration
caused by a closed web space which does not respond to
anti ungal therapy. nterdigital tinea must also be distin
guished rom gram negati e toe web in ection. Diabetic
patients de elop interdigital ungal in ections at a younger age
than patients without diabetes.
richoph ton mentagroph tes o ten produces acutely in am
matory multilocular bullae ( ig. ). The burning and itching
that accompany the ormation o the esicles may cause great
discom ort which is relie ed by opening the tense esicles.
They contain a tenacious clear straw colored uid. tensi e
or acute eruptions on the soles may be incapacitating. The s
sures between the toes as well as the esicles may become
secondarily in ected with pyogenic cocci which may lead to
291
 recurrent attac s o lymphangitis and inguinal adenitis. Gram
15 negati e toe web in ections may also super ene. yperhidro
sis is re uently present in this type o dermatophytosis. The
sweat between the toes and on the soles has a high p and
damp eratin is a good culture medium or the ungi.
Diseases Resulting from Fungi and Yeasts
Dermatophytid o the hands may be associated with in am
matory tinea o the eet and begins with the appearance o
groups o minute clear esicles on the palms and ngers. The
itching may be intense. As a rule both hands are in ol ed
and the eruption tends to be symmetric; in some cases
howe er only one hand is a ected. The dorsa and sides o the
eet may also be a ected.
Diagnosis
Demonstration o the ungus by microscopic e amination o
the scrapings ta en rom the in ol ed site establishes the diag
nosis. Copious dry scale rom the instep heel and sides o the
oot can be gathered by scraping with the edge o a glass
microscope slide. Bullae should be unroo ed and either the
entire roo is mounted intact or scrapings are made rom the
underside o the roo . A drop o a solution is
added to the material on the glass slide. A co erslip is placed
o er the specimen and pressed down rmly. Gentle heat is
applied until the scales are thoroughly macerated. The addi
tion o D S speeds clearing o eratin without the
need or heating. A staining method using mg o chlora ol
blac dye in mL o D S and adding it to a a ueous
solution o can be help ul. Toluidine blue . can also
be used on thin specimens but contains no clearing agent to
dissol e eratin.
The mycelia may be seen under low power microscopy but
better obser ation o both hyphae and spores is obtained by
the × ob ecti e with the condenser cran ed down or the light
aperture closed by two thirds ( ig. ). The lines o uncture
o normal epidermal cells dissol e into a branching networ
that may easily be mista en or ungus structures ( mosaic
alse hyphae ). This is the most common arti act misinter
preted as a positi e e amination. Cotton and synthetic
bers rom soc s may also mimic hyphae.
aterial may also be placed on Sabouraud de trose agar
Sabouraud agar with chloramphenicol ycosel agar or DT .
The last three agars inhibit growth o bacterial or saprophytic
contaminants. The last two may inhibit some pathogenic non
dermatophytes. The al aline metabolites produced by growth
o dermatophytes change the color o the p indicator in DT
medium rom yellow to red.
Fig. 15-10 Positive KOH examination.
292
tahir99 - UnitedVRG
Prophylaxis
yperhidrosis is a predisposing actor or tinea in ections.
Because the disease o ten starts on the eet the patient should
be ad ised to dry the toes thoroughly a ter bathing. Cold
water laundering does not inacti ate ungal elements in soc s
which may ser e as a source o recoloni ation. Dryness is
essential to reduce the incidence o symptomatic rein ection.
The use o a good antiseptic powder on the eet a ter bathing
particularly between the toes is strongly ad ised or suscep
tible persons. Tolna tate powder (Tinactin) or easorb medi
cated powder is an e cellent dusting powder or the eet. Plain
talc cornstarch or rice powder may be dusted into soc s and
shoes to eep the eet dry. Periodic use o a topical anti ungal
agent may be re uired especially when hot occlusi e ootwear
is worn.
Treatment
Clotrima ole micona ole sulcona ole o icona ole ciclopiro
econa ole etocona ole na ti ne terbina ne utrima ol
bi ona ole e nacona ole and butena ne are e ecti e topical
anti ungal agents. When there is signi cant maceration
between the toes the toes may be separated by oam or cotton
inserts in the e ening. Aluminum chloride solution or
aluminum acetate part to parts o water can be bene cial.
nterdigital tinea can also be treated with anti ungal
impregnated soc s. Topical antibiotic ointments such as gen
tamicin (Garamycin) that are e ecti e against gram negati e
organisms are help ul additions in some moist interdigital
lesions. n the ulcerati e type o gram negati e toe web in ec
tions systemic antibiotic therapy is necessary (see Chapter ).
eratolytic agents containing salicylic acid resorcinol lactic
acid and urea may be use ul in some cases although all may
lead to maceration i occluded.
Treatment o ungal in ection o the s in o the eet and
hands with griseo ul in mg day can be e ecti e.
Dosage or children is mg g day. The period o
therapy depends on the response o the lesions. Repeated
scrapings and cultures should be negati e. uch shorter
courses are possible with newer anti ungal agents. Recom
mended adult dosing or terbina ne is mg day or
wee s; or itracona ole mg twice daily or wee ; and or
ucona ole mg once wee ly or wee s. Abbre iated
schedules and intermittent dosing with other agents may be
possible but re uire urther study. n one small study itracon
a ole mg twice daily was gi en immediately a ter meals
on consecuti e days. The regimen produced good to e cel
lent responses in all patients within days.
Onychomycosis (tinea unguium)
nychomycosis is de ned as the in ection o the nail plate by
ungus and represents up to o diagnosed super cial
ungal in ections. rubrum accounts or most cases but many
ungi may be causati e. ther etiologic agents include E oc
cosum and arious species o Microsporum and richoph ton
ungi. t may also be caused by yeasts and nondermatophytic
molds.
The our classic types o onychomycosis are as ollows
. Distal subungual onychomycosis primarily in ol es the
distal nailbed and the hyponychium with secondary
in ol ement o the underside o the nail plate o
ngernails and toenails ( ig. ). t is usually caused
by rubrum

Fig. 15-11 Distal subungual onychomycosis and tinea pedis.
Fig. 15-12 White
proximal subungual
onychomycosis.
-
. White super cial onychomycosis (leu onychia
trichophytica) is an in asion o the toenail plate on the
9
sur ace o the nail. t is produced by mentagroph tes
ri 9
Cephalosporium spergillus and usarium ox sporum
ungi. n the V positi e population it is typically
caused by rubrum
. Pro imal subungual onychomycosis in ol es the nail
h
plate mainly rom the pro imal nail old producing a
speci c clinical picture ( ig. ). t is produced by
a
rubrum and richoph ton megninii and may be an
t
indication o V in ection.
. Can i a onychomycosis produces destruction o the nail
and massi e nail bed hyper eratosis. t is caused by
C albicans and is seen in patients with chronic
mucocutaneous candidiasis.
nychomycosis caused by rubrum usually starts at the
distal corner o the nail and in ol es the unction o the nail
and its bed. A yellowish discoloration occurs which spreads
pro imally as a strea in the nail. Later subungual hyper era
tosis becomes prominent and spreads until the entire nail is
a ected. Gradually the entire nail becomes brittle and sepa
rated rom its bed as a result o the piling up o subungual
eratin. ingernails and toenails present a similar appearance
and the s in o the soles is li ely to be in ol ed with charac
teristic branny scaling and erythema.
nychomycosis caused by mentagroph tes is usually
super cial and there is no paronychial in ammation. The
in ection generally begins with scaling o the nail under
the o erhanging cuticle and remains locali ed to a portion o
the nail. n time howe er the entire nail plate may be in ol ed.
White super cial onychomycosis is the name gi en to one type
o super cial nail in ection caused by this ungus in which
small chal y white spots appear on or in the nail plate. These
are so super cial that they may be easily sha ed o . viola
Tinea of hands and feet
ceum schoenleinii and tonsurans occasionally in ade the
nails as does richosporon beigelii
Scopulariopsis brevicaulis has been in re uently isolated rom
onychomycosis. n ection usually begins at the lateral edge o
the nail burrows beneath the plate and produces large uanti
ties o cheesy debris. attrassia mangiferae en ersonula toru
loi ea and Sc tali ium h alinum ha e been reported to cause
onychomycosis as well as a moccasin type tinea pedis. n
addition to the more common eatures o onychomycosis such
as nail plate thic ening opaci cation and onycholysis ea
tures o in ection with these ungi include lateral nail in asion
alone paronychia and trans erse racture o the pro imal nail
plate. When these agents are suspected culture must be done
with a medium that does not contain cyclohe imide ( ound in
ycosel agar). ral etocona ole and griseo ul in are not
G
e ecti e in the treatment o these organisms.
The pathogen is hea ily in uenced by heredity geography
R
and ootwear. n the nited States most tinea pedis and ony
chomycosis are caused by rubrum n a rural school in
V
e ico where most people wear nonocclusi e leather sandals
richosporon cutaneum Can i a spp. and mentagroph tes
d
accounted or most in ections. rubrum was not isolated in
any patient. Cutaneous Sc tali ium in ections are common in
ti e
patients rom the tropics especially the West ndies and A rica.
They usually carry the organism with them e en when they
emigrate to more temperate climates.
n
Diagnosis
U
The demonstration o ungus is made by microscopic e ami
nation or by culture. The submitted clippings or curettings
must include dystrophic subungual debris. Samples obtained
by a drilling techni ue may ha e a higher yield than those
obtained by curettage. mmediate e amination may be made
i ery thin sha ings or curettings are ta en rom the diseased
nail bed and e amined with solution with or without an
added stain. istologic e amination polymerase chain reac
tion (PCR) and calco uor white microscopy and culture ha e
also been used.
istopathologic e amination with periodic acid Schi
(PAS) stain has been ound to be sensiti e in arious
studies. t has pro ed more sensiti e than either or
culture in se eral studies. n one study in which histology was
sensiti e dissolution and centri ugation combined
with PAS was sensiti e with calco uor white uorescent
staining and chlora ol blac were each sensiti e. mmu
no uorescent microscopy without calco uor white is compa
rable to PAS staining but high bac ground eosin uorescence
can ma e the sections di cult to read. Culture on Sabouraud
agar with chloramphenicol and cyclohe imide ( ycosel) agar
was sensiti e. ther studies ha e shown the sensiti ity
o culture to be . Combining and culture has
yielded sensiti ities in the range o .
Both o ce and central laboratories can be used to isolate
ungi but alse negati e results are common in both settings.
n one study o ce DT culture was positi e in o
patients ( ) and the central laboratory detected the
in ection in o ( ). The two tests were in agreement
(both positi e or both negati e) in o patients ( ).
n a similar study DT cultures were positi e in (n =
) and central laboratory cultures were positi e in
(n = ). The two cultures were in agreement in o cases.
Dermatophytes accounted or about o the con rmed
293
 in ections in each study. PCR is emerging as an alternati e
15 method o detection.
Because no single method o ers sensiti ity a ariety
o methods are still in use. has the ad antage o being
per ormed rapidly in the o ce. istologic e amination usually
Diseases Resulting from Fungi and Yeasts
pro ides results within h whereas culture can ta e days to
wee s. denti cation o genus and species is only possible
with culture or PCR.
Differential diagnosis
Dystrophic nails can be produced by psoriasis lichen planus
ec ema and contact dermatitis and may be clinically indis
tinguishable rom ungal nails. Con rmatory tests to identi y
the ungus are mandatory to establish a diagnosis. Psoriasis
may in ol e other nails with pitting onycholysis oil spots
and salmon patches or by heaped up subungual eratini a
tion. Typical eatures o psoriasis may be present on other
areas o s in. Lichen planus may produce rough nails or
pterygium ormation and may in ol e the oral mucosa or
s in. c ema and contact dermatitis a ect the ad acent nail
old. yper eratotic ( orwegian ) scabies can also produce
dystrophic nails but this is associated with generali ed
hyper eratosis.
nychomycosis among psoriasis patients is reported with
arying pre alence but occurs in about compared
with or patients with other s in diseases. nychomyco
sis occurs more re uently in men than in women with
psoriasis.
Treatment
any patients with onychomycosis are not symptomatic and
may not see treatment. Patients with diabetes or peripheral
neuropathy may be at higher ris or complications related to
onychomycosis and the bene ts o treatment may be greater
in this population. These actors as well as cost ris o recur
rence and spread to other amily members should be consid
ered as part o the decision to treat onychomycosis.
The topical management o onychomycosis has impro ed
with the introduction o ciclopiro and amorol ne nail lac
uers. These agents are modestly e ecti e at moderate cost. A
lac uer containing encecalin e tract o geratina pichinchensis
e nacona ole and topical bi ona ole ollowing urea ablation
also appear promising. ost other topical agents are o
minimal bene t and no topical agent achie es the cure rates
possible with oral therapy.
or disease in ol ing ngernails terbina ne is gi en in
doses o mg day or wee s. or toenails the course o
treatment is generally wee s. tracona ole is generally
gi en as pulsed dosing mg twice daily or wee o each
month or months when treating ngernails and or
months when treating toenails. lucona ole mg once
wee ly or months appears to be e ecti e. Albacona ole
also appears promising. About o patients will not respond
to treatment. The presence o a dermatophytoma within the
nail may be associated with a higher ris o ailure. Dermato
phytomas present as yellow strea s within the nail and
may respond to unroo ng and curettage. Recurrence rates
may be lower with itracona ole than with terbina ne mono
therapy and combined therapy does not result in a lower rate
o recurrence.
Se eral studies suggest that continuous therapy with terbin
a ne or months is cost e ecti e compared with other pos
sible agents and regimens. ost clinical trials ha e been
industry sponsored howe er and little independent research
is a ailable or re iew. or onychomycosis in children topical
294
tahir99 - UnitedVRG
treatment with ciclopiro lac uer may be more e ecti e
than in adults and may be worth a clinical trial. Terbina ne
itracona ole and ucona ole ha e all been shown to be e ec
ti e. Dosage depends on body weight as pre iously indicated.
Duration o treatment is the same as or adults.
Treatment with systemic anti ungals is generally e ecti e in
onychomycosis caused by spergillus spp. Scopulariopsis brevi
caulis and usarium spp. in ection is di cult to eradicate and
treatment with both systemic anti ungals and topical nail lac
uers may be appropriate. ail a ulsion represents another
option. Can i a onychomycosis is always a sign o immuno
depression. Systemic treatment with itracona ole or ucon
a ole is usually e ecti e but relapses are the rule. When
treating Can i a in ections combinations o topical and sys
temic treatment can be used or synergistic e ect. The combi
nation o topical amorol ne and oral itracona ole which
inter eres with di erent steps o ergosterol synthesis has been
shown to e hibit substantial synergy in this setting. Combina
tion treatment with topical amorol ne and two pulses o itra
cona ole may be as e ecti e as three pulses o itracona ole
with lower cost.
The .S. ood and Drug Administration ( DA) has issued a
health ad isory to announce serious ris s associated with the
use o itracona ole and terbina ne. The ad isory states that
both ha e been associated with serious li er problems result
ing in li er ailure the need or transplantation and death.
There is a small but real ris o de eloping congesti e heart
ailure associated with the use o itracona ole. Terbina ne has
been associated with subacute cutaneous L . Signi cant drug
interactions may occur in patients ta ing itracona ole who are
also treated with drugs metaboli ed by the C P pathway.
nteractions with terbina ne and the tricyclic antidepressant
desipramine ha e been reported.
tracona ole pulsed treatment has been shown to ha e a low
incidence o li er unction abnormalities (alanine transami
nase ALT aspartate transaminase AST al aline phospha
tase total bilirubin). Product labeling recommends li er
unction tests (L Ts) or patients recei ing continuous itracon
a ole or periods e ceeding month. onitoring is re uired
or the pulsed regimen i the patient has a history o hepatic
disease has abnormal baseline L Ts or de elopment o signs
or symptoms suggesti e o li er dys unction. Phenobarbital
shows potential or the cytoprotection o hepatocytes to
itracona ole induced but not ucona ole induced cytoto ic
ity in itro suggesting the possibility o regimens to reduce
the ris o to icity urther.
olds are sensiti e to o one gas V light and isible light.
rubrum in culture has been shown to be susceptible to VC
radiation photodynamic therapy (PDT) psoralen with VA
(P VA) and arious orms o laser light. owe er the mech
anism o action and degree o e ecti eness o these therapies
re uire urther study. or PDT with broad band white light
the phthalocyanines and Photo rin displayed a ungistatic
e ect whereas porphyrins caused photodynamic illing o the
dermatophyte. ris( methylpyridinium) phenyl
( ) porphine trichloride and deuteroporphyrin mono
methylester showed superior results in itro. urther study o
arious methods o phototherapy is warranted.
Barot BS, et al: Drug delivery to the nail: therapeutic options and
challenges for onychomycosis. Crit Rev Ther Drug Carrier Syst 2014;
31:459–494.
Becker C, et al: Lasers and photodynamic therapy in the treatment of
onychomycosis: a review of the literature. Dermatol Online J 2013;
19(9):19611.
Bonifaz A, et al: Dermatophyte isolation in the socks of patients
with tinea pedis and onychomycosis. J Dermatol 2013;
40(6):504–505.
 Bristow IR: The effectiveness of lasers in the treatment of
onychomycosis: a systematic review. J Foot Ankle Res 2014; 7:34.
Carney C, et al: Treatment of onychomycosis using a submillisecond
1064-nm neodymium:yttrium-aluminum-garnet laser. J Am Acad
Dermatol 2013; 69(4):578–582.
El-Gohary M, et al: Topical antifungal treatments for tinea cruris and
tinea corporis. Cochrane Database Syst Rev 2014; 8:CD009992. doi:
10.1002/14651858.CD009992.pub2.
Elewski BE, et al: Onychomycosis: an overview. J Drugs Dermatol 2013;
12(7):s96–s103.
Friedlander SF, et al: Onychomycosis does not always require systemic
treatment for cure: a trial using topical therapy. Pediatr Dermatol 2013;
30(3):316–322.
Ghannoum MA, et al: Molecular analysis of dermatophytes suggests
spread of infection among household members. Cutis 2013;
91(5):237–245.
Gupta AK, et al: Recurrences of dermatophyte toenail onychomycosis
during long-term follow-up after successful treatments with mono- and
combined therapy of terbinafine and itraconazole. J Cutan Med Surg
2013; 17(3):201–206.
Gupta AK, et al: Medical devices for the treatment of onychomycosis.
Dermatol Ther 2012; 25(6):574–581.
Idriss MH, et al: The diagnostic value of fungal fluorescence in
onychomycosis. J Cutan Pathol 2013; 40(4):385–390.
Jarratt M, et al: Luliconazole for the treatment of interdigital tinea
pedis: A double-blind, vehicle-controlled study. Cutis 2013;
91(4):203–210.
Lanternier F, et al: Deep dermatophytosis and inherited CARD9
deficiency. N Engl J Med 2013; 369(18):1704–1714.
Miyajima Y, et al: Rapid real-time diagnostic PCR for Trichophyton
rubrum and Trichophyton mentagrophytes in patients with tinea
unguium and tinea pedis using specific fluorescent probes. J Dermatol
Sci 2013; 69(3):229–235.
Neri I, et al: Corkscrew hair: a trichoscopy marker of tinea capitis in an
adult white patient. JAMA Dermatol 2013; 149(8):990–991.
Shemer A: Update: medical treatment of onychomycosis. Dermatol
Ther 2012; 25(6):582–593.
Shemer A, et al: Treatment of tinea capitis—griseofulvin versus
fluconazole—a comparative study. J Dtsch Dermatol Ges 2013;
11(8):737–741, 737–742.
-
Tietz HJ, et al: Efficacy of 4 weeks topical bifonazole treatment for
onychomycosis after nail ablation with 40% urea: a double-blind,
randomized, placebo-controlled multicenter study. Mycoses 2013;
9
56(4):414–421.
Yuen CW, et al: Treatment of interdigital-type tinea pedis with a
ri 9
2-week regimen of wearing hygienic socks loaded with antifungal
microcapsules: a randomized, double-blind, placebo-controlled
study. J Am Acad Dermatol 2013; 69(3):495–496.
h
CANDIDIASIS
t a
Candidiasis is also nown as candidosis or moniliasis. Can i a
albicans is a common inhabitant o the human gastrointestinal
(G ) and genitourinary tracts and s in. nder the right condi
tions C albicans becomes a pathogen causing lesions o the
s in nails and mucous membranes. The intertriginous areas
are re uently a ected. ere warmth moisture and macera
tion o the s in permit the organism to thri e. The areas most
o ten in ol ed are the perianal and inguinal olds abdominal
creases in ramammary creases interdigital areas nail olds
and a illae.
Can i a albicans is largely an opportunistic organism acting
as a pathogen in the presence o impaired immune response
or where local conditions a or growth. Warmth and moisture
a or candidal growth as can reductions in competing ora
during antibiotic therapy. igher s in p also a ors candidal
growth. Diapers panty liners and other occlusi e products
raise s in p and may predispose to s in in ections o C
albicans. A topical acidic bu er may be help ul as a pre enti e
measure or recurrent Can i a induced s in rash.
Diagnosis
icroscopically the preparation may show spores and
pseudohyphae. n Gram stain the yeast orms dense gram
positi e o oid bodies μm in diameter. A combination o
Candidiasis
Gomori methenamine sil er (G S) and Congo red staining
can be help ul in the di erential diagnosis o ungal in ections.
lastom ces and Pit rosporum are positi e or both whereas
Can i a and istoplasma are G S positi e and Congo red
negati e.
Can i a proli erates in both budding and mycelial orms in
the stratum corneum or super cial mucosa. Budding yeast
and pseudohyphae are easier to detect in histologic section
with a PAS stain. Whereas dermatophyte hyphae tend to run
parallel to the s in sur ace Can i a pseudohyphae are more
prone to ertical orientation.
n culture C albicans should be di erentiated rom other
orms o Can i a that are only rarely pathogenic such as
C rusei C stellatoi ea C tropicalis C pseu otropicalis and
C guilliermon ii Culture on Sabouraud glucose agar shows a
G
growth o creamy grayish moist colonies in about days. n
time the colonies orm small rootli e penetrations into the
R
agar. icroscopic e amination o the colony shows clusters o
budding cells. When inoculated into cornmeal agar culture
V
thic walled round chlamydospores characteristic o C albi
cans are produced.
d
ti e
Topical anticandidal agents
ost o the topical agents mar eted or tinea are also e ecti e
or candidiasis. These include clotrima ole (Lotrimin ycele )
n
econa ole (Specta ole) etocona ole ( i oral) micona ole
( onistat Derm Lotion icatin) o icona ole ( istat) sul
U
cona ole ( elderm) na ti ne ( a tin) tercona ole ciclopiro
olamine (Lopro ) butena ne ( enta ) terbina ne (Lamisil)
nystatin and topical amphotericin B lotion. lder agents such
as gentian iolet Castellani paint and boric acid are still some
times used. ral nystatin is as e ecti e as intra enous ( V)
ucona ole at pre enting in asi e Can i a in ections in
preterm neonates. The oral preparation is more easily admin
istered and is lower in cost.
Other agents
lucona ole has a remar able sa ety record e en when used
long term in patients with Can i a related to genodermatoses.
Posacona ole itracona ole oricona ole echinocandins anid
ula ungin and amphotericin B are also used in arious set
tings. Various a onoid compounds including apigenin and
aemp erol al aloid ibogaine (an indole) and the protober
berine al aloid berberine ha e been studied or their inhibi
tory e ects. aemp erol has shown a sur i al bene t in
patients with systemic in ections. Topical application o each
o these agents accelerated elimination rom cutaneous sites o
inoculation.
Oral candidiasis (thrush)
The mucous membrane o the mouth may be in ol ed in
healthy in ants. n the newborn in ection may be ac uired
rom contact with the aginal tract o the mother. n older
children and adults thrush is o ten seen a ter antibiotic
therapy. t may also be a sign o immunosuppression.
Grayish white membranous pla ues are ound on the sur ace
o the mucous membrane. The base o these pla ues is moist
295
 Fig. 15-13 Thrush.
15
Diseases Resulting from Fungi and Yeasts
reddish and macerated ( ig. ). n its spread the angles
o the mouth may become in ol ed and lesions in the inter
triginous areas may occur especially in marasmic in ants. The
diaper area is especially susceptible to candidiasis. ost o the
intertriginous areas and e en the e posed s in may be
in ol ed with small pustules that uic ly turn into macerated
and erythematous scaling patches.
n adults the appearance may resemble that seen in children
or may be drier and more erythematous. Sali a inhibits the
growth o Can i a and a dry mouth predisposes to candidal
growth. Broad spectrum antibiotics also predispose to candi
diasis. The papillae o the tongue may appear atrophic with
the sur ace smooth gla ed and bright red. re uently the
in ection e tends onto the angles o the mouth to orm per
l che. This appearance is common in elderly debilitated and
malnourished patients and in patients with diabetes. t is o ten
the rst mani estation o A DS and is present in almost all
untreated patients with ull blown A DS. The obser ation o
oral thrush in an adult with no nown predisposing actors
warrants a search or other e idence o in ection with V e erts anti in ammatory as well as anticandidal e ects. Pro
such as lymphadenopathy leu openia or V antibodies in
the serum.
Various treatment options or oral candidiasis are a ailable.
n ants are usually treated with oral nystatin suspension. An
adult can let clotrima ole troches dissol e in the mouth. A
single mg dose o ucona ole is e ecti e or many muco
cutaneous in ections in adults. n immunosuppressed patients
mg day is the starting dose but much higher doses are
o ten needed. tracona ole mg day or days can
also be e ecti e. Although terbina ne is o ten regarded as a
dermatophyte drug it can also be e ecti e or Can i a in ec
tions at doses o mg day.
Perlèche
Perl che or angular cheilitis is characteri ed by maceration
and trans erse ssuring o the oral commissures. The earliest
lesions are poorly de ned grayish white thic ened areas with
slight erythema o the mucous membrane at the oral commis
sure. When more ully de eloped this thic ening has a bluish
white or mother o pearl color and may be contiguous with a
wedge shaped erythematous scaling dermatitis o the s in
portion o the commissure. issures maceration and crust
ormation ensue. So t pinhead si ed papules may appear.
n ol ement is usually bilateral. Perl che is re uently
related to C albicans but may also harbor coagulase positi e
296
tahir99 - UnitedVRG
Staph lococcus aureus and gram negati e bacteria. Similar
changes may occur in ribo a in de ciency or other nutritional
de ciency.
dentical ssuring occurs at the mucocutaneous unction
rom drooling in persons with malocclusion caused by poorly
tting dentures and in older patients in whom atrophy o the
al eolar ridges ( closing the bite) has caused the upper lip to
o erhang the lower at the commissures. There is sometimes a
ertical shortening o the lower third o the ace.
in ection is caused by C albicans anticandidal creams are
e ecti e but the response is more rapid i they are used in
combination with a midstrength topical corticosteroid. the
perl che is caused by ertical shortening o the lower third o
the ace dental or oral surgical inter ention may be help ul.
n ection o collagen into the depressed sulcus at the oral com
missure can be bene cial.
Candidal vulvovaginitis
Can i a albicans is a common inhabitant o the aginal tract.
ergrowth can cause se ere pruritus burning and discharge.
The labia may be erythematous moist and macerated and the
cer i hyperemic swollen and eroded showing small esicles
on its sur ace. The aginal discharge is not usually pro use and
aries rom watery to thic and white or curdli e.
Candidal in ection may de elop during pregnancy in dia
betes or secondary to therapy with broad spectrum antibiot
ics. Among diabetic patients candidal o ergrowth is related
to the degree o hyperglycemia. Recurrent ul o aginal can
didiasis has also been associated with long term tamo i en
treatment. Candidal balanitis may be present in an uncircum
cised se ual partner. Diagnosis is established by the clinical
symptoms and ndings as well as the demonstration o the
ungus by microscopic e amination and culture.
ral ucona ole mg gi en once is easy and e ecti e.
n some patients with predisposing actors longer courses o
ucona ole mg day or itracona ole mg day
or days may be needed. Topical options include micon
a ole nystatin clotrima ole and tercona ole. Clotrima ole
biotic anticandidal bacteria and yogurt ha e demonstrated
some ability to decrease Can i a coloni ation.
Can i a glabrata aginitis may be re ractory to a ole drugs
and can be di cult to eradicate. Topical boric acid amphoteri
cin B and ucytosine may be help ul.
Candidal intertrigo
The pruritic intertriginous eruptions caused by C albicans
may arise between the olds o the genitals; in groins or
armpits; between the buttoc s; under large pendulous
breasts; under o erhanging abdominal olds; or in the umbi
licus. The pin to red intertriginous moist patches are sur
rounded by a thin o erhanging ringe o somewhat macerated
epidermis ( collarette scale). Some eruptions in the inguinal
region may resemble tinea cruris but usually there is less
scaliness and a greater tendency to ssuring. Persistent e co
riation and subse uent licheni cation and drying may modi y
the original appearance o er time. ten tiny super cial
white pustules are obser ed closely ad acent to the patches.
When present Can i a can cause ares o in erse psoriasis
although pre alence o Can i a is not increased in the inter
triginous areas o patients with either psoriasis or atopic
dermatitis.
Topical anticandidal preparations are usually e ecti e but
recurrence is common. Combinations o a topical anticandidal

Fig. 15-14 Diaper candidiasis.
agent with a midstrength corticosteroid may lead to more
rapid relie . Castellani paint may also be help ul. Patients o ten
pre er colorless paint.
Diaper candidiasis
The diagnosis o candidiasis may be suspected rom in ol e
ment o the olds and occurrence o many small erythematous
des uamating satellite or daughter lesions scattered along
the edges o the larger macules ( ig. ). Topical anticandi
dal agents are e ecti e sometimes compounded in inc o ide
ointment to act as a barrier against the irritating e ect o urine.
Recurrent diaper candidiasis may be associated with oral and
gut coloni ation and may respond to the addition o oral
nystatin suspension.
Congenital cutaneous candidiasis
Premature rupture o membranes together with a birth canal
in ected with C albicans may lead to congenital cutaneous
candidiasis. The eruption is usually noted within a ew hours
o deli ery. rythematous macules progress to thin walled
pustules which rupture dry and des uamate within about
wee . Lesions are usually widespread in ol ing the trun
nec and head and sometimes the palms and soles including
the nail olds. The oral ca ity and diaper area are spared in
contrast to the usual type o ac uired neonatal in ection. The
di erential diagnosis includes other neonatal esiculopustular
disorders such as listeriosis syphilis staphylococcal and
herpes in ections erythema to icum neonatorum transient
neonatal pustular melanosis miliaria rubra drug eruption
and congenital ichthyosi orm erythroderma. in ection is sus
pected early the amniotic uid placenta and cord should be
e amined or e idence o in ection.
n ants with candidiasis limited to the s in ha e a orable
outcomes; howe er systemic in ol ement may occur. Dis
seminated in ection is suggested by e idence o respiratory
distress or other laboratory or clinical signs o neonatal sepsis.
Dissemination is more common in in ants who weigh less than
g. Treatment with broad spectrum antibiotics and altered
immune responsi eness can also predispose to dissemination.
n ants with congenital cutaneous candidiasis and any o the
pre ious actors may be considered or systemic anti ungal
therapy.
Perianal candidiasis
n ection with C albicans may present as pruritus ani. Perianal
dermatitis with erythema oo ing and maceration is present.
Pruritus and burning can be e tremely se ere. Satellite lesions
Candidiasis
may be present but their absence does not e clude candidia
sis. Can i a growth is also enhanced on abnormal tissue such
as e tramammary Paget s disease. the tissue does not return
to normal a ter the candidiasis is treated a biopsy may be
warranted.
Candidal paronychia
n ammation o the nail old produces redness edema and
tenderness o the pro imal nail olds and gradual thic ening
and brownish discoloration o the nail plates. sually only the
ngernails are a ected. Patients re uently ha e an atopic
bac ground.
Although acute paronychia is usually staphylococcal in
origin chronic paronychia is typically multi actorial. rritant
dermatitis and candidiasis may play important roles. n one
study treatment with a topical corticosteroid was superior to
treatment with an anticandidal agent. A oidance o irritants
and wet wor is essential. Anticandidal agents may be help ul
and may be used in combination with a topical corticosteroid.
Candidal paronychia is re uently seen in diabetic patients
and part o the treatment is bringing the diabetes under
control. The a oidance o chronic e posure to moisture and
irritants is also essential in these patients. topical treatment
ails oral ucona ole once a wee or itracona ole in pulsed
dosing can be e ecti e.
Repetiti e contact urticaria or allergic contact dermatitis to
oods and spices may mimic candidal paronychia. Patch and
radioallergosorbent testing (RAST) may be o alue.
Erosio interdigitalis blastomycetica
A orm o candidiasis erosio interdigitalis blastomycetica is
seen as an o al shaped area o macerated white s in on the
web between and e tending onto the sides o the ngers.
sually at the center o the lesion there are one or more s
sures with raw red bases. As the condition progresses the
macerated s in peels o lea ing a pain ul raw denuded area
surrounded by a collar o o erhanging white epidermis. t is
almost always the third web between the middle and ring
ngers that is a ected. The moisture beneath the ring macer
ates the s in and predisposes to in ection. The disease is also
seen in patients with diabetes and those who do wet wor .
ntertriginous lesions between the toes are similar. sually
the white sodden epidermis is thic and does not peel o
reely. n the eet it is the ourth interspace that is most o ten
in ol ed but the areas are apt to be multiple. Clinically this
may be indistinguishable rom tinea pedis. Diagnosis o erosio
interdigitalis blastomycetica is made by culture. Lesions may
respond to drying topical anticandidal agents or application
o lter paper soa ed with Castellani paint.
Chronic mucocutaneous candidiasis
The term chronic mucocutaneous candidiasis (C CC) desig
nates a heterogeneous group o patients whose in ection with
Can i a is chronic but limited to mucosal sur aces s in and
nails. nset is typically be ore age years. nset in adult li e
may herald the occurrence o thymoma. These cases may be
either inherited or sporadic. nherited types may be associated
297
 T cell tolerance within the thymus with decreased numbers
15 o L T cells. allmar s o the syndrome include C CC
chronic hypoparathyroidism hypothyroidism and Addison s
disease.
Abnormalities o type cyto ine production in response to
Diseases Resulting from Fungi and Yeasts

Can i a ha e been reported. Speci cally there may be greatly

impaired L production and dramatically increased le els
o L and L . Reductions in natural iller ( ) cells ha e
also been noted. n a e generation talian amily with C CC
a ecting only the nails low serum intercellular adhesion mol
ecule ( CA ) was noted. The de ect was lin ed to a c
pericentromeric region on chromosome .
Systemic ucona ole itracona ole or etocona ole is neces
sary to control C CC. Courses are typically prolonged
repeated and gi en at higher doses than the usual recom
mended dose. Patients with achlorhydria may ha e problems
with absorption o itracona ole and etocona ole. Cimetidine
Fig. 15-15 Hand and nail involvement in chronic mucocutaneous
was reported to restore de cient cell mediated immunity in
candidiasis.
our adults rom one amily at a dose o mg our times
daily. Granulocyte colony stimulating actor (G CS ) in usion
has been reported to restore L secretion with subse uent
Fig. 15-16 Chronic
clinical remission.
mucocutaneous
candidiasis. (Courtesy
of Leslie Castelo-
Soccio, MD.) Systemic candidiasis
Can i a albicans is capable o causing disseminated disease and
sepsis in ariably when host de enses are compromised.
Patients at high ris include those with malignancies espe
cially leu emia and lymphoma who may ha e impaired
immune de enses; A DS patients; debilitated and malnour
ished patients; those with a transplant who re uire prolonged
immunosuppressi e therapy; patients recei ing oral cortisone;
those who ha e had multiple surgical operations especially
cardiac surgery; and patients with indwelling V catheters. V
drug users also are at high ris .
The initial sign o systemic candidiasis may be e er o
un nown origin pulmonary in ltration G bleeding end
ocarditis renal ailure meningitis osteomyelitis endophthal
mitis peritonitis pro imal muscle wea ness and tenderness
or a disseminated maculopapular e anthema. The cutaneous
lesions begin as erythematous macules that may become
papular pustular hemorrhagic or ulcerati e. Deep abscesses
may occur. The trun and e tremities are the usual sites o
in ol ement. Pro imal muscle tenderness re uently accom
panies the e anthema and may be a aluable clue to the correct
with endocrinopathy. ral lesions are di use and perl che diagnosis.
and lip ssures are common. The nails become thic ened and The demonstration o microorganisms or a positi e culture
dystrophic with associated paronychia. yper eratotic horn will substantiate a diagnosis o candidiasis only i the micro
li e or granulomatous lesions are o ten seen ( igs. organism is ound in tissues or uids ordinarily sterile or
and ). Can i a and i the clinical picture is compatible. Can i a colo
Chronic mucocutaneous candidiasis occurs in a number o ni ation o endotracheal tubes used in supporting low birth
syndromes. Autosomal dominant signal transducer and acti weight neonates predisposes to systemic disease. Can i a is
ator o transcription S gain o unction mutation cultured within the rst wee o li e there is a high rate o
impairing interleu in ( L ) producing T cell de elop systemic disease.
ment is the best described abnormality. Autosomal recessi e The mortality attributed to systemic candidiasis has declined
L RA and autosomal dominant L de ciencies ha e because o early empiric anti ungal treatment and better pro
been reported in C CC patients. Autosomal dominant hyper phyla is. Data in children are similar to those in adults.
g syndrome is related to S mutations resulting in low Although amphotericin B remains the gold standard o treat
L T cell numbers. Dectin and L encoding genes mod ment in systemic candidiasis other sa er options are a ailable.
ulate the response to Can i a in ections through a T helper cell Amphotericin B is now a ailable in liposome encapsulated
type (Th ) mechanism although dectin does not appear orms which appear to be less to ic. lucona ole has been
to be critical in some models o mucosal candidiasis. CARD e ecti e as prophyla is with bone marrow transplantation
de ciency predisposes to in asi e candidiasis as well as in a as well as in the treatment o oropharyngeal candidosis and
si e and disseminated dermatophytosis. Autoimmune poly candidemia in nonneutropenic patients. At high doses
endocrinopathy candidiasis ectodermal dystrophy is an ucona ole is sometimes used or Can i a in neutropenic
autosomal recessi e syndrome caused by mutations o the patients. Voricona ole a newer tria ole anti ungal acts by
autoimmune regulator gene E resulting in ailure o inhibiting synthesis o ergosterol in the ungal cell membrane.
298

tahir99 - UnitedVRG
Posacona ole is a tria ole acti e against Can i a although
some problems with resistance ha e been reported. Caspo un
gin is an echinocandin anti ungal that inhibits β D glucan
synthesis in the cell wall. ica ungin and anidula ungin are
echinocandins. The newer tria oles and echinocandins ha e
broad spectrums and are e ecti e against in asi e spergillus
and Can i a in ections. Voricona ole has produced li er
abnormalities rash and isual disturbances and these must
be monitored during therapy. A meta analysis o studies o
Can i a sepsis concluded that clinical e cacy was similar
among the agents studied but microbiologic ailure was more
common with ucona ole than with amphotericin B or anidu
la ungin. Amphotericin B had a higher rate o ad erse e ents
than ucona ole or the echinocandins. Some data a or caspo
ungin or mica ungin o er anidula ungin in neutropenic
patients. The antiarrhythmic drug amiodarone has some
ungicidal acti ity and low doses o amiodarone produced a
synergistic e ect with ucona ole in ucona ole resistant
C albicans
Despite ad ances in treatment mortality associated with
systemic candidiasis remains high with o erall mortality o
and attributable mortality o appro imately . pulmonary orms are similar to candidal in ection. can i um
Candidid
As in dermatophytosis patients with candidiasis may de elop
secondary id reactions (candidid). These are much less
common than the reactions seen with acute in ammatory der
matophytosis. The reactions which ha e been reported to
clear with treatment o candidal in ection are usually o the
erythema annulare centri ugum or chronic urticaria type.
Antibiotic (iatrogenic) candidiasis
The use o oral antibiotics such as the tetracyclines and their
related products may induce clinical candidiasis in ol ing the
mouth G tract or perianal area. n addition ul o aginitis
may occur. t has been suggested that perhaps the bacterial
ora in the G system are changed by suppression o some
o the antibiotic sensiti e bacteria thereby permitting other
organisms such as Can i a to ourish. lucona ole mg
once will treat this ade uately i antibiotic therapy is gi en
or a limited time. or more prolonged courses o antibiotic
therapy the dose o ucona ole may ha e to be repeated or
a longer course o a topical agent may be used.
Al Rushood M, et al: Autosomal dominant cases of chronic
mucocutaneous candidiasis segregates with mutations of signal
transducer and activator of transcription 1, but not of toll-like receptor
3. J Pediatr 2013; 163(1):277–279.
Autmizguine J, et al: Pharmacokinetics and pharmacodynamics of
antifungals in children: clinical implications. Drugs 2014;
74:891–909.
Dias MF, et al: Treatment of superficial mycoses: review. Part II. An Bras
Dermatol 2013; 88:937–944.
Dias MF, et al: Update on therapy for superficial mycoses: review article
part I. An Bras Dermatol 2013; 88:764–774.
Griffin AT, Hanson KE: Update on fungal diagnostics. Curr Infect Dis Rep
2014; 16:415.
Puel A, et al: Inborn errors of human IL-17 immunity underlie chronic
mucocutaneous candidiasis. Curr Opin Allergy Clin Immunol 2012;
12(6):616–622.
Schimke LF, et al: A novel gain-of-function IKBA mutation underlies
ectodermal dysplasia with immunodeficiency and polyendocrinopathy.
J Clin Immunol 2013; 33(6):1088–1099.
Wildbaum G, et al: Continuous G-CSF therapy for isolated chronic
mucocutaneous candidiasis: complete clinical remission with restoration
of IL-17 secretion. J Allergy Clin Immunol 2013; 132(3):761–764.
Wilson D, et al: Clotrimazole dampens vaginal inflammation and
neutrophil infiltration in response to Candida albicans infection.
Antimicrob Agents Chemother 2013; 57(10):5178–5180.
Tinea nigra
GEOTRICHOSIS
eotrichum can i um is an ascomycetous anamorph yeastli e
ungus ound as part o the natural ora o mil . t is also
ound on ruit and tomatoes and in soil. t is used commer
cially as a maturing agent or cheese. ndi idual strains may
be more moldli e or yeastli e. Substantial genetic polymor
phism has been noted in can i um Strains with a moldli e
phenotype tend to ha e larger genomes than those with a
yeastli e phenotype.
n immunosuppressed indi iduals can i um or eo
trichum capitatum lastoschi om ces capitatus may act as an
opportunistic pathogen causing disseminated or mucocutane
ous geotrichosis. ucocutaneous disease is characteri ed by
erythema pseudomembranes and mucopurulent sputum
similar to that seen in thrush. The intestinal bronchial and
is usually isolated as a saprophyte. cultured repeatedly
rom diseased tissue it should be assumed to be acting as a
pathogen.
The diagnosis is made by the repeated demonstration o the
organism by microscopic e amination and by its culture
rom sputum on Sabouraud de trose agar. Direct e amination
shows branching septate mycelium and chains o rectangular
cells. n culture there is a mealy growth at room temperature.
The hyphae orm rectangular arthrospores.
Treatment o mucocutaneous disease can be accomplished
with oral nystatin or nystatin ( ycostatin) suspension in
some cases. or more se ere or disseminated disease liposo
mal amphotericin B caspo ungin oricona ole itracona ole
ucytosine or combinations o these agents ha e been
e ecti e.
Martins N, et al: Candidiasis: predisposing factors, prevention,
diagnosis and alternative treatment. Mycopathologia 2014;
177:223–240.
TINEA NIGRA
ortaea wernec ii ( ormerly Phaeoannellom ces wernec ii) is a
blac yeastli e hyphomycete that is widely distributed in hot
humid en ironments. The organism is common in the tropics.
n the nited States the in ection is seen along the Gul Coast.
ew ta onomic analysis has led some to classi y Cla osporium
castellanii as the etiologic agent o tinea nigra in humans and
con rmed that this ungus is the same as Stenella araguata.
Tinea nigra presents as one or se eral brown or blac spots
on the palms or soles. The lesions may be mista en or ne i or
melanoma. The pigment is con ned to the stratum corneum
and scrapes o easily. Dermoscopy has also been used to di
erentiate the lesions rom melanocytic tumors. The ungus
can easily be demonstrated by means o or culture. n
preparations the hyphae appear brown or golden in
color. oung colonies are glossy blac and yeastli e but
older colonies are lamentous and grayish. The pigment pro
duced by the ungal hyphae is melanin. Culture will identi y
the organism and PCR can be use ul or rapid identi cation
o wernec ii
Topical imida oles and allylamines such as clotrima ole
micona ole etocona ole sulcona ole econa ole and terbin
a ne ha e been reported as e ecti e. Griseo ul in is not e ec
ti e. Simply sha ing away the super cial epidermis with a
blade is re uently both diagnostic and curati e o tinea nigra.
299

15 PIEDRA
n blac piedra dar pinhead to pebble si ed ormations
occur on the hairs o the scalp brows lashes or beard. These
Diseases Resulting from Fungi and Yeasts
nodules are distributed irregularly along the length o the
sha t. White piedra is typically caused by richosporon richo
sporum beigelii or richosporon in in and occurs more o ten in
temperate climates. Based on molecular analysis the ta on
beigelii has been replaced by se eral species. A synergistic
corynebacterial in ection is o ten present in white piedra as
demonstrated by culture and electron microscopy. beigelii
has also been implicated as a cause o onychomycosis. in in
is implicated as an etiologic agent o pubic white piedra.
richosporon asahii causes white piedra and onychomycosis
and has been isolated rom blac piedra. richosporon spp. can
also cause disseminated disease in immunosuppressed
patients and asahii has produced disseminated cutaneous
in ections in immunocompetent hosts. n white piedra patients
present with yellow or beige colored so t slimy sheaths
coating the hair sha ts ( ig. ). The sheaths are composed
o hyphae arthrospores and bacteria. The culture shows so t
cream colored colonies composed o blastospores and septate
hyphae which ragment into arthrospores.
Blac piedra usually caused by Pie raia hortai occurs mostly
in the tropics especially in South America and Asia. The
nodeli e masses in preparations show numerous
o al asci containing two to eight ascospores and mycelium.
Cultures produce blac colonies composed o hyphae and
chlamydospores.
Treatment in ol es cutting or sha ing the hair but this may
not be acceptable to the patient. ral and topical terbina ne
ha e been e ecti e in blac piedra. or white piedra oral
itracona ole topical imida oles ciclopiro olamine sele
nium sul de precipitated sul ur in petrolatum chlorhe i
dine solutions Castellani paint inc pyrithione amphotericin
B lotion and glutaraldehyde ha e all been used
success ully.
ssential oils deri ed rom C mbopogon winterians Mentha
piperita Cinnamomum e lanicum Melaleuca alternifolia and
Fig. 15-17 White piedra.
300
tahir99 - UnitedVRG
Eucal ptus globulus ha e demonstrated e cacy against richo
sporon ovoi es
Richini-Pereira VB, et al: White piedra: molecular identification of
Trichosporon inkin in members of the same family. Rev Soc Bras Med
Trop 2012; 45(3):402–404.
Saxena S, et al: Inhibitory effect of essential oils against Trichosporon
ovoides causing piedra hair infection. Braz J Microbiol 2012;
43(4):1347–1354.
Uniyal V, et al: Screening of some essential oils against Trichosporon
species. J Environ Biol 2013; 34(1):17–22.
TINEA VERSICOLOR (PITYRIASIS VERSICOLOR)
Tinea ersicolor is caused by Malasse ia spp. although con
trary to prior belie Malasse ia furfur is not the predominant
species isolated rom clinical lesions. The ma or implicated
species is Malasse ia globosa although M restricta M s mpo
ialis M furfur M obtusa and M sloof ae ha e also been
implicated. Tinea ersicolor typically presents as hypopig
mented or hyperpigmented coalescing scaly macules on the
trun and upper arms ( ig. ). Pin atrophic and tri
chrome ariants e ist and can produce stri ing clinical pic
tures. The eruption is more common during the summer
months and a ors oily areas o s in. Sites o predilection are
the sternal region and the sides o the chest abdomen bac
pubis nec and intertriginous areas. ild itching and
in ammation around the patches may be present. n some
patients many ollicular papules are present. The ace and
scalp may be a ected. acial lesions may occur in in ants and
immunocompromised patients. The disease may e en occur
on the scalp palms and soles. Penile lesions may de elop as
well and the organism is commonly isolated rom patients
with balanoposthitis.
n hypopigmented tinea ersicolor abnormally small and
poorly melani ed melanosomes are produced and are not
trans erred to eratinocytes properly. This becomes most con
spicuous in dar s inned people. This hypopigmentation may
persist or wee s or months a ter the ungal disease is cured
unless an e ort is made to regain the lost pigmentation through
V e posure.
Diagnosis
The Malasse ia ungus is easily demonstrated in scrapings o
the pro use scales that co er the lesions. Tape stripping o
the lesions can also be per ormed. icroscopically there are
short thic ungal hyphae and large numbers o ariously
Fig. 15-18 Tinea versicolor.
si ed spores. This combination o strands o mycelium and
numerous spores is commonly re erred to as spaghetti and
meatballs. The ungus can be highlighted by a ariety o
stains including Par er blue blac in (mi ed with
) Chicago s y blue B with and Gram stain.
denti cation by culture re uires lipid enrichment o the
media and is rarely done to establish the diagnosis. Wood s
light e amination accentuates pigment changes and may dem
onstrate yellow green uorescence o the lesions in ad acent
ollicles. Biopsy will demonstrate a thic bas et wea e stratum
corneum with hyphae and spores. n the atrophic ariant
epidermal coloni ation with hyphae and spores is accompa
nied by e acement o the rete ridges subepidermal bropla
sia pigment incontinence and elastolysis.
Differential diagnosis
Tinea ersicolor must be di erentiated rom seborrheic der
matitis pityriasis rosea pityriasis rubra pilaris pityriasis alba
ansen s disease syphilis and itiligo. n the atrophic ariant
the lesions may suggest parapsoriasis mycosis ungoides
anetoderma L or steroid atrophy. The diagnosis in all orms
o tinea ersicolor is generally easily established by
e amination. n seborrheic dermatitis the patches ha e an
erythematous yellowish tint and the scales are so t and greasy
whereas in tinea ersicolor the scales are ur uraceous ( u y).
acular syphilid consists o aint pin lesions less than cm
in diameter irregularly round or o al which are distributed
principally on the nape sides o the trun and e or aspects
o the e tremities. The lesions are slightly indurated with a
peripheral scale and may be copper colored. General adenop
athy may be present. Serologic tests are positi e in this phase
o syphilis but pro one reactions may occur and the serum
may re uire dilution.
Treatment
mida oles tria oles selenium sul de ciclopiro olamine
inc pyrithione sul ur preparations salicylic acid prepara
tions propylene glycol and ben oyl pero ide ha e been
used success ully as topical agents. Selenium sul de lotion is
ery cost e ecti e and can be applied daily or a wee ; it is
washed o a ter min and is also e ecti e in a single o er
night application which can be repeated monthly as prophy
la is. The scalp can be shampooed monthly with selenium
sul de to reduce scalp coloni ation. inc pyrithione soap is
also cost e ecti e and well tolerated or treatment and
prophyla is.
etocona ole in mg doses repeated at monthly inter
als is ery e ecti e but the DA has warned against the use
o etocona ole as a rst line treatment ma ing its use prob
lematic. ral itracona ole mg once daily or days is
e ecti e and can be ollowed by prophylactic treatment with
itracona ole mg twice daily on day a month. n a study
o patients mg single dose itracona ole was e ui alent
to mg day o itracona ole or days. lucona ole mg
once may also be e ecti e and can be repeated monthly. n a
study o patients wee ly dosing with two mg cap
sules o ucona ole or wee s was e ui alent to wee ly
dosing o two mg tablets o etocona ole or wee s. The
e ect o a single dose not repeated in wee s was not
assessed in this study and may ha e pro ed ust as e ecti e.
Although oral terbina ne has been ine ecti e it is e ecti e
topically. Twice daily applications are superior to once daily
applications. Alternati ely aminole ulinic acid PDT has
been reported as e ecti e.
Patients should be in ormed that the hypopigmentation
or hyperpigmentation will ta e time to resol e and is not a
sign o treatment ailure. Relapse is li ely i prophylactic
doses are not gi en occasionally but many prophylactic
options are a ailable. A ter initial therapy patients may
Tinea versicolor (pityriasis versicolor)
pre er wee ly washing with a topical inc pyrithione bar or
single o ernight applications o selenium sul de etocon
a ole econa ole or bi ona ole shampoo e ery days or
monthly oral therapy.
Pityrosporum folliculitis
Pit rosporum olliculitis has been a contro ersial entity but
its prompt response to anti ungal agents suggests that Pit
rosporum yeast (the yeast phase o Malasse ia spp.) are indeed
pathogenic. Criteria or diagnosis include characteristic mor
phology demonstration o yellow green Wood s light uo
rescence o the papules or identi cation o Pit rosporum yeast
in smears or biopsies and prompt response to anti ungal
treatment. ungal stains Gram stain and ay Gr nwald
Giemsa stain ha e been used. Lesions tend to be chronic
moderately itchy dome shaped ollicular papules and tiny
pustules in ol ing the upper bac and ad acent areas. The
ace and scalp may be in ol ed and the lesions are some
times ound in association with either tinea ersicolor or seb
orrheic dermatitis. Pit rosporum olliculitis is more common
in organ or marrow transplant recipients. Pit rosporum yeast
is a normal part o the ollicular ora so alterations in ora
may a or uncontrolled growth o the yeast. Such a case
occurs when Propionibacterium acnes is suppressed by tetracy
cline therapy.
The eruption responds to oral ucona ole mg once;
etocona ole mg once; or itracona ole mg day or
days. As pre iously noted the DA strengthened warn
ings about etocona ole use. Topical therapy with . sele
nium sul de applied o ernight is also generally e ecti e.
ther treatments include propylene glycol in water
and topical imida ole creams. PDT may be considered in
re ractory disease. Relapses are common but prophyla is may
be success ul with monthly applications o selenium sul de or
maintenance doses o topical econa ole.
Akaza N, et al: Malassezia globosa tends to grow actively in summer
conditions more than other cutaneous Malassezia species. J Dermatol
2012; 39(7):613–616.
Durdu M, et al: Epidemiological characteristics of Malassezia folliculitis
and use of the May-Grünwald-Giemsa stain to diagnose the infection.
Diagn Microbiol Infect Dis 2013; 76(4):450–457.
Gupta AK, Lyons DC: Pityriasis versicolor: an update on
pharmacological treatment options. Expert Opin Pharmacother 2014;
15:1707–1713.
Gupta AK, et al: Systematic review of systemic treatments for tinea
versicolor and evidence-based dosing regimen recommendations. J
Cutan Med Surg 2014; 18:79–90.
Lee JW, et al: Topical photodynamic therapy with methyl
aminolevulinate may be an alternative therapeutic option for the
recalcitrant Malassezia folliculitis. Int J Dermatol 2011;50(4):488–490.
Mostafa WZ, et al: Hair loss in pityriasis versicolor lesions: a descriptive
clinicopathological study. J Am Acad Dermatol 2013; 69(1):e19–e23.
Saad M, et al: Molecular epidemiology of Malassezia globosa and
Malassezia restricta in Sudanese patients with pityriasis versicolor.
Mycopathologia 2013; 175(1-2):69–74.
Spence-Shishido A, et al: In vivo Gram staining of tinea versicolor. JAMA
Dermatol 2013; 149(8):991–992.
THE DEEP MYCOSES
ost deep cutaneous ungal in ections are a mani estation o
systemic in ection rom inhalation o aerosoli ed ungus.
301
 When primary in ection is introduced directly into the s in
15 rom puncture wounds abrasions or other trauma a chancri
orm or errucous lesion will orm that may be accompanied
by secondary lymphangitis. Chest radiographs should be
ta en when in estigating patients with deep mycoses e cept
Diseases Resulting from Fungi and Yeasts

or the classic inoculation types such as sporotrichosis myce

toma chromoblastomycosis and phaeohyphomycosis.

COCCIDIOIDOMYCOSIS
Coccidioidomycosis is also nown as coccidioidal granuloma
alley e er and San Joa uin Valley e er.

Primary pulmonary coccidioidomycosis

nhalation o Cocci ioi es immitis or C posa asii ollowed by an
incubation period o days to se eral wee s produces a
respiratory in ection that may be mild with only a low grade
e er resembling a uli e illness. Appro imately o
in ected persons are entirely asymptomatic. Se ere symptoms
o chills high e er night sweats se ere headache bac ache
and malaise may ensue in a minority. A large percentage o
patients show lung changes on radiographic e amination.
These include hilar adenopathy peribronchial in ltration or
an in ltrate compatible with bronchopneumonia. At the time
o onset a generali ed maculopapular eruption may be
present which may be con used with a drug eruption measles
or scarlet e er.
Within a ew wee s the pulmonary symptoms subside. n
about o women and in o men s in mani estations
appear in the orm o erythema nodosum o er the shins and
sometimes o er the thighs hips and buttoc s. These tender
lesions may become con uent gradually turn rom purple to
brown and then disappear in about wee s. rythema
nodosum is a a orable prognostic sign and occurs mostly in
white indi iduals with transient sel limited disease. Some
times erythema multi orme may de elop in a similar clinical
setting.
Although alley e er is usually sel limited and patients
reco er spontaneously a small percentage steadily progress
into the chronic progressi e disseminated orm. The propen
sity or disseminated disease is se eral old higher in ispan
ics and ati e Americans and many times higher or A rican
Americans ilipinos and Vietnamese. n women pregnancy
may predispose to systemic disease. n ants the elderly popu
lation persons with blood types B or AB and immunosup
pressed patients such as those with A DS a history o organ
transplantation or a hematogenous malignancy or those
recei ing immunosuppressi e therapy are also at increased
ris or se ere disease. Donor deri ed organ transplant trans
mission has been documented many times; ris is primarily in
the rst year a ter transplant. Autosomal dominant inter eron γ
receptor de ciency also may predispose to disseminated
disease.
Disseminated coccidioidomycosis
(coccidioidal granuloma)
Dissemination occurs in less than o in ections but its
incidence is hea ily in uenced by the actors pre iously
listed. Target organs include the bones oints iscera brain
meninges and s in. A single organ or multiple organs may
be in ol ed. S in lesions occur in o patients with
disseminated disease and may appear as errucous nodules
( ig. ) as pin papules resembling basal cell carcinoma
or as subcutaneous abscesses. The ace is re uently in ol ed.
302
Fig. 15-19 Disseminated coccidioidomycosis. (Courtesy of Curt
Samlaska, MD.)
Some chronic lesions de elop into pla ues that resemble
mycosis ungoides or orth American blastomycosis. n A DS
patients umbilicated papules may mimic molluscum conta
giosum. mbilicated papules are more o ten associated with
cryptococcosis but can occur with a ariety o ungi.
Primary cutaneous coccidioidomycosis
The primary orm occurs rarely and s in disease should be
considered a mani estation o disseminated disease unless
there is a de nite history o inoculation or a coloni ed splinter
is ound in the lesion. Between and wee s a ter inoculation
an indurated nodule de elops that may ulcerate. Later nodules
appear along the lymphatic essels. Spontaneous reco ery
may result a ter se eral wee s although most patients are
treated with systemic agents.
Etiology and pathology
The causati e organism C immitis has been isolated rom the
soil and rom egetation. t is commonly ound in the burrows
o rodents o ten at a depth o about cm. pidemics occur
when the soil is disrupted to a depth o cm or more. This
can occur as a result o road wor laying o telephone or
electric cable dust storms and earth ua es. utbrea s occur
sporadically in Cali ornia and Ari ona.
Cocci ioi es immitis is dimorphous reproducing brittle
mycelia at room temperature and spherules in tissue. Spher
ules are unencapsulated with a thic re ractile wall and a
granular interior. They measure μm in diameter but
a erage μm. ndosporulation can occur and although the
organism can resemble hinospori ium Cocci ioi es is typically
much smaller and more uni orm in si e. t also lac s the small
central nucleus that is uni ormly present in nonsporulating
hinospori ium

tahir99 - UnitedVRG
Culture
Cocci ioi es is readily grown at room temperature and is highly
in ectious. or this reason culture o deep ungi should ne er
be attempted in the o ce setting. Cultures should be per
ormed only in laboratories with biocontainment hoods. The
colonies appear on Sabouraud de trose agar within days
as small slightly raised dis s penetrating the medium. lder
cultures become co ered with a dusty layer o aerial hyphae
and assume a brownish color with age. n culture spherical
bodies throw out laments o barrel shaped arthrospores.
ycelia are branched and septate μm in diameter. PCR
primers and a D A hybridi ation probe test that targets
organism speci c ribosomal R A are a ailable or rapid
identi cation.
Epidemiology
Coccidioidomycosis principally occurs in limited areas in the
Western emisphere. The original diagnosis was in a soldier
rom Argentina where the disease is endemic in the Gran
Chaco area. t is also endemic in northern e ico Vene uela
and the southwestern nited States (lower Sonoran Li e one).
n highly endemic areas most residents will ha e been
in ected and new residents ha e a good chance o becoming
in ected within months. Very ew will de elop disseminated
disease although the attac rate has recently increased in both
Cali ornia and Ari ona.
Differential diagnosis
Clinically it is e tremely di cult to di erentiate coccidioi
domycosis rom blastomycosis which it closely resembles.
De nite diagnosis depends on serologic testing and the dem
onstration o C immitis or C posa asii microscopically cultur
ally or by PCR or animal inoculation. Guinea pigs inoculated
with C immitis die rom the systemic in ection whereas no
e idence o in ection is apparent a ter inoculation with lasto
m ces ntradermal testing with coccidioidin or spherulin has
largely been replaced by serologic testing. A positi e reaction
o the delayed tuberculin type de elops early and remains
high in those who resist the disease well. A negati e s in test
occurs with dissemination.
Immunology
Precipitin late agglutination immunodi usion a widely
used nuclei acid hybridi ation test and complement ation
serologic tests ha e been de eloped. The precipitin immuno
di usion en yme lin ed immunosorbent assay ( L SA) and
late agglutination tests are use ul in recent in ection because
a ma imum titer is reached in wee s. They permit detec
tion o coccidioidal g in early coccidioidomycosis. n later
in ections the complement ation test is use ul. n primary
coccidioidomycosis the titer is low whereas in subse uent
dissemination there is a rapid rise in titer. When the disease
has disseminated cerebrospinal syno ial and peritoneal uid
can be tested or coccidioidal antibody. The Cocci ioi es speci c
L SA detects antigenuria in about o patients with coc
cidioidomycosis and is negati e in more than o controls
without ungal in ections. Cross reactions with other systemic
mycoses occur in . o patients. An isolated positi e
en yme immunoassay ( A) g test usually means dissemi
nated disease. Serologic titers may be alsely negati e in
patients recei ing immunosuppressi e therapy.
Treatment
lucona ole mg day or itracona ole mg three
times daily ha e similar e cacy in progressi e nonmeningeal
disease. Treatment must be continued or to months.
Histoplasmosis
any patients will re uire ongoing suppressi e therapy. n
patients in ected with V li etime suppressi e doses o
mg day are ad ised and potent antiretro iral therapy is
associated with impro ed outcomes. n coccidioidomycotic
meningitis ucona ole mg day or itracona ole
plus intrathecal amphotericin B is gi en with the a ole therapy
continued inde nitely. Liposomal amphotericin is e ecti e in
animal models o meningeal disease without the need or
intrathecal administration. ewer agents that ha e acti ity
against C immitis include oricona ole caspo ungin and
posacona ole. Voricona ole has been used success ully in
meningeal disease. These are second line agents. A ole resis
tance has been reported and should be suspected in patients
with re ractory disease.
Adam RD, et al: The spectrum and presentation of disseminated
coccidioidomycosis. Am J Med 2009; 122:770–777.
Ampel NM: New perspectives on coccidioidomycosis. Proc Am Thorac
Soc 2010; 7:181–185.
Carpenter JB, et al: Clinical and pathologic characteristics of
disseminated coccidioidomycosis. J Am Acad Dermatol 2010;
62:831–837.
Cummings KC, et al: Point-source outbreak of coccidioidomycosis in
construction workers. Epidemiol Infect 2010; 138:507–511.
Fernandez-Flores A, et al: Morphological findings of deep
cutaneous fungal infections. Am J Dermatopathol 2014;
36:531–553.
Kim MM, et al: Treatment of refractory coccidioidomycosis with
voriconazole or posaconazole. Clin Infect Dis 2011;
53:1061–1066.
Masannat FY, et al: Coccidioidomycosis in patients with HIV-1
infection in the era of potent antiretroviral therapy. Clin Infect Dis
2010; 50:1–7.
Miller SS, et al: Disseminated coccidioidomycosis in a patient managed
with adalimumab for Crohn’s disease. Nat Rev Gastroenterol Hepatol
2010; 7:231–235.
Ondo AL, et al: Primary cutaneous coccidioidomycosis. Clin Exp
Dermatol 2010; 35:e42–e43.
Tessari G, et al: Incidence and clinical predictors of primary
opportunistic deep cutaneous mycoses in solid organ transplant
recipients. Clin Transplant 2010; 24:328–333.
Vin DC, et al: Refractory disseminated coccidioidomycosis and
mycobacteriosis in interferon-gamma receptor 1 deficiency. Clin Infect
Dis 2009; 49:e62–e65.
Welsh O, et al: Coccidioidomycosis. Clin in Dermatol 2012; 30:
573–591.
HISTOPLASMOSIS
istoplasmosis is caused by inhalation o airborne spores. t
may be asymptomatic or may cause limited lung disease. Dis
semination to other organs including the s in occurs in about
in patients with acute in ection. mmunode ciency old
age and systemic corticosteroids predispose to widespread
disease. Donor deri ed organ transplant transmission has
o ten been documented. Cases misdiagnosed as sarcoidosis
and treated with corticosteroids ha e disseminated widely. n
disseminated disease mucous membranes are in ol ed much
more re uently than s in. Primary cutaneous disease is
e ceedingly rare.
Primary pulmonary histoplasmosis
Primary pulmonary histoplasmosis is usually a benign sel
limited orm o acute pneumonitis characteri ed by e er
303
 malaise night sweats chest pain cough and hilar adenopa
15 thy. Resolution o the pneumonitis occurs rapidly and the
only residua may be calci cations in the lung and a positi e
s in test to histoplasmin. owe er serious pneumonitis
caused by histoplasmosis does occur. Such cases ha e been
Diseases Resulting from Fungi and Yeasts
reported among ca e wor ers in e ico and tra elers return
ing rom Central America. A chronic pulmonary orm may
occur in patients with emphysema.
Appro imately o patients with acute symptomatic
in ection de elop arthritis and erythema nodosum. During a
large idwestern .S. epidemic about o patients diag
nosed with histoplasmosis presented with erythema nodosum.
rythema multi orme has also been described.
Progressive disseminated histoplasmosis
ost patients who de elop this se ere progressi e dissemi
nated orm are immunocompromised or ta ing systemic
corticosteroids. Leu emia lymphoma lupus erythematosus
renal transplantation or A DS are re uent predisposing dis
eases. Cases ha e also been reported in patients recei ing low
dose methotre ate or psoriasis and in patients recei ing
anti T therapy. Appro imately ha e no identi able
ris actor.
The reticuloendothelial system genitourinary tract adre
nals G tract adrenal glands and heart may be in ol ed.
lcerations and granulomas o the oronasopharyn are the
most common mucocutaneous lesions occurring in about
o patients with disseminated histoplasmosis ( ig. ).
Beginning as solid indurated pla ues the lesions ulcerate and
become deepseated pain ul and secondarily in ected. Peri
anal lesions may also occur.
S in lesions are present in appro imately o patients
with dissemination but may occur in o patients with
A DS and in renal transplant recipients. The morphologic pat
terns are nonspeci c and protean including umbilicated
nodules papules pla ues ( ig. ) ulcers cellulitis
abscesses pyoderma pustules and uruncles. Demonstration
o the organisms is readily made rom histologic sections and
cultures o the e udate. The most common mani estation
in children is purpura which usually appears a ew days
be ore death and is probably caused by se ere in ol ement
o the reticuloendothelial system with emaciation chronic
e er and se ere G symptoms. n the V positi e popula
tion dyspnea platelet count less than mm and
lactate dehydrogenase le el more than two old the upper limit
o normal are poor prognostic actors and independently asso
ciated with death during the rst days o anti ungal
treatment.
Fig. 15-20 Ulcer of disseminated histoplasmosis.
304
tahir99 - UnitedVRG
Primary cutaneous histoplasmosis
The rare primary cutaneous orm is characteri ed by a chancre
type lesion with regional adenopathy.
African histoplasmosis
A rican histoplasmosis is caused by istoplasma capsulatum
ar. uboisii S in lesions are much more common and include
super cial cutaneous granulomas subcutaneous granulomas
and osteomyelitic lesions with secondary in ol ement o the
s in (cold abscesses). Papular nodular circinate ec ematoid
and psoriasi orm lesions may be seen. The granulomas are
dome shaped nodules painless but slightly pruritic. There
may be s in and mucous membrane mani estations such as
ulcerations o the nose mouth pharyn genitals and anus.
These ulcers are chronic super cial lesions with no induration
or noticeable in ammatory reaction. rythema nodosum
occurs re uently. maciation and chronic e ers are common
systemic signs.
Etiology and pathology
istoplasmosis was rst disco ered in Panama by S.T. Darling
in . t is caused by capsulatum a dimorphic ungus that
e ists as a soil saprophyte. The organism is re uently ound
in bat and bird eces.
n tissue there are μm round bodies within the cyto
plasm o large macrophages. A pseudocapsule surrounds each
organism. The organisms bear a stri ing resemblance to those
o leishmaniasis but lac a inetoplast and are distributed
e enly throughout the cytoplasm whereas leishmanial organ
isms o ten line up at the periphery o the cell. Budding orms
may rarely be present and mycelial and pleomorphic budding
orms are sometimes seen in ca itary pulmonary disease
endocardial disease aortic pla ues or s in lesions. orpho
logically these orms resemble Can i a more than typical
intracellular istoplasma n direct e amination the organism
may be demonstrated in the peripheral blood sputum bron
chial washings cerebrospinal uid sternal marrow lymph
node touch smears or ulcers when stained with Giemsa PAS
or G S. n A rican histoplasmosis the organisms are
μm in diameter and are typically ound within multinucleated
giant cells.
The mycelial phase may be demonstrated on Sabouraud
de trose agar ycosel medium or brain heart in usion agar
to which blood has been added. A white u y colony is
ound with microconidia and echinulate macroconidia. ne
set o cultures should be inoculated at room temperature to
demonstrate the mycelial phase and another at C to produce
Fig. 15-21
Disseminated
histoplasmosis.
(Courtesy of Shyam
Verma, MD.)
the yeast phase. n disseminated disease the bone marrow is
re uently in ol ed. Blood urine and tissue rom oral and
s in lesions should also be cultured. PCR probes are a ailable
or rapid culture con rmation.
Epidemiology
Although histoplasmosis occurs throughout the world it is
most common in orth America especially in the central .S.
states along the ississippi Ri er basin. istoplasmosis is
ound re uently in ri er alley areas in the tropical and tem
perate ones. The ile Ri er Valley seems to be one e ception.
Besides the ississippi and hio ri er alleys it has been
ound along the Potomac Delaware udson and St. Law
rence ri ers. t has been reported in the ma or ri er alleys o
South America Central A rica China and Southeast Asia. The
disease is hea ily endemic in Puerto Rico and icaragua.
Transmission o the disease does not occur between indi
iduals; instead the in ection is contracted rom the soil by
inhalation o the spores especially in a dusty atmosphere.
eces o birds and bats contain the ungus. The spores ha e
been demonstrated in the e creta o starlings chic ens
tur eys and bats. The disease may be contracted by persons
who enter ca es inhabited by bats or birds. pidemics ha e
been reported rom e posure to silos abandoned chic en
houses and storm cellars.
n the histoplasmosis outbrea in ndianapolis ndiana
clinically recogni ed cases occurred and had dissemi
nated disease. The actual number in ected persons was prob
ably well o er . ineteen died none o whom was
under age year. atal or disseminated in ections occurred in
o immunosuppressed persons compared with . o to cause death. Radiographic studies will re eal disease at
those not immunosuppressed. Age o er was a worse prog
nostic actor than chronic lung disease in nonimmunosup
pressed persons. Disseminated histoplasmosis is seen as an
opportunistic in ection in V in ected patients.
Immunology
The best diagnostic test or histoplasmosis has been urinary
L SA but PCR assays are now a ailable and demonstrate
e cellent sensiti ity. Serologic testing or antibodies re uires
that the patient has normal immune responsi eness and is
urther limited by a high rate o alse positi e and alse
negati e results especially cross reactions with blastomycosis.
The complement ation test when positi e at a titer o
or greater indicates acti e or recent in ection. Because o
the limitations o serologic studies culture remains the gold
standard.
Treatment
Whereas minimal disease heals spontaneously in the ma ority
o patients with histoplasmosis moderate to se ere disease
re uires therapy. Amphotericin B is the treatment o choice in
se erely ill patients and all immunocompromised patients. n
V in ected patients a suppressi e dose o itracona ole
mg day ollows the V amphotericin and may be needed
as li elong treatment. or moderate disease in immunocompe
tent patients itracona ole mg three times daily or days
ollowed by mg once or twice daily depending on se erity
or months may be gi en. ost patients initially treated with
amphotericin B respond uic ly and can be switched to itra
cona ole. Voricona ole or posacona ole may be used in
patients with inade uate response to this therapy.
Akin L, et al: Oral presentation of disseminated histoplasmosis. J
Oral Maxillofac Surg 2011; 69:535–541.
Buitrago MJ, et al: A case of primary cutaneous histoplasmosis
acquired in the laboratory. Mycoses 2011; 54:e859–e861.
Chang P, et al: Skin lesions of histoplasmosis. Clin Dermatol 2012;
Cryptococcosis
30:592–598.
Galandiuk S, et al: Infliximab-induced disseminated histoplasmosis in a
patient with Crohn’s disease. Nat Clin Pract Gastroenterol Hepatol
2008; 5:283–287.
Kauffman CA: Diagnosis of histoplasmosis in immunosuppressed
patients. Curr Opin Infect Dis 2008; 21:421–425.
Rosaado-Odom VM, et al: Cutaneous presentation of progressive
disseminated histoplasmosis nine years after renal transplantation.
Transpl Infect Dis 2013; 15:e64–e69.
Sun NZ, et al: Cutaneous histoplasmosis in renal transplant recipients.
Clin Transplant 2014; 28:1069–1074.
Tsiodras S, et al: African histoplasmosis following mudbaths. Am J Trop
Med Hyg 2012; 86:261–263.
CRYPTOCOCCOSIS
Cryptococcosis generally begins as a pulmonary in ection and
remains locali ed to the lung in o patients. n the remain
ing the organisms hematogenously disseminate to other
organs with the C S and the s in the two most common
secondary sites. Patients in the group are usually immu
nocompromised or debilitated. The incidence o dissemination
is much higher in patients with A DS occurring in up to
o this population.
Primary pulmonary cryptococcosis in ection may be so
mild that the symptoms o e er cough and pain may be
absent. n the other hand some cases may be se ere enough
this stage.
When dissemination occurs the organism has a special
a nity or the C S. Cryptococcosis is the most common cause
o mycotic meningitis. The patient may ha e restlessness hal
lucinations depression se ere headache ertigo nausea and
omiting nuchal rigidity epilepti orm sei ures and symp
toms o intraocular hypertension. ther organs such as the
li er s in spleen myocardium and s eletal system as well
as the lymph nodes may be in ol ed. Disseminated crypto
coccosis can present in many organ systems; hepatitis osteo
myelitis prostatitis pyelonephritis peritonitis and s in
in ol ement ha e all been reported as initial mani estations o
disease. The incidence o s in in ol ement in patients with
cryptococcosis is although it is lower in the V
in ected population. Cutaneous lesions may precede o ert
systemic disease by months.
S in in ection with cryptococcosis occurs most re uently
on the head and nec . A ariety o morphologic lesions ha e
been reported including subcutaneous swellings abscesses
blisters tumorli e masses molluscum contagiosum li e
lesions draining sinuses ulcers ec ematous pla ues granu
lomas papules nodules pustules acnei orm lesions pla ues
and cellulitis ( ig. ). Appro imately o patients
with V and disseminated cryptococcosis will de elop mol
luscum contagiosum li e lesions. n these patients there is
o ten a central hemorrhagic crust. Lesions may rst become
e ident in V in ected patients during highly acti e antiret
ro iral therapy ( AART). Solitary cutaneous lesions and
indolent cellulitis may be the presenting signs o dissemi
nated disease.
Primary inoculation cryptococcosis is a rare disease. To
establish the diagnosis there should be a clear history o
implantation or a oreign body ound in association with the
organism. sually primary inoculation disease presents as a
solitary s in lesion on an e posed area re uently in the orm
305

15
Diseases Resulting from Fungi and Yeasts
Fig. 15-22 Disseminated cryptococcosis.
o a whitlow. Ris actors include outdoor acti ities and e po
sure to bird droppings. Cr ptococcus neoformans serotype D
is more o ten associated with primary cutaneous disease.
Although primary cutaneous disease e ists or all practical
purposes identi cation o cryptococci in the s in indicates
disseminated disease with a poor prognosis and it re uires a
search or other sites o in ol ement.
Etiology and pathology
The causati e organism is C neoformans or in subtropical or
tropical areas Cr ptococcus gattii t appears in tissue as a pleo
morphic budding yeast. The organisms ary greatly in si e
and shape in contrast to most other ungal organisms. The
capsule is usually prominent although it is in ersely propor
tional to the e tent o the granulomatous reaction. Generally
the capsule is easily identi ed in hemato ylin and eosin (
sections although mucicarmine methylene blue or alcian
blue staining can also be used. sually multiple yeast share a
common capsule. Cr ptococcus stains well with the ontana
asson stain or melanin.
Epidemiology
Cryptococcosis has a worldwide distribution and a ects
both humans and animals. The organism has been reco
ered rom human s in soil dust and pigeon droppings;
when deposited on window ledges in large cities pigeon
droppings are a source o in ection. The patient with dis
seminated cryptococcosis usually has a concomitant debili
tating disease such as A DS cancer leu emia lymphoma
renal ailure hepatitis al eolar proteinosis se ere diabetes
mellitus sarcoidosis tuberculosis or silicosis. Long term
oral prednisone or immunosuppressi e therapy or chronic
illnesses such as renal transplantation sarcoidosis or con
necti e tissue disease may also be a actor. Cases are being
reported in association with anti tumor necrosis actor
(T ) α biologic agents. The portal o entry is the lung.
ales outnumber emales . Cryptococcosis is most re
uent in persons age years.
Patients with A DS are particularly at ris or disseminated
disease. Cryptococcosis is the ourth leading cause o oppor
tunistic in ection and the second most common ungal oppor
tunist with o patients mani esting symptomatic disease.
Dissemination occurs in o patients with A DS with s in
in ol ement reported in . characteri ed by thic crusts warty egetations discharging
306
tahir99 - UnitedVRG
Immunology
The late slide agglutination test is sensiti e and speci c. t
may gi e alse positi e results in the presence o rheumatoid
actor. Direct microscopic e amination and late agglutination
ha e been used with lesional s in scrapings to aid in rapid
diagnosis. The complement ation test or cryptococcal poly
saccharide indirect uorescence test and L SA or crypto
coccal antigen detection are all help ul although L SA is
capable o detecting the presence o antigen earlier and at a
lower concentration than the other two tests.
Mycology
or direct e amination a drop o serum or e udate is placed
on a slide and a co erslip inserted. e amination shows yeast
drop o can be added to hal the co erslip and
drop o ndia in to the other hal to demonstrate the capsule.
The organism produces a moist shiny white colony on Sab
ouraud de trose agar. With aging the culture may turn to a
cream and then a tan color. Subcultures rom Sabouraud agar
may be made onto cornmeal agar and urea medium to aid in
distinguishing the yeast rom Can i a and other yeasts. A com
mercially a ailable D A probe detection assay allows rapid
culture con rmation.
Treatment
n seriously ill patients amphotericin B intra enously initially
ollowed by ucona ole orally is standard treatment. n less
se erely ill non A DS patients ucona ole mg day
or wee s may be e ecti e. n non A DS meningitis
ucytosine is gi en in combination with amphotericin B and
in patients in ected with V ucona ole is gi en inde nitely
at a suppressi e dose o mg day. n one study o A DS
) patients with cryptococcal meningitis mg day o ucon
a ole or itracona ole showed e cacy. The a ailability o ori
cona ole has e panded the number o options a ailable. n
disease re ractory to other drugs oricona ole has shown a
response rate o . Caspo ungin has limited acti ity against
cryptococcosis.
Hoang JK, et al: Localized cutaneous Cryptococcus albidus infection in
a 14-year-old boy on etanercept therapy. Pediatr Dermatol 2007;
24:285–288.
Ikeda T, et al: Disseminated cryptococcosis-induced skin ulcers in a
patient with autoimmune hepatitis. Case Rep Dermatol 2014;
6:98–102.
Nasser N, et al: Primary cutaneous cryptococcosis in an
immunocompetent patient. An Gras Dermatol 2011; 86:1178–1180.
Negroni R: Cryptococcosis. Clin Dermatol 2012; 30:599–609.
Pietras TA, et al: Coexistent Kaposi sarcoma, cryptococcosis, and
Mycobacterium avium intracellulare in a solitary cutaneous nodule in a
patient with AIDS. J Am Acad Dermatol 2010; 62:676–680.
Vazquez-Gonzalez D, et al: Opportunistic yeast infections. J Dtsch
Dermatol Ges 2013; 11:381–393.
Wilson ML, et al: Primary cutaneous cryptococcosis during therapy with
methotrexate and adalimumab. J Drugs Dermatol 2008; 7:53–54.
NORTH AMERICAN BLASTOMYCOSIS
orth American blastomycosis is also nown as Gilchrist s
disease blastomycosis and blastomycetic dermatitis.
ost cutaneous blastomycosis is the result o dissemination
rom a primary pulmonary ocus. The lesions are chronic
slowly progressi e errucous and granulomatous and are

Fig. 15-23 North American blastomycosis.
sinuses and pustules along the ad ancing edge ( ig. ).
The lesions are o ten multiple and are located mostly on
e posed s in. Papillomatous proli eration is most pronounced
in lesions on the hands and eet where the patches become
ery thic . The patches tend to in olute centrally and to orm
white scars as they spread peripherally. The crusts are thic
and dirty gray or brown. Beneath the crusts e uberant granu
lations are co ered with a seropurulent e udate which oo es
out o small sinuses that e tend down to indolent subcutane
ous abscesses. Lower e tremity nodules and pla ues clinically
and histologically suggesti e o Sweet syndrome ha e also
been described.
The primary in ection is almost always in the upper or
middle lobes o the lungs and most cases o blastomycosis
ne er de elop cutaneous dissemination. When dissemination
does occur the most common site is the s in accounting or
at least o cases o disseminated disease. t also re uently
disseminates to bone especially the ribs and ertebrae. ther
targets are the C S li er spleen and genitourinary system.
Cutaneous blastomycosis rarely occurs as a result o primary
cutaneous inoculation. Such patients ha e a clear history o
inoculation and present with a small primary nodule and sub
se uent secondary nodules along the draining lymphatics
creating a picture similar to sporotrichosis. ealing ta es place
within se eral months.
Etiology and pathology
The ungus lastom ces ermatiti is causes orth American
blastomycosis and was rst described by Gilchrist in . t
is re uently ound in soil and animal habitats. ermatiti is
is a dimorphic ungus with a mycelial phase at room tem
perature and a yeast phase at C. Direct microscopic e am
ination o a slide o the specimen should always be
made since culture o the ungus is di cult and the organ
ism may be ound in purulent e udates obtained rom s in
lesions. The specimen should be cultured by a uali ed labo
ratory on Sabouraud de trose agar ycosel and brain heart
in usion agar to which blood has been added. Aerial myce
lium will de elop in days orming a white cottony
growth that turns tan with age. The structures are septate
mycelia with characteristic conidia on the sides o hyphae.
The conidia are μm and ariously shaped rom round to
o al orms. Culture at C produces a slow growing wrin
led yeast with spherules single budding cells and some
aborti e hyphae. A D A probe detection assay is a ailable
or rapid culture con rmation.
Cutaneous blastomycosis usually demonstrates mar ed
pseudoepitheliomatous hyperplasia o the epidermis with
neutrophilic abscesses. Giant cells are re uently present in the
dermal in ltrate. rganisms are typically ew in number and
are most re uently ound within giant cells or intraepidermal
North American blastomycosis
abscesses. The organism is a thic walled yeast usually
μm in diameter although giant orms ha e been reported in
tissue. ermatiti is lac s a capsule but has a thic and dis
tinctly asymmetric re ractile wall. Broad based budding may
occasionally be noted. Rarely acute s in lesions may lac
pseudoepitheliomatous hyperplasia and demonstrate a di use
neutrophilic dermal in ltrate. They may present as cutaneous
nodules sometimes with a locali ed distribution.
Primary cutaneous blastomycosis demonstrates a neutro
philic in ltrate with many budding cells o blastomycetes. n
later lesions a granulomatous in ltrate is ound. The lymph
nodes may show mar ed in ammatory changes giant cells
containing the organisms lymphocytes and plasma cells.
Lung in ol ement may show many changes that are sugges
ti e o tuberculosis with tubercle ormation. Purulent abscesses
may occur in the lungs and bone.
Epidemiology
orth American blastomycosis is pre alent in the southeast
ern nited States and the hio and ississippi ri er basins
reaching epidemic proportions in entuc y and ississippi;
the latter has the highest pre alence o blastomycosis in orth
America. There is a male emale ratio o appro imately
and most patients are o er age . ten the cutaneous orm
occurs in patients without a nown history o pulmonary
lesions.
utdoor acti ity a ter periods o hea y rain is a ris actor
or acute pulmonary disease. Bea er lodges are a common site
or the ungus and some reports ha e lin ed outbrea s o
disease with outings near a bea er lodge. Blastomycosis has
also been reported rom the bite o a dog with pulmonary
blastomycosis. Transmission has been reported between men
with prostatic in ol ement and their se ual partners.
Ris actors or symptomatic disease include pree isting
illness. n one study one uarter o patients with blastomyco
sis had underlying immunosuppression including those with
organ transplantation and had diabetes mellitus. n the
southern states blac s ha e a higher incidence than whites
and mortality is also higher among A rican Americans.
Immunology
Serologic tests are per ormed by immunodi usion or L SA.
Commercial antigen test its are a ailable or rapid diagnosis.
Differential diagnosis
Blastomycosis may closely resemble halogenoderma
blastomycosis li e pyoderma pemphigus egetans tubercu
losis errucosa cutis syphilis granuloma inguinale drug
eruptions and trichophytic granuloma. The diagnosis is estab
lished by demonstration o ermatiti is or serologic testing.
The course o blastomycosis is more rapid and in ol ement
more e tensi e than in errucous tuberculosis. Vegetati e
lesions o tertiary syphilis are usually accompanied by other
signs o the disease and ha e a predilection or the scalp and
mucocutaneous unctions. Bromide and iodide eruptions are
generally more acutely in ammatory but may be indistin
guishable rom blastomycosis. Biopsy drug history and blood
307
 iodine or bromine le els may be re uired to distinguish the
15 two conditions.
Treatment
Diseases Resulting from Fungi and Yeasts
tracona ole mg day or months is the treatment
o choice or orth American blastomycosis. Amphotericin B
or a total dose o . g may be re uired or e tremely ill
patients. Some data suggest that or those with li e threatening
disease initial treatment with a lipid ormulation o ampho
tericin B should be ollowed by a prolonged course o oral
oricona ole. lucona ole mg day or at least
months is e ecti e in o patients with non li e threaten
ing disease. Voricona ole has also been used alone or patients
with less serious blastomycosis.
Azar MM, et al: Cutaneous blastomycosis masquerading as pyoderma
gangrenosum. J Clin Microbiol 2014; 52:1298–1300.
Brick KE, et al: Cutaneous and disseminated blastomycosis. Pediatr
Dermatol 2013; 30:23–28.
Kauffman CA, et al: Endemic fungal infections in solid organ and
hematopoietic cell transplant recipients enrolled in the TRANSNET.
Transpl Infect Dis 2014; 16:213–224.
Lopez-Martinez R, et al: Blastomycosis. Clin Dermatol 2012;
30:565–572.
Patel AJ, et al: Diagnosis of blastomycosis in surgical pathology and
cytopathology: correlation with microbiologic culture. Am J Surg Pathol
2010; 34:256–261.
Rucci J, et al: Blastomycosis of the head and neck. Am J Otolaryngol
2014; 35:390–395.
SOUTH AMERICAN BLASTOMYCOSIS
ucocutaneous in ol ement in South American blastomyco
sis also nown as paracoccidioidomycosis is almost always a
sign o disseminated disease primarily in the lungs. Rare cases
may arise rom inoculation. n Bra il the disease causes about
deaths per year.
The mucocutaneous type usually begins in the mouth where
small papules and ulcerations appear. Gingi al lesions are
most common ollowed by lesions o the tongue and lips.
With time ad acent tissues are a ected and e tensi e ulcer
ations e entually destroy the nose lips and ace ( ig. ).
S in lesions may show ulcerations pseudoepitheliomatous
hyperplasia and microabscesses. The lymphangitic type man
i ests itsel by enlargement o the regional lymph nodes soon
a ter the appearance o the initial lesions about the mouth. The
adenopathy may e tend to the supracla icular and a illary
regions. odes may become greatly enlarged and brea down
Fig. 15-24 Paracoccidioidomycosis. (Courtesy of Maria Silvia
Negrao, MD.)
308
tahir99 - UnitedVRG
with ulcerations that secondarily in ol e the s in causing
se ere pain and dysphagia with progressi e cache ia and
death. Primary s in lesions are less common. The in ection
may closely simulate odg in disease especially when the
suprahyoid preauricular or retroauricular groups o lymph
nodes are in ol ed.
There is a isceral type caused by hematogenous spread o
the disease to the li er adrenal glands spleen intestines
and other organs. There is also a mi ed type that has the
combined symptomatology o the mucocutaneous lymphan
gitic and isceral types. South American blastomycosis may
present as a rapidly progressi e acute disease or ollow a
subacute course or it may occur as a chronic slowly ad anc
ing orm.
Etiology and pathology
Lut rst described South American blastomycosis in Bra il in
. t is caused by the ungus Paracocci ioi es brasiliensis
Biopsies may demonstrate pseudoepitheliomatous hyper
plasia abscess ormation or ulceration. A granulomatous
in ammatory in ltrate is re uently present consisting o
lymphocytes epithelioid cells and Langerhans giant cells. The
organism appears as a round cell μm in diameter with
a delicate wall. ultiple buds may be present creating a
resemblance to a mariner s wheel.
This chronic granulomatous disease is endemic in Bra il and
also occurs in Argentina and Vene uela. ccasional cases ha e
been reported in the nited States e ico Central America
urope and Asia. ost o these patients ha e a tra el history
to endemic areas. The disease is generally ound among labor
ers mostly in men. Although the initial in ection is usually
respiratory some indi iduals may become in ected by pic ing
their teeth with twigs or rom chewing lea es. Armadillos may
harbor the disease.
South American blastomycosis is times more common in
men which is o particular interest because it has been shown
that β estradiol inhibits transition rom the mycelial to the
tissue in asi e yeast orm. P brasiliensis can lodge in peri
odontal tissues and some cases start a ter e traction o teeth.
any cases ha e been reported in patients with A DS or organ
transplant recipients in whom the course is usually acute and
se ere.
Mycology
n culture the ungal colony is cream colored compact and
powdery. Chlamydospores are round or o al. longate lateral
conidia may be present.
Immunology
Complement ation tests are positi e in o se ere cases
and the titer rises as the blastomycosis becomes more se ere.
With impro ement the titer decreases. mmunodi usion tests
are o ten used or diagnosis and posttherapy ollow up. The
test is highly speci c but only about sensiti e.
Treatment
tracona ole mg day or months is the treatment
o choice or most patients with South American blastomy
cosis because it is well tolerated and shows an e cellent
response in . etocona ole mg day or months
is e ually e ecti e but not as well tolerated. Trimethoprim
sul ametho a ole (T P S ) at mg two to three
times daily or days then mg day or years is
e ecti e in about o patients although sul a resistance
has been reported. Patients with se ere disease or those intol
erant to the prior therapies may respond to amphotericin B.
When V patients are in ected li elong therapy is the rule.
Bonifaz A, et al: Endemic systemic mycoses. J Dtsch Dermatol Ges
2011; 9:705–715.
Borges SR, et al: Itraconazole vs. trimethoprim-sulfamethoxazole: a
comparative cohort study of 200 patients with paracoccidioidomycosis.
Med Mycol 2014; 52:303–310.
Marques SA. Paracoccidioidomycosis: epidemiological, clinical,
diagnostic and treatment up-dating. An Bras Dermatol 2013;
88:700–711.
Safe IP, et al: Extra-pulmonary manifestations of
paracoccidioidomycosis associated with acquired immunodeficiency
syndrome. An Bras Dermatol 2014; 89:150–153.
Zavascki AP, et al: Paracoccidioidomycosis in organ transplant recipient.
Rev Inst Med Trop São Paulo 2004; 46:279–281.
SPOROTRICHOSIS
Sporotrichosis usually results rom direct inoculation by a
thorn cat s claw or other minor penetrating in ury. The earli
est mani estation may be a small nodule that may heal and
disappear be ore the onset o other lesions. n the course o a
ew wee s nodules generally de elop along the draining lym
phatics ( ig. ). These lesions are at rst small dus y red
painless and rm. n time the o erlying s in becomes adher
ent to them and may ulcerate. When the lesions occur on the
ace the lymphatic drainage is radial rather than linear and
secondary nodules occur as rosettes around the primary lesion.
Regional lymphangitic sporotrichosis is the common type
accounting or o cases. i ed cutaneous sporotrichosis is
seen in o cases and is characteri ed by a solitary ulcer
pla ue or crateri orm nodule without regional lymphangitis
( ig. ). t may also present as locali ed rosacea li e lesions
o the ace without regional lymphangitis. ncreased host resis
tance a smaller inoculum acial location and ariations in
strain pathogenicity ha e all been suggested as triggers or the
Fig. 15-25
Sporotrichosis.
ed cutaneous orm. The distribution in children is similar to
that in adults.
Disseminated sporotrichosis is the least common orm.
actors that predispose to e tracutaneous disease include oral
prednisone therapy other immunosuppressi e drugs (includ
Sporotrichosis
ing T α inhibitors) chronic alcoholism diabetes mellitus
hematologic malignancies and A DS. Systemic in asion may
produce cutaneous pulmonary G articular and brain
lesions. Arthritis or bone in ol ement occurs in most patients.
The cutaneous lesions are reddish tender nodules which
so ten orm cold abscesses and e entually suppurate lea ing
chronic ulcers or stulas. These are usually around arthritic
oints and the ace and scalp but may occur anywhere on the
s in. At times only internal in ol ement is apparent.
Etiology and pathology
Sporotrichosis is caused by the Sporothrix schenc ii comple
with more than si species identi ed by molecular techni ues.
These ungi are dimorphic in that they grow in a yeast
orm at C and in a mycelial orm at room temperature.
Cutaneous disease typically presents with palisading granulo
matous dermatitis surrounding a stellate suppurati e abscess.
rganisms appear as cigar shaped yeast in tissue but are
rarely seen in orth American cases. n Asian cases o sporo
trichosis the organisms are re uently more numerous. Aster
oid bodies and mycelial elements are pre alent in regional
lymphangitic sporotrichosis. PCR methods o detection ha e
been de eloped.
Epidemiology
There seems to be no geographic limitation to the occurrence
o sporotrichosis. ost o ten the primary in asion is seen as
an occupational disease in gardeners orists and laborers
ollowing in uries by thorns straw or sphagnum moss. The
pathogen typically li es as a saprophyte on grasses shrubs
and other plants. Carnations rose bushes barberry shrubs
and sphagnum moss are common sources. igh humidity and
high temperature a or in ection. perimentally it has been
produced in many laboratory animals and spontaneous cases
ha e been obser ed in horses mules dogs cats mice and
rats. n cats sporotrichosis usually produces disseminated
disease. The organism may be ound on the claws and may be
transmitted to humans through cat scratches. pidemics
related to cat e posure ha e been documented. This is becom
ing the most common mode o transmission in many areas o
the world. ultiple amily members or eterinary wor ers
may be in ected by a single cat.
Fig. 15-26 Fixed
cutaneous
sporotrichosis.
309
 Mycology
15 n Sabouraud agar a moist white colony de elops within
days. The sur ace becomes wrin led and olded. Later the
culture turns tan and ultimately blac because the organism is
Diseases Resulting from Fungi and Yeasts
capable o producing melanin. n slide culture preparations
the colony shows septate branching mycelia. Conidia are
ound in clusters or in slee eli e arrangements on delicate
sterigmata. the culture is grown at C grayish yellow
el ety yeastli e colonies are produced. Cigar shaped round
or o al budding cells hyphae and conidia may be seen
microscopically.
Immunology
Culture e tracts rom S schenc ii nown as sporotrichins will
produce a delayed tuberculin type reaction in persons who
ha e had sporotrichosis. The test is airly reliable but only
indicates pre ious e posure. Agglutination testing has been
de eloped but clinical diagnosis biopsy and culture remain
the most common means o establishing a diagnosis.
Differential diagnosis
Demonstration by culture establishes the diagnosis and it is
important to di erentiate sporotrichosis rom other lymphan
gitic in ections. Atypical mycobacteriosis (especially M cobac
terium marinum) leishmaniasis and nocardiosis all produce
lymphangitic spread. n contrast tuberculosis cat scratch
disease tularemia glanders melioidosis lymphogranuloma
enereum and anthra produce ulceroglandular syndromes
(ulcer with regional lymphadenopathy rather than ulcer with
nodules along lymphatic essels).
Treatment
tracona ole is e ecti e or cutaneous and lymphocutaneous
sporotrichosis at a dose o mg day or wee s a ter all
lesions ha e resol ed usually months. there is no
response the dose may be doubled or terbina ne mg two
times daily is a urther option. Lesser doses o itracona ole
mg day and terbina ne mg day ha e been used
with e cellent cure rates.
or cutaneous orms potassium iodide g day remains
an e ecti e and ine pensi e therapeutic option and may be
e ecti e when itracona ole therapy ails. Decades o e peri
ence demonstrate the e ecti eness o potassium iodide despite
the absence o published high le el e idence. odide therapy
usually re uires wee s o treatment. Generally it is best
to begin with drops o the saturated solution in grape ruit
or orange uice three times daily a ter meals. The drops can
also be put in mil but strong a ored citrus uices are better
at mas ing the taste. The dose should be gradually increased
up to drops three times daily. Potassium iodide is not
suitable or pregnant women. Ad erse e ects o iodide therapy
include nausea omiting parotid swelling acnei orm rash
cory a snee ing swelling o the eyelids hypothyroidism a
brassy taste increased lacrimation and sali ation ares o
psoriasis and occasionally depression. ost o the side e ects
can be controlled by stopping the drug or a ew days and
reinstituting therapy at a reduced dosage.
Application o local hot compresses hot pac s or a heating
pad twice a day has been ad ocated as a use ul ad unct
because S schenc ii is intolerant to temperatures abo e . C
( ).
310
tahir99 - UnitedVRG
n adult disseminated sporotrichosis amphotericin B gi en
as a lipid ormulation at
ollowed by
mg g daily is recommended
mg twice daily or at least year. n immu
nocompromised patients treatment with mg day may
need to be li elong. Sporothrix schenc ii is more sensiti e to
itracona ole than oricona ole or posacona ole although the
latter drugs also represent therapeutic options.
Bonifaz A, et al: Sporotrichosis in childhood. Pediatr Dermatol 2007;
24:369–372.
De Lima Barros MB, et al: Treatment of cutaneous sporotrichosis with
itraconazole: study of 645 patients. Clin Infect Dis 2011;
52:e200–e206.
Francesconi G, et al: Terbinafine (250 mg/day): an effective and safe
treatment of cutaneous sporotrichosis. J Eur Acad Dermatol Venereol
2009; 23:1273–1276.
Freitas DF, et al: Sporotrichosis in HIV-infected patients. Med Mycol
2012 ;50:170–178.
Gewehr P, et al: Sporotrichosis in renal transplant patients. Can J Infect
Dis Med Microbiol 2013; 24:e47–e49.
Hay RJ, et al: Outbreaks of sporotrichosis. Curr Opin Infect Dis 2008;
21:119–121.
Kauffman CA, et al: Clinical practice guidelines for the management of
sporotrichosis: 2007 update by the Infectious Diseases Society of
America. Clin Infect Dis 2007; 45:1255–1265.
Macedo PM, et al: New posology of potassium iodide for the
treatment of cutaneous sporotrichosis. J Eur Acad Dermatol
Venereol 2014; Sep 17.
Schubach A, et al: Epidemic sporotrichosis. Curr Opin Infect Dis 2008;
21:129–133.
Sharon VR, et al: Disseminated cutaneous sporotrichosis. Lancet Infect
Dis 2013; 13:95.
Tang MM, et al: Cutaneous sporotrichosis. Int J Dermatol 2012;
51:702–708.
Vásquez-del-Mercado E, et al: Sporotrichosis. Clin Dermatol 2012;
30:437–443.
Yamada K, et al: Cutaneous sporotrichosis treatment with potassium
iodide. Rev Inst Med Trop São Paulo 2011; 53:89–93.
CHROMOBLASTOMYCOSIS
Chromoblastomycosis usually a ects one o the lower e tremi
ties ( ig. ). t occurs as a result o direct inoculation o the
organism into the s in. As a rule lesions begin as a small pin
scaly papule or warty growth on some part o the oot or lower
leg then slowly spread through direct e tension and satellite
lesions. With time they de elop a errucous or nodular border
and central atrophy and scarring. Small lesions may resemble
common warts. Regional lymphadenitis may result rom sec
ondary bacterial in ection and a lymphangitic pattern o in ec
tion has been reported. n rare cases the disease begins on an
upper e tremity or the ace. Rarely C S in ol ement has been
reported both with and without associated s in lesions.
There is a male predominance and armers account or
almost o patients with chromoblastomycosis. The disease
is slowly progressi e and the a erage time between the
appearance o lesions and diagnosis is almost years. Lesions
occur at sites o minor trauma. S uamous cell carcinoma may
occur in long standing cases.
Etiology and pathology
ost cases are caused by one o se eral dematiaceous ungi.
onsecaea pe rosoi is the most common cause and accounts or
or more o the cases reported in South America. t has also
been reported as the most common cause in other parts o the
world. ther agents include Phialophora verrucosa onsecaea
compacta Cla osporium carrionii and hinocla iella a uaspersa
Exophiala spinifera and Exophiala jeanselmei ha e been reported
 Fig. 15-27
Chromoblastomycosis.
(Courtesy of Maria
Silvia Negrao, MD.)
in isolated cases. Patients may ha e more than one organism
and cutaneous lesions caused by both paracoccidioidomycosis
and chromoblastomycosis ha e been reported in the same
patient. Patients may also ha e chromoblastomycosis concur
rently with mycetoma or in asi e phaeohyphomycosis.
istopathologically lesions are characteri ed by pseudoepi
theliomatous hyperplasia with intraepidermal abscess a
dermal granulomatous reaction and the presence o pig
mented ungal sclerotic bodies. The ungi o ten appear in clus
ters that reproduce by e uatorial septation rather than by
budding. The presence o sclerotic bodies ( edlar bodies
copper pennies ) rather than hyphae distinguishes the in ec
tion rom in asi e phaeohyphomycosis. The organisms are
o ten seen in association with an embedded splinter. edlar
bodies are usually easily identi ed but iehl eelsen and
Wade ite stains ha e also been used to identi y the patho
genic organisms as has duple PCR.
Staining or ungal antigens has demonstrated that they
accumulate in macrophages and occasionally in actor a There are many types o clinical lesions caused by these
positi e dendrocytes or Langerhans cells. The immune
response to the organism appears to a ect the clinical and
histologic presentation. Patients with errucous pla ues dem
onstrate a T helper type (Th ) immunologic response
whereas those with erythematous atrophic pla ues ha e a Th
response.
Epidemiology
Chromoblastomycosis was rst recogni ed in Bra il by
Pedroso in . Since then it has been ound in other parts
o South America and the Caribbean adagascar South Asia
ast Asia the nited States Russia and many other countries.
Bare ooted arm wor ers bear the largest burden o in ection.
Trauma rom wood products and soil e posure results in
implantation o the organism and dissemination is rare.
Mycology
The microorganisms produce blac slowly growing heaped
up colonies. The genera di er according to the type o conid
iophore produced. All produce melanin.
Phaeohyphomycosis
Treatment
Treatment is di cult and chromoblastomycosis o ten a ects
those who cannot a ord medication. n some series only
about o patients were cured although almost
impro ed. About ail therapy and recrudescence o the
disease is noted in more than o patients. Smaller lesions
are best treated by surgical e cision or cryotherapy. n one
study o patients the number o cryosurgeries aried rom
to and treatment lasted or up to months. nly three
patients did not respond. the lesions are e tensi e chronic
or burrowing itracona ole mg day is gi en or
months or until there is a response. Terbina ne mg
day alone or in combination with itracona ole mg
day has been e ecti e in some patients as has posacona ole
mg day. Cryotherapy C laser apori ation PDT and
local hyperthermia are ad uncts. Combination amphotericin
B and itracona ole has been used in resistant cases as has
isolated limb in usion with melphalan and actinomycin D.
Despite these options some lesions remain resistant and
amputation may be una oidable in some patients.
Ameen M: Chromoblastomycosis. Clin Exp Dermatol 2009; 34:849–854.
Garnica M, et al: Difficult mycoses of the skin: advances in the
epidemiology and management of eumycetoma, phaeohyphomycosis
and chromoblastomycosis. Curr Opin Infect Dis 2009; 22:559–563.
Krzysciak PM, et al: Chromoblastomycosis. Postepy Dermatol
Allergol 2014; 31:310–321.
Naveen KN, et al: Chromoblastomycosis presenting as a phagedenic
ulcer on the face. Int J Dermatol 2012; 51:576–578.
Queiroz-Telles F, et al: Challenges in the therapy of
chromoblastomycosis. Mycopathologia 2013; 175:477–488.
Torres E, et al: Chromoblastomycosis associated with lethal squamous
cell carcinoma. An Bras Dermatol 2010; 85:267–270.
Torres-Guerrero E, et al: Chromoblastomycosis. Clin Dermatol 2012;
30:403–408.
PHAEOHYPHOMYCOSIS
This heterogeneous group o mycotic in ections is caused by
dematiaceous ungi with morphologic characteristics in tissue
that include hyphae yeastli e cells or a combination o these.
This contrasts with chromomycosis in which the organism
orms round sclerotic bodies.
organisms. Tinea nigra is an e ample o super cial in ection.
Alternariosis can also present as a super cial pigmented
ungal in ection in immunocompetent patients. Subcutaneous
disease occurs most re uently as indolent abscesses at the site
o minor trauma (so called phaeomycotic cyst ). Exophiala
jeanselmei is the most common cause o this presentation in
temperate climates. Systemic phaeohyphomycosis is largely a
disease o immunocompromised patients including solid
organ transplant recipients although primary cerebral orms
occur in immunocompetent patients. Locali ed orms gener
ally result rom primary inoculation o the organism into the
s in. Disseminated disease may also begin as a s in in ection
although catheter sepsis is a recogni ed cause o disseminated
in ection. The lesions usually appear as dry blac leathery
eschars with a scalloped erythematous edematous border
( ig. ). ipolaris spicifera is the most common cause o
disseminated disease although Sce osporium proli cans has
311

15
Diseases Resulting from Fungi and Yeasts
Fig. 15-28 Phaeohyphomycosis.
been reported as the most common organism in some areas.
The presence o melanin in the cell wall may be a irulence
actor or these ungi. osinophilia is noted in about o pathogens but also as a cause o human in ection. As a pig
patients with disseminated disease. Phaeohyphomycosis o ten
disseminates to many organs. ndocarditis is mostly reported
on porcine al es. n some series mortality rom disseminated
disease is about . ore than hal o patients with primary
C S disease ha e no nown underlying immunode ciency.
ortality rates rom C S in ections are high regardless o
immune status.
Etiology and pathology
any blac molds are capable o causing phaeohyphomycosis
including E jeanselmei spicifera lternaria spp. Dact laria
gallopava Phialophora parasitica Cla osporium sphaerospermum
angiella ermatiti is Exserohilum rostratum Cla ophialophora
bantiana allemia sebi and Chaetomium globosum Some ungi
such as Phialophora verrucosa can cause both phaeohyphomy
cosis and chromoblastomycosis. Some ungi such as E jeansel
mei may cause mycetoma (characteri ed by grain ormation)
in some patients and phaeohyphomycosis or chromoblasto
mycosis in others.
All these organisms produce pigmented hyphae in tissue
and culture although the pigment may only be isible ocally
in some histologic sections. elanin can be stained by the
ontana asson method but many molds produce enough
melanin to stain positi e and a positi e stain should not be
misinterpreted as proo o phaeohyphomycosis. rganisms as
di erse as ygomycetes and dermatophytes can stain with
ontana asson. When hyphae appear brown in tissue there
is little uestion as to the diagnosis but when the organism
appears hyaline in tissue the presence o melanin staining
must be interpreted in the conte t o the ungal morphology.
ost organisms o phaeohyphomycosis produce thic re rac
tile walls and ha e prominent bubbly cytoplasm. This con
trasts with the thin delicate walls o organisms such as
spergillus usarium and dermatophytes. ygomycetes are
aseptate and usually appear hollow in tissue sections. Their
thic re ractile wall usually stains intensely red with
contrasting with the pale wall o a phaeomycotic organism.
Some organisms such as ipolaris produce round dilated
structures that resemble spores in tissue. The mi o round
structures and hyphae is a help ul clue to the presence o a
blac mold in tissue.
312
tahir99 - UnitedVRG
Treatment
Phaeomycotic cysts are best treated with e cision. Super cial
phaeohyphomycosis may respond to topical anti ungal agents
and super cial debridement. or in asi e and disseminated
disease surgical e cision should generally be combined with
anti ungal therapy. tracona ole has the best record o treating
this group o in ections and doses o mg day or higher
are usually needed or at least months. Reproducible ungal
sensiti ity studies are a ailable through a ew re erence labo
ratories but the process is slow and patients with dissemi
nated disease ha e little time to spare. Case reports indicate
success with oricona ole and terbina ne or itracona ole and
terbina ne. or C S disease posacona ole has been e ecti e
as may combinations o amphotericin B ucytosine and itra
cona ole. Complete e cision o primary brain lesions may be
prudent when possible. n widely disseminated disease
e cision o lesions becomes impractical but debul ing o s in
disease may be o some alue.
ALTERNARIOSIS
lternaria is a genus o molds recogni ed as common plant
mented ungus it is one cause o phaeohyphomycosis. ost
reported cases o in asi e in ection ha e occurred in immuno
compromised patients with the most re uent ris actors
being solid organ transplantation and Cushing syndrome.
Cutaneous alternariosis usually presents as ocal ulcerated
papules and pla ues or pigmented patches on e posed s in o
the ace orearms and hands or nees o immunocompetent
patients. Topical corticosteroids may predispose to local in ec
tion. Locali ed disease in immunocompetent patients may
respond to local debridement hyperthermia wide surgical
e cision or ohs micrographic surgery. tracona ole has been
success ul although resistance has also been reported. Terbi
na ne posacona ole oricona ole etocona ole caspo un
gin and intralesional micona ole ha e also been used
success ully.
Coutinho I, et al: Cutaneous alternariosis—a case series of an
increasing phaeohyphomycosis. J Eur Acad Dermatol Venereol 2014;
Jun 9.
Fukai T, et al: A case of phaeohyphomycosis caused by Exophiala
oligosperma successfully treated with local hyperthermia. Med Mycol J
2013; 54:297–301.
Isa-Isa R, et al: Subcutaneous phaeohyphomycosis (mycotic cyst). Clin
Dermatol 2012; 30:425–431.
Pastor FJ, et al: Alternaria infections: laboratory diagnosis and relevant
clinical features. Clin Microbiol Infect 2008; 14:734–746.
Schieffelin JS, et al: Phaeohyphomycosis fungal infections in solid
organ transplant recipients: clinical presentation, pathology, and
treatment. Transpl Infect Dis 2014; 16:270–278.
Seyfarth F, et al: Successful treatment of cutaneous alternariosis with
caspofungin in a renal transplant patient. Mycoses 2012;
55:457–462.
Tong Z, et al: Generalized subcutaneous phaeohyphomycosis caused
by Phialophora verrucosa. Mycopathologia 2013; 175:301–306.
MYCETOMA
ycetoma also nown as adura oot and maduromycosis
is a chronic granulomatous subcutaneous in ammatory
disease caused by lamentous bacteria (actinomycetoma) or
true ungi (eumycetoma). The organisms enter the s in by
traumatic inoculation. Both orms o mycetoma present as a
triad o progressi e subcutaneous swelling with sinus tracts
that discharge grains ( ig. ).
 Fig. 15-29 Mycetoma.
(Courtesy of Shyam
Verma, MD.)
The disease progresses slowly. ycetomas generally begin
on the instep or the toe webs. The lesion usually is relati ely
painless nontender and rm. The o erlying s in may be
normal or attached to the underlying tumor. ature lesions
o ten ha e nodules and draining sinuses. ot only the s in
and subcutaneous tissues but also the underlying ascia and
bone are in ol ed. ther parts o the body such as the hands
arms chest aw and buttoc s may be in ol ed. posed sites
are most common and lesions in co ered areas are almost
always actinomycetomas.
Etiology and pathology
ycetoma is di ided into actinomycetoma produced by bac
teria and eumycetoma produced by true ungi. Actinomyce
tomas are caused by ocar ia ctinoma ura and Streptom ces
umycetomas are caused by true ungi including pigmented
ungi such as Ma urella spp. and hyaline ungi such as Pseu
allescheria Causati e dematiaceous organisms include Ma
urella grisea M m cetomatis Leptosphaeria senegalensis L
tomp insii Exophiala jeanselmei P renochaeta romeri Phialophora
verrucosa Curvularia lunata and C geniculate The hyaline or
white ungi that cause mycetoma include Pseu allescheria
bo ii (which may occasionally disseminate as the anamorph
or ase ual orm Sce osporium apiospermum) cremonium falci
forme recifei usarium moniliform solanii spergillus ni u
lans and eotestu ina rosatii amples o actinomycetomas
are those caused by ocar ia asteroi es brasiliensis caviae
otiti iscaviarum ctinoma ura ma urae ctinoma ura pellet
ieri ctinom ces israelii and Streptom ces somaliensis israelii
is the ma or cause o lumpy aw a orm o mycetoma.
Almost all actinomycetomas produce light colored grains
as do hyaline ungi. Red grains are usually produced by
pelletieri. Pigmented ungi produce dar grains.
istologic sections demonstrate stellate abscesses contain
ing grains. Gram stain o an actinomycotic grain shows gram
positi e thin laments μm thic embedded in a
gram negati e amorphous matri . Club ormation in the
periphery o a grain may be seen. Special stains or demonstra
Mycetoma
tion o ungi such as PAS and G S will clearly show hyphae
and other ungal structures within the grain. yphae o
μm in thic ness suggest true ungal mycetoma.
Epidemiology
The mycetoma belt stretches between the latitudes o south
and north. Relati ely arid areas ha e higher rates o in ec
tion than humid areas. n the Western emisphere the inci
dence is highest in e ico ollowed by Vene uela and
Argentina. n A rica it is ound most re uently in Senegal
Sudan and Somalia. ycetomas are also reported in large
numbers in ndia. Actinomycetomas outnumber eumyceto
mas by which is ortunate because actinomycetomas
are much more responsi e to therapy. The male emale ratio
aries rom to .
Mycology
or true ungi (eumycetoma) cultures are made rom the
grains on Sabouraud de trose agar containing . yeast
e tract and suitable antibiotics. Cultures should be incubated
at C and room temperature. or actinomycetes grains
culture should be made in brain heart in usion agar incubated
aerobically and anaerobically at C and on Sabouraud de
trose agar with . yeast e tract incubated aerobically at
C and room temperature. The specimen or culture should
be ta en rom a deep site pre erably rom the base o a biopsy.
Cultures should be processed by a re erence laboratory and
should not be grown in an o ce laboratory.
Diagnosis
ycetoma may be diagnosed with consideration o the triad
o signs tume action sinuses and granules. Pus gathered
rom a deep sinus will show the granules when e amined
microscopically. The slide containing the specimen should
ha e drop o a added and a co erslip placed on
top. A biopsy may be re uired. Radiographs will show the
bone in ol ement and magnetic resonance images may show
the dot in a circle sign corresponding to grains.
Treatment
Actinomycetomas generally respond to antibiotic therapy
although patients with ad anced disease may also need
surgery. n israelii in ection penicillin in large doses is cura
ti e. asteroi es or brasiliensis is usually treated with sul
onamides. A combination o ri ampicin and cotrimo a ole
has also been used. Se ere re ractory disease may respond to
imipenem.
Patients in the early stage o eumycetoma may be success
ully treated by surgical remo al o the area. n the more
ad anced stages a combination o anti ungal therapy and
surgery may be success ul. n some patients with eumyce
toma amputation will be necessary. Voricona ole alone or
combined with surgical e cision is the treatment o choice or
cases caused by P bo ii other options include surgery com
bined with itracona ole mg twice daily until clinically
313
 well or with posacona ole mg twice daily. P bo ii is not Fig. 15-30
15 generally responsi e to amphotericin. Lobomycosis.
(Courtesy of Maria
Ameen M, et al: Efficacy of imipenem therapy for Nocardia
actinomycetomas refractory to sulfonamides. J Am Acad Dermatol Silvia Negrao, MD.)
Diseases Resulting from Fungi and Yeasts

2010; 62:239–246.
Bonifaz A, et al: Subcutaneous mycoses. J Dtsch Dermatol Ges 2010;
8:619–628.
Castro LG, et al: Clinical and mycologic findings and therapeutic
outcome of 27 mycetoma patients from São Paulo, Brazil. Int J
Dermatol 2008; 47:160–163.
Gosselink C, et al: Nocardiosis causing pedal actinomycetoma: a
case report and review of the literature. J Foot Ankle Surg 2008;
47:457–462.
Van de Sande WW: Global burden of human mycetoma. PLoS Negl Trop
Dis 2013; 7:e2550.
Welsh O, et al: Lobomycosis. Ther Clin Risk Manag 2014; 10:851–860.

KELOIDAL BLASTOMYCOSIS
(LOBOMYCOSIS OR LACAZIOSIS)
eloidal blastomycosis was originally described by Jorge Lobo
in . ost cases ha e occurred in countries in Central and
South America. ne case occurred in an a uarium attendant
in urope who cared or an in ected dolphin; and another in
an American who had wal ed under the pounding water o
Angel alls on a trip to South America. n the nited States
the disease has been identi ed in a signi cant proportion o
Fig. 15-31
dolphins inhabiting the ndian Ri er Lagoon in lorida and
Rhinosporidiosis.
estuarine waters near Charleston South Carolina. Low
albumin le els and a de ecti e immune response are ound in
in ected dolphins and in ection is lin ed to reshwater e u
ents emptying into the bodies o water.
eloidal blastomycosis may in ol e any part o the body
and the lesions appear characteristically eloidal ( ig. ).
istulas may occur. The nodules gradually increase in si e by
in asion o the surrounding normal s in or through the super
cial lymphatics. Long standing cases may in ol e the regional
lymph nodes. A common location is the ear which may resem
ble the cauli ower ear o a bo er. Disseminated disease has
also been described.
The ungus is probably ac uired rom water soil or egeta
tion in orested areas where the disease is pre alent. Agricul
tural laborers ha e been most re uently a ected with o
cases occurring in men.
The causati e organism Laca ia loboi is an obligate parasite.
Culture has not been success ul but the organism can grow in Francesconi VA, et al: Lobomycosis. Ther Clin Risk Manag 2014;
mouse ootpads. istologically the epidermis is atrophic. The 10:851–60.
organisms are thic walled re ractile spherules larger than Francesconi F, et al: Lobomycosis. N Engl J Med 2012; 364:e2.
those o P brasiliensis. ne or two buds may be seen but ne er Paniz-Mondolfi A, et al: Lobomycosis. Mycoses 2012; 55:298–309.
multiple budding as in Paracocci ioi es brasiliensis. The organ Talhari S, et al: Lobomycosis. Clin Dermatol 2012; 30:420–424.
isms are typically numerous and appear in chains o spheres
connected by short narrow tubes. The cellular in ltrate is
composed o histiocytes giant cells and lymphocytes. n RHINOSPORIDIOSIS
dolphin tissue the organism appears signi cantly smaller
than in human tissue. This may be a mani estation o the host Rhinosporidiosis is a polypoid disease usually in ol ing
response or may indicate that the organism in the two hosts mucosal sur aces especially the nasal mucosa ( ig. ).
may not be identical. Con uncti al lacrimal oral and urethral tissues may also be
Surgical e cision o the a ected areas may be curati e when in ol ed and genital lesions may resemble condylomata. The
the lesions are small but recurrence is common. Complete lesions begin as small papillomas and de elop into peduncu
resolution o eloidal blastomycosis has been reported in a lated tumors with ssured and warty sur aces. Grayish white
patient treated or year with a combination o itracona ole ec s may be noted on the tissue corresponding to transepi
mg day and clo a imine mg day. Combination thelial elimination o large sporangia. Bleeding occurs easily.
therapy with e cision itracona ole and cryotherapy has also Disseminated cutaneous lesions are rare. Con uncti al lesions
been reported. begin as small pin ish papillary nodules which later become
Carneiro FP, et al: Lobomycosis: diagnosis and management of larger dar and lobulated. Rectal and aginal lesions ha e
relapsed and multifocal lesions. Diagn Microbiol Infect Dis 2009; been reported. As with penile lesions they may resemble con
65:62–64. dylomata or polyps. Widespread dissemination rarely occurs
314

tahir99 - UnitedVRG
and bone in ol ement has been described. The disease is
endemic in Sri Lan a and ndia but also occurs in parts o ast
Asia and in Latin America. Rhinosporidiosis has been seen in
the southern nited States the nited ingdom and taly.
hinospori ium seeberi a lower a uatic ungus ound in stag
nant water is the causati e organism. The organisms appear
as spherules μm in diameter which are contained within
large cystic sporangia that may be as large as μm in diam
eter. When the organism does not orm endospores it resem
bles Cocci ioi es immitis spherules but di ers by the regular
presence o a central nucleus within each organism. The organ
isms are usually present within a polypoid structure. A granu
lomatous response is seen in about o patients and
gigantic oreign body giant cells can rarely be noted lled with
organisms.
Suppurati e in ammation may be obser ed at the site o
rupture o sporangia. Transepithelial elimination o sporangia
is common. Destruction o the in ol ed area by e cision or
electrosurgery is the most common method o treatment. Anti
ungal agents ha e been o little alue. Culture o the organism
is easiest when it is grown together with the cyanobacterium
Microc stis aeruginosa These are unicellular pro aryotic organ
isms ound in pond water together with seeberi. The two
organisms ha e also been shown to grow together in tissue
suggesting that rhinosporidiosis may represent a synergistic
in ection o the ungus and cyanobacterium. Drugs such as
cipro o acin are acti e against M aeruginosa so trials o anti
biotic therapy may be o alue.
Ganne P, et al: Conjunctival rhinosporidiosis. JAMA Ophthalmol 2014;
Nov 6.
Sudarshan V, et al: Rhinosporidiosis in Raipur, Chhattisgarh: a report of
462 cases. Indian J Pathol Microbiol 2007; 50:718–721.
Verma R, et al: A case of disseminated cutaneous rhinosporidiosis
presenting with multiple subcutaneous nodules and a warty growth.
Indian J Dermatol Venereol Leprol 2012; 78:520.
ZYGOMYCOSIS (PHYCOMYCOSIS)
There are a number o important pathogens in the class ygo
mycetes. The two orders within this class that cause cutaneous
in ection most o ten are the ucorales and ntomophthorales.
Entomophthoromycosis
n ections caused by the order ntomophthorales ha e been
named entomophthoromycosis rhinoentomophthoromycosis
conidiobolomycosis or basidiobolomycosis. n ection occurs
usually in healthy indi iduals and unli e mucormycosis
o ten runs an indolent course. The in ections may be classi ed
as cutaneous subcutaneous isceral or disseminated. Subcu
taneous lesions occur in two basic types each in ol ing di
erent anatomic sites either as well circumscribed subcutaneous
masses in ol ing the nose paranasal tissue and upper lip or
as nodular subcutaneous lesions located on the e tremities
buttoc s and trun .
Etiology
Coni iobolus coronatus typically causes the perinasal disease
whereas asi iobolus ranarum causes the type o subcutaneous
disease seen on the ace.
Epidemiology
ccurrence is worldwide. ntomophthoromycosis was rst
reported in ndonesia where it is pre alent. Since then reports
ha e come rom A rica Asia and the Americas. Generally
in ection occurs in a belt between north and south o
the e uator.
Diagnosis
Zygomycosis (phycomycosis)
solation and identi cation o the causati e ungus are unda
mental to the diagnosis. Culture on Sabouraud de trose
agar is made o nasal discharge abscess uid or biopsy speci
mens. Biopsy specimens will show broblastic proli eration
and an in ammatory reaction with lymphocytes plasma cells
histiocytes eosinophils and giant cells. The organisms appear
as broad hyphae that are generally aseptate and may be
branched at right angles. The Splendore oeppli phenomenon
is common and appears as eosinophilic slee es around the
hyphae. Pythiosis caused by P thium insi iosum a primiti e
a uatic hyphal organism that acts as a oonotic pathogen may
a ect humans and has a similar appearance.
Treatment
Potassium iodide has been the drug o choice or entomo
phthoromycosis although amphotericin B cotrimo a ole
etocona ole itracona ole and ucona ole ha e also been
used success ully. cision o small lesions is an alternati e
method o management but the recurrence rate is signi cant.
Rare human cases o pythiosis ha e responded to amphoteri
cin B.
Mucormycosis
ucormycosis re ers to in ections caused by the order uco
rales o the class ygomycetes. When in asi e in ections char
acteristically are acute rapidly de eloping and o ten atal. n
some series mortality is about . ost in ections occur in
etoacidotic patients with diabetes but leu emia lymphoma
A DS iatrogenic immunosuppression in transplant patients
chronic renal ailure and malnourishment all predispose to
these in ections. n ection has also been associated with meth
otre ate prednisone and in i imab therapy. ealthy indi
iduals may also de elop these in ections. n them primary
cutaneous disease occurs o ten a ter trauma burns or as a
result o contaminated surgical dressings.
The e ma or clinical orms o mucormycosis (rhinocerebral
pulmonary cutaneous G disseminated) all demonstrate as
culotropism o the organisms. This leads to in arction gangrene
and the ormation o blac necrotic purulent debris. lcer
ation cellulitis ecthyma gangrenosum li e lesions and necrotic
abscesses may occur. The in ection may in ol e the s in through
traumatic implantation or by hematogenous dissemination.
Etiology
The ungi that cause this in ection are ubi uitous molds
common in the soil on decomposing plant and animal matter
and in the air. The pathogenic genera include hi opus bsi ia
Mucor Cunninghamella poph som ces hi omucor Sa senaea
Mortierella and Co erom ces.
Diagnosis
Tissue obtained by biopsy or curettage is e amined micro
scopically and cultured. Prompt diagnosis o mucormycosis
is essential in this rapidly atal in ection. istologically
the organism generally appears as eosinophilic thic walled
hyphae that loo hollow in cross section. The organism is uite
irregular in outline and right angle branching is common. The
315
 organisms are highly asculotropic and dissect along the
15 media o muscular essels resulting in in arction o tissue.

Treatment
Diseases Resulting from Fungi and Yeasts

A combination o e cision o a ected tissue and anti ungal

therapy usually with liposomal amphotericin B is necessary
in most patients with mucormycosis. The alternati e is
posacona ole mg twice daily with meals. Very limited
disease may be treated with e cision alone but this approach
may be ris y.
ohs micrographic surgery has been used or margin
control during e cision o in ected tissue. This approach may
be curati e in primary cutaneous disease in an immunocom
petent patient. The speed o interpretation o each stage and
the potential or tissue conser ation are ad antages o this
method. ungal stains such as G S ha e been used in this
setting but ygomycetes show ariable staining with ungal
stains. ten is the optimal stain and the organisms may
stain a idly with a tissue Gram stain.
Davuodi S, et al: Fatal cutaneous mucormycosis after kidney transplant.
Exp Clin Transplant 2014; Nov 5.
El-Shabrawi MH, et al: Entomophthoromycosis: a challenging
emerging disease. Mycoses 2014; Oct 16.
Gordon CL, et al: Entomophthoromycosis caused by Basidiobolus
ranarum in tropical northern Australia. Pathology 2012;
44:375–379.
Krajaejun T, et al: Clinical and epidemiological analyses of human
pythiosis in Thailand. Clin Infect Dis 2006; 43:569–576.
Petrikkos G, et al: Epidemiology and clinical manifestations of
mucormycosis. Clin Infect Dis 2012; 54(Suppl 1):S23–S34.
Rüping MJ, et al: Forty-one recent cases of invasive zygomycosis
from a global clinical registry. J Antimicrob Chemother 2010;
65:296–302.
Skiada A, et al: Global epidemiology of cutaneous zygomycosis. Clin
Dermatol 2012; 30:628–632.
Skiada A, et al: Diagnosis and treatment of mucormycosis in
patients with hematological malignancies. Haematologica 2013;
98:492–504.
HYALOHYPHOMYCOSIS
The term hyalohyphomycosis contrasts with phaeohyphomy
cosis and re ers to opportunistic mycotic in ections caused by
nondematiaceous molds. ost o these organisms are septate
and compared with blac molds most ha e delicate walls.
rganisms include Penicillium cremonium richo erma Sce
osporium and Paecilom ces Disseminated in ections with
Sce osporium apiospermum (ase ual orm o Pseu allescheria
bo ii) are also grouped in this category. Some authors use
the term broadly to encompass in ections with all light
colored molds including usarium Although spergillus is a
light colored mold that appears similar in tissue to other
orms o hyalohyphomycosis it is usually grouped sepa
rately because organisms other than spergillus are more
li ely to cause wide dissemination and C S disease in some
reported series.
These organisms are ubi uitous; they occur as saprophytes
in soil or water or on decomposing organic debris. They gener
ally do not cause disease e cept in immunocompromised
patients. usarium solani ( eratomycosis) and usarium
ox sporum (white super cial onychomycosis) are e ceptions.
Locali ed hyalohyphomycosis has also occurred in immuno
competent patients a ter traumatic implantation. There is no
classic clinical morphology to the lesions but eratotic masses
ulcerations ecthyma gangrenosum li e lesions erythematous
nodules dar eschars and disseminated erythema ha e been
described ( ig. ).
316
Fig. 15-32 Hyalohyphomycosis caused by Paecilomyces. (Courtesy
of Dan Loo, MD.)
Penicillium marneffei in ection is an indicator o V disease
especially in Southeast Asia. This organism is dimorphic and
appears in tissue as small intracellular organisms within
histiocytes. The histologic similarity to histoplasmosis is
stri ing.
ost o these in ections are treated with a combination o
e cision and amphotericin B. Sce osporium and Paecilom ces
respond in some cases to oricona ole or posacona ole. n
Penicillium in ections in V patients itracona ole is used
inde nitely a ter initial therapy with amphotericin B.
FUSARIOSIS
usarium has emerged as an important pathogen especially in
patients with hematologic malignancy neutropenia and T cell
immunode ciency particularly those with hematopoietic
stem cell transplants and gra t ersus host disease (GV D).
S in in ol ement is present in about o patients and the
in ection may begin in the s in and then disseminate. any
cases begin in the lungs or sinuses then disseminate to the
s in. Blood cultures usually are positi e but s in biopsies
pro ide the highest diagnostic yield. Contaminated hospital
plumbing may be a source o usariosis. usarium has been
cultured rom drains water tan s sin aucet aerators and
shower heads. Aerosoli ation o usarium spp. by shower
heads has been documented.
The mortality rate is high but has impro ed with the a ail
ability o new anti ungal agents. eutropenia a actor predict
ing mortality must be controlled with colony stimulating
actors. Liposomal amphotericin B is the drug o choice; ori
cona ole and posacona ole are second line drugs. Posacon
a ole can raise calcineurin inhibitor le els in the blood and
these must be closely monitored during therapy.
ASPERGILLOSIS
Aspergillosis is second only to candidiasis in re uency o
opportunistic ungal disease in patients with leu emia and
other hematologic neoplasia. eutropenia remains the ey
ris actor or in asi e aspergillosis in this population. Lym
phocytes especially cells are also critical in host de ense
and immunosuppressi e agents create a ris o in ection.
ther ris actors include prolonged corticosteroid therapy
GV D and cytomegalo irus in ection. Solid organ transplant

tahir99 - UnitedVRG
patients are also predisposed to spergillus in ections. Pulmo
nary in ol ement is usually present in in asi e disease; s in
lesions are present in only about o patients. Biopsy o a
s in lesion may establish the diagnosis when other studies
ha e ailed. Blood culture is an insensiti e method o
diagnosis.
spergillus fumigatus is the most common cause o dissemi
nated aspergillosis with cutaneous in ol ement. The organ
ism grows on media without cyclohe imide in h or longer.
n tissue the organisms appear as slender hyphae with deli
cate walls and bubbly cytoplasm. The appearance is identical
to that o usarium e cept or the lac o esicular swellings
along hyphae. The hyphae in both are septate with degree
branching. Both tend to be asculotropic and are associated
with cutaneous necrosis. spergillus avus rarely causes ungus
balls in the lungs but is a common cause o ungal sinusitis
and s in lesions. spergillus niger is a rare cause o dissemi
nated in ection with s in lesions. n third degree burns sper
gillus o ten coloni es the eschar. Deep incisional biopsies are
re uired to distinguish in asi e disease rom coloni ation.
Primary cutaneous aspergillosis
Primary cutaneous aspergillosis is a rare disease. ost cases
occur at the site o V cannulas in immunosuppressed patients.
emorrhagic bullae and necrotic ulcers may be present ( ig.
). avus is most re uently associated with this orm
o in ection. Patients must be treated aggressi ely because the
ungus may disseminate rom the s in lesion.
spergillus is a re uent contaminant in cultures rom thic
ened riable dystrophic nails and arious spergillus spp.
ha e been implicated as true etiologic agents o onychomyco
sis. ail in ection may respond to itracona ole.
Otomycosis
The ear canal may be in ected by spergillus fumigatus
avus and niger Pathogenic bacteria especially Pseu omo
nas aeruginosa are o ten ound concurrently. The coloni ation
may be benign but malignant otitis may occasionally occur
especially in diabetic or iatrogenically immunosuppressed
patients. n asi e disease must be treated with systemic
agents. Topical clotrima ole ear drops are e ecti e in immu
nocompetent patients.
Fig. 15-33 Primary
aspergillosis.
Treatment
Voricona ole is the treatment o choice or in asi e aspergil
losis although isual disturbances photosensiti ity s in
cancer and s in eruptions can be a problem with this drug.
Aspergillosis
Liposomal amphotericin B caspo ungin mica ungin posacon
a ole and itracona ole are alternate therapies.
Das S, et al: Acremonium species. Mycopathologia 2010;
170:361–375.
Gardner JM, et al: Chronic cutaneous fusariosis. Arch Dermatol 2005;
141:794–795.
Karthaus M, et al: Invasive aspergillosis. Curr Pharm Des 2013;
19:3569–3594.
Keskar VS, et al: Subcutaneous hyalohyphomycosis caused by
Fusarium in a kidney transplant recipient. Ren Fail 2014;
36:1129–1132.
Naggie S, et al: Molds: hyalohyphomycosis, phaeohyphomycosis, and
zygomycosis. Clin Chest Med 2009; 30:337–353.
Ozen M, et al: Invasive aspergillosis in children with hematological
malignancies. Expert Rev Anti Infect Ther 2011; 9:299–306.
Rogdo B, et al: Primary cutaneous aspergillosis in a preterm neonate.
BMJ Case Rep 2014; Sept 1.
Segal BH: Aspergillosis. N Engl J Med 2009; 360:1870–1884.
Vennewald I et al: Otomycosis. Clin Dermatol 2010; 28:202–211.
Yang YS, et al: A rare skin presentation of Penicillium marneffei infection
in an AIDS patient. Int J STD AIDS 2012; 23:64–65.
DISEASE CAUSED BY ALGAE (PROTOTHECOSIS)
Protothecosis is caused by the Prototheca genus o saprophytic
achloric (nonpigmented) algae. These organisms reproduce
ase ually by internal septation or morulation. This reproduc
ti e method along with the absence o glucosamine and
muramic acid in the cell wall separates the genus rom the
bacteria and ungi. Two Prototheca species cause disease in
humans Prototheca wic erhamii and Prototheca op i Stagnant
water tree slime and soil appear to be the source o in ection
in most cases.
S in lesions may present as errucous lesions ulcers papu
lonodular lesions or crusted papules with umbilication. Pro
tothecosis o the olecranon bursa is usually seen in healthy
indi iduals but cutaneous in ections ha e been most o ten
reported in patients recei ing immunosuppressi e therapy
and in those with renal ailure li er disease A DS hemato
logic malignancy or diabetes mellitus. eutropenia is not a
common ris actor.
Prototheca spp. are easily recogni ed in PAS stained tissue
specimens when the characteristic morulating cells are isible.
These are more common in P wic erhamii The organism also
appears with a single blac nucleus and a thic slightly asym
metric re ractile wall. t grows on most routine mycologic
media but cyclohe imide will suppress growth o Prototheca
spp. Colonies on Sabouraud agar are smooth creamy and
yeastli e. The use o uorescent antibody reagents permits the
rapid and reliable identi cation o Prototheca spp. in culture
and tissue.
ntra enous amphotericin B remains the most e ecti e
agent or disseminated Prototheca in ections. P wic erhamii is
susceptible to oricona ole in itro and P op i appears sus
ceptible to posacona ole. tracona ole and ucona ole ha e
been success ul in indi idual cases. Surgery as well as topical
amphotericin B and do ycycline has been used or isolated
cutaneous disease.
Hillesheim PB, et al: Cutaneous protothecosis. Arch Pathol Lab Med
2011; 135:941–944.
Lu S, et al: Cutaneous prothecosis. Int J Dermatol 2012;
51:328–331.
Mayorga J, et al: Protothecosis. Clin Dermatol 2012; 30:432–436.
317
15 Bonus images for this chapter can be found online at expertconsult.inkling.com
eFig. 15-1 Endothrix hair mount; note spores
within the hair shaft.
Diseases Resulting from Fungi and Yeasts
eFig. 15-2 Id reaction.
eFig. 15-3 Tinea faciei.
eFig. 15-4 Tinea corporis.
eFig. 15-5 Majocchi granuloma.
eFig. 15-6 Tinea imbricata.
eFig. 15-7 Superficial white onychomycosis.
eFig. 15-8 Candida intertrigo.
eFig. 15-9 Tinea nigra.
eFig. 15-10 Tinea nigra; note golden color
of mycelia.
318
eFig. 15-11 White piedra.
eFig. 15-12 Tinea versicolor.
eFig. 15-13 Coccidioidomycosis. (Courtesy of
Larry Anderson, MD, Brooke Army Medical
Center Teaching File.)
eFig. 15-14 Molluscumlike lesions of
cryptococcosis.
eFig. 15-15 Single budding yeast of North
American blastomycosis.
eFig. 15-16 Paracoccidioidomycosis. (Courtesy
of Maria Silvia Negrao, MD.)
eFig. 15-17 Paracoccidioidomycosis. (Courtesy
of Maria Silvia Negrao, MD.)
tahir99 - UnitedVRG
eFig. 15-18 Sporotrichosis transmitted by cat
scratch.
eFig. 15-19 Mycetoma.
eFig. 15-20 Lobomycosis. (Courtesy of Maria
Silvia Negrao, MD.)
eFig. 15-21 Lobomycosis. (Courtesy of Maria
Silvia Negrao, MD.)
eFig. 15-22 Paecilomyces demonstrated
histologically from biopsy. (Courtesy of Dan
Loo, MD.)
eFig. 15-23 Aspergillus demonstrated
microscopically.
 Aspergillosis
eFig. 15-1 Endothrix hair mount; note spores within the hair shaft. eFig. 15-5 Majocchi granuloma.

eFig. 15-2 Id reaction. eFig. 15-6 Tinea imbricata.

eFig. 15-3 Tinea faciei.

eFig. 15-4 Tinea

eFig. 15-7 Superficial white onychomycosis.
corporis.

318.e1
 eFig. 15-8 Candida
15 intertrigo.
Diseases Resulting from Fungi and Yeasts

eFig. 15-11 White piedra.

eFig. 15-9 Tinea nigra. eFig. 15-12 Tinea versicolor.

eFig. 15-13
Coccidioidomycosis.
(Courtesy of Larry
Anderson, MD,
Brooke Army Medical
Center Teaching File.)

eFig 15-10 Tinea nigra; note golden color of mycelia.

318.e2

tahir99 - UnitedVRG
 Aspergillosis
eFig. 15-17 Paracoccidioidomycosis. (Courtesy of Maria Silvia
Negrao, MD.)

eFig. 15-14 Molluscumlike lesions of cryptococcosis.

eFig. 15-18
Sporotrichosis
transmitted by cat
scratch.

eFig. 15-15 Single budding yeast of North American blastomycosis.

eFig. 15-16 Paracoccidioidomycosis. (Courtesy of Maria Silvia

Negrao, MD.)

eFig. 15-19 Mycetoma.

318.e3
 eFig. 15-20
15 Lobomycosis.
(Courtesy of Maria
Silvia Negrao, MD.)
Diseases Resulting from Fungi and Yeasts

eFig. 15-22 Paecilomyces demonstrated histologically from biopsy.

(Courtesy of Dan Loo, MD.)

eFig. 15-21 Lobomycosis. (Courtesy of Maria Silvia Negrao, MD.)

eFig. 15-23 Aspergillus demonstrated microscopically.

318.e4

tahir99 - UnitedVRG
 Bonus images for this chapter can be found online at
Mycobacterial Diseases
TUBERCULOSIS
o ideal classi cation scheme e ists or cutaneous tuberculo
sis but the system listed here is logical and ta es into account
the mechanism o disease ac uisition. n ortunately unli e in
ansen s disease these categories do not correlate per ectly to
host immunity. The our ma or categories o cutaneous tuber
culosis are as ollows
. noculation rom an e ogenous source (primary
inoculation tuberculosis tuberculosis errucosa cutis)
. ndogenous cutaneous spread contiguously or by
autoinoculation (scro uloderma tuberculosis cutis
ori cialis)
. ematogenous spread to the s in (lupus ulgaris; acute
miliary tuberculosis; tuberculosis ulcer gumma or
abscess; tuberculous cellulitis) (Lupus ulgaris can also
occur ad acent to lesions o scro uloderma suggesting
that both hematogenous spread and local spread are
capable o triggering this reaction pattern.)
. Tuberculids (erythema induratum Ba in disease
papulonecrotic tuberculid lichen scro ulosorum)
The nding o mycobacterial D A by polymerase chain
reaction (PCR) in tuberculids suggests that tuberculids also
represent hematogenous dissemination o tuberculosis (TB)
which is uic ly controlled by the host usually resulting in
the absence o detectable organisms by culture and histologic
methods. iliary TB is the orm with least e ecti e host
immunity. Tuberculous ulcer abscess cellulitis and tubercu
losis cutis ori cialis are conditions o poor host immunity
against M cobacterium tuberculosis Bacilli are prominent in
these orms o cutaneous TB and histologic and microbiologic
con rmation is usually straight orward. This is ortunate
since cellular based diagnostic modalities (puri ed protein
deri ati e PPD inter eron γ release assay GRA ) may be
negati e. Tuberculosis errucosa cutis and lupus ulgaris are
conditions o high host immunity to TB and tuberculin s in
tests and GRA or TB will usually be positi e. Scro uloderma
is usually associated with a positi e PPD and identi cation
by culture and histologic methods is positi e in only and
o cases respecti ely. n its initial stage primary inocula
tion TB will be multibacillary and culture positi e. As host
immunity de elops the s in test becomes positi e and the
number o organisms on biopsy diminishes. The tuberculids
also represent high host immune response mani estations o
TB and bacilli are rarely ound.
Epidemiology
The increase in the numbers o cases o TB that started in the
mid s in the nited States was associated with three phe
nomena large numbers o immigrants rom high pre alence
expertconsult.inkling.com
16
countries the human immunode ciency irus ac uired
immunode ciency syndrome ( V A DS) epidemic and an
increasing number o persons in congregati e acilities (shel
ters or homeless persons prisons). Asians A rican Ameri
cans and ispanics ha e the greatest ris or de eloping TB
in the nited States. Aggressi e diagnosis and treatment pro
grams ha e led to a reduction in new .S. cases o TB. The
in ection rate in the .S. born population o adults is now at
the lowest recorded . cases per population. owe er
local poc ets o TB are still ound in .S. regions o otherwise
ery low incidence. This is partly attributable to the persis
tently high in ection rate in the oreign born .S. population
which has also allen dramatically o er the years but is still at
. cases per .
n the de eloping world TB is a tremendous health problem.
n A rica reside o all persons with TB worldwide. The
incidence o TB in A rica doubled between and with
new cases appearing at a rate o more than in some
countries. This has been dri en largely by the V A DS epi
demic. ne third or more o V in ected persons in A rica
are also in ected with M tuberculosis Latent TB is times
more li ely to reacti ate in persons with V in ection and
V in ected persons are much more li ely to ac uire new
tuberculous in ection. n countries such as ndia although
great progress has been made TB is still common with .
million new cases diagnosed e ery year or new cases per
population per year. n ection rates are particularly high
in ndia among health care wor ers with new cases o TB
or e ery medical residents per year.
Tuberculosis has increasingly become resistant to rst line
treatments. Strains classi ed as multidrug resistant tubercu
losis ( DR TB) are resistant to at least isonia id and ri ampin.
tensi ely drug resistant tuberculosis ( DR TB) is in addi
tion resistant to any uoro uinolone and at least one o
capreomycin anamycin or ami acin. The emergence o
these resistant strains o TB has made treatment more costly
and more di cult. owe er aggressi e treatment protocols
using multiple drugs or up to years and when indicated
surgical techni ues can cure up to o e en DR TB
patients.
Cutaneous TB is an uncommon complication o tuberculous
in ection with less than o TB patients ha ing s in lesions
e en in highly endemic areas. The types o cutaneous lesion
that the patient will de elop depend on the ollowing host
actors
. ge: About o scro uloderma cases and most cases o
lichen scro ulosorum occur in children.
. en er: Women are times more li ely to de elop
erythema induratum but men are two to three times
more li ely to ha e other orms o cutaneous TB.
. natomic location: Lupus ulgaris occurs on the ace and
e tremities whereas tuberculosis errucosa cutis occurs
predominantly on the hands.
319
 . utritional status: Tuberculous abscesses and
16 scro uloderma are associated with malnutrition.
The pattern o cutaneous TB has been changing o er the last
ew decades and is di erent in de eloped than in de eloping
Mycobacterial Diseases
nations. The a erage age o patients with cutaneous TB has
increased in de eloped countries and tuberculids especially
erythema induratum represent a larger proportion o cases.
n ong ong o cases o cutaneous TB are tuberculids.
This suggests that most cutaneous TB in adults will be ound
in patients in ected in the distant past who are reacti ating
their disease not recently in ected persons. Cutaneous TB is
uncommon in immunosuppressed hosts; when they ac uire
new TB or reacti ate their TB it usually reacti ates at a non
cutaneous site and is diagnosed be ore s in disease occurs.
iliary TB is the most re uently reported orm o cutaneous
TB in the V in ected patient. n areas o high TB endemicity
in the de eloping world cutaneous TB is still common. ore
than o cases will occur be ore age . The li elihood o
nding associated systemic TB is higher in children than
adults. onetheless unli e in all other orms o e trapulmo
nary TB ailure to nd an underlying ocus o TB in patients
with cutaneous TB can occur. Between and o patients
with cutaneous TB will ha e an abnormal chest radiograph.
ost o ten TB o the lymph nodes will be ound.
Tuberculin testing
The tuberculin s in test (TST) is designed to detect a memory
cell mediated immune response to M tuberculosis. The test
becomes positi e wee s a ter in ection and remains posi
ti e or many years although it may wane with age. PPD
preparations are currently used or testing in the nited States
and Canada at a dose o T (tuberculin units). The intrader
mal or antou test is the standard and o ers the highest
degree o consistency and reliability. The test is read
a ter intradermal in ection. nduration measuring mm or
more is considered positi e in V in ected patients in those
with ris actors or de eloping TB (e.g. patients who will
recei e anti T therapy) in recent close contacts or in those
with chest ray ndings consistent with healed TB. Because
children are at increased ris o de eloping acti e TB a ter
e posure a mm or larger reaction in contact in estigations
is considered positi e. the PPD measures more than mm
it is considered positi e in in ection (intra enous) drug users
( D s) V negati e D s those born in oreign countries o
high TB pre alence mycobacteriology laboratory personnel
residents and employees in high ris congregate acilities and
those with medical conditions that predispose to TB. indura
tion is more than mm it is positi e in all others; mm
induration is negati e.
The lower the threshold or positi ity or the TST the less
this represents true positi ity (the higher number o alse
positi es). This is why a TST o less than mm is considered
positi e only in patients at higher ris or ha ing latent TB.
Con ersely as the cuto or true positi ity is raised the
number o in ected persons the TST detects will decrease (the
number o alse negati es increases). A TST o o er mm will
detect o persons with latent TB o er mm will detect
and o er mm will detect only o latently in ected
patients. At least o patients with latent TB will ha e a
completely negati e TST. any intermediate TST responses
may represent cross reaction with atypical mycobacteria.
Bacillus (bacille) Calmette Gu rin (BCG) immuni ation leads
to a positi e tuberculin result in immuni ed children but this
reaction usually does not persist beyond years. Repeated
BCG immuni ation or BCG administration a ter age years is
320
tahir99 - UnitedVRG
more li ely to result in a persistently positi e TST on this basis.
owe er positi e reactions in adults should not automati
cally be attributed to childhood BCG administration.
Reacti ity to the tuberculin protein is impaired in certain
conditions in which cellular immunity is impaired. Lympho
proli erati e disorders sarcoidosis corticosteroid and immu
nosuppressi e drugs (including tumor necrosis actor T
inhibitors) se ere protein de ciency chronic renal ailure and
numerous in ectious illnesses including V in ection are
capable o diminishing tuberculin reacti ity. n o erwhelming
TB (miliary disease) more than o patients ha e a
negati e s in test be ore beginning therapy. A negati e or
doubt ul reaction to a PPD preparation does not rule out TB
in ection particularly in the patient with suggesti e symp
toms and signs.
ntil recently the TST had been the gold standard to
con rm the presence o in ection with M tuberculosis TST has
signi cant limitations howe er including low sensiti ity in
persons with a compromised immune system negati e tests
in a substantial number o patients with acti e TB (sensiti ity
only ) repeat isits to interpret technical competence
o person applying the test booster e ect o repeat testing
creating potential alse positi e results and alse positi e tests
in persons with prior BCG accination. To o ercome these
obstacles antigen speci c in itro assays ha e been de el
oped. These assays measure the amount o inter eron ( ) γ
released by peripheral blood T cells ( GRAs; e.g. uanti R
TB Gold L SpotPL S T SP T). Results are ariable with
respect to the sensiti ity and speci city o these assays but
they appear to be aluable in certain settings. GRAs are no
more sensiti e or only slightly more sensiti e than TST in
detecting latent TB. owe er the assays are considerably
more speci c in the BCG accinated population in whom the
TST is only speci c whereas GRAs are speci c. n
addition in V in ected patients and those recei ing cortico
steroids GRAs are much more li ely to be positi e than a TST
h in those with M tuberculosis in ection. The clinical settings in
which TSTs and GRAs gi e either alse positi e or alse
negati e alues are di erent. the TST is combined with an
GRA and the tests are concordant alse negati e results are
and alse positi e tests only . This suggests that the
combination o TST and GRA would be the optimal testing to
assess or M tuberculosis in ection (latent or acti e). ither the
two tests can be done simultaneously or i screening or latent
TB in an otherwise immunologically normal person TST can
be applied rst then GRA per ormed in all persons with a
positi e TST o more than mm.
Appropriate screening be ore initiating anti T therapy or
immunosuppression in a dermatology patient would include
the ollowing
. Screen or acti e TB by history and physical e amination
(and chest ray where suspicion or TB is ele ated).
. Administer a TST and perhaps an GRA.
. nterpret the test results with caution in patients already
on signi cant iatrogenic immunosuppressi e or anti T
treatments.
. Regularly monitor patients on anti T agents or the
de elopment o TB with appropriate history physical
e amination and laboratory testing; and suspect and
screen or TB i clinical symptoms may indicate in ection.
BCG vaccination
Bacille Calmette Gu rin is a li e attenuated strain o M cobac
terium bovis used in most parts o the world (e cept orth
America and Western urope) to immuni e in ants. t enhances
immunity to TB and is e ecti e in reducing childhood TB
especially i gi en to neonates. nce the patient has been ac
cinated the TST becomes positi e and remains so or a period
o less than years (unless the person is BCG immuni ed
a ter age or repeatedly immuni ed). n an adult who was
accinated as a child in a oreign country with a high pre a
lence o TB and whose TST measures more than mm acti e
TB should be assumed. The use o BCG instillation in the
bladder to treat bladder cancer has been associated with dis
seminated disease usually pneumonitis hepatitis prostatitis
and abdominal aneurysms.
Dermatologic complications o BCG accination are rarely
seen. Locali ed abscesses and regional suppurati e adenitis
occur at a rate o about . per accines. cessi e ulcer
ation may occur i the BCG is inoculated too deeply. Scro ulo
derma is rare. Disseminated in ection is seen in cases per
million in ants accinated and is associated with high mor
tality. Disseminated BCG de elops only in the setting o
immunode ciency. Lupus ulgaris can occur rarely at the ac
cination site or at a distant site and will respond to appropriate
antituberculous treatment. Papular and papulonecrotic tuber
culids as well as erythema induratum can occur a ter BCG
immuni ation appearing days to se eral months a ter ac
cination. Treatment may not be necessary or the BCG induced
tuberculids; they re uently heal in a ew months with no
treatment.
Inoculation cutaneous tuberculosis
from exogenous source
Primary inoculation tuberculosis (primary
tuberculous complex, tuberculous chancre)
Primary inoculation TB de elops at the site o inoculation o
tubercle bacilli into a TB ree indi idual ( ig. ). Regional
lymphadenopathy usually occurs completing the comple .
t occurs chie y in children and a ects the ace or e tremities.
The inoculation can occur during tattooing medical in ections
nose piercing or e ternal physical trauma. The earliest lesion
Fig. 16-1 Primary
inoculation
tuberculosis.
appearing wee s a ter inoculation is a painless brown red
papule that de elops into an indurated nodule or pla ue that
may ulcerate. This is the tuberculous chancre. Prominent
regional lymphadenopathy appears wee s a ter in ection
and occasionally suppurati e and draining lesions may
Tuberculosis
appear o er in ol ed lymph nodes. Primary tuberculous
comple occurs on the mucous membranes in about one third
o patients. Spontaneous healing usually occurs within year
with the s in lesion healing rst then the lymph node which
is o ten persistently enlarged and calci ed. Delayed suppura
tion o the a ected lymph node lupus ulgaris o erlying the
in ol ed node and occasionally dissemination may ollow
this orm o cutaneous TB.
istologically there is a mar ed in ammatory response
during the rst wee s with many polymorphonuclear leu
ocyte neutrophils (P s) and tubercle bacilli. During the
ne t wee s the picture changes. Lymphocytes and epitheli
oid cells appear and replace the P s. Distinct tubercles
de elop within or wee s o inoculation. Simultaneously
with the appearance o epithelioid cells the number o tuber
cle bacilli decreases rapidly.
The di erential diagnosis o primary inoculation TB e tends
o er the spectrum o chancri orm conditions o deep ungal or
bacterial origin such as sporotrichosis blastomycosis histo
plasmosis coccidioidomycosis nocardiosis syphilis leish
maniasis yaws tularemia and atypical mycobacterial disease.
Pyogenic granuloma and cat scratch disease must also be
considered.
Paucibacillary cutaneous tuberculosis
from exogenous or endogenous source
in persons with high immunity
Tuberculosis verrucosa cutis
Tuberculosis errucosa cutis occurs rom e ogenous inocula
tion o bacilli into the s in o a pre iously sensiti ed person
with strong immunity against M tuberculosis The tuberculin
test is strongly positi e. The prosecutor s wart resulting rom
inoculation during an autopsy is the prototype o tuberculosis
errucosa cutis.
Clinically the lesion begins as a small papule which becomes
hyper eratotic resembling a wart. The lesion enlarges by
peripheral e pansion with or without central clearing some
times reaching se eral centimeters or more in diameter ( ig.
). issuring o the sur ace may occur discharging purulent
e udate. Lesions are almost always solitary and regional
Fig. 16-2 Tuberculosis verrucosa cutis.
321
 adenopathy is usually present only i secondary bacterial
16 in ection occurs. re uent locations or tuberculosis errucosa
cutis are on the dorsa o the ngers and hands in adults and
the an les and buttoc s in children. The lesions are persistent
but usually super cial and limited in e tent. Local scarring as
Mycobacterial Diseases
seen in lupus ulgaris can occur. Although sometimes sepa
rated by e udati e or suppurati e areas the lesions seldom
ulcerate and may heal spontaneously.
istologically there is pseudoepitheliomatous hyperplasia
o the epidermis and hyper eratosis. Suppurati e and granu
lomatous in ammation is seen in the upper and middle
dermis sometimes per orating through the epidermis. Case
ation is rare. The number o acid ast bacilli (A B) is usually
scant and ailure to nd A B should not be used to e clude
the diagnosis. Culture will be positi e in slightly more than
o cases.
Differential diagnosis
Tuberculosis errucosa cutis is di erentiated only by culture
rom atypical mycobacteriosis caused by M cobacterium
marinum t must also be distinguished rom orth American
blastomycosis chromoblastomycosis errucous epidermal
ne us hypertrophic lichen planus halogenoderma and
erruca ulgaris.
Lupus vulgaris
Lupus ulgaris may appear at sites o inoculation in scro u
loderma scars or most re uently at distant sites rom the
initial in ectious ocus probably by hematogenous dissemina
tion. Appro imately hal o such cases will ha e e idence o
TB elsewhere so a complete e aluation is mandatory. Because
lupus ulgaris is associated with moderately high immunity
to TB most patients will ha e a positi e tuberculin test.
Lupus ulgaris typically is a single pla ue composed o
grouped red brown papules which when blanched by dia
scopic pressure ha e a pale brownish yellow or apple elly
color. The papules called lupomas tend to heal slowly in one
area and progress in another. They are minute translucent
and embedded deeply and di usely in the in ltrated dermis
e panding by the de elopment o new papules at the periph
ery which coalesce with the main pla ue ( igs. and ).
The pla ues are slightly ele ated. The disease is destructi e
re uently causes ulceration and on in olution lea es de orm
ing scars as it slowly spreads peripherally o er the years.
Fig. 16-3 Lupus vulgaris. (Courtesy of Dr Tavares-Bello, MD.)
322
tahir99 - UnitedVRG
Lupus ulgaris lesions o the head and nec can be associated
with lymphangitis or lymphadenitis in some cases. lesions
in ol e the nose or the earlobes these structures are shrun en
and scarred as i nibbled away. Atrophy is prominent and
ectropion and eclabion may occur. The tip o the nose may be
sharply pointed and bea li e or the whole nose may be
destroyed with only the ori ces and the posterior parts o the
septum and turbinates isible. The upper lip a site o predilec
tion may become di usely swollen and thic ened with s
sures adherent thin crusts and ulcers. n the trun and
e tremities lesions may be annular or serpiginous or may
orm gyrate patterns. n the hands and eet and around the
genitals or buttoc s lesions may cause mutilation by destruc
tion scar ormation warty thic enings and elephantiasic
enlargement.
An unusual orm o lupus ulgaris may ollow measles or
another signi cant ebrile illness. The window o immune
de ciency caused by the acute illness results in dissemination
o the TB hematogenously rom a single ocus o lupus ul
garis. ultiple erythematous papules in a generali ed distri
bution appear a month or more a ter the illness. These lesions
e ol e to small papules and pla ues clinically and histologi
cally resembling lupus ulgaris. The TST is negati e during
the immediate period ollowing the ebrile illness then rapidly
re erts to strongly positi e. This is called lupus ulgaris
poste anthematicus.
Although classically considered a scarring and atrophying
process lesions o the lips and ears may be uite hyperplastic.
The lips may resemble cheilitis granulomatosis clinically and
histologically. ni orm hyperplasia o the ear pinna and lobe
may closely mimic tur ey ear as described in sarcoidosis.
When the mucous membranes are in ol ed the lesions become
papillomatous or ulcerati e. They may appear as circum
scribed grayish macerated or granulating pla ues. n the
tongue irregular deep pain ul ssures occur sometimes
associated with microglossia to the degree that nutrition is
compromised.
The rate o progression o lupus ulgaris is slow and a
lesion may remain limited to a small area or se eral decades.
The onset may be in childhood and persist throughout li e. t
may slowly spread and new lesions may de elop in other
Fig. 16-4 Lupus
vulgaris. (Courtesy of
Dr. Debabrata
Bandyopadhyay.)
regions. n some patients the lesions become papillomatous
egetati e or thic ly crusted with a rupioid appearance.
S uamous cell carcinoma may de elop in long standing
lesions.
istologically classic tubercles are the hallmar o lupus
ulgaris. Caseation within the tubercles is seen in about hal
the cases and is rarely mar ed. Sarcoidosis may be simulated.
The epidermis is a ected secondarily sometimes attened
and at other times hypertrophic. A B are ound in or less
o cases with standard acid ast stains. PCR still lac s the sen
siti ity and speci city to diagnose paucibacillary orms o
cutaneous TB reproducibly and will be positi e in up to one
uarter o cases. Cultures o the s in lesions grow M tubercu
losis in about hal the cases.
Colloid milia acne ulgaris sarcoidosis and rosacea may
simulate lupus ulgaris. Di erentiation rom tertiary syphilis
chronic discoid lupus erythematosus ansen s disease sys
temic mycoses and leishmaniasis may be more di cult and
biopsy and tissue cultures may be re uired.
Cutaneous tuberculosis from endogenous
source by direct extension (scrofuloderma
and periorificial tuberculosis)
Scro uloderma is tuberculous in ol ement o the s in by
direct e tension rom an underlying ocus o in ection. t
occurs most re uently o er the cer ical lymph nodes but also
may occur o er bone or around oints i these are in ol ed.
Clinically the lesions begin as subcutaneous masses which
enlarge to orm nodules. Suppuration occurs centrally. They
may be erythematous or s in colored and usually the s in
temperature is not increased o er the mass. Lesions may drain
orming sinuses or they may ulcerate with reddish granula
tion at the base ( igs. and ). Surgical procedures may
incite lesions o scro uloderma o er oints or the abdominal
ca ity apparently by releasing the loculated ocus and con
taminating the trac along which instruments are inserted.
Scro uloderma heals with characteristic cordli e scars re
uently allowing the diagnosis to be made many years later.
Fig. 16-5 Scrofuloderma. (Courtesy of Dr. Debabrata
Bandyoopadhyay.)
Perianal TB is characteri ed by a chronic anal stula charac
teristically in men age . The intestinal tract especially the
rectum is in ol ed in most o these cases. Anal strictures and
in ol ement o the scrotum may occur i disease is untreated.
istologically in scro uloderma the tuberculous process
Tuberculosis
begins in the underlying lymph node or bone and e tends
through the deep dermis. ecrosis occurs with ormation o a
ca ity lled with li ue ed debris and P s. At the periphery
more typical granulomatous in ammation is seen along with
A B obser ed in slightly less than hal o cases.
Scro uloderma should be di erentiated rom atypical myco
bacterial in ection sporotrichosis actinomycosis coccidioido
mycosis and hidradenitis suppurati a. Lymphogranuloma
enereum (LGV) a ors the inguinal and perineal areas with
positi e serologic tests or LGV.
Tuberculosis cutis ori cialis is a orm o cutaneous TB that
occurs at the mucocutaneous borders o the nose mouth anus
urinary meatus and agina and on the mucous membrane o
the mouth or tongue. t is caused by autoinoculation rom
underlying acti e isceral TB particularly o the laryn lungs
intestines and genitourinary tract. t indicates ailing resis
tance to the disease. Conse uently tuberculin positi ity is
ariable but usually positi e. Lesions ulcerate rom the begin
ning and e tend rapidly with no tendency to spontaneous
healing. The ulcers are usually so t and punched out and ha e
undermined edges. istologically the ulcer base is usually
composed largely o granulation tissue in ltrated with P s.
Deep and lateral to the ulcer granulomatous in ammation
may be ound and A B are numerous.
Cutaneous tuberculosis from hematogenous spread
Miliary (disseminated) tuberculosis
iliary TB appears in the setting o ulminant TB o the lung
or meninges. Generally patients ha e other unmista able
signs o se ere disseminated TB. t is most common in children
but may occur in adults. ost reported cases o cutaneous TB
seen in patients with A DS are o this type. iliary TB may
also ollow in ectious illnesses that reduce immunity espe
cially measles. Because this represents uncontrolled hematog
enous in ection the TST is negati e. Lesions are generali ed
and may appear as erythematous macules or papules pus
tules subcutaneous nodules and purpuric asculitic lesions.
lceration may occur and the pain in the in arcted lesions
may be substantial. The prognosis is guarded.
S in biopsies show di use suppurati e in ammation o
the dermis or subcutis with predominantly P s at times
orming abscesses. Caseating granulomas may be seen. A B
are abundant.
Fig. 16-6
Scrofuloderma.
323

16 Metastatic tuberculous abscess,
ulceration, or cellulitis
The hematogenous dissemination o mycobacteria rom a
Mycobacterial Diseases
primary ocus may result in rm nontender erythematous
pla ues (resembling cellulitis) or nodules. The nodules can
e ol e to orm abscesses ulcers or draining sinus tracts. This
orm o cutaneous TB is usually seen in children and most
patients ha e decreased immunity rom malnutrition in ec
tion or an immunode ciency state. Patients presenting with
tuberculous s in ulcers may or may not ha e other oci o TB
identi ed. Aerosoli ation o mycobacteria may occur during
incision and drainage and during dressing changes leading to
secondary cases among surgical and nursing sta treating
these ulcers. istologically abscess ormation and numerous
A B are seen.
Sporotrichoid tuberculosis
Although TB is usually thought to be spread either by direct
e tension or hematogenously in about o patients with
cutaneous TB the lesions occur in a sporotrichoid pattern
suggesting lymphatic spread. Classically this begins with a
distal lesion and new lesions appearing more pro imally. Less
o ten a pro imal lesion is present initially and new lesions
appear distally (retrograde lymphatic spread). The draining
pro imal lymph nodes may be enlarged. The indi idual
lesions ha e the same morphology in any gi en patient but
di erent patients can ha e di erent morphologies. A string o
lupus ulgaris li e lesions is most common. Less o ten a
string o deep nodules may become uctuant drain to the
sur ace or ulcerate orming linear scro uloderma li e lesions.
The draining lymph node may be enlarged (more o ten than
in sporotrichoid atypical mycobacterial in ection). The TST is
positi e. nderlying oci o systemic TB are o ten not ound.
Biopsy o the lesions (and a ected lymph nodes) typically
shows granulomatous in ammation but A B stains are
usually negati e. Culture may be positi e.
This orm o TB presents signi cant diagnostic problems
because sporotrichoid lesions would more o ten result rom
atypical mycobacteria or sporotrichosis. Since atypical myco
bacteria especially M marinum may result in a positi e TST
con rming the diagnosis is di cult e en i A B are ound on
biopsy. This is a clinical scenario in which GRA to analy e the
patient s immunologic response speci cally to M tuberculosis
with PCR to speciate the in ecting organism rom the biopsy
can be use ul.
Tuberculous mastitis
Rarely TB will present as subcutaneous nodules on the
breast. The lesions can suppurate orming abscesses or
brea down orming sinus tracts. The condition a ors
women o childbearing age but can also a ect men. Tubercu
lous mastitis may closely resemble breast cancer so biopsies
are re uently done. Abscesses may be incised and drained.
The conse uence o the ongoing in ammation destroying
the at o the breast and the surgical procedures can be a
se erely dis gured breast. An underlying ocus o TB may be
present in the underlying bone or at a distant site in some
cases. TST is positi e. istology shows granulomatous
in ammation with negati e A B stains. Culture is usually
negati e. The diagnosis o tuberculous mastitis should be
considered in all patients with granulomatous mastitis rom
endemic areas o TB.
324
tahir99 - UnitedVRG
Tuberculids
Tuberculids are a group o s in eruptions associated with an
underlying or silent ocus o TB. They are diagnosed by their
characteristic clinical eatures histologic ndings a positi e
TST or GRA sometimes by the nding o TB at a distant site
and resolution o the eruption with antituberculous therapy.
Tuberculids represent cutaneous lesions induced by hematog
enous dissemination o tubercle bacilli to the s in. Lupus ul
garis may de elop at the sites o tuberculids and M tuberculosis
D A may be ound in tuberculid lesions by PCR. Tuberculids
usually occur in persons with a strong immunity to TB (and
thus a positi e PPD). This results in rapid destruction o the
bacilli and autoin olution o indi idual lesions in many cases.
ew lesions continue to appear howe er since hematoge
nous dissemination rom the underlying ocus continues.
Tuberculids tend to be bilaterally symmetric eruptions because
they result rom hematogenous dissemination.
Papulonecrotic tuberculid
Papulonecrotic tuberculid is usually an asymptomatic chronic
disorder presenting in successi e crops. Lesions are symmet
rically distributed on the e tensor e tremities especially on
the tips o the elbows and on the nees; dorsal sur aces o the
hands and eet; buttoc s; ace and ears; and glans penis.
Lesions may a or pernio prone sites and may be worse
during winter months. Two thirds o cases occur be ore age
and emales are a ected o er males. idence o prior
or acti e TB is ound in one third to two thirds o patients
especially in the lymph nodes. The TST is positi e and may
generate a necrotic reaction.
Typical lesions ary in si e rom to mm and are rm
in ammatory papules that become pustular or necrotic.
Lesions resol e slowly o er se eral wee s but occasional
ulcers persist longer. Varioli orm scarring ollows the lesions.
Crops recur o er months to years.
Papulonecrotic tuberculids may appear in association with
other cutaneous mani estations o TB particularly erythema
induratum or scro uloderma. Associated clinical phenomena
ha e included tuberculous arteritis with gangrene in young
adult A ricans and de elopment o lupus ulgaris rom the
lesions. V in ected persons may de elop papulonecrotic
tuberculid.
istologically the epidermis is ulcerated in well de eloped
lesions. A palisaded collection o histiocytes surrounds an
o oid or wedge shaped area o dermal necrosis. Well ormed
tubercles are not seen e cept in nonhealing lesions e ol ing
into lupus ulgaris. Vascular changes are prominent ranging
rom a mild lymphocytic asculitis to brinoid necrosis and
thrombotic occlusion o essels. This is not a neutrophilic leu
ocytoclastic asculitis but rather a chronic granulomatous
small essel asculitis. Capillaries enules and arterioles
may be in ol ed. A B stains are negati e but PCR may detect
mycobacterial D A in up to hal o patients with papulone
crotic tuberculid.
Papulopustular secondary syphilis pityriasis lichenoides et
arioli ormis acuta Churg Strauss granuloma lymphomatoid
papulosis per orating granuloma annulare per orating col
lagenosis and necroti ing or septic asculitis share clinical
and histologic eatures with papulonecrotic tuberculid.
Lichen scrofulosorum
Lichen scro ulosorum consists o groups o indolent minute
eratotic discrete papules scattered o er the trun . The lesions
are mm ollicular or para ollicular and yellow pin to
reddish brown. They are rm and at topped or surmounted
by a tiny pustule or thin scale. The lesions are arranged in
nummular or discoid groups where they persist unchanged
or months and cause no symptoms. They may slowly undergo
spontaneous in olution ollowed at times by recurrence.
About o cases o lichen scro ulosorum occur in children
and adolescents under age . Acti e TB at a distant site
usually the bones or lymph nodes is present in about three
uarters o patients. The tuberculin test is always positi e.
istologically lichen scro ulosorum shows noncaseating
tuberculoid granulomas ust beneath the epidermis between
and surrounding hair ollicles. ormally tubercle bacilli are
not seen in the pathologic specimens and cannot be cultured
rom biopsy material.
Lichen nitidus lichen planus secondary syphilis and sar
coidosis should be considered in the di erential diagnosis.
Erythema induratum and vascular reactions
caused by tuberculosis (nodular tuberculid
and nodular granulomatous phlebitis)
rythema induratum (Ba in disease) is chronic and occurs
predominantly ( ) in women o middle age. Lesions a or
the posterior lower cal which may also show acrocyanosis.
ndi idual lesions are tender erythematous or iolaceous
cm subcutaneous nodules ( ig. ). Lesions resol e
spontaneously with or without ulceration o er se eral
months and can heal with scarring. A clinically similar but less
common condition called nodular granulomatous phlebitis
also a ects women primarily but in ol es both the lower legs
and the thighs usually along the course o the saphenous ein.
ndi idual lesions e ol e o er wee s to months but may recur
or years in a seasonal pattern. They do not ulcerate or heal
with scarring. The TST is positi e. diopathic nodular asculi
tis unassociated with TB may ha e identical clinical and his
tologic eatures and this diagnosis is made when the PPD is
negati e.
The primary pathology occurs in the subcutaneous at which
shows lobular panniculitis with at necrosis. Granulomatous
in ammation occurs in two thirds o cases and is noncaseating.
n addition a granulomatous asculitis o arterioles can be
present in the at and is the apparent cause o the at necrosis.
Biopsies o nodular granulomatous phlebitis show thrombosis
o and granulomatous in ammation centered around eins in
the deep dermis. A B are not ound on special stains or cul
tures o the biopsy. PCR may help to con rm these diagnoses;
howe er the positi e PPD ob iates the need or it. At times
necroti ing asculitis is present at the dermohypodermal unc
tion. This reaction has been termed nodular tuberculid. The
Fig. 16-7 Erythema
induratum. (Courtesy
of Curt Samlaska,
MD.)
histology o nodular tuberculid may be identical or ery similar
to polyarteritis nodosa. ore rarely small essel asculitis
(leu ocytoclastic asculitis) or Sweet syndrome li e lesions
may be seen as a reaction to an underlying ocus o TB.
rythema induratum must be distinguished rom erythema
Tuberculosis
nodosum nodular asculitis polyarteritis nodosa tertiary
syphilis and other in ectious and in ammatory panniculiti
des. rythema nodosum is o relati ely short duration de el
ops rapidly and chie y a ects the anterior rather than the
posterior cal es. t produces tender pain ul scarlet or contu
si orm nodules that appear simultaneously and do not ulcer
ate. istology demonstrates a septal panniculitis. n erythema
induratum patients the pain is less se ere and the lesions
tend to e ol e serially or in crops. A syphilitic gumma is
usually unilateral and single or may appear as a small distinct
group o lesions.
Diagnosis of cutaneous tuberculosis
Biopsy with acid ast staining should be done when the history
and physical e amination suggest cutaneous TB. PCR is
increasingly used to identi y mycobacterial D A in tissue
specimens and other biologic samples. t may be positi e
when both stains and cultures are negati e; in paucibacillary
disease howe er PCR is not reliably positi e. Culture remains
the gold standard and pro ides the means to determine anti
biotic sensiti ity and response to treatment.
Treatment
Testing or V is recommended or all patients diagnosed
with TB because V in ected patients may re uire longer
courses o therapy. n addition e ery e ort should be made
to culture the organism or sensiti ity testing because DR TB
is common in some communities. or all orms o cutaneous
TB multidrug chemotherapy is recommended. The recom
mendations o the local health clinics that manage other orms
o TB should be ollowed. Three drug or our drug regimens
are usually recommended or initial empiric treatment.
Directly obser ed therapy is a strategy designed to ensure
cure. Priority patients are those with prior treatment ailure
pulmonary TB with a positi e smear V coin ection current
or prior drug use drug resistant disease psychiatric illness
memory impairment or pre ious nonadherence to therapy.
Surgical e cision is use ul or the treatment o isolated lesions
o lupus ulgaris and tuberculosis errucosa cutis and surgi
cal inter ention also may bene t some patients with scro ulo
derma. n many cases o cutaneous TB the organism has not
been identi ed by either histology or culture so treatment is
inherently empiric. Virtually all orms o cutaneous TB will
ha e begun to respond to treatment by wee s. ailure to
respond within this period should result in reconsideration o
the diagnosis assessment or compliance and concern about
drug resistance.
Almagro M, et al: Metastatic tuberculosis abscesses in an
immunocompetent patient. Clin Exp Dermatol 2005; 30:247.
Camacho D, et al: Lichen scrofulosorum mimicking lichen planus. Am J
Dermatopathol 2011; 33:186–191.
Canpolat F, et al: Acquired cutaneous lymphangiectasia secondary
to scarring from scrofuloderma. Int Soc Dermatol 2010;
49:595–596.
Dias MF, et al: Update on cutaneous tuberculosis. An Bras Dermatol
2014; 89:925–938.
Doherty S, et al: National Psoriasis Foundation consensus statement on
screening for latent tuberculosis infection in patients with psoriasis
treated with systemic and biologic agents. J Am Acad Dermatol 2008;
59:209.
325
 Dongre AM, et al: Papulonecrotic tuberculid at the site of tuberculin test
16 in a patient with concomitant erythema induratum and papulonecrotic
tuberculid. Indian J Dermatol Venerol Leprol 2013; 79:248–250.
Dorman SE, et al: Interferon-γ release assays and tuberculin skin testing
for diagnosis of latent tuberculosis infection in healthcare workers in
Mycobacterial Diseases
the United States. Am J Respir Crit Care Med 2014; 1889:77–87.
Fernandez C, et al: Papulonecrotic tuberculid in a human
immunodeficiency virus type-1 patient with multidrug-resistant
tuberculosis. J Eur Acad Dermatol Venereol 2004; 18:369.
Fraser SJ, et al: Cutaneous tuberculosis revealed by infliximab therapy
for presumed sarcoidosis. Clin Exp Dermatol 2009; 35:e141–e142.
Ghosh S, et al: Tuberculosis verrucosa cutis presenting as diffuse
plantar keratoderma. Indian J Dermatol 2014; 59:80–81.
Gyldenlove M, et al: Cutaneous necrotic ulceration due to BCG
re-vaccination. Hum Vaccin Immunother 2012; 8:424.
Haase O, et al: Recurrent abscesses of the neck: scrofuloderma. JAMA
Dermatol 2014; 150:909–910.
Heller MM, et al: Fatal case of disseminated BCG infection after
vaccination of an infant with in utero exposure to infliximab. J Am Acad
Dermatol 2011; 65:870.
Jimenez-Gallo D, et al: Tuberculosis cutanea periorificial vulvar. Actas
Dermosifiliogr 2012; 103:929–930.
Joshi HS, et al: Lichen scrofulosorum. BMJ Case Rep 2014; pii:
bcr2013200858.
Kar S, et al: Scrofuloderma: a case series from rural India. Indian J
Tuberc 2011; 58:189–195.
Khaira A, et al: Tuberculosis verrucosa cutis in a renal transplant
recipient. Int J Dermatol 2009; 48:516–517.
Kim JE, et al: Tuberculous cellulitis as a manifestation of military
tuberculosis in a patient with malignancy-associated dermatomyositis.
J Am Acad Dermatol 2011; 65:450–452.
Kumar U, et al: Psoriasiform type of lichen scrofulosorum: Pediatr
Dermatol 2011; 28:532–534.
Laws PM, et al: Nonhealing vegetating plaque on the finger: Cutis 2011;
87:30–33.
Leocata P, et al: Squamous cell carcinoma arising from long-term
(50-year) lupus vulgaris: Infez Med 2009; 17:249–253.
Leon-Mateo A, et al: Perianal ulceration: a case of tuberculosis cutis
orificialis. J Eur Acad Dermatol Venereol 2005; 19:364.
Lin CY, et al: Perianal tuberculosis during neutropenia: a rare case
report and review of literature. Ann Hematol 2006; 85:547.
Ljubenovic MS, et al: Cutaneous tuberculosis and squamous-cell
carcinoma. An Bras Dermatol 2011; 86:541–544.
Makkar VR, et al: Lupus vulgaris postexanthematicus: a rare variant of
lupus vulgaris with sarcoid-like histopathology. Clin Exp Dermatol
2005; 30:187.
McHugh A, et al: Nodular granulomatous phlebitis: a phlebitic
tuberculid. Australas J Dermatol 2008; 49:220.
Motswaledi HM, et al: Superficial thrombophlebitic tuberculide. Int J
Dermatol 2006; 45:1337.
Motswaledi MH, Doman C: Lupus vulgaris with squamous cell
carcinoma. J Cutan Pathol 2007; 34:939.
Mukherjee A, et al: Status and current role of interferon gamma release
assays vs. tuberculin skin testing in diagnosis of tubercular disease.
Indian J Pediatr 2013; 80:334–336.
Projapati V, et al: Erythema induratum: J Cutan Med Surg 2013; Suppl
1:6–11.
Rajagopala S, Agarwal R: Tuberculosis mastitis in men: case report and
systematic review. Am J Med 2008; 121:539.
Ramesh V: Sporotrichoid cutaneous tuberculosis. Clin Exp Dermatol
2007; 32:680.
Regnier S, et al: Cutaneous military resistant tuberculosis in a patient
infected with human immunodeficiency virus: Clin Exp Dermatol 2009;
34:e690–e692.
Rhodes J, et al: Lupus vulgaris: Australas J Dermatol 2013;
54:e53–e55.
Romy RMC, et al: Cutaneous complication after BCG vaccination:
J Dermatol Treat 2011; 22:315–318.
Sethuraman G, et al: Cutaneous tuberculosis in children. Pediatr
Dermatol 2013; 30:7–16.
Shibuya R, et al: Cutaneous miliary tuberculosis in a patient with
long-term steroid treatment for microscopic polyangiitis. Eur J
Dermatol 2013; 23:286–287.
Singal A, et al: Lichen scrofulosorum: a prospective study of 39
patients. Int J Dermatol 2005; 44:489.
326
tahir99 - UnitedVRG
Singal A, et al: Ulcerated lupus vulgaris at the site of bacille Calmette-
Guérin vaccination. Pediatr Dermatol 2013; 30:147–148.
Takeuchi G et al: Disseminated lupus vulgaris diagnosed more than 63
years after onset due to early misdiagnosis as a port wine stain. Clin
Exp Dermatol 2010; 35:e28–e29.
Tekbas G, et al: Skin ulcers: Respir Care 2011; 56:1853–1856.
Tissot C, et al: Life-threatening disseminated tuberculosis as a
complication of treatment by infliximab for Crohn’s disease: J Crohns
Colitis 2012; 6:946–949.
Vera-Kellet C, et al: Usefulness of interferon-γ release assays in the
diagnosis of erythema induratum. Arch Dermatol 2011; 147:949–952.
Wang H, et al: Cutaneous tuberculosis: a diagnostic and therapeutic
study of 20 cases. J Dermatol Treat 2011; 22:310–314.
Williams C, et al: Turkey ear: a diagnosis or a physical sign? Br J
Dermatol 2007; 157:816.
Wolf T, et al: Tuberculosis skin test, but not interferon-γ-releasing
assays, is affected by BCG vaccination in HIV patients. J Infect 2013;
66:376–380.
Wong HW, et al: Papular eruption on a tattoo: a case of primary
inoculation tuberculosis. Australas J Dermatol 2005; 46:84.
Yodmalai S, et al: Cutaneous military tuberculosis in a renal transplant
patient: Southeast Asian J Trop Med Public Health 2011; 42:674–678.
ATYPICAL MYCOBACTERIOSIS
any acultati e pathogens and saprophytes which are acid
ast mycobacteria but do not cause TB or ansen s disease are
grouped under the designation atypical mycobacteria. They
e ist in a wide ariety o natural sources such as soil water
and animals; most human disease is ac uired rom the en i
ronment. The number o cases o human in ection with these
organisms is increasing or increasingly recogni ed. This is a
result o impro ed culture and identi cation techni ues and
the increasingly large immunocompromised population.
Classification of mycobacteria
The old Runyon classi cation scheme based on identi ying
atypical mycobacteria in the laboratory was as ollows
Group photochromogens M cobacterium marinum
M ansasii M simiae
Group scotochromogens M cobacterium scrofulaceum
M gor onae M xenopi M s ulgai
Group nonchromogens M cobacterium avium
intracellulare comple M haemophilum M ulcerans
M malmaoense M terrae M genavense M bovis
M nonchromogenicum
Group V rapid growers M cobacterium fortuitum
M chelonae M smegmatis M abscessus M immunogenum
M mucogenicum M goo ie M wolins i M cosmeticum
M fran linii
M cobacterium marinum M ulcerans and M haemophilum are
now recogni ed as common pathogens in certain settings and
geographic locations. Rapidly growing mycobacteria o the
M cobacterium fortuitum chelonae and abscessus group are
usually associated with pre ious surgery in ection or trauma.
An increasing number o patients recei ing anti T therapy
and those with solid organ or stem cell transplants ha e been
reported with in ections caused by atypical mycobacteria.
nly select organisms that most re uently a ect the s in are
discussed in detail here.
The number o new species o nontuberculous mycobacteria
has been growing dramatically with now at least nown
species. any o these organisms do not cause in ection and
are simply commensals or saprophytes. They are ound in
water and soil and their identi cation a ter contamination o
clinical specimens has at times been responsible or pseudo
outbrea s o in ection.
The clinical care o the patient with atypical mycobacterial
in ection depends on culturing and identi ying the responsible
agent rom tissue specimens. The laboratory should be amil
iar with the special media necessary incubation times and
temperature and identi cation characteristics o these organ
isms. en with modern techni ues reco ery o these organ
isms rom in ections is not uni ersal. Granuloma ormation
may not occur in histologic sections and A B stains may be
negati e. or this reason i atypical mycobacteria in ection is
suspected a biopsy should be done part o which should be
cultured at high and low temperatures and on special media;
A B stains o the tissue should be per ormed; and in select
patients PCR or speci c species rom resh tissue or the
para n ed material should be considered. n some patients
a clinical diagnosis must be made and empiric therapy gi en.
Swimming pool granuloma (aquarium granuloma)
M cobacterium marinum is ound in resh and salt water and
can in ect sh o ten illing home a uarium sh. t grows
optimally at C. The ast ma ority o in ections in the nited
States and urope are now associated with home a uariums.
ishermen sh sellers and persons in ol ed in a uaculture
are also at ris . S in lesions a or males ( ). istory o an
in ury preceding or simultaneous with e posure to contami
nated water is usually present. posure can be indirect such
as contact with a buc et used to empty an a uarium.
An indolent lesion usually starts about wee s a ter e po
sure as a small papule or nodule located on the hands nees
elbows or eet. t o ten has a eratotic or warty sur ace. A
sporotrichoid pattern with a succession o nodules ascending
the arm is common ( ig. ). Less o ten ulcers and abscesses
may be the presentation especially in immunosuppressed
hosts. Tenosyno itis bursitis arthritis and osteitis are the
most re uent orms o deep structure in ol ement. There
may be in ol ement o the tendon sheaths o the dorsal hands
and less re uently the palms. This may limit range o motion
and result in signi cant thic ening and induration. Such
patients may re uire surgical as well as medical management.
The natural history is or slow progression and lesions may
be relati ely indolent or years. Spontaneous resolution may
occur in o patients with s in lesions only a ter many
months. mmunosuppressed patients may de elop widely
disseminated lesions that are progressi e.
istopathologically there is a suppurati e and granuloma
tous reaction with o erlying hyper eratosis and acanthosis.
Fig. 16-8 Sporotrichoid
Mycobacterium
marinum infection.
Acid ast organisms are ound in only about o cases.
Tissue culture will be positi e in about three uarters o cases.
The TST and GRA to M tuberculosis usually become positi e
in those who ha e had M marinum in ection.
Treatment is determined by the e tent o the in ection and
Atypical mycobacteriosis
the patient s immune status. ptimal treatment has not yet
been established and a orable outcome cannot be related to
any speci c antibiotic or antibiotic combination. ailure o
e ery antibiotic used has been documented. Single agent
therapy is acceptable or immunocompetent patients with
in ections limited to s in and so t tissue. inocycline mg
twice daily seems to be the single best agent with do ycycline
( mg twice daily) clarithromycin ( mg twice daily)
or trimethoprim sul ametho a ole (T P S mg
twice daily) as alternati e therapy. Some patients ha e ailed
do ycycline therapy but responded to minocycline. Combina
tion treatment with minocycline plus clarithromycin or with
ri ampin ri abutin or ami acin added to minocycline and or
clarithromycin seems appropriate based on in itro sensiti i
ties o numerous isolates. thambutol and the uinolones ha e
poor minimum inhibitory concentration and their use is asso
ciated with treatment ailure. The sensiti ities o the organism
isolated can be used in cases ailing initial empiric treatment.
mmunosuppressed hosts and patients with in ol ement o
deep structures should recei e combination treatment. or
locali ed lesions in the immunocompetent host treatment is
recommended or at least months a ter resolution o
lesions which is usually months in total. ore than
o such patients will be cured. nly about o patients with
deep structure in ections will be cured with antibiotics with
or without supplemental surgery. n this situation treatment
is o ten prolonged many months to years.
Buruli ulcer
Buruli ulcer is also nown as Bairnsdale ulcer and Searl ulcer.
This is the third most common type o mycobacterial s in
in ection in immunocompetent people. n A rica o cases
occur in children and elderly persons are disproportionately
a ected. n endemic areas in Australia elderly people are
se en times more li ely to be in ected. Lesions a or the
e tremities. The lesion begins as a solitary hard painless
subcutaneous nodule called the preulcerati e stage. There
can be signi cant local edema at this point. untreated some
lesions ulcerate and e pand by undermining the surrounding
s in ( ig. ). They may become ery large e posing muscle
Fig. 16-9 Buruli ulcer.
327
 and tendon o er a large portion o an a ected e tremity.
16 Despite their appearance the lesions are remar ably painless.
Persons with hemoglobin SS or SC are as much as e times
more li ely to de elop osteomyelitis rom M ulcerans. isto
logically there is e tensi e coagulati e necrosis minimal cel
Mycobacterial Diseases
lular in ltrate and numerous clumps o A B in the center o
the necrotic area.
M cobacterium ulcerans is the cause o Buruli ulcer. This
organism occurs in Australia numerous A rican nations (espe
cially in Central and West A rica) Asia rench Guyana Peru
Suriname e ico and Bra il. The pathogenesis o this in ec
tion is now well de ned. M ulcerans produces a to in myco
lactone responsible or the e tensi e necrosis and ulceration.
n addition to ha ing cellular to icity mycolactone is also
locally immunosuppressi e. Tissue necrosis creates a micro
aerophilic en ironment that a ors the growth o M ulcerans.
Strains o M ulcerans lac ing mycolactone are not capable o
producing disease. This to in is also critical in maintaining the
li e cycle o the organism.
M cobacterium ulcerans grows under a bio lm on a uatic
plants. Snails and other water animals eat the contaminated
plants and carni orous insects eat the plant consuming mol
luscs. M ulcerans mo es rom the gut o the carni orous insects
to their sali ary glands. nly M ulcerans species producing
mycolactone are capable o establishing a reser oir in the
insect sali ary gland. M ulcerans is ound in no other tissue in
the biting insects and produces no bio lm in the insect sali ary
gland. When these insects bite a human they inoculate the
mycobacteria into the host and begin the in ection. n ection
in the human is again associated with the production o the
bio lm which ma es treatment di cult. This e plains the
association between in ection and e posure to water espe
cially swampy water. nterestingly being repeatedly bitten by
these carni orous insects results in the production o antibod
ies against the insect sali ary contents. This immune response
to the insect sali a is protecti e against M ulcerans in ection
e plaining why persons wor ing regularly in swampy water
are at lower ris or in ection than those isiting the area and
perhaps why children and elderly persons are at greater ris
or in ection because o reduced production o these antibod
ies. n Australia mos uito bites are associated with the de el
opment o M ulcerans in ection and the bacteria can be isolated
rom trapped insects in areas o M ulcerans epidemics. Whether
the mos uitoes carry the in ection by the same mechanism as
the carni orous water insects is un nown.
The diagnosis o Buruli ulcer is o ten made clinically in areas
o endemicity. A B smears o the edge o ulcerati e lesions or
o aspirates rom the center o preulcerati e lesions culture o
the lesion PCR and histologic e amination all can con rm the
diagnosis. A B stains are positi e in up to o lesions.
Culture has a similar positi ity rate. PCR may be slightly less
sensiti e. When A B smears culture and PCR were all done
on the same lesion one test was positi e in o cases two
were positi e in and only o cases yielded positi e
results by all three methods. About o cases will be nega
ti e with all three tests. Preulcerati e lesions gi e the highest
culture results because ulcerati e lesions contain ewer organ
isms and are contaminated. A B smears and PCR ha e similar
sensiti ity in preulcerati e and ulcerati e lesions. M ulcerans
is ery stable in transport and has been cultured up to
wee s a ter sample collection i transported to the laboratory
appropriately.
Treatment o Buruli ulcer includes systemic antibiotics and
surgery. Daily obser ed treatment or wee s with strepto
mycin mg g intramuscularly and ri ampin mg g
orally is dramatically e ecti e. The o erall e cacy o this
treatment regimen was o patients and in lesions less
than cm in diameter (early lesions) without surgery. ealing
328
tahir99 - UnitedVRG
is slow with hal o lesions healing by wee s (with only
wee s o antibiotic treatment) and some re uiring more than
months to heal. Clarithromycin . mg g orally once daily
may be substituted or the last wee s o streptomycin therapy
with irtually e ual e cacy. n larger lesions (> cm) and in
lesions ailing antibiotic treatment alone surgical e cision
with delayed gra ting is the standard treatment o ered. n a
large series o more than patients all patients who com
pleted the ull course o antibiotics with or without surgery
were cured a success rate o by months a ter the
antibiotics were completed. At year ollow up only . o
patients had recurrence.
Se ere scarring can result rom untreated and large lesions
leading to contracture de ormity or amputation. the periocu
lar tissues are a ected enucleation o the eye may be re uired.
ultiple metastatic s in lesions can occur. Bone lesions are
uncommon and in three uarters o patients occur at a site
distant rom the primary Buruli ulcer. Rarely death may
result.
Other atypical mycobacterial infections
Mycobacterium haemophilum
M cobacterium haemophilum most o ten in ects immunosup
pressed patients with A DS with organ transplant recei ing
anti T agents or with leu emia or lymphoma. The reser
oir or the organism is un nown but thought to be water.
Because M haemophilum grows pre erentially at C
s in lesions at acral sites predominate. Papules pla ues (at
times cellulitis li e) and dermal or subcutaneous nodules
are the primary lesions. These initial lesions brea down in
many cases orming pain ul draining ulcers. Cutaneous in ec
tions a ter acupuncture ollowing application o permanent
eyebrow ma eup and within tattoos ha e been reported in
immunocompetent and immunosuppressed patients. Septic
arthritis osteomyelitis and pulmonary nodules may occur. M
haemophilum has speci c growth re uirements so isolation is
not possible using routine laboratory culture techni ues. M
haemophilum in ection is suspected the laboratory should be
noti ed so that it can prepare the special media necessary to
isolate it. M haemophilum is sensiti e to cipro o acin clar
ithromycin ami acin ri ampin and ri abutin. t is resistant
to ethambutol isonia id and pyra inamide. Combination
therapy is recommended. Treatment is or year.
Rapidly growing mycobacteria
The organisms o the M cobacterium fortuitum group and M
chelonae abscessus group usually cause subcutaneous abscesses
or cellulitis. These rapidly growing mycobacteria (RG ) are
re uently resistant to standard antituberculosis medications.
n ections usually occur a ter trauma in immunocompetent
patients. n ections may ollow a ariety o cosmetic surgery
procedures (e.g. C laser resur acing laser hair remo al
in ection with dermal llers mesotherapy liposuction) s in
piercing or catheteri ation and may occur within tattoos. ut
brea s o leg abscesses caused by M fortuitum ha e been
ac uired in nail salon whirlpool ootbaths. ost RG cases
are restricted to the s in and start as small erythematous
papules many o which spontaneously heal. thers progress
to large uctuant abscesses which are uite pain ul and can
ulcerate ( ig. ). Sporotrichoid or disseminated disease
may occur in immunocompromised patients ( ig. ) but
pro imal adenopathy is rarely ound. Sha ing o the legs
be ore isiting the nail salon appears to be a ris actor or
 Fig. 16-10
Mycobacterium
fortuitum infection.
Fig. 16-11
Disseminated
Mycobacterium
chelonae infection.
ac uiring in ection with RG . n renal transplant patients
tender nodular lesions o the legs are most common. Deep
e tension into bone underlying a chronic ulcer can occur. Since
these in ections on the s in are indolent and the organisms
grow rapidly waiting or susceptibilities can be considered.
Treatment is determined by e tent o disease and immune
status o the patient. or M chelonae abscessus in ections clar
ithromycin mg twice daily or months or more is e ec
ti e and well tolerated in many patients with disseminated
cutaneous in ection. onotherapy may allow resistance to
occur but this rarely happens in immunocompetent patients
with simple s in in ections. n se ere cases and in the setting
o immunosuppression combination treatment should be
used. Tobramycin ami acin line olid clarithromycin and
tigecycline ha e the highest percentage o susceptible isolates
Atypical mycobacteriosis
Fig. 16-12 Mycobacterium avium-intracellulare complex, primary
inoculation in a healthy woman.
o M chelonae abscessus. The optimal regimen or treatment o
M fortuitum has not been de ned and combination treatment
is o ten recommended. Ami acin plus ce o itin and proben
ecid or a uinolone can be recommended or initial therapy
or wee s ollowed by do ycycline or T P S or up to
year. only oral agents are to be used or s in limited
disease minocycline ( g twice daily) do ycycline ( mg
twice daily) T P S ( double strength tablet twice daily)
or le o o acin ( mg once daily) are acceptable agents.
Surgical e cision debridement and drainage may reduce
duration o therapy.
A newly recogni ed RG species that has been separated
rom M chelonae is M cobacterium fran linii t is distinct ta o
nomically similar in epidemiology but is distinguished by its
susceptibility to ce o itin.
Mycobacterium avium-intracellulare complex
The M avium intracellulare comple was an uncommon cause
o s in in ection be ore the A DS epidemic. n patients with
A DS who de elop disseminated M avium intracellulare in ec
tions the s in may be in ol ed by hematogenous dissemina
tion and may present as nodules ulcers or pustules or may
ha e a cellulitis li e appearance. mmunocompromised chil
dren with chronic pulmonary in ections are also at ris .
nly occasional reports o immunocompetent patients with
inoculation type lesions ha e been reported ( ig. ).
Therapy or disseminated in ection is underta en with at least
three agents most o ten clarithromycin or a ithromycin eth
ambutol and ri abutin. Ade uate antiretro iral therapy
should be assured in V in ected persons.
Mycobacterium kansasii
M cobacterium ansasii rarely causes s in in ection usually
a ter minor trauma. Three uarters o cases occur in immuno
suppressed persons. Lesions can be papules nodules pus
tules cellulitis or sporotrichoid. Treatment is not standardi ed
but initial treatment with isonia id ri ampin and ethambutol
until months a ter clearing has been proposed. A ithromy
cin or clarithromycin can be added i necessary. owe er
indi idual cases ha e responded to single agent therapy with
minocycline or erythromycin. Surgical remo al can be bene
cial i practical. n immunosuppressed patients cutaneous
lesions can occur through hematogenous dissemination and
a isceral source especially pulmonary should be sought.
329

16
Aslam A, et al: Cutaneous Mycobacterium haemophilum infection in a
patient receiving infliximab for psoriasis. Br J Dermatol 2013;
168:446–447.
Atkins BL, et al: Skin and soft tissue infections caused by
nontuberculous mycobacteria. Curr Opin Infect Dis 2014; 27:137–145.
Mycobacterial Diseases
Boleira M, et al: Buruli ulcer. An Bras Dermatol 2010; 85:281–298.
Caron J, et al: Aggressive cutaneous infection with Mycobacterium
marinum in two patients receiving anti–tumor necrosis factor-alfa
agents. J Am Acad Dermatol 2011; 65:1060–1062.
Chany A-C, et al: History, biology and chemistry of Mycobacterium
ulcerans infections (Buruli ulcer disease). Nat Prod Rep 2013;
30:1527–1567.
Cheung JP, et al: Mycobacterium marinum infection on the hand and
wrist. J Orthop Surg 2012; 20:214–218.
Collins CS, et al: Disseminated Mycobacterium haemophilum infection in
a 72-year-old patient with rheumatoid arthritis on infliximab. BMJ Case
Rep 2013; pii: bcr2012008034.
Conejero R, et al: Infeccion por Mycobacterium chelonae en paciente en
tratamiento con adalimumab. Actas Dermosifliogr 2012; 103:69–71.
Converse PJ, et al: Treating Mycobacterium ulcerans disease (Buruli
ulcer): Future Microbiol 2011; 6:1185–1198.
Culton DA, et al: Nontuberculous mycobacterial infection after
fractionated CO2 laser resurfacing. Emerg Infect Dis 2013; 19:365–370.
Drage LA, et al: An outbreak of Mycobacterium chelonae infections in
tattoos. J Am Acad Dermatol 2010; 62:501–506.
Ducharlet K, et al: Recurrent Mycobacterium haoemophilum in a renal
transplant recipient. Nephrology 2014; Suppl 1:14–17.
Eberst E, et al: Epidemiological, clinical, and therapeutic pattern of
Mycobacterium marinum infection. J Am Acad Dermatol 2012;
66:e15–e16.
Ferreira J, et al: Mycobacterium marinum. Am Coll Gastroenterol 2012;
107:1268–1269.
Fowler J, et al: Localized cutaneous infections in immunocompetent
individuals due to rapidly growing mycobacteria. Arch Pathol Lab Med
2014; 138:1106–1109.
Giulieri S, et al: Outbreak of Mycobacterium haemophilum infections
after permanent makeup of the eyebrows. Clin Infect Dis 2011;
52:488–491.
Goldman J, et al: Outbreak of Mycobacterium chelonae in France. BMJ
2010: 341:906.
Guevara-Patino A, et al: Soft tissue due to Mycobacterium fortuitum
following acupuncture: a case report and review of the literature. J
Infect Dev Ctries 2010: 4:521–525.
Han SH, et al: Disseminated Mycobacterium kansasii infection
associated with skin lesions. J Korean Med Sci 2010; 25:304–308.
Iyengar KP, et al: Mycobacterium chelonae hand infection following
ferret bite. Infection 2013; 41:237–241.
Jacobs S, et al: Disseminated Mycobacterium marinum infection in a
hematopoietic stem cell transplant recipient. Transpl Infect Dis 2012;
14:410–414.
Kay MK, et al: Tattoo-associated Mycobacterium haemophilum skin
infection in immunocompetent adult. Emerg Infect Dis 2011;
17:1734–1736.
Kelley CF, et al: Disseminated Mycobacterium haemophilum infection.
Lancet Infect Dis 2011; 11:571–578.
Kennedy BS, et al: Outbreak of Mycobacterium chelonae infection
associated with tattoo ink. N Engl J Med 2012; 367:1020–1024.
Kim MJ, et al: Mycobacterium chelonae wound infection after
liposuction. Emerg Infect Dis 2010; 16:1173–1175.
Kump PK, et al: A case of opportunistic skin infection with
Mycobacterium marinum during adalimumab treatment in a patient with
Crohn’s disease. J Crohns Colitis 2013; 7:e15–e18.
330
tahir99 - UnitedVRG
Lavendar CJ, et al: Risk of Buruli ulcer and detection of Mycobacterium
ulcerans in mosquitoes in southeastern Australia. PLoS Negl Trop Dis
2011; 5:e1305.
Lavender CJ, et al: Buruli ulcer disease in travelers and differentiation of
Mycobacterium ulcerans strains from northern Australia. J Clin
Microbiol 2012: 50:3717–3721.
Lindeboom JA, et al: Clinical manifestations, diagnosis, and treatment of
Mycobacterium haemophilum infections. Clin Microbiol Rev 2011;
24:701–717.
Lopez Aventin D, et al: Mycobacterium fortuitum infection in continuous
subcutaneous insulin infusion sites. Br J Dermatol 2014; 171:418–420.
Macente S, et al: Disseminated folliculitis by Mycobacterium fortuitum in
an immunocompetent woman. An Bras Dermatol 2013; 88:102–104.
Merritt RW, et al: Ecology and transmission of Buruli ulcer disease: a
systemic review. PLoS Negl Trop Dis 2010: 4:e911.
Mitha M, et al: Cutaneous Mycobacterium kansasii infection in a patient
with AIDS post initiation of antiretroviral therapy. J Infect Dev Ctries
2011; 5:553–555.
Mustaq RF, et al: Skin, subcutaneous tissue, and allograft infection with
Mycobacterium fortuitum in a renal transplant recipient. Saudi J Kidney
Dis Transpl 2014; 25:1248–1250.
Nakanaga K, et al: Nineteen cases of Buruli ulcer diagnosed in Japan
from 1980 to 2010. J Clin Microbiol 2011; 49:3829–3836.
Oh CC, et al: Mycobacterium haemophilum in an elderly Chinese
woman. Int J Dermatol 2014; 53:1129–1132.
Palm MD, et al: Mycobacterium chelonae infection after fractionated
carbon dioxide facial resurfacing (presenting as an atypical acneiform
eruption). Dermatol Surg 2010; 36:1473–1481.
Quinones C, et al: An outbreak of Mycobacterium fortuitum cutaneous
infection associated with mesotherapy. J Euro Acad Dermatol Venereol
2010; 24:604–606.
Rao J, et al: Atypical mycobacterial infection following blepharoplasty
and full-face skin resurfacing with CO2 laser. Dermatol Surg 2012;
28:768–771.
Rodriguez JM, et al: Mycobacterium chelonae facial infections following
injection of dermal filler. Aesthet Surg J 2013; 33:265–269.
Sergeant A, et al: Mycobacterium chelonae infection: a complication of
tattooing. Clin Exp Dermatol 2013; 38:140–142.
Simmon KE, et al: Mycobacterium chelonae-abscessus complex
associated with sinopulmonary disease, northeastern USA. Emerg
Infect Dis 2011; 17:1692–1700.
Suvanasuthi S, et al: Mycobacterium fortuitum cutaneous infection from
amateur tattoo. J Med Assoc Thai 2012; 95:834–837.
Thanou-Stravraki A, et al: Noodling and Mycobacterium marinum
infection mimicking seronegative rheumatoid arthritis complicated by
anti–tumor necrosis factor α therapy. Arthritis Care Res 2011;
63:160–164.
Wu TS, et al: Fish tank granuloma caused by Mycobacterium marinum.
PLoS One 2012; 7:e41296.
Bonus images for this chapter can be found online at
expertconsult.inkling.com
eFig. 16-1 Mycobacterium marinum infection.
eFig. 16-2 Disseminated Mycobacterium marinum infection in
systemic lupus erythematosus. (Courtesy of Curt Samlaska, MD.)
eFig. 16-3 Mycobacterium avium-intracellulare complex ulceration.
 eFig. 16-1
Mycobacterium
marinum infection.

Atypical mycobacteriosis
eFig. 16-3 Mycobacterium avium-intracellulare complex ulceration.

eFig. 16-2 Disseminated

Mycobacterium marinum
infection in systemic lupus
erythematosus. (Courtesy
of Curt Samlaska, MD.)

330.e1
 Bonus images for this chapter can be found online at
expertconsult.inkling.com

Hansen’s Disease
17
multibacillary cases. n ected women are li ely to present
EPIDEMIOLOGY during or immediately a ter pregnancy.
The mode o transmission remains contro ersial. cept or
The World ealth rgani ation (W ) has committed itsel cases associated with armadillo e posure other patients with
to eliminating ansen s disease as a public health problem. ansen s disease are thought to be the only possible source o
limination (not eradication) is considered as a pre alence o in ection. Rarely tattooing or other penetrating in ury to the
less than case in persons in any country. This target s in can be the route o in ection. ultibacillary cases are
was globally met in . The number o new cases worldwide much more in ectious than paucibacillary cases so the nature
o ansen s disease declined rom more than in o the source case is the most important actor in transmission.
to in . ansen s disease is endemic in certain Contact is associated with ac uiring in ection. ousehold con
regions with o cases reported rom countries. Bra il tacts represent o new ansen s disease patients; there is
ndia and ndonesia account or o all cases worldwide. an times greater ris o ac uiring disease i the household
n the nited States new cases o ansen s disease were contact has lepromatous disease ersus only times i the
reported in . Although o diagnosed .S. cases are contact has tuberculoid leprosy. n o all new cases o
imported ansen s disease is endemic in the coastal south ansen s disease there is a clear history o social contact with
eastern nited States and in awaii. n the southeastern states an untreated patient with ansen s disease. PCR can detect M
cases may be related to e posure to armadillos a natural host leprae on the intact s in by saline washings in up to o
or the in ectious agent. multibacillary patients with a high bacterial load (bacterial
t is belie ed that more than o persons e posed to inde B > ). p to o nasal swabs are similarly positi e.
M cobacterium leprae are able to resist in ection. n endemic Whereas the swabs rom the patients remain positi e a ter
areas between . and o the population is seropositi e months o DT the swabs o household contacts become
or antibodies to leprosy speci c antigens suggesting wide negati e suggesting that the bacilli seen in patients are non i
spread e posure to the bacillus. About o household con able and that the ris o transmission is substantially reduced
tacts o multibacillary patients ha e M leprae which is a ter the inde patient is treated. n ortunately persons may
detectable by polymerase chain reaction (PCR) on s in swabs be in ectious rom their s in or nasal secretions with no clini
with detectable in nasal swabs. This clears a ter the multi cal e idence o ansen s disease (multibacillary patients who
bacillary patient has been treated with multidrug therapy are not yet symptomatic and without identi able s in lesions).
( DT) or months. Thus although many persons can be This may ma e strategies relying on treatment o contacts o
transiently in ected they apparently are able to resist o ert nown ansen s disease patients ine ecti e in eradicating the
clinical in ection. disease. n nonendemic areas transmission to contacts is rare
There appears to be a genetic basis or susceptibility to a reassuring act or the amilies o patients diagnosed in areas
ac uire ansen s disease. ono ygotic twins ha e concor where ansen s disease is uncommon. The last case o second
dant disease in o cases and di ygotic twins in only ary transmission o ansen s disease in the nited ingdom
. umerous genes ha e been identi ed as possibly ( ) was in
con erring susceptibility to in ection with M leprae Di erent
genes ha e been identi ed in di erent populations suggest
ing that multiple genetic causes o susceptibility to in ection THE INFECTIOUS AGENT
are possible with M leprae Tight genetic lin age with the
PAR PACRG regulatory region LA DRB and lympho ntil recently it had been thought that all cases o human and
to in A (LTA+ ) has been detected. P is a gene in ol ed animal leprosy are caused by the same organism M cobacte
in the de elopment o Par inson s disease and LTA+ is a rium leprae This is a wea ly acid ast organism that has not
low production lymphoto in A allele associated with malaria been success ully cultured in itro. M leprae grows best at
parasitemia. nterleu in ( L) single nucleotide polymor temperatures ( C) below the core body temperature o
phism (S P) is associated with an increased susceptibility to humans. This e plains the locali ation o ansen s disease
ansen s disease and type reactions in paucibacillary lesions to cooler areas o the body and the sparing o the
patients. n Chinese patients susceptibility was lin ed to mul midline and scalp. The organism may be culti ated in mouse
tiple genes including CCDC C orf and a series o genes ootpads and most e ecti ely in armadillos whose lower
nown to be associated with susceptibility to other mycobacte body temperature is more optimal or growth o M leprae
rial diseases including OD L P and S Phenolic glycolipid (PGL ) is a sur ace glycolipid uni ue to
n adult cases men outnumber women . . Although an the leprosy bacillus. n in ected tissues the leprosy bacillus
sen s disease occurs at all ages most cases appearing or a ors intracellular locations within macrophages and ner es.
ac uired in endemic areas present be ore age . Patients The genome o the leprosy bacillus has been se uenced and
e posed to armadillos present on a erage at age . The latency compared to its close relati e the tuberculous bacillus. The
period between e posure and o ert signs o disease is usually genome o M leprae contains only unctional genes
years or paucibacillary cases and an a erage o years in apparently the result o signi cant reducti e e olution. As
331

tahir99 - UnitedVRG
 with other intracellular parasites and in the absence o the
17 ability to share D A with other bacteria M leprae has lost
many nonessential genes including those in ol ed in energy
metabolism ma ing it dependent on the intracellular en iron
ment or essential nutrients. This may e plain the e tremely
Hansen’s Disease
long generation time days and the inability to culture
M leprae in itro.
A second organism ycobacterium lepromatosis has
been isolated rom ansen s disease patients in e ico and
reported as the ma or cause o leprosy in some regions. Some
patients are in ected with both M leprae and M lepromatosis
This second mycobacterium is speci cally associated with the
di use type o lepromatous leprosy (DLL) also nown as
Lucio s leprosy. These are the patients who de elop Lucio s
phenomenon. n asion o the endothelial cells characteri es
in ection with the new organism. Although not all researchers
accept . lepromatosis as a second separate species capable
o causing ansen s disease it does suggest more than one
causati e organism or leprosy.
DIAGNOSIS
A diagnosis o ansen s disease must be considered in any
patient with neurologic and cutaneous lesions. The diagnosis
is re uently delayed in the de eloped world; clinicians do not
readily thin o ansen s disease because they may ne er
ha e seen it. n the nited States this diagnostic delay a er
ages 1 1 2 years. n the in more than o patients with
ansen s disease the correct diagnosis was not suspected
during the initial medical e aluation.
ansen s disease is diagnosed as with other in ectious dis
eases by identi ying the in ectious organism in a ected tissue.
Because the organism cannot be cultured this may be ery
di cult. Biopsies rom s in or ner e lesions stained or the
bacillus with ite araco stain are usually per ormed in the
de eloped world. n some ansen s disease clinics and in
the de eloping world where the disease is endemic organisms
are identi ed in slit smears o the s in. Smears are ery spe
ci c but o all patients with ansen s disease ha e nega
ti e smears. Smears are ta en rom lesions and cooler areas o
the s in such as the earlobes elbows and nees. organisms
are ound on s in smears the patient is said to be multibacil
lary. the results o s in smears are negati e (and there are
e or ewer lesions) the patient is called paucibacillary.
er e in ol ement is detected by enlargement o peripheral
ner es and lesional loss o sensation. nlarged ner es are
ound in more than o patients with multibacillary an
sen s disease and in o patients with paucibacillary
disease. About o lesions ha e reduced sensation but
Table 17-1 Spectrum of host-parasite relationship in Hansen’s disease
High resistance
Borderline
Tuberculoid (TT) tuberculoid (BT)
Lesions 1–3 Few
Smear for bacilli 0 1+
Lepromin test 3+ 2+
Histology Epithelioid cells decreasing
Nerve destruction, sarcoidlike granuloma
Modified from Dr. J.H. Petit.
332
lesional dysesthesia is not detected in patients with multibacil
lary ansen s disease the most in ectious orm.
Serologic tests to detect antibodies against M leprae uni ue
antigens (PGL ) and PCR to detect small numbers o organ
isms in in ected tissue ha e not impro ed diagnosis. These are
uni ersally positi e in patients with multibacillary disease in
whom the diagnosis is not di cult. n paucibacillary patients
these tests are o ten negati e and in endemic areas there is a
high bac ground rate o positi ity o serologic tests. These
tests are there ore o no real alue in the diagnosis o patients
with cutaneous ansen s disease. n pure neural ansen s
disease howe er about o patients are seropositi e and
serologic testing might be o use. Seropositi ity might also be
used to identi y persons in endemic areas at ris o de eloping
ansen s disease and these persons could recei e chemopro
phyla is. Also seropositi ity or antibodies to PGL may be
used as a surrogate eld mar er or high bacterial load (mul
tibacillary status) and to identi y patients who might re uire
longer therapy to cure their in ection. Since PGL antibody
tests are best or detecting patients with poor cell mediated
immunity against M leprae and who conse uently ha e high
humoral immunity against M leprae and multibacillary
disease there is a need or a diagnostic test to identi y those
persons who ha e ade uate cell mediated immunity but who
may be at ris o de eloping paucibacillary ansen s disease.
The lepromin s in test has not ser ed this need in contrast to
tuberculin s in testing. Based on the technology o the T cell
inter eron γ ( γ) production based assays or M tuberculo
sis in ection researchers ha e identi ed uni ue peptides o M
leprae and de eloped a research γ release assay ( GRA).
This was able to detect all paucibacillary cases in a ansen s
disease cohort. n addition o household contacts o
ansen s disease patients were positi e with GRA. deally in
endemic areas both serologic and cell based assays can be
used to detect all patients with ansen s disease.
n endemic areas acti e sur eillance o contacts is recom
mended. n Bra il about o both in domicile and e trado
miciliary contacts are ound to ha e ansen s disease. ost
cases are associated with patients who ha e multibacillary
ansen s disease.
CLASSIFICATION
ansen s disease may present with a broad spectrum o clini
cal diseases. The Ridley and Jopling scale classi es cases based
on clinical bacteriologic immunologic and histopathologic
eatures (Table ). n many e posed patients the in ection
apparently clears spontaneously and no clinical lesions
de elop. Patients who do de elop clinical disease are broadly
Unstable resistance No resistance
Borderline
Borderline (BB) lepromatous (BL) Lepromatous (LL)
Few or many Many Numerous and
asymmetric symmetric
2+ 3+ 4+
+ + 0
Increasing histiocytes, foam cells,
granuloma, xanthomalike
classi ed into two groups or the purposes o treatment and
or trials that compare treatment strategies. Paucibacillary
patients ha e ew or no organisms in their lesions and usually
ha e three to e lesions or ewer ( or treatment purposes the
nding o acid ast bacilli by stains or smears classi es a
patient as ha ing multibacillary ansen s disease). ultibacil
lary patients ha e multiple symmetric lesions and organisms
detectable by biopsy or smears. The indi idual s cell mediated
immune response to the organism determines the orm that
ansen s disease will ta e in the indi idual. the cell
mediated immune response against M leprae is strong the
number o organisms will be low (paucibacillary) and con
ersely i this response is inade uate the number o organ
isms will be high (multibacillary).
The most common outcome a ter e posure is probably spon
taneous cure. s in disease does appear the initial clinical
lesion may be a single hypopigmented patch perhaps with
slight anesthesia. This is called indeterminate disease since
the course o the disease cannot be predicted at this stage. The
lesion may clear spontaneously or may progress to any other
orm o ansen s disease.
The spectrum o ansen s disease has two stable poles the
tuberculoid and lepromatous orms (see Table ). These
so called polar orms do not change; the patient remains in one
or the other orm throughout the course o the disease. The
polar tuberculoid orm (called TT) the type with high cell
mediated immunity is characteri ed by less than e lesions
(o ten only one) and ery ew organisms (paucibacillary
disease). The patient has strong cell mediated immunity
against the organism. The natural history o many TT leprosy
patients is or spontaneous cure o er se eral years. The polar
lepromatous orm (LL) has ery limited cell mediated immu
nity against the organism; lesions are numerous and contain
many organisms (multibacillary). Between these two poles is
e ery possible degree o in ection orming the borderline spec
trum. Cases near the tuberculoid pole are called borderline
tuberculoid (BT) those near the lepromatous pole are called
borderline lepromatous (BL) and those in the middle are called
borderline borderline (BB). Borderline ansen s disease is
characteristically unstable and with time cases mo e rom the
TT to the LL pole a process called downgrading.
ansen s disease may in ol e only the ner es. This pure
neural disease may be indeterminate tuberculoid or leproma
tous (paucibacillary or multibacillary) and is so classi ed. n
epal and ndia pure neural ansen s disease may represent
as much as o all new cases.
Early and indeterminate Hansen’s disease
sually the onset o ansen s disease is insidious. Prodromal
symptoms are generally so slight that the disease is not recog
ni ed until the appearance o a cutaneous eruption. Actually
the rst clinical mani estation in o patients is numbness
and years may elapse be ore s in lesions or other signs are
identi ed. The earliest sensory changes are loss o the senses
o temperature and light touch most o ten in the eet or hands.
The inability to discriminate hot rom cold may be lost be ore
pinpric sensibility. Such dissociation o sensibility is espe
cially suspicious. The distribution o these neural signs and
their intensity will depend on the type o disease that is
e ol ing.
ten the rst lesion noted is a solitary poorly de ned
hypopigmented macule that merges into the surrounding
normal s in. Less o ten erythematous macules may be present.
Such lesions are most li ely to occur on the chee s upper
arms thighs and buttoc s. amination re eals that sensory
unctions are either normal or minimally altered. Peripheral
tahir99 - UnitedVRG
Fig. 17-1 Tuberculoid
leprosy.
Classification
ner es are not enlarged and pla ues and nodules do not
occur. istologically a ariable lymphocytic in ltrate (without
granulomas) is seen sometimes with in ol ement o the cuta
neous ner es. sually no bacilli or only a ew are seen on
biopsy o this indeterminate orm. t is the classi cation not
the diagnosis that is indeterminate. ew cases remain in this
state; they e ol e into lepromatous tuberculoid or borderline
types or (i cell mediated immunity is good) o ten spontane
ously resol e and ne er de elop other signs or symptoms o
ansen s disease.
Tuberculoid leprosy
Tuberculoid lesions are solitary or ew in number ( e or less)
and asymmetrically distributed. Lesions may be hypopig
mented or erythematous and are usually dry scaly and hair
less ( ig. ). The typical lesion o tuberculoid leprosy is the
large erythematous pla ue with a sharply de ned and ele
ated border that slopes down to a attened atrophic center.
This has been described as ha ing the appearance o a saucer
right side up. Lesions may also be macular and hypopig
mented or erythematous resembling clinically indeterminate
lesions. The presence o palpable induration and neurologic
ndings distinguish tuberculoid lesions rom indeterminate
lesions clinically. The most common locations are the ace
limbs or trun ; the scalp a illae groin and perineum are not
in ol ed.
A tuberculoid lesion is anesthetic or hypesthetic and anhi
drotic and super cial peripheral ner es ser ing or pro imal
to the lesion are enlarged tender or both. The greater auricu
lar ner e and the super cial peroneal ner e may be isibly
enlarged. er e in ol ement is early and prominent in tuber
culoid leprosy leading to characteristic changes in the muscle
groups ser ed. There may be atrophy o the interosseous
muscles o the hand with wasting o the thenar and hypothe
nar eminences contracture o the ngers paralysis o the acial
muscles and ootdrop. acial ner e damage dramatically
increases the ris or ocular in ol ement and ision loss.
The e olution o the lesions is generally slow. There is o ten
spontaneous remission o the lesions in about years or
remission may result sooner with treatment. Spontaneous
in olution may lea e pigmentary disturbances.
Borderline tuberculoid (BT) leprosy
Borderline tuberculoid lesions are similar to tuberculoid
lesions e cept that they are smaller and more numerous
333
 Fig. 17-2 Borderline
17 tuberculoid leprosy.
Hansen’s Disease
( ig. ). Satellite lesions around large macules or pla ues
are characteristic.
Borderline borderline (BB) leprosy
n borderline leprosy the s in lesions are numerous (but
countable) and consist o red irregularly shaped pla ues.
Small satellite lesions may surround larger pla ues. Lesions
are generali ed but asymmetric. The edges o lesions are not
as well de ned as the ones seen at the tuberculoid pole. er es
may be thic ened and tender but anesthesia is only moderate
in the lesions.
Borderline lepromatous (BL) leprosy
n borderline lepromatous leprosy the lesions are symmetric
and numerous (too many to count) and may include macules
papules pla ues and nodules ( ig. ). The number o
small lepromatous lesions outnumbers the larger borderline
type lesions. er e in ol ement appears later; ner es are
enlarged tender or both and it is important to note that
in ol ement is symmetric. Sensation and sweating o er indi
idual lesions are normal. Patients usually do not show the
eatures o ull blown lepromatous leprosy such as madarosis
(loss o the eyebrows) eratitis nasal ulceration and leonine
acies.
Lepromatous leprosy
Lepromatous leprosy may begin as such or de elop ollowing
indeterminate leprosy or rom downgrading o borderline
leprosy. The cutaneous lesions o lepromatous leprosy consist
mainly o pale macules ( ig. ) or di use in ltration o
the s in. There is a tendency or the disease to become progres
si ely worse without treatment. Lepromatous leprosy may be
334
Fig. 17-3 Borderline
lepromatous leprosy.
Fig. 17-4 Lepromatous
leprosy.
di ided into a polar orm (LLp) and a subpolar orm (LLs);
these orms may beha e di erently.
acular lepromatous lesions are di usely and symmetri
cally distributed o er the body. Tuberculoid macules are large
and ew in number whereas lepromatous macules are small
and numerous. Lepromatous macules are poorly de ned
show no change in s in te ture and blend imperceptibly into
the surrounding s in. There is minimal or no loss o sensation
o er the lesions no ner e thic ening and no change in sweat
ing. A slow progressi e loss o hair ta es place rom the outer
third o the eyebrows then the eyelashes and nally the body;
howe er the scalp hair usually remains unchanged.
Lepromatous in ltrations may be di ided into the di use
pla ue and nodular types. The di use type is characteri ed
by the de elopment o a di use in ltration o the ace espe
cially the orehead madarosis and a wa y shiny appearance
o the s in sometimes described as arnished. Di use
leprosy o Lucio (DLL) is a stri ing orm uncommon e cept
in western e ico and certain other Latin American areas
where almost one third o lepromatous cases may be o this
type. This orm o lepromatous leprosy is characteri ed by
di use lepromatous in ltration o the s in; locali ed lepromas
 Fig. 17-5 Lepromatous
leprosy, ear
involvement.
Fig. 17-6 Histoid
leprosy.
do not orm. A uni ue complication o this subtype is the
reactional state re erred to as Lucio s phenomenon (erythema
necroticans).
The in ltrations may be mani ested by the de elopment o
nodules called lepromas. The early nodules are poorly de ned
and occur most o ten in acral parts ears ( ig. ) brows
nose chin elbows hands buttoc s or nees.
er e in ol ement in ariably occurs in lepromatous leprosy
but de elops ery slowly. As with the s in lesions ner e
disease is bilaterally symmetric usually in a stoc ing glo e
pattern. This is re uently misdiagnosed as diabetic neuropa
thy in the nited States i it is the presenting mani estation.
Histoid leprosy
istoid leprosy is an uncommon orm o multibacillary an
sen s disease in which s in lesions appear as large yellow red
shiny papules and nodules in the dermis or subcutaneous
tissue ( ig. ). Lesions appear on a bac ground o normal
s in. They ary in si e rom to mm in diameter and may
appear anywhere on the body but a or the buttoc s lower
bac ace and bony prominences. They may closely resemble
molluscum contagiosum. This pattern may appear de no o
but has mostly been described in patients with resistance to
dapsone.
NERVE INVOLVEMENT
er e in ol ement is characteristic and uni ue to ansen s
disease. This neural predilection or neurotropism is a histo
tahir99 - UnitedVRG
pathologic hallmar o ansen s disease. er e in ol ement
is responsible or the clinical ndings o anesthesia within
lesions (paucibacillary and borderline leprosy) and o a pro
gressi e stoc ing glo e peripheral neuropathy (lepromatous
leprosy). The neuropathy is termed primary impairments
Nerve involvement
(W grade ). Secondary (or isible) impairments (W
grade ) are a conse uence o the neuropathy and include s in
ssures wounds clawing o digits contractures shortening
o digits and blindness. eural damage leads to de ormities
and in endemic regions results in ansen s disease being a
ma or cause o limitations o acti ity ( ormerly called dis
ability) and restrictions in social participation ( ormerly
termed handicap). europathy is present in . . o pauci
bacillary patients and . o multibacillary patients
undergoing DT. Secondary impairments occur in o
multibacillary patients. europathy may progress e en a ter
e ecti e DT and secondary impairments may continue to
appear or years as a conse uence o the neuropathy. This
re uires patients with neuropathy to be constantly monitored
e en though they are cured o their in ection.
er e enlargement is rare in other s in diseases so the
nding o s in lesions with enlarged ner es should suggest
ansen s disease. er e in ol ement tends to occur with s in
lesions and the pattern o ner e in ol ement parallels the s in
disease. Tuberculoid leprosy is characteri ed by asymmetric
ner e in ol ement locali ed to the s in lesions. Lepromatous
ner e in ol ement is symmetric and not associated with s in
lesions. er e in ol ement without s in lesions called pure
neural leprosy can occur and may be either tuberculoid (pauc
ibacillary) or lepromatous (multibacillary). er e disease can
be symptomatic or asymptomatic.
Leprosy bacilli may be deli ered to the ner es through the
perineural and endoneural blood essels. nce the bacilli
transgress the endothelial basal lamina and are in the endo
neurium they enter resident macrophages or selecti ely enter
Schwann cells. Damage to the ner es could then occur by the
ollowing mechanisms
. bstruction o neural essels
. Vasculitis o neural essels
. nter erence with metabolism o the Schwann cell
ma ing it unable to support the neuron
. mmunologic attac on endothelium or ner es
. n ltration and proli eration o M leprae in the closed
and relati ely none pandable endoneural and
perineural spaces
Di erent and multiple mechanisms may occur in di erent
orms o ansen s disease and in the same patient o er time.
The selecti e ability o M leprae to enter Schwann cells is
uni ue among bacteria. M leprae uni ue PGL e pressed
abundantly on the sur ace o leprosy bacilli binds selecti ely
to the α G module o laminin . This α chain is tissue restricted
and speci cally e pressed on peripheral ner e Schwann cells.
The binding o M leprae to laminin places it in apposition to
the Schwann cell basement membrane when laminin binds
to the dystroglycan comple on the Schwann cell membrane.
These bound M leprae bacteria are endocytosed into the
Schwann cells gi ing M leprae selecti e access to the inside o
Schwann cells. ther accessory binding molecules may acili
tate the binding and endocytosis. The ner es become immuno
logic targets when they present M leprae antigens on their
sur ace in the conte t o ma or histocompatibility comple
( C) class molecules. Schwann cells and thus ner es are
usually protected rom immunologic attac mediated by the
adapti e immune system because they rarely present C
class antigens on their sur ace. n ansen s disease e pres
sion o these immunologic molecules occurs on the sur ace o
335
 Schwann cells ma ing them potential targets or CD + cyto
17 to ic T cells. This mechanism may be important in the ner e
damage that occurs in type (re ersal) reactions.
Schwann cells ha e been in ected with M leprae in itro.
n ected Schwann cells with high bacterial load are repro
Hansen’s Disease

grammed into mesenchymal stem cell li e cells. n association

with Schwann cells these dedi erentiated cells attract histio
cytes and orm granulomas. The attracted histiocytes are
in ected by the mycobacteria containing Schwann cells and
are released rom the granulomas. this process also occurs
in i o it may be the mechanism by which multibacillary
disease is spread throughout the body rom a reser oir o
in ected ner es.
The neural signs in ansen s disease are dysesthesia ner e
enlargement muscular wea ness and wasting and trophic
changes. The lesions o the asomotor ner es accompany the
sensory disturbances or may precede them. Dysesthesia de el
ops in a progressi e manner. The rst symptom is usually an
inability to distinguish hot and cold. Subse uently the percep
tion o light touch is lost then that o pain and lastly the sense
o deep touch. At times the sensory changes in large ansen s Fig. 17-7 Claw hand of Hansen’s disease.
disease lesions are not uni orm because o the ariation in the
in ol ement o the indi idual neural laments supplying the
area. There ore the areas o dysesthesia may not con orm to
the distribution o any particular ner e and e cept in lepro
matous cases are not symmetric.
er e in ol ement mainly a ects (and is most easily
obser ed in) the more super cial ner e trun s such as the
ulnar median radial peroneal posterior tibial th and
se enth cranial and especially the great auricular ner e.
Beaded enlargements nodules or spindle shaped swellings
may be ound which at rst may be tender. eural abscesses
may orm. The ulnar ner e near the internal condyle o the
humerus may be as thic as the little nger round and sti
and is o ten easily elt se eral centimeters abo e the elbow.
Because the presentation o neural in ol ement in ansen s
disease is ariable the diagnosis is o ten not suspected espe
cially in nonendemic areas. en in endemic areas the diag
nosis may be delayed. Between one hal and one third o
patients with pure neural ansen s disease a biopsy o hyp
esthetic s in can show speci c leprotic s in changes and i
nonspeci c in ammation is considered con rmatory the posi
ti ity o such biopsies is greater than . There ore s in Fig. 17-8 Lepromatous leprosy with collapse of nasal bridge.
biopsy o a hypesthetic s in site should be considered be ore
ner e biopsy when pure neural ansen s disease is a
possibility. opacity a ascular eratitis pannus ormation interstitial er
As a result o the ner e damage areas o anesthesia paraly atitis and corneal lepromas. The corneal opacities enlarge and
sis and trophic disorders in the peripheral parts o the e trem nally orm isible white ec s called pearls. When (in bor
ities gradually de elop. uscular paralysis and atrophy derline lepromatous or lepromatous cases only) the iris and
generally a ect the small muscles o the hands and eet or the ciliary body become in ol ed miliary lepromas (iris
some o the acial muscles producing wea ness and progres pearls) nodular lepromas chronic granulomatous iritis and
si e atrophy. Deeper motor ner es are only rarely in ol ed. acute di use iridocyclitis may result. multibacillary
The ngers de elop contractures with the ormation o a patients . . are blind at diagnosis and will ha e a
clawhand ( ig. ). Also as the result o resorption o pha potentially blinding process.
langeal bones ngers and toes become shorter. Ptosis ectro
pion and a mas li e appearance occur rom damage to the
th and se enth cranial ner es. MUCOUS MEMBRANE INVOLVEMENT
Subse uent to ner e damage ulceration hyper eratosis
bullae alopecia anhidrosis and mal per orans pedis can The mucous membranes may also be a ected especially in the
de elop. Trophic ulceration usually mani ests as a per orating nose mouth and laryn . The nasal mucosa is most re uently
ulcer on the ball or heel o the oot. in ol ed and lepromatous patients re uently complain o
chronic nasal congestion. By ar the most common lesions in
the nose are in ltrations and nodules. Per oration o the nasal
OCULAR INVOLVEMENT septum may occur in patients with ad anced ansen s disease
with collapse o the nasal bridge ( ig. ). Saddle nose de or
Corneal erosions e posure eratitis and ulcerations may mities and loss o the upper incisor teeth can occur.
result rom in ol ement o the se enth cranial ner e in an odules occurring on the ocal cords will produce
sen s disease patients. Speci c changes may include corneal hoarseness.
336

VISCERAL INVOLVEMENT
n lepromatous leprosy the body is di usely in ol ed and
bacteremia occurs. cept or the gastrointestinal tract lungs
and brain irtually e ery organ can contain leprosy bacilli.
The lymph nodes bone marrow li er spleen and testicles are
most hea ily in ected. Visceral in ection is restricted mostly to
the reticuloendothelial system which despite e tensi e
in ol ement rarely produces symptoms or ndings. Testicular
atrophy with loss o androgens can result in gynecothelia
(hypertrophy o nipple) and or gynecomastia or premature
osteoporosis. Secondary amyloidosis with renal impairment
may complicate multibacillary leprosy. Glomerulonephritis
occurs in more than and perhaps as many as o an
sen s disease patients and is not correlated with bacillary load
or the presence o erythema nodosum leprosum.
SPECIAL CLINICAL CONSIDERATIONS
AND HANSEN’S DISEASE
Pregnancy
ansen s disease may be complicated in se eral ways by preg
nancy. As a state o relati e immunosuppression pregnancy
may lead to an e acerbation or reacti ation a ter apparent
cure. n addition pregnancy or more o ten the period imme
diately a ter deli ery may be associated with the appearance
o reactional states in patients with ansen s disease. Pregnant
patients with ansen s disease cannot be gi en certain medi
cations used to treat the disease such as thalidomide o o a
cin and minocycline. DT is tolerated by pregnant women i
these restricted agents are a oided.
Human immunodeficiency virus
uman immunode ciency irus ( V) in ection although a
cause o pro ound immunosuppression o the cell mediated
immune system does not seem to ha e an ad erse e ect on
the course o ansen s disease. Patients are treated with the
same agents and can be e pected to ha e similar outcomes in
general. Duration o treatment with DT may need to be
e tended in patients with V in ection. Treatment o V histologic eatures o ansen s disease correlate with the clini
in ected patients with ansen s disease using e ecti e antiret
ro iral drugs may be associated with the appearance o
reactional states (usually type ) as part o the immune recon
stitution syndrome. This irtually always occurs in the rst
months o anti iral therapy.
Organ transplantation
ansen s disease has been reported in organ transplant recipi
ents (renal li er heart and bone marrow). the disease has
been treated and the patient is then gi en a transplant an
sen s disease can recur apparently as a result o the immuno
suppressi e regimen. n addition transplant patients may
present with new ansen s disease most re uently toward
the lepromatous pole (BL or LL). rythema nodosum lepro
sum may occur. The correct management o the organ trans
plant recipient with ansen s disease is not nown but DT
with highly acti e agents is usually gi en.
Patients with ansen s disease may also ac uire a second
cutaneous mycobacterial in ection. This may occur as a com
plication o corticosteroid treatment or reactional states.
tahir99 - UnitedVRG
M cobacterium fortuitum has been reported in one case and one
o the authors has seen coin ection with M haemophilum n
these patients the DT plan should include agents e ecti e
against both ansen s disease and the second mycobacterial
in ection.
Histopathology
IMMUNOPATHOGENESIS
The patient s immune reaction to the leprosy bacillus is a criti
cal element in determining the outcome o in ection. Tubercu
loid patients ma e well ormed granulomas that contain
helper T cells whereas lepromatous patients ha e poorly
ormed granulomas and suppressor T cells predominate. The
cyto ine pro le in tuberculoid lesions is good cell mediated
immunity with γ and interleu in ( L ) present. n lep
romatous patients these cyto ines are reduced and L L
and L cyto ines that downregulate cell mediated immu
nity and enhance suppressor unction and antibody produc
tion are prominent. Lepromatous leprosy thus represents
a classic T helper cell type (Th ) response to M leprae.
Lepromatous patients ha e polyclonal hypergammaglobu
linemia and high antibody titers to M leprae uni ue antigens
and may ha e alse positi e syphilis serology rheumatoid
actor and antinuclear antibodies. Although the cell mediated
immune response o lepromatous patients to M leprae is
reduced these patients are not immunosuppressed or other
in ectious agents. Tuberculosis beha es normally in patients
with lepromatous leprosy.
HISTOPATHOLOGY
deally biopsies should be per ormed rom the acti e border
o typical lesions and should e tend into the subcutaneous
tissue. Punch biopsies are usually ade uate. ite araco stain
is optimal or demonstrating M leprae. Because the diagnosis
o ansen s disease is associated with signi cant social impli
cations e aluation must be complete including e aluation o
multiple sections in paucibacillary cases. Consultation with a
pathologist e perienced in the diagnosis o ansen s disease
can be help ul i the diagnosis is suspected but organisms
cannot be identi ed in the a ected tissue especially in pauci
bacillary disease and reactional states. PCR has not been ery
use ul; it is positi e in only o paucibacillary cases. The
cal pattern o disease. er e in ol ement is characteristic and
histologic perineural and neural in ol ement should suggest
ansen s disease.
Tuberculoid leprosy
Dermal tuberculoid granulomas consisting o groups o epi
thelioid cells with giant cells are ound in tuberculoid
leprosy. The granulomas are elongated and generally run
parallel to the sur ace ollowing neuro ascular bundles. The
epithelioid cells are not acuolated or lipidi ed. The granulo
mas e tend up to the epidermis with no gren one. Lym
phocytes are ound at the periphery o the granulomas.
Acid ast bacilli are rare. The most important speci c diag
nostic eature besides nding bacilli is selecti e destruction
o ner e trun s and the nding o perineural concentric
brosis. An S stain may show this selecti e neural
destruction by demonstrating unrecogni able ner e rem
nants in the in ammatory oci. Bacilli are most re uently
ound in ner es but the subepidermal one and arrector pili
muscles are other ruit ul areas.
337
 Borderline tuberculoid leprosy
17 The histopathology o borderline tuberculoid leprosy is similar
to that seen in the tuberculoid ariety. owe er epithelioid
cells may show some acuolation bacilli are more abundant
Hansen’s Disease
and a gren one separates the in ammatory in ltrate rom
the o erlying epidermis in BT leprosy.
Borderline leprosy
n borderline leprosy granulomas are less well organi ed
giant cells are not seen the macrophages ha e some oamy
cytoplasm and organisms are abundant.
Borderline lepromatous leprosy
n borderline lepromatous lesions oamy histiocytes rather
than epithelioid cells ma e up the ma ority o the granuloma.
Lymphocytes are still present and may be numerous in the
granulomas but are dispersed di usely within them not orga
ni ed at the periphery. Perineural in ol ement with lympho
cyte in ltration may be present. rganisms are abundant and
may be ound in clumps.
Lepromatous leprosy
n lepromatous leprosy granulomas are composed primarily
o bacilli laden and lipid laden histocytes. These are the
so called lepra cells or oam cells o Virchow. The in ltrate is
locali ed in the dermis and may be purely peri ascular or
sheetli e and separated rom the epidermis by a well de ned
gren one. Acid ast bacilli are typically abundant and appear
as round clumps (globi). Pure polar lepromatous leprosy
di ers rom the subpolar type primarily in the paucity o
lymphocytes in the pure polar orm.
REACTIONAL STATES
Reactions are a characteristic and clinically important aspect
o ansen s disease. About o patients will e perience a
reaction a ter the institution o DT. n addition to antibiotic
therapy intercurrent in ections accination pregnancy
itamin A iodides and bromide may trigger reactions. Reac
tions can be se ere and are an important cause o permanent
ner e damage in borderline patients. Reactional states re
uently appear abruptly unli e ansen s disease itsel which
changes slowly. A reaction is there ore a common reason why
patients see consultation. n addition i a patient belie es
that the chemotherapy is triggering the reaction the patient
will tend to discontinue the treatment leading to treatment
ailure.
Reactional states are di ided into two orms called type
and type reactions. Type reactions are caused by cell
mediated immune in ammation within e isting s in lesions.
These generally occur in patients with borderline leprosy (BT
BB BL). Type reactions are mediated by immune comple es
and occur in lepromatous patients (BL LL).
Type 1 reactions (reversal, lepra,
and downgrading reactions)
Type reactions represent an enhanced cell mediated immune
response to M leprae and usually occur a ter treatment is
338
Fig. 17-9 Type 1 reaction in Hansen’s disease. (Courtesy of Curt
Samlaska, MD.)
initiated. the reactions occur with antibiotic chemotherapy
they are called re ersal reactions and i they occur as border
line disease shi ts toward the lepromatous pole (downgrad
ing) they are called downgrading reactions. These two reaction
types are clinically identical. Patients in all parts o the border
line spectrum may be a ected by type reactions but these
are most se ere in patients with borderline lepromatous
leprosy who ha e a large amount o M leprae antigen and
there ore ha e prolonged and repeated reactions during
treatment.
Type reactions clinically present with in ammation o
e isting lesions ( ig. ). The patient has no systemic symp
toms such as e er chills or arthralgias. Lesions swell become
erythematous and are sometimes tender simulating cellulitis.
n se ere cases ulceration can occur.
Patients may state that new lesions appeared with the reac
tion but these probably represent subclinical lesions that were
highlighted by the reaction. The ma or complication o type
reactions is ner e damage. As the cell mediated in ammation
attac s M leprae antigen any in ected tissue compartment can
be damaged. Because bacilli are pre erentially in ner es neural
symptoms and ndings are o ten present. Re ersal reaction
occurring within a ner e may lead to sudden loss o ner e
unction and permanent damage to that ner e. This ma es
type reactions an emergency. n this setting a ected ner es
are enlarged and tender. n other patients the neuritis may be
subacute or chronic and o limited acute symptomatology but
may still result in se ere ner e damage. istologically s in
lesions show peri ascular and perineural edema and large
numbers o lymphocytes. Se ere reactions may demonstrate
tissue necrosis. Bacilli are reduced.
Type 2 reactions (erythema nodosum leprosum)
rythema nodosum leprosum ( L) occurs in hal o patients
with borderline lepromatous or lepromatous leprosy o
the time within a ew years o institution o antibiotic treat
ment or ansen s disease or during pregnancy. L is a
circulating immune comple mediated disease. As such in
contrast to type reactions type ( L) can result in multi
system in ol ement and is usually accompanied by systemic
symptoms ( e er myalgias arthralgias anore ia). S in lesions
are characteristically erythematous subcutaneous and dermal
nodules that are widely distributed ( ig. ). They do not
occur at the sites o e isting s in lesions. Se ere s in lesions
can ulcerate. nli e classic erythema nodosum lesions o L
are generali ed and a or the e tensor arms and medial thighs.

Fig. 17-10 Erythema nodosum leprosum.
Fig. 17-11 Lucio’s
phenomenon, early
bullous lesions.
A multisystem disease L can produce con uncti itis
neuritis eratitis iritis syno itis nephritis hepatospleno
megaly orchitis and lymphadenopathy. The intensity o the
reaction may ary rom mild to se ere and may last rom a
ew days to wee s months or e en years. istologically L relapse occurring
demonstrates a leu ocytoclastic asculitis. Laboratory e alua
tion will re eal an ele ated sedimentation rate increased
C reacti e protein and a neutrophilia.
Lucio’s phenomenon
Lucio s phenomenon is an uncommon and unusual reaction
that occurs in patients with di use lepromatous leprosy (DLL)
o the la bonita type most o ten ound in western e ico.
Some consider it a subset o L but Lucio s reaction di ers
in that it lac s neutrophilia and systemic symptoms. t is not
associated with institution o antibiotic treatment as is L s in smears or s in biopsy ≤ lesions indeterminate and
and Lucio s phenomenon is re uently the reason or initial
presentation in a ected patients. Purpuric macules e ol e to
bullous lesions that rapidly ulcerate especially below the
nees ( ig. ). These may be pain ul but may also be
relati ely asymptomatic. istologically bacilli are numerous
and in addition to being in the dermis are seen within blood
tahir99 - UnitedVRG
essel walls with thrombosis o middermal essels resulting
in cutaneous in arction. e er splenomegaly lymphaden
opathy glomerulonephritis anemia hypoalbuminemia poly
clonal gammopathy and hypocalcemia may be associated
conditions. the patient is diagnosed early be ore signi cant
Treatment
metabolic and in ectious complications occur the outcome is
a orable.
TREATMENT
Be ore dapsone monotherapy was the standard treat
ment or ansen s disease; it was e ecti e in many patients
but primary and secondary dapsone resistant cases occurred.
n addition multibacillary patients re uired li elong treat
ment which had inherent compliance problems. To circum
ent these problems and shorten therapeutic courses W
proposed multidrug therapy. DT has been ery e ecti e in
treating acti e cases o ansen s disease. The number o anti
biotics used and the duration o treatment are determined by
the bacterial load the patient e hibits. This can be assessed by
slit s in smear where nding any bacilli classi es the patient
as multibacillary. n s in biopsy the same criterion is used
nding any bacilli identi es the patient as multibacillary. The
number o lesions constitutes the eld classi cation system
and patients are classi ed as ha ing lesion lesions in one
anatomic region (paucibacillary) or more than (multibacil
lary). This classi cation can result in undertreatment o
patients with ew lesions but who are actually multibacillary.
Three other actors can result in undertreatment o patients as
ollows
. ailure or inability to do a s in biopsy
. Classi ying patients with more than e lesions as
tuberculoid and thus paucibacillary
. ailure to understand that although the patient has
histologic and clinical eatures o tuberculoid disease
organisms are identi ed on s in biopsy and thus the
patient re uires treatment or multibacillary disease
All patients with more than e lesions and those with
organisms identi ed on s in biopsy should be treated or mul
tibacillary ansen s disease. ailure may also result rom non
compliance drug resistance relapse a ter apparent clinical
and bacteriologic cure and persistence. Persisters are iable
organisms that by mouse ootpad testing are sensiti e to the
antimicrobial agents gi en but persist in tissue despite bacte
ricidal tissue le els in the patient. They are usually ound
in macrophages or ner es. These persisters correlate with
years a ter DT. Since relapses may
occur many years a ter DT where ade uate health care
resources e ist multibacillary patients should be ollowed
annually to e amine or e idence o relapse reaction or pro
gression o neuropathy.
There are se eral di erent sets o DT recommendations
but only two are gi en here those recommended by the .S.
Public ealth Ser ice or patients in the nited States and
those recommended by W . Because dapsone resistance is
less common in .S. patients and e ecti e compliance pro
grams can be de eloped to enhance monotherapy dapsone
monotherapy may still be considered a ter DT in the nited
States. or paucibacillary patients (no organisms ound on
tuberculoid leprosy) in .S. patients the recommendation is
mg day o ri ampin and mg day o dapsone or
months. Paucibacillary patients who relapse with paucibacil
lary disease are treated with an appropriate regimen or mul
tibacillary disease. n the nited States multibacillary patients
recei e mg day o dapsone mg day o clo a imine
339
 Fig. 17-12 intensi e regimen or months that can be ollowed by a
17 Lepromatous leprosy
with discoloration
continuous phase or another months. Ri apentine
appears superior to ri ampin in these combinations. Proposed
mg

secondary to newer intensi e drug regimens or ri ampin sensiti e mul

clofazimine. tibacillary patients include ri apentine mg; mo i o acin
Hansen’s Disease

mg; and clarithromycin mg (or minocycline mg)

all once monthly or months. or ri ampin resistant patients
mo i o acin mg; clo a imine mg; clarithromycin
mg; and minocycline mg are gi en daily super ised
or months. The continuous phase o treatment could com
prise mo i o acin mg; clarithromycin mg; and
minocycline mg once monthly super ised or an addi
tional months.
Drug resistance is widespread and has e en recently been
reported in the nited States. t should be suspected i the
patient ails to respond to treatment. There are currently a ail
able PCR techni ues to detect drug resistance rom biopsy
specimens.
At the end o treatment isible s in lesions are o ten still
present especially with the W short duration treatments.
Paucibacillary lesions tend to clear years a ter the month
treatment course. n the nited States treatment could be
continued until s in lesions are clear e en i the recommended
duration o treatment has been passed. With short duration
DT it is ery di cult to distinguish clinical relapse ( ailure
o treatment) rom late type reactions causing s in lesions to
reappear. Pathologic e amination (biopsy) or an empiric trial
and mg day o ri ampin or a standard W regimen (see o prednisone or se eral months may be considered in these
ne t) or years ( ig. ). or multibacillary patients who patients.
re use clo a imine mg o minocycline or mg day o Signi cant disagreement surrounds the e ecti eness o the
o o acin may be substituted. Clarithromycin mg day year or year W recommended DT regimens. Relapse
may also be used in treatment regimens. Patients with multi rates or multibacillary patients treated with DT or or
bacillary relapses whether the initial diagnosis was pauci years ha e been reported to be as high as o erall and
bacillary or multibacillary disease should ha e a mouse with B o or greater at diagnosis. Based on this
ootpad sensiti ity study and should recei e an appropriate in ormation patients with BL LL disease with a B o or
multidrug regimen or years ollowed by daily li elong greater are at highest ris or relapse and should be treated
dapsone or clo a imine depending on sensiti ity testing. beyond the year recommended period with treatment con
The W recommended protocols are shorter and less tinued until smear negati ity.
e pensi e than the .S. recommendations. There is concern Treatment o ansen s disease patients with e ecti e anti
that the reduction o DT rom years to year may lead to biotic regimens usually does not result in regaining o neuro
increased numbers o relapses especially among patients with logic de cits. When de cits do reco er it appears to be mostly
high bacillary loads (B > on s in smear). The W recom rom elimination o the perineural in ammation rather than
mendation or paucibacillary disease (no bacilli on smears or regeneration o the a ected ner es. There ore early treatment
biopsy ≤ lesions indeterminate and tuberculoid patients) is o patients when neurologic de ects are minimal and aggres
mg o ri ampin under super ision once monthly or si e treatment o type reactions are the ey to limiting neural
months and mg day o dapsone or months unsuper damage in ansen s disease.
ised with completion o the treatment within months. or
single lesion paucibacillary disease a single dose o mg o
ri ampin mg o o o acin and mg o minocycline Adjunctive treatments
(R ) all at one time is gi en. This one dose R treatment
is less e ecti e than the month regimen or paucibacillary nce neurologic complications ha e occurred patients with
disease. ultibacillary patients (BT BB BL and LL; > lesions; ansen s disease should be o ered occupational therapy. This
any bacilli seen on smears or biopsies) are treated with ri ampin should include training on how to a oid in ury to insensiti e
mg and clo a imine mg once monthly under super i s in o the hands and eet. Special shoes may be re uired.
sion with dapsone mg day and clo a imine mg day. cular complications are common and an ophthalmologist
Treatment is or months. or patients intolerant o clo a i with speci c s ill in treating patients with ansen s disease is
mine an alternati e regimen is ri ampin mg; o o acin an in aluable member o the treatment team.
mg; and minocycline mg all once monthly or
doses. An alternati e or the patient intolerant o or resistant
to ri ampin or dapsone is clo a imine mg; o o acin mg; MANAGEMENT OF REACTIONS
and minocycline mg daily or months ollowed by
months o clo a imine mg daily plus either o o acin en though reactions may appear a ter drug treatment is
mg day or minocycline mg day. instituted it is not ad isable to discontinue or reduce ant
ewer regimens ha e been proposed that could be more ileprosy medication because o these. n mild reactions those
e ecti e and o shorter duration or may re uire only monthly without neurologic complications or se ere systemic symp
treatment. These can be considered especially in patients with toms or ndings treatment may be supporti e. Bed rest and
compromised immunity and in those with multibacillary administration o aspirin or nonsteroidal anti in ammatory
disease with a ery high bacterial load. Therapies consist o an drugs may be used.
340
 Type reactions are usually managed with systemic corti
costeroids. Prednisone is gi en orally starting at a dose o
mg day. euritis and eye lesions are urgent indications
or systemic steroid therapy. er e abscesses may also need
to be surgically drained immediately to preser e and reco er
ner e unction. The corticosteroid dose and duration are deter
mined by the clinical course o the reaction. nce the reaction
is controlled the prednisone may need to be tapered slowly
o er months to years. The minimum dose re uired and
alternate day treatment should be used in corticosteroid
courses more than month in duration. Clo a imine appears
to ha e some acti ity against type reactions and may be
added to the treatment in doses o up to mg day i toler
ated. Cyclosporine can be used i steroids ail or as a steroid
sparing agent. The starting dose would be mg g.
during treatment the unction o some ner es ails to impro e
while the unction o others normali es the possibility o
mechanical compression should be e aluated by surgical
e ploration. Transposition o the ulnar ner e does not seem to
be more e ecti e than immunosuppressi e treatment or
ulnar ner e dys unction.
Thalidomide has been demonstrated to be uni uely e ecti e
against L and is the treatment o choice. Thalidomide is a
potent teratogen and should not be gi en to women o child
bearing age. The initial recommended dosage is up to mg
day in patients weighing more than g. This dose is highly
sedating in some patients and patients may complain o
central ner ous system side e ects e en at doses o mg
day. or this reason such a high dose should be used or only
a brie period or in milder cases treatment may be started at
a much lower dose such as mg day. n patients with
an acute episode o L the drug may be discontinued a ter
a ew wee s to months. n chronic type reactions an attempt
to discontinue the drug should be made e ery months. Sys
temic corticosteroids are also e ecti e in type reactions but
long term use may lead to complications. Clo a imine in
higher doses up to mg day is e ecti e in L and may
be used alone or to reduce corticosteroid or thalidomide doses.
The combination o pento i ylline mg twice daily
and clo a imine mg day can be gi en to patients with
L when thalidomide cannot be used or to a oid the use o
systemic steroids to manage se ere L. Pento i ylline alone
is in erior to steroids and thalidomide but can be considered
in milder cases. Tumor necrosis actor (T ) inhibitors spe
ci cally in i imab ha e been reported to be e ecti e in treat
ing recurrent L.
Lucio s phenomenon is poorly responsi e to both corticoste
roids and thalidomide. ecti e antimicrobial chemotherapy
or lepromatous leprosy is the only recommended treatment
combined with wound management or leg ulcers.
PREVENTION
Because a de ect in cell mediated immunity is inherent in the
de elopment o ansen s disease accine therapies are being
tested. Bacille Calmette Gu rin (BCG) accination alone pro
ides about protection against M leprae in ection n
the BCG immuni ation is gi en to household contacts
younger than years. Vaccines ha e been produced and are
e ecti e. t is unclear i accine will be needed e cept in the
areas o highest endemicity because DT has been e ecti e
in reducing the pre alence o ansen s disease. Since o
patients ha e contact with multibacillary patients pre ention
depends on treating acti e multibacillary patients and e amin
ing e posed persons on an annual basis to detect early e i
dence o in ection. Prophylactic antibiotic regimens ha e been
used in such e posed patients and demonstrate a reduction in
tahir99 - UnitedVRG
new ansen s disease cases by more than in the rst
years. nterestingly patients who had less contact with the
source patient bene ted more. n the close contacts under
age whose source case was lepromatous are gi en ri ampin
mg g once monthly or months. Se eral trials o chemo
Prevention
prophyla is in whole endemic regions (once yearly DT
with single dose ri ampin minocycline and clo a imine) ha e
shown early promise and may be use ul in hyperendemic
regions.
Alcaïs A, et al: Stepwise replication identifies a low-producing
lymphotoxin-α allele as a major risk factor for early-onset leprosy. Nat
Genet 2007; 39:517.
Araújo S, et al: Unveiling healthy carriers and subclinical infections
among household contacts of leprosy patients who play potential roles
in the disease chain of transmission. Mem Inst Oswaldo Cruz 2012;
107:5.
Ardalan M, et al: Lepromatous leprosy in a kidney transplant recipient:
a case report. Exp Clin Transpl 2011; 9:203.
Balamayooran G, et al: The armadillo as an animal model and reservoir
host for Mycobacterium leprae. Clin Dermatol 2015; 33:108.
Batista M, et al: Leprosy reversal reaction as immune reconstitution
inflammatory syndrome in patients with AIDS. Clin Infect Dis 2008;
46:56.
Brito e Cabral P, et al: Anti-PGL1 salivary IgA/IGM, serum IgG/IgM and
nasal Mycobacterium leprae DNA in individuals with household contact
with leprosy. Int J Infect Dis 2013; 17:e1005.
Bruce S, et al: Armadillo exposure and Hansen’s disease: an
epidemiologic survey in southern Texas. J Am Acad Dermatol 2000;
43:223.
Chaitanya VS, et al: Interleukin-17F single-nucleotide polymorphism
(7488T>C) and its association with susceptibility to leprosy. Int J
Immunogenet 2013; 41:131.
Chander R, et al: Molluscum contagiosum–like lesions in histoid leprosy
in a 10-year-old Indian boy. Pediatr Dermatol 2013; 30:e261.
Chopra R, et al: Mapping of PARK2 and PACRG overlapping regulatory
region reveals LD structure and functional variants in association with
leprosy in unrelated Indian population groups. PLoS Genet 2013;
9:e1003578.
Deps P, et al: Clinical and histological features of leprosy and human
immunodeficiency virus co-infection in Brazil. Clin Exp Dermatol 2013;
38:470.
Dogra S, et al: Clinical characteristics and outcome in multibacillary
(MB) leprosy patients treated with 12 months WHO MDT-MBR: a
retrospective analysis of 730 patients from a leprosy clinic at a tertiary
care hospital of Northern India. Lepr Rev 2013; 84:65.
Dos Santos DS, et al: Kinship and leprosy in the contacts of leprosy
patients: cohort at the Souza Araújo Outpatient Clinic, Rio de Janeiro,
RJ, 1986–2010. J Trop Med 2013; 2013:596316.
Eichelmann K, et al: Leprosy: an update—definition, pathogenesis,
classification, diagnosis, and treatment. Actas Dermosifiliogr 2013;
104:554.
Eiglmeier K, et al: The decaying genome of Mycobacterium leprae. Lepr
Rev 2001; 72:387.
Faber WR, et al: Treatment of recurrent erythema nodosum leprosum
with infliximab. N Engl J Med 2006; 17:355.
Fava V, et al: Genetics of leprosy reactions: an overview. Mem Inst
Oswaldo Cruz 2012; 107:132.
Garbino JA, et al: Primary neural leprosy: systematic review. Arq
Neuropsiquiatr 2013; 71:397.
Gelber RH: Relapse rate in MB leprosy patients treated with 2 years of
WHO-MDT is not low. Int J Lepr Other Mycobact Dis 2004; 72:493.
Geluk A: Biomarkers for leprosy: would you prefer T (cells)? Lepr Rev
2013; 84:3.
Geluk A, et al: Rational combination of peptides derived from different
Mycobacterium leprae proteins improves sensitivity for
immunodiagnosis of M. leprae infection. Clin Vaccine Immunol 2008;
15:522.
Ghorpade A: Inoculable leprosy. Int J Dermatol 2009; 48:1267.
Global leprosy: update on the 2012 situation. Wkly Epidemiol Rec 2013;
88:365.
Guditi S, et al: Leprosy in a renal transplant recipient: review of the
literature. Transpl Infect Dis 2009; 11:557.
Han XY, Jessurun J: Severe leprosy reactions due to Mycobacterium
lepromatosis. Am J Med Sci 2013; 345:65.
341
 Han XY, et al: The leprosy agents Mycobacterium lepromatosis and
17 Mycobacterium leprae in Mexico. Int J Dermatol 2012; 51:952.
Hossain D: Using Methotrexate to treat patients with ENL unresponsive
to steroids and clofazimine: a report on 9 patients. Lepr Rev 2013;
84:105.
Hansen’s Disease
Illarramendi X, et al: Cutaneous lesions, sensory impairment, recovery,
and nerve regeneration in leprosy patients. Mem Inst Oswaldo Cruz
2012; 107:68.
Jaiswal AK, Subbarao NT: Gynecothelia—a common yet ignored sign of
multibacillary leprosy in males: a case series with review of literature.
Lepr Rev 2012; 83:384.
Job CK, et al: Transmission of leprosy: a study of skin and nasal
secretions of household contacts of leprosy patients using PCR. Am J
Trop Med Hyg 2008; 78:518.
Jurado F, et al: Lucio’s leprosy: A clinical and therapeutic challenge.
Clin Dermatol 2015; 33:66.
Kar HK, Gupta R: Treatment of leprosy. Clin Dermatol 2015; 33:55.
Klioze AM, Ramos-Caro FA: Visceral leprosy. Int J Dermatol 2000;
39:641.
Li J, et al: Association study of the single nucleotide polymorphisms of
PARK2 and PACRG with leprosy susceptibility in Chinese population.
Eur J Hum Genet 2012; 20:488.
Manickam P, et al: Efficacy of single-dose chemotherapy (rifampicin,
ofloxacin and minocycline—ROM) in PB leprosy patients with 2 to 5
skin lesions, India: randomised double-blind trial. Indian J Lepr 2012;
84:195.
Manzoni C: LRRK2 and autophagy: a common pathway for disease.
Biochem Soc Trans 2012; 40:1147.
Masaki T, et al: Reprogramming adult Schwann cells to stem cell–like
cells by leprosy bacilli promotes dissemination of infection. Cell 2013;
152:51.
Massone C, et al: Histopathology of the lepromatous skin biopsy. Clin
Dermatol 2015; 33:38.
Menicucci LA, et al: Microscopic leprosy skin lesions in primary neuritic
leprosy. J Am Acad Dermatol 2005; 52:648.
Modi K, et al: Lepromatous leprosy in a heart transplant recipient. Am J
Transplant 2003; 3:1600.
Moet FJ, et al: Effectiveness of single-dose rifampicin in preventing
leprosy in close contacts of patients with newly diagnosed leprosy:
cluster randomised controlled trial. Br Med J 2008; 5:761.
Moschella S: An update on the diagnosis and treatment of leprosy.
J Am Acad Dermatol 2004; 51:417.
Moura ML, et al: Active surveillance of Hansen’s disease (leprosy):
importance for case finding among extra-domiciliary contacts. PLoS
Negl Trop Dis 2013; 7:32093.
Nair SP, Nanda Kumar G: A clinical and histopathological study of histoid
leprosy. Int J Dermatol 2013; 52:580.
Nath I, et al: Immunology of leprosy and diagnostic challenges. Clin
Dermatol 2015; 33:90.
Orlova M, et al: Gene set signature of reversal reaction type I in leprosy
patients. PLoS Genet 2013; 9:e1003624.
Polycarpou A, et al: New findings in the pathogenesis of leprosy and
implications for the management of leprosy. Curr Opin Infect Dis 2013;
26:413.
Rao PN, Jain S: Newer management options in leprosy. Indian J
Dermatol 2013; 58:6.
Reja AH, et al: Fite-Faraco staining in combination with multiplex
polymerase chain reaction: a new approach to leprosy diagnosis.
Indian J Dermatol Venereol Leprol 2013; 79:693.
342
Richardus JH, Oskam L: Protecting people against leprosy:
chemoprophylaxis and immunoprophylaxis. Clin Dermatol 2015; 33:19.
Sauer ME, et al: Genetics of leprosy: expected and unexpected
developments and perspectives. Clin Dermatol 2015; 33:99.
Sales AM, et al: Profession of leprosy disability after discharge: is
multidrug therapy enough? Trop Med Int Health 2013; 18:1145.
Santos VS, et al: Evaluation of agreement between clinical and
histopathological data for classifying leprosy. Int J Infect Dis 2013;
17:e189.
Savage JA, Levis WR: The utility of QuantiFERON-TB Gold assay in
patients with leprosy: a possible measure of anergy. J Am Acad
Dermatol 2014: 71:996.
Scharschmidt TC, et al: Immune reconstitution reactions in human
immunodeficiency virus–negative patients. JAMA Dermatol 2013;
149:74.
Scollard DM, et al: Mechanisms of nerve injury in leprosy. Clin Dermatol
2015; 33:46.
Scollard DM, et al: Risk factors for leprosy reactions in three endemic
countries. Am J Trop Med Hyg 2014. [Epub ahead of print.]
Scollard DM, et al: Hansen’s disease (leprosy) complicated by
secondary mycobacterial infection. J Am Acad Dermatol 2011; 64:593.
Spierings E, et al: The role of Schwann cells, T cells and Mycobacterium
leprae in the immunopathogenesis of nerve damage in leprosy.
Leprosy Rev 2000; 71:S121.
Talhari C, et al: Clinical aspects of leprosy. Clin Dermatol 2015; 33:26.
Trindade MA, et al: Leprosy in transplant recipients: report of a case
after liver transplantation and review of the literature. Transpl Infect Dis
2011; 13:63.
Velayati AA, et al: Case report: interferon-gamma receptor-1 gene
promoter polymorphisms and susceptibility to leprosy in children of a
single family. Am J Trop Med Hyg 2011; 84:627.
Vera-Cabrera L, et al: Case of diffuse lepromatous leprosy associated
with “Mycobacterium lepromatosis.” J Clin Microbiol 2011; 49:4366.
Walker SL, et al: International workshop on erythema nodosum
leprosum (ENL): consensus report. The formation of ENLIST, the ENL
International Study Group. Lepr Rev 2012; 83:396.
Wegner, M: Mighty bugs: leprosy bacteria turn Schwann cells into stem
cells. Cell 2013; 152:15.
Williams DL, et al: Primary multi-drug resistant leprosy, United States.
Emerg Infect Dis 2013; 19:179.
Bonus images for this chapter can be found online at
expertconsult.inkling.com
eFig. 17-1 Lepromatous leprosy.
eFig. 17-2 Lepromatous leprosy, multiple papules and nodules.
eFig. 17-3 Borderline tuberculoid leprosy.
eFig. 17-4 Borderline leprosy.
eFig. 17-5 Type 1 reaction in Hansen’s disease.
eFig. 17-6 Lepromatous leprosy, acral burns caused by peripheral
sensory neuropathy.
 Prevention
eFig. 17-4 Borderline leprosy.
eFig. 17-1 Lepromatous leprosy.

eFig. 17-2 eFig. 17-5 Type 1

Lepromatous leprosy, reaction in Hansen’s
multiple papules and disease.
nodules.

eFig. 17-6
Lepromatous leprosy,
acral burn caused by
peripheral sensory
neuropathy.

eFig. 17-3 Borderline tuberculoid leprosy.

342.e1

tahir99 - UnitedVRG
 Bonus images for this chapter can be found online at
Syphilis, Yaws, Bejel, and Pinta
SYPHILIS
Syphilis also nown as lues is a contagious se ually trans
mitted disease caused by the spirochete reponema palli um
subspecies palli um The only nown host is the human. The
spirochete enters through the s in or mucous membranes
where the primary mani estations are seen. n congenital
syphilis the treponeme crosses the placenta and in ects the
etus. The ris o ac uiring in ection rom se ual contact with
an in ected partner in the pre ious days is . Syphilis
results in multiple patterns o s in and isceral disease and
can be li elong.
Syphilis yaws pinta and endemic syphilis are closely
related in ectious conditions caused by genetically monomor
phic bacteria with less than di erence in the genomes o
the treponemes (treponemas) that cause these in ections. is
torically yaws rst arose with humans in A rica and spread
with human migrations to urope and Asia. ndemic syphilis
e ol ed rom yaws and became endemic in the iddle ast
and the Bal ans at some later date. aws mo ed with human
migration to the ew World and became endemic in South
America. Syphilis palli um palli um may ha e originated
in the ew World rom palli um pertenue the organism
causing yaws much as human immunode ciency irus ( V)
e ol ed in A rica rom simian immunode ciency irus (S V).
A tribe in Guyana with a spirochetal in ection with eatures o
both yaws and syphilis was identi ed. Se uencing the genome
o this spirochete suggested that it was the ancestor o pal
li um palli um This lends support to the theory that syphilis
originated more recently in the ew World and was brought
bac to urope by sailors who went to the ew World with
Christopher Columbus. actly how and when it became pri
marily a enereally transmitted disease is unclear but appar
ently this happened toward the end o the th century.
reponema palli um is a delicate spiral spirochete that is
acti ely motile. The number o spirals aries rom to and
the entire length is μm. t can be demonstrated in prepa
rations rom resh primary or secondary lesions by dar eld
microscopy or by uorescent antibody techni ues. The motil
ity is characteristic consisting o three mo ements a pro ec
tion in the direction o the long a is a rotation on its long a is
and a bending or twisting rom side to side. The precise uni
ormity o the spiral coils is not distorted during these mo e
ments. icroscopic characteristics o palli um cannot be
distinguished rom commensal oral treponemes so dar eld
e amination o oral lesions is unreliable. Direct uorescent
antibody testing can be used or con rmation.
The genome o palli um has been se uenced and contains
about one uarter o the number o genes o most bacteria. t
lac s signi cant metabolic capacity. t is ery sensiti e to tem
perature with some en ymes wor ing poorly at typical body
temperature (perhaps e plaining why e er therapy was e ec
ti e). These two actors may contribute to the inability to
expertconsult.inkling.com
18
culture the organism in itro. palli um is an e ecti e patho
gen because it disseminates widely and rapidly a ter in ection.
t is in the bloodstream within hours o intratesticular in ection
and in numerous organs including the brain within hours
a ter inoculation. nce the organisms reach a tissue they are
able to persist or decades. n each tissue the number o organ
isms is ery low perhaps below a critical antigenic mass. n
addition palli um e presses ery ew antigenic targets on
its sur ace (only about as many as Escherichia coli). The
outer membrane proteins o palli um also undergo rapid
mutation so that during an in ection the host accumulates
numerous subpopulations o organisms with di erent sur ace
antigens. This low in ection load widespread dissemination
poor sur ace antigen e pression and rapid e olution o anti
genically distinct subpopulations may allow the in ection to
persist despite the de elopment by the host o antigen speci c
antibodies and immune cells.
Syphilis remains a ma or health problem worldwide despite
a highly e ecti e and economical treatment or more than
years. The story o the .S. and world epidemiology o syphi
lis illustrates a mo ement o in ection rom one population to
another due to changing social conditions and beha iors. Just
as the health systems respond to one epidemic another
appears. sing serologic testing contact tracing and penicillin
treatment .S. health departments reduced the incidence o
syphilis dramatically rom the turn o the th century through
the mid s. The incidence then gradually increased through
the ne t two decades and into the s. n the early s
hal the cases o syphilis diagnosed were in men who ha e se
with men ( S ). Changes in se ual beha ior patterns among
gay men in response to the ac uired immunode ciency syn
drome (A DS) epidemic reduced the number o these cases
but in the late s syphilis again began to increase dramati
cally associated with drug use especially crac cocaine. The
incidence o syphilis increased disproportionately among
socioeconomically disad antaged minority populations espe
cially in ma or cities. Throughout the s the rate o syphilis
ell in the nited States so that by the national rate o
. cases in population was the lowest le el e er
recorded. n addition hal o new cases were concentrated in
counties mainly in the southeastern nited States and in
select urban areas. With the ad ent o e ecti e antiretro iral
therapy or V there was a change in se ual beha ior in
S including those with V in ection. pidemics o syphi
lis in this group ha e now occurred in many ma or orth
American uropean and Asian cities. This epidemic is char
acteri ed by an older a erage age anonymous se partners
(o ten met on the nternet) use o amphetamines and sildena l
citrate (Viagra) V positi e status and oral se as the sole
se ual e posure. n addition there was a syphilis epidemic in
Russia and the newly independent states starting in the late
s with rates o syphilis times that o Western urope.
Beginning in the mid s China had a syphilis epidemic
a ecting primarily unmarried men emale se wor ers and
343
 S so that in one pro ince in China (Guangdong) had
18 more syphilis cases than the whole uropean nion.
Worldwide an estimated million persons are in ected
annually with syphilis million o whom are pregnant
women. The .S. Centers or Disease Control (CDC) and the
Syphilis, Yaws, Bejel, and Pinta
World ealth rgani ation (W ) ha e underta en cam
paigns to eradicate syphilis. The shi ting epidemiology o
syphilis o er more than e decades suggests it will not be an
easy tas without an e ecti e accine. ntil then reporting o
all cases to public health departments or tracing and treat
ment o contacts should be continued along with widespread
screening o persons at ris including all pregnant women
emale se wor ers S and men with V in ection.
Serologic tests
Serologic testing or in ection with palli um as in tubercu
losis is undergoing changes that incorporate newer technolo
gies into establishing the diagnosis. Currently most testing in
the nited States uses older technologies while in the nited
ingdom ( ) newer technologies ha e been adopted. Tests
are considered either treponemal or nontreponemal.
Treponemal tests detect speci c antitreponemal antibodies by
en yme immunoassay ( A) or palli um particle assay
(TPPA). These new treponemal tests ha e speci city and sen
siti ity e ceeding e en in patients with primary syphilis.
These generate more positi e tests that re uire urther testing
than do older strategies. ontreponemal tests are based on the
act that serum o persons with syphilis aggregates a
cardiolipin cholesterol lecithin antigen. This aggregation can
be iewed directly in tubes or on cards or slides or it can be
e amined in an autoanaly er. Because these tests use lipoidal
antigens rather than palli um or its components they are
called nontreponemal antigen tests. The most widely used
nontreponemal tests are the rapid plasma reagin (RPR) and
Venereal Disease Research Laboratories (VDRL) tests. These
nontreponemal tests are the standard tests used in the nited
States and generally become positi e within wee s o
in ection shortly be ore the chancre heals. Tests are usually
strongly positi e throughout the secondary phase e cept in
rare patients with A DS whose response is less predictable
and usually become negati e during therapy especially i
therapy is begun within the rst year o in ection. Results may
also become negati e a ter a ew decades e en without treat
ment. A tests are a ailable that detect both gG and g
speci c antibodies against palli um The g becomes
detectable wee s a ter in ection about the time the chancre
appears. The gG test becomes positi e at wee s; thus the
g test is much more use ul in diagnosing primary syphilis.
The treponemal tests used in the nited States are the micro
hemagglutination assay or palli um ( A TP) or the uo
rescent treponemal antibody absorption ( TA ABS) test. These
speci c treponemal tests are also positi e earlier than the non
treponemal tests and may be used to con rm the diagnosis o
primary syphilis in a patient with a negati e RPR VDRL. The
A TPPA TA ABS and A TP remain positi e or li e in
the ma ority o patients although in o patients these
tests will become negati e with treatment regardless o stage
and V status. The g A test howe er becomes negati e
ollowing treatment in early syphilis so that at year o than months are categori ed as chronic. Acute B P reac
these patients are negati e on the g A.
All these tests can ha e alse positi e results so all positi e
results are con rmed by another test. n most .S. cities this
in ol es screening the patient with a nontreponemal test
usually an RPR and con rming all positi es with a speci c
treponemal test usually an A TP. a treponemal test
such as the TPPA or A is used or initial screening either a
344
tahir99 - UnitedVRG
nontreponemal test or the other speci c treponemal test
should be used to con rm the rst test. A nontreponemal
RPR VDRL is also per ormed on all positi es to determine the
titer and monitor treatment success. the initial screening
treponemal speci c test is positi e but the nontreponemal test
is negati e a history o prior syphilis and treatment should be
sought. prior syphilis and ade uate treatment can be docu
mented and i e amination shows no e idence o either
primary or late syphilis the patient is ollowed and considered
sero ast a ter treatment. the nontreponemal test is negati e
but a second treponemal test is positi e and i no prior history
o syphilis and its treatment can be ound the patient is con
sidered to ha e late latent syphilis (less li ely recent in ection)
and is treated appropriately. This patient is considered nonin
ectious. the two treponemal tests are discordant one posi
ti e and the other negati e a third treponemal speci c test can
be ordered or the case can be re erred to a public health
department or e pert consultation. Because the nontrepone
mal tests are alsely negati e in or more o patients with
primary syphilis and in up to with late syphilis in these
patients a speci c treponemal test should also be per ormed
as a screening test.
n resource poor countries serologic testing or syphilis is
largely una ailable because reagents re uire re rigeration or
the tests re uire electrical e uipment or processing. n Ban
gladesh and in some countries in sub Saharan A rica and
South America more than o women recei e prenatal
care but only about recei e prenatal syphilis screening.
Syphilis is endemic in these regions with in ection rates in
pregnant women e ceeding and thus millions o pregnant
women with syphilis go undiagnosed. ore than hal a million
babies die o congenital syphilis in sub Saharan A rica e ery
year. ew rapid treponemal speci c tests that can be used in
these resource poor countries ha e been de eloped. They cost
only . . ( .S.) per test and await a ailable unding to
be put into use.
ontreponemal tests are ery aluable in ollowing the
e cacy o treatment in syphilis. By diluting the serum seri
ally the strength o the reaction can be stated in dilutions;
the number gi en is the highest dilution gi ing a positi e
test result. n primary in ection the titer may be only ; in
secondary syphilis it is regularly high or higher;
in late syphilis generally much lower perhaps or .
The rise o titer in early in ection is o great potential diag
nostic alue as is the all a ter proper treatment or the rise
again i there is rein ection or relapse. Patients with ery
high antibody titers as occur in secondary syphilis may
ha e a alse negati e result when undiluted serum is tested.
This pro one phenomenon will be o ercome by diluting
the serum.
Biologic false-positive test results
Biologic alse positi e (B P) is used to denote a positi e
serologic test or syphilis in persons with no history or clinical
e idence o syphilis. The term B P is usually applied to the
situation o a positi e nontreponemal test and a negati e
treponemal test. About o B P test results are o low titer
(< ). Acute B P reactions are de ned as those that re ert
to negati e in less than months; those that persist or more
tions may result rom accinations in ections (in ectious
mononucleosis hepatitis measles typhoid aricella in u
en a lymphogranuloma enereum malaria) and pregnancy.
Chronic B P reactions are seen in connecti e tissue diseases
especially systemic lupus erythematosus (SL ) ( ) chronic
li er disease multiple blood trans usions intra enous drug
use and ad ancing age.
 alse positi e results to speci c treponemal tests are less
common but ha e been reported to occur in lupus erythema
tosus drug induced lupus scleroderma rheumatoid arthritis
smallpo accination pregnancy other related treponemal
in ections (see ne t) and genital herpes simple in ections. A
o an anal chancre include an anal sore or ssure and irritation
or bleeding on de ecation. Anal chancre must be ruled out in
any anal ssure not at the or o cloc positions. When there
is a secondary eruption no isible chancre and the glands
below Poupart s ligament are greatly enlarged anal chancre

Syphilis
pattern o beaded uorescence associated with TA ABS should be suspected.
testing may be ound in the sera o patients without trepone Atypical chancres are common. Simultaneous in ection by a
mal disease who ha e SL . The beading phenomenon spirochete and another microbial agent may produce an atypi
howe er is not speci c or SL or e en or connecti e tissue cal chancre. The mi ed chancre caused by in ection with ae
diseases. mophilus ucre i and reponema palli um will produce a lesion
that runs a course di erent rom either chancroid or primary
syphilis alone. Such a sore begins a ew days a ter e posure
Cutaneous syphilis since the incubation period or chancroid is short and later
the sore may trans orm into an indurated syphilitic lesion. A
Chancre (primary stage) phagedenic chancre results rom the combination o a syphi
litic chancre and contaminating bacteria that may cause se ere
The chancre is usually the rst cutaneous lesion appearing tissue destruction and result in scarring. dema indurati um
days a ter in ection. The typical incipient chancre is a or penile enereal edema is mar ed solid edema o the labia
small red papule or a crusted super cial erosion. n a ew days or the prepuce and glans penis accompanying a chancre.
to wee s it becomes a round or o al indurated slightly ele Chancre redu is relapse o a chancre with insu cient treat
ated papule with an eroded but not ulcerated sur ace that ment accompanied by enlarged lymph nodes. Pseudochancre
e udes a serous uid ( ig. ). n palpation it has a carti
lageli e consistency. The lesion is usually but not in ariably
painless. This is the uncomplicated or classic hunterian Fig. 18-2 Multiple
chancre. The regional lymph nodes on one or both sides are syphilitic chancres in
usually enlarged rm and nontender and do not suppurate. a woman.
Adenopathy begins or wee s a ter the chancre appears.
The hunterian chancre lea es no scar when it heals.
Chancres generally occur singly although they may be mul
tiple especially on the penis in S who are in ected through
oral intercourse ( ig. ). The lesions ary in diameter rom
a ew millimeters to se eral centimeters. The genital chancre
is less o ten obser ed in women because o its location within
the agina or on the cer i . tensi e edema o the labia or
cer i may occur. n men the chancre is commonly located in
the coronal sulcus or on either side o the renum. A chancre
in the prepuce being too hard to bend will ip o er all at once
when the prepuce is drawn bac a phenomenon called a
dory op (resembling a broad beamed s i or dory being
turned upside down). ntreated the chancre tends to heal
spontaneously in months. About the time it disappears or
slightly be ore constitutional symptoms and ob ecti e signs o
generali ed (secondary) syphilis occur ( ig. ).
tragenital chancres may be larger than those on the geni
talia. They a ect the lips tongue tonsil emale breast inde
nger and especially in S the anus. ral chancres orm
rm eroded papules on the lip tongue u ula or tonsillar
pillar and are associated with a history o oral se . nilateral
cer ical adenopathy can be present. The presenting complaints

Fig. 18-3 Primary syphilis, chancre on shoulder with secondary

Fig. 18-1 Primary syphilis, chancre. lesions present.
345
 redu is a gumma occurring at the site o a pre ious chancre;
18 it is distinguished rom relapsing chancre by the absence o
lymphadenopathy and a negati e dar eld e amination.
Syphilitic balanitis o ollmann may occur in the absence o a
chancre. The lesions may be e udati e circinate or erosi e.
Syphilis, Yaws, Bejel, and Pinta
istologic e aluation o a syphilitic chancre re eals an ulcer
co ered by neutrophils and brin. Sub acent there is a dense
in ltrate o lymphocytes and plasma cells. Blood essels are
prominent with plump endothelial cells. Spirochetes are
numerous in untreated chancres and can be demonstrated
with an appropriate sil er stain such as the Warthin Starry
Le aditi or Steiner methods or by immunopero idase stain
ing. Spirochetes are best ound in the o erlying epithelium or
ad acent or o erlying blood essels in the upper dermis.
n a patient who presents with an acute genital ulceration
dar eld e amination should be per ormed i a ailable. The
nding o typical palli um in a sore on the cutaneous sur ace
establishes a diagnosis o syphilis. reponema pertenue which
causes yaws and reponema carateum which causes pinta are
both indistinguishable morphologically rom palli um but
the diseases that they produce are usually easy to recogni e.
Commensal spirochetes o the oral mucosa are indistinguish
able rom palli um ma ing oral dar eld e aminations
unreliable. the dar eld e amination results are negati e
the e amination should be repeated daily or se eral days
especially i the patient has been applying a topical antibacte
rial agent.
The lesion selected or e amination is cleansed with water
and dried. t is grasped rmly between the thumb and inde
nger and abraded su ciently to cause clear or aintly blood
stained plasma to e ude when s uee ed. n the case o an
eroded chancre a ew igorous rubs with dry gau e are
usually su cient. the lesion is made to bleed it is necessary
to wait until ree bleeding has stopped to obtain satis actory
plasma. The sur ace o a clean co erslip is touched to the
sur ace o the lesion so that plasma adheres. Then it is dropped
on a slide and pressed down so that the plasma spreads out
in as thin a lm as possible. mmersion oil orms the inter ace
between the condenser and slide and between the co erslip
and ob ecti e. The specimen must be e amined uic ly be ore
the thin lm o plasma dries.
An alternati e to dar eld microscopy is the direct uores
cent antibody test (D AT TP) or the identi cation o palli
um in lesions. Serous e udate rom a suspected lesion is
collected as ust described placed on a slide and allowed to
dry. any health departments will e amine such specimens
with uorescent antibodies speci c to palli um The method
unli e the dar eld e amination can be used or diagnosing
oral lesions. ultiple polymerase chain reaction (PCR) is also
an accurate and reproducible method or diagnosing genital
ulcerations with the ad antage o being able to diagnose mul
tiple in ectious agents simultaneously. n genital ulcer disease
outbrea s PCR should be made a ailable.
The results o serologic tests or syphilis are positi e in
(nontreponemal tests) to (treponemal tests) o patients
with primary syphilis; both these tests should be per ormed
in e ery patient with suspected primary syphilis. The li eli
hood o positi ity depends on the duration o in ection. the
chancre has been present or se eral wee s test results are
usually positi e.
A syphilitic chancre must be di erentiated rom chancroid.
The chancre has an incubation period o wee s; is usually
a painless erosion not an ulcer; has no surrounding in am
matory one; and is round or o al. The edge is not under
mined and the sur ace is smooth and at the le el o the s in.
t has a dar el ety red lac uered appearance; it has no
o erlying membrane; and it is cartilage hard on palpation.
Lymphadenopathy may be bilateral and is nontender and
346
tahir99 - UnitedVRG
nonsuppurati e. Chancroid on the other hand has a short
incubation period o days; the ulcer is acutely in amed is
e tremely pain ul and has a surrounding in ammatory one.
The ulcer edge is undermined and e tends into the dermis. t
is co ered by a membrane and eels so t. Lymphadenopathy
is usually unilateral and tender and may suppurate. Chan
croid lesions are usually multiple and e tend into each other.
Cultures or chancroid on special media con rm the diagnosis.
owe er since a combination o a syphilitic chancre and
chancroid (mi ed sores) is indistinguishable rom chancroid
alone appropriate direct and serologic testing should be per
ormed to in estigate the presence o syphilis. Again multi
ple PCR allows or the simultaneous diagnosis o many
in ectious agents in genital ulcer diseases.
The primary lesion o granuloma inguinale begins as an
indurated nodule that erodes to produce hypertrophic egeta
ti e granulation tissue. t is so t and bee y red and bleeds
readily. A smear o clean granulation tissue rom the lesion
stained with Wright or Giemsa re eals Dono an bodies in the
cytoplasm o macrophages.
The primary lesion o lymphogranuloma enereum (LGV)
is usually a small painless transient papule or a super cial
nonindurated ulcer. t most o ten occurs on the coronal sulcus
prepuce or glans in men or on the ourchette agina or cer i
in women. A primary genital lesion is noticed by about
o in ected heterose ual men but less re uently in women.
Primary lesions are ollowed in days by adenopathy o
the regional lymph nodes. LGV is con rmed by serologic tests.
erpes simple begins with grouped esicles o ten accom
panied or preceded by burning pain. A ter rupture o the
esicles irregular scalloped tender so t erosions orm.
Secondary syphilis
Cutaneous lesions
The s in mani estations o secondary syphilis occur in or
more o patients with secondary syphilis. The early eruptions
are symmetric more or less generali ed super cial nonde
structi e e anthematous transient and macular; later they
are maculopapular or papular eruptions which are usually
polymorphous and less o ten scaly pustular or pigmented.
The early mani estations tend to be distributed o er the ace
shoulders an s palms and soles and anal or genital regions.
The se erity aries widely. The presence o lesions on the
palms and soles is strongly suggesti e. owe er a general
i ed syphilid can spare the palms and soles. The indi idual
lesions are generally less than cm in diameter e cept in the
later secondary or relapsing secondary eruptions.
Macular eruptions
The earliest orm o macular secondary syphilis begins with
the appearance o an e anthematous erythema wee s
a ter the de elopment o the chancre which may still be
present. The syphilitic e anthem e tends rapidly so that it is
usually pronounced a ew days a ter onset. t may be e anes
cent lasting only a ew hours or days or it may last se eral
months or partially recur a ter ha ing disappeared. This
macular eruption appears rst on the sides o the trun about
the na el and on the inner sur aces o the e tremities.
ndi idual lesions o macular secondary syphilis consist o
round indistinct macules that are noncon uent and rarely
may be slightly ele ated or urticarial. The color aries rom a
light pin or rose to brownish red. The macular eruption may
not be noticed on blac s in and may be so aint that it is also
not recogni ed on other s in colors. Pain burning and itching
are usually absent although pruritus may be present in
o patients. Simultaneous with the onset o the eruption there

Fig. 18-4 Secondary syphilis, lichenoid lesions.
Fig. 18-5 Secondary syphilis.
is a generali ed shotty adenopathy most readily palpable in
the posterior cer ical a illary and epitrochlear areas. Rarely
secondary syphilis may cause li edo reticularis. The macular
eruption may disappear spontaneously a ter a ew days or
wee s without residua or may result in postin ammatory
hyperpigmentation. A ter a arying inter al macular syphilis
may be ollowed by other eruptions.
Papular eruptions
Papular eruptions usually arise slightly later than the macular
eruption. The ully de eloped lesions are round and o a
raw ham or coppery shade ( ig. ). Although papules most
re uently are mm in diameter nodules coalescing to large
pla ues can occur ( ig. ). Lesions o ten are only slightly
raised but a deep rm in ltration is palpable. The sur ace is
smooth sometimes shiny and at other times co ered with a
thic adherent scale. When this des uamates it lea es a char
acteristic collarette o scales o erhanging the border o the
papule.
Papules are re uently distributed on the ace and e ures
o the arms and lower legs and are o ten distributed all o er
the trun . Palmar and plantar in ol ement characteristically
appears as indurated yellowish red spots ( ig. ). llen
dor s (Busch e llendor ) sign is present; the papule is
e uisitely tender to the touch o a blunt probe. ealing
lesions re uently lea e hyperpigmented spots that especially
on the palms and soles may persist or wee s or months. Split
papules are hypertrophic ssured papules that orm in the
creases o the alae nasi and at the oral commissures. These may
persist or a long period. The papulos uamous syphilids in
Syphilis
Fig. 18-6 Secondary syphilis; red, flat-topped papules of the palms
and soles.
Fig. 18-7 Annular secondary syphilis.
which the adherent scales co ering the lesions more or less
dominate the picture may produce a psoriasi orm eruption.
ollicular or lichenoid syphilids appear as minute scale
capped papules. they are at the ostia o hair ollicles syphi
lids are li ely to be conical; elsewhere on the s in they are
domed. ten syphilids are grouped to orm scaling pla ues
in which the tiny coalescing papules are still discernible.
As with the other syphilids papular eruptions tend to be
disseminated but may also be locali ed asymmetric con gu
rate hypertrophic or con uent. The arrangement may be cor
ymbose or in patches rings or serpiginous patterns.
The annular syphilid as with sarcoidosis which it may
mimic is more common in blac s ( ig. ). t is o ten located
on the chee s especially close to the angle o the mouth where
it may orm annular arcuate or gyrate patterns o delicate
slightly raised in ltrated nely scaling ridges. These ridges
are made up o minute at topped papules and the boundar
ies between ridges may be di cult to discern. An old term or
annular syphilids was nic els and dimes.
The corymbose syphilid is another in re uent ariant
usually occurring late in the secondary stage in which a large
central papule is surrounded by a group o tiny satellite
papules. The pustular syphilids are among the rarer mani es
tations o secondary syphilis. They occur widely scattered o er
the trun and e tremities but they usually in ol e the ace
especially the orehead. The pustule usually arises on a red
347
 in ltrated base. n olution is usually slow resulting in a small
18 rather persistent crust co ered super cial ulceration. Lesions
in which the ulceration is deep are called ecthymatous. Closely
related is the rupial syphilid a lesion in which a relati ely
super cial ulceration is co ered with a pile o terraced crusts
Syphilis, Yaws, Bejel, and Pinta
resembling an oyster shell. Lues maligna is a rare orm o
secondary syphilis with se ere ulcerations pustules or rupioid
lesions accompanied by se ere constitutional symptoms. This
orm o secondary syphilis appears to be more common in
V in ected men.
n ol ement o the palms and soles is a characteristic eature
o secondary syphilis. n some cases instead o discrete lesions
the whole area o the palms and soles can be symmetrically
in ol ed resembling eratoderma blennorrhagicum hyper
eratotic hand ec ema or e en an ac uired eratoderma such
as owel ans syndrome. Similarly cutaneous lesions can
be ery psoriasi orm and i they de elop in a person with
nown psoriasis lesions can be mista en or a are o that
disease. Anetoderma may occur a ter treatment o secondary
syphilis.
Condylomata lata are papular lesions relati ely broad and
at located on olds o moist s in especially around the geni
talia and anus but also at the angles o the mouth nasolabial
old and toe webs. They may become hypertrophic and
instead o in ltrating deeply protrude abo e the sur ace
orming a so t red o ten mushroomli e mass cm in diam
eter usually with a smooth moist weeping gray sur ace ( ig.
). Condyloma lata may be lobulated but are not co ered
by the digitate ele ations characteristic o enereal warts (con
dylomata acuminata). Secondary syphilis may initially present
with perianal erosions and pla ues that may mimic cutaneous
Crohn s disease.
Syphilitic alopecia is irregularly distributed so that the scalp
has a moth eaten appearance. t is unusual occurring in about
o patients with secondary syphilis. Smooth circular areas
o alopecia mimic ing alopecia areata may occur in syphilis
and an ophiasis pattern may rarely be seen.
ucous membrane lesions are present in one third o
patients with secondary syphilis and may be the only mani
estation o the in ection. The most common mucosal lesion in
the early phase is the syphilitic sore throat a di use pharyn
gitis that may be associated with tonsillitis or laryngitis.
oarseness and sometimes complete aphonia may be present.
n the tongue smooth small or large well de ned patches
de oid o papillae may be seen most re uently on the dorsum
near the median raphe ( ig. ). lcerations may occur on
the tongue and lips during the late secondary period at times
resembling aphthae or ma or aphthae. A rare ariant o syphi
lis is one presenting with oral and cutaneous erosions that
Fig. 18-8 Condylomata lata.
348
tahir99 - UnitedVRG
histologically show the eatures o pemphigus ulgaris with
a suprabasilar acantholytic blister as well as positi e direct
and indirect immuno uorescence ndings o pemphigus.
ucous patches are the most characteristic mucous mem
brane lesions o secondary syphilis. They are macerated at
grayish rounded erosions co ered by a delicate soggy mem
brane. These highly in ectious lesions are about mm in diam
eter and teem with treponemas. They occur on the tonsils
tongue pharyn gums lips and buccal areas or on the geni
talia chie y in women in whom the lesions are most common
on the labia minora aginal mucosa and cer i . Such mucous
erosions are transitory and change rom wee to wee or e en
rom day to day. Lesions o the oral mucosa re uently contain
plasma cells so the oral pathologist may not consider syphilis.
Because the oral lesions o secondary syphilis are usually
teeming with spirochetes a palli um speci c immunoper
o idase stain is use ul in con rming the diagnosis.
Relapsing secondary syphilis
The early lesions o syphilis undergo in olution either spon
taneously or with treatment. Relapses occur in about o
untreated patients within the rst year. Such relapses
may ta e place at the site o pre ious lesions on the s in or in
the iscera. Recurrent eruptions tend to be more con gurate
or annular larger and asymmetric.
Systemic involvement
The lymphatic system in secondary syphilis is characteristi
cally in ol ed. The lymph nodes most re uently a ected are
the inguinal posterior cer ical postauricular and epitroch
lear. The nodes are shotty rm slightly enlarged nontender
and discrete.
Acute glomerulonephritis gastritis or gastric ulceration
proctitis hepatitis acute meningitis unilateral sensorineural
hearing loss iritis anterior u eitis optic neuritis Bell palsy
multiple pulmonary nodular in ltrates periostitis osteomy
elitis polyarthritis and tenosyno itis may all be seen in sec
ondary syphilis.
Histopathology
acules o secondary syphilis eature super cial and deep
peri ascular in ltrates o lymphocytes macrophages and
plasma cells without epidermal change or accompanied by
slight acuolar change at the dermoepidermal unction.
Papules and pla ues o secondary syphilis usually show
dense super cial and deep in ltrates o lymphocytes macro
phages and plasma cells. These cells are usually distributed
in a bandli e pattern in the papillary dermis and cu ed around
Fig. 18-9 Mucous
patches of secondary
syphilis.
blood essels accompanied by psoriasi orm epidermal hyper
plasia and hyper eratosis. Clusters o neutrophils are usually
present within the stratum corneum. The presence o numer
ous macrophages o ten gi es the in ltrates a pallid appear
ance under scanning magni cation. Vacuolar degeneration o
Latent syphilis
A ter the lesions o secondary syphilis ha e in oluted a latent
period occurs. This may last or a ew months or continue or
the remainder o the in ected person s li e. Between and

Syphilis
eratinocytes is o ten present gi ing the lesions a psoriasi o untreated in ected patients remain latently asymptom
orm and lichenoid histologic pattern with slender elongated atic or li e. During this latent period there are no clinical signs
rete ridges. Plasma cells are reportedly absent in o o syphilis but the serologic tests or syphilis are reacti e.
cases. As lesions age macrophages become more numerous During the early latent period in ecti ity persists; or at least
so that in late secondary lues granulomatous oci are o ten years a woman with early latent syphilis may in ect her
present mimic ing sarcoidosis or less o ten a granuloma unborn child. or treatment purposes it is important to dis
annulare li e pattern. Condylomata lata show spongi orm tinguish early latency (< year duration) rom late latency (>
pustules within areas o papillated epithelial hyperplasia and year or un nown duration).
spirochetes are numerous.
n early syphilis s in lesions spirochetes are most numer
ous within the epidermis and around super cial essels. Sil er Late syphilis
stains are technically di cult but since the number o organ
isms is high in early syphilis the tests are usually positi e. or treatment purposes late syphilis is de ned by the CDC as
PCR and immunopero idase assay may identi y palli um in ection o more than year in duration and by the W as
in ection when sil er stains are negati e. owe er immuno more than years in duration. nly about one third o patients
pero idase stains may be negati e and sil er stains positi e; with late syphilis will de elop complications o their
there ore i suspicion o early syphilis is high both sil er in ection.
stains and immunopero idase assays may need to be
per ormed. Tertiary cutaneous syphilis
Diagnosis and differential diagnosis Tertiary syphilids most o ten occur years a ter in ection.
About o untreated patients will de elop tertiary lesions
Syphilis has long been nown as the great imitator because o the s in mucous membrane bone or oints. S in lesions
the arious cutaneous mani estations may simulate almost tend to be locali ed to occur in groups to be destructi e and
any cutaneous or systemic disease. Pityriasis rosea may be to heal with scarring. Treponemas are usually not ound by
mista en or secondary syphilis especially because both sil er stains or dar eld e amination but may be demon
begin on the trun . The herald patch the o al patches with a strated by immunopero idase techni ues.
ne scale at the edge patterned in the lines o s in clea age Two main types o cutaneous tertiary syphilis are recog
the absence o lymphadenopathy and in re uent mucous ni ed the nodular syphilid and the gumma although the
membrane lesions help to distinguish pityriasis rosea rom distinction is sometimes di cult to ma e. The nodular nodu
secondary syphilis. Drug eruptions may produce a similar loulcerati e or tubercular type consists o rm reddish brown
picture to secondary syphilis but tend to be morbilli orm and or copper colored papules or nodules mm in diameter or
also pruritic whereas secondary syphilis is not. Drug erup larger. The indi idual lesions are usually co ered with adher
tions in pityriasis rosea are o ten pruritic whereas those in ent scales or crusts ( ig. ). The lesions tend to orm rings
secondary syphilis usually are not. and to undergo in olution as new lesions de elop ust beyond
Lichen planus may resemble papular syphilid. The charac them producing characteristic circular or serpiginous pat
teristic papule o lichen planus is at topped and polygonal terns. A distincti e type is the idney shaped lesion which
has Wic ham s striae and e hibits oebner phenomenon.
Pruritus is se ere in lichen planus but is less common and less
se ere in syphilis. Psoriasis may be distinguished rom papu Fig. 18-10 Tertiary
los uamous secondary syphilis by the presence o adenopa syphilis.
thy mucous patches and alopecia in the latter. Sarcoidosis
may produce lesions morphologically identical to secondary
syphilis. istologically multisystem in ol ement adenopa
thy and granulomatous in ammation are common to both
diseases. Serologic testing and biopsy specimens will distin
guish sarcoidosis rom syphilis.
The di erential diagnosis o mucous membrane lesions o
secondary syphilis is o importance. n ectious mononucleo
sis may cause a biologic alse positi e test or syphilis but is
diagnosed by serology. Geographic tongue may be con used
with the des uamati e patches o syphilis or with mucous
patches. Lingua geographica occurs principally near the
edges o the tongue in relati ely large areas which are o ten
used and ha e lobulated contours. t continues or se eral
months or years and changes in e tent and degree o in ol e
ment rom day to day. Recurrent aphthous ulceration pro
duces one or se eral pain ul ulcers mm in diameter
surrounded by hyperemic edges with a grayish co ering
membrane on non eratini ed mucosal epithelium especially
in the gingi al sulcus. A prolonged recurrent history is char
acteristic. Syphilis o the lateral tongue may resemble oral
hairy leu opla ia.
349
 Fig. 18-11 Destruction
18 of the central face in
tertiary syphilis.
Syphilis, Yaws, Bejel, and Pinta
typically occurs on the e tensor sur aces o the arms and on
the bac . ndi idual lesions are composed o nodules in di
erent stages o de elopment so that scars and pigmentation
o ten are ound together with resh as well as ulcerated lesions.
n the ace the nodular eruption closely resembles lupus
ulgaris. When the disease is untreated the process may last
or years slowly marching across large areas o s in. The
nodules may enlarge and e entually brea down to orm pain
less rounded smooth bottomed ulcers a ew millimeters
deep. These punched out ulcers arise side by side and orm
serpiginous syphilitic ulcers palm si ed in aggregate endur
ing or many years ( ig. ).
Gummas may occur as unilateral isolated single or dis
seminated lesions or in serpiginous patterns resembling those
o the nodular syphilid. They may be restricted to the s in or
originating in the deeper tissues brea down and secondarily
in ol e the s in. The indi idual lesions which begin as small
nodules slowly enlarge to se eral centimeters. Central necro
sis is e tensi e and may lead to the ormation o a deep
punched out ulcer with steep sides and a gelatinous necrotic
base. Again progression may ta e place in one area while
healing proceeds in another. Perhaps the most re uent site o
isolated gummas is the lower legs where deep punched out
ulcers are ormed o ten in large in ltrated areas. n the lower
e tremities gummas are re uently mista en or erythema
induratum.
Lesions may be isolated to the mucous membranes o ten the
tongue on which nonindurated punched out ulcers occur. A
super cial glossitis may cause irregular ulcers atrophy o the
papillae and smooth shiny scarring a condition nown as
smooth atrophy. n interstitial glossitis there is an underlying
induration. n the ad anced stages tertiary syphilis o the
tongue may lead to a di use enlargement (macroglossia). Per
oration o the hard palate rom gummatous in ol ement is a
characteristic tertiary mani estation. t generally occurs near
the center o the hard palate. Destruction o the nasal septum
may also occur.
istologically nodular lesions o late syphilis usually ha e
changes that resemble those o secondary lesions with
the addition o tuberculoid granulomas containing arying
numbers o multinucleate giant cells. The epidermis is o ten
atrophic rather than hyperplastic. n gummas necrosis within
granulomas and brosis occur as lesions resol e. Spirochetes
are scant.
or diagnosis o late syphilis clinicians rely hea ily on spe
ci c treponemal tests. The nontreponemal tests such as the
VDRL and RPR are positi e in appro imately o patients.
When there are mucous membrane lesions or which a diag
nosis o carcinoma must also be considered histologic e ami
350
tahir99 - UnitedVRG
nation is per ormed. Dar eld e amination is not indicated
since it is always negati e. When not ulcerated lesions o
tertiary syphilis must be distinguished rom malignant tumors
leu emids and sarcoidosis. The ulcerated tertiary syphilids
must be di erentiated rom other in ections such as scro ulo
derma atypical mycobacterial in ection and deep ungal
in ection. Wegener s granulomatosis and ulcerated cutaneous
malignancies must be considered. istology and appropriate
cultures may be re uired.
Late osseous syphilis
ccasionally gummatous lesions in ol e the periosteum and
the bone. S eletal tertiary syphilis most o ten a ects the head
and ace and the tibia. Late mani estations o syphilis may
produce periostitis osteomyelitis osteitis and gummatous
osteoarthritis. steocope (bone pain) most o ten at night is a
suggesti e symptom.
Syphilitic oint lesions also occur with the Charcot oint
being the most pre alent mani estation. These are o ten associ
ated with tabes dorsalis and occur most re uently in men.
Although any oint may be in ol ed the nees and an les are
most o ten a ected. There is hydrops then loss o the contours
o the oint hypermobility and no pain. Joint lesion is readily
diagnosed by ray e amination.
Neurosyphilis
Central ner ous system (C S) in ection can occur at any stage
o syphilis e en the primary stage. p to o patients
with syphilis may de elop C S in ection but in it is
spontaneously cleared by the immune system. This e plains
why most persons with C S in ol ement ha e no symptoms.
About one third o patients who do not spontaneously clear
their C S in ection will de elop symptomatic neurosyphilis.
inding cerebrospinal uid (CS ) pleocytosis or a positi e
CS VDRL test has been used to con rm the diagnosis o C S
in ection by palli um n ortunately a signi cant propor
tion o patients with CS in ection with palli um will ha e
a negati e CS VDRL ( ) and nondiagnostic CS pleocyto
sis (< white blood cells μL) ( ). n patients with a nega
ti e CS VDRL but pleocytosis TA test can be per ormed on
CS thought by many to be sensiti e but not speci c or
C S syphilis. Combining this with ow cytometry to loo or
B cells in the CS which is speci c but only sensi
ti e will allow the con rmation or e clusion o neurosyphilis
in most patients with CS pleocytosis. The li elihood o ha ing
C S in ection is old greater in persons with RPR o
or greater. V negati e persons with negati e CS e amina
tions ha e almost no ris o de eloping neurosyphilis.
owe er CS e aluations are not routinely per ormed in
asymptomatic persons with early syphilis so identi ying those
at ris or symptomatic neurosyphilis is problematic. palli
um C S in ection may also be strain dependent and e entu
ally typing the in ecting strain may predict those at highest
ris or neurosyphilis.
Because C S in ection is common and the recommended
treatments with ben athine penicillin do not reach treponemi
cidal le els in the CS persistent concern surrounds the ailure
to diagnose and treat asymptomatic neurosyphilis. Appar
ently although treatment does not clear the spirochetes rom
the CS most non V in ected persons are able to clear the
C S in ection spontaneously. CS e aluation is recommended
in all patients with syphilis with any neurologic auditory
or ophthalmic signs or symptoms possibly resulting rom
syphilis independent o stage or V status. n borderline
cases those with RPR o or greater should ha e CS
e aluation. The indications or lumbar puncture in patients
with coe istent V in ection and early syphilis (< or years
duration) remains unclear. The two actors predicting the li e
lihood o C S in ection are RPR o or more and CD
count o cells μL or less. Patients with latent syphilis or
syphilis o un nown duration should ha e CS e aluation i
they are V positi e or ail initial therapy or i therapy other
than penicillin is planned or syphilis o more than year in
duration. Patients with tertiary syphilis should ha e CS e al
uation be ore treatment to e clude neurosyphilis. An appro
priate all in the serum RPR a ter treatment or neurosyphilis
predicts clearing o the C S in ection so a repeat lumbar
puncture a ter therapy is not re uired in V negati e or V
positi e patients ade uately treated or neurosyphilis.
Early neurosyphilis
arly neurosyphilis is mainly meningeal occurs in the years
o in ection and a ects . o untreated persons with
syphilis. eningeal neurosyphilis mani ests as meningitis
with e er headache sti nec nausea omiting cranial ner e
disorders (loss o hearing o ten unilateral and acial wea
ness) photophobia blurred ision sei ures and delirium.
Meningovascular neurosyphilis
eningo ascular neurosyphilis most re uently occurs
years a ter in ection a ecting about o untreated syphilis
patients. t is caused by thrombosis o essels in the C S and
presents as in other C S ischemic e ents with acute onset
o symptoms. emiplegia aphasia hemianopsia trans erse
myelitis and progressi e muscular atrophy may occur. Cranial
ner e palsies may also occur such as eighth ner e dea ness
and eye changes. The eyes may show ed pupils Argyll
Robertson pupils or anisocoria.
Late (parenchymatous) neurosyphilis
Parenchymatous neurosyphilis tends to occur more than
years a ter in ection. There are two classic clinical patterns
tabes dorsalis and general paresis.
Tabes dorsalis is the degeneration o the dorsal roots o the
spinal ner es and o the posterior columns o the spinal cord.
The symptoms and signs are numerous. Gastric crisis with
se ere pain and omiting is the most re uent symptom. ther
symptoms are lancinating pains urination di culties pares
thesias (numbness tingling burning) spinal ata ia diplopia
strabismus ertigo and dea ness. The signs that may be
present are Argyll Robertson pupils absent or reduced re e es
Romberg sign deep tendon tenderness loss o proprioception
and ibratory sensation atonic bladder trophic changes
malum per orans pedis Charcot oints and optic atrophy.
Paresis has prodromal mani estations o headache atigabil
ity and inability to concentrate. Later personality changes
occur along with memory loss and apathy. Grandiose ideas
megalomania delusions hallucinations and nally dementia
may occur.
Late cardiovascular syphilis
Late cardio ascular syphilis occurs in about o untreated
patients. Aortitis is the basic lesion o cardio ascular syphilis
resulting in aortic insu ciency coronary artery disease and
ultimately aortic aneurysm.
Congenital syphilis
Congenital syphilis has reappeared with heterose ual syphilis
epidemics. There were cases o congenital syphilis reported
in ew or City rom to . Cases are also reported
rom Asia and urope. n sub Saharan A rica where prenatal
syphilis testing is not a ailable e en or women with prenatal
care congenital syphilis is common. A total o o all peri
natal deaths in sub Saharan A rica are caused by congenital
syphilis. Prenatal syphilis is ac uired in utero rom the mother
who usually has early syphilis. n ection through the placenta
Syphilis
usually does not occur be ore the ourth month so treatment
o the mother within the rst two trimesters will almost always
pre ent negati e outcomes. or this reason prenatal care with
syphilis serologies done in the early second trimester and at
deli ery (and any time in between i there is clinical suspicion
o syphilis or high ris o ac uisition o syphilis) is recom
mended. Common causes or ailure to pre ent congenital
syphilis in mothers who recei ed prenatal care are ( ) lac o
documented treatment o syphilis diagnosed be ore preg
nancy ( ) absence o serologic testing during pregnancy ( )
late or no maternal treatment and ( ) treatment with a non
penicillin regimen. any o these is noted in the maternal
history congenital syphilis should still be suspected.
Recent reports rom China suggest that preschool children
may ac uire syphilis by nonse ual close contact. n all cases
a caregi er had in ectious syphilis but se ual abuse was
apparently e cluded. This report suggests that the diagnosis
o syphilis should be considered whene er the clinical mani
estations suggest this possibility.
the mother has early syphilis and prenatal in ection occurs
soon a ter the ourth month etal death and miscarriage occur
in about o pregnancies. During the remainder o the
pregnancy in ection is e ually li ely to produce characteristic
physical de elopmental stigmata or a ter the eighth month
acti e in ectious congenital syphilis. About o pregnant
women with untreated early syphilis will ha e a syphilitic
in ant. n ant mortality rom congenital syphilis can e ceed
. n utero in ection o the etus is rare when the pregnant
mother has had syphilis or or more years. Two thirds o
neonates with congenital syphilis are normal at birth and only
detected by serologic testing. Lesions occurring within the rst
years o li e are called early congenital syphilis and those
de eloping therea ter late congenital syphilis. The clinical
mani estations o these two syndromes are di erent.
Early congenital syphilis
arly congenital syphilis describes those cases presenting
within the rst years o li e. Cutaneous mani estations
usually appear during the third wee o li e but sometimes
occur as late as months a ter birth. eonates born with nd
ings o congenital syphilis are usually se erely a ected. They
may be premature and are o ten marasmic ret ul and dehy
drated. The ace is pinched and drawn resembling that o an
old man or woman. ultisystem disease is characteristic.
Snu es a orm o rhinitis is the most re uent and o ten
the rst speci c nding. The nose is bloc ed o ten with blood
stained mucus and a copious discharge o mucus runs down
o er the lips. The nasal obstruction o ten inter eres with the
child s nursing. n persistent and progressi e snu es ulcer
ations de elop that may in ol e the bones and ultimately
cause per oration o the nasal septum or de elopment o
saddle nose which are important stigmata later in the disease.
Cutaneous lesions o congenital syphilis resemble those o
ac uired secondary syphilis and occur in o in ants
with syphilis. The early s in eruptions are usually morbilli
orm and more rarely purely papular. The lesions are at rst
a bright or iolaceous red later ading to a coppery color. The
papules may become large and in ltrated; scaling o ten is
pronounced. There is secondary pustule ormation with crust
ing especially in lesions that appear year or more a ter birth.
The eruption shows a mar ed predilection or the ace arms
buttoc s legs palms and soles.
351
 Syphilitic pemphigus a bullous eruption usually on the
18 palms and soles is a relati ely uncommon lesion. Lesions are
present at birth or appear in the rst wee o li e. They are
teeming with spirochetes. The bullae uic ly become purulent
and rupture lea ing weeping erosions. They are ound also
Syphilis, Yaws, Bejel, and Pinta
on the eponychium wrists an les and in re uently on other
parts o the body. en in the absence o bullous lesions des
uamation is common o ten preceded by edema and ery
thema especially on the palms and soles.
Various morphologies o cutaneous lesions occur on the
ace perineum and intertriginous areas. These are usually
ssured lesions resembling mucous patches. n these sites
radial scarring o ten results leading to rhagades. Condylo
mata lata large moist hypertrophic papules are ound
around the anus and in other olds o the body. They are more
common about the rst year o li e than in the newborn period.
n the second or third year recurrent secondary eruptions are
li ely to ta e the papulopustular orm. Annular lesions occur
similar to those in adults. ucous patches in the mouth or on
the ul a are seen in re uently.
Bone lesions occur in o in ants with early congenital
syphilis. piphysitis is common and apparently causes pain
on motion leading to the in ant re using to mo e (Parrot pseu
doparalysis). Radiologic eatures o the bone lesions in con
genital syphilis during the rst months a ter birth are uite
characteristic and ray lms are an important part o the
e aluation o a child suspected o ha ing congenital syphilis.
Bone lesions occur chie y at the epiphyseal ends o the long
bones. The changes may be classi ed as osteochondritis osteo
myelitis and osteoperiostitis.
A general enlargement o the lymph nodes usually occurs
with enlargement o the spleen. Clinical e idence o li er
in ol ement is common mani ested by both hepatomegaly
and ele ated li er unction test results and interstitial hepati
tis is a re uent nding at autopsy. The nephrotic syndrome
and less o ten acute glomerulonephritis ha e been reported in
congenital syphilis.
Symptomatic or asymptomatic neurosyphilis as demon
strated by a positi e CS serologic test may be present.
in ants with congenital syphilis diagnosed by clinical and
laboratory ndings born to mothers with untreated early
syphilis will ha e C S in ol ement compared with only
o those with no clinical or laboratory ndings. All in ants
with early congenital syphilis are treated as i they ha e neu
rosyphilis because it is ery common and CS VDRL test may
be negati e e en in documented C S in ection. Clinical mani
estations may not appear until the third to si th month o li e
and are meningeal or meningo ascular in origin. eningitis
obstructi e hydrocephalus cranial ner e palsies and cerebro
ascular accident (stro e) may all occur.
Late congenital syphilis
Although no sharp line can be drawn between early and late
congenital syphilis children who appear normal at birth and
de elop the rst signs o the disease a ter age years show a
di erent clinical picture. Lesions o late congenital syphilis are
o two types persistent in ammatory oci and mal ormations
o tissue a ected at critical growth periods (stigmata).
Inflammatory lesions
Lesions o the cornea bones and C S are the most important.
nterstitial eratitis which begins with intense pericorneal
in ammation and persists to characteristic di use clouding o
the cornea without sur ace ulceration occurs in o
children with late congenital syphilis. persistent it leads to
permanent partial or complete opacity o the cornea. Syphi
litic interstitial eratitis must be di erentiated rom Cogan
352
tahir99 - UnitedVRG
syndrome consisting o nonsyphilitic interstitial eratitis
usually bilateral associated with estibuloauditory symp
toms such as dea ness tinnitus ertigo nystagmus and
ata ia. t is congenital.
Perisyno itis (Clutton oints) which a ects the nees leads
to symmetric painless swelling. Gummas may also be ound
in any o the long bones or in the s ull. lcerating gummas
are re uently seen and probably begin more o ten in the so t
parts or in the underlying bone than in the s in itsel . When
they occur in the nasal septum or palate ulcerating gummas
may lead to painless per oration.
The C S lesions in late congenital syphilis are as in late
adult neurosyphilis usually parenchymatous (tabes dorsalis
or generali ed paresis). Sei ures are a re uent symptom in
congenital cases.
Malformations (stigmata)
The destructi e e ects o syphilis in young children o ten
lea e scars or de elopmental de ects called stigmata which
persist throughout li e and con rm a diagnosis o congenital
syphilis. utchinson emphasi ed the diagnostic importance o
changes in the incisor teeth opacities o the cornea and eighth
cranial ner e dea ness which ha e since become nown as the
utchinson triad. utchinson s teeth corneal scars saber
shins rhagades o the lips saddle nose and mulberry molars
are o diagnostic importance ( ig. ).
utchinson s teeth are a mal ormation o the central upper
incisors that appear in the secondary or permanent teeth. The
characteristic teeth are cylindrical rather than attened the
cutting edge is narrower than the base and in the center o
the cutting edge a notch may de elop ( ig. ). The mul
berry molar usually the rst molar and appearing about age
years is a hyperplastic tooth; its at occlusal sur ace is
co ered with a group o little nobs representing aborti e
cusps. asal chondritis in in ancy results in attening o the
nasal bones orming a so called saddle nose. The unilateral
thic ening o the inner third o one cla icle ( igoum na i s
sign) is a hyperostosis resulting rom syphilitic osteitis in indi
iduals who ha e had late congenital syphilis. The lesion
appears typically on the right side in right handed persons
and on the le t side in le t handed persons.
Diagnosis
n ants o women who meet the ollowing criteria should be
e aluated or congenital syphilis
Fig. 18-12 Frontal bossing, interstitial keratitis, and saddle nose in
congenital syphilis.

Fig. 18-13 Hutchinson’s teeth in congenital syphilis.
. aternal untreated syphilis inade uate treatment or no
documentation o ade uate treatment
. Treatment o maternal syphilis with nonpenicillin
regimen
. Treatment less than month be ore deli ery
. nade uate maternal response to treatment
. Appropriate treatment be ore pregnancy but insu cient
serologic ollow up to document ade uacy o therapy
The results o serologic tests or syphilis or e ery woman
deli ering a baby must be nown be ore the discharge o that
baby rom the hospital. Serologic testing o the mother and
child at deli ery are recommended. aluation o the children
as ust noted might include the ollowing
. A complete physical e amination or ndings o
congenital syphilis
. ontreponemal serology o the in ant s serum (not cord
blood)
. Central ner ous system e aluation
. Pathologic e aluation o the placenta using speci c
antitreponemal antibody staining
Treatment
Penicillin remains the drug o choice or treatment o all stages
o syphilis. rythromycin is not recommended or treatment
o any stage or orm o syphilis. V testing is recommended
in all patients with syphilis. Treatment or V in ected
patients is discussed later. Patients with primary secondary
or early latent syphilis nown to be o less than year in dura
tion can be treated with a single intramuscular in ection o .
million units (megaunits ) o ben athine penicillin G. n
nonpregnant penicillin allergic V negati e patients tetra
cycline mg orally our times daily or do ycycline mg
orally twice daily or wee s is recommended. Ce tria one
g intramuscularly or intra enously or days is an
acceptable alternati e i the patient cannot tolerate the pre i
ous options. A ithromycin and erythromycin can no longer be
recommended as treatment or syphilis because o the world
wide presence o macrolide resistance caused by a mutation
in the gene encoding part o the ribosome responsible or
binding macrolides. Close ollow up is recommended or all
patients treated with non penicillin based regimens. These
alternati e agents are not recommended or persons with V
in ection and syphilis.
The recommended treatment o late or late latent syphilis o
more than year duration in an V negati e patient is
ben athine penicillin G . intramuscularly once wee ly
or wee s. n a penicillin allergic nonpregnant V negati e
patient tetracycline mg orally our times daily or do y
cycline mg orally twice daily or days is recommended.
CS e aluation is recommended i neurologic or ophthalmo
Syphilis
logic ndings are present i there is e idence o acti e late
(tertiary) syphilis i treatment has pre iously ailed i the
nontreponemal serum titer is or higher or i any regimen
not based on penicillin is planned.
Recommended treatment regimens or neurosyphilis include
penicillin G crystalline intra enously e ery h or
days or procaine penicillin . day intramuscu
larly plus probenecid mg orally our times daily both or
days. These regimens are shorter than those or treat
ment o late syphilis so they may be ollowed by ben athine
penicillin G . intramuscularly once wee ly or wee s.
Patients allergic to penicillin should ha e their allergy con
rmed by s in testing. allergy e ists desensiti ation and
treatment with penicillin are recommended.
Treatment o congenital syphilis in the neonate is comple .
Therapy should be underta en in consultation with a pediatric
in ectious disease specialist. anagement strategies can be
ound in the CDC ui elines for the Management of Sexuall
ransmitte Diseases lder children with congenital syphilis
should ha e a CS e aluation and should be treated with
a ueous crystalline penicillin G g day
intra enously or intramuscularly ( e ery h) or
days.
Pregnant women with syphilis should be treated with peni
cillin in doses appropriate or the stage o syphilis. A second
dose o ben athine penicillin . intramuscularly may be
administered wee a ter the initial dose in pregnant women
with primary secondary or early latent syphilis. Sonographic
e aluation o the etus in the second hal o pregnancy or
signs o congenital in ection may acilitate management and
counseling. pert consultation should be sought when e i
dence o etal syphilis is ound because etal treatment ailure
is increased in this situation. ollow up uantitati e serologic
tests should be per ormed monthly until deli ery. Pregnant
women who are allergic to penicillin should be s in tested and
desensiti ed i test results are positi e.
Jarisch-Herxheimer or Herxheimer reaction
A ebrile reaction o ten occurs a ter the initial dose o anti
syphilitic treatment especially penicillin is gi en. Although
historically reported to occur in more than o patients
treated or early syphilis a recent report ound a rate o only
. The reaction generally occurs h a ter treatment and
consists o sha ing chills e er malaise sore throat myalgia
headache tachycardia and e acerbation o the in ammatory
reaction at sites o locali ed spirochetal in ection. A esicular
er heimer reaction can occur. A er heimer reaction in
pregnancy may induce premature labor and etal distress.
ery e ort should be made to a oid this complication. arly
in pregnancy women should rest and ta e acetaminophen or
e er. Women treated a ter wee s o pregnancy should see
obstetric e aluation i they e perience e er decreased etal
mo ement or regular contractions within h o treatment.
ncreased in ammation in a ital structure may ha e serious
conse uences as when aneurysm o the aorta or iritis is
present. When the C S is in ol ed a oiding the er heimer
reaction is especially important e en though the paralyses
that may result are o ten transitory. t is important to distin
guish the er heimer reaction rom a drug reaction to penicil
lin or other antibiotics. The reaction has also been described
in other spirochetal diseases such as leptospirosis and louse
borne relapsing e er.
353
 Treatment of sex partners
18 Se ual partners o persons with syphilis should be identi ed.
Persons who are e posed within days o the diagnosis o
primary secondary or early latent syphilis e en i seronega
Syphilis, Yaws, Bejel, and Pinta
ti e should be treated presumpti ely. the e posure occurred
be ore days o diagnosis but ollow up is uncertain pre
sumpti e treatment should be gi en. the in ectious source
has a serologic titer o greater than the patient should be
presumed to ha e in ectious early syphilis and se ual part
ners should be treated. At ris partners are identi ed as those
e posed within months plus the duration o the primary
lesions or months plus the duration o the secondary
lesions or year or latent syphilis. Treatment o se ual part
ners is based on their clinical and serologic ndings. they
are seronegati e but had e posures as pre iously outlined
treatment would be as or early syphilis with ben athine peni
cillin . intramuscularly as one dose.
Serologic testing after treatment
Be ore therapy and then regularly therea ter uantitati e
VDRL or RPR testing should be per ormed on patients who
are to be treated or syphilis to ensure appropriate response.
or primary and secondary syphilis in an V negati e non
pregnant patient testing is repeated e ery months in the rst
year e ery months in the second year and yearly therea ter.
At least a our old decrease in titer would be e pected
months a ter therapy but o patients with recommended
treatment will not achie e this serologic response by year.
Patients with prior episodes o syphilis may respond more
slowly. response is inade uate V testing (i V status is
un nown) and CS e aluation are recommended. or V setting o
negati e patients who ail to respond and who ha e a normal
CS e aluation optimal management is unclear. Close
ollow up must be ensured. it is decided to retreat the
patient in ection o ben athine penicillin G . wee ly or
wee s is recommended. A our old increase in serologic titer
clearly indicates treatment ailure or rein ection. These patients
should ha e V testing and CS analysis with treatment
determined by test results.
The serologic response or patients with latent syphilis is
slower but a our old decrease in titer should be seen by
months. no such response occurs V testing and CS e al
uation are recommended. Patients treated or latent or late
syphilis may be sero ast so ailure to obser e a titer all in
these patients does not in itsel indicate a need or retreatment.
the titer is less than the possibility o a sero ast state
e ists and retreatment should be planned on an indi idual
basis.
Serore ersion in speci c treponemal tests can occur. By
months o patients treated or early syphilis had a nega
ti e TA ABS and had a negati e A TP.
Syphilis and HIV disease
Syphilis and other genital ulcer diseases enhance the ris o
transmission and ac uisition o V. This may result rom
early lesions o syphilis containing mononuclear cells with
enhanced e pression o CCR the co receptor or V . V
testing is recommended in all patients with syphilis.
ost V in ected patients with syphilis e hibit the classic
clinical mani estations with appropriate serologic titers or
that stage o disease. Response to treatment both clinical and
serologic in V in ected patients with syphilis generally
ollow the clinical and serologic patterns seen in patients
without coe isting V in ection. n a large study that com
354
tahir99 - UnitedVRG
pared V positi e and V negati e patients with syphilis
the ormer were more li ely to present with secondary syphilis
( s. ) and were more li ely to ha e a chancre that
persisted when they had secondary syphilis ( s. ).
nusual clinical mani estations o syphilis in V range rom
orid s in lesions to ew atypical ones but these are e cep
tions not the rule. Because most V in ected patients in large
urban areas in the nited States and Western urope who
ac uire syphilis are S chancres may be in atypical loca
tions such as the lips tongue or anus.
n general the nontreponemal tests are o higher titer in
V in ected persons. Rarely the serologic response to in ec
tion may be impaired or delayed and seronegati e secondary
syphilis has been reported. Biopsy o the s in lesions and
histopathologic e aluation with special stains will con rm the
diagnosis o syphilis in such patients. This approach along
with dar eld e amination o appropriate lesions should be
considered i the clinical eruption is characteristic o syphilis
and the serologic tests yield negati e results.
eurosyphilis has been re uently reported in V in ected
persons e en a ter appropriate therapy or early syphilis.
ani estations ha e been those o early neurosyphilis or men
ingeal or meningo ascular syphilis. These ha e included
headache e er hemiplegia and cranial ner e (C ) de cits
especially dea ness (C V ) decreased ision (C ) and
ocular palsies (C s and V ). Whether V in ected persons
are at increased ris or these complications or whether they
occur more uic ly is un nown. t is nown that spirochetes
are no more li ely to remain in the CS a ter treatment in V
in ected persons than in V negati e persons. Whether the
impaired host immunity allows these residual spirochetes to
cause clinical relapse more re uently or more uic ly in the
V is un nown.
Patients with V in ection who ha e primary or secondary
syphilis who are not allergic to penicillin and who ha e no
neurologic or psychiatric ndings should be treated with ben
athine penicillin G . intramuscularly. There is no e i
dence that additional treatment will reduce the ris o
treatment ailure. Patients who are allergic to penicillin should
be desensiti ed and treated with penicillin. ollowing treat
ment the patient should ha e serologic ollow up with uan
titati e nontreponemal tests at and months.
ailure o the titer to all is an indication or ree aluation
including lumbar puncture. actors associated with treatment
ailure in V disease include a low initial serological titer
(RPR < ) a history o prior syphilis and a CD count less
than cells mL.
Because o the concerns about neurologic relapse in the
syphilitic patient with V disease more care ul C S e alua
tion is ad ocated. Lumbar puncture is recommended in V
in ected patients with latent syphilis (o any duration) with
late syphilis (e en with a normal neurologic e amination) and
with any neurologic or psychiatric signs or symptoms. RPR
is or greater and CD count is less than cells mL
neurosyphilis is more li ely and lumbar puncture can be con
sidered. Treatment in these patients will be determined by the
result o their CS e aluation. V in ected patients with
primary or secondary syphilis should be counseled about their
possible increased ris o C S relapse.
Ben athine penicillin . intramuscularly should be
used to treat all V in ected contacts o patients with syphilis
who are at ris o ac uiring in ection.
Andrade P, et al: Solitary frontal ulcer: a syphilitic gumma. Dermatol
Online J 2010; 16:5.
Aquilina C, et al: Secondary syphilis simulating oral hairy leukoplakia.
J Am Acad Dermatol 2003; 49:749.
Barbosa IG, et al: Neurosyphilis presenting as mania. Bipolar Disord
2012; 14:309.
Battistella M, et al: Extensive nodular secondary syphilis with prozone
phenomenon. Arch Dermatol 2008; 144:1078.
Bekkali,N, et al: An annular patch of the scalp reveals tertiary syphilis.
Int J Dermatol 2014; 53:e185.
Bernabeu-Wittel J, et al: Primary syphilitic chancre on the hand with
regional adenopathy. Sex Transm Dis 2010; 37:467.
Bowring J, et al: Stroke in pregnancy associated with syphilis. J Obstet
Gynaecol Res 2008; 34:405.
Centers for Disease Control and Prevention: Syphilis testing algorithms
using treponemal tests for initial screening—four laboratories, New
York City, 2005–2006. MMWR 2008; 57:872.
Centers for Disease Control and Prevention: Sexually transmitted diseases
treatment guidelines 2010. MMWR 2010; 59:1.
Cha JM, et al: Rectal syphilis mimicking rectal cancer. Yonsei Med J
2010; 51:276.
Chan SY, et al: Syphilis causing hearing loss. Int J STD AIDS 2008;
19:721.
Chen JQ, et al: Photo quiz: asymptomatic plaques on toe web. Clin
Infect Dis 2012; 55:1164.
Cheng S, French P: Unilateral penile swelling: an unusual presentation of
primary syphilis. Int J STD AIDS 2008; 19:640.
Chiu HY, Tsai TF: A crusted plaque on the right nipple. JAMA 2012;
308:403.
Cid PM, et al: Pathologically confirmed malignant syphilis using
immunohistochemical staining: report of 3 cases and review of the
literature. Sex Transm Dis 2014; 41:94.
Cordato DJ, et al: Prevalence of positive syphilis serology and
meningovascular neurosyphilis in patients admitted with stroke and TIA
from a culturally diverse population (2005-09). J Clin Neurol 2013; 20:943.
Czerninski R, et al: Oral syphilis lesions: a diagnostic approach and
histologic characteristics of secondary stage. Quintessence Int 2011;
42:883.
Emer J, et al: Generalized anetoderma after intravenous penicillin
therapy for secondary syphilis in an HIV patient. J Clin Aesthet
Dermatol 2013; 6:23.
Farhi D, Dupin N: Management of syphilis in the HIV-infected patient:
facts and controversies. Clin Dermatol 2010; 28:539.
Flynn TR, et al: A 37-year-old man with a lesion on the tongue. N Engl J
Med 2010; 362:740.
Galvao TF, et al: Safety of benzathine penicillin for preventing congenital
syphilis: a systematic review. PLoS One 2013; 8:e56463.
Ghanem KG: Neurosyphilis: a historical perspective and review. CNS
Neurosci Ther 2010; 16:e157.
Ghanem KG, Workowski KA: Management of adult syphilis. Clin Infect Dis
2011; 53:S110.
Grillo E, et al: Multiple penile lesions: a case study. Aust Fam Physician
2012; 41:701.
Harding AS, Ghanem KG: The performance of cerebrospinal fluid
treponemal-specific antibody tests in neurosyphilis: a systematic
review. Sex Transm Dis 2012; 39:291.
Hawkes SJ, et al: Early antenatal care: does it make a difference to
outcomes of pregnancy associated with syphilis? A systematic review
and meta-analysis. PLoS One 2013; 8:e56713.
Ho EL, Lukehart SA: Syphilis: using modern approaches to understand
an old disease. J Clin Invest 2011; 121:4584.
Hu QH, et al: Risk factors associated with prevalent and incident
syphilis among an HIV-infected cohort in Northeast China. BMC Infect
Dis 2014; 14:658.
Hunt R, et al: Circumscribed lenticular anetoderma in an HIV-infected
man with a history of syphilis and lichen planus. Dermatol Online J
2011; 17:2.
Husein-El Ahmed H, Ruiz-Carrascosa JC: Secondary syphilis presenting
as rash and annular hyperkeratotic lesions. Int J Infect Dis 2011;
15:e220.
Hwang SW, et al: A case of syphilitic keratoderma concurrent with
syphilitic uveitis. Ann Dermatol 2009; 21:399.
Ibrahim FW, Malu MK: Sudden deafness in a patient with secondary
syphilis. J Laryngol Otol 2009; 123:1262.
Jalili A, et al: Malignant syphilis in an HIV-infected patient. Sex Transm
Dis 2010; 37:1.
Jeans AR, et al: Sensorineural hearing loss due to secondary syphilis.
Int J STD AIDS 2008; 19:355.
Jinno S, et al: Predictors of serological failure after treatment in
HIV-infected patients with early syphilis in the emerging era if universal
antiretroviral therapy use. BMC Infect Dis 2013; 13:605.
Kenyon C, et al: Syphilis reinfections pose problems for syphilis
diagnosis in Antwerp, Belgium—1992 to 2012. Euro Surveill 2014;
19:22.
Kim JK, et al: Congenital syphilis presenting with a generalized bullous
and pustular eruption in a premature newborn. Ann Dermatol 2011;
Syphilis
23:S127.
Knaute DF, et al: Serological response to treatment of syphilis according
to disease stage and HIV status. Clin Infect Dis 2012; 55:1615.
Larson BA, et al: Finding a needle in the haystack: the costs and
cost-effectiveness of syphilis diagnosis and treatment during
pregnancy to prevent congenital syphilis in Kalomo district of Zambia.
PLoS One; 9:e113868. doi: 10.1371/journal.pone.0113868. eCollection
2014.
Lee SH, et al: Early congenital syphilis presenting with vesicobullous
eruptions beyond palmoplantar regions. Acta Derm Venereol 2014;
94:321.
Leuci S, et al: Oral syphilis: a retrospective analysis of 12 cases and a
review of the literature. Oral Dis 2013; 19:738.
Long FQ, et al: Acquired secondary syphilis in preschool children by
nonsexual close contact. Sex Transm Dis 2012; 39:588.
Marra C, et al: Normalization of serum rapid plasma reagin titer predicts
normalization of cerebrospinal fluid and clinical abnormalities after
treatment of neurosyphilis. Clin Infect Dis 2008; 47:893.
McComb ME, et al: Secondary syphilis presenting as pseudolymphoma
of the skin. J Am Acad Dermatol 2003; 49:S174.
Mignogna MD, et al: Secondary syphilis mimicking pemphigus vulgaris.
J Eur Acad Dermatol Venereol 2008; 23:479.
Miller WM, et al: Jarisch-Herxheimer reaction among syphilis patients in
Rio de Janeiro, Brazil. Int J STD AIDS 2010; 21:806.
Monastirli A, et al: Lichen planus–like secondary syphilis in an
83-year-old woman. Clin Exp Dermatol 2008; 33:780.
Morshed MG, Singh AE: Recent trends in the serologic diagnosis of
syphilis. Clin Vaccine Immunol [Epub ahead of print.]
Oanţă A, Irimie M: Syphilitic balanitis of Follman. Int J Dermatol 2013;
53:830.
Parker SR, et al: Seronegative syphilis: another case for the great
imitator. Int J Infect Dis 2014; 18:104.
Pastuszczak M, Wojas-Pelc A: Current standards for diagnosis and
treatment of syphilis: selection of some practical issues, based on the
European (IUSTI) and U.S. (CDC) guidelines. Postepy Dermatol Alergol
2013; 30:203.
Patel SJ, et al: Missed opportunities for preventing congenital syphilis
infection in New York City, Obstet Gynecol 2012; 120:882.
Pinto-Almeida T, et al: Secondary syphilis on a psoriatic patient under
cyclosporine: a challenging case. Int J Dermatol 2014; 53:e35.
Pintye J, et al: Association between male circumcision and incidence of
syphilis in men and women: a prospective study in HIV-1
serodiscordant heterosexual African couples. Lancet Glob Health
2014; 2:e664.
Punia V, et al: Stroke after initiating IV penicillin for neurosyphilis: a
possible Jarisch-Herxheimer reaction. Case Rep Neurol Med 2014;
2014:548179.
Qiao J, Fang H: Syphilitic chancre of the mouth. CMAJ 2011;
183:2015.
Qiao J, Fang H: Moth-eaten alopecia: a sign of secondary syphilis.
CMAJ 2013; 185:61.
Rajan J, et al: Malignant syphilis with human immunodeficiency virus
infection. Indian Dermatol Online J 2011; 2:19.
Rallis E, Paparizos V: Malignant syphilis as the first manifestation of HIV
infection. Infect Dis Rep 2012; 4:e15.
Rodriguez-Caruncho C, et al: Picture of the Mont—quiz case: early
congenital syphilis. Arch Pediatr Adolesc Med 2012; 166:767.
Rodriguez-Cerdeira C, et al: Congenital syphilis in the 21st century. Actas
Dermosifilogr 2012; 103:679.
Rysgaard C, et al: Nodular secondary syphilis with associated
granulomatous inflammation: case report and literature review. J Cutan
Pathol 2014; 41:370.
Schotanus M, et al: A patient with multifocal tabetic arthropathy: a case
report and review of the literature. Sex Transm Dis 2013; 40:251.
Sezer E, et al: Secondary syphilis with an interstitial granuloma
annulare–like histopathologic pattern. J Cutan Pathol 2011; 38:439.
Shockman S, et al: Syphilis in the United States. Clin Dermatol 2014;
32:213.
Simms I, Broutet N: Congenital syphilis re-emerging. J Dtsch Dermatol
Ges 2008; 6:269.
355
 Ŝ majs D, et al: Genetic diversity in Treponema pallidum: implications for Yaws (pian, frambesia, bouba)
18 pathogenesis, evolution and molecular diagnostics of syphilis and
yaws. Infect Genet Evol 2012; 12:191. aws is caused by reponema palli um subsp. pertenue t is
Streit E, et al: Solitary lesion on finger. Primary syphilitic lesion on finger. transmitted nonse ually by contact with in ectious lesions.
Acta Derm Venereol 2013; 93:251.
aws predominantly a ects children younger than years.
Syphilis, Yaws, Bejel, and Pinta

Tipple C, Taylor GP: Syphilis testing, typing, and treatment follow-up: a

new era for an old disease. Curr Opin Infect Dis [Epub ahead of print.]
Tucker JD, et al: An expanding syphilis epidemic in China:
epidemiology, behavioral risk and control strategies with a focus on
low-tier female sex workers and men who have sex with men. Sex
Transm Infect 2011; 87:ii16.
Unemo M, Janier M: The 2014 European guideline on the management
of syphilis has now been published. Euro Surveill 2014; 19:42.
Vasconcelos P, et al: Secondary syphilis mimicking inflammatory bowel
disease. Sex Transm Infect 2013; 89:98.
Veraldi S, et al: Multiple aphthoid syphilitic chancres of the oral cavity.
Int J STD AIDS 2008; 19:486.
Vinay K, et al: Malignant syphilis. Int J Infect Dis 2013; 17:e930.
Wang H, et al: A case of lues maligna in an AIDS patient. Int J STD
AIDS 2012; 23:599.
Wendel GD, et al: Treatment of syphilis in pregnancy and prevention of
congenital syphilis. Clin Infect Dis 2002; 35:S200.
Yayli S, et al: Late secondary syphilis with nodular lesions mimicking
Kaposi sarcoma in a patient with human immunodeficiency virus. Int J
Dermatol 2014; 53:e71.
Zhang HL, et al: Clinical spectrum of neurosyphilis among HIV-negative
patients in the modern area. Dermatology 2013; 226:148.
Zheng S, et al: Primary syphilis presenting as bilateral nipple-areola
eczematoid lesions. Acta Derm Venereol 2014; 94:617.
NONVENEREAL TREPONEMATOSES: YAWS,
ENDEMIC SYPHILIS, AND PINTA
This group o diseases is called the endemic or non enereal
treponematoses. They share many epidemiologic and patho
logic eatures. As with enereal syphilis the clinical mani esta
tions are di ided into early and late stages. arly disease is
considered in ectious and lasts or appro imately years.
There are periods o latency. The histology is similar in all the
diseases and resembles enereal syphilis. Cutaneous mani es
tations are prominent. The bones and mucosa may also be
in ol ed in some cases (e cept in pinta). Cardio ascular and
ner ous system in ol ement and congenital disease are not
seen. Children younger than years are primarily a ected.
Person to person contact or sharing o a drin ing essel is the
mode o transmission.
The endemic treponematoses are closely related to po erty
and a lac o a ailable health ser ices. They are described as
occurring where the road ends. These diseases tend to occur
in the tropics especially yaws and the wearing o ew clothes
and a hot humid climate are associated with higher pre a
lence. n endemic areas as hygiene impro es attenuated
orms o yaws and endemic syphilis appear. A larger percent
age o the population is latently in ected and secondary
lesions are ewer in number drier and limited to moist s in
olds. nstead o se eral crops o eruptions lasting months
to years in ected persons ha e only a single crop. Transmis
sion is thus reduced although a large percentage o the popu
lation may be in ected.
aws has been eradicated rom many pre iously endemic
areas and the number o cases currently is less than o that
years ago. n ortunately yaws is still ocally endemic in
A rica (especially among the pygmies) ndonesia Timor
Leste Papua ew Guinea the Solomon slands and Vanuatu.
The disco ery o treponemal in ection with a high genetic
similarity to yaws in mon eys in A rica suggests a possible
animal reser oir or this in ection urther complicating eradi
cation e orts.
356
The disease has a disabling course a ecting the s in bones
and oints and is di ided into early (primary and secondary)
and late (tertiary) disease.
Early yaws
A primary papule or group o papules appears at the site o
inoculation a ter an incubation period o about wee s (
days to months) during which there may be headache
malaise and other mild constitutional symptoms. The initial
lesion becomes crusted and larger ( cm) and is nown as
the mother yaw (maman pian). The crusts are amber yellow.
They may be noc ed o orming an ulcer with a red pulpy
granulated sur ace but uic ly re orm so that the typical
yaws lesion is crusted. The lesion is not indurated. There may
be some regional adenopathy.
posed parts are most re uently in ol ed the e tremi
ties particularly the lower legs eet buttoc s and ace
although the mother s breasts and trun may be in ected
by her child. The lesion is almost always e tragenital and
when genital is a result o accidental contact rather than inter
course. A ter being present or about months the mother
yaw spontaneously disappears lea ing slight atrophy and
depigmentation.
Wee s or months a ter the primary lesion appears second
ary yaws de elops. Secondary lesions resemble the mother
yaw but they are smaller and may appear around the primary
lesions or in a generali ed pattern. The secondary lesions may
clear centrally and coalesce peripherally orming annular
lesions (ringworm yaws or tinea yaws) ( ig. ). The palms
and soles may be in ol ed resembling secondary syphilis. n
some sites especially around the body ori ces and in the
armpits groins and gluteal crease condylomatous lesions
may arise resembling condyloma latum o secondary syphilis.
n drier endemic regions and during drier seasons lesions
tend to be ewer less papillomatous and more scaly and
instead o being generali ed a or the olds o the a illae
groin and oral ca ity. aws in the dry seasons and dry geo
graphic areas closely resembles endemic syphilis. The palms
and soles may de elop thic hyper eratotic pla ues that
ssure. They are pain ul resulting in a crabli e gait (crab
yaws). At times there is paronychia. Generali ed lymphade
nopathy arthralgias headaches and malaise are common.
Fig. 18-14 Yaws, secondary lesions.

tahir99 - UnitedVRG
With impro ed nutrition and hygiene an attenuated orm
with only scattered at gray lesions in intertriginous areas
has been described.
er a ew wee s or months the secondary lesions may
undergo spontaneous in olution lea ing either no s in
changes or hypopigmented macules that later become hyper
pigmented. owe er the eruption may persist or many
months as a result o resh recurrent outbrea s. The course is
slower in adults than in children in whom the secondary
period rarely lasts longer than months. During latency s in
lesions may relapse or as long as years. Pain ul osteoperi
ostitis and polydactylitis may present in early yaws as usi
orm swelling o the hands eet arms and legs.
Late yaws
The disease usually terminates with the secondary stage but
in about o patients it progresses to the late stage usually
years a ter initial in ection. The typical late yaws s in
lesions are gummas that present as indolent ulcers with
clean cut or undermined edges. They tend to use and orm
con gurate and occasionally serpiginous patterns clinically
indistinguishable rom those o tertiary syphilis. n healing
these lesions scar leading to contractures and de ormities.
yper eratotic palmoplantar pla ues and eratoderma re
uently recur in the late stage.
Similar processes may occur in the s eletal system and other
deep structures leading to pain ul nodes on the bones or
destruction o the palate and nasal bone (gangosa). There may
be periostitis particularly o the tibia (saber shin saber tibia)
epiphysitis chronic syno itis and u ta articular nodules.
Goundou is a rare proli erati e osteitis initially a ecting the
nasal aspects o the ma illa. Two large hard tumors orm on
the lateral aspects o the nose. These can signi cantly obstruct
ision. The process may e tend into other bones o the central
ace a ecting the palate and nose and resulting in protrusion
o the whole central ace as a mass. Although yaws is classi
cally thought to spare the eye and ner ous system abnormal
CS ndings in early yaws and scattered reports o eye and
neurologic ndings in patients with late yaws suggest that
yaws li e syphilis has the potential to cause neurologic or
ophthalmic se uelae although rarely.
Histopathology
arly yaws shows epidermal edema acanthosis papillomato
sis neutrophilic intraepidermal microabscesses and a moder
ate to dense peri ascular in ltrate o lymphocytes and plasma
cells. Treponemas are usually demonstrable in the primary
and secondary stages with the use o the same sil er stains
employed in diagnosing syphilis. Tertiary yaws shows ea
tures identical to the gumma o tertiary syphilis.
Diagnosis
The diagnosis should be suspected rom the typical clinical
appearance in a person li ing in an endemic region. The pres
ence o eratoderma palmaris et plantaris in such a person is
highly suggesti e o yaws. Dar eld demonstration o spiro
chetes in the early lesions and a reacti e VDRL or RPR test can
be used to con rm primary and secondary yaws.
Endemic syphilis (bejel)
Be el is a Bedouin term or this non enereal treponematosis
which occurs primarily in the seminomadic tribes who li e
in the arid regions o orth A rica Southwest Asia and the
eastern editerranean. The etiologic agent o be el is repo
nema palli um subsp. en emicum t occurs primarily in child
hood and is spread by s in contact or rom mouth to mouth
by issing or use o contaminated drin ing essels. The s in
oral mucosa and s eletal system are primarily in ol ed.
Nonvenereal treponematoses: yaws, endemic syphilis, and pinta
Primary lesions are rare probably occurring undetected in
the oropharyngeal mucosa. The most common presentation is
with secondary oral lesions resembling mucous patches. These
are shallow relati ely painless ulcerations occasionally
accompanied by laryngitis. Split papules angular cheilitis
condylomatous lesions o the moist olds o the a illae and
groin and a nonpruritic generali ed papular eruption may be
seen. Generali ed lymphadenopathy is common. steoperios
titis o the long bones may occur causing nocturnal leg
pains.
ntreated secondary be el heals in months. The tertiary
stage can occur between months and se eral years a ter the
early symptoms resol e. n the tertiary stage leg pain (perios
titis) and gummatous ulcerations o the s in nasopharyn and
bone occur. Gangosa (rhinopharyngitis mutilans) can result.
Rarely reported neurologic se uelae seem to be restricted to
the eye including u eitis choroiditis chorioretinitis and optic
atrophy. As with yaws with impro ed nutrition an attenuated
orm o endemic syphilis occurs o ten presenting with leg pain
rom periostitis. The diagnosis o be el is con rmed by the same
means as or enereal syphilis.
Pinta
Pinta is an in ectious non enereal endemic treponematosis
caused by reponema carateum. The mode o transmission is
un nown but repeated direct lesion to s in contact is li ely.
nly s in lesions occur. By contrast with yaws and be el pinta
a ects persons o all ages a oring those years old. t
was once pre alent in the orests and rural areas o Central
and South America and Cuba but it is now rarely reported.
The mani estations o pinta may be di ided into primary sec
ondary (early) and tertiary (late) stages. istorically howe er
patients may describe continuous e olution rom secondary
dyspigmented lesions to the characteristic achromic lesions o
tertiary pinta.
Primary stage
t is belie ed that the initial lesion appears days a ter
inoculation. The lesion begins as a tiny red papule that becomes
an ele ated poorly de ned erythematous in ltrated pla ue
up to . cm in diameter o er months. pansion o
the primary lesion may occur by usion with surrounding
satellite macules or papules. ltimately it becomes impossible
to distinguish the primary lesion rom the secondary lesions.
At no time is there erosion or ulceration such as occurs in the
syphilitic chancre. ost initial lesions o pinta de elop on the
legs and other unco ered parts. The RPR and VDRL tests are
nonreacti e in the primary stage. Dar eld e amination may
be positi e.
Secondary stage
The secondary stage o pinta appears months to year or
more a ter in ection. t begins with small scaling papules that
may enlarge and coalesce simulating psoriasis ringworm
ec ema syphilis or ansen s disease. The papules are located
mostly on the e tremities and ace and re uently are some
what circinate. er time the initially red to iolaceous lesions
show postin ammatory hyperpigmentation in shades o
gray blue or brown or hypopigmentation. Secondary lesions
357
 are classi ed as erythematous des uamati e hypochromic
18 or hyperchromic. ultiple di erent morphologies may be
present simultaneously gi ing a ery polymorphous appear
ance. ontreponemal tests or syphilis are reacti e in the sec
ondary stage in about o pinta patients. Dar eld
Syphilis, Yaws, Bejel, and Pinta
e amination may show spirochetes.
Late dyschromic stage
ntil the s the late pigmentary changes were the only
recogni ed clinical mani estations o pinta. These ha e an
insidious onset usually in adolescents or young adults o
widespread depigmented macules resembling itiligo. The
lesions are located chie y on the ace waistline wrist e ures
and trochanteric region although di use in ol ement may
occur so that large areas on the trun and e tremities are
a ected. The lesions are symmetric in more than one third o
patients. emipinta is a rare ariety o the disease in which
the pigmentary disturbances a ect only hal the body. n the
late dyschromic stage o pinta the serologic test or syphilis is
positi e in nearly all patients.
Histopathology
S in lesions in early pinta show moderate acanthosis; occa
sionally lichenoid changes with basal layer acuoli ation; and
an upper dermal peri ascular in ltrate o lymphocytes and
plasma cells. elanophages are prominent in the upper
dermis. Spirochetes may be demonstrated in the epidermis by
special stains in primary secondary and hyperpigmented
lesions o tertiary pinta. n tertiary pinta the depigmented s in
shows a loss o basal pigment pigmentary incontinence and
irtually no dermal in ammatory in ltrate. Spirochetes are
rarely ound in depigmented tertiary lesions.
Treatment
The treatment o choice or all endemic treponematoses is
ben athine penicillin G . . intramuscularly ( . .
or children under age ). n penicillin allergic patients
tetracycline mg our times daily or adults or erythromy
cin mg g our times daily or children or days is
recommended. Penicillin resistant yaws has been reported
rom ew Guinea. n tertiary pinta the blue color gradually
disappears as do the areas o partial depigmentation. The
itiliginous areas i present or more than years are
permanent.
radication o the endemic treponematoses is possible with
persistent and e ecti e treatment strategies including the
ollowing
. Screening o the whole population in endemic areas
. Diagnosis o patients seen at health ser ices and by
community outreach
. ealth education
. mpro ed hygiene (soap and water)
358
tahir99 - UnitedVRG
more than o the population is a ected the whole
population is treated (mass treatment). o the popula
tion is a ected treat all acti e cases all children younger
than and all contacts ( u enile mass treatment). less than
o the population is in ected treat all acti e cases and
all household and close personal contacts (selecti e mass treat
ment). n ortunately with the areas a ected by the endemic
treponematoses also struggling with epidemics o V tuber
culosis and malaria eradication programs ha e been largely
discontinued.
Asiedu K, et al: Eradication of yaws: historical efforts and achieving
WHO’s 2020 target. PLoS Negl Trop Dis 2014; 8:e3016.
Ayove T, et al: Sensitivity and specificity of a rapid point-of-care test for
active yaws: a comparative study. Lancet Glob Health 2014; 2: e415.
Fanella S, et al: Local transmission of imported endemic syphilis,
Canada, 2011. Emerg Infect Dis 2012; 18:1002.
Giacani L, Lukehart SA: The endemic treponematoses. Clin Microbiol
Rev 2014; 27:89.
Kazadi WM, et al: Epidemiology of yaws: an update. Clin Epidemiol
2014; 6:119.
Marks M, et al: Endemic treponemal diseases.Trans R Soc Trop Med
Hyg 2014; 108:601.
Marks M, et al: Yaws. Int J STD AIDS 2014 [Epub ahead of print.]
Maurice J: Neglected tropical diseases. Oral antibiotic raises hopes of
eradicating yaws. Science 2014; 344:142.
Mitja O, et al: Outcome predictors in treatment of yaws. Emerg Infect
Dis 2011; 17:1083.
Mitja O, et al: Short report: challenges in recognition and diagnosis of
yaws in children in Papua New Guinea. Am J Trop Med Hyg 2011;
85:113.
Mitja O, et al: Single-dose azithromycin versus benzathine
benzylpenicillin for treatment of yaws in children in Papua New Guinea:
an open-label, non-inferiority, randomized trial. Lancet 2012; 379:342.
Mitja O, et al: Advances in the diagnosis of endemic treponematoses:
yaws, bejel, and pinta. PLoS Negl Trop Dis 2013; 7:e2283.
Mitja O, et al: Yaws. Lancet 2013; 381:763.
Satter EK, Tokarz VA: Secondary yaws: an endemic treponemal
infection. Pediatr Dermatol 2010; 27:364.
Vabres P: Endemic treponemal infections in international adoptees and
immigrant children: how common are they? Pediatr Dermatol 2011;
28:214.
Bonus images for this chapter can be found online at
expertconsult.inkling.com
eFig. 18-1 Primary syphilis, chancre with induration and erosion.
eFig. 18-2 Primary syphilis, chancre of the upper lip.
eFig. 18-3 Primary syphilis, atypical chancres.
eFig. 18-4 Secondary syphilis.
eFig. 18-5 Secondary syphilis; late, larger lesions.
eFig. 18-6 Secondary syphilis; red, flat-topped papules of the soles.
eFig. 18-7 Secondary syphilis, psoriasiform papules.
eFig. 18-8 Alopecia of secondary syphilis.
eFig. 18-9 Condylomata of the scrotum.
eFig. 18-10 Tertiary syphilis.
eFig. 18-11 Pinta, late dyschromic stage.
eFig. 18-1 Primary
syphilis, chancre with
induration and
erosion.

Nonvenereal treponematoses: yaws, endemic syphilis, and pinta

eFig. 18-4 Secondary syphilis.

eFig. 18-5 Secondary

syphilis; late, larger
lesions.

eFig. 18-2 Primary

syphilis, chancre of
the upper lip.

eFig. 18-3 Primary

syphilis, atypical
chancres.

eFig. 18-6 Secondary syphilis; red, flat-topped papules of the soles.

358.e1
 eFig. 18-9
18 Condylomata of the
scrotum.
Syphilis, Yaws, Bejel, and Pinta

eFig. 18-7 Secondary syphilis, psoriasiform papules.

eFig. 18-8 Alopecia of

secondary syphilis.
eFig. 18-10 Tertiary syphilis.

358.e2

tahir99 - UnitedVRG
 eFig. 18-11 Pinta, late dyschromic stage.

Nonvenereal treponematoses: yaws, endemic syphilis, and pinta

358.e3
 Bonus images for this chapter can be found online at
Viruses are obligatory intracellular parasites. The structural
components o a iral particle ( irion) consist o a central core
o nucleic acid a protecti e protein coat (capsid) and (in
certain groups o iruses only) an outermost membrane or
en elope. The capsid o the simplest iruses consists o many
identical polypeptides (structural units) that old and interact
with one another to orm morphologic units (capsomeres). The
number o capsomeres is belie ed to be constant or each irus
with cubic symmetry and it is an important criterion in the
classi cation o iruses. The protein coat determines serologic
speci city protects the nucleic acid rom en ymatic degrada
tion in biologic en ironments controls host speci city and
increases the e ciency o in ection. The outermost membrane
o the en eloped iruses is essential or the attachment to and
penetration o host cells. The en elope also contains impor
tant iral antigens.
Two main groups o iruses are distinguished D A and
R A. The D A irus types are par o irus papo a irus
adeno irus herpes irus and po irus. R A iruses are
picorna irus toga irus reo irus corona irus orthomy o i
rus retro irus arena irus rhabdo irus and paramy o irus.
Some iruses are distinguished by their mode o transmission
arthropod borne iruses respiratory iruses ecal oral or
intestinal iruses enereal iruses and penetrating wound
iruses.
HERPESVIRUS GROUP
The herpes iruses are medium si ed iruses that contain
double stranded (ds) D A and replicate in the cell nucleus.
They are characteri ed by the ability to produce latent but
li elong in ection by in ecting immunologically protected cells
(immune cells and ner es). ntermittently they ha e replica
ti e episodes with ampli cation o the iral numbers in ana
tomic sites conduci e to transmission rom one host to the ne t
(genital s in orolabial region). The ast ma ority o in ected
persons remain asymptomatic. Viruses in this group are
aricella oster irus (V V; V ) herpes simple irus
types and ( SV SV ) cytomegalo irus (C V)
pstein Barr irus ( BV) human herpes iruses ( V t together as pieces o a pu le. Although the techni ue is
V V ) erpesvirus simiae (B irus) and other iruses
o animals.
Herpes simplex
n ection with SV is one o the most pre alent in ections
worldwide. SV in ection the cause o most cases o orola
bial herpes is more common than in ection with SV the
cause o most cases o genital herpes. Between and
o adults (depending on the country and group tested) are
seropositi e or SV although seropre alence o SV has
tahir99 - UnitedVRG
expertconsult.inkling.com
Viral Diseases
19
decreased by more than in the nited States among ado
lescents (age years) o er the last decade. Seropre alence
or SV is lower and it appears at the age o onset o se ual
acti ity. n Scandina ia the rate o in ection with SV
increases rom in year olds to in year olds.
About . o adults become in ected annually with SV in
their third decade o li e. n the nited States about o
adults are in ected with SV with blac men and women
twice as li ely to be SV in ected as whites. n se ually
transmitted disease (STD) clinic patients the in ection rate is
. n sub Saharan A rica in ection rates are .
Worldwide the seropre alence is higher in persons in ected
with human immunode ciency irus ( V). Serologic data
show that many more people are in ected than gi e a history
o clinical disease. or SV about o in ected persons
gi e a history o orolabial lesions. or SV o in ected
persons are completely asymptomatic (latent in ection)
ha e recurrent genital herpes they recogni e and ha e
clinical lesions that they do not recogni e as genital herpes
(subclinical or unrecogni ed in ection). ost persons with
SV in ection are symptomatic but the ma ority do not rec
ogni e that their symptoms are caused by SV. All persons
in ected with SV and SV are potentially in ectious e en
i they ha e no clinical signs or symptoms.
erpes simple in ections are classi ed as either rst
episode or recurrent. ost patients ha e no lesions or nd
ings when they are initially in ected with SV. When patients
ha e their rst clinical lesion this is usually a recurrence.
Because the initial clinical presentation is not associated with
a new in ection the pre ious terminology o primary in ec
tion has been abandoned. nstead the initial clinical presenta
tion is called a rst episode and may represent a true primary
in ection or a recurrence. Persons with chronic or acute
immunosuppression may ha e prolonged and atypical clinical
courses.
n ections with SV or SV are diagnosed by speci c
and nonspeci c methods. The most common procedure used
in the o ce is the T anc smear. t is nonspeci c because both
SV and V V in ections result in the ormation o multinucle
ate epidermal giant cells. The multiple nuclei are molded or
rapid its success depends hea ily on the s ill o the inter
preter. The accuracy rate is with a alse positi e rate
o . The direct uorescent antibody (D A) test is more
accurate and will identi y irus type; results can be a ailable
in hours i a irology laboratory is nearby. Viral culture is ery
speci c and relati ely rapid compared with serologic tests
because SV is stable in transport and grows readily and
rapidly in culture. Results are o ten a ailable in h. Poly
merase chain reaction (PCR) is as speci c as iral culture but
our times more sensiti e and can be per ormed on dried or
ed tissue. S in biopsies o lesions can detect iropathic
changes caused by SV and with speci c SV antibodies
359
 immunopero idase ( P) techni ues can accurately diagnose
19 in ection. The accuracy o arious tests depends on lesion mor
phology. nly acute esicular lesions are li ely to be positi e
with T anc smears. Crusted eroded or ulcerati e lesions
are best diagnosed by iral culture D A histologic methods
Viral Diseases
occur where er the irus was inoculated or proli erated during
the initial episode ( ig. ). Recurrences may be seen on the
chee s eyelids and earlobes. ral recurrent SV usually
a ects the eratini ed sur aces o the hard palate and attached
gingi a. utbrea s are ariable in se erity partly related to

or PCR. the trigger o the outbrea . Some outbrea s are small and
Serologic tests are generally not used in determining whether resol e rapidly whereas others may be se ere in ol ing both
a s in lesion is caused by SV in ection. A positi e serologic the upper and the lower lip. n se ere outbrea s lip swelling
test indicates only that the indi idual is in ected with that is o ten present. Patient symptomatology is ariable. A pro
irus not that the iral in ection is the cause o the current drome o up to h o tingling itching or burning may
lesion. Second generation en yme lin ed immunosorbent precede the outbrea . Local discom ort as well as headache
assay ( L SA) tests and G protein speci c Western blot sero nasal congestion or mild uli e symptoms may occur. ltra
logic tests can detect speci c in ection with SV and SV iolet ( V) e posure especially VB is a re uent trigger o
but cannot determine the duration or source o that in ection. recurrent orolabial SV and se erity o the outbrea may
n addition to determining the in ection rate in arious popu correlate with intensity o the sun e posure. Surgical and
lations serologic tests are most use ul in e aluating couples in dental procedures o the lips (or other areas pre iously a ected
which only one partner gi es a history o genital herpes (dis with SV) may trigger recurrences and a history o prior SV
cordant couples) in couples (i childbearing) at ris or neo should be solicited in all patients in whom such procedures
natal herpes in ection and or possible SV accination (when are recommended (see ne t).
a ailable). n most patients recurrent orolabial herpes represents more
o a nuisance than a disease. Because VB radiation is a
Orolabial herpes common trigger use o a sunbloc daily on the lips and acial
s in may reduce recurrences. All topical therapies or the acute
rolabial herpes is irtually always caused by SV . n
or less o newly in ected persons herpetic gingi ostomatitis
de elops mainly in children and young adults ( ig. ). The
onset is o ten accompanied by high e er regional lymphade
nopathy and malaise. The herpetic lesions in the mouth are
usually bro en esicles that appear as erosions or ulcers
co ered with a white membrane. The erosions may become
widespread on the oral mucosa tongue and tonsils and the
gingi al margin is usually eroded. erpetic gingi ostomatitis
produces pain oul breath and dysphagia. n young children
dehydration may occur. t may cause pharyngitis with ulcer
ati e or e udati e lesions o the posterior pharyn . The dura
tion untreated is wee s. the initial episode o herpetic
gingi ostomatitis or herpes labialis is so se ere that intra e
nous ( V) administration is re uired V acyclo ir mg g
three times daily is recommended. ral therapeutic options
include acyclo ir suspension mg g e times daily or
days; alacyclo ir g twice daily or days; or amciclo ir
mg twice daily or days. This therapy reduces the dura
Fig. 19-2 Orolabial, recurrent herpes simplex
tion o the illness by more than .
The most re uent clinical mani estation o orolabial herpes
is the cold sore or e er blister. Recurrent SV is the Fig. 19-3 HSV-1, eyelid
cause o or more o cases and typically presents as grouped infection from a “kiss”
blisters on an erythematous base. The lips near the ermilion from an infected adult.
are most re uently in ol ed ( ig. ) although lesions may

Fig. 19-1 Herpetic gingivostomatitis, extensive erosions of the oral

mucosa.
360
treatment o recurrent orolabial herpes ha e limited e cacy Fig. 19-4 Herpetic
reducing disease duration and pain by day or less. Tetracaine sycosis.
cream penciclo ir cream and acyclo ir cream (not ointment)
ha e some limited e cacy. Topical acyclo ir ointment and
docosanol cream pro ide minimal to no reduction in healing

Herpesvirus group
time or discom ort. The minimal bene t rom these topical
agents suggests that they should not be recommended when
patients present to dermatologists or signi cant symptomatic
orolabial herpes outbrea s. oral therapy is contemplated or
patients with se erely symptomatic recurrences o orolabial
SV it must be remembered that much higher doses o oral
anti irals are re uired than or treatment o genital herpes.
ntermittent treatment with alacyclo ir g twice daily or
day or amciclo ir . g as a single dose starting at the onset
o the prodrome are simple and e ecti e oral day regimens.
Since the patient s own in ammatory reaction against the
irus contributes substantially to the se erity o lesions o
orolabial herpes simple topical therapy with a high potency
topical corticosteroid ( uocinonide gel . three times
daily) in combination with an oral anti iral agent more rapidly
reduces pain and reduces ma imum lesion area and time to
healing. n nonimmunosuppressed patients i episodic treat
ment or orolabial SV is recommended and an oral agent is
used the addition o a high potency topical corticosteroid
should be considered.
Although most patients with orolabial herpes simple do
not re uire treatment certain medical and dental procedures
may trigger outbrea s o SV. the cutaneous sur ace has
been damaged by the surgical procedure (e.g. dermabrasion
chemical peel laser resur acing) the surgical site can be
in ected by the irus and may result in prolonged healing and
possible scarring. Prophyla is is regularly used be ore such
surgeries in patients with a history o orolabial herpes simple .
amciclo ir mg twice daily and alacyclo ir mg
twice daily or oral acyclo ir mg three times daily are
prophylactic options to be begun h be ore the procedure.
Duration o treatment in part depends on se erity o the s in
insult and rate o healing but should be at least wee and
could be as long as days. or routine surgeries at sites o
SV recurrences (upper or lower lip) acyclo ir mg e
times daily; amciclo ir mg three times daily; or alacy
clo ir g twice daily starting days be ore the procedure
and continuing or days can be considered. Prophyla is
could also be considered be ore s iing or tropical acations
Fig. 19-5 Herpes gladiatorum, cheek and neck lesions of HSV-1.
and be ore e tensi e dental procedures at the same dosages.
Reacti ation o orolabial herpes has also been associated with
hyaluronic acid ller in ections in about . o patients; and
e tensi e acial SV in ection has ollowed intense inhaled o eroded lesions will usually be positi e in the rst days
corticosteroid therapy. issing o the penis during ritual o the eruption.
Jewish circumcision can lead to penile SV in ection which
can present acutely or e en years a ter the initial e posure. Herpes gladiatorum
Some o these in ants ha e died o disseminated or central
ner ous system SV in ection. n ection with SV is highly contagious to susceptible
persons who wrestle with an in ected indi idual with an
Herpetic sycosis acti e lesion. ne third o susceptible wrestlers will become
in ected a ter a single match. n tournaments and wrestling
Recurrent or initial herpes simple in ections (usually rom camps outbrea s can be epidemic a ecting up to o all
SV ) may primarily a ect the hair ollicle. The clinical participants. Lesions usually occur on the lateral side o the
appearance may ary rom a ew eroded ollicular papules nec the side o the ace and the orearm all areas in direct
(resembling acne e cori e) to e tensi e lesions in ol ing the contact with the ace o the in ected wrestler ( ig. ). Vesi
whole beard area in men ( ig. ). Close ra or blade sha ing cles appear days a ter e posure o ten preceded by h
immediately be ore initial e posure or in the presence o an o malaise sore throat and e er. cular symptoms may
acute orolabial lesion may be associated with a more e tensi e occur. Lesions are re uently misdiagnosed as a bacterial ol
eruption. The onset may be acute (o er days) or more subacute liculitis. Any wrestler with a con rmed history o orolabial
or chronic. Diagnostic clues include the tendency or erosions herpes should be ta ing suppressi e anti iral therapy during
a sel limited course o wee s and an appropriate ris all periods o training and competition. Rugby players espe
beha ior. The diagnosis may be con rmed by biopsy. Although cially orwards who participate in scrums; mi ed martial arts
the herpes in ection is primarily in the ollicle sur ace cultures ghters; and e en bo ers are also at ris .
361

tahir99 - UnitedVRG

19
Viral Diseases
Fig. 19-6 Herpetic whitlow, classic grouped vesicles.
Herpetic whitlow
erpes simple in ection may occur in re uently on the ngers
or periungually. Lesions begin with tenderness and erythema
usually o the lateral nail old or on the palm. Deep seated
blisters de elop h a ter symptoms begin ( ig. ). The
blisters may be tiny re uiring care ul inspection to detect
them. Deep seated lesions that appear unilocular may be mis
ta en or a paronychia or other in ammatory process. Lesions
may progress to erosions or may heal without e er impairing
epidermal integrity because o the thic stratum corneum in
this location. erpetic whitlow may simulate a elon. Swelling
o the a ected hand can occur. Lymphatic strea ing and swell
ing o the epitrochlear or a illary lymph nodes may occur
mimic ing a bacterial cellulitis. Repeated episodes o herpetic
lymphangitis may lead to persistent lymphedema o the
a ected hand. erpetic whitlow has become much less
common among health care wor ers since the institution o
uni ersal precautions and glo e use during contact with the
oral mucosa. Currently most cases are seen in persons with
herpes elsewhere. Children may be in ected while thumb
suc ing or nail biting during their initial herpes outbrea or
by touching an in ectious lesion o an adult. erpetic whitlow
is bimodal in distribution with about o cases occurring
in children younger than years and o cases in adults
between ages and . Virtually all cases in children are
caused by SV and there is o ten a coe isting herpetic
gingi ostomatitis. n adults up to three uarters o cases are
caused by SV . Among adults herpetic whitlow is twice as
common in women. erpetic whitlow in health care wor ers
can be transmitted to patients. n patients whose oropharyn
is e posed to the unglo ed hands o health care wor ers with
herpetic whitlow de elop herpetic pharyngitis.
Herpetic keratoconjunctivitis
erpes simple in ection o the eye is a common cause o
blindness in the nited States. t occurs as a punctate or mar
ginal eratitis or as a dendritic corneal ulcer which may cause
disci orm eratitis and lea e scars that impair ision. Topical
corticosteroids in this situation may induce per oration o the
cornea. Vesicles may appear on the lids and preauricular
nodes may be enlarged and tender. Recurrences are common.
cular symptoms in any person with an initial outbrea o
SV could represent ocular SV and an ophthalmologic
e aluation should be per ormed to e clude this possibility.
Genital herpes
Genital herpes in ection is usually caused by SV . n the
mid s the pre alence o genital herpes caused by SV
362
began to increase because o changes in se ual habits and
decreasing pre alence o orolabial SV in ection in de el
oped nations. n women under age SV represents more
than o cases o genital herpes whereas in women o er
and in men o all ages SV remains the most common
cause o genital herpes. SV in the genital area is much less
li ely to recur. nly o patients ha e a recurrence;
when it does recur the a erage patient e periences only about
one outbrea per year.
Genital herpes is spread by s in to s in contact usually
during se ual acti ity. The incubation period a erages days.
Acti e lesions o SV contain li e irus and are in ectious.
Persons with recurrent genital herpes shed irus asymptom
atically between outbrea s (asymptomatic shedding). en
persons who are SV in ected but ha e ne er had a clinical
lesion (or symptoms) shed irus so e eryone who is SV
in ected is potentially in ectious to a se ual partner. Asymp
tomatic shedding occurs simultaneously rom se eral
anatomic sites (penis agina cer i rectum) and can occur
through normally appearing intact s in and mucosae. n addi
tion persons with SV in ection may ha e lesions they do
not recogni e as being caused by SV (unrecogni ed out
brea ) or ha e recurrent lesions that do not cause symptoms
(subclinical outbrea ). ost transmission o genital herpes
occurs during subclinical or unrecogni ed outbrea s or while
the in ected person is shedding asymptomatically.
The ris o transmission in monogamous couples in which
only one partner is in ected is about annually with
women being at much greater ris than men or ac uiring
SV rom their in ected partner. Prior SV in ection does
not reduce the ris o being in ected with SV but does
ma e it more li ely that initial in ection will be asymptomatic.
There is no strategy that absolutely pre ents herpes transmis
sion. All pre ention strategies are more e ecti e in reducing
the ris o male to emale transmission than emale to male
transmission. Condom use or all se ual e posures and a oid
ing se ual e posure when acti e lesions are present ha e been
shown to be e ecti e strategies as has chronic suppressi e
therapy o the in ected partner with alacyclo ir mg day.
The symptomatology during ac uisition o in ection with
SV has a broad clinical spectrum rom totally asymptom
atic to se ere genital ulcer disease (erosi e ul o aginitis or
proctitis). nly o new SV in ections are symptomatic.
Clinically the ma ority o symptomatic initial herpes lesions
are classic grouped blisters on an erythematous base. At
times the initial clinical episode is that o typical grouped
blisters but with a longer duration o days. Although
uncommon and representing or ewer o new in ections
se ere rst episode genital herpes can be a signi cant systemic
illness. Grouped blisters and erosions appear in the agina in
the rectum or on the penis with continued de elopment o
new blisters o er days. Lesions are bilaterally symmetric
and o ten e tensi e and the inguinal lymph nodes can be
enlarged bilaterally. e er and uli e symptoms may be
present but in women the ma or complaint is aginal pain and
dysuria (herpetic ul o aginitis). The whole illness may last
wee s or more. the inoculation occurs in the rectal area
se ere proctitis may occur rom e tensi e erosions in the anal
canal and on the rectal mucosa. The initial clinical episode o
genital herpes is treated with oral acyclo ir mg e times
or mg three times daily; amciclo ir mg three times
daily; or alacyclo ir mg twice daily all or days.
t is clinically di cult to distinguish true initial (or primary)
SV in ection rom a recurrence so all patients with their
initial clinical episode recei e the same therapy. nly serology
can determine whether the person is totally SV na e and
e periencing a true primary episode is partially immune rom
prior SV in ection or is already SV in ected with rst
clinical presentation actually a recurrence. n act
initial clinical episodes o genital herpes are actually
recurrences.
Virtually all persons in ected with SV will ha e recur
rences e en i the initial in ection was subclinical or asymp
o Recurrent genital herpes is a problematic disease because o
the associated social stigma. Because it is not curable patients
re uently ha e a signi cant emotional response when rst
diagnosed including anger (at presumed source o in ection)
depression guilt and eelings o unworthiness. During the

tomatic. SV in ection results in recurrences in the genital
area si times more re uently than SV . Twenty percent o
persons with SV in ection are truly asymptomatic ne er
ha ing had either an initial lesion or a recurrence. Twenty
percent o patients ha e lesions they recogni e as recurrent
genital herpes and ha e clinical lesions that are culture
positi e or SV but that are unrecogni ed by the patient
as being caused by genital herpes. This large group o persons
with subclinical or unrecogni ed genital herpes are in ectious
at least intermittently and represent one actor in the increas
ing number o new SV in ections.
Typical recurrent genital herpes begins with a prodrome o
burning itching or tingling. sually within h red papules
appear at the site progress to blisters lled with clear uid
o er h orm erosions o er the ne t h and heal in
another days ( ig. ). The a erage total duration o a
typical outbrea o genital herpes is days. Lesions are usually
grouped blisters and e ol e into coalescent grouped erosions
which characteristically ha e a scalloped border. rosions or
ulcerations rom genital herpes are usually ery tender and
not indurated (unli e chancre o primary syphilis). Lesions
tend to recur in the same anatomic region although not at
e actly the same site (unli e ed drug eruption). Less classic
clinical mani estations are tiny erosions or linear ssures on
the genital s in. Lesions occur on the ul a agina and cer i
cal mucosa as well as on the penile and ul al s in. The upper
buttoc is a common site or recurrent genital herpes in both
men and women. ntraurethral genital herpes may present
with dysuria and a clear penile discharge and is usually mis
diagnosed as a more common nongonococcal urethritis such
as Chlam ia or Ureaplasma in ection. nguinal adenopathy
may be present. Loo ing into the urethra and culturing any
erosions will establish the diagnosis. Recurrent genital herpes
usually heals without scarring.
The natural history o untreated recurrent genital herpes is
not well studied. er the rst ew years o in ection the
re uency o recurrences usually stays the same. er periods
longer than years the re uency o outbrea s decreases in
at least two thirds o patients treated with suppressi e anti i
ral therapy.
Fig. 19-7 Recurrent
genital herpes.
Herpesvirus group
isit the health care wor er should as about the patient s
eelings and any psychological complications. This psycho
logical component o genital herpes must be recogni ed
addressed directly with the patient and managed properly or
the therapy o recurrent genital herpes to be success ul.
anagement o recurrent genital herpes should be indi idu
ali ed. A care ul history including a se ual history should be
obtained. amination should include seeing the patient
during an acti e recurrence so that the in ection can be con
rmed. The diagnosis o recurrent genital herpes should not
be made on clinical appearance alone because o the psycho
logical impact o the diagnosis. The diagnosis is best con
rmed by a iral culture or D A e amination allowing or
typing o the causati e irus. clinical lesions are not present
serology can determine i the patient is in ected with SV .
the patient is SV seropositi e but SV seronegati e
the possibility o genital SV disease cannot be e cluded.
Treatment depends on se eral actors including the re
uency o recurrences se erity o recurrences in ection status
o the se ual partner and psychological impact o the in ection
on the patient. or patients with ew or mildly symptomatic
recurrences treatment is o ten unnecessary. Counseling
regarding transmission ris is re uired. n patients with se ere
but in re uent recurrences and in those with se ere psycho
logical complications intermittent therapy may be use ul. To
be e ecti e intermittent therapy must be initiated at the earli
est sign o an outbrea . The patient must be gi en the medica
tion be ore the recurrence so that treatment can be started by
the patient when the rst symptoms appear. ntermittent
therapy only reduces the duration o the a erage recurrence
by about day. owe er it is a power ul tool in the patient
who is totally o erwhelmed by each outbrea . The treatment
o recurrent genital herpes is acyclo ir mg e times daily
or mg twice daily or amciclo ir mg twice daily
or days. Shorter regimens that are e ually e ecti e include
alacyclo ir mg twice daily or days; acyclo ir mg
three times daily or days; or amciclo ir g twice daily
or day.
or patients with re uent recurrences (> yearly) sup
pressi e therapy may be more reasonable. Acyclo ir mg
twice daily mg three times daily or mg once daily
will suppress o recurrences and o patients will be
recurrence ree during suppressi e therapy. Valacyclo ir
mg day (or mg day or those with > recurrences
year) or amciclo ir mg twice daily is an e ually e ecti e
alternati e. p to o immunocompetent patients will
ha e signi cant recurrences on these doses and the dose o
the anti iral may need to be increased. Chronic suppressi e
therapy reduces asymptomatic shedding by almost . A ter
years o suppressi e therapy many patients can stop treat
ment with substantial reduction in re uency o recurrences.
Chronic suppressi e therapy is sa e and laboratory monitor
ing is not re uired.

Intrauterine and neonatal herpes simplex

eonatal herpes in ection occurs in to li e
births resulting in cases o neonatal herpes annu
ally in the nited States. ighty e percent o neonatal
herpes simple in ections occur at deli ery; occur in utero
with intact membranes; and occur rom nonmaternal
sources a ter deli ery. n utero in ection may result in etal
anomalies including s in lesions and scars limb hypoplasia
363

tahir99 - UnitedVRG
 microcephaly microphthalmos encephalitis chorioretinitis
19 and intracerebral calci cations. t is either atal or complicated
by permanent neurologic se uelae.
Se enty percent o neonatal herpes simple in ections are
caused by SV . eonatal SV in ections are usually
Viral Diseases
ac uired postnatally through contact with a person with oro
labial disease but can also occur intrapartum i the mother is
genitally in ected with SV . The clinical spectrum o peri
natally ac uired neonatal herpes can be di ided into the ol
lowing three orms
. Locali ed in ection o the s in eyes and or mouth
(S )
. Central ner ous system (C S) disease
. Disseminated disease (encephalitis hepatitis pneumonia
and coagulopathy).
The pattern o in ol ement at presentation is important prog
nostically. With treatment locali ed disease (s in eyes or
mouth) is rarely atal whereas brain or disseminated disease
is atal in o neonates so a ected. n treated neonates
long term se uelae occur in o in ants with locali ed
disease. ore than o patients with C S or disseminated
neonatal herpes ha e neurologic disability.
n o in ected babies s in esicles are the presenting
sign and are a good source or irus reco ery. owe er
o neonates with disseminated disease with C S disease
and with S disease ne er de elop esicular s in
lesions. Because the incubation period may be as long as
wee s and a erages about wee s in lesions and symptoms
may not appear until the child has been discharged rom the
hospital.
The diagnosis o neonatal herpes is con rmed by iral
culture or pre erably immediate D A staining o material rom
s in or ocular lesions. C S in ol ement is detected by PCR o
the cerebrospinal uid (CS ). PCR o the CS is negati e in
o neonatal C S herpes in ections so pending other
testing empiric therapy may be re uired. eonatal herpes
in ections are treated with V acyclo ir mg g day or
days or S disease and or days or C S and dissemi
nated disease.
Se enty percent o mothers o in ants with neonatal herpes
simple are asymptomatic at deli ery and ha e no history o
genital herpes. Thus e tended history ta ing is o no alue in
predicting which pregnancies may be complicated by neonatal
herpes. The most important predictors o in ection appear to
be the nature o the mother s in ection at deli ery ( rst episode
s. recurrent) and the presence o acti e lesions on the cer i
agina or ul ar area. The ris o in ection or an in ant deli
ered aginally when the mother has acti e recurrent genital
herpes in ection is whereas it is i the maternal
in ection at deli ery is a rst episode. ne strategy to pre ent
neonatal SV would be to pre ent transmission o SV to
at ris women during pregnancy eliminating initial SV epi
sodes during pregnancy. To accomplish this pregnant women
and their partners would be tested to identi y discordant
couples or SV and SV . the woman is SV negati e
and the man is SV positi e orogenital contact during preg
nancy should be a oided and a condom used or all episodes
o se ual contact. Valacyclo ir suppression o the in ected
male could also be considered but might ha e limited e cacy.
the woman is SV seronegati e and her partner is SV
seropositi e barrier protection or se ual contact during
gestation is recommended and alacyclo ir suppression o
the man could be considered. Abstinence rom intercourse
during the third trimester would also reduce the chances o an
at ris mother ac uiring genital herpes that might rst present
perinatally. These strategies ha e not been tested and could
not be guaranteed to pre ent all cases o neonatal SV. At a
364
Fig. 19-8 Neonatal herpes; a scalp monitor was associated with
infection of this infant.
minimum discordant couples should be in ormed o the
increased ris to the etus rom the mother s ac uisition o
SV during pregnancy.
The appropriate management o pregnancies complicated
by genital herpes is comple and still contro ersial. Routine
prenatal cultures are not recommended or women with recur
rent genital herpes because they do not predict shedding at
deli ery. Such cultures may be o alue in women with
primary genital herpes during pregnancy. Scalp electrodes
should be a oided in deli eries where cer ical shedding o
SV is possible; they can increase the ris o neonatal in ection
by up to se en old ( ig. ). Vacuum assisted deli ery also
increases the relati e ris o neonatal transmission o SV
times. Genital SV in ection appears to be much more
re uently transmitted intrapartum than SV . The current
recommendation is still to per orm cesarean section in the
mother with acti e genital lesions or prodromal symptoms.
This will reduce the ris o transmission o SV to the in ant
rom to or women who are culture positi e rom the
cer i at deli ery. owe er this approach will not pre ent all
cases o neonatal herpes is e pensi e and has a high maternal
morbidity ( S . million to pre ent each case o neonatal
herpes e cess cesarean sections or e ery poor outcome
case o neonatal SV pre ented and . maternal deaths or
e ery neonatal death pre ented.) Because the ris o neonatal
herpes is much greater in mothers who e perience their initial
episode during pregnancy anti iral treatment o all initial
episodes o genital SV in pregnancy is recommended (e cept
in the rst month o gestation when there may be an increased
ris o spontaneous abortion). Standard acyclo ir doses or
initial episodes mg three times daily or days are rec
ommended. This is especially true or all initial episodes in the
third trimester. Chronic suppressi e therapy with acyclo ir
has been used rom wee s gestation to deli ery in women
with an initial episode o genital SV during pregnancy to
reduce outbrea s and pre ent the need or cesarean section.
This approach has been recommended by the American
College o bstetrics and Gynecology and may also be consid
ered or women with recurrent genital herpes.
The condition o e tensi e congenital erosions and esicles
healing with reticulate scarring may represent intrauterine
neonatal herpes simple ( ig. ). The condition is rare
because intrauterine SV in ection is rare and usually atal.
Probably only a ew children sur i e to present later in li e
with the characteristic widespread reticulate scarring o the
whole body. This may e plain the associated C S mani esta
tions seen in many a ected children. ne author treated a
child with this condition who de eloped in re uent wide
 Fig. 19-9 Extensive
congenital erosions
and vesicles healing
with reticulate scarring
(erosion on arm was
culture positive for
HSV-1).
spread cutaneous blisters rom which SV could be cultured.
odern obstetric practices which screen or herpes in preg
nant women and prophylactic treatment with acyclo ir in the
third trimester may pre ent the condition e plaining the lac
o recent cases.
Eczema herpeticum (Kaposi varicelliform eruption)
n ection with herpes irus in patients with atopic dermatitis
(AD) may result in spread o herpes simple throughout the
ec ematous areas called ec ema herpeticum ( ) or aposi
aricelli orm eruption ( V ). n a large series de elopment o
was associated with more se ere AD higher g le els
ele ated eosinophil count ood and en ironmental allergies
(as de ned by radioallergosorbent testing RAST ) and onset
o AD be ore age years. patients are also more li ely to
ha e Staph lococcus aureus and molluscum contagiosum in ec
tions. All these eatures identi y AD patients who ha e signi
cant T helper type cell (Th ) shi t o their immune system.
The use o topical calcineurin inhibitors (TC s) has been
repeatedly associated with de elopment. Bath or hot tub
e posure has been reported as a ris actor. The Th shi t
o the immune system and TC s are both associated with a
decrease in antimicrobial peptides in the epidermis an impor
tant de ense against cutaneous SV in ection. ncreased
interleu in ( L ) producing proin ammatory monocytes
lead to local e pansion o regulatory T cells and may contrib
ute to the de elopment o . LA B and local L e pres
sion are also associated with . n Japan polymorphisms in
the gene or L are associated with complicating TC
treatment. The repair o the epidermal lipid barrier with physi
ologic lipid mi tures re erses some o the negati e e ects o
the TC s and may reduce the ris o . decreases to pretreatment le els. ral anti irals pre ent this
Cutaneous dissemination o SV or SV may also occur
in se ere seborrheic dermatitis scabies Darier s disease
benign amilial pemphigus pemphigus ( oliaceus or ulgaris)
pemphigoid cutaneous T cell lymphoma Wis ott Aldrich
syndrome allergic and photoallergic contact dermatitis and
burns. n its se erest orm hundreds o umbilicated esicles
may be present at the onset with e er and regional adenopa
thy. Although the cutaneous eruption is alarming the disease
is o ten sel limited in healthy indi iduals. uch milder cases
are considerably more common and probably go unrecog
ni ed and untreated. They present as a ew super cial erosions
or e en small papules ( ig. ). n patients with systemic
immunosuppression in addition to an impaired barrier such
tahir99 - UnitedVRG
Herpesvirus group
Fig. 19-10 Eczema herpeticum, sudden appearance of uniform
erosions, accentuated in areas of active dermatitis.
as patients with pemphigus and cutaneous T cell lymphoma
V can be atal usually rom S aureus septicemia but also
rom isceral dissemination o herpes simple .
Psoriasis patients treated with immunosuppressi es may
de elop V as well although this is less common. t usually
occurs in the setting o worsening disease or erythroderma.
Patients present with erosi e lesions in the a illa and erosions
o the psoriatic pla ues. Lesions e tend cephalad to caudad
and the de elopment o large ulcerated pain ul pla ues can
occur. The lesions are o ten coin ected with bacteria and yeast.
Cultures positi e or other pathogens do not e clude the diag
nosis o V and speci c iral culture D A and biopsy
should be done i diagnosis o V is suspected. Gi en the
limited to icity o systemic anti iral therapy treatment should
be started immediately pending the return o laboratory con
rmation. Depending on the se erity o the disease either V
or oral anti iral therapy should be gi en or V patients.
Immunocompromised patients
n patients with suppression o the cell mediated immune
system by cytoto ic agents corticosteroids or congenital or
ac uired immunode ciency primary and recurrent cases o
herpes simple are more se ere persistent and symptomatic
and more resistant to therapy. n some settings such as in bone
marrow transplant recipients the ris o se ere reacti ation is
so high that prophylactic systemic anti irals are administered.
n immunosuppressed patients any erosi e mucocutaneous
lesion should be considered to be herpes simple until pro ed
otherwise especially lesions in the genital and orolabial
regions. Atypical morphologies are also seen. SV reacti a
tion is common with institution o e ecti e antiretro iral
therapy and can be part o the immune reconstitution in am
matory syndrome ( R S). A ter months SV shedding
reacti ation and can be considered in the V in ected patient
who will recei e antiretro iral therapy
Typically lesions appear as erosions or crusts ( ig. ).
The early esicular lesions may be transient or ne er seen. The
three clinical hallmar s o SV in ection are pain an acti e
esicular border and a scalloped periphery. ntreated erosi e
lesions may gradually e pand but they may also remain ed
and e en become papular or egetati e mimic ing a wart or
granulation tissue. n the oral mucosa numerous erosions may
be seen in ol ing all sur aces unli e the hard eratini ed
sur aces usually in ol ed by recurrent oral herpes simple in
the immunocompetent host. The tongue may be a ected with
geometric ssures on the central dorsal sur ace ( ig. ).
365
 Fig. 19-11 Herpes
19 simplex, HSV-2, in
patient receiving
chronic prednisone
therapy.
Viral Diseases
Fig. 19-12
Immunocompromised
patient with tongue
ulcer and fissures
secondary to HSV.
Symptomatic stomatitis associated with cancer chemotherapy
may be caused or e acerbated by SV in ection. erpetic
whitlow presents as a pain ul paronychia that is initially esic
ular and in ol es the lateral or pro imal nail olds. ntreated
it may lead to loss o the nail plate and ulceration o a large
portion o the digit.
Despite the re uent and se ere s in in ections caused by
SV in the immunosuppressed patient isceral dissemination
is unusual. tension o oral SV into the esophagus or
trachea may de elop spontaneously or as a complication o
intubation through an in ected oropharyn . cular in ol e
ment can occur rom direct inoculation and i lesions are
present around the eye care ul ophthalmologic e aluation is
re uired.
n an immunosuppressed host most herpetic lesions are
ulcerati e and not esicular. Viral cultures ta en rom the
ulcer margin are positi e. D A testing is speci c rapid and
help ul in immunosuppressed hosts who re uire e peditious
therapeutic decision ma ing. At times these tests are negati e
but a s in biopsy will show typical herpetic changes in the
epithelium ad acent to the ulceration. an ulceration does not
respond to treatment in h and cultures are negati e a
biopsy is recommended since it may be the only techni ue
that demonstrates the associated herpes irus in ection.
Therapy o ten can be instituted on clinical grounds pending
con rmatory tests. Acyclo ir mg orally three times daily;
amciclo ir mg twice daily; or alacyclo ir g twice
daily all or a minimum o days is used. Therapy should
continue until lesions are essentially healed. n se ere in ec
tion or in the hospitali ed patient with moderate disease V
acyclo ir ( mg g) can be gi en initially to control the
366
disease. n patients with ac uired immunode ciency syn
drome (A DS) and those with persistent immunosuppression
consideration should be gi en to chronic suppressi e therapy
with acyclo ir mg two or three times daily or ala
cyclo ir or amciclo ir mg twice daily.
n the immunosuppressed host (but not in the immunocom
petent host) long term treatment with acyclo ir and its
analogs or treatment o large herpetic ulcerations may be
complicated by the de elopment o acyclo ir resistance. This
resistance may be caused by selection o acyclo ir resistant
wild type irus which is present in large numbers on the
sur ace o such large herpes lesions. n the immunocompetent
host these acyclo ir resistant mutants are ew in number and
eradicated by the host s immune system. The immunosup
pressed host has much more SV in the lesions and the host s
immune system is ine ecti e in illing the irus. These
acyclo ir resistant iral strains may be di cult to culture and
may be identi ed only by s in biopsy or PCR o the ulceration.
Anti iral resistance is suspected i ma imum oral doses o
acyclo ir alacyclo ir or amciclo ir do not lead to impro e
ment. V acyclo ir e cept i gi en by constant in usion will
also in ariably ail in such patients. Resistance to one drug is
associated with resistance to all three o these drugs usually
rom loss o the iral thymidine inase. SV isolates can be
tested or sensiti ity to acyclo ir and some other anti irals.
The standard treatment o acyclo ir resistant herpes simple
is V oscarnet. n patients intolerant o or resistant to oscar
net V cido o ir may be used. Smaller lesions can sometimes
be treated with topical tri uorothymidine (Viroptic) with or
without topical or intralesional inter eron ( ) alpha or
topical or intralesional cido o ir. mi uimod may be o bene t
in healing these lesions perhaps through acti ation o cystatin
A. Destruction o small lesions by desiccation ollowed by the
pre ious therapies may also be curati e. an V in ected
patient with pre ious acyclo ir resistant genital herpes has a
recurrence hal will be acyclo ir sensiti e so a trial o stan
dard anti irals is acceptable. an A DS patient has a nonheal
ing genital ulcer that harbors SV there may be dual in ection
with cytomegalo irus and only treatment with an agent acti e
against both SV and C V will lead to impro ement.
Histopathology
The esicles o herpes simple are intraepidermal. The a ected
epidermis and ad acent in amed dermis are in ltrated with
leu ocytes. Ballooning degeneration o the epidermal cells
produces acantholysis. The most characteristic eature is the
presence o multinucleated giant cells which tend to mold
together orming a crude igsaw pu le appearance. The steel
gray color o the nucleus and peripheral condensation o the
nucleoplasm may be clues to SV in ection e en i multinu
cleate cells are not seen. P stains can detect SV in ection e en
in para n ed tissue allowing the diagnosis to be absolutely
con rmed rom histologic material.
Differential diagnosis
erpes labialis most o ten must be di erentiated rom impe
tigo. erpetic lesions are composed o groups o tense small
esicles whereas in bullous impetigo the blisters are unilocu
lar occur at the periphery o a crust and are accid. A mi ed
in ection is not unusual and should especially be suspected in
immunosuppressed hosts and when lesions are present in the
typical herpetic regions around the mouth. erpes oster pres
ents with clusters o lesions along a dermatome but early on
i the number o oster lesions is limited it can be relati ely
indistinguishable rom herpes simple . n general herpes
oster will be more pain ul and o er hours will progress to
in ol e more o the a ected dermatome. D A testing can
rapidly ma e this distinction.
A genital herpes lesion especially on the glans or corona can
be mista en or a syphilitic chancre or chancroid. Dar eld
e amination multiple PCR and cultures or aemophilus
ucre i on selecti e media will aid in ma ing the diagnosis as
will diagnostic tests or SV (T anc culture or D A). Com
bined in ections occur in up to o patients so nding a
single pathogen may not complete the diagnostic e aluation.
erpetic gingi ostomatitis is o ten di cult to di erentiate
rom aphthosis streptococcal in ections diphtheria co sac i
e irus in ections and oral erythema multi orme. Aphthae
tend to occur mostly on the buccal and labial mucosae. They
usually orm shallow grayish erosions generally surrounded
by a prominent ring o hyperemia. Aphthae typically occur on
nonattached mucosa whereas recurrent herpes o the oral
ca ity primarily a ects the attached gingi a and palate.
Aga IE, Hollier LM: Managing genital herpes infections in pregnancy.
Womens Health (Lond) 2009; 5:165.
Bal A, et al: Fulminant hepatitis due to father-to-newborn transmission
of herpes simplex virus type 1. Open Virol J 2013; 7:96.
Beck LA, et al: Phenotype of atopic dermatitis subjects with a history of
eczema herpeticum. J Allergy Clin Immunol 2009; 124:260.
Bernstein DI, et al: Epidemiology, clinical presentation, and antibody
response to primary infection with herpes simplex virus type 1 and
type 2 in young women. Clin Infect Dis 2013; 56:344.
Bisaccia E, Scarborough D: Herpes simplex virus prophylaxis with
famciclovir in patients undergoing aesthetic facial CO2 laser
resurfacing. Cutis 2003; 72:327.
Bradley H, et al: Seroprevalence of herpes simplex virus types 1 and
2—United States, 1999–2010. J Infect Dis 2014; 209:325.
Brown ZA, et al: Effect of serologic status and cesarean delivery on
transmission rates of herpes simplex virus from mother to infant. JAMA
2003; 289:203.
Butler DF, et al: Acquired lymphedema of the hand due to herpes
simplex virus type 2. Arch Dermatol 1999; 135:1125.
Cárdenas AM, et al: Development and optimization of a real-time PCR
assay for detection of herpes simplex and varicella-zoster viruses in
skin and mucosal lesions by use of the BD Max Open System. J Clin
Microbiol 2014; 52:4375.
Centers for Disease Control and Prevention: Neonatal herpes simplex
virus infection following Jewish ritual circumcisions that included
direct orogenital suction—New York City, 2000–2011. MMWR 2012;
61:405.
Chen CY, Ballard RC: The molecular diagnosis of sexually transmitted
genital ulcer disease. Methods Mol Biol 2012; 903:103.
Chia KY, et al: A less known dermatological emergency. Ann Acad Med
Singapore 2012; 41:366.
Chosidow O, et al: Valacyclovir as a single dose during prodrome of
herpes facialis: a pilot randomized double-blind clinical trial. Br J
Dermatol 2003; 148:142.
Corey L, et al: Once-daily valacyclovir to reduce the risk of transmission
of genital herpes. N Engl J Med 2004; 354:11.
Dickson N, et al: HSV-2 incidence by sex over four age periods to age
38 in a birth cohort. Sex Transm Infect 2014; 90:243.
Elangovan S, et al: Hospital-based emergency department visits with
herpetic gingivostomatitis in the United States. Oral Surg Oral Med
Oral Pathol Oral Radiol 2012; 113:505.
Fatahzadeh M, Schwartz RA: Human herpes simplex virus infections:
epidemiology, pathogenesis, symptomatology, diagnosis, and
management. J Am Acad Dermatol 2007; 57:737.
Garceau R, et al: Herpes simplex virus type 1 is the leading cause of
genital herpes in New Brunswick. Can J Infect Dis Med Microbiol 2012;
23:15.
Garcia-Medina JJ, et al: Herpetic blepharitis and inhaled budesonide.
Ophthamology 2011; 118:2520.e5.
Gazzola R, et al: Herpes virus outbreaks after dermal hyaluronic acid
filler injections. Aesthet Surg J 2012; 32:770.
Gupta AK, et al: Extensive congenital erosions and vesicles healing with
reticulate scarring. J Am Acad Dermatol 1987; 17:369.
Hirokawa D, et al: Treatment of recalcitrant herpes simplex virus with
topical imiquimod. Cutis 2011; 88:276.
tahir99 - UnitedVRG
Hoff NP, Gerber PA: Herpetic whitlow. CMAJ 2012; 184:E924.
Hollier LM, et al: Third trimester antiviral prophylaxis for preventing
maternal genital herpes simplex virus (HSV) recurrences and
neonatal infection. Cochrane Database Syst Rev 2008;
1:CD004946.
Herpesvirus group
Johansson AB, et al: Lower-limb hypoplasia due to intrauterine infection
with herpes simplex virus type 2: possible confusion with intrauterine
varicella-zoster syndrome. Clin Infect Dis 2004; 38:e57.
Jones CA, et al: Antiviral agents for treatment of herpes simplex virus
infection in neonates. Cochrane Database Syst Rev 2009;
3:CD004206.
Kan Y, et al: Imiquimod suppresses propagation of herpes simplex virus
1 by upregulation of cystatin A via the adenosine receptor A1 pathway,
J Virol 2012; 86:10338.
Karpathios T, et al: HSV-2 meningitis disseminated from a herpetic
whitlow. Paediatr Int Child Health 2012; 32:121.
Kim BE, et al: IL-25 enhances HSV-1 replication by inhibiting filaggrin
expression, and acts synergistically with Th2 cytokines to enhance
HSV-1 replication. J Invest Dermatol 2013; 133:2678.
Kim M, et al: Topical calcineurin inhibitors compromise stratum
corneum integrity, epidermal permeability and antimicrobial barrier
function. Exp Dermatol 2010; 19:501.
Kimberlin DW: The scarlet H. J Infect Dis 2014; 209:315.
Kohelet D, et al: Herpes simplex virus infection after vacuum-assisted
vaginally delivered infants of asymptomatic mothers. J Perinatol 2004;
24:147.
Kortekangas-Savolainen O, et al: Epidemiology of genital herpes simplex
virus type 1 and 2 infections in southwestern Finland during a 10-year
period (2003–2012). Sex Transm Dis 2014; 41:268.
Kotzbauer D, et al: Clinical and laboratory characteristics of central
nervous system herpes simplex virus infection in neonates and young
infants. Pediatr Infect Dis J 2014; 33:1187.
Lanzafame M, et al: Unusual, rapidly growing ulcerative genital mass
due to herpes simplex virus in a human immunodeficiency virus–
infected woman. Br J Dermatol 2003; 149:193.
Lautenschlager S, Eichmann A: Urethritis: an underestimated clinical
variant of genital herpes in men? J Am Acad Dermatol 2002;
46:307.
Leung DY: Why is eczema herpeticum unexpectedly rare? Antiviral Res
2013; 98:153.
Lubbe J, et al: Adults with atopic dermatitis and herpes simplex and
topical therapy with tacrolimus: what kind of prevention? Arch
Dermatol 2003; 139:670.
Mathais RA, et al: Atopic dermatitis complicated by eczema herpeticum
is associated with HLA B7 and reduced interferon-γ-producing CD8+ T
cells. Br J Dermatol 2013; 169:700.
McKeough MB, Spruance SL: Comparison of new topical treatments for
herpes labialis: efficacy of penciclovir cream, acyclovir cream, and
n-docosanol cream against experimental cutaneous herpes simplex
virus type 1 infection. Arch Dermatol 2001; 137:1153.
Money D, et al: Guideline for the management of herpes simplex virus
in pregnancy. J Obstet Gynaecol 2008; 208:518.
Muluneh B, et al: Successful clearance of cutaneous acyclovir-resistant,
foscarnet-refractory herpes virus lesions with topical cidofovir in an
allogeneic hematopoietic stem cell transplant patient. J Oncol Pharm
Pract 2013; 19:181.
Osawa K, et al: Relationship between Kaposi’s varicelliform eruption in
Japanese patients with atopic dermatitis treated with tacrolimus
ointment and genetic polymorphisms in the IL-19 gene promoter
region. J Dermatol 2007; 34:531.
Pichler M, et al: Premature newborns with fatal intrauterine herpes
simplex virus-1 infection: first report of twins and review of the
literature. J Eur Acad Dermatol Venereol 2014 [Epub ahead of print.]
Robinson JL, et al: Prevention, recognition and management of neonatal
HSV infections. Expert Rev Anti Infect Ther 2012; 10:675.
Rojek NW, Norton SA: Diagnosis of neonatal infection with herpes
simplex virus. JAMA 2014: 311:527.
Sacks SL: Efficacy of docosanol. J Am Acad Dermatol 2003;
49:558.
Santmyire-Rosenberger BR, et al: Psoriasis herpeticum: three cases of
Kaposi’s varicelliform eruption in psoriasis. J Am Acad Dermatol 2005;
53:52.
Schoenfeld J, et al: Cutaneous co-infected cytomegalovirus and herpes
simplex virus perigenital ulcers in human immunodeficiency virus
patients. J Clin Aesthet Dermatol 2013; 6:41.
367
 Seang S, et al: Long-term follow-up of HIV-infected patients once
19 diagnosed with acyclovir-resistant herpes simplex virus infection. Int J
STD AIDS 2014; 25:676.
Shenoy R, et al: Eczema herpeticum in a wrestler. Clin J Sport Med
2014 [Epub ahead of print.]
Viral Diseases

Spruance SL, McKeough MB: Combination treatment with famciclovir

and a topical corticosteroid gel versus famciclovir alone for
experimental ultraviolet radiation–induced herpes simplex labialis:
a pilot study. J Infect Dis 2000; 181:1906.
Spruance SL, et al: Single-dose, patient-initiated famciclovir: a
randomized, double-blind, placebo-controlled trial for episodic
treatment of herpes labialis. J Am Acad Dermatol 2006; 55:47.
Takahashi R, et al: Pathological role of regulatory T cells in the initiation
and maintenance of eczema herpeticum lesions. J Immunol 2014;
192:969.
Tobian AA, et al: Reactivation of herpes simplex virus type 2 after
initiation of antiretroviral therapy. J Infect Dis 2013; 208:839.
Tuokko H, et al: Herpes simplex virus type 1 genital herpes in young
women: current trend in Northern Finland. Sex Transm Infect 2014;
90:160. Fig. 19-13 Varicella.
Walker D, et al: JAAD Grand Rounds quiz. A painful eruption in a
woman with Darier disease. J Am Acad Dermatol 2012; 67:1089.
Wanat KA, et al: Intralesional cidofovir for treating extensive genital
verrucous herpes simplex virus infection. JAMA Dermatol 2013;
149:811.
Whitley RJ: Changing epidemiology of herpes simplex virus infections.
Clin Infect Dis 2013; 56:352.
Wilson EK, et al: Cutaneous infections in wrestlers. Sports Health 2013;
5:423.
Wollenberg A, et al: Predisposing factors and clinical features of
eczema herpeticum: a retrospective analysis of 100 cases. J Am Acad
Dermatol 2003; 49:198.
Yossepowitch O, et al: Penile herpes simplex virus type 1 infection
presenting two and a half years after Jewish ritual circumcision of an
infant. Sex Transm Dis 2013; 40:516.

Varicella
Varicella commonly nown as chic enpo is the primary
in ection with the aricella oster irus. n temperate regions
o cases occur in children younger than years with the Fig. 19-14 Varicella with bullous impetigo as a complication.
highest age speci c incidence in ages in un accinated chil
dren. ore than o adults in temperate countries ha e
e idence o prior in ection and are immune to aricella. n Varicella is characteri ed by a esicular eruption consisting
tropical countries howe er aricella tends to be a disease o o delicate teardrop esicles on an erythematous base ( ig.
teenagers and only o adults are immune serologically. ). The eruption starts with aint macules that de elop
utbrea s among non .S. born crew members ha e occurred rapidly into esicles within h. Successi e resh crops o
on cruise ships. esicles appear or a ew days mainly on the trun ace and
The incubation period o V V is days usually oral mucosa. nitially the e anthem may be limited to sun
days. Transmission is by the respiratory route and less e posed areas the diaper area o in ants or sites o in amma
o ten by direct contact with the lesions. A susceptible person tion. The esicles uic ly become pustular and umbilicated
may de elop aricella a ter e posure to the lesions o herpes then crusted. Since the lesions appear in crops lesions o
oster. n ected persons are in ectious rom days be ore the arious stages are present at the same time a use ul clue to
eruption appears and are most in ectious days be ore the the diagnosis. Lesions tend not to scar but larger lesions and
rash appears. n ecti ity usually ceases days a ter the erup those that become secondarily in ected may heal with a char
tion appears. There is an initial iral replication in the naso acteristic round depressed scar.
pharyn and con uncti a ollowed by iremia and in ection Secondary bacterial in ection with Staph lococcus aureus or a
o the reticuloendothelial system (li er spleen) between days streptococcus is the most common complication o aricella
and . A secondary iremia occurs at days resulting ( ig. ). Rarely it may be complicated by osteomyelitis
in in ection o the epidermis and the appearance o the char other deep seated in ections or septicemia. ther complica
acteristic s in lesions. Low grade e er malaise and headache tions are rarer. Pneumonia is uncommon in normal children
are usually present but slight. The se erity o the disease is age but is seen in in adults with aricella. t may be bacterial
dependent with adults ha ing more se ere disease and a or caused by V V a di cult di erential diagnosis. Cerebellar
greater ris o isceral disease. n healthy children mortality ata ia and encephalitis are the most common neurologic com
rom aricella is . in cases; in adults . in plications. Asymptomatic myocarditis and hepatitis may occur
cases. Pregnant women ha e e times greater ris o an in children with aricella but rarely are signi cant and resol e
ad erse outcome. As with most iral in ections immunosup spontaneously with no treatment. Reye syndrome with hepa
pression may worsen the course o the disease. Li elong immu titis and acute encephalopathy is associated with the use o
nity ollows aricella and second episodes o aricella aspirin to treat the symptoms o aricella. Aspirin is absolutely
indicate either immunosuppression or another iral in ection contraindicated in patients with aricella. Any child with ari
such as co sac ie irus. cella and se ere omiting should be re erred immediately to
368
e clude Reye syndrome. Symptomatic thrombocytopenia is a
rare mani estation o aricella which can occur either with the
e anthem or se eral wee s a ter. Purpura ulminans a orm
o disseminated intra ascular coagulation associated with low
le els o proteins C and S may complicate aricella.
The diagnosis o aricella is easily made clinically. T anc
smear rom a esicle will usually show characteristic multi
nucleate giant cells. needed the most use ul clinical test is
D A which is rapid and will both con rm the in ection and
type the irus. V V grows poorly and slowly in the labora
tory so iral culture is rarely indicated.
Treatment
Both immunocompetent children and adults with aricella
bene t rom acyclo ir therapy i started early within ho
the eruption s appearance. Therapy does not seem to alter the
de elopment o ade uate immunity to rein ection. Because the
complications o aricella are in re uent in children routine
treatment is not recommended; therapeutic decisions are
made on a case by case basis. Acyclo ir therapy appears
mainly to bene t secondary cases within a household which
tend to be more se ere than the inde case. n this setting
therapy can be instituted earlier. Therapy does not return chil
dren to school sooner howe er and the impact on parental
wor days missed is not nown. The dose o acyclo ir is
mg g ma imum mg per dose our times daily or
days. Aspirin and other salicylates should not be used as anti
pyretics in aricella because their use increases the ris o Reye
syndrome. Topical antipruritic lotions oatmeal baths dress
ing the patient in light cool clothing and eeping the en iron
ment cool may all relie e some o the symptomatology.
Children li ing in warm homes and ept ery warm with
clothing ha e anecdotally been obser ed to ha e more numer
ous s in lesions. Children with AD Darier s disease congeni
tal ichthyosi orm erythroderma diabetes cystic brosis
conditions re uiring chronic salicylate or steroid therapy and
inborn errors o metabolism should be treated with acyclo ir
because they may ha e more complications or e acerbations
o their underlying illness with aricella.
Varicella is more se ere and complications are more common
in adults. Between and o adults will ha e pulmonary
in ol ement. Smo ers and those with pree isting lung disease
(but not asthma) are at increased ris . The pneumonitis can
progress rapidly and be atal. Adults with aricella and at least
one other ris actor should be e aluated with physical e ami
nation pulse o imetry and chest radiography. Anti iral treat
ment is recommended in all adolescents and adults ( and
older) with aricella. The dose is mg our or e times
daily or days. Se ere ulminant cutaneous disease and is
ceral complications are treated with V acyclo ir mg g
e ery h ad usted or creatinine clearance. the patient is
hospitali ed or therapy strict isolation is re uired. Patients
with aricella should not be admitted to wards with immuno
compromised hosts or to pediatric wards but rather are best
placed on wards with healthy patients reco ering rom acute
trauma.
Pregnant women and neonates
aternal V V in ection may result in se ere illness in the
mother and i the in ection occurs be ore wee s o gesta
tion and especially be ore wee s a ris o in ection o the
etus (congenital aricella syndrome). n one study o se ere aricella is irtually
women with aricella in pregnancy de eloped aricella pneu
monia. The ris or spontaneous abortion by wee s is ; detectable antibody also ha e reduced se erity o aricella
in an additional . o pregnancies etal death occurs a ter
wee s. The ris o preterm labor as reported in arious
tahir99 - UnitedVRG
studies has aried rom no increased ris to a three old
increase. Se ere aricella and aricella pneumonia or dissemi
nated disease in pregnancy should be treated with V acyclo
ir. All aricella in pregnancy should be treated with oral
acyclo ir mg e times daily or days e cept perhaps
Herpesvirus group
during the rst month when a specialist should be consulted.
n all women past wee s o gestation or with increased ris
o premature labor admission and V acyclo ir mg g
three times daily should be recommended. The patient should
be e aluated or pneumonia renal unction should be care
ully monitored and the patient should be switched to oral
therapy once lesions stop appearing (usually in h).
Varicella oster immune globulin (V G) should not be
gi en once the pregnant woman has de eloped aricella.
V G should be gi en or signi cant e posures (see ne t
section) within the rst h to ameliorate maternal ari
cella and pre ent complications. ts use should be limited to
seronegati e women because o its cost and the high rate o
asymptomatic in ection in .S. patients. The lac o a history
o prior aricella is associated with seronegati ity in only
or ewer o the .S. population.
Congenital aricella syndrome is characteri ed by a series
o anomalies including hypoplastic limbs (usually unilateral
and lower e tremity) cutaneous scars and ocular and C S
disease. This may not be identi ed until months a ter in ec
tion. Repeated sonographic e amination can be used to
monitor at ris pregnancies. emale etuses are a ected more
o ten than males. The o erall ris or this syndrome is about
. ; the highest ris about is rom maternal aricella
between wee s and . n ection o the etus in utero may
result in oster occurring postnatally o ten in the rst years
o li e. This occurs in about o aricella complicated preg
nancies and the ris or this complication is greatest in ari
cella occurring in wee s o gestation. The alue o V G
in pre enting or modi ying etal complications o maternal
aricella is un nown. n one study howe er o patients
with aricella in pregnancy treated with V G none had com
plications o congenital aricella syndrome or in antile oster
suggesting some e cacy or V G. Although apparently sa e
in pregnancy acyclo ir s e cacy in pre enting etal complica
tions o maternal aricella is un nown.
the mother de elops aricella between days be ore and
days a ter deli ery neonatal aricella can occur and may be
se ere because o inade uate transplacental deli ery o anti
aricella antibody. These neonates de elop aricella at
days o age. n such cases administration o V G is war
ranted and V acyclo ir therapy should be considered.
Varicella vaccine
Li e attenuated iral accine or aricella is a currently recom
mended childhood immuni ation. Two doses are now recom
mended one between age and months and the second at
years. This double accination schedule is recommended
since epidemics o aricella still occurred in children ages
in well immuni ed communities suggesting a waning o
immunity by this age. Complications o aricella accination
are uncommon. A mild s in eruption rom which irus usually
cannot be isolated occurring locally at the in ection site within
days or generali ed wee s a ter immuni ation occurs in
o children. any o the brea through cases in accinated
children are mild and many reported s in lesions were not
esicular (see odi ed aricella li e syndrome). Pre ention o
e en when the accine is
gi en within h o e posure. mmuni ed children with no
a ter e posure. Secondary complications o aricella including
scarring are irtually eliminated by accination.
369
 ousehold e posure o immunosuppressed children to
19 recently immuni ed siblings does not appear to pose a
great ris . Children whose leu emia is in remission are also
protected by the accine but may re uire three doses. Leu e
mic children still recei ing chemotherapy ha e a complication
Viral Diseases
rate rom accination (usually a aricella li e eruption)
approaching . They may re uire acyclo ir therapy. npro
tected close contacts de elop aricella o the time. n
leu emic children ade uate immuni ation results in complete
immunity in some and partial immunity in the others protect
ing them rom se ere aricella. mmuni ation also reduces the
attac rate or oster in leu emic children.
Modified varicella-like syndrome
Children immuni ed with li e attenuated aricella accine
may de elop aricella o reduced se erity on e posure to
natural aricella. This has been called modi ed aricella li e
syndrome ( VLS). The re uency o VLS is between and
. per year and children with lower antibody titers are
more li ely to de elop the illness. VLS occurs an a erage o
days a ter e posure to aricella and consists primarily o
macules and papules with relati ely ew esicles. The a erage
number o lesions is about compared with natural ari
cella which usually has about lesions. The ma ority o
patients are a ebrile and the illness is mild lasting ewer than
days on a erage.
Immunocompromised patients
Varicella cases can be e tremely se ere and e en atal in
immunosuppressed patients especially in indi iduals with
impaired cell mediated immunity. Be ore e ecti e anti iral
therapy almost one third o children with cancer de eloped
complications o aricella and died. n this setting ari
cella pneumonia hepatitis and encephalitis are common.
Prior aricella does not always protect the immunosup
pressed host rom multiple episodes. The s in lesions in the
immunosuppressed host are usually identical to aricella in
the healthy host; howe er the number o lesions may be
numerous ( ig. ). n an immunosuppressed patient the
lesions more re uently become necrotic and ulceration may
occur. en i the lesions are ew the si e o the lesion may
be large up to se eral centimeters and necrosis o the ull
thic ness o the dermis may occur. n patients with V in ec
tion aricella may be se ere and atal. Atypical cases o a
ew scattered lesions without a dermatomal distribution
usually represent reacti ation disease with dissemination.
Chronic aricella may complicate V in ection resulting
in ulcerati e (ecthymatous) or hyper eratotic ( errucous)
lesions. These patterns o in ection may be associated with
acyclo ir resistance.
The degree o immunosuppression li ely to result in se ere
aricella has been debated. There are case reports o se ere
and e en atal aricella in otherwise healthy children gi en
short courses o oral corticosteroids or e en using only inhaled
corticosteroids. n a case control study howe er corticoste
roid use did not appear to be a ris actor or de elopment o
se ere aricella. n the nited ingdom ( ) any patient
recei ing or ha ing recei ed systemic corticosteroids in the
prior months regardless o dose is considered at increased
ris or se ere aricella. nhaled steroids are not considered an
indication or prophylactic V G or anti iral treatment. A
high ris or signi cant e posure is de ned as ollows
. ousehold contact (i.e. li ing in same house as a patient
with chic enpo or oster)
. ace to ace contact or at least min with a patient who
has chic enpo
370
Fig. 19-15 Varicella in
a patient with
advanced Hodgkin
disease.
. Contact indoors or more than h with a patient who has
chic enpo or herpes oster or in a hospital setting a
patient with chic enpo or herpes oster in an ad acent
bed or the same open ward
mmunosuppressed children with no prior history o ari
cella and a high ris e posure should be treated with V G as
soon as possible a ter e posure (within h). Preengra tment
bone marrow transplant patients should recei e the same
therapy. V G treatment does not reduce the re uency o
in ection but it does reduce the se erity o in ection and com
plications. The alue o prophylactic anti irals is un nown.
Parents o immunosuppressed children and their physicians
should be aware that se ere disease can occur and counseled
to return immediately a ter signi cant e posure or i aricella
de elops.
An unusual ariant o recurrent aricella is seen in elderly
patients with a history o aricella in childhood who ha e a
malignancy o the bone marrow and are recei ing chemo
therapy. They de elop a mild illness with widespread
lesions and usually no systemic ndings. This type o recur
rent aricella tends to relapse. t is di erent rom typical ari
cella because all the lesions are in a single stage o de elopment
and thus it could be easily con used with smallpo .
deally management o aricella in the immunocompro
mised patient would in ol e pre ention through aricella ac
cination be ore immunosuppression. Vaccination is sa e i the
person is more than year rom induction chemotherapy i
chemotherapy is halted about the time o accination and i
lymphocyte count is higher than mm . V acyclo ir
mg g three times daily (or mg m in children) is gi en
as soon as the diagnosis o aricella is suspected. V therapy is
continued until days a ter all new esicles ha e stopped. ral
anti irals are continued or a minimum o days o treatment.
V G is o no pro en bene t once clinical disease has de el
oped but may be gi en i the patient has li e threatening
disease and is not responding to V acyclo ir.
n V in ected adults treatment is indi iduali ed. Persons
with typical aricella should be e aluated or the presence o
pneumonia or hepatitis. Valacyclo ir g three times daily;
amciclo ir mg three times daily; or acyclo ir mg
e ery h may be used i no isceral complications are present.
Valacyclo ir and amciclo ir may be pre erable to acyclo ir
because o their enhanced oral bioa ailability. Visceral disease
mandates V therapy. the response to oral anti iral agents is
not rapid V acyclo ir therapy should be instituted. The
optimal duration o oral anti iral treatment is un nown but
must be at least until all lesions are crusted and ha e no ele
ated or acti e borders. Gi en the sa ety and e cacy o oral
anti irals treatment duration o at least days and perhaps
longer should be considered. ost cases o chronic or acyclo ir
resistant V V in ection are associated with initial inade uate
oral doses o acyclo ir (too short in duration too low a dose or
in patients with gastrointestinal G disease in whom reduced
G absorption may be associated with inade uate blood le els
o acyclo ir). Patients with atypical disseminated disease must
be treated aggressi ely until all lesions resol e. The diagnosis
o acyclo ir resistant V V in ection may be di cult. Acyclo ir
resistant V V strains may be di cult to culture and sensiti ity
testing is still not standardi ed or readily a ailable or V V.
Acyclo ir resistant aricella is treated with oscarnet or in
nonresponsi e patients with cido o ir.
Bate J, et al: Varicella postexposure prophylaxis in children with cancer:
urgent need for a randomized controlled trial. Arch Dis Child 2012;
97:853.
Baxter R, et al: Long-term effectiveness of varicella vaccine: a 14-year
prospective cohort study. Pediatrics 2013; 131:e1389.
Centers for Disease Control and Prevention: Evolution of varicella
surveillance—selected states, 2000–2010. MMWR 2012; 61:609.
Centers for Disease Control and Prevention: FDA approval of an extended
period for administering VariZIG for postexposure prophylaxis of
varicella. MMWR 2012; 61:212.
Clements DA: Modified varicella-like syndrome. Infect Dis Clin North Am
1996; 10:617.
Cramer EJ, et al: Management and control of varicella on cruise ships:
a collaborative approach to promoting public health. J Travel Med
2012; 19:226.
Creed E, et al: Varicella zoster vaccines. Dermatol Ther 2009; 22:143.
Feeney S, et al: Varicella infection and the impact of late entry into the
Irish healthcare system. J Infect Public Health 2012; 3:106.
Ferrada MA: A man with skin lesions and ataxia: a case of
disseminated varicella zoster. Int J Infect Dis 2014 [Epub ahead of
print.]
Flatt A, Breuer J: Varicella vaccines. Br Med Bull 2012; 103:115.
Gershon AA, Gershon MD: Pathogenesis and current approaches to
control of varicella-zoster virus infections. Clin Microbiol Rev 2013;
26:728.
Gnann JW: Varicella-zoster virus: prevention through vaccination. Clin
Obstet Gynecol 2012; 55:560.
Kao CM, et al: Child and adolescent immunizations: selected review of
recent U.S. recommendations and literature. Curr Opin Pediatr 2014;
26:383.
Kasper WJ, et al: Fatal varicella after a single course of corticosteroids.
Pediatr Infect Dis 1990; 9:729.
Lamont RF, et al: Varicella-zoster virus (chickenpox) infection in
pregnancy. Br J Obstet Gynecol 2011; 118:1155.
Levin MJ: Varicella-zoster virus and virus DNA in the blood and
oropharynx of people with latent or active varicella-zoster virus
infections. J Clin Virol 2014; 61:487.
Marin M, et al: Varicella prevention in the United States: a review of
successes and challenges. Pediatrics 2008; 122:e744.
Patel H, et al: Recent corticosteroid use and the risk of complicated
varicella in otherwise immunocompetent children. Arch Pediatr Adolesc
Med 1996; 150:409.
Posfay-Barbe KM, et al: Varicella-zoster immunization in pediatric liver
transplant recipients: safe and immunogenic. Am J Transplant 2012;
12:2974.
Sharma CM, Sharma D: A classical case of neonatal varicella. J Clin
Neonatol 2013; 2:200.
Shinjoh M, et al: Updated data on effective and safe immunizations with
live-attenuated vaccines for children after living donor liver
transplantation. Vaccine 2014 [Epub ahead of print.]
Souty C, et al: Vaccination against varicella as post-exposure
prophylaxis in adults: a quantitative assessment. Vaccine 2014 [Epub
ahead of print.]
tahir99 - UnitedVRG
Sugiura K, et al: Varicella zoster virus-associated generalized pustular
psoriasis in a baby with heterozygous IL36RN mutation. J Am Acad
Dermatol 2014; 71:e216.
Tongsong T, et al: Prenatal sonographic diagnosis of congenital varicella
syndrome. J Clin Ultrasound 2012; 40:176.
Herpesvirus group
Tunbridge AJ, et al: Chickenpox in adults: clinical management. J Infect
2008; 57:95.
Wilson DA, et al: Should varicella-zoster virus culture be eliminated? A
comparison of direct immunofluorescence antigen detection, culture,
and PCR with a historical review. J Clin Microbiol 2012; 50:4120.
Zampogna JC, Flowers FP: Persistent verrucous varicella as the initial
manifestation of HIV infection. J Am Acad Dermatol 2001; 44:391.
Zhang X, et al: The epidemiology and risk factors for breakthrough
varicella in Beijing Fengtai district. Vaccine 2012; 30:6186.
Zoster (shingles, herpes zoster)
oster is caused by reacti ation o V V. ollowing primary
in ection or accination V V remains latent in the sensory
dorsal root ganglion cells. The irus begins to replicate at some
later time tra eling down the sensory ner e into the s in.
mmunosuppression including use o tumor necrosis actor
inhibitors and age related de ciency o cell mediated immu
nity are the two most common causes o oster. A amily
history o oster is associated with an increased ris o de el
oping oster suggesting a genetic ris component. Patients on
hemodialysis and those with comorbidities ha e increased
ris o oster possibly related to the association between
oster ris and cholesterol le el. Statin use also slightly
increases the ris or oster. oster patients are more li ely to
be subse uently diagnosed with a malignancy especially a
lymphoid malignancy. The ris is greatest in the rst days
but persists or se eral years.
The incidence o oster increases with age. nder age the
annual incidence is less than in persons. Among patients
older than the rate is more than our times greater. or
white persons older than the li etime ris o de eloping
oster is . erall about one in three un accinated
persons will de elop herpes oster. or un nown reasons
being nonwhite reduces the ris or herpes oster with A rican
Americans our times less li ely to de elop oster. mmuno
suppression especially hematologic malignancy and V
in ection dramatically increases the ris or oster. n V
in ected patients annual incidence is in persons or an
annual ris o . With the uni ersal use o aricella accina
tion and decrease in pediatric and adolescent aricella cases
older persons will no longer ha e periodic boosts o the anti
V V immune acti ity. This could result in an increase in the
incidence o oster.
erpes oster classically occurs unilaterally within the dis
tribution o a cranial or spinal sensory ner e o ten with some
o er ow into the dermatomes abo e and below. The derma
tomes most re uently a ected are the thoracic ( ) cranial
( with the trigeminal ner e being the most common single
ner e in ol ed) lumbar ( ) and sacral ( ). The cutaneous
eruption is re uently preceded by one to se eral days o pain
in the a ected area although the pain may appear simultane
ously or e en ollowing the s in eruption or the eruption may
be painless. The eruption initially presents as papules and
pla ues o erythema in the dermatome ( ig. ). Within
hours the pla ues de elop blisters. Lesions continue to appear
or se eral days. The eruption may ha e ew lesions or reach
total con uence in the dermatome. Lesions may become hem
orrhagic necrotic or bullous. Rarely the patient may ha e
pain but no s in lesions ( oster sine herpete). Pain se erity
correlates with e tent o the s in lesions and elderly persons
tend to ha e se erer pain. n patients under age the pain
may be minimal. Scattered lesions can occur outside the der
matome usually ewer than . n the typical case new
371

19
Viral Diseases
Fig. 19-16 Herpes zoster, classic dermatomal distribution.
Fig. 19-17 Oral zoster.
esicles appear or days become pustular crust and heal.
The total duration o the eruption depends on three actors
patient age se erity o eruption and presence o underlying
immunosuppression. n younger patients the total duration is
wee s whereas in elderly patients the cutaneous lesions
o oster may re uire wee s or more to heal. Scarring is more
common in elderly and immunosuppressed patients. Scarring
also correlates with the se erity o the initial eruption. Lesions
may de elop on the mucous membranes within the mouth in
oster o the ma illary di ision ( ig. ) or mandibular
di ision o the acial ner e or in the agina with oster in the
S or S dermatome. oster may appear in recent surgical
scars and may ollow in ections o botulinum to in.
oster may rarely be seen in children under age year. This
can result rom intrauterine e posure to V V or e posure to
V V during the rst ew months o li e. The maternal antibod
ies still present result in muted e pression o aricella
subclinical or ery mild disease. The immaturity o the in ant s
immune system results in poor immune response to the in ec
tion allowing or early relapse in the orm o oster.
Disseminated herpes zoster
Disseminated herpes oster is de ned as more than lesions
outside the a ected dermatome. t occurs chie y in older or
debilitated indi iduals especially in patients with lymphore
ticular malignancy or A DS. Low le els o serum antibody
against V V are a highly signi cant ris actor in predicting
dissemination o disease. The dermatomal lesions are some
times hemorrhagic or gangrenous. The outlying esicles or
bullae which are usually not grouped resemble aricella and
372
Fig. 19-18 Herpes
zoster, involvement of
the V1 dermatome.
are o ten umbilicated and may be hemorrhagic. Visceral dis
semination to the lungs and C S may occur in the patient with
disseminated oster. Disseminated oster re uires care ul
e aluation and systemic anti iral therapy. nitially V acyclo
ir is gi en which may be changed to an oral anti iral agent
once isceral in ol ement has been e cluded and the patient
has recei ed at least days o V therapy.
Ophthalmic zoster
n herpes oster ophthalmicus the ophthalmic di ision o the
th cranial ner e is in ol ed. the e ternal di ision o the
nasociliary branch is a ected with esicles on the side and tip
o the nose ( utchinson s sign) the eye is in ol ed o the
time compared with when it is not in ol ed ( ig. ).
Vesicles on the lid margin are irtually always associated with
ocular in ol ement. n any case the patient with ophthalmic
oster should be seen by an ophthalmologist. Systemic anti i
ral therapy should be started immediately pending ophthal
mologic e aluation. cular in ol ement is most o ten in the
orm o u eitis ( ) and eratitis ( ). Less common but
more se ere complications include glaucoma optic neuritis
encephalitis hemiplegia and acute retinal necrosis. These
complications are reduced rom o patients to
with e ecti e anti iral therapy. nli e the cutaneous lesions
ocular lesions o oster and their complications tend to recur
sometimes as long as years a ter the oster episode.
Other complications
otor ner e neuropathy occurs in about o patients with
oster and is three times more common i oster is associated
with underlying malignancy. About o patients slowly
reco er lea ing with some residual motor de cit.
Thoracic oster may be associated with motor neuropathy o
the abdominal muscles resulting in a bulge on the an or
abdomen called a postherpetic pseudotumor. the sacral
dermatome S or less o ten S or S is in ol ed urinary hesi
tancy or actual urinary retention may occur. ematuria and
pyuria may also be present. The prognosis is good or com
plete reco ery. Similarly pseudo obstruction colonic spasm
dilation obstipation constipation and reduced anal sphincter
tone can occur with thoracic (T T ) lumbar or sacral oster.
Reco ery is complete. a illary and mandibular al eolar
bone necrosis may occur an a erage o days a ter oster o
the ma illary or mandibular branches o the trigeminal ner e.
Limited or widespread loss o teeth may result.
Ramsay unt syndrome results rom in ol ement o the
acial and auditory ner es by V V. erpetic in ammation o
the geniculate ganglion is thought to be the cause o this syn
drome. The presenting eatures include oster o the e ternal
ear or tympanic membrane; herpes auricularis with ipsilateral
acial paralysis; or herpes auricularis acial paralysis and
auditory symptoms. Auditory symptoms include mild to
se ere tinnitus dea ness ertigo nausea and omiting and
nystagmus.
erpes oster can be associated with delayed complications
many o which are caused by asculopathies a ecting the C S
or e en the peripheral arteries. Delayed contralateral hemipa
resis simulating cerebro ascular accident (stro e) is a rare but
serious complication o herpes oster that occurs wee s to
months (mean wee s) a ter an episode o oster a ecting the
rst branch o the trigeminal ner e. By direct e tension along
the intracranial branches o the trigeminal ner e V V gains
access to the C S and in ects the cerebral arteries. Patients
present with headache and hemiplegia. Arteriography is diag
nostic demonstrating thrombosis o the anterior or middle
cerebral artery. This orm o asculopathy can also occur ol
lowing aricella and may be the cause o up to one third o
ischemic stro es in children. The recogni ed asculopathic
complications o V V ha e been e panded to include changes
in mental status aphasia ata ia hemisensory loss and both
hemianopia and monocular isual loss. onocular ision loss
can occur up to months ollowing oster. Aneurysm sub
arachnoid or cerebral hemorrhage carotid dissection and
e en peripheral ascular disease are other recogni ed orms
o V V asculopathy. The asculopathy may be multi ocal
and in ol e both large and small arteries. n more than one
third o cases V V asculopathy occurs without a rash. ag
netic resonance imaging ( R ) is irtually always abnormal.
The diagnosis is con rmed by V V PCR and anti V V gG
antibody testing o the CS . Since this is caused by acti e iral
replication in the essels the treatment is V acyclo ir
mg g three times daily or a minimum o days. n
some patients months o oral anti irals are gi en i symptoms
are slow to resol e. A short burst o systemic corticosteroids
is also gi en in some cases.
Treatment
iddle age and elderly patients with herpes oster are urged
to restrict their physical acti ities or e en stay home in bed or
a ew days. Bed rest may be o paramount importance in the
pre ention o neuralgia. ounger patients may usually con
tinue with their customary acti ities. Local applications o
heat as with an electric heating pad or a hot water bottle are
recommended. Simple local application o gentle pressure with
the hand or with an abdominal binder o ten gi es great relie .
Anti iral therapy is the cornerstone in the management o
herpes oster. Because anti iral therapy does not reduce the
rate o oster associated pain clinicians may underappreciate
the tremendous bene t that anti irals pro ide. The main
bene t o therapy is reduction o the duration and se erity o
oster associated pain. There ore treatment in immunocom
petent patients is indicated or those at highest ris or persis
tent pain those o er age . t is also recommended to treat
all patients with pain ul or se ere oster ophthalmic oster
Ramsay unt syndrome immunosuppression cutaneous or
isceral dissemination and motor ner e in ol ement. n the
most se ere cases especially in ophthalmic oster and dis
seminated oster initial V therapy may be considered.
Therapy should be started as soon as the diagnosis is sus
pected pending laboratory con rmation. t is pre erable or
tahir99 - UnitedVRG
treatment to be instituted within the rst or days. n immu
nocompetent patients the e cacy o starting treatment beyond
this time is un nown. Treatment leads to more rapid resolu
tion o the s in lesions and most importantly substantially
decreases the duration o oster associated pain. Valacyclo ir
Herpesvirus group
mg and amciclo ir mg may be gi en three times
daily. These agents are as e ecti e as or superior to acyclo ir
mg e times daily probably because o better absorption
and the higher blood le els achie ed. Valacyclo ir and amci
clo ir are as sa e as acyclo ir and i not contraindicated are
pre erred. Side by side trials ha e demonstrated alacyclo ir
and amciclo ir to be o similar e cacy but one study rom
Japan showed amciclo ir to result in more rapid reduction in
acute oster pain.
n the immunocompetent host a total o days o treatment
has been as e ecti e as days. Valacyclo ir and amciclo ir
must be dose ad usted in patients with renal impairment. n
an elderly patient i the renal status is un nown the alacy
clo ir and amciclo ir may be started at twice daily dosing
(which is almost as e ecti e) pending e aluation o renal
unction or acyclo ir can be used. or patients with renal
ailure (creatinine clearance < mL min) acyclo ir is pre er
able. n the patient with nown or ac uired renal ailure acy
clo ir neuroto icity can occur rom V acyclo ir or oral
alacyclo ir therapy. This can present in the acute setting as
hallucinations or with prolonged ele ated blood le els disori
entation di iness loss o decorum incoherence photopho
bia di culty spea ing delirium con usion agitation and
death delusion. Because acyclo ir can reduce renal unction
the patient s baseline renal unction may ha e been normal
but high doses o acyclo ir may ha e reduced renal unction
leading to neuroto ic acyclo ir le els.
n the immunosuppressed patient an anti iral agent should
always be gi en because o the increased ris o dissemination
and oster associated complications. The doses are identical to
those used in immunocompetent hosts. mmunosuppressed
patients with ophthalmic oster disseminated oster or
Ramsay unt syndrome and those ailing oral therapy should
recei e V acyclo ir mg g three times daily ad usted or
renal unction.
Since some o the pain during acute oster (acute oster neu
ritis) may ha e an in ammatory component corticosteroids
ha e been used during the acute episode. The use o corticoste
roids in this setting is contro ersial. n selected older patients
corticosteroid use is associated with better uality o li e mea
sures reduction in time to uninterrupted sleep uic er return
to usual acti ities and reduced analgesic use. A tapering dose
o systemic corticosteroids starting at about mg g and
lasting days is ade uate to achie e these bene ts. Sys
temic corticosteroids should not be used in immunosuppressed
patients or when there is a contraindication. All actors consid
ered the bene ts o corticosteroid therapy during acute oster
appear to outweigh the ris s in treatment eligible patients.
Reduction in postherpetic neuralgia by corticosteroids has
ne er been documented despite multiple studies but this is
also true o anti iral therapy which reduces the se erity and
duration but not the pre alence o postherpetic neuralgia.
Zoster-associated pain (postherpetic neuralgia)
Pain is the most troublesome symptom o oster; o
patients o er age will ha e pain preceding the eruption
and will ha e pain with the eruption. Various terminolo
gies are used to classi y the pain. The simplest approach is to
re er to all pain occurring immediately be ore or a ter oster
as oster associated pain ( AP). Another classi cation
system separates acute pain (within rst days) subacute
pain ( days) and chronic pain (> days).
373
 Two di erent mechanisms are proposed to cause AP sen
19 siti ation and dea erentation. ociceptors (sensory ner es
mediating pain) become sensiti ed a ter in ury resulting in
ongoing discharge and hypere citability (peripheral sensiti a
tion). Prolonged discharge o the nociceptor enhances the
Viral Diseases
dorsal horn neurons to a erent stimuli and e pands the dorsal
horn neuron s recepti e eld (central sensiti ation) leading to
allodynia and hyperalgesia. n addition neural destruction
causes spontaneous acti ity in dea erented central neurons
generating constant pain. The spinal terminals o mechanore
ceptors may contact receptors ormerly occupied by C bers
leading to hyperalgesia and allodynia. The loss o unction or
death o dorsal horn neurons which ha e an inhibitory e ect
on ad acent neurons contributes to increased acti ity trans
mitted up the spinal cord. The central sensiti ation is initially
temporary (sel limited) but may become permanent.
The uality o the pain associated with herpes oster aries
but three basic types ha e been described the constant monot
onous usually burning or deep aching pain; the shooting
lancinating (neuritic) pain; and triggered pain. The last is
usually allodynia (pain with normal nonpain ul stimuli such
as light touch) or hyperalgesia (se ere pain produced by a
stimulus normally producing mild pain). The character and
uality o acute oster pain are identical to the pain that per
sists a ter the s in lesions ha e healed although these may be
mediated by di erent mechanisms.
The rate o resolution o pain a ter herpes oster is reported
o er a wide range. The ollowing data are rom a prospecti e
study and do not represent selected patients as are recruited
in drug trials or herpes oster. The tendency to ha e persistent
pain is age dependent occurring or longer than month in
only o persons under age . i ty percent o persons o er
age and o those o er continue to ha e pain beyond
month. Although the natural history is or gradual impro e
ment in persons o er age ha e some pain at months
and ha e pain at year. Se ere pain lasting longer than
year is uncommon but o persons o er ha e mild pain
and still ha e moderate pain at year.
The AP especially that o long duration is ery di cult
to manage. Ade uate medication should be pro ided to
control the pain rom the rst isit. nce established neuro
pathic pain is di cult to control. ery e ort should be made
to pre ent neuronal damage. n addition chronic pain may
lead to depression complicating pain management. Patients
with persistent moderate to se ere pain may bene t rom
re erral to a pain clinic. With this bac ground the importance
o early and ade uate anti iral therapy and pain control
cannot be o eremphasi ed.
ral anti iral agents are recommended in all patients o er
age with pain who still ha e blisters e en i the drugs are
not gi en within the rst h o the eruption. ral analgesia
should be ma imi ed using acetaminophen nonsteroidal
anti in ammatory drugs ( SA Ds) and opiate analgesia as
re uired. The combination o oral gabapentin and alacyclo
ir was reported to reduce postherpetic neuralgia (P ) but
there was no control group in this study and gabapentin
alone has not been shown to be highly e ecti e in other oster
trials. Capsaicin applied topically e ery ew hours may reduce
pain but the application itsel may cause burning and the
bene ts are modest. Local anesthetics such as lidocaine
in gel orm lidocaine prilocaine or lidocaine patches
(Lidoderm) may acutely reduce pain. These topical measures
may pro ide some short term analgesic e ect but do not
appear to ha e any long term bene t in reducing the se erity
or pre alence o AP. Patients with P ha e lower itamin
C le els than controls and itamin C supplementation intra
enously (not orally) has been associated with P reduc
tion. Sublesional anesthesia epidural bloc s (with or without
374
etamine) and sympathetic bloc s with and without cortico
steroids are reported in large series (but rarely studied in
controlled trials) to pro ide acute relie o pain. Although the
bene t o ner e bloc s in pre enting or treating persistent
AP remains to be pro ed these are a reasonable consider
ation in the acute setting i the patient is ha ing se ere pain
(unable to eat or sleep) and i oral therapy has yet to be e ec
ti e. er e bloc s may also be used in patients who ha e
ailed the standard therapies listed ne t. A transcutaneous
electrical ner e stimulation (T S) unit may be bene cial or
persistent neuralgia. Botulinum to in spread out o er
the a ected area in a chec erboard or anli e pattern with
per route has dramatically impro ed P in anecdotal
reports.
Despite this ast array o medication options P is typi
cally di cult to treat or two reasons. irst the recommended
medications are simply o ten not e ecti e. Second in elderly
patients who are most se erely a ected by P these medi
cations ha e signi cant and o ten intolerable side e ects limit
ing the dose that can be prescribed. multiple agents are
combined to reduce the to icity o any one agent their side
e ects o erlap (sedation depression constipation) and drug
drug interactions may occur limiting combination treatment
options.
Three classes o medication are used as standard therapies
to manage AP and P tricyclic antidepressants (TCAs)
antisei ure medications and long acting opiates. opiate
analgesia is re uired it should be pro ided by a long acting
agent and the duration o treatment should be limited and the
patient transitioned to another class o agent. Constipation is
a ma or side e ect in elderly persons. During pain ul oster
these patients ingest less uid and ber enhancing the consti
pating e ects o the opiates. Bul la ati es should be recom
mended. Tramadol is an option or acute pain control but
drug interactions with the TCAs must be monitored. TCAs
such as amitriptyline (or nortriptyline) and desipramine are
well tested and documented as e ecti e or the management
o P and are considered rst line agents. The TCAs are
dosed at mg night (or mg or those o er age ). The
dose is increased by the same amount nightly until pain
control is achie ed or the ma imum dose is reached. The ulti
mate dose is between and mg in a single nightly dose.
The early use o amitriptyline was able to reduce the pain
pre alence at months suggesting that early inter ention is
optimal. Venla a ine ( e or) may be used in patients who do
not tolerate TCAs at a starting dose o mg night gradually
titrated upward as re uired. Gabapentin ( eurontin) and pre
gabalin (Lyrica) ha e been documented as helping to reduce
oster associated pain. The starting dose o gabapentin is
usually mg three times daily escalating up to mg
day. A minimum total dose o mg or more is needed to
obtain optimal bene t. Pregabalin has impro ed pharmaco i
netics and is gi en at mg or mg daily depending on
renal unction with better absorption and steadier blood
le els. The anticon ulsants diphenylhydantoin carbama e
pine and alproate; neuroleptics such as chlorprothi ene and
phenothia ines; and bloc ers such as cimetidine cannot be
recommended because they ha e been not been studied criti
cally many are poorly tolerated by elderly patients and some
are associated with signi cant side e ects. the patient ails
to respond to local measures oral analgesics (including
opiates) TCAs gabapentin and enla a ine re erral to a pain
center is recommended.
Immunosuppressed patients
The use o tumor necrosis actor (T ) inhibitors increases the
ris o de elopment o oster by . times (or ). This is
signi cant enough that prophylactic immuni ation should be
considered i not contraindicated be ore a patient starts a
T inhibitor. V V immuni ation o patients already recei
ing T inhibition who ha e had prior aricella has not led
to increased oster or ad erse e ents and it has reduced the
osteri orm herpes simple can also ha e a positi e T anc
smear but the number o lesions is usually more limited
and the degree o pain substantially less than with oster.
Beyond T anc preparation D A testing is pre erred to a
iral culture because it is rapid types the irus and has a

Herpesvirus group
rate o oster with anti T therapy. This strategy should be higher yield than culture. Compared with documented V V
considered on a case by case basis perhaps in consultation in ections T anc smear was positi e (with up to
with an in ectious disease specialist. alse positi es and high ariability depending on s ill o
Patients with malignancy especially odg in disease and e aminer) and culture only positi e. PCR testing is
leu emia are e times more li ely to de elop oster than positi e. n atypical lesions biopsy may be necessary to dem
their age matched counterparts. Patients who also ha e a onstrate the typical herpes irus cytopathic e ects. P stain
higher incidence o oster include those with de cient immune tests can then be per ormed on para n ed tissue to iden
systems such as indi iduals who are immunosuppressed or ti y V V speci cally. When acyclo ir ails clinically iral
organ transplantation or by connecti e tissue disease or by culture may be attempted and acyclo ir sensiti ity testing
the agents used to treat these conditions especially corticoste per ormed. t is not as standardi ed or V V as it is or SV
roids chemotherapeutic agents cyclosporine sirolimus and and its a ailability is limited.
tacrolimus. A ter stem cell transplantation or leu emia up to
o patients will de elop herpes oster in the rst Histopathology
months (median months). The cumulati e incidence o V V
reacti ation in this group may e ceed in the rst years. As with herpes simple the esicles in oster are intraepider
Since oster is times more common in V in ected persons mal. Within and at the sides o the esicle are large swollen
the oster patient under age should be uestioned about cells called balloon cells which are degenerated cells o the
V ris actors. n pediatric patients with V in ection and spinous layer. Acidophilic inclusion bodies similar to those
in other immunosuppressed children oster may rapidly
ollow primary aricella.
The clinical appearance o oster in the immunosuppressed Fig. 19-19 Recurrent
patient is usually identical to typical oster but the lesions zoster in AIDS patient.
may be more ulcerati e and necrotic and may scar more
se erely. Dermatomal oster may appear progress to in ol e
the dermatome and persist without resolution. ultiderma
tomal oster is more common in immunosuppressed patients
including the rare ariant herpes oster duple bilateralis
with in ol ement o two di erent contralateral dermatomes.
Visceral dissemination and atal outcome are e tremely rare
in immunosuppressed patients (about . ) but cutaneous
dissemination is possible occurring in o cancer patients
especially those with hematologic malignancies. n bone
marrow transplant patients with oster de elop dissemi
nated oster and isceral dissemination. Dissemi
nated oster may be associated with the syndrome o
inappropriate antidiuretic hormone secretion (S AD ) and
present with hyponatremia abdominal pain and ileus. This
later presentation has been reported in stem cell transplant
patients. Despite treatment with V acyclo ir the S AD can
be atal. n this patient the number o s in lesions may be
small and the lesions resemble papules rather than esicles.
ortality in patients with oster who ha e undergone bone
marrow transplantation is . V V gG serostatus is deter
mined be ore transplant and all seropositi e patients recei e
prophyla is with either acyclo ir mg twice daily or ala
cyclo ir mg twice daily or year or longer i the patient
is recei ing immunosuppressi e therapy. n A DS patients
ocular and neurologic complications o herpes oster are
increased. mmunosuppressed patients o ten ha e recurrences
o oster up to in patients with A DS ( ig. ).
Two atypical patterns o oster ha e been described in A DS
patients ecthymatous lesions which are punched out ulcer
ations with a central crust and errucous lesions ( ig. ).
These patterns were not reported be ore the A DS epidemic.
Atypical clinical patterns especially the errucous pattern
may correlate with acyclo ir resistance.

Diagnosis
The same techni ues used or the diagnosis o aricella are
used to diagnose herpes oster. The clinical appearance is
o ten ade uate to suggest the diagnosis and an in o ce
T anc smear can rapidly con rm the clinical suspicion. Fig. 19-20 Verrucous zoster in AIDS patient.
375

tahir99 - UnitedVRG
 seen in SV are present in the nuclei o the cells o the esicle
19 epithelium. ultinucleated eratinocytes nuclear molding
and peripheral condensation o the nucleoplasm are character
istic and con rmatory o an in ection with either SV or V V.
n the icinity o the esicle there is mar ed intercellular and
Viral Diseases
intracellular edema. n the upper part o the dermis ascular
dilation edema and peri ascular in ltration o lymphocytes
and polymorphonuclear leu ocytes (P s) are present. Atyp
ical lymphocytes may also be ound. An underlying leu ocy
toclastic asculitis suggests V V in ection o er SV.
n ammatory and degenerati e changes are also noted in the
posterior root ganglia and in the dorsal ner e roots o the
a ected ner e. The lesions correspond to the areas o inner a
tion o the a ected ner e ganglion with necrosis o the ner e
cells.
Differential diagnosis
The distincti e clinical picture o oster permits a diagnosis
with little di culty. A unilateral pain ul eruption o grouped
esicles along a dermatome with hyperesthesia and on occa
sion regional lymph node enlargement is typical. ccasion
ally segmental cutaneous paresthesias or pain may precede
the eruption by or days. n such patients prodromal symp
toms are easily con used with the pain o angina pectoris
duodenal ulcer biliary or renal colic appendicitis pleuro
dynia or early glaucoma. The diagnosis becomes ob ious once
the cutaneous eruption appears. erpes simple and herpes
oster are con used i the lesions o SV are linear ( osteri
orm SV) or i the number o oster lesions is small and
locali ed to one site (not in ol ing whole dermatome). D A
testing or iral culture will distinguish them; D A is generally
pre erred because it is rapid and sensiti e.
Prevention of zoster
A accine using the same attenuated irus as in the aricella
accination but at much higher titers has been licensed or
the pre ention o herpes oster ( osta a ). t is recommended
in all persons years or older. This accination reduces the
incidence o oster by . n addition P was lower
in the accine recipients and duration o AP was shortened.
Burden o illness was also reduced. Those accinated between
ages and had a greater reduction in oster incidence than
those o er but in both groups P and burden o illness
were reduced similarly. Since it is a li e irus accine persons
ta ing anti iral medications must stop them hours be ore
immuni ation and not ta e them or days a ter immuni a
tion. mmunosuppressed patients can be sa ely immuni ed
ollowing speci c guidelines.
nstitutionali ed patients who de elop herpes oster are
in ectious to other patients and the health care team. Prior
immuni ation with aricella accine and ade uate serologic
titers may not pre ent ac uiring in ection especially in
immunosuppressed patients. Co ering the cutaneous lesions
speci cally with semipermeable dressings (not ust gau e ban
dages) appears to reduce transmission.
Inflammatory skin lesions after zoster infection
(isotopic response)
ollowing oster in ammatory s in lesions may rarely occur
within the a ected dermatome. Lesions usually appear within
month or rarely longer than months a ter the oster.
Clinically the lesions are usually at topped or annular
papules in the dermatome. istologically such papules most
re uently demonstrate arious patterns o granulomatous
376
Fig. 19-21 Dermatome previously affected by zoster developed a
granulomatous dermatitis histologically consistent with granuloma
annulare.
in ammation rom typical granuloma annulare to sarcoidal
reactions or e en granulomatous asculitis ( ig. ). Persis
tent iral genome has not been detected in these lesions sug
gesting that continued anti iral therapy is not indicated.
Persistent V V glycoproteins may be the triggering antigens.
Topical and intralesional therapy with corticosteroids is ben
e cial but the natural history o these lesions is generally
spontaneous resolution. Less o ten other in ammatory s in
diseases ha e been reported in areas o prior oster including
lichen planus lichen sclerosus itiligo aposi sarcoma gra t
ersus host disease (GV D) morphea and benign or e en
atypical lymphoid in ltrates. Leu emic in ltrates and lym
phomas may a ect oster scars as can metastatic carcinomas
(in ammatory oncota is) or nonmelanoma s in cancers.
Antoniou T, et al: Statins and the risk of herpes zoster: a population-
based cohort study. Clin Infect Dis 2014; 58:350.
Asahi T, et al: Valacyclovir neurotoxicity: clinical experience and review
of the literature. Eur J Neurol 2009; 16:457.
Au WY, et al: Disseminated zoster, hyponatremia, severe abdominal
pain and leukaemia relapse: recognition of a new clinical quartet after
bone marrow transplantation. Br J Dermatol 2003; 149:862.
Beal B, et al: Gabapentin for once-daily treatment of post-herpetic
neuralgia: a review. Clin Interv Aging 2012; 7:249.
Borumandi F: Jaw necrosis after herpes zoster infection due to HIV/
AIDS as underlining disease. Aust Dent J 2013; 58:539.
Breuer J: Herpes zoster: new insights provide an important wake-up
call for management of nosocomial transmission. J Infect Dis 2008;
197:635.
Breuer J, et al: Herpes zoster as a risk factor for stroke and TIA: a
retrospective cohort study in the UK. Neurology 2014; 82:206.
Castronovo C, Nikkels AF: Chronic herpes zoster duplex bilateralis. Acta
Derm Venereol 2012; 92:148.
Che H, et al: Risk of herpes/herpes zoster during anti–tumor necrosis
factor therapy in patients with rheumatoid arthritis: systematic review
and meta-analysis. Joint Bone Spine 2014; 81:215.
Chen JY, et al: Plasma vitamin C is lower in postherpetic neuralgia
patients and administration of vitamin C reduces spontaneous pain but
not brush-evoked pain. Clin J Pain 2009; 25:562.
Chen PH, et al: Herpes zoster associated voiding dysfunction: a
retrospective study and literature review. Arch Phys Med Rehabil 2002;
83:1624.
Chewrnev I: Herpes zoster duplex bilateralis. Dermatol Online J 2014;
20:3.
Chiu HY, Lin SJ: A painful bulge in the left flank. JAMA 2013; 310:639.
Chodkiewicz HM, et al: Ramsay Hunt syndrome revisited. Cutis 2013;
91:181.
Cohen JI: Strategies for zoster vaccination in immunocompromised
patients. J Infect Dis 2008; 197:S237.
Cohen JI: Herpes zoster. N Engl J Med 2013; 369:255.
Donati D, et al: Successful response on non-recovering Ramsay Hunt
syndrome to intravenous high dose methylprednisolone. J Neurol Sci
2012; 318:160.
Fett N: Gabapentin not shown to prevent postherpetic neuralgia. Arch
Dermatol 2012; 148:400.
Fleming J, et al: Varicella zoster virus brachioplexitis associated with
granulomatous vasculopathy. Clin Exp Dermatol 2013; 38:378.
Gilden D, et al: Varicella zoster virus vasculopathies: diverse clinic
manifestations, laboratory features, pathogenesis, and treatment.
Lancet 2009; 8:731.
Graber EM, et al: Two cases of herpes zoster appearing after botulinum
toxin type A injections. J Clin Aesthet Dermatol 2011; 4:49.
Green CB, Stratman EJ: Prevent rather than treat postherpetic neuralgia
by prescribing gabapentin earlier in patients with herpes zoster. Arch
Dermatol 2011; 147:908.
Gupta S, et al: Necrodestructive herpes zoster. Indian J Dermatol 2012;
57:136.
Harpaz R, et al: Prevention of herpes zoster. MMWR 2008; 57:1.
He L, et al: Corticosteroids for preventing postherpetic neuralgia.
Cochrane Library 2009; 3.
Hedge S, et al: Extensive herpes zoster involvement following
mycophenolate mofetil therapy for sarcoidosis. J Ophthalm Inflamm
Infect 2012; 2:47.
Hernandez PO, et al: Family history and herpes zoster risk in the era of
shingles vaccination. J Clin Virol 2011; 52:344.
Hui F, et al: A randomized controlled trial of a multifaceted integrated
complementary-alternative therapy for chronic herpes zoster–related
pain. Altern Med Rev 2012; 17:57.
Iglar K, et al: Herpes zoster as a marker of underlying malignancy.
Open Med 2013; 7:e68.
Izu K, et al: Herpes zoster occurring as a solitary nodule on the index
finger. Br J Dermatol 2004; 150:365.
Joesoef RM, et al: Chronic medical conditions as risk factors for herpes
zoster. Mayo Clin Proc 2012; 87:961.
Kakuta R, et al: Unusually extensive disseminated herpes zoster with
multiple ulcer formation in a methotrexate-treated rheumatoid arthritis
patient. J Dermatol 2014; 41:181.
Kanodia SK, et al: Dose-related efficacy of gabapentin in acute herpetic
neuralgia among geriatric patients. Indian J Dermatol 2012; 57:362.
Kapoor S: Vitamin C for attenuating postherpetic neuralgia pain: an
emerging treatment alternative. J Headache Pain 2012; 13:591.
Kawai K, et al: Cost-effectiveness of vaccination against herpes zoster
and postherpetic neuralgia: a critical review. Vaccine 2014; 32:1645.
Kolšek M: TENS—an alternative to antiviral drugs for acute herpes
zoster treatment and postherpetic neuralgia prevention. Swiss Med
Wkly 2012; 141:w13229.
Kuo CC, et al: Risk of herpes zoster in patients treated with long-term
hemodialysis: a matched cohort study. Am J Kidney Dis 2012; 59:428.
Kurlan JG, et al: Herpes zoster in the first year of life following postnatal
exposure to varicella-zoster virus. Arch Dermatol 2004; 140:1268.
Lapolla W, et al: Incidence of postherpetic neuralgia after combination
treatment with gabapentin and valacyclovir in patients with acute
herpes zoster: open label study. Arch Dermatol 2011; 147:901.
Lasserre A, et al: Herpes zoster: family history and psychological
stress: case-control study. J Clin Virol 2012; 55:153.
Lee CK, Baek BJ: Lingual zoster. N Engl J Med 2011; 365:1726.
Lee JY, et al: The effect of ketamine as an additive in epidural block on
the intractable herpetic neuralgia: a case report. Korean J Anesthesiol
2014; 66:64.
Li Q, et al: Antiviral treatment for preventing postherpetic neuralgia.
Cochrane Library 2009; 3.
Liu YC, et al: Herpes zoster is associated with an increased risk of
subsequent lymphoid malignancies: a nationwide population-based
matched-control study in Taiwan. BMC Cancer 2012; 12:503.
Lo CH, Chiang CP: Herpes zoster duplex bilateralis. Intern Med 2013;
52:2841.
Long MD, et al: Increased risk of herpes zoster among 108,604 patients
with inflammatory bowel disease. Aliment Pharmacol Ther 2013;
37:420.
Mahajan VK, et al: Spontaneous tooth exfoliation after trigeminal herpes
zoster: a case series of an uncommon complication. Indian J Dermatol
2013; 58:244.
Makharita MY, et al: Single paravertebral injection for acute thoracic
herpes zoster: a randomized controlled trial. Pain Pract 2014; Feb 17.
[Epub ahead of print.]
tahir99 - UnitedVRG
Mehra T, et al: Isotopic response of graft versus host disease following
herpes zoster infection: case report and review of the literature. Acta
Derm Venereol 2012; 92:339.
Nalamachu S, et al: Influence of anatomic location of lidocaine patch
5% on effectiveness and tolerability for postherpetic neuralgia. Patient
Herpesvirus group
Prefer Adherence 2013; 7:551.
Nikkels AF, et al: Atypical recurrent varicella in 4 patients with
hemopathies. J Am Acad Dermatol 2003; 48:442.
Ono F, et al: Comparison between famciclovir and valacyclovir for acute
pain in adult Japanese immunocompetent patients with herpes zoster.
J Dermatol 2012; 39:902.
Pirmohamed M: Statins, immunomodulation, and infections: a complex
and unresolved relationship. Clin Infect Dis 2014; 58:357.
Puri N: Modified Jaipur block for the treatment of post-herpetic
neuralgia. Int J Dermatol 2011; 50:1417.
Rabaud C, et al: Early antiviral treatment fails to completely prevent
herpes-related pain. Med Mal Infect. 2013; 43:461.
Ruocco E, et al: Segmental immune disorders related to herpes zoster.
Int J Dermatol 2014; 53:e303.
Sabatowski R, et al: Safety and efficacy outcomes of long-term
treatment up to 4 years with 5% lidocaine medicated plaster in patients
with post-herpetic neuralgia. Curr Med Res Opin 2012; 28:1337.
Sampathkumar P, et al: Herpes zoster (shingles) and postherpetic
neuralgia. Mayo Clin Proc 2009; 84:274.
Sang CN, et al: Gastroretentive gabapentin (G-GR) formulation reduces
intensity of pain associated with postherpetic neuralgia (PHN). Clin J
Pain 2013; 29: 281.
Schencking M, et al: Intravenous vitamin C in the treatment of shingles:
results of a multicenter prospective cohort study. Med Sci Monit 2012;
18:CR215.
Snedecor SJ, et al: Systematic review and meta-analysis of
pharmacological therapies for pain associated with postherpetic
neuralgia and less common neuropathic conditions. Int J Clin Pract
2014; 68:900.
Song HJ, et al: Herpes zoster complicated by delayed intracranial
haemorrhage. Clin Exp Dermatol 2008; 34:518.
Sotiriou E, et al: Severe post-herpetic neuralgia successfully treated with
botulinum toxin A: three case reports. Acta Derm Venereol 2009;
89:214.
Stidd DA, et al: Peripheral nerve stimulation for trigeminal neuropathic
pain. Pain Physician 2012; 15:27.
Styczyski J, et al: Management of HSV, VZV and EBV infections in
patients with hematological malignancies and after SCT: guidelines
from the Second European Conference on Infections in Leukemia.
Bone Marrow Transpl 2009; 43:757.
Terao M, et al: Vitiligo exacerbated after herpes zoster. J Dermatol
2012; 39:938.
Tsai J, et al: Zoster paresis: asymptomatic MRI lesions far beyond the
site of rash and focal weakness. J Neurol Sci 2013; 330:119.
Tyring SK: Management of herpes zoster and postherpetic neuralgia.
J Am Acad Dermatol 2007; 57:S136.
Umezawa Y, et al: Risk of herpes zoster in psoriatic patients undergoing
biologic treatment. J Dermatol 2014; 41:168.
Uscategui T, et al: Antiviral therapy for Ramsay Hunt syndrome (herpes
zoster oticus with facial palsy) in adults. Cochrane Library 2009; 3.
Watanabe K, Funaki M: Zoster of the tympanic membrane. N Engl J Med
2011; 365:e40.
Watanabe T, et al: Papules on the nape: postherpetic granuloma
annulare–like reaction (Wolf isotopic response). Arch Dermatol 2009;
145:589.
Weinberg JM: Herpes zoster: epidemiology, natural history, and
common complications. J Am Acad Dermatol 2007; 57:S130.
Yan C, et al: Herpes zoster duplex bilateralis in a immunocompetent
adolescent boy: a case report and literature review. Pediatr Dermatol
2014; 31:341.
Zhang J, et al: Association between vaccination for herpes zoster and
risk of herpes zoster infection among older patients with selected
immune-mediated diseases. JAMA 2012; 308:43.
Epstein-Barr virus
pstein Barr irus ( BV) is a γ herpes irus. t in ects human
mucosal epithelial cells and B lymphocytes and in ection per
sists or the li e o the host. BV in ection may be latent not
377
 producing irions but simply spread rom mother cell to both
19 daughter cells by copying the iral D A with each host cell
replication. ntermittently in ection may be producti e result
ing in production and release o in ectious irions. BV in ec
tion may transit between latent and producti e in ection many
Viral Diseases
times. The ability o BV to maintain persistent in ection is
aided by the e pression o the BV nuclear antigen ( B A )
iral gene product which pre ents cytoto ic T lymphocyte
response to the irus.
nitial in ection with BV occurs in childhood or early adult
hood so that by their early twenties o the population
has been in ected. The irus is shed into the sali a so contact
with oral secretions is the most common route o transmission.
Primary in ection may be asymptomatic or may produce only
a mild nonspeci c ebrile illness especially in younger chil
dren. n young adults primary in ection is more li ely to be
symptomatic and in o cases produces a syndrome termed
in ectious mononucleosis ( ). The incubation period is
wee s. is characteri ed by a constellation o ndings e er
(up to C) headache lymphadenopathy splenomegaly and
pharyngitis (sore throat).
Cutaneous and mucous membrane lesions are present in
about o patients. anthems occur in less than
more o ten in children. dema o the eyelids and a macular or
morbilli orm eruption are most common. The eruption is
usually on the trun and upper e tremities. ther less
common eruptions are urticarial esicular bullous petechial
erythema multi orme and purpuric types. Cold urticaria tran
siently occurs in o patients with . Leu ocytoclastic as
culitis and large essel arteritis ha e been seen in chronic BV
in ection o ten in the setting o immunode ciency. The
mucous membrane lesions consist o distincti e pinhead si ed
petechiae in number at the unction o the so t and hard
palate ( orchheimer spots). Gianotti Crosti syndrome (GCS)
and the papular purpuric glo e and stoc ing (or glo es and
soc s) syndrome are two speci c iral e anthem patterns that
may occur in the patient with asymptomatic primary BV
in ection. BV is now the leading cause o GCS worldwide.
BV reacti ation has been in re uently associated with drug
induced hypersensiti ity syndrome. BV is also associated
with enhanced insect bite reactions.
Pain ul genital ulcerations may precede the symptomatic
phase o especially in premenarcheal girls. The ulcerations
are up to cm in diameter single or multiple and may be
accompanied by mar ed swelling o the labia. Lesions last
se eral wee s and heal spontaneously o ten as the patient is
de eloping symptoms o . Transmission to patients through
orogenital se has been proposed but the irus may also reach
the ul ar mucosa hematogenously. BV has been reco ered
by culture rom these genital ulcerations. The lesions closely
resemble herpetic ulcerations and ed drug eruption which
must be considered in the di erential diagnosis.
Laboratory e aluation in patients with re uently shows
an absolute lymphocytosis o greater than and monocyto
sis with abnormally large atypical lymphocytes. The white
blood cell (WBC) count ranges rom to cells
mm . Li er unction tests (L Ts) may be ele ated. eterophile
antibodies will be present in or more o cases. n acute
primary BV in ection g antibodies to early antigen ( A)
and iral capsid antigen (VCA) are ound in high titer and
decrease during reco ery. Antibodies to VCA and B A
appear in the reco ering phase and persist or years a ter
primary in ection. There is no speci c therapy and in most
patients no treatment is re uired. Acyclo ir is not e ecti e in
altering the length or se erity o although it is acti e against
BV in doses used or V V. patients ha e se ere pharyngeal
in ol ement with encroachment on the airway days o oral
corticosteroid therapy ( mg day o prednisone) is use ul
378
Fig. 19-22 Oral hairy leukoplakia.
to induce a prompt reduction in pharyngeal swelling. ost
patients reco er completely.
Patients with treated with ampicillin amo icillin or
other semisynthetic penicillins typically de elop a general
i ed pruritic erythematous to copper colored macular e an
them on the th th day o therapy. The eruption starts on
the pressure points and e tensor sur aces generali es and
becomes con uent. The eruption lasts about wee and
resol es with des uamation. The eruption o ten does not recur
when these medications are gi en a ter the acute mononucleo
sis has resol ed.
ral hairy leu opla ia ( L) is a distincti e condition
strongly associated with V. t appears as poorly demar
cated corrugated white pla ues seen on the lateral aspects o
the tongue ( ig. ). Lesions on the other areas o the oral
mucosa are simply white pla ues without the typical corruga
tions. L can be distinguished rom thrush by the act that
L cannot be remo ed by rm scraping with a tongue blade.
ore than one third o patients with A DS ha e L but is
not restricted to patients with V in ection; it also occurs in
other immunosuppressed hosts especially renal and bone
marrow transplant recipients and those using inhaled steroids
or chronic obstructi e pulmonary disease. L can be a part
o the immune reconstitution in ammatory syndrome ( R S).
BV does not establish in ection in the basal cell layer o the
oral epithelium but is maintained by repeated direct in ection
o the epithelium by BV in the oral ca ity. nly chronically
immunosuppressed patients continuously shed BV in their
oral secretions thus e plaining the restriction o L to
immunosuppressed hosts. n normal persons a similar mor
phologic and histologic picture can be seen (pseudo L) but
BV is not ound in these patients lesions. Thus the nding
o L warrants immunologic e aluation. A biopsy o the
L lesions searching or BV in the epithelium can be use ul
in this setting. L is usually asymptomatic and re uires no
treatment. treatment is re uested in immunosuppressed
patients podophyllin applied or s to min to the lesions
once each month is the simplest approach. Tretinoin gel
applied topically twice daily or oral acyclo ir mg e
times daily is also e ecti e. Lesions recur when treatment is
discontinued.
n immunosuppressed and immunocompetent hosts BV
may be responsible or benign and malignant disorders some
o which can be atal. These include i uchi disease (histiocytic
necroti ing lymphadenitis) hydroa accini orme ( V) and
V li e lymphoma hypereosinophilic syndrome leiomyomas
and leiomyosarcomas lymphomatoid granulomatosis ery
thema multi orme and multiple types o lymphoma and lym
phoproli erati e disorders especially in organ transplant
recipients. Richter syndrome (de elopment o lymphoma in
the patient with chronic lymphocytic leu emia) can present in
the s in and may be associated with udarabine treatment o
BV in ection.
Cytomegalic inclusion disease
Congenital cytomegalo irus (C V) in ection as documented
by C V e cretion is ound in o newborns o prednisolone. Acta Derm Venereol 2013; 93:200.
whom are asymptomatic. Clinical mani estations in in ants
may include aundice hepatosplenomegaly cerebral calci
cations chorioretinitis microcephaly mental retardation
and dea ness. Cutaneous mani estations may result rom
thrombocytopenia with resultant petechiae purpura and
ecchymoses. Purpuric lesions which may be macular papular
or nodular may show e tramedullary hematopoiesis (dermal
erythropoiesis) producing the blueberry mu n baby. A
generali ed esicular eruption may rarely occur. ost symp
tomatic cases occur within the rst months o li e. eonatal
disease is more se ere and se uelae are more re uent in neo
nates o mothers with primary rather than recurrent C V
disease in pregnancy.
Between and o immunocompetent adults and up
to o V in ected men who ha e se with men ( S )
are in ected with C V. n ection in adults may be ac uired by
e posure to in ected children se ual transmission and trans
usion o C V in ected blood. Symptomatic primary in ection
in adults is unusual and is identical to caused by BV. An
urticarial or morbilli orm eruption or erythema nodosum may
occur in primary C V in ection in immunocompetent adults.
Ampicillin and amo icillin administration will o ten result in
a morbilli orm eruption in acute C V in ection similar to that
seen in acute BV in ection.
n ection with C V is common in A DS patients most re
uently causing retinitis ( o patients) colitis ( ) chol
angitis encephalitis polyradiculomyopathy and adrenalitis.
t occurs in the setting o ery ad anced V in ection usually
with CD counts below and has become much less common
in the era o highly acti e antiretro iral therapy ( AART).
Cytomegalo irus in ection in tissues is usually identi ed by
the histologic nding o a typical C V cytopathic e ect. n a
ery small percentage o A DS patients with C V in ection
s in lesions may occur that contain such cytopathic changes.
n most cases C V is ound in association with another in ec
tious process and the treatment o that other in ection will lead
to resolution o the C V in the s in without its treatment. This
is especially true o perianal SV ulcerations. C V may e en
be ound in totally normal s in in C V iremic A DS patients
suggesting that nding the C V cytopathic e ect is insu
cient alone to imply a causal relationship o the C V to any
cutaneous lesion. nly in the case o perianal and oral ulcer
ations has the pathogenic role o C V been documented. n
unusual cases o e tremely pain ul genital ulcerations only
C V in ection is ound histologically or the ulceration persists
a ter e ecti ely treating SV with C V identi ed histologi
cally. The C V cytopathic changes may be noted in the ner es
at the base o these ulcerations suggesting that C V neuritis
may be producing the se ere pain that characteri es these
cases. The diagnosis o C V ulceration is one o e clusion.
C V cytopathic changes must be seen in the lesion and cul
tures and histologic e idence o any other in ectious agent
must be negati e. n these ulcerations clinically suggested by
their location (genital or oral) and pain ul nature speci c treat
ment with alganciclo ir oscarnet or cido o ir will lead to
healing o the ulceration and dramatic resolution o the pain.
The C V in ecting endothelial cells may produce a ascu
lopathy in C V iremic or partially reacti ating patients. This
tahir99 - UnitedVRG
can lead to prominent asculopathic changes including
Raynaud phenomenon deep enous thrombosis digital gan
grene and reticulated purpura. Anticardiolipin antibodies
may be positi e. Anti C V therapy can re erse the syndrome
and clear the anticardiolipin antibodies.
Herpesvirus group
Ardalan M: Rare presentations of cytomegalovirus infection in renal
allograft recipients. Nephro-Urol Mon 2012; 4:431.
Chiu HY, et al: Concurrent cytomegalovirus and herpes simplex virus
infection in pemphigus vulgaris treated with rituximab and
Dauden E, et al: Mucocutaneous presence of cytomegalovirus
associated with human immunodeficiency virus infection. Arch
Dermatol 2001; 137:443.
Durkin J, et al: A 7-week-old Nepali girl with a perianal ulcer: brief
report. Pediatr Dermatol 2014; 31:e65.
Fernandez-Flores A: Epstein-Barr virus in cutaneous pathology. Am J
Dermatopathol 2013; 35:763.
Gabrib G, et al: Atypical presentation of exophytic herpes simplex virus
type 2 with concurrent cytomegalovirus infection: a significant pitfall in
diagnosis. Am J Dermatopathol 2013; 35:371.
Hancox JG, et al: Perineal ulcers in an infant: an unusual presentation of
postnatal cytomegalovirus infection. J Am Acad Dermatol 2006; 54:536.
Klion AD, et al: Chronic active Epstein-Barr virus infection: a novel
cause of lymphocytic variant hypereosinophilic syndrome. Blood 2013;
121:2364.
Lee HY, et al: Primary Epstein-Barr virus infection associated with
Kikuchi’s disease and hemophagocytic lymphohistiocytosis: a case
report and review of the literature. J Microbiol Immunol Infect 2010;
43:253.
Lehloenya R, Meintjes G: Dermatologic manifestations of the immune
reconstitution inflammatory syndrome. Dermatol Clin 2006; 24:549.
Mendoza N: Mucocutaneous manifestations of Epstein-Barr virus
infection. Am J Clin Dermatol 2008; 9:295.
Molina-Ruiz AM, et al: Cytomegalovirus-induced cutaneous
microangiopathy manifesting as lower limb ischemia in a human
immunodeficiency virus–infected patient. J Cutan Pathol 2012; 39:945.
Nakai H, et al: A case of erythema multiforme associated with primary
Epstein-Barr virus infection. Pediatr Dermatol 2011; 28:23.
Pahlow Mose A, et al: Antiviral treatment of a boy with EBV-associated
hydroa vacciniforme. BMJ Case Rep 2014 [Epub ahead of print.]
Park BM, et al: Chronic active Epstein-Barr virus infection–associated
hydroa vacciniforme–like eruption and Behçet’s-like orogenital ulcers.
Dermatol 2013; 226:212.
Piperi E, et al: Oral hairy leukoplakia in HIV-negative patients: report of
10 Cases. Int J Surg Pathol 2010; 18:177.
Ramdial PK, et al: Cytomegalovirus neuritis in perineal ulcers. J Cutan
Pathol 2002; 29:439.
Ramdial PK, et al: Dermal Epstein Barr virus–associated
leiomyosarcoma: tocsin of acquired immunodeficiency syndrome in
two children. Am J Dermatopathol 2011; 33:392.
Ramirez-Amador VA, et al: Identification of oral candidosis, hairy
leukoplakia and recurrent oral ulcers as distinct cases of immune
reconstitution inflammatory syndrome. Int J STD AIDS 2009; 20:250.
Ryan, C et al: Cytomegalovirus-induced cutaneous vasculopathy and
perianal ulceration. J Am Acad Dermatol 2011; 64:1216.
Tetzlaff MT, et al: Epstein-Barr virus–associated leiomyosarcoma with
cutaneous involvement in an African children with human
immunodeficiency virus: a case report and review of the literature.
J Cutan Pathol 2011; 38:731.
Yu L, et al: Cutaneous Richter syndrome: report of 3 cases from one
institution. J Am Acad Dermatol 2012; 67:e187.
Human herpesviruses 6 and 7
n ection with V is almost uni ersal in adults with sero
positi ity in the range in the nited States and sero
pre alence almost in children. There are intermittent
periods o iral reacti ation throughout li e; persistent in ec
tion occurs in se eral organs particularly in the C S. Acute
serocon ersion to V and to V each appears to be
responsible or about one third o roseola cases and in the
remaining third neither is ound. V in ection occurs
379
 earlier than V and second episodes o roseola in V The bac ground seropre alence rate o
19 seropositi e children may be caused by
tion with
V . Primary in ec
V is associated with roseola in only o cases
and o children with serocon ersion ha e a rash. Primary
in ection may occur with only e er and no rash or rash
Viral Diseases
without e er. ther common ndings include otitis media
diarrhea and bulging ontanelles sometimes with ndings o
meningoencephalitis. n re uently hepatitis intussusception
and e en atal multisystem disease may occur. n adults acute
V in ection resembles acute mononucleosis.
As with other herpes iruses the pattern o disease in V V precedes and predicts subse uent de elopment o S
may be di erent in immunosuppressed hosts. V reacti
ation is common a ter transplantation a ter solid organ
and a ter bone marrow transplantation. These patients
can be uite ill with e er diarrhea and ele ated L Ts simu
lating GV D. ngra tment can be delayed. V iremia
detected by PCR can con rm the diagnosis. Chronic macular
erythema has been reported in se eral cases. Care ul histologic
e aluation has identi ed V in ected lymphocytes and
histiocytes in the macular erythema con rming the diagnosis.
Anti iral therapy with ganciclo ir oscarnet or alganciclo ir
can lead to impro ement.
Roseola infantum (exanthem subitum, sixth disease)
Roseola in antum is a common cause o sudden une plained
high e er in young children between and months o age.
Prodromal e er is usually high and may be accompanied by
con ulsions and lymphadenopathy. Suddenly on about the
ourth day the e er drops. Coincident with the decrease in
temperature a morbilli orm erythema o discrete rose colored
macules appears on the nec trun and buttoc s and some
times on the ace and e tremities. ten there is a blanched
halo around the lesions. The eruption may also be papular or
rarely e en esicular. The mucous membranes are spared.
Complete resolution o the eruption occurs in days. A case
o spontaneously healing generali ed erupti e histiocytosis
has been reported ollowing e anthem subitum.
Human herpesvirus 8
A γ herpes irus V is most closely related to BV. V and other cyto ines. n
has been ound in all patients with aposi sarcoma ( S)
including those who ha e A DS ( ig. ) in A rican cases;
in elderly men rom the editerranean basin; and in trans
plant patients. n addition the seropositi ity rate (in ection
rate) or this irus correlates with the pre alence o S in a
gi en population.
Fig. 19-23 Kaposi sarcoma.
380
V in orth
America and orthern urope is near ero. Seropre alence is
highest in S endemic areas in sub Saharan A rica ( ).
n the general population in taly the seropre alence is
( in children under age a ter age ). n south
central taly and in Sardinia seropre alence rates are higher
or the general population. n taly high rates o
V seropositi ity are also seen in V in ected gay men
(up to ) in emale prostitutes ( ) and in heterose ual
men who ha e had se with prostitutes ( ). n ection with
in V in ected men. n addition to S lesions V can be
ound in sali a and in circulating blood cells in V
in ected patients. V is also ound in the semen o up to
o S patients. eterose ual partners o patients with
classic S ha e high rates o V seropositi ity (> ).
These epidemiologic eatures all strongly support se ual
transmission as an important mechanism o the spread o
V . The nding o a signi cant number o in ections in
prepubertal children howe er suggests that nonse ual
methods o transmission also e ist. V seropre alence rate
in heterose ual V drug users and persons with V in ection
ac uired through blood trans usion are not increased abo e
that in the general population suggesting that V is
poorly transmitted by blood and blood products.
uman herpes irus is present in a rare type o B cell lym
phoma called body ca ity based B cell lymphoma or primary
e usion lymphoma (P L) which presents with pleural peri
cardial and peritoneal malignant e usions. Rarely this orm
o lymphoma may be associated with s in lesions or may
present as an intra ascular lymphoma. The cutaneous lesions
can resemble a CD positi e anaplastic large T cell lym
phoma. V is also ound in all patients with multicentric
Castleman s disease ( CD) associated with V in ection and
in o V negati e patients with CD. Cyto ine pro
duction speci cally L rom aposi syndrome herpes irus
( S V) in ected cells ( L ) and host in ammatory cells
(h L ) appears causal. anthems and cutaneous nodules
may accompany CD and V has been identi ed in the
s in lesions. S V in ammatory cyto ine syndrome ( CS)
is an in ammatory syndrome analogous to CD but lac ing
the prominent lymphadenopathy. t is also mediated by L
V associated CD and CS
V iral loads are much higher than in patients with S
perhaps aiding in the diagnosis.
Cattani P, et al: Age-specific seroprevalence of human herpesvirus 8 in
Mediterranean regions. Clin Microbiol Infect 2003; 9:274.
Crane GM, et al: HHV-8-positive and EBV-positive intravascular
lymphoma: an unusual presentation of extracavitary primary effusion
lymphoma. Am J Surg Pathol 2014; 38:426.
Galan A, et al: Fatal HHV6 infection in an immunocompromised
patient presenting with skin involvement. J Cutan Pathol 2010;
37:277.
Li MF, et al: Human herpesvirus 8–associated lymphoma mimicking
cutaneous anaplastic large T-cell lymphoma in a patient with
human immunodeficiency virus infection. J Cutan Pathol 2012;
39:274.
Müzes G, et al: Successful tocilizumab treatment in a patient with
human herpesvirus 8–positive and human immunodeficiency
virus–negative multicentric Castleman’s disease of plasma cell
type nonresponsive to rituximab-CVP therapy. APMIS 2013;
121:668.
Peker D, et al: Complete remission in 4 patients with human herpesvirus
8–associated multicentric Castleman disease using rituximab and
liposomal doxorubicin, a novel chemotherapy combination. Clin Adv
Hematol Oncol 2012; 10:204.
Polizzotto MN, et al: Clinical manifestations of Kaposi sarcoma
herpesvirus lytic activation: multicentric Castleman disease (KSHV-
MCD) and the KSHV inflammatory cytokine syndrome. Front Microbiol
2012; 3:73.
 Roux J, et al: Human herpesvirus-6 cytopathic inclusions: an
exceptional and recognizable finding on skin biopsy during HHV6
reactivation after autologous stem-cell transplantation. Am J
Dermatopathol 2012; 34:e73.
Sayer R, et al: Can plasma HHV8 viral load be used to differentiate
multicentric Castleman disease from Kaposi sarcoma? Int J STD AIDS
2011; 22:585.
Schwartz RA, et al: Kaposi sarcoma: a continuing conundrum. J Am
Acad Dermatol 2008; 59:179.
Tamiya H, et al: Generalized eruptive histiocytoma with rapid
progression and resolution following exanthema subitum. Clin Exper
Dermatol 2005; 30:294.
Wolz MM, et al: Human herpesvirus 6, 7, and 8 from a dermatologic
perspective. Mayo Clin Proc 2012; 87:1004.
Yoshida M, et al: Exanthem subitum (roseola infantum) with vesicular
lesions. Br J Dermatol 1995; 132:614.
B virus
B irus erpesvirus simiae is endemic in Asiatic ld World
mon eys (maca ues) and may in ect other mon eys housed in
close uarters with in ected mon eys. n maca ues simiae
disease is a recurrent esicular eruption analogous to SV in
humans with irus shed rom con uncti a oral mucosa and
urogenital area. umans become in ected a ter being bitten
scratched or contaminated by an animal shedding B irus.
sually patients are animal handlers or researchers. Rare cases
o respiratory or human to human contact spread ha e been
reported. Within a ew days o the bite esicles erythema
necrosis or edema appear at the site o inoculation. Regional
lymph nodes are enlarged and tender. e er is typically
present. n a substantial number o human in ections rapid
progression to neurologic disease occurs. This is initially mani
ested by peripheral ner e in ol ement (dysesthesia paresthe
sia) then progresses to spinal cord in ol ement (myelitis and
ascending paralysis with hypore e ia) and nally to brain
disease (decreased consciousness sei ures respiratory depres
sion). reported patients ha e died and all sur i ors
o encephalitis had se ere neurologic se uelae. Treatment with
acyclo ir or ganciclo ir has been success ul in some but other
patients similarly treated ha e died.
Estep RD, et al: Simian herpesviruses and their risk to humans. Vaccine
2010; 285:878.
Fan Q, et al: Herpes B virus utilizes human nectin-1 but not HVEM or
PILR for cell-cell fusion and virus entry. J Virol 2012; 86:4468.
INFECTIOUS HEPATITIS
Hepatitis B virus
epatitis B irus ( BV) is a dsD A irus that is spread by
blood and blood products and se ually in urope and the
Western emisphere. n A rica and Asia in ection o ten
occurs perinatally. BV is the primary cause o hepatocellular
carcinoma and may also cause li er ailure and cirrhosis.
Acute in ection with BV is associated with anore ia nausea
right upper uadrant pain and malaise. Between and
o patients with acute BV in ection ha e a serum sic ness
li e illness with urticaria arthralgias and occasionally arthri
tis glomerulonephritis or asculitis. These symptoms appear
wee s be ore onset o clinically apparent li er disease.
mmune comple es containing hepatitis B sur ace antigen
( BsAg) and hypocomplementemia are ound in serum and
oint uid. The process spontaneously resol es as antigen is
cleared rom the blood.
epatitis B is associated with polyarteritis nodosa (PA ) but
in only o patients because o widespread immuni ation.
PA usually occurs within the rst months o in ection e en
tahir99 - UnitedVRG
during the acute phase but may occur as long as years a ter
in ection. nli e the urticarial reaction which is usually associ
ated e entually with de elopment o clinical hepatitis BV
in ection associated with PA may be silent.
mmunosuppressi e treatments can lead to reacti ation o
Infectious hepatitis
silent BV in ection. Be ore initiating treatment with an
immunosuppressi e agent (including T inhibitors) the
patient should be screened or BV in ection by chec ing
hepatitis B core antibody (and possibly BsAg and antibody).
nly two thirds o patients who recei e immunomodulators
will be BsAg positi e. Although o BV in ected
patients will remain asymptomatic during immunomodulator
treatment a third will de elop se ere hepatitis and more than
will die or de elop ulminant hepatitis. Ritu imab and
cyclophosphamide cause reacti ation early. ost o these
patients would be candidates or preempti e anti iral therapy
so all patients with serologic e idence o BV in ection in
whom immunosuppressi e treatment or T inhibitor therapy
is being considered should be re erred to a hepatologist be ore
initiating immunosuppressi e therapy.
A highly e ecti e accine is a ailable to pre ent BV in ec
tion. t is recommended as a part o standard childhood immu
ni ations and all health care wor ers should be immuni ed.
Patients who will recei e T inhibitor treatment and who are
not immuni ed may be considered or immuni ation.
Hepatitis C virus
epatitis C irus ( CV) is a single stranded (ss) R A irus
that causes most cases o non A non B iral hepatitis. ow
that a serologic test is a ailable to screen blood products
or CV in ection the ast ma ority o new cases o CV
in ection are parenterally transmitted by V drug use. Com
pared with hepatitis B se ual transmission is uncommon
(< transmission year o e posure). other to in ant spread
occurs in o cases. nly about one third o patients are
symptomatic during acute in ection. Between and o
patients will ha e chronic in ection. Although most patients
ha e minimal symptoms or the rst one to two decades o
in ection cirrhosis and li er ailure as well as hepatocellular
carcinoma are common se uelae. Chronic CV in ection is
associated with arious s in disorders either by direct e ect
or rom the associated hepatic damage.
Cutaneous necroti ing asculitis which is usually associated
with a circulating mi ed cryoglobulin occurs in appro imately
o patients with chronic CV in ection. n o patients
with type cryoglobulinemia CV in ection is present. The
most common clinical presentation is palpable purpura o the
lower e tremities ( o cases). Li edo reticularis urticaria
and subcutaneous nodules showing a granulomatous asculi
tis may also occur. Arthropathy glomerulonephritis and neu
ropathy re uently accompany the s in eruption. Leg ulcers
can occur in . istologically a leu ocytoclastic ascu
litis is seen in all patients. n some the asculitis may in ol e
small arteries gi ing a histologic pattern similar to that seen
in PA . n arious studies o patients with PA were
CV positi e suggesting that both BV and CV can cause
PA . The presence o anti CV antibodies should not be used
as the sole diagnostic test in patients with PA because PA
may cause a alse positi e L SA test or CV. Rheumatoid
actor a type cryoglobulin and hypocomplementemia are
ound in up to o cases. CV in ected patients with mi ed
cryoglobulinemia are times more li ely to de elop non
odg in lymphoma usually o the B cell type.
Patients with porphyria cutanea tarda (PCT) o ten ha e
hepatocellular abnormalities. Depending on the pre alence o
CV in ection in the population studied o sporadic
381

19
Viral Diseases
Fig. 19-24 Necrolytic acral erythema.
(not amilial) PCT cases are CV associated. Treatment o the
CV in ection may lead to impro ement o the PCT.
epatitis C in ection has been associated with lichen planus
with about a our old increased ris or its de elopment in the
CV positi e patient. The li elihood o identi ying CV
in ection in a patient with lichen planus is greatest in geo
graphic regions with high rates o CV in ection. Patients
with mucosal ulcerati e lichen planus are also more li ely to
be CV in ected. Serologic testing in a patient should be con
sidered i the patient has CV ris actors or abnormal L Ts
or is rom a geographic region where or rom population in
whom CV in ection is common. CV may also be associated
with cutaneous B cell lymphoma. n studies rom Japan and
srael patients with CV in ection were almost twice as li ely
to de elop psoriasis especially men o er years. They were
less obese but had higher rates o hypertension and diabetes
mellitus. Appro imately o patients with CV in ection
ha e pruritus. Pruritus irtually always is associated with
ad anced li er disease and abnormal L Ts. Patients with pru
ritus and normal L Ts and no history o hepatitis rarely will
be in ected with CV.
ecrolytic acral erythema is an uncommon condition
uni uely associated with CV in ection. t a ects uni uely
persons o A rican origin and occurs in less than o CV
in ected patients in the nited States. t resembles the de
ciency dermatoses e cept that it has an acral distribution.
The clinical lesions are pain ul or pruritic eratotic well
de ned pla ues with raised red scaly borders or di use hyper
eratosis ( ig. ). rosion and accid blisters may occur
contributing to the discom ort. The dorsal eet (less o ten the
dorsal hands) as well as the lower e tremities may be in ol ed.
istologically there is necrosis o the super cial portion o the
epidermis along with hyper eratosis papillomatosis loss o
the granular cell layer and para eratosis. ntraepidermal
spongiotic oci are present which may be macroscopic at
times with the clea age plane between the necrotic and iable
epidermis. inc essential atty acid and glucagon le els are
normal but the patients may be hypoalbuminemic and ha e
low serum amino acids because o their li er disease. Treat
ment o the associated CV in ection with and riba irin
plus inc and li er transplantation has resulted in resolu
tion. yperalimentation was also partially e ecti e in some
patients as was amino acid supplementation with inc.
A combination o alpha and riba irin is used to treat
patients with chronic CV in ection with sustained responses
in slightly o er o patients. Combined and riba irin
therapy may be complicated by an ec ematous eruption with
pruritus in about o patients and se ere pruritus in about
. c ema typically a ects the distal e tremities dorsal
382 hands ace nec and less re uently the trun a illae and
buttoc s. The eruption may be photodistributed and photoe
acerbated. These ec ematous eruptions typically begin
months a ter initiation o treatment. n a ected patients prior
treatment with alone was usually not associated with an
ec ematous eruption. istologically the eruptions show a
spongiotic dermatitis. The eruption resol es completely i treat
ment is stopped or wee s but will recur when treatment is
restarted. Aggressi e therapy with antihistamines emollients
and potent topical corticosteroids will usually control the
ec ema allowing uninterrupted continuation o treatment.
Adding telapre ir an CV protease inhibitor greatly
enhances the response o CV in ection to treatment espe
cially or CV and CV serotypes which respond less
well to with riba irin. This newer agent howe er is asso
ciated with a high rate o ad erse s in reactions ( o
patients). About two thirds o reactions occur in the rst
days o telapre ir administration although these can continue
to appear or wee s. ore than o telapre ir associated
drug reactions are graded as mild (locali ed grade ) or mod
erate (di use grade ) and can be treated with topical agents
and oral antipruritics and telapre ir therapy can be contin
ued. Reactions are ec ematous but can ha e a photoe acerba
tion. reactions are progressi e systemic corticosteroids ha e
been used. The median time to resolution was days with
some reactions lasting longer than year. Grade reactions
(any epidermal detachment targets or purpura nonblanching
erythema) occur in o patients and treatment must be
stopped. Three cases o Ste ens Johnson syndrome and
cases ( . o treated patients) o drug induced hypersensiti
ity syndrome (DR SS) occurred in the Phase trials. A wide
spread papulos uamous eruption closely resembling pityriasis
rubra pilaris has been reported. Patients recei ing alpha
or CV in ection may de elop unsightly granulomatous
nodules at ller in ection sites.
Albeldawi M, et al: A cutaneous marker of hepatitis C virus.
Gastroenterology 2013; 144:275.
Birkenfeld S, et al: A study on the association with hepatitis B and
hepatitis C in 1557 patients with lichen planus. J Eur Acad Dermatol
Venereol 2011; 25:436.
Cacoub P, et al: Dermatological side effects of hepatitis C and its
treatment: patient management in the era of direct-acting antivirals.
J Hepatol 2012; 56:455.
Descamps V, et al: Facial cosmetic filler injections as possible target for
systemic sarcoidosis in patients treated with interferon for chronic
hepatitis C: two cases. Dermatology 2008; 217:81.
Droz D, et al: Kinetic profiles and management of hepatitis B virus
reactivation in patients with immune-mediated inflammatory disease.
Arthritis Care Res 2013; 65:1504.
Hall LD, et al: Epstein-Barr virus: dermatologic associations and
implications. Part I. Mucocutaneous manifestations of Epstein-
Barr virus and nonmalignant disorders. J Am Acad Dermatol
2015; 72:1.
Imafuki S, et al: Possible association of hepatitis C virus infection with
late-onset psoriasis: a hospital-based observational study. J Dermatol
2013; 40:813.
Kishi A, et al: Biphasic skin reactions during telaprevir-based therapy of
Japanese patients infected with hepatitis C virus. J Am Acad Dermatol
2014; 70:584.
Montaudié H, et al: Drug rash with eosinophilia and systemic symptoms
due to telaprevir. Dermatology 2010; 221:303.
Motaparthi K, et al: From the Medical Board of the National Psoriasis
Foundation: recommendations for screening for hepatitis B infection
prior to initiating anti–tumor necrosis factor-alfa inhibitors or other
immunosuppressive agents in patients with psoriasis. J Am Acad
Dermatol 2013; 70:178.
Raphael BA, et al: Low prevalence of necrolytic acral erythema in
patients with chronic hepatitis C virus infection. J Am Acad Dermatol
2012; 67:962.
Rebora A: Skin diseases associated with hepatitis C virus: facts and
controversies. Clin Dermatol 2010; 28:489.
Roujeau JC, et al: Telaprevir-related dermatitis. JAMA Dermatol 2013;
149:2.
 Stalling SS, et al: Telaprevir-induced pityriasis rubra pilaris–like drug
eruption. Arch Dermatol 2012; 148:1215.
Tsilika K, et al: Secondary hyperpigmentation during interferon alfa
treatment for chronic hepatitis C virus infection. JAMA Dermatol 2013;
149:675.

Poxvirus group
Vazquez-Lopez F, et al: Eczema-like lesions and disruption of therapy in
patients treated with interferon-alfa and ribavirin for chronic hepatitis C:
the value of an interdisciplinary assessment. Br J Dermatol 2004;
150:1028.

Gianotti-Crosti syndrome (papular acrodermatitis of

childhood, papulovesicular acrolocated syndrome)
Gianotti Crosti syndrome (GCS) is a characteristic iral e an
them. t was initially associated with the early anicteric phase
o BV in ection. With uni ersal BV immuni ation BV is
now a rare cause o GCS. BV is now the most common cause Fig. 19-25 Gianotti-Crosti syndrome.
o GCS worldwide. ther implicated in ectious agents ha e
included adeno irus C V entero iruses (co sac ie A B
and B ) accinia irus rota irus hepatitis A and C respira
Fig. 19-26 Papules on
tory syncytial irus parain uen a irus par o irus B the leg, Gianotti-Crosti
rubella irus V streptococcus and M cobacterium avium syndrome. (Courtesy
mmuni ations against polio irus diphtheria pertussis Japa of Curt Samlaska,
nese encephalitis in uen a and hepatitis B and measles MD.)
(together) ha e also caused GCS.
The clinical eatures are identical independent o the cause.
GCS typically a ects children months to years o age
(median age years o cases occurring be ore the age o
) and may rarely be seen in adults (women only). Proposed
diagnostic criteria in ol e the ollowing positi e clinical ea
tures o GCS
. onomorphous at topped pin brown papules or
papulo esicles o mm in diameter ( igs. and
)
. Any three or all our sites in ol ed ace buttoc s
orearms and e tensor legs
. Symmetry
. Duration o at least days
egati e clinical eatures include
. tensi e truncal lesions
. Scaly lesions
The lesions de elop o er a ew days but last longer than
most iral e anthems (> days and up to many wee s).
Lesion numbers may ary rom a ew to a generali ed erup
tion coalescing to orm pla ues co ering the ace trun and
upper e tremities. arly in the course o the eruption the
lesions will demonstrate a oebner phenomenon. Pruritus is
ariable and the mucous membranes are spared e cept when
in amed by the associated in ectious agent. Depending on the
cause the lymph nodes mainly inguinal and a illary are
moderately enlarged or months. o treatment appears to
shorten the course o GCS which is sel limited.
Brandt O, et al: Gianotti-Crosti syndrome. J Am Acad Dermatol 2006;
54:136.
Hall LD, et al: Epstein-Barr virus: dermatologic associations and
implications. Part I. Mucocutaneous manifestations of Epstein-Barr in routine histologic material. olluscum contagiosum irus
virus and nonmalignant disorders. J Am Acad Dermatol 2015; 72:1. and the now eliminated ariola irus are the only po iruses
May J, Pollack R: Giannoti-Crosti syndrome associated with type A or which humans represent the primary host and reser oir.
influenza. Pediatr Dermatol 2011; 28:733. The other po iruses are primarily in ections o animals
Roeskop AK, et al: Gianotti-Crosti syndrome after H1N1-influenza
rom whom humans accidentally become in ected. The ortho
vaccine. Pediatr Dermatol 2011; 28:596.
po iruses that ha e in ected humans include accinia
mon eypo cowpo bu alopo and camelpo . The parapo
iruses causing human disease include or bo ine papular
POXVIRUS GROUP stomatitis and sealpo . any other genera o po iruses ha e
recently been disco ered but are primarily pathogens in wild
The po iruses are D A iruses o a high molecular weight. animals so human disease is e tremely rare or is not yet
The iruses are nm in diameter and thus can be seen identi ed. 383

tahir99 - UnitedVRG

19
Viral Diseases
Fig. 19-27 Smallpox scars. (Courtesy of Shyam Verma, MD.)
Variola major (smallpox)
Smallpo was eradicated worldwide in . t continues to be
o interest to dermatologists as a potential biologic war are
agent. Variola is spread by the respiratory route with
o un accinated contacts becoming in ected. The incubation
period or smallpo is days (a erage days). The
prodromal phase consists o days o high e er (> C)
se ere headache and bac ache. The e er subsides and an
e anthem co ers the tongue mouth and oropharyn . This is
ollowed in day by the appearance o s in lesions distributed
in a centri ugal pattern with the ace arms and legs more
hea ily in ol ed than the trun . Lesions appear rst on the
palms and soles and eel li e rm BBs under the s in. Begin
ning as erythematous macules (days ) the lesions all in
synchrony become mm papules (days ) and e ol e to
mm esicles (days ) and mm pustules (days ).
The pustules umbilicate collapse and orm crusts beginning
in the second wee . The total e olution a erages wee s.
Lesions on the palms and soles persist the longest. The crusts
separate a ter about more wee lea ing scars ( ig. ) description are considered e ui ocal and such persons cannot
which are permanent in o the sur i ors. Patients are
in ectious rom the onset o the e anthem through the rst
days o the eruption. A ariety o complications occur includ
ing pneumonitis blindness caused by iral eratitis or second
ary in ection ( o patients) encephalitis (< o patients)
arthritis ( o children) and osteitis. mmunity is li elong.
The mortality rate was in unde eloped countries (and
be ore current intensi e care and anti iral management).
Diagnosis is made by electron microscopy iral culture and
PCR. Special laboratories usually associated with city and
state health departments in the nited States can process
these specimens and con rm the diagnosis. The di erential
diagnosis is primarily aricella especially the more se ere
orm seen in adults. n aricella the prodrome lasts or
days; e er begins with onset o the eruption (not preceding it
by days as in ariola); the eruption is concentrated on the
torso (not centri ugally); and indi idual lesions o di erent
stages are present and e ol e rom esicles to crust within
h. The diagnostic test o choice in these patients is a T anc
smear or D A test which can rapidly con rm aricella.
Treatment o smallpo includes strict isolation and protec
tion o health care wor ers. nly accinated persons should
384
treat the patient and any o those e posed should immedi
ately be accinated because this modi es the disease. Cido o
ir modi es in ections by other orthopo iruses and may be
indicated.
Breman JG, Henderson DA: Diagnosis and management of smallpox.
N Engl J Med 2002; 346:1300.
Jahrling PB, Tomori O: Variola virus archives: a new century, a new
approach. Lancet 2014; 383:1525.
Thèves C, et al: The rediscovery of smallpox. Clin Microbiol Infect 2014;
20:210.
Vaccinia
The accinia irus has been propagated in laboratories or
immuni ation against smallpo . There are multiple strains
used in accines and the rates o complications ary some
what depending on the strain used. The a ailable anti iral
agents with acti ity against accinia are limited. a case o
accinia is encountered the state health department or the .S.
Centers or Disease Control and Pre ention (CDC) should be
contacted immediately or optimal management. Vaccinia
irus (VACV) appears to ha e been initially isolated by Jenner
rom horse hoo es and is closely related to horsepo irus.
There ha e been epidemics o VACV in ections on the teats o
dairy cattle the mouths o their cal es and the hands o dairy
armers in Bra il since the s. VACV has also been isolated
rom wild rodents in Bra il.
Vaccination
Vaccination is inoculation o li e accinia irus into the epi
dermis and upper dermis by the multiple puncture techni ue.
Between and days a ter inoculation a papule orms which
becomes esicular at days then pustular reaching a
ma imum si e at days . The pustule dries rom the center
outward re ealing the pathognomonic umbilicated pustule
and orms a scab that separates days a ter accination
resulting in a pitted scar. ormation by days o a papule
esicle ulcer or crusted lesion surrounded by a rim o ery
thema and induration is termed a ma or reaction or ta e.
The rim o erythema a erages . cm in diameter in new
accinees and pea s on days . Repeat accinees ha e reac
tions o a similar time course but the ma imum diameter o
the erythema is only cm. Reactions that do not match this
be considered immune; re accination should be considered. A
large accination reaction or robust ta e is the de elop
ment o a pla ue o erythema and induration greater than
cm at the site o inoculation. This occurs in o initial
accinees. t pea s at days and resol es without treat
ment within h. Cellulitis secondary to accination occurs
on days a ter accination or a ter se eral wee s and pro
gresses without treatment. anagement should be e pectant
but a bacterial culture may be ta en. Vaccinated patients may
ha e e er on days a ter accination so culture is not
help ul in separating cellulitis rom a robust ta e. Rarely
patients will de elop lesions at the site o accination an
a erage o months later. Their nature is un nown but these
lesions ha e not been identi ed as containing li e irus and
are sel limited.
Vaccination in ol es the inoculation o a li e irus. Compli
cations result rom an abnormal response to the accination
by the host or rom inad ertent transmission to another person.
Persons with de ecti e cutaneous or systemic immunity are at
particular ris or ad erse outcomes rom accination. Because
some complications may be atal e tremely care ul steps must
be ta en to a oid complications.
 Fig. 19-28
Autoinoculation
vaccinia.
Inadvertent inoculation and autoinoculation
nad ertent inoculation o accinia may occur by transmis
sion o irus by hands or omites rom the accination site to
another s in area or the eye or to another person. Accidental
autoinoculation occurs in about in accinees. Autoin
oculation most o ten occurs around the eyes and elsewhere
on the ace but the groin and other sites may be in ol ed
( ig. ). These lesions e ol e in parallel with the primary
accination site and e cept or ocular lesions cause no
se uelae e cept scarring at times. Any e idence o ocular
in ammation in a recently accinated indi idual could repre
sent ocular accinia in ection and re uires immediate oph
thalmologic e aluation. Transmission to others (secondary
trans er) is rare i the accination site is ept co ered until it
heals ( . in primary accinees). t usually occurs
within a household or through intimate contact. Serial trans
mission can occur among male sports partners and has been
reported in serial se ual partners. Correct bandaging o the
accination site using oam or occlusi e dressings not gau e
bandages and treating the inoculation site with po idone
iodine ointment beginning days a ter immuni ation both
can reduce iral shedding and might reduce autoinoculation
and secondary cases.
Generalized vaccinia
rom to days a ter accination a generali ed accinia erup
tion may occur in about per million new accinees or
per million repeat accinees. The lesions are papulo esicles
that become pustules and in olute in wee s although suc
cessi e crops may occur within that time. Generali ed accinia
may be accompanied by e er but patients do not appear ill.
Lesions may be generali ed or limited to one anatomic region
and can number rom a ew to hundreds. They can be con
used with multisite autoinoculation as well as erythema mul
ti orme. The diagnosis is con rmed by biopsy iral culture
or PCR. Generali ed accinia is sel limited and does not
re uire treatment in the immunocompetent host. n the patient
with underlying immunode ciency early inter ention with
accinia immune globulin intra enous (V G V) may be
bene cial.
tahir99 - UnitedVRG
Poxvirus group
Fig. 19-29 Vaccinia necrosum.
Eczema vaccinatum
c ema accinatum is analogous to ec ema herpeticum rep
resenting accinia irus in ection superimposed on a chronic
dermatitis especially atopic dermatitis. Patients with Darier s
disease etherton syndrome and other disorders o corni ca
tion may also be at ris . Since patients with atopic dermatitis
or any past history o atopic dermatitis should not be acci
nated most cases o ec ema accinatum represent secondary
trans er to an at ris indi idual rom a recent accinee usually
a amily member. The esicles appear suddenly mostly in
areas o acti e dermatitis. The lesions are sometimes umbili
cated and appear in crops resembling smallpo or chic en
po . The onset is sudden and resh esicles appear or se eral
days. Scarring is common. ten cer ical adenopathy and
e er occur and a ected persons are systemically ill (unli e
those with generali ed accinia). Secondary bacterial in ection
can complicate ec ema accinatum. The mortality rate or
ec ema accinatum is i untreated. V G V reduces
mortality to . ultiple doses o V G V and perhaps treat
ment with e ecti e anti irals may be re uired.
Progressive vaccinia (vaccinia necrosum,
vaccinia gangrenosum)
Progressi e accinia is a rare se ere and o ten atal complica
tion o accination that occurs in immunode cient persons.
ost cases occur when in ants with undiagnosed immunode
ciency are immuni ed. The initial accination site continues
to progress and ails to heal a ter more than days. The ac
cination site is characteri ed by a painless but progressi e
necrosis and ulceration ( ig. ) with or without metastatic
lesions to distant sites (s in bones iscera). o in ammation
is present at the sites o in ection e en histologically. ntreated
progressi e accinia is irtually always atal. Progressi e ac
cinia is diagnosed by s in biopsy iral culture or PCR. V G V
should be gi en and anti iral antibiotics a ailable rom the
CDC ha e been e ecti e in this rare condition.
Cutaneous immunologic complications
A spectrum o erythematous eruptions ollows accination.
These eruptions are more common than generali ed accinia
with which they are o ten con used. Cases o Ste ens Johnson
385
 syndrome a ter accination ha e been seen in the past primar
19 ily in children but apparently are rare in adult accinees.
Benign hypersensitivity reactions to vaccinia
About . o accinees will de elop a di use cutaneous
Viral Diseases
eruption during the second wee a ter accination around the
pea o the immuni ation site reaction. These reactions ha e
been classi ed as e anthematous (by ar the most common)
urticarial and erythema multi orme ( ) li e (the most rare).
A ollicular eruption has also been reported (see ne t section).
All these reaction patterns e ol e o er days and resol e
o er days. Patients may ha e mild symptoms but are a ebrile.
At times the eruption may e ol e rom around the inoculation
site and generali e called roseola accinia in the past.
Primary accinees are more li ely to de elop these reactions.
istology is nonspeci c showing eatures o a iral e anthem
(mild spongiotic dermatitis). These reactions are distinguished
rom generali ed accinia by a later onset (end o second wee
s. days a ter accination) prominent erythema lac o
esicles and pustules and negati e laboratory testing or ac
cinia irus. The eruptions described as li e lac mucosal
in ol ement and blistering and more closely resemble urti
caria multi orme (see Chapter ). They are distinguished rom
Ste ens Johnson syndrome by the absence o atypical
purpuric or typical targetoid lesions lac o mucosal in ol e
ment and histologic e aluation.
Postvaccination follicular eruption
A generali ed ariant o the eruption occurred in . o pharyngeal lesions.
new accinees and a locali ed ariant in . during a trial
o A entis Pasteur smallpo accine. n the second wee
days a ter accination multiple ollicular erythematous
papules appeared primarily on the ace trun and pro imal
e tremities. Lesions were mildly pruritic. er se eral days
the lesions e ol ed to pustules which resol ed without
scarring. Lesions were simultaneously at di erent stages o
de elopment. The number o lesions was usually limited and
rarely e ceeded . Lesions spontaneously resol ed o er a
ew days. istologic e aluation re ealed a suppurati e ol
liculitis. o irus was detected in the lesions by PCR or iral
culture.
Other skin lesions at vaccination scars
elanomas basal cell carcinomas and s uamous cell carcino
mas ha e all occurred in accination scars. Benign lesions with
a tendency to occur in scars such as dermato bromas sarcoid
osis and granuloma annulare also can occur in accination
scars.
Bessinger GT, et al: Benign hypersensitivity reactions to smallpox
vaccine. Int J Dermatol 2007; 4:460.
Bruner DI, Butler BS: Smallpox vaccination-associated myopericarditis is
more common with the newest smallpox vaccination. J Emerg Med
2014; 46:e85.
Bunick CG, et al: Expanding the histologic findings in smallpox-related
post-vaccinial non-viral folliculitis. J Cutan Pathol 2013; 40:305.
Centers for Disease Control and Prevention: Secondary and tertiary
transmission of vaccinia virus after sexual contact with a smallpox
vaccine—San Diego, California, 2012. MMWR 2013; 62:145.
Curry JL, et al: Occurrence of a basal cell carcinoma and
dermatofibroma in a smallpox vaccination scar. Dermatol Surg 2008;
34:132.
De Assis FL, et al: Reemergence of vaccinia virus during zoonotic
outbreak, Pará State, Brazil. Emerg Infect Dis 2013; 19:2017.
Hammarlund E, et al: Traditional smallpox vaccination with reduced risk
of inadvertent contact spread by administration of povidone iodine
ointment. Vaccine 2008; 26:430.
Hivnor C, James W: Autoinoculation vaccinia. J Am Acad Dermatol
2003; 50:139.
Montgomery JR, et al: Case report: chest pain in service members
386 following smallpox vaccination. MSMR 2012; 19:6.
Human monkeypox
uman mon eypo ( irus P V) caused by an orthopo i
rus is a sporadic oonosis that occurs in remote areas o the
tropical rain orests in central and western A rica primarily the
Democratic Republic o Congo. The mortality rate is .
The number o cases has dramatically increased since the
s. The main ector or mon eypo is wild A rican rodents
and mon eys. umans are accidental hosts. Direct contact
with an in ected animal or person appears to be re uired to
ac uire the in ection . n A rica more than o cases occur
in children under years o age in whom the atality rate is
. The secondary attac rate in A rican households is
. An outbrea o cases o mon eypo occurred in
the nited States. Prairie dogs became in ected when housed
with in ected A rican rodents. Persons who purchased the
prairie dogs become in ected most re uently through bites
or scratches or areas o damaged s in. The pattern o mon ey
po seen in the .S. cases was di erent rom that o A rican
cases; transmission was belie ed to be by inoculation and
many o the a ected persons were pre iously immuni ed
with accinia. Primary s in lesions occurred at sites o inocula
tion and limited spread occurred therea ter with the appear
ance o additional satellite and disseminated lesions o er
se eral days. Patients o ten had e er respiratory symptoms
and characteristic lymphadenopathy ( ). About one uarter
re uired hospitali ation and only two children had serious
clinical illness one with encephalitis and one with se ere oro
n A rica mon eypo is clinically similar to smallpo with
an incubation period o days. Patients de elop headache
( ); e er sweats and chills ( ); and lymphadenopathy
( ). Lymphadenopathy is not a eature o smallpo . The
prodrome lasts days ollowed by the appearance o mm
papules. The lesions spread centri ugally and progress rom
papules to esicles then pustules all in days. n o
patients the lesions are largely monomorphic but are more
pleomorphic than smallpo . The distribution is generali ed
and the buccal mucosa can be a ected. Lesions resol e with
hemorrhagic crusts. The disease is sel limited. t is less se ere
in persons pre iously accinated against smallpo .
Buffalopoxvirus
Bu alopo irus (BP V) is an orthopo irus closely related to
VACV. t a ects bu alo cows and humans and multiple
outbrea s ha e occurred in ndia. Wild rodents are probably
the natural reser oir. Lesions occur on the hands and arms o
animal handlers and resemble a milder orm o cowpo .
amily members may be a ected and children ha e de el
oped lesions resembling ec ema accinatum.
Zoonotic poxvirus infections
The diagnosis o oonotic po irus in ection is usually by
epidemiologic history clinical eatures and electron micros
copy which can separate the arious po irus genera. Labora
tory culture is slow and PCR analysis o the iral D A allows
or speciation. Rarely is anti iral therapy indicated; most dis
eases are sel limited. Cido o ir would be thought to ha e
acti ity against the oonotic po iruses.
Cowpox
Cowpo ( irus CP V) is an orthopo irus that is geographi
cally restricted to the urope Russia and ad acent states.
t is largely a oonosis that rarely a ects cattle. The domestic

Fig. 19-30 Milker’s nodule.
cat is the usual source o human in ection. Cats ac uire in ec
tion rom wild animal reser oirs (small wild rodents such as
mice and oles). Lesions rst appear on the head and then on
the paws and ears. eline in ection may be asymptomatic or
the cat may be ery ill. ost human cases occur in the late
summer and in all. The recent popularity o pet rats in urope
has led to se eral cases o rat to human transmission o CP V
especially in children too young to ha e recei ed smallpo
accination.
The incubation period o CP V is about days. There is then
an abrupt onset o e er malaise headache and muscle pain.
Lesions are usually solitary ( ) with co primary lesions in
o cases. Lesions occur on the hands and ngers in hal
the cases and the ace in another third. Pet rats seem to in ect
children usually on the nec . Secondary lesions are uncom
mon and generali ed disease is rare usually occurring in
patients with atopic dermatitis and Darier s disease. The lesion
progresses rom a macule through a esicular stage then a
pustule that becomes blue purple and hemorrhagic. A hard
pain ul cm indurated eschar de elops a ter wee s
and may resemble cutaneous anthra . n anthra howe er
the eschar orms by day . Lesions are always pain ul and
there is local lymphadenopathy which is usually tender. The
amount o surrounding edema and induration is much more
mar ed than in or . Patients are systemically ill until the eschar
stage. ealing usually ta es wee s. Scarring is common
a ter cowpo .
Farmyard pox
Because closely related parapo iruses o sheep and cattle
cause similar disease in humans or and mil er s nodules
ha e been collecti ely called armyard po . The epidemiologic
eatures are discussed separately but the clinical and histo
logic eatures which are identical are discussed ointly. The
diagnosis o these in ections is based on ta ing an accurate
history and can irtually always be con rmed by routine his
tologic e aluation.
Bovine-associated parapoxvirus infections:
milker’s nodules, bovine papular stomatitis
(BPSV), and pseudocowpox (PCPV)
Bo ine associated parapo irus in ections cause worldwide
occupational disease o mil ers or eterinarians most o ten
transmitted directly rom the udders (mil er s nodules) or
mu les (bo ine papular stomatitis) o in ected cows. Lesions
are usually solitary or ew in number and are con ned to the
hands or orearms ( ig. ). umerous lesions ha e been
reported in healing rst degree and second degree burns in
tahir99 - UnitedVRG
Fig. 19-31 Orf.
Poxvirus group
mil er s nodules. These cases occurred on arms with in ected
cattle but the patients had not had direct contact with the
cattle suggesting indirect iral transmission.
Orf
Also nown as ecthyma contagiosum or is a common disease
in goat arming and sheep arming regions throughout the
world. Direct transmission rom acti e lesions on lambs is most
common but in ection rom omites also re uently occurs
because the irus is resistant to heat and dryness. Autoinocula
tion to the genital area can occur but human to human trans
mission is rare. ne patient recei ing etanercept de eloped a
giant lesion and progressi e disease. e was success ully
treated with surgical remo al cryotherapy and topical imi ui
mod with discontinuation o the etanercept.
Clinical features
The incubation period or armyard po is about wee . Lesions
are usually solitary and occur on the hands ngers ( ig. )
or ace. Lesions e ol e through the ollowing si stages
. A papule orms which then becomes a target lesion with
a red center surrounded by a white ring and then a red
halo.
. n the acute stage a red weeping nodule appears
resembling pyogenic granuloma.
. n a hairy area temporary alopecia ensues.
. n the regenerati e stage the lesion becomes dry with
blac dots on the sur ace.
. The nodule then becomes papillomatous.
. The nodule nally attens to orm a dry crust e entually
healing.
Lesions are usually about cm in diameter e cept in immu
nosuppressed patients in whom giant lesions may occur.
Spontaneous resolution occurs in about wee s lea ing
minimal scarring. ild swelling e er pain and lymphadeni
tis may accompany the lesions but these symptoms are milder
than those seen in cowpo . r may be associated with an
li e eruption in about o patients. Treatment is sup
porti e although sha e e cision may accelerate healing.
Topical cido o ir and imi uimod ha e been e ecti e.
Histologic features
istologic eatures o armyard po correlate with the clinical
stage. odules show a characteristic pseudoepitheliomatous
hyperplasia co ered by a para eratotic crust. eratinocytes
always demonstrate iropathic changes o nuclear acuoli a
tion and cytoplasmic μm eosinophilic inclusions sur
rounded by a pale halo. The papillary dermis is se erely
edematous. The dermal in ltrate which is dense and e tends
rom the inter ace to the deep dermis consists o lymphocytes
histiocytes neutrophils and eosinophils. assi e capillary
proli eration and dilation are present in the upper dermis. 387
 Human tanapox Molluscum contagiosum
19 Tanapo in ection is a yatapo irus in ection endemic to e ua olluscum contagiosum ( C) is caused by up to our closely
torial A rica. t is spread rom its natural hosts nonhuman related types o po irus CV to CV and their ari
primates through minor trauma. uman to human transmis ants. Although the proportion o in ection caused by the
Viral Diseases

sion is rare. Tanapo in ection is mani ested by mild e er o
abrupt onset lasting days ollowed by the appearance
o one or two poc lesions. Lesions are rm and cheesy resem
bling cysts. The disease is sel limited and smallpo accina
tion would not be e pected to be protecti e. Rare cases ha e
been imported into urope and the nited States.
Assis FL, et al: Group 2 vaccinia virus, Brazil. Emerg Infect Dis 2012;
18:2035.
Blacklaws BA, et al: Molecular characterization of poxviruses associated
with tattoo skin lesions in UK cetaceans. PLoS One 2013; 8:e71734.
Cann JA, et al: Comparative pathology of smallpox and monkeypox in
man and macaques. J Comp Pathol 2013; 148:6.
Centers for Disease Control and Prevention: Update: multistate outbreak
of monkeypox—Illinois, Indiana, Kansas, Missouri, Ohio, and
Wisconsin, 2003. Arch Dermatol 2003; 139:1229.
arious types aries geographically CV in ections are
most common worldwide. n small children irtually all in ec
tions are caused by CV . There is no di erence in the ana
tomic region o isolation with regard to in ecting type in
contrast to SV or e ample. n patients in ected with V
howe er CV causes the ma ority o in ections ( ) sug
gesting that V associated molluscum does not represent
recrudescence o childhood molluscum.
n ection with CV is worldwide and increasing. Three
groups are primarily a ected young children (highest in ages
years) se ually acti e young adults (ages ) and
immunosuppressed persons especially those with V in ec
tion. C is most easily transmitted by direct s in to s in
contact especially i the s in is wet. Bathing with a ected
siblings may be a ris actor. Swimming pools ha e been asso

G
Damon IK: Status of human monkeypox: clinical disease, epidemiology ciated with in ection sometimes e en plantar lesions.
and research. Vaccine 2011; 295:D54. n all orms o C in ection the lesions are relati ely similar.

R
Dhar AD, et al: Tanapox infection in a college student. N Engl J Med ndi idual lesions are smooth sur aced rm dome shaped
2004; 350:361. pearly papules a eraging mm in diameter ( ig. ).
Dina J, et al: Genital ulcerations due to a cowpox virus: a misleading

V
Giant lesions may be up to se eral centimeters in diameter.
diagnosis of herpes. J Clin Virol 2011; 50:345.
Elsendoorn A, et al: Severe ear chondritis due to cowpox virus A central umbilication is characteristic. rritated lesions may

d
transmitted by a pet rat. J Infect 2011; 63:391. become crusted and e en pustular simulating secondary bac
Favier A, et al: Necrotic ulcerated lesion in a young boy caused by terial in ection. This may precede spontaneous resolution.

cowpox virus infection. Case Rep Dermatol 2011; 3:186.
Haase O, et al: Generalized cowpox infection in a patient with Darier
disease. Br J Dermatol 2011; 164:1107.
Herder V, et al: Poxvirus infection in a cat with presumptive human
ti e
Lesions that rupture into the dermis may elicit a mar ed sup
purati e in ammatory reaction that resembles an abscess.
The clinical pattern depends on the ris group a ected. n
young children the lesions are usually generali ed and

n
transmission. Vet Dermatol 2011; 22:220. number rom a ew to more than . Lesions tend to be on
Koufakis T, et al: Orf disease: a report of a case. Braz J Infect Dis 2014;
the ace trun and e tremities. Genital lesions as part o a
18:568.

U
Lederman ER, et al: Progressive vaccinia: case description and
wider distribution occur in o childhood cases. When C
laboratory-guided therapy with vaccinia immune globulin, ST-246, and is restricted to the genital area in a child se ual abuse must

-
CMX001. J Infect Dis 2012; 206:1372. be considered. Children with atopic dermatitis (AD) either
Lieu TJ, et al: Photo quiz: a generalized eruption in a rancher. Clin acti e or inacti e are our times more li ely than nonatopic
Infect Dis 2013; 56:1613. children to ha e more than lesions. Transmission rom the

9
MacNeil A, et al: Diagnosis of bovine-associated parapoxvirus infections mother s s in can occur during aginal deli ery and may be
in humans: molecular and epidemiological evidence. Zoonoses Public associated with presentation in the rst ew months o li e.

ri 9
Health 2010; 57:e161. Se eral orms o in ammation occur in children with C.
McCollum AM, Damon IK: Human monkeypox. Clin Infect Dis 2014; The most common in ammatory response seen in o
58:260.
a ected children is molluscum dermatitis. ore common
McCollum AM, et al: Investigation of the first laboratory-acquired
in atopic children it is a mild ec ematous eruption surround

h
human cowpox virus infection in the United States. J Infect Dis 2012;
206:63. ing the indi idual lesions. This is not associated with more
rapid resolution o the C and treatment o this dermatitis

a
Nougairede A, et al: Sheep-to-human transmission of orf virus during

t
Eid al-Adha religious practices, France. Emerg Infect Dis 2013; 19:102. with topical corticosteroids does not appear to lead to increased
Orgaz-Molina J, et al: Multiple finger nodules and an erythematous rash: C. n amed C is characteri ed by erythema and swelling
a case study. Aust Fam Physician. 2012; 41:885.
Quenelle DC, et al: Cutaneous infections of mice with vaccinia or
cowpox viruses and efficacy of cidofovir. Antiviral Res 2004; 63:33.
Rørdam OM, et al: Giant orf with prolonged recovery in a patient with
psoriatic arthritis treated with etanercept. Acta Derm Venereol 2013;
93:487.
Reynolds MG, Damon IK: Outbreaks of human monkeypox after
cessation of smallpox vaccination. Trends Microbiol 2012; 20:80.
Rütten A, et al: Acute circumscribed necrosis on the left cheek in a
19-year-old woman. J Dtsch Dermatol Ges 2012; 10:843.
Schupp CJ, et al: A 14-year-old girl with a vesicle on her finger and
lymphadenitis. J Clin Virol 2011; 50:1.
Shcelkunov SN: An increasing danger of zoonotic orthopoxvirus
infection. PLoS Pathog 2013; 9:e1003756.
Simmons JF, et al: Painless, red nodule on the finger of a veterinary
student. Am Fam Physician 2012; 86:77.
Turan E, et al: A case of orf (ecthyma contagiosum) with multiple
lesions. J Pak Med Assoc 2013; 63:786.
Vogel S, et al: The Munich outbreak of cutaneous cowpox infection:
transmission by infected pet rats. Acta Derm Venereol 2012; 92; 126.
Zijlstra M, et al: BMJ Case Rep 2013; 2013 Sep 2. Fig. 19-32 Molluscum contagiosum.
388
 Fig. 19-33 Molluscum
contagiosum of the
penis.
Fig. 19-34 Molluscum
contagiosum in child
with atopic dermatitis.
o the indi idual lesions sometimes with pustulation or uc
tuance. t occurs in o children with C and usually
heralds the resolution o disease. The rarest in ammatory
response is a GCS li e reaction occurring in o children
with C. t presents as numerous edematous erythematous
papules or papulo esicles distant rom the C lesions and
a ors the elbows and nees but also a ects the buttoc s and
ace. Pruritus is prominent.
n adults C is se ually transmitted and other STDs may
coe ist. There are usually ewer than lesions; these a or
the lower abdomen upper thighs and penile sha t in men ( ig.
). Pubic hair remo al by sha ing clipping or wa ing is
a ris actor or ac uiring C by se ual contact. ucosal
in ol ement is ery uncommon.
mmunosuppression either systemic T cell immunosup
pression (usually V but also sarcoidosis immunosuppres
si e medications and malignancies) or abnormal cutaneous
immunity (as in atopic dermatitis or topical steroid use) pre
disposes the indi idual to in ection. n AD patients lesions
tend to be con ned to dermatitic s in ( ig. ).
Secondary in ection may occur but most in amed C and two large trials ha e shown that it is no more e ecti e
are not in ected but rather undergoing spontaneous in olu
tion by the immune response. Rarely erythema annulare
tahir99 - UnitedVRG
centri ugum may be associated with C. Lesions on the
eyelid margin or con uncti a may be associated with a con
uncti itis or eratitis. Rarely the molluscum lesions may
present as a cutaneous horn. Between and o A DS
patients not recei ing antiretro iral therapy (ART) ha e C.
Poxvirus group
Virtually all V in ected patients with C already ha e an
A DS diagnosis and a helper T cell (Th) count o less than
. n untreated V disease lesions a or the ace (espe
cially the chee s nec and eyelids) and genitalia. Lesions
may be ew or numerous orming con uent pla ues. Giant
lesions can occur and may be con used with a s in cancer.
n ol ement o the oral and genital mucosa may occur irtu
ally always indicati e o ad anced A DS (Th count < ).
acial dis gurement with numerous lesions can occur. Recur
rence or new appearance o C may be seen in A DS patients
starting ART as a part o R S.
olluscum contagiosum has a characteristic histopathology.
Lesions primarily a ect the ollicular epithelium. The lesion is
acanthotic and cup shaped. n the cytoplasm o the pric le
cells numerous small eosinophilic and later basophilic inclu
sion bodies orm called molluscum bodies or enderson
Paterson bodies. entually their bul compresses the nucleus
to the side o the cell. n the ully de eloped lesion each lobule
empties into a central crater. n ammatory changes are slight
or absent. Characteristic bric shaped po irus particles are
seen on electron microscopy in the epidermis. Latent in ection
has not been ound e cept in untreated A DS patients in
whom e en normal appearing s in may contain iral parti
cles. Resol ing and in amed lesions may contain a dense
in ammatory in ltrate o lymphocytes and neutrophils. Some
o the lymphocytes may be large and CD positi e. CV
contains an L binding protein gene that it apparently
ac uired rom humans. This bloc s the host s initial e ecti e
Th immune response against the irus by reducing local
γ production.
The diagnosis o C is easily established in most cases
because o the distincti e central umbilication o the dome
shaped lesion. This may be enhanced by light cryotherapy
which lea es the umbilication appearing clear against a white
( ro en) bac ground. or con rmation the pasty core o a
lesion is e pressed s uashed between two microscope slides
(or slide and co erslip) and stained with Wright Giemsa or
Gram. irm compression between the slides is re uired.
Treatment is determined by the clinical setting. n young
immunocompetent children especially those with numerous
lesions the most practical course may be not to treat or to use
only topical tretinoin. Aggressi e treatment may be emotion
ally traumatic and can cause scarring. Spontaneous resolution
is irtually a certainty in this setting a oiding these se uelae.
ndi idual lesions last months each; duration o in ection
is about years. Continuous application o surgical tape to
each lesion daily a ter bathing or wee s led to cure in
o children. Topical cantharidin applied or h to appro i
mately lesions per setting led to resolution in o
patients and o patients impro ed. This therapy is well
tolerated has a ery high satis action rate or patients and
their parents and complications are rare. lesions are limited
and the child is cooperati e nic ing the lesions with a blade
to e press the core (with or without comedo e tractor) s uee
ing the lesion with a tissue orceps light cryotherapy applica
tion o trichloroacetic acid (TCA ) and remo al by
curettage are all alternati es. The application o lidocaine
prilocaine ( LA) cream or h be ore any pain ul treatments
has made the management o C in children much easier. o
controlled trials ha e con rmed the e cacy o imi uimod
than placebo; it cannot be recommended or C treatment.
ntralesional immunotherapy with candidal antigen in ections
389
 in up to three lesions led to complete resolution o all lesions
19 in o children. ral cimetidine has been similarly used or
its immunomodulatory e ects. ydrogen pero ide cream
ingenol mebutate pulse dye laser and potassium hydro ide
are other reported therapies.
Viral Diseases
n adults with genital molluscum remo al by cryotherapy
or curettage is ery e ecti e. either imi uimod nor podo
phylloto in has been demonstrated to be e ecti e. n act the
ailure o these agents to impro e genital warts suggests the
diagnosis o genital C. Se ual partners should be e amined;
screening or coe istent STDs is mandatory.
n patients with AD application o LA ollowed by curet
tage or cryotherapy is most practical. Caustic chemicals should
not be used on atopic s in. Topical corticosteroid application
to the area should be reduced to the minimum strength pos
sible. n immunosuppressed patients especially those with
A DS management o C can be di cult. Aggressi e treat
ment o the V in ection with ART i it leads to impro ement
o the Th count is predictably associated with a dramatic reso
lution o the lesions. This response is delayed months rom
the institution o treatment so reports o resolution with
certain agents in the V patient is con ounded by the coe is
tent ART therapy which is probably the acti e component o
the treatment coc tail. C occurs re uently in the beard area
so sha ing with a blade ra or should be discontinued to
pre ent its spread. lesions are ew curettage or core remo al
with a blade and comedo e tractor is most e ecti e. LA
application may permit treatment without local anesthesia.
Cantharone or TCA may be applied to indi idual lesions.
Temporary dyspigmentation and slight sur ace irregularities
may occur. Cryotherapy may be e ecti e but must be used
with caution in persons o color. When lesions are numerous
n
or con uent treatment o the whole a ected area may be
re uired because o possible latent in ection. TCA peels abo e
U
concentration (medium depth) or daily applications o
uorouracil ( ) to the point o s in erosion may eradicate
-
lesions at least temporarily. At times remo al by curette is
re uired. n patients with V in ection continuous applica
tion o tretinoin cream once nightly at the highest concentra
9
tion tolerated seems to reduce the rate o appearance o new
lesions. Topical cido o ir application and systemic in u
ri 9
sion o this agent ha e been reported to lead to dramatic reso
lution o molluscum in patients with A DS.
Arora S, et al: Idiopathic CD4 lymphocytopenia presenting as recurrent
h
giant molluscum contagiosum. Indian J Dermatol Venereol Leprol
2013; 79:555.
a
Bansal S, et al: Disseminated molluscum contagiosum in a patient on
t
methotrexate therapy for psoriasis. Indian J Dermatol Venereol Leprol
2014; 80:179.
Berbegal-DeGracia L: Neonatal molluscum contagiosum: five new cases
and a literature review. Australas J Dermatol 2013; Dec 18. [Epub
ahead of print.]
Berger EM, et al: Experience with molluscum contagiosum and
associated inflammatory reactions in a pediatric dermatology practice.
Arch Dermatol 2012; 148:1257.
Butala N, et al: Molluscum BOTE sign: a predictor of imminent
resolution. Pediatrics 2013; 131:e1650.
Can B, et al: Treatment of pediatric molluscum contagiosum with
10% potassium hydroxide solution. J Dermatolog Treat 2014;
25:246.
Chen X, et al: Molluscum contagiosum virus infection. Lancet Infect Dis
2013; 13:877.
Cohen PR, Tschen JA: Plantar molluscum contagiosum: a case report of
molluscum contagiosum occurring on the sole of the foot and a review
of the world literature. Cutis 2012; 90:35.
Desreuelles F, et al: Pubic hair removal: a risk factor for “minor” STI
such as molluscum contagiosum. Sex Transm Infect 2013; 89:212.
Drain PK, et al: Recurrent giant molluscum contagiosum immune
reconstitution inflammatory syndrome (IRIS) after initiation of
antiretroviral therapy in an HIV-infected man. Int J STDS AIDS 2014;
390 25:235.
Enns LL, Evans MS: Intralesional immunotherapy with Candida antigen
for the treatment of molluscum contagiosum in children. Pediatr
Dermatol 2011; 28:254.
Erickson C, et al: Efficacy of intravenous cidofovir in the treatment of
giant molluscum contagiosum in a patient with human
immunodeficiency virus. Arch Dermatol 2011; 147:652.
Foissac M, et al: Efficacy and safety of intravenous cidofovir in the
treatment of giant molluscum contagiosum in an immunosuppressed
patient. Ann Dermatol Venereol 2014; 141:620.
Heng YK, et al: Verrucous plaques in a pemphigus vulgaris patient on
immunosuppressive therapy. Int J Dermatol 2012; 51:1044.
Hoyt BS, et al: Molluscum contagiosum of the areola and nipple: case
report and literature review. Dermatol Online J 2013; 19:18965.
Javed S, Tyring SK: Treatment of molluscum contagiosum with ingenol
mebutate. J Am Acad Dermatol 2014; 70:e105.
Katz, KA: Imiquimod is not an effective drug for molluscum
contagiosum. Lancet 2014; 14:372.
Kim MS, et al: Atypical molluscum contagiosum accompanied by
CD30-positive lymphoid infiltrates. Pediatr Dermatol 2013; 30:141.
Lao M, et al: Safe and speedy cantharidin application. J Am Acad
Dermatol 2013; 69:e47.
Le Treut C, et al: Molluscum contagiosum surrounded by a white halo
G
and Sezary syndrome. J Eur Acad Dermatol Venereol 2014 [Epub
Ahead of Print.]
R
McCollum AM, et al: Molluscum contagiosum in a pediatric American
Indian population: incidence and risk factors. PLoS One 2014;
9:e103419.
V
Moye VA, et al: Safety of cantharidin: a retrospective review of
cantharidin treatment in 405 children with molluscum contagiosum.
d
Pediatr Dermatol 2014; 13:458.
Nguyen HP, et al: Treatment of molluscum contagiosum in adult, pediatric,
ti e
and immunodeficient populations. J Cutan Med Surg 2014; 18:299.
Olsen JR, et al: Epidemiology of molluscum contagiosum in children:
a systematic review. Fam Pract 2014; 31:130.
Omi T, et al: Recalcitrant molluscum contagiosum successfully treated
with the pulsed dye laser. Laser Ther 2013; 22:51.
Osio A, et al: Clinical characteristics of molluscum contagiosum in
children in a private dermatology practice in the greater Paris area,
France: a prospective study in 661 patients. Dermatology 2011;
222:314.
Pereira de Carvalho CH, et al: Intraoral molluscum contagiosum in a
young immunocompetent patient. Oral Surg Oral Med Oral Pathol Oral
Radiol 2012; 114:e57.
Pompei DT, et al: Cantharidin therapy: practice patterns and attitudes of
health care providers. J Am Acad Dermatol 2013; 68:1045.
Potassium hydroxide 5% for the treatment of molluscum contagiosum.
Drug Ther Bull 2014; 52:118.
Semkova K, et al: Hydrogen peroxide 1% cream under occlusion for
treatment of molluscum contagiosum in an 8-month-old infant: an
effective and safe treatment option. Clin Exp Dermatol 2014; 39:560.
Shinkai K, Fox LP: The diagnosis: inflamed molluscum contagiosum as
a manifestation of immune reconstitution inflammatory syndrome. Cutis
2012; 89:219.
Siah TW, et al: Gross generalized molluscum contagiosum in a patient
with autosomal recessive hyper-IgE syndrome, which resolved
spontaneously after haematopoietic stem-cell transplantation. Clin Exp
Dermatol 2013; 38:197.
Sim JH, Lee ES: Molluscum contagiosum presenting as a cutaneous
horn. Ann Dermatol 2011; 23:262.
Van der Wouden JC, et al: Interventions for cutaneous molluscum
contagiosum. Cochrane Database Syst Rev 2009; 4:CD004767.
Villa L, et al: Molluscum contagiosum: a 20-year study in a sexually
transmitted infections unit. Sex Transm Dis 2010; 37:423.
Woldow AB, et al: The diagnosis: molluscum contagiosum on the sole
of the foot. Cutis 2011; 87:172.
Xiang Y, Moss B: Molluscum contagiosum virus interleukin-18 (IL-18)
binding protein is secreted as a full-length form that binds cell surface
glycosaminoglycans through the C-terminal tail and a furin-cleaved
form with only IL-18 binding domain. J Virol 2003; 77:2623.
PICORNAVIRUS GROUP
Picorna irus designates iruses that were originally called
entero iruses (polio iruses co sac ie iruses and echo i
ruses) plus the rhino iruses. The picorna iruses are small
ssR A icosahedral iruses arying in si e rom to nm. lesions disappear in days. Treatment is supporti e con
nly the co sac ie iruses echo iruses and entero irus types sisting o topical anesthetics.
and are signi cant causes o s in disease. erpangina is di erentiated rom aphthosis and primary
herpetic gingi ostomatitis by the location o the lesions in the
posterior oropharyn and by isolation o an entero irus. Co

Picornavirus group
Enterovirus infections sac ie irus A causes acute lymphonodular pharyngitis a
ariant o herpangina characteri ed by discrete yellow white
Person to person transmission occurs by the intestinal oral papules in the same distribution as herpangina.
route and less o ten the oral oral or respiratory routes. ntero
iruses are identi ed by type speci c antigens. The type Hand-foot-and-mouth disease
speci c antibodies appear in the blood about wee a ter
in ection has occurred and attain their ma imum titer in and oot and mouth disease ( D) is usually a mild
wee s. Viral cultures obtained rom the rectum pharyn eye illness caused primarily by co sac ie irus A but also other
and nose may isolate the in ecting agent. sually the diagno coc sac ie A and B iruses as well as entero irus . t pri
sis is by clinical characteristics and e cept in speci c clinical marily a ects children age years but e posed adults may
settings the causati e irus is not identi ed. ntero iral in ec also de elop disease. n ection begins with a e er and sore
tions most re uently occur in children between ages months mouth. n o patients oral lesions de elop; these consist
and years. o small ( mm) rapidly ulcerating esicles surrounded by
any nonspeci c e anthems and e anthems that occur a red areola on the buccal mucosa tongue so t palate and
during the summer and early all are caused by co sac ie irus gingi a. Lesions on the hands and eet are asymptomatic red
or echo irus. The e anthems most typically are di use macular papules that uic ly become small gray mm esicles sur
or morbilli orm erythemas which sometimes also contain rounded by a red halo. They are o ten o al linear or crescentic
esicular lesions or petechial or purpuric areas. cho irus and run parallel to the s in lines on the ngers and toes
has caused an eruption resembling acute meningococcemia. ( ig. ). They are distributed sparsely on the dorsa o the
ach type o e anthem has been associated with many sub ngers and toes and more re uently on the palms and soles.
types o co sac ie irus or echo irus (one e anthem many specially in children who wear diapers esicles and ery
possible iral causes). cho irus the most pre alent entero thematous edematous papules may occur on the buttoc s
irus causes a morbilli orm e anthem initially on the ace and
nec then the trun and e tremities. nly occasionally is there
an eruption on the palms and soles. Small red or white lesions Fig. 19-35 Herpangina.
on the so t palate may occur. The most common speci c erup
tions caused by entero iruses are hand oot and mouth
disease herpangina and roseola li e illnesses. Rare reported
presentations o entero irus in ection include a unilateral
esicular eruption simulating herpes oster caused by echo
irus ; a atal dermatomyositis li e illness in a patient with
hypogammaglobulinemia caused by echo irus ; and a
widespread esicular eruption in AD that simulated aposi
aricelli orm eruption caused by co sac ie irus A . Pleco
naril and other new antientero iral agents may be use ul in
se ere entero iral in ections.
Although the cutaneous eruptions caused by these iruses
are uite benign in ections with entero irus can be se ere
with the de elopment o brainstem encephalitis and atal neu
rogenic pulmonary edema as well as ascending accid paraly
sis resembling poliomyelitis. pidemics with se ere disease Fig. 19-36 Hand-foot-
ha e been reported in Bulgaria ungary ong ong Japan and-mouth disease.
Australia alaysia and Singapore. Taiwan had the worst
epidemic a ecting more than million people with deaths
in .

Herpangina
erpangina a disease o children worldwide is caused by
multiple types o co sac ie irus (most re uently A A
and A ) echo iruses and entero irus . n the se ere out
brea s in Taiwan o patients with atal cases had herpan
gina. t begins with acute onset o e er headache sore throat
dysphagia anore ia and sometimes sti nec . The most sig
ni cant nding which is present in all patients is one or more
yellowish white slightly raised mm esicles in the throat
usually surrounded by an intense areola ( ig. ). The
lesions are ound most re uently on the anterior aucial
pillars tonsils u ula or so t palate. nly one or two lesions
might appear during the course o the illness or the entire
isible pharyn may be studded with them. The lesions o ten
occur in small clusters and later coalesce. sually the indi
idual or coalescent esicles ulcerate lea ing a shallow
punched out grayish yellow crater mm in diameter. The 391

tahir99 - UnitedVRG
 Fig. 19-37 Hand-foot-
19 and-mouth disease.
Viral Diseases
( ig. ). The in ection is usually mild and seldom lasts
more than wee .
Coc sac ie irus A (CVA ) has become a common cause o
atypical D in urope the nited States and Asia.
CVA can cause typical D but also a more widespread
eruption with numerous lesions on the trun in addition to
the characteristic locations. Perioral lesions suggest CVA
D and when se ere can suggest Ste ens Johnson syn
drome. ospitali ation may be re uired or se ere dehydra
tion and pain management. Child to adult transmission can
occur because most adults are not immune to CVA . n adults
numerous widespread purpuric lesions can occur simulating
a asculitis or the atypical targets o ma or. n children
with AD CVA causes a esicular and erosi e eruption con
centrated in the areas o dermatitis similar to ec ema herpe
ticum called ec ema coc sac ium. Treatment is supporti e
with oral or topical anesthetics. The use o oral glucocorticoids
is associated with worse outcomes. nychomadesis may
n
ollow entero iral in ection and D about month a ter
the acute iral syndrome.
U
n the se ere Taiwanese entero irus outbrea o
cases with C S disease had the s in lesions o D. o
-
cases o D associated with C S disease were caused by
co sac ie irus A and C S disease also appears uncommon
with CVA D. The irus may be reco ered rom the s in
9
esicles. istopathologic ndings are those o an intraepider
mal blister ormed by acuolar and reticular degeneration o
ri 9
eratinocytes similar to other iral blisters. nclusion bodies
and multinucleated giant cells are absent. D is distin
guished rom herpangina by the distribution o the oral lesions
and the presence o s in lesions. D usually re uires no
h
treatment.
a
Eruptive pseudoangiomatosis
t
rupti e pseudoangiomatosis has been described in two clus
ters in the editerranean region and in South orea. t a ors
the summer months in both regions. The disorder is character
i ed by the sudden appearance o mm blanchable red
papules that resemble angiomas. n children it is usually asso
ciated with a iral syndrome but most a ected adults ha e no
iral symptoms. n adults emales outnumber males . The
red papules blanch on pressure and are o ten surrounded by
a mm pale halo. Lesions o ten number about but may
be much more numerous. ost lesions appear on the e posed
sur aces o the ace and e tremities but the trun may also be
a ected. n children lesions are short li ed irtually always
resol ing within days. Lesions may last slightly longer in
adults. Annual recrudescences may occur. pidemics ha e
been described in adults and e en health care wor ers caring
or patients with erupti e pseudoangiomatosis ha e de el
oped lesions. istologically dilated upper dermal essels but
not increased numbers o blood essels with prominent endo
thelial cells are seen. cho iruses and had been impli
392
cated in the initial reports. The occurrence in young children
and the presence o miniepidemic outbrea s suggest an in ec
tious trigger. This disorder closely resembles erythema punc
tatum iguchi which is common in Japan and nown to be
caused by Culex pipiens pallens bites. t appears that mos uito
bites iral in ection or enhanced insect bite reaction due to
intercurrent iral in ection are possible pathogenic causes o
erupti e pseudoangiomatosis.
Ben-Chetrit E, et al: Coxsackievirus A6–related hand foot and mouth
disease: skin manifestations in a cluster of adult patients. J Clin Virol
2014; 59:201.
Chung WH, et al: Clinicopathologic analysis of coxsackievirus A6 new
variant induced widespread mucocutaneous bullous reactions
mimicking severe cutaneous adverse reactions. J Infect Dis 2013;
208:1968.
Feder HM, et al: Atypical hand, foot, and mouth disease: a
vesiculobullous eruption caused by Coxsackie virus A6. Lancet Infect
Dis 2014; 14:83.
He Y, et al: Risk factors for critical disease and death from hand, foot,
and mouth disease. Pediatr Infect Dis 2014; 33:966.
Hubiche T, et al: Dermatological spectrum of hand, foot and mouth
G
disease from classical to generalized exanthema. Pediatr Infect Dis J
2014; 33:e92.
R
Kaminska K, et al: Coxsackievirus A6 and hand, foot and mouth
disease: three case reports of familial child-to-immunocompetent adult
transmission and a literature review. Case Rep Dermatol 2013; 5:203.
V
Kim JE, et al: Clinicopathologic review of eruptive pseudoangiomatosis
in Korean adults: report of 32 cases. Int J Dermatol 2013; 52:41.
d
Lott JP, et al: Atypical hand-foot-and-mouth disease associated with
coxsackievirus A6 infection. J Am Acad Dermatol 2013; 69:736.
ti e
Mathes EF, et al: “Eczema coxsackium” and unusual cutaneous findings
in an enterovirus outbreak. Pediatrics 2013; 132:3149.
Matsuzawa M, et al: Coxsackie A16 virus–associated atypical hand-foot-
and-mouth disease. Intern Med 2014; 53:643.
Oka K, et al: Two cases of eruptive pseudoangiomatosis induced by
mosquito bites. J Dermatol 2012; 39:301.
Sabanathan S, et al: Enterovirus 71 related severe hand, foot and mouth
disease outbreaks in South-East Asia: current situation and ongoing
challenges. J Epidemiol Community Health 2014; 68:500.
Shin JY, et al: A clinical study of nail changes occurring secondary to
hand-foot-mouth disease: onychomadesis and Beau’s lines. Ann
Dermatol 2014; 26:280.
Stewart CL, et al: Coxsackievirus A6–induced hand-foot-mouth disease.
JAMA Dermatol 2013; 149:1419.
FILOVIRUS
The iruses in the ilo irus genus are single stranded with
negati e polarity. n electron micrographs they appear la
mentous hence the name. This group o iruses is most closely
related to the human iruses that cause measles and rabies.
ilo iruses are among the most irulent and ha ardous patho
gens or humans and nonhuman primates. There are two
genera arburg irus ( ARV) and bola irus ( B V). The
animal reser oir or these iruses is our ruit bat species
ound in A rica. Transmission occurs in humans through
contact with emale bat blood and in ected nonhuman pri
mates and by contact with the bodily uids o in ected humans
(including but not limited to blood urine sweat semen and
breast mil ). n ected humans can transmit the irus rom the
time they become ebrile. The diagnoses o these agents is by
detection o B V R A ia PCR.
The case atality rate approaches in A rican outbrea s
but appears to be much lower i aggressi e supporti e medical
care is a ailable. Due to the highly contagious nature o these
iruses healthcare wor ers are particularly at ris o becom
ing in ected and special precautions must be ta en when man
aging in ected patients.
The incubation period is to days. The initial symptom
atic phase (phase ) is characteri ed by abrupt onset o e er
headache (usually occipital) myalgias and arthralgias. Phase
starts to days a ter symptom onset and lasts or to
days. Abdominal pain watery diarrhea and iolent sore
throat occur. n phase a nonpruritic morbilli orm eruption
resembling measles appears to days a ter symptom onset
in more than hal o patients. The onset o the eruption begins
as pinpoint dar red ollicular papules. The e anthema may
begin acrally and spread centripetally to the trun or ice
ersa beginning pro imally and e tending centri ugally. By
day the s in has a generali ed dar li id erythema. The
eruption resol es o er a ew days in the sur i ors ollowed
by des uamation o the a ected s in especially o the palms
and soles. ucosal lesions are also seen in hal o patients with
bilateral con uncti al congestion aphthousli e oral lesions
gingi itis glossitis and with e tension down the throat dys
phagia. The oral lesions can ha e a gray e udate or small
(tapioca granule) white lesions on the so t palate. Phase is
the terminal phase with shoc and multiorgan ailure. n this
stage supporti e care can maintain the patient until the spon
taneous eradication o the irus. Con alescence is prolonged
with intense atigue and migratory arthralgias. eutrali ing
antibodies rom sur i ors and e perimental anti irals are
being tested as therapies.
n the nonepidemic setting the initial presentation o the
symptoms and s in ndings are not speci c and can be mis
ta en or iral or bacterial gastroenteritis Lassa e er Dengue
Chi ungunya and e en measles which ha e o erlapping
signs and symptoms. n the epidemic setting rapid recogni
tion establishment o high uality isolation acilities to treat
ictims and absolutely rigid in ection control measures to
handle in ected persons corpses and B V in ected material
are essential.
Dixon MG, et al: Ebola viral disease outbreak—West Africa 2014.
MMWR Morb Mortal Wkly Rep 2014; 63:548.
Gatherer D: The 2014 Ebola virus disease outbreak in West Africa. J
Gen Virol 2014; 95:1619.
Nkoghe D, et al: Cutaneous manifestations of Filovirus infections. Int J
Dermatol 2012; 51:1037.
PARAMYXOVIRUS GROUP
The paramy o iruses are R A iruses that range in si e rom
to nm. n this group the iral diseases o dermatologic
interest are measles (rubeola) and German measles (rubella).
ther iruses o this group are mumps irus parain uen a
irus ewcastle disease irus and respiratory syncytial irus.
Measles
easles is a highly in ectious and potentially atal iral in ec
tion. ighly e ecti e two dose accines are a ailable and
when countries reach a rate o accination measles elimi
nation has been achie ed. owe er measles remains a ma or
health problem in many nations including de eloped coun
tries that pro ide immuni ations to their population. ore
than cases o measles occurred in urope o er years
. This epidemic is ongoing and has spurred an elimi
nation program. umerous hospitali ations and e en deaths
rom measles are still occurring in these de eloped nations.
The ma ority o cases are in un accinated persons supporting
the concept that accination (speci cally two doses) is protec
ti e and that these measles epidemics and deaths are pre ent
able. Low accination le els e ist in these countries or many
reasons both philosophic and socioeconomic. Since the chil
dren in un accinated groups may share common schools
camps and social networ s they pro ide a prime breeding
tahir99 - UnitedVRG
ground or epidemics. Some de eloped uropean and Asian
countries (notably Japan with cases annually) ha e
not been able to achie e high immuni ation le els meaning
that their populations are still at ris . The lac o herd
immunity in these nations lea es at particular ris those
Paramyxovirus group
in ants and susceptible children who cannot be immuni ed
because o other medical conditions. Cases o measles continue
to be imported into the nited States which ha e resulted in
numerous outbrea s due to signi cant numbers o nonim
mune persons. A ected persons ha e not been ade uately
immuni ed and when e posed to a person rom an endemic
area de elop disease. Dermatologists and pediatricians in the
Americas need to be alert or cases o measles when seeing
persons rom these countries or un accinated persons rom
the Americas who ha e tra eled to nations nown to ha e
ongoing measles outbrea s.
Also nown as rubeola and morbilli measles was a world
wide disease that most o ten a ected children under months
o age. n the current epidemics howe er older children ado
lescents and adults can be a ected. The ast ma ority o those
de eloping disease ha e not been ade uately immuni ed.
easles is spread by respiratory droplets and has an incuba
tion period o days.
The prodrome consists o e er malaise con uncti itis and
prominent upper respiratory symptoms (nasal congestion
snee ing cory a cough). A ter days the e anthem appears
usually as macular or morbilli orm lesions on the anterior scalp
line and behind the ears. Lesions begin as discrete erythema
tous papules that gradually coalesce. The rash spreads uic ly
o er the ace ( ig. ) then by the second or third day (unli e
the more rapid spread o rubella) e tends down the trun to
the e tremities. By the third day the whole body is in ol ed.
Lesions are most prominent and con uent in the initially
in ol ed areas and may be more discrete on the e tremities.
Purpura may be present especially on the e tremities and
should not be con used with blac measles a rare dissemi
nated intra ascular coagulation li e complication o measles.
opli spots which are pathognomonic appear during the
prodrome ( ig. ). The spots appear rst on the buccal
mucosa nearest to the lower molars as mm white papules on
an erythematous base. They may spread to in ol e other areas
o the buccal mucosa and pharyn . They ha e been less re
uently reported in recent outbrea s. A ter days the e an
them clears with simultaneous subsidence o the e er.
Fig. 19-38 Measles.
393

19
Viral Diseases
Fig. 19-39 Koplik spots.
Complications include otitis media pneumonia encephali
tis and thrombocytopenic purpura. ncephalitis although
rare (< o cases) can be atal. n ection in pregnant patients
is associated with etal death. Complications and atalities are
more common in children who are undernourished or ha e
T cell de ciencies. n V in ected children the e anthem
may be less prominent.
odi ed measles occurs in a partially immune host as a
result o prior in ection persistent maternal antibodies or
immuni ation and this is a milder disease. Patients may ha e
only e er or e er and a rash. The course is shorter the e an
them less con uent and opli spots may be absent. t is
n
di cult to di erentiate modi ed measles rom other iral
e anthems.
U
A diagnosis o measles is established by the presence o a
high e er opli spots the characteristic con uncti itis upper
-
respiratory symptoms and typical e anthem. Lymphopenia is
common with a decreased WBC count. Biopsies o s in lesions
may show syncytial eratinocytic giant cells similar to those
9
seen in respiratory secretions. Laboratory con rmation can be
with acute and con alescent serologic tests. denti cation o
ri 9
irus speci c g ( days a ter the rash presents) is highly
suggesti e o in ection in an unimmuni ed indi idual. done
too early howe er a serum g assay may lead to a alse
negati e result and the test should be repeated. Virus isolation
h
is also possible. The combination o g serologic testing and
irus isolation is the current gold standard or diagnosis. ew
ta
PCR based technologies can rapidly detect the measles irus
genome in urine oropharyngeal secretions and blood and are
highly use ul in modi ed and pre iously accinated patients.
Rubella scarlet e er secondary syphilis entero irus in ec
tions and drug eruptions are in the di erential diagnosis.
Administration o high doses o itamin A will reduce the
morbidity and mortality o hospitali ed children with measles.
Two doses o retinyl palmitate h apart are rec
ommended or all children months o age immunode
cient children children with malnutrition or e idence o
itamin A de ciency and recent immigrants rom areas o
high measles mortality. therwise treatment is symptomatic
with bed rest analgesics and antipyretics.
Li e irus accination is recommended at age months
with a booster be ore entering school (age years). A aint
maculopapular e anthem may occur days a ter immuni
ation. Prophyla is with accination and immune globulin
should be o ered to e posed susceptible persons. t must be
pro ided within the rst ew days a ter e posure so identi
cation o susceptible persons is critical. Vaccination can be
e ecti e i gi en within days o e posure and immune
394
globulin is gi en at a dose o . mL g up to days a ter
contact. n an Australian outbrea
o possible secondary cases.
these strategies pre ented
Rubella
Rubella commonly nown as German measles is caused by a
toga irus and probably spreads by respiratory secretions. The
incubation period is days (usually ). Li e irus
accination is highly e ecti e pro iding li elong immunity.
There is a prodrome o days consisting o e er malaise
sore throat eye pain headache red eyes runny nose and
adenopathy. Pain on lateral and upward eye mo ement is
characteristic. The e anthem begins on the ace and progresses
caudad co ering the entire body in h and resol ing by the
third day. The lesions are typically pale pin morbilli orm
macules smaller than those o rubeola. The eruption may
resemble roseola or erythema in ectiosum. An e anthem o
pinhead si ed red macules or petechiae on the so t palate and
G
u ula ( orchheimer s sign) may be seen. Posterior cer ical
suboccipital and postauricular lymphadenitis occurs in more
R
than hal o cases. Rubella is in general a much milder disease
than rubeola. Arthritis and arthralgias are common complica
V
tions especially in adult women lasting month or longer.
The diagnosis is con rmed by nding rubella speci c g in
d
oral uids or the serum. This g de elops rapidly but
o sera drawn on the rst day o the rash are negati e. The
ti e
irus is rapidly cleared rom the blood being absent by day
o the rash. owe er the irus is ound in oral secretions or
days a ter the rash has appeared. PCR based techni ues
to identi y irus in oral secretions may detect in ection more
e ecti ely in earlier samples. The combination o PCR based
irus detection tests and identi cation o rubella irus speci c
g will result in rapid con rmation o most cases o rubella
within the rst ew days o appearance o disease symptoms.
Congenital rubella syndrome
n ants born to mothers who had rubella during the rst tri
mester o pregnancy may ha e congenital cataracts cardiac
de ects and dea ness. umerous other mani estations such as
glaucoma microcephaly and arious isceral abnormalities
may emerge. Among the cutaneous e pressions are thrombo
cytopenic purpura; hyperpigmentation o the na el orehead
and chee s; bluish red in ltrated mm lesions ( blueberry
mu n type) which represent dermal erythropoiesis; chronic
urticaria; and reticulated erythema o the ace and e tremities.
Andersen DV, Jørgensen IM: MMR vaccination of children with egg
allergy is safe. Dan Med J 2013; 60:A4573.
Caseris M, et al: French 2010–2011 measles outbreak in adults: report
from a Parisian teaching hospital. Clin Microbiol Infect 2014; 20:O242.
Centers for Disease Control and Prevention: Recommendations from an
ad hoc meeting of the WHO Measles and Rubella Laboratory Network
(LabNet) on use of alternative diagnostic samples for measles and
rubella surveillance. MMWR 2009; 57:657.
Gahr P, et al: An outbreak of measles in an undervaccinated community.
Pediatrics 2014; 134:e220.
Giusti D, et al: Virological diagnosis and management of two cases of
congenital measles. J Med Virol 2013; 85:2136.
Muscat M, et al: Measles in Europe: an epidemiological assessment.
Lancet 2009; 373:383.
Nagai M, et al: Modified adult measles in outbreaks in Japan, 2007–
2008. J Med Virol 2009; 81:1094.
Nakayama T: Laboratory diagnosis of measles and rubella infection.
Vaccine 2009; 27:3228.
Ortega-Sanchez IR, et al: The economic burden of sixteen measles
outbreaks on United States public health departments in 2011;
Vaccine 2014; 32:1311.
 Sammons JS: Ready or not: responding to measles in the
postelimination era. Ann Intern Med 2014; 161:145.
Sheikine Y, et al: Histopathology of measles exanthem: a case with
characteristic features and eosinophils. J Cutan Pathol 2012; 39:667.
Sheppeard V, et al: The effectiveness of prophylaxis for measles
about e ery years. The irus is spread by the respiratory
route and in ection rates are ery high within households.
ost in ections are asymptomatic. The propensity or par o
irus B to a ect the bone marrow is re ected by the presence
o thrombocytopenia or leu openias during the acute in ec

contacts in NSW. NSW Public Health Bull 2009; 20:81.
Tanne JH: Rise in US measles cases is blamed on unimmunized
travelers. BMJ 2014; 348:g3478.
Tapisiz A, et al: Prevention of measles spread on a paediatric ward.
Epidemiol Infect 2014; May 30. [Epub ahead of print.]
Tod B, et al: Dermatological manifestations of measles infection in
hospitalized paediatric patients observed in the 2009–2011 Western
Cape epidemic. S Afr Med J 2012; 102:356.
Young MK, et al: Post-exposure passive immunization for preventing
measles. Cochrane Database Syst Rev 2014; 4:CD010056.
Zipprich J, et al: Measles—California, January 1–April 18, 2014. MMWR
2014; 63:362.
Asymmetric periflexural exanthem
of childhood (APEC)
This clinical syndrome also nown as unilateral laterothoracic
e anthem occurs primarily in the late winter and early spring
and appears to be most common in urope. t a ects girls
more o ten than boys ( . to ). t occurs in children
months to years o age but most cases are between and
years. ultiple cases ha e been reported in adults. The cause
is un nown but a iral origin has been proposed because it
occurs in young children and is seasonal and secondary cases
in amilies ha e been reported. o reproducible iral etiology
has been implicated; howe er at least three cases attributed
to par o irus B ha e been reported. Clinically two thirds
to three uarters o a ected children ha e symptoms o a mild
upper respiratory or G in ection usually preceding the erup
tion. The lesions are usually discrete mm erythematous
papules that coalesce to poorly marginated morbilli orm
pla ues. Pruritus is usually present but is mild. Lesions begin
unilaterally close to a e ural area usually the a illa ( o begins consisting o discrete erythematous macules and
cases). Spread is centri ugal with new lesions appearing on
the ad acent trun and pro imal e tremity. ormal s in may
inter ene between lesions. The contralateral side is in ol ed
in o cases a ter days but the asymmetric nature is
maintained throughout the illness. Lymphadenopathy o the
nodes on the initially a ected side occurs in about o
patients. The AP C syndrome lasts wee s on a erage but
may last more than months and resol es spontaneously.
Topical corticosteroids and oral antibiotics are o no bene t
but oral antihistamines may help associated pruritus. isto
logically a mild to moderate lymphocytic (CD + T cell) in l
trate surrounds and in ol es the eccrine ducts but not the
secretory coils. There may be an accompanying inter ace der
matitis o the upper eccrine duct and ad acent epidermis.
Arun B, Salim A: Transient linear eruption: asymmetric periflexural
exanthem or blaschkitis. Pediatr Dermatol 2010; 27:301.
Chan PKS, et al: Asymmetric periflexural exanthema in an adult. Clin
Exp Dermatol 2004; 29:311.
Guimera-Martin-Neda G, et al: Asymmetric periflexural exanthem of
childhood: report of two cases with parvovirus B19. J Eur Acad
Dermatol Venereol 2006; 20:461.
Parvovirus group
tion. Par o irus B is the prototype or the concept o one
irus many e anthems. The patient may ha e multiple types
o e anthems simultaneously or se uentially. rythema in ec
tiosum and papular purpuric glo es and soc s syndrome are
both strongly associated with par o irus B in ection. Par o
irus B may also play a role in some cases o GCS and AP C.
ther nown complications o this iral in ection include
arthropathy (especially in middle age emales) aplastic crisis
in hereditary spherocytosis and sic le cell disease and chronic
anemia in immunosuppressed patients. n ection o a pregnant
woman leads to transplacental in ection in o cases and a
etal loss rate o . Acute iral myocarditis and pericarditis
are re uently secondary to par o irus B in ection.
Erythema infectiosum (fifth disease)
rythema in ectiosum is a worldwide benign in ectious e an
them that occurs in epidemics in the late winter and early
spring. n normal hosts (but not immunosuppressed or sic le
cell patients in crisis) iral shedding has stopped by the time
the e anthem appears ma ing isolation unnecessary. The
incubation period is days (a erage days). n re uently
a mild prodrome o headache runny nose and low grade
e er may precede the rash by or days.
rythema in ectiosum has three phases. t begins abruptly
with an asymptomatic erythema o the chee s re erred to
as slapped chee . The erythema is typically di use and
macular but tiny translucent papules may be present. t is
most intense beneath the eyes and may e tend o er the chee s
in a butter y wing pattern. The perioral area lids and chin
are usually una ected. A ter days the second phase
papules on the pro imal e tremities and later the trun . This
e ol es into a reticulate or lacy pattern ( ig. ). These two
phases typically last days. A characteristic third phase is
the recurring stage. The eruption is greatly reduced or in isi
ble only to recur a ter the patient is e posed to heat (especially
Fig. 19-40 Erythema
infectiosum.

PARVOVIRUS GROUP
Par o irus B is the most common agent in this Er throvirus
genus to cause human disease. n ection is worldwide occur
ring in o persons by age . The ast ma ority o elderly
adults are seropositi e. n ections are more common in the
spring in temperate climates. pidemics in communities occur
395

tahir99 - UnitedVRG

19
Viral Diseases
Fig. 19-41 Papular-purpuric gloves-and-socks syndrome.
when bathing) or sunlight or in response to crying or e ercise.
About o children with erythema in ectiosum ha e arthral
gias whereas o adults especially women ha e oint
in ol ement. ecroti ing lymphadenitis may also occur in the
cer ical epitrochlear supracla icular and intra abdominal
lymph nodes. Children with aplastic crisis caused by par o i
rus B usually do not ha e a rash. owe er e en healthy
children can de elop signi cant bone marrow complications
although transient and sel limited.
Papular-purpuric gloves-and-socks syndrome
n
The papular purpuric glo es and soc s (or glo e and stoc
ing) syndrome (PPGSS) which is less common than erythema
U
in ectiosum occurs primarily in teenagers and young adults.
Pruritus edema and erythema o the hands and eet appear
-
and a e er is present. The lesions are sharply cut o at the
wrists and an les ( ig. ). er a ew days they become
purpuric. There is a mild erythema o the chee s elbows
9
nees and groin olds. ral erosions shallow ulcerations aph
thous ulcers on the labial mucosa erythema o the pharyn
ri 9
opli spots or petechial lesions may be seen on the buccal
or labial mucosa. The lips may be red and swollen. Vul ar
edema and erythema accompanied by dysuria may be seen.
An unusual ariant is a unilateral petechial and erythematous
h
eruption o the a illa. The acral erythema may rarely mo e
pro imally along lymphatics simulating a lymphangitis.
a
t
Transient lymphocytopenia decreased platelet count and
ele ated L Ts may be seen. PPGSS resol es within wee s.
idence o serocon ersion or par o irus B has been ound
in most reported patients. istologically a dermal in ltrate o
CD + T lymphocytes surrounds the upper dermal essels.
There is an inter ace component and prominent e tra asation
o red blood cells in petechial lesions. Par o irus B antigen
has been ound in the endothelial cells sweat glands and
ducts and epidermis. Because the antigen is located in the
endothelial cells a leu ocytoclastic asculitis picture both
clinically and histologically may be seen. Similarly. a Degos
disease li e morphology can occur. n V in ected patients
who de elop PPGSS the eruption is more persistent lasting
wee s to months and is associated with anemia.
ot all cases o PPGSS are caused by par o irus B . n
adults it may be associated with BV in ection. n children
the syndrome occurs at an a erage age o months. The
eruption lasts an a erage o wee s. Also in children C V
and BV are the most common documented causes in Taiwan
where PPGSS appears to be ery common in the last uarter
o the year.
396
Other skin findings attributed to parvovirus B19
n some patients the e anthem o par o irus B a ects pri
marily the e ural areas especially the groin. This may present
as AP C (see earlier) petechiae in the groin or an erythema
studded with pustules in the groin and to a lesser degree in
the a illae resembling baboon syndrome. The petechial erup
tion o PPGSS may also in ol e the perioral area and has been
termed the acropetechial syndrome. An outbrea in erala
ndia described children mostly under age years who
presented with high e er and a di use intensely erythema
tous tender s in eruption. The children were ery irritable
and cried when held. Their s in was e tremely swollen and
whole body edema was present. The acute e anthem was ol
lowed by di use des uamation. There were no secondary
cases. g or par o irus B was detected in o cases
tested. The authors called this red baby syndrome.
n ection with par o irus B may trigger a hemophagocytic
(or macrophage acti ation) syndrome. This presents with pro
gressi e cytopenias li er dys unction coagulopathy high er
G
ritin le el and hemophagocytosis. umerous nonspeci c
eruptions ha e been described with hemophagocytic syn
R
drome including nodules ulcers purpura and panniculitis.
The diagnostic hemophagocytic cells may occasionally be iden
V
ti ed in s in biopsies. n ection with par o irus B may lead
to cutaneous necrosis in persons with a hypercoagulable state
d
such as paro ysmal nocturnal hemoglobinuria. The presence
o edema purpuric lesions acial erythema e er cytopenias
ti e
and hypocomplementemia e en with positi e antinuclear
antibodies allows or se ere cases o par o irus B in ection
to be con used with systemic lupus erythematosus.
Bello S, et al: Papular-purpuric gloves and socks syndrome due to
parvovirus B19: a report of two simultaneous cases in cohabitant
families. Reumatismo 2013; 65:40.
Butler GJ, et al: Parvovirus B19 infection presenting as “bathing trunk”
erythema with pustules. Australas J Dermatol 2006; 47:286.
Cooray M, et al: Parvovirus infection mimicking systemic lupus
erythematosus. CMAJ 2013; 185:1342.
Cugler T, et al: Severe glomerulonephritis and encephalopathy
associated with parvovirus B19 infection mimicking systemic lupus
erythematosus. Scand J Rheumatol 2012, 41:79.
Cunha BA, Chandrankunnel J: Parvovirus B19 with a scarlatiniform/
rubelliform rash and small joint arthritis mimicking rubella in an adult.
Trav Med Infect Dis 2012; 10:208.
Dyrsen ME, et al: Parvovirus B19–associated catastrophic
endothelialitis with a Degos-like presentation. J Cutan Pathol 2008;
35:20.
Eng S, et al: Fever and petechial rash in a 9-year-old boy. Pediatr Rev
2012; 33:369.
Fruhauf J, et al: Bullous papular-purpuric gloves and socks syndrome in
a 42-year-old female: molecular detection of parvovirus B19 DNA in
lesional skin. J Am Acad Dermatol 2008; 60:691.
Gutermuth J, et al: Papular-purpuric gloves and socks syndrome.
Lancet 2011; 378:198.
Hashimoto H, Yuno T: Parvovirus B19-associated purpuric-petechia
eruption. J Clin Virol 2011; 52:269.
Mage V, et al: Different patterns of skin manifestations associated with
parvovirus B19 primary infection in adults. J Am Acad Dermatol 2014;
71:62.
McNeeley M, et al: Generalized petechial eruption induced by
parvovirus B19 infection. J Am Acad Dermatol 2005; 52:S109.
Pedrossa AF, et al: Haemophagocytic syndrome with a fatal outcome
triggered by parvovirus B19 infection in the skin. Clin Exp Dermatol
2014; 39:216.
Sakai H, et al: Hemophagocytic syndrome presenting with a facial
erythema in a patient with systemic lupus erythematosus. J Am Acad
Dermatol 2007; 57:S111.
Santonja C, et al: Immunohistochemical detection of parvovirus B19 in
“gloves and socks” papular purpuric syndrome: direct evidence for
viral endothelial involvement—report of three cases and review of the
literature. Am J Dermatopathol 2011; 33:790.
 Sasidharan CK, et al: Red baby syndrome: a new disease due to
parvovirus B-19 observed in Kerala. Indian J Pediatr 2009; 76:309.
Valentin MN, Cohen PJ: Pediatric parvovirus B19: spectrum of clinical
manifestations. Cutis 2013; 92:179.
Wiggli B, et al: Water, water, everywhere. Lancet 2013; 381:776.
ARBOVIRUS GROUP (TOGAVIRIDAE)
The arbo iruses comprise the numerous arthropod borne
R A iruses. These iruses multiply in ertebrates as well as
in arthropods. The ertebrates usually act as reser oirs and
the arthropods as ectors o the arious diseases.
West Nile fever
West ile irus (W V) is a a i irus that is endemic in ast
A rica. t rst appeared in eastern orth America in and
reached Cali ornia by . t is primarily an in ection o the
crow amily (crows ra ens magpies and blue ays). t is
spread by Culex mos uitoes. Appro imately o in ected
persons will ha e no symptoms. A ter an incubation period
o days a ebrile illness o sudden onset occurs. ead
ache myalgia arthralgia con uncti itis pharyngitis cough
adenopathy abdominal pain hepatitis pancreatitis and myo
carditis are recogni ed clinical mani estations. The primary
complications howe er are neurologic disease including sei
ures ( o symptomatic adults) ascending accid paraly
sis (as in poliomyelitis) ata ia meningitis encephalitis
myelitis cranial neuropathies optic neuritis and reduced
le el o consciousness. A signi cant percentage o a ected
persons are le t with permanent neurologic se uelae. About
o hospitali ed patients will ha e an e anthem. The e an
thema o W V is nonpruritic and composed o ery
thematous poorly de ned macules . cm in diameter
primarily on the trun and pro imal e tremities. t lasts
days and resol es without scaling.
Sandfly fever
Sand y e er is also nown as phlebotomus e er and pap
pataci e er. The ector Phlebotomus papatasii is ound in the
editerranean area (Sicilian e er aples e er and Toscana
irus) Russia China and ndia. Sicilian and aples sand y
e er iral in ections disappeared or dramatically decreased
with mos uito eradication programs Toscana irus in ection
is still common. Although most in ected persons are asymp
tomatic o aseptic meningitis cases in the summer in
endemic areas are caused by this agent. Small pruritic papules
appear on the s in a ter the sand y bite and persist or days.
A ter an incubation period o another days e er headache
malaise nausea con uncti al in ection sti nec and abdomi
nal pains suddenly de elop. The s in mani estations consist
o a scarlatini orm eruption on the ace and nec . Reco ery is
slow with recurring bouts o e er. o speci c treatment is
a ailable.
Dengue
ore than million cases o dengue occur annually world
wide and the global pre alence is growing. n uropean hos
pitals that e aluate patients with e er a ter trips to the tropics
dengue is the most common ebrile illness in tra elers return
ing rom Southeast Asia who de elop a e er within month
o the trip. t is transmitted by e es mos uitoes which ha e
tahir99 - UnitedVRG
adapted well to li ing around humans in urban en ironments.
t a ects primarily tropical regions where temperatures rarely
drop below C a oring the reproduction o the mos uito
ector. Southeast Asia and the Western Paci c are the most
se erely a ected regions but ndia Cuba and the tropical
Arbovirus group (Togaviridae)
Americas also ha e numerous cases. There ha e been se eral
.S. outbrea s in ouston Te as and ey West lorida and
many o these cases appear not to ha e been imported sug
gesting dengue is potentially endemic in these climates.
Persons o A rican ancestry seem to be at much less ris o
de eloping dengue.
Dengue e er begins days a ter the in ectious mos uito
bite. The clinical eatures are characteristic and consist o the
sudden onset o high e ers accompanied by myalgias head
ache retro orbital pain and se ere bac ache (brea bone e er).
Common associated laboratory ndings include ele ated L Ts
(about three times normal on a erage) thrombocytopenia
(platelet count < in o patients) and a leu openia.
These are present during the acute illness and help to suggest
dengue as the correct diagnosis. About o patients will
de elop a characteristic s in eruption. n o patients the
eruption begins between days and o the illness o ten as
the e er de er esces. The s in eruption occurs in less than
o patients be ore the onset o e er. The eruption is most o ten
generali ed ( ) or in ol es only the e tremities ( ) or the
trun ( ). Lesions are macular or morbilli orm and are
usually con uent characteristically sparing small islands o
normal s in islands o white in a sea o red ( ig. ).
Persistent blanching a ter pressing the s in can also be seen.
acial ushing may be prominent. The rash is either asymp
tomatic or only mildly pruritic. Petechiae may be present but
the nding o cutaneous hemorrhage should raise the suspi
cion o dengue hemorrhagic e er dengue shoc syndrome
(D DSS se ere dengue) . Complete reco ery occurs in
days. Biopsy o the e anthem shows minimal ndings and is
o no alue in predicting the se erity o the patient s condition
or in identi ying D DSS se ere dengue.
There are our serotypes o dengue. A ter in ection with one
serotype the indi idual is resistant to rein ection with that
serotype. owe er i that person becomes in ected with
another serotype the indi idual is at ris o de eloping se ere
complications rom the second episode o dengue. The patient s
antidengue antibodies are incapable o pre enting in ection by
or replication o the new dengue irus type. owe er antibod
ies do trigger increased iral phagocytosis by mononuclear
cells and ampli ed cyto ine production. The World ealth
Fig. 19-42 Dengue.
397
 rgani ation (W ) classi cation system di ides cases
19 into dengue without warning signs dengue with warning
signs and se ere dengue. This more ob ecti e schema is more
sensiti e in identi ying patients with early se ere dengue. The
potentially atal syndromes that can occur in dengue in ection
Viral Diseases
are characteri ed by hemorrhage (dengue hemorrhagic e er
D ) at times with e tensi e plasma lea age (dengue shoc
syndrome DSS se ere dengue). The atality rate or se ere
dengue may be as high as . The diagnosis o dengue is
made by detection o dengue speci c g in the sera by L SA
with acute and con alescent serologies demonstrating sero
con ersion. Some laboratories can detect iral R A in acute
serum samples. An e ecti e accine has not been de eloped;
the only pre enti e strategy or tra elers is to a oid mos uito
bites. n children dengue e er and awasa i disease ha e
occurred simultaneously. These two syndromes may be almost
identical in their presentation so this di erential diagnosis can
be e tremely di cult. When both diagnoses ha e been made
simultaneously the patient had persistent e er (> wee ) a
reacti e thrombocytosis a ter the initial thrombocytopenia
and in some cases characteristic cardiac lesions.
Alphavirus
Sindbis virus
n inland Sindbis irus in ection is transmitted by the Culi
seta mos uito. An eruption o multiple erythematous mm
papules with a surrounding halo is associated with e er and
prominent arthralgias. The eruption and symptoms resol e
o er a ew wee s. istologically the s in lesions show a peri
ascular lymphocytic in ltrate with large atypical cells simu
lating lymphomatoid papulosis. CD does not stain the large
cells howe er allowing their distinction.
Chikungunya virus
Chi ungunya irus is transmitted by the e es mos uito.
Deri ed rom the a onde language o sub Saharan A rica
chi ungun a means that which bends up describing the
characteristic stooped posture resulting rom the oint symp
toms o the disease. t is endemic in A rica ndia Sri Lan a
Southeast Asia the Philippines ong ong the islands o the
ndian cean and the Caribbean region. The rst .S. cases
o chi ungunya in ection were reported during summer
in southern lorida. The incubation period is days. The
patient presents with abrupt onset o high e er. Signi cant
oint symptoms are characteristic and occur in o in ected
patients. ost o ten there is swelling and pain in the small
oints o the hands and eet. The oint symptoms may persist
or wee s to months with about o patients still ha ing
some symptoms at months. Patients may de elop neuro
pathic acral ndings including Raynaud phenomenon eryth
romelalgia or se ere acral coldness as late se uelae. eadache
occurs in o patients and nausea and omiting in . notably dengue and chikungunya infections. Am J Trop Med Hyg
Lymphopenia thrombocytopenia and ele ated L Ts can be
obser ed in the rst wee o the illness. Although generally a
non atal and sel limited illness se ere complications can
occur with chi ungunya in ection causing death in about in
in ected patients.
About hal to three uarters or more o patients with chi
ungunya irus in ection de elop a rash. t is pruritic in
o the patients. The most common and characteristic
e anthem is described as morbilli orm and most re uently
a ects the arms upper trun and ace. t can be con uent and
islands o sparing can be seen. t appears by the second day o
the e er in more than hal o patients and in another on
398 the third or ourth day; only about one th o patients de elop
the eruption a ter the th day o the illness. cchymoses may
appear during the acute illness. Aphthousli e ulcerations can
occur in the oral penoscrotal and less o ten the a illary
regions. These may be preceded by intense erythema and pain
in the a ected area. A ter acute chi ungunya in ection hyper
pigmentation o the s in may occur.
A bullous eruption may occur in acute chi ungunya irus
in ection. About o those with a bullous eruption are
under year o age and most o the se ere cases occur be ore
age months. n children de elop a esiculobullous com
ponent to their eruption compared with only o adults.
There is an initial e anthem ollowed in hours or days by
accid or tense nonhemorrhagic blisters that rupture easily.
i ols y s sign is positi e. The genitalia palms and soles are
spared. There is a close resemblance to to ic epidermal necrol
ysis (T ) and up to o the total body sur ace area may
become denuded. igh titers o irus are reco ered rom
blister uid (in e cess o that present in blood). Biopsy dem
onstrates an intraepidermal blister with acantholytic cells
oating ree in the blister ca ity. These patients are managed
similar to burn patients and most reco er. S in gra ting
usually is not re uired.
The diagnosis o chi ungunya irus in ection is made by
detecting irus speci c g in the serum. Con rmation is by
serocon ersion o er the ne t se eral months with de elop
ment o irus speci c gG. PCR based methods may detect
iral genome in the blisters or serum during the acute illness.
t may be di cult to di erentiate dengue rom chi ungunya
e er because both are endemic in the same geographic
regions and their clinical symptoms and laboratory ndings
are similar. Arthralgias occur in a signi cant percentage o
patients with chi ungunya irus in ection approaching
in those with a rash but also occur in patients with dengue.
eutropenia is seen in o dengue patients and only
o chi ungunya patients. A positi e tourni uet test does not
distinguish these two in ections but thrombocytopenia is more
common in dengue ( + ) than chi ungunya ( ) patients.
Bandyopadhyay D, et al: Mucocutaneous features of chikungunya fever:
a study from an outbreak in west Bengal, India. Int J Dermatol 2008;
47:1148.
Borgherini G, et al: Outbreak of chikungunya on Reunion Island: early
clinical and laboratory features in 157 adult patients. Clin Infect Dis
2007; 44:1401.
Bouri N, et al: Return of epidemic dengue in the United States:
implications for the public health practitioner. Public Health Rep 2012;
127:259.
Chen TC, et al: Dengue hemorrhagic fever complicated with acute
idiopathic scrotal edema and polyneuropathy. Am J Trop Med Hyg
2008; 78:8.
Dang TN, et al: A replication study confirms the association of GWAS-
identified SNPs at MICB and PLCE1 in Thai patients with dengue
shock syndrome. BMC Med Genet 2014; 15:58.
De la C, et al: Race: a risk factor for dengue hemorrhagic fever. Arch
Virol 2007; 152:533.
Del Giudice P, et al: Skin manifestations of West Nile virus infection.
Dermatology 2005; 211:348.
Hochedez P, et al: Management of travelers with fever and exanthema,
2008; 87:710.
Ju H, Brasier AR: Variable selection methods for developing a biomarker
panel for prediction of dengue hemorrhagic fever. BMC Res Notes
2013, 6:365.
Kenzaka T, Kumabe A: Skin rash from dengue fever. BMJ Case Rep
2013; Nov 25; bcr2013201598.
Lupi O, Tyring SK: Tropical dermatology: viral tropical diseases. J Am
Acad Dermatol 2003; 49:979.
Macedo GA, et al: Sensitivity and specificity of the World Health
Organization dengue classification schemes for severe dengue
assessment in children in Rio de Janeiro. PLoS One 2014;
9:e96314.
Mahboob A, et al: Dermatological manifestations of dengue fever.
J Ayub Med Coll Abbottabad 2012; 24:52.
 Murray KO, et al: Identification of dengue fever cases in Houston, Texas,
with evidence of autochthonous transmission between 2003 and 2005.
Vector Borne Zoonotic Dis 2013; 13:835.
Rathakrishnan A, et al: Clinical and immunological markers of dengue
progression in a study cohort from a hyperendemic area in Malaysia.
PLoS One 2014; 9:e92021.
Ribeiro E, et al: Primary dengue fever associated with hemophagocytic
syndrome: a report of three imported cases, Bordeaux, France. Intern
Med 2014; 53:899.
Robin S, et al: Severe bullous skin lesions associated with chikungunya
virus infection in small infants. Eur J Pediatr 2010; 169:67.
Saadiah S, et al: Skin histopathology and immunopathology are not of
prognostic value in dengue haemorrhagic fever. Br J Dermatol 2008;
158:836.
Singh S, et al: Dengue fever and Kawasaki disease: a clinical dilemma.
Rheumatol Int 2009; 29:717.
Thomas EA, et al: Mucocutaneous manifestations of dengue fever.
Indian J Dermatol 2010; 55:79.
Valassina M, et al: A Mediterranean arbovirus: the Toscana virus.
J Neurovirol 2003; 9:577.
Wong JG, et al: Self-reported pain intensity with the numeric reporting
scale in adult dengue. PLoS One 2014; 9:e96514.
PAPOVAVIRUS GROUP
Papo a iruses are na ed dsD A iruses characteri ed as slow
growing. They replicate inside the nucleus. Because papo a i
ruses contain no en elope they are resistant to drying ree
ing and sol ents. n addition to the human papilloma iruses
which cause warts papilloma iruses o rabbits and cattle
polyoma iruses o mice and acuolating iruses o mon eys
are some o the other iruses in the papo a irus group.
Warts (verruca)
There are more than types o human papilloma irus
( PV). The genome o PV consists o early genes (E E E
E E and E ) two late genes (L and L ) and in between an
upstream regulatory region ( RR). L and L code or the
ma or and minor capsid proteins. L encodes or the ma or
capsid protein and sel assembles into irusli e particles
(VLPs). These VLPs are the antigens in currently a ailable
PV accines. The L gene encodes the minor capsid protein
and has at least two important unctions. L protein helps
e pose the eratinocyte binding determinant o the L protein
allowing or the PV to bind onto the basal eratinocyte and
to be ta en into the cell. The processing o PV sur ace pro
teins in the s in ta es up to hours allowing or e posure
to anti PV antibodies. The L protein also is immunomodu
latory downregulating the unction o Langerhans cells
through the phosphoinositide inase pathway. A new PV
type is de ned when there is less than D A homology
with any other nown type in the L and E genes. Viruses
with homology are classi ed as subtypes. The gene
se uences rom PVs throughout the world are similar. ost
PV types cause speci c types o warts and a or certain
anatomic locations such as plantar warts common warts and
genital warts. PVs and cause the ast ma ority o
cutaneous (nongenital) warts. PV is associated with plantar
warts in children younger than years. PV is more
common in hand warts. PV and PV are associated
with common and plantar warts in adults (> years). ternal
genital warts are caused by PV and anogenital dyspla
sia by PV . A large proportion o the PV types rarely
cause warts and appear to be pathogenic only in immunosup
pressed patients or those with epidermodysplasia erruci or
mis. owe er many persons may carry or may be latently
in ected with these rare wart types e plaining the uni ormity
o gene se uence and clinical presentation worldwide. n the
tahir99 - UnitedVRG
immunosuppressed patient PV types may cause warty
lesions o a di erent clinical morphology than in an immuno
competent host.
n ection with PV may be clinical subclinical or latent.
Clinical lesions are isible by gross inspection. Subclinical
Papovavirus group
lesions may be seen only by aided e amination (e.g. acetic
acid soa ing). Latent in ection describes the presence o PV
or iral genome in apparently normal s in. Latent in ection is
thought to be common especially in genital warts and e plains
in part the ailure o destructi e methods to eradicate warts.
n ection with PV is e tremely common; most people will
e perience in ection during their li etime. n Australia
and in The etherlands o schoolchildren were ound to
ha e nongenital cutaneous warts. Common warts are ound
in about o children plantar warts in (higher
in The etherlands than Australia) and at warts are only
reported in schoolchildren rom Australia ( ). White persons
ha e isible cutaneous warts twice as re uently as other eth
nicities. Genital warts begin to appear with se ual acti ity
with o women ac uiring PV in ection be ore they ha e
intercourse suggesting oral digital genital to genital contact
is capable o transmitting PV. PV in ection rates including
latent in ection e ceed in se ually acti e populations in
many parts o the world.
uman papilloma iruses ha e coe isted with humans
or many millennia and humans are their primary host and
reser oir. PVs ha e been success ul pathogens o human
because they e ade the human immune response. This is
achie ed primarily through a oiding the e pression o anti
gens on the sur ace o eratinocytes until the eratinocytes are
abo e the le el o the antigen presenting cells in the epider
mis. PVs also reduce Langerhans cells in the icinity o in ec
tion and inacti ate them through the L protein on their
sur ace. Through E and E PV reduces local production o
ey immune reactants (e.g. TLR L ) muting the local
immune response. PVs thus li e in e uilibrium with their
human hosts through a combination o immune e asion and
programmed immune suppression (tolerance).
anagement o warts is based on their clinical appearance
and location and the patient s immune status. n general warts
o all types are more common and more di cult to treat in
persons with suppressed immune systems. cept in W
syndrome (warts hypogammaglobulinemia in ection and
myelo athe is gain o unction mutation o C C ) syn
dromes o reduced immunoglobulin production or B cell unc
tion are not associated with increased PV in ection. edical
conditions or treatments associated with suppression o cell
mediated immunity are associated with high rates o clinical
PV in ection and PV induced neoplasias. The common
clinical scenarios are iatrogenic medications (e.g. in organ
transplant recipients) iral in ections that result in T cell de
ciency (e.g. V) and congenital syndromes o T cell immu
node ciency. Patients with GATA de ciency re uently
present with e tensi e warts. W LD syndrome is the associa
tion o primary lymphedema disseminated warts and ano
genital dysplasia with depressed cell mediated immunity and
probably represents GATA de ciency. diopathic CD lym
phopenia and autosomal recessi e hyper g syndrome
caused by D C de ciency are two other T cell immunode
ciency states associated with PV in ection. Because warts
in some anatomic regions are important co actors in cancer
histologic e aluation o warty lesions in the immunode cient
patient can be critically important.
Verruca vulgaris
Common warts are a signi cant cause o concern and rustra
tion or patients ( igs. and ). Social acti ities can be
a ected lesions can be uncom ortable or bleed and treatment 399

19
Viral Diseases
Fig. 19-43 Verruca vulgaris.
Fig. 19-44 Verruca, nail biter with perioral warts.
is o ten pain ul and rustratingly ine ecti e. uman papillo
ma irus types and cause common warts.
Common warts occur mainly between ages and and only
occur a ter age . re uent immersion o hands in water
is a ris actor or common warts. a ing amily members and
schoolmates with warts is associated with ha ing warts; public
e posures such as swimming pools public showers and going
bare oot are associated to a lesser degree. eat handlers
(butchers) sh handlers and other abattoir wor ers ha e a
high incidence o common warts o the hands. The pre alence
reaches in those who ha e direct contact with meat. Warts
in butchers are caused by PV and PV ; up to o plantar warts e cept or their hyperpigmentation. They are
hand warts rom butchers are caused by PV which is
ound only on the hands where there is direct contact
with meat. PV is rarely ound in warts in the general popu
lation (< . ). The source o PV is un nown but PV
is not bo ine papilloma irus and does not come rom the
slaughtered animals. PV has been reported to cause dys
trophy o all ngernails with mar ed subungual hyper
eratosis and destruction o the nail plate without periungual
in ol ement.
The natural history o common warts is or spontaneous
resolution. Reported clearance rates in children are at
months at months at year at years
and o er years. Common warts are usually located on
the hands a oring the ngers and palms. Periungual warts
are more common in nail biters and may be con uent in ol
ing the pro imal and lateral nail olds. issuring may lead to
bleeding and tenderness. Lesions range in si e rom pinpoint
to more than cm most a eraging about mm. They grow in
si e or wee s to months and usually present as ele ated
rounded papules with a rough grayish sur ace which is so
400
Fig. 19-45 Verruca
plana, flat wart with
koebnerization.
characteristic that it has gi en us the word errucous used
to describe lesions with similar sur ace character (e.g. sebor
rheic eratosis). n some cases a single wart (mother wart)
appears and grows slowly or a long time and then suddenly
many new warts erupt. n the sur ace o the wart tiny blac
dots may be isible representing thrombosed dilated capil
laries. Trimming the sur ace eratin ma es the capillaries
more prominent and may be used as an aid in diagnosis. Warts
do not ha e dermatoglyphics ( ngerprint olds) in contrast to
calluses in which these lines are accentuated.
Common warts may occur anywhere on the s in apparently
spreading rom the hands by autoinoculation. n nail biters
warts may be seen on the lips and tongue usually in the
middle hal and in re uently in the commissures. Digitate or
li orm warts tend to occur on the ace and scalp and present
as single or multiple spi es stuc on the sur ace o the s in.
Pigmented warts
Pigmented warts ha e re uently been reported in Japan. They
appear on the hands or eet and resemble common warts or
caused by PVs and . The pigmentation is caused by
melanocytes in the basal cell layer o the PV in ected tissue
which contain large amounts o melanin. This is proposed to
be caused by melanocyte bloc ade or the inability o the
melanocytes to trans er melanin to the PV in ected cells.
Flat warts (verruca plana)
uman papilloma irus types and most o ten cause
at warts. Children and young adults are primarily a ected.
Sun e posure appears to be a ris actor or ac uiring at
warts. They are common on swimmers and on the sun e posed
sur aces o the ace and lower legs. lat warts present most
o ten as mm at topped papules that are slightly ery
thematous or brown on pale s in and hyperpigmented on
dar er s in. They are generally multiple and are grouped on
the ace nec dorsa o the hands wrists elbows or nees ( ig.
). The orehead chee s and nose and particularly the
area around the mouth and the bac s o the hands are the
a orite locations. n men who sha e their beards and in
 Fig. 19-46 Plantar
warts, verruca
plantaris.
women who sha e their legs numerous at warts may de elop
as a result o autoinoculation. A use ul nding is the tendency
or the warts to undergo oebneri ation orming linear
slightly raised papular lesions. yperpigmented lesions
occur and when scarcely ele ated may be con used with len
tigines or ephelides. Pla ueli e lesions may be con used with
errucous ne us lichen planus and molluscum contagiosum.
When lesions occur only on the central ace and are erythema
tous they can be easily con used with papular acne ulgaris.
all clinical PV in ections at warts ha e the highest rate
o spontaneous remission.
Plantar warts (verruca plantaris)
uman papilloma iruses and cause plantar warts.
These warts generally appear at pressure points on the ball o
the oot especially o er the midmetatarsal area but may be
anywhere on the sole. re uently se eral lesions de elop on
one oot ( ig. ). Sometimes they are grouped or se eral
contiguous warts use so that they appear as one. Such a pla ue
is nown as a mosaic wart. The so t pulpy cores are sur
rounded by a rm horny ring. er the sur ace o the plantar
wart most clearly i the top is sha ed o multiple small blac
points may be seen that represent dilated capillary loops within
elongated dermal papillae. Plantar warts may be con used
with corns or calluses but ha e a so t central core and blac or
bleeding points when pared down eatures that calluses lac .
The myrmecia type o erruca occurs as smooth sur aced
deep o ten in amed and tender papules or pla ues mostly
on the palms or soles but also beside or beneath the nails or
less o ten on the pulp o the digits ( ig. ). They are dis
tincti ely dome shaped and much bul ier beneath the sur ace
than they appear. yrmecia are caused by PV . They can
be mista en or a paronychia or digital mucinous cyst.
uman papilloma iruses causes a peculiar type o plantar
wart called a ridged wart because o the persistence o the
dermatoglyphics across the sur ace o the lesion. Typically the
warts are slightly ele ated s in colored mm papules.
They occur on non weight bearing areas and lac the typical
tahir99 - UnitedVRG
Papovavirus group
Fig. 19-47 Myrmecia.
eatures o plantar warts. PV also causes plantar erru
cous cysts . cm epithelium lined cysts on the plantar
sur ace. These cysts tend to occur on weight bearing areas
suggesting that PV in ected epidermis is implanted into the
dermis orming the cyst. t is common to see ridged warts near
plantar errucous cysts.
Histologic features
Typical nongenital warts rarely re uire histologic con rma
tion although a biopsy may be use ul in se eral settings. is
tology can be used to distinguish warts rom corns and other
eratotic lesions that they resemble. This is enhanced by P
staining or PV capsid antigen. Cytologic atypia and e ten
sion into the dermis suggest the diagnosis o an PV induced
s uamous cell carcinoma. There is a correlation between PV
type and the histologic eatures o the wart allowing identi
cation o the PV types that cause speci c lesions a use ul
eature in the diagnosis o epidermodysplasia erruci ormis
or e ample.
Treatment
The uality o e idence regarding the e cacy o therapies or
common and plantar warts is ery low. Studies ha e not used
standard treatment protocols and until recently PV type has
not been e aluated along with treatment response. This hinders
the de elopment o e idence based guidelines. The orm o
therapy used depends on the type o wart being treated the
patient s age and immune status and pre ious therapies used
and their success or ailure. With any treatment modality at
least months o sustained management is considered a rea
sonable therapeutic trial. With immunologic treatments this
may be insu cient to see a response. o treatment should be
abandoned too uic ly. Since many nongenital warts will
spontaneously regress the treatment algorithm should allow
or nonaggressi e options and the patient should be o ered
the option o no treatment. ndications or treatment are pain
inter erence with unction social embarrassment and ris o
malignancy. The ideal aims o therapy are as ollows
. To result in the wart(s) disappearing
. ot to produce scarring or permanent se uelae rom the
treatment
. deally to induce li elong immunity to that PV type to
pre ent recurrence
Flat warts
lat warts re uently undergo spontaneous remission so
therapy should be as mild as possible and potentially scarring
401
 therapies should be a oided. lesions are ew light cryother
19 apy is a reasonable consideration. Topical salicylic acid prod
ucts can also be used. Treatment with topical tretinoin once or
twice daily in the highest concentration tolerated to produce
mild erythema o the warts without ran dermatitis can be
Viral Diseases
e ecti e o er se eral months. Ta arotene cream or gel may also
be e ecti e. mi uimod cream used up to once daily can be
e ecti e. the warts ail to react initially to the imi uimod
tretinoin may be used in con unction. Should this ail
cream applied twice daily may be e ecti e. Anthralin
although staining could be similarly used or its irritant e ect.
or re ractory lesions laser therapy in ery low uences or
photodynamic therapy (PDT) might be considered be ore elec
trodesiccation because o the reduced ris o scarring. Raniti
dine mg twice daily cleared o re ractory at warts in
one study with similar results using cimetidine ( mg
g). Three months o oral isotretinoin therapy at mg day
was highly success ul and might be considered when the pre i
ous topical approaches ha e ailed. mmunotherapy with dini
trochloroben ene (D CB) s uaric acid or diphencyprone or
intralesional Can i a or other antigens can be used on limited
areas o at warts with the hope that the immune response will
clear distant warts. The induced dermatitis re uires care ul
dose monitoring when treating acial lesions.
Common warts
Treatments or common warts in ol e two basic approaches
destruction o the wart and induction o local immune reac
tions (immunotherapy). Destructi e methods are most o ten
used as initial therapy by most practitioners. Cryotherapy is a
reasonable rst line therapy or most common warts. or non
plantar warts it is more e ecti e than salicylic acid. The cure
rate is with repeated applications o er se eral months.
The wart should be ro en ade uately to produce a blister a ter
or days. This correlates with a thaw time o s or
most common warts. A sustained s ree e with a spray gun
was ound to be more e ecti e than simply ree ing to obtain
a mm halo around the wart. Aggressi e cryotherapy can
produce signi cant blistering and may be complicated by sig
ni cant postprocedural pain or se eral days. A single ree e
thaw cycle was ound to be as e ecti e as two cycles. The ideal
re uency o treatment is e ery or wee s ust as the old
blister peels o . A spray de ice while more costly is uic er
and cannot spread in ectious diseases (especially iral hepati
tis) rom one patient to the ne t. Children may be rightened
by such a de ice so a cotton tipped swab is an option or
them. Cryotherapy can be e ecti e or periungual warts.
Damage to the matri is unusual or rare because periungual
warts usually a ect the lateral nail olds not the pro imal one.
Complications o cryotherapy include hypopigmentation
in re uently scarring and rarely damage to the digital ner e
rom ree ing too deeply on the side o the digit. Patients with
anconi anemia cryoglobulinemia poor peripheral circula
tion and Raynaud phenomenon may de elop se ere blisters
when cryotherapy is used to treat their warts. Doughnut
warts with central clearing and an annular recurrence may
complicate cryotherapy.
Products containing salicylic acid with or without lactic acid
are e ecti e patient applied treatments. Results ha e been
con icting with some studies showing e ual e cacy with
cryotherapy and others showing mar ed in eriority to cryo
therapy. To optimi e salicylic acid treatment the ollowing
treatment approach is suggested. A ter the wart a ected area
is soa ed in water or min the topical medication is
applied allowed to dry and co ered with a strip bandage or
h. This is repeated daily. The super cial eratinous debris
may be remo ed by scraping with a table ni e pumice stone
or emery board.
402
Alternati ely a small amount o Cantharone ( . canthari
din) is applied to the wart allowed to dry and co ered with
occlusi e tape or h or until the patient e periences burning.
A blister similar to that produced by cryotherapy de elops
in h. These blisters may be as pain ul as or more pain ul
than those ollowing cryotherapy. Treatment is repeated e ery
wee s. Perhaps more than any other method cantharidin
tends to produce doughnut warts a round wart with a central
clear one at the site o the original wart. onetheless Can
tharone is a ery use ul ad unct in the management o di cult
to treat errucae. t also has the ad antage it can be applied
painlessly to children.
The initial enthusiasm or occlusi e therapy with tape (e.g.
duct tape) has not been substantiated by ollow up studies.
cclusi e therapy is in erior to cryotherapy and success rates
in adults are about the same as with placebo. occlusi e
therapy is contemplated a relati ely impermeable tape should
be used and the wart ept occluded at least 6 1 2 and up to
days o the wee . The ey appears to be eeping the wart
occluded as much o the time as possible. Duct tape moles in
or transparent tape (Blenderm) is a practical option. enes
trated and semipermeable dressings ha e not been studied
and may not be e ecti e. cclusi e therapy is a good initial
option or young children (< years) with plantar warts in
whom spontaneous resolution is high and or others unwill
ing to ha e alternate orms o treatment. n ortunately in
adults the e cacy o duct tape or common warts is ery low.
Two months o treatment resol ed common warts in only
o patients and o resol ed warts recurred.
Bleomycin has high e cacy and is an important treatment
or recalcitrant common warts. t is used at a concentration
o mL which is in ected into and immediately beneath
the wart until it blanches. The multipuncture techni ue o
Shelley deli ering the medication into the wart by multiple
punctures with a needle through a drop o bleomycin may
also be used as may an air et in ector. en a concentration
o . mL in ected by this method can be e ecti e. or small
warts (< mm) . mL is used and or larger warts . mL.
The in ection is pain ul enough to re uire local anesthesia in
some patients. Pain can occur or up to wee . The wart
becomes blac and the blac eschar separates in wee s.
Treatment may be repeated e ery wee s but it is unusual
or common warts to re uire more than one or two treatments.
Scarring is rare. Response rates ary by location but a erage
with two treatments or most common nonplantar warts
e en periungual ones. Treatment o nger warts with bleomy
cin in re uently may be complicated by locali ed Raynaud
phenomenon o treated ngers. Bleomycin treatment o digital
warts may rarely result in digital necrosis and permanent nail
dystrophy so e treme caution should be used in treating
warts around the nail olds. Lymphangitis cellulitis is a rare
complication. n a patient recei ing a total o or plantar
warts agellate urticaria ollowed by characteristic bleomycin
agellate hyperpigmentation occurred. ntralesional and
topical ha e been used with ariable results. Trials in
which cream was applied a ter cryotherapy demon
strated no additional bene t o er the cryotherapy alone.
Surgical ablation o warts can be e ecti e treatment but
e en complete destruction o a wart and the surrounding s in
does not guarantee that the wart will not recur. Surgical
methods should be reser ed or warts that are re ractory to
more conser ati e approaches. Pulsed dye laser therapy ini
tially appeared to ha e similar e cacy to cryotherapy but
low uences were used. n recent reports therapies with high
e cacy or re ractory warts ( ) used uences o
. J cm (a erage J cm in one study). Local anesthe
sia is re uired in the ma ority o patients. A short pulse dura
tion ( . ms) is most e ecti e. A mm spot si e is used and
treatment is e tended mm beyond the isible wart. The cryo
spray is inacti ated because epidermal destruction is the goal.
mmediately a ter treatment the s in has a gray blac discol
oration rom thermal damage. The treated area becomes an
eschar o er days. Treatment is repeated e ery wee s
as soon as the eschar alls o and multiple treatments may be
re uired. n immunocompetent patients response rates or
re ractory common and plantar warts are with this
approach. The pulsed dye laser can also be used to treat warts
around the nail that may ha e e tended below the nail plate
because the laser will penetrate the nail plate. Carbon dio ide
(C ) laser destruction re uires local anesthesia causes scar
ring and may lead to nail dystrophy. cacy is in
re ractory warts. A potentially in ectious plume is produced
with the C laser. re uency doubled neodymium ytrrium
aluminum garnet ( d AG) laser nm potassium titanyl
phosphate ( TP) laser and PDT are options in re ractory cases.
ral cimetidine mg g day has been anecdotally
reported to lead to resolution o common warts perhaps
because o its immunomodulatory e ects. When used as a
single agent howe er in both children and adults the e cacy
is low ( ) comparable with placebo. Cimetidine may be
bene cial as an ad unct to other methods especially or
patients using immunotherapy without a bris response to the
antigen. Side e ects appear to be limited. eat treatment
either locali ed to the wart and deli ered by radio re uency
or applied to the a ected part by soa ing it in a hot bath has
been reported to be e ecti e. Treatment or min at C paring salicylic acid with cryotherapy or plantar warts ersus
( . ) to as short as s at higher temperatures has
been used. treme caution must be e ercised to a oid scald
ing. ral administration o acitretin or isotretinoin may also
be used in re ractory cases.
mmunotherapy with topical and intralesional agents has
become a mainstay o wart therapy. The goal is not only that
the wart will be eradicated but that the immune reaction
induced in the wart may also lead to widespread and perma
nent immunity against warts. The agents typically used are
topical D CB s uaric acid dibutyl ester and diphencyprone
as well as intralesional Can i a or mumps antigen. n a popula
tion pre iously immuni ed with bacille Calmette Gu rin BCG
antigen may be used. or the topical immunogens patients
may be initially sensiti ed at a distant site (usually the inner
upper arm) with the topical agents or the agents may be
applied initially to the warts directly. Two treatment approaches
are used and their e cacies ha e not been compared. Some
practitioners apply topical agents in the o ce in higher con
centrations ( ) but only about e ery wee s. thers gi e
their patients ta e home prescriptions to use up to daily
although initially at lower concentrations ( . . ). n most
cases the agents are dissol ed in acetone. The treated wart
should be ept co ered or h a ter application. the reaction
is o erly se ere the strength o the application may be reduced.
Wart tenderness may indicate the need to reduce treatment
concentration. Warts may begin to resol e within or wee s
but on a erage months or more o treatment is re uired.
or intralesional Can i a antigen treatments are repeated
e ery wee s. erall cure rates or all three topical sensiti
ers and or intralesional antigen in ection is . Side e ects
o treatment include local pruritus local pain and mild ec em
atous dermatitis. ntralesional Can i a in ections may be asso
ciated with cyto ine mediated side e ects such as swelling
e er sha ing chills and a uli e eeling. These begin
hours a ter treatment and resol e o er hours. Patients
should be ad ised o these possible side e ects. ost patients
ha e no limitation o acti ities or unction with topical immu
notherapy. Scarring has not been reported.
The e cacy o imi uimod or common warts appears to be
signi cantly less than with cryotherapy or topical immuno
tahir99 - UnitedVRG
therapy and is considerably more e pensi e. The routine use
o imi uimod in the treatment o common or plantar warts
cannot be recommended. npublished placebo controlled
trials demonstrated no better response than placebo with cure
rates o about . Topical cido o ir has been used in di cult
Papovavirus group
situations and in immunosuppressed patients. t is com
pounded in a concentration and applied directly to the
wart once or twice daily. The method o compounding is criti
cal to the e cacy o topical cido o ir so a reliable source
nown to compound an acti e gel is important. t is e tremely
e pensi e howe er and local irritation and erosion may
occur. Cido o ir may also be deli ered intralesionally in up to
concentration.
The alue o uadri alent PV accination or the treatment
o common warts is un nown. ne study reported resolution
o common and plantar warts in our young persons (three
under years) a ter PV immuni ation.
Plantar warts
n general plantar warts are more re ractory to any orm o
treatment than are common warts. The e ception is PV
induced plantar warts in children under years which ha e
a high response rate (> ). nitial treatment usually in ol es
daily application o salicylic acid in li uid lm or plaster a ter
soa ing. n ailures cryotherapy or cantharidin application
may be attempted. A second ree e thaw cycle is bene cial
when treating plantar warts with cryotherapy. n trials com
common warts cryotherapy is no more e ecti e than patient
applied salicylic acid. n act no trial has demonstrated cryo
therapy to be superior to placebo in treating plantar warts.
Bleomycin in ections laser therapy or immunotherapy as
pre iously discussed may be used in re ractory cases. Com
bination use o bleomycin in ections or Can i a antigen in ec
tions with pulse dye laser may be use ul in particularly
re ractory periungual and plantar warts. Surgical destruction
with cautery or blunt dissection should be reser ed or ailures
with nonscarring techni ues since a plantar scar may be per
sistently pain ul. C laser may also result in plantar scars.
PDT may be e ecti e in some cases. The optimum photosen
siti ing agent and light source are un nown.
Genital warts (external genital warts)
Genital warts are the most common STD. Among se ually
acti e young adults in the nited States and urope in ection
rates as high as in some cohorts ha e been ound using
sensiti e PCR techni ues. t is estimated that the li etime ris
or in ection in se ually acti e young adults may be as high as
. The number o new .S. cases o genital wart in ection
diagnosed yearly may approach million. n the about two
thirds o couples in whom one has e idence o PV in ection
the partner will be ound to be concordantly in ected. A large
portion o genital PV in ection is either subclinical or latent.
n ortunately the in ecti ity o subclinical and latent in ec
tion is un nown. Subclinical and latent in ection is probably
responsible or most recurrences a ter treatment o genital
warts. Because the methodology or determining PV in ec
tion in men is less accurate and women ha e the ma or com
plication o PV in ection cer ical cancer irtually all data
on PV in ection rates and epidemiology are deri ed rom
studies o women.
Genital PV in ection is closely lin ed to cancer o the
cer i glans penis anus ul o aginal area and periungual
s in. Cancer occurs when there is integration o the PV
genome into the host D A. n high ris genital PV types E
and E gene products bind to and inacti ate p and retino
blastoma protein (pRb) respecti ely. This is thought to be
403
 Fig. 19-48 Squamous
19 cell carcinoma in
persistent HPV
infection.
Viral Diseases

Fig. 19-49 Condylomata acuminata.

Fig. 19-50 Genital

warts.

important in their ability to cause cancer. n most persons

genital PV in ection appears to be transient lasting about
years and results in no se uelae. n a small proportion about
o immunocompetent persons in ection persists and in a
small proportion o those with persistent PV in ection
cancer may de elop ( ig. ). Certain co actors such as the
PV type causing the in ection location o in ection cigarette
smo ing uncircumcised status and immunosuppressed
status are associated with progression to cancer. The transi
tion ones o the cer i and anus are at highest ris or the
de elopment o cancer.
ore than PV types are associated with genital warts.
Patients are typically in ected with multiple PV types
although one PV type probably causes most o the clinical
lesions. any PV types are ound in studies where the
sur ace is sampled but deeper in the epithelium one type o
PV predominates ma ing studies that use sur ace sampling
di cult to interpret. The PV types producing genital in ec
tion are di ided into two broad categories those that produce
benign lesions or low ris types and those associated with
cancer the so called high ris or oncogenic types. The most
common low ris genital PV types are PV and PV
and most PV induced genital dysplasias are caused by PV in ection. n men ris o genital PV in ection is associ
PV and PV . A strong correlation e ists between the ated with being uncircumcised ha ing had se be ore age
PV type and the clinical appearance o PV induced genital ha ing had more than si se ual partners in their li etime and
lesions. Virtually all condylomata acuminata are caused by ha ing had se with pro essional se wor ers. Smo ers are at
benign PV and PV . igh ris PV produce increased ris to de elop genital warts.
at or sessile o ten hyperpigmented lesions. or this reason
biopsy and PV typing o typical condyloma is rarely Condylomata acuminata
necessary. Condylomata on the s in sur ace appear as lobulated papules
Genital PV in ection is strongly associated with se ual that a erage mm in si e but they may range rom micro
e posure. emale irgins rarely harbor PV (about ). or scopic to many centimeters in diameter and height. Lesions
women inserti e aginal intercourse is strongly associated are re uently multi ocal. umerous genital warts may appear
with ac uiring genital PV in ection with o women during pregnancy. Condylomata acuminata occur in men
testing positi e or genital PV within years o the rst anywhere on the penis ( ig. ) or about the anus. Scrotal
se ual intercourse. owe er se ual contact does not need to condylomata occur in only o immunocompetent male
be penile aginal; the ris o ac uiring genital PV in ection patients with warts ( ig. ). ntraurethral condylomata
was in women who had nonpenetrati e se ual e posure may present with terminal hematuria altered urinary stream
ersus o women who had no such e posure. This suggests or urethral bleeding. n women lesions appear on the mucosal
oral digital genital genital e posure can transmit PV in ec sur aces o the ul a or cer i on the perineum or about the
tion to the introital s in. This in ection may then be spread to anus. Cauli ower li e masses may de elop in moist occluded
other sites by sel inoculation. or this reason women who areas such as the perianal s in ul a and inguinal olds. As
ha e se with women may ha e genital PV in ection and still a result o accumulation o purulent material in the cle ts
re uire regular gynecologic e aluation. Condom use may be these may be malodorous. Their color is generally gray pale
partly but not completely protecti e or ac uisition o genital yellow or pin . When perianal lesions occur a prior history
404

Fig. 19-51 Genital warts, bowenoid papulosis.
o recepti e anal intercourse will usually predict whether
intra anal warts are present and will help to determine the
need or anoscopy. mmunosuppressed indi iduals and those
with in ection by nown high ris PV types at other sites
should ha e routine anal Papanicolaou (Pap) smears to detect
malignant change.
Genital warts are se ually transmitted and other STDs may
be ound in patients with genital warts. A complete history
should be ta en and the patient screened or other STDs as
appropriate. The whole genital area should be care ully e am
ined because e ternal genital wart ( GW) in ection is o ten
multi ocal. V testing is recommended. Women with GWs
should ha e a routine cer ical cytologic screening to detect
cer ical dysplasia but the presence o GWs alone does not
re uire more re uent Pap smears or gynecologic e aluation.
Bowenoid papulosis and HPV-induced genital dysplasias
Bowenoid papulosis is characteri ed by at o ten hyperpig
mented papules a ew millimeters to se eral centimeters in
diameter. These occur singly or more o ten may be ound in
multiples on the penis near the ul a or perianally ( ig.
). At times similar lesions are seen outside the genital
area in the absence o genital bowenoid papulosis. They occur
most re uently on the nec or ace and are more common in
men. They contain PV PV or other high ris PV
types. n the new standard terminology or lower anogenital
s uamous lesions this is called S L (high grade s uamous
intraepithelial lesion). t is usually caused by PV . n the
glabrous e ternal genitalia bowenoid papulosis usually
beha es similar to other GWs but may progress to s uamous
cell carcinoma (SCC). Patients may simultaneously ha e
bowenoid papulosis o the genitalia and SCC in situ especially
in the periungual area both caused by the same PV type. n
the glans penis o an uncircumcised male and on the cer ical
aginal or rectal mucosa progression to in asi e SCC is more
li ely ( ig. ). emale partners o men with bowenoid
papulosis and women with bowenoid papulosis ha e an
increased ris o cer ical dysplasia. istologically the biop
sies o s uamous cell carcinoma in situ and S L caused by
PV (bowenoid papulosis) are ery similar. Pigmentation o
the epithelium and numerous mitoses especially in meta
phase are characteristic but not diagnostic o PV induced
S L on the e ternal genitalia.
Giant condyloma acuminatum
(Buschke-Lowenstein tumor)
Giant condyloma acuminatum is a rare aggressi e wartli e
growth that is a errucous carcinoma. nli e other PV
tahir99 - UnitedVRG
Fig. 19-52 Genital
Bowen’s disease.
Papovavirus group
induced genital carcinomas this tumor is usually caused by
PV . t occurs most o ten on the glans or prepuce o an
uncircumcised male; less o ten it may occur on perianal s in
or the ul a. Despite its bland histologic picture it may in ade
deeply and in re uently it may metastasi e to regional lymph
nodes. Treatment is by complete surgical e cision. Recurrence
a ter radiation therapy may be associated with a more aggres
si e course.
Diagnosis
en in women with con rmed cer ical PV in ection sero
logic tests are positi e in only ma ing serologic diagnosis
o PV in ection o no use to the practicing clinician. PV
cannot be cultured. PV typing by in situ hybridi ation or
PCR is use ul in managing PV in ection o the cer i and in
some cases o prepubertal PV in ection but not in the man
agement o GW. Virtually all condylomata can be diagnosed
by inspection. Bright lighting and magni cation should be
used when e amining or genital PV in ection. lat sessile
and pigmented lesions suggest bowenoid papulosis and may
re uire a biopsy. Subclinical and latent in ections are no longer
sought or in estigated because they are ery common and no
management strategy is nown to eradicate these orms o
PV in ection. Soa ing with acetic acid is not generally neces
sary but may be help ul to detect early lesions under the ore
s in. n patients with multiple recurrences acetic acid soa ing
may determine the e tent o in ection helping to de ne the
area or application o topical therapies. The procedure is per
ormed by soa ing the e ternal genitalia in men and the agina
and cer i in women with acetic acid or up to min.
Genital warts turn white (acetowhitening) ma ing them easily
identi able. Any process that alters the epidermal barrier will
be acetowhite (e.g. dermatitis) howe er so only typical ace
towhite lesions should be treated as warts. n atypical cases a
wee trial is attempted with a hydrocortisone prepara
tion plus a topical anticandidal imida ole cream. the aceto
whitening persists a biopsy is per ormed and histologic
e idence o PV in ection sought. P or in situ hybridi ation
( S ) methods may aid in e aluation. PCR should probably
not be per ormed on such biopsied specimens e cept possibly
in childhood cases. The high bac ground rate o latent in ec
tion (up to ) ma es interpretation o a positi e PCR impos
sible. n contrast chromogenic S clearing demonstrates the
locali ation o positi e nuclei within the lesion and can con rm
a lesion to be PV induced.
405

19 Treatment
Because no e ecti e irus speci c agent e ists or their treat
ment genital warts re uently recur. Treatment is not pro ed
to reduce transmission to se ual partners or to pre ent pro
Viral Diseases
gression to dysplasia or cancer. Speci cally the treatment o
male se ual partners o women with genital warts does not
reduce the recurrence rate o warts in these women. There ore
the goals o treatment must rst be discussed with the patient
and perhaps with the se ual partner. bser ation represents
an acceptable option or some patients with typical condylo
mata acuminata. n some patients only wart ree periods are
achie ed. Because genital warts may cause discom ort genital
pruritus oul odor bleeding and substantial emotional dis
tress treatment is indicated i re uested by the patient. Bleed
ing genital warts may increase the se ual transmission o V results in a signi cant reduction in recurrences (
and hepatitis B and C. Bowenoid papulosis may be treated as
discussed ne t when it occurs on the e ternal genitalia. Lesions
with atypical histology (high grade s uamous intraepithelial)
on mucosal sur aces and periungually are special cases and
treatment must be associated with histologic con rmation o
eradication in patients recei ing topical treatments.
The treatment chosen is in part dictated by the si e o the
warts and their location. The number o GWs at the initial
e aluation is strongly predicti e o wart clearance. Patients
with our or ewer GWs will be clear with three or ewer
treatments whereas only o patients with or more
GWs will be clear a ter three treatments. nly o patients
with one to our GWs will still ha e lesions a ter eight treat
ments but o patients with or more GWs will still
ha e lesions a ter eight treatments. A more e ecti e or aggres
si e treatment approach might be considered in patients with
high numbers o GWs.
Podophyllin is more e ecti e in treating warts on occluded
or moist sur aces such as on the mucosa or under the prepuce.
t is a ailable as a crude e tract usually in concentration
in tincture o ben oin. t is applied wee ly by the physician
and can be washed o h later by the patient depending
on the se erity o the reaction. A ter si consecuti e wee ly
treatments appro imately o patients are ree o warts
and are ree o warts at months a ter treatment. Puri ed
podophylloto in . solution or gel is applied by the
patient twice daily or consecuti e days o each wee in to
wee treatment cycles. cacy approaches or typical
condylomata and side e ects are ewer than with standard
physician applied podophyllin preparations. There ore when
e er possible podophylloto in should be used instead o
classic podophyllin solutions.
mi uimod an immune response modi er that induces
locally at the site o application has e cacy similar to cryo
therapy (about ) and yields a low recurrence rate ( ).
mi uimod is a ailable in a mg sachet containing a
cream ormulation and in a . . g pump dispensing
. g. ne sachet can co er up to cm when applied
appropriately allowing or se eral treatments with a single
sachet i the treatment area is limited. The cream is applied
daily or e ery other day or up to wee s. The . cream
is applied daily or wee s ollowed by a wee rest period
to a ma imum o wee s o treatment. mi uimod cream
is more e ecti e than podophylloto in in treating women
with GW in ection but only e ually or slightly less e ecti e
in men especially or warts on the penile sha t. mi uimod is
less e ecti e than cryotherapy in the treatment o GWs. The
. cream is less e ecti e than the cream resulting in
only a clearance. Therapeutic response to imi uimod is
slow re uiring se eral wee s in some patients to see any
e ect. Treatment results in mild to moderate irritation less
than with podophyllin or cryotherapy in men but with a
406
similar side e ect pro le in women. The . cream has less
side e ects. Rare complications reported with the cream
include aring o psoriasis and psoriatic arthritis itiligo li e
hypopigmentation induction o genital ulcers in a patient with
Beh et s disease and the production o a local neuropathy.
mi uimod should be used cautiously in persons with psoria
sis. europathy is associated with application o e cessi e
amounts occlusion o the medication and application to an
eroded mucosa.
mi uimod may be used to treat penile condyloma in cir
cumcised and uncircumcised men anal and perianal condy
loma and ul ar condyloma. t may be used as the initial
treatment or when recurrence has been re uent a ter attempt
ing other orms o treatment. Se eral trials demonstrated that
the use o imi uimod a ter electrosurgical destruction o warts
s.
in one study and s. in another). Although the per
centage o recurrences di ered signi cantly in these studies
the imi uimod treated patients in both studies had a three old
to our old reduction in wart recurrence. The use o imi ui
mod a ter surgical destruction o condyloma should be con
sidered in all immunocompetent patients especially those
with recurrence a ter a pre ious surgical procedure. t is
unclear whether the imi uimod should be started be ore the
surgical procedure or a ter postsurgical healing. The duration
o continued imi uimod therapy a ter ablation is also
un nown but most recurrences are during the rst
months so months o therapy would be reasonable. Applica
tion o imi uimod three times wee ly a ter surgery may be
more e ecti e than only twice wee ly although these two
approaches ha e not been compared. Suppositories containing
about mg o imi uimod appear to reduce the ris o recur
rence o anal condyloma in immunocompetent men a ter sur
gical ablation o e tensi e anal disease. mi uimod has been
e ecti e in the treatment o bowenoid papulosis.
The topical application o green tea e tract containing sin
ecatechins (Polyphenon or Veregen) can be e ecti e in treat
ing GWs. A ointment applied three times daily leads to
GW clearance in o women and o men. Placebo
cleared o patients in this blinded study. only the
patients treated in the nited States are considered complete
clearance occurred in o patients. The a erage time to
complete clearance is wee s. rythema and erosions at the
application site occur in o patients and had moder
ate to se ere reactions.
Bichloracetic acid or TCA can be applied to condy
lomata wee ly or biwee ly. TCA is sa e or use in pregnant
patients. Compared with cryotherapy TCA has the same or
lower e cacy and causes more ulcerations and pain. t is not
generally recommended or GWs because other a ailable
treatments are more e ecti e and cause less morbidity.
Cryotherapy with li uid nitrogen is more e ecti e than
podophyllin and imi uimod approaching resolution
during treatment and at months a ter treatment. ne or
two ree e thaw cycles are applied to each wart e ery
wee s. A one o mm beyond the lesion is ro en. Cryo
therapy is e ecti e in dry as well as moist areas. Perianal
lesions are more di cult to eradicate than other genital sites
and two ree e thaw cycles are recommended in this location.
Cryotherapy is sa e to use in pregnant patients. LA cream
with or without subse uent lidocaine in ltration may be ben
e cial in reducing the pain o cryotherapy. The addition o
podophyllin to cryotherapy does not result in statistically
better results a ter months o therapy and cannot be recom
mended as standard treatment.
lectro ulguration or electrocauteri ation with or without
snip remo al o the condyloma is more e ecti e than TCA
cryotherapy imi uimod or podophyllin. Wart clearance
during therapy is almost and wart cure at months
e ceeds . Local anesthesia is re uired and scarring may
occur. Surgical remo al is ideal or large e ophytic warts that
might re uire multiple treatments with other methods. t has
high acceptance in patients who ha e had recurrences rom
other methods because results are immediate and cure rates
higher.
The use o C laser in the treatment o genital warts has
not been shown to be more e ecti e than simpler surgical
methods. Although isible warts are eradicated by the laser
PV D A can still be detected at the pre ious site o the wart.
The C laser has the ad antage o being bloodless but it is
costlier and re uires more technical s ill to a oid complica
tions. t should be reser ed or treatment o e tensi e lesions
in which more cost e ecti e methods ha e been attempted
and ailed. Ad uncti e PDT does not pre ent recurrence o
GW a ter C laser ablation. Compared with C laser abla
tion o GWs aminole ulinic acid (ALA) with PDT demon
strated higher e cacy and ewer recurrences and was less
pain ul. ALA PDT response rate is about . ALA PDT
should be considered be ore C laser ablation or the treat
ment o multiple small but re ractory condyloma.
Any surgical method that generates a smo e plume is poten
tially in ectious to the surgeon. PV D A is detected in the
plumes generated during C laser or electrocoagulation
treatment o genital warts. The laser generated plume results
in longer duration PV aerosol contamination and wider
spread o detectable PV D A. these methods o wart treat
ment are used an appro ed ace mas should be worn a
smo e e acuator used at the surgical site during the procedure
to remo e the plume and the e uipment decontaminated a ter
the surgery.
luorouracil cream applied twice daily may be e ec
ti e especially in the treatment o at hyperpigmented
lesions such as those in bowenoid papulosis. Care must be
ta en to a oid application to the scrotum because scrotal s in
is prone to pain ul erosions. Twice daily instillation o
into the urethra can be used to treat intraurethral condylo
mata. The cone rom a tube o lidocaine ( ylocaine) elly will
t onto the thread o the tube or the cream may be
instilled with a syringe. t is typically le t in place or h be ore
the patient oids. Care should be ta en that drips o urine
containing the medication do not contact the scrotum.
may also be used to treat intra aginal warts by instillation in
the agina but this is o ten associated with se ere irritation.
ntermittent therapy (twice wee ly or wee s) is better tol
erated than daily therapy. is not usually recommended
or the treatment o typical GWs because other methods o
treatment are a ailable.
mmunotherapy can also be e ecti e or re ractory GWs.
This is usually deli ered by in ection o Can i a BCG puri ed
protein deri ati e (PPD) or some other antigen rather than
through topical application because o the di culty in pre
enting e posure o normal s in with a topical solution.
mmunotherapy may be combined with destructi e methods
in re ractory cases. The in ection o PV VLPs was ound to
speed the clearance o warts simultaneously treated with cryo
therapy podophyllin or TCA.
Human papillomavirus vaccination
The PV irusli e particles (VLPs) are composed o spontane
ously assembling L molecules and ha e been used to de elop
a poly alent accine against PVs and . This
accine is highly e ecti e and is now appro ed in more than
countries or the immuni ation o prepubertal girls and
boys. Vaccination is recommended or un accinated emales
through age and males age . V in ected men and
women should recei e immuni ation through age . n older
tahir99 - UnitedVRG
women (age ) the accine is also e ecti e and may be
gi en as a catch up accine in women with no e idence o
prior genital PV in ection with PVs or . Since
PV and PV are the primary types associated with
cer ical cancer it is hoped that the rate o cancers induced by
Papovavirus group
these high ris genital PV types can be reduced by accina
tion. The protection thought to be type speci c did not appear
to pre ent de elopment o s uamous intraepithelial lesions
rom other PV types in study participants. owe er in
countries where PV accination was widely applied
the burden o PV disease caused by PV and PV has
decreased suggesting some bene t across PV types. Cur
rently uadri alent accination is widely gi en and the ris
o de elopment o condyloma is clearly dose dependent with
most bene t rom three doses. The e ect o widespread immu
ni ation is most dramatically demonstrated by the data rom
Australia which had an aggressi e campaign o uni ersal
immuni ation o girls and young women; more than co
erage was achie ed. There was a reduction in PV related
in ections in the accine eligible women and a reduction
in GWs. en condyloma in non accinated women and men
(who were not yet eligible or immuni ation) were reduced
demonstrating herd immunity. PV related genital S L was
also reduced by in ully accinated women.
Genital warts in children
Children can ac uire genital warts through ertical transmis
sion perinatally and through digital inoculation or autoinocu
lation omite or social nonse ual contact and se ual abuse.
PV typing has demonstrated that most warts in the genital
area o children are genital PV types and most children
with genital warts ha e amily members with a genital PV
in ection.
uman papilloma irus typing can be per ormed. owe er
the presence o genital types o PV does not pro e abuse
and nding a nongenital PV type does not e clude se ual
abuse. n children younger than year ertical transmission
is possible and is probably the most common means o ac uisi
tion. The ris or se ual abuse is highest in children older than
years. When abuse is suspected children should be re erred
to child protection ser ices i the practitioner is not s illed in
e aluating children or se ual abuse. Children years old
are primarily non erbal and are di cult to e aluate. anage
ment o such patients is on a case by case basis. ther STDs
should be screened or in children who ha e a genital PV
in ection.
sually management o children with anogenital warts
re uires a multidisciplinary team that should include a pedia
trician ( ig. ). Genital warts in children o ten spontane
ously resol e ( ) so no inter ention may be a reasonable
consideration. Genital warts in children usually respond
uic ly to topical therapy such as podophylloto in imi ui
mod or light cryotherapy. n re ractory cases surgical remo al
or electrocautery may be used. A topical anesthetic is recom
mended be ore treatment.
Recurrent respiratory (laryngeal) papillomatosis
Papillomas associated with PV may occur throughout the
respiratory tract rom the nose to the lungs. Recurrent respira
tory papillomatosis has a bimodal distribution in children
under age years and a ter age . A ected young children
are born to mothers with genital condylomata and present
with hoarseness. The PV types ound in these lesions PV
and PV are the types seen in genital condylomata. Car
cinoma that is o ten atal de elops in o patients e en in
young children. The incidence o carcinoma is higher in those
treated with radiation therapy. These patients o ten ha e
407
19
Viral Diseases
Fig. 19-53 Perianal warts in 18-month-old infant.
recurrences and re uire numerous surgeries usually with
the C laser. Scarring can result rom re uent ablations
leading to speech and breathing di culties. Ad uncti e cido
o ir has been combined with surgical ablation to help reduce
recurrences with some positi e preliminary results. Also
PV accination has been combined with laser ablation with
preliminary results demonstrating reduced recurrences. t is
hoped that PV immuni ation o young women will reduce
the pre alence o PV induced condyloma and thus o
respiratory papillomatosis. Routine immuni ation o children
age may also ha e some bene t in pre enting the cases
that occur a ter age ; thus the re uency o this diagnosis is
being monitored in some countries.
Heck’s disease
Small white to pin ish papules occur di usely in the oral
ca ity in ec s disease also nown as ocal epithelial hyper
plasia. t occurs most re uently in ati e Americans o orth
Central and South America; in nuits; in Greenland s imos;
and in descendants o hoi San in South A rica. n these popu
lations pre alence rates can be as high as . t is e times
more common in emales. PV and PV ha e been
classically associated with ec s disease. Clinically the
lesions may be papular or papillomatous and a or the buccal
and labial mucosa and the commissures o the mouth. Lesions
may spontaneously resol e. Treatment options include cryo
surgery C laser electrosurgery and topical intralesional
or systemic . V s in cancers. The SCCs may appear de no o but usually
Epidermodysplasia verruciformis
pidermodysplasia erruci ormis ( V) is a rare inherited dis
order characteri ed by widespread PV in ection and cutane
ous SCCs. Virtually always V is inherited as an autosomal
recessi e trait although autosomal dominant and lin ed
inheritance ha e also been reported. About o V patients
are rom consanguineous marriages. PV types associated
with this syndrome include those in ecting normal hosts such
as PV and PV as well as many uni ue PV types
o ten β PVs. These PV types are called V PVs and
include PVs and .
PV and PV are ound in o the s in cancers in V
patients. The genetic mutations causing V are ound in two
closely lin ed genes E E and E E About o all V
cases worldwide ha e homo ygous in alidating mutations in
408
Fig. 19-54 Epidermodysplasia verruciformis.
one o these two genes. The E E genes are transmembrane
channel li e genes so E E is also MC and E E is also
MC The unction o these genes and how they cause this
syndrome are un nown.
The condition presents in childhood and continues through
out li e. S in lesions include at wart li e lesions o the dorsal
hands e tremities ace and nec . They appear in childhood
or young adulthood apparently earlier in sunnier climates.
The characteristic lesions are atter than typical at warts and
may be uite abundant growing to con uence ( ig. ).
Typical PV induced at warts may be admi ed. n
addition lesions on the trun are red tan or brown patches
pla ues or hypopigmented slightly scaly pla ues resembling
tinea ersicolor. Pla ues on the elbows may resemble psoria
sis. Seborrheic eratosis li e lesions may also be seen on the
orehead nec and trun . Common warts are reported to
occur in re uently in some V cohorts. n other V patients
common warts o the hands and eet may be present as well.
The histologic eatures o an V speci c PV in ection are
ery characteristic. The cells o the upper epidermis ha e a
clear smo y or light blue pale cytoplasm and a central py
notic nucleus.
n about one third o V patients SCCs de elop an a erage
o years a ter the appearance o the characteristic V s in
lesions. ost o ten s in cancers appear on sun e posed sur
aces but they can appear on any part o the body. SCCs begin
to appear at age again earlier in patients li ing in
regions with high sun e posure. S in cancers are less common
in A rican patients suggesting a protecti e e ect o s in pig
mentation. PV and PV are ound in more than o
appear on the bac ground o numerous actinic eratoses and
lesions o Bowen s disease ( ig. ). Surgical treatment is
recommended. Radiation therapy is contraindicated. s in
gra ting is re uired the gra ts should be ta en rom sun
protected s in such as the buttoc s or inner upper arm.
Aside rom surgical inter ention or s in cancer treatment
or V consists largely o pre enti e measures. Strict sun
a oidance and protection should be started as soon as the
syndrome is diagnosed. An approach similar to that or chil
dren with eroderma pigmentosa could be instituted. ALA
PDT topical imi uimod and oral retinoids may all be
used to treat the lesions o patients with V but when treat
ment is discontinued lesions usually recur.
The mechanism by which cancer occurs in patients with V
is unclear. PV proteins do not bind to p or pRb. The p
mutations present in the SCCs o patients with V are charac
teristic o those induced by VB light con rming the close
association o V e posure and the de elopment o cancer in
 Fig. 19-55 Multiple
SCCs in
epidermodysplasia
verruciformis.
patients with V. PV D A o V has been reported in
o the general population in ery low copy number suggest
ing that the presence o these V PVs alone is not the cause
o the s in cancers. Rather the E E genes apparently control
important immune responses in the epidermis that control
PV replication and in their absence iral replication goes
unchec ed and can e entually lead to s in cancer in sun
damaged s in. Supporting this concept is the recent report o
a polyoma irus positi e er el cell carcinoma in an V
patient. n ection with V PV types has been reported in
immunosuppressed patients especially those with V. This
has been called ac uired V. Typical at scaly lesions
resembling tinea ersicolor are most common. SCC has not
been reported in these patients. Some patients with e tensi e
(> ) common and plantar warts that ne er resol e and
simply grow to con uence ha e been called generali ed er
rucosis. These patients do not de elop s in cancers and li e
into adulthood. Some o these patients ha e been identi ed
with mutations in DOC or C C or with idio
pathic CD lymphopenia. Some o these patients unli e V
patients are at high ris or anogenital PV disease and its
complications.
Immunosuppressed patients
Patients with de ects in cell mediated immunity may ha e
an increased re uency o PV in ection. Predisposing con
ditions include organ transplantation immunosuppressi e
medications congenital immunode ciency diseases lym
phoma and V in ection.
rgan transplant recipients begin to de elop warts soon
a ter transplantation and by years up to o transplant
patients ha e warts. nitially these are common and plantar
warts but later numerous at warts appear particularly in
sun e posed areas. Genital warts are also increased and espe
cially in women genital dysplasias are more re uent. The
presence o eratotic lesions o any type on the s in is a strong
predictor or de elopment o nonmelanoma s in cancer
( SC) in transplant patients. t is especially important in
immunosuppressed patients to monitor the genital and anal
tahir99 - UnitedVRG
areas regularly or changing lesions and to ha e a low thresh
old or per orming a biopsy.
n V disease common plantar at oral and genital
warts are all common. Warty eratoses at the angle o the
mouth o ten bilateral are a characteristic mani estation o
Papovavirus group
PV in ection in patients with A DS. The warts are caused
predominantly by PVs and . PV can be ound in
cutaneous oral and perioral warts in nonbutchers with V
in ection. PV may be ound in common warts. Genital
warts are increased old among V in ected women. i ty
percent or more o V in ected S ha e e idence o anal
PV in ection. Genital neoplasia associated with PV and
PV occurs much more re uently in V in ected women
and S . n re uently V patients de elop PV
induced V li e lesions. Although nongenital s in cancers are
also common in some air s inned V patients PV has not
been demonstrated in the nongenital SCCs o these patients.
With antiretro iral therapy warts may disappear. Parado i
cally increased rates o genital and oral warts may be seen in
V patients in the rst se eral years o ade uate control o
their V in ection part o R S. The li elihood o clearance
o common warts in persons with V is related to the nadir
o their Th cell count. V in ected persons whose Th count
ne er alls below cells are more li ely to ha e sustained
remission o their warts.
The treatment o warts in immunosuppressed hosts can be
challenging. Although standard methods are used their e
cacy may be reduced. or common and plantar warts surgi
cally ablati e methods cryotherapy bleomycin in ections
PDT and aggressi e pulsed dye laser therapy would be
e pected to be more e ecti e because the agents designed to
induce an immune response would be less e ecti e in the
immunosuppressed patient. n one study using intralesional
Can i a antigen or common warts the response rate was
less than in V patients and no patient showed a
distant bene t or untreated warts. mi uimod has low e
cacy in these patients; only had complete clearance o
common warts and had no response. or genital warts
treatment is determined by si e. Any wart larger than cm
should be sent or consideration o surgical remo al and
histologic e aluation. Smaller warts can be treated with elec
trosurgery cryotherapy topical and ALA PDT. mi ui
mod can be attempted and is most e ecti e or GWs on
occluded s in (intra anal under the prepuce). ost trans
plant patients tolerate imi uimod well without inducing
enough systemic immune response to cause re ection o their
transplanted organ. owe er widespread use o imi uimod
in one renal transplant patient led to acute renal ailure.
Topical cido o ir ( concentration) and intralesional cido
o ir ( . mg mL) ha e been e ecti e in re ractory anogeni
tal and common warts in immunode cient patients. Although
topical cido o ir is ery e pensi e is irritating and can cause
s in erosion and ulceration it is acti e against the PV and
thus does not re uire participation o the patient s immune
system to eradicate the wart. Addition o sirolimus to
the immunosuppressi e regimen may be associated with a
decrease in the number o warts in organ transplant patients.
n our pediatric transplant patients substitution o le uno
mide or mycophenolate in the immunosuppressi e regimen
with monitoring o le unomide metabolites or months
or more resulted in clearance or dramatic impro ement o
cutaneous warts and molluscum contagiosum. ycopheno
late was reinstituted and le unomide stopped without
recurrence o the warts. n organ transplant patients with
widespread actinic damage and many precancerous lesions
PDT can be considered.
Ahmed I, et al: Liquid nitrogen cryotherapy of common warts: cryo-
spray vs. cotton wool bud. Br J Dermatol 2001; 144:1006.
409
 Alghamdi KM, Khurram H: Successful treatment of periungual warts with
19 diluted bleomycin using translesional multipuncture technique: a pilot
prospective study. Dermatol Surg 2011; 37:486.
Ali H, et al: Decline in in-patient treatments of genital warts among
young Australians following the national HPV vaccination program.
Viral Diseases
BMC Infect Dis 2013; 13:140.
Ayer J, et al: Successful treatment of Buschke-Lowenstein tumour of
the penis with carbon dioxide laser vaporization. Acta Derm Venereol
2012; 92:585.
Bavinck JN, et al: Treatments for common and plantar warts. BMJ 2011;
342:d3119.
Bleeker MCG, et al: Penile lesions and human papillomavirus in male
sexual partners of women with cervical intraepithelial neoplasia. J Am
Acad Dermatol 2002; 47:351.
Borgogna C, et al: Characterization of skin lesions induced by skin-
tropic α- and β-papillomaviruses in a patient with epidermodysplasia
verruciformis. Br J Dermatol 2014; Jun 5. [Epub ahead of print.]
Bouwes Bavinck JN, et al: Keratotic skin lesions and other risk factors
are associated with skin cancer in organ-transplant recipients: a
case-control study in The Netherlands, United Kingdom, Germany,
France, and Italy. J Invest Dermatol 2007; 127:1647.
Broganelli P, et al: Intralesional cidofovir for the treatment of multiple
and recalcitrant cutaneous viral warts. Dermatol Ther 2012; 25:468.
Brown T, et al: Vitiligo-like hypopigmentation associated with imiquimod
treatment of genital warts. J Am Acad Dermatol 2005; 52:715.
Bruggink SC, et al: Cutaneous wart-associated HPV types: prevalence
and relation with patient characteristics. J Clin Virol 2012; 55:250.
Bruggink SC, et al: HPV type in plantar warts influences natural course
and treatment response: secondary analysis of a randomised
controlled study. J Clin Virol 2013; 57:227.
Bruggink SC, et al: Natural course of cutaneous warts among primary
schoolchildren: a prospective cohort study. Ann Fam Med 2013; 11:437.
Bruggink SC, et al: Warts transmitted in families and schools: a
prospective cohort. Pediatrics 2013; 131:928.
Carrasco D, et al: Treatment of anogenital warts with imiquimod 5%
cream followed by surgical excision of residual lesions. J Am Acad
Dermatol 2002; 47:S212.
Chen K, et al: Comparative study of photodynamic therapy vs CO2 laser
vaporization in treatment of condylomata acuminata, a randomized
clinical trial. Br J Dermatol 2007; 156:516.
Chirila M, Bolboaca SD: Clinical efficiency of quadrivalent HPV (types of
6/11/16/18) vaccine in patients with recurrent respiratory
papillomatosis. Eur Arch Otorhinolaryngol 2014; 271:1135.
Chow EP, et al: Ongoing decline in genital warts among young
heterosexuals 7 years after the Australian human papillomavirus (HPV)
vaccination programme. Sex Transm Infect 2014 [Epub ahead of print.]
Clarke E, et al: Why are anogenital warts diagnoses decreasing in the
UK: bivalent human papillomavirus (HPV) vaccine cross-protection or
failure to examine? Sex Transm Infect 2014; 90:587.
Cockayne S, et al: Cryotherapy versus salicylic acid for the treatment of
plantar warts (verrucae): a randomised controlled trial. BMJ 2011;
342:d3271.
Connolly M, et al: Cryotherapy of viral warts: a sustained 10-s freeze is
more effective than the traditional method. Br J Dermatol 2001;
145:554.
Daniel BS, Murrell DF: Complete resolution of chronic multiple verruca
vulgaris treated with quadrivalent human papillomavirus vaccine. JAMA
Dermatol 2013; 149:370.
Dharancy S, et al: Conversion to sirolimus: a useful strategy for
recalcitrant cutaneous viral warts in liver transplant recipients. Liver
Transpl 2006; 12:1883.
Dicle O, et al: Choice of immunosuppressants and the risk of warts in
renal transplant recipients. Acta Derm Venereol 2008; 88:294.
Dobson JS, Harland CC: Pulsed dye laser and intralesional bleomycin for
the treatment of recalcitrant cutaneous warts. Laser Surg Med 2014;
46:112.
Durani BK, Jappe U: Successful treatment of facial plane warts with
imiquimod. Br J Dermatol 2002; 147:1018.
Fahey LM, et al: A major role for the minor capsid protein of human
papillomavirus type 16 in immune escape. J Immunol 2009; 183:6151.
Fausch SC, et al: Human papillomavirus can escape immune
recognition through Langerhans cell phosphoinositide 3-kinase
activation. J Immunol 2005; 174:7172.
Garden JM, et al: Viral disease transmitted by laser-generated plume
(Aerosol). Arch Dermatol 2002; 138:1303.
410
Garg M, et al: Giant Buschke-Lowenstein tumour: clinical appraisal of a
rare entity. BMJ Case Rep 2013; May 24; bcr2013009678.
Garland SM: The Australian experience with the human papillomavirus
vaccine. Clin Ther 2014; 36:17.
Gianino MM, et al: A retrospective analysis of the costs and
management of genital warts in Italy. BMC Infect Dis 2013; 13:470.
Gibbs S: Topical immunotherapy with contact sensitizers for viral warts.
Br J Dermatol 2002; 146:705.
Gormley RH, Kovarik CL: Human papillomavirus–related genital disease
in the immunocompromised host. Part I. J Am Acad Dermatol 2012;
66:867.e1.
Gormley RH, Kovarik CL: Human papillomavirus–related genital disease
in the immunocompromised host. Part II. J Am Acad Dermatol 2012;
66:883.e1.
Grasso M, et al: Use of cidofovir in HPV patients with recurrent
respiratory papillomatosis. Eur Arch Otorhinolaryngol 2014; 271:2983.
Gul U, et al: Clinical aspects of epidermodysplasia verruciformis and
review of the literature. Int J Dermatol 2007; 46:1069.
Herweijer E, et al: Association of varying number of doses of
quadrivalent human papillomavirus vaccine with incidence of
condyloma. JAMA 2014; 311:597.
Hivnor C, et al: Intravenous cidofovir for recalcitrant verruca vulgaris in
the setting of HIV. Arch Dermatol 2004; 140:13.
Horn TD, et al: Intralesional immunotherapy of warts with mumps,
Candida and Trichophyton skin test antigens: a single-blinded,
randomized and controlled trial. Arch Dermatol 2005; 141:589.
Howell-Jones R, et al: Declining genital warts in young women in
England associated with HPV 16/18 vaccination: an ecological study. J
Infect Dis 2013; 208:1397.
Jardine D, et al: A randomized trial of immunotherapy for persistent
genital warts. Hum Vaccin Immunother 2012; 8:623.
Kallikourdis M, et al: The CXCR4 mutations in WHIM syndrome impair
the stability of the T-cell immunologic synapse. Blood 2013; 122:666.
Karaman G, et al: Ranitidine therapy for recalcitrant warts in adults: a
preliminary study. J Eur Acad Dermatol Venereol 2001; 15:486.
Kaspari M, et al: Application of imiquimod by suppositories (anal
tampons) efficiently prevents recurrences after ablation of anal canal
condyloma. Br J Dermatol 2002; 147:757.
Kimura U, et al: Long-pulsed 1064-nm neodymium:yttrium-aluminum-
garnet laser treatment for refractory warts on hands and feet. J
Dermatol 2014; 41:252.
Kines RC, et al: The initial steps leading to papillomavirus infection
occur on the basement membrane prior to cell surface binding. Proc
Natl Acad Sci USA 2009; 106:20458.
Kostaki M, et al: Giant warts in a kidney transplant patient: regression
with sirolimus. Br J Dermatol 2010; 162:1138.
Kralund HH, et al: Substantial effect of topical cidofovir 1% on
recalcitrant warts in a renal-transplanted adolescent: a case report.
Transplantation 2011; 91:e52.
Kreuter A, Wieland U: Giant condyloma acuminatum of Buschke and
Löwenstein. N Engl J Med 2011; 365:17.
Kumei A, et al: Multiple linear bowenoid papulosis without surrounding
papules. J Dermatol 2012; 39:862.
Kwok CS, et al: Topical treatments for cutaneous warts. Cochrane
Database Syst Rev 2012; 9:CD001781.
Leiding JW, Holland SM: Warts and all: human papillomavirus in primary
immunodeficiencies. J Allergy Clin Immunol 2012; 130:1030.
Leval A, et al: Incidence of genital warts in Sweden before and after
quadrivalent human papillomavirus vaccine availability. J Infect Dis
2012; 206:860.
Lin JH, et al: Resolution of warts in association with subcutaneous
immunoglobulin in immune deficiency. Pediatr Dermatol 2009;
26:155.
Mammas IN, et al: Human papilloma virus (HPV) infection in children
and adolescents. Eur J Pediatr 2009; 168:267.
Martinelli C, et al: Resolution of recurrent perianal condylomata
acuminata by topical cidofovir in patients with HIV infection. J Eur
Acad Dermatol Venereol 2001; 15:568.
Mavrogianni P, et al: Therapeutic combination of radiofrequency surgical
dissection and oral acitretin in the management of perianal Buschke-
Löwenstein tumour: a case report. Int J STD AIDS 2012; 23:362.
M’barek LB, et al: 5% Topical imiquimod tolerance in transplant
recipients. Dermatol 2007; 215:130.
McCalmont TH: Whither bowenoid papulosis? J Cutan Pathol 2013;
40:209.
McDermott DH, et al: A Phase I clinical trial of long-term, low-dose
treatment of WHIM syndrome with the CXCR4 antagonist Plerixafor.
Blood 2014; 123:2308.
Micali G, et al: Treatment of cutaneous warts with squaric acid
dibutylester: a decade of experience. Arch Dermatol 2000; 136:557.
Mizuki D, et al: Successful treatment of topical photodynamic therapy
using 5-aminolevulinic acid for plane warts. Br J Dermatol 2003;
149:1087.
Moresi JM, et al: Treatment of anogenital warts in children with topical
0.05% podofilox gel and 5% imiquimod cream. Pediatr Dermatol 2001;
18:448.
Nambudiri VE, et al: Successful treatment of perianal giant condyloma
acuminatum in an immunocompromised host with systemic
interleukin-2 and topical cidofovir. JAMA Dermatol 2013; 149:1068.
Nguyen L, et al: Conversion from tacrolimus/mycophenolic acid to
tacrolimus/leflunomide to treat cutaneous warts in a series of four
pediatric renal allograft recipients. Transplant 2012; 94:450.
Nofal A, et al: Intralesional antigen immunotherapy for the treatment of
warts: current concepts and future prospects. Am J Clin Dermatol
2013; 14:253.
Nofal A, et al: Treatment of recalcitrant warts with bacille Calmette-
Guérin: a promising new approach. Dermatol Ther 2013; 26:481.
Olguin-Garcia MG, et al: A double-blind, randomized, placebo-controlled
trial of oral isotretinoin in the treatment of recalcitrant facial flat warts. J
Dermatolog Treat 2014; Feb 19. [Epub ahead of print.]
Padilla Espana L, et al: Topical cidofovir for plantar warts. Dermatol Ther
2014; 27:89.
Paraskevas KI, et al: Surgical management of giant condyloma
acuminatum (Buschke-Lowenstein tumor) of the perianal region.
Dermatol Surg 2007; 33:638.
Peterson CL, et al: Hand warts successfully treated with topical
5-aminolevulinic acid and intense pulsed light. Eur J Dermatol 2008;
18:207.
Ruiz R, et al: Focal epithelial hyperplasia. Lancet 2014; 384(9938):173.
Said AK, et al: Focal epithelial hyperplasia: an update. J Oral Pathol
Med 2013; 42:435.
Santos-Juanes J, et al: Acute renal failure caused by imiquimod 5%
cream in a renal transplant patient: review of the literature on side
effects of imiquimod. Dermatology 2011; 222:109.
Scheinfeld N: Update on the treatment of genital warts. Dermatol Online
J 2013; 19:3.
Schiller JT, Lowy DR: Understanding and learning from the success of
prophylactic human papillomavirus vaccines. Nat Rev Microbiol 2012;
10:681.
Sherrard J, Riddell L: Comparison of the effectiveness of commonly
used clinic-based treatments for external genital warts. Int J STD AIDS
2007; 18:365.
Shi H, et al: Clinical analysis of five methods used to treat condylomata
acuminata. Dermatology 2013; 227:338.
Shim WH, et al: Bowenoid papulosis of the vulva and subsequent
periungual Bowen’s disease induced by the same mucosal HPVs. Ann
Dermatol 2011; 23:493.
Shimizu A, et al: Bowenoid papulosis successfully treated with
imiquimod 5% cream. J Dermatol 2014; 41:545.
Shofer H, et al: Randomized, comparative trial on the sustained efficacy
of topical imiquimod 5% cream versus conventional ablative methods
in external anogenital warts. Eur J Dermatol 2006; 16:642.
Sparreboom EE, et al: Pulsed dye laser treatment for recalcitrant viral
warts: a retrospective case series of 227 patients. Br J Dermatol 2014;
171:1270.
Stefanaki C, et al: Comparison of cryotherapy to imiquimod 5% in the
treatment of anogenital warts. Int J STD AIDS 2008; 19:441.
Szarewski A, et al: Efficacy of the HPV-16/18 AS04-Adjuvanted vaccine
against low-risk HPV types (PATRICIA randomized trial): an unexpected
observation. J Infect Dis 2013; 208:1391.
Szeimies RM, et al: Adjuvant photodynamic therapy does not prevent
recurrence of condylomata acuminata after carbon dioxide laser
ablation: a Phase III, prospective, randomized, bicentric, double-blind
study. Dermatol Surg 2009; 35:757.
Takayama A, et al: Coexistence of bowenoid papulosis and Bowen’s
disease in a patient with systemic lupus erythematosus. J Dermatol
2012; 39:646.
Tripoli M, et al: Giant condylomata (Buschke-Löwenstein tumours): our
case load in surgical treatment and review of the current therapies. Eur
Rev Med Pharmacol Sci 2012; 16:747.
tahir99 - UnitedVRG
Turnbull JR, et al: Regression of multiple viral warts in human
immunodeficiency virus–infected patient treated by triple antiretroviral
therapy. Br J Dermatol 2002; 146:330.
Van Haalen FM, et al: Warts in primary schoolchildren: prevalence and
relation with environmental factors. Br J Dermatol 2009; 161:148.
Papovavirus group
Vanhooteghem O, et al: Raynaud phenomenon after treatment of verruca
vulgaris of the sole with intralesional injection of bleomycin. Pediatr
Dermatol 2001; 18:249.
Vicente A, et al: High-risk alpha-human papillomavirus types: detection
in HIV-infected children with acquired epidermodysplasia verruciformis.
J Am Acad Dermatol 2012; 68:343.
Videla S, et al: Natural history of human papillomavirus infections
involving anal, penile and oral sites among HIV-positive men. Sex
Transm Dis 2013; 40:3.
Wang YS, et al: Photodynamic therapy with 20% aminolevulinic acid for
the treatment of recalcitrant viral warts in an Asian population. Int J
Dermatol 2007; 46:1180.
West ES, et al: Generalized verrucosis in a patient with GATA2
deficiency. Br J Dermatol 2014; 170:1182.
Wiley DJ, et al: Smoking enhances risk for new external genital warts in
men. Int J Environ Res Public Health 2009; 6:1215.
Wong A, Crawford RI: Intralesional candida antigen for common warts in
people with HIV. J Cutan Med Surg 2013; 17:313.
Wu JK, et al: Psoriasis induced by topical imiquimod. Australas J
Dermatol 2004; 45:47.
Wulf HS, et al: Topical photodynamic therapy for prevention of new skin
lesions in renal transplant recipients. Acta Derm Venereol 2006; 86:25.
Yew YW, Pan JY: Complete remission of recalcitrant genital warts with a
combination approach of surgical debulking and oral isotretinoin in a
patient with systemic lupus erythematosus. Dermatol Ther 2014; 27:79.
Zamanian A, et al: Efficacy of intralesional injection of mumps-measles-
rubella vaccine in patients with wart. Adv Biomed Res 2014; 3:107.
Zampetti A, et al: Acquired epidermodysplasia verruciformis: a
comprehensive review and a proposal for treatment. Dermatol Surg
2013; 39:974.
Zhao Y, et al: Relationship between cervical disease and infection with
human papillomavirus types 16 and 18, and herpes simplex virus 1
and 2. J Med Virol 2012; 84:1920.
Trichodysplasia spinulosa
mmunosuppressed patients with lymphoreticular malignan
cies and organ transplant recipients on immunosuppressi e
regimens will rarely de elop a characteristic eruption o ery
thematous mm acial papules. The mid ace glabella and
chin are primarily a ected. Lesions are numerous may reach
con uence and can cause nasal distortion similar to that seen
in rosacea and sarcoidosis ( ig. ). Some papules ha e a
central eratotic white e crescence. Alopecia o the eyebrows
and eyelashes may occur but the scalp is spared. istology is
characteristic showing massi ely distended bulbous ollicles
with e pansion o the inner root sheath cells and containing
numerous trichohyaline granules. Abrupt inner root sheath
type corni cation is present. Aborti e hair sha t li e material
may be present in the a ected ollicles. lectron microscopy
demonstrates numerous iral particles in the a ected hair
Fig. 19-56 Trichodysplasia. (Courtesy of Len Sperling, MD.)
411
 ollicles. This irus has been identi ed as a uni ue polyoma
19 irus called trichodysplasia spinulosa associated polyoma i
rus. t di ers rom the er el cell polyoma irus. Treatments
that may bene t patients with trichodysplasia spinulosa
include reduction o the immunosuppressi e regimen topical
Viral Diseases
cido o ir and oral alganciclo ir.
Berk DR, et al: Trichodysplasia spinulosa in an adolescent with cystic
fibrosis and lung transplantation. Int J Dermatol 2013; 52:1567.
Burns A, et al: Keratotic “spiny” papules in an immunosuppressed
child. Arch Dermatol 2011; 147:1215.
Celeiro-Munoz C, et al: Viral-assoicated trichodysplasia secondary to
antineoplastic treatment in a patient with lymphoblastic leukemia. Am J
Dermatopathol 2014; 36:e105.
Fischer MK, et al: Specific detection of trichodysplasia spinulosa–
associated polyomavirus DNA in skin and renal allograft tissues in a
patient with trichodysplasia spinulosa. Arch Dermatol 2012; 148:726.
Jawa P, et al: Trichodysplasia spinulosa. Kidney Int 2014; 85:715.
Kazem S, et al: The trichodysplasia spinulosa–associated polyomavirus:
virological background and clinical implications. APMIS 2013; 121:770.
Lee YY, et al: Trichodysplasia spinulosa: a benign adnexal proliferation
with follicular differentiation associated with polyomavirus. Australas J
Dermatol 2014; 55:e33.
Matthews MR, et al: Viral-associated trichodysplasia spinulosa: a case
with electron microscopic and molecular detection of the
trichodysplasia spinulosa–associated human polyomavirus. J Cutan
Pathol 2011; 38:420.
RETROVIRUSES
These onco iruses are uni ue in that they contain R A which
is con erted by a irally coded re erse transcriptase to D A
in the host cell. The target cell population is primarily CD +
lymphocytes (primarily helper T cells) but also in some cases
macrophages. or this reason the retro iruses are called
human T lymphotropic iruses ( TLVs). Transmission may
be through se ual intercourse blood products V drug use
and rom mother to child during childbirth and breast eeding.
There is o ten a ery long latent period rom time o in ec
tion until presentation with clinical disease.
Human T-lymphotropic virus 1
uman T lymphotropic irus is endemic in Japan the Carib
bean region South America (Bra il Peru Columbia) sub
Saharan A rica and Romania; among Australian Aborigines;
and in the southeastern nited States. n endemic areas in ec
tion rates may be uite high with only a small percentage o
in ected patients e er de eloping clinical disease (estimated
). TLV is spread primarily by mother to in ant trans
mission during breast eeding but also can be transmitted se u
ally (primarily male to emale) or through blood trans usion
or V drug use. TLV uses the GL T glucose transporter to
enter cells. TLV is responsible or se eral clinical syn
dromes. About o in ected persons will de elop adult
T cell leu emia lymphoma (ATL) with more TLV in ected
persons in Japan de eloping ATL than in other populations.
n ection in childhood through breast eeding seems to be a
ris actor or de eloping ATL. TLV associated myelopa
thy or tropical spastic paraparesis ( A TSP) is a less
common degenerati e neurologic syndrome.
There are our orms o ATL smoldering chronic acute and
lymphomatous usually progressing in that order. ATL is char
acteri ed by lymphadenopathy hepatosplenomegaly hyper
calcemia and s in lesions ( o patients). S in lesions in
ATL include erythematous papules or nodules ( ig. ).
Prurigo may be a prodrome to the de elopment o ATL. is
tologically the cutaneous in ltrates are pleomorphic atypical
412 lymphocytes with characteristic ower cells representing
Fig. 19-57 HTLV-1–associated adult T-cell leukemia-lymphoma.
TLV in ected lymphocytes. pidermotropism may be
present mimic ing mycosis ungoides.
Three uarters or more o TLV in ected patients will
ha e an abnormal s in e amination. The most common s in
conditions are dermatophytosis ( ) seborrheic dermatitis
( ) and erosis ac uired ichthyosis (up to ). Vitiligo is
also associated. n patients with A TSP chronic ec ema
photosensiti ity occurs in up to . Biopsies rom the areas
o chronic ec ema photosensiti ity may show eatures o ATL
in up to o patients (smoldering ATL). Scabies is seen in
o asymptomatic TLV in ected patients and in o
those with A TSP. The scabies may be o the hyper era
totic (crusted) type and the presence o hyper eratotic scabies
in a person rom an TLV endemic region should trigger
serologic testing or the irus. The spectrum o s in disease
seen in symptomatic TLV in ected patients is remar ably
similar to that seen in V in ected patients with C S disease
erosis ec ema seborrheic dermatitis and scabies.
n ecti e dermatitis in ecti e dermatitis associated with
TLV in ection ( D ) or TLV associated in ecti e der
matitis ( A D) occurs in children and less re uently in adults
with TLV in ection. t is much rarer in Japan than other
TLV endemic more tropical countries suggesting climate
and malnutrition socioeconomic actors may play a role.
n ecti e dermatitis is diagnosed by ma or and minor criteria.
Clinically the children present at an early age ( months
onward) with a chronic ec ema o the scalp a illa groin
e ternal auditory canal retroauricular area eyelid margins
paranasal areas and nec . n ol ement o the scalp and retro
auricular area is uni ersal ollowed by the body olds (nec
a illae groin paranasal s in and ears). udation and crust
ing are the hallmar s o the s in lesions. Pruritus is mild.
Clinically in ecti e dermatitis resembles a cross between
in ected AD and in ected seborrheic dermatitis. There is a
chronic nasal discharge. Cultures rom the s in and nares are
positi e or Staph lococcus aureus or β hemolytic streptococcus
and the condition responds rapidly to antibiotics and topical
corticosteroids. n ecti e dermatitis is relapsing and recurrent.
S in biopsies show a nonspeci c dermatitis; howe er close
e amination may show atypical CD + cells in ltrating the epi
dermis at times simulating ATL or cutaneous T cell lym
phoma. Care ul neurologic e amination o children with D
will o ten re eal abnormal neurologic ndings wea ness
lumbar pain dysesthesias and urinary disturbances.
De Oliveira M, et al: Infective dermatitis associated with human T-cell
lymphotropic virus type 1: evaluation of 42 cases observed in Bahia,
Brazil. Clin Infect Dis 2012; 54:1714.
Einsiedel L, et al: Clinical associations of human T-lymphotropic virus
type 1 infection in an indigenous Australian population. PLoS Negl
Trop Dis 2014; 8:e2643.
 Hlela C, Bittencourt A: Infective dermatitis associated with HTLV-1
mimics common eczemas in children and may be a prelude to severe
systemic diseases. Dermatol Clin 2014; 32:237.
McGill NK, et al: HTLV-1-assoicated infective dermatitis: updates on the
pathogenesis. Exp Dermatol 2012; 21:815.
Okajima R, et al: High prevalence of skin disorders among HTLV-1
infected individuals independent of clinical status. PLoS Negl Trop Dis
2013; 7:e2546.
Terada T, et al: T-cell lymphoma of the penis as the first manifestation of
adult T-cell lymphoma/leukemia. Int J Dermatol 2012; 51:973.
Human immunodeficiency virus
uman immunode ciency irus ( V) in ects human helper
T (Th) cells leading to a progressi e immunode ciency
disease. n its end stages V in ection is called ac uired
immunode ciency syndrome (A DS). Cutaneous mani esta
tions are prominent a ecting up to o V in ected
persons. any patients ha e multiple s in lesions o di erent
types. The s in lesions or combinations o s in conditions are
so uni ue that the diagnosis o V in ection or A DS can
o ten be suspected rom the s in e amination alone. The s in
ndings can be classi ed into three broad categories in ec
tions in ammatory dermatoses and neoplasms. The s in
conditions also tend to appear at a speci c stage in V pro
gression ma ing them use ul mar ers o the stage o V comple o mani estations is called the immune reconstitution
disease.
The natural history o V in ection in the ast ma ority o
patients is a gradual loss o Th cells. The rate o this decline is
ariable with some patients progressing rapidly and others
ery slowly or not at all (long term nonprogressors). Soon
a ter in ection there is a serocon ersion syndrome called
primary V in ection or acute in ection (group ). Patients
reco er rom this syndrome and enter a relati ely long latent
period (asymptomatic in ection or group ) which a erages
about years. During this period patients may ha e persis
tent generali ed lymphadenopathy (group ). When symp
toms begin to appear they are o ten nonspeci c and include
e er weight loss chronic diarrhea and mucocutaneous
disease (group VA). Th counts in group and VA
patients usually range rom to cells. The s in ndings
at this stage (originally called A DS related comple ARC)
include seborrheic dermatitis psoriasis Reiter syndrome
atopic dermatitis herpes oster acne rosacea oral hairy leu
opla ia onychomycosis warts S aureus s in and so t tissue
in ections (including recurrent RSA) and mucocutaneous
candidiasis.
nce the Th count is cells or less the patient is de ned
as ha ing A DS. n this stage o V disease the s in lesions
are more characteristic o immunode ciency and include char
acteristic opportunistic in ections chronic herpes simple
molluscum contagiosum bartonellosis (bacillary angiomato
sis) systemic ungal in ections (cryptococcosis histoplasmosis
coccidioidomycosis penicilliosis) and mycobacterial in ec
tion. Parado ically patients at this stage also ha e hyperreac
ti e s in and re uently in ammatory o ten pruritic s in
diseases. These s in conditions include eosinophilic olliculitis
granuloma annulare drug reactions enhanced reactions to
insect bites re ractory seborrheic dermatitis atopic dermatitis
and photodermatitis.
When the Th count alls below cells the patient is o ten
said to ha e ad anced A DS. These patients may ha e ery
unusual presentations o their opportunistic in ections includ
ing multicentric re ractory molluscum contagiosum; chronic
herpes simple ; chronic cutaneous aricella oster in ection;
cutaneous C V ulcerations cutaneous acanthamebiasis
cutaneous atypical mycobacterial in ections (including M co
bacterium avium comple and M cobacterium haemophilum)
penicilliosis and crusted scabies. Treatment o their in ec
tahir99 - UnitedVRG
tions is o ten di cult because o the signi cant chronic
immunosuppression.
t is now clear that V itsel is the cause o the loss o Th
cells and that e ecti e treatment o V in ection may halt or
re erse the natural history o V disease. The numerous
Retroviruses
antiretro iral agents are usually used in combinations called
coc tails. This combination treatment is called highly acti e
antiretro iral therapy ( AART). A signi cant percentage o
V in ected patients respond to AART and may show dra
matic impro ement o their V disease. V disappears rom
the blood and Th cell counts rise. As e pected in patients who
respond to AART opportunistic in ections no longer occur
and subse uently mortality decreases. This is also true o
cutaneous in ectious conditions. V associated psoriasis
usually impro es substantially especially i the patient did not
ha e psoriasis be ore V in ection. Since ull reconstitution
o the immune system with AART may ta e se eral years
some s in conditions may be slow to resol e (seborrheic der
matitis). thers such as molluscum contagiosum and aposi
sarcoma generally begin to impro e within months.
AART is typically associated with resolution o all orms
o V related cutaneous complications. owe er some con
ditions may initially appear or be e acerbated by the sudden
impro ement o the immune status that occurs with eradica
tion o V iremia and with increase in Th cell counts. This
in ammatory syndrome. R S occurs in o V
in ected persons started on AART. Persons with an oppor
tunistic in ection ( ) speci cally cryptococcosis tuberculosis
penicilliosis leprosy or Pneumoc stis pneumonia may be at
higher ris i AART is started as the is being treated. This
mar ed in ammatory syndrome can be se ere and in
resource poor countries o A DS related deaths in treated
patients can be attributed to R S during the rst year o
AART therapy. al o R S related conditions are dermato
logic. The ollowing three orms o R S occur
. A hidden is unmas ed as the reconstituted
immune system attac s the hidden pathogen. The
presentation may be atypical. The appearance o
cutaneous mycobacterial in ections with AART is
an e ample.
. n the setting o a documented when AART is
started the patient has worsening o the in ection with
new ndings. This is not treatment ailure but enhanced
immune response to the pathogen. This typically occurs
with tuberculosis or cryptococcosis.
. The de elopment o new disorders is seen in ectious
or in ammatory or enhanced in ammatory responses
around malignancies especially aposi sarcoma.
osinophilic olliculitis acne ares drug eruptions
Reiter syndrome lupus erythematosus alopecia
uni ersalis at times PV in ections (especially oral
and genital) increased outbrea s o genital and
orolabial herpes simple molluscum contagiosum
herpes oster C V ulcerations type reactions in
ansen s disease cutaneous mycobacterial and ungal
in ections leishmaniasis tattoo and oreign body
granulomas and sarcoidosis can be part o R S in
the s in.
n ection with V is now being e ecti ely controlled in
many patients through AART. owe er the constant
struggle o the immune system to control iral replication
and side e ects rom multiple medications has led to senes
cence o the immune system similar to that seen with chrono
logic aging. Chronic V disease is characteri ed by the same
combination o immunode ciency and in ammation that
occurs with aging. This has led to increased rates and
earlier onset o cardio ascular disease metabolic disorders 413
 osteoporosis and some cancers in V disease. railty or the
19 ariability with which persons ac uire health problems and
the conse uent inability to tolerate stressors ( ulnerability) is
becoming the primary conse uence o V in ection in many
countries.
Viral Diseases
Primary HIV infection
(acute seroconversion syndrome)
Se eral wee s a ter in ection with V an acute illness de el
ops in a large proportion o indi iduals. The clinical syndrome
is similar to primary BV in ection with e er sore throat
cer ical adenopathy a rash and oral genital and rectal ulcer
ation. The s in eruption can be polymorphous ( igs. and
). ost characteristic is a papular eruption o discrete
slightly scaly o al lesions o the upper trun . The lesions ha e
a super cial resemblance to pityriasis rosea but the peripheral
scale is not prominent and there is ocal hemorrhage in the
lesions. A Gianotti Crosti li e papular eruption may also
occur. Purpuric lesions along the margins o the palms and
soles as seen in immune comple disease ha e been reported.
The mucosal erosions resemble aphthae but are larger and can
a ect all parts o the mouth pharyn esophagus and anal
mucosa. Dysphagia may be prominent. The Th cell count alls
abruptly during serocon ersion. The le el o immune impair
ment may allow oral candidiasis or e en Pneumoc stis jiroveci
( ormerly P carinii) pneumonia to de elop. The diagnosis
should be suspected in any at ris indi idual with the correct
Fig. 19-58 Primary HIV infection.
Fig. 19-59 Primary HIV
infection. (Courtesy of
Ginat Mirowski, MD.)
414
constellation o symptoms. A direct measurement o V iral
load will con rm the diagnosis. Combination anti iral therapy
is instituted immediately.
HIV-associated pruritus
rom early in the V epidemic it was clear that pruritus was
a mar er o V in ection throughout the world occurring in
up to o patients. Pruritus is usually not caused by V
disease itsel but is related to in ammatory dermatoses associ
ated with the disease. Papular pruritic eruption is not a
speci c disease but rather a wastebas et diagnosis used to
encompass patients with many orms o V associated
pruritus. Worldwide it most o ten represents enhanced insect
bite reactions. These pruritic eruptions are best subdi ided
into ollicular and non ollicular eruptions. The relati e pre a
lence o these two patterns o pruritic eruptions is geographi
cally distinct. n tropical and semitropical regions where
biting insects are prominent non ollicular eruptions are most
common and probably represent insect bite hypersensiti ity.
n temperate regions ollicular pruritic eruptions are more
common.
osinophilic olliculitis ( ) is the most common pruritic
ollicular eruption. t is seen in patients with a Th count o
about cells. Clinically presents with urticarial ollicular
papules on the upper trun ace scalp and nec ( ig. ).
Pustular lesions are uncommon; pustules are usually smaller
than in bacterial olliculitis and represent end stage lesions.
These lesions are in re uently seen because the pruritus is so
se ere that the pustules are e coriated be ore the lesion e ol es
to this degree. About o lesions occur abo e the nipple
line on the anterior trun and lesions typically e tend down
the midline o the bac to the lumbar spine. wa es and
wanes in se erity and may spontaneously clear only to are
unpredictably. A peripheral eosinophilia may be present and
the serum g le el may be ele ated suggesting this is a dis
order mediated by Th cells. istologically an in ltrate o
mononuclear cells and eosinophils is seen around the upper
portion o the hair ollicle at the le el o the sebaceous gland.
As lesions e ol e eosinophils and lymphocytes enter the ol
licular structure and the sebaceous glands. Pustules are ormed
late and represent aggregates o eosinophils in the uppermost
part o the ollicle. Rarely there will be increased mucin within
Fig. 19-60 Eosinophilic
folliculitis. (Courtesy of
Curt Samlaska, MD.)
the ollicular epithelium ma ing distinction rom ollicular
mucinosis di cult.
nitial treatment o is topical corticosteroids and antihis
tamines. the patient ails to respond phototherapy ( VB or
P VA) or itracona ole mg twice daily may be e ecti e.
n some patients repeated applications o permethrin (e ery
other night or up to wee s) may be o bene t. Permethrin
therapy is directed at Demo ex mites which may be the anti
genic trigger o . sotretinoin is also e ecti e o ten a ter a
ew months in a dose o about . mg g day. AART
may lead to a are o (as part o R S) but usually leads
e entually to its resolution. Staphylococcal olliculitis which
may be se erely pruritic in patients with V disease and
Pit rosporum olliculitis should be included in the di erential
diagnosis. These are e cluded by bacterial culture and s in
biopsy respecti ely. Demo ex olliculitis should also be in the
di erential.
The other pruritic dermatoses that are not ollicular can be
di ided into the primarily papular eruptions and the ec ema
tous reactions. The papular eruptions include scabies insect
bites transient acantholytic dermatosis granuloma annulare
and prurigo nodularis. The ec ematous dermatoses include
atopic li e dermatitis seborrheic dermatitis nummular
ec ema erotic ec ema photodermatitis and drug eruptions.
Patients may ha e multiple eruptions simultaneously ma ing
di erential diagnosis di cult. A s in biopsy rom a represen
tati e lesion o e ery morphologic type on the patient may
elucidate the true diagnosis(es). Treatment is determined by
the diagnosis and is similar to treatment in persons without
V in ection with these same dermatoses. Special consider
ations in A DS patients include the use o topical therapy plus
i ermectin or crusted scabies and thalidomide or prurigo
nodularis and photodermatitis. Both these systemic agents are
ery e ecti e i used appropriately.
HIV-associated neoplasia
eoplasia is prominent in V in ection and in some cases is
highly suggesti e o V in ection. aposi sarcoma is an
e ample. ther common neoplasms seen in patients with V
in ection include super cial basal cell carcinomas (BCCs) o
the trun s uamous cell carcinomas (SCCs) in sun e posed
areas genital PV induced SCC and e tranodal B cell and
T cell lymphomas. Lipomas angiolipomas and dermato bro
mas may occur. n the case o lipomas their appearance is
usually related to the peripheral at loss that occurs with some
V treatment regimens and with V disease itsel .
onmelanoma s in cancers ( SCs) are ery common in
V patients. AART does not protect against the de elop
ment o SC in V in ection. BCCs usually occur as super
cial multicentric lesions on the trun in air s inned men in
their twenties to ties. The ratio o BCC to SCC is not re ersed
in V disease as it is in organ transplant recipients. BCCs
beha e in the same manner as they do in the immunocompe
tent host and standard management is usually ade uate.
Actinically induced SCCs are also uite common and present
in the standard manner as nodules eratotic papules or ulcer
ations. n most cases their beha ior is relati ely benign and
standard management is ade uate. Remo al o SCCs in sun
e posed areas by curettage and desiccation in patients with
V in ection is associated with an unacceptably high recur
rence rate o about . Complete e cision is there ore recom
mended. n a small subset o patients with A DS actinic SCCs
can be ery aggressi e; they may double in si e o er wee s
and may metastasi e to regional lymph nodes or iscerally
leading to the death o the patient.
Genital SCCs including cer ical aginal anal penile and
periungual SCC all occur in patients with V in ection.
tahir99 - UnitedVRG
These neoplasms are increased in re uency and the progres
sion rom PV in ection to neoplasia appears to be acceler
ated. This is analogous to the situation in organ transplant
and other immunosuppressed patients. t appears that these
cancers are associated with primarily high ris PV types.
Retroviruses
igh ris genital PV in ection in patients with V can
produce perianal dysplasia in S who ha e a history o
recepti e anal intercourse. Dysplasia in this area may present
as el ety white or hyperpigmented pla ues in ol ing the
whole anal area and e tending into the anal canal. These
lesions may erode or ulcerate. istology will demonstrate SCC
in situ. The ris o progression o the lesions to anal SCC is
un nown but is estimated to be at least times higher than
the rate o cer ical cancer in women in the general population.
The management o such lesions is unclear but regular
ollow up is clearly indicated and any masses in the anal canal
should be immediately re erred or biopsy. At some centers
Pap smear e ui alents are per ormed. mi uimod has been
used as an ad unct in the management o genital warts and
PV associated genital in situ dysplasias (not genital SCC).
Although it may be o bene t in patients with reconstituted
immune systems recei ing AART especially in combination
with surgical ablation the response rate is much lower than
in immunocompetent patients. n the only placebo controlled
trial done be ore standard AART was a ailable imi uimod
was no more e ecti e than placebo in clearing genital warts
( ) in V in ection. Small case series o patients recei ing
AART suggest clearance rates o about . Topical cido
o ir can be used to treat genital PV in ection in patients with
low ris and high ris PV types.
The ul ar and penile s in may de elop at white or hyper
pigmented macules rom a ew millimeters to se eral centime
ters in diameter. These show SCC in situ and are analogous to
bowenoid papulosis in the immunocompetent host. Lesions o
the penile sha t and glabrous ul ar s in not at a transition
one or on mucosal sur aces ha e a low ris o progressing to
in asi e SCC. Lesions o the glans penis that are red and ed
should be biopsied. the changes o SCC in situ are ound
these should be managed aggressi ely as SCC in situ. Topical
and super cial radiation therapy are e ecti e. Close
clinical ollow up is indicated. Periungual SCC has also been
seen in patients with V in ection. Any persistent eratotic
or hyperpigmented lesion in the periungual area must be care
ully e aluated. anagement is surgical e cision. Perianal and
ul o aginal lesions should be managed as intraepithelial
neoplasia types A and V respecti ely.
tranodal B cell and less o ten T cell lymphomas are asso
ciated with the ad anced immunosuppression o A DS. The
B cell lymphomas and some o the T cell lymphomas present
as iolaceous or plum colored papules nodules or tumors.
nce the diagnosis is established by biopsy systemic chemo
therapy is re uired. BV is ound in some cases. AART is
both protecti e against the de elopment o non odg in lym
phoma ( L) and odg in disease in V and substantially
impro es prognosis o V in ected patients with L.
ycosis ungoides can also be seen in patients with V in ec
tion o ten in those who ha e not yet de eloped A DS. t pres
ents with pruritic patches or pla ues and may progress to
tumor stage. BV is not ound in these cases. CD + pseudo
lymphoma is also seen in patients with untreated V in ec
tion and may resol e with AART.
alignant melanoma ( ) is seen at increased rates in
persons with V in ection. V in ected melanoma patients
demonstrate the same ris actors as other melanoma patients
multiple ne i air s in type and prior intermittent but intense
sun e posure. V patients with melanoma in the pre AART
era had signi cantly shorter disease ree sur i al and reduced
o erall sur i al. any air s inned patients in ected with V
415

19
Viral Diseases
Fig. 19-61 Kaposi sarcoma in AIDS patient.
complain o the new onset o atypical moles (analogous to
organ transplant patients). Whether these con er an increased
ris o melanoma is un nown.
AIDS and Kaposi sarcoma
aposi sarcoma ( S) was along with Pneumoc stis pneumo
nia the harbinger o the A DS epidemic. any S and
bise ual men presented with this tumor in the early s ling S and liposomal do orubicin may need to be added to
with a pre alence o up to in some cohorts. V a
γ herpes irus has been identi ed in these lesions. The clinical
eatures o S in patients with A DS are di erent than those
seen in elderly men who do not ha e A DS. Patients with A DS
present with symmetric widespread lesions o ten numerous.
Lesions begin as macules that may progress to tumors or
nodules ( ig. ). Any mucocutaneous sur ace may be
in ol ed but areas o predilection include the hard palate
ace trun penis and lower legs and soles. Visceral disease
may be present and progressi e. dema may accompany
lower leg lesions and i signi cant it is o ten associated with
lymph node in ol ement in the inguinal area.
A diagnosis o S is established by s in biopsy which
should be ta en rom the center o the most in ltrated pla ue.
cessi e bleeding is not usually a problem. arly macular
lesions show atypical angulated ectatic essels in the upper
dermis associated with an in ammatory in ltrate containing
plasma cells. Pla ue lesions show aggregates o small essels
and endothelial cells in the upper dermis and surrounding
adne al structures. odules and tumors show the classic
pattern o a spindle cell neoplasm with prominent e tra asa
tion o red blood cells.
AART has reduced the incidence o S in V in ected
patients by old. owe er S remains an important com
plication o V in ection or the ollowing two reasons
. V associated S is still common in sub Saharan A rica.
With AART therapy sur i al in A rica or V
in ected persons or more than year is almost i Castelnuovo B, et al: Cause-specific mortality and the contribution of
they do not ha e S. n patients with V disease and
S howe er sur i al is only . This results rom the
lac o e ecti e cytoto ic therapy or S in A rica.
V S is more common in women than men in some
clinics in A rica.
. Although AART has substantially reduced the
pre alence o S in V disease in the de eloped world
AART has not eliminated the disease. n act there
remains a airly substantial proportion o primarily gay
men with V disease who also ha e S (up to o Res 2001; 7:3031.
416
some cohorts). Twenty percent or more o these A DS S
patients ha e well controlled V disease with long term
undetectable iral load and CD counts abo e . These
patients ha e an o erall good prognosis but still may
re uire cytoto ic or radiation therapy to control their S.
Patients with A DS S and lower CD counts and
detectable iral loads are more li ely to ha e isceral
disease. p to one third o these A DS S patients died
despite AART and chemotherapy suggesting that
A DS S in the setting o poor V control is a poor
prognostic nding.
The treatment o A DS associated S depends on the e tent
and aggressi eness o the disease. ecti e AART a ter
about months is associated with in olution o S lesions in
o patients. This should be the initial management in most
patients with mild to moderate disease (< lesions and <
new lesions month) who are not recei ing anti V treat
ment. ntralesional inblastine . . mg mL can be in l
trated into lesions (as or hypertrophic scar) and lesions will
in olute o er se eral wee s. yperpigmentation usually
remains. Cryotherapy is also e ecti e but will lea e postin
ammatory hypopigmentation in pigmented persons. Persis
tent indi idual lesions and lesions o the soles and penis
respond well to local irradiation therapy (one single treatment
o Gy or ractionated treatments to Gy). or patients
with moderate disease (> lesions or mucosal or isceral
in ol ement) AART alone may not be ade uate in control
the treatment. or patients with symptomatic isceral disease
aggressi e s in disease mar ed edema and pulmonary
disease systemic chemotherapy is indicated.
Afonso JP, et al: Pruritus papular eruption and eosinophilic folliculitis
associated with human immunodeficiency virus (HIV) infection: a
histopathological and immunohistochemical comparative study. J Am
Acad Dermatol 2012; 67:269.
Agaba PA, et al: Presentation and survival of patients with AIDS-
related Kaposi’s sarcoma in Jos, Nigeria. Int J STD AIDS 2009;
29:410.
Alberici F, et al: Ivermectin alone or in combination with benzyl
benzoate in the treatment of human immunodeficiency virus–
associated scabies. Br J Dermatol 2000; 142:969.
Al-Dawsari NA, et al: Pigmented Bowen’s disease of the penis and
scrotum in a patient with AIDS. Dermatol Online J 2014; 20:22337.
Amerson EH, Maurer TA: Immune reconstitution inflammatory syndrome
and tropical dermatoses. Dermatol Clin 2011; 29:39.
Annam V, et al: Clinicopathological study of itch folliculitis in HIV-
infected patients. Indian J Dermatol Venereol Leprol 2010; 76:259.
Blaser N, et al: Impact of viral load and the duration of primary infection
on HIV transmission: systematic review and meta-analysis. AIDS 2014;
28:1021.
Bonnet F, et al: Malignancy-related causes of death in human
immunodeficiency virus–infected patients in the era of highly active
antiretroviral therapy. Cancer 2004; 101:317.
Brothers TD, et al: Frailty in people aging with human immunodeficiency
virus (HIV) infection. J Infect Dis 2014; 210:1170.
Bussone G, et al: Unmasking leprosy: an unusual immune reconstitution
inflammatory syndrome in a patient infected with human
immunodeficiency virus. Am J Trop Med Hyg 2010; 83:13.
immune reconstitution inflammatory syndrome in the first 3 years after
antiretroviral therapy initiation in an urban African cohort. Clin Infect Dis
2009; 49:965.
Cusini M, et al: 5% Imiquimod cream for external anogenital warts in
HIV-infected patients under HAART therapy. Int J STD AIDS 2004;
15:17.
Davidson A, et al: Malignancies in South African children with HIV.
J Pediatr Hematol Oncol 2014; 36:111.
Diaz-Arrastia C, et al: Clinical and molecular responses in high-grade
intraepithelial neoplasia treated with topical imiquimod 5%. Clin Cancer
Farsani TT, et al: Etiology and risk factors associated with a pruritus
papular eruption in people living with HIV in India. J Int AIDS Soc 2013;
16:17325.
Frater J, et al: HIV-1-specific CD4+ responses in primary HIV-1 infection
predict disease progression. AIDS 2014; 28:699.
Meyer T, et al: Human immunodeficiency virus (HIV)—associated
eosinophilic folliculitis and follicular mucinosis in a black women.
Int J Dermatol 2010; 49:1308.
Moussa R, et al: Buschke-Loewenstein lesion: another possible
manifestation of immune restoration inflammatory syndrome? AIDS

Grinsztejn B, et al: Effects of early versus delayed initiation of
antiretroviral treatment on clinical outcomes of HIV-1 infection: results
from the Phase 3 HPTN 052 randomised controlled trial. Lancet 2014;
14:281.
Husak R, et al: Refractory human papillomavirus–associated oral warts
treated topically with 1–3% cidofovir solutions in human
immunodeficiency virus type 1–infected patients. Br J Dermatol 2005;
153:382.
Jagannathan P, et al: Life-threatening immune reconstitution
inflammatory syndrome after Pneumocystis pneumonia: a cautionary
case series. AIDS 2009; 23:13.
Khalil EA, et al: Post-Kala-Azar dermal leishmaniasis: a paradigm of
paradoxical immune reconstitution syndrome in non-HIV/AIDS patients.
J Trop Med 2013; 2013:275253.
Kim TG, et al: Skin disorders in Korean patients infected with human
immunodeficiency virus and their association with a CD4 lymphocyte
count: a preliminary study. J Eur Acad Dermatol Venereol 2010;
24:1476.
Kreuter A, et al: Clinical spectrum and virologic characteristics of anal
intraepithelial neoplasia in HIV infection. J Am Acad Dermatol 2005;
52:603.
Lehloenya R, Meintjes G: Dermatologic manifestations of the immune
reconstitution inflammatory syndrome. Dermatol Clin 2006; 24:549.
Mani D, et al: A retrospective analysis of AIDS-associated Kaposi’s
sarcoma in patients with undetectable HIV viral loads and CD4 counts
greater than 300 cells/mm3. J Int Assoc Physicians AIDS Care 2009;
8:279.
Martin-Carbonero L, et al: Pegylated liposomal doxorubicin plus highly
active antiretroviral therapy versus highly active antiretroviral therapy
alone in HIV patients with Kaposi’s sarcoma. AIDS 2004; 18:1737.
Massad LS, et al: Effect of antiretroviral therapy on the incidence of
genital warts and vulvar neoplasia among women with the human
immunodeficiency virus. Am J Obstet Gynecol 2004; 190:1241.
Retroviruses
2004; 18:1221.
Olson CM, et al: Risk of melanoma in people with HIV/AIDS in the
pre- and post-HAART eras: a systematic review and meta-analysis of
cohort studies. PLoS One 2014; 9:e95096.
Post WS, et al: Associations between HIV infection and subclinical
coronary atherosclerosis. Ann Intern Med 2014; 160:458.
Rodgers S, Leslie KS: Skin infections in HIV-infected individuals in the
era of HAART. Curr Opin Infect Dis 2011; 2:124.
Rodrigues LKE, et al: Altered clinical course of malignant melanoma in
HIV-positive patients. Arch Dermatol 2002; 138:765.
Seoane Reula E, et al: Role of antiretroviral therapies in mucocutaneous
manifestations in HIV-infected children over a period of two decades.
Br J Dermatol 2005; 153:382.
Sherin K, et al: What is new in HIV infection? Am Fam Physician 2014;
89:265.
Stammler Jaliff B, et al: Outcome and reinfection after
Staphylococcus aureus bacteriemia in individuals with and without
HIV-1 infection: a case-control study. BMJ Open 2014; 4:e004075.
Stover KR, et al: A fatal case of Kaposi sarcoma due to immune
reconstitution inflammatory syndrome. Am J Med Sci 2012;
343:421.
Weiss DA, et al: Condyloma overgrowth caused by immune
reconstitution inflammatory syndrome. Urology 2009; 74:1013.
Worodria W, et al: Incidence and predictors of mortality and the effect
of tuberculosis immune reconstitution inflammatory syndrome in a
cohort of TB/HIV patients commencing antiretroviral therapy. J Acquir
Immune Defic Syndr 2011; 58:32.
Xuan L, et al: Alopecia areata and vitiligo as primary presentations in a
young male with human immunodeficiency virus. Indian J Dermatol
2014; 59:209.
Yokobayashi H, et al: Analysis of serum chemokine levels in patients
with HIV-associated eosinophilic folliculitis. J Eur Acad Dermatol
Venereol 2013; 27:212.

Bonus images for this chapter can be found online at expertconsult.inkling.com

eFig. 19-1 Initial episode of genital herpes,
HSV-2.
eFig. 19-2 Herpes gladiatorum.
eFig. 19-3 Herpes gladiatorum, neck lesions of
HSV-1.
eFig. 19-4 Recurrent genital herpes.
eFig. 19-5 Genital herpes, solitary ulceration.
eFig. 19-6 Genital herpes, HSV-2, infected
areas spontaneously heal while new erosions
appear.
eFig. 19-7 Herpes simplex, HSV-1, in patient
with AIDS.
eFig. 19-8 Varicella.
eFig. 19-9 Herpes zoster.
eFig. 19-10 Herpes zoster, necrotic, in elderly
patient.
eFig. 19-11 Herpes zoster, classic dermatomal
distribution.
eFig. 19-12 Herpes zoster, motor nerve
involvement.
eFig. 19-13 Ecthymatous zoster in AIDS patient.
eFig. 19-14 Herpes zoster, early lesions. eFig. 19-27 Genital molluscum contagiosum.
eFig. 19-15 Oral hairy leukoplakia. eFig. 19-28 Molluscum contagiosum in AIDS
eFig. 19-16 Oral Kaposi sarcoma in AIDS patient.
patient. eFig. 19-29 Viral enanthem.
eFig. 19-17 Porphyria cutanea tarda associated eFig. 19-30 Rubella.
with hepatitis C. Papular-purpuric gloves-and-
eFig. 19-31
eFig. 19-18 Papules on the arms, Gianotti- socks syndrome.
Crosti syndrome. (Courtesy of Dr. Curt eFig. 19-32 Orf.
Samlaska) eFig. 19-33 Verruca vulgaris, wart at site of
eFig. 19-19 Vaccinia, typical reaction at about 1 trauma.
week. eFig. 19-34 Verruca plana.
eFig. 19-20 Smallpox scars. (Courtesy of eFig. 19-35 Common warts, verruca vulgaris.
Shyam Verma, MD.)
eFig. 19-36 Grouped warts in area of atopic
eFig. 19-21 Autoinoculation vaccinia. dermatitis.
eFig. 19-22 Roseola vaccinia. eFig. 19-37 Verruca, nail biter with periungual
eFig. 19-23 Molluscum contagiosum. warts.
eFig. 19-24 Molluscum contagiosum. eFig. 19-38 Verruca vulgaris, doughnut wart.
eFig. 19-25 Molluscum contagiosum and eFig. 19-39 Epidermodysplasia verruciformis.
condyloma acuminatum (HPV infection)
occurring together.
eFig. 19-26 Molluscum contagiosum.

417

tahir99 - UnitedVRG
eFig. 19-1 Initial eFig. 19-4 Recurrent
episode of genital genital herpes.
herpes, HSV-2.

Retroviruses
eFig. 19-2 Herpes
gladiatorum.

eFig. 19-5 Genital

herpes, solitary
ulceration.

eFig. 19-3 Herpes

gladiatorum, neck
lesions of HSV-1.

eFig. 19-6 Genital herpes in AIDS, HSV-2, infected areas

spontaneously heal while new erosions appear.
417.e1
 eFig. 19-7 Herpes
19 simplex, HSV-1, in
patient with AIDS.
Viral Diseases

eFig. 19-10 Herpes zoster, necrotic, in elderly patient.

eFig. 19-11 Herpes

zoster, classic
dermatomal
distribution.

eFig. 19-8 Varicella.

eFig. 19-12 Herpes

zoster, motor nerve
involvement.

eFig. 19-9 Herpes zoster.

417.e2

tahir99 - UnitedVRG
 eFig. 19-16 Oral
Kaposi sarcoma in
AIDS patient.

Retroviruses
eFig. 19-13 Ecthymatous zoster in AIDS patient.

eFig. 19-14 Herpes

zoster, early lesions.

eFig. 19-17 Porphyria cutanea tarda associated with hepatitis C.

eFig. 19-18 Papules on the arms, Gianotti-Crosti syndrome.

(Courtesy of Dr. Curt Samlaska)

eFig. 19-19 Vaccinia,

typical reaction at
about 1 week.

eFig. 19-15 Oral hairy leukoplakia.

417.e3
 eFig. 19-20 Smallpox eFig. 19-22 Roseola
19 scars. (Courtesy of
Shyam Verma, MD.)
vaccinia.
Viral Diseases

eFig. 19-21 eFig. 19-23 Molluscum

Autoinoculation contagiosum.
vaccinia.

eFig. 19-24 Molluscum contagiosum.

417.e4

tahir99 - UnitedVRG
 eFig. 19-25 Molluscum eFig. 19-28 Molluscum
contagiosum and contagiosum in AIDS
condyloma patient.
acuminatum (HPV
infection) occurring

Retroviruses
together.

eFig. 19-26 Molluscum

contagiosum.

eFig. 19-29 Viral enanthem.

eFig. 19-30 Rubella.

eFig. 19-27 Genital molluscum contagiosum.

417.e5
 eFig. 19-34 Verruca
19 plana.
Viral Diseases

eFig. 19-31 Papular-purpuric gloves-and-socks syndrome.

eFig. 19-35 Common

warts, verruca
vulgaris.

eFig. 19-32 Orf.

eFig. 19-36 Grouped

warts in area of atopic
dermatitis.

eFig. 19-33 Verruca

vulgaris, wart at site
of trauma.

417.e6

tahir99 - UnitedVRG
eFig. 19-37 Verruca, eFig. 19-39
nail biter with Epidermodysplasia
periungual warts. verruciformis.

Retroviruses
eFig. 19-38 Verruca
vulgaris, doughnut
wart.

417.e7
 Bonus images for this chapter can be found online at
expertconsult.inkling.com
20 Parasitic Infestations, Stings, and Bites
The ma or groups o animals responsible or bites stings and
parasitic in ections in humans belong to the phyla Arthrop
oda Chordata Cnidaria ( ormerly Coelenterata) emathel
minthes Platyhelminthes Annelida and Proto oa. This
chapter re iews parasitic diseases and the ma or causes o
bites and stings as well as strategies or pre ention.
PHYLUM PROTOZOA
The proto oa are one celled organisms di ided into classes
according to the nature o their locomotion. Class Sarcodina
organisms mo e by temporary pro ections o cytoplasm (pseu
dopods); class astigophora by means o one or more agella;
and class Ciliata by short hairli e pro ections o cytoplasm
(cilia). Class Sporo oa ha e no special organs o locomotion.
CLASS SARCODINA
Amebiasis cutis
Entamoeba histol tica is an intestinal parasite transmitted by the
ecal oral route or by se ual contact. Cutaneous ulcers usually
result rom e tension o an underlying amebic abscess; the
most common sites are the trun abdomen buttoc s genita
lia and perineum. Those on the abdomen may result rom
hepatic abscesses. Penile lesions are usually se ually ac uired.
ost lesions begin as deep abscesses that rupture and orm
ulcerations with distinct raised cordli e edges and an ery
thematous halo appro imately cm wide. The base is co ered
with necrotic tissue and hemopurulent pus containing amebas.
These lesions are rom a ew centimeters to cm wide.
Without treatment slow progression o the ulcer occurs in an
increasingly debilitated patient until death ensues. Patients
may also present with stulas ssures polypoid warty lesions
or nodules. Deep lesions are more li ely to be associated with
isceral lesions.
The sole mani estation o early amebiasis may be chronic
urticaria. An estimated million in asi e cases occur annu
ally most o them in the tropics. n ection may be asymptom
atic or bloody diarrhea and hepatic abscesses may be present.
n the nited States the disease occurs chie y in institutional
i ed patients world tra elers recent immigrants migrant
wor ers and men who ha e se with men ( S ). Penile
ulcers are associated with inserti e anal intercourse.
The histologic ndings are those o a necrotic ulceration
with many lymphocytes neutrophils plasma cells and eosin
ophils. E histol tica is ound in the tissue within blood and
lymph essels. The organism measures μm in diameter
and has basophilic cytoplasm and a single eccentric nucleus
with a central aryosome. The organism is re uently demon
strable in resh material rom the base o the ulcer by direct
smear. Culture o the proto oa con rms the diagnosis. ndirect
418
tahir99 - UnitedVRG
hemagglutination test results remain ele ated or years a ter
the initial onset o in asi e disease whereas the results o gel
di usion precipitation tests and counterimmunoelectrophore
sis become negati e at months. This property can be used to
test or recurrent or acti e disease in persons coming rom
endemic areas.
When the perianal or perineal areas are in ol ed granu
loma inguinale lymphogranuloma enereum deep mycosis
and syphilis must be considered. n chronic urticaria resh
stool e aminations by a trained technician are necessary.
The treatment o choice is metronida ole ( lagyl) mg
orally three times daily or days. Abscesses may re uire
surgical drainage.
Other amebas
Amebas o the genera canthamoeba and alamuthia may also
cause s in lesions in in ected hosts. These organisms are ubi
uitous in the en ironment and are ound in soil water and
air. Granulomatous amebic encephalitis is the most common
mani estation o in ection with these amebas. n the case o
canthamoeba in asi e in ections are almost always in immu
nocompromised indi iduals including those with ac uired
immunode ciency syndrome (A DS) and organ transplant
patients although canthamoeba can also in ol e the cornea
in those who use homemade contact lens solution. Dissemi
nated lesions present as pin or iolaceous nodules that then
enlarge suppurate and orm ulcers with a necrotic eschar
( ig. ). ther ndings include e er nasal congestion or
discharge epista is cough headaches lethargy altered
mental status and sei ures. n patients in ected with can
thamoeba who ha e disease o the central ner ous system
(C S) death usually occurs within days to wee s. The organ
isms are isible on s in biopsy and culture is de niti e. n
patients without C S in ol ement mortality is with suc
cess ully treated cases o ten managed with a combination o
uorocytosine and sul adia ine. n patients in ected with
alamuthia man rillaris in ol ement o the central ace is
typical. Treatment paradigms are changing and in itro e i
dence suggests that dimina ene aceturate is more acti e than
milte osine or pentamidine ( ig. ). Chlorhe idine topically
and surgical debridement are local ad uncti e measures that
may pro e bene cial.
Abdolrasouli A, et al: Sexually transmitted penile amoebiasis in Iran: a
case series. Sex Transm Infect 2012; 88(8):585–588.
Ahmad AF, et al: The in vitro efficacy of antimicrobial agents against the
pathogenic free-living amoeba Balamuthia mandrillaris. J Eukaryot
Microbiol 2013; 60(5):539–543.
Centers for Disease Control and Prevention: Investigational drug available
directly from CDC for the treatment of infections with free-living
amebae. MMWR 2013; 62(33):666.
Cabello-Vílchez AM, et al: The isolation of Balamuthia mandrillaris from
environmental sources from Peru. Parasitol Res 2014; 13:2509–2513.
 Fig. 20-1 Disseminated
acanthameba in HIV
disease.
Fig. 20-2 Balamuthia
infection. (Courtesy of
Paco Bravo, MD.)
CLASS MASTIGOPHORA
rganisms belonging to this class the mastigophorans are
also nown as agellates. any ha e an undulating mem
brane with agella along their crest.
Trichomoniasis
richomonas ul o aginitis is a common cause o aginal pru
ritus with burning and a rothy leu orrhea. The aginal
mucosa appears bright red rom in ammation and may be
mottled with pseudomembranous patches. The male urethra
may also harbor the organism; in the male it causes urethritis
and prostatitis. ccasionally men may de elop balanoposthi
tis. rosi e lesions on the glans and penis or abscesses o the
median raphe may occur. eonates may ac uire the in ection
during passage through the birth canal but they re uire treat
ment only i symptomatic or i coloni ation lasts more than
wee s. Because this is otherwise almost e clusi ely a se u
ally transmitted disease (STD) richomonas ul o aginitis in
Class mastigophora
a child should prompt suspicion o se ual abuse.
Trichomoniasis is caused by richomonas vaginalis a color
less piri orm agellate μm long. vaginalis is demon
strated in smears rom a ected areas. Testing by direct
immuno uorescence is sensiti e and speci c and polymerase
chain reaction (PCR) analysis is now a ailable.
etronida ole g in a single oral dose is the treatment o
choice. Alternati ely mg twice daily or days may be
gi en and intra aginal metronida ole micona ole is also
e ecti e. Patients should be warned not to drin alcohol or
h a ter or dosing because o the disul ram type e ects o
this medication. ale se partners should also be treated. The
use o metronida ole is contraindicated in pregnant women
and clotrima ole applied intra aginally at mg a night or
wee s may be used instead. Disul ram and nithiamide
show in itro e idence o acti ity and could pro e use ul or
resistant organisms.
McGowin CL, et al: Trichomonas vaginalis: common, curable and in the
diagnostic spotlight. Clin Lab Sci 2014; 27:53–56.
Schwebke JR, et al: Intravaginal metronidazole/miconazole for the
treatment of vaginal trichomoniasis. Sex Transm Dis 2013;
40(9):710–714.
Leishmaniasis
Cutaneous leishmaniasis American mucocutaneous leish
maniasis and isceral leishmaniasis ( ala a ar) which
includes in antile leishmaniasis and post ala a ar dermal
leishmaniasis are all caused by morphologically indistin
guishable proto oa o the amily Trypanosomidae called
Leishmania (pronounced leesh may nea). The clinical eatures
o the leishmaniases di er and in general these diseases ha e
di erent geographic distribution. The ariable clinical mani
estations may result rom the di ersity o the organism and
the person s immune status and genetic ability to initiate an
e ecti e cell mediated immune response to the speci c in ect
ing organism. t is nown that the antigen speci c T cell
responses which lead to the production o inter eron ( )
and interleu in ( L ) are important or healing o the
lesions and the induction o li elong species speci c immu
nity to rein ection that results a ter natural in ection. Both
CD + and CD + lymphocytes appear to be acti e in the
immune response. L producing natural regulatory T cells
may play a role in the downregulation o in ection induced
immunity.
Cutaneous leishmaniasis
There are se eral types o lesion. All tend to occur on e posed
parts because all are transmitted by the sand y. ld World
leishmaniasis mani ests mainly in the s in and has also been
called Baghdad boil riental sore leishmaniasis tropica
Bis ra button Delhi boil Aleppo boil andahar sore and
Lahore sore. ild isceral disease may occur. S in lesions o
ew World in ection ha e been termed uta pian bois and bay
sore or chiclero ulcer.
Clinical features
n ld World leishmaniasis lesions may present in two distinct
types. ne is the moist or rural type a slowly growing indu
rated li id indolent papule ( ig. ) which enlarges in a ew
months to orm a nodule that may ulcerate in a ew wee s to
419
 Fig. 20-3 Old World
20 leishmaniasis.
Parasitic Infestations, Stings, and Bites

A
orm an ulcer as large as cm in diameter. Spontaneous healing
usually ta es place within months lea ing a characteristic
scar. This type is contracted rom rodent reser oirs such as
gerbils ia the sand y ector. The incubation period is rela
ti ely short ( wee s). The dry or urban type has a longer
incubation period ( months or longer) de elops much more
slowly and heals more slowly than the rural type. n both
types the ulcer or crust orms on a bed o edematous tissue.
Rarely a ter the initial or mother lesion is healed at the
borders o the healed area a ew so t red papules may appear
that are co ered with whitish scales and ha e the apple elly
characteristics o granulomatous diseases such as lupus ul
garis. These spread peripherally on a common erythematous
base and are the lupoid type. This is also nown as leishmani
asis recidi ans and occurs most o ten with the urban type o
disease caused by Leishmania tropica ew World disease may
also induce purely cutaneous lesions o aried morphology. B
The primary papule may become nodular errucous uruncu
lar or ulcerated with an in ltrated red border ( ig. ). Fig. 20-4 A and B, New World leishmaniasis.
Subcutaneous peripheral nodules which e entually ulcerate
may signal e tension o the disease. A linear or radial lymphan Fig. 20-5 Chiclero
gitic (sporotrichoid) pattern may occur with lymphadenopa ulcer in leishmaniasis.
thy and the nodes may rarely yield organisms. acial lesions
may coalesce and resemble erysipelas. Recidi ans lesions are
unusual in the ew World orm o disease. n ucatan and
Guatemala a subtype o ew World disease e ists the chiclero
ulcer. The most re uent site o in ection is the ear ( ig. ).
The lesions ulcerate and occur most re uently in wor ers who
har est chicle or chewing gum in orests where there is high
humidity. This orm is a more chronic ulcer that may persist or
years destroying the ear cartilage and leading to de ormity.
The etiologic agent is Leishmania mexicana and the sand y
ector Lut om ia aviscutellata
ta is a term used by Peru ians or leishmaniasis occurring
in mountainous territory at m abo e sea le el. The
ulcerating lesions are ound on e posed sites and mucosal
lesions do not occur.
Disseminated cutaneous leishmaniasis may be seen in both
ew and ld World disease. ultiple nonulcerated papules
and pla ues chie y on e posed sur aces characteri e this
type. The disease begins with a single ulcer nodule or pla ue
rom which satellite lesions may de elop and disseminate to
co er the entire body. The disease is progressi e and treat
ment is usually ine ecti e. t is characteri ed by anergy to the
organism. This type o leishmaniasis must be di erentiated
rom lepromatous leprosy anthoma tuberosum paracoccidi
oidal granuloma Lobo s disease and malignant lymphoma. cutaneous leishmaniasis. Purely cutaneous leishmaniasis is
also caused by se eral species present in the ew World. L
Etiologic factors mexicana does not induce mucosal disease. Leishmania bra ilien
sis gu anensis produces cutaneous disease as does L b bra il
Leishmania tropica L major L aethiopica and L infantum the iensis and L b panamensis; howe er the latter two may also
cause o editerranean isceral leishmaniasis may cause result in mucocutaneous disease.
420

tahir99 - UnitedVRG

Epidemiology
Cutaneous leishmaniasis is endemic in Asia inor and to a
lesser e tent in many countries around the editerranean.
ran and Saudi Arabia ha e a high occurrence rate. n endemic
areas deliberate inoculation on the thigh is sometimes prac
ticed so that scarring on the ace a re uent site or riental
sore may be a oided. Purely cutaneous lesions may also be
ound in the Americas. n the nited States leishmaniasis is
largely restricted to southern Te as although rare reports o
human cutaneous disease ha e occurred as ar north as Penn
syl ania and isceral leishmaniasis in immunosuppressed
humans is being recogni ed as an emerging in ection in areas
not pre iously thought to be endemic or the disease.
Pathogenesis
The leishmania proto oan has an alternate li e in ertebrates
and in insect hosts. umans and other mammals such as dogs
and rodents are the natural reser oir hosts. The ector hosts
are Phlebotomus sand ies or the ld World type and Phlebo
tomus perniciosus and Lut om ia sand ies or ew World cuta
neous leishmaniasis. A ter the insect has ed on blood the
agellates (leptomonad promastigote) de elop in the gut in
days a ter which migration occurs into the mouth parts;
rom here transmission into humans occurs by a bite. n
humans the agella are lost and a leishmanial orm (amasti
gote) is assumed.
Histopathology
An ulcer with a hea y in ltrate o histiocytes lymphocytes
plasma cells and polymorphonuclear leu ocytes is seen.
The parasiti ed histiocytes orm tuberculoid granulomas in
the dermis. Pseudoepitheliomatous hyperplasia may occur in
the edges o the ulcer. Leishmanias are nonencapsulated and
contain a nucleus and a paranucleus. Wright Giemsa and
monoclonal antibody staining may be help ul in identi ying
the organisms within histiocytes where they o ten line up at
the periphery o a acuole. PCR primers are a ailable or a
ariety o species. PCR is more sensiti e than microscopy but
less sensiti e than culture.
Diagnosis
n endemic areas the diagnosis is not di cult. n other locali
ties cutaneous leishmaniasis may be con used with syphilis
yaws lupus ulgaris and pyogenic granulomas. The diagno
sis is established by demonstration o the organism in smears.
A punch biopsy specimen rom the acti e edge o the ulcer is
ideal or culture. t can be placed in icolle o y ac eal
( ) medium and shipped at room temperature. Parasites
can also be cultured rom tissue uid. A hypodermic needle
is inserted into the normal s in and to the edge o the ulcer
base. The needle is rotated to wor loose some material and
serum which is then aspirated. A culture on medium at
C( . ) is recommended to demonstrate the lep
tomonads. As e pected PCR is the most sensiti e diagnostic
test or cutaneous leishmaniasis.
Treatment
Spontaneous healing o primary cutaneous lesions occurs
usually within months shorter or ld World disease.
Reasons to treat a sel limited in ection include a oiding dis
guring scars in e posed areas a oiding secondary in ection
controlling disease in the population and ailure o spontane
ous healing. n the di use cutaneous and recidi ans types
leishmaniasis may persist or years i not treated.
n areas where locali ed cutaneous leishmaniasis is not com
plicated by recidi ans or sporotrichoid orms or by mucocu
taneous disease treatment with such topical modalities as
paromomycin sul ate plus methylben ethonium chloride
etocona ole cream under occlusion cryotherapy local
heat photodynamic therapy and laser ablation or with intra
lesional sodium stibogluconate antimony or emetine hydro
chloride may be e ecti e and sa e.
Class mastigophora
n the setting o ld World cutaneous leishmaniasis some
data suggest that intramuscular meglumine antimoniate in
combination with intralesional meglumine antimoniate may
be superior to intralesional therapy alone. A meta analysis o
studies o ld World cutaneous leishmaniasis concluded that
pentamidine was similar in e cacy to penta alent antimoni
als and that both were superior to the other agents studied.
Since then a Pa istani study concluded that itracona ole was
more e ecti e and more economical and had ewer side e ects
than meglumine antimoniate in both wet and dry types o
cutaneous leishmaniasis. The number o patients studied was
relati ely small and other studies ha e been disappointing.
ral ucona ole and inc sul ate ha e been used to treat Leish
mania major in ection. A similar meta analysis o studies o
ew World cutaneous leishmaniasis concluded that meglu
mine might be the best agent in its class. ntralesional therapy
may be acceptable or small solitary lesions in areas with a
low ris o mucosal disease. A ithromycin has been used in
ew World disease but is in erior to antimonials. Perilesional
in ections o γ ha e also been reported to be e ecti e but
are e pensi e.
n immunosuppressed patients or those who ac uire in ec
tion in areas where mucocutaneous disease may occur sys
temic therapy is recommended. As with topical treatment
many alternati es ha e been reported to be e ecti e. Sodium
antimony gluconate (sodium stibogluconate) solution is gi en
intramuscularly or intra enously mg g day in two
di ided doses or days. t can be obtained rom the .S.
Centers or Disease Control and Pre ention (CDC) Drug Ser ice
(Atlanta GA ). Repeated courses may be gi en. Antimony
n methyl glutamine (Glucantime) is used more o ten in Central
and South America because o its local a ailability.
ther systemic medications reported to be e ecti e include
ucona ole ( mg day or wee s) etocona ole dapsone
ri ampicin and allopurinol. Some o these ha e not been sub
ected to controlled clinical trials as is true o most topical
treatments. The recidi ans and disseminated cutaneous types
may re uire prolonged courses or ad u ant therapy.
Amphotericin B may be used in antimony resistant disease.
Lipid ormulations o amphotericin B are highly e ecti e in
short courses but are e pensi e. Liposomal amphotericin B
may be especially help ul or Leishmania bra iliensis and L
gu anensis in ections. ntramuscular pentamidine is also used
or L gu anensis cutaneous leishmaniasis because this in ec
tion is resistant to systemic antimony. ilte osine is being
used or cutaneous disease in some areas o the world and may
pro e to be the treatment o choice or di use cutaneous leish
maniasis and post ala a ar dermal leishmaniasis. owe er
some studies ha e shown milte osine to be ine ecti e in L
major and L bra iliensis in ections. Posacona ole has been used
in ld World disease. Control depends chie y on the success
o anti y measures ta en by health authorities and personal
protection with protecti e clothing screening and repellents.
Vaccines are being in estigated but are not a ailable.
Mucocutaneous leishmaniasis
(leishmaniasis americana, espundia)
Clinical features
The initial leishmanial in ection which occurs at the site o the
y bite is a cutaneous ulcer. Secondary lesions on the mucosa
usually occur at some time during the ne t years ( ig. ).
421

20
Parasitic Infestations, Stings, and Bites
Fig. 20-6 Mucocutaneous leishmaniasis.
Fig. 20-7 Severe
destructive
mucocutaneous
leishmaniasis.
(Courtesy of Debra
Kalter, MD.)
The earliest mucosal lesion is usually hyperemia o the nasal
septum with subse uent ulceration which progresses to
in ade the septum and later the paranasal ossae. Per oration
o the septum e entually ta es place. or some time the nose
remains unchanged e ternally despite the internal destruc
tion. At rst only a dry crust is obser ed or a bright red
in ltration or egetation on the nasal septum with symptoms
o obstruction and small hemorrhages. Despite the mutilating
and destructi e character o leishmaniasis it ne er in ol es
the nasal bones. When the septum is destroyed the nasal
bridge and tip o the nose collapse gi ing the appearance o
a parrot bea camel nose or tapir nose.
t is important to recall that the our great chronic in ections
syphilis tuberculosis ansen s disease and leishmaniasis
ha e a predilection or the nose. The ulcer may e tend to the
lips ( ig. ) and continue to ad ance to the pharyn attac
ing the so t palate u ula tonsils gingi a and tongue. The
e entual mutilation is called espundia. Two perpendicular
groo es at the union o the osseous palate and so t tissues in
the midst o the egetati e in ltration o the entire pharyn
are called the palate cross o espundia.
nly in e ceptional cases does American leishmaniasis
in ade the genital or ocular mucous membranes. The re
uency o mucous membrane in ol ement is ariable. n
ucatan and Guatemala it is an e ception; in other countries
such as Bra il it may occur in o cases.
Etiologic factors
ucocutaneous leishmaniasis is mainly caused by Leishmania
( iannia) bra iliensis bra iliensis and L b panamensis although
some ld World organisms including L infantum L major
and L tropica can cause mucosal ulceration. Leishmania has
two orms the non agellated orm or leishmania which is
ound in the tissues o humans and animals susceptible to the
422
tahir99 - UnitedVRG
inoculation o the parasite; and the agellated orm or lepto
monad which is ound in the digesti e tract o the ector
insect (Lut om ia in mucocutaneous disease) and in cultures.
The typical morphology o leishmania as ound in ertebrates
is round or o al usually with one e tremity more rounded
than the other measuring μm × . . μm with cyto
plasm nucleus and blepharoplast or inetoplast.
Epidemiology
ucocutaneous leishmaniasis is predominantly a rural disease.
t most o ten occurs in damp and orested regions. The disease
can be contracted at any time o the year but the ris is highest
ust a ter the rainy season. All ages and races and both genders
are e ually a ected. pidemics parallel the l i o cycle.
Histopathology
n ulcerous leishmaniasis mar ed irregular acanthosis and
sometimes pseudoepitheliomatous hyperplasia can be ound.
The dermis shows a dense in ltration o histiocytes lympho
cytes and plasma cells. n new lesions some neutrophils are
obser ed. Large Langhans giant cells or typical tubercles are
occasionally seen. umerous organisms are present (mostly in
histiocytes) which are nonencapsulated and contain a nucleus
and a paranucleus. Wright Giemsa and monoclonal antibody
staining may be help ul in identi ying the organisms. n
patients with granulomatous in ltrates containing intracellu
lar parasites within histiocytes leishmaniasis is one o se eral
diseases to be considered including rhinoscleroma histo
plasmosis granuloma inguinale Chagas disease Penicillium
marneffei in ection and to oplasmosis. Touch smears stained
with Giemsa are help ul in many cases o cutaneous and
mucocutaneous leishmaniasis.
Laboratory findings
Leishmania is demonstrated in the cutaneous and mucous
membrane lesions by direct smears or cultures. n Wright
stained biopsy material intracellular and e tracellular organ
isms are seen with typical morphology o two chromatic
structures nucleus and parabasal body. n later mucosal
lesions the scarcity o parasites ma es identi cation di cult.
The culture is done on medium or leptomonads. PCR
is now widely used and specimens obtained rom lesion scari
cation and blood sample enriched leu ocytes compare
a orably with indirect immuno uorescence reaction and
culture techni ues.
Prophylaxis
Although it is impractical to eliminate the insect ector it is
still the only alid measure or the control o this pre alent
disease. ecti e accines are not a ailable or mucocutane
ous leishmaniasis.
Treatment
Treatment is the same as described or cutaneous leishmaniasis
e cept that antimony resistance is common in mucocutaneous
disease. Combination therapy using antimonials with drugs
such as ri ampin or a ithromycin or adding immunomodula
tors such as γ L or imi uimod may result in cure.
Amphotericin B treatment may be necessary.
Visceral leishmaniasis
(kala-azar, dumdum fever)
Clinical features
The earliest lesion is the cutaneous nodule or leishmanioma
which occurs at the site o the initial sand y inoculation.
 ala a ar meaning blac e er ac uired its name because
o the patchy macular dar ening o the s in caused by depos
its o melanin that de elop in the later course o the disease.
These patches are most mar ed o er the orehead and temples
periorally and on the midabdomen.
The primary target or the parasites is the reticuloendothelial
system; the spleen li er bone marrow and lymph nodes are
attac ed. The incubation period is months. An intermittent
e er with temperatures ranging rom to C( ) delayed up to
ushers in the disease. epatosplenomegaly agranulocytosis
anemia and thrombocytopenia occur. Chills e er emacia
tion weight loss wea ness epista is and purpura de elop as
the disease progresses. Susceptibility to secondary in ection
may produce pulmonary and gastrointestinal (G ) in ection
ulcerations in the mouth (cancrum oris) and noma. Death
occurs about years rom onset in untreated indi iduals.
ost in ections are subclinical or asymptomatic. n patients
with A DS papular and nodular s in lesions may occur.
Dermato broma type or aposi sarcoma li e brown to
purple nodules are most re uently reported although random
biopsies o normal s in will re eal organisms. There ore clini
cal correlation is necessary to attribute s in ndings to Leish
mania speci cally.
Etiologic factors
Leishmania onovani spp. onovani infantum and chagasi cause
isceral leishmaniasis and are parasites o rodents canines
and humans. They are non agellate o al organisms about
mm in diameter nown as Leishman Dono an bodies. n
the sand y it is a leptomonad orm with agella.
Epidemiology
Leishmania onovani onovani causes isceral leishmaniasis in
ndia with the ma or reser oir being humans and the ector
being Phlebotomus argentipes L onovani infantum occurs in
China A rica the ear ast and iddle ast and the editer
ranean littoral where the ma or reser oirs are dogs; Phleboto
mus perniciosus and P ariasi are the ectors o the editerranean
type. American isceral leishmaniasis is caused by L onovani
chagasi and is transmitted by the sand y Lut om ia longipalpis
American isceral leishmaniasis principally a ects domestic
dogs although e plosi e outbrea s o the human in ection
occur sporadically when the number o Lut om ia longipalpis
builds up to a high le el in the presence o in ected dogs.
Canine isceral in ections with Leishmania infantum ha e been
reported in o hounds in arious parts o the nited States
and Canada.
Diagnosis
Leishman Dono an bodies may be present in the blood in
indi iduals with ala a ar o ndia. Specimens or e amina
tion in descending order o utility include spleen pulp sternal
marrow li er tissue and e udate rom lymph nodes. Cultur
ing on medium may also re eal the organisms.
Treatment
General supporti e measures are essential. Penta alent anti
mony has long been the drug o choice. n areas o drug resis
tance amphotericin B is usually e ecti e but it is e pensi e
and to ic and re uires intra enous administration. ilte os
ine an oral al yl phosphocholine analog has pro ed as e ec
ti e as amphotericin B in some trials. t is o ten used to treat
isceral disease in ndia and thiopia. i ed in ections in ol
ing both Leishmania and r panosoma cru i are becoming
increasingly common in Central and South America because
o o erlapping endemic areas. Amiodarone has been used as
an uncon entional antiparasitic drug in this setting in addition
to standard therapy.
Post–kala-azar dermal leishmaniasis
n ala a ar the leishmanoid (amastigote) orms may be
widely distributed throughout apparently normal s in.
During and a ter reco ery rom the disease a special orm o
Class mastigophora
dermal disease nown as post ala a ar dermal leishmania
sis appears. This condition appears during or shortly a ter
treatment in the A rican orm but its appearance may be
years a ter treatment in the ndian orm. t
ollows the treatment o isceral leishmaniasis in o
Sudanese patients and o those seen in ndia. There
are two constituents o the eruption a macular depigmented
eruption ound mainly on the ace arms and upper part o
the trun and a warty papular eruption in which amasti
gotes can be ound. Because it may persist or up to years
these patients may act as a chronic reser oir o in ection.
This condition closely resembles ansen s disease. igh con
centrations o L in the blood o isceral leishmaniasis
patients predict those who will be a ected by post ala a ar
dermal leishmaniasis. ilte osine may become the drug o
choice.
Viscerotropic leishmaniasis
Twel e .S. soldiers de eloped systemic in ection with Leish
mania tropica while ghting in peration Desert Storm in ra
and uwait. one had symptoms o ala a ar but most had
e er atigue malaise cough diarrhea or abdominal pain
and none had cutaneous disease. Diagnostic tests yielded
positi e results on bone marrow aspiration; lymph node
in ol ement was also documented. Treatment with sodium
stibogluconate led to impro ement.
Blum J, et al: Local or systemic treatment for New World cutaneous
leishmaniasis? Re-evaluating the evidence for the risk of mucosal
leishmaniasis. Int Health 2012; 4(3):153–163.
Elmahallawy EK, et al: Diagnosis of leishmaniasis. J Infect Dev Ctries
2014; 13:961–972.
Layegh P, et al: Children and cutaneous leishmaniasis: a clinical report
and review. J Infect Dev Ctries 2013; 7(8):614–617.
Mansueto P, et al: Leishmaniasis in travelers: a literature review.
Travel Med Infect Dis 2014; 12:563–581.
Neitzke-Abreu HC, et al: Detection of DNA from leishmania (viannia):
accuracy of polymerase chain reaction for the diagnosis of cutaneous
leishmaniasis. PLoS One 2013; 8(7):e62473.
Ravis WR, et al: Pharmacokinetics and absorption of paromomycin
and gentamicin from topical creams used to treat cutaneous
leishmaniasis. Antimicrob Agents Chemother 2013;
57(10):4809–4815.
Shirian S, et al: Three Leishmania/L. species—L. infantum, L. major, L.
tropica—as causative agents of mucosal leishmaniasis in Iran. Pathog
Glob Health 2013; 107(5):267–272.
Singh OP, Sundar S: Immunotherapy and targeted therapies in treatment
of visceral leishmaniasis: current status and future prospects. Front
Immunol 2014; 26:296.
Human trypanosomiasis
Three species o trypanosome are pathogenic to humans r
panosoma gambiense and rho esiense in A rica and cru i in
America. The s in mani estations are usually obser ed in the
earlier stages o trypanosomiasis as e anescent erythema ery
thema multi orme and edema especially angioedema.
n the early stage o A rican trypanosomiasis a trypanosome
chancre may occur at the site o a tsetse y bite. rythema with
circumscribed swellings o angioedema then occurs with
enlargement o the lymph nodes e er malaise headache
and oint pains. n the West A rican (Gambian) orm the
illness is chronic lasting se eral years with progressi e
423
 deterioration whereas the ast A rican (Rhodesian) orm is an
20 acute illness with a stormy atal course o wee s to months.
The Rhodesian orm is more o ten associated with cutaneous
signs. Annular or deep erythema nodosum li e lesions are
re uent mani estations ( ig. ). Lymphadenopathy is gen
Parasitic Infestations, Stings, and Bites
erali ed but re uently there is a pronounced enlargement o
the posterior cer ical group (Winterbottom s sign).
n American trypanosomiasis (Chagas disease) similar
changes ta e place in the s in. The redu iid bug ( issing bug
assassin bug) usually bites at night re uently at mucocutane
ous unctions where the bug s in ected eces are deposited
when it eeds ( ig. ). The unsuspecting sleeping person
rubs the eces into the bite and becomes in ected. the bite o
the in ected bug occurs near the eye Romana s sign de elops
consisting o unilateral con uncti itis and edema o the eyelids
with an ulceration or chagoma in the area. The bite o a issing
bug becomes e tremely swollen and red whether or not try
panosomes are in ol ed. Acute Chagas disease is usually a
mild illness o e er malaise edema o the ace and lower
e tremities and generali ed lymphadenopathy. S in lesions
occurring in this phase include nodules at the site o inocula
tion disseminated nodules or morbilli orm and urticarial
lesions. n chronic Chagas disease which occurs in o compound is the treatment o choice. When the C S is
in ected persons years to decades later the heart (myocarditis
arrhythmias thromboembolism cardiac ailure) and G system
(megaesophagus megacolon) are most o ten in ol ed. During
the remaining in ected but asymptomatic indeterminate phase
patients may transmit the disease through trans usion. When
such patients become immunosuppressed (with A DS or
Fig. 20-8 African trypanosomiasis.
Fig. 20-9 Triatome reduviid bug.
424
tahir99 - UnitedVRG
organ transplantation) reacti ation s in lesions may occur
with a wide range o morphologies including panniculitis.
Rhodesian trypanosomiasis is endemic among the cattle
raising tribes o ast A rica with the sa annah habitat o the
ectors determining its geographic distribution. Wild game
and li estoc are reser oir hosts in addition to humans. The
tsetse y lossina morsitans is the principal ector.
or Gambian trypanosomiasis humans are the only erte
brate host and the palpalis group o tsetse ies is the in erte
brate host. These ies are ound close to the water and their
astidious biologic re uirements restrict their distribution and
thus that o the disease. ncidence is seasonal with humidity
and temperature being determining actors. The highest inci
dence is in men age in tropical areas o West and Central
A rica.
Chagas disease is pre alent in Central and South America
rom the nited States to Argentina and Chile; the highest
incidence is in Vene uela Bra il ruguay Paraguay and
Argentina. Appro imately o all male deaths in the
age group in Bra il are attributed to Chagas disease.
Be ore C S in ol ement has occurred in the Rhodesian
orm suramin a comple non metal containing organic
in ol ed melarsoprol is the drug o choice. Pentamidine ise
thionate is the drug o choice or the Gambian disease. or
nithine appears to be a good alternati e to melarsoprol or
second stage West A rican trypanosomiasis. or American
trypanosomiasis treatment is o limited e cacy. i urtimo
and ben nida ole clear the parasitemia and reduce the se er
ity o the acute illness but there is a high incidence o ad erse
e ects. Although ben nida ole reduces parasite load during
the acute phase it does not pre ent chronic cardiac lesions.
Ruthenium comple ation impro es bioa ailability o ben ni
da ole and has the potential to impro e outcomes. Conser a
ti e treatment is the typical approach to the patient with
congesti e heart ailure rom Chagas myocarditis but recent
data suggest that clomipramine a tricyclic antidepressant that
inhibits r panosoma cru i s trypanothione reductase impro es
the course o cardiac disease in animal models. G complica
tions may be treated surgically.
Alviano DS, et al: Conventional therapy and promising plant-derived
compounds against trypanosomatid parasites. Front Microbiol 2012;
3:283.
Chatelain E: Chagas disease drug discovery: toward a new era. J
Biomol Screen 2015; 20:22–35.
Hemmige V, et al: Trypanosoma cruzi infection: a review with emphasis
on cutaneous manifestations. Int J Dermatol 2012; 51(5):501–508.
Sekhar GN, et al: Delivery of antihuman African trypanosomiasis drugs
across the blood-brain and blood-CSF barriers. Adv Pharmacol 2014;
71:245–275.
CLASS SPOROZOA
Toxoplasmosis
To oplasmosis is a oonosis caused by a parasitic proto oan
oxoplasma gon ii. n ection may be either congenital or
ac uired. Cerebral disease has been reported in the setting o
ritu imab therapy and widespread lesions can mimic mela
noma metastases on positron emission tomography (P T)
scans. Congenital in ection occurs rom placental transmission.
Abortion or stillbirth may result. owe er a ull term child
deli ered to an in ected mother may ha e a triad o hydro
cephalus chorioretinitis and cerebral calci cation. n addition
there may be hepatosplenomegaly and aundice. S in changes
in to oplasmosis are rare and clinically nonspeci c.
 n congenital to oplasmosis macular and hemorrhagic
eruptions predominate. Blueberry mu n lesions re ecting
dermatoerythropoiesis may be seen. ccasionally abnormal
hair growth and e oliati e dermatitis ha e also been obser ed.
The di erential diagnosis o congenital to oplasmosis is the
T RC syndrome (to oplasmosis other agents rubella cyto
megalo irus and herpes simple ). n ac uired to oplasmosis
early s in mani estations consist o cutaneous and subcutane
ous nodules and macular papular and hemorrhagic erup
tions. These may be ollowed by scarlatini orm des uamation
eruptions mimic ing roseola erythema multi orme and der
matomyositis or lichen planus as well as e oliati e dermati
tis. As a rule the e anthem is accompanied by high e er and
general malaise.
Diagnosis o ac uired to oplasmosis is o special impor
tance to three groups o adults healthy pregnant women con
cerned about recent e posure; adults with lymphadenopathy
e er and myalgia who might ha e some other serious disease
(e.g. lymphoma); and immunocompromised persons such as
patients with A DS in whom to oplasmosis might be atal. t
is the most common cause o ocal encephalitis in A DS
patients and this may be accompanied by a widespread
papular eruption.
oxoplasma gon ii is a crescent shaped o al or round proto
oan that can in ect any mammalian or a ian cell. To oplas
mosis is o ten ac uired through contact with animals
particularly cats. Reser oirs o in ection ha e been reported in
dogs cats cattle sheep pigs rabbits rats pigeons and chic
ens. The two ma or routes o transmission o gon ii in
humans are oral and congenital. eats consumed by humans
may contain tissue cysts thus ser ing as a source o in ection
when eaten raw or undercoo ed. There is no e idence o direct
human to human transmission other than rom mother to
etus.
The diagnosis cannot be made on clinical grounds alone. t
may be established by isolation o gon ii; demonstration
o the proto oa in tissue sections smears or body uids
by Wright or Giemsa stain; characteristic lymph node histol
ogy; and serologic methods. n the patient with bone marrow
transplantation the organism has caused inter ace dermatitis
creating the potential or misdiagnosis as gra t ersus host
disease.
A combination o pyrimethamine (Daraprim) and sul adia
ine acts synergistically and orms an e ecti e treatment.
Dosages and total treatment time ary according to the age
and immunologic competence o the in ected patient.
Ivanova K, et al: Acute toxoplasmosis mimicking melanoma
metastases: review of conditions causing false-positive results on (18)
F-FDG PET/CT. Dermatology 2012; 225(4):349–353.
Safa G, et al: Cerebral toxoplasmosis after rituximab therapy. JAMA
Intern Med 2013; 173(10):924–926.
Vidal CI, et al: Cutaneous toxoplasmosis histologically mimicking
graft-versus-host disease. Am J Dermatopathol 2008; 30(5):492–493.
PHYLUM CNIDARIA
The cnidarians include the elly sh hydroids Portuguese
men o war corals and sea anemones. These are all radial
marine animals li ing mostly in ocean water.
Portuguese man-of-war dermatitis
Stings by the Portuguese man o war (Ph salia ph salis in
Atlantic or much smaller Ph salia utriculus or bluebottle in
Paci c cean) are characteri ed by linear lesions that are ery
thematous urticarial and e en hemorrhagic. The orearms
sides o the trun thighs and eet are common sites o in ol e
ment. The usual local mani estation is sharp stinging and
intense pain. nternally there may be se ere dyspnea prostra
tion nausea abdominal cramps lacrimation and muscular
pains. Death may occur i the areas stung are large in relation
Class sporozoa
to the patient s si e.
The uid o the nematocysts contains to in that is carried
into the ictim through barbs along the tentacle. The enom is
a neuroto ic poison that can produce mar ed cardiac changes.
ach Portuguese man o war is a colony o symbiotic organ
isms consisting o a blue to red oat or pneumatophore with
a gas gland se eral gastro ooids measuring mm repro
ducti e polyps and the shing tentacles bearing the nemato
cysts rom which the barbs are e ected. The hydroid is ound
most re uently along the southeastern lorida coastline and
in the Gul o e ico as well as on windward coasts through
out the mid Paci c and South Paci c. Sa e Sea a barrier cream
has been reported as being e ecti e at pre enting elly sh
stings o the coast o lorida but studies o barrier creams in
general ha e been mi ed.
Jellyfish dermatitis
Jelly sh dermatitis produces lesions similar to those o the
Portuguese man o war e cept that the lesions are not so
linear ( ig. ). mmediate allergic reactions occur in re
uently as urticaria angioedema or anaphyla is. Delayed and
persistent lesions also rarely occur.
The Australian sea wasp Chironex ec eri which is colorless
and transparent is the most dangerous o all elly sh with a
sting that is o ten atal. Another sea wasp Car b ea marsupialis
is much less dangerous and occurs in the Caribbean Sea. ho
pilema noma ica common in the editerranean Sea has been
reported to cause se ere delayed dermatitis.
Seabather s eruption is an acute dermatitis that begins a ew
hours a ter bathing in the waters along the Atlantic coast. t
a ects co ered areas o the body as cnidarian lar ae become
entrapped under the bathing suit and the nematocyst releases
its to in because o e ternal pressure. Thus the buttoc s and
waist are a ected primarily with the breast also in ol ed in
women ( ig. ). rythematous macules and papules
appear and may de elop into pustules or esicles. rticarial
pla ues are also present in a smaller number o patients. Crops
o new lesions may occur or up to h and the eruption
persists or days on a erage. t is uite pruritic.
utbrea s in lorida are usually caused by lar ae o the
thimble elly sh Linuche unguiculata which patients report as
Fig. 20-10 Jellyfish sting. (Courtesy of Dr. Anthony Slagel.)
425
 Fig. 20-11 Seabather’s
20 eruption.
Parasitic Infestations, Stings, and Bites

Fig. 20-12 Sea anemone.

blac dots in the water or their bathing suits. The lar ae o

the sea anemone E war stella lineata caused one epidemic o
seabather s eruption in Long sland ew or . This organ
ism also has nematocysts; thus the mechanism o the eruption
is the same as with the elly sh induced eruption. t is li ely
that di erent cnidarian en enomations in di erent waters
produce a similar clinical picture. ther reports ocus on
spring plants dino agellates proto oans or crustaceans as
potential causes. Because the eruption results rom trapping
o cnidarian lar ae with their nematocysts or other to ic or
irritant substances under the bathing suit it may be limited
by seabathers who remo e their suit and shower soon a ter
lea ing the water. Fig. 20-13 Coral cuts. (Courtesy of Dr. Curt Samlaska.)

Hydroid, sea anemone, and coral dermatitis

Patients contacting the small marine hydroid alecium may
de elop a dermatitis. The organism grows as a cm thic coat
o moss on the submerged portions o essels or pilings. Sea
anemones ( ig. ) produce reactions similar to those rom
elly sh and hydroids. Coral cuts are in uries caused by the
e os eleton o the corals Milleporina ( ig. ). They ha e a
reputation or becoming in amed and in ected and or delayed
healing. The combination o implantation o ragments o coral
s eleton and in ection (since cuts occur most o ten on eet)
probably accounts almost entirely or these symptoms. Deto i
cation as soon as possible a ter the in ury is recommended
or all these types o sting or cut.
Treatment of stings and cuts
ot water immersion may be an e ecti e remedy or many
stings but scald in uries must be a oided. ndischarged
nematocytes may be remo ed with sea water but ne er with
resh water because this may cause them to discharge. Paci c
Chironex (bo elly sh) nematocytes should always be inacti
ated with acetic acid ( inegar) when it is a ailable but
Paci c Ph salia (bluebottle) nematocytes may discharge on
contact with inegar. Large isible tentacles may be remo ed
with orceps in a double glo ed hand. Remaining nematocysts
may be remo ed by applying a layer o sha ing cream and
426
sha ing the area gently. eat tenderi er may cause tissue
damage and has been shown to be no better than placebo in
some studies.
Pressure dressings and abrasion will worsen the en enom
ation. Topical anesthetics or steroids may be applied a ter
decontamination. Systemic reactions may occur through either
large amounts o enom or a pre iously sensiti ing e posure
rom which anaphyla is may result and systemic treatment
with epinephrine antihistamines or corticosteroids may be
needed. Speci c anti enin is a ailable or the bo elly sh
Chironex ec eri This should be administered intra enously to
limit myonecrosis. agnesium sul ate ( gS ) may also be o
alue in the setting o bo elly sh en enomation. Recurrent
elly sh reactions ha e shown partial responses to tacrolimus
ointment . .
Sponges and bristleworms
Sponges ha e horny spicules o silicon dio ide and calcium
carbonate. Some sponges produce dermal irritants such as
halito in and o adaic acid and others may be coloni ed by
Cnidaria. Allergic or irritant reactions may result. Bristle
worms may also produce stinging. All these may be treated
by rst using adhesi e tape to remo e the spicules then apply
ing inegar soa s as pre iously described and lastly topical
corticosteroids.

tahir99 - UnitedVRG
Sea urchin injuries
Puncture wounds in icted by the brittle ragile spines o sea
urchins mainly o genus Dia ema or Echinothrix are stained
blue blac by the blac spines and may contain ragments o
the spines. The spines consist o calcium carbonate crystals
which most re uently induce an irritant reaction with pain
and in ammation o se eral days duration. oreign body or
sarcoidli e granulomas may de elop as may a esicular
hypersensiti ity reaction days a ter e posure. n uries by
spines o the genus ripneustes ha e been reported to cause
atal en enomation but this genus is not ound on .S. coasts.
Star sh also ha e thorny spines that can sting and burn i
they are stepped on or handled. Se eral di erent types o
stinging sh also produce puncture wounds. Stingrays scor
pion sh stone sh cat sh and wea er sh may cause such
en enomations.
These wounds should be immersed in nonscalding water
( C ) or min or until the pain subsides. Calci
ed ragments may be isible on ray e aluation with uo
roscopy guiding e traction o spines especially on the hands
and eet. Sea urchin spines ha e been e ecti ely remo ed
using the erbium yttrium aluminum garnet ( AG) laser.
Debridement and possibly antibiotic therapy or deep punc
ture wounds o the hands and eet are recommended. There
is a speci c anti enin or stone sh stings.
Seaweed dermatitis
Although caused by a marine alga and not by an animal
seaweed dermatitis deser es mention with other problems
associated with swimming or wading. The dermatitis occurs
h a ter the indi idual emerges rom the ocean. The distri
bution is in parts co ered by a bathing suit scrotum penis
perineum and perianal area. The dermatitis is caused by a
marine plant L ngb a majuscula Gomont. t has been obser ed
only in bathers swimming o the windward shore o ahu
awaii. Seabather s eruption clam digger s itch and swim
mer s itch must be di erentiated rom seaweed dermatitis
caused by marine algae. Prophyla is is achie ed by re raining
rom swimming in waters that are turbid with such algae.
Swimmers should shower within min o swimming. Acti e
treatment in se ere cases is the same as or acute burns.
Dogger Bank itch
Dogger Ban itch is an ec ematous dermatitis caused by the
sea cher il lc oni rium hirsutum a seaweedli e animal
colony. These sea mosses or sea mats are ound on the Dogger
Ban an immense shel i e ele ation under the orth Sea
between Scotland and Denmar .
Cegolon L, et al: Jellyfish stings and their management: a review. Mar
Drugs 2013; 11(2):523–550.
Kabigting FD, et al: Sea urchin granuloma secondary to
Strongylocentrotus purpuratus and Strongylocentrotus franciscanus.
Dermatol Online J 2009; 15(5):9.
Ottuso P: Aquatic dermatology: encounters with the denizens of the
deep (and not so deep): a review. Part I. The invertebrates. Int J
Dermatol 2013; 52(2):136–152.
Suput D: Interactions of cnidarian toxins with the immune system.
Inflamm Allergy Drug Targets 2011; 10(5):429–437.
PHYLUM PLATYHELMINTHES
Phylum Platyhelminthes includes the atworms o which two
classes trematodes and cestodes are parasitic to humans. The
trematodes or blood u es parasiti e human s in or internal
organs. The cestodes are segmented ribbon shaped atworms
that inhabit the intestinal tract as adults and in ol e the sub
cutaneous tissue heart muscle and eye in the lar al orm.
This is encased in a sac that e entually becomes calci ed.
Class trematoda
CLASS TREMATODA
Schistosome cercarial dermatitis
Cercarial dermatitis is a se erely pruritic widespread papular
dermatitis caused by cercariae o schistosomes or which
humans are not hosts; the usual animal hosts are water owl
and rodents such as mus rats. The eggs in the e creta o
these animals when deposited in water hatch into swimming
miracidia. These enter a snail where urther de elopment
occurs. rom the snail the ree swimming cercariae emerge
to in ade human s in on accidental contact. The swimming
colorless multicellular organisms are slightly less than mm
long. posure to cercariae occurs when a person swims or
more o ten wades in water containing them. They attac by
burrowing into the s in where they die. The species that
causes this eruption cannot enter the bloodstream or deeper
tissues.
A ter coming out o the water the bather begins to itch and
a transient erythematous eruption appears but a ter a ew
hours the eruption subsides together with the itching. A ter
a uiescent period o h the symptoms then recur and
erythematous macules and papules de elop throughout the
e posed parts that were in the water ( ig. ). A ter se eral
days the dermatitis heals spontaneously. There are two types
the reshwater swimmer s itch and the saltwater marine
dermatitis or clam digger s itch. Cercarial dermatitis is not
communicable.
Various genera and species o organism ha e been reported
rom arious locations worldwide. An outbrea o cercarial
dermatitis was reported rom Delaware in in which the
a ian schistosome Microbilhar ia variglan is was implicated as
the causati e organism. Schistosoma spin ale cercaria caused a
recent epidemic in southern Thailand.
Thoroughly washing then drying with a towel a ter e po
sure can pre ent the disease. Some ad ocate rubbing with
alcohol as an additional pre enti e measure. Snail popula
tions can be controlled or water owl may be treated with
medicated eedcorn to destroy the adult schistosomes and
pre ent outbrea s o swimmer s itch.
Fig. 20-14 Swimmer’s itch.
427
 Visceral schistosomiasis (bilharziasis)
20 The cutaneous mani estation o schistosomiasis may begin
with mild itching and a papular dermatitis o the eet and
other parts a ter swimming in polluted streams containing
Parasitic Infestations, Stings, and Bites
cercariae. The types o schistosome causing this disease can
penetrate into the bloodstream and e entually inhabit the
enous system draining the urinary bladder Schistosoma hae
matobium or the intestines (Schistosoma mansoni or Schistosoma
japonicum). A ter an asymptomatic incubation period the
person may de elop a sudden illness with e er and chills
pneumonitis and eosinophilia. Petechial hemorrhages may
occur.
Cutaneous schistosomal granulomas most re uently
in ol e the genitalia perineum and buttoc s. The eggs o S
haematobium or S mansoni usually cause these bilhar iomas
( ig. ). Vegetating so t cauli ower shaped masses stu
lous tracts and e tensi e hard masses occur; these are riddled
by sinuses that e ude a seropurulent discharge with a charac
teristic odor. Phagedenic ulcerations and pseudoelephantiasis
o the scrotum penis or labia are sometimes encountered.
istologically the nodules contain bilhar ial o a undergoing
degeneration with calci cation and a surrounding cellular
reaction o histiocytes eosinophils and occasional giant cells.
n some cases e entual malignant changes ha e been noted in
chronic lesions. Animal studies ha e shown a moderate helper
T cell type (Th ) response to parasite antigens in most
tissues but a strong Th response that propagates brogenesis
within the li er. n re uently ectopic or e tragenital lesions
may occur mainly on the trun . This is a papular eruption
tending to group in pla ues and become dar ly pigmented
and scaly. A se ere urticarial eruption nown as urticarial
e er or atayama e er is re uently present along with S
japonicum in ection; it occurs with the beginning o o iposi
tion wee s a ter in ection. This condition is seen mainly
in China Japan and the Philippines. n addition to the urti
caria e er malaise abdominal cramps arthritis and li er
spleen in ol ement are seen. This is thought to be a serum
sic ness li e reaction.
Pre enti e measures include reducing in ection sources
pre enting contamination by human e creta o snail bearing
waters control o snail hosts and a oiding e posure to
cercaria in ested waters. Prophylactic measures are constantly
sought to control one o the world s worst parasitic diseases
but as yet none has been ound to be practical. or both S
haematobium and S mansoni pra i uantel (Biltricide) mg
g orally or each o two treatments in day is the therapy o
choice. S japonicum treatment re uires mg g in three
Thick wall
Lateral spine
Fig. 20-15 Ova of Schistosoma mansoni are characterized by a thick
chitinous wall and lateral spine.
428
tahir99 - UnitedVRG
doses in day. Schistosomicides e hibit to icity or the host
as well as or the parasite and the ris o undesirable side
e ects may be enhanced by concomitant cardiac renal or
hepatosplenic disease.
Lichtenbergová L, et al: Pathogenicity of Trichobilharzia spp. for
vertebrates. J Parasitol Res 2012; 2012:761968.
Soldánová M, et al: Swimmer’s itch: etiology, impact, and risk factors in
Europe. Trends Parasitol 2013; 29(2):65–74.
Cysticercosis cutis
The natural intermediate host o the por tapeworm aenia
solium is the pig but under some circumstances humans act
in this role. The lar al stage o solium is C sticercus cellulosae
n ection ta es place by the ingestion o ood contaminated
with the eggs or by re erse peristalsis o eggs or proglottides
rom the intestine to the stomach. ere the eggs hatch reeing
the oncospheres. These enter the general circulation and orm
cysts in arious parts o the body such as striated muscles
brain eye heart and lung.
n the subcutaneous tissues the lesions are usually painless
nodules that contain cysticerci. They are more or less
stationary usually numerous and o ten calci ed and are
there ore demonstrable radiographically. Pain and ulceration
may accompany the lesions. The disease is most pre alent in
countries where pigs eed on human eces. t may be con used
with gumma lipoma and epithelioma. A positi e diagnosis
is established solely by incision and e amination o the
interior o the calci ed tumor where the parasite will be
ound. ine needle aspiration has also been used to establish
the diagnosis.
Albenda ole or pra i uantel is e ecti e; howe er the status
o the C S spinal and ocular in ol ement needs to be thor
oughly assessed be ore treatment. The length o therapy and
use o concomitant corticosteroids depend on the location o
the cysts. owe er none o the regimens clears the calci ed
parasites which need to be surgically remo ed.
Sacchidanand S, et al: Disseminated cutaneous cysticercosis and
neurocysticercosis: a rare occurrence. Indian Dermatol Online J 2012;
3(2):135–137.
Trung DD, et al: Assessing the burden of human cysticercosis in
Vietnam. Trop Med Int Health 2013; 18(3):352–356.
Sparganosis
Sparganosis is caused by the lar a o the tapeworm Spirometra
The adult tapeworm li es in the intestines o dogs and
cats. This is a rare tissue in ection occurring in two orms.
Application sparganosis occurs when an ulcer or in ected
eye is poulticed with the esh o an in ected intermediate
host (such poultices are re uently used in the rient).
The lar ae become encased in small nodules in the in ected
tissue. ngestion sparganosis occurs when humans ingest
inade uately coo ed meat such as sna e or rog or when a
person drin s water that is contaminated with C clops which
is in ected with plerocercoid lar ae. ne or two slightly pru
ritic or pain ul nodules may orm in the subcutaneous tissue
or on the trun breast genitalia or e tremities. Cerebral
disease may also occur. Diagnosis is usually made by e cision
o the nodule although nonin asi e imaging has also
been used.
umans are the accidental intermediate host o the sparga
num which is the alternati e name or the plerocercoid lar a.
Treatment is surgical remo al or ethanol in ection o the
in ected nodules ( ig. ). This may be di cult because o
the swelling and e tensi e ascularity.
 Fig. 20-16
Sparganosis.
Anantaphruti MT, et al: Human sparganosis in Thailand: an overview.
Acta Trop 2011; 118(3):171–176.
Koonmee S, et al: Molecular identification of a causative parasite
species using formalin-fixed paraffin embedded (FFPE) tissues of a
complicated human pulmonary sparganosis case without decisive
clinical diagnosis. Parasitol Int 2011; 60(4):460–464.
Echinococcosis
chinococcosis is also nown as hydatid disease. n humans
in ection is produced by the o a reaching the mouth rom the
hands in ood or rom containers soiled by o a contaminated
eces rom an in ected dog. This leads to Echinococcus granulo
sus in estation o the li er and the lungs. So t uctuating
semitranslucent cystic tumors may occur in the s in some
times in the supraumbilical area as stulas rom underlying
li er in ol ement. These tumors become brotic or calci ed
a ter the death o the lar a. osinophilia intractable urticaria
and pruritus and e en acute generali ed e anthematous pus
tulosis may be present. Such reacti e ndings may be present
as s in mani estations o many o the helminthic in ections
including other types o tapeworm. The treatment is e cision
with care being ta en to a oid rupturing the cyst. Albenda ole
combined with percutaneous drainage may also be used.
menolepis nana is a cosmopolitan dwar tapeworm endemic
in the tropics that may cause a treatment resistant pruritic
papular eruption associated with eosinophilia. Stool speci
mens or o a and parasites are de niti e and pra i uantel is
curati e.
Islam MN, et al: Hepatic hydatid cyst presenting as cutaneous abscess.
Mymensingh Med J 2012; 21(1):165–169.
Korwar V, et al: Hydatid disease presenting as cutaneous fistula: review
of a rare clinical presentation. Int Surg 2011; 96(1):69–73.
PHYLUM ANNELIDA
LEECHES
Leeches o the class irudinea are o marine reshwater or
terrestrial types. A ter attaching to the s in they secrete an
anticoagulant hirudin and then engorge themsel es with
blood. Local symptoms at the site o the bite may include
bullae hemorrhage pruritus whealing necrosis or ulcer
ation. Allergic reactions including anaphyla is may result.
Leeches may be remo ed by applying salt alcohol or inegar
or by use o a match ame. Bleeding may then be stopped by
direct pressure or by applying a styptic pencil to the site.
Leeches may be used medicinally to sal age tissue aps that
are threatened by enous congestion. owe er bleeding
eromonas in ection anetoderma and pseudolymphoma may
be complications o their attachment.
Abdualkader AM, et al: Leech therapeutic applications. Indian J Pharm
Sci 2013; 75(2):127–137.
Khelifa E, et al: Cutaneous pseudolymphomas after leech therapy. J
Dermatol 2013; 40(8):674–675.
Class nematoda
PHYLUM NEMATHELMINTHES
Phylum emathelminthes includes the roundworms both
ree li ing and parasitic orms. ultiplication is usually
outside the host. Both the lar al and the adult stage may in ect
humans.
CLASS NEMATODA
Enterobiasis (pinworm infection, seatworm
infection, oxyuriasis)
The chie symptom o pinworm in estation which occurs most
re uently in children is nocturnal pruritus ani. There is
intense itching accompanied by e coriations o the anus
perineum and pubic area. The agina may become in ested
with the gra id pinworms. A pruritic papular dermatosis o
the trun and e tremities may be obser ed in re uently. Rest
lessness insomnia enuresis and irritability are a ew o the
many symptoms ascribed to this e ceedingly common in esta
tion. acerbation o mastocytosis has been described.
yuriasis is caused by the roundworm Enterobius vermicu
laris which may in est the small intestines cecum and large
intestine o humans. The worms especially gra id ones
migrate toward the rectum and at night emerge to the perianal
and perineal regions to deposit thousands o o a; then the
worm dries and dies outside the intestine. These o a are then
carried bac to the mouth o the host on the hands. The lar ae
hatch in the duodenum and migrate into the e unum and
ileum where they reach maturity. ertili ation occurs in the
cecum thus completing the li e cycle.
umans are the only nown host o the pinworm which
probably has the widest distribution o all the helminths.
n ection occurs rom hand to mouth transmission o ten rom
handling soiled clothes bedsheets and other household
articles. a under the ngernails are a common source o
autoin ection. a may also be airborne and collect in dust
that may be on urniture and the oor. n estigation may
show that all members o the amily o an a ected person
also harbor the in ection. t is common in orphanages and
mental institutions and among people li ing in communal
groups.
Rarely is it easible to identi y a dead pinworm in the stool.
Diagnosis is best made by demonstration o o a in smears
ta en rom the anal region early in the morning be ore the
patient bathes or de ecates. Such smears may be obtained with
a small eye curette and placed on a glass slide with a drop o
saline solution. t is also possible to use cellophane tape
looping the tape stic y side out o er a tongue depressor and
then pressing it se eral times against the perianal region. The
tape is then smoothed out on a glass slide. A drop o a solution
containing iodine in ylol may be placed on the slide be ore
the tape is applied to acilitate detection o any o a. These tests
should be repeated on consecuti e days to rule out in ection.
a may be detected under the ngernails o the in ected
person.
Albenda ole mg or mebenda ole mg or pyrantel
pamoate mg g (ma imum g) gi en once and repeated
in wee s is e ecti e. Personal hygiene and cleanliness at
home are important. ingernails should be cut short and
scrubbed re uently; nails should be thoroughly cleaned on
429
 arising be ore each meal and a ter using the toilet. Sheets
20 underwear towels pa amas and other clothing o the a ected
person should be laundered thoroughly and separately.
Patrizi A, et al: Cutaneous mastocytosis exacerbated by pinworms in a
Parasitic Infestations, Stings, and Bites
young boy. Pediatr Dermatol 2012; 29(2):229–230.
Raghallaigh SN, et al: Enterobius vermicularis dermatitis. Clin Exp
Dermatol 2010; 35(3):e32–e33.
Hookworm disease (ground itch, uncinariasis,
ancylostomiasis, necatoriasis)
The earliest s in lesions (ground itch) are erythematous
macules and papules which in a ew hours become esicles.
These itchy lesions usually occur on the soles toe webs and
an les; they may be scattered or in groups. The content o the
esicles rapidly becomes purulent. These lesions are produced
by in asion o the s in by the nc lostoma or ecator lar ae
and they precede the generali ed symptoms o hoo worm
disease by or months. The cutaneous lesions last less than
wee s be ore the lar ae continue their human li e cycle.
There may be as high as eosinophilia about the th day
o in ection.
The onset o the constitutional disease is insidious and is
accompanied by progressi e iron de ciency anemia and debil
ity. During the course o hoo worm disease urticaria o ten
occurs. The s in ultimately becomes dry and pale or yellowish.
oo worm is a speci c communicable disease caused by
nc lostoma uo enale or ecator americanus n the soil under
propitious circumstances hoo worms attain the stage o in ec
ti e lar ae in days. When they come into accidental contact
with bare eet these tiny lar ae (which can scarcely be seen
with a small poc et lens) penetrate the s in and reach the cap
illaries. They are carried in the circulation to the lungs where
they pass through the capillary walls into the bronchi. They
mo e up the trachea to the pharyn and a ter being swal
lowed e entually reach their habitat in the small intestine.
ere they bury their heads in the mucosa and begin their
se ual li e.
oo worm is pre alent in most tropical and subtropical
countries and is o ten endemic in swampy and sandy localities
in temperate ones. n these latter regions the lar ae are illed
o each winter but the soil is again contaminated rom human
sources the ollowing summer. americanus pre ails in the
Western emisphere Central and South A rica South Asia
Australia and the Paci c islands.
The de ecation habits o in ected indi iduals in endemic areas
are largely responsible or its widespread distribution as is the
use o human eces or ertili ation in many parts o the world.
n addition the climate is usually such that people go bare oot
because o the heat or because they cannot a ord shoes. n ec
tion is thereby acilitated especially through the toes.
inding the eggs in the eces o a suspected indi idual
establishes the diagnosis. The o a appear in the eces about
wee s a ter the onset o in ection. The eggs may be ound in
direct ecal lms i the in ection is hea y but in light in ections
it may be necessary to resort to inc sul ate centri ugal otation
or other concentration methods. i ed in ections re uently
occur.
Albenda ole mg once or mebenda ole mg twice
daily or days or mg once or pyrantel pamoate mg
g (ma imum g) each day or days is e ecti e. Prophy
la is is largely a community problem and depends on pre ent
ing ecal contamination o the soil. This is best attained by
proper sanitary disposal o eces protecting indi iduals rom
e posure by educating them about sanitary procedures and
mass treatment through public health methods.
430
tahir99 - UnitedVRG
Nematode dermatitis
A patient in one report de eloped a persistent widespread
olliculitis caused by nc lostoma caninum t was apparently
ac uired by lying in grass contaminated by the droppings o
the patient s pet dogs and cats. A biopsy re ealed hoo worm
lar ae within the hair ollicle. ral thiabenda ole was
curati e.
Creeping eruption (larva migrans)
Creeping eruption is a term applied to twisting winding linear
s in lesions produced by the burrowing o lar ae. People who
go bare oot on the beach children playing in sandbo es car
penters and plumbers wor ing under homes and gardeners
are o ten ictims. The most common areas in ol ed are the
eet buttoc s genitals and hands.
Slight local itching and the appearance o papules at the sites
o in ection characteri e the onset. ntermittent stinging pain
occurs and thin red tortuous lines are ormed in the s in. The
lar al migrations begin days a ter inoculation and progress
at the rate o about cm day. owe er they may remain
uiescent or se eral days or e en months be ore beginning to
migrate. The linear lesions are o ten interrupted by papules
that mar the sites o resting lar ae ( ig. ). As the erup
tion ad ances the old parts tend to ade although purulent
mani estations may be caused by secondary in ection in some
cases; erosions and e coriations caused by scratching re
uently occur. the progress o the disease is not interrupted
by treatment the lar ae usually die in wee s with resolu
tion o the eruption although rarely it has been reported to
persist or up to year. At times the lar ae are remo ed rom
the s in by the ngernails in scratching. osinophilia may be
present.
Loe er syndrome consisting o a patchy in ltrate o the
lungs and eosinophilia as high as in the blood and
in the sputum may complicate creeping eruption.
The ma ority o .S. cases o lar a migrans occur along the
southeast coast and are caused by penetration by the lar ae o
a cat and dog hoo worm nc lostoma bra iliense t is ac uired
rom body contact with damp sand or earth that has been
contaminated by the e creta o dogs and cats. The lar ae o
caninum which also in ests the dog and the cat rarely produce
a similar dermatitis. The diagnosis is typically made clinically
although biopsy may sometimes demonstrate the organism
and e en dermoscopy has been used.
Fig. 20-17 Cutaneous larva migrans.
 ermectin μg g generally gi en as a single mg
dose and repeated the ne t day or albenda ole mg day
or days is an e ecti e treatment. Criteria or success ul
therapy are relie o symptoms and cessation o tract e ten
sion which usually occurs within wee . Topical thiabenda
ole compounded as a suspension or a cream used
our times daily will result in mar ed relie rom pruritus in
days and the tracts become inacti e in wee . Topical met
ronida ole has also been reported to be e ecti e.
Another condition not to be con used with this helminthic
disease which also is called creeping eruption (or sandworm
as it is nown in South A rica particularly in atal and ulu
land) is caused by a small mite about μm long that tunnels
into the super cial layers o the epidermis.
Gnathostomiasis
igratory intermittent erythematous urticarial pla ues char
acteri e human gnathostomiasis. ach episode o painless
swelling lasts rom days and recurs e ery wee s.
o ement o the underlying parasite may be as much as
cm h. The total duration o the illness may be years.
istopathologic e amination o the s in swelling will demon
strate eosinophilic panniculitis. The clinical mani estation has
been called lar a migrans pro undus.
The nematode nathostoma olorosi or spinigerum is the
cause; most cases occur in Asia or South America. ating raw
esh rom the second intermediate host most o ten reshwater
sh in such preparations as sashimi and ce iche allows
humans to become the de niti e host. ating raw s uid or
sna e is a less common e posure. As the lar al cyst in the esh
is digested it becomes motile and penetrates the gastric
mucosa usually within h o ingestion. Symptoms then
occur as migration o the parasite continues. Surgical remo al
is the treatment o choice i the parasite can be located. This
may be combined with albenda ole mg day or twice
daily or days or i ermectin μg g day or days.
Creeping eruption caused by a recently recogni ed caus
ati e parasite o the nematode super amily Spiruroidea has
been reported in Japan. ating raw s uid was associated with
the onset o long narrow lesions that were pruritic linear and
migratory. Surgical remo al is the treatment o choice cur
rently as data on i ermectin are mi ed.
Larva currens
ntestinal in ections with Strong loi es stercoralis may be asso
ciated with a perianal lar a migrans syndrome called lar a
currens because o the rapidity o lar al migration (currens
means running or racing ). Lar a currens is an autoin ec
tion caused by penetration o the perianal s in by in ectious
lar ae as they are e creted in the eces. An urticarial band is
the prominent primary lesion o cutaneous strongyloidiasis.
Strongyloidiasis as with the creeping eruption secondary to
it is o ten a chronic disease; in ections may persist or more
than years. Appro imately one third o patients in ected are
asymptomatic.
Signs and symptoms o systemic strongyloidiasis include
abdominal pain diarrhea constipation nausea omiting
pneumonitis urticaria eosinophilic olliculitis and a periph
eral eosinophilia. The s in lesions originate within cm o
the anus and characteristically e tend as much as cm day.
atal cases o hyperin ection occur in immunocompromised
patients; the parasite load increases dramatically and can
produce a ulminant illness. Widespread petechiae and
purpura are help ul diagnostic signs o disseminated in ection
and chronic urticaria is a possible presenting sign. Periumbili
cal ecchymoses may appear as i they were caused by a
thumbprint.
Administration o i ermectin μg g day or days or
thiabenda ole mg g day in two doses (ma imum g
Class nematoda
day) or days is the treatment o choice. mmunosuppressed
hosts may be treated with thiabenda ole mg g twice
daily or days.
ree li ing strongyloides nown as Pelo era can also produce
a creeping eruption. n one reported case widespread ollicu
lar erythematous dome shaped papules and pustules
appeared on the patient within h o wor ing under a house.
This eruption persisted or month be ore presentation. Scrap
ing the lesions re ealed li e and dead lar ae o the ree li ing
soil nematode Pelo era strong loi es Treatment with oral thia
benda ole led to resolution.
Laga AC, et al: Cutaneous gnathostomiasis: report of 6 cases with
emphasis on histopathological demonstration of the larva. J Am Acad
Dermatol 2013; 68(2):301–305.
Showler A, et al: Strongyloidiasis presenting as larva currens 38 years
after presumed exposure. J Cutan Med Surg 2012; 16(6):433–435.
Upendra Y, et al: Cutaneous larva migrans. Indian J Dermatol Venereol
Leprol 2013; 79(3):418–419.
Dracunculiasis (Guinea worm disease,
dracontiasis, Medina worm)
Guinea worm disease is now limited to remote illages in
se eral sub Saharan A rican countries. t is caused by Dracun
culus me inensis and is contracted through drin ing water that
has been contaminated with in ected water eas in which Dra
cunculus is parasitic. n the stomach the lar ae penetrate into
the mesentery where they mature se ually in wee s. The
emale worm then burrows to the cutaneous sur ace to deposit
her lar ae and thus causes the speci c s in mani estations. As
the worm approaches the sur ace it may be elt as a cordli e
thic ening and orms an indurated cutaneous papule. The
papule may esiculate and a pain ul ulcer de elops usually
on the leg. The worm is o ten isible. When the parasite comes
in contact with water the worm rapidly discharges its lar ae
which are ingested by water eas C clops contaminating the
water.
The cutaneous lesion is usually on the lower leg but it may
occur on the genitalia buttoc s or arms ( ig. ). n addi
tion to the ulcers on the s in there may be urticaria G upset
eosinophilia and e er.
Fig. 20-18 Dracunculiasis.
431
 Dracunculiasis may be pre ented by boiling drin ing water
20 pro iding sa e drin ing water through boreholes or ltering
the water through mesh bers. ati e treatment consists o
gradually e tracting the worm a little each day ta ing care not
to rupture it; otherwise the lar ae escape into the tissues and
Parasitic Infestations, Stings, and Bites
produce ulminating in ammation. Surgical remo al is the
treatment o choice. etronida ole mg day resol es the
local in ammation and permits easier remo al o the worm.
mmersion in warm water promotes emergence o the worm.
Global eradication is within reach and Guinea worm disease
may become a historical ootnote.
Gulanikar A: Dracunculiasis: two cases with rare presentations. J
Cutan Aesthet Surg 2012; 5(4):281–283.
Hopkins DR, et al: Dracunculiasis eradication: and now, South Sudan.
Am J Trop Med Hyg 2013; 89(1):5–10.
Filariasis
Elephantiasis tropica (elephantiasis arabum)
ilariasis is a widespread tropical disorder caused by in esta
tion with larial worms o uchereria bancrofti rugia mala i
or rugia timori species. t is characteri ed by lymphedema
with resulting hypertrophy o the s in and subcutaneous
tissues and by enlargement and de ormity o the a ected
parts usually the legs scrotum or labia ma ora. The disease
occurs more re uently in young men than women.
The onset o elephantiasis is characteri ed by recurrent
attac s o acute lymphangitis in the a ected part associated
with chills and e er (elephantoid e er) that last or se eral
days to se eral wee s. These episodes recur o er se eral
months to years. A ter each attac the swelling subsides only
partially and as recrudescences super ene thic ening and
hypertrophy become increasingly pronounced. The o erlying
epidermis becomes stretched thin and shiny and o er years
leathery insensiti e and errucous or papillomatous rom
secondary pyogenic in ection. The patient may ha e a do en
or more attac s in a year.
n addition to in ol ement o the legs and scrotum the
scalp ul a penis emale breasts and arms can be a ected
either alone or in association with the other regions. The
mani estations ary according to the part in ol ed. When the
legs are attac ed both are usually a ected somewhat sym
metrically with the principal changes occurring on the poste
rior aspects abo e the an les and on the dorsa o the eet.
At rst the thic ening may be slight and associated with
edema that pits on pressure. Later the parts become massi e
and pachydermatous the thic ened integument hanging
in apposing olds between which there is a etid e udate
( ig. ).
When the scrotum is a ected it gradually reaches an enor
mous si e and the penis becomes hidden in it. The s in which
at rst is gla ed is later coarse and errucous or in ar
ad anced cases ulcerated or gangrenous. Resistant urticaria
may occur. ilarial orchitis and hydrocele are common. A tes
ticle may enlarge rapidly to the si e o an apple and may be
e tremely pain ul. The swelling may subside within a ew
days or the enlargement may be permanent. As a result o
obstruction and dilation o the thoracic duct or some o its
lower abdominal tributaries into the urinary tract chyle
appears in the urine which assumes a mil y appearance. Lob
ulated swellings o the inguinal and a illary glands called
aricose glands are caused by obstructi e ari and dilation
o the lymphatic essels.
ilaria are transmitted person to person by the bites o a
ariety o mos uitoes o the Culex e es and nopheles
432
tahir99 - UnitedVRG
Fig. 20-19 Filarial elephantiasis.
species. The adult worms are threadli e cylindrical and
creamy white. The emales are cm long. icro larial
embryos may be seen as coiled each in its own membrane
near the posterior tip. ully grown sheathed micro lariae
are μm long. The adult worms li e in the lymphatic
system where they produce micro lariae. These either
remain in the lymphatic essels or enter the peripheral blood
stream. An intermediate host is necessary or the urther
de elopment o the parasite.
t is important to reali e that in estation by the laria is o ten
asymptomatic and elephantiasis usually occurs only i hun
dreds o thousands o mos uito bites occur o er a period o
years with episodes o intercurrent streptococcal lymphangi
tis. ilariasis was endemic in the considerable Samoan popula
tion o awaii or hal a century and only one case o
elephantiasis has occurred among this group.
The micro lariae should be sought on resh co erslip lms
o blood (collected at night) urine or other body uid and
e amined with a low power ob ecti e lens. Calci ed adult
worms may be demonstrated on ray e amination and ultra
sound can detect adult worms. At times adult lariae are
ound in abscesses or in material ta en or pathologic e ami
nation. Speci c serologic tests and a simple card test or larial
antigen are a ailable. The prognosis in regard to sur i al is
good but li ing becomes burdensome unless the condition is
alle iated.
Diethylcarbama ine in increasing doses o er a day
period is the treatment o choice. This regimen clears micro
lariae but not adult worms. A single dose o i ermectin may
also be e ecti e. Do ycycline ills the intracellular symbiotic
bacteria olbachia This leads to long term sterility o adult
emale worms. Do ycycline is being studied to determine its
place in the treatment o both bancro tian lariasis and oncho
cerciasis. A worldwide e ort to eliminate these diseases is
underway. Surgical procedures ha e been de ised to remo e
the edematous subcutaneous tissue rom the scrotum and
breast. Prophylactic measures consist o appropriate mos uito
control. Diethylcarbama ine has been e ecti e in mass pro
phyla is. a trip o o er month to areas with endemic
uchereria bancrofti is planned and e tensi e e posure to mos
uitoes is li ely ta ing diethylcarbama ine mg day or
days each month is recommended.
Nutman TB: Insights into the pathogenesis of disease in
human lymphatic filariasis. Lymphat Res Biol 2013;
11(3):144–148.

A B
Fig. 20-20 A and B, Loiasis. (Courtesy of Curt Samlaska, MD.)
Loiasis (Loa loa, Calabar swelling,
tropical swelling, fugitive swelling)
n ection with Loa loa is o ten asymptomatic. n in ected
persons the parasite de elops slowly and e en years can
elapse between in ection and appearance o symptoms
although the usual inter al is year. The rst sign is o ten
pain ul locali ed subcutaneous nonpitting edema called
Calabar or ugiti e swelling ( ig. A). ne or more
slightly in amed edematous transient swellings occur
usually about the si e o a hen s egg. They typically last a ew
days and then subside although recurrent swellings at the
same site may e entually lead to a permanent cystli e protu
berance. These swellings may result rom hypersensiti ity to
the adult worm or to materials elaborated by it. osinophilia
may be as high as and o ten is .
The lariae may be noticed subcutaneously in the ngers
breasts eyelids or submucosally under the con uncti ae. The
worm may be in the anterior chamber o the eye the myocar
dium or other sites. t has a predilection or loose tissues such
as the eye region the renum o the tongue and the genitalia.
The wanderings o the adult parasite may be noticed because
o a tingling and creeping sensation. The death o the laria in
the s in may lead to the ormation o uctuant cystic lesions.
Loiasis is widely distributed in West and Central A rica
where it is transmitted by the mango y Chr sops imi ia or
Chr sops silacea This y bites only in the daytime. umans are
the only important reser oir or the parasite. The obser ation
o the worm under the con uncti a Calabar swellings eosino
philia and micro lariae in peripheral blood establish the diag
nosis. Demonstration o the characteristic micro lariae in the
blood during the day is possible in only about o patients.
Speci c serologic tests are a ailable and luci erase immuno
precipitation systems can pro ide rapid diagnostic results
with impro ed sensiti ity and speci city compared with
en yme lin ed immunosorbent assay ( L SA).
Remo al o the adult parasite whene er it comes to the
sur ace o the s in is mandatory ( ig. B). This must be
done uic ly by sei ing the worm with orceps and placing a
suture under it be ore cutting down to it. Worms that are not
securely and rapidly grasped may escape into the deeper
tissues.
Diethylcarbama ine ills both adults and micro lariae and
is gi en in increasing doses or days. n regions where
onchocerciasis and loiasis both are endemic and where
Class nematoda
i ermectin is used in a community based elimination strategy
or onchocerciasis simultaneously in ected patients with a
high L loa load ha e a greater ris o serious side e ects.
i ermectin treatment o these patients is underta en
proper monitoring and appropriate supporti e treatment
should be a ailable in anticipation o this ris . Diethylcarbam
a ine is an e ecti e chemopre enti e therapy using mg
wee in temporary residents o regions o A rica where L loa
is endemic.
Boussinesq M: Loiasis: new epidemiologic insights and proposed
treatment strategy. J Travel Med 2012; 19(3):140–143.
Gantois N, et al: Imported loiasis in France: a retrospective analysis of
47 cases. Travel Med Infect Dis 2013; 11(6):366–373.
Onchocerciasis
The s in lesions o onchocerciasis are characteri ed by pruri
tus dermatitis and onchocercomas. The dermatitis is ariable
in appearance probably related to chronicity o in ection age
o the patient geographic area where ac uired and relati e
immune responsi eness. arly in the course o the in ection
an itchy papular dermatitis may occur and in isitors who
become in ected this may be locali ed to one e tremity ( ig.
). n Central America papules may appear only on the
head and nec area. This unusual locali ation o insect bite
appearing papules with e coriations may lead to the diagnosis
in tra elers returning to their home countries. n Central
America another mani estation o the acute phase o oncho
cerciasis is acute swelling o the ace with erythema and
itching nown as erisipela de la costa. n aire and Central
America an acute urticarial eruption is seen. The in amma
tion which is accompanied by hyperpigmentation is nown
as mal morado.
As time passes the dermatitis becomes chronic and remains
papular; howe er thic ening licheni cation and depigmen
tation occur ( ig. ). Later atrophy may super ene. When
the depigmentation is spotted it is nown as leopard s in;
when the s in is thic ened it is called elephant s in. When
local edema and thic ened wrin led dry dermatitic changes
predominate it is sometimes called li ard s in.
n Saudi Arabia emen and ast A rica a locali ed type
o onchocerciasis e ists called sowda Arabic or blac .
t is characteri ed by locali ed pruritic asymmetric usually
dar ly pigmented chronic licheni ed dermatitis o one leg or
one body region. t is also nown as the chronic hyperreacti e
433
 Fig. 20-21 Early
20 onchocerciasis.
Parasitic Infestations, Stings, and Bites
Fig. 20-22
Onchocerciasis.
(Courtesy of Debra
Kalter, MD.)
type and an association with antide ensin antibodies suggests
a reason or this enhanced reacti ity against the parasite.
A ter a time rm subcutaneous nodules pea si ed or larger
de elop on arious sites o the body. These nodules are oncho
cercomas containing myriad micro lariae. These occur in
crops are re uently pain ul and their site aries. n parts o
A rica where nati es are wholly or nearly unclothed the
lesions occur on the trun a illae groin and perineum. n
434
tahir99 - UnitedVRG
Fig. 20-23
Onchocerciasis.
Central and South America the head especially the scalp is
the usual site o in ol ement. irm nontender lymphadenop
athy is a common nding in patients with chronically in ected
onchocerciasis. anging groin describes the loose atrophic
s in sac that contains these large inguinal nodes ( ig. ).
n about o a ected persons serious eye lesions arise late
in the disease gradually leading to blindness.
nchocerciasis is caused by Onchocerca volvulus which is
transmitted to humans by the bite o the blac y o the genus
Simulium t breeds in ast owing streams. When the blac y
bites it introduces lar ae into the wound. The lar ae reach
adulthood in the subdermal connecti e tissue in about year.
illions o the progeny then migrate bac into the dermis and
the a ueous humor o the eye.
nchocerciasis occurs in A rica on the west coast in the
Sahara Sudan and the Victoria ile di ision where it is
nown as ri er blindness. n Central and South America this
disease can be ound in Guatemala Bra il Vene uela and
southern e ico.
The presence o eosinophilia s in lesions and onchocerco
mas with ocular lesions is highly suggesti e in endemic areas.
re uently the micro lariae may be ound in s in sha ings or
dermal lymph e en when no nodules are detectable. The
scapular area is the a orite site or procuring specimens or
e amination by means o a s in snip. This is per ormed in the
eld or o ce by li ting the s in with an inserted needle and
then clipping o a small super cial portion o the s in with
a sharp ni e or scissors. The specimen is laid in a drop o
normal saline solution on a slide with a co erslip and e am
ined under the microscope. The lariae wriggle out at the
edges o the s in slice.
Speci c serologic and PCR based diagnostic tests rom
blood and s in biopsies are a ailable. ther larial parasites
can be detected in similar systems. When patients with sus
pected onchocerciasis were gi en a single oral dose o mg
o diethylcarbama ine a reaction consisting o edema itching
e er arthralgias and e acerbation o pruritus was described
as a positi e a otti test reaction which supported the diag
nosis o onchocerciasis.
nchocercomas may be surgically e cised whene er easi
ble. ermectin as a single oral dose o μg g is the drug
o choice. S in micro laria counts remain low at the end o
months obser ation. ermectin should be repeated e ery
months to suppress the dermal and ocular micro larial counts.
ore re uent dosing does not appear to reduce micro larial
counts urther.
Do ycycline ills the intracellular symbiotic bacteria
olbachia that appear to cause a otti reactions and is being
tested or long term e ects and determination o its place in
the treatment o onchocerciasis and bancro tian lariasis.
there is eye in ol ement prednisone mg g should be
started se eral days be ore treatment with i ermectin. o
idectin and emodepside also appear promising as alternati e
drugs. Community based treatment protocols ha e the ob ec
ti e o eliminating onchocerciasis rom endemic areas. Se ere
reactions may occur in patients simultaneously in ected with
Loa loa
Barry MA, et al: Global trends in neglected tropical disease control and
elimination: impact on child health. Arch Dis Child 2013;
98(8):635–641.
Salam RA, et al: Community-based interventions for the prevention and
control of helmintic neglected tropical diseases. Infect Dis Poverty
2014; 31:23.
Trichinosis
ngestion o richinella spiralis lar a containing cysts in inad
e uately coo ed por bear or walrus meat may cause trichi
nosis. t usually causes a pu y edema o the eyelids redness
o the con uncti ae and sometimes urticaria or angioedema
associated with hyperpyre ia headache erythema G symp
toms muscle pains and neurologic signs and symptoms. Ten
percent o patients de elop a bilateral asymptomatic hand
swelling that is especially prominent o er the digits as well
as erythema along the perimeters o the palms and olar sur
aces o the digits which progresses to des uamation. n
o cases a nonspeci c macular or petechial eruption occurs
and splinter hemorrhages are occasionally present. osino
philia is not constant but may be as high as . n the a erage
patient eosinophilia begins about wee a ter in ection and
attains its height by the ourth wee .
The immuno uorescence antibody test has the greatest
alue in establishing early diagnosis. The bentonite occula
tion test L SA and other serologic tests are limited by their
inability to detect in ection until the third or ourth wee .
Diagnosis is con rmed by a muscle biopsy that demonstrates
lar ae o spiralis in striated muscle. n ortunately trichinae
cannot usually be demonstrated unless eosinophilic asculitis
and granulomas ha e been described on biopsy. A mm thic
slice o the muscle biopsy may be compressed between two
glass slides to demonstrate the cysts.
Trichinosis is treated with albenda ole mg twice daily
or days. Corticosteroid agents are e ecti e in controlling
the o ten se ere symptoms and should be gi en at doses o
mg day.
Knopp S, et al: Nematode infections: soil-transmitted helminths and
trichinella. Infect Dis Clin North Am 2012; 26(2):341–358.
PNEUMOCYSTOSIS
Pneumoc stis jiroveci ( ormerly P carinii) has eatures charac
teristic o both proto oa and ungi. t is an opportunistic in ec
tion occurring primarily as a pulmonary in ection in A DS
patients. trapulmonary in ol ement is uncommon and
usually occurs in the reticuloendothelial system. S in ndings
may occur. At least hal o reported cases are o nodular
growths in the auditory canal with the remainder ha ing
nonspeci c pin to s in colored papules and nodules that
may ulcerate. n biopsy the dermis contains oamy material
within which Giemsa positi e organisms are identi ed. i ed
cutaneous in ection with Cr ptococcus has been reported; the
s in lesions appeared anthomatous. Cutaneous botryomyco
sis caused by combined Staph lococcus aureus and P jiroveci has
been reported in patients with human immunode ciency
irus ( V) in ection. A wee course o trimethoprim
sul ametho a ole is the treatment o choice. n combined
in ections all pathogens re uire treatment. Dapsone prophy
Pneumocystosis
la is has been associated with acute generali ed e anthema
tous pustulosis.
Peña ZG, et al: Mixed Pneumocystis and Cryptococcus cutaneous
infection histologically mimicking xanthoma. Am J Dermatopathol
2013; 35(1):e6–e10.
Vas A, et al: Acute generalised exanthematous pustulosis induced by
Pneumocystis jirovecii pneumonia prophylaxis with dapsone. Int J STD
AIDS 2013; 24(9):745–747.
PHYLUM ARTHROPODA
Phylum Arthropoda contains more species than all the other
phyla combined. The classes o dermatologic signi cance are
yriapoda nsecta and Arachnida. os uitoes ies tic s
and eas transmit diseases throughout the world. Although
always pre alent bites and stings increase dramatically a ter
natural disasters such as hurricanes and ooding.
Prevention of arthropod-related disease
os uitoes remain the most important ectors o arthropod
borne disease and mos uito control programs are an essential
component o the public health e orts o many .S. states.
nsect repellents are e ecti e in pre enting disease transmis
sion and are especially important during tra el to areas where
ector borne disease is endemic. ost are based on D T
( diethyl methylben amide pre iously called
diethyl m toluamide). D T has been tested against a wide
range o arthropods including mos uitoes sand ies tic s
and chiggers. The American Academy o Pediatrics recom
mends concentrations o or less in products intended or
use in children. Some e idence suggests that children do not
ha e a higher incidence o ad erse reactions than adults but
e en in adults neuroto icity has been occasionally reported.
igh concentrations o D T can produce erythema and irri
tation or bullous eruptions. tended release products reduce
the need or repeated application and appear to minimi e the
ris o complications. erall D T has a good sa ety record
in widespread use. Picaridin ( BR ) is a piperidine
deri ed repellent ingredient that is also e ecti e against a
range o arthropods. Some studies ha e shown that picaridin
is less irritating than D T while pro iding comparable e
cacy. The best studies or the e aluation o repellents are eld
trials that in ol e a range o arthropods. Arm bo studies
are still per ormed but must be interpreted with caution.
Citronella candles ha e little documented e cacy but neem
oil is an e ecti e mos uito repellent used in many areas o the
world that are endemic or malaria. Geraniol candles show
some e cacy but only in the area immediately surrounding
the candles. Repellency decreases signi cantly at a distance
o e en m. Candles with geraniol are twice as e ecti e as
those with linalool and e times as e ecti e as those with
citronella. R (ethyl butyl acetyl aminopropionate) in a
ariety o ormulations has also demonstrated good e cacy
against mos uitoes with complete protection in eld trials o
. . h.
Tra elers to malaria endemic areas should ollow CDC
guidelines or malaria prophyla is. They should also a oid
nighttime outdoor e posure and use protecti e measures such
as repellents and bed netting. The anopheline mos uitoes that
carry malaria tend to bite at night so bed nets and screens are
435
 important measures. os uitoes that carry dengue mostly
20 bite during the day. Repellents play a greater role in protection
against dengue because it is more di cult to limit daytime
outdoor acti ity. os uito control programs depend largely
on drainage o stagnant water and spraying o breeding areas.
Parasitic Infestations, Stings, and Bites
be a ris y enture compared with other orms o tic control.
ther natural orms o tic control ha e been in estigated
because o their potential to become sel sustaining in the en i
ronment at least or a time; ungi and nematodes show some
promise. n southern .S. states re ants control tic popula

n de eloping countries water barrels may be stoc ed with tions by eating tic eggs.
sh or turtles to consume mos uito lar ae. Both can soil the
water howe er and the relati e ris s must be e aluated; some
studies clearly show the ris a ors stoc ing the barrel. os Prevention of flea-borne illness
uito traps (e.g. os uito agnet) ha e been e ecti e or the
control o mos uitoes in limited areas. Generally mos uitoes leas are important ectors o plague and endemic typhus.
y upwind to bite and downwind to return to their resting They may also be ectors o cat scratch disease. Lu enuron is
area. os uito traps must be positioned between the breeding a maturation inhibitor that pre ents eas rom breeding. t is
and resting areas and the area to be protected. os uito traps o ten used in oral and in ectable orms or the pre ention o
commonly use carbon dio ide (C ) heat and chemical ea in estation in cats and dogs. ipronil is used topically or
attractants. Some Culex mos uitoes are repelled by octenol the pre ention o ea and tic in estation. ther agents in use
and the manu acturer may pro ide guidelines or areas where include imidacloprid selamectin and nitenpyram. ouse
the attractant should not be used. sprays o ten include pyrethroids or pyripro y en. Powdered
boric acid may be help ul or the treatment o in ested carpets
or oor boards. A nowledgeable eterinarian and an e ter
Prevention of disease from ticks and chiggers minator should be consulted.
Moro ML, et al: Knowledge, attitudes and practices survey after an
Tic borne diseases include ric ettsial e ers ehrlichiosis outbreak of chikungunya infections. Int Health 2010; 2(3):223–227.
Lyme disease babesiosis relapsing e er and tularemia. ost Rappo TB, et al: Tick bite anaphylaxis: incidence and management in
re uire a sustained tic attachment o more than h or e ec an Australian emergency department. Emerg Med Australas 2013;
ti e transmission and re uent tic chec s with prompt 25(4):297–301
remo al o tic s is an important strategy or the pre ention o
tic borne illness. n ortunately tic inspections re uently
ail to identi y the tic in time or prompt remo al. Some data CLASS MYRIAPODA
suggest that adult tic s are ound and remo ed only o
the time within h o attachment. ymphal tic s are e en orphologically and genetically the class yriapoda is dis
more di cult to detect and may be remo ed in as ew as tinct rom other groups o arthropod. This group contains the
o patients within the rst h. Because o this repellents and centipedes and millipedes both capable o producing signi
acaricides remain critical or pre enting tic borne illness. cant s in mani estations.
Permethrin has illing acti ity against a wide range o
arthropods. Some orth A rican alomma tic s are resistant
to permethrin and may e hibit a parado ic pheromoneli e Centipede bites (Chilopoda)
attachment response when e posed to the agent but perme
thrin per orms ery well with other species o tic as well as Centipede bites are mani ested by paired hemorrhagic mar s
mos uitoes and chiggers. t can be used to treat clothing that orm a che ron shape caused by the large paired mouth
sleeping bags mos uito netting and tents. Permethrin treated parts ( ig. ). The bite is surrounded by an erythematous
clothing used in con unction with a repellent pro ides e cep swelling ( ig. ) that may progress into a brawny edema
tional protection against bites in most areas o the world. Per
methrin has a good record o sa ety although there is a report
o congenital leu emia with MLL rearrangement in a Fig. 20-24 Centipede.
preterm emale in ant whose mother had abused permethrin
because o a pathologic ear o spiders. Permethrin can induce
clea age o the MLL gene in cell culture pro iding a plausible
lin between the agent and the leu emia. t should be empha
si ed that permethrin in this case was not used according to
the manu acturer s instructions and the theoretic ris o car
cinogenicity should be weighed against the ery real ris o
death rom arthropod borne disease. Cardiac glycosides ha e
also been used topically as acaricides and ha e per ormed well
in limited studies.
xo es scapularis is the ma or orth American ector or
Lyme disease human granulocytic ehrlichiosis and human
babesiosis. A Lyme accine mar eted in the nited States was
a commercial ailure and withdrawn. Pre ention o Lyme
disease now centers on pre ention o tic attachments and
prompt tic remo al. Bac yards and recreational areas ad a
cent to wooded areas ha e higher rates o tic in estation. Tic
numbers can be reduced by deer encing remo al o lea
debris application o an acaricide and creation o border beds
with wood chip mulch or gra el. Bait bo es and deer eeding
stations can deli er a topical acaricide while the animal eeds.
Parasitic wasps control tic numbers in nature but wasp pop
ulations may uctuate and in estment in wasp control may
436

tahir99 - UnitedVRG

Fig. 20-25 Centipede bite.
or lymphangitis. Locally there may be intense itching and
pain o ten associated with to ic constitutional symptoms.
ost centipede bites run a benign sel limited course and
treatment is only supporti e. Children are o ten bitten when
they try to handle centipedes. Some species o Scolopen ra in
the western nited States will attain a length o cm and
the child may describe it as a sna e. Recognition o the char
acteristic che ron shape is important to a oid inappropriate
treatment with sna e anti enin. n the eastern nited States
the common house centipede Scutigera coleoptrata does not
bite humans. Scolopen ra subspinipes in awaii in icts a
pain ul bite. As e otic species appear more o ten at pet stores
and swap meets en enomation by them will become more
common.
n some tropical and subtropical areas centipede bites
account or about o all en enomations compared with
caused by sna es and by scorpions. ost bites occur
at home and in ol e an upper e tremity. Local pain and
edema occur in up to o patients depending on the species
in ol ed. Treatment is largely symptomatic. Rest ice and
ele ation may be su cient but topical or intralesional anes
thetics may be re uired in some cases. Tetanus immuni ation
should be considered i the patient has not been immuni ed
within the past years. Centipede bites can result in Wells
syndrome re uiring topical or intralesional corticosteroids.
Rarely bites may produce more serious to ic responses
including rhabdomyolysis myocardial ischemia proteinuria
and acute renal ailure. These ha e been reported ollowing
the bite o Scolopen ra heros the giant desert centipede.
Although centipedes ha e sometimes been ound in associa
tion with corpses in uries rom the centipede tend to be post
mortem and are rarely the cause o death. ngestion o
centipedes by children is usually associated with transient
sel limited to ic mani estations.
Fung HT, et al: Centipede bite victims: a review of patients presenting to
two emergency departments in Hong Kong. Hong Kong Med J 2011;
17(5):381–385.
Guerrero AP: Centipede bites in Hawai’i: a brief case report and review
of the literature. Hawaii Med J 2007; 66(5):125–127.
Yildiz A, et al: Acute myocardial infarction in a young man caused by
centipede sting. Emerg Med J 2006; 23(4):e30.
Millipede burns (Diplopoda)
Some millipedes secrete a to ic li uid that causes a brownish
pigmentation or burn when it comes into contact with s in.
Burns may progress to intense erythema and esiculation. il
lipedes may be ound in laundry hung out to dry and
Fig. 20-26 Millipede.
Class insecta
millipede burns in children ha e been misinterpreted as signs
o child abuse. Recognition o the characteristic cur ed shape
o the burn can be help ul in pre enting misdiagnosis. Some
millipedes can s uirt their enom and ocular burns are
reported. Washing o the to in as soon as possible will limit
the to ic e ects. ther treatment is largely symptomatic.
Diplopods ha e e ol ed a comple array o chemicals or
sel de ense ( ig. ). Some primates ta e ad antage o
these chemicals. Two millipede compounds methyl
ben o uinone and metho y methyl ben o uinone
demonstrate a repellent e ect against e es aeg pti mos ui
toes. Tu ted and white aced capuchin mon eys anoint them
sel es with the secretions to ward o mos uitoes. ecti e
commercial repellents are a ailable or human use; millipede
uice is not recommended.
Dar NR, et al: Millipede burn at an unusual site mimicking child abuse
in an 8-year-old girl. Clin Pediatr (Phila) 2008; 47(5):490–492.
Hendrickson RG: Millipede exposure. Clin Toxicol (Phila) 2005;
43(3):211–212.
CLASS INSECTA
Order Lepidoptera
rder Lepidoptera includes butter ies moths and their lar al
orms caterpillars. Se ere systemic reactions ha e resulted
rom ingestion o some caterpillars and with some species the
sting alone can produce se ere to icity. Lonomia achelous
ound in Latin America can cause a atal bleeding diathesis.
The Spanish pine caterpillar haumetopoea pit ocampa causes
both dermatitis and anaphylactoid symptoms. Pine caterpil
lars are also an important cause o systemic reactions in China
and srael. The tussoc moth Org ia pseu otsugata causes
respiratory symptoms in orestry wor ers in regon.
Caterpillar dermatitis
rritation is produced by contact o caterpillar hairs with the
s in. To ins in the hairs can produce se ere pain local
pruritic erythematous macules and wheals depending on
the species. the hairs embed in the clothing widespread
persistent dermatitis may result. ot only the caterpillars
but also their egg co ers and cocoons usually contain sting
ing hairs. n the nited States the most common caterpillars
o medical importance are the brown tail moth caterpillar
gmia phoeorrhoea puss caterpillar Megalop ge opercularis
( igs. and ) saddlebac caterpillar (Sibine stimu
late ig. ) io moth caterpillar utomeris io crin led
437
 Fig. 20-27 Puss Moth dermatitis
20 caterpillar.
oth dermatitis may be initiated by the hairs o the brown tail
moth Euproctis chr sorrhoea goat moth Cossus cossus puss
moth Dicranura vinula gypsy moth L mantria ispar and
Parasitic Infestations, Stings, and Bites

Douglas r tussoc moth emenocampa pseu otsugata n

Latin America the moths o the genus lesia are most re
uently the cause o moth dermatitis. Se ere con uncti itis and
pruritus are the rst signs and may persist or wee s aboard
ships that ha e doc ed in ports where the moth is common.
Caripito itch is named a ter Caripito Vene uela a port city
where the moth is ound. orean yellow moth dermatitis is
caused by Euproctis ava Bremer.
Topical applications o arious analgesics antibiotics and
oral antihistaminics are o little help. Topical or oral cortico
steroids are sometimes help ul as is scrubbing and tape strip
ping o s in. Contaminated clothing may need to be discarded
i dermatitis persists a ter the clothing is washed.
Haddad V Jr, et al: Tropical dermatology: venomous arthropods and
human skin. Part I. Insecta. J Am Acad Dermatol 2012; 67(3):331.
e1–e14; quiz 345.
Hossler EW: Caterpillars and moths. Part I. Dermatologic manifestations
of encounters with Lepidoptera. J Am Acad Dermatol 2010;
62(1):1–10.
Hossler EW: Caterpillars and moths. Part II. Dermatologic
manifestations of encounters with Lepidoptera. J Am Acad Dermatol
2010; 62(1):13–28.
Jourdain F, et al: The moth Hylesia metabus and French Guiana
lepidopterism: centenary of a public health concern. Parasite 2012;
19(2):117–128.
Paniz-Mondolfi AE, et al: Cutaneous lepidopterism: dermatitis from
contact with moths of Hylesia metabus (Cramer 1775) (Lepidoptera:
Saturniidae), the causative agent of Caripito itch. Int J Dermatol 2011;
50(5):535–541.

Fig. 20-28 Characteristic “railroad track” purpura of a puss caterpillar
sting.
Order Hemiptera
The true bugs belong to the order emiptera. The order
includes bedbugs water bugs chinch bugs stin bugs s uash
bugs and redu iid bugs ( issing bugs assassin bugs). The
latter are ectors o South American trypanosomiasis. n most
true bugs the wings are hal sclerotic and hal membranous
and typically o erlap. n bedbugs the wings are estigial.

Cimicosis (bedbug bites)

Bedbugs ha e at o al bodies and retro erted mouthparts
used or ta ing blood meals ( ig. ). Cimex lectularius is the
most common species in temperate climates and Cimex

Fig. 20-30 Bedbug.

Fig. 20-29 Saddleback caterpillar.

annel moth caterpillar Megalop ge crispata lahoma

puss caterpillar Lagoa crispata Douglas r tussoc
moth caterpillar Org ia pseu otsugata buc moth caterpillar
emileuca maia and annel moth caterpillar orape cretata
The hairs o the uropean processionary caterpillar haume
topoea processionea are especially dangerous to the eyes but
ophthalmia nodosa (papular reaction to embedded hairs) can
be seen with a wide ariety o caterpillars and moths. Air
borne processionary caterpillar hairs ha e caused large epi
demics o caterpillar dermatitis.
438

tahir99 - UnitedVRG
 Class insecta
Fig. 20-31 Bedbug bites.

hemipterus is most common in tropical climates. Both are

reddish brown and about the si e o a tic . C hemipterus is
somewhat longer than C lectularius They breed through trau Fig. 20-32 Triatome bite.
matic insemination in which the male punctures the emale
and deposits sperm into her body ca ity. Bedbugs hide in
crac s and cre ices then descend to eed while the ictim
sleeps. t is common or bedbugs to in ict a series o bites in
a row ( brea ast lunch and dinner ). Bites may mimic urti
caria and patients with papular urticaria commonly ha e anti
bodies to bedbug antigens. nilateral eyelid swelling has been
described as a common sign o bedbug bites in children.
Bullous and urticarial reactions also occur ( ig. ). Bedbugs
ha e been suggested as ectors or Chagas disease and hepa
titis B although data are sparse.
Bedbugs o ten in est bats and birds and these hosts may be
responsible or in estation in houses. anagement o the in es
tation may re uire elimination o bird nests and bat roosts.
Crac s and cre ices should be eliminated and the area treated
with an insecticide such as dichlor os or permethrin. Because
most insecticides ha e poor residual e ect on mud bric s
wood and abric re uent retreatment may be necessary.
icroencapsulation o insecticides enhances persistence.
Permethrin impregnated bednets ha e been shown to be e ec
ti e against bedbugs in tropical climates. ermectin treatment
is emerging as a potential ancillary measure. Bedbugs that ed Fig. 20-33 Crab louse.
once on humans hours a ter they recei ed μg g o oral
i ermectin had mortality and sur i ors were unable to
complete their li e cycle. rubbed into the bite. American trypanosomiasis can produce
Bernardeschi C, et al: Bed bug infestation. BMJ 2013; 346:f138. heart ailure and megacolon. Triatome bugs in est thatch
Delaunay P: Human travel and traveling bedbugs. J Travel Med 2012; crac s and cre ices and in estation is associated with poor
19(6):373–379. housing conditions. n nonendemic areas bites are sporadic
Sfeir M, Munoz-Price LS: Scabies and bedbugs in hospital outbreaks. and o ten ollowed by a red swelling suggesti e o cellulitis.
Curr Infect Dis Rep 2014; 16:412. Anaphyla is has also occurred. A related arthropod the wheel
Sheele JM, et al: Ivermectin causes Cimex lectularius (bedbug) bug rilus cristatus is widely distributed and has an e tremely
morbidity and mortality. J Emerg Med 2013; 45(3):433–440. pain ul de ensi e bite but it is not nown to carry disease.
Vaidyanathan R, et al: Bed bug detection: current technologies and
future directions. Am J Trop Med Hyg 2013; 88(4):619–625. Elston DM: What’s eating you? Wheel bug (Reduviidae: Arilus cristatus).
Cutis 1998; 61:189.
Kapoor R, et al: What’s eating you? Triatome reduviids. Cutis 2011;
Reduviid bites 87(3):114–115.

Triatome redu iid bugs ( issing bugs assassin bugs conenose

bugs) descend on their ictims while they sleep and eed on Order Anoplura
an e posed area o s in. The bite is typically painless although
the bugs are capable o producing a more pain ul de ensi e Pediculosis
bite. Swelling and itching occur within hours o the bite ( ig.
). any Latin American species ha e a pronounced gas Three arieties o the attened wingless Anoplura insects
trocolic re e and de ecate when they eed. Romana s sign is in est humans Pe iculus humanus ar. capitis (head louse) P
unilateral eye swelling a ter a nighttime encounter with a tria humanus ar. corporis (body louse) and Phthirus pubis (pubic
tome bug. t resembles the eyelid sign associated with or crab louse) ( ig. ). Rarely oonotic lice or louseli e
bedbugs. r panosoma cru i is transmitted by the eces and psocids will cause in estation.
439
20 Pediculosis capitis
Pediculosis capitis is more common in children but also occurs
in adults. Patients present with intense pruritus o the scalp
and o ten ha e posterior cer ical lymphadenopathy. coria
Parasitic Infestations, Stings, and Bites
tions and small spec s o louse dung are noted on the scalp
and secondary impetigo is common. Lice may be identi ed
especially when combing the hair. its may be present
throughout the scalp but are most common in the retroauricu
lar region. Generally only those o a close to the scalp are
iable and nits noted along the distal hair sha t are empty egg
cases. n e tremely humid climates howe er iable o a may
be present along the entire length o the hair sha t. Peripilar
eratin (hair) casts are remnants o the inner root sheath that
encircle hair sha ts and may be mista en or nits. Whereas nits
are rmly cemented to the hair casts mo e reely along the
hair sha t. ead lice readily sur i e immersion in water but
remain ed to scalp hairs. There is no e idence that swim
ming pools contribute to the spread o head lice.
ecti e therapeutic agents must ill or remo e both lice
and o a. les a (containing ben yl alcohol) is the rst
nonneuroto ic .S. ood and Drug Administration ( DA)
appro ed treatment or lice and represents a signi cant
ad ancement. Topical spinosad dimeticone li uid gel
malathion gel and topical i ermectin are other inno ations in
the treatment o head lice but permethrin remains the most
widely used pediculicide in the nited States despite wide
spread resistance. t is a ailable as an o er the counter ( TC)
cream rinse ( i ) and a prescription cream ( limite)
that is mar eted or the treatment o scabies. The cream
rinse must be applied a ter shampooing and drying the hair
completely. Applying to dry hair lessens dilution o the medi
cation. Product labeling states the medication should be
applied or min then rinsed o but longer applications
may be re uired. Shampooing should not ta e place or h ac ets should be stored separately under each child s des .
a terward. Permethrin has a a orable sa ety pro le although
congenital leu emia has been reported as noted earlier and
the use o insecticidal shampoos is statistically associated
with leu emia. ther reported side e ects include acute onset
o stuttering in a toddler. Pyrethrins combined with pipero
nyl buto ide (R D A R+C shampoo) are other TC
products. Lindane is rarely used because o low e cacy and
potential neuroto icity. Carbaryl is used in many parts o the
world but not in the nited States. Because o the potential
to icity associated with chemical pediculicides uture thera
pies will be asphy iating agents such as those containing
ben yl alcohol or dimeticone. Cure rates with dimeticone are
signi cantly higher than with permethrin in some studies.
ther agents that asphy iate or desiccate contain isopropyl
myristate . ha e lice scabies and ea in estation.
it combing is an important ad unct to treatment but is
impractical as a primary method o therapy. etal combs are
more e ecti e than plastic combs. Acidic cream rinses ma e
the hair easier to comb but do not dissol e nit cement which
is similar in composition to amyloid. Various natural rem
edies are mar eted that contain coconut oil anise oil and
ylang ylang oil but these agents are potential contact aller
gens and data are sparse regarding their sa ety and e cacy.
Some data support the e cacy o tea tree oil which is more
potent than la ender or lemon oil. ther studies also support
combination lotions containing la ender peppermint and
eucalyptus oils or eucalyptus and peppermint oils in
arious combinations o water and alcohol. The addition o
dodecanol impro es e cacy.
Aliphatic alcohols show promise as pediculicides and crota
miton ( ura ) an antiscabietic agent has some e cacy in the
treatment o pediculosis. Because no treatment is reliably o i
cidal retreatment in wee is reasonable or all patients.
440
tahir99 - UnitedVRG
Fig. 20-34 Body lice in seams of clothing.
Resistance to pediculicides is an emerging problem in many
parts o the world. The emergence o resistance to an agent is
related to the re uency o its use. noc down resistance
( DR) is a common mechanism o resistance that mani ests as
lac o immobili ation o the lice. Responsible gene mutations
( and L ) ha e been identi ed and can be used to
screen or DR. Cross resistance among pyrethroids is typical.
n the nited ingdom resistance to malathion has been
reported and multidrug resistant lice ha e been identi ed.
DR results in slower illing o lice but this may be o ercome
to some degree by longer applications. onoo ygenase based
resistance to pyrethrins may be o ercome by synergism with
piperonyl buto ide.
Simple public health measures are also o alue when epi
demics o louse in estation occur in schools. ats scar es and
Louse education and inspections by the school nurse acilitate
targeted treatment o in ested indi iduals.
Pediculosis corporis
Pediculosis corporis (pediculosis estimenti agabond s
disease ) is caused by body lice that lay their eggs in the seams
o clothing ( ig. ). The parasite obtains its nourishment
by descending to the s in and ta ing a blood meal. General
i ed itching is accompanied by erythematous blue and
copper colored macules wheals and licheni cation. Second
ary impetigo and urunculosis are common.
Body louse in estation is di erentiated rom scabies by the
lac o in ol ement o the hands and eet although in estation
by both lice and scabies is common and a gi en patient may
Lice may li e in clothing or month without a blood meal.
discarding the clothing is easible this is best. Destruction
o body lice can also be accomplished by laundering the cloth
ing and bedding. Clothing placed in a dryer or min at C
( ) is reliably disin ected. Pressing clothing with an iron
especially the seams is also e ecti e. Permethrin spray or
malathion powder can be used to treat clothing and reduce the
ris o rein estation.
Body lice are ectors or relapsing e er trench e er and
epidemic typhus. These diseases are most pre alent among
re ugee populations. The trench e er organism is also an
important cause o endocarditis among homeless persons.
Pediculosis pubis (crabs)
Phthirus pubis the crab louse is ound in the pubic region as
well as hairy areas o the legs abdomen chest a illae and
arms. Pubic lice may also in est the eyelashes and scalp. The
lice spread through close physical contact and are usually
transmitted se ually. A diagnosis o pediculosis pubis should
initiate a search or other STDs including V in ection. Con
taminated bedding is also a source o in estation. Pubic louse
nits are attached to the hairs at an acute angle. ther than the
presence o lice and nits in the hair the signs and symptoms
are similar to those o body louse in estation.
ccasionally blue or slate colored macules occur in associa
tion with pediculosis pubis. Called maculae ceruleae these are
located chie y on the sides o the trun and the inner aspects
o the thighs and are probably caused by altered blood
pigments.
Treatment o pediculosis pubis is similar to that or head
lice. The a ected person s se ual contacts should be treated
simultaneously. or eyelash in ol ement a thic coating o
petrolatum can be applied twice daily or days ollowed by
mechanical remo al o any remaining nits. luorescein and
pilocarpine gel are also e ecti e. Clothing and omites should
be washed and dried by machine or laundered and ironed.
Ahmad HM, et al: Assessment of topical versus oral ivermectin as a
treatment for head lice. Dermatol Ther 2014; 27:307–310.
Burgess IF, et al: Single application of 4% dimeticone liquid gel versus
two applications of 1% permethrin creme rinse for treatment of head
louse infestation: a randomised controlled trial. BMC Dermatol 2013;
13:5.
Chosidow O, et al: Topical ivermectin lotion for head lice. N Engl J Med
2013; 368(10):968.
Feldmeier H: Treatment of pediculosis capitis: a critical appraisal of the
current literature. Am J Clin Dermatol 2014; 15:401–412.
Goodman DM, et al: Head lice (Patient page). JAMA 2013; 309(22):2398.
Lapeere H, et al: AEfficacy of products to remove eggs of Pediculus
humanus capitis (Phthiraptera: Pediculidae) from the human hair. J
Med Entomol 2014; 51:400–407.
Pariser DM, et al: Topical ivermectin lotion for head lice. N Engl J Med
2013; 368(10):967.
Order Diptera
rder Diptera includes the two winged biting ies and mos
uitoes. Adult dipterids bite and spread disease while lar ae
parasiti e humans in the orm o myiasis. edically important
amilies o ies include the Tabanidae (horse y deer y
gad y) which in ict e tremely pain ul bites and the usci
dae (house y stable y tsetse y). Tsetse y bites transmit
A rican trypanosomiasis. Simulidae include the blac y by
(bu alo gnat tur ey gnat) the ector o onchocerciasis. These
ies are dar colored and hunchbac ed. They may produce
e tremely pain ul bites that may be associated with e er
chills and lymphadenitis. Blac ies are seasonal annoyances
in the northern nited States and Canada.
Psychodidae sand ies (Diptera Phlebotominae) are small
hairy winged ies that transmit leishmaniasis sand y e er
and erruga peruana. Sand y e er iruses are a problem in
A rica the editerranean basin and Central Asia and are
carried by Phlebotomus ies. Lut om ia ies are common in
Latin America and south Te as.
Culicidae or mos uitoes are ectors o many important
diseases such as lariasis malaria dengue and yellow e er.
Their bites may cause se ere urticarial reactions. Ceratopogo
nidae the biting midges or gnats y in swarms and produce
erythematous edematous lesions at the site o their bite.
Mosquito bites
oisture warmth C estrogens and lactic acid in sweat
attract mos uitoes. Drin ing alcohol also stimulates mos uito
attraction. os uito bites are a common cause o papular urti
caria. ore se ere local reactions are seen in young children
indi iduals with immunode ciency and those with new
e posure to indigenous mos uitoes. mmediate type hyper
sensiti ity can be controlled with antihistamines and prophy
lactic rupatadine mg daily has been e ecti e in the
treatment o immediate mos uito bite allergy. Both necroti
ing asciitis and the hemophagocytic syndrome ha e been
Class insecta
reported a ter mos uito bites and e aggerated hypersensiti
ity reactions to mos uito bites are noted in a wide ariety o
pstein Barr irus ( BV) associated lymphoproli erati e dis
orders especially natural iller ( ) cell proli erations. os
uito bites may play a ey role in reacti ation o latent BV
in ection.
Enayati AA, et al: Electronic mosquito repellents for preventing
mosquito bites and malaria infection. Cochrane Database Syst Rev
2007; (2):CD005434.
Karppinen A, et al: Rupatadine 10 mg in the treatment of immediate
mosquito-bite allergy. J Eur Acad Dermatol Venereol 2012;
26(7):919–22.
Singh S, et al: Insect bite reactions. Indian J Dermatol Venereol Leprol
2013; 79(2):151–164.
Ked itch
The sheep ed Melophagus ovinus eeds by thrusting its sharp
mouthparts into the s in and suc ing blood. ccasionally it
attac s woolsorters and sheepherders causing pruritic o ten
hemorrhagic papules typically with a central punctum. Deer
eds attac humans in a similar way. The papules are persis
tent and may last or up to months. a orite locations are
the hips and abdomen.
Myiasis
yiasis is the in estation o human tissue by y lar ae. orms
o in estation include wound myiasis uruncular myiasis
pla ue myiasis creeping dermal myiasis and body ca ity
myiasis. Wound myiasis occurs when ies lay their eggs in an
open wound. uruncular myiasis o ten in ol es a mos uito
ector that carries the y egg. Pla ue myiasis typically in ol es
many maggots and occurs a ter ies lay their eggs on clothing.
Creeping myiasis de elops when the lar ae o the asterophi
lus y wander intradermally. The most common species are
asterophilus nasalis and asterophilus intestinalis An itching
pin papule de elops ollowed by a tortuous line that e tends
cm a day. Body ca ity myiasis may in ol e the orbit
nasal ca ity G tract or urogenital system.
The human bot y Dermatobia hominis is a common cause o
uruncular myiasis in the neotropical regions o the ew
World ( ig. ). The emale glues its eggs to the body o a
Fig. 20-35 Myiasis.
441
 mos uito stable y or tic . When the unwitting ector punc
20 tures the s in by biting the lar a emerges rom the egg and
enters the s in through the puncture wound. er se eral
days a pain ul uruncle de elops in which the lar a is present.
ther lar ae that re uently cause uruncular lesions in orth
Parasitic Infestations, Stings, and Bites
America are the common cattle grub po erma lineatum
rabbit bot y Cuterebra cuniculi and ohlfahrtia vigil The
vigil y can penetrate in ant s in but not adult s in so almost
all reported cases ha e occurred in in ants. The ew World
screw worm Cochliom ia hominivorax o ten in ol es the head
and nec region. Lar ae o Calliphoridae ies especially Phae
nicia sericata the green blow y cause wound myiasis. ther
blow ies esh ies (Sarcophagidae) and humpbac ed ies
(Phoridae) are less common causes o wound myiasis. n tropi
cal A rica the Tumbu y Cor lobia anthropophaga deposits
her eggs on the ground or on clothing. The young maggots
penetrate the s in and o ten orm a pla ue with many
uruncular appearing lesions. Cor lobia ruan ae and Cor lo
bia ro haini are less re uent causes o pla ue myiasis. Oestrus
ovis causes ophthalmomyiasis that may be misdiagnosed as
bacterial con uncti itis.
Remo al o the maggots o uruncular myiasis can be accom
plished by in ection o a local anesthetic into the s in which
causes the lar a to bulge outward. The opening o the uruncle
can also be occluded with hair gel surgical lubricant lard
petrolatum or bacon causing the lar a to migrate outward.
Success ul treatment with i ermectin has also been reported.
Akdemir MO, et al: External ophthalmomyiasis caused by Oestrus ovis
misdiagnosed as bacterial conjunctivitis. Trop Doct 2013;
43(3):120–123.
Fydryszewski NA: Myiasis: diagnosis, treatment and medical use of
maggots. Clin Lab Sci 2013; 26(2):76–81.
McGraw TA, et al: Cutaneous myiasis. J Am Acad Dermatol 2008;
58(6):907–926.
Order Coleoptera
Blister beetle dermatitis
Blister beetle dermatitis occurs a ter contact with se eral
groups o beetle ( ig. ). The eloidae and edemeridae
amilies produce in ury to the s in by releasing a esicating
Fig. 20-36 Blister
beetle.
442
tahir99 - UnitedVRG
agent cantharidin. embers o the amily Staphylinidae
(genus Pae erus) contain a di erent esicant pederin. one o
the beetles bites or stings; rather they e ude their blistering
uid i they are brushed against pressed or crushed on the
s in. any blister beetles are attracted at night by uorescent
lighting.
Slight burning and tingling o the s in occur within minutes
ollowed by the ormation o bullae o ten arranged linearly.
issing lesions are obser ed when the blister beetle s e cre
tion is deposited in the e ures o the elbows or other olds.
ngestion o beetles or cantharidin results in poisoning pre
senting with hematuria and abdominal pain. n many tropical
and subtropical habitats ro e beetles (genus Pae erus) produce
a patchy or linear erythematous esicular eruption (dermatitis
linearis) ( ig. ). n parts o South America it is nown as
podo. t occurs re uently during the rainy season and appears
predominantly on the nec and e posed parts. Lymphade
nopathy and e er are common. n the southwestern nited
States outbrea s o ro e beetle dermatitis ha e ollowed
unusually rainy periods. n southeastern Australia corneal
erosions are caused by small Corylophidae beetles (Orthoperus
spp). Blister beetle deri ati es including cantharidin norcan
tharidin cantharidimide and norcantharimide ha e signi
cant potential as phosphoprotein phosphatase inhibitors in
cancer treatment.
Treatment o blister beetle dermatitis consists o draining the
bullae and applying cold wet compresses and topical antibi
otic preparations. arly cleansing with acetone ether soap or
alcohol may be help ul to remo e cantharidin.
Other beetles
Papulo esicular and urticarial dermatitis is caused by the
common carpet beetle (Dermestidae nthrenus scrophulariae).
The eruption in ol es the chest nec and e tremities. The
lar ae inhabit warm houses throughout the winter months.
They are reddish brown usi orm about mm long and
co ered by hairs. A generali ed pruritic eruption has been
attributed to the lar ae o the carpet beetle nthrenus verbasci
Bombardier beetles o the amily Carabidae (sub amily Bra
chininae) can cause s in burns with a deep yellow brown
color. Chemicals released when these beetles are crushed
include acids phenols hydrocarbons and uinines. When the
beetle is threatened chemical reactions produce an e plosi e
spray o boiling hot ben o uinones rom the tip o the
abdomen. Dermestidae (s in beetles) and Cleridae (bone
beetles) in est e posed human remains and are use ul in
Fig. 20-37 Paederus dermatitis. (Courtesy of Dr. Shyam Verma.)
estimating the postmortem inter al. Rare cases o allergic
angioedema ha e been reported a ter e posure to ladybugs.
Elston DM: What’s eating you? Blister beetles. Cutis 2004;
74(5):285–286.

Class insecta
Singh A, et al: Blister beetle dermatitis: few observations helping in
diagnosis. Int J Prev Med 2013; 4(2):241.

Order Hymenoptera
ymenopterids include bees wasps hornets and ants. Stings
by any o these may mani est the characteristic clinical and
histologic eatures o eosinophilic cellulitis (Wells syndrome)
complete with ame gures.

Bees and wasps

ellow ac ets are the principal cause o allergic reaction to
insect stings because they nest in the ground or in walls and
are disturbed by outdoor acti ity such as gardening or lawn Fig. 20-38 Sterile pustules at the site of fire ant stings.
mowing. Bees are generally docile and sting only when
pro o ed although A ricani ed bees display aggressi e
beha ior. The allergens in espid enom are phospholipase
hyaluronidase and a protein nown as antigen . Bee enom
contains histamine mellitin hyaluronidase a high molecular
weight substance with acid phosphatase acti ity and phos
pholipase A. The barbed o ipositor o the honeybee is torn out
o the bee and remains in the s in a ter stinging. The bumble
bee wasp and hornet are able to withdraw their stinger.
The reaction to these stings ranges rom pain and mild local
edema to e aggerated reactions that may last or days. Serum
sic ness characteri ed by e er urticaria and oint pain may
occur days a ter the sting. Se ere anaphylactic shoc and
death may occur within minutes o the sting. ost hypersen
siti ity reactions ha e been shown to be mediated by speci c
g antibodies. Anaphyla is to espids may also be the pre
Fig. 20-39 Cat flea.
senting symptom o mastocytosis with no demonstrable
speci c g against wasp enom. Granuloma annulare and
subcutaneous granulomatous reactions ha e been reported.
Contact allergy to propolis is common among bee eepers. Stritzke AI, et al: Age-dependent sting recurrence and outcome in
Treatment o local reactions consists o immediate applica immunotherapy-treated children with anaphylaxis to Hymenoptera
tion o ice pac s or topical anesthetics. Chronic reaction sites venom. Clin Exp Allergy 2013; 43(8):950–955.
may be in ected with triamcinolone suspension diluted to
mg mL with lidocaine. ral prednisone may be re uired
or se ere local reactions. Order Siphonaptera
or se ere systemic reactions . mL o epinephrine (
a ueous solution) is in ected intramuscularly. This may need leas are wingless with highly de eloped legs or umping.
to be repeated a ter min. Susceptible persons should carry They are blood suc ing parasites in esting most warm
a source o in ectable epinephrine. Corticosteroids and epi blooded animals. leas are important ectors o plague
nephrine may be re uired or se eral days a ter se ere reac endemic typhus brucellosis melioidosis and erysipeloid.
tions. yposensiti ation by means o enom immunotherapy
can reduce the ris o anaphyla is in people at ris . Those at Pulicosis (flea bites)
ris should be e aluated by an allergist. Rush desensiti ation
regimens e ist and ultrarush sublingual immunotherapy The species o ea that most re uently attac humans are the
loo s promising. cat ea (Ctenocephali es felis ig. ) human ea Pulex
irritans dog ea Ctenocephali es canis and oriental rat ea
Ants ( enops lla cheopis ig. ). The stic tight ea Echi noph
aga gallinacea mouse ea Leptops lla segnis and chic en ea
The sting o most ants is pain ul but that o re ants (Solenopsis Ceratoph llus gallinae are sometimes implicated.
invicta S s geminata or S richteri) is especially pain ul. ire leas are small brown insects about . mm long at rom
ants are icious and will produce many burning pain ul side to side with long hind legs. They slip into clothing or
stings within seconds i their mound is disturbed. The sting ump acti ely when disturbed. They bite about the legs and
causes intense pain and whealing. Later an intensely pruritic waist and may be troublesome in houses where there are dogs
sterile pustule de elops at the site ( ig. ). Anaphyla is or cats. The lesions are o ten grouped and may be arranged in
sei ures and mononeuropathy ha e been reported. The sting ig ag lines. ypersensiti ity reactions may appear as papular
o har ester ants and soldier ants may produce similar urticaria nodules or bullae. Camphor and menthol prepara
reactions. Treatment options are similar to those or espid tions topical corticosteroids and topical anesthetics can be o
stings. bene t.
443

20 Vectors of disease
enops lla cheopis and enops lla bra iliensis are ectors o
plague and endemic typhus. The cat ea Ctenocephali es felis
Parasitic Infestations, Stings, and Bites
is the ector or ic ettsia felis a cause o endemic typhus.
Plague and tularemia are transmitted by the s uirrel ea
Diamanus montanus Se eral species o ea are intermediate
hosts o the dog tapeworm and rat tapeworm which may be
an incidental parasite o humans.
Tungiasis
unga penetrans is also nown as nigua the chigoe sand ea
or igger. t is a reddish brown ea about mm long. t resides
in the Caribbean e uatorial A rica Central and South America
ndia and Pa istan. t was rst reported in crewmen who
sailed with Christopher Columbus.
The emale chigoe burrows into the s in o ten ad acent to a
toenail where she may be seen with the aid o dermoscopy.
nce embedded the ea becomes impregnated and o a
de elop. S in lesions are pruritic swellings the si e o a small
pea ( ig. ). These may occur on the an les eet and soles
as well as the anogenital areas. The lesions become e tremely
pain ul and secondarily in ected. Wearing open shoes and the
presence o pigs in the area are ris actors or disease.
Curettage or e cision o the burrows is recommended.
Topical i ermectin metri onate or thiabenda ole can be used
Fig. 20-40 Oriental rat flea.
Fig. 20-41 Tungiasis.
444
tahir99 - UnitedVRG
and oral thiabenda ole mg g day has been e ecti e in
hea ily in ested patients. Antibiotics should be used or the
secondary in ection and tetanus prophyla is gi en. These
lesions can be pre ented by the wearing o shoes. n ested
ground and buildings may be disin ected with insecticides
and growth inhibitors.
Criado PR, et al: Tungiasis under dermoscopy: in vivo and ex vivo
examination of the cutaneous infestation due to Tunga penetrans. An
Bras Dermatol 2013; 88(4):649–651.
Karunamoorthi K: Tungiasis: a neglected epidermal parasitic skin
disease of marginalized populations—a call for global science and
policy. Parasitol Res 2013; 112(10):3635–3643.
Thielecke M, et al: The fate of the embedded virgin sand flea Tunga
penetrans: hypothesis, self-experimentation and photographic
sequence. Travel Med Infect Dis 2013; 11(6):440–443.
CLASS ARACHNIDA
Arachnida includes the tic s mites spiders and scorpions.
Adult and nymph stages o arachnids ha e our pairs o legs
and lar al orms ha e si legs. Their bodies consist o cepha
lothora and abdomen in contrast to insects which ha e three
body segments.
Order Acarina
Tick bite
Se eral arieties o the amily odidae (hard tic s) and Argas
idae (so t tic s) will attac human s in but only hard tic s
remain attached. n the nited States Ornitho oros hermsi O
turicata and O par eri transmit tic borne relapsing e er. The
wood tic Dermacentor an ersoni is an important disease
ector in western states. t carries Roc y ountain spotted
e er tularemia ehrlichiosis and Colorado tic e er. The dog
tic (Dermacentor variabilis ig. ) is pre alent in the
eastern .S. states and is the most common ector o Roc y
ountain spotted e er. t also carries tularemia. Dermacentor
marginatus transmits tic borne lymphadenopathy in Spain.
The brown dog tic hipicephalus sanguineus is a ector o
Roc y ountain spotted e er tularemia and boutonneuse
e er. The lone star tic ( mbl omma americanum ig. )
carries Roc y ountain spotted e er tularemia and human
monocytic ehrlichiosis. xo es ricinus in urope and scapularis
and paci cus in the nited States transmit orrelia burg orferi
the cause o Lyme disease. xo es tic s also transmit human
granulocytic ehrlichiosis and babesiosis. The ris o disease
transmission increases with the duration o tic attachment.
n ortunately tic s o ten attach in areas where they are not
noticed allowing them to engorge and transmit disease.
Fig. 20-42
Dermacentor variabilis.
 Fig. 20-43 Lone star
tick.
Fig. 20-44 Tick attached to skin. (Courtesy of Dr. Don Adler.)
The emale hard tic attaches itsel to the s in by stic ing its
proboscis into the esh to suc blood rom the super cial
essels. The insertion o the hypostome is generally unnoticed
by the sub ect. The attached tic may be mista en by the
patient or a new mole ( ig. ). The parasite slowly
becomes engorged and then alls o . During this time which
may last or days the patient may ha e e er chills
headache abdominal pain and omiting (tic bite pyre ia).
Remo al o the engorged tic causes a subsidence o the
general symptoms in h.
The bites may be ollowed by small se erely pruritic brous
nodules (tic bite granulomas) that persist or months or by
pruritic circinate and arci orm locali ed erythemas that may
also persist o er months. Tic bite induced alopecia has been
reported and both mbl omma americanum and xo es tic
bites are associated with the de elopment o g antibodies to
the carbohydrate galactose α galactose causing delayed
urticaria and anaphyla is a ter consumption o red meat.
istologically bite reactions demonstrate wedge shaped
necrosis with a neutrophilic in ltrate and ascular thrombosis
or hemorrhage. Chronic bite reactions o ten ha e atypical
CD + lymphocytes and eosinophils. Pseudolymphomas and
immunocytomas may occur.
Tick paralysis
Tic paralysis most o ten a ects children and carries a mortal
ity rate o about . laccid paralysis begins in the legs then
the arms and nally the nec resembling Landry Guillain
Barr syndrome. Bulbar paralysis dysarthria dysphagia and
death rom respiratory ailure may occur. Prompt reco ery
occurs i the tic is ound and remo ed be ore the terminal
stage. Dermacentor tic s in orth America and xo es tic s in
Class arachnida
Fig. 20-45 Scabies.
Fig. 20-46 Scabies.
Australia are the most important causes o tic paralysis.
Because Dermacentor tic s typically attach to the scalp they
may go unnoticed.
Commins SP, et al: Tick bites and red meat allergy. Curr Opin Allergy
Clin Immunol 2013; 13(4):354–359.
Garza Ocañas L, et al: Images in clinical medicine: cutaneous
loxoscelism. N Engl J Med 2013; 369(5):e6.
Hamsten C, et al: Identification of galactose-α-1,3-galactose in the
gastrointestinal tract of the tick Ixodes ricinus: possible relationship
with red meat allergy. Allergy 2013; 68(4):549–552.
Kennedy JL, et al: Galactose-α-1,3-galactose and delayed anaphylaxis,
angioedema, and urticaria in children. Pediatrics 2013;
131(5):e1545–e1552.
Saleh H, et al: Anaphylactic reactions to oligosaccharides in red meat:
a syndrome in evolution. Clin Mol Allergy 2012; 10(1):5.
Wolver SE, et al: A peculiar cause of anaphylaxis: no more steak? The
journey to discovery of a newly recognized allergy to galactose-α-1,3-
galactose found in mammalian meat. J Gen Intern Med 2013;
28(2):322–325.
Mites
Scabies
Sarcoptes scabiei the itch mite is an o al entrally attened
mite with dorsal spines. The ertili ed emale burrows into the
stratum corneum and deposits her eggs. Scabies is character
i ed by pruritic papular lesions e coriations and burrows.
Sites o predilection include the nger webs ( ig. ) wrists
a illae ( ig. ) areolae umbilicus lower abdomen geni
tals ( ig. ) and buttoc s ( ig. ). An imaginary circle
intersecting the main sites o in ol ement a illae elbow
445

20
Parasitic Infestations, Stings, and Bites
Fig. 20-47 Scabies. (Courtesy of Dr. Shyam Verma.)
Fig. 20-48 Scabies.
e ures wrists and hands and crotch has long been called
the circle o ebra. n adults the scalp and ace are usually
spared but in in ants lesions are usually present o er the
entire cutaneous sur ace. The burrows appear as slightly ele
ated grayish tortuous lines in the s in. A esicle or pustule
containing the mite may be noted at the end o the burrow
especially in in ants and children. To identi y burrows uic ly
a drop o ndia in or gentian iolet can be applied to the
in ested area then remo ed with alcohol. Thin threadli e
burrows retain the in .
The eruption aries considerably depending on the length
o in estation pre ious sensiti ation and prior treatment. t
also aries with climate and the host s immunologic status.
Licheni cation impetigo and urunculosis may be present.
Bullous lesions may contain many eosinophils resembling
446
tahir99 - UnitedVRG
Fig. 20-49 Scabies.
bullous pemphigoid. Positi e immuno uorescent ndings
may also be noted. Scabies has also been reported to trigger
epidermolysis bullosa ( B) pruriginosa a ariant o dystro
phic B. Scabies may also resemble Langerhans cell histiocy
tosis clinically and histologically. isdiagnosis has led to
systemic treatment with to ic agents.
Dull red nodules may appear during acti e scabies; these
are mm in diameter may or may not itch and persist on
the scrotum penis ( ig. ) and ul a. ntralesional ste
roids tar or e cision are methods o treatment or this trouble
some condition termed nodular scabies. istologically the
lesions may suggest lymphoma.
Crusted scabies ( orwegian or hyper eratotic scabies) is
ound in immunocompromised or debilitated patients includ
ing those with neurologic disorders Down syndrome organ
transplants gra t ersus host disease adult T cell leu emia
ansen s disease or A DS. n these patients the in estation
assumes a hea ily scaling and crusted appearance. Crusts and
scales teem with mites and the ace is in ol ed especially the
scalp. tching may be slight. Psoriasis li e scaling is noted
around and under the nails. The tips o the ngers are swollen
and crusted and the nails distorted. Se ere ssuring and
scaling o the genitalia and buttoc s may be present. Pressure
bearing areas are the sites o predilection or the hea y era
totic lesions in which the mites may abound.
Scabies is usually contracted by close personal contact
although it may also be transmitted by contaminated linens
and clothing. Screening or other STDs is appropriate. Sensiti
ation begins about wee s a ter onset o in ection. During
this time the parasites may be on the s in and may burrow
into it without causing pruritus or discom ort. Se ere itching
begins with sensiti ation o the host. n rein ections itching
begins within days and the reaction may be clinically more
intense. The itching is most intense at night whereas during
the daytime the pruritus is tolerable but persistent. The erup
tion does not in ol e the ace or scalp in adults. n women
itching o the nipples associated with a generali ed pruritic
papular eruption is characteristic; in men itchy papules on the
scrotum and penis are e ually typical. When more than one
member o the amily has pruritus scabies should be sus
pected. Whene er possible howe er it is ad isable to identi y
the mite because a diagnosis o scabies usually re uires treat
ment o close physical contacts in addition to the patient.
Because scabies cannot always be e cluded by e amination
treatment on presumption o scabies is sometimes necessary.

Fig. 20-50 Scabies mite, ova, and feces.
Positi e diagnosis is made only by the demonstration o the
mite under the microscope ( ig. ). A burrow is sought
and position o the mite determined. A surgical blade or sterile
needle is used to remo e the parasite. A drop o mineral or
immersion oil can be placed on a lesion and gently scraped
away with the epidermis beneath it. The ma ority o mites are
ound on the hands and wrists less re uently (in decreasing
order) at the elbows genitalia buttoc s and a illae. Children
ha e o ten gathered mites and o a under the nails when
scratching. A blunt curette can be used to gather material rom
under the nails or e amination. onin asi e techni ues
include dermoscopy and digital photography.
Permethrin cream ( limite) is the most widely used and
most e ecti e medication or scabies. t is a synthetic pyre
throid that is lethal to mites and has low to icity or humans
although some concern has been raised about the association
between topical insecticides and lymphoma. Lindane
(γ ben ene he achloride) is also e ecti e with a low incidence
o ad erse e ects when used properly. Because o the a ail
ability o less to ic agents lindane is rarely used as a rst line
agent and is banned in some locations. n much o the world
ben yl ben oate and precipitated sul ur in white petrola
tum are used to treat scabies. inospora cor ifolia lotion appears
promising. The scabicide should be thoroughly rubbed into
the s in rom the nec to the eet with particular attention
gi en to the creases perianal areas umbilicus and ree nail
edge and olds. t is washed o h later. Clothing and bed
linen are changed and laundered thoroughly. Crotamiton
( ura ) has a lower cure rate than other a ailable agents.
When used it should be applied on e successi e nights and
washed o h a ter the last use.
ermectin has been used to control onchocerciasis since
and is mar eted in the nited States or the treatment o
strongyloidiasis. umerous publications attest to its e cacy
in treating scabies. t is supplied as mg and mg pills and
is usually gi en at a dose o μg g. Although an oral treat
ment is con enient it may not be any more e ecti e than
topical therapy. n the crusted type o scabies i ermectin
should be used in con unction with a topical agent. t may
need to be repeated two or three times at inter als o
wee s. ermectin appears to ha e a good margin o sa ety
although neuroto icity may be possible. Topical i ermectin
has been shown to be e ecti e as well.
ndi iduals in close contact with the patient should be
treated. Scabies in long term health care acilities is an increas
ing problem. Delays in treating close contacts may result in
large numbers o persons re uiring treatment.
Fig. 20-51
Nonburrowing cat
mite (Cheyletiella
blakei).
Class arachnida
Animal scabies
oonotic scabies and scab mites may a ect humans who come
in close contact with the animal. The reaction resembles scabies
but typically runs a sel limited course. Burrows are usually
absent.
Other mite diseases
Demodex mites
Demo ex folliculorum is a ermi orm mite that inhabits the pilo
sebaceous units o the nose orehead chin and scalp. The mite
has a attened head our pairs o short pegli e legs and an
elongated abdomen. Demo ex brevis is shorter and more o ten
ound on the trun .
n dogs the lesions o demodectic mange contain numerous
mites. n humans there are con incing reports o demodectic
blepharitis demodectic olliculitis demodectic abscess and
demodectic alopecia that respond to eradication o the mites.
Some rosacea li e lesions may also be caused by Demo ex
Treatment o the eruptions in which Demo ex has been impli
cated consists o applying permethrin sul ur lindane ben yl
ben oate or ben oyl pero ide. ral i ermectin and metroni
da ole ha e also been used.
Cheyletiella dermatitis
Che letiella asguri Che letiella bla ei ( ig. ) and Che leti
ella parasitovorax are three species o nonburrowing mite that
are parasitic on dogs cats and rabbits respecti ely where
they present as wal ing dandru . They may bite humans
when there is close contact with the animals producing an
itchy dermatitis resembling scabies or immunobullous disease.
The mites are similar in diameter to Sarcoptes scabiei but are
elongated and ha e prominent anterior hoo ed palps. They
may be ound by brushing the animal s hair o er a dar piece
o paper. The brushings can be placed in alcohol where the
scales and hair sin while the mites oat. The pet should be
treated by a uali ed eterinarian.
Chigger bite
The trombiculid mites are nown as chiggers mower s mites
or red bugs. n orth America rombicula Eutrombicula
alfre ugesi attac s humans and animals. n urope the har est
mite eotrombicula autumnalis is a common nuisance. Attac s
occur chie y during the summer and all when indi iduals
ha e more re uent contact with mite in ested grass and
bushes. The lesions occur chie y on the legs ( ig. ) and
at the belt line and other sites where clothing causes constric
tion. Penile lesions are common in males. Lesions generally
consist o se erely pruritic hemorrhagic puncta surrounded
by red swellings. n the an les intensely pruritic grouped
e coriated papules are noted. Se eral arieties o trombiculid
mite in ast Asia and the South Paci c are ectors o scrub
typhus (tsutsugamushi e er).
447

20 Gamasoidosis
Gamasoidosis is caused by two genera o mites Ornithon ssus
and Derman ssus and occurs a ter contact with canaries
pigeons and poultry. Because o the association with pigeons
Parasitic Infestations, Stings, and Bites
the dermatitis is common among urban dwellers and because
o the small si e o the mites and their tendency to lea e the
host a ter biting the diagnosis may not be considered. n pet
stores bird mites may be transmitted to rodents with human
disease related to contact with a gerbil or hamster. The mites
are acti e at night and hide during the day. The resulting
dermatosis occurs chie y on the hands and arms as itchy
macules papules or esicles. Any body area may be attac ed
and common additional sites are the groin areolae umbilicus
ace and scalp. The mites may wander rom bird nests as soon
as the young birds begin to y and they may in est terrace
cushions and patio urniture. The tropical owl mite (Ornitho
n ssus bursa and the red chic en mite Derman ssus gallina
are the ma or culprits. Derman ssus mites may carry Er sipelo
thrix rhusiopathiae
Grocer’s itch
Grocer s itch is a pruritic dermatitis o the orearms with
occasional in ammatory and urticarial papules on the trun .
t results rom the handling o gs dates and prunes when it
is caused by Carpogl phus passularum or rom e posure to the
cheese mite l ciphagus omesticus This must be distin
guished rom grocer s ec ema which is caused by sensiti a
tion to our sugar cinnamon chocolate and similar items.
Grain itch
Grain itch is also nown as straw itch barley itch mattress
itch and prairie itch. Causati e mites include P emotes tritici
P emotes ventricosus Che letus malaccensis and rophagus
putrescentiae (copra itch mite). Those mainly a ected are har
esters o wheat hay barley oats and other cereals or arm
hands and pac ers who ha e contact with straw. Grain itch
has a typical lesion consisting o an urticarial papule on which
there is a small esicle. There is intense pruritus with lesions
occurring predominantly on the trun . re uently an initial
central hemorrhagic punctum rapidly turns into an ecchymo
sis with hemosiderin pigmentation.
Other mite-related dermatitides
Dermatophagoi es pteron ssinus and D farinae are dust mites
implicated in atopic diseases. Lepi ogl phus estructor is the
hay mite. There ha e been outbrea s o P emotes bo lei bites
in homes umigated or termites. Although mites do not
Fig. 20-52 Chigger bites.
448
tahir99 - UnitedVRG
appear capable o sur i al when orced to share an en iron
ment with termites they thri e in locations where there are
termite carcasses. Vanillism is a dermatitis caused by carus
siro and occurs in wor ers handling anilla pods. Copra itch
occurs on persons handling copra who are sub ect to ropha
gus longior mite bites. Coolie itch is ound on tea plantations
in ndia and is caused by hi ogl phus parasiticus it causes sore
eet. Rat mite itch caused by Ornithon ssus bacoti the tropical
rat mite may result in an intensely pruritic dermatitis. This
papulo esicular urticarial eruption is seen in wor ers in stores
actories warehouses and stoc yards. The rat mite may trans
mit endemic typhus ric ettsialpo e uine encephalitis tula
remia plague and relapsing e er. eather pillow dermatitis
is a pruritic papular dermatitis traced to the Psoroptid carpet
mite Dermatophagoi es scheremetews i which may in est
eather pillows. The house mouse mite llo erman ssus (Lipo
n ssoi es) sanguineus is the ector o ic ettsia a ari the caus
ati e organism o ric ettsialpo .
Alasaad S, et al: Advances in studies of disease-navigating webs:
Sarcoptes scabiei as a case study. Parasit Vectors 2014; 7:16.
Elston CA, et al: Treatment of common skin infections and infestations
during pregnancy. Dermatol Ther 2013; 26(4):312–320.
Engelman D, et al: Opportunities to investigate the effects of ivermectin
mass drug administration on scabies. Parasit Vectors 2013; 6:106.
FitzGerald D, et al: Interventions for preventing the spread of infestation
in close contacts of people with scabies. Cochrane Database Syst Rev
2014 Feb 24;2:CD009943.
Ito T: Mazzotti reaction with eosinophilia after undergoing oral
ivermectin for scabies. J Dermatol 2013; 40(9):776–777.
Kim J, et al: Epidermolysis bullosa pruriginosa triggered by scabies
infestation. J Dermatol 2013; 40(7):562–563.
Shimose L, et al: Diagnosis, prevention, and treatment of scabies. Curr
Infect Dis Rep 2013; 15(5):426–431.
Suwandhi P, Dharmarajan TS: Scabies in the nursing home. Curr Infect
Dis Rep 2015; 17:453.
Order Scorpionidae
Scorpion sting
Scorpions are di erent rom other arachnids in that they ha e
an elongated abdomen ending in a stinger ( ig. ). They
also ha e a cephalothora our pairs o legs pincers and
mouth pincers. Two poison glands in the bac o the abdomen
empty into the stinger. Scorpions are ound worldwide espe
cially in the tropics. They are nocturnal and hide during the
daytime under tabletops and in closets shoes and olded
blan ets. Ground scorpions may burrow into gra el and
children s sandbo es. Buthid scorpions include the most en
omous species o medical importance. mportant scorpions
Fig. 20-53 Common
Centruroides scorpion.
include it us serrulatus ound in Bra il; uthotus tamulus in Fig. 20-54 Black
ndia; Leiurus uin uestriatus and n roctonus crassicau a in widow.
orth A rica and southwest Asia; and Centruroi es suffusus
in e ico. Centruroi es exilicau a and C sculpturatus are the
most to ic scorpions in the nited States. aejovis scorpions in

Class arachnida
the southeastern nited States ha e been reported to cause
brown recluse li e dermonecrotic reactions.
Scorpions sting only by accident or in sel de ense. The
enom causes pain paresthesia and ariable swelling at the
site. The sting o the gyptian scorpion L uin uestriatus has
a mortality rate o in children. The neuroto ic enom may
produce numbness at the sting site laryngeal edema pro use
sweating and sali ation cyanosis nausea and paresthesia o
the tongue. There is minimal or no isible change at the sting
site and some studies ha e con rmed the typical absence o
histologic in ammation. Death may occur rom cardiac or Fig. 20-55 Brown
respiratory ailure especially in children. Renal and hepatic recluse spider.
to icity may also occur.
Treatment depends on the species and to ic symptoms.
Antiarrhythmics antiadrenergic agents asodilators and
calcium channel bloc ers may be re uired. Anti enin is a ail
able or many species o scorpion.
Fialho EM, et al: Immune cells recruitment and activation by Tityus
serrulatus scorpion venom. Toxicon 2011; 58(6-7):480–485.

Order Arachnidae
Arachnidism
Spiders are pre alent throughout the world. ost are bene cial
to humans trapping many insects but a ew species are danger
ous. any spider enoms are not well characteri ed and in
most cases o en enomation the responsible spider is ne er
identi ed. The Bra ilian armed spider Phoneutria nigriventer
is well characteri ed. ts enom contains neuroto ins that may
be atal in children. Various reactions to spider bites ha e been
reported including dermonecrotic reactions systemic to icity
and acute generali ed e anthematous pustulosis.
Latrodectism
The arious species o Latro ectus ha e similar to ins and
cause similar reactions in humans. The blac widow spider
Latro ectus mactans is o chie concern in the continental
nited States. t may also be ound in the Caribbean region.
Blac widows are web building spiders and are typically
ound in woodpiles and under outhouse seats. Their enom
may be less potent than that o related brown widow spiders
but blac widows in ect more enom. Latro ectus curacaviensis
is nati e to South America and Australia and ew ealand
ha e related red bac spiders Latro ectus mactans hasselti Lat
ro ectus in istinctus is ound in A rica and the brown widow
Latro ectus geometricus is nati e to southern A rica and
adagascar.
The emale L mactans spider is mm long and shiny blac
with a red hourglass shaped mar ing on its abdomen ( ig.
). The legs are long with a spread o up to cm. The
blac widow spider is not aggressi e and bites only when
disturbed. Se ere pain usually de elops within a ew minutes
and spreads throughout the e tremities and trun . Within
a ew hours the ictim may ha e chills omiting iolent
cramps delirium or partial paralysis spasms and abdominal
rigidity. The abdominal pains are re uently most se ere and
may be mista en or appendicitis colic or ood poisoning.
To ic morbilli orm erythema may occur. yocarditis has also
been reported.
Anti enin is indicated or se ere symptoms o en enom
ation. Ben odia epines reduce the associated tetany.
Loxoscelism
The brown recluse spider Loxosceles reclusa is the ma or cause
o necrotic arachnidism in the nited States ( ig. ). t is
most common in the lower idwest and Southwest. This
reclusi e spider may be identi ed by a dar iolin shaped
mar ing o er the cephalothora and three sets o eyes rather
than the usual our. t is light brown and about cm long with
a small body and long delicate legs. t is ound in storage
closets basements and cupboards and among clothing. ut
doors it has been ound in woodpiles in grass on roc y blu s
and in barns. t stings in sel de ense and is not an aggressi e
spider. The incidence o brown recluse bites is grossly o eres
timated. Loxosceles rufescens L eserta and L ari onica cause
lesser degrees o s in necrosis. Loxosceles laeta L interme ia L
gaucho and L similis are ound in Latin America and produce
changes similar to those o L reclusa The enom contains a
phospholipase en yme sphingomyelinase D which is the
ma or to in. yaluronidase contributes to a gra ity dependent
spread o the necrotic lesions.
n the locali ed type o reaction nown as necrotic cutane
ous lo oscelism e tensi e local necrosis de elops ( ig. ).
A pain ul se ere edematous reaction occurs within the rst
h with de elopment o a bulla with surrounding ones o
erythema and ischemia. n about wee the central portion
becomes dar demarcated and gangrenous. Systemic lo os
celism is rare but may be associated with minor appearing bite
reactions. Systemic to ic symptoms are associated with dis
seminated intra ascular coagulation.
Treatment
Treatment o lo oscelism consists o rest ice and ele ation.
Tetanus to oid should be gi en i the patient has not recei ed
449

20
Parasitic Infestations, Stings, and Bites
Fig. 20-56 Brown recluse spider bite.
the immuni ation within years. Some data suggest a trend
toward better outcomes with in ection o intralesional triam
cinolone with anecdotal reports o the in ection site being
spared necrosis but the areas abo e and below the site showing
necrosis. Antibiotics and conser ati e debridement may be
needed or necrotic wounds. Dapsone has been used but some
studies show that it is no better than placebo; dapsone also
may be to ic especially in the setting o enom induced
hemolysis. Colchicine has also been disappointing in animal
models but tetracyclines show some promise and deser e
urther study.
Funnel web spiders
unnel web spiders include egenaria agrestis (hobo spider or
aggressi e house spider o Paci c orthwest) and trax robus
tus (Sydney unnel web spider o Australia). Australian unnel
web spiders are dangerous but anti enin is a ailable.
Tarantulas (lycosidae: theraphosidae)
Tarantulas are large hairy hunting spiders. American species
ha e urticating hairs that produce cutaneous wheal and are
reactions and embed in the cornea causing ophthalmia nodosa.
Chatzaki M, et al: Cutaneous loxoscelism caused by Loxosceles similis
venom and neutralization capacity of its specific antivenom. Toxicon
2012; 60(1):21–30.
Garza Ocañas L, et al: Cutaneous loxoscelism. N Engl J Med 2013;
369(5):e6.
Isbister GK, et al: Spider bite. Lancet 2011; 378(9808):2039–2047.
Malaque CM, et al: Clinical picture and laboratorial evaluation in human
loxoscelism. Toxicon 2011; 58(8):664–671.
PHYLUM CHORDATA
Stingray injury
The two stingray amilies Dasyatidae and yliobatidae are
among the most enomous sh nown to humans. Attac s
generally occur as a result o an unwary ictim stepping on a
partially buried stingray. A puncture type wound occurs
about the an les or eet and later ulcerates. Sharp shooting
pain de elops immediately with edema and cyanosis. Symp
toms o shoc may occur. istologically granulomatous der
matitis and panniculitis with necrosis ha e been reported.
Persons wading in shallow muddy waters where stingrays
may be ound should shu e their eet through the mud to
righten the sh away. Success ul treatment is usually attained
450
tahir99 - UnitedVRG
by immersing the in ured part in hot water or min. The
water should be as hot as can be tolerated since the enom is
deto i ed by heat. eperidine hydrochloride administered
intra enously or intramuscularly may be necessary. the
ulcer remains unhealed a ter wee s e cision is indicated.
Snakebite
Bites by enomous sna es are a serious problem in some parts
o the world. n the nited States the rattlesna e water (cot
tonmouth) moccasin copperhead and coral sna e are the
enomous sna es most re uently encountered. Patients are
usually young men with o bites on the e tremities most
o ten the hands or arms. n urope o en enomations rom
e otic pets are sna ebites rom rattlesna es cobras mambas
or other enomous sna es. Almost en ymes are ound in
sna e enom most o which are hydrolases. Sna e enom has
e ects on the cardio ascular hematologic respiratory and
ner ous systems. Se ere en enomation may mimic brain death
with loss o other brainstem re e es. Local e ects at the bite
site include the rapid onset o swelling erythema and ecchy
mosis. n more se ere reactions bullae and lymphangitis may
appear. ang mar s are o ten isible and pain is common
e cept with o a e rattlesna e bites. Anti enin is used in
se ere en enomation and antitetanus measures are indicated.
n the eastern nited States copperheads in ict most sna e
bites ollowed by rattlesna es and cottonmouths. ost o these
children can be managed conser ati ely although Crotalidae
anti enin antibiotics and asciotomy may be needed.
Lizard bite
elo erma suspectum the Gila monster is ound chie y in
Ari ona and ew e ico. Another enomous li ard is the
beaded li ard o southwestern e ico elo erma horri um
Bites rom these poisonous li ards may cause paralysis
dyspnea and con ulsions. Systemic to icity usually resol es
spontaneously with supporti e care within or days. Death
is rare. There is no anti enin.
Jarvis HC, et al: Stingray injury to the webspace of the foot.
Orthopedics 2012; 35(5):e762–e765.
Tartar D, et al: Clinical and histopathologic findings in cutaneous sting
ray wounds: a case report. Dermatol Online J 2013; 19(8):19261.
Bonus images for this chapter can be found online at
expertconsult.inklingcom
eFig. 20-1 New World leishmaniasis.
eFig. 20-2 New World leishmaniasis.
eFig. 20-3 New World leishmaniasis.
eFig. 20-4 Leishmaniasis recidivans.
eFig. 20-5 Mucocutaneous leishmaniasis. (Courtesy of James
Fitzpatrick, MD.)
eFig. 20-6 Disseminated cutaneous leishmaniasis.
eFig. 20-7 Cutaneous larva migrans.
eFig. 20-8 Dracunculosis.
eFig. 20-9 Filarial elephantiasis.
eFig. 20-10 Trichinosis.
eFig. 20-11 Engorged bedbugs.
eFig. 20-12 Human flea.
eFig. 20-13 Stick-tight flea.
eFig. 20-14 Rhipicephalus tick, engorged female.
eFig. 20-15 Scabies.
eFig. 20-16 Snakebite.
 Class arachnida
eFig. 20-1 New World leishmaniasis.
eFig. 20-4 Leishmaniasis recidivans.

eFig. 20-2 New World eFig. 20-5

leishmaniasis. Mucocutaneous
leishmaniasis.
(Courtesy of James
Fitzpatrick, MD.)

eFig. 20-3 New World

leishmaniasis.

eFig. 20-6 Disseminated cutaneous leishmaniasis.

450.e1
 eFig. 20-7 Cutaneous eFig. 20-10 Trichinosis.
20 larva migrans.
Parasitic Infestations, Stings, and Bites

eFig. 20-11 Engorged

bedbugs.

eFig. 20-8
Dracunculosis.

eFig. 20-12 Human

flea.
No combs
Single hair
No pleural rod

eFig. 20-13 Stick-tight

flea.

Two hairs
Flattened head
Broad lacinia

eFig. 20-9 Filarial elephantiasis.

450.e2

tahir99 - UnitedVRG
eFig. 20-14
Rhipicephalus tick,
engorged female.

Class arachnida
eFig. 20-16 Snakebite.

eFig. 20-15 Scabies.

450.e3
 Bonus images for this chapter can be found online at
Chronic Blistering Dermatoses
n noninherited chronic blistering ( esicular or bullous) der
matoses the cause o blistering is usually an autoimmune
reaction and the pattern o immuno uorescence is critical in
establishing the diagnosis. sually antibodies are bound in
perilesional and nonbullous lesional s in whereas blistered
s in o ten ails to demonstrate deposits. Lower e tremity s in
should be a oided i possible because it may be prone to
alse negati e reactions.
Salt split s in preparations are use ul in determining the site
o deposition o the autoantibodies. A solution o sodium
chloride ( aCl) predictably splits s in at the le el o the lamina
lucida. Locali ation o immune deposits to the roo or oor o
this split is diagnostically use ul. The identi cation o n serrated
and u serrated patterns o immunoglobulin deposition pro
ides the same in ormation and may ma e salt split s in
immuno uorescence unnecessary in many cases. An n serrated
pattern corresponds to a split abo e the basal lamina whereas
a u serrated pattern corresponds to a sub lamina densa split
(see images on pertConsult). The patterns are best seen in
areas where the basement membrane one (B ) cur es.
mmunoprecipitation en yme lin ed immunosorbent assay
( L SA) and immunoblotting ha e helped to de ne the molec
ular targets o the autoantibodies and ha e re olutioni ed
testing or immunobullous diseases. Data ary concerning the
sensiti ity and speci city o these tests. n the setting o bullous
pemphigoid L SA can produce apparent alse positi e results
at rates o or higher based on non C a antibodies as well
as on anti BP antibodies that bind to the pathogenic C a
domain but do not produce clinical disease and are not associ
ated with positi e indirect immuno uorescent ndings. alse
negati e results also occur and are discussed below.
Transient acantholytic dermatosis (Gro er s disease) is an
idiopathic nonimmune esiculobullous disease that may
mimic the histologic patterns o immunobullous disease but
shows no speci c ndings on direct immuno uorescence
(D ). Speci c dermatoses o pregnancy are discussed under
the di erential diagnosis o herpes gestationis.
The outloo or immunobullous diseases has impro ed since
the introduction o ritu imab intra enous immunoglobulins
and less to ic immunosuppressi e regimens. ral and ocular
in ol ement o ten re uires a multidisciplinary approach.
Arbache ST, et al: Immunofluorescence testing in the diagnosis of
autoimmune blistering diseases: overview of 10-year experience. An
Bras Dermatol 2014; 89:885–889.
Braunstein I, et al: Treatment of dermatologic connective tissue disease
and autoimmune blistering disorders in pregnancy. Dermatol Ther
2013; 26(4):354–363.
Fine JD: Prevalence of autoantibodies to bullous pemphigoid antigens
within the normal population. Arch Dermatol 2010; 146(1):74–75.
Segura S, et al: High-dose intravenous immunoglobulins for the treatment
of autoimmune mucocutaneous blistering diseases: evaluation of its use
in 19 cases. J Am Acad Dermatol 2007; 56(6):960–967.
tahir99 - UnitedVRG
expertconsult.inkling.com
21
PEMPHIGUS VULGARIS
Clinical features
Pemphigus ulgaris (PV) is characteri ed by mucosal erosions
and by thin walled relati ely accid easily ruptured bullae
that appear on apparently normal s in and mucous mem
branes or on erythematous bases ( ig. ). The uid in the
bulla is clear at rst but may become hemorrhagic or e en
seropurulent. The bullae rupture to orm erosions. The
denuded areas soon become partially or totally co ered with
crusts that ha e little or no tendency to heal. When they nally
heal lesions o ten lea e hyperpigmented patches but no
scarring.
sually PV appears rst in the mouth ( o cases; ig.
) or at the site o a burn radiation therapy or other s in
in ury. ther common sites include the groin scalp ace nec
a illae and genitals. i ols y s sign is present (intact epider
mis shearing away rom underlying dermis lea ing a moist
sur ace). The sign is elicited by slight pressure twisting or
rubbing. The bulla spread phenomenon (Asboe ansen
sign) is elicited by pressure on an intact bulla gently orcing
the uid to spread under the ad acent s in.
Short li ed bullae uic ly rupture to in ol e most o the
mucosa with pain ul erosions. The lesions e tend onto the lips
and orm hea y ssured crusts on the ermilion. n ol ement
o the throat produces hoarseness and di culty in swallow
ing. The mouth odor is o ensi e. The esophagus may be
in ol ed and sloughing o its entire lining in the orm o a
cast (esophagitis dissecans super cialis) may occur e en
when the cutaneous disease appears to be well controlled
because mucosa lac s desmoglein and depends entirely on
desmoglein . The con uncti a nasal mucosa agina penis
and anus may also be in ol ed. Chronic lesions may in ol e
the ace scalp ( ig. ) or e ures. Widespread cutaneous
disease may cause death through sepsis or uid and electro
lyte imbalance ( ig. ).
The diagnosis is made by histology immuno uorescence
pattern o perilesional s in or pluc ed hairs indirect immu
no uorescence ( ) testing o serum or L SA testing or
anti desmoglein (Dsg ) and anti Dsg autoantibodies. As in
other autoimmune diseases speci c antibodies may be present
in relati es o patients with pemphigus who do not mani est
signs o disease.
Epidemiology
Pemphigus ulgaris occurs with e ual re uency in men and
women usually in the th and si th decades o li e. t is rare
in young persons. PV occurs more o ten in Jewish people and
those o editerranean descent.
451
21
Chronic Blistering Dermatoses
Fig. 21-1 Pemphigus vulgaris. (Courtesy of Dr. Lawrence Lieblich.)
Fig. 21-2 Oral pemphigus vulgaris.
Fig. 21-3 Chronic pemphigus vulgaris of the scalp.
Etiologic factors
Antibodies in PV are most o ten directed against Dsg . The
presence o antibodies to both Dsg and Dsg correlates with
mucocutaneous disease. autoantibodies are only directed
against Dsg mucosal lesions predominate. Both humoral and
cellular autoimmunity are important in the pathogenesis o
s in lesions. Antibody alone can produce acantholysis without
complement or in ammatory cells. Both gG and gG
452
Fig. 21-4 Pemphigus vulgaris.
autoantibodies to Dsg occur in patients with pemphigus but
some data suggest that the gG antibodies are pathogenic.
Plasminogen acti ator is associated with antibody mediated
acantholysis. n ol ed T cells are usually CD cells that secrete
a T helper type (Th ) li e cyto ine pro le although Th
cells may also be in ol ed in antibody production in chronic
disease. gG is ound in both in ol ed and clinically normal
s in. C deposits are hea ier in acantholytic areas. D may
remain positi e or years a ter clinical remission and con er
sion to negati e predicts sustained remission a ter withdrawal
o therapy. Pemphigus may be associated with myasthenia
gra is and thymoma.
The PV antigen ( D transmembrane desmosomal glyco
protein) shows homology with the cadherin amily o calcium
dependent cell adhesion molecules. With circulating
antibodies can be demonstrated in o patients. Circu
lating intercellular antibodies may also be present in patients
with thermal or actinic burns and in patients with drug erup
tions. These antibodies are not directed against Dsg . They do
not bind to the epidermis in i o and are o ten directed against
AB blood group antigens.
Penicillamine treatment o rheumatoid arthritis has induced
pemphigus most o ten o the oliaceous type. Almost all the
reported cases ha e had a positi e D and more than hal
ha e had a positi e . Penicillamine and captopril may
induce acantholysis in organ e plant cultures in the absence
o autoantibody. The doses responsible or induction o disease
ha e ranged rom to mg day and the drugs were
ta en or an a erage o months be ore the onset o pemphi
gus. A long list o drugs including captopril enalapril penicil
lin thioproline interleu in ( L ) ni edipine piro icam and
ri ampicin has also been reported to induce pemphigus. any
o these contain either a sul hydryl or an amide group. nly
o patients with drug induced pemphigus ha e had
oral lesions. ost disease resol es when the medication is
discontinued but some cases ha e persisted or many months.
any studies ha e indicated a genetic predisposition to
pemphigus and an association with other autoimmune dis
eases. Statistical analysis shows a s ewed distribution o
arious human leu ocyte antigens ( LAs). ost patients are
o LA phenotype DR or DR . n addition an LA D
restriction ragment has been identi ed in many patients with
pemphigus. LA G is associated with pemphigus in Jewish
patients. Thus there may be a genetically inherited suscepti
bility to the disease. Additionally a predisposition to de elop
other autoimmune diseases may occur in relati es o pemphi
gus patients.
Histopathology
The characteristic ndings o PV consist o suprabasilar acan
tholysis with intraepidermal blister ormation. Acantholytic
cells are round and show no intercellular bridges. Regenera
tion o the epidermis occurs and may cause the split to appear
to be higher as cells regenerate beneath the cle t. At least some
areas typically still demonstrate the characteristic tombstone
row o basal eratinocytes underneath the bulla. An early
intact bulla shows the most characteristic histology. Asboe
ansen modi cation o i ols y s test may be used to e tend
the bulla beyond its original margin to where secondary
regenerati e changes ha e not ta en place.
n early disease spongiosis with eosinophils may be noted
in the epidermis in the absence o acantholysis. n the setting
o immunobullous disease spongiosis with eosinophils is
more li ely to represent pemphigoid than pemphigus and
immuno uorescent ndings readily distinguish the two. D
demonstrates a chic en wire pattern o intercellular gG in
perilesional s in or pluc ed hairs. C may also be present. The
staining is uni orm not granular. shows a similar pattern
o staining. Pro one reactions occur so the serum should be
tested at a wide range o dilutions. Positi e tests may be con
rmed with L SA or the antibody.
Treatment
Large scale prospecti e double blinded studies are ew and
the management o PV is based largely on smaller open trials
and clinical e perience. A sur ey o e perienced clinicians
showed that hal used prednisone in doses o mg g day
and hal used higher doses. Ad u ant steroid sparing agents
were re uently employed with almost hal the respondents
reporting the use o a athioprine. Because o its tolerability
and simpler dosing schedule mycophenolate mo etil ( ) agent at a dose o
is o ten used in place o a athioprine. ther agents used less
re uently include cyclophosphamide and methotre ate.
Almost o the clinicians aimed to replace prednisone with
a steroid sparing agent whereas others were content to con
tinue a low dose o prednisone. The sur ey suggests that e en
among the world s e perts there is signi cant ariation in
how this di cult disease is managed. Ritu imab and intra e
nous immune globulin ( V G) therapy ha e produced dra
matic responses in some patients with re ractory disease and
some authorities now consider ritu imab appropriate rst line
therapy or patients with se ere disease.
ost agents used to treat the disease are immunosuppres
si e although the mechanism o action may not merely be
suppression o T cells and antibody production. ethylpred
nisolone can directly bloc pemphigus antibody induced
acantholysis. t also upregulates e pression o the genes encod
ing Dsg and peripla in; increases measurable le els o
cadherin Dsg and Dsg ; and inter eres with phosphoryla
tion o these adhesion molecules. any o these e ects antago
ni e those o pemphigus antibodies. Re ersion o D to
negati e predicts sustained remission a ter withdrawal o
medication. Pluc ed hairs are an alternati e to s in biopsy to
pro ide a specimen or immuno uorescence; the pilar sheath
epithelium o the anagen hair typically demonstrates immu
no uorescence comparable to s in.
Topical treatment
The s in lesions are e tremely pain ul in ad anced cases.
When there are e tensi e raw sur aces prolonged daily baths
are help ul in remo ing the thic ened crusts and reducing the
oul odor. Sil er sul adia ine (Sil adene) widely used or
tahir99 - UnitedVRG
local therapy o burns is an e ecti e topical antimicrobial
agent suitable or treatment o limited disease. Sil er nitrate
impregnated cotton batting manu actured or burn units can
be used in more e tensi e disease. Very locali ed areas can be
treated with sil er nitrate impregnated dressings. Pain ul
Pemphigus vulgaris
ulcerations o the lips and mouth may bene t rom topical
application o a mi ture o e ual parts o simethicone ( aalo )
and eli ir o diphenhydramine hydrochloride (Benadryl) or
iscous lidocaine ( ylocaine) especially be ore meals. The
arious commercial antiseptic mouthwashes are help ul in
alle iating discom ort and malodor. Potent topical corticoste
roids and topical tacrolimus ha e been success ul in some
patients with limited disease. The li elihood o complete
remission is correlated with age o onset and initial mucosal
in ol ement. n ection is a common complication and relates
to se erity o the pemphigus and the presence o diabetes
mellitus.
Systemic therapy
A common method o treatment or se ere PV is to begin with
doses o prednisone ade uate to control the disease. igh
doses o prednisone ( mg) are sometimes needed but
prolonged high doses are associated with signi cant morbid
ity and mortality so ad u ant therapy should be started early.
During the early phase o therapy i prednisone at mg g
day pro es inade uate the drug is usually increased to a split
dose o mg g twice daily. As the course o corticosteroid
therapy is typically longer than initially anticipated it is good
practice to begin itamin D calcium weight bearing e ercise
and bisphosphonate therapy early in the course o treatment.
Common agents include alendronate mg w ; risedronate
mg w or mg mo; ibandronate mg mo; teripara
tide μg d; or oledronic acid mg in usion yearly.
ycophenolate mo etil is usually chosen as a steroid sparing
. g twice daily. Gastrointestinal (G )
intolerance is the most common side e ect and blood counts
must be monitored. the disease does not respond either
plasmapheresis or V G is added to the regimen. A athioprine
is less e pensi e than and is o ten used as an alternati e
when cost is an o erriding issue. A athioprine is best dosed
based on measurement o the patient s thiopurine methyl
trans erase (TP T) le el. ost patients metaboli e the drug
uic ly and may be underdosed i TP T is not measured.
Patients with high le els o the en yme may re uire . mg
g day o a athioprine; patients with midrange le els are
treated with . mg g day. Patients de cient in TP T
may be treated with ery low doses o a athioprine or with a
di erent agent. Allopurinol inter eres with metabolism o a a
thioprine and increased serum le els may lead to to icity.
Patients with re ractory disease may be treated with ritu
imab V G or cyclophosphamide either alone or with plas
mapheresis. Plasmapheresis alone is ollowed by rebound o
antibody production but the rebounding clone o plasma cells
is sensiti ed to the e ects o cytoto ic agents. Both daily cyclo
phosphamide dosing and pulse dosing schedules can be used
alone or in combination with de amethasone. Pulse dosing is
usually gi en with mesna rescue and is associated with less
bladder to icity. Both dosing schedules should be planned
early in the day with igorous hydration to minimi e the ris
o bladder to icity. Blood counts must be monitored closely.
ther ris s o therapy with high doses o corticosteroids and
immunosuppressants include diabetes in ection hyperten
sion and cardiorespiratory disease. All these ris s must be
monitored and all patients must recei e gentle wound care
and uid and electrolyte management. n patients who cannot
tolerate cyclophosphamide chlorambucil has been used but
it is associated with a greater ris o hematologic malignancy.
453
 mmunoadsorption represents a no el approach to therapy
21 that could replace plasmapheresis. n addition to the use o
V G as an ad u ant to con entional therapy it has also been
gi en as monotherapy. nset o action is airly rapid and may
be seen within wee s. There is a trend toward using ritu
Chronic Blistering Dermatoses
imab early in the course o treatment i patients ha e signi
cant disease.
The sooner the diagnosis o PV is established and the sooner
treatment is gi en the more a orable the prognosis. The
therapeutic e ects are estimated by the number o new lesions
per day and the rate o healing o new lesions. n patients with
and Dsg antibodies mucosal disease may still be acti e when
cutaneous disease appears to be in remission. Pemphigus anti
body titers can be per ormed on esophageal substrate watch
ing or a all in titer. a ter wee s o treatment new
blister ormation is not suppressed prednisone dosage may
be increased to mg day. Dosage ad ustments are made
more re uently and aggressi ely in se ere progressi e
disease. Di iding the daily dose will usually result in greater
e cacy but will also result in greater adrenal suppression.
Additionally intra enous pulse therapy with megadose corti
costeroids such as methylprednisolone (Solu edrol) at a
dose o g day o er h repeated daily or days may be
employed or patients unresponsi e to oral doses. ntreated
disease is o ten atal but the clinician should remember that
in treated patients side e ects o therapy are the most common
cause o death. Ad u ant therapy to decrease steroid depen
dence has reduced mortality.
edication is continued until clinical disease is suppressed
and pemphigus antibody disappears rom the serum. nce the
antibody is no longer present a D test is repeated. A nega
ti e D is predicti e o sustained remission a ter withdrawal
o therapy.
mmunosuppressant therapy alone has been reported as a
success ul treatment o patients with early stable PV. a Almugairen N, et al: Assessment of the rate of long-term complete
contraindication to the use o corticosteroids e ists or i
only limited disease is present these may be used as single
agents. n general howe er combined treatment with cortico
steroids is superior in gaining early control o the disease.
De amethasone cyclophosphamide therapy was studied in
patients with PV. onthly pulses consisted o V de a
methasone mg or consecuti e days monthly with V
cyclophosphamide mg on the second day. Daily oral
cyclophosphamide mg and oral tapered courses o oral
corticosteroids were gi en in the inter als between the pulses.
All patients responded. Partial remissions were noted a ter
pulses; pulses were re uired to achie e complete remis
sion. The duration o pulsed therapy correlated with both the
disease se erity and the time to achie e remission. ral cyclo
phosphamide was success ul in o patients who had
ailed therapy with prednisone and an antimetabolite. The
median time to achie e complete remission was . months
and the median duration o treatment was months. Plasma
pheresis was used in nine patients. ematuria de eloped in
e patients and in ections were noted in si . ne patient
de eloped bladder cancer years a ter therapy.
ntramuscular or oral gold is no longer commonly used.
Gold is less e ecti e than immunosuppressi e therapy but its
ad antages include lac o carcinogenicity and in ertility. A
minimum o months is re uired to udge the e ecti eness o
gold therapy. Ritu imab an anti CD monoclonal antibody
has been used success ully but may be associated with serious
in ections and progressi e multi ocal leu oencephalopathy.
tracorporeal photochemotherapy has been used in a ew
patients and dapsone may ha e some alue as a steroid
sparing agent. icotinamide and tetracycline can be tried in
patients with milder disease; in one study this was success ul
in two o si patients but in another only success ul in o
454
patients. Data on the e ecti eness o cyclosporine ha e
been mi ed. tanercept and in i imab ha e been used suc
cess ully in some patients.
PEMPHIGUS VEGETANS
Pemphigus egetans may present as locali ed pla ues in the
scalp or in two classic orms the eumann type which gener
ally begins and ends as typical pemphigus and the allopeau
type which usually remains locali ed. Both types show pseu
doepitheliomatous hyperplasia and the allopeau type is char
acteri ed by eosinophil microabscesses within the epidermis.
Pemphigus egetans may begin with accid bullae that
become erosions and orm ungating egetations or papillo
matous proli erations especially in body olds or on the scalp.
The tongue o ten shows cerebri orm morphologic eatures
early in the course o the disease. At times the lesions tend to
coalesce to orm large patches or to arrange themsel es into
groups or gurate patterns.
The laboratory ndings etiologic actors epidemiology
pathogenesis and treatment o pemphigus egetans are the
same as those or pemphigus ulgaris. Captopril induced
pemphigus egetans has been reported.
Pemphigus egetans must be di erentiated rom other con
ditions characteri ed by pseudoepitheliomatous hyperplasia
and microabscesses including halogenoderma chromoblasto
mycosis blastomycosis granuloma inguinale blastomycosis
li e pyoderma condyloma lata and amebic granulomas. The
allopeau type is distinguished by the presence o eosino
phils and both types by immuno uorescent ndings.
Alexandru A, et al: Direct immunofluorescence on hair follicles:
present and future perspectives. Am J Dermatopathol 2013;
35(4):472–476.
remission off therapy in patients with pemphigus treated with different
regimens including medium- and high-dose corticosteroids. J Am
Acad Dermatol 2013; 69(4):583–588.
Atzmony L, et al: Treatment of pemphigus vulgaris and pemphigus
foliaceus: a systematic review and meta-analysis. Am J Clin Dermatol
2014; 15:503–515.
Kalantari-Dehaghi M, et al: Mechanisms of mitochondrial damage in
keratinocytes by pemphigus vulgaris antibodies. J Biol Chem 2013;
288(23):16916–16925.
Kamran B, et al: Adjuvant rituximab in the treatment of pemphigus
vulgaris: a Phase II clinical trial. Int J Dermatol 2013; 52(7):862–867.
McCarty M, Fivenson D: Two decades of using the combination of
tetracycline derivatives and niacinamide as steroid-sparing agents in
the management of pemphigus: defining a niche for these low toxicity
agents. J Am Acad Dermatol 2014; 71:475–479.
Rao R, et al: Monitoring the disease activity in pemphigus by direct
immunofluorescence of plucked hair: a pilot study. Indian J Dermatol
2013; 58(2):164.
Ruocco E, et al: Pemphigus: associations and management
guidelines—facts and controversies. Clin Dermatol 2013;
31(4):382–390.
Ruocco V, et al: Pemphigus: etiology, pathogenesis, and inducing or
triggering factors—facts and controversies. Clin Dermatol 2013;
31(4):374–381.
Sharma VK, et al: Evaluation of cyclophosphamide pulse therapy as an
adjuvant to oral corticosteroid in the management of pemphigus
vulgaris. Clin Exp Dermatol 2013; 38(6):659–664.
PEMPHIGUS FOLIACEUS
Pemphigus oliaceus (P ) is characteri ed by accid bullae
and locali ed or generali ed e oliation. Antibodies target
Dsg . Lesions start as small accid bullae that rupture almost
as they appear leading to crusting. Below each crust is a moist

Fig. 21-5 Pemphigus foliaceus.
Fig. 21-6 Pemphigus
foliaceus.
sur ace with a tendency to bleed. i ols y s sign may be easily
elicited by rubbing the s in ( ig. ). A ter a time the e olia
ti e characteristics predominate with ew bullae ( ig. ).
Adherent scale crusts may resemble corn a es. A ariant o
pemphigus that has clinical eatures suggesti e o dermatitis
herpeti ormis but has immunologic eatures o pemphigus has
been called herpeti orm pemphigus. ost o these patients
represent a clinical ariant o P with the remainder being
pemphigus ulgaris (PV) patients. A ew ha e also demon
strated desmocollin antibodies.
i ols y s sign is present in P . ral lesions are rarely seen
and then only as super cial erosi e stomatitis. This may be
because Dsg present throughout the epithelium is unaltered
in P and pro ides enough adherence to maintain clinical
integrity. Se eral patients ha e been described whose clinical
picture shi ted rom P to PV or ice ersa with an accompa
nying change in antibody pro le.
ost patients with P are not se erely ill. They complain o
burning pain and pruritus. The lesions may persist or many
years without a ecting general health. P occurs mostly in
adults age but has also been reported in children. The
genders are a ected e ually. Pre alence o P in people o
Jewish heritage is much less than with PV. The drugs listed
under PV more re uently induce P .
tahir99 - UnitedVRG
The principal histologic nding in P consists o acantholy
sis in the upper epidermis usually in the granular layer. The
stratum corneum may be missing entirely or separated rom
the underlying epidermis. ndi idual elongated acantholytic
cells are noted abo e the epidermis or clinging to the under
Endemic pemphigus (fogo selvagem)
side o the stratum corneum. D demonstrates intercellular
gG throughout the epidermis although the deposits may be
somewhat more prominent in the upper epidermis. is posi
ti e in most patients although pro one reactions occur and a
wide range o dilutions should be tested. A sensiti e and spe
ci c L SA or detecting antibodies to Dsg is now a ailable
to con rm positi e results.
Patients with a distinct clinical picture o P or PV may ha e
a mi o antibodies. Western blot has shown Dsg in about
o P patients and o PV patients. L SA has shown
anti Dsg antibodies in up to o P patients and o
PV patients. n one study antibodies to Dsg were detected in
o patients with P and ogo sel agem who had only
cutaneous disease. The antibody was capable o producing
disease in laboratory animals suggesting it was pathogenic in
the P patients. There ore L SA studies must always be
interpreted in the conte t o clinical histologic and immuno
uorescent ndings. n PV Dsg mediates mucosal disease
and cutaneous disease is associated with antibodies to Dsg .
A shi t to predominantly Dsg antibodies has accompanied a
clinical shi t rom PV to P . Patients ha e also shi ted rom a
pemphigus to a pemphigoid phenotype.
Dsg the antigen in P was rst identi ed by immunopre
cipitation consisting o polypeptides o molecular weight
and ilodaltons ( D). The D molecule is a comple
o the D and D polypeptides. The P antibody binds
to a D glycoprotein e tracted rom normal epidermis.
This glycoprotein is identical to Dsg . The D glycoprotein
is pla oglobulin a desmosomal and adherens unction
associated molecule. Desmogleins are cadherin type adhesion
molecules ound in desmosomes. The terminal e tracellular
domain o Dsg contains the dominant autoimmune epitopes
in both P and PV. Antibodies include both gG and gG
subclasses. gG antibodies appear to be pathogenic in most
patients. n a subset o patients gG autoantibodies are patho
genic. cadherin autoantibodies o ten cross react with Dsg .
Treatment
Treatment o P is similar to that or PV and the two diseases
o ten re uire similarly aggressi e treatment. n act many
clinical trials include patients with both diseases. P patients
are generally less ill and may not need oral corticosteroid
therapy. Dapsone and hydro ychloro uine may be use ul
either alone in mild cases or to reduce the steroid dose le el.
Very mild disease may be treated with topical corticosteroids
or topical calcineurin inhibitors. icotinamide and tetracy
cline may be more e ecti e than in PV. A athioprine
or cyclophosphamide may be needed as in PV. The anti CD
antibody ritu imab the anti L receptor antibody tocili
umab V G and immunoablati e high dose cyclophospha
mide without stem cell rescue ha e been used or re ractory
disease. tanercept has been used and immunoadsorption
with tryptophan lin ed poly inyl alcohol adsorbers or adsorp
tion with plant lectins such as wheat germ agglutinin has
been e ecti e and holds promise as ad u ant therapy.
ENDEMIC PEMPHIGUS (FOGO SELVAGEM)
ndemic pemphigus is ound in tropical regions mostly in
certain interior areas o Bra il and Colombia but also in orth
455
 A rica including Tunisia. i teen percent o cases are amilial.
21
The disease is common in children adolescents and young
adults with about one third o cases occurring be ore age
and two thirds by years. The initial lesions may be accid
bullae but later lesions are ec ematoid psoriasi orm impe
Chronic Blistering Dermatoses
tiginous or seborrheic in appearance. The mid acial areas may
be in ol ed. elanoderma and errucous egetati e lesions
are not unusual and e oliati e dermatitis may occur. The
mucous membranes usually are not in ol ed. i ols y s sign
is present. The disease is o ten seen in those with arthropod
e posure and may be initiated by an in ectious agent possibly
carried by mos uitoes or blac ies.
istologically and immunohistologically ogo sel agem is
identical to P . As with P antibodies to desmosomal cadherins
and cadherin may be present. The anti Dsg autoantibodies
cross react with sand y sali ary LJ antigen. ndemic
pemphigus has also been lin ed to the issing bug riatoma
matogrossensis and to mercury poisoning. Peripheral blood
mononuclear cells rom patients produce more L β than
those rom healthy controls. A strong Th bias is also obser ed.
g anti Dsg antibodies are common in ogo sel agem but
not in other orms o pemphigus.
A distinct subset has been described in a rural area in north
eastern Colombia. This subset di ers rom pre iously
described orms o endemic pemphigus and shares some
immunoreacti ity with paraneoplastic pemphigus. t is not
howe er associated with malignant tumors. Clinically the
disease resembles Senear sher syndrome. A systemic orm
may a ect internal organs and has a poorer prognosis. All
patients appear to ha e antibodies to Dsg . n addition many
sera react with desmopla in en opla in and peripla in.
Direct immuno uorescence is noted in the pilosebaceous unit
ad acent neuro ascular bundles and meibomian glands.
A ew Bra ilian sera also react with pla ins. one o the
Colombian patients sera reacted with Dsg but about hal o
Bra ilian patients sera reacted with Dsg . This area o Colom
bia is a mining region and the population is e posed to high
en ironmental le els o mercuric sul des and selenides; these
compounds ha e been ound in the s in o patients with
endemic pemphigus.
PEMPHIGUS ERYTHEMATOSUS
(SENEAR-USHER SYNDROME)
n Senear sher syndrome the early lesions are circumscribed
patches o erythema and crusting that clinically resemble lupus
erythematosus and are immunopathologically positi e or the
lupus band in o patients. The lesions are erythematous
and thic ly crusted bullous or e en hyper eratotic. These are
usually locali ed on the nose chee s and ears sites re uently
a ected by lupus erythematosus. n addition crusting and
impetiginous lesions appear amid bullae on the scalp chest
and e tremities. n most patients the disease runs an indolent
course. Ce uro ime induced disease has been described.
The histopathology o pemphigus erythematosus is that o
P . D shows gG and complement locali ed in both intercel
lular and B sites. At the dermoepidermal unction (D J)
the deposits are continuous and granular as in lupus. n the
epidermis they resemble those o pemphigus. Antinuclear
antibody is present in low titer in o patients. Patients
ha e demonstrated anti Dsg but not anti Dsg autoantibod
ies. Additional autoantibodies may be directed against bullous
pemphigoid antigen (BP ) and peripla in. Patients o ten
respond to low doses o prednisone and may respond well to
topical corticosteroids and sunscreens. mmunosuppressants
may be needed in se ere cases.
456
Aoki V, et al: Pathogenesis of endemic pemphigus foliaceus. Dermatol
Clin 2011; 29(3):413–418.
Assumpção TC, et al: An insight into the sialotranscriptome of Triatoma
matogrossensis, a kissing bug associated with fogo selvagem in South
America. Am J Trop Med Hyg 2012; 86(6):1005–1014.
Atzmony L, et al: Treatment of pemphigus vulgaris and pemphigus
foliaceus: a systematic review and meta-analysis. Am J Clin Dermatol
2014; 15:503–515.
Baroni A, et al: Cefuroxime-induced pemphigus erythematosus in a
young boy. Clin Exp Dermatol 2009; 34(6):708–710.
Caso F, et al: Refractory pemphigus foliaceus and Behçet’s disease
successfully treated with tocilizumab. Immunol Res 2013;
56(2-3):390–397.
Chatterjee M, et al: Pemphigus foliaceus masquerading as IgA
pemphigus and responding to dapsone. Indian J Dermatol 2012;
57(6):495–497.
Di Zenzo G, et al: Endemic pemphigus foliaceus: towards understanding
autoimmune mechanisms of disease development. J Invest Dermatol
2012; 132(11):2499–2502.
Flores G, et al: IgG autoantibody response against keratinocyte
cadherins in endemic pemphigus foliaceus (fogo selvagem). J Invest
Dermatol 2012; 132(11):2573–2580.
Pérez-Pérez ME, et al: Autoantibodies in Senear-Usher syndrome:
cross-reactivity or multiple autoimmunity? Autoimmune Dis 2012;
2012:296214.
Qian Y, et al: Cutting edge: Brazilian pemphigus foliaceus anti-
desmoglein 1 autoantibodies cross-react with sand fly salivary LJM11
antigen. J Immunol 2012; 189(4):1535–1539.
Robledo MA: Chronic methyl mercury poisoning may trigger endemic
pemphigus foliaceus “fogo selvage.” Med Hypotheses 2012;
78(1):60–66.
PARANEOPLASTIC PEMPHIGUS
n Anhalt et al. described e patients with underlying
neoplasms who presented with pain ul mucosal ulcerations
and polymorphous s in lesions which progressed to blister
ing eruptions on their trun and e tremities. ost patients
described since then ha e had associated neoplasms or Castle
man s disease. The mucosal lesions o paraneoplastic pemphi
gus (P P) may appear lichenoid or more re uently may
resemble Ste ens Johnson syndrome with crusting o the lips
( ig. ). The s in lesions may appear as erythematous
macules lichenoid lesions erythema multi orme ( ) li e
lesions accid bullae and erosions typical o pemphigus or
with tense more deep set bullae.
istologically the lesions demonstrate epidermal acanthol
ysis suprabasal cle t ormation dys eratotic eratinocytes
Fig. 21-7 Paraneoplastic pemphigus.
and acuolar change o the basal epidermis. Biopsies that dem
onstrate both acantholysis and lichenoid change or indi idual
cell necrosis should raise the suspicion o P P.
t should be noted that all orms o pemphigus may be para
neoplastic. owe er the speci c disease dubbed paraneo

Intraepidermal neutrophilic IgA dermatosis

plastic pemphigus has a characteristic clinical appearance as
well as diagnostic immunologic ndings but it is not uni er
sally associated with a neoplasm. D re eals gG and C
deposition in the intercellular spaces o the epithelium.
shows a similar pattern in a wide range o strati ed s uamous
epithelium and transitional epithelium (e.g. rat bladder).
About o cases will be negati e and some may be
alsely positi e. mmunoprecipitation is the de niti e test. t
re eals a comple immune response with autoantibodies
directed against our high molecular weight eratinocyte pro
teins. Antibody targets include desmopla in ( D) en o
pla in ( D) the ma or pla ue protein o hemidesmosomes
BPAg ( D) and peripla in ( D). any cases also
recogni e an additional antigen at D. Antibodies to Dsg
Dsg and anti α macroglobulin li e are re uently present.
L SA has also been used to detect antien opla in and anti
peripla in autoantibodies. n D some cases also demon
strate a linear or granular gG and or C at the B . Detection
o the characteristic immunologic pattern may be delayed and
tests should be repeated i the inde o suspicion is high.
Whereas the dominant epitopes in PV reside in terminal
regions o Dsg epitopes on Dsg in P P are distributed more
broadly through the e tracellular domain. The terminal
domains are still recogni ed more re uently than the
C terminal domains. gG subclasses in P P are gG and gG
dominant contrasting with the gG dominance in PV. There
is a signi cant association in P P with LA DRB allele
( . o those studied). n one study eight o nine atal P P
cases had distincti e cell sur ace antibodies detected in a
beaded pattern by complement indirect immuno uorescence
(C ) tests on mon ey esophagus. Three long term sur i ors
with P P lac ed this pattern suggesting the test may ha e
Fig. 21-8 Intraepidermal neutrophilic IgA dermatosis.
prognostic alue.
A wide ariety o both benign and malignant tumors are
seen in these patients and some ha e no identi able neo
plasm. The most common associations are non odg in scarring occurred when the dermatosis healed. o mucosal
lymphoma chronic lymphocytic leu emia (CLL) Castleman lesions were present and the distal e tremities ace and nec
tumor sarcoma and thymoma. ost reported patients die were spared. either grouping nor symmetry was present.
rom their tumor. thers ha e died rom bronchiolitis istologic ndings consisted o neutrophilic e ocytosis and
obliterans. in some areas neutrophils were arranged linearly at the D J.
Therapy or the bullous dermatoses with prednisone and Later intraepidermal abscesses were ormed; no acantholysis
or immunosuppressi e agents should be balanced with treat was present. D repeatedly showed an intercellular deposi
ment o the tumor. mmunoablati e high dose cyclophospha tion o gA within the epidermis with minimal staining o the
mide without stem cell rescue cyclosporin A plasmapheresis basal layer. o circulating antibodies were ound.
immunoapheresis and ritu imab and alemtu umab (in CLL Since that report many additional patients with intraepider
patients) ha e been success ul in some cases. en with treat mal gA deposition ha e been described. They ha e been clas
ment mortality remains higher than or other immunobullous si ed as belonging to two subsets one closely mimic ing
diseases. pemphigus and the second simulating subcorneal pustular
Arbache ST, et al: Immunofluorescence testing in the diagnosis of dermatosis (SPD). The ormer starts with esicles that become
autoimmune blistering diseases: overview of 10-year experience. An pustular within a ew days enlarge peripherally and rupture
Bras Dermatol 2014; 89:885–889. in the center then orm a crust ( ig. ). Continued periph
Numata S, et al: Anti-α-2-macroglobulin–like-1 autoantibodies are eral esiculation may lead to a owerli e appearance. The
detected frequently and may be pathogenic in paraneoplastic head nec and trun are re uent sites o in ol ement. n
pemphigus. J Invest Dermatol 2013; 133(7):1785–1793. some patients the condition is induced by ultra iolet ( V) A
light. The second subset SPD presents similar to Sneddon
Wil inson disease with serpiginous and annular pustules. A
INTRAEPIDERMAL NEUTROPHILIC pemphigus egetans li e pattern has also been described.
IgA DERMATOSIS Some cases ha e been induced by granulocyte macrophage
colony stimulating actor (G CS ). Some patients ha e had
n u et al. reported the case o an elderly man ha ing associated malignancies and gA pemphigus with P P li e
a chronic bullous dermatosis with uni ue histologic and clinical eatures has been described showing gA antibodies
immunopathologic ndings. Clinically the patient had gener to Dsg and desmocollin as well as gG and gA antibod
ali ed accid bullae which rapidly ruptured and crusted; no ies to the B .
457

tahir99 - UnitedVRG
 istologically intraepidermal bullae with neutrophils some
21 eosinophils and acantholysis are seen. D shows intraepider
mal gA deposition usually throughout the epidermis and
may re eal circulating autoantibody that binds to the same
location. There is e idence that the gA speci city in indi id
Chronic Blistering Dermatoses
erythematous patches and urticarial pla ues ( ig. ) with
a tendency to central clearing. These patches and pla ues may
be present without bullae early in the course o the disease.
Later bullae o ten occur on an urticarial base. Sometimes
targetoid lesions are present.

ual cases may be directed at either Dsg or Dsg . Some patients
ha e concurrent gG intercellular antibodies directed at Dsg
and some ha e a monoclonal gA gammopathy. The antigen
in SPD type gA pemphigus is desmocollin a type o desmo
somal cadherin. Some patients ha e a circulating gA mono
clonal gammopathy. t should be noted that gA antibodies to
Dsg and Dsg may occur in PV P and P P. ndi idual
patients may e press both anti desmocollin and anti Dsg
antibodies.
Therapy with topical corticosteroids may be e ecti e in
patients with mild intraepidermal neutrophilic gA dermato
sis. Dapsone is o ten e ecti e e en at doses as low as mg
day in some patients. ral corticosteroids may be necessary
and some resistant cases ha e re uired immunosuppressi e
agents and plasmapheresis. Colchicine acitretin adalimumab
and isotretinoin ha e been e ecti e in some patients.
Moreno AC, et al: IgA pemphigus: case series with emphasis on
therapeutic response. J Am Acad Dermatol 2014; 70:200–201.
Wolz MM, et al: Pemphigus vegetans variant of IgA pemphigus, a
variant of IgA pemphigus and other autoimmune blistering disorders.
Am J Dermatopathol 2013; 35(3):e53–e56.
Bullous pemphigoid may begin at a locali ed site re uently
on the shins. The disease may also be limited to areas o radia
tion therapy burns or pla ues o psoriasis. BP may remain
locali ed throughout its course or e entuate in generali ed
pemphigoid. Cases o the locali ed disease in which a esicu
lar eruption is limited to the palms or soles (dyshidrosi orm
pemphigoid) are occasionally obser ed. oung girls may
present with locali ed ul ar erosions and ulcers that resem
ble the signs o child abuse ( ig. ). These locali ed ariet
ies ha e been shown to ha e circulating gG antibody which
immunoprecipitates the D BP antigen.
any other ariants o BP ha e been described. A esicular
ariant mani ested by tense small occasionally grouped
blisters is termed esicular pemphigoid. ther patients
mostly women ha e papules and nodules o the scalp and
e tremities with sparing o the mucous membranes in a
Fig. 21-10 Urticarial
bullous pemphigoid.

BULLOUS PEMPHIGOID
Clinical features

Bullous pemphigoid (BP) was described by Le er in .

Clinically BP is characteri ed by large tense subepidermal
bullae with a predilection or the groin a illae trun thighs
( ig. ) and e or sur aces o the orearms. ey eatures
distinguishing BP rom other immunobullous diseases include
subepidermal separation at the D J an in ammatory cell in l
trate that tends to be rich in eosinophils and antibodies directed
against two hemidesmosomal antigens BP and BP .
Antibody detection rates ary by method and many normal
patients will ha e positi e serologic tests but negati e .
A ter the bullae rupture large denuded areas are seen but
the bullae and denuded areas do not tend to increase in si e
as they do in PV. nstead the denuded areas tend to heal Fig. 21-11 Vulvar
spontaneously. n addition to the bullae there o ten are pemphigoid.

Fig. 21-9 Bullous pemphigoid.

458

Fig. 21-12 Childhood bullous pemphigoid.
pattern resembling prurigo nodularis (pemphigoid nodularis).
Cases resembling pemphigus egetans but with gG and C at
the B are occasionally obser ed (pemphigoid egetans).
rythroderma may be present (erythrodermic pemphigoid) or
there may be no bullae at all (nonbullous ariant). The latter
type may present as generali ed pruritus pruritic ec ema or
urticarial eruptions with peripheral eosinophilia. erall inci
dence o oral in ol ement is about but in ol ement o the
pharyn laryn nasal mucosa ul a urethra and eye is rare.
Bullous pemphigoid occurs most re uently in the elderly
population. The age o onset a erages years. BP also
occurs in young children but with clinical and pathologic
ndings similar to those in adults. any o these cases begin
with hand and oot bullae ( ig. ). acial in ol ement may
be somewhat more common in children. n children the course
o disease is usually under year with most cases lasting
months or less.
n patients with lichen planus a bullous eruption similar to
BP may de elop. This condition called lichen planus pemphi
goides is sometimes related to the D antigen the D alse negati e tests are somewhat more common on the lower
antigen or a uni ue D subepidermal antigen. A nonscar
ring eruption with acute onset widespread erosions and
se ere mucous membrane in ol ement resembling to ic epi
dermal necrolysis or PV has been re erred to as anti p
pemphigoid. Linear gG and C are noted at the B . The
D antigen is ound in the lower portion o the lamina
lucida.
Etiologic factors
Circulating B antibodies o the gG class are present in
appro imately o patients with BP. n most cases the
antibodies complement in itro in contrast to pemphigus
antibodies which ail to do so. Complement is acti ated by
both the classical and the alternate pathway. o close correla
tion e ists between the titer o antibodies and clinical disease
acti ity. Passi e trans er mouse models suggest that subepi
dermal blistering is initiated by anti BP antibodies. Blister
ormation in ol es complement acti ation mast cells and
neutrophils. B damage is caused by proteinases and reac
ti e o ygen species released by the in ltrating neutrophils.
The site o gG binding has been locali ed to the lamina
lucida with accentuation near hemidesmosomes. BP antigen
(BPAg ) is synthesi ed by the eratinocyte and is an intra
cytoplasmic hemidesmosomal pla ue protein o D with
disul de lin ed chains. The second BP antigen ( D Relati ely ew controlled trials ha e been per ormed and
BPAg ) is a transmembrane protein with a long C terminal
collagenous domain that pro ects into the e tracellular region
below the hemidesmosome. The antibody to BPAg is the
tahir99 - UnitedVRG
primary pathogenic actor. The noncollagenous ( C) A
domain harbors the ma or epitopes o autoantibodies in BP. A
predominance o the gG subclass has been obser ed in
se eral studies. n addition to this humoral response in ltrat
ing T helper lymphocytes with a mi ed Th Th cyto ine
Bullous pemphigoid
pro le may play a role in blister ormation. Peripheral blood
eosinophilia is present in o pemphigoid patients.
Bullous pemphigoid has occasionally been associated with
other diseases such as diabetes mellitus rheumatoid arthritis
P dermatomyositis ulcerati e colitis myasthenia gra is and
thymoma. Drugs reported to induce BP include penicillamine
urosemide captopril penicillin sul asala ine nalidi ic acid
and enalapril.
Histopathology
The histologic changes o BP are characteri ed by subepider
mal bullae the absence o acantholysis and a super cial
dermal in ltrate containing many eosinophils. The amount o
in ammatory in ltrate aries and indi idual bullae may be
in ltrate poor or in ltrate rich. ten the in ltrate con
tains many eosinophils although neutrophil predominant
cases e ist. Spongiosis with eosinophils occurs more re uently
than in pemphigus. rticarial lesions o ten demonstrate eosin
ophils lined up along the D J.
Atypical presentations are airly common. n one study o
new cases o BP only o biopsy specimens showed
subepidermal blister ormation and only o these had a
predominance o eosinophils in the blister ca ity. n o
patients the biopsy was not particularly suggesti e o BP. D
immunoblot analysis and L SA are critical in establish
ing the diagnosis in such patients.
The D test is more sensiti e than as in pemphigus. n
a positi e test continuous linear (tubular or toothpaste pattern)
immuno uorescence is seen along the B . gG and or C
are best ound in nonbullous lesional or perilesional s in.
e tremities. When using perilesional or nonbullous lesional
s in o the trun a positi e D test is ound in a high percent
age o patients with C most o ten present and gG present in
about o cases. gA and g are occasionally present.
About o patients ha e negati e staining or gG on D
e en though C is present. n some o these patients gG may
be present at subthreshold le els that cannot be detected. Also
the ma or subclass gG shows limited reacti ity with most
commercial antihuman gG con ugates. Double sandwich
antibody immuno uorescence methods ha e been de eloped
that o er greater sensiti ity or gG antibodies.
All histologic eatures present in BP may also be seen in
epidermolysis bullosa ac uisita ( BA). There ore immuno
uorescence testing on salt split s in is sometimes per ormed
to di erentiate BA rom BP. Salt split s in may be replaced
by assessment o u serrated ( BA) and n serrated (BP) immu
noglobulin patterns in D specimens and by serologic testing.
C deposition is almost always present in BP whereas it may
be absent in BA. Type V collagen mapping in BP locali es
to the base o the blister; in BA it stains the roo .
Bullous scabies can also mimic both the histology and the
D ndings o BP.
Treatment
many recommendations or BP therapy are based on e peri
ence and consensus o opinion. sing Cochrane criteria se en
randomi ed controlled trials (RCTs) were identi ed through
459
 enrolling a total o patients. ne comparing pred
21 nisolone . mg g day with prednisolone . mg g
day ound no statistical di erence between the two treat
ments. The same was true o a trial comparing methylpred
nisolone with prednisolone. igher doses o prednisolone
Chronic Blistering Dermatoses
were associated with more se ere side e ects in these studies.
Two trials con rmed that ad u ant therapy with a athioprine
or plasma e change could reduce the re uired corticosteroid
dose. Another trial ailed to con rm the superiority o combi
nation treatment (with either a athioprine or plasma e change)
o er corticosteroid alone and one trial ound no statistically
signi cant di erence between prednisolone and a combina
tion o tetracycline and niacinamide. The steroid treated group
had more side e ects. Another study compared ultrapotent
topical corticosteroid treatment (clobetasol propionate cream
g day) with oral prednisone ( . mg g day). n those
with se ere disease year sur i al was better in the topical
corticosteroid group ( s. ). Disease control at wee s
was also better in the clobetasol than in the prednisone group
( s. ). Side e ects were common in both groups but
more common in the prednisone group ( s. ). Among
those with moderate disease there were no signi cant di er
ences between the two groups.
en in those with airly e tensi e disease topical cortico
steroid treatment should be attempted. Prednisone has long
been the standard approach to oral therapy but the complica
tion rate must be weighed care ully especially in those with
se ere disease. ral therapy with tetracycline mg our
times daily combined with niacinamide mg three times
daily is e ecti e in some patients. ccasionally patients with
BP may respond to tetracycline or nicotinamide alone. Ritu
imab has pro ed e ecti e in adults and has been used in
in ancy. Dapsone is also e ecti e in some patients. mmuno
suppressi e therapy may still be necessary in resistant cases
either in combination with systemic or topical corticosteroids
or as sole therapy. A athioprine and demonstrate similar
e cacy when used as steroid sparing agents and cumulati e
corticosteroid doses are similar. is more e pensi e but is
easier to dose and associated with less to icity. ethotre ate
cyclophosphamide chlorambucil V G and cyclosporine ha e
also pro ed e ecti e in some patients and some data suggest
that outcomes are better with methotre ate than with predni
sone. Low dose oral methotre ate has been shown to induce
apoptosis o tissue eosinophils in patients with BP. The e ec
ti eness o V G is impro ed by the addition o an immunosup
pressi e agent. n e ceptionally se ere cases pulse therapy
with methylprednisolone mg g in mL o bacteriostatic
water o er min day or three doses can be rapidly e ec
ti e. Again some patients may also respond to dapsone as
well as sul apyridine; these agents tend to be more e ecti e in
neutrophil rich BP. ral erythromycin and topical macrolac
tams ha e pro ed e ecti e in some patients.
Double ltration plasmapheresis (D PP) may be more e ec
ti e than con entional plasma e change possibly because it
remo es pathogenic cyto ines. D PP reduces a ariety o cyto
ines including L tumor necrosis actor (T ) α and L .
V G produces aster clearance o antibody titers and may be
help ul in inducing and maintaining remission. Some data
suggest that single chain ariable ragments o anti collagen
V antibodies can inter ere with pathogenic binding o auto
antibodies suggesting that inter erence with antibody binding
may represent an alternati e treatment approach to BP.
Course and prognosis
Bullous pemphigoid is usually sel limited o er years.
This period is generally a year or less in children. Relapse
460
occurs in o patients once therapy is discontinued. The
presence o circulating anti BP
BP
antibodies but not anti
is associated with a statistically increased mortality ris
in the rst year a ter diagnosis. ther ris actors or death
during the rst year include older age higher daily steroid
dosage at discharge low serum albumin and erythrocyte sedi
mentation rate greater than mm h. uch o the morbidity
and mortality now relate to in ection and side e ects o drug
therapy but with impro ements in treatment pemphigoid
patients ha e similar mortality to age matched controls.
Although titers do not always correlate with disease acti
ity L SA measurements o BP C a show better correla
tion. The presence o g autoantibodies to BP correlate
with a more se ere course.
Bakker CV, et al: Bullous pemphigoid as pruritus in the elderly: a
common presentation. JAMA Dermatol 2013; 149(8):950–953.
Chuah SY, et al: A retrospective review of the therapeutic response with
remission in patients with newly diagnosed bullous pemphigoid.
Australas J Dermatol 2014; 55:149–151.
Hertl M, et al: Underrecognition of the heterogeneous clinical spectrum
of bullous pemphigoid. JAMA Dermatol 2013; 149(8):954–955.
Khumalo N, et al: Interventions for bullous pemphigoid. Cochrane
Database Syst Rev 2005; 20:CD002292.
Lehman JS, et al: Infection in autoimmune bullous diseases: a
retrospective comparative study. J Dermatol 2013; 40(8):613–619.
Lo Schiavo A, et al: Bullous pemphigoid: etiology, pathogenesis, and
inducing factors—facts and controversies. Clin Dermatol 2013;
31(4):391–399.
Ludwig RJ, et al: Emerging treatments for pemphigoid diseases. Trends
Mol Med 2013; 19(8):501–512.
Shetty S, et al: Treatment of bullous pemphigoid with rituximab: critical
analysis of the current literature. J Drugs Dermatol 2013;
12(6):672–677.
Sladden C, et al: Biopsy location for direct immunofluorescence in
patients with suspected bullous pemphigoid impacts probability of a
positive test result. J Cutan Med Surg 2014; 18:392–396.
Spivey J, et al: Bullous pemphigoid: corticosteroid treatment and
adverse effects in long-term care patients. Consult Pharm 2013;
28(7):455–462.
PEMPHIGOID GESTATIONIS (HERPES GESTATIONIS)
Clinical features
Pemphigoid gestationis (PG) is an autoimmune in amma
tory bullous disease with onset during pregnancy or during
the postpartum period. t occurs in appro imately in
pregnancies. The onset is usually during the second trimester
with urticarial pla ues and papules de eloping around the
umbilicus and e tremities. Targetoid lesions may be present
( ig. ). As the disease progresses lesions may spread
o er the abdomen bac chest and e tremities including the
palms and soles. The ace scalp and oral mucosa are usually
spared. Within the in ltrated erythematous pla ues tense
esicles and bullae erupt o ten in an annular or polycyclic
con guration. Pruritus is se ere and may be paro ysmal. The
disease will o ten are shortly a ter deli ery and then remit
spontaneously usually within months. There is no scarring
e cept that caused by e coriations or secondary in ections.
Recurrences with subse uent pregnancies are common and
the disease may be pro o ed by subse uent menstrual periods
or oral contracepti es ( Cs). A number o cases o persistent
disease ha e been reported.
ost study data suggest that etal loss is not statistically
increased although in ants are o ten born prematurely and are
small or gestational age. n ewer than o cases in ants
mani est the disease in the orm o urticarial lesions or bullae.
The lesions are usually limited and clear spontaneously
without the need or therapy. eonatal con ulsions ha e been
reported.
Etiologic factors
Pemphigoid gestationis is an autoimmune antibody mediated
disease. A complement ing gG antibody is present in the
serum and is deposited in the lamina lucida. The antigen
transmembrane collagen V is a component o etal mem
branes and promotes migration o placental cytotrophoblastic
cells. The antigenic epitopes are usually restricted to the
terminal portion o the e tracellular domain o BP
(BPAg ). The antigenic terminal portion o CW is
located in the noncollagenous domain ( C A) o BP
ther antigens are located nearby and our ma or PG epitopes
are clustered within a amino acid region o the BP ect
odomain. L SA based assays correlate antibody le els to
disease acti ity. Both gG and gG subtypes ha e been
noted but a more recent study ound gG to be the predomi
nant subtype as in BP.
Studies ha e documented an increased re uency o LA
DR DR and C null alleles in patients with PG. A woman
may ha e antibodies directed against her husband s LA
antigens. Blac women rarely mani est PG possibly related to
the low incidence o LA DR in American blac persons
( ig. ). There is an increased re uency o Gra es disease
in PG patients.
Fig. 21-13 Pemphigoid gestationis.
Fig. 21-14 Pemphigoid gestationis.
tahir99 - UnitedVRG
Pathogenesis
Pathogenesis is similar to that o BP. owe er hormonal
actors in uence the disease mani estation. n addition to
being seen in pregnant patients menstruating women and
Other pregnancy-related dermatoses
those ta ing Cs the disease may occur in association with
hydatidi orm mole and choriocarcinoma. The gG antibodies
bind to the lamina lucida and complement. Acti ated
eosinophils neutrophils and T cells with a predominant Th
phenotype are in ol ed in blister ormation. idence o etal
microchimerism is lac ing.
Patients with chronic PG tend to be older and multigra id
with a history o PG during pre ious pregnancies. They o ten
ha e widespread cutaneous and mucosal in ol ement. The
. gG subclass is o ten present. Antibodies to a C terminal
portion o BP ha e been noted in a patient with chronic PG.
This same region is targeted in patients with cicatricial pem
phigoid and some with BP.
Histopathology
A subepidermal bulla with eosinophils and some neutrophils
is usually present in PG. n the urticarial stage eosinophils
may line up along the D J as in urticarial BP. Ci atte bodies
may be present. n D all patients ha e C deposited in a
linear pattern at the D J; also ha e detectable gG.
n con entional testing appro imately o patients
ha e a circulating gG anti B antibody but in almost
the PG actor a complement ing gG antibody can be
demonstrated by complement enhanced immuno uorescence.
mmunoelectron microscopy has demonstrated that the blister
occurs at the le el o the lamina lucida with deposition o C
and gG at this site e actly as in BP.
Differential diagnosis
The main diagnosis to be considered is pruritic urticarial
papules and pla ues o pregnancy (P PPP). The di erential
diagnosis o PG also includes drug reactions and bullous
scabies. Acrodermatitis enteropathica has also been reported
to are as a bullous eruption with each pregnancy. Biopsy
immuno uorescence ndings and clinical course establish the
diagnosis.
Treatment
The use o potent topical steroids may be ade uate in some
patients with milder PG. Prednisone about mg day orally
is usually e ecti e in the remaining women. The dose is
tapered to the lowest e ecti e amount gi en on alternate days.
Pyrido ine has been reported to be e ecti e in some patients.
Persistent PG a ter deli ery has been treated with arious
tetracyclines together with nicotinamide. A ew women with
se ere PG ha e re uired treatment with ritu imab cyclophos
phamide dapsone methotre ate V G or plasmapheresis.
OTHER PREGNANCY-RELATED DERMATOSES
Intrahepatic cholestasis of pregnancy
(prurigo gravidarum)
Women with prurigo gra idarum ha e no primary s in lesions
and usually mani est only se ere generali ed pruritus and
461

21
Chronic Blistering Dermatoses
Fig. 21-15 Pruritic urticarial papules and plaques of pregnancy.
aundice. Secondary e coriations may be present. The disease
is caused by cholestasis occurs late in pregnancy resol es
a ter deli ery and recurs with subse uent pregnancies. There
is an increased incidence o etal complications. t has been
estimated to occur in . o pregnancies. Both ursode
o ycholic acid and S adenosylmethionine impro e pruritus
but the ormer is more e ecti e in impro ing li er unction.
Deli ery at wee s is associated with better outcomes.
Polymorphic eruption of pregnancy
Some in estigators ha e proposed grouping all the pruritic
in ammatory dermatoses o pregnancy into the designation
polymorphic eruption o pregnancy. This argument has
some merit because many o the pruritic eruptions o
pregnancy are nonspeci c or ariable mani estations o
P PPP and there are no consistent hormonal or immuno
pathogenetic actors that reliably separate them. These erup
tions occur in appro imately in pregnancies. They
are more common with male etuses and multiple gestation
pregnancies.
Pruritic urticarial papules and plaques of pregnancy
Lawley et al. rst reported this eruption in se en patients
under the name pruritic urticarial papules and pla ues o
pregnancy in . P PPP is characteri ed by erythematous
papules and pla ues that begin as mm or mm lesions
within the abdominal striae ( ig. ). These then spread
o er a ew days to in ol e the abdomen buttoc s thighs and
in some cases the arms and legs. The upper chest ace and
mucous membranes are generally spared. The lesions coalesce
to orm urticarial pla ues sometimes in gurate patterns and
occasionally spongiotic esicles are present. ntense pruritus
is characteristic. n contrast to PG postpartum onset or e ac
erbation is uncommon. etal and maternal outcomes are not
a ected by this eruption and only rarely do newborns mani
est transient lesions o P PPP.
This eruption occurs in primigra idas o the time and
rarely recurs with subse uent pregnancies. t begins late in the
third trimester and resol es with deli ery. any studies ha e
in estigated the relationship o maternal weight gain to the
de elopment o this dermatosis. Patients with P PPP a erage
more weight gain and greater abdominal distention than those
without the disease. t is more common in those carrying twins
or triplets.
istologic ndings consist o a peri ascular lymphohistio
cytic in ltrate in the upper and middle dermis with a ariable
462
number o eosinophils and dermal edema. The epidermis is
usually normal although ocal spongiosis para eratosis or
scales or crust may be present. The results o a D test are
negati e or nonspeci c.
sually potent topical corticosteroids are re uired to control
the eruption. A ew patients re uire prednisone. P PPP remits
a ter deli ery.
Papular dermatitis of pregnancy
Papular dermatitis o pregnancy is a contro ersial entity. t is
de ned as a pruritic generali ed eruption o mm ery
thematous papules each surmounted by a small rm central
crust. The lesions may erupt at any time during pregnancy and
usually resol e with deli ery. ar ed ele ation o the hour
urinary chorionic gonadotropin has been cited as a mar er or
the condition. Administration o systemic corticosteroids is
reportedly e ecti e in controlling the eruption. Papular der
matitis may recur in subse uent pregnancies. The high inci
dence o etal deaths reported by Spangler is now thought to
ha e been o erstated.
Prurigo gestationis (Besnier)
Prurigo gestationis consists o pruritic e coriated papules o
the pro imal limbs and upper trun occurring most o ten
between the th and th wee s o gestation. t clears in the
postpartum period and usually does not recur. Therapy with
potent topical corticosteroids is recommended. o ad erse
e ects on maternal or etal health are seen. This eruption may
simply be an e pression o atopic dermatitis in pregnancy.
Pruritic folliculitis of pregnancy
Se eral authors ha e reported on pruritic olliculitis in gra id
women with small ollicular pustules scattered widely o er
the trun appearing during the second or third trimester and
resol ing by or wee s a ter deli ery. Acute olliculitis and
ocal spongiosis with e ocytosis o polymorphonuclear leu o
cytes are present on biopsy and D results are negati e. This
condition may be a type o hormonally induced acne.
Linear IgM dermatosis of pregnancy
n Alcalay et al. described a woman who de eloped
small red ollicular papules and pustules that on immuno
uorescence testing showed linear deposits o g . This
nding is common in a wide ariety o dermatoses and is
nonspeci c.
Impetigo herpetiformis
mpetigo herpeti ormis is a orm o se ere pustular psoriasis
occurring in pregnancy. t consists o an acute usually ebrile
onset o grouped pustules on an erythematous base which
begins in the groin a illae and nec . There is a high periph
eral white blood cell count and hypocalcemia may be present.
The histopathology is that o pustular psoriasis. The condition
resol es with deli ery but recurrences with subse uent preg
nancies may be e pected. etal death can occur and results
rom placental insu ciency. nitial treatment is with systemic
corticosteroids in the range o mg day o oral predni
sone. mpetigo herpeti ormis is discussed in more detail in
Chapter .
Ambros-Rudolph CM, et al: The specific dermatoses of pregnancy
revisited and reclassified: results of a retrospective two-center study on
505 pregnant patients. J Am Acad Dermatol 2006; 54(3):395–404.
Guldrís EM, et al: Pemphigoid gestationis. J Obstet Gynaecol Can 2013;
35(8):687.
 Lehrhoff S, et al: Specific dermatoses of pregnancy and their treatment.
Dermatol Ther 2013; 26(4):274–284.
Massone C, et al: Histopathological diagnosis of atopic eruption of
pregnancy and polymorphiceruption of pregnancy: a study on 41
cases. Am J Dermatopathol 2014; 36:812–821.
The bullae may occur on the ace scalp nec inguinal region
( ig. ) or e tremities. Generali ed lesions may also occur.
Some o these patients will ha e circulating antibodies tar
geted against the classic BP antigens and should be classi ed
as mucosal predominant BP. Some ha e secondary antibodies

Cicatricial pemphigoid (benign mucosal pemphigoid)

Rimoin LP, et al: Female-specific pruritus from childhood to
postmenopause: clinical features, hormonal factors, and treatment against other antigens. Some patients ha e BA because the
considerations. Dermatol Ther 2013; 26(2):157–167. gG autoantibody was ound to target type V collagen. Veg
etating intertriginous lesions ha e been dubbed CP egetans.
n Brunsting Perry pemphigoid there are no mucosal
lesions but one or se eral circumscribed erythematous patches
CICATRICIAL PEMPHIGOID de elop on which recurrent crops o blisters appear. lti
(BENIGN MUCOSAL PEMPHIGOID) mately atrophic scarring results. Generally the areas o
in ol ement are con ned to the head and nec . The a erage
n Le er suggested the designation benign mucosal age at onset is with a male emale ratio. n contrast to
pemphigoid or what had pre iously been called ocular pem BP CP shows little tendency or remission. Although the
phigus cicatricial pemphigoid or essential shrin age o the disease is chronic and produces signi cant morbidity the
con uncti a. Because o its scarring nature the designation patient s general health is usually not eopardi ed.
cicatricial pemphigoid (CP) has gained predominance. The
term encompasses a group o immunologically distinct immu
nobullous diseases with scarring. Etiologic factors
Circulating autoantibodies target the hemidesmosomal protein
Clinical features BP but the target epitopes di er rom those usually tar
geted in BP. Whereas most BP patients react with the noncol
Cicatricial pemphigoid usually occurs in older women with a lagenous domain ( C a) on the e tracellular terminal
emale male ratio o appro imately . CP is characteri ed portion o BP most CP antibodies target C terminal
by e anescent esicles that rupture uic ly lea ing behind domains. luorescence typically is ound on the epidermal
erosions and ulcers. n most patients the esicles primarily side o aCl split s in.
occur on the mucous membranes especially the con uncti a
( ig. ) and oral mucosa. ral lesions occur in appro i
mately o patients and con uncti al lesions in . The
oral mucosa may be the only a ected site or years. Des uama
ti e gingi itis di use erythema o the marginal and attached
mucosa associated with mucosal des uamation and pain is
o ten the presenting sign ( ig. ). The mucosa readily peels
away in response to pressure rom a cotton tipped applicator
or stream o air rom a dental air hose. The gingi ae are almost
always in ol ed and the lingual sur aces less regularly. The
palate tongue and tonsillar pillars may be in ol ed.
The disorder is chronic. n ocular cases CP leads to scarring
and progressi e shrin age o the ocular mucous membranes.
Blindness may result. t is usually bilateral and associated with
redness and accid esicles on the con uncti a erosis and
brous adhesions (symblepharon). ntropion trichiasis and
corneal opacities de elop and ultimately the adhesions attach
both lids to the eyeball and narrow the palpebral ssure. Scar
ring may also de elop in the pharyn esophagus laryn and
anogenital mucosa. sophageal stricture may occur and dea Fig. 21-17 Desquamative gingivitis secondary to cicatricial
ness has been reported. pemphigoid.
Cutaneous lesions are seen in appro imately o CP
patients. These begin as tense bullae similar to those in BP.

Fig. 21-18 Antilaminin cicatricial pemphigoid with inguinal

involvement. Blisters began at the same time colonic cancer was
Fig. 21-16 Cicatricial pemphigoid. diagnosed.
463

tahir99 - UnitedVRG
 Although patients share a similar phenotype CP is a hetero
21 geneous group o autoimmune subepidermal blistering dis
eases. Although most patients autoantibodies target BP
others target laminin (antiepiligrin cicatricial pemphigoid)
or the β subunit o α β integrin. Some patients with a CP
Chronic Blistering Dermatoses
phenotype ha e antibodies to multiple epitopes including the
β subunit BP and BP . ther subsets o patients target
ing uni ue B antigens will li ely be identi ed.
A sensiti e L SA test or laminin antibodies has made it
easier to identi y this subset o patients. Among those whose
antibodies target laminin (antiepiligrin CP) most e hibit
antibodies to the α subunit especially the G domains o
the α subunit. Antibodies may also target the β and γ
subunits. ther patients ha e been ound to ha e autoantibod
ies that react with both laminin and laminin prompting
the proposed designation o antilaminin cicatricial pemphi
goid n antilaminin cicatricial pemphigoid gG anti B
autoantibodies bind to the dermal side o aCl split s in.
Some data suggest an increased relati e ris or solid cancers
(mostly adenocarcinomas) in these patients. Tumors are
usually ound during the rst year o the disease. As with
other orms o CP the disease rarely remits spontaneously. n
contrast to the increased tumor ris in antilaminin CP some
data suggest that patients with antibodies to the β integrin
subunit ha e a decreased ris o cancer. ther data suggest
that antilaminin autoantibodies are associated with se ere
mucous membrane pemphigoid ( P) but not malignancy.
Histopathology
The histologic ndings o CP are identical to those o BP
e cept that brosis and scarring may be present in the upper
dermis. Basement membrane separation occurs in the lamina
lucida or below the lamina densa depending on the targeted
antibody. The in ammatory in ltrate is ariable. D testing
o perilesional s in or mucosa re eals C and gG at the lamina
lucida in o patients. The B o mucosal glands
stains as well. gA may be ound occasionally. A circulating
antibody to the B is ound by in about o CP
patients. mmunoelectron microscopy shows that lamina
lucida antibodies bind at a deeper le el than with BP. ost
positi e cases show gG binding to the epidermal side o
salt split s in although combined staining and dermal stain
ing may be present in di erent subtypes as pre iously noted.
Laser scanning con ocal microscopy using uorescein
isothiocyanate con ugated antihuman gG antibody has been
employed to determine the locali ation o gG at the B and
may be o alue in patients with negati e . noc out s in
substrates and uorescent o erlay antigen mapping ha e also
been used to di erentiate between antiepiligrin CP and BA.
Treatment
A re iew o studies using the Cochrane criteria ound two
small RCTs both in patients with se ere eye in ol ement. n
one months o cyclophosphamide was superior to predni
sone. n the second RCT o patients responded well to
months o cyclophosphamide but only o responded
to dapsone. Based on these limited data and other uncon
trolled trials the re iewers concluded that patients with se ere
ocular CP respond best to cyclophosphamide combined with
corticosteroids and that those with mild to moderate disease
may respond to dapsone. and ritu imab ha e also been
used e ecti ely.
n patients with mild CP oral hygiene topical corticoste
roids intralesional triamcinolone topical calcineurin inhibi
464
tors or topical steroids occluded under inyl inserts may be
e ecti e or des uamati e gingi itis and other oral genital or
cutaneous disease. Cream and gel ormulations may be
used or the steroid may be compounded in rabase. Topical
sucral ate suspension may decrease the pain and healing time
o the oral and genital ulcers. There ha e been reports o
e cacy o thalidomide tetracycline combined with niacina
mide dapsone V G etanercept systemic corticosteroids and
immunosuppressi e drugs.
Bernard P, et al: Prevalence and clinical significance of anti-laminin 332
autoantibodies detected by a novel enzyme-linked immunosorbent
assay in mucous membrane pemphigoid. JAMA Dermatol 2013;
149(5):533–540.
Grau AE, et al: How to do conjunctival and buccal biopsies to
investigate cicatrising conjunctivitis: improving the diagnosis of ocular
mucous membrane pemphigoid. Br J Ophthalmol 2013;
97(4):530–531.
Lee YJ, et al: Application for tacrolimus ointment in treating refractory
inflammatory ocular surface diseases. Am J Ophthalmol 2013;
155(5):804–813.
Nottage JM, et al: Treatment of mucous membrane pemphigoid with
mycophenolate mofetil. Cornea 2013; 32(6):810–815.
Petruzzi M: Mucous membrane pemphigoid affecting the oral cavity:
short review on etiopathogenesis, diagnosis and treatment.
Immunopharmacol Immunotoxicol 2012; 34(3):363–367.
Saadoun D, et al: Biotherapies in inflammatory ocular disorders:
interferons, immunoglobulins, monoclonal antibodies. Autoimmun Rev
2013; 12(7):774–783.
Shetty S, et al: Critical analysis of the use of rituximab in mucous
membrane pemphigoid: a review of the literature. J Am Acad Dermatol
2013; 68(3):499–506.
Srikumaran D, et al: Mucous membrane pemphigoid: recent advances.
Curr Opin Ophthalmol 2012; 23(6):523–527.
Suelves AM, et al: Analysis of a novel protocol of pulsed intravenous
cyclophosphamide for recalcitrant or severe ocular inflammatory
disease. Ophthalmology 2013; 120(6):1201–1209.
Xu HH, et al: Mucous membrane pemphigoid. Dent Clin North Am
2013; 57(4):611–630.
EPIDERMOLYSIS BULLOSA ACQUISITA
Criteria or epidermolysis bullosa ac uisita ( BA) were pro
posed in by Roenig and included the ollowing
. Clinical lesions o dystrophic epidermolysis bullosa
including increased s in ragility trauma induced
blistering with erosions ( ig. ) atrophic scarring
milia o er e tensor sur aces and nail dystrophy
. Adult onset
. Lac o a amily history o epidermolysis bullosa
Fig. 21-19 Epidermolysis bullosa acquisita.
 . clusion o all other bullous diseases such as porphyria
cutanea tarda pemphigoid pemphigus dermatitis
herpeti ormis and bullous drug eruption
n Roenig et al. e tended these criteria to include
. gG at the basement membrane one by D
. Demonstration o blister ormation beneath the basal
lamina
. Deposition o gG beneath the basal lamina
The antibodies ha e been ound to target type V collagen
a ma or component o anchoring brils. The target is the same
as that in bullous lupus erythematosus. n some patients it has
been shown that autoantibodies bind to the C domain o
collagen V within the lamina densa. studies re eal circu
lating anti B antibodies in appro imately hal o cases. B
cells dendritic cells and macrophages are re uired to induce
the CD helper T cell response that results in the ormation o
pathogenic antibodies. Type V collagen L SA using the
C and C domains is use ul or diagnosis and antibody
le els ha e been shown to correlate with disease se erity.
The nonin ammatory clinical presentation o BA is the
most re uently recogni ed type. The association o BA with
many systemic diseases such as myeloma in ammatory
bowel disease (especially Crohn s disease) diabetes lym
phoma leu emia amyloidosis hepatitis C in ection and car
cinoma is well established.
n Gammon described patients with generali ed
in ammatory bullous disease that resembled BP clinically
( ig. ) but with immunologic and ultrastructural eatures
o BA. any o these patients ha e associated diabetes mel
litus are LA DR positi e and progress to the trauma
induced scarring type o BA in the long term. Appro imately
o patients re erred to medical centers as ha ing BP
may actually ha e BA.
Patients with BA usually ha e a predominance o neutro
phils o er eosinophils although this is ariable. n BA
patients are more li ely to ha e linear gG without concomi
tant C deposition than are patients with BP. mmuno uores
cence on salt split s in allows di erentiation o the ma ority
o cases without the need to resort to immunoblot techni ues
or immunoelectron microscopy. By D testing o the patient s
salt split s in biopsy BA will mani est gG deposition only
on the dermal side o the split whereas the ma ority o BP
patients will ha e gG bound only to the epidermal side or to
both sides. The nding o a u serrated pattern on D may
ma e the salt split s in assay unnecessary. As noted earlier
some patients with BP ha e antibodies that target sub lamina
densa antigen. Absolute di erentiation o these diseases is
obtained by immunoelectron microscopy or immunoblot
Fig. 21-20 Inflammatory epidermolysis bullosa acquisita.
tahir99 - UnitedVRG
ndings. n BA immunoblotting identi es D and
D proteins corresponding to type V collagen. Blistering
appears to be T cell dependent.
Bullous systemic lupus erythematosus (SL ) and BA dem
onstrate clinical and histologic o erlap but the ollowing ea
Epidermolysis bullosa acquisita
tures a or BA s in ragility predilection or traumati ed
areas and healing with scars and milia. n bullous SL sun
e posed s in is in ol ed by pre erence and the patient has a
diagnosis o SL established by American College o Rheuma
tology criteria; bullous SL patients usually ha e a dramatic
response to dapsone. n addition to the cases o bullous SL
that show linear gG staining below the lamina densa with
circulating gG autoantibodies to the D and D anti
gens some patients will show granular staining o gG at the
B without circulating gG. BA li e eruptions are rarely
seen as a result o penicillamine therapy.
Purely gA mediated BA has been described. The patients
resemble linear gA dermatosis or in ammatory gG mediated
BA. nly a minority demonstrate milia or scarring. mmu
noblotting or uorescence o erlay antigen mapping using
laser scanning con ocal microscopy can distinguish the two
diseases.
Treatment
A re iew o the literature using Cochrane criteria ailed to iden
ti y any RCTs. BA is o ten resistant to therapy but good
responses ha e been reported in some patients treated with
systemic corticosteroids alone or in combination with a athio
prine or dapsone. ther agents reported to be e ecti e include
ritu imab V G cyclosporine colchicine plasmaphere
sis photophoresis in i imab and the humani ed murine
monoclonal anti Tac antibody dacli umab. Supporti e therapy
including control o in ection care ul wound management and
maintenance o good nutrition should be emphasi ed.
Arbache ST, et al: Immunofluorescence testing in the diagnosis of
autoimmune blistering diseases: overview of 10-year experience. An
Bras Dermatol 2014; 89:885–889.
Hellberg L, et al: Methylprednisolone blocks autoantibody-induced
tissue damage in experimental models of bullous pemphigoid and
epidermolysis bullosa acquisita through inhibition of neutrophil
activation. J Invest Dermatol 2013; 133(10):2390–2399.
Iwata H, et al: B cells, dendritic cells, and macrophages are
required to induce an autoreactive CD4 helper T cell response in
experimental epidermolysis bullosa acquisita. J Immunol 2013;
191(6):2978–2988.
Kim JH, et al: Serum levels of anti-type VII collagen antibodies detected
by enzyme-linked immunosorbent assay in patients with epidermolysis
bullosa acquisita are correlated with the severity of skin lesions. J Eur
Acad Dermatol Venereol 2013; 27(2):e224–e230.
Kim JH, et al: Successful treatment of epidermolysis bullosa acquisita
with rituximab therapy. J Dermatol 2012; 39(5):477–479.
Komorowski L, et al: Sensitive and specific assays for routine serological
diagnosis of epidermolysis bullosa acquisita. J Am Acad Dermatol
2013; 68(3):e89–e95.
Ludwig RJ: Clinical presentation, pathogenesis, diagnosis, and
treatment of epidermolysis bullosa acquisita. ISRN Dermatol 2013;
2013:812029.
Reddy H, et al: Epidermolysis bullosa acquisita and inflammatory bowel
disease: a review of the literature. Clin Exp Dermatol 2013;
38(3):225–229.
Terra JB, et al: The n- vs. u-serration is a learnable criterion to
differentiate pemphigoid from epidermolysis bullosa acquisita in direct
immunofluorescence serration pattern analysis. Br J Dermatol 2013;
169(1):100–105.
Wozniak K, et al: Fluorescence overlay antigen mapping using laser
scanning confocal microscopy differentiates linear IgA bullous
dermatosis from epidermolysis bullosa acquisita mediated by IgA. Br J
Dermatol 2013; 168(3):634–638.
465
 Fig. 21-21 Dermatitis
21 herpetiformis.
Chronic Blistering Dermatoses
DERMATITIS HERPETIFORMIS
(DUHRING DISEASE)
Clinical features
Dermatitis herpeti ormis (D ) is a chronic relapsing se erely
pruritic disease characteri ed by grouped symmetric lesions
on e tensor sur aces the scalp nuchal area and buttoc s. The
lesions are se erely pruritic and thus generally present as
e coriations. The eruption usually occurs on an erythematous
base and may be papular papulo esicular esiculobullous
( ig. ) bullous or urticarial. Linear petechial lesions may
be noted on the olar sur aces o the ngers as well as the
palms (see e ig. online). Pigmented spots alone o er
the lumbosacral region should arouse suspicion o D . The
mucous membranes are in ol ed in rare cases mostly when
bullae are numerous. Laryngeal lesions may mani est as
hoarseness. tching is usually intense but spontaneous remis
sions lasting as long as wee and terminating abruptly with
a new crop o lesions are a characteristic eature o the disease.
Perimenstrual ares may occur.
Between and o patients with D and gA deposits
in the s in are LA B positi e a similar re uency to that
obser ed in gluten sensiti e enteropathy (GS ). LA antigens
DR and D w are also increased in re uency. Blac and
Asian patients are uncommon possibly because o LA di
erences. These LA mar ers are associated with other auto
immune diseases and indicate patients who appear to ha e an
o eracti e immune response to common antigens and who
may clear immune comple es slowly. D is more common in
those with a ected amily members.
n childhood D is usually similar to the adult type has
identical histologic and immuno uorescent ndings and has
a high incidence o LA B and DR and abnormal e unal
biopsies. Palmar blisters and brown hemorrhagic purpuric
macules may be more common than in adults. Treatment
with sul ones results in prompt response in children as in
adults.
Gluten a protein ound in cereals e cept or rice and corn
pro o es ares o the disease. Villous atrophy o the e unum
and in ammation o the small bowel occur. gA is bound to
the s in and this apparently acti ates complement primarily
through the alternate pathway. ral iodides will cause a are
o the disease. Patch tests with potassium iodide in pet
rolatum produce a bulla in uncontrolled D but only e cep
tionally in patients controlled by a gluten ree diet or by
sul one therapy.
466
Associated disease
Thyroid disorders are increased in incidence in patients with
D . eurologic disease including ata ia may occur. An
increased incidence o malignancy especially small bowel
lymphoma has also been noted in some studies although
others ha e reported this increase with celiac disease but not
D . n act the incidence o breast cancer may be lower in
those with D than in the general population.
Enteropathy
Between and o patients with D ha e abnormali
ties in the e unal mucosa but most are asymptomatic.
gi en a high gluten diet irtually all patients with D
de elop ndings indistinguishable rom celiac disease and
D a ects appro imately o patients presenting with
celiac disease.
The dapsone re uirement in D is usually decreased a ter
months o a gluten ree diet. The ma ority o patients who
adhere to a strict gluten ree diet can e entually stop their
medication or signi cantly reduce the dosage. A gluten ree
diet is not easy to ollow but may decrease the incidence o
intestinal lymphoma.
Diagnosis
The distinction o D rom linear gA bullous dermatosis is
o ten clinically impossible. ther conditions considered in
the di erential diagnosis at times are BP bullous scabies
contact dermatitis atopic dermatitis nummular ec ema neu
rotic e coriations insect bites and chronic bullous disease
o childhood. The nding o gA in a granular pattern at
the D J with accentuation in the dermal papillae is speci c
or D .
Autoantibodies
Circulating gA antibodies against the smooth muscle cell
endomysium (antiendomysial antibodies) are present in
o D patients in almost all patients with acti e celiac disease
and almost ne er in other conditions. Tissue transglutaminase
(TTG) is the ma or autoantigen in GS . gA antibodies directed
at TTG are common in patients with D or celiac disease but
epidermal transglutaminase (TTG ) appears to be the most
important antigen. Dietary e posure to gliadin proteins in
wheat and related proteins rom barley and rye induce ares
o the disease. These proteins are high a nity substrates or
TTG. The two are o ten tightly bound which may e plain why
an antibody response is generated against both gliadin and
TTG. Gliadins can also be ound in rice corn and oats but
these proteins are poor substrates or TTG.
Epidemiology
This disease has an e ual male to emale incidence. The
a erage age o onset is years. D does occur with some
re uency in children. Blac and Asian persons are rarely
a ected.
Histopathology
The initial changes o D are noted at the tips o the
dermal papillae where edema ocal brin and neutrophilic
microabscesses are seen. The cellular in ltrate contains many
neutrophils but may also include a ew eosinophils. A subepi
dermal separation is noted histologically. ltrastructurally
the split may begin in the lamina lucida. n a study o
patients with con rmed D . had nonspeci c ndings
on hemato ylin and eosin ( ) staining including a lym
phocytic in ltrate ectatic capillaries and brosis in the dermal
papillae. Because o the potential or nonspeci c biopsy nd
ings D studies are essential. istologic di erentiation o
linear gA bullous dermatosis rom D is e tremely di cult
unless D is per ormed. D o nonin ol ed perilesional s in
re eals deposits o gA alone or together with C arranged in
a granular pattern at the D J. The deposits are typically accen
tuated in the dermal papillae. g and gG deposits are occa
sionally obser ed in association with gA. Deposits may be
ocal so multiple biopsies may be needed and the deposits o
antibody are more o ten seen in pre iously in ol ed s in or
normal appearing s in ad acent to in ol ed s in. gA is
obser ed by immunoelectron microscopy either alone or in
con unction with C gG or g as clumps in the upper
dermis. A ertically oriented brillar staining pattern e ists in
a subset o patients with immune deposits along dermal
micro brils creating a pic et ence pattern o immuno uo
rescence. The brillar pattern is present in a third o Japanese
patients and this group lac s the typical distribution o s in
lesions and has a low association with celiac disease. A ew
patients will ha e negati e D despite typical clinical ndings
and e idence o antiendomysial antibodies. is rarely
positi e.
Treatment
The drugs chie y used or D are dapsone and sul apyridine.
The most e ecti e sul one is diaminodiphenylsul one
(dapsone). The dose aries between and mg day
usually starting with mg day and increasing gradually to
an e ecti e le el or until side e ects occur. nce a a orable
response is attained the dosage is decreased to the minimum
that does not permit recurrence o signs and symptoms. When
dapsone is discontinued abruptly large bullae similar to those
seen in BP re uently occur. emolytic anemia leu openia
methemoglobinemia agranulocytosis or peripheral neuropa
thy may occur with dapsone. Acute hemolytic anemia (which
may be se ere) occurs in patients with glucose phosphate
dehydrogenase (G PD) de ciency; there ore G PD le el
should be measured be ore therapy. n those whose ethnic
bac ground ma es G PD de ciency unli ely some authori
ties begin dapsone at a low starting dose ( mg day) and
watch the patient closely or dar urine. The patient should be
warned to report by telephone any incident o red or brown
urine or blue nail beds or lips. A blood count should be done
wee ly or wee s bimonthly or the ne t months and
e ery months therea ter. Li er unction tests should be
monitored bimonthly or the rst months then chec ed with
the hematologic studies e ery months.
Agranulocytosis is rare. t typically occurs months a ter
initiation o drug therapy and presents with sore throat
aphthae or e idence o in ection. The ris o agranulocytosis
is higher in older patients (> years) and nonwhite persons.
The incidence aries with the disease. t is rarely seen in
patients with ansen s disease but patients with D ha e a
old to old increased ris .
Sul apyridine can also be used to treat the disease. A ter a
test dose o . g o sul apyridine tablet ( . g) is gi en
our times daily. The dose is then increased i necessary or
reduced i possible. sually g day is re uired or good
control. The drug is less water soluble than dapsone and
patients should remain hydrated. Sul asala ine mg three
tahir99 - UnitedVRG
times daily increased to . g three times daily as tolerated
may also be used since sul apyridine is a metabolic product.
G intolerance may limit the dosage. n rare patients it is nec
essary to nd alternati es to the sul one drugs. Tetracycline
nicotinamide and colchicine ha e controlled indi idual
Dermatitis herpetiformis (Duhring disease)
patients.
Gluten-free diet
Patients must strictly a oid wheat barley and rye. oderate
amounts o oats may be tolerated. n Canada standards or
growing processing testing and labeling o pure uncontami
nated oats ha e allowed adults to consume up to g (about
one hal to three uarters cup) o oats and children to consume
up to g (one uarter cup) daily without ares o disease.
Corn and rice are generally well tolerated corresponding to
the poor binding o their gliadin proteins to TTG but e acer
bation o disease related to cornstarch has been reported. a
gluten ree diet is ollowed strictly the patient will almost
certainly be able to ta e less medication or stop it altogether.
Some e idence suggests that this may decrease the incidence
o associated malignancy; howe er it is a ery di cult diet to
ollow.
nce a prolonged remission has been obtained some gluten
may be tolerated in a subset o patients. n one study
patients who had ollowed a gluten ree diet or a mean
o years reintroduced gluten to their diets. Thirty one
e perienced recurrence within an a erage o months but
se en remained in remission or a mean ollow up o years.
gA deposits did not recur in their s in. This report suggests
that clinical and histologic remission can be maintained in
some patients with D despite the reintroduction o dietary
gluten.
or most patients howe er a gluten ree diet remains
an important aspect o disease management. ortunately many
grocery stores now ha e a section de oted to gluten ree prod
ucts. Support may be obtained rom the American Celiac Society
Dietary Support Coalition (www.americanceliacsociety
.org diet.html) or rom celiac societies (www.nowheat.com
gr nowheat primer celisoc.htm or www.enabling.org ia
celiac groups groupsus.html). A commercial website with a
search engine can be ound at www.celiac.com. Another
commercial source or products can be ound at www
.gluten reemall.com. An nternet search using the terms celiac
society or gluten ree diet is a good starting point or patients
with the disease who want more in ormation about the diet and
commercially a ailable products.
Al-Niaimi F, et al: Dermatitis herpetiformis exacerbated by cornstarch.
J Am Acad Dermatol 2010; 62(3):510–511.
Antiga E, et al: Clinical and immunopathological features of 159 patients
with dermatitis herpetiformis: an Italian experience. G Ital Dermatol
Venereol 2013; 148(2):163–169.
Fabbri P, et al: Novel advances in dermatitis herpetiformis. Clin Dev
Immunol 2012; 2012:450109.
Fasano A: Novel therapeutic/integrative approaches for celiac disease
and dermatitis herpetiformis. Clin Dev Immunol 2012; 2012:
959061.
Huber C, et al: Negative direct immunofluorescence and nonspecific
histology do not exclude the diagnosis of dermatitis herpetiformis
Duhring. Int J Dermatol 2013; 52(2):248–249.
Jakes AD, et al: Dermatitis herpetiformis. BMJ 2014; 348:g2557.
Nakajima K: Recent advances in dermatitis herpetiformis. Clin Dev
Immunol 2012; 2012:914162.
Ohata C, et al: Distinct characteristics in Japanese dermatitis
herpetiformis: a review of all 91 Japanese patients over the last 35
years. Clin Dev Immunol 2012; 2012:562168.
Tu H, et al: Acral purpura as leading clinical manifestation of dermatitis
herpetiformis: report of two adult cases with a review of the literature.
Dermatology 2013; 227(1):1–4.
467

21 LINEAR IGA BULLOUS DERMATOSIS
Linear gA bullous dermatosis (LAD) is characteri ed by sub
epidermal blisters a neutrophilic in ltrate and a circulating
Chronic Blistering Dermatoses
gA anti B antibody with linear B deposits on D . As
with CP LAD is really a group o diseases with a similar
immuno uorescent pattern.
Adult linear IgA disease
Adult patients with LAD may present with a clinical pattern
o esicles indistinguishable rom D or with esicles and
bullae ha ing a BP li e appearance. They may ha e urticarial
lesions and bullae may occur on an urticarial base as in BP
( ig. ). nusual ariants include morbilli orm prurigo
li e and ec ematous presentation. ucous membrane in ol e
ment may occur in up to o patients. n some oral and
con uncti al lesions dominate the presentation and scarring
may occur as in CP. n the ma ority o patients there is no
association with enteropathy or with LA B . The disease
remits a ter se eral years in appro imately o patients.
gA is typically directed against a D antigen in the lamina
lucida. Some patients demonstrate both gA and gG antibod
ies to BP and gA to LAD . gA and gG reacti ity has
been ound to all three portions o the BP ectodomain. n
some patients the strongest reacti ity is to the C terminal
portion o BP (ma or antigenic area in CP). This may e plain
cases o clinical o erlap with CP. Antigenic targets or LAD
are e pressed by both eratinocytes and broblasts.
Linear gA dermatosis re uently occurs as a drug induced
disease. n drug induced LAD the eruption is sel limited
there is less mucosal in ol ement and usually no detectable
circulating autoantibody. The gA may be deposited in the
sub basal lamina area. mplicated drugs include ancomycin
lithium amiodarone carbama epine captopril penicillin
amo icillin mo i o acin P VA urosemide o apro in L
inter eron ( ) α phenytoin diclo enac statins tea tree oil
angiotensin receptor antagonists sul asala ine buprenor
phine uste inumab and glibenclamide. The antigen identi
ed may be the D antigen the D BP antigen or the
D BP antigen.
Fig. 21-22 Adult linear
IgA disease.
468
Some cases ha e been associated with internal malignancy
paraproteinemia or in ection. Sporadic reports ha e lin ed
single cases with dermatomyositis rheumatoid arthritis
ac uired hemophilia and multiple sclerosis although these
may be ortuitous associations.
Biopsies typically demonstrate papillary dermal microab
scess with neutrophils. As in D eosinophils may be present.
n D a homogeneous linear (tubular or toothpaste) pattern
o gA is present at the B . Some patients will ha e both
linear gA and gG in combination at the B . A lac o C
may be a clue that both immunoglobulins recogni e the D
antigen.
By only a minority o LAD patients will ha e circulating
gA autoantibody with anti B speci city and this is usually
present in low titer. n salt split s in deposition may occur
on the roo or base or a combination o the two.
n drug induced disease the drug must be stopped. any
cases resol e uic ly but some patients re uire drug therapy
with a corticosteroid or dapsone. diopathic disease generally
responds to dapsone in doses similar to that described or D .
ther patients re uire topical or systemic corticosteroids in
addition or as sole treatment. A combination o tetracycline
g day and nicotinamide . g day may be e ecti e.
ther patients ha e responded to V G colchicine
trimethoprim sul ametho a ole or erythromycin. The rare
patients with associated GS may respond to a gluten ree diet.
Childhood linear IgA disease (chronic bullous
disease of childhood)
Chronic bullous disease o childhood (CBDC) is an ac uired
sel limited bullous disease that may begin by the time the
patient is or years old and usually remits by age ( ig.
). The a erage age o onset is years. Bullae de elop on
either erythematous or normal appearing s in pre erentially
in ol ing the lower trun buttoc s genitalia and thighs. Peri
oral and scalp lesions are common and oral mucous mem
brane lesions may occur in up to o patients. Bullae are
o ten arranged in rosettes or an annular array the so called
string o pearls con guration ( ig. ). Tense indi idual
bullae similar to those in BP are also seen. Pruritus is o ten
se ere.
Fig. 21-23 Chronic
bullous disease of
childhood.

Fig. 21-24 Chronic bullous disease of childhood. (Courtesy Dr.
Shyam Verma.)
The prime histologic nding is the presence o a subepider
mal bulla lled with neutrophils. osinophils may be present
and in some cases they predominate. D re eals a linear
deposition o gA at the B identical to that seen in the adult
orms o the disease. is positi e or circulating gA anti
B antibodies in appro imately o patients usually in
low titer. n contrast to adults with LAD children demonstrate
an increased re uency o B DR and D and may be
homo ygous or these antigens. As in the adult disease immu
noelectron microscopy and immunomapping studies may
demonstrate immune deposits within the lamina lucida below
the lamina densa or both. Also as in adult disease some chil
dren ha e both gG and gA deposits. GS is rare but gA
nephropathy may occur. Childhood linear gA disease has
occurred in con unction with Crohn s disease.
any patients antibodies target the D peptide. Some
children with sub basal lamina deposits target type V col
lagen and ha e BA. Patients with only gA or with both gG
and gA circulating autoantibodies may target BP or BP . lytic ariant o Dowling Degos disease that may resemble
ndi idual patients may ha e a combination o gA against the
D peptide and gG against BP and BP . Collagen
V BP is a transmembrane protein with a soluble D PV P benign amilial pemphigus or spongiotic dermatitis.
ectodomain. n linear gA dermatosis and CBDC gA targets
the soluble ectodomain more e ciently than the ull length
protein. Some sera target the Col domain.
The untreated disease runs a ariable course typically with
e entual spontaneous resolution by adolescence. Treatment
with either dapsone or sul apyridine is usually success ul.
ccasional cases respond to topical corticosteroids alone and
systemic corticosteroids are sometimes necessary. ther
patients ha e responded to colchicine topical calcineu
rin inhibitors or diclo acillin.
Becker JG, et al: Development of linear IgA bullous dermatosis in a
patient with psoriasis taking ustekinumab. J Am Acad Dermatol 2012;
67(4):e150–e151.
Chen S, et al: Linear IgA bullous dermatosis. Eplasty 2013; 13:ic49.
Maruta Y, et al: Linear IgA bullous dermatosis with a prurigo nodularis–
like appearance. Eur J Dermatol 2013; 23(1):107–109.
tahir99 - UnitedVRG
Transient acantholytic dermatosis (Grover’s disease)
Fig. 21-25 Transient acantholytic dermatosis.
TRANSIENT ACANTHOLYTIC DERMATOSIS
(GROVER’S DISEASE)
n Gro er described a new dermatosis that occurred
predominantly in persons o er years o age and consisted
o a sparse eruption o limited duration. The lesions were
ragile esicles that rapidly turned into crusted and eratotic
erosions. e termed the condition transient acantholytic der
matosis (TAD). Since then the ma ority o cases ha e been
ound to persist or recur and the term persistent and recur
rent acantholytic dermatosis may be a more accurate descrip
tion o the disorder. The distribution is predominantly limited
to the chest or shoulder girdle area and upper abdomen and
there is a strong male predominance ( ig. ). The condi
tion o ten appears or ares during periods o heat sweating
or hospitali ation. any patients are asymptomatic and the
condition may be an incidental nding on e amination. ther
patients complain o pruritus. Asteatotic ec ema occurs e
times as o ten among patients with TAD as in controls. The
disorder has been described in the setting o a ariety o malig
nancies but it may be associated with the hospitali ation or
type B symptoms rather than the malignancy itsel . TAD has
been reported with cetu imab. Patients on strict bed rest
appear to ha e a higher incidence o the disease. The clinical
di erential diagnosis includes Galli Galli disease an acantho
TAD clinically.
There are e histologic types resembling Darier s disease
The Darier type predominates. ten two or more types can
be ound in a single biopsy specimen. D studies yield nega
ti e or nonspeci c results. Although heat and sweating are
signi cant ris actors only a minority o cases are associated
with acrosyringia histologically. mpairment o eratinocytic
cholinergic receptors has been suggested as a pathogenic
mechanism.
About o patients respond to topical corticosteroids.
Control o e er hospital discharge and a oidance o sun and
sweating o ten result in impro ement. Sustained remission
has been described a ter a course o systemic corticosteroids.
Topical antibiotics isotretinoin and dapsone ha e been suc
cess ul in some patients. Psoralen plus VA (P VA) has been
reported to result in an initial are ollowed by slow clearance
and VB therapy may produce clearing in some patients. Pho
todynamic therapy with red light and aminole ulinic acid
469
 has been reported as success ul and ritu imab has produced
21 clearing o TAD in patients being treated or lymphoma.
Gilchrist H, et al: Galli-Galli disease: a case report with review of the
literature. J Am Acad Dermatol 2008; 58(2):299–302.
Chronic Blistering Dermatoses
5-aminolevulinic acid photodynamic therapy. Dermatol Surg 2013;
39(6):960–961.
Paslin D: Grover disease may result from the impairment of
keratinocytic cholinergic receptors. J Am Acad Dermatol 2012;
66(2):332–333.

Liu S, et al: Successful novel treatment of recalcitrant transient

acantholytic dermatosis (Grover disease) using red light

Bonus images for this chapter can be found online at expertconsult.inkling.com

eFig. 21-1 An n-serrated immunofluorescent
pattern.
eFig. 21-2 A u-serrated immunofluorescent
pattern.
eFig. 21-3 Oral pemphigus vulgaris.
eFig. 21-4 Nonhealing crusted lesions of
pemphigus vulgaris.
eFig. 21-5 Nonhealing erosions of pemphigus
vulgaris.
eFig. 21-6 Pemphigus foliaceus.
eFig. 21-7 Pemphigus foliaceus.
eFig. 21-8 Pemphigus erythematosus.
eFig. 21-9 Intraepidermal neutrophilic IgA
dermatosis.
eFig. 21-10 Pemphigoid in psoriatic plaques
(psoriasis pemphigoides).
eFig. 21-11 Bullous pemphigoid.
eFig. 21-12 Urticarial bullous pemphigoid.
eFig. 21-13 Bullous pemphigoid.
eFig. 21-14 Bullous lesions of pemphigoid
gestationis. (Courtesy of Dr. Martha
McCollough.)
eFig. 21-15 Cicatricial pemphigoid.
eFig. 21-16 Antilaminin cicatricial pemphigoid.
eFig. 21-17 Brunsting-Perry pemphigoid.
eFig. 21-18 Epidermolysis bullosa acquisita.
eFig. 21-19 Characteristic linear petechial
lesions on the digits in a patient with
dermatitis herpetiformis.
eFig. 21-20 Dermatitis herpetiformis,
neutrophilic microabscesses within dermal
papillae.
eFig. 21-21 Direct immunofluorescence of linear
IgA disease.
eFig. 21-22 Chronic bullous disease of
childhood.

470
 Transient acantholytic dermatosis (Grover’s disease)
eFig. 21-4 Nonhealing crusted lesions of pemphigus vulgaris.

eFig. 21-1 An n-serrated immunofluorescent pattern.

eFig. 21-5 Nonhealing erosions of pemphigus vulgaris.

eFig. 21-2 A u-serrated immunofluorescent pattern.

eFig. 21-3 Oral pemphigus vulgaris.

470.e1

tahir99 - UnitedVRG
 eFig. 21-6
21 Pemphigus
foliaceus.
Chronic Blistering Dermatoses

eFig. 21-8 Pemphigus erythematosus.

eFig. 21-7 Pemphigus

foliaceus.

eFig. 21-9 Intraepidermal neutrophilic IgA dermatosis.

eFig. 21-10 Pemphigoid in psoriatic plaques (psoriasis

pemphigoides).

470.e2
 Transient acantholytic dermatosis (Grover’s disease)
eFig. 21-11 Bullous pemphigoid.

eFig. 21-14 Bullous lesions of pemphigoid gestationis. (Courtesy of

Dr. Martha McCollough.)

eFig. 21-15 Cicatricial

eFig. 21-12 Urticarial bullous pemphigoid. pemphigoid.

eFig. 21-13 Bullous

pemphigoid.

eFig. 21-16 Antilaminin

cicatricial pemphigoid.

470.e3

tahir99 - UnitedVRG
 eFig. 21-19
21 Characteristic linear
petechial lesions on
the digits in a patient
with dermatitis
Chronic Blistering Dermatoses

herpetiformis.

eFig. 21-17 Brunsting-Perry pemphigoid.

eFig. 21-20 Dermatitis herpetiformis, neutrophilic microabscesses

within dermal papillae.

eFig. 21-18 Epidermolysis bullosa acquisita. eFig. 21-21 Direct immunofluorescence of linear IgA disease.

470.e4
 Transient acantholytic dermatosis (Grover’s disease)
eFig. 21-22 Chronic bullous disease of childhood.

470.e5

tahir99 - UnitedVRG
 Bonus images for this chapter can be found online at
A nutritional disease is caused either by insu ciency or less
o ten by e cess o one or more dietary essentials. utritional
diseases are particularly common in underde eloped tropical
countries. n ants and children are particularly at ris or de
ciency states especially malnutrition. re uently patients
ha e eatures o se eral o these disorders i their diet has
generally been restricted. An intertriginous or acral eruption
a seborrheic dermatitis li e acial eruption atrophic glossitis
and alopecia are common eatures o many nutritional de
ciencies. This occurs because these nutrients are essential to
o erlapping metabolic pathways o atty acid metabolism
resulting in abnormal di erentiation o the epidermis and
de ecti e barrier unction. The histologic ndings in many
types o nutritional dermatosis are also similar.
n de eloped countries alcoholism is the main cause o
nutritional diseases. utritional diseases should also be sus
pected in postoperati e patients; psychiatric patients includ
ing those with anore ia ner osa and bulimia; patients on
unusual diets; patients with surgical or in ammatory bowel
dys unction especially Crohn s disease; patients who ha e
had bowel bypass surgery; cystic brosis patients; and patients
with se ere oral erosi e disease (e.g. pemphigus) that pre
ents eating. n the pediatric setting nutritional de ciency
may also occur because o parental ignorance o the nutritional
re uirements o their in ants.
The diagnosis o nutritional de ciency is o ten missed
because physicians ail to ta e an ade uate dietary history.
The edema o protein malnutrition may mas the problem;
malnourished children may gain weight through edema
staying on the growth cur e. The dermatitis produced by
ele ated glucagon le els rom islet cell tumors o the pancreas
(necrolytic migratory erythema) and a similar dermatosis seen
in hepatitis C in ection and other orms o hepatic insu ciency
(necrolytic acral erythema pseudoglucagonoma) probably
also represent nutritional de ciency dermatoses. De ciency
states caused by inborn errors o metabolism are discussed in
Chapter . n most cases the clinical ndings and socioeco
nomic scenario are ade uate to lead to suspicion o a speci c
de ciency state and replacement therapy can con rm the
diagnosis. Laboratory testing may be costly and inaccurate in
some de ciency states and patients with poor nutrition are
o ten de cient in many nutrients simultaneously. Testing is
indicated to con rm the diagnosis o inc de ciency in assess
ing essential atty acid de ciency and in e aluating or pos
sible glucagonoma syndrome.
Lee LW, et al: Skin manifestations of nutritional deficiency disease in
children. Int J Dermatol 2012; 51:1407–18.
expertconsult.inkling.com
Nutritional Diseases
22
VITAMIN A
Hypovitaminosis A (phrynoderma)
Vitamin A is a at soluble itamin ound as retinyl esters in
mil sh oil li er and eggs and as carotenoids in plants.
Vitamin A de ciency is common in children in the de eloping
world. t is rare in de eloped countries where it is most o ten
associated with diseases o at malabsorption such as bowel
bypass surgery or obesity pancreatic insu ciency Crohn s
disease celiac disease cystic brosis and li er disease. Vitamin
A is re uired or the normal eratini ation o many mucosal
sur aces. When it is de cient the resultant abnormal eratini
ation leads to increased mortality rom in ammatory disease
o the gut and lung diarrhea and pneumonia (especially in
rubeola). Vitamin A supplementation o day or
days is recommended or children with rubeola.
Although phrynoderma had classically been ascribed to
and thought to be speci c or itamin A de ciency it is in act
most re uently ound as a disorder o multiple de ciencies
including itamins A B C and and essential atty acids.
Replacing all these de ciencies leads to rapid impro ement.
Correcting only the B itamin de ciency leads to more
rapid impro ement than replacing the itamin A. This e plains
patients in whom the cutaneous ndings o phrynoderma
were ound without the classic eye ndings o itamin A de
ciency. The s in eruption termed ollicular hyper eratosis or
phrynoderma ( toads in ) resembles eratosis pilaris. t con
sists o eratotic papules o arious si es distributed o er the
e tremities and shoulders surrounding and arising rom the
pilosebaceous ollicles. ndi idual lesions are rm pigmented
papules containing a central intra ollicular eratotic plug
which pro ects rom the ollicle as a horny spine and lea es a
pit when e pressed. Lesions are o two si es mm papules
closely resembling eratosis pilaris and the more diagnostic
large mm crateri orm papules lled with a central era
totic plug. These latter lesions may simulate a per orating dis
order. The eruption o small lesions usually begins on the
anterolateral aspect o the thighs or the posterolateral aspect
o the upper arms. t then spreads to the e tensor sur aces o
both the upper and the lower e tremities the shoulders
abdomen bac and buttoc s and nally reaches the ace and
posterior aspect o the nec . The hands and eet are not
in ol ed and lesions occur only occasionally on the midline
o the trun or in the a illary and anogenital areas. n the ace
the eruption resembles acne because o the presence o many
large comedones but it di ers rom acne in regard to dryness
o the s in. The large dome shaped nodules are on the elbows
and nees and ha e a surrounding red or brown rim. The
471
 whole s in displays dryness ne scaling and hyperpigmenta
22 tion. air casts may also be seen.
Vitamin A de ciency may mimic itamin C de ciency
because both conditions cause ollicular hyper eratosis and
bleeding and gingi al disease can be a eature o itamin A
Nutritional Diseases
de ciency as well as scur y. The histologic ndings o de
ciency dermatitis which are common to many de ciency
states ( inc essential atty acids amino acids glucagonoma
cystic brosis) are not eatures o either itamin A or itamin
C de ciency.
n itamin A de ciency eye ndings are prominent and
o ten pathognomonic. These include night blindness an
inability to see bright light erophthalmia erosis corneae
and eratomalacia. The earliest nding is delayed adaptation
to the dar (nyctalopia). Some patients ha e circumscribed
areas o erosis o the con uncti a lateral to the cornea occa
sionally orming well de ned white spots (Bitot spots); these
are triangular with the ape toward the canthus. Vitamin A
de ciency is a ma or cause o blindness in children in de elop
ing countries.
The histologic ndings o itamin A de ciency are hyper
eratosis horny plugs in the upper portion o the hair ollicle
coiled hairs in the upper part o the ollicle se ere atrophy o
the sebaceous glands and s uamous metaplasia o the secre
tory cells o the eccrine sweat glands. the ollicles rupture
peri ollicular granulomatous in ammation is ound.
The diagnosis o itamin A de ciency is con rmed by deter
mination o the serum retinol le el. The treatment is oral
itamin A day or days ollowed by the rec
ommended dietary re uirement. Serum retinol le els are mon
itored to determine ade uacy o supplementation and to a oid
itamin A to icity.
Hypervitaminosis A
Because the s in ndings o hyper itaminosis A are similar to
the side e ects o synthetic retinoid therapy they are well
recogni ed by most dermatologists. Children are at greater
ris or to icity than adults. cess mega itamin ingestion
may be the cause. n adults doses as small as day
may lead to to icity especially in persons with hepatic com
promise rom alcoholic iral or medication induced hepatitis.
Dialysis patients also are at increased ris because itamin A
is not remo ed by dialysis. Standard hyperalimentation solu
tions contain signi cant amounts o itamin A and in burn
ictims with renal compromise itamin A to icity can occur.
the patient is ta ing a synthetic retinoid all itamin A sup
plementation should be stopped.
ost cases o chronic hyper itaminosis A ha e been reported
in children. There is loss o hair and coarseness o the remain
ing hair loss o the eyebrows e oliati e cheilitis generali ed
e oliation and pigmentation o the s in and clubbing o the
ngers. oderate widespread itching may occur. epatomeg
aly splenomegaly hypochromic anemia depressed serum
proteins and ele ated li er unction tests may be ound. Bone
growth may be impaired by premature closure o the epiphy
ses in children. Pseudotumor cerebri with papilledema may
occur early be ore any other signs appear. n in ants this may
present as a bulging ontanelle.
n adults the early signs are dryness o the lips and anore ia.
These may be ollowed by oint and bone pains ollicular
hyper eratosis branny des uamation o the s in ssuring
o the corners o the mouth and nostrils dryness and loss o
scalp hair and eyebrows and dystrophy o the nails. atigue
myalgia depression anore ia headache ( rom pseudotumor
cerebri) strabismus and weight loss re uently occur. Li er
disease may be progressi e and may lead to cirrhosis with
472
tahir99 - UnitedVRG
chronic to icity. ypercalcemia o ten occurs in dialysis
patients. Retinoids are teratogens and birth de ects may occur
with e cess itamin A supplementation during pregnancy.
Bremner NA, et al: Vitamin A toxicity in burns patients on long-term
enteral feed. Burns 2007; 22:266.
Brown CA, et al: Medical complications of self-induced vomiting. Eat
Disord 2013; 21:287–294.
Cheruvattath R, et al: Vitamin A toxicity: when one a day doesn’t keep
the doctor away. Liver Transpl 2006; 12:1888.
Girard C, et al: Vitamin A deficiency phrynoderma associated with
chronic giardiasis. Pediatr Dermatol 2006; 23:346.
Grauel E, et al: Necrolytic acral erythema. J Drugs Dermatol 2012;
11:1370.
Halawi A, et al: Bariatric surgery and its effects on the skin and skin
diseases. Obes Surg 2013; 23:408–413.
Jen M, et al: Syndromes associated with nutritional deficiency and
excess. Clin Dermatol 2010; 28:669–685.
Khasru MR, et al: Acute hypervitaminosis A in a young lady.
Mymensingh Med J 2010; 19:294.
Ocon J, et al: Phrynoderma. J Parenter Enteral Nutr 2012; 36:361–364.
Raphael BA, et al: Low prevalence of necrolytic acral erythema in
patients with chronic hepatitis C virus infection. J Am Acad Dermatol
2012; 67:962–968.
Romano ME, et al: Dermatologic findings in the evaluation of
adolescents with suspected eating disorders. Adolesc Med State Art
Rev 2011; 22:119–128.
Tiang S, et al: Nyctalopia. BMJ Case Reports 2010; Aug 26.
VITAMIN D
Although acti e itamin D is produced in the s in de ciency
o itamin D has no s in mani estations e cept or alopecia.
lderly persons ha e decreased itamin D cutaneous photo
synthesis because o decreased sun e posure and poor inta e
o itamin D both o which predispose them to osteomalacia.
Aggressi e photoprotection may also reduce itamin D le els.
Patients with cutaneous lupus and other photosensiti e dis
eases who are counseled to a oid the sun and use high sun
protection actor (SP ) sunscreens are at particular ris . ther
patients at ris include those who are debilitated with limited
sun e posure; those ta ing anticon ulsants; those with at
malabsorption; and patients with human immunode ciency
irus ( V) in ection especially dar s inned patients li ing
in northern climes. Vitamin D supplementation o
day should be recommended in all these groups o patients or
those up to age and or older patients. Dermatolo
gists who ha e patients at ris should also consider measuring
itamin D blood le els.
Malloy PJ, et al: The role of vitamin D receptor mutations in the
development of alopecia. Mol Cell Endocrinol 2011; 347:90–96.
Pinzone MR, et al: Vitamin D deficiency in HIV infection. Eur Rev Med
Pharmacol Sci 2013; 17:1218.
Vanchinathan V, et al: A dermatologist’s perspective on vitamin D. Mayo
Clin Proc 2012; 87:372–380.
VITAMIN K DEFICIENCY
Dietary de ciency o itamin a at soluble itamin usually
does not occur in adults because it is synthesi ed by bacteria
in the large intestine. owe er de ciency may occur in adults
because o malabsorption caused by biliary disease malab
sorption syndromes cystic brosis or anore ia ner osa. Li er
disease o all causes produces de ciency. Drugs such as cou
marin salicylates cholestyramine and perhaps the cephalo
sporins may induce a de ciency state. ewborns o mothers
ta ing coumarin or phenytoin and premature in ants with an
uncoloni ed intestine can be itamin de cient. Standard
practice since has been to administer intramuscular ( )
itamin at birth; howe er some parents decline this and
those children are at times greater ris o de eloping
itamin bleeding than those who do recei e it. Additionally
a rare condition e ists that predisposes to bleeding called
hereditary combined de ciency o the itamin dependent
clotting actors. The result o itamin de ciency is a decrease
in the itamin dependent clotting actors V and .
The resulting cutaneous mani estations are purpura hemor
rhage and ecchymosis. Treatment is mg day o
itamin or se eral days. n acute crises resh ro en plasma
is used.
Burke CW: Vitamin K deficiency bleeding. J Pediatr Health Care 2013;
27:215–221.
Centers for Disease Control and Prevention: Late vitamin K deficiency
bleeding in infants whose parents declined vitamin K prophylaxis.
MMWR 2013; 62:901–902.
Lapecorella M, et al: Effective hemostasis during minor surgery in a
case of hereditary combined deficiency of vitamin K–dependent
clotting factors. Clin Appl Thromb Hemost 2010; 16:221.
Napolitano M, et al: Hereditary combined deficiency of the vitamin
K–dependent clotting factors. Orphanet J Rare Dis 2010; 5:21.
VITAMIN B1 DEFICIENCY
Vitamin B (thiamine) de ciency results in beriberi. The
s in mani estations are limited to edema and red burning
tongue. Peripheral neuropathy is common and congesti e
heart ailure may de elop.
Lee LW, et al: Skin manifestations of nutritional deficiency disease in
children. Int J Dermatol 2012; 51:1407–1418.
VITAMIN B2 DEFICIENCY
Vitamin B (ribo a in) de ciency is seen most o ten in alco
holic patients; howe er phototherapy or neonatal icterus
acute boric acid ingestion hypothyroidism and chlorproma
ine therapy ha e also been reported as causes. The classic
ndings are the oral ocular genital syndrome. The lips are
prominently a ected with angular cheilitis (perl che) and
cheilosis. The tongue is atrophic and magenta in color ( ig.
). A seborrheic li e dermatitis with ollicular eratosis
around the nares primarily a ects the ace. Genital dermatitis
is worse in men than in women who ha e ribo a in de
ciency. There is a con uent dermatitis o the scrotum sparing
the midline with e tension onto the thighs. n its mildest orm
the dermatitis is slightly irritating and pruritic especially
when sweating. As the de ciency progresses the scrotum goes
through a mild acute dry phase with erythema and slight
Fig. 22-1 Magenta
tongue in riboflavin
deficiency.
scale to a se ere chronic dry phase with con uent red papules
that spread to in ol e the perianal area and inner thighs
accompanied by ssuring and pain. Balanitis and phimosis
may occur re uiring circumcision. n se ere de ciency the
entire scrotum becomes wet with increasing pain and ssur
Vitamin B12 deficiency
ing. The nal stage is accompanied by massi e swelling and
the scrotum may reach the si e o a ootball. Photophobia and
blepharitis angularis occur. The response to mg day o ribo
a in is dramatic.
Reamy BV, et al: Common tongue conditions in primary care. Am Fam
Physician 2010; 81:627–634.
Roe DA: Riboflavin deficiency. Semin Dermatol 1991; 10:293.
VITAMIN B6
Pyridoxine deficiency
Pyrido ine ( itamin B ) de ciency may occur in patients
with uremia and cirrhosis as well as with the use o certain
pharmacologic agents. S in changes include a seborrheic
dermatitis li e eruption atrophic glossitis with ulceration
angular cheilitis con uncti itis and intertrigo. ccasionally a
pellagrali e eruption may occur. eurologic symptoms
include somnolence con usion and neuropathy.
Pyridoxine excess
A patient who ingested large doses o pyrido ine de eloped
a subepidermal esicular dermatosis and sensory peripheral
neuropathy. The bullous dermatosis resembled epidermolysis
bullosa ac uisita.
Friedman MA, et al: Subepidermal vesicular dermatosis and sensory
peripheral neuropathy caused by pyridoxine abuse. J Am Acad
Dermatol 1986; 14:915.
VITAMIN B12 DEFICIENCY
Vitamin B (cyanocobalamin) is absorbed through the distal
ileum a ter binding to gastric intrinsic actor in an acid p .
De ciency is caused mainly by gastrointestinal (G ) abnor
malities such as a de ciency o intrinsic actor achlorhydria
(including that induced by medications) ileal diseases and
malabsorption syndromes resulting rom pancreatic disease or
sprue. Aggressi e treatment or the eradication o elicobacter
p lori may cause B de ciency as can met ormin administra
tion and long term antacid ingestion. n ood cobalamin mal
absorption syndrome the body is unable to release itamin
B rom ood or intestinal transport proteins especially
with accompanying achlorhydria. These patients ha e ade
uate dietary itamin B but o ten ha e atrophic gastritis. A
Schilling test will be normal. Congenital lac o transcobala
min can also produce B de ciency. Because o the large
body stores o B in adults de ciency occurs years a ter
G abnormalities.
Glossitis hyperpigmentation and canities are the main der
matologic mani estations o itamin B de ciency. The tongue
is bright red sore and atrophic. Linear atrophic lesions may
be an early sign. The hyperpigmentation is generali ed but
more o ten it is accentuated in e posed areas such as the ace
and hands and in the palmar creases and e ures resembling
Addison s disease. The nails may be pigmented. Premature
gray hair may occur parado ically. egaloblastic anemia is
o ten present. Wea ness paresthesias numbness ata ia and
other neurologic ndings occur.
473
 Parenteral replacement with in ections o B mg wee Fig. 22-2 Scurvy,
22 or month then mg month leads to a re ersal o the pig
mentary changes in the s in nails mucous membranes and
perifollicular
hemorrhage and
hair. egadose oral replacement o mg day may replace follicular
body stores by simple di usion independent o intrinsic hyperkeratosis.
Nutritional Diseases

actor. eurologic de ects may or may not impro e with

itamin B replacement.

FOLIC ACID DEFICIENCY

Di use hyperpigmentation glossitis cheilitis and megalo
blastic anemia identical to itamin B de ciency occur in olic
acid de ciency. Low olic acid is associated with neural tube
de ects which are more common in light s inned people sug
gesting an association between ultra iolet ( V) light e posure
and reduction in olic acid.
De Giuseppe R, et al: Burning mouth syndrome and vitamin B12
deficiency. J Eur Acad Dermatol Venereol 2011; 25:868–870.
Downham TF, et al: Hyperpigmentation and folate deficiency. Arch
Dermatol 1976; 112:562.
Graells J, et al: Glossitis with linear lesions: an early sign of vitamin B12
deficiency. J Am Acad Dermatol 2009; 60:498.
Pontes HA, et al: Oral manifestations of vitamin B12 deficiency. J Can
Dent Assoc 2009; 75:533–537.
Stabler SP: Vitamin B12 deficiency. N Engl J Med 2013; 368:149-160.
Stoopler ET, et al: Glossitis secondary to vitamin B12 deficiency anemia.
CMAJ 2013; 185:E582.

SCURVY
Scur y or itamin C de ciency is the de ciency disease most
o ten diagnosed by dermatologists since cutaneous mani esta
tions are early and prominent eatures. lderly male alcoholics
and psychiatric patients on restricti e diets are most re uently
a ected. Dialysis patients are also at ris . Smo ing is a ris
actor or low itamin C le els. n the nited ingdom up to
o men and o women in the low income population
had itamin C le els in the de cient range.
The our s are characteristic o scur y hemorrhagic
signs hyper eratosis o the hair ollicles hypochondriasis and
hematologic abnormalities. Peri ollicular petechiae are the Fig. 22-3 Corkscrew hairs in scurvy.
characteristic nding ( ig. ). n addition ecchymoses o
arious si es especially on the lower e tremities are common.
These may be associated with tender nodules (subcutaneous
and intramuscular hemorrhage) and subperiosteal hemor
rhage leading to pseudoparalysis in children. Woody edema
may be present simulating cellulitis. Subungual subcon unc
ti al intramuscular periosteal and intra articular hemorrhage
may also occur. The re erring diagnosis is o ten asculitis.
Another characteristic nding is eratotic plugging o the hair
ollicles chie y on the anterior orearms abdomen and pos
terior thighs. The hair sha ts are curled in ollicles capped by
eratotic plugs a distincti e nding called cor screw hairs
( ig. ). emorrhagic gingi itis occurs ad acent to teeth and
presents as swelling and bleeding o the gums ( ig. ). The
teeth are loose and the breath is oul. Gingi al disease may be
absent or may be the sole sign o scur y. dentulous areas do
not de elop gingi itis and those with good oral hygiene ha e
less prominent gingi al in ol ement. pista is delayed
wound healing and depression may also occur. re uently
anemia is present and may be the result o blood loss or associ
ated de ciencies o other nutrients such as olate.
The diagnosis o scur y is usually made on clinical grounds
and con rmed by a positi e response to itamin C supplemen
tation. A biopsy will e clude asculitis and demonstrate
ollicular hyper eratosis coiled hairs and peri ollicular Fig. 22-4 Scurvy, gingivitis.
474

tahir99 - UnitedVRG
hemorrhage in the absence o in ammation. Serum ascorbic
acid le els may be con rmatory in unusual cases. Treatment
is with ascorbic acid mg day or a ew days to wee
and a maintenance dose o mg day should be considered.

Niacin deficiency (pellagra)

Arron ST, et al: Scurvy: a presenting sign of psychosis. J Am Acad
Dermatol 2007; 57:S8.
Bacci C, et al: A rare case of scurvy in an otherwise healthy child.
Pediatr Dent 2010; 32:536–538.
Chisolm C, et al: Lower extremity purpura in a woman with psychosis.
Arch Dermatol 2010; 146:1167–1172.
Duggan CP, et al: Case 23-2007: a 9-year-old boy with bone pain, rash,
and gingival hypertrophy. N Engl J Med 2009; 357:392.
Fossitt DD, et al: Classic skin findings of scurvy. Mayo Clin Proc 2014;
89:e61.
Krutzman D, et al: Fatigue and lower extremity ecchymosis in a
36-year-old woman. Arch Dermatol 2012; 148:1073–1078.
Kocaturk E, et al: Scurvy in a housewife manifesting as anemia and
ecchymoses. Eur J Dermatol 2010; 20:849–850.
Li R, et al: Gingival hypertrophy: a solitary manifestation of scurvy. Am
J Otolaryngol 2008; 29:426.
Maltos AL, et al: Scurvy in a patient with AIDS. Rev Soc Bras Med Trop
2011; 44:122–123.
Singer R, et al: High prevalence of ascorbate deficiency in an Australian
peritoneal dialysis population. Nephrology 2008; 13:17.
Swanson AM, et al: Acute inpatient presentation of scurvy. Cutis 2010;
86:205–207.
Woodier N, et al: Scurvy. Emerg Med J 2012; 29:103.

NIACIN DEFICIENCY (PELLAGRA)

Pellagra usually results rom a de ciency o nicotinic acid
(niacin itamin B ) or its precursor amino acid tryptophan. t
is associated classically with a diet almost entirely composed
o corn millet or sorghum. t can occur within days o
dietary niacin de ciency. alnutrition or other itamin de
ciencies especially pyrido ine which inter ere with the con
ersion o tryptophan to niacin o ten coe ist. n de eloped
countries most cases o pellagra occur in alcoholics. ther
possible causes o pellagra are as ollows
Carcinoid tumors which di ert tryptophan to serotonin
artnup disease (impaired absorption o tryptophan)
Gastrointestinal disorders (e.g. Crohn s disease G
surgery)
Prolonged intra enous supplementation
Psychiatric disease including anore ia ner osa
Restricti e diets in adult patients with atopic dermatitis
concerned about ood allergy
Pellagra can also be induced by medications most o ten
isonia id a athioprine (and its metabolite mercaptopurine)
uorouracil ethionamide protionamide and pyra inamide.
These medications may induce pellagra by inter ering with
niacin biosynthesis. The anticon ulsants including hydanto
ins phenobarbital and carbama epine may rarely produce
pellagra in a dose dependent manner.
Clinical features
Pellagra is a chronic disease a ecting the G tract ner ous
system and s in; thus the mnemonic o the three Ds
diarrhea dementia and dermatitis.
The most characteristic cutaneous nding is the photosensi
ti e eruption which worsens in the spring and summer. t
occurs symmetrically on the ace nec and upper chest (Casal
nec lace; ig. ); e tensor arms; and bac s o the hands.
nitially there is erythema and swelling a ter sun e posure
accompanied by itching and burning or pain. n se ere cases
Fig. 22-5 Pellagra. (Courtesy of Shyam Verma, MD.)
the eruption may be esicular or bullous (wet pellagra). Com
pared with normal sunburn the pellagrous s in ta es about
our times longer to reco er rom the acute phototo ic in ury.
A ter se eral phototo ic e ents thic ening scaling and
hyperpigmentation o the a ected s in occur. The s in has a
copper or mahogany hue. n protracted cases the s in ulti
mately becomes dry smooth paper thin and glassy with a
parchmentli e consistency. Scarring rarely occurs.
The nose is airly characteristic. There is dull erythema o
the bridge o the nose with ne yellow powdery scales o er
the ollicular ori ces (sul ur a es). The eruption resembles
seborrheic dermatitis e cept or its location. Plugs o inspis
sated sebum may pro ect rom dilated ori ces on the nose
gi ing it a rough appearance.
At the onset the patient has wea ness loss o appetite
abdominal pain diarrhea mental depression and photosensi
ti ity. S in lesions may be the earliest sign with phototo icity
the presenting symptom in some cases. eurologic and G
symptoms can occur without s in changes. Delusions o para
sitosis ha e been reported in pellagra. n the later stages the
neurologic symptoms may predominate. Apathy depression
muscle wea ness paresthesias headaches and attac s o di
iness or alling are typical ndings. allucinations psycho
sis sei ures dementia neurologic degeneration and coma
may de elop. Pellagra is progressi e and can be atal i
untreated.
Histopathology
istologically the ndings in the s in ary according to the
stage o the disease. The most characteristic nding is pallor
475
 and acuolar changes o the eratinocytes in a band in the
22 upper layers o the stratum malpighii ust below the granular
cell layer which may be attenuated. mar ed a cle t may
orm in the upper epidermis correlating with the blistering
seen in wet pellagra.
Nutritional Diseases
Diagnosis and treatment
the characteristic s in ndings are present the diagnosis o
pellagra is not di cult clinically. Dietary treatment to correct
the malnutrition is essential. Animal proteins eggs mil and
egetables are bene cial. Supplementation with nicotinamide
mg three times daily or se eral wee s should be gi en.
luid and electrolyte loss rom diarrhea should be replaced
and in patients with G symptoms possibly inter ering with
absorption initial V supplementation should be considered.
Within h o niacin therapy initiation the s in lesions begin
to resol e con rming the diagnosis. Alcoholism must be
treated i present and the actors that may ha e led to pellagra
must be corrected.
Bell HK, et al: Cutaneous manifestations of the malignant carcinoid
syndrome. Br J Dermatol 2005; 152:71.
Bilgili SG, et al: Isoniazid-induced pellagra. Cutan Ocul Toxicol 2011;
30:317–319.
Desai NK, et al: Dermatitis as one of the 3 Ds of pellagra. Mayo Clin
Proc 2012; 87:e113.
Frank GP, et al: Pellegra. Trop Doct 2012; 42:182–184.
Kleyn CE: Cutaneous manifestations of the malignant carcinoid
syndrome. J Am Acad Dermatol 2004; 50:P437.
Ladoyanni E, et al: Pellagra occurring in a patient with atopic
dermatitis and food allergy. J Eur Acad Dermatol Venereol 2006;
21:394.
Oliveira A, et al: Azathioprine-induced pellagra. J Dermatol 2011;
38:1035–1037.
Savvidou S: Pellagra. Clin Pract 2014; 4:637.
Wan P, et al: Pellagra. Br J Dermatol 2011; 164:1188–1200.
BIOTIN DEFICIENCY
Biotin is uni ersally a ailable and is produced by intestinal
bacteria. There ore de ciency is rare but can occur in patients
with a short gut or malabsorption. Sometimes biotin de
ciency occurs in patients ta ing antibiotics or recei ing paren
teral nutrition. ngestion o a idin ound in raw egg white
may bind biotin leading to de ciency. The three autosomal
recessi e syndromes o holocarbo ylase synthetase de ciency
(multiple carbo ylase de ciency) biotinidase de ciency and
the rare syndrome o inability to transport biotin into cells all
ha e similar clinical eatures re erred to as multiple carbo
ylase de ciency. The holocarbo ylase de ciency presents
earlier and is termed the neonatal orm whereas the biotini
dase de ciency may present later and is termed the u enile
orm. Clinical presentation is ariable with some patients
mani esting only certain eatures.
The s in and ner ous system are primarily a ected. Derma
titis similar to that ound in patients with inc de ciency and
essential atty acid de ciency is seen. This periori cial derma
titis is characteri ed by patchy red eroded lesions on the ace
and groin. Can i a is regularly present on the lesions. Alope
cia in some cases total including loss o the eyebrows and
eyelashes can occur. Congenital trichorrhe is nodosa may be
present and con uncti itis may occur. eurologic ndings are
prominent; in adults these include depression lethargy hal
lucinations and limb paresthesias and in in ants hypotonia
lethargy a withdrawn beha ior ata ia sei ures dea ness
and de elopmental delay.
476
tahir99 - UnitedVRG
The diagnosis o the inherited orms is made by detecting
organic aminoaciduria o hydro yiso aleric acid. easure
ment o serum biotinidase can distinguish biotinidase de
ciency rom holocarbo ylase de ciency.
Treatment consists o mg o biotin day but depending
on the se erity o the en yme mutation higher doses may be
re uired. S in lesions resol e rapidly but the neurologic
damage may be permanent; thus the importance o early diag
nosis. ne report suggested that alproic acid treatment in
children especially at doses o mg g day or higher may
lead to partial biotinidase de ciency and that the s in lesions
(seborrheic dermatitis li e rash and alopecia) impro ed with
biotin supplementation at mg day.
Bassi A, et al: A 2-month-old boy with desquamative skin fold
dermatitis. J Pediatr 2014; 164:211.
Esparza EM, et al: What syndrome is this? Pediatr Dermatol 2011;
28:333–334.
Fleischman MH, et al: Case report and review of congenital biotinidase
deficiency. J Am Acad Dermatol 2004; 50:P513.
Hove JLK, et al: Management of a patient with holocarboxylase
synthetase deficiency. Mol Genet Metab 2008; 95:201.
Lunnemann L, et al: Hair-shaft abnormality in a 7-year-old girl:
trichorrhexis nodosa due to biotinidase deficiency. JAMA Dermatol
2013; 149:357–363.
Rathi N, Rathi M: Biotinidase deficiency with hypertonia as unusual
feature. Indian Pediatr 2009; 46:65.
Tammachote R, et al: Holocarboxylase synthetase deficiency. Clin Genet
2010; 78:88–93.
ZINC DEFICIENCY
inc de ciency may be an inherited abnormality acroderma
titis enteropathica or it may be ac uired. Acrodermatitis
enteropathica is an autosomal recessi e disorder caused by
mutations in the SLC gene which encodes the inc trans
porter P . Ac uired cases are termed ac uired acroder
matitis enteropathica or acrodermatitis enteropathica li e
syndrome. Premature in ants are at particular ris because o
inade uate body inc stores suboptimal absorption and
high inc re uirements. ormally human breast mil has
ade uate inc and weaning classically precipitates clinical
inc de ciency in premature in ants and in in ants with acro
dermatitis enteropathica. owe er clinical inc de ciency
may occur in ull term and premature in ants still breast eed
ing. This results rom either low maternal breast mil inc
le els or a higher inc re uirement by the in ant than the breast
mil can pro ide (e en though inc le el in breast mil
is normal). A rare syndrome o congenital myopathy recurrent
diarrhea microcephaly and dea ness has been associated with
a neonatal bullous eruption characteristic o nutritional de
ciency. These children ha e re uired ery high doses o inc
supplementation.
Parenteral nutrition without ade uate inc content may lead
to inc de ciency. Ac uired inc de ciency also occurs in alco
holics as a result o poor nutritional inta e and increased
urinary e cretion; as a complication o malabsorption in am
matory bowel disease ( BD) or G surgery; and occasionally
in patients with anore ia ner osa and ac uired immunode
ciency syndrome (A DS). Patients with se ere erosi e oral
disease such as pemphigus or gra t ersus host disease may
de elop inc de ciency rom malnourishment. inc re uire
ments increase during metabolic stress so symptomatic
de ciency may present during in ections a ter trauma or
surgery with malignancy during pregnancy and with renal
disease. Diets containing mainly cereal grains are high in
phytate which binds inc and ha e caused endemic inc
de ciency in certain areas o the iddle ast and orth
A rica.
 Fig. 22-6 Zinc
deficiency, acquired in
a patient who had
severe nausea after
gastric bypass
procedure and was
unable to eat.
Fig. 22-7 Acrodermatitis enteropathica.
The dermatitis ound in all orms o inc de ciency is pus
tular and bullous with an acral and periori cial distribution
( ig. ). n the ace in the groin and in other e ors there
is a patchy red dry scaling with e udation and crusting.
Angular cheilitis and stomatitis may be present ( ig. ). The
periungual areas are erythematous and scaling and may ha e
super cial accid pustules. ail dystrophy may result with
thinning o the nails and accentuated longitudinal ridges. Low
inc le els ha e been ound in patients with burning mouth
syndrome and inc supplementation may alle iate the symp
toms. Chronic lesions may be more psoriasi orm. Generali ed
alopecia may occur.
Diarrhea is present in most cases. Growth retardation oph
thalmic ndings impaired wound healing and central ner ous
system mani estations occur. Patients are particularly irritable
and emotionally labile.
The histopathology o ac uired and hereditary inc de
ciency is identical. There is acuolation o the eratinocytes o
the upper stratum malpighii. These areas o acuolation may
become con uent orming a subcorneal bulla. n larger lesions
there may be total epidermal necrosis with subepidermal
blister ormation. eutrophils are typically present. n the late
stages o acrodermatitis enteropathica this characteristic
upper epidermal pallor is re uently absent and the biopsy
demonstrates only a psoriasi orm dermatitis.
The diagnosis o inc de ciency should be suspected in
at ris indi iduals with acral or periori cial dermatitis. n par
ticular chronic diaper rash with diarrhea in an in ant should
lead to e aluation or inc de ciency ( ig. ). The diagnosis
Fig. 22-8
Acrodermatitis
enteropathica.
Zinc deficiency
can be con rmed by low serum inc le els. A low le el o
serum al aline phosphatase a inc dependent en yme may
be a aluable ad uncti e test in which the serum inc le el is
normal or near normal. n some patients e en i the inc le el
is in the normal range a trial o inc supplementation should
be considered i the s in lesions are characteristic. Replace
ment is with inc sul ate mg g day ( mg o elemental
inc per mg inc sul ate tablet).
n ac uired cases transient treatment and addressing the
underlying condition are ade uate. n patients with acroder
matitis enteropathica inc supplementation is mg g day
and should be li elong. er ealous inc supplementation
should be a oided because it may lead to low serum copper
le els.
Afrin LB: Fatal copper deficiency from excessive use of zinc-based
denture adhesive. Am J Med Sci 2010; 340:164–168.
Alhaj E, et al: Diffuse alopecia in a child due to dietary zinc deficiency.
Skinmed 2007; 6:199.
Bock DE, et al: Picture of the month. Arch Pediatr Adolesc Med 2009;
163:763.
Centers for Disease Control and Prevention: Zinc deficiency dermatitis in
cholestatic extremely premature infants after a nationwide shortage of
injectable zinc. MMWR 2013; 62:136–137.
Cho GS, et al: Zinc deficiency may be a cause of burning mouth
syndrome as zinc replacement therapy has therapeutic effects. J Oral
Pathol Med 2010; 39:722–727.
Chue CD, et al: An acrodermatitis enteropathica–like eruption secondary
to acquired zinc deficiency in an exclusively breast-fed premature
infant. Int J Dermatol 2008; 46:372.
Corbo MD, et al: Zinc deficiency and its management in the pediatric
population. J Am Acad Dermatol 2013; 69:616–624.
Cunha SF, et al: Acrodermatitis due to zinc deficiency after combined
vertical gastroplasty with jejunoileal bypass. São Paulo Med J 2012;
130:330–335.
Inzinger M, et al: Acquired zinc deficiency due to long-term tube
feeding. Eur J Dermatol 2011; 21:633–634.
Jensen SL, et al: Bullous lesions in acrodermatitis enteropathica
delaying diagnosis of zinc deficiency: a report of two cases and review
of the literature. J Cutan Pathol 2008; 35:1.
Karashima T, et al: Oral zinc therapy for zinc deficiency–related telogen
effluvium. Dermatol Ther 2012; 25:210–213.
Macdonald JB, et al: Think zinc deficiency: acquired acrodermatitis
enteropathica due to poor diet and common medications. Arch
Dermatol 2012; 148:961–963.
477
 Mankaney GN, et al: Images in clinical medicine. N Engl J Med 2014;
22 371:67.
Maverakis E, et al: Acrodermatitis enteropathica and an overview of zinc
metabolism. J Am Acad Dermatol 2007; 56:116.
Salle A, et al: Zinc deficiency: a frequent and underestimated
Nutritional Diseases
complication after bariatric surgery. Obes Surg 2010; 20:1660–1670.
Tran KT, et al: Acquired acrodermatitis enteropathica caused by
anorexia nervosa. J Am Acad Dermatol 2005; 53:361.
ESSENTIAL FATTY ACID DEFICIENCY
ssential atty acid ( A) de ciency may de elop in multiple
settings including low birth weight in ants cystic brosis G
abnormalities (e.g. BD intestinal surgery) and prolonged
parenteral nutrition without A supplementation. The result
ing dermatitis is similar to that seen in inc and biotin
de ciency although characteristically more widespread and
with less prominent periori cial mucous membrane and nail
in ol ement. There is a generali ed erosis because As con
stitute up to one uarter o the atty acids o the stratum
corneum and are re uired or normal epidermal barrier unc
tion. Widespread erythema and an intertriginous weeping
eruption are seen. The hair becomes lighter in color and di use
alopecia is present. Poor wound healing growth ailure and
increased ris o in ection may occur. There is a decrease in
linoleic acid and an increase in palmitoleic and oleic acids. A
ratio o eicosatrienoic acid to arachidonic acid o more than .
is diagnostic o A de ciency. V lipid therapy with ntralipid
re erses the process. n patients who de elop pancreatitis
rom the at emulsion in usion topical sa ower oil emulsion
or soybean oil applications may be considered as a stopgap
measure waiting or the pancreatitis to impro e. Topical treat
ment does not maintain li er and tissue stores.
The nutrient de ciency eruption seen in children with cystic
brosis has been termed C nutrient de ciency dermatitis
or C DD. t shares eatures o acrodermatitis enteropathica
washior or and A de ciency. t presents at wee s to
months o age with erythematous papules that may be annular.
The diaper area and perioral periorbital regions are initially
a ected. t spreads to the e tremities and progresses to wide
spread pla ues. The hair may turn gray then repigment on
supplementation. Laboratory abnormalities include anemia
hypoalbuminemia ele ated li er unction tests (e.g. al aline
phosphatase) low or normal inc low itamin and at times
A de ciency. Biopsy shows psoriasi orm dermatitis but the
upper dermal pallor may be absent. Treatment o C DD is
general enhancement o the child s nutrition addressing inc
protein and A de ciencies as well as other nutritional de
cits. inc therapy alone does not impro e C DD.
Bernstein ML, et al: Cutaneous manifestations of cystic fibrosis. Pediatr
Dermatol 2008; 25:150.
Dalgic B, et al: Gray hair and acrodermatitis enteropathica–like
dermatitis. Eur J Pediatr 2011; 170:1305–1308.
Marcason W: Can cutaneous application of vegetable oil prevent an
essential fatty acid deficiency? J Am Diet Assoc 2007; 107:1262.
Peroni DG, et al: Severe refractory dermatitis and cystic fibrosis. Arch
Dis Child 2012; 97:205.
Roongpisuthipong W, et al: Essential fatty acid deficiency while a patient
receiving fat regimen total parenteral nutrition. BMJ Case Rep 2012;
Jun 14.
Wenk KS, et al: Cystic fibrosis presenting with dermatitis. Arch Dermatol
2010; 146:171–174.
IRON DEFICIENCY
ron de ciency is common especially among acti ely men
struating women and particularly i they ha e minimal red
478
tahir99 - UnitedVRG
meat in their diets and ha e not made an e ort to replace their
losses with other oods. ucocutaneous ndings include oil
onychia glossitis angular cheilitis pruritus and telogen e u
ium di use hair loss. Plummer Vinson syndrome is the
combination o microcytic anemia dysphagia and glossitis
seen almost entirely in middle age women. The lips are thin
and the opening o the mouth is small and inelastic creating
a rather characteristic appearance. Smooth atrophy o the
tongue is pronounced. oilonychia is present in o
patients and alopecia may be present. An esophageal web in
the postcricoid area may occur presenting as di culty swal
lowing or the eeling that ood is stuc in the throat. The
diagnosis is con rmed by measuring the serum iron le el.
Treatment consists o iron sul ate supplementation mg
three times daily.
Reveiz L, et al: Treatments for iron-deficiency anaemia in pregnancy.
Cochrane Database Syst Rev 2011; CD003094.
St Pierre SA, et al: Iron deficiency and diffuse nonscarring scalp
alopecia in women. J Am Acad Dermatol 2010; 63:1070–1076.
SELENIUM DEFICIENCY
Selenium de ciency occurs in patients recei ing parenteral
nutrition in areas where soil selenium content is poor and in
low birth weight in ants. ani estations in children include
hypopigmentation o the s in and hair (pseudoalbinism).
Leu onychia and Terry li e nails ha e been reported. Cardio
myopathy muscle pain and wea ness with ele ated le els o
muscle en ymes are the ma or eatures. Treatment consists o
μg g day o selenium.
Vinton NE, et al: Macrocytosis and pseudoalbinism: manifestations of
selenium deficiency. J Pediatr 1987; 111:711.
PROTEIN-ENERGY MALNUTRITION
Protein energy malnutrition is a spectrum o related diseases
including marasmus washior or and marasmic washior
or. These conditions are endemic in the de eloping world.
arasmus represents prolonged de ciency o protein and
calories and is diagnosed in children who are below
o their ideal body weight without edema or hypoprotein
emia. washior or occurs with protein de ciency but a rela
ti ely ade uate caloric inta e and is diagnosed in children
at o their ideal body weight with edema or hypo
proteinemia. arasmic washior or shows eatures o both
conditions and is diagnosed in children who are less than
o their ideal body weight with eatures o edema or
hypoproteinemia.
These conditions are rare in de eloped countries but occa
sionally washior or may occur as a result o se ere dietary
restrictions instituted to impro e in antile atopic dermatitis. n
the nited States this may occur when rice be erage which
lac s protein is substituted or cow s mil and soy in the diets
o in ants sur i ing largely on bottle eedings. ost cases
there ore are in in ants younger than year o age.
Marasmus
n cases o marasmus the s in is dry wrin led and
loose because o mar ed loss o subcutaneous at. The
mon ey acies caused by loss o the buccal at pad is char
acteristic. n contrast to washior or there is no edema or
dermatosis.
 Fig. 22-9 “Flaky paint”
sign, kwashiorkor.
Kwashiorkor
washior or produces hair and s in changes edema impaired
growth and the characteristic potbelly. n diagnosed .S.
cases caused by dietary restriction or social chaos edema has
mas ed growth ailure delaying the diagnosis o malnutri
tion. The hair and s in changes are usually stri ing. A ricans
call the ictims o washior or red children. The hair is
hypopigmented arying in color rom a reddish yellow to
gray or e en white. The hair is dry and lusterless; curly hair
becomes so t and straight; and mar ed scaling (crac led hair)
is seen. specially stri ing is the ag sign a ecting long
normally dar hair. The hair grown during periods o poor
nutrition is pale so that alternating bands o pale and dar
hair can be seen along a single strand indicating alternating
periods o good and poor nutrition. The nails are so t and thin.
The s in lesions are hypopigmented on dar s in and
erythematous or purple on air s in. Lesions rst appear in
areas o riction or pressure the e ures groin buttoc s and
elbows. yperpigmented patches occur with slightly raised
edges. As they progress lesions resemble old dar deteriorat
ing enamel paint with peeling or des uamation. This has been
described ariously as cra y pa ement crac led s in
mosaic s in enamel paint and a y paint ( ig. ). n se ere
cases the peeling lea es pale ulcerated hypopigmented areas
with hyperpigmented borders.
Buno IJ, et al: The enamel paint sign in the dermatologic diagnosis of
early-onset kwashiorkor. Arch Dermatol 1998; 134:107.
Cox JA, et al: Flaky paint dermatosis. JAMA Dermatol 2014; 150:85–86.
Diamanti A, et al: Iatrogenic kwashiorkor in three infants on a diet of
rice beverages. Pediatr Allerg Immunol 2011; 22:878–879.
Grover Z, et al: Protein energy malnutrition. Pediatr Clin North Am 2009;
56:1055–1068.
Carotenemia and lycopenemia
Heath ML, Sidbury R: Cutaneous manifestations of nutritional deficiency.
Curr Opin Pediatr 2006; 18:417.
Mann D, et al: Cutaneous manifestations of kwashiorkor. An Bras
Dermatol 2011; 86:1174–1177.
Tierney EP, et al: Kwashiorkor from a severe dietary restriction in an
8-month infant in suburban Detroit, Michigan. Int J Dermatol 2010;
49:500–506.
CAROTENEMIA AND LYCOPENEMIA
cessi e ingestion o ruits and egetables containing large
amounts o β carotene and lycopene can result in a yellowish
discoloration o the s in which is especially prominent on
the palms soles and central ace (areas o high sweat gland
density). The sclerae are spared. n ants are most re uently
a ected perhaps since pureeing ruits and egetables ma es
these pigments more a ailable or absorption. Carotenemia
may also result rom e cess ingestion o β carotene nutritional
supplements and can be seen in hypothyroidism and anore ia
ner osa.
Kaimal S, et al: Diet in dermatology. Indian J Dermatol Venereol Leprol
2010; 76:103–1015.
Sivaramakrishnan VK, et al: Carotenemia in infancy and its association
with prevalent feeding practices. Pediatr Dermatol 2006; 23:571.
Yuko T, et al: A case of carotenemia associated with ingestion of
nutrient supplements. J Dermatol 2006; 2:132.
Bonus images for this chapter can be found online at
expertconsult.inkling.com
eFig. 22-1 Perlèche in riboflavin deficiency.
eFig. 22-2 Scurvy, large ecchymosis of the leg.
eFig. 22-3 Pellagra. (Courtesy of Shyam Verma, MD.)
eFig. 22-4 Kwashiorkor, anasarca, hypopigmentation, and scaling skin
in a child who had milk allergy and was given rice milk instead.
eFig. 22-5 Scurvy, gingivitis.
eFig. 22-6 Pellagra, erosive photosensitive eruption.
479
 eFig. 22-3 Pellagra.
(Courtesy of Shyam
Verma, MD.)

Carotenemia and lycopenemia

eFig. 22-1 Perlèche in riboflavin deficiency.

eFig. 22-2 Scurvy,

large ecchymosis of
the leg.

eFig. 22-4
Kwashiorkor,
anasarca,
hypopigmentation,
and scaling skin in a
child who had milk
allergy and was given
rice milk instead.

479.e1

tahir99 - UnitedVRG
22
Nutritional Diseases

eFig. 22-5 Scurvy, gingivitis. eFig. 22-6 Pellagra, erosive photosensitive eruption.

479.e2
 Bonus images for this chapter can be found online at
expertconsult.inkling.com
23 Diseases of Subcutaneous Fat
An in ammatory disorder that is primarily locali ed in the
subcutaneous at is termed a panniculitis. This group o disor
ders may be challenging or both the clinician and the derma
topathologist. Clinically in all orms o panniculitis lesions
present as subcutaneous nodules. istopathologically the sub
cutaneous at is a rather homogeneous tissue and in amma
tory processes may show considerable o erlap. ne way o
classi ying panniculitis is to separate erythema nodosum as
the prototypic septal panniculitis rom those processes that
primarily in ol e the at lobules the lobular panniculitides.
Some lobular panniculitides are caused by asculitis (e.g.
polyarteritis nodosa) and are discussed in other chapters.
The remaining lobular panniculitides are categori ed by
their pathogenesis. Weber Christian disease Rothmann a ai
disease lipomembranous or membranocystic panniculitis and
eosinophilic panniculitis are reaction patterns and are not spe
ci c entities. eutrophilic panniculitis may be in ectious or
may represent a ariant o Sweet syndrome with primary
in ol ement o the panniculus.
Gi en the depth o lesions in the panniculus the choice o
biopsy is critical in establishing the diagnosis. An incisional or
e cisional biopsy narrow at the s in sur ace and wider in the
panniculus is the optimal procedure. An alternati e double
punch method using a mm punch rst ollowed by a
mm punch at the depth o the rst punch may be consid
ered but it is less ideal. Panniculitis is an area o dermatopa
thology where the s ill o the dermatopathologist is critical in
establishing good clinicopathologic correlation. the biopsy
report rom an ade uate specimen does not match the clinical
ndings the clinician should repeat the biopsy or as or a
second opinion on the original specimen.
Requena L: Normal subcutaneous fat, necrosis of adipocytes and
classification of the panniculitides. Semin Cutan Med Surg 2007;
26(2):66–70.
Zelger B: Panniculitides, an algorithmic approach. G Ital Dermatol
Venereol 2013; 148(4):351–370.
SEPTAL PANNICULITIS (ACUTE AND
CHRONIC ERYTHEMA NODOSUM)
rythema nodosum ( ) is the most common in ammatory
panniculitis. t occurs in two orms acute which is common
and chronic which is rare. Acute may occur at any age
and in both genders but most cases occur in young adult
women ( emale male ratio to ). The eruption consists
o bilateral symmetric deep tender nodules and pla ues
cm in diameter. sually there are up to lesions but
in se ere cases many more may be ound. nitially the s in
o er the nodules is red smooth slightly ele ated and shiny
( ig. ). The most common location is the pretibial area and
lateral shins.
480
tahir99 - UnitedVRG
n general the lesions should be primarily anterior rather
than posterior cal . Lesions may also be seen on the upper legs
e tensor arms nec and rarely the ace. The onset is acute and
is re uently associated with malaise leg edema and arthritis
or arthralgia usually o the an les nees or wrists. e er
headache episcleritis con uncti itis and arious gastrointes
tinal (G ) complaints may also be present. er a ew days
the lesions atten lea ing a purple or blue green color resem
bling a deep bruise (erythema contusi orme). lceration does
not occur and the lesions resol e without atrophy or scarring.
The natural history is or the nodules to last a ew days or
wee s appearing in crops and then slowly in olute. is
much less common in children than adults and a ects boys
and girls e ually.
Acute is a reacti e process. t is re uently associated
with a streptococcal in ection and in children this is by ar
the most common precipitant. Tuberculosis (TB) remains an
important cause in areas where TB is endemic. ntestinal in ec
tion with ersinia Salmonella or Shigella may precipitate .
ther in ectious causes include systemic ungal in ections
(coccidioidomycosis histoplasmosis sporotrichosis blasto
mycosis) and to oplasmosis. li e lesions ha e been
described in other in ectious diseases such as elicobacter sep
ticemia brucellosis psittacosis and cat scratch e er. Because
these organisms are astidious it has not always been possible
to e clude the possibility that the li e lesions seen in these
diseases actually represent septic oci in the panniculus. Sar
coidosis may present with e er cough oint pains hilar ade
nopathy and . This symptom comple nown as L gren
syndrome is especially common in Scandina ian rish and
Puerto Rican women. t generally responds well to therapy
and runs a sel limited course. is re uently seen in patients
with in ammatory bowel disease ( BD) more o ten Crohn s
disease than ulcerati e colitis. n BD patients is not associ
ated with o erall disease se erity but is strongly associated
with emale gender eye and oint in ol ement and isolated
colonic in ol ement. has been rarely reported in associa
tion with arious hematologic malignancies but this is less
common than in patients with Sweet syndrome or pyoderma
gangrenosum.
Drugs may also induce . The bromides iodides and sul
onamides were once the most re uent causati e agents. Cur
rently oral contracepti es and hormone replacement therapy
are the most common medications inducing . This associa
tion the predominance in young women and the occurrence
o in pregnancy suggest that estrogens may predispose to
the de elopment o . chinacea herbal therapy and emu
ra enib treatment o metastatic melanoma can also induce .
Although in i imab has been used to treat associated with
Crohn s disease it has also produced on multiple chal
lenges in the setting o an ylosing spondylitis.
rythema nodosum li e lesions ha e been described in
Beh et syndrome and Sweet syndrome and probably
 Fig. 23-1 Erythema
nodosum.
-
9
ri 9
Fig. 23-2 Chronic erythema nodosum.
h
t a
represent these in ammatory processes occurring in the at
rather than the coe istence o two disorders. istologically
the subcutaneous lesions o Beh et syndrome show eatures
di erent rom a lobular or mi ed lobular and septal
pattern and most importantly a asculitis that may be lym
phocytic or leu ocytoclastic or that may in ol e a small arte
riole. This asculitis is proposed to be the primary e ent
producing the subcutaneous lesions in Beh et syndrome.
A more chronic ariant o called chronic erythema
nodosum migrans or subacute migratory panniculitis o
Vilano a and Pi ol is well described. This orm o septal pan
niculitis is much less common than acute . t is distin
guished rom acute because it is unilateral or asymmetric
i bilateral ( ig. ); it tends to occur in older women; and it
is not associated with associated systemic symptoms e cept
arthralgias. Additionally the lesions in chronic begin as a
single red nodule that tends to resol e but migrates centri u
gally orming annular pla ues o subcutaneous nodules with
central clearing. The lesions are painless or less tender than
acute and they ha e a prolonged course o months to
years.
n the di erential diagnosis o other orms o pannicu
litis must be considered. rythema induratum usually a ects
primarily the posterior cal es alone and runs a more chronic
course with the possibility o ulceration and scarring. Syphi
litic gummas as well as the nodules o sporotrichosis are
Septal panniculitis (acute and chronic erythema nodosum)
generally unilateral. Subcutaneous at necrosis associated with
pancreatitis and nodular asculitis may also occur on the
shins but associated clinicohistologic eatures allow the di
erentiation rom . Subacute in ectious processes such as
elicobacter cellulitis and atypical mycobacterial in ection may
closely mimic . n most cases the classic picture o the acute
onset o symmetric red tender nodules on the anterior shins
o a young woman readily lead to the diagnosis o without
a biopsy. owe er i the case is atypical or does not e ol e
typically a biopsy should be per ormed. When the diagnosis
o has been made in error either the clinical eatures were
atypical and a biopsy was not per ormed or was inade uate
(punch biopsy) or the biopsy was misinterpreted by the
pathologist.
rythema nodosum is a septal panniculitis; the in amma
G
tory in ltrate principally in ol es the connecti e tissue septa
between at lobules throughout the e olution o the lesion. The
R
in ltrate may be composed o either neutrophils (early) or
lymphocytes and other mononuclear cells (later) or a mi ture
V
depending on the stage at which the lesion is biopsied. n older
lesions histiocytes and multinucleate giant cells may predom
d
inate. at lobules are only secondarily a ected by the in am
mation but some oamy histiocytes may be seen in the
ti e
e olution o the lesions. eischer radial granulomas which
are aggregates o histiocytes around stellate cle ts are charac
teristic but not diagnostic o . Leu ocytoclastic asculitis is
not a histologic eature o . n chronic septal brosis
n
and septal granulomas composed o epithelioid histiocytes are
seen.
U
The management o in ol es three components identi y
ing the trigger rest and ele ation o the a ected e tremities
and speci c anti in ammatory medications. Since streptococ
cus is a common trigger throat culture and antistreptolysin
(AS ) titer are indicated. A complete history o any preceding
illness will o ten lead to clues; or e ample pre ious diarrhea
might suggest ersinia in ection. A tra el and e posure history
is especially important when considering endemic ungal
in ections. Since o patients with histoplasmosis present
with this cause should be e cluded in endemic areas. arly
treatment o the in ectious cause does not appear to shorten
the duration o the although triggered by in ections
tends to last longer with a more chronic in ection and
streptococcal induced tends to be shorter than TB triggered
. Bed rest is o great alue and may be all that is re uired
in mild cases especially in children. Gentle support hose are
also help ul. Curtailing igorous e ercise during the acute
attac s will shorten the course and restriction o physical
acti ities might pre ent e acerbations and recurrences. Aspirin
and nonsteroidal anti in ammatory drugs ( SA Ds) such as
indomethacin are o ten help ul. Potassium iodide is a sa e and
e ecti e treatment. As a supersaturated solution drops three
times a day increased by drop per dose per day up to
drops three times a day is one easy to remember dose sched
ule. As a tablet the dose is one mg tablet three times daily.
nduction o hypothyroidism by prolonged iodide therapy
should be chec ed. nce controlled the therapy is gradually
reduced o er wee s. ntralesional corticosteroid in ections
will control persistent lesions. Systemic corticosteroids will
result in rapid resolution o lesions i not contraindicated by
the underlying precipitating cause. n acute lesions colchicine
is o ten rapidly e ecti e at a dose o . mg twice daily. or
chronic saturated solution o potassium iodide (SS ) is
o ten e ecti e. n re ractory cases antimalarials may be tried.
481
 The prognosis in patients with acute is usually good
23 with the attac running its course in wee s. Recurrences
do occur especially i the underlying condition or in ection is
still present or i physical acti ity is resumed too uic ly.
Chronic or atypical lesions should suggest an alternati e diag
Diseases of Subcutaneous Fat
nosis and re uire a biopsy.
Acosta KA, et al: Etiology and therapeutic management of erythema
nodosum during pregnancy: an update. Am J Clin Dermatol 2013;
14(3):215–222.
Dengen A, et al: Erythema nodosum in a patient undergoing
vemurafenib therapy for metastatic melanoma. Eur J Dermatol 2013;
23(1):118.
Kisacik B, et al: Multiclinical experiences in erythema nodosum:
rheumatology clinics versus dermatology and infection diseases
clinics. Rheumatol Int 2013; 33(2):315–318.
Passarini B, et al: Erythema nodosum. G Ital Dermatol Venereol 2013;
148(4):413–417.
LOBULAR PANNICULITIS
VESSEL-BASED LOBULAR PANNICULITIS
n ammation or thrombosis o blood essels may lead to at
necrosis caused by ischemia. This can occur in primary orms
o asculitis such as polyarteritis nodosa and Churg Strauss
syndrome in metabolic disorders such as o alosis and calci
phyla is with atheromatous emboli with heparin and couma
rin necrosis and with arious coagulopathies. These entities
are discussed in other chapters.
Nodular vasculitis and erythema induratum
Clinically and histologically nodular asculitis is identical to
erythema induratum ( ). The two di er only by the presence
o TB as a precipitating actor in . odular asculitis pres
ents as tender subcutaneous nodules on the cal es o middle
aged thic legged women ( ig. ). Venous insu ciency
may be present. Lesions are bilateral and less red and tender
Fig. 23-3 Nodular
vasculitis.
482
tahir99 - UnitedVRG
than ; they o ten ulcerate drain oily li uid and recur o er
years.
The early lesions may show a suppurati e asculopathy
proposed by arious authors to be an arteritis a enulitis or
both. n some cases no asculitis is ound and despite its
name the presence o a asculitis is not re uired to establish
the diagnosis. odular asculitis results in substantial lobular
necrosis o adipocytes with suppuration. ecrosis o the lobule
results in loss o the lipocyte membrane and pooling o lipid
into ariably si ed round aggregates. As lesions e ol e the at
becomes increasingly necrotic orming microcysts and the
disease progresses to the point where it may per orate through
the epidermis orming ulceration. Granulomatous in amma
tion appears ad acent to areas o at necrosis and e entually
lesions resol e with brosis.
ontuberculous nodular asculitis must be distinguished
rom . Because clinicopathologic eatures are identical the
di erentiation is made by searching or tuberculous in ection
in the patient applying a tuberculin s in test. this is positi e
the appropriate diagnosis is . Polymerase chain reaction
(PCR) o the a ected tissue may re eal the D A o M cobac
terium tuberculosis in o cases o . As a tuberculid
is a mani estation o cellular immunity to TB and the puri ed
protein deri ati e (PPD) test will always be positi e. PCR o
the tissue is not recommended in patients who are tuberculin
s in test negati e. t should be noted that e en in areas where
TB is pre alent is rare representing only o cutaneous
mani estations o TB in one study. When present may
signal serious genitourinary in ol ement including tubercu
lous epididymo orchitis.
rythema induratum re uires antibiotic therapy or the
underlying TB. Treatment o nodular asculitis is usually
SS as outlined or . This is e ecti e in about hal o
patients. n the others trials o colchicine antimalarials
SA Ds mycophenolate mo etil ( ) and systemic cortico
steroids may be attempted. Support stoc ings ele ation and
treatment o associated enous insu ciency may also impro e
nodular asculitis.
Chen S, et al: Mycobacterium tuberculosis infection is associated with
the development of erythema nodosum and nodular vasculitis. PLoS
One 2013; 8(5) e62653.
Gilchrist H, et al: Erythema nodosum and erythema induratum (nodular
vasculitis): diagnosis and management. Dermatol Ther 2010;
23(4):320–327.
Larsen S, et al: Extraintestinal manifestations of inflammatory bowel
disease: epidemiology, diagnosis, and management. Ann Med 2010;
42(2):97–114.
Mascaró JM Jr, et al: Erythema induratum of Bazin. Dermatol Clin 2008;
26(4):439–445.
Misago N, et al: Erythema induratum (nodular vasculitis) associated with
Crohn’s disease: a rare type of metastatic Crohn’s disease. Am J
Dermatopathol 2012; 34(3):325–329.
Taverna JA, et al: Case reports: nodular vasculitis responsive to
mycophenolate mofetil. J Drugs Dermatol 2006; 5(10):992–993.
Lipodermatosclerosis
Lipodermatosclerosis or sclerosing panniculitis occurs pri
marily on the medial lower third o the lower legs o women
older than ( ig. ) with an abo e a erage body mass
inde (B ). t is o ten bilateral. n the acute phase red to
purple poorly demarcated indurated pla ues are present on
the lower legs. They are uite pain ul and may easily be
misdiagnosed as cellulitis phlebitis or in ammatory
morphea. n the chronic phase there is mar ed woody indura
tion in a stoc ing distribution resulting in cal es that resemble
in erted champagne bottles. This thic tight hyperpigmented
s in results rom brosis in the subcutaneous at which may
 Fig. 23-4
Lipodermatosclerosis.
occur without the primary in ammatory panniculitis e er
being clinically obser ed. ibrosis occurs multi ocally and
microscopically throughout the a ected area.
t is now recogni ed that the etiology o lipodermatosclerosis
is enous insu ciency. These patients may ha e enous ari
cosities super cial thrombophlebitis deep enous thrombosis
or se eral o these conditions. en when enous disease is not
clinically e ident e aluation o the enous system o the lower
leg will re uently re eal insu ciency. Laboratory e aluation
may re eal a genetic mutation in the brinolytic system result
ing in increased thrombosis in these patients. Venous insu
-
ciency results in hypo ia necrosis o at in ammation and
e entual brosis. hypo emia is present rom other causes
such as pulmonary disease sclerosing panniculitis may be
9
more se ere. Angiosarcoma has been reported as a rare com
plication in the setting o postphlebitic lipodermatosclerosis.
ri 9
The histologic eatures o sclerosing panniculitis are charac
teristic but not all eatures may be seen on e ery biopsy
because the histologic eatures change o er time within the
lesion. The o erlying dermis re uently shows changes o
h
stasis with nodular proli eration o thic walled essels hemo
siderin deposition brosis and atrophy. n early lesions there
a
t
is ischemic necrosis in the center o the at lobules mani ested
as ghost cells pale cell walls with no nuclei. There is a
sparse lymphocytic in ltrate in the at septa. As the lesions
e ol e the septa are thic ened and brosed and there is a
mi ed in ammatory in ltrate o lymphocytes plasma cells
and macrophages. oamy histiocytes are present around the
areas o at necrosis. at microcysts are characteristic (but not
diagnostic) and appear as small cysts with eathery eosino
philic remnants o adipocytes lining the cyst ca ity and resem
bling rost on a window so called lipomembranous at necrosis.
n lesions later these microcysts collapse and are replaced by
brosis. Despite these characteristic eatures biopsy should be
a oided in these patients. Biopsies heal poorly and may lead
to chronic leg ulcers. The diagnosis can usually be made clini
cally and nonin asi e techni ues such as magnetic resonance
imaging ( R ) ha e been used to a oid poorly healing wounds
related to a biopsy. a biopsy must be per ormed it should be
rom the most pro imal edge o in ol ement.
This diagnosis can be clinically con rmed i a care ul ascu
lar e aluation is per ormed. The location on the lower medial
cal is unusual or . ost other panniculitides a or the
posterior midcal . The gradual progression rom the an les
pro imally is characteristic o sclerosing panniculitis and not
other orms o lobular panniculitis.
The treatment o sclerosing panniculitis may be di cult.
ibrotic areas may be irre ersible. Graded compression stoc
Physical panniculitis
ings and ele ation standard treatments or enous insu
ciency are most e ecti e in this condition. Application o
pressure dressings such as an nna boot can produce dra
matic i temporary impro ement. Greater compression
nna boot with Coban and a oam buttress (bolster material
to apply e tra pressure to the red in amed area) or the Pro ore
boot can be bene cial. n ortunately some patients cannot
tolerate compression because o the pain o the lesions. ntra
lesional triamcinolone and ultrasound therapy ha e been
used but this is most e ecti e when used in con unction with
compression. Pento iphylline mg three times daily
is use ul especially in patients not responding to compression
and ele ation alone or in patients who are initially intolerant
o compression dressings. The addition o hydro ychloro
uine to pento iphylline may pro ide additional impro e
G
ment. Apparently by enhancing the brinolytic capacity o
a ected patients stano olol mg or o androlone mg
R
twice daily may bene t some patients. This is rarely re uired
howe er i appropriate pressure dressings are applied and the
V
patient is able to ta e ull doses o pento iphylline. Stano olol
and o androlone may be irili ing or women and should be
d
a oided i possible in women o childbearing age. Stano olol
may induce hepatitis. Surgical treatment o aricosities and
ti e
incompetent per orators may result in dramatic impro ement
in some patients.
Chan CC, et al: Magnetic resonance imaging as a diagnostic tool for
n
extensive lipodermatosclerosis. J Am Acad Dermatol 2008;
58(3):525–527.
Choonhakarn C, et al: Lipodermatosclerosis. J Am Acad Dermatol 2012;
U
66(6):1013–114.
Damian DL, et al: Ultrasound therapy for lipodermatosclerosis. Arch
Dermatol 2009; 145(3):330–332.
Heymann WR: Lipodermatosclerosis. J Am Acad Dermatol 2009;
60(6):1022–1023.
Huang T-M, et al: Lipodermatosclerosis. J Cutan Pathol 2009;
36:453–460.
Jeong, K-H, et al: Refractory lipodermatosclerosis treated with
intralesional platelet-rich plasma. J Am Acad Dermatol
65(5):e157–e158.
Jowett AJ, et al: Angiosarcoma in an area of lipodermatosclerosis. Ann
R Coll Surg 2008; 90(5):W15–W16.
Miteva M, et al: Lipodermatosclerosis. Dermatol Ther 2010;
23:375–388.
Segura S, et al: Lipomembranous fat necrosis of the subcutaneous
tissue. Dermatol Clin 2008; 26(4):509–517.
Vesić S, et al: Acute lipodermatosclerosis: an open clinical trial of
stanozolol in patients unable to sustain compression therapy. Dermatol
Online J 2008; 14(2):1.
Walsh SN, et al: Lipodermatosclerosis. J Am Acad Dermatol 2010;
62(6):1005–1012.
PHYSICAL PANNICULITIS
The category o panniculitis includes processes in the at that
occur rom physical actors. Some are characteri ed by the
presence o needleli e cle ts sclerema neonatorum subcutane
ous at necrosis and poststeroid panniculitis. n ants and chil
dren are most re uently a ected and in all these disorders
metabolic di erences in at seem to be important pathogeni
cally. ypothermia or cold is re uently associated in some
orms (cold panniculitis sclerema subcutaneous at necrosis).
t may be di cult in some patients to separate mild cases o
sclerema neonatorum clearly rom subcutaneous at necrosis
or to di erentiate cold panniculitis rom subcutaneous at
483
 necrosis o the newborn i the lesions are at sites o cold e po
23 sure. n general cold panniculitis re ers to locali ed cases with
a patient history o local cold e posure; sclerema re ers to cases
presenting in se erely ill children soon a ter birth with a poor
prognosis; and subcutaneous at necrosis (the most common
Diseases of Subcutaneous Fat
ariant) re ers to cases with more limited lesions occurring in
the rst wee s o li e sometimes with associated hypercalce
mia. Traumatic at necrosis results rom damage to the subcu
taneous at caused by trauma. All these conditions are treated
supporti ely and in all e cept sclerema neonatorum sponta
neous and complete reco ery is e pected.
Sclerema neonatorum
Sclerema neonatorum is the se erest and rarest disorder o the
physical panniculitides. t a ects premature neonates who are
seriously ill or other reasons or ha e e perienced pro ound
hypothermia. A ected neonates usually die unless the under
lying diseases can be re ersed. n the rst ew days o li e the
s in begins to harden usually initially on the buttoc s or
lower e tremities then rapidly spreads to in ol e the whole
body. The s in on the palms soles and genitalia is spared. The
s in becomes dry li id cold rigid and boardli e limiting the
mobility o the parts. The s in in the in ol ed areas cannot be
pic ed up. The s in o the entire body may appear hal ro en
and is yellowish white. Visceral at may also be in ol ed.
Therapy is mostly supporti e but some data suggest e change
trans usion may impro e sur i al.
istologically adipocytes are enlarged and lled with need
leli e cle ts in a radial array Recently this unusual histologic
nding was documented in a reaction to gemcitabine. A ected
at cells undergo necrosis. There is sparse in ammation and
histiocytes containing needleli e cle ts are rare possibly
because most children die be ore granulomas can orm.
Subcutaneous fat necrosis of the newborn
Subcutaneous at necrosis o the newborn (S ) occurs during
the rst wee s o li e (hal in the rst wee ) in term or post
term in ants. A history o etal distress birth asphy ia and
meconium aspiration is common. aternal cocaine use se ere
neonatal anemia thrombocytopenia and septicemia ha e also
been associated with S . Widespread lesions ha e occurred
a ter use o hypothermia or the treatment o hypo ic ischemic
encephalopathy. Pain ul rm to rubbery erythematous
nodules appear usually on the upper bac buttoc s chee s
or pro imal e tremities ( ig. ). Lesions may use to orm
Fig. 23-5 Subcutaneous fat necrosis.
484
tahir99 - UnitedVRG
pla ues and resol e spontaneously within months with no
scarring. n general the in ants remain well; howe er hypo
glycemia thrombocytopenia hypertriglyceridemia lactic aci
dosis and potentially li e threatening hypercalcemia may
occur. Some degree o hypercalcemia occurred in more than
o recently reported cases and in o consecuti e cases
seen at one institution. The hypercalcemia may appear wee s
to months a ter the appearance and resolution o the s in
lesions. Periodic serial serum calcium determinations or
the rst months o li e ha e been recommended. yper
calcemia may result in ailure to thri e irritability apathy
hypotonia sei ures and renal ailure. The hypercalcemia
is treated with hyperhydration calcium wasting diuretics
( urosemide) and ormulas low in calcium and itamin D.
Systemic corticosteroids calcitonin and bisphosphonates may
also be e ecti e when other methods ail to reduce the
hypercalcemia.
istologically S is a lobular panniculitis with granular
necrosis o adipocytes. eedle shaped cle ts are arranged radi
ally within histiocytes and multinucleate oamy histiocytes
are present. Degranulating eosinophils may also be present.
Lesions may resol e with calci cation and brosis. ine needle
aspiration and touch preparations ha e con rmed this diag
nosis and characteristic ultrasound and R ndings ha e
been reported.
Cold panniculitis
n ants and young children are particularly predisposed to
cold panniculitis. t has been described in children who suc
on ice ro en teething rings or popsicles (popsicle panniculi
tis); in the scrotum o prepubertal males ( ig. ); and in
in ants treated or supra entricular tachycardia with the appli
cation o cold pac s to the ace. Lesions occur within a ew
days o the cold application and appear as slightly erythema
tous nontender rm subcutaneous nodules. uestrian pan
niculitis on the upper outer thighs o women riding horses in
the cold more closely resembles a orm o perniosis rather than
true panniculitis (see Chapter ). erlapping histology may
occur in adults using ice pac s or pain relie .
The typical patient with at necrosis o the scrotum is a pre
pubertal (age ) boy who is hea yset or e en obese with
scrotal swelling usually bilateral associated with mild to
moderate pain. The gait is o ten guarded and broad based.
Fig. 23-6 Cold panniculitis.
There is a lac o systemic complaints and no symptoms
related to oiding. The scrotal masses are bilateral and sym
metric in most cases. owe er the lesions may be unilateral
and there may be more than two. The masses are rm and
tender and do not transmit light. The o erlying scrotal s in is
normal or red. Cryptorchidism may be seen. The most common
location o the lesions is near the perineum consistent with
the area o greatest concentration o scrotal at in children. The
adult scrotum lac s this atty tissue. Without treatment lesions
resol e o er se eral days to wee s.
istologically there is necrosis o adipocytes within lobules
o the upper subcutaneous at ad acent to the lower dermis. A
mi ed in ammatory in ltrate o lymphocytes neutrophils
and oam cells is present and microcysts sometimes occur.
This histology is not speci c and the diagnosis o cold pan
niculitis relies largely on obtaining a history o cold e posure.
Akcay A, et al: Hypercalcemia due to subcutaneous fat necrosis in a
newborn after total body cooling. Pediatr Dermatol 2013;
30(1):120–123.
Akin MA, et al: Post-operative subcutaneous fat necrosis in a newborn.
Fetal Pediatr Pathol 2011; 30(6):363–369.
Bolotin D, et al: Cold panniculitis following ice therapy for cardiac
arrhythmia. Pediatr Dermatol 2011; 28(2):192–194.
Bournas VG, et al: Images in emergency medicine. Ann Emerg Med
2011; 58:216.
Hogeling M, et al: Extensive subcutaneous fat necrosis of the newborn
associated with therapeutic hypothermia. Pediatr Dermatol 2012;
29(1):59–63.
Lopez V, et al: Usefulness of fine-needle aspiration in subcutaneous fat
necrosis of the newborn diagnosis. Pediatr Dermatol 2010;
27(3):317–318.
Mahé E, et al: Subcutaneous fat necrosis of the newborn: a systematic
evaluation of risk factors, clinical manifestations, complications and
outcome of 16 children. Br J Dermatol 2007; 156(4):709–715.
Mir-Bonafé JM, et al: Gemcitabine-associated livedoid thrombotic
microangiopathy with associated sclerema neonatorum–like
microscopic changes. J Cutan Pathol 2012; 39(7):707–711.
Patel AR, et al: Circular erythematous patch in a febrile infant. Pediatr
-
Dermatol 2012; 29(5):659–660.
Pekki A, et al: Cold panniculitis in Finnish horse riders. Acta Derm
Venereol 2011; 91:463–490.
9
Samedi VM, et al: Neonatal hypercalcemia secondary to subcutaneous
fat necrosis successfully treated with pamidronate. AJP Rep 2014;
ri 9
4:e93–e96.
Schubert PT, et al: Fine-needle aspiration cytology of subcutaneous fat
necrosis of the newborn. Diagn Cytopathol 2012; 40(3):245–247.
Stewart CL, et al: Equestrian perniosis. Am J Dermatopathol 2013;
h
35(2):237–240.
Vasireddy S, et al: MRI and US findings of subcutaneous fat necrosis of
a
the newborn. Pediatr Radiol 2009; 39(1):73–76.
t
West SE, et al: Ice-pack dermatosis. JAMA Dermatol 2013;
149(11):1314–1318.
Zeb A, et al: Sclerema neonatorum: a review of nomenclature, clinical
presentation, histological features, differential diagnoses and
management. J Perinatol 2008; 28(7):453–460.
Poststeroid panniculitis
This rare orm o panniculitis occurs predominantly in chil
dren treated acutely with high doses o systemic corticoste
roids during rapid corticosteroid withdrawal. Substantial
weight gain has usually occurred during the corticosteroid
therapy. irm subcutaneous nodules begin to appear within
month o tapering the corticosteroids. Areas o abundant sub
cutaneous at are a ored the chee s trun and pro imal
e tremities. ost cases resol e spontaneously within wee s
but i se ere the corticosteroids must be reinstituted and
tapered more slowly.
istologically the changes are identical to those seen in
subcutaneous at necrosis o the newborn. There is a lobular
panniculitis with necrosis o adipocytes and needle shaped
cle ts in both adipocytes and histiocytes. oamy histiocytes are
also present.
Sacchidanand SA, et al: Post-steroid panniculitis. Indian Dermatol Online
J 2013 Oct; 4(4): 318-320.
Physical panniculitis
Traumatic panniculitis
Accidental trauma to the s in may induce necrosis o the at.
This is most common on the trun and breasts o women. The
prior history o trauma is re uently not recalled. Lesions
present similar to a lipoma as a rm mobile subcutaneous
mass ( ormerly reported as mobile encapsulated lipoma).
Airbag in ury may induce at necrosis. The term myospheru
losis (spherulocytosis) has been used to describe subcutaneous
cystic lesions induced by trauma with hemorrhage into areas
o high lipid content. any cases are caused by e ogenous
lipids rom postoperati e pac ing o ten in parasinus tissues
or subcutaneous at. The structures resemble the sporangia o
rhinosporidiosis but represent degenerated red blood cells
G
rather than true ungal organisms. Accidental trauma to the
upper anterolateral thigh rom a des or chair may result
R
in semicircular bands o atrophy o at called lipoatrophia
semicircularis.
V
istologically there is a granulomatous lobular panniculitis
with oamy histiocytes membranous at necrosis and micro
d
cysts. Lesions heal with brosis o the septa. n myospherulo
sis large round structures containing many smaller round
ti e
eosinophilic bodies are noted. These represent degenerated
erythrocytes.
Boyd AS, et al: Revision: cutaneous Munchausen syndrome. J Cutan
n
Pathol 2014; 41(4):333–336.
Grassi S, et al: Post-surgical lipophagic panniculitis. G Ital Dermatol
Venereol 2013; 148(4):435–441.
U
Lee DJ, et al: Traumatic panniculitis with hypertrichosis. Eur J Dermatol
2011; 21(2):258–259.
Moreno A, et al: Traumatic panniculitis. Dermatol Clin 2008;
26(4):481–483.
Factitial panniculitis
Sel induced panniculitis is rarely reported but it does occur.
t may be induced by the in ection o organic materials po i
done eces sali a aginal uid and oils. n many cases ulcer
ation will occur. actitial trauma may also induce a panniculitis.
edical personnel are at ris because they ha e ready access
to syringes and needles. Pointed detailed uestioning o
the patient may identi y inconsistencies in the history or the
underlying cause or the beha ior (e.g. attention see ing
re enge malingering).
The clinician must ha e a high inde o suspicion with
patients in whom the clinical pattern is not characteristic o a
nown orm o panniculitis. nspection o early lesions or
telltale healing in ection sites may help con rm the diagnosis.
A biopsy is o ten re uired. Culture may demonstrate a consis
tent pattern o ecal oral or aginal ora. Biopsy demonstrates
an acute lobular panniculitis with at necrosis and a neutro
philic in ltrate. Care ul e aluation o the biopsy material with
polari ation may identi y oreign material. When the suspi
cion is high and no oreign material can be seen in the tissue
special e aluation by incineration and mass spectroscopy may
identi y the in ected substance. lectron microscopy with ray
emission spectrography can identi y inorganic substances.
Radiographs may demonstrate ractured needles or oreign
bodies.
Sanmartín O, et al: Factitial panniculitis. Dermatol Clin 2008;
26(4):519–527.
485
 Sclerosing lipogranuloma Fig. 23-7 Pancreatic
23 Sclerosing lipogranuloma describes the granulomatous and
fat necrosis. (Courtesy
of Dr. Misha
brotic reaction that occurs in the panniculus rom the in ec Rosenbach.)
tion o silicone or mineral oils. n most cases the in ections are
Diseases of Subcutaneous Fat

intentional and cosmetic. The time rom in ection to onset

o symptoms may be months to more than years. Topical
application o an antibacterial ointment to an open wound can
rarely result in the ormation o lipogranuloma. enatide
in ections or type diabetes may induce such changes as well.
Lesions are usually locali ed to the penis scrotum breasts
nose and buttoc s o ten a ter an attempt to augment the area
by in ection. The o erlying s in is hyperpigmented and ery
thematous. Lesions are re uently diagnosed initially as
cellulitis. n palpation the s in is indurated and cannot be
pic ed up between the ngers. The subcutaneous tissue is
indurated thic ened and lumpy. Some patients will ha e
ocal ulceration. The in ected material will re uently migrate
locally e tending beyond the sites o implantation. n some
cases it is carried to other tissues speci cally the lymphore
ticular system and lungs. epatosplenomegaly and pulmo
nary brosis may occur.
istologically the panniculus is replaced by the in ected
material which is in arious si ed acuoles gi ing the a ected
tissue a Swiss cheese appearance. Because the material is
usually washed out during the tissue processing the material
itsel is not seen only the spaces it occupied in the tissue in
i o. The acuoles are surrounded by histiocytes many o
which ha e ingested the material gi ing their cytoplasm a
acuolated appearance. ibrosis may be prominent. ro en
section can be used to demonstrate the lipid.
Eun YS, et al: A woman with a nose like an “elephant’s trunk.” J
Cosmet Laser Ther 2014; 16(3):153–154.
Foxton G, et al: Sclerosing lipogranuloma of the penis. Australas J
Dermatol 2011; 52(3):e12–e14.
Nyirády P, et al: Treatment and outcome of Vaseline-induced sclerosing
lipogranuloma of the penis. Urology 2008; 71(6):1132–1137.
Shan SJ, et al: Exenatide-induced eosinophilic sclerosing lipogranuloma
at the injection site. Am J Dermatopathol 2014; 36(6):510–512.
ENZYME-RELATED PANNICULITIS
The en yme related category includes panniculitis induced
by en ymes that damage at (pancreatic panniculitis) and
panniculitis caused by the absence o an en yme critical
in pre enting tissue in ammation a ter in ury (alpha
antitrypsin).
PANCREATIC PANNICULITIS
(SUBCUTANEOUS FAT NECROSIS)
Subcutaneous at necrosis is most o ten associated with pan
creatitis or pancreatic carcinoma and rarely with anatomic
pancreatic abnormalities pseudocysts hypertriglyceridemia
in association with nephrotic syndrome endoscopic retro
grade cholangiopancreatography and drug induced pancre
atitis. en outnumber women in cases o pancreatitis and
in cases o pancreatic carcinoma. n cases associated with
pancreatic carcinoma acinar cell carcinoma is most common.
en metastatic pancreatic carcinoma with no residual tumor
in the pancreas may induce the syndrome. n o patients
the s in lesions are the rst symptom o the underlying pan
creatic pathology and there ore represent an important clue to
the diagnosis.
486
S in lesions appear as tender or painless erythematous sub
cutaneous nodules cm in diameter ( ig. ). The lower
leg is the most common location and is a ected in more than
o cases. Subcutaneous at elsewhere may also be a ected
e cept rarely on the head and nec . The number o lesions is
usually ewer than but may reach the hundreds. n most
patients the lesions in olute lea ing an atrophic scar. the
at necrosis is se ere howe er the lesion de elops into a
sterile abscess that may brea down draining a thic brown
oily material.
Pancreatic panniculitis is re uently accompanied by a con
stellation o ndings related to at necrosis in other organs.
mportantly abdominal symptoms may be completely absent.
Arthritis is ound in o patients and may be monoar
ticular oligoarticular and rarely polyarticular. The arthritis
may be intermittent migratory or persistent and is usually in
oints ad acent to the lesions o panniculitis. amination o
the oint uid re eals the presence o ree atty acids suggest
ing it is caused by at necrosis ad acent to the oint space. ther
ndings are medullary at necrosis o bone polyserositis and
pulmonary in ltrates or embolism.
Laboratory e aluation is use ul in establishing the diagnosis.
n most patients the amylase or lipase (or both) is ele ated. n
many cases howe er one o the tests may be normal and the
other abnormal so both tests must be per ormed. About
o patients with pancreatic carcinoma and subcutaneous at
necrosis will ha e a peripheral eosinophilia.
The histologic eatures o pancreatic panniculitis are diag
nostic. These include ocal areas o at necrosis with anucleate
ghost cells ; nely stippled basophilic material representing
calcium within the residual rim o the necrotic cells and at the
periphery o the a ected oci; and a dense in ammatory poly
morphous in ltrate at the periphery o the a ected at. The
a ected necrotic areas are relati ely acellular. Se eral reports
ha e suggested that the early eatures are those o a septal
panniculitis resembling . This may ha e represented sam
pling error but does indicate that i the initial sample is not
diagnostic another perhaps more ade uate sample o a more
ad anced lesion should be considered. Panniculitis caused by

tahir99 - UnitedVRG
inter eron beta in ections can ha e a histologic appearance
similar to pancreatic panniculitis.
The necrosis o at at all a ected sites is at least partly caused
by the release o at digesting en ymes lipases rom the
a ected pancreatic tissue. These lipases spread hematoge
nously to the a ected sites.
rythema nodosum represents the primary di erential
consideration since pancreatic panniculitis may not ha e
abdominal symptoms also a ors the lower legs and may be
accompanied by oint symptoms. The distinction can be made
by s in biopsy serum amylase and lipase determinations and
especially i eosinophilia is present a search or a pancreatic
neoplasm.
Treatment mainly in ol es treating the cause o the pancre
atitis. bstruction or stenosis o ducts should be repaired
pseudocysts drained and in the case o pancreatic carcinoma
surgery or other inter entions as indicated.
Ball, NJ, et al: Lobular panniculitis at the site of subcutaneous interferon
beta injections for the treatment of multiple sclerosis can histologically
mimic pancreatic panniculitis. J Cutan Pathol 2009; 36:331–337.
Hu JC, et al: Pancreatic panniculitis after endoscopic retrograde
cholangiopancreatography. J Am Acad Dermatol 2011;
64(5):e72–e75.
Lueangarun S, et al: Pancreatic panniculitis. J Med Assoc Thai 2011;
94(Suppl 1):S253–S257.
Manawish K, et al: Pancreatic panniculitis. BMJ Case Rep Aug
22;2014.
Tran KT, et al: Tender erythematous plaques on the legs. Clin Exp
Dermatol 2010; 35:e65–366.
ALPHA-1-ANTITRYPSIN DEFICIENCY PANNICULITIS
Alpha antitrypsin is the most abundant antiprotease in cir
culation and a potent and irre ersible inacti ator o neutrophil
elastase. etero ygous de ciency o this en yme occurs in
-
in persons and homo ygous de ciency in in persons
o uropean descent. mphysema and li er disease are the
most common mani estations o antitrypsin de ciency. A
9
small percentage o patients with homo ygous de ciency and
the Pi or PiS phenotypes will de elop panniculitis.
ri 9
The panniculitis usually appears between ages and but
can occur in childhood. Both genders are e ually a ected.
Lesions appear a ter relati ely minor trauma and present as
pain ul nodules on the e tremities or trun . They may spon
h
taneously drain an oily brown li uid. ultiple draining sinus
tracts can occur with lesions coalescing into large draining
t a
pla ues.
The histologic ndings in this orm o panniculitis depend
on the stage o the lesion. arly lesions show neutrophils
splaying the collagen o the reticular dermis and subcutaneous
septa. ore ully e ol ed lesions show dissolution o the
septa with islands o normal at oating in the spaces that
represented the destroyed septa. This later nding is consid
ered diagnostic by some. lastic tissue stains may re eal
decreased elastic tissue in the a ected areas.
The clinical and histologic di erential diagnosis is actitial
panniculitis. This is not surprising because trauma produces
both lesions and in the case o alpha antitrypsin de ciency
the in ammation produced en ymes are simply not inacti
ated leading to more pronounced lesions than would be
e pected rom that degree o trauma.
Replacement o the de cient antitrypsin will lead to resolu
tion o the s in lesions but is costly. Dapsone colchicine
and do ycycline can also be e ecti e. These agents can reduce
the re uirement or en yme replacement and should be
considered as maintenance treatment in a ected patients. Sys
temic corticosteroids may e acerbate the panniculitis. Li er
transplantation leads to normal le els o alpha antitrypsin
and resolution o the panniculitis. Gene therapy and stem cell
therapy appear promising.
Laureano A, et al: Alpha-1-antitrypsin deficiency–associated panniculitis.
Gouty panniculitis
Dermatol Online J 2014; 20(1):21245.
Olson JM, et al: Panniculitis in alpha-1 antitrypsin deficiency treated with
enzyme replacement. J Am Acad Dermatol 2012; 66(4):e139–e141.
Valverde R, et al: Alpha-1-antitrypsin deficiency panniculitis. Dermatol
Clin 2008; 26(4):447–451.
CYTOPHAGIC HISTIOCYTIC PANNICULITIS
Cytophagic histiocytic panniculitis (C P) is a multisystem
disease characteri ed by widespread erythematous pain ul
subcutaneous nodules which may occasionally become ecchy
motic or brea down and orm crusted ulcerations. There is a
progressi e ebrile illness with hepatosplenomegaly pancy
topenia hypertriglyceridemia and li er dys unction. These
G
result rom the proli eration o benign appearing histiocytes
which ha e a mar ed phagocytic capacity and e tensi ely
R
in ol e the reticuloendothelial system. Some patients progress
to a terminal phase characteri ed by pro ound cytopenia li er
V
ailure and a terminal hemorrhagic diathesis. C P represents
a spectrum o disease that occurs in children and adults. Some
d
cases are triggered by iral in ections such as pstein Barr
irus ( BV) or human immunode ciency irus ( V) or
ti e
iral accines and others represent subcutaneous B cell or
T cell lymphomas. The benign cases are BV negati e and the
lymphoma associated cases are BV positi e.
istologically there is in ltration o the lobules o subcuta
n
neous at by histiocytes and in ammatory cells primarily
helper T cells with at necrosis and hemorrhage. The charac
U
teristic cell is a beanbag cell a histiocyte stu ed with phago
cyti ed red blood cells lymphocytes neutrophils platelets or
ragments o these cells. These beanbag cells are not diagnostic
o C P and can be seen in re uently in other panniculitides
especially lupus pro undus. The presence o atypical lympho
cytes or the detection o a clonal B cell or T cell proli eration
supports the diagnosis o subcutaneous lymphoma in patients
with C P.
The treatment o C P is di cult. malignancy cannot be
detected cyclosporine has been e ecti e in many patients and
combined treatment with high dose corticosteroids cyclospo
rine and ana inra has been reported. Tacrolimus is another
option that has impro ed some patients. malignancy is
detected aggressi e chemotherapy and perhaps bone marrow
transplantation may be considered.
Bader-Meunier B, et al: Clonal cytophagic histiocytic panniculitis in
children may be cured by cyclosporine A. Pediatrics 2013;
132:e545–e549.
Krilis M, et al: Cytophagic histiocytic panniculitis with
haemophagocytosis in a patient with familial multiple lipomatosis and
review of the literature. Mod Rheumatol 2012; 22:158–162.
Miyabe Y, et al: Successful treatment of cyclosporine-A–resistant
cytophagic histiocytic panniculitis with tacrolimus. Mod Rheumatol
2011; 21(5):553–556.
MISCELLANEOUS FORMS OF PANNICULITIS
GOUTY PANNICULITIS
ric acid crystals may deposit initially in the subcutaneous at
o patients with gouty panniculitis leading to lesions resem
bling other orms o panniculitis. istologically there is a
lobular panniculitis with necrosis o adipocytes and in ltration
487
 o polymorphonuclear leu ocytes. eathery needleli e crys
23 tals in shea es are present.
Pattanaprichakul P, et al: Disseminated gouty panniculitis. Dermatol
Pract Concept 2014; 4:33–35.
Diseases of Subcutaneous Fat
Penaranda-Parada E, et al: Gouty arthritis and panniculitis. J Clin
Rheumatol 2012; 18(3):142–143.
LIPODYSTROPHY (LIPOATROPHY)
The lipodystrophies are conditions characteri ed by a mar ed
reduction in subcutaneous at. Lipodystrophies can be gener
ali ed (total) partial or locali ed and may be congenital or
ac uired. n the congenital types women are more re uently
and more se erely a ected. ypertriglyceridemia and diabe
tes mellitus (D ) with insulin resistance occur in many o the
congenital and ac uired orms o lipodystrophy. These syn
dromes were uite rare until the s. With the ad ent o
combination anti iral therapy or V in ection (highly acti e
antiretro iral therapy AART) ac uired lipodystrophy has
become common in geographic regions where V in ection
is pre alent. n addition locali ed at loss can be a conse
uence o therapeutic in ections into the at.
Congenital lipodystrophies
Congenital generalized lipodystrophy
Congenital generali ed (total) lipodystrophy also nown as
Berardinelli Seip syndrome is a rare autosomal recessi e con
dition. rom birth there is an e treme paucity o at in the
subcutaneous tissue and other adipose tissues gi ing a ected
persons a generali ed muscular appearance. The mechanical
at o the palms soles oints orbits and scalp is not a ected
in some types o this syndrome. The children ha e a oracious
appetite. They ha e increased height and height elocity
ad anced bone age muscular hypertrophy and a masculine
habitus. This habitus plus enlargement o the genitalia in
in ancy (clitoromegaly) can lead to the misdiagnosis o preco
cious puberty. Scalp hair is abundant and curly and there is
generali ed hypertrichosis and hyperhidrosis. The abdomen
is protuberant and the li er and spleen are enlarged. The
o erall appearance is acromegalic ( ig. ) rom enlarge
ment o the mandible hands and eet. Acanthosis nigricans is
in ariably present and o ten generali ed. yperinsulinemia
Fig. 23-8 Congenital
generalized
lipodystrophy.
488
tahir99 - UnitedVRG
insulin resistance and D appear o ten at about puberty. The
D resists insulin and oral hypoglycemic therapy but eto
acidosis does not occur. ypertriglyceridemia occurs and
can produce erupti e anthomas pancreatitis and atty li er
which may e entuate in cirrhosis. ypertrophic cardiomyopa
thy and mild mental retardation may occur. Li e span is short
ened with patients re uently dying in young adulthood rom
complications o diabetes or rom li er or heart disease.
utations in our genes encoding or acylglycerol
phosphate O acyltrans erase P seipin ca eolin
C and ca in cause di erent subtypes o congenital
generali ed lipodystrophy. Type B mandibuloacral dysplasia
rom MPS E mutations proteasome associated autoin
ammatory syndromes caused by beta subunit type muta
tions (e.g. seemingly ac uired lipodystrophies seen in Candle
syndrome and three other subtypes) glycosylation disorders
mutations and c os and mutations are other
causes o generali ed lipodystrophies that are inherited. A
no el subtype with preser ation o bone marrow at congeni
tal muscular wea ness and cer ical spine instability has also
been described. Serum leptin and adiponectin le els are
e tremely low in arious types. leptin le els are low leptin
replacement decreases serum triglycerides and impro es
hyperglycemia. Some patients with congenital generali ed
lipodystrophy do not ha e mutations in these genes suggest
ing there are other genetic causes.
Familial partial lipodystrophy
amilial partial lipodystrophy is a heterogeneous autosomal
dominant group o disorders with distinct phenotypes. The
most common ariant is the Dunnigan type. Patients are
normal at birth but at about puberty subcutaneous tissue is
gradually lost rom the arms and legs and ariably rom the
chest and anterior abdomen. at gain occurs in the ace nec
and intra abdominally resulting in a cushingoid appearance.
D hypertriglyceridemia and atherosclerosis occur more re
uently in emale patients. The hypertriglyceridemia may
result in pancreatitis and atty li er but cirrhosis has not been
reported. The genetic de ect in the Dunnigan ariant o partial
lipodystrophy is in the gene encoding lamins A and C LM
Lamins are intermediate laments integral to the nuclear en e
lope. The site o the mutation determines the phenotype
e pressed. yopathy muscular dystrophy cardiomyopathy
and conducting system disturbances can occur in a minority
o patients.
A second characteri ed orm o amilial partial lipodystro
phy is related to mutations in the PP γ gene. This rare
syndrome is associated with mar ed loss o subcutaneous
tissue o the orearms and cal es and less prominently on the
upper arms and thighs. The trun is spared and there is no
e cess at on the nec . D hypertriglyceridemia hyperten
sion and hirsutism also occur. ther orms o amilial partial
lipodystrophy not associated with the pre ious two mutations
ha e been described suggesting additional genetic causes o
this syndrome.
andibuloacral dysplasia is an e tremely rare autosomal
recessi e condition with hypoplasia o the mandible and cla
icle acro osteolysis oint contractures mottled cutaneous pig
mentation s in atrophy alopecia a birdli e acies and dental
anomalies. Two distinct patterns o lipodystrophy occur. Type
A is characteri ed by loss o subcutaneous at rom the arms
and legs but normal to e cess at o the ace and nec . yper
insulinemia insulin resistance D and hyperlipidemia occur
in some patients. utations in the LM gene ha e been
reported in type A patients. utations in the inc metallopro
teinase MPS E which is in ol ed in the processing o
prelamin A ha e also been responsible or mandibuloacral

A B
Fig. 23-9 Partial lipodystrophy, acquired. A, Face. B, Hypertrophy of subcutaneous fat on lower half of
the body.
dysplasia. ther gene mutations responsible or rarer types
include those o C DEC and perilipin. Autosomal reces
n
si e neonatal progeroid syndrome is characteri ed by near
total absence o at rom birth with sparing o the sacral and
U
gluteal areas.
-
Acquired lipodystrophy
9
ost cases o ac uired lipodystrophy are related to antiretro
iral therapy and the se erity may be related to genetic aria
ri 9
tions in resistin. Lipodystrophy occurs in up to o emaciated and the patient has sun en chee s ( ig.
V in ected patients most o whom are being treated with
combination anti V therapy ( AART). The at o the ace
(especially buccal at pads) buttoc s and limbs is lost. There
h
is increased at deposition in other areas especially the nec
upper bac (bu alo hump) and intra abdominally. t is related
t a
to nonnucleoside re erse transcriptase inhibitors which also
inhibit the γ D A polymerase o mitochondria leading to adi
pocyte apoptosis. As with the other ac uired and inherited
orms o lipodystrophy patients may ha e hypertriglyceride
mia hypercholesterolemia and insulin resistance especially i
a protease inhibitor is a part o their treatment. et ormin
therapy at a dose o mg twice daily or use o
the thia olidinediones combined with e ercise reduces the
B and waist circum erence as well as insulin resistance.
Antiretro iral associated lipoatrophy slowly impro es with
prolonged rosiglita one. Growth hormone reduces isceral
at but the e ects are short li ed unli e with the growth
hormone releasing actor analogue tesamorelin which has
long term bene t. Various in ectable agents may pro ide cos
metic impro ement.
Ac uired lipodystrophy has se eral idiopathic orms and it
can be partial or generali ed. n addition hyperinsulinemia
hyperlipidemia and D may occur in patients with ac uired
lipodystrophy. anagement in ol es controlling the hyperin
sulinemia and its complications.
Lipodystrophy (lipoatrophy)
R G
V
d
ti e
Acquired partial lipodystrophy
(Barraquer-Simons syndrome)
ntil AART associated lipodystrophy appeared the
ac uired partial type was the most common orm o lipodys
trophy. A ected emales outnumber males . The syndrome
presents in the rst and second decades o li e. This progres
si e at disorder is characteri ed by a di use and progressi e
loss o the subcutaneous at that usually begins in the ace and
scalp progressing downward as ar as the iliac crests but
sparing the lower e tremities. The upper hal o the body loo s
A).
There is an apparent and sometimes real adiposity o the
buttoc s thighs and legs especially in a ected women ( ig.
B). The onset is insidious with no discom ort or in am
mation in the areas o at loss. A ew patients ha e de eloped
other autoimmune diseases including systemic lupus erythe
matosus and u enile dermatomyositis.
istologically the s in is normal e cept or the absence o
at. ost patients with ac uired partial lipodystrophy ha e
reduced le els o C resulting rom a circulating polyclonal
gG called C nephritic actor. Proteinuria caused by mem
branoproli erati e glomerulonephritis occurs in about o
patients appearing about years a ter the onset o the lipo
dystrophy. C nephritic actor stabili es C b Bb (C con er
tase) leading to unopposed acti ation o the alternati e
complement system and e cessi e consumption o C .
Acquired generalized lipodystrophy
This rare orm o lipodystrophy appears during childhood or
adolescence. emales with ac uired generali ed lipodystro
phy outnumber males . The at loss a ects large areas o
the body particularly the ace arms and legs. echanical at
o the palms and soles may be lost but ocular and bone
marrow at are spared. Acanthosis nigricans is present. epatic
steatosis and oracious appetite may be present. Cirrhosis
occurs in about o patients due to hepatitic steatosis or
489
 autoimmune hepatitis. D and hypertriglyceridemia may
23 occur.
About o patients will ha e a preceding in ammatory
panniculitis at the onset o the syndrome. These patients tend
to ha e less se ere mani estations. Another o patients
Diseases of Subcutaneous Fat
with ac uired generali ed lipodystrophy ha e an associated
connecti e tissue disease especially u enile dermatomyositis.
al the patients gi e no history o panniculitis and ha e no
connecti e tissue disease. ther associations include gra t
ersus host disease and glucocorticoid administration.
Centrifugal abdominal lipodystrophy
ost cases o lipodystrophia centri ugalis abdominalis in an
tilis as described by mamura et al. ha e been reported rom
a single region o Japan. The cause is un nown. t is almost
in ariably a disease o childhood; o cases begin at age .
Girls outnumber boys . t is characteri ed by depression o
the s in caused by loss o at in the groin ( o patients) or
a illa ( ). The atrophic area slowly enlarges centri ugally
or years in most patients o ten stopping with the onset
o puberty. n the depressed area was surrounded by a
discrete erythematous border with scale. ne third o patients
ha e multiple lesions and regional lymph nodes are enlarged
in . The a ected children are otherwise well. When the
lesion stops e panding the erythematous rim and lymphade
nopathy disappear. A ter the progression stops the s in
returns to normal within or years.
Lipoatrophia annularis
(Ferreira-Marques syndrome)
Lipoatrophia annularis primarily a ects women and usually
in ol es the upper e tremity. The lipoatrophy may be pre
ceded by erythema a bracelet shaped swelling and tender
ness o the entire e tremity. This is ollowed by loss o
subcutaneous at with the arm di ided into two parts by a
depressed atrophic braceletli e constriction. The depressed
band is usually about cm wide and up to cm in depth.
Arthralgias and pain o the a ected e tremity precede and
accompany the process. The band persists or up to years.
The histology shows atrophy o the subcutaneous at. The
cause is un nown.
Localized lipodystrophy
Si months to years a ter the initiation o insulin in ections
locali ed atrophy o at may de elop at the sites more
490
tahir99 - UnitedVRG
re uently in children and women than in men. Locali ed
lipodystrophy may be a mani estation o connecti e tissue
disease. This dystrophic change may resol e i patients are
switched to human insulin. uch less o ten insulin in ections
may result in lipohypertrophy. Rarely in ections o other med
ications may result in lipoatrophy or in the case o peg iso
mant lipohypertrophy.
Buyuktas D, et al: Lipodystrophy during pegvisomant therapy. Clinics
2010; 65(9):931–933.
Chan JL, et al: Clinical classification and treatment of congenital and
acquired lipodystrophy. Endocr Pract 2010; 16(2):310–323.
De Waal R, et al: Systematic review of antiretroviral-associated
lipodystrophy. PLoS One 2013; 8(5):e63623, 1–15.
Eren E, et al: Acquired generalized lipodystrophy associated with
autoimmune hepatitis and low serum C4 level. J Clin Res Pediatr
Endocrinol 2010; 2(1):39–42.
Florenza CG, et al: Lipodystrophy. Nat Rev 2011; 7:137–150.
Holstein A, et al: Lipoatrophy associated with the use of insulin
analogues. Expert Opin Drug Saf 2010; 9(2):225–231.
Kerns MJ, et al: Annular lipoatrophy of the ankles. Pediatr Derm 2011;
28(2):142–145.
Sarni RO, et al: Lipodystrophy in children and adolescents with
acquired immunodeficiency syndrome and its relationship with the
antiretroviral therapy employed. J Pediatr 2009; 85(4):329–334.
Shuck J, et al: Autologous fat grafting and injectable dermal fillers for
human immunodeficiency virus–associated facial lipodystrophy. Plast
Reconstr Surg 2013; 131(3):499–506.
Spooner LM, et al: Tesamorelin. Ann Pharmacother 2012;
46(2):240–247.
Tierney EP, et al: “Bullfrog neck,” a unique morphologic trait in HIV
lipodystrophy. Arch Dermatol 2010; 146(11):1279–1282.
Tsoukas MA, et al: Leptin in congenital and HIV-associated
lipodystrophy. Metabolism 2015; 64:47–59.
Vantyghem M-C, et al: How to diagnose a lipodystrophy syndrome. Ann
Endocrinol 2012; 73:170–189.
Bonus images for this chapter can be found online at
expertconsult.inkling.com
eFig. 23-1 Erythema nodosum.
eFig. 23-2 Erythema nodosum, erythematous tender nodules on the
anterior shins.
eFig. 23-3 Chronic erythema nodosum.
eFig. 23-4 Cold panniculitis.
eFig. 23-5 Pancreatic fat necrosis.
eFig. 23-6 Acquired partial lipodystrophy.
eFig. 23-7 Insulin-induced lipohypertrophy.
 eFig. 23-1 Erythema
nodosum.

Lipodystrophy (lipoatrophy)
eFig. 23-2 Erythema
nodosum,

R G
V
erythematous tender
nodules on the

d
anterior shins.

ti e
n
eFig. 23-3 Chronic erythema nodosum.

U
-
9
ri 9
a h
t eFig. 23-4 Cold panniculitis.

490.e1
 eFig. 23-5 Pancreatic
23 fat necrosis.
Diseases of Subcutaneous Fat

eFig. 23-7 Insulin-induced lipohypertrophy.

eFig. 23-6 Acquired

partial lipodystrophy.

490.e2

tahir99 - UnitedVRG
 Bonus images for this chapter can be found online at
The s in interacts with the endocrine system in many ways.
Some o these are discussed in this chapter.
Jabbour SA, et al: Skin manifestations of hormone-secreting tumors.
Dermatol Ther 2010; 23:643–650.
Quatrano NA, et al: Dermatologic manifestations of endocrine disorders.
Curr Opin Pediatr 2012; 24:487–493.
Saggini A, et al: Skin lesions in hereditary endocrine tumor syndromes.
Endocr Pract 2011; (Suppl 3):47–57.
ACROMEGALY
cess growth hormone (G ) in prepubertal children leads to
gigantism whereas once the epiphyseal growth plates close
such e cess leads to acromegaly. n acromegaly changes in the
so t tissues and bones orm a characteristic syndrome. n asso
ciation with the well nown changes in the acial eatures
caused by gigantic hypertrophy o the chin nose and supra
orbital ridges there is thic ening reddening and wrin ling o
the orehead and e aggeration o the nasolabial groo es. The
lips and tongue are thic . Cutis erticis gyrata is present in
appro imately o patients. The hands and eet enlarge
( ig. ) and there is gradual growth o the ngertips until
they resemble drumstic s. There is di use hypertrophy o the
s in which is at least partly caused by deposition o colloidal
iron positi e material in the papillae and reticular dermis. This
increased s in thic ness can be demonstrated in lateral radio
graphs o the heel with re ersal toward normal a ter treat
ment. S in thic ness does not correlate well with G le els at
the time o diagnosis. S in tags are o ten present and the s in
has an oily eel. ypertrichosis hyperpigmentation and
hyperhidrosis occur in many patients. The iscera also enlarge
and patients may de elop a ariety o rheumatologic cardio
ascular metabolic and respiratory complications.
The clinical changes may suggest the leonine acies o an
sen s disease as well as Paget s disease my edema and
pachydermoperiostosis. Acromegaloid acial appearance syn
drome is an inherited condition in which only the acial
changes are present and no abnormality o growth hormone
e ists. Pseudoacromegaly is an ac uired condition that may
be seen in patients with se ere insulin resistant diabetes
which appears to be a broblast de ect or in patients recei ing
long term mino idil.
The cause o o acromegaly is hypersecretion o G by
a pituitary adenoma. Rare cases o ectopic G releasing
hormone (G R ) producing tumors o the lung and pancreas
ha e been reported. The pea age o diagnosis is in the orties.
easurement o serum insulinli e growth actor ( G somato
medin C) and o serum G a ter a glucose load and magnetic
resonance imaging ( R ) o the pituitary are diagnostic tests.
t may occur as one o the mani estations o Carney comple
cCune Albright syndrome or multiple endocrine neoplasia
( ) type .
The currently pre erred treatment is a transsphenoidal micro
surgical e cision o the tumor. edical therapy may be used as
expertconsult.inkling.com
Endocrine Diseases
24
a primary treatment or those unsuitable or surgery as a pre
operati e treatment or as secondary therapy a ter ailed
surgery. ctreotide and lanreotide are potent long acting
inhibitors o G (somatostatin analogs) that are gi en as once
monthly or biwee ly intramuscular ( ) depot in ections.
atigue paresthesias and headaches impro e rapidly. With
continuous treatment so t tissue swelling and acial coarsening
impro e as G le els decline in almost all patients. A ter
months o therapy o patients will completely normali e
with the e ception o hyperhidrosis which persists in most
patients. The dopamine agonists bromocriptine and cabergo
line suppress G secretion and are used as an ad u ant medical
therapy in some cases. The growth hormone receptor antago
nist peg isomant is another medical option to normali e
growth hormone secretion. Radiation is generally reser ed or
recalcitrant cases.
Borson-Chazot F, et al: Acromegaly induced by ectopic secretion of
GHRH. Ann Endocrinol 2012; 73:497–502.
Davidovici BB, et al: Cutaneous manifestations of pituitary gland
diseases. Clin Dermatol 2008; 26:288.
Jallad RS, et al: The place of medical treatment of acromegaly. Expert
Opin Pharmacother 2013; 14:1001–1015.
Killinger Z et al: Arthropathy in acromegaly. Rheum Dis Clin North Am
2010; 36:713–720.
Ribeiro-Oliveira A, et al: The changing face of acromegaly: advances in
diagnosis and treatment. Nat Rev 2012; 8:605–611.
Yaqub A, et al: Insulin-mediated pseudoacromegaly. WV Med J 2008;
1104:12–15.
Zen PR, et al: Acromegaloid facial appearance and hypertrichosis: a
case suggesting autosomal recessive inheritance.. Clin Dysmorphol
2004; 13:49–50.
CUSHING SYNDROME
Chronic e cess o glucocorticoids leads to a wide ariety o
signs and symptoms. The most prominent eatures o Cushing
syndrome include central obesity a ecting the ace nec
trun and especially the abdomen but sparing the limbs.
There is classically deposition o at o er the upper bac
re erred to as a bu alo hump. This may be treated with lipo
suction. The ace becomes moon shaped being wide and
round. The pea age o onset is in the twenties and thirties.
The stri ing and distressing s in changes include hypertri
chosis dryness acne susceptibility to super cial dermato
phyte and Pit rosporon in ections a plethora o er the chee s
anterior nec and V o the chest and the characteristic pur
plish atrophic striae that may in ol e the abdomen ( ig. )
buttoc s bac breasts upper arms and thighs. S in ragility
and thinning occur such that easy bruising and a cigarette
paper type wrin ling are present. The s in may easily pull o
when adhesi e tape is remo ed (Liddle s sign). The thinning
o the s in can be demonstrated and measured in lateral radio
graphs o the heels. There is re ersal with treatment. Women
who are a ected our times more re uently than men in
noniatrogenic cases de elop acial lanugo hypertrichosis
491
 with thinning o the scalp hair. ccasionally there may be
24 li edo reticularis purpura ecchymosis or brownish pigmen
tation. Poi iloderma li e changes ha e been obser ed. ppor
tunistic ungal in ections occur either with organisms that are
not normally pathogenic or as uncommon presentations o
Endocrine Diseases
common in ections.
Patients with Cushing syndrome usually ha e hypertension
and mar ed generali ed arteriosclerosis with progressi e
wea ness prostration and pains in the bac limbs and
abdomen; yphosis o the dorsal spine also occurs accentuat
ing the bu alo hump appearance. steoporosis occurs and
there is generally a loss o libido. n o patients a distur
bance in carbohydrate metabolism de elops with hyperglyce
mia glycosuria and diabetes mellitus.
These aried symptoms indicate a mar ed and widespread
disturbance caused by the hyperacti e adrenal corte . When
microadenomas o the pituitary gland produce these clinical
ndings it is re erred to as Cushing s disease; this accounts
or only o patients. Between and o additional
cases are caused by increased adrenocorticotropic hormone
(ACT corticotropin) production by the pituitary but no
adenoma is identi ed. Adrenal adenomas and carcinomas
with ectopic production o ACT by other tumors account or
the remainder o cases o noniatrogenic Cushing syndrome.
Fig. 24-1 Acromegaly. Patient with acromegaly of hand on the left
compared with normal-sized hand on the right.
Fig. 24-2 Cushing
syndrome.
492
tahir99 - UnitedVRG
atrogenic Cushing syndrome is usually secondary to systemic
administration o corticosteroids; howe er absorption rom
topical corticosteroids to the s in or e en the gingi a may
occur especially in children. Primary pigmented nodular
adrenocortical disease leading to Cushing syndrome occurs in
o patients with Carney comple . t is a rare eature o
cCune Albright and type syndrome. With alcohol
abuse the clinical ndings o Cushing syndrome may be mim
ic ed producing the pseudo Cushing syndrome.
A rapid screening test or Cushing syndrome consists o oral
administration o mg o de amethasone at P ollowed
at A by a uorometric determination o plasma cortisol. A
cortisol le el below μg dL essentially rules out Cushing syn
drome e cept or the iatrogenic ariety in which there is
adrenocortical hypoplasia and the serum cortisol le el is ery
low e en without de amethasone suppression. this test is
positi e it must be con rmed by doing a hour urinary ree
cortisol test. A alue o at least three times the upper limit o
normal is sensiti e and speci c. A serum ACT is
then obtained to determine i the source is the adrenal glands
or i it is a pituitary tumor or an ectopic tumor (low normal
or high and ery high respecti ely). Treatment is primarily
surgical remo al o the tumor; howe er radiation chemo
therapy or medication that bloc s steroid synthesis is occa
sionally used.
Besemer F, et al: Alcohol-induced Cushing syndrome. Neth J Med 2011;
69(7):318–323.
Brown RJ, et al: Cushing syndrome in the McCune-Albright syndrome. J
Clin Endocrinol Metab 2010; 95(4):1508–1515.
Davidovici BB, et al: Cutaneous manifestations of pituitary gland
diseases. Clin Dermatol 2008; 26:288–295.
Ejaz S, et al: Cushing syndrome secondary to ectopic
adrenocorticotropic hormone secretion. Cancer 2011;
117(19):4381–4389.
Fraser LA, et al: Work-up for Cushing syndrome. CMAJ 2010;
182(6):584–587.
Pichardo-Lowden A, et al: Cushing syndrome related to gingival
application of a dexamethasone-containing preparation. Endocr Pract
2010; 16(2):336.
Pluta RM, et al: Cushing syndrome and Cushing disease. JAMA 2011;
306(24):2742.
Starker LF, et al: Subclinical Cushing syndrome. Surg Clin North Am
2014; 94(3):657–668.
ADDISON’S DISEASE
Adrenal insu ciency is mani ested in the s in primarily by
hyperpigmentation ( ig. ). t is di use but most
Fig. 24-3 Hyperpigmentation in Addison’s disease.
prominently obser ed in sun e posed areas and sites e posed
to recurrent trauma or pressure. The a illae perineum and
nipples are also a ected. Palmar crease dar ening in patients
o lighter s in type scar hyperpigmentation and dar ening o
ne i mucous membranes hair and nails may all be seen. An
erupti e onset o multiple new ne i may be an early sign o
Addison s disease. ccasionally pigmentation may not occur;
this is re erred to as white Addison s disease. Decreased a il
lary and pubic hair is seen in women because their androgen
production primarily occurs in the adrenals. ibrosis and cal
ci cation o the pinnae o the ears are rare complications.
Systemic signs such as weight loss nausea omiting diar
rhea wea ness atigue and hypotension add speci city to the
cutaneous abnormalities. Addison s disease is usually the
result o autoantibody destruction o adrenocortical tissue;
howe er in ection hemorrhage or in ltration may be the
cause o adrenal insu ciency. n young boys suspected o
ha ing Addison s disease adrenoleu odystrophy must be
considered. yperpigmentation may precede neurologic
signs so ery long chain atty acid le els should be deter
mined. Addison s disease may be part o polyglandular auto
immune syndrome types and V in which arious
combinations o hypoparathyroidism chronic candidiasis
itiligo or autoimmune thyroiditis and diabetes may occur.
Diagnosis o Addison s disease is made by obtaining a
serum cortisol ollowed by stimulation with cosyntropin.
ailure to see an ele ation abo e μg dL in h is diagnostic.
Plasma ACT is ele ated in primary insu ciency but normal
to low in patients with secondary adrenal insu ciency in
whom the damage is in the hypothalamic pituitary a is. The
adrenals should be imaged with computed tomography (CT)
to e clude in ltration or in ection.
Treatment o Addison s disease is replacement o the gluco
corticoids and mineralocorticoids.
Betterle C, et al: Addison’s disease. Eur J Endocrinol 2013;
169(6):773–784.
Napier C, et al: Autoimmune Addison’s disease. Autoimmune Endocr
Dis 2012; 41:e626–e635.
Prat C, et al: Longitudinal melanonychia as the first sign of Addison’s
disease. J Am Acad Dermatol 2008; 58:522–524.
Vaidya B, et al: Addison’s disease. BMJ 2009; 339:b2385.
Wilhelm L, et al: Histoplasmosis associated with Addison’s disease.
Rev Soc Bras Med Trop 2013; 46(1):123.
PANHYPOPITUITARISM AND
GROWTH HORMONE DEFICIENCY
Pituitary ailure results in many changes in the s in hair
and nails because o the absence o pituitary hormone action
on these sites. Pale thin dry s in is seen. ypohidrosis is
present. Di use loss o body hair occurs with a illary pubic
and head hair being especially thin. The nails are thin ragile
and opa ue and grow slowly. Compromise o the pituitary
gland is usually caused by a pituitary tumor although
in ltration in ection trauma hemorrhage or hypothalamic
tumors may be the etiology. Thyroid hormone glucocorti
coids se steroids and growth hormones are low and re uire
replacement. A pituitary R will screen or tumors or in l
trati e processes.
Davidovici BB, et al: Cutaneous manifestations of pituitary gland
diseases. Clin Dermatol 2008; 26:288–295.
De Lange TE, et al: A case of cocaine-induced panhypopituitarism with
human neutrophil elastase-specific anti-neutrophil cytoplasmic
antibodies. Eur J Endocrinol 2009; 160(3):499–502.
Sariguzel N, et al: Dobrava hantavirus infection complicated by
panhypopituitarism, Istanbul, Turkey, 2010. Emerg Infect Dis 2012;
18(7):1180–1183.
ANDROGEN-DEPENDENT SYNDROMES
The androgen dependent syndromes are caused by the e ces
si e production o adrenal or gonadal androgens by adrenal
Androgen-dependent syndromes
adenomas carcinoma or hyperplasia Leydig cell tumors in
men and arrhenoblastomas and polycystic o arian syndrome
(PC S) in women. PC S is de ned as the association o bio
chemical or clinical androgenism with chronic ano ulation
without speci c underlying disease o the adrenal or pituitary
glands.
The cutaneous signs o e cessi e androgen in women
include acne hirsutism temporal balding and androgen
induced patterned scalp hair loss seborrhea enlargement o
the clitoris and decreased breast si e. yperpigmentation o
the s in areolae genitalia palmar creases and buccal mucosa
de elops in some patients. Acanthosis nigricans is common in
PC S re ecting insulin resistance. Diabetes mellitus cardio
ascular complications and sleep apnea are associated comor
bidities o PC S. The association o endometrial cancer is
suggested but remains unpro ed in women. emales may also
de elop a deepening oice increased muscle mass galactor
rhea and irregular or absent periods.
n the congenital adrenogenital syndrome e cess androgen
is produced by an inherited de ect in any o the e en ymatic
steps re uired to con ert cholesterol to cortisol. The ormation
o inade uate amounts o cortisol stimulates the pituitary to
secrete e cessi e ACT which leads to e cess androgen pro
duction. n boys precocious puberty results. n girls mascu
lini ation occurs with the prominent cutaneous signs o e cess
androgen production ( ig. ). These signs may include
acne. Acne with onset between ages and with physical
ndings suggesti e o a hormonal disorder such as se ual
precocity irili ation and growth abnormalities should be
re erred to a pediatric endocrinologist. Acne that begins rom
ages to o ten mani ests primarily as comedonal lesions in
the central ace. nless there are other signs o androgen
e cess these patients do not need a wor up. Accelerated bone
growth with early closure o the epiphyseal plates results in
short stature. arly appearance o pubic and a illary hair is
also seen.
Testing includes serum total testosterone and dehydroepi
androsterone sul ate (D A S) le els. the total testosterone
concentration is greater than ng dL o arian imaging is
indicated to assess or an o arian tumor. D A S le el is
two to three times the upper limit an adrenal mass should be
suspected and CT scan o the adrenals is re uired. n congeni
tal adrenal hyperplasia testing should include le els o
cortisol aldosterone and precursor hormones and in some
Fig. 24-4 Adrenogenital syndrome.
493
 patients cosyntropin (Cortrosyn) stimulation tests. onclassic
24 adrenal hyperplasia is most o ten related to hydro ylase
de ciency and may present as PC S. t is best diagnosed by
a corticotropin stimulated hydro yprogesterone ( P)
le el greater than ng mL ( . nmol L). The diagnosis can
Endocrine Diseases
be con rmed by genotyping o the C P gene. The baseline
P le el has been used as a screening test. Although the
sensiti ity and speci city o the test ha e been challenged
le els o P lower than ng mL ( . nmol L) ha e a airly
good negati e predicti e alue and le els greater than ng
mL ( . nmol L) ha e a airly good positi e predicti e alue.
The uestion remains whether treatment with corticosteroid
replacement results in better outcomes than empiric antian
drogen therapy.
Treatment o the cutaneous signs o androgen e cess is suc
cess ul with an oral contracepti e and o ten also an androgen
bloc ing agent such as cyproterone acetate utamide or
nasteride. Spironolactone which competes or the androgen
cytosol receptors has pro ed use ul as a systemic antiandrogen
in the treatment o hirsutism and acne. Laser hair remo al and
standard acne therapy are also e ecti e. Adrenal androgenic
emale pattern alopecia may impro e with topical mino idil
or spironolactone. et ormin is re uently used to impro e
insulin responsi eness. Chorionic illous biopsy may identi y
homo ygous adrenogenital emale etuses and allow or de a
methasone therapy to pre ent intrauterine irili ation o the
e ternal genitalia.
Auchus RJ et al: Approach to the patient: the adult with congenital
adrenal hyperplasia. J Clin Endocrinol Metab 2013; 98(7):2645–2655.
Azziz R, et al: The Androgen Excess and PCOS Society criteria for the
polycystic ovary syndrome. Fertil Steril 2009; 91:456–488.
Lee AT, et al: Dermatologic manifestations of polycystic ovary
syndrome. Am J Clin Dermatol 2007; 8:201–219.
Martin KA, et al: Evaluation and treatment of hirsutism in
premenopausal women. J Clin Endocrinol Metab 2008; 93:1105–1120.
Nisenblat V, et al: Androgens and polycystic ovary syndrome. Curr Opin
Endocrinol Diabetes Obes 2009; 16:224–231.
Setji TL, et al: Polycystic ovary syndrome. Am J Med 2014; 127:
912–919.
Sirmans SM, et al: Epidemiology, diagnosis, and management of
polycystic ovary syndrome. Clin Epidemiol 2013; 18(6):1–13.
Voutilainen R, et al: Premature adrenarche. J Steroid Biochem Mol Biol
2014 Jun 9; pii: S0960-0760(14)00118-6.
HYPOTHYROIDISM
ypothyroidism is a de ciency o circulating thyroid hormone
or rarely peripheral resistance to hormonal action. De ciency
may be caused by iodine de ciency late stage ashimoto
autoimmune thyroiditis or pituitary or hypothalamic disease
causing central hypothyroidism or it may be iatrogenic
secondary to surgery radioacti e iodine treatment or drug
therapy with lithium inter eron multi inase inhibitors al
proic acid or be arotene. t may also complicate anticon ul
sant and minocycline hypersensiti ity syndromes appearing
appro imately months a ter the eruption has resol ed.
ypothyroidism produces arious clinical mani estations
depending on the age when it occurs and on its se erity.
iddle age women are the adults most o ten a ected. Patients
with Turner and Down syndrome are predisposed to hypo
thyroidism and the production o thyroid autoantibodies.
There are a wide array o immunologic conditions associated
with ashimoto thyroiditis including polyglandular autoim
mune syndrome types and itiligo connecti e tissue
disease and autoimmune urticaria.
An autosomal recessi e ariant o ectodermal dysplasia
has been described as A T R syndrome alopecia nail
dystrophy ophthalmic complications thyroid dys unction
494
tahir99 - UnitedVRG
hypohidrosis ephelides and enteropathy and respiratory
tract in ections.. Recent associations with hypothyroidism
include lichen planopilaris and cutaneous sarcoidosis.
Congenital hypothyroidism
Thyroid de ciency in etal li e produces the characteristic
picture o cretinism at birth and in the ne t ew months o li e.
Various mutations in the thyroglobulin gene the thyroid per
o idase gene and the thyroid stimulating hormone (TS )
receptor may be causati e. Depending on the degree o thyroid
de ciency a wide ariety o signs and symptoms may be
e ident. The main conse uence o e treme thyroid de ciency
is cretinism and its attendant mental retardation but much
more pre alent are lesser degrees o intellectual and neuro
logic de cits seen in areas o the world where iodi ed salt is
still not routinely a ailable.
The person with cretinism has cool dry pasty white to yel
lowish s in. Disturbances in the amount te ture and distribu
tion o the hair with patchy alopecia are common. Pigmentation
is less than normal a ter e posure to sunlight. Sweating is
greatly diminished. The lips are pale thic and protuberant.
The tongue is usually enlarged and there is delayed dentition.
Wide set eyes a broad at nose and periorbital pu ness
characteri e the ace. A protuberant abdomen with umbilical
hernia; acral swelling; coarse dry brittle nails; a cla icular at
pad; and hypothermia with cutis marmorata are also seen.
Myxedema
When lac o secretion o thyroid hormone is se ere my
edema is produced. The s in becomes rough and dry and in
se ere cases o primary my edema ichthyosis ulgaris may be
simulated. The acial s in is pu y; the e pression is o ten dull
and at; macroglossia swollen lips and a broad nose are
present; and chronic periorbital in ltration secondary to depos
its o mucopolysaccharides re uently de elops ( ig. A).
Such in ltrate can lead to a cutis erticis gyrata appearance o
the scalp. Carotenemia may cause a yellow tint in the s in that
is especially prominent on the palms and soles. Di use hair loss
is common and the outer third o the eyebrows is shed ( ig.
B). The hair becomes coarse and brittle. The ree edges o
the nails brea easily and onycholysis may occur.
Mild hypothyroidism
Lesser degrees o thyroid de ciency are common and much
less easily diagnosed. Coldness o hands and eet in the
absence o ascular disease sensiti ity to cool weather lac o
sweating tendency to put on weight need or e tra sleep
drowsiness in the daytime and constipation all suggest pos
sible hypothyroidism and the need or appropriate tests. Pal
moplantar eratoderma may be a sign o hypothyroidism and
will resol e a ter thyroid hormone replacement is gi en.
Diagnosis and treatment
An increased TS test is the best diagnostic test or primary
hypothyroidism. Triiodothyronine (T ) and thyro ine (T ) are
low. n ashimoto thyroiditis the most common cause o
hypothyroidism in the nited States thyroid pero idase anti
bodies are present in o patients and antithyroglobulin
antibodies in . n those with positi e antibodies but normal
thyroid unction hypothyroidism will de elop at a rate o

B
A Fig. 24-5 A, Periorbital infiltration with mucopolysaccharides. B, Loss
of lateral eyebrow.
per year. Thyroid hormone replacement will re erse the s in
ndings o hypothyroidism.
Abduljabbar MA, et al: Congenital hypothyroidism. J Pediatr Endocrinol
Metab 2012; 25(1-2):13–29.
Almandoz JP, et al: Hypothyroidism. Med Clin North Am 2012;
96:203–221,
Anolik RB, et al: Thyroid dysfunction and cutaneous sarcoidosis. J Am
Acad Dermatol 2012; 66(1):167–168.
Mesinkovska NA, et al: Association of lichen planopilaris with thyroid
disease. A retrospective case-control study J Am Acad Dermatol.
2014; 70:889–892.
Brown RJ, et al: Minocycline-induced drug hypersensitivity syndrome
followed by multiple autoimmune sequelae. Arch Dermatol 2009;
145:63–66.
Doshi DN, et al: Cutaneous manifestations of thyroid disease. Clin
Dermatol 2008; 26:283–287.
Funakoshi T, et al: Risk of hypothyroidism in patients with cancer treated
with sunitinib. Acta Oncol 2013; 52(4):691–702.
Persani L, et al: Clinical review: central hypothyroidism. J Clin
Endocrinol Metab 2012; 97(9):3068–3078.
Persani L, et al: Genetics and phenomics of hypothyroidism due to TSH
resistance. Mol Cell Endocrinol 2010; 322(1-2):72–82.
Ris-Stalpers C, et al: Genetics and phenomics of hypothyroidism and
goiter due to TPO mutations. Mol Cell Endocrinol 2010;
322(1-2):38–43.
Targovnik HM, et al: Thyroglobulin gene mutations in congenital
hypothyroidism. Horm Res Paediatr 2011; 75(5):311–321.
HYPERTHYROIDISM
cessi e uantities o circulating thyroid hormone may be
caused by Gra es thyroiditis (di use to ic goiter) a multi
nodular to ic goiter (Plummer s disease) or a single to ic
thyroid nodule early ashimoto autoimmune thyroiditis a
TS secreting pituitary adenoma pituitary resistance to
thyroid hormone metastatic thyroid cancer or e cessi e
human chorionic gonadotropin. The most common etiology is
Gra es disease which accounts or about o cases; it is
mediated by thyroid stimulating antibodies that bind to the
TS receptor mimic the e ects o TS and induce hyperthy
roidism. any s in changes are common to all orms o hyper
thyroidism. The cutaneous sur ace is warm moist and smooth.
Hyperthyroidism
Palmar erythema or acial ushing may be seen. The hair is
thin and has a downy te ture and nonscarring di use alope
cia may be obser ed. The s in may dar en to produce a
bron ed appearance or melanoderma; melasma o the chee s
is seen is some cases. ail changes are present in appro i
mately o patients with Plummer nails a conca e contour
o the plate with characteristic distal onycholysis. yperhidro
sis may be noted.
Gra es disease has a emale male ratio o and the pea
age o onset is years. t is the most common cause o
noniatrogenic hyperthyroidism. phthalmopathy pretibial
my edema and thyroid acropachy are ndings almost always
limited to patients with Gra es disease ( ig. ). Thyroid
acropachy seen in appro imately . o Gra es patients
is characteri ed by digital clubbing so t tissue swelling o the
hands and eet and diaphyseal proli eration o the periosteum
in acral and distal long bones (tibia bula ulna radius). t
usually occurs a ter treatment o hyperthyroidism and is
re uently associated with e ophthalmos and pretibial my
edema. t may howe er occasionally precede the thyroto i
cosis and has been recogni ed in euthyroid and hypothyroid
patients. t can be con used clinically with acromegaly pachy
dermoperiostosis pulmonary osteoarthropathy or osteoperi
ostitis but the radiologic ndings are pathognomonic.
Pretibial my edema consisting o bilateral locali ed cuta
neous accumulations o glycosaminoglycans occurs in o
patients who ha e or ha e had Gra es disease. The morphol
ogy may ary rom a nonpitting in ltration to nodules pla ues
and e en an elephantiasic orm where the s in is thic ened
rm and hyperpigmented rom ust below the nees to the
eet. t may also occur in re uently during the course o ashi
moto thyroiditis and primary hypothyroidism. Patients with
pretibial my edema regularly ha e associated ophthalmopa
thy and occasionally thyroid acropachy. Although usually not
clinically apparent appro imately hal o patients with Gra es
disease ha e mucopolysaccharide deposition in the preradial
area o the e tensor aspects o the orearms. Lesions o the
shoulder hands thigh and scalp ha e been reported.
mpro ement in the pla ues o pretibial my edema
has resulted rom intralesional in ections o triamcinolone ace
tonide and with high potency topical corticosteroids under
495
 occlusion. Systemic corticosteroids may also be help ul. Com
24 pression stoc ings or complete decongesti e physiotherapy
and a combination o manual lymphatic drainage bandaging
and e ercise are use ul and sa e. With intra enous immune
globulin ( V G) administration impro ement o the s in eye
Endocrine Diseases
and immunologic parameters has been reported in small series
o patients. Pento i ylline octreotide plasmapheresis and
cytoto ic drugs ha e all been reported to help in small numbers
o patients but negati e reports also e ist.
Vitiligo is present in o patients with Gra es disease and
occurs with an increased re uency in ashimoto thyroiditis.
rticaria may be seen in patients with thyroid autoantibodies
and may clear with the administration o thyroid hormone
e en in euthyroid patients. A wide range o other autoimmune
disorders may be seen in patients with Gra es disease or
ashimoto autoimmune thyroiditis.
The TS le el is low in all patients e cept those with a TS
secreting pituitary adenoma. ree T and T are ele ated. Anti
TS antibodies are present in almost all Gra es patients. A
hour radioiodine scan will also help de ne the etiology.
Treatment is with radioacti e iodine or antithyroid drugs such
as methima ole or propylthiouracil.
Artantas S, et al: Skin findings in thyroid diseases. Eur J Intern Med
2009; 20:158.
Brinster NS, et al: Localized myxedema of thyroid disease. J Am Acad
Dermatol 2013; 68(6):e189–e190.
Heymann W (ed): Thyroid Disorders with Cutaneous Manifestations.
Heidelberg: Springer, 2008.
Shirai K, et al: Dramatic effect of low-dose oral steroid on elephantiasic
pretibial myxedema. J Dermatol 2014; 41:941–942.
Fig. 24-6 A, Thyroid acropachy and pretibial myxedema.
B, Exophthalmos.
496
tahir99 - UnitedVRG
Takasu N, et al: Treatment of pretibial myxedema (PTM) with topical
steroid ointment application with sealing cover (steroid occlusive
dressing technique). Intern Med 2010; 49:665–669.
Vannucchi G, et al: Treatment of pretibial myxedema with
dexamethasone injected subcutaneously by mesotherapy needles.
Thyroid 2013; 23(5):626–632.
HYPOPARATHYROIDISM
Varied changes in the s in and its appendages may be e ident
in parathyroid hormone (PT parathormone) de ciency.
ost pronounced is aulty dentition when hypoparathyroid
ism is present during de elopment o the permanent teeth.
The s in is dry and scaly. A di use scantiness o the hair and
complete absence o a illary and pubic hair may be ound. The
nails are brittle and mal ormed. nycholysis with ungal
in ection may be present. patients with idiopathic hypo
parathyroidism de elop mucocutaneous candidiasis.
ypoparathyroidism is the most re uent endocrine abnor
mality present in patients with the AP C D (autoimmune
polyendocrinopathy candidiasis ectodermal dystrophy) syn
drome. n autoimmune polyendocrinopathy syndrome type
hypoparathyroidism is present in association with Addison s
disease and chronic candidiasis. ypoparathyroidism may
also occur in DiGeorge syndrome or with parathyroid in ltra
tion or their inad ertent surgical remo al during thyroid
surgery. The causati e genetic de ects and speci c autoanti
bodies responsible or PT de ciency and pseudohypopara
thyroidism are well de ned. ypoparathyroidism with
resultant hypocalcemia may trigger bouts o impetigo herpeti
ormis or pustular psoriasis.
Pseudohypoparathyroidism (P ) is an autosomal dominant
or lin ed inherited disorder characteri ed by end organ
unresponsi eness to PT . The PT and phosphorus le els are
high whereas the serum calcium is low. The typical clinical
ndings include short stature; obesity; round ace; prominent
orehead; low nasal bridge; attached earlobes; short nec ;
short wide nails; delayed dentition; mental de ciency; amen
orrhea; blue sclerae; and cataracts. Brachycephaly microceph
aly and shortened metacarpals or metatarsals especially o
the ourth and th digits occur because o premature epiphy
seal closure. This results in short stubby ngers and toes with
dimpling o er the metacarpophalangeal oints (Albright s
sign; ig. ). Subcutaneous calci cation and ossi cation
occur re uently in P as they may in pseudopseudohypo
parathyroidism (PP ) which has the same phenotype but
Fig. 24-7 Albright’s sign in pseudohypoparathyroidism.
patients ha e normal serum and calcium le els. P and PP
are two types o Albright hereditary osteodystrophy.
Al-Azem H, et al: Hypoparathyroidism. Best Pract Res Clin Endocrinol
Metab 2012; 26(4):517–522.
Bilezikian JP, et al: Hypoparathyroidism in the adult. J Bone Miner Res
2011; 26(10):2317–2337.
Brandi ML, et al: Genetics of hypoparathyroidism and
pseudohypoparathyroidism. J Endocrinol Invest 2011; 34(7):27–34.
De Sanctis V, et al: Hypoparathyroidism. Curr Opin Endocrinol Diabetes
Obes 2012; 19: 435-442.
Mantovani G, et al: Clinical review: pseudohypoparathyroidism. J Clin
Endocrinol Metab 2011; 96(10):3020–3030.
HYPERPARATHYROIDISM
Whereas PT regulates calcium le els calcinosis cutis may
de elop rom e cess PT . This can occur when the serum
calcium phosphorus product is greater than mg dL. This
may mani est as large subcutaneous nodules or white o ten
linearly arranged papules centered around oints. Addition
ally calciphyla is although most common in the patient
with secondary hyperparathyroidism and renal ailure may
be seen occasionally in primary hyperparathyroidism.
ultiple endocrine neoplasia type ( ) is characteri ed
by tumors o the parathyroid glands endocrine pancreas ante
rior pituitary thyroid and adrenal glands. The most re uently
obser ed abnormality is hypercalcemia rom hypersecreting
tumors o the parathyroid glands. This autosomal dominantly
inherited disease usually presents in the ourth decade o li e
with clinical symptoms related to hypersecretion o hormone.
Patients may also mani est multiple angio bromas collageno
mas ca au lait macules lipomas con etti li e hypopigmenta
tion and gingi al macules. The angio bromas are smaller and
less numerous than those present in tuberous sclerosis. Tumors
in both and tuberous sclerosis arise because o abnor
malities within a tumor suppressor gene. is caused by
ME mutations and type V (or also called
) which also has associated parathyroid tumors is
caused by mutations o CD
Thakker RV, et al: Multiple endocrine neoplasia type 1 (MEN1) and type
4 (Men4). Mol Cell Endocrinol 2014; 386(1-2):2–15.
Thakker RV et al: Clinical practice guidelines for multiple endocrine
neoplasia type 1 (MEN1). J Clin Endocrinol Metab 2012;
97(9):2990–3011.
Vidal A, et al: Cutaneous lesions associated to multiple endocrine
neoplasia syndrome type 1. J Eur Acad Dermatol Venereol 2008; 22:835.
ACANTHOSIS NIGRICANS
Acanthosis nigricans (A ) is characteri ed by hyperpigmenta
tion and el et te tured pla ues which are symmetrically
distributed. The regions a ected may be the ace nec a illae
( ig. ) e ternal genitals groin inner aspects o the thighs
e or and e tensor sur ace o the elbows and nees dorsal
oints o the hands umbilicus and anus. With e tensi e
in ol ement lesions can be ound on the areolae con uncti
ae lips and buccal mucosa and around the umbilicus.
Rarely the in ol ement may be almost uni ersal. The color o
the patches is grayish brownish or blac . The palms or soles
may show thic ening o the palmar or plantar s in with
e aggeration o the dermatoglyphs. n se ere cases a rugose
hypertrophy occurs and can be a sign o malignancy. Small
papillomatous nonpigmented lesions and pigmented macules
may occasionally be ound in the mucous membranes o the
mouth pharyn and agina. Acrochordons are a re uent
accompaniment in the a illae and groin. There is a clear
Acanthosis nigricans
Fig. 24-8 Obesity-related acanthosis nigricans.
predisposition or certain racial groups to mani est A with
ati e Americans most o ten a ected ollowed by A rican
Americans and ispanics all abo e the rates in Caucasians.
A is obesity independent.
Type I: acanthosis nigricans associated
with malignancy
The rare type A may either precede ( ) accompany
( ) or ollow ( ) the onset o the internal cancer. t is
generally the most stri ing type clinically rom both the e tent
o in ol ement and the pronounced nature o the lesions ( ig.
). ost cases are associated with adenocarcinoma espe
cially o the gastrointestinal tract ( stomach) lung and
breast or less o ten the gallbladder pancreas esophagus
li er prostate idney colon rectum uterus and o aries.
ther types o cancer and lymphoma may be seen as well. A
ew cases ha e been obser ed in childhood but most begin
a ter puberty or in adulthood. Type A should be highly
suspected i widespread lesions de elop in a nonobese male
o er age .
Tripe palms (acanthosis palmaris) are characteri ed by
thic ened el ety palms with pronounced dermatoglyphics;
occur in patients with cancer and are seen with A
( ig. ). n o these patients tripe palms are the pre
senting sign o an undiagnosed malignancy. only the palms
are in ol ed lung cancer is most common whereas in tripe
palms associated with A gastric cancer is most re uent.
Type II: familial acanthosis nigricans
The e ceedingly rare type A is present at birth or may
de elop during childhood. t is commonly accentuated at
puberty. t is not associated with an internal cancer and is
inherited in an autosomal dominant manner. Some patients
will ha e a mutation in the broblast growth actor receptor
gene as also occurs in Cru on s and other syndromes with
associated A .
Type III: acanthosis nigricans associated
with insulin-resistant states and syndromes
Type is the most common ariety o A . t presents as a
grayish el ety thic ening o the s in o the sides o the nec
497

24
Endocrine Diseases
A B
Fig. 24-10 Tripe palms.
a illae and groins. t occurs in obese persons with or without
endocrine disorders. t also occurs in acromegaly and gigan
tism pseudoacromegaly PC S Cushing syndrome diabetes
mellitus R A syndrome (mental retardation o er
growth remar able ace and A ) Addison s disease Prader
Willi syndrome Alstr m syndrome ata ia telangiectasia
hyperandrogenic states hypogonadal syndromes and the
arious well recogni ed insulin resistant states. These states
include lipoatrophic diabetes leprechaunism pinealoma
(Rabson endenhall syndrome) and acral hypertrophy syn
drome as well as type A syndrome with a de ect in insulin
receptor and postreceptor pathways or a lamin A mutation
and type B syndrome with the presence o autoantibodies to
the insulin receptor. Whereas both type A and type B syn
drome occur most o ten in blac emales type A predominates
in young children with hyperandrogenic mani estations.
any o the conditions associated with insulin resistance and
A mani est as hyperandrogenism and ha e been termed the
A R A syndrome. n one group o women with hirsutism
obesity and hyperandrogenism ul ar A was present in all
patients with other sites less re uently in ol ed. Type B syn
drome is seen in middle age patients with autoimmune disease
( ig. ). ost i not all patients with this type o A
may ha e either clinical or subclinical insulin resistance and
patients should ha e a glucose and insulin le el drawn
498
tahir99 - UnitedVRG
Fig. 24-9 A and B, Extensive acanthosis
nigricans in patient with stomach cancer.
Fig. 24-11 Diffuse
acanthosis nigricans
in type B syndrome.
simultaneously. n adults a glucose to insulin ratio o less than
. is abnormal while in prepubertal children less than is
abnormal. asting glucose and lipoprotein pro le hemoglobin
A c body weight blood pressure and an alanine transami
nase (ALT) test or e aluation or atty li er are other in esti
gations that are use ul in assessing patients with suspected
insulin resistant states.
Diagnosis and treatment
Acanthosis nigricans may occur in broblast growth actor
receptor de ect syndromes such as Beare Ste enson cutis
gyrata syndrome Crou on syndrome se ere achondroplasia
with de elopmental delay and A (SADDA ) and thanato
phoric dysplasia. ther associated syndromes that also mani
est A include Bloom syndrome Costello syndrome Wilson s
disease benign encephalopathy irschowit syndrome
Capo ucca syndrome Down syndrome ermans y Pudlac
syndrome abu i syndrome hypothyroidism Rud syn
drome and primary biliary cirrhosis. Drugs nown to induce
A include nicotinic acid niacinamide somatotrophin
testosterone tria inate diethylstilbestrol oral contracepti es
insulin protease inhibitors and glucocorticoids. Appro i
mately o renal transplant patients ha e A .
The histopathology o A shows papillomatosis without
thic ening o the malpighian layer. Acanthosis was applied
here to indicate the clinical bristly thic ening o the s in and
not as a histologic term. yper eratosis and slight hyperpig
mentation o the basal layer is present in most cases; it appears
howe er that the clinically obser ed hyperpigmentation is
caused by hyper eratosis and clinical thic ening rather than
by melanin.
The di erential diagnosis includes intertriginous granular
para eratosis and se eral disorders o reticulated hyperpig
mentation including con uent and reticulated papillomatosis
(Gougerot Carteaud syndrome) Dowling Degos disease
aber syndrome and acropigmentatio reticularis o itamura.
Granular para eratosis presents as erythematous to brownish
hyper eratotic papules and pla ues o the intertriginous
regions. t is most o ten seen in middle age women in the
a illae; howe er the inguinal olds and submammary areas
may be in ol ed. istology re eals a thic ened stratum
corneum se ere compact para eratosis with retention o era
tohyalin granules and ascular proli eration and ectasia. The
cause is li ely to be an irritant response to rubbing or to anti
perspirants or deodorants. Dowling Degos disease is a amil
ial ne oid anomaly with delayed onset in adult li e. There is
progressi e brown blac hyperpigmentation o e ures with
associated so t bromas and ollicular hyper eratoses. Pitted
acnei orm scars occur periorally.
Treatment o type A associated with malignancy con
sists o nding and remo ing the causal tumor. arly recogni
tion and treatment may be li esa ing. A occurring with
obesity (type ) usually impro es with weight loss. there
is associated endocrinopathy it must be treated as well. ne
patient with lipodystrophic diabetes impro ed during dietary
supplementation with sh oil. tretinate met ormin or other
medications to control insulin resistance as well as tretinoin
calcipotriol urea salicylic acid C laser ablation and long
pulsed ale andrite laser therapy ha e been reported as suc
Acanthosis nigricans
cess ul treatments in indi idual cases.
Costa MC, et al: Acanthosis nigricans and “tripe palm” as
paraneoplastic manifestations of metastatic tumor. An Bras Dermatol
2012; 87(3):498–500.
Fabroni C, et al: Tripe palms associated with malignant acanthosis
nigricans in a patient with gastric adenocarcinoma. Dermatol Online J
2012; 18(11):15.
Higgins SP, et al: Acanthosis nigricans: a practical approach to
evaluation and management. Dermatol Online J 2008; 15:2.
Jeong KH, et al: Generalized acanthosis nigricans related to type B
insulin resistance syndrome. Cutis 2010; 86(6):299–302.
Lee AT, et al: Dermatologic manifestations of polycystic ovary
syndrome. Am J Clin Dermatol 2007; 8:201.
Malek R, et al: Treatment of type B insulin resistance. J Clin Endocrinol
Metab 2010; 95:3641.
Mir A, et al: Cutaneous features of Crouzon syndrome with acanthosis
nigricans. JAMA Dermatol 2013; 149(6):737–741.
Rafalson L, et al: The association between acanthosis nigricans and
dysglycemia in an ethnically diverse group of eighth grade students.
Obesity 2013; 21(3):E328–E333.
Sinha S, et al: Juvenile acanthosis nigricans. J Am Acad Dermatol
2007; 57:502.
Bonus images for this chapter can be found online at
expertconsult.inkling.com
eFig. 24-1 Acromegaly.
eFig. 24-2 Pretibial myxedema. (Courtesy of Lawrence Lieblich, MD.)
eFig. 24-3 Acanthosis nigricans.
499
eFig. 24-1 Acromegaly.

Acanthosis nigricans
eFig. 24-3 Acanthosis nigricans.

eFig. 24-2 Pretibial

myxedema. (Courtesy
of Lawrence Lieblich,
MD.)

499.e1

tahir99 - UnitedVRG
 Bonus images for this chapter can be found online at
expertconsult.inkling.com
25 Abnormalities of Dermal Fibrous and
Elastic Tissue
COLLAGEN
any types o collagen ha e been identi ed in tissues o er
tebrates (Table ). ibrillar collagens (types V and
) orm brils that are among the most abundant proteins in
the body. Type collagen accounts or o the dry
weight o s in ligaments and deminerali ed bone. Type
collagen is abundant in etal s in and blood essels. t com
prises o the collagen in normal adult s in but up to
in in amed s in in the setting o contact dermatitis. Basement
membrane associated collagen is made up o types V and V .
iber associated collagens (types V and V) are ound
on the sur ace o type and collagens and are belie ed
to ser e as e ible spacers among brils. ibril associated
collagens with interrupted triple helices ( AC Ts) do not
orm brils themsel es but are ound attached to the sur aces
o pree isting brils o the bril orming collagens. AC Ts
are composed o types V V and
. etwor orming collagens are sheets ormed rom types
V and . Studies on types V V and demonstrate
their widespread presence in basement membranes particu
larly ascular endothelium which may represent a new
subgroup o collagens associated with angiogenic and
pathologic processes. Type V collagen is also nown as
BP and contains the target antigens or se eral immuno
bullous diseases. Type V collagen contains the target
antigens or bullous lupus and epidermolysis bullosa ac uis
ita. Type collagen contains the target antigens or relapsing
polychondritis.
The regulation o collagen synthesis and degradation is
comple . Dermal brosis is largely related to increases in type
collagen mediated by proα and proα collagen genes.
Trans orming growth actor beta (TG β) results in increased
type procollagen synthesis. Angiotensin type receptor
stimulation increases collagen production and inhibits colla
gen degradation whereas type receptor stimulation e erts
the re erse e ects.
Czarny-Ratajczak M, et al: Collagens, the basic proteins of the human
body. J Appl Genet 2000; 41:317.
ELASTOSIS PERFORANS SERPIGINOSA
n Lut described a chronic papular eratotic eruption
in an arci orm shape located on the sides o the nape o
the nec ( ig. ). The papules range rom to mm in
diameter and are grouped in a serpiginous or horseshoe
shaped arrangement. Although the lesions typically occur on
the nec other sites may be in ol ed such as the upper arms
ace lower e tremities and rarely the trun . Disseminated
lesions may occur in Down syndrome. lastosis per orans
serpiginosa ( PS) is most common in young adults. en out
number women . The disease runs a ariable course with
500
spontaneous resolution o ten occurring rom months to
years a ter onset. ten atrophic scarring remains.
Appro imately one third o PS cases occur in patients with
associated diseases; the most common concomitant disorder is
Down syndrome. Appro imately o patients with Down
syndrome ha e PS and the lesions are li ely to be more
e tensi e and persistent than in other patients. Progressi e
aso occlusi e disease with stro e has been reported. hlers
Danlos syndrome osteogenesis imper ecta ar an syndrome
Rothmund Thomson syndrome acrogeria systemic sclerosis
morphea syndrome and renal disease ha e also been
associated with PS. Reports o PS associated with pseudo
anthoma elasticum ha e occurred with penicillamine admin
istration. aluation or associated disease should be dri en
by associated signs and symptoms.
The distincti e histopathologic changes o PS consist o
elongated tortuous channels in the epidermis into which
eosinophilic elastic bers per orate. The bers are e truded
rom the dermis. There is degeneration and alteration o the
elastic tissue in the ad acent papillary dermis with an accom
panying in ammatory response. n penicillamine associated
disease the bers may ha e an irregular (bramble bush)
contour when e amined with electron microscopy.
Treatment o PS is di cult but indi idual lesions may
resol e ollowing li uid nitrogen cryotherapy. Some cases
ha e responded to carbon dio ide (C ) erbium yttrium
aluminum garnet ( r AG) or pulsed dye laser therapy.
Topical retinoids ha e been reported to be o bene t.
Kim SW, et al: A clinicopathologic study of thirty cases of acquired
perforating dermatosis in Korea. Ann Dermatol 2014; 26:162–171.
Lee SH, et al: Elastosis perforans serpiginosa. Ann Dermatol 2014;
26:103–106.
Vearrier D, et al: What is standard of care in the evaluation of elastosis
perforans serpiginosa? A survey of pediatric dermatologists. Pediatr
Dermatol 2006; 23(3):219–224.
Yang JH, et al: Treatment of elastosis perforans serpiginosa with the
pinhole method using a carbon dioxide laser. Dermatol Surg 2011;
37(4):524–526.
REACTIVE PERFORATING COLLAGENOSIS
n ehregan reported a rare amilial nonpruritic s in
disorder characteri ed by papules that grow to a diameter o
mm and de elop a central area o umbilication in which
eratinous material is lodged. The discrete papules may be
numerous and in ol e sites o re uent trauma such as the
bac s o the hands the orearms elbows and nees. The lesion
reaches a ma imum si e o about mm in wee s and then
regresses spontaneously in wee s. The lesions are broader
than those o PS and a broad crust containing collagen bers
is e truded centrally. oebneri ation is o ten obser ed. oung
children are most re uently a ected. ost reports support an
autosomal recessi e mode o inheritance although apparent
 Table 25-1 Collagen types
Collagen type Gene* Chromosome Tissue distribution

Pseudoxanthoma elasticum
I COL1A1–2 17q21.3–q22 Skin, bone, tendon
I-trimer Tumors, cell cultures, skin, liver
II COL2A1 7q21.3–q22 Cartilage, vitreous
III COL3A1 12q13–q14 Fetal skin, blood vessels, intestines
IV COL4A1–6 13q34, 2q35–q37, Xq22 Basement membranes
V COL5A1–3 9q34.2–q34.3 Ubiquitous
VI COL6A1–3 21q22.3, 2q37 Aortic intima, placenta
VII COL7A1 3p21 Amnion, anchoring fibrils
VIII COL8A1–2 3q12–q13.1, 1p32.3–p34.3 Endothelial cell cultures
IX COL9A1–3 6q12–q14, 1p32 Cartilage, type II collagen tissue
X COL10A1 6q12–q22 Cartilage
XI COL11A1–2, COL2A1 1p21 Cartilage, skin
XII COL12A1 6 Skin, cartilage, cornea, limbal
XIII COL13A1 10q22 Ubiquitous
XIV COL14A1 8q23 Ubiquitous, fetal hair follicles, basement membranes
XV COL15A1 9q21–22 Skin hemidesmosomes, kidney, liver, spleen
XVI COL16A1 1p34–35 Ubiquitous
XVII COL17A1 10q24.3 Skin hemidesmosomes (BP180)
XVIII COL18A1 21q22.3 Ubiquitous, basement membranes
XIX COL19A1 6q12–q14 Ubiquitous, basement membranes
XX COL20A1 Corneal epithelium, embryonic skin, sternal cartilage,
tendon
XXI COL21A1 6p11.2–12.3 Blood vessel walls
XXII COL22A1 8q24.2 Tissue junctions such as basement membrane zone of
anagen hair follicle
XXIII Rat prostate carcinoma cells
XXIV Fetal cornea and bone
XXV Precursor to Alzheimer amyloid plaque component
XXVI Testis, ovary
XXVII Chondrocytes; developing tissues, including stomach,
lung, gonad, skin, cochlea, teeth
*A dash denotes a series of genes; e.g., COL14A1–2 indicates both the COL14A1 and the COL14A2 gene.

autosomal dominant inheritance was reported in one amily.

Ac uired reacti e per orating collagenosis is discussed urther
in Chapter .
o speci c treatment is typically indicated or reacti e per
orating collagenosis because the lesions in olute spontane
ously. Topical retinoids may be help ul in patients who re uire
treatment.
Kumar V, et al: Familial reactive perforating collagenosis. J Dermatol
1998; 25:54–56.
Ramesh V, et al: Familial reactive perforating collagenosis: a clinical,
histopathological study of 10 cases. J Eur Acad Dermatol Venereol
2007; 21(6):766–770.

Fig. 25-1 Elastosis perforans serpiginosa.
PSEUDOXANTHOMA ELASTICUM
Pseudo anthoma elasticum (P ) is an inherited disorder
in ol ing the connecti e tissue o the s in eye and cardio as
cular system. any cases appear to be sporadic. n amilial
501

tahir99 - UnitedVRG
 Fig. 25-2 A and B,
25 Pseudoxanthoma
elasticum.
Abnormalities of Dermal Fibrous and Elastic Tissue
A hypercalcinosis solar elastosis neuro bromatosis Sturge
B in
cases both a recessi e and a dominant inheritance pattern
ha e been reported with the recessi e orm apparently more
common. The s in changes generally present as small circum
scribed yellow to cream colored papules on the sides o the
nec and e ures gi ing the s in a pluc ed chic en s in
appearance ( ig. ). La redundant olds o s in may be
present ( ig. ). uchal comedones and milia en pla ue
may also be seen. Characteristic e aggerated nasolabial olds
and mental creases are common. ental creases appearing in
patients under age are highly suggesti e o P . n addi
tion the inguinal periumbilical and periauricular s in as
well as the mucosa o the so t palate inner lip stomach
rectum and agina may be in ol ed.
The characteristic retinal change is the angioid strea which
is the result o brea s in Bruch s elastic membrane. P can
be demonstrated in more than hal o patients with angioid
strea s and o P patients will ha e retinal ndings.
The angioid strea s appear earlier than the s in changes
so most cases are disco ered by ophthalmologists. Angioid
strea s may be the only sign o the disease or years. n such
patients biopsies o the midportions o old scars may be diag
nostic o P . The association o the s in lesions with angioid
strea s is called Gr nblad Strandberg syndrome. Angioid
strea s may also be seen in hlers Danlos syndrome Paget s
disease o bone diabetes hemochromatosis hemolytic anemia
502
Fig. 25-3 Pseudoxanthoma elasticum.
Weber syndrome tuberous sclerosis myopia sic le cell
anemia trauma lead poisoning hyperphosphatemia pitu
itary disorders and intracranial disorders. P Paget s disease
o the bone and sic le cell disease account or the ast ma ority
o patients with angioid strea s.
n unduscopic e amination a reddish brown band is
e ident around the optic dis rom which glistening strea s
e tend. n uorescent photography early uorescence o the
angioid strea s and macular lesions is noted. n addition there
may be hemorrhages and e udates. Progressi e loss o ision
o ten starts a ter minor trauma to the eye. Drusenli e spots are
o ten present and show increased auto uorescence unli e
age related drusen.
Vascular in ol ement re uently leads to hemorrhage.
These ascular e ents are caused by the degeneration o the
elastic bers in the ascular media. Gastric hemorrhage occurs
o patients and on gastroscopy di use rather than
ocal bleeding is common. pista is occurs re uently but
hematuria is rare. P a ects the elastic tissue o the cardiac
al es myocardium and pericardium. n one study mitral
al e prolapse was ound in o patients e amined.
ypertension occurs in many patients older than age . Any
patient with hypertension at a young age should be e amined
or stigmata o P . Leg cramps and intermittent claudication
occur prematurely and peripheral pulses are diminished or
absent. Calci cation o peripheral arteries is seen in many
patients o er age and may be detected by radiography.
Accelerated coronary artery disease (CAD) can occur espe
cially in association with hypertension. tensi e cutaneous
calci cation and renal and testicular stones may occur.
utations in the adenosine triphosphate (ATP) binding cas
sette transporter protein sub amily C member gene CC
on the short arm o chromosome ha e been implicated in
the pathogenesis o P in a ma ority o patients who also
ha e a higher incidence o CAD. Although the most prominent
mani estations o the disease are in the s in eye gut and
heart minerali ation o elastic bers can be ound in many
organs.
istologically elastic bers are ragmented and minerali ed
with calcium. The bers stain gray blue with hemato ylin and
eosin ( ) and are twisted curled and bro en suggesting
ra eled wool. Blind biopsies o scars or a illary s in in
patients with a amily history o P or with angioid strea s
may show early changes o P . Calcium stains are help ul in
identi ying early disease.
 The di erential diagnosis includes P li e papillary
dermal elastolysis per orating calci c elastosis and cutis la a.
Patients with P li e papillary dermal elastolysis may ha e
cobblestoned yellow papules on the nec similar to P
but lac any retinal or ascular alterations and the typical

Ehlers-Danlos syndromes
ragmentation o elastic bers with calcium deposition on his
tology. Penicillamine may induce similar clinicohistologic ea
tures in patients with Wilson s disease or homocystinuria.
o de niti e therapy is a ailable to treat the s in disease.
Some data suggest that P patients bene t rom limiting
dietary calcium and phosphorus to the minimal daily re uire
ment. ntra itreal be aci umab has been used to treat choroi
dal neo asculari ation. Ator astatin treatment appears
promising in a mouse model.
Finger RP, et al: Intravitreal bevacizumab for choroidal
neovascularisation associated with pseudoxanthoma elasticum. Br J
Ophthalmol 2008; 92(4):483–487.
Guo H, et al: Atorvastatin counteracts aberrant soft tissue mineralization Fig. 25-4 Ehlers-Danlos syndrome.
in a mouse model of pseudoxanthoma elasticum (Abcc6 (−/−). J Mol
Med (Berl) 2013; 91(10):1177–1184.
Hendig D, et al: New insights into the pathogenesis of pseudoxanthoma
elasticum and related soft tissue calcification disorders by identifying
genetic interactions and modifiers. Front Genet 2013; 4:114.
Plomp AS, et al: Proposal for updating the pseudoxanthoma elasticum
classification system and a review of the clinical findings. Am J Med
Genet 2010; 152A(4):1049–1058.
Uitto J, et al: Pseudoxanthoma elasticum: diagnostic features,
classification, and treatment options. Expert Opin Orphan Drugs 2014;
2:567–577.

PERFORATING CALCIFIC ELASTOSIS

Also nown as periumbilical per orating P and locali ed
ac uired cutaneous P per orating calci c elastosis is
an ac uired locali ed cutaneous disorder most re uently
ound in obese multiparous middle age women. La well
circumscribed reticulated or cobblestoned pla ues occur in
the periumbilical region with eratotic sur ace papules. t is a
distinct disorder that shares some eatures o P . As in P
patients may ha e calci c elastosis in the middermis; howe er
hereditary P rarely causes per orating channels. one o
the systemic eatures o P occurs in per orating calci c
elastosis.
t is suggested that repeated trauma o pregnancy obesity
and abdominal surgery promote elastic ber degeneration
resulting in locali ed disease. P can cause periumbilical
lesions and in the absence o documented per oration e alu
ations to e clude P should be per ormed. There is no e ec
ti e therapy or per orating calci c elastosis.
Budania A, et al: Periumbilical perforating pseudoxanthoma elasticum:
an acquired perforating disorder. Int J Dermatol 2012; 51(4):439–441.
EHLERS-DANLOS SYNDROMES
hlers Danlos syndromes ( DSs) also nown as cutis hyper
elastica ndia rubber s in and elastic s in are a group o
genetically distinct connecti e tissue disorders characteri ed
by e cessi e stretchability and ragility o the s in ( ig. ) nees hands and elbows produces cigarette paper thin scars.
with hypere tensibility o the oints ( ig. ) and a tendency
toward easy scar ormation and ormation o brous or calci
ed pseudotumors. Atrophic scarring on the distal ngers
and wide atrophic sh mouth scars are typical. Patients
demonstrate reduced thic ness o the dermis as determined
by high resolution ultrasound. The reduction in thic
ness is most mar ed on the chest and distal lower leg. Rare
oral mani estations ha e been reported including supernu
merary teeth and odontogenic eratocysts.
Fig. 25-5 Ehlers-Danlos syndrome, hyperextensible joints.
Classically DS has been di ided into numeric types the
salient eatures o which are listed in Table . Type DS
an allelic ariant o en es disease is now reclassi ed as the
occipital horn syndrome and is identical to lin ed cutis la a.
t is related to mutations in an lin ed gene P Patients
with types V V and V DS ha e hypere tensible
s in; the integument may be stretched li e a rubber band and
snaps bac with e ual resilience. This rubbery s in is most
pronounced on the elbows nec and sides o the abdomen.
The s in is el ety in appearance and eels li e wet chamois
cloth. inor trauma may produce a gaping sh mouth
wound with large hematomas underneath. The subcutaneous
calci cations are mm o al nodules mostly on the legs.
Two types o nodules occur in patients with DS. olluscoid
pseudotumors are so t eshy nodules seen in easily trauma
ti ed areas such as the ulnar orearms and shins. Spheroids
are hard subcutaneous nodules that become calci ed and
probably result rom at necrosis. Trauma o er the shins
Appro imately o these patients can touch the tip o the
nose with their tongue (Gorlin s sign) compared with o
persons without the disorder. Aortic root dilation is seen in up
to o patients with DS and is more common in types
and than type .
Patients with type V DS ha e thin translucent s in char
acteristic acial eatures and ascular ragility. They are prone
to arterial rupture and o ten ha e e tensi e bruising. Per ora
tions o the intestines and uterus may occur. Atlantoa ial
503

tahir99 - UnitedVRG
25 Table 25-2 Features of Ehlers–Danlos syndromes (EDSs)
Ehlers-Danlos type Gene Inheritance* Molecular abnormality Clinical features
Abnormalities of Dermal Fibrous and Elastic Tissue

I COL5A1–2† AD Type V collagen Gravis type: joint laxity, skin

hyperextensibility
II COL5A1–2 AD Type V collagen Mitis type: same as EDS type I
but less severe
III TNXB haploid AD Unknown Hypermobility
IV COL3A1 AD Type III procollagen Thin skin, bruising, ruptured blood
AR vessels and viscera
V Unknown Skin hyperextensibility, easy
bruising
VI LH1, PLOD AR Lysyl hydroxylase Severe eye defects and scoliosis
deficiency
VIIA, VIIB COL1A1–2 AD Type I procollagen Arthrochalasis, subluxations,
moderate skin stretchability
VIIC AR Procollagen peptidase Dermatosparaxis, severe
deficiency stretchability, redundant skin
VIII Heterogeneous, only AD Unknown Same as EDS types I and II,
some map to periodontitis
chromosome 12p13
Old-type IX, reclassified as a ATP7A X-linked Lysyl oxidase Abnormal facies; skeletal
variant of Menkes disease/ abnormalities, including occipital
occipital horn syndrome horns, chronic diarrhea, and
genitourinary abnormalities
X (new-type IX) AR Fibronectin Bruising
Old-type XI (new-type X) Familial joint Relationship to EDS unclear
hypermobility syndrome
Spondylocheirodysplastic SLC39A13 AR Hyperelastic bruisable skin, joint
hypermobility, contractures,
tapered digits, skeletal dysplasia
*AD, Autosomal dominant; AR, autosomal recessive.
†
COL5A1–2 indicates both the COL5A1 and the COL5A2 gene.

sublu ation has been noted. Protein analysis o collagen in
cultured broblasts usually shows a de ect. Some type V
patients demonstrate no abnormalities o collagen although
a mutation in the COL gene is identi ed. Type V patients
ha e clinical eatures that are similar to the gra is mitis
orm and some data suggest that more than o patients
who satis y all these ma or criteria or the disease harbor a type
V collagen (C LLV) de ect. Tenascin haploinsu ciency
causes oint hypermobility and appears to be protecti e against
cardio ascular disease.
Patients with type V DS may ha e microcornea retinal
detachment and glaucoma as well as scoliosis. n normal
indi iduals the ratio o hydro ylysylpyridinoline ( P) to
lysylpyridinoline (LP) in urine is about . n patients with
type V DS the P LP ratio is reduced ranging rom to
. The spondylocheirodysplastic orm is autosomal reces
si e and caused by mutations in the inc transporter gene
SLC This orm includes hyperelastic bruisable s in
oint hypermobility contractures protuberant eyes bluish
sclerae short stature nely wrin led palms thenar atrophy
and tapered digits. S eletal dysplasia includes platyspondyly
osteopenia and widened metaphyses. The urinary P LP
ratio is appro imately . orations in DS type V ha e been managed with porcine
Patients with type V A and V B DS ha e mar ed oint
hypermobility and moderate cutaneous elasticity. Dislocation
o the large oints such as the hips is common. Type V C DS
the autosomal recessi e orm is re erred to as dermatosp
ara is; patients ha e se ere s in ragility and sagging
504
redundant s in. Type V DS mani ests as periodontitis as
well as easy bruising. Reductions o collagen type alone or
together with a reduction in type ha e been reported. When
type DS was rede ned as a ariant o en es syndrome
some reclassi ed old type DS as new type . t is charac
teri ed by hypermobile oints easy bruising sh mouth scars
mitral al e prolapse and platelets resistant to aggregation
with collagen and adenosine diphosphate (ADP) reagents. A
ualitati e de ciency o bronectin was the suggested cause
although ne er con rmed. Since the deletion o old type
some ha e reclassi ed old type as new type or the amil
ial oint hypermobility syndrome.
Because o the disco ery o new types and con usion about
the numbered types an alternate classi cation scheme has
been proposed that groups DS by associated signs and symp
toms as well as nown genetic mutations. This new classi ca
tion combines numeric types and because they share the
same mutations (Bo ).
Collagen bers may appear thin. actor a positi e
dermal dendrocytes may be greatly reduced in the ad entitial
dermis and almost absent in the reticular dermis.
Patients must be counseled to a oid trauma. ntestinal per
small intestine submucosal gra ts. n ortunately in asi e
cardio ascular procedures ha e generally not impro ed out
comes or patients with se ere disease. atri metalloprotein
ase ( P) inhibitors produce changes in connecti e tissue
and are being e aluated as possible therapeutic agents.
 Box 25-1 New classification for Ehlers-Danlos
syndrome (EDS)
1. Classic type (gravis—EDS type I, and mitis II)*
2. Hypermobility type (hypermobile—EDS III)
3. Vascular types (arterial-ecchymotic—EDS type IV, Qatarian
EDS)†
4. Kyphoscoliosis type (ocular-scoliotic—EDS type VI)
5. Arthrochalasia type (arthrochalasis multiplex congenita—EDS
type VIIA and VIIB)
6. Dermatosparaxis type (human dermatosparaxis—EDS type VIIC)
7. Miscellaneous forms (X-linked—EDS type V, periodontitis;
EDS type VIII, fibronectin-deficient EDS; EDS type X, familial
hypermobility syndrome [formerly EDS type XI]; progeroid
EDS; and unspecified forms).
Some progeroid EDS is related to galactosyltransferase I
deficiency.
*Mutations in the genes for collagen α1(V) chain (COL5A1), collagen
α2(V) chain (COL5A2), tenascin-X (TNX), and collagen α1(I) chain
(COL1A1) have been characterized in patients with classical EDS. All are
autosomal dominant, except the tenascin-X–related type, which is
autosomal recessive.
†
A distinct vascular type of EDS was described in an extended family in
Qatar. Features of the syndrome include skin hyperextensibility, joint
hypermobility, tortuous systemic arteries, epicanthic folds, flat saggy
cheeks, elongated facies, micrognathia, hernias, an elongated aortic arch,
aortic aneurysms, bifid pulmonary artery, pulmonic stenosis, hypotonia,
and arterial rupture. Linkage to the major loci of other types of EDS was
excluded
Bergqvist D, et al: Treatment of vascular Ehlers-Danlos syndrome: a
systematic review. Ann Surg 2013; 258(2):257–261.
Callewaert B, et al: Ehlers-Danlos syndromes and Marfan syndrome.
Best Pract Res Clin Rheumatol 2008; 22(1):165–189.
Malfait F, De Paepe A. The Ehlers-Danlos syndrome. Adv Exp Med Biol
2014; 802:129–143.
Müller T, et al: Loss of dermatan sulfate epimerase (DSE) function
results in musculocontractural Ehlers-Danlos syndrome. Hum Mol
Genet 2013; 22(18):3761–3772.
Petersen JW, et al: Tenascin-X, collagen, and Ehlers-Danlos syndrome:
tenascin-X gene defects can protect against adverse cardiovascular
events. Med Hypotheses 2013; 81(3):443–447.
Wiesmann T, et al: Recommendations for anesthesia and perioperative
management in patients with Ehlers-Danlos syndrome(s). Orphanet J
Rare Dis 2014; 9:109.
MARFAN SYNDROME
ar an syndrome is an autosomal dominant disorder o con
necti e tissue caused by mutations in the gene encoding
brillin . t is one o the more common inherited diseases
with estimated incidence rates o in in the nited
States. mportant abnormalities include tall stature loose
ointedness a dolichocephalic s ull high arched palate arach
nodactyly ( ig. ) pigeon breast pes planus poor muscle
tone and large de ormed ears. The aorta chordae tendineae
and aortic and mitral al es are o ten in ol ed. Ascending
aortic aneurysm and mitral al e prolapse are re uently seen.
ctopia lentis e tensi e striae o er the hips and shoulders
dental anomalies and rarely elastosis per orans serpiginosa
ha e been reported. Se eral cases document the occasional
occurrence o spontaneous pneumothora and congenital lung
abnormalities.
ar an syndrome is caused by a gene de ect locali ed to
chromosome and producing abnormal elastic tissue in
brillin (aorta ad entitia suspending ligaments o lens and
s in) and brillin (elastin orientation in cartilage aortic
tahir99 - UnitedVRG
Homocystinuria
Fig. 25-6 Marfan syndrome.
media bronchi and all tissues rich in elastin). Gene de ects
include substitutions deletions duplication missense rame
shi t splice site and nonsense mutations. ctopia lentis is
more common in patients whose mutations in ol e a cysteine
substitution in the gene or brillin and less pre alent in
those with premature termination mutations. Death may
result rom aortic root aneurysm rupture or dissection.
chocardiography is help ul or early detection o cardio
ascular in ol ement. Surgical inter ention may be re uired
or aneurysms o the aortic root or or aortic dissection. Long
term administration o propranolol may signi cantly reduce
the rate o aortic dilation as does angiotensin bloc ade with
losartan. Long term do ycycline may be help ul to inhibit
Ps. Some e idence suggests do ycycline may be more
e ecti e than atenolol in pre enting progression o thoracic
aortic aneurysms. Antisense ribo ymes are promising or gene
therapy.
Brooke BS, et al: Angiotensin II blockade and aortic-root dilation in
Marfan’s syndrome. N Engl J Med 2008; 358(26):2787–2795.
Groenink M, et al: Losartan reduces aortic dilatation rate in adults with
Marfan syndrome: a randomized controlled trial. Eur Heart J 2013;
34(45):3491–3500.
HOMOCYSTINURIA
omocystinuria an inborn error in the metabolism o methio
nine is characteri ed by the presence o homocysteine in
the urine and de ciency o the en yme cystathionine synthe
tase or methylenetetrahydro olate reductase. Cystathionine
β synthase is a heme containing en yme that cataly es pyri
do al ′ phosphate dependent con ersion o serine and homo
cysteine to cystathionine. ore than gene mutations ha e
been described. The de ect results in increased le els o homo
cysteine and methionine and decreased le els o cysteine. The
incidence o the disorder aries rom in worldwide to
in in reland where homocystinuria is more common.
Signs o homocystinuria include ectopia lentis genu algum
yphoscoliosis pigeon breast de ormity and re uent rac
tures. Generali ed osteoporosis arterial and enous thrombo
sis and mental retardation are eatures o homocystinuria not
ound in ar an syndrome. al o all patients will ha e a
serious ascular e ent be ore age and e perience a
serious e ent be ore age . The acial s in has a characteristic
ush especially on the malar areas and the color tends to
become iolaceous when the patient is reclining. lsewhere
the s in is blotchy red suggesti e o li edo reticularis. The hair
is typically ne sparse and blond and the teeth are irregularly
505
 aligned. Downward dislocation o the lens unli e the upward
25 displacement seen in ar an syndrome is a prominent eature.
Treatment with pyrido ine olic acid and itamin B
produces ariable results in homocystinuric patients. A
methionine restricted cysteine supplemented diet is generally
Abnormalities of Dermal Fibrous and Elastic Tissue
recommended. Betaine supplementation has been shown to be
e ecti e. Wheat our is rich in betaine but the amounts
ingested are smaller than those needed to treat the disease.
Some recommend that methionine ree ormulas be supple
mented with mg dL o betaine. Al al a and bean sprouts
contain ample homocysteine and e cessi e amounts should
be a oided. ther egetables do not contain large amounts o
homocysteine. Vitamin C ameliorates endothelial dys unction
and the e ect appears to be independent o homocysteine
concentration. Some o the bene cial e ects o olate are also
independent o homocysteine reduction. n an animal model
o homocystinuria methyltetrahydro olate decreased mor
tality but olic acid did not.
Li D, et al: Mefolinate (5-methyltetrahydrofolate), but not folic acid,
decreases mortality in an animal model of severe
methylenetetrahydrofolate reductase deficiency. J Inherit Metab Dis
2008; 31(3):403–411.
Walter JH, et al: Newborn screening for homocystinuria. Cochrane
Database Syst Rev 2013; 8:CD008840.
CUTIS LAXA (GENERALIZED ELASTOLYSIS)
Cutis la a also nown as dermatomegaly dermatolysis chala
oderma and pachydermatocele is characteri ed by inelastic
loose redundant s in. Around the eyelids chee s and nec
the drooping s in produces a bloodhound li e acies. sually
the entire integument is in ol ed. The shoulder girdle s in
may resemble that o a St. Bernard dog. The abdomen is re
uently the site o large pendulous olds. There are two well
described genetic orms o cutis la a the autosomal dominant
and autosomal recessi e types. The dominant orm is primarily
a cutaneous cosmetic orm with a good prognosis. The reces
si e orm is more common and associated with signi cant
internal in ol ement including hernias di erticula pulmo
nary emphysema cor pulmonale aortic aneurysm dental
caries large ontanelles and osteoporosis. Pulmonary emphy
sema cor pulmonale and right sided heart ailure are o ten
seen already in in ancy. rameshi t and splicing mutations in
the elastin gene ha e been reported in autosomal dominant
disease. Both homo ygous and hetero ygous missense muta
tions in the gene or bulin ha e been reported in some
patients with the disease especially in amilies with the reces
si e orm. Gene mutations or bulin may cause autosomal
recessi e cutis la a associated with emphysema ascular tor
tuosity ascending aortic aneurysm inguinal and diaphrag
matic hernia oint la ity and pectus e ca atum. lin ed
recessi e cutis la a is now nown as the occipital horn syn
drome ( ormerly type DS). t is caused by a mutation in the
copper binding ion transporting ATPase P and is allelic
to another lin ed disorder en es disease. on amilial
cases ha e been associated with urticaria lupus erythemato
sus glomerulonephritis plasma cell dyscrasias and systemic
amyloidosis ( ig. ). These ac uired cases may ha e a pre
ceding in ammatory phase with large numbers o interstitial
neutrophils eosinophils or macrophages engul ng elastic
bers. solated acral disease has been associated with myeloma
and rheumatoid arthritis.
The Costello syndrome is characteri ed by increased prena
tal growth postnatal growth retardation coarse acies loose
s in that resembles cutis la a cardiomyopathy and gregari
ous personality. Patients are predisposed to abdominal and
pel ic rhabdomyosarcoma in childhood. The disorder appears
506
Fig. 25-7 Acquired cutis laxa.
to be inherited as an autosomal dominant trait. The de Barsy
syndrome is associated with se ere cutis la a mental and
growth retardation oint la ity ocular abnormalities and s el
etal disease.
iddermal elastolysis is an ac uired noninherited condi
tion that usually a ects young women. Wide areas o s in
demonstrate atrophic wrin ling. istologically elastic tissue
is absent rom the middle dermis. any cases appear to be
induced or aggra ated by ultra iolet light e posure.
Callewaert B, et al: Comprehensive clinical and molecular analysis of 12
families with type 1 recessive cutis laxa. Hum Mutat 2013;
34(1):111–121.
Mohamed M, et al: Cutis laxa. Adv Exp Med Biol 2014; 802:161–184.
Tas A, et al: Oculoplastic approach to congenital cutis laxa syndrome.
Aesthetic Plast Surg 2013; 37(2):417–420.
BLEPHAROCHALASIS
n blepharochalasis the eyelid s in becomes la and alls in
redundant olds o er the lid margins. The condition may a ect
young adults in whom a preceding in ammatory phase pres
ents with episodes o lid swelling. ost cases are bilateral but
unilateral in ol ement may occur. Rarely elastolysis o the
earlobes may accompany blepharochalasis. t is generally spo
radic but a dominantly inherited orm has been described.
Biopsy shows lac o elastic bers and abundant gA deposits
ha e been demonstrated in some cases possibly binding to
bulin and bronectin. Se uelae include e cess thin s in at
herniation lacrimal gland prolapse ptosis blepharophimosis
pseudoepicanthic old proptosis con uncti al in ection and
cysts entropion and ectropion.
Ascher syndrome consists o progressi e enlargement o the
upper lip and blepharochalasis. The minor sali ary glands o
the a ected areas are in amed resulting in super uous olds
o mucosa gi ing the appearance o a double lip. There is a
super cial resemblance to angioedema.
Treatment is generally by surgical correction although suc
cess ul medical treatment has been reported with systemic
aceta olamide in combination with topical hydrocortisone
cream. Do ycycline has also been reported as e ecti e pre
sumably through P inhibition.
Drummond SR, et al: Successful medical treatment of blepharochalasis:
a case series. Orbit 2009; 28(5):313–316.
Karaconji T, et al: Doxycycline for treatment of blepharochalasis via
inhibition of matrix metalloproteinases. Ophthal Plast Reconstr Surg
2012; 28(3):e76–e78.
Sacchidanand SA, et al: Transcutaneous blepharoplasty in
blepharochalasis. J Cutan Aesthet Surg 2012; 5(4):284–286.

ANETODERMA (MACULAR ATROPHY)
Anetoderma is characteri ed by locali ed loss o elastic tissue
resulting in herniation o subcutaneous tissue. The lesions pro
trude rom the s in ( ig. ) and on palpation ha e less
resistance than the surrounding s in producing the button
hole sign identical to a neuro broma. The sur ace s in may
be slightly shiny white and crin ly. The usual locations are
the trun especially on the shoulders the upper arms and
thighs. The inter ening s in is normal.
p to hal o patients with anetoderma ha e an accom
panying abnormality such as lupus antiphospholipid antibod
ies Gra es disease scleroderma hypocomplementemia
hypergammaglobulinemia autoimmune hemolysis or human
immunode ciency irus ( V) in ection. Screening or
antiphospholipid antibodies is o particular importance because
these may produce a prothrombotic state and some patients
ul ll criteria or the antiphospholipid syndrome. The antibod
ies may be detected as anticardiolipin antibodies anti β
glycoprotein antibodies or a lupus anticoagulant. Patients
may e perience recurrent etal loss recurrent stro es or recur
rent deep ein thrombosis. Thrombosis associated anetoderma
with ulceration has been related to antithrombin de ciency.
Some cases o anetoderma may be related to borreliosis. Rare
amilial cases ha e been noted. Secondary anetoderma may be
associated with pre ious lesions o acne secondary syphilis
measles lupus erythematosus ansen s disease sarcoidosis
tuberous anthoma aricella granuloma annulare mastocyto
sis and lymphoreticular malignancy.
Anetoderma o prematurity (congenital anetoderma) occurs
in premature in ants and may be related to pressure adhe
si es or changes in ow o ions or water under monitor leads.
ntrauterine borreliosis has also been implicated.
istologically loss o elastic tissue is noted with special
stains. n the late stage the s in loo s normal in sections.
n the acute stage a neutrophilic lymphoid or granulomatous
response may be noted. Ablati e laser treatment has been
reported as help ul in some patients with anetoderma.
Clark ER, et al: Thrombosis-induced ulcerations of the lower legs with
coexistent anetoderma due to anti-thrombin III deficiency. J Am Acad
Dermatol 2011; 65(4):880–881.
Emer J, et al: Generalized anetoderma after intravenous penicillin
therapy for secondary syphilis in an HIV patient. J Clin Aesthet
Dermatol 2013; 6(8):23–28.
Fig. 25-8 Anetoderma.
tahir99 - UnitedVRG
Haider M, et al: Lupus erythematosus–associated primary and
secondary anetoderma. J Cutan Med Surg 2012; 16(1):64–67.
Hodak E, et al: Primary anetoderma and antiphospholipid antibodies:
review of the literature. Clin Rev Allergy Immunol 2007; 32(2):
162–166.
Striae distensae
STRIAE DISTENSAE
Striae distensae are depressed lines or bands o thin reddened
s in which later become white smooth shiny and depressed.
lastotic striae ha e a yellow gold iridescent appearance.
Striae occur in response to changes in weight or muscle mass
and s in tension such as that induced by weightli ting. They
are common on the abdomen during and a ter pregnancy
(striae gra idarum) and on the breasts a ter lactation. They
also occur on the buttoc s and thighs the inguinal areas and
o er the nees and elbows in children during the growth spurt
o puberty. Cushing syndrome either endogenous or induced
by systemic corticosteroid treatment is a re uent cause o
striae and they may occur a ter application o potent topical
corticosteroid preparations especially under occlusion or in
olds. Striae are common in patients with ar an syndrome.
The histologic ndings are ariable and depend on the stage
o de elopment. n some early lesions peri ascular and inter
stitial in ltration o lymphocytes and sometimes eosinophils
is noted. n older lesions the primary changes are in the con
necti e tissue. The collagen o the upper dermis is decreased
and thin collagen bundles lie parallel to the o erlying epider
mis as in a scar. lastic tissue o ten appears increased but this
may result rom a loss o collagen in many cases. Dilated
upper dermal essels may be prominent.
A Cochrane re iew ound no high uality e idence to
support the use o any topical preparation or the pre ention
o stretch mar s during pregnancy. er time striae become
less noticeable without treatment. Both silicone gel and placebo
ha e demonstrated some positi e e ects in clinical studies
complicating interpretation o results. Topical tretinoin and
ascular lasers may produce some impro ement in appear
ance although the bene ts are more mar ed in the early
erythematous phase. Pulsed dye lasers ( nm) result in a
moderate decrease in erythema in striae rubra. Although the
total collagen per gram o dry weight increases in striae treated
with pulsed dye laser this change may not result in a clinically
e ident change in striae alba. Pulsed dye laser has also been
used in con unction with a radio re uency de ice. ntense
pulsed light has also demonstrated potential or impro ement
in the appearance o some striae although with greater ris
and lower e cacy in dar er s in types. Some data suggest that
nm light is more e ecti e than nm light. ractional
photothermolysis has been used in a ariety o s in types or
both rubra and alba types o striae.
Al-Dhalimi MA, et al: A comparative study of the effectiveness of intense
pulsed light wavelengths (650 nm vs 590 nm) in the treatment of striae
distensae. J Cosmet Laser Ther 2013; 15(3):120–125.
Brennan M, et al: Topical preparations for preventing stretch marks in
pregnancy. Cochrane Database Syst Rev 2012; 11:CD000066.
Chantes A, et al: Clinical improvement of striae distensae in Korean
patients using a combination of fractionated microneedle
radiofrequency and fractional carbon dioxide laser. Dermatol Surg
2014; 40:699.
Kim BJ, et al: Fractional photothermolysis for the treatment of striae
distensae in Asian skin. Am J Clin Dermatol 2008; 9(1):33–37.
Naeini FF, et al: Comparison of the fractional CO2 laser and the
combined use of a pulsed dye laser with fractional CO2 laser in striae
alba treatment. Adv Biomed Res 2014; 3:184.
Ud-Din S, et al: A double-blind controlled clinical trial assessing the
effect of topical gels on striae distensae (stretch marks): a non-
invasive imaging, morphological and immunohistochemical study. Arch
Dermatol Res 2013; 305(7):603–617.
507
25
Abnormalities of Dermal Fibrous and Elastic Tissue
Fig. 25-9 Linear focal elastosis on lower back of elderly man.
LINEAR FOCAL ELASTOSIS (ELASTOTIC STRIAE)
This elastosis ariant presents with asymptomatic palpable
or atrophic yellow lines o the middle and lower bac thighs
arms and breasts ( ig. ). Linear ocal elastosis is more
common in males. istologically increased elastic bers are
seen characteri ed by thin wa y and elongated as well as
ragmented bundles. lectron microscopy re eals thin elon
gated irregularly shaped swollen elastic bers with degenera
ti e changes.
Pui JC, et al: Linear focal elastosis: histopathologic diagnosis of an
uncommon dermal elastosis. J Drugs Dermatol 2003; 2:79–83.
ACRODERMATITIS CHRONICA ATROPHICANS
Patients with acrodermatitis chronica atrophicans present
with di use thinning o the s in on the e tremities sometimes
associated with brous bands. This condition is re iewed with
bacterial in ections in Chapter since it results rom orrelia
in ection.
OSTEOGENESIS IMPERFECTA
steogenesis imper ecta ( ) also nown as Lobstein syn
drome a ects the bones oints eyes ears and s in. t is esti
mated to a ect appro imately persons in the nited
States ( in population). There are se en recogni ed
orms based on di erences in clinical presentation and bone
architecture. Types and V ha e only an autosomal dominant
inheritance whereas types and ha e both autosomal
dominant and autosomal recessi e orms. i ty percent o
patients ha e the type orm. The type orm is lethal and
deaths usually occur within the rst wee o li e.
The brittle bones result rom a de ect in the collagenous
matri . ractures occur early in li e sometimes in utero. Loose
ointedness may be stri ing and dislocation o oints can be a
problem. Blue sclerae when present are a aluable diagnostic
clue ( ig. ). Scoliosis and de ecti e teeth may be present.
Dea ness de elops in many patients by the second decade o
li e and is audiologically indistinguishable rom otosclerosis.
The s in is thin and translucent and healing wounds result in
spreading atrophic scars. lastosis per orans serpiginosa may
occur. Some patients e perience unusual bruisability proba
bly rom a structural de ect in either the blood essel wall or
the supporting dermal connecti e tissue.
508
Fig. 25-10 Blue sclerae of osteogenesis imperfecta in patient with
Graves’ disease. (Courtesy of Lawrence Lieblich, MD.)
The basic de ect is abnormal collagen synthesis resulting in
type collagen o abnormal structure. ost orms o result
rom mutations in the genes or the proα or proα chains o
type collagen. Types V V and V are not associated with
type collagen gene de ects. n type (blue scleral dominant)
there is diminished type collagen with a mutation o COL
gene; in type (perinatal lethal) there is diminished type col
lagen synthesis and decreased integrity o the helical domain
o the α ( ) gene; in type (progressi e de orming) there is
delayed secretion o type collagen with altered mannosyl
ation; and in type V (white sclerae dominant) there is a de ec
ti e proα ( ) gene. A distinct subset o type V with clinical
impro ement o er time has been mapped to chromosome .
The ma or causes o death attributed to are respiratory
ailure secondary to se ere yphoscoliosis and head trauma
mostly obser ed in type disease. Aortic dissection has also
been described. Patients with type and type V disease ha e
a normal li e span. Brac syndrome is a combination o and
arthrogryposis multiple .
Treatment includes surgical inter ention such as intramed
ullary stabili ation. Bisphosphonates and calcitriol are the
most e ecti e pharmacologic agents. Speci cally cyclic pami
dronate therapy has been shown to suppress bone turno er
reduce bone pain and racture incidence and increase bone
density and le el o ambulation. Gene therapy is promising
but is complicated by the genetic heterogeneity o the disease.
ost o the mutations result in a mutant allele product that
inter eres with the unction o the normal allele. This sort o
abnormality presents greater challenges or gene therapy than
simple replacement o a missing en yme but gene and stem
cell trans er research is ongoing.
Alcausin MB, et al: Intravenous pamidronate treatment in children with
moderate-to-severe osteogenesis imperfecta started under three years
of age. Horm Res Paediatr 2013; 79(6):333–340.
Ben Amor M, et al: Osteogenesis imperfecta. Pediatr Endocrinol Rev
2013; 10(Suppl 2):397–405.
Zhang Z, et al: Phenotype and genotype analysis of Chinese patients
with osteogenesis imperfecta type V. PLoS One 2013; 8(8):e72337.
Bonus images for this chapter can be found online at
expertconsult.inkling.com
eFig. 25-1 Cutis laxa.
eFig. 25-1 Cutis laxa.

Osteogenesis imperfecta

508.e1

tahir99 - UnitedVRG
 Bonus images for this chapter can be found online at
AMYLOIDOSIS
Amyloid is a material deposited in the s in and other
organs that is eosinophilic homogeneous and hyaline in
appearance. t represents beta pleated sheet orms o arious
host synthesi ed molecules processed into this con guration
by host cells.
Amyloidosis can be classi ed as systemic locali ed and
heredo amilial types. The systemic types can deposit amyloid
in multiple organs and all are related to an o erproduction
o a host protein that cannot be ade uately e creted or meta
boli ed by the host. The e cess protein is metaboli ed into
amyloid precursors that interact with tissue proteoglycans
glycosaminoglycans orming soluble amyloid oligomers. These
oligomers comple with serum amyloid P (SAP) orming
amyloid deposits in the a ected organ. n all orms o amyloid
the pattern o deposition is characteristic although there can
be o erlap between arious orms. The diagnosis o a speci c
type o amyloid should only be made i the clinical eatures are
characteristic and i the deposited protein is identi ed histo
chemically. Primary locali ed amyloidosis (also called primary
cutaneous amyloidosis when the s in is a ected) is ery
common and o importance to the dermatologist. Rare amilial
syndromes may be complicated by secondary systemic amy
loidosis or may ha e genetic de ects that lead to amyloid depo
sition (heredo amilial amyloidosis). Classi cation o cutaneous
amyloidoses is as ollows.
. Systemic amyloidosis
A. Primary (myeloma associated) systemic amyloidosis
B. Secondary systemic amyloidosis
C. Dialysis related amyloidosis
D. Senile systemic amyloidosis
. Cutaneous amyloidosis
A. acular amyloidosis
B. Lichen amyloidosis
C. odular amyloidosis
D. Secondary (tumor associated) cutaneous amyloidosis
. amilial primary cutaneous amyloidosis
. Pharmaceutical amyloidosis
. eredo amilial amyloidosis
All orms o amyloid ha e relati ely identical histologic
and electron microscopic ndings. The amyloid in all orms
is made up o three distinct components protein deri ed
amyloid bers amyloid P component (about o amyloid)
and ground substance. The protein deri ed amyloid bers are
those that di er among the arious orms o amyloid.
Amyloid is wea ly periodic acid Schi (PAS) positi e and
diastase resistant Congo red positi e purple with crystal
iolet and positi e with thio a in T. Amyloid stained with
Congo red e hibits apple green bire ringence under polari ed
light. Secondary systemic amyloid (AA amyloid) loses its
expertconsult.inkling.com
Errors in Metabolism
26
bire ringence a ter treatment with potassium permanganate
whereas primary and locali ed cutaneous orms do not.
Amyloid stains an intense bright orange with cotton dyes
such as Dylon Pagoda red R T Scarlet o. or R T Cardinal
red o. . ltrastructurally amyloid has a characteristic bril
lar structure that consists o straight nonbranching nonanas
tomosing o ten irregularly arranged laments nm in
diameter. n most cases speci c antibodies against the protein
component should be used to con rm the type o amyloidosis.
Because amyloid substance P is present in all orms o amyloid
immunopero idase staining against this component will stain
all orms o amyloid. n addition since SAP is a idly bound
to amyloid radiolabeled highly puri ed SAP can be used to
locali e amyloidosis determine the e tent o organ in ltration
study progression o disease and determine i therapy reduces
the amount o amyloid in arious organs. Special centers ha e
the capability o doing body scans (radiolabeled SAP scintig
raphy) and ha e the reagents to identi y the speci c amyloid
proteins immunohistochemically. n atypical cases consulting
such centers may be warranted.
SYSTEMIC AMYLOIDOSES
Primary systemic amyloidosis (AL amyloidosis)
Primary systemic amyloidosis typically in ol es the idneys
li er heart gastrointestinal (G ) tract or peripheral ner e
tissue and s in. yeloma associated amyloidosis is included
in this category. The amyloid bril proteins in primary sys
temic amyloidosis are composed o the protein AL amyloid a
portion o the immunoglobulin ( g) light chain. t is usually o
the lambda (λ) subtype and certain germline g light chain V
chains ( aVλV and rVλ ) are responsible or AL amyloido
sis in o patients. About o patients will ha e the g
ragment detectable in the serum or urine; in the other
the serum ree light chain assay will detect a clear e cess o
one o the light chains (κ or λ) con rming the diagnosis. Also
reduction o the urine ree light chains by more than cor
relates with substantial bene t rom treatment.
Cutaneous mani estations occur in appro imately o
patients with primary systemic amyloidosis. The cutaneous
eruption usually begins as shiny smooth rm at topped or
spherical papules o wa y color that ha e the appearance o
translucent esicles. These lesions coalesce to orm nodules
and pla ues o arious si es and in some cases bandli e
lesions. The regions around the eyes nose mouth and muco
cutaneous unctions are re uently in ol ed ( ig. ). Vul ar
lesions may resemble giant condylomata. Lesions may also be
uni orm small papules resembling milia or e en lymphangi
oma. ollicular plugging may occur resulting in milia.
Purpuric lesions and ecchymoses occur in about o
patients and are the most common cutaneous mani estation o
509

26
Errors in Metabolism
Fig. 26-1 Systemic amyloidosis.
Fig. 26-2 Macroglossia and translucent papules in amyloidosis.
(Courtesy of Lawrence Lieblich, MD.)
primary systemic amyloidosis. There are se eral mechanisms
by which AL amyloid leads to purpura. Amyloid may in l
trate blood essels ma ing them ragile. AL amyloid may also
bind actor contributing to the purpura. Lastly amyloid
in ltration o the li er may lead to reduced production o
brinogen and actor ad ersely a ecting clotting. Purpura
chie y in ol es the eyelids limbs and oral ca ity. t typically
occurs a ter trauma (pinch purpura) and can be reproduced
by the physician by rubbing a pen or dull instrument o er the
s in analogous to trying to demonstrate dermatographism.
Purpuric lesions also classically appear a ter actions or proce
dures that result in increased pressure in the essels o the
ace such as a ter omiting coughing proctoscopic e amina
tion or pulmonary unction testing.
Glossitis with macroglossia occurs in at least o matory bowel disease and Beh et s disease. The newer and
patients may be an early symptom and can lead to dysphagia.
The tongue becomes greatly enlarged and urrows de elop
( ig. ). The lateral aspects show indentations rom the
teeth. Papules or nodules sometimes with hemorrhage occur
on the tongue.
Bullous amyloidosis is a rare but important clinical mani es
tation o amyloidosis. S in ragility and tense hemorrhagic
or clear nonin ammatory bullae appear at areas o trauma
510
tahir99 - UnitedVRG
usually the hands orearms and eet. Lesions heal with scar
ring and milia. The esophagus and oropharyngeal mucosae
may also be in ol ed. istologically the lesions are subepi
dermal and pauci in ammatory. pidermolysis bullosa
ac uisita and porphyria cutanea tarda are the di erential
diagnoses. Amyloid staining may yield negati e results and
direct immuno uorescence (D ) may be alsely positi e
because o AL protein deposition at the dermoepidermal unc
tion (D J). The diagnosis is con rmed by e aluation o the
patient s serum and urine or g ragments and by amyloid
stains or electron microscopy o the s in biopsies which will
demonstrate the amyloid.
A di use or patchy alopecia cutis erticis gyrata and a
scleroderma li e scleromy edema li e or a cutis la a li e
appearance ha e also rarely been described. Cutis la a li e
ndings may be generali ed or locali ed to the acral parts.
Lesions in the e ors and lateral nec may resemble pseudo
anthoma elasticum (P ). At times lesions with cutis la a
li e or P li e appearance may show amyloid bound to
elastic bers. The nail matri may be in ltrated resulting in
atrophy o the nail plate presenting as longitudinal striae
partial anonychia splitting and crumbling o the nail plate.
Cordli e thic ening along blood essels can also occur. Bilat
eral stenosis o the e ternal auditory canals has been reported.
Patients with systemic amyloidosis are at increased ris or
s in cancer.
Patients may present with or de elop a plethora o systemic
ndings. ost characteristically they de elop carpal tunnel
syndrome other peripheral neuropathies a rheumatoid arthri
tis (RA) li e arthropathy o the small oints orthostatic hypo
tension G bleeding nephrotic syndrome and cardiac disease.
Cardiac troponins are ele ated and are power ul prognostic
determinants in AL amyloidosis. le ated troponins are asso
ciated with a month sur i al. AL patients may appear to
ha e prominent deltoid muscles as a result o deposition o
amyloid in the muscles (shoulder pad sign). Cardiac arrhyth
mias and right sided congesti e heart ailure are common
causes o death.
The prognosis or patients with primary systemic amyloido
sis is poor. Those presenting with neurologic ndings
sur i e longer than patients presenting with cardiac disease.
i teen percent o patients with AL amyloidosis will ha e
myeloma and o patients with myeloma will ha e AL
amyloidosis.
Secondary systemic amyloidosis (AA amyloidosis)
Secondary systemic amyloidosis is caused by a chronic in ec
tious or in ammatory process. n these conditions the precur
sor protein serum amyloid A (SAA) an acute phase reactant
is chronically ele ated and cannot be ade uately cleared rom
the body. t is processed to AA amyloid in a ected tissues.
With modern control o chronic in ections (especially tubercu
losis schistosomiasis osteomyelitis bronchiectasis pyelone
phritis and decubitus ulcer) in ection related AA amyloid is
much less common. ost cases are now related to chronic
in ammatory conditions especially RA u enile idiopathic
arthritis an ylosing spondylitis adult Still s disease in am
more aggressi e management strategies or these in amma
tory conditions ha e led to reduced numbers or delayed onset
o AA amyloidosis in these patients. aintaining SAA below
mg L is associated with a good outcome in AA amyloidosis.
The common organs in ol ed by AA amyloidosis are the
idneys adrenals li er and spleen. The s in is not in ol ed
but biopsy o s in in patients with AA amyloidosis will detect
amyloid deposits in the dermis peri ascularly. Certain s in
conditions such as hidradenitis suppurati a stasis ulcers
psoriatic arthritis and dystrophic epidermolysis bullosa may
be complicated by AA amyloidosis. any inherited conditions
associated with ele ated SAA may be complicated by AA
amyloidosis as well. These include amilial editerranean
e er cryopyrin associated periodic syndromes and tumor
necrosis actor (T ) receptor associated periodic syndrome
(TRAPS).
Dialysis-associated amyloidosis
(β2-microglobulin amyloidosis)
β icroglobulin is e creted primarily by the idneys. n
patients with se ere renal ailure on dialysis or predialysis
the e cess β microglobulin may be processed to amyloid in
certain tissues. Almost o patients recei ing dialysis or
years or more will de elop this orm o amyloidosis. t
primarily a ects the syno ium causing musculos eletal
symptoms o ten carpal tunnel syndrome and less o ten
trigger nger bone cysts and spondyloarthropathy. Rarely
the s in may be in ol ed usually as a subcutaneous tumor
o ten o the buttoc s o erlying the sacrum. Pedunculated
sacral masses lichenoid papules and locali ed hyper
pigmentation can also be seen. The diagnosis is con rmed by
biopsy which demonstrates that the amyloid material is β
microglobulin on immunohistochemical stains. The treatment
is high u dialysis or idney transplantation.
Senile systemic amyloidosis
Senile systemic amyloidosis is increasingly recogni ed as an
important cause o cardiac disease in the elderly population
(> years). Carpal tunnel syndrome can also occur. Senile
systemic amyloidosis is caused by deposition o normal trans
thyretin a transporter protein in tissue. S in lesions ha e not
been reported but ascular deposition has led to tongue
necrosis. The diagnosis can be con rmed in about three uar
ters o patients with a deep abdominal at biopsy.
CUTANEOUS AMYLOIDOSIS
Primary localized cutaneous amyloidosis
The primary locali ed cutaneous amyloidoses ha e been
di ided into our orms macular lichen nodular and amilial.
acular and lichen orms o amyloidosis are also called
eratinocyte deri ed amyloidosis rictional amyloidosis
and rictional melanosis. Some cases o these two orms o
cutaneous amyloidosis are amilial but the relationship
between these and cases o amilial primary locali ed cutane
ous amyloidosis is unclear. Patients with macular and lichen
amyloidosis o ten ha e coe istent atopic dermatitis. odular
and amilial cases o cutaneous amyloidosis are rare and ha e
a uni ue pathogenesis.
on amilial macular and lichen amyloidosis ha e the same
pathogenic basis (rubbing and riction) and o erlap cases
(biphasic cutaneous amyloidosis) can be seen. ndi iduals o
Asian ispanic or iddle astern ancestry seem to be pre
disposed. n Asia the use o abrasi e de ices during bathing
is o ten the precipitant. n cases o ac uired macular and lichen
amyloidosis the deposited amyloid material contains eratin
(primarily eratin ) as its protein component strongly sug
gesting that traumatic damage to basal eratinocytes results
in the deposits. Why only certain indi iduals are a ected
is un nown. A rare orm locali ed to the conchae has been
described. on amilial macular and lichen amyloidosis may
be associated with e tremely pruritic s in conditions such as
primary biliary cirrhosis and chronic renal ailure.
The histologic picture o ac uired macular and lichen amy
loidosis is similar; the only di erence is the si e o the amyloid
Cutaneous amyloidosis
deposits and the e tent o the o erlying epidermal changes.
The o erlying epidermis is re uently hyper eratotic and
ocally acanthotic a result o the chronic rubbing. ocal
necrotic eratinocytes may be obser ed in the basal cell layer.
icroscopic and rarely macroscopic bullae (analogous to those
in lichen planus) may be seen. Dermal papillae are e panded
by amorphous deposits o amyloid that abut immediately
below the epidermis. elanin deposits are classically present
in the amyloid. n all cases o postin ammatory hyperpigmen
tation with incontinence o pigment the architecture o the
areas o dermal melanosis should be e amined care ully to
e clude amyloidosis. Systemic amyloidosis is e cluded by the
absence o amyloid deposits around blood essels. Special
stains may be used to con rm the diagnosis but this is rarely
re uired i the classic histology is ound. n di cult cases
immunopero idase or eratin will stain the amyloid deposits
and con rm the diagnosis o primary cutaneous amyloidosis.
D may demonstrate immunoglobulin (usually g ) in a
globular pattern in the eratin deri ed cutaneous amyloido
ses but this is caused by passi e absorption rather than spe
ci c deposition. This phenomenon is seen in all disorders with
prominent apoptosis o eratinocytes.
Macular amyloidosis
Typically patients with macular amyloidosis e hibit moder
ately pruritic brown rippled macules characteristically
located in the interscapular region o the bac ( ig. ).
Women outnumber men by or more. Pigmentation is gen
erally not uni orm gi ing the lesions a salt and pepper or
rippled appearance. otalgia paresthetica is locali ed to the
same sites and most cases o macular amyloid between the
scapulae probably result rom rubbing dysesthetic areas o
notalgia paresthetica. ccasionally the thighs shins arms
breasts and buttoc s may be in ol ed and these more di use
cases are usually associated with di use pruritus. acular
amyloidosis is a chronic condition.
Lichen amyloidosis
Lichen amyloidosis is characteri ed by the appearance o par
o ysmally itchy lichenoid papules irtually always appearing
Fig. 26-3 Macular amyloid. (Courtesy of Dr. Debabrata
Bandyopadhyay.)
511
 Fig. 26-4 Lichen
26 amyloidosis.
Errors in Metabolism
bilaterally on the shins ( ig. ). Some patients may deny
itching. en outnumber women . The primary lesions are
small brown discrete slightly scaly papules that group to
orm large in ltrated pla ues. Less re uently these may
occur on the thighs orearms ace and e en the upper bac .
Treatment
Treatment o lichen and macular cutaneous amyloidosis is
re uently unsatis actory. Reducing riction is critical. denti y
ing the cause o the rubbing and whether it is habit pruritus
or neuropathy (as in notalgia paresthetica) directs treatment.
cclusion plays a ma or role because it both enhances topical
treatments and pro ides a physical bloc to pre ent trauma to
the s in. Administration o topical high potency corticosteroid
agents can be bene cial as can intralesional corticosteroid
therapy when small areas are in ol ed. Topical tacrolimus
. ointment psoralen plus ultra iolet A light (P VA) and
with retinoids (Re P VA) ultra iolet B ( VB) light tar and
calcipotriol bene t indi idual patients. Amitriptyline ( or
itching) oral retinoids thalidomide and systemic immuno
suppressi es including corticosteroids may be used in
re ractory cases. The pigmentation o macular amyloidosis
reportedly has been impro ed by laser therapy especially the
nm switched neodymium doped yttrium aluminum
garnet ( d AG) laser.
Nodular amyloidosis
odular amyloidosis is a rare orm o primary locali ed cuta
neous amyloidosis in which single or less o ten multiple
nodules or tume actions pre erentially in ol e the acral areas
( ig. ). owe er trun genital or acial lesions may be
seen as well. The lesions are asymptomatic ary in si e rom
se eral millimeters to se eral centimeters and may grow
slowly a ter their initial appearance. The o erlying epidermis
may appear atrophic and lesions may resemble large bullae.
umerous conditions ha e been associated with nodular
primary locali ed cutaneous amyloidosis ( PLCA) especially
S gren syndrome but also systemic sclerosis (including
CR ST) and RA. n S gren syndrome the nodular amyloido
sis typically appears about age more re uently in emales
and may precede the diagnosis o S gren syndrome by many
512
tahir99 - UnitedVRG
Fig. 26-5 Nodular amyloidosis.
years. The dermis and subcutis may be di usely in ltrated
with amyloid. The lesions may contain numerous plasma cells
and are best considered to be isolated plasmacytomas. The
amyloid in these patients is g deri ed AL as is seen in primary
systemic amyloidosis and is unrelated to eratinocyte related
amyloid or to AA amyloid. Progression to systemic amyloido
sis may occur in about o cases so they should be regularly
e aluated or progression. Treatment is physical remo al or
destruction o the lesion with sha e remo al and destruction
o the base.
Secondary cutaneous amyloidosis
A ter P VA therapy and in benign and malignant cutaneous
neoplasms deposits o amyloid may be ound. ost re
uently the associated neoplasms are nonmelanoma s in
cancers or seborrheic eratoses. Discoid lupus dermatomyo
sitis and gra t ersus host disease (GV D) as inter ace der
matoses with apoptosis o eratinocytes can occasionally
demonstrate amyloid in the upper dermis. n all cases this is
eratin deri ed amyloid.
Hereditary cutaneous amyloidosis syndromes
amilial primary locali ed cutaneous amyloidosis ( PLCA) is
an autosomal dominant syndrome associated with chronic
itching and cutaneous lesions resembling macular and lichen
amyloidosis. t is seen most o ten in Japan Bra il China and
Taiwan. The age o onset is years. n some amilies sun
e posure may be an e acerbating actor. Lesions are o ten
widespread on the limbs chest and upper and lower bac .
The buttoc s conchae and dorsal eet and hands may also be
in ol ed. Some patients may deny pruritus. n amilies rom
numerous countries with PLCA mutations in the OSM β or
interleu in receptor A L genes are ound. These
two genes orm the two subunits o the transmembrane recep
tor or L . A ected amilies ha e only mutation o one gene
and all mutations occur on the membrane pro imal domain
re uired or downstream signaling. L induces the secre
tion o monocyte chemotactic protein ( CP ) and le els o
CP e pression are ery low in PLCA. CP recruits
monocytes to clear the cellular debris resulting rom eratino
cyte damage. n the absence o this signal cellular debris accu
mulates and the eratin is processed to amyloid. Rare cases
o macular amyloidosis in an incontinentia pigmenti li e dis
tribution suggest that mosaicism or PLCA can be seen
gi ing this unusual cutaneous distribution. Some PLCA
cases demonstrate e tensi e poi ilodermatous lesions and
less re uently a patient may ha e multiple morphologies o
lichen amyloid poi iloderma and dyschromica and e en
small bullous lesions.
Amyloidosis cutis dyschromica is a distinct type o PLCA
with onset in childhood no pruritus a dotted reticular hyper
pigmentation with hypopigmented spots without papulation
co ering almost all the body and small oci o amyloid ust
below the epidermis. The nature o the amyloid is unclear.
ost a ected amilies are rom Japan Taiwan and ndia. VB
hypersensiti ity is o ten reported by these patients. ultiple
endocrine neoplasia type A ( A) syndrome and amil
ial medullary thyroid carcinoma ( TC) are both caused by
mutations in the E proto oncogene. Cutaneous amyloidosis
most o ten eratin deri ed macular amyloidosis may be seen
in these patients. The macular amyloid may be restricted to
the upper bac and also unilateral (associated with notalgia
paresthetica) or it may be bilateral and more e tensi e. Age
o onset is usually be ore . Thirty o patients with A atopic dermatitis. J Eur Acad Dermatol Venereol 2014; 28:810.
had cutaneous amyloidosis be ore the diagnosis o A Choi JY, et al: Acitretin for lichen amyloidosis. Australas J Dermatol
was made. n a patient with macular amyloidosis o early
onset (be ore age ) a care ul amily history should be ta en
or endocrine neoplasias the s in and mucosa e amined or
neuromas the blood pressure ta en (chec ing or pheochro
mocytoma) and the thyroid palpated. A serum calcitonin le el
should be ordered and i ele ated a thyroid ultrasound
per ormed.
Pharmaceutical amyloidosis
When in ected into the s in insulin can create deposits o
amyloid composed o the A and B subunits o insulin. This is
termed A ns. Lesions present as deep subcutaneous nodules
usually on the lower abdomen. patients in ect into these
sites their glucose control may be impaired and their insulin
dose may increase. n ecting into new areas or surgically
remo ing the nodules impro es glucose control. n u irtide
a human immunode ciency irus ( V) usion inhibiting
peptide administered subcutaneously can produce similar
lesions.
FAMILIAL SYNDROMES ASSOCIATED WITH
AMYLOIDOSIS (HEREDOFAMILIAL AMYLOIDOSIS)
ost orms o amilial amyloidosis are caused by abnormal
host proteins that cannot be ade uately processed resulting
in their deposition in arious tissues in the orm o amyloid.
nly o patients with hereditary amyloidosis will ha e a
positi e amily history. Li er idney heart eye and ner ous
system may be in ol ed. Se eral types o hereditary amyloi
dosis ha e been identi ed; some orms are caused by genetic
de ects in transthyretin. These are autosomal dominant syn
dromes and most a ected patients are hetero ygotes. thers
are caused by a genetic de ect in apolipoprotein A or A
by a de ect in gelsolin brinogen A α cystatin C or lyso yme.
These syndromes must o ten be diagnosed by genetic testing
or immunohistochemical identi cation o the deposited patho
genic protein.
Al-Niaimi F, et al: Brown nodules and plaques on the neck. Clin Exp
Familial syndromes associated with amyloidosis (heredofamilial amyloidosis)
Dermatol 2013; 38:200.
Alvarez-Ruiz SB, et al: Unusual clinical presentation of amyloidosis:
bilateral stenosis of the external auditory canal, hoarseness and a
rapid course of cutaneous lesions. Int J Dermatol 2007; 46:503.
An Q, et al: Dramatic improvement of primary cutaneous amyloidosis
with thalidomide. Eur J Dermatol 2011; 21:270.
An Q, et al: Thalidomide improves clinical symptoms of primary
cutaneous amyloidosis: report of familiar and sporadic cases.
Dermatol Ther 2013; 26:263.
Arnold SJ, Bowling JC: “Shiny white streaks” in lichen amyloidosis: a
clue to diagnosis. Australas J Dermatol 2012; 53:272.
Bandhlish A, et al: A clinic-epidemiological study of macular amyloidosis
from North India. Indian J Dermatol 2012; 57:269.
Barja J, et al: Systemic amyloidosis with an exceptional cutaneous
presentation. Dermatol Online J 2013; 19:11.
Baykal C, et al: Multiple cutaneous neuromas and macular amyloidosis
associated with medullary thyroid carcinoma. J Am Acad Dermatol
2007; 56:S33.
Brown AJ, et al: Multiple lesions of primary cutaneous nodular
amyloidosis in Sjögren syndrome. J Am Acad Dermatol 2012; 67:e267.
Castanedo-Cazares JP: Lichen amyloidosis improved by 0.1% topical
tacrolimus. Dermatology 2002; 205:420.
Chandran NS, et al: Case of primary localized cutaneous amyloidosis
with protean clinical manifestations: lichen, poikiloderma-like,
dyschromic and bullous variants. J Dermatol 2011; 38:1066.
Chia B, et al: Primary localized cutaneous amyloidosis: association with
2008; 49:109.
Clos AL, et al: Formation of immunoglobulin light chain amyloid
oligomers in primary cutaneous nodular amyloidosis. Br J Dermatol
2011; 165:1349.
Clos AL, et al: Role of oligomers in the amyloidogenesis of primary
cutaneous amyloidosis. J Am Acad Dermatol 2011; 65:1023.
D’Souza A, et al: Pharmaceutical amyloidosis associated with
subcutaneous insulin and enfuvirtide administration. Amyloid 2014;
21:71.
Funai N, et al: Multiple milia and comedones as a skin manifestation of
systemic amyloidosis. Eur J Dermatol 2011; 21:638.
Gan EY, Tey HL: Primary cutaneous nodular amyloidosis initially
presenting with eczema. Singapore Med J 2010; 51:3158.
Garg T, et al: Pruritic patches on the back and papules on the legs.
Arch Dermatol 2007; 143:255.
Garg T, et al: Amyloidosis cutis dyschromica: a rare pigmentary
disorder. J Cutan Pathol 2011; 38:823.
Grimmer J, et al: Successful treatment of lichen amyloidosis with
combined bath PUVA photochemotherapy and oral acitretin. Clin Exp
Dermatol 2007; 32:39.
Haemel A, et al: Keratinocyte-derived amyloidosis as a manifestation of
chronic graft-versus-host disease. J Cutan Pathol 2013; 40:291.
Hanami Y, Yamamoto T: Secondary amyloid deposition in a melanocytic
nevus. Int J Dermatol 2013; 52:1031.
Hemminki K, et al: Cancer risk in amyloidosis patients in Sweden with
novel findings on non-Hodgkin lymphoma and skin cancer. Ann Oncol
2014; 25:511.
Ikeda SI, et al: Diagnostic value of abdominal wall fat pad biopsy in
senile systemic amyloidosis. Amyloid 2011; 18:211.
Jin AGT, et al: Comparative study of phototherapy (UVB) vs
photochemotherapy (PUVA) vs topical steroids in the treatment of
primary cutaneous lichen amyloidosis. Photodermatol Photoimmunol
Photomed 2001; 17:42.
Kalajian AH, et al: Nodular primary localized cutaneous amyloidosis
after trauma: a case report and discussion of the rate of progression
to systemic amyloidosis. J Am Acad Dermatol 2007; 57:S26.
Kandhari R, et al: Asymptomatic conchal papules. Indian J Dermatol
Venereol Leprol 2013; 79:445.
Koh M, et al: A rare case of primary cutaneous nodular amyloidosis of
the face. J Eur Acad Dermatol Venereol 2008; 22:1011.
Konopinski JC, et al: A case of nodular cutaneous amyloidosis and
review of the literature. Dermatol Online J 2013; 19:10.
513
 Kumar S, et al: Skin involvement in primary systemic amyloidosis.
26 Mediterr J Hematol Infect Dis 2013; 5:e2013005.
Kurian SS, et al: Amyloidosis cutis dyschromica. Indian Dermatol Online
J 2013; 4:344.
Lee DD, et al: Association of primary cutaneous amyloidosis with atopic
Errors in Metabolism
dermatitis: a nationwide population-based study in Taiwan. Br J
Dermatol 2011; 164:148.
Lin JR, et al: Tongue necrosis and systemic vascular amyloidosis.
Human Pathol 2011; 42:734.
Love WE, et al: The spectrum of primary cutaneous nodular
amyloidosis: two illustrative cases. J Am Acad Dermatol 2008; 58:S33.
Meijer JM, et al: Sjögren’s syndrome and localized nodular cutaneous
amyloidosis: coincidence or a distinct clinical entity? Arthritis Rheum
2008; 58:1992.
Merchand A, et al: Cutaneous amyloid elastosis revealing multiple
myeloma with systemic amyloidosis. Acta Derm Venereol 2013;
93:204.
Mohty D, et al: Cardiac amyloidosis: updates in diagnosis and
management. Arch Cardiovasc Dis 2013; 106:528.
Nagaste T, et al: Insulin-derived amyloidosis and poor glycemic control:
a case series. Am J Med 2014; 127:450.
Ostovari N, et al: 532-nm and 1064-nm Q-switched Nd:YAG laser
therapy for reduction of pigmentation in macular amyloidosis patches.
J Eur Acad Dermatol Venereol 2008; 22:442.
Pardo Arranz L, et al: Familial poikylodermic cutaneous amyloidosis. Eur
J Dermatol 2008; 18:289.
Park MY, Kim YC: Macular amyloidosis with an incontinentia pigmenti–
like distribution. Eur J Dermatol 2008; 18:477.
Powell AM, et al: Discoid lupus erythematosus with secondary
amyloidosis. Br J Dermatol 2005; 153:746.
Renker T, et al: Systemic light-chain amyloidosis revealed by
progressive nail involvement, diffuse alopecia and sicca syndrome:
report of an unusual case with a review of the literature. Dermatology
2014; 228:97.
Rothberg AE, et al: Familial medullary thyroid carcinoma associated with
cutaneous lichen amyloidosis. Thyroid 2009; 19:651.
Sakuma TH, et al: Familial primary localized cutaneous amyloidosis in
Brazil. Arch Dermatol 2009; 145:695.
Salim T, et al: Lichen amyloidosis: a study of clinical, histopathologic
and immunofluorescence findings in 30 cases. Indian J Dermatol
Venereol Leprol 2005; 71:166.
Shiao YM, et al: MCP-1 as an effector of IL-31 signaling in familial
primary cutaneous amyloidosis. J Invest Dermatol 2013; 133:1375.
Takayama K, et al: Dialysis-related amyloidosis on the buttocks. Acta
Derm Venereol 2008; 88:72.
Taniquchi Y, et al: Cutaneous amyloidosis associated with amyopathic
dermatomyositis. J Rheumatol 2009; 36:1088.
Tong PL, et al: Primary localized cutaneous nodular amyloidosis
successfully treated with cyclophosphamide. Australas J Dermatol
2013; 54:e12.
Wang WH, et al: A new c.1845A→T of oncostatin M receptor-β mutation
and slightly enhanced oncostatin M receptor-β expression in a Chinese
family with primary localized cutaneous amyloidosis. Eur J Dermatol
2012; 22:29.
Wat H, et al: Primary systemic (amyloid light-chain) amyloidosis
masquerading as pseudoxanthoma elasticum: recognizing a novel
clinicopathological pattern. JAMA Dermatol 2014; 150:1091.
Wettle C, et al: Cutaneous haemorrhage induced by minimal trauma as
a sign of light chain–associated amyloidosis. B J Haematol 2012;
159:383.
Wey SJ, et al: Primary Sjögren syndrome manifested as localized
cutaneous nodular amyloidosis. J Clin Rheumatol 2011; 17:368.
Wu JJ, et al: Macular amyloidosis presenting in an incontinentia
pigmenti–like pattern with subepidermal blister formation. J Eur Acad
Dermatol Venereol 2008; 22:635.
Yang W, et al: Amyloidosis cutis dyschromica in two female siblings:
cases report. BMC Dermatol 2011; 11:4.
Yasuyuki F, et al: Nail dystrophy and blisters as sole manifestations in
myeloma-associated amyloidosis. J Am Acad Dermatol 2006; 54:712.
Yew YW, Tey HL: Itch in familial lichen amyloidosis: effective treatment
with amitriptyline in two cases. Dermatol Ther 2014; 27:12.
Yoshida A, et al: Lichen amyloidosis induced on the upper back by
long-term friction with a nylon towel. J Dermatol 2009; 36:56.
Zhao JY, et al: A case of systemic amyloidosis beginning with purpura.
Chin Med J 2012; 125:555.
514
tahir99 - UnitedVRG
Zuo YG, et al: Lack of evidence for OSMR and RET gene mutations in
a Chinese family with friction melanosis. Clin Exp Dermatol 2009;
35:282.
PORPHYRIAS
Porphyrinogens are the building bloc s o all the hemopro
teins including hemoglobin and the cytochrome en ymes
and are produced primarily in the li er and bone marrow.
ach orm o porphyria has now been associated with a de
ciency in an en yme in the metabolic pathway o heme syn
thesis. These en yme de ciencies lead to accumulation o the
precursor molecules be ore the mutation. The precursors are
porphyrins and the diseases are called porphyrias.
nderstanding the biosynthetic pathway o heme has
clari ed the biochemical basis o the porphyrias. Delta
aminole ulinic acid (dALA) is synthesi ed in the mitochon
dria by dALA synthetase. rom it are ormed successi ely
porphobilinogen uroporphyrin coproporphyrin and
protoporphyrin . This orm reenters the mitochondrion to
be acted on by errochelatase to produce heme. ach step in
this process is cataly ed by a speci c en yme. eme by nega
ti e eedbac represses the production or acti ity o dALA
synthetase. heme is inade uate dALA synthetase acti ity
may be increased leading to the production o more porphy
rins. Because this en yme system is inducible medications
that increase the cytochrome drug metaboli ing system in the
li er can lead to e acerbation o the porphyrias by increasing
the production o the porphyrin intermediates.
The current grouping o the porphyrias is based on the
primary site o increased porphyrin production either li er or
bone marrow the hepatic or erythropoietic porphyrias
respecti ely. Some include a hepatoerythropoietic category.
Congenital erythropoietic porphyria (C P) lin ed domi
nant protoporphyria ( LDPP) and erythropoietic protopor
phyria ( PP) are the erythropoietic orms. Acute intermittent
porphyria (A P) ALA dehydratase de ciency (ADP) heredi
tary coproporphyria ( CP) ariegate porphyria (VP) and
porphyria cutanea tarda (PCT) are the hepatic orms. epato
erythrocytic porphyria ( P) has been classi ed as either a
hepatic or a hepatoerythropoietic type.
Another way to classi y the porphyrias is by their symp
tomatology. This system di ides those diseases that ha e
acute episodes called the acute porphyrias and those that
ha e s in ndings called the cutaneous porphyrias. Some
conditions ha e both s in disease and acute episodes. The
acute porphyrias are ADP A P CP and VP. The cutaneous
porphyrias are PCT C P LDPP and PP. VP and CP can
ha e both acute attac s and s in lesions. The acute attac s
are induced by conditions that acti ate the heme biosynthesis
pathway. Due to the en ymatic bloc s as the pathway is
acti ated large amounts o the heme precursors (speci cally
dALA and porphobilinogen) are produced by the li er and
dumped into the bloodstream. These substances are neuro
to ic and a ect primarily the autonomic and peripheral
ner es. n the cutaneous porphyrias photosensiti ity is
obser ed. The photosensiti ity is caused by the absorption o
V radiation in the Soret band ( nm) by increased
porphyrins primarily in the blood essels o the upper
dermis. These acti ated porphyrins are unstable and as they
return to a ground state they trans er energy to o ygen cre
ating reacti e o ygen species. These unstable o ygen species
interact with biologic systems primarily plasma and lyso
somal membranes causing tissue damage. ediators
released rom mast cells and polymorphonuclear leu ocytes
acting through complement and metalloproteinase eico
sanoids or actor pathways may augment tissue e ects.
The s in lesions are determined by the biochemical nature o
the e cess porphyrin. ydrophobic protoporphyrin has more
a nity to lipid membranes speci cally endothelial cells.
This correlates with acute burning and purpura e hibited in
PP as well as the prominent reduplication o the basement
membranes (seen as peri ascular hyaline deposits) o the
trichosis o the ace is seen especially o er the chee s and
temples. The ace and nec especially in the periorbital area
may show a pin to iolaceous tint. Sclerodermatous thic en
ings may de elop on the bac o the nec in the preauricular
areas ( ig. ) or on the thora ngers and the scalp with

Porphyria cutanea tarda

upper dermal essels rom constant repair o the phototo ic
damage to the endothelial cells. The more water soluble por
phyrins (uroporphyrin and coproporphyrins) di use into
and accumulate in the dermis and along the D J. The result
ing s in lesions subepidermal blisters are caused by the
phototo ic damage in this region.
The porphyrias ha e classically been diagnosed by identi y
ing characteristic clinical and biochemical abnormalities typi
cally ele ated le els o porphyrins in the urine serum red
blood cells (RBCs) or stool. Because there is some clinical
o erlap biochemical testing should be per ormed to con rm
any diagnosis o porphyria. n the acute porphyrias patients
are o ten asymptomatic between attac s. During attac s por
phyrin assays will be abnormal in all orms o porphyria.
Between attac s some patients with A P may ha e normal
porphyrin assays. The genetic de ect and the points o the most
common mutations or each gene are now nown or most
orms o the porphyrias. Genetic testing is now recommended
in most porphyrias e cept PCT and PP. This allows or the
diagnosis o A P between attac s. There is considerable clini
cal o erlap in these rarer porphyrias; dual porphyrias e ist
with mutations in two di erent heme synthesis genes; and
low le el mutations causing atypical presentations are now
well described. Accurate diagnosis in such cases re uires
determination o the genetic de ect. This also allows or genetic
counseling and prenatal diagnosis.
associated alopecia. A direct relationship between the le els o
uroporphyrins in the urine and sclerodermatous changes has
been reported.
Li er disease is re uently present in patients with PCT. A
history o alcoholism is common. PCT is a well recogni ed
cutaneous complication o hepatitis C irus ( CV) in ection.
All PCT patients should be screened or CV in ection. ron
o erload in the li er is re uently ound in patients with PCT
as a result o chemical or iral li er damage or because a
signi cant number o patients with PCT ha e a C muta
tion (and a ew with D mutation) the genetic cause o
hemochromatosis ( ig. ). The net result o all these li er
and iron metabolism abnormalities is an increase in erritin
with hepatic iron o erload. epatocellular carcinoma may
rarely present with PCT and PCT patients are at . times the
ris o de eloping hepatocellular carcinoma.
Fig. 26-7 Porphyria
cutanea tarda with
sclerosis.

PORPHYRIA CUTANEA TARDA

Porphyria cutanea tarda is the most common type o
porphyria. Patients with PCT present most o ten in midli e
a eraging years o age at disease onset. The disease is char
acteri ed by photosensiti ity resulting in bullae especially on
sun e posed parts. The dorsal hands and orearms ears and
ace are primarily a ected. The bullae are nonin ammatory
and rupture easily to orm erosions or shallow ulcers ( ig.
). These heal with scarring milia and dyspigmentation.
Lesions on the legs especially the shins and dorsal eet occur
primarily in women. n addition patients re uently complain
o s in ragility in a ected areas. There is hyperpigmentation
o the s in especially o the ace nec and hands. yper

Fig. 26-8 Porphyria cutanea tarda with hemochromatosis. (Courtesy

Fig. 26-6 Porphyria cutanea tarda. of Curt Samlaska, MD.)
515
 Porphyria cutanea tarda has been re uently associated with
26 other diseases. t is estimated that adult onset (type ) diabetes
mellitus occurs in o patients with PCT. Diabetes
usually occurs about a decade a ter the PCT diagnosis. Type
diabetes and the metabolic syndrome is associated with
Errors in Metabolism
hyper erritinemia. t has been proposed that in some patients
nonalcoholic steatohepatitis ( AS ) o diabetes may contrib
ute to the de elopment o PCT and in one patient weight
reduction led to impro ement o PCT. Antimalarial treatment
o PCT leads to enhanced glucose control. oderate smo ing
(> cigarettes day) may lead to earlier presentation o PCT
by almost a decade. umerous cases o lupus erythematosus
concomitant with PCT ha e been reported. Patients may ha e
systemic and or purely cutaneous lupus and either disease
may present initially. The pathogenesis o this association is
unclear.
Porphyria cutanea tarda can occur in patients with V walls in a granular linear pattern.
in ection. This is not related only to coe istent CV in ection
which is increased in some ris groups o V in ected persons.
Subtle porphyrin abnormalities are ound in V disease but
the porphyrin le els are well below those capable o inducing
clinical disease. ther ris actors such as alcoholism should
be e aluated and the e istence o PCT should not be attributed
to the V disease alone. owe er e ecti e anti V therapy
has led to impro ement o PCT in one V CV in ected
patient.
strogen treatment is associated with the appearance o PCT
by an un nown mechanism. Be ore oral contracepti es were
introduced PCT cases occurred predominantly among men
but in most recent series o cases occurred in men and
in women. en treated with estrogens or prostate cancer
may de elop PCT.
Porphyria cutanea tarda is caused by a de ciency in the
en yme uroporphyrinogen decarbo ylase ( R D). Se eral
types ha e been described. The most common is the spo
radic non amilial orm which represents about o months usually re uiring a total o
cases. n ymatic acti ity o R D is abnormal in the li er
but normal in other tissues. This is the orm associated with
the co actors pre iously listed. The en yme de ciency is
related to loss o en yme acti ity caused by the li er damage
or estrogens triggering the PCT. The en yme R D is inhib
ited by iron so conditions that lead to iron o erload in the
li er (cirrhosis alcoholism CV in ection type diabetes
hemochromatosis) are all associated with PCT. Remo al o
this iron in the li er may result in impro ement o PCT. With
remission the en yme acti ity in the li er may return to
normal.
The second or amilial type o PCT is an autosomal domi
nant inherited de ciency o R D in the li er and RBCs o
patients and o clinically una ected amily members. Both the
acti ity and the concentration o the en yme decrease by about
. ultiple genetic de ects ha e been reported that produce
the same phenotype. amilial PCT tends to present at an
earlier age and de elopment o PCT be ore age strongly
suggests amilial PCT.
A third orm ac uired to ic PCT is associated with acute
or chronic e posure to hepatoto ins speci cally polyhaloge
nated hydrocarbons such as he achloroben ene and dio in.
These patients ha e biochemical and clinical eatures identical
to those o patients with sporadic and amilial PCT.
A diagnosis o PCT can be strongly suspected on clinical
grounds. A use ul con rmatory test that can be per ormed in
the o ce is the characteristic pin or coral red uorescence o
a random urine specimen under Wood s light. A hour urine
specimen usually contains less than μg o porphyrins in
a normal indi idual whereas in the PCT patient it may range
rom μg to se eral thousand. The ratio o uroporphyrins
to coproporphyrins in PCT is typically distinguishing
516
tahir99 - UnitedVRG
PCT rom ariegate porphyria. Plasma porphyrins will also
be abnormal and may be detected by pea plasma uores
cence at less than nm. The diagnosis o hereditary PCT
is made by demonstrating reduced R D acti ity in
erythrocytes.
Biopsy o a blister re eals a nonin ammatory subepidermal
bulla with an undulating estooned base. PAS positi e thic
ening o blood essel walls in the upper and middle dermis is
present. A use ul and highly characteristic but not diagnostic
eature is the presence o the so called caterpillar bodies. These
eosinophilic elongated wa y structures are present in the
lower and middle epidermis and lie parallel to the basement
membrane one (B ). They stain positi ely with PAS and
are positi e or type V collagen and laminin suggesting they
represent B material present in the epidermis. D o
in ol ed s in shows gG and C at the D J and in the essel
nitial treatment o PCT in ol es remo al o all precipitating
en ironmental agents such as alcohol and medications. This
may lead to su cient impro ement so that urther therapy is
not re uired. Chemical sunscreens are o little alue because
they do not typically absorb radiation in the near isible VA
range. Barrier sunscreens such as titanium dio ide and inc
o ide may be more bene cial but physical barriers such as
hats and glo es should be encouraged while therapy is
initiated.
Phlebotomy is a highly e ecti e treatment or PCT. R D
is inhibited by iron and remo al o hepatic iron may there
ore lead to reco ery o en yme acti ity. Typically phlebot
omy o mL at wee inter als is per ormed until the
hemoglobin reaches g dL or the serum iron μg dL.
deally serum erritin will become normal as well. rinary
porphyrin e cretion initially increases but gradually hour
uroporphyrin le els are greatly reduced with most patients
able to achie e normal le els. This process ta es se eral
phlebotomies. As
the porphyrins all the s in lesions also in olute. nitially
blistering impro es then s in ragility decreases and nally
the cutaneous sclerosis and hypertrichosis can e entually
re erse. A common error in management is coadministration
o oral iron supplementation during the phlebotomies to
treat the anemia.
Antimalarial therapy is an alternati e to phlebotomy and
may be combined with phlebotomy in di cult cases. Antima
larials comple the e cess porphyrins enhancing their e cre
tion. ull doses o antimalarials may produce a se ere
hepatoto ic reaction. The initial dose is mg o chloro uine
or mg o hydro ychloro uine twice wee ly. mpro e
ment is gradual and parallels the reduction in porphyrins.
The duration o treatment to reach a biochemical remission
is the same or phlebotomy and antimalarial therapy about
months. This remission may last many years. the
patient relapses these treatments can be repeated. Alterna
ti e treatments which are rarely re uired include des erri
o amine or de erasiro (iron chelation) and erythropoietin
treatment. rythropoietin may be combined with phlebot
omy. PCT in renal ailure may respond to erythropoietin
and low olume phlebotomy des errio amine gi en at the
end o dialysis or renal transplantation. CV in ection
coe ists inter eron al a treatment o the CV in ection may
lead to impro ement o the PCT. The management o PCT
associated with hemodialysis is much more di cult. igh
u high e ciency hemodialysis should be instituted.
acetylcysteine mg o powder dissol ed in orange uice
twice daily can be added to augment dialysis. rythropoie
tin at times at ery high dose in combination with mini
phlebotomy can be used in anuric patients with PCT not
controlled by other methods.

Fig. 26-9 Pseudoporphyria cutanea tarda from tetracycline in a
young woman.
PSEUDOPORPHYRIA
n certain settings patients de elop blistering and s in ragil
ity identical to PCT with the histologic eatures o PCT but
with normal urine and serum porphyrins. ypertrichosis
dyspigmentation and cutaneous sclerosis do not occur. This
pseudoporphyria is most o ten caused by medications typi
cally a nonsteroidal anti in ammatory drug ( SA D) usually
napro en . ther SA Ds such as nabumetone diclo enac
and ro eco ib as well as oricona ole tetracycline ( ig. ) protoporphyrin in adulthood predicts reedom rom both s in
tolterodine imatinib mesylate and sunitinib met ormin
nasteride estrogen and multiple other medications can
cause a similar clinical picture. Tanning bed use can also
produce pseudo PCT. Some patients on hemodialysis de elop
a similar PCT li e picture. Less re uently dialysis patients
de elop true PCT. n the anuric dialysis patient true PCT and
pseudo PCT are distinguished by analysis o serum porphy
rins in a laboratory nowledgeable in the normal porphyrin
le els in patients undergoing hemodialysis. The treatment o
pseudoporphyria is physical sun protection and discontinu
ance o any inciting medication. bupro en is a sa er alternati e
SA D that usually does not cause pseudoporphyria. n
medication induced PCT blistering resol es o er se eral
months once the medication is stopped. S in ragility may
persist or much longer. acetylcysteine and glutamine ha e
been reported to impro ed dialysis associated pseudo PCT.
HEPATOERYTHROPOIETIC PORPHYRIA
epatoerythropoietic porphyria ( P) is a ery rare orm o
porphyria that is inherited as an autosomal recessi e trait. P
is the homo ygous orm o PCT. t is caused by a homo ygous
or compound hetero ygous de ciency o R D which is
about o normal in both the li er and the erythrocytes. The
biochemical abnormalities are similar to but more mar ed than
those in PCT although the clinical eatures are similar to con
genital erythropoietic porphyria (C P). Dar urine is usually
present rom birth. n in ancy esicles occur in sun e posed
s in ollowed by sclerodermoid scarring hypertrichosis pig
mentation red uorescence o the teeth under Wood s light
and nail damage. eurologic disease has been reported. The
diagnosis o P is con rmed by abnormal urinary uropor
phyrins (as seen in PCT) ele ated erythrocyte protopor
phyrins and increased coproporphyrins in the eces. n C P
uroporphyrins are ele ated in the erythrocytes allowing
di erentiation rom P. Sun protection is necessary but
o ten inade uate. Bone marrow transplantation as in C P
may be re uired or P patients.
Hereditary coproporphyria
VARIEGATE PORPHYRIA
Variegate porphyria (VP) is also nown as mi ed porphyria
South A rican genetic porphyria and mi ed hepatic por
phyria. VP has an autosomal dominant inheritance with a high
penetrance. t results rom a decrease in acti ity o protopor
phyrinogen o idase (PP ). Between and o patients
with VP ha e s in symptoms ha e acute attac s and
only ha e both acute attac s and s in symptoms. any
a ected relati es ha e silent VP in which there is reduced
en yme acti ity but no clinical lesions. Such persons should
be identi ed and e aluated.
Variegate porphyria is characteri ed by the combination o
the s in lesions o PCT and the acute G and neurologic disease
o acute intermittent porphyria (A P). n o VP patients
s in lesions are the presenting nding. Vesicles and bullae with
erosions especially on sun e posed areas are the chie mani
estations. n addition hypertrichosis is seen in the temporal
area especially in women. yperpigmentation o sun e posed
areas is also a eature. acial scarring and thic ening o the s in
may gi e the patient a prematurely aged appearance.
The presence o VP should be suspected in a patient when
ndings indicate both PCT and A P especially i the patient
is o South A rican ancestry. ecal coproporphyrins and pro
toporphyrins are always ele ated and during attac s urine
porphobilinogen and ALA are ele ated. ormal le els o ecal
symptoms and acute attac s. rinary coproporphyrins are
increased o er uroporphyrins distinguishing VP rom PCT.
rinary coproporphyrin le el greater than nmol day
predicts increased ris or acute attac s and s in symptoms
and indicates the need or pre enti e treatment to reduce por
phyrins. A nding in the plasma o a uni ue uorescence at
nm is characteristic o VP and distinguishes it rom
all other orms o porphyria. Lymphocyte PP can be
measured but because o the pro ound ounder e ect in this
condition genetic testing should be used to con rm the
diagnosis.
Treatment o the s in lesions is symptomatic because anti
malarials and phlebotomy are not e ecti e in modi ying cuta
neous disease in VP. Gonadotropin releasing hormone (GnR )
analogs may pre ent premenstrual attac s and hemin and
glucose loading can be used or acute attac s. VP patients as
well as those with other acute porphyrias ( CP and A P) are
at increased ris or hepatocellular carcinoma and regular
li er imaging should be per ormed a ter age . ducation o
patients and una ected PP de cient relati es is essential to
a oid triggering medications.
omo ygous VP is a ery rare autosomal recessi e condi
tion that presents in childhood with PCT li e acral blistering
ermiculate scarring o the chee s nger shortening and
de elopmental delay. Brain myelin is completely absent.
HEREDITARY COPROPORPHYRIA
ereditary coproporphyria ( CP) is a rare autosomal domi
nant porphyria resulting rom a de ciency o coproporphy
rinogen o idase (CP ). About one third o patients are
photosensiti e with blistering similar to but less se ere than
in VP. About ha e acute attac s with G and neurologic
symptoms similar to those seen in A P and VP. ecal copropor
phyrin is always increased; urinary coproporphyrin ALA
517
 and porphobilinogen (PBG) are increased only during attac s.
26 Plasma uorescence at nm is seen. utation screening can
be used to con rm the diagnosis and identi y una ected
but CP de cient relati es. omo ygous hereditary copro
porphyria or harderoporphyria is caused by a homo ygous
Errors in Metabolism
de ect o CP with patients ha ing or less o normal
acti ity. Children present with photosensiti ity hypertricho
sis and hemolytic anemia. The biochemical ndings in plasma
eces and urine are identical to CP but more mar ed. ar
deroporphyrin is the natural intermediate between copropor
phyrinogen and protoporphyrinogen.
ERYTHROPOIETIC PROTOPORPHYRIA
rythropoietic protoporphyria ( PP) is an autosomal recessi e
disorder. The errochelatase ( C ) acti ity is always below
and usually o normal in a ected persons. This
low le el o en yme acti ity inherited as a pseudodominant
trait (true dominant inheritance should result in only
reduction in en yme acti ity) occurs because all a ected
persons are in act compound hetero ygotes. n urope up to
o the population carries a low e pression (hypo
morphic) allele that is only as acti e as the wild type
en yme. the patient also inherits a loss o unction mutation
this combination leads to about en yme acti ity below
the critical acti ity re uired to remain disease ree. Auto
somal recessi e PP results rom inheritance o two genes
with signi cant loss o unction but not a common hypo
morphic allele.
Typically PP presents early in childhood ( months to
years) although presentation late in adulthood can occur. The
diagnosis o PP in children is re uently delayed because o
its rarity and the general lac o awareness o pediatricians o
its e istence. lder children at times are re erred to psychia
trists until the diagnosis is suspected.
ni ue among the more common orms o porphyria is an
immediate burning o the s in on sun e posure. Because the
ele ated protoporphyrin absorbs both in the Soret band and
at nm isible light through window glass or in the
operating room may precipitate symptoms. n ants cry when
e posed to sunlight. rythema pla ueli e edema and wheals
such as those seen in solar urticaria can be seen. These lesions
appear solely on sun e posed areas. n se ere cases purpura
is seen in the sun e posed areas.
With repeated e posure the s in de elops a weather beaten
appearance. Shallow linear or elliptical scars wa y thic ening
and pebbling o the s in on the nose and chee s and o er
metacarpophalangeal oints and atrophy o the rims o the
ears ha e been described ( ig. ). Perioral urrowli e scars
are characteristic. The dorsal hands and ace o PP patients
appear much older than their chronologic age.
About . o patients with PP ha e a seasonal palmar
eratoderma. t is worse in the summer and resol es in winter
or with occlusion o the palm by a plaster cast. The erato
derma is wa y and may co er the whole palm or may be local
i ed to the rst web space. t is sharply demarcated at the wrist
and has no red border. The thic ening is moderate in se erity.
The nails are usually una ected but may show minimal ony
cholysis. Patients with nail changes all ha e true autosomal
recessi e PP with lower le els o erythrocyte protoporphyrin
but increased le els o ecal total porphyrin compared with
pseudodominant PP patients. n act their erythrocyte proto
porphyrin may be near normal. About o patients with
autosomal recessi e PP ha e this eratoderma.
Between and o PP patients ha e li er complica
tions because o e cessi e porphyrin deposits in hepatocytes.
This can occur anywhere along the spectrum rom mild
518
tahir99 - UnitedVRG
Fig. 26-10 Linear scars and erosions in erythropoietic protoporphyria.
ele ation o li er unction tests to cirrhosis. nly o patients
with PP and li er disease de elop hepatic ailure or .
o all PP patients. Li er transplantation may be re uired.
Autosomal recessi e inheritance o PP may be a ris actor
or the de elopment o li er ailure. There is currently no
mar er or progressi e li er disease (not laboratory porphy
rins or genetic de ect) so all patients must be monitored. Ten
percent o patients de elop gallstones o ten in childhood. A
mild microcytic anemia is present in o patients with PP
but therapy with iron should be used only i iron de ciency is
detected since it may e acerbate symptoms. Because o sun
a oidance itamin D de ciency can occur.
The rare syndrome o PP appearing de no o in adults has
been reported multiple times. These cases are associated with
a myeloproli erati e disorder or myelodysplastic syndrome.
The malignant cells in the bone marrow caused by a transloca
tion lose the EC gene on chromosome and the patient
ac uires a C de ciency. Bone marrow transplantation
is associated with resolution o this orm o PP.
istologically there is prominent ground glass PAS
positi e material in the upper dermis mostly peri ascularly.
This material is type V collagen. n D gG and C may be
ound peri ascularly. an acute purpuric lesion is biopsied
the eatures o a leu ocytoclastic asculitis may be seen.
A diagnosis o PP can usually be suspected on clinical
grounds especially i both the acute symptoms and the chronic
s in changes are ound. Because protoporphyrin is not
water soluble urine porphyrin le els are normal. rythrocyte
protoporphyrin is ele ated and can be detected by RBC uo
rescence. rythrocyte plasma and ecal protoporphyrin can
also be assayed to con rm the diagnosis. rythrocyte proto
porphyrin le els in a ected persons may range rom se eral
hundred to se eral thousand micrograms per mL o
pac ed RBCs (normal alues < μg mL o pac ed RBCs).
Plasma uorescence shows a pea at nm.
The di erential diagnosis o PP includes hydroa accin
i orme eroderma pigmentosa and solar urticaria. n in ancy
be ore the appearance o the chronic s in changes erythrocyte
porphyrins may need to be screened to con rm the diagnosis.
nce chronic changes are present a s in biopsy will con rm
the diagnosis.
The treatment o PP patients consists o protection rom
e posure to sunlight with clothing and barrier sunscreens con
taining titanium dio ide or inc o ide. Beta carotene
mg day in adults and mg day or children to
maintain a serum le el o μg mL pro ides some
modest protection. As the child grows the dose must be
increased to maintain ade uate tissue le els. arly spring
hardening with narrow band VB or P VA (wa elengths
below the action spectrum o the incriminated porphyrins) is
being increasingly used. Preliminary trials o colestipol g
daily and oral inc sul ate mg daily ha e led to substan
tial increases in light tolerance in PP patients. A amelanotide
(Scenesse) has been demonstrated to increase light tolerance
in patients with PP in a mg sustained release orm
implanted e ery months.
X-LINKED DOMINANT PROTOPORPHYRIA
lin ed dominant protoporphyria ( LDPP) is caused by dele
tions in the dALA synthetase ( L S ) gene. These mutations
result in gain o unction o the L S gene with increased
production o protoporphyrin. rythrocyte protoporphyrins
are ele ated rom this o erproduction o protoporphyrin
which e ceeds the capacity o the errochelatase to incorporate
the protoporphyrin into heme resulting in e cess protopor
phyrin. Patients present with symptoms identical to PP.
About o patients in orth America with PP actually
ha e LDPP. ore se ere photosensiti ity and more re uent
li er disease ( ) occur in LDPP due to higher le els o
protoporphyrins about two times higher than in PP patients.
ne case o late onset LDPP associated with myelodysplasia
has been reported. ntra enous iron therapy has impro ed
s in symptoms.
CONGENITAL ERYTHROPOIETIC PORPHYRIA
Congenital erythropoietic porphyria (C P) is a ery rare orm
o porphyria s inherited as an autosomal recessi e trait. t
is caused by a homo ygous de ect o the en yme uropor
phyrinogen synthase ( R S). The coinheritance o a gain
o unction mutation in L S can lead to a more se ere
phenotype. ne amily with a mutation also de el
oped C P.
Congenital erythropoietic porphyria presents soon a ter
birth with the appearance o red urine (noticeable on diapers).
Se ere photosensiti ity occurs and may result in immediate
pain and burning so that the a ected child screams when
e posed to the sun. The laser used in pulse o imeters may lead
to s in lesions o the nail bed. Redness swelling and blistering
occur and result in scarring o the ace dorsal hands and scalp
(with subse uent alopecia). ctropion can occur with subse
uent corneal damage and loss o ision. rythrodontia o
both deciduous and permanent teeth is also characteristic
( ig. ). This phenomenon is demonstrated by the coral
red uorescence o the teeth when e posed to Wood s light.
utilating scars especially on the ace and hypertrichosis o
the chee s with pro use eyebrows and long eyelashes occur.
ther eatures seen in C P include growth retardation hemo
lytic anemia thrombocytopenia porphyrin gallstones osteo
penia and increased racturing o bones.
A diagnosis o C P can be easily suspected when an in ant
has dar urine and is se erely photosensiti e. There is a direct
correlation among the se erity o the disease the le els o
plasma porphyrins and the residual acti ity o R S. Abnor
mally high amounts o uroporphyrin and coproporphyrin
are ound in urine stool and RBCs. There is stable red uo
rescence o erythrocytes. n biopsy a subepidermal bulla is
seen identical to that in PCT.
Treatment o C P patients is strict a oidance o sunlight and
in some cases splenectomy or the hemolytic anemia. ral
acti ated charcoal is e cacious presumably impairing the
absorption o endogenous porphyrins. Repeated trans usions
o pac ed RBCs are gi en at olumes su cient to maintain the
Acute intermittent porphyria
Fig. 26-11 Erythrodontia in congenital erythropoietic porphyria.
hematocrit le el at turn o the demand or heme and
reduce porphyrin production. Bone marrow transplantation
should be considered in se erely a ected children typically
those with trans usion re uiring anemia or thrombocytopenia
but also those with progressi e photomutilation and geno
types associated with poor outcome. Proteosome inhibitors
and induced pluripotent stem cells are newer treatment
opportunities.
Adult onset C P is e tremely rare presenting as a mild
photosensiti e blistering disease resembling PCT. sually
patients with C P li e into adulthood. Preauricular brosis
with loss o earlobes occurs. A corticobasal syndrome resem
bling Par inson s disease can also occur.
ACUTE INTERMITTENT PORPHYRIA
Acute intermittent porphyria (A P) the second most common
orm o porphyria a ter PCT is characteri ed by periodic
attac s o abdominal pain (up to o patients) G distur
bances (up to o patients) pain and paresis ( )
sei ures ( ) and mental symptoms ( ) including
agitation hallucinations and depression. S in lesions do not
occur because the ele ated porphyrin precursors are not pho
tosensiti ers. A P is inherited as an autosomal dominant trait
and is caused by a de ciency in porphobilinogen deaminase
which has acti ity in a ected persons. nly o those
with the genetic de ect de elop disease but all may be at ris
or primary li er cancer. A P is particularly common in Scan
dina ia especially Lapland. A P usually presents a ter puberty
in young adulthood and women outnumber men . .
Se ere abdominal colic is most o ten the initial symptom o
A P. Patients usually ha e no abdominal wall rigidity
although tenderness and distention are present. ausea om
iting and diarrhea or constipation accompany the abdominal
pain. Peripheral neuropathy mostly motor is present. Se ere
pain in the e tremities occurs. ptic atrophy diaphragmatic
wea ness respiratory paralysis accid uadriplegia acial
palsy and dysphagia are some o the many neurologic signs.
Attac s o A P are triggered by certain medications and
other conditions. These triggers re uently re uire increased
hepatic heme synthesis (e.g. to ma e the cytochrome P
en ymes re uired or metabolism o medications). Progester
one is one trigger e plaining the increased pre alence o A P
in women and the relationship to menses. Anticon ulsants
griseo ul in ri ampin and sul onamides are common drugs
implicated in triggering A P. The implicated medication list
is constantly being modi ed as new drugs enter the mar et.
519
 The website o the uropean Porphyria nitiati e is the best
26 source or an up to date list o both patients and health care
pro iders (www.porphyria europe.com). Crash dieting ciga
rette smo ing in ections and surgery are additional triggers.
A diagnosis o A P is established by nding ele ated le els
Errors in Metabolism
o urinary porphobilinogen and increased dALA in the plasma
and urine during attac s. During remissions the diagnosis can
be con rmed in o patients by detecting ele ated urinary
porphobilinogen. A normal test between attac s suggests less
li elihood o subse uent attac s. rythrocyte and ecal por
phyrin le els are normal. A P must be distinguished rom VP
CP and ALA dehydratase de ciency porphyria (ALAD) an
autosomal recessi e condition presenting in an almost identi
cal manner to A P. ncreased dALA in the urine is ound in
ALAD patients and those with lead poisoning.
o speci c treatment is a ailable or A P. t is important or
the patient to a oid such precipitating actors as a wide ariety
o medications including se steroid hormones and to main
tain ade uate nutrition. Glucose loading has been used e ten
si ely and appears to be bene cial in many cases. ematin
in usions in the orm o heme arginate result in clinical
impro ement and a mar ed decrease in ALA and porphobi
linogen e cretion. arly treatment may ameliorate attac s. The
phenothia ines (e.g. chlorproma ine) may be help ul or pain;
opiates and propo yphene are also use ul or analgesia. Since
o patients with A P die o hepatoma (without the de el
opment o cirrhosis) yearly ultrasound and alpha etoprotein
determination should be underta en in all A P patients o er
age .
TRANSIENT ERYTHROPORPHYRIA OF INFANCY
(PURPURIC PHOTOTHERAPY-INDUCED ERUPTION)
Paller et al. reported se en in ants e posed to nm blue
lights or the treatment o indirect hyperbilirubinemia who
de eloped mar ed purpura in s in e posed to V light.
tensi e blistering and erosions occurred in one patient.
Biopsies o the s in showed hemorrhage without epidermal
changes in the cases associated with purpura and a pauci
in ammatory subepidermal bulla in the patient with blister
ing. The in ants had all recei ed trans usions. le ated plasma
coproporphyrins and protoporphyrins were ound in the our
in ants e amined. The pathogenesis is un nown.
Allo G, et al: Bone mineral density and vitamin D levels in erythropoietic
protoporphyria. Endocrine 2013; 44:803.
Arunachalam M, et al: Scleroderma-like hands in a 16-year-old boy.
JAMA Dermatol 2013; 149:969.
Azak A, et al: Pseudoporphyria in a hemodialysis patient successfully
treated with oral glutamine. Hemodial Int 2013; 17:466.
Badadams EL, et al: Cascade testing of primary care blood
samples with hyperferritinaemia identifies subjects with iron
overload and porphyria cutanea tarda. Ann Clin Biochem 2014;
51:499.
Balwani M, et al: Erythropoietic protoporphyria, autosomal recessive. In
Pagon RA, et al (eds): GeneReview 2013. [Epub.]
Balwani M, et al: Loss-of-function ferrochelatase and gain-of-
function erythroid-specific 5-aminolevulinate synthase mutations
causing erythropoietic protoporphyria and X-linked protoporphyria
in North American patients reveal novel mutations and a high
prevalence of X-linked protoporphyria. Mol Med 2013; 19:26.
Bedel A, et al: Metabolic correction of congenital erythropoietic
porphyria with iPSCs free of reprogramming factors. Am J Human
Genet 2012; 91:109.
Bentley DP, Meek EM: Clinical and biochemical improvement following
low-dose intravenous iron therapy in a patient with erythropoietic
protoporphyria. Br J Haematol 2013; 163:277.
Berghoff AT, English JC: Imatinib mesylate–induced pseudoporphyria. J
Am Acad Dermatol 2011; 63:e14.
520
tahir99 - UnitedVRG
Bishop DF, et al: Molecular expression and characterization of erythroid-
specific 5-aminolevulinate synthase gain-of-function mutations causing
X-linked protoporphyria. Mol Med 2013; 19:18.
Blouin JM, et al: Therapeutic potential of proteasome inhibitors in
congenital erythropoietic porphyria. Proc Natl Acad Sci USA 2013;
110:18238.
Chan CC, Lin SJ: Porphyria cutanea tarda. N Engl J Med 2011;
365:1128.
Crawford RI, et al: Transient erythroporphyria of infancy. J Am Acad
Dermatol 1996; 35:833.
DeGiovanni CV, Darley CR: Pseudoporphyria occurring during a course
of ciprofloxacin. Clin Exp Dermatol 2008; 33:109.
Ergen EN, et al: Is non-alcoholic steatohepatitis a predisposing factor to
porphyria cutanea tarda? Photodermatol Photoimmunol Photomed
2013; 29:106.
Erwin A, et al: Congenital erythropoietic porphyria. In Pagon RA, et al
(eds): GeneReview 2013. [Epub.]
Frank J, Poblate-Gutiérrez P: Delayed diagnosis and diminished quality
of life in erythropoietic protoporphyria: results of a cross-sectional
study in Sweden. J Intern Med 2011; 269:270.
Frank J, et al: Photosensitivity in the elderly—think of late-onset
protoporphyria. J Invest Dermatol 2013; 133:1467.
García-Martín P, et al: Phototolerance induced by narrow-band UVB
phototherapy in severe erythropoietic protoporphyria. Photodermatol
Photoimmunol Photomed 2012; 28:261.
Gibson GE, et al: Coexistence of lupus erythematosus and porphyria
cutanea tarda in 15 patients. J Am Acad Dermatol 1998; 38:569.
Gonzalez-Estrada A, Garcia-Morillo JS: Successful treatment of
congenital erythropoietic porphyria using matched unrelated
hematopoietic stem cell transplantation. Mayo Clin Proc 2014;
89:e11.
Gonzalez-Estrada A, et al: Sporadic porphyria cutanea tarda: treatment
with chloroquine decreases hyperglycemia and reduces development
of metabolic syndrome. Eur J Intern Med 2014; 25:e76.
Graham-Brown MP, Ilchyshyn A: Development of acute phototoxic
reaction during surgery in a patient with erythropoietic protoporphyria.
Clin Exp Dermatol 2013; 38:566.
Gyldenløve M, et al: Pseudoporphyria: a case report. J Eur Acad
Dermatol Venereol 2014; Mar 11. [Epub ahead of print.]
Harms JH, et al: An α-melanocyte–stimulating hormone analogue in
erythropoietic protoporphyria N Engl J Med 2009; 360:306.
Harms JH, et al: Mitigating photosensitivity of erythropoietic
protoporphyria patients by an agonistic analog of α-melanocyte
stimulating hormone. Photochem Photobiol 2009; 85:1434.
Heithaus RE, Hogan R: Unblinded by the lights. N Engl J Med 2013;
367:659.
Hivnor C, et al: Cyclosporine-induced pseudoporphyria. Arch Dermatol
2003; 139:1373.
Holme SA, et al: Seasonal palmar keratoderma in erythropoietic
protoporphyria indicates autosomal recessive inheritance. J Invest
Dermatol 2009; 129:599.
Kapoor R, Johnson RA: Porphyria cutanea tarda and hypertrichosis. N
Engl J Med 2013; 369:1356.
Katoulis AC, et al: Pseudoporphyria associated with nonhemodialyzed
renal insufficiency, successfully treated with oral N-acetylcysteine.
Case Rep Dermatol Med 2013; 2013:271873.
Katugampola RP, et al: A management algorithm for congenital
erythropoietic porphyria derived from a study of 29 cases. Br J
Dermatol 2012; 167:888.
Katugampola RP, et al: Congenital erythropoietic porphyria: a single-
observer clinical study of 29 cases. Br J Dermatol 2012; 167:901.
Lenfestey A, et al: Metformin-induced pseudoporphyria. J Drugs
Dermatol 2012; 11:1272.
Liu LU, et al: Porphyria cutanea tarda, type II. In Pagon RA, et al (eds):
GeneReview 2013. [Epub.]
Livideanu CB, et al: Late-onset X-linked dominant protoporphyria: an
etiology of photosensitivity in the elderly. J Invest Dermatol 2013;
133:1688.
Martinez Peinado C, et al: Successful treatment of congenital
erythropoietic porphyria using matched unrelated hematopoietic stem
cell transplantation. Pediatr Dermatol 2013; 30:484.
Massone C, et al: Successful outcome of haemodialysis-induced
pseudoporphyria after short-term oral N-acetylcysteine and
switch to high-flux technique dialysis. Acta Derm Venereol 2006;
86:538.
Mendez M: A homozygous mutation in the ferrochelatase gene
underlies erythropoietic protoporphyria associated with palmar
keratoderma. Br J Dermatol 2009; 160:1330.
Muñoz-Santos C, et al: The association between porphyria cutanea tarda
and diabetes mellitus: analysis of a long-term follow-up cohort. Br J
Dermatol 2011; 165:486.
Oh C, et al: Pseudoporphyria secondary to narrowband UVB
phototherapy for psoriasis. Australas J Dermatol 2006; 47:134.
Okano J, et al: Interferon treatment of PCT associated with chronic
hepatitis type C. Hepatogastroenterology 1997; 44:525.
Oshikawa Y, et al: Photosensitivity and acute liver insufficiency in
late-onset erythropoietic protoporphyria with a chromosome 18q
abnormality. Case Rep Dermatol 2012; 4:144.
Paller AS, et al: Purpuric phototherapy-induced eruption in transfused
neonates. Pediatrics 1997; 100:360.
Pandya AG, et al: Deferasirox for porphyria cutanea tarda. Arch
Dermatol 2012; 148:898.
Panton NA, et al: Iron homeostasis in porphyria cutanea tarda: mutation
analysis of promoter regions of CP, CYBRD1, HAMP and SLC0A1. J
Clin Pathol 2013; 66:160.
Pérez NO, et al: Pseudoporphyria induced by imatinib mesylate. Int J
Dermatol 2014; 43:e143.
Perez-Bustillo A, et al: Torsemide-induced pseudoporphyria. Arch
Dermatol 2008; 144:812.
Petersen AB, et al: Zinc sulphate: a new concept of treatment of
erythropoietic protoporphyria. Br J Dermatol 2012; 166:1121.
Pham HP, et al: Therapeutic plasma exchange in a patient with
erythropoietic protoporphyria status post orthothopic liver
transplantation as a bridge to hematopoietic stem cell transplantation.
J Clin Apher 2014; 29:341.
Pinder VA, et al: Homozygous variegate porphyria presenting with
developmental and language delay in childhood. Clin Exp Dermatol
2013; 38:737.
Quansah R, et al: Hepatitis C– and HIV-induced porphyria cutanea
tarda. Am J Case Rep 2014; 15:35.
Santo Domingo D, et al: Finasteride-induced pseudoporphyria. Arch
Dermatol 2011; 147:747.
Sarkany RP, et al: Acquired erythropoietic protoporphyria as a result of
myelodysplasia causing loss of chromosome 18. Br J Dermatol 2006;
155:464.
Schanbacher CF, et al: Pseudoporphyria. Mayo Clin Proc 2001;
76:488.
Schneider-Yin X, et al: Hepatocellular carcinoma in a variegate
porphyria: a serious complication. Acta Derm Venereol 2010;
90:512.
Schulenburg-Brand D, et al: The cutaneous porphyrias. Dermatol Clin
2014; 32:369.
Seager MJ, et al: X-linked dominant protoporphyria: a new porphyria.
Clin Exp Dermatol 2014; 39:35.
Sharp MT, Horn TD: Pseudoporphyria induced by voriconazole. J Am
Acad Dermatol 2005; 53:341.
Shieh S, et al: Management of porphyria cutanea tarda in the setting of
chronic renal failure: a case report and review. J Am Acad Dermatol
2000; 42:645.
Sidorsky TI, et al: Development of corticobasal syndrome in a patient
with congenital erythropoietic porphyria. Parkinsonism Relat Disord
2014; 20:349.
Singal AK, Anderson KE: Variegate porphyria. In Pagon RA, et al (eds):
GeneReview 2013. [Epub.]
Singal AK, et al: Low-dose hydroxychloroquine is as effective as
phlebotomy in treatment of patients with porphyria cutanea tarda. Clin
Gastroenterol Hepatol 2012; 10:1402.
Singal AK, et al: Liver transplantation in the management of porphyria.
Hepatology 2014; 60:1082.
Sivaramakrishnan M, et al: Narrowband ultraviolet B phototherapy in
erythropoietic protoporphyria: a case series. Br J Dermatol 2014;
170:987.
Spelt JM, et al: Vitamin D deficiency in patients with erythropoietic
protoporphyria. J Inherit Metab Dis 2010; 33:S1.
Tewari A, et al: A case of extensive hyaline deposition in facial skin
caused by erythropoietic protoporphyria. Br J Dermatol 2014;
171:412.
Thom G, et al: Leukocytoclastic vasculitis masking chronic vascular
changes in previously undiagnosed erythropoietic protoporphyria J
Cutan Pathol 2013; 40:966.
Tishler PV, Rosner B: Treatment of erythropoietic protoporphyria with the
oral sorbent colestipol: a proof-of-concept clinical trial. J Am Acad
Dermatol 2013; 70:391.
To-Figueras J, et al: ALAS2 acts as a modifier gene in patients with
congenital erythropoietic porphyria. Blood 2011; 118:1443.
Dystrophic calcinosis cutis
Tolland JP, et al: Voriconazole-induced pseudoporphyria. Photodermatol
Photoimmunol Photomed 2007; 23:29.
Tremblay J-F, et al: Pseudoporphyria associated with hemodialysis
treated with N-acetylcysteine. J Am Acad Dermatol 2003; 49:1189.
Turnbull N, et al: Diclofenac-induced pseudoporphyria: an under-
recognized condition? Clin Exper Dermatol 2014; 39:348.
Van Tuyll van Serooskerken AM, et al: Digenic inheritance of mutations in
the coproporphyrinogen oxidase and protoporphyrinogen oxidase
genes in a unique type of porphyria. J Invest Dermatol 2011;
131:2249.
Van Tuyll van Serooskerken AM, et al: Extended haplotype studies in
South African and Dutch variegate porphyria families carrying the
recurrent p.R59W mutation confirm a common ancestry. Br J Dermatol
2012; 166:261.
Vasconcelos P, et al: Desferrioxamine treatment of porphyria cutanea
tarda in a patient with HIV and chronic renal failure. Dermatol Ther
2014; 27:16.
Verma A, et al: Congenital erythropoietic porphyria: a case where
symptoms have been precipitated by an unrelated anaemia. Br J
Dermatol 2014; 171:422.
Vieria FM, et al: Precipitating factors of porphyria cutanea tarda in
Brazil with emphasis on hemochromatosis gene (HFE) mutations:
study of 60 patients. An Bras Dermatol 2013; 88:530.
Wahlin S, et al: Liver transplantation for erythropoietic protoporphyria in
Europe. Liver Transpl 2011; 17:1021.
Whatley SD, Badminton MN: Role of genetic testing in the management
of patients with inherited porphyria and their families. Ann Clin
Biochem 2013; 50:204.
CALCINOSIS CUTIS
Cutaneous calci cation results rom deposits o calcium and
phosphorus in the s in. Calcinosis cutis is di ided into e
orms. Dystrophic calcinosis includes conditions in which cal
ci cation occurs in damaged tissue usually collagen or elastic
tissue. Serum calcium and phosphorus le els are normal. Der
matomyositis is a classic e ample o dystrophic calcinosis.
etastatic calci cation re ers to deposition o calcium result
ing rom ele ated serum le els o calcium or phosphorus.
yperparathyroidism is an e ample o this orm o calci ca
tion. atrogenic and traumatic calcinosis is associated with
medical procedures or occupational e posures that may
in ol e both tissue damage and local ele ated calcium concen
trations. diopathic calcinosis cutis re ers to the orms o cuta
neous calci cation o un nown cause with normal serum
calcium. n osteoma cutis true bone is ormed in the s in.
Calciphyla is is discussed in Chapter .
DYSTROPHIC CALCINOSIS CUTIS
The dystrophic type occurs in a pree isting lesion or in am
matory process. Systemic calcium metabolism is normal and
lesions a ect the s in only. Dystrophic calcinosis cutis presents
as small deposits o chal y granular material around the ngers
and on the elbows at areas o trauma. The deposits may spon
taneously e trude rom the s in. istologically they are local
i ed to the dermis (or in the case o panniculitides in the at).
The dystrophic orm o ten occurs in limited scleroderma (the
CR ST syndrome calcinosis cutis Raynaud phenomenon
esophageal disorders sclerodactyly and telangiectasia) ( ig.
). Pancreatic and lupus panniculitis typically demonstrate
dystrophic calci cation but the process tends to remain micro
scopic. Patients with Werner syndrome and PCT may also
de elop calci cations within the scleroderma li e lesions.
521
 Fig. 26-12 Calcinosis
26 cutis in CREST
syndrome.
Errors in Metabolism
Calcinosis cutis occurs in about o patients with derma
tomyositis (D ) especially u enile cases. ingertip ulcers
and disease duration are associated with calcinosis cutis.
Autoantibodies to P increase the ris or cutaneous calci
nosis in D by old. Calci cation can occur in multiple
orms including hard nodules or pla ues in the subcutaneous
or periarticular areas tumors; deposits in the intermuscular
ascia leading to decreased mobility; and as an e os eleton.
Various benign and malignant neoplasms may de elop cal
ci cation or ossi cation with pilomatri omas and pilar cysts
most re uently reported. ephrogenic systemic brosis
utchinson Gil ord progeria and poi iloderma with neutro
penia (Clericu io type) may all be complicated by calcinosis
cutis.
The treatment o dystrophic calci cation is determined by
the location si e e tent and underlying condition. Limited
surgical remo al as needed to control discom ort can be ery
bene cial. Curetting out the calcium deposits around the
ngers can bring dramatic relie to the patients with CR ST
and D . Systemic therapies ha e not been consistently bene
cial with some patients ha ing dramatic response and the
same treatment or the same disease ha ing no e ect in other
patients. Bisphosphonates (alendronate etidronate pamidro
nate) diltia em ( mg day) war arin anti in ammatory
agents tumor necrosis actor (T ) inhibitors intra enous
immune globulin ( V G) thalidomide and colchicine ha e all
been used as single agents or in combination. Sodium thiosul
ate by topical application and . mg mL by
in ection has reduced dystrophic calci cations in arious
areas. ight patients with dystrophic calci cation treated with
lithotripsy had a decrease in si e o the calcium deposits and
a dramatic reduction in pain.
METASTATIC CALCINOSIS CUTIS
etastatic calcinosis cutis is a rare entity characteri ed by
calci cations in the s in ele ated serum calcium and some
times hyperphosphatemia. t is o ten associated with bone loss
or destruction with the bone pro iding the source o the ele
ated serum calcium. Conditions associated with metastatic
calcinosis include parathyroid neoplasms primary hyperpara
thyroidism chronic renal ailure hyper itaminosis D sarcoid
osis and e cessi e inta e o mil and al ali. Destruction o
bone by osteomyelitis leu emia Paget s disease o the bone
522
tahir99 - UnitedVRG
myeloma and metastatic carcinoma may lead to ele ated
serum calcium and metastatic calci cation. n calcinosis cutis
with hyperparathyroidism many s in mani estations are
seen with small rm white papules about mm in diam
eter occurring symmetrically in the popliteal ossae o er the
iliac crests and in the posterior a illary lines. At times meta
static calcinosis cutis locali es to areas o damaged elastic
tissue (e.g. striae solar elastosis).
The most common metabolic condition associated with met
astatic calci cation is renal ailure. sually there is an ele ated
phosphorus le el and secondary hyperparathyroidism result
ing in high calcium and phosphorus production and deposi
tion o calcium phosphate in tissues. Less o ten cutaneous
calci cation in renal disease can occur with normal serum
calcium and phosphorus le els. Three orms o cutaneous cal
ci cation in renal disease ha e been described tumoral calci
nosis calci ying panniculitis and calciphyla is. Tumoral
calcinosis is a rare complication o renal disease. anaging the
metabolic abnormalities may lead to resolution o the large
deposits o calcium.
ten calci ying panniculitis and calciphyla is occur in the
same patient at the same time suggesting a common patho
genesis. solated rm indurated nodules usually on the legs
or thighs in the subcutaneous at ha e been called calci ying
panniculitis. sually these are seen with the most se ere com
plication o the abnormal calcium and phosphorus metabolism
o renal disease calciphyla is. This li e threatening condition
leads to li edo reticularis and ischemic tissue necrosis (see
Chapter ).
IATROGENIC AND TRAUMATIC CALCINOSIS CUTIS
edical procedures that may inad ertently introduce calcium
into tissue in association with tissue trauma may lead to
cutaneous calci cation. This has been reported a ter e tra asa
tion o calcium chloride or calcium gluconate in usion and
a ter electroencephalography or electromyography. The elec
trode paste is high in calcium and the s in is traumati ed
during the procedure leading to calci cations at the sites o
electrode insertion. The most common setting is on the scalp
o children. Lesions spontaneously resol e o er months. Per
orming re uent heel stic s in neonates has led to similar
lesions. n ections o low molecular weight calcium containing
heparins in patients with renal ailure may result in calci ca
tion at the sites o in ection. re uent subcutaneous in ection
o inter eron beta in the abdomen has resulted in locali ed
calci cation in the at.
During li er transplantation hypocalcemia can result rom
calcium chelation by the citrate in trans used blood products.
ntra enous calcium in usions are regularly gi en. Calci ca
tions on the upper e tremities ha e been reported occurring
wee s a ter transplantation and resol ing o er months.
Traumatic calcinosis may occur as a result o occupational
e posure to calcium containing materials as in the cases
reported in oil eld wor ers and coal miners. posure o the
s in to cloth sac s o calcium chloride limewater compresses
and re rigerant calcium chloride can all cause calcinosis cutis.
IDIOPATHIC CALCINOSIS CUTIS
Idiopathic scrotal calcinosis
diopathic scrotal calcinosis is the most common orm o
idiopathic calcinosis cutis. Lesions present in young to middle
age adult men as multiple asymptomatic rm round yellow
papules rom se eral millimeters up to cm in diameter

Fig. 26-13 Scrotal calcinosis.
( ig. ). The papules resemble in undibular ollicular
cysts. Similar lesions usually mm to se eral millimeters in
si e may be seen rarely in girls or women on the labia ma ora.
n men with scrotal lesions similar lesions rarely will be ound
on the sha t o the penis termed idiopathic calcinosis cutis o
the penis. Calcinosis o the areola can ha e a similar appear
ance and is e tremely rare. istologically locali ed deposits
o calcium are surrounded by a oreign body reaction. At least
some are calci ed scrotal in undibular cysts. Why they ha e
such a high procli ity to calci cation at this anatomic location
is unclear. Treatment is not re uired but surgical remo al
cures indi idual lesions.
Subepidermal calcified nodule and milia-like
idiopathic calcinosis cutis
These two similar conditions are uncommon but distinct types
o idiopathic calcinosis. Subepidermal calci ed nodule occurs
most re uently as one or a ew lesions on the scalp or ace o
children ( ig. ). ales outnumber emales by almost
and the a erage age at onset is years. Lesions present as
ed unin amed papules that closely resemble those o mol
luscum contagiosum with a central umbilication. The a ected
children usually do not ha e an underlying medical condition.
A similar condition milia li e idiopathic calcinosis cutis has
a wider distribution; eyelids hands eet elbows and nees
are common sites. Two thirds o patients ha e Down syn
drome. Treatment is not re uired but surgical remo al will
cure any indi idual lesion.
Tumoral calcinosis
n estigation o the rare cases o tumoral calcinosis disco ery
o the causal genes and de elopment o animal models
ha e led to impro ed understanding o the mechanisms o
ectopic minerali ation. amilial tumoral calcinosis has two
genetic causes. ormophosphatemic amilial tumoral calcino
sis ( TC) is seen in young adults primarily A rican nati es.
Lesions are associated with antecedent trauma. The genetic
cause is mutation in S MD . yperphosphatemic amilial
tumoral calcinosis ( TC) is characteri ed by periarticular
calci cations. utations in three genes ha e been described as
causing this syndrome broblast growth actor ( )
L and LO O ost patients present be ore the
Fig. 26-14
Subepidermal
calcified nodules.
Osteoma cutis
second decade o li e. Three uarters o these indi iduals ha e
a ected siblings. ultiple lesions predominate and there is
no preceding history o trauma. The serum calcium le el is
normal but serum phosphorus and calcitriol le els are
ele ated.
Lesions in both types present as large subcutaneous masses
o calcium o erlying pressure areas and large oints usually
the hips elbows shoulders or nees. S in in ol ement apart
rom the tumoral masses is e tremely rare but may occur as
locali ed calcinosis cutis. The internal organs are not in ol ed
and serum calcium le els are generally normal. Surgical e ci
sion has been the mainstay o therapy; howe er recurrences
are re uent a ter incomplete remo al. Various dietary restric
tions to lower calcium and phosphorus inta e ha e shown
some success. The combination o a phosphate binder and a
carbonic anhydrase inhibitor along with a low phosphorus
diet led to dramatic impro ement in one patient allowing or
surgical remo al.
OSTEOMA CUTIS
Bone ormation within the s in may be primary occurring in
cases with no preceding lesion; metastatic in cases associated
with abnormalities o parathyroid metabolism; or dystrophic
in which ossi cation occurs in a pre e isting lesion or in am
matory process.
Primary osteoma cutis occurs in se eral clinically distinct
disorders Albright s hereditary osteodystrophy (A ) pseu
dohypoparathyroidism (P P) progressi e osseous heteropla
sia (P ) and widespread or single plateli e osteoma cutis
(PL C). utations in all our o these conditions occur in the
S gene.
Progressi e osseous heteroplasia is a rare orm o cutaneous
ossi cation initially seen between birth and months o age
o ten in the rst month o li e. emales are pre erentially
a ected. Lesions begin as small papules that can coalesce to
large pla ues. Sometimes these pla ues will ha e small rm
calci ed papules o erlying them. Lesions are randomly dis
tributed and may be unilateral or may in ol e only one ana
tomic area. There is no preceding trauma or in ammatory
phase. Serum calcium phosphorus parathyroid hormone
523

26
Errors in Metabolism
Fig. 26-15 Osteoma cutis. (Courtesy of Dr. Don Adler.)
(PT ) and calcitriol are normal but al aline phosphatase
(ALP) lactate dehydrogenase (LD ) and creatine phospho i
nase (CP ) may be ele ated indicating increased bone orma
tion (ALP) or muscle destruction (CP and LD ). istologically
the lesions re eal intramembranous bone ormation and can
a ect the so t tissues as well as s in. nly calci cation without
ossi cation may be ound in super cial dermal biopsies so a
deep biopsy including subcutaneous at may be re uired to
con rm the diagnosis. The condition is progressi e and can
lead to serious se uelae including ulceration in ection and
se ere pain. Plateli e osteoma cutis occurs in newborns or
young children but also in adults. t is not associated with
dysmorphic eatures or abnormalities o calcium or phospho
rus metabolism but shows intramembranous bone ormation
histologically. These disorders are most li ely polar ends o a
spectrum o disease; one amily has been described with
members ha ing either condition. A is characteri ed by
childhood de elopment o intramembranous bone ormation
in the dermis and subcutaneous tissue (see Chapter ). The
cutaneous ossi cations may be noted soon a ter birth and are
usually multiple small super cial pla ues that a or the
scalp hands eet periarticular regions abdomen and chest
wall. Small lesions are o little conse uence but large subcu
taneous masses may disrupt underlying structures. The patient
may ha e characteristic dysmorphic eatures and pseudohy
poparathyroidism or pseudopseudohypoparathyroidism.
A also is associated with mutations o the S gene.
ultiple miliary osteomas o the ace are clinically the most
common orm o osteoma cutis. These are usually seen in
women ( ig. ). The osteomas probably represent dystro
phic ossi cation because they occur in patients with acne are
locali ed to the ace and are associated with acne scars. oral
tetracycline or minocycline is ta en to treat the acne the cuta
neous osteomas may be pigmented or may uoresce under
Wood s light. mpro ement with topical tretinoin erbium AG
laser or incision curettage and primary closure has been
reported.
Aggarwal N, Shrestha S: Images in clinical medicine. Dystrophic
calcinosis cutis. N Engl J Med 2013; 368:e28.
Altman JF, et al: Treatment of primary miliary osteoma cutis with
incision, curettage, and primary closure. J Am Acad Dermatol 2001;
44:96.
524
tahir99 - UnitedVRG
Bair B, Fivenson D: A novel treatment for ulcerative calcinosis cutis.
Cutis 201; 10:1042.
Balin SJ, et al: Calcinosis cutis occurring in association with
autoimmune connective tissue disease. Arch Dermatol 2012;
148:455.
Chabra IS, Obagi S: Evaluation and management of multiple military
osteoma cutis: case series of 11 patients and literature review.
Dermatol Surg 2014; 40:66.
Chantorn R, Shwayder T: Poikiloderma with neutropenia: report of three
cases including one with calcinosis cutis. Pediatr Dermatol 2012;
29:463.
Chauhan NS, Sharma YP: A child with skin nodules and extensive soft
tissue calcification. Br J Radiol 2012; 85:193.
Cheng PS, Lai FJ: Sporotrichoid-like calcinosis cutis and calcifications in
vessel walls and eccrine sweat glands following intravenous infusion
and calcium gluconate. Br J Dermatol 2012; 166:892.
Cho E, et al: Subcorneal milia-like idiopathic calcinosis cutis: a rare
presentation. Ann Dermatol 2013; 25:249.
Cohen PR, Tschen JA: Idiopathic calcinosis cutis of the penis. J Clin
Aesthet Dermatol 2012; 5:23.
Dominguez-Fernandez I, et al: Calcinosis cutis following extravasation of
calcium salts. J Eur Acad Dermatol Venereol 2008; 22:505.
Eastham AB, et al: Diffuse dystrophic calcinosis cutis of the scalp
discoid lupus erythematosus and a systemic lupus erythematosus.
JAMA Dermatol 2013; 149:246.
Ehsani AH: Calcinosis cutis complicating liver transplantation. Dermatol
Online J 2006; 12:23.
Elli FM, et al: Screening for GNAS genetic and epigenetic alterations in
progressive osseous heteroplasia: first Italian series. Bone 2013;
56:276.
Falsey RR, Ackerman L: Eruptive, hard cutaneous nodules in a 61-year-
old woman. JAMA Dermatol 2013; 149:975.
Fox GN, et al: Acral milia-like idiopathic calcinosis cutis in a child
with Down syndrome: report of a case, review of the literature, and
description of dermoscopic findings. Pediatr Dermatol 2013;
30:263.
Hershkovitz D, et al: Functional characterization of SAMD9, a protein
deficient in normophosphatemic familial tumoral calcinosis. J Invest
Dermatol 2011; 131:662.
Hoşcan MB, et al: Massive idiopathic scrotal calcinosis. Urology 2012;
80:e71.
Huh JY, et al: Novel nonsense GNAS mutation in a 14-month-old boy
with plate-like osteoma cutis and medulloblastoma. J Dermatol 2014;
41:319.
Jang EJ, et al: Milia-like idiopathic calcinosis cutis occurring in a toddler
born as a premature baby. Ann Dermatol 2011; 23:490.
Kim HS, et al: Multiple subepidermal calcified nodules on the thigh
mimicking molluscum contagiosum. Pediatri Dermatol 2011;
28:191.
Kucukemre Aydin B, et al: Osteoma cutis. Pediatr Int 2013; 55:257.
Lee YW, et al: Four cases of subepidermal calcified nodule on a child’s
sole. Int J Dermatol 2012; 51:316.
Li Q, Uitto J: Mineralization/anti-mineralization networks in the skin and
vascular connective tissues. Am J Pathol 2013; 183:10.
Lim PP, et al: Calcinosis cutis following contact with calcium chloride
solution. Australas J Dermatol 2012; 55:e66.
Livingood M, Newman SA: An unusual presentation of perforating
metastatic calcinosis cutis. Skinmed 2013; 11:314.
Lykoudis EG, et al: Huge recurrent tumoral calcinosis needing extensive
excision and reconstruction: report of a rare case and brief literature
review. Aesth Plast Surg 2012; 36:1194.
Macbeth AE, et al: Calcified subcutaneous nodules: a long-term
complication of interferon beta-1a therapy. Br J Dermatol 2007;
157:624.
Martin J, et al: Infantile osteoma cutis as a presentation of a GNAS
mutation. Pediatr Dermatol 2012; 29:483.
Myllylä RM, et al: Multiple military osteoma cutis is a distinct disease
entity: four case reports and review of the literature. Br J Dermatol
2011; 164:544.
Nagai Y, et al: Nephrogenic systemic fibrosis with multiple calcification
and osseous metaplasia. Acta Derm Venereol 2008; 88:597.
Nakamura S, et al: Hutchinson-Gilford progeria syndrome with severe
skin calcinosis. Clin Exp Dermatol 2007; 32:525.
Nakamura Y, Muto M: Subepidermal calcified nodule of the knee with
transepidermal elimination of calcium. J Dermatol 2012; 39:965.
 Ozuguz P, et al: Multiple sub-epidermal calcified nodule mimicking
eruptive xanthoma: a case report and review of the literature. Indian J
Dermatol 2013; 58:406.
Piombino L, et al: A novel surgical approach to calcinosis cutis using a
collagen-elastin matrix. J Wound Care 2013; 22:22.

Xanthomas
Reiter N, et al: Calcinosis cutis. Part I. Diagnostic pathway. J Am Acad
Dermatol 2011; 65:1.
Reiter N, et al: Calcinosis cutis. Part II. Treatment options. J Am Acad
Dermatol 2011; 65:15.
Riahi RR, Cohen PR: Multiple military osteoma cutis of the face after
initiation of alendronate therapy for osteoporosis. Skinmed 2011;
9:258.
Schimmel RJ, et al: GNAS-associated disorders of cutaneous
ossification: two different clinical presentations. Bone 2010; 46:868.
Shah V, Shet T: Scrotal calcinosis results from calcification of cysts
derived from hair follicles: a series of 20 cases evaluating the
spectrum of changes resulting in scrotal calcinosis. Am J Fig. 26-16 Tuberous xanthomas.
Dermatopathol 2007; 29:172.
Shin BS, et al: Recurrent milia-like idiopathic calcinosis cutis on the
upper eyelid. Ann Dermatol 2013; 25:520.
Shinjo SK, Souza FH: Update on the treatment of calcinosis in and medications (e.g. systemic retinoids) can also cause
dermatomyositis. Rev Bras Reumatol 2013; 53:211. hyperlipidemias and result in anthomas. The names o the
Slavin RE, et al: Tumoral calcinosis—a pathogenetic overview: a arious orms o cutaneous anthomas are based on clinical
histological and ultrastructural study with a report of two new cases, morphology. umerous genetic mutations ha e been identi
one in infancy. Int J Surg Pathol 2012; 20:462. ed all o which result in hyperlipidemias. Se eral di erent
Smith GP: Intradermal sodium thiosulfate for exophytic calcinosis
genetic diseases may present with similar cutaneous anthoma
cutis of connective tissue disease. J Am Acad Dermatol 2013;
69:e146. patterns so re erral to a lipid clinic is recommended or
Sultan-Bichat N, et al: Treatment of calcinosis cutis by extracorporeal anthoma patients with amilial patterns o hyperlipidemia as
shock-wave lithotripsy. J Am Acad Dermatol 2011;66:424. well as or those without an ob ious medical cause or their
Talsania N, et al: Platelike osteoma cutis. J Am Acad Dermatol 2009; dyslipidemia. The morphologies are relati ely speci c or the
64:613. associated ele ated lipid howe er with erupti e anthomas
Tomazzini E, et al: Vulvar calcinosis in childhood. Int J Gynaecol Obstet seen with hypertriglyceridemia and other orms o anthomas
2008; 103:263. seen with increased cholesterol.
Tomita H, et al: Periorbital milia-like calcinosis. Clin Exp Dermatol 2012;
37:786.
Valenzuela A, et al: Identification of clinical features and autoantibodies
associated with calcinosis in dermatomyositis. JAMA Dermatol 2014; Xanthoma tuberosum
150:724.
Vashi N, et al: Acquired plate-like osteoma cutis. Dermatol Online J Tuberous anthomas are ariously ound as at or ele ated
2011; 17:1. and rounded grouped yellowish or orange nodules located
Ward S, et al: Three cases of osteoma cutis occurring in infancy: a brief o er the oints particularly on the elbows and nees ( ig.
overview of osteoma cutis and its association with pseudo- ). The lesions are indurated and tend to coalesce. They
pseudohypoparathyroidism. Australas J Dermatol 2011; 52:127. may also occur o er the ace nuc les toe oints a illary and
Wolf EK, et al: Topical sodium thiosulfate therapy for leg ulcers with inguinal olds and buttoc s. Solitary lesions may be ound.
dystrophic calcification. Arch Dermatol 2008; 144:1560. arly lesions are usually bright yellow or erythematous; older
Yong AS, et al: Vitamin D deficiency–associated calcinosis cutis, with
lesions tend to become brotic and lose their color. Peduncu
secondary granulomatous changes. Clin Exp Dermatol 2013; 38:814.
lated ssured and suppurati e nodules may also be seen.

LIPID DISTURBANCES Xanthoma tendinosum

XANTHOMAS
anthomas are deposits o lipids in tissue. or the dermatolo
gist the important areas to loo or lipid deposits are on the
s in tendon and eyes. anthomas appear when abnormalities
o lipid amount or processing occur in the body and thus are
important mar ers o underlying dyslipidemia and potentially
increased cardio ascular ris . The histologic eatures in all
arieties o anthoma are similar characteri ed by the pres
ence o numerous large anthoma or oam cells which are
phagocytes ( at laden histiocytes). The cells may be multinu
cleated. n addition to the oam cells giant cells o the Touton
type occur. Cle ts representing cholesterol and atty acids dis
sol ed by processing agents may be noted. Generally a con
necti e tissue reaction occurs around the nests o oam cells
and in old lesions most o the oam cells are replaced with
brosis. CD and adipophilin immunopero idase may aid in
identi ying oam cells.
n addition to inherited genetic de ects o molecules in ol ed
in lipid homeostasis systemic diseases (e.g. diabetes mellitus)
Papules or nodules mm in diameter are ound in the
tendons especially in e tensor tendons on the bac s o the
hands and dorsa o the eet and in the Achilles tendons ( ig.
). These predominate in conditions with ele ated low
density lipoprotein (LDL) cholesterol and can be seen in asso
ciation with tuberous anthomas and anthelasma. The lesions
also occur in obstructi e li er disease diabetes my edema
cerebrotendinous anthomatosis and phytosterolemia.
Eruptive xanthoma
anthoma erupti um consists o small yellowish orange to
reddish brown papules that appear in crops o er the entire
body ( ig. ). The papules may be surrounded by an ery
thematous halo and may be grouped in arious a ored loca
tions such as the buttoc s e tensor sur aces o the arms and
thighs nees inguinal and a illary olds and oral mucosa.
oebneri ation may occur. Pruritus is ariable. rupti e an
thomas strongly suggest the presence o ele ated triglyceride
525
 Fig. 26-17 Tendinous
26 xanthomas.
Errors in Metabolism
Fig. 26-18 Eruptive xanthomas.
le els. rupti e anthomas are seen most o ten in poorly con
trolled type diabetes mellitus but can also be seen in chronic
renal ailure hypothyroidism and treatment with estrogens
corticosteroids or systemic retinoids.
Xanthoma planum (plane xanthoma)
Plane anthomas appear as at macules or slightly ele ated
pla ues with a yellowish tan or orange coloration o the s in
spread di usely o er large areas Characteristically plane an
thomas may occur around the eyelids nec trun shoulders
or a illae ( ig. ). These well de ned macular patches may
be situated on the inner sur ace o the thighs and antecubital
and popliteal spaces. Although these can be seen as a compli
cation o ele ated lipid le els as in primary biliary cirrhosis
they are the one orm o anthoma that may not be associated
with increased lipids. ormolipemic plane anthomas are
most re uently seen in patients with myeloma or a monoclo
nal gammopathy and less o ten in other myelodysplasias such
as mycosis ungoides lymphoma leu emia and adult T cell
lymphoma leu emia caused by human lymphotropic irus
type ( TLV ). n myeloma and monoclonal gammopathy
the paraprotein comple es with LDL and these comple es are
phagocytosed by histiocytes in tissue orming the plane an
thomas. n patients with monoclonal gammopathy associated
anthoma a reduced C and reduced C (both in o and physical e amination. Consultation with a lipid clinic
patients) are also usually detected as well as a decreased C
526
tahir99 - UnitedVRG
Fig. 26-19 Plane
xanthoma.
inhibitor le el ( ) and the presence o a cryoglobulin ( ).
Treatment o the underlying myelodysplasia may lead to reso
lution o the anthomas.
A rare orm o normolipemic anthomatosis can occur in
childhood termed normolipemic papuloerupti e anthomato
sis. ellowish papules mm in diameter occur on the ace.
They can coalesce to orm large con uent pla ues especially
on the ace nape o the nec and a illae. Spontaneous in olu
tion occurs. t is unclear whether this is a rare disease in its
own right or a se ere ariant o benign cephalic histiocytosis
or papular anthoma o childhood.
Palmar xanthomas
Palmar anthomas consist o nodules and irregular yellowish
pla ues in ol ing the palms and e ural sur aces o the
ngers ( ig. ). Striated anthomas appear as yellowish
strea s that ollow the distribution o creases o the palms and
soles. These lesions are seen in amilial dysbetalipoprotein
emia multiple myeloma and primary biliary cirrhosis.
Xanthelasma palpebrarum (xanthelasma)
anthelasma is the most common type o anthoma. t occurs
on the eyelids and is characteri ed by so t chamois colored
or yellowish orange oblong pla ues usually near the inner
canthi ( ig. ). They usually appear between ages and
. The anthelasmas ary rom to mm in length and are
usually symmetric. anthelasmas are typically seen without
other orms o anthomas and o ten with normal lipids. n
o anthelasma patients howe er dyslipidemia is
detected. ew patients with anthelasma should be e alu
ated with a ull lipoprotein pro le as well as a care ul history
may be appropriate. arly (childhood) onset o anthelasma

Fig. 26-20 Xanthomas of palmar striae.
Fig. 26-21 Xanthelasma.
should suggest a hereditary lipid abnormality especially
amilial hypercholesterolemia.
Treatment o anthelasma is discussed here because o its
uni ueness among the anthomas in that surgical therapy is
o ten success ul. The best method is surgical e cision. The
anestheti ed lesion is grasped with mouse tooth orceps and
clipped o with scissors and the s in edges are undermined
and sutured. cellent cosmetic results are obtained e en i
the wound is not closed. ulguration trichloroacetic acid cau
teri ation and carbon dio ide (C ) erbium AG or d AG
laser therapy are other methods. Complete remo al o the
lesions does not preclude the possibility that other new lesions
will de elop.
PRIMARY HYPERLIPOPROTEINEMIAS
rederic son classi ed hyperlipoproteinemias into si types
on the basis o electrophoretic patterns now called the World
ealth rgani ation nternational Classi cation o Diseases
(W CD) hyperlipoprotein ( LP) phenotypes as ollows.
LP type e cess chylomicrons
LP A type a e cess β lipoprotein
LP B type b e cess β lipoprotein with slightly
ele ated ery low density lipoproteins (VLDLs)
LP type increased intermediate density (remnant)
lipoproteins ( DLs)
LP type V increased pre β lipoprotein
LP type V increased pre β lipoproteins and
chylomicrons
Although this phenotypic classi cation has been use ul or
Primary hyperlipoproteinemias
many years ad ances in the understanding o lipoprotein
metabolism and transport coupled with new nowledge o
molecular de ects that result in these phenotypes has led to
the use o a genetic classi cation o lipoproteinemias. two
or more gene products are re uired at any point in lipoprotein
metabolism genetic de ciency o any molecule will lead to a
similar phenotype. ultiple genotypes lead to the same
phenotype.
Lipoprotein metabolism may be iewed according to the
lipid source an e ogenous and an endogenous category.
ogenous lipids in the diet are absorbed and incorporated
into triglyceride rich chylomicrons. These are hydroly ed by
the action o lipoprotein lipase and certain co actors including
apoprotein C . The resulting remnants are ta en up by the
li er. ndogenously produced VLDLs are synthesi ed in the
li er and again through the action o lipoprotein lipase are
connected to cholesterol rich DLs and e entually into LDLs.
These are then a ailable or upta e by peripheral tissues as
well as by the li er. The upta e o LDL DL and chylomicron
remnants depends on speci c receptors. Abnormalities o lipo
protein lipase the apolipoproteins co actors receptors or
stimulators or retarders o endogenous production or catabo
lism whether on a genetic or a sporadic basis may accelerate
or bloc the pathway in di erent areas. bloc ade occurs
early and results in ele ation o triglyceride rich particles
erupti e anthoma may result. a de ect occurs later in the
pathway and cholesterol rich particles accumulate anthe
lasma tuberous anthomas and tendinous anthomas should
be e pected along with premature atherosclerotic cardio as
cular disease.
Lipoprotein lipase deficiency
Lipoprotein lipase de ciency causes LP disease (chylomi
cronemia) early in li e. t is rare results rom a homo ygous
de ect and is associated with highly ele ated triglycerides.
With le els abo e mg dL a high ris o pancreatitis and
erupti e anthomas e ists ( ig. ). As patients age their
VLDLs increase.
Familial apoprotein CII deficiency
Patients with the rare amilial apoprotein C de ciency lac
lipoprotein lipase acti ator and ha e ery high triglyceride
le els up to mg dL. They are at ris or pancreatitis
and erupti e anthomas.
Familial hypertriglyceridemia
n amilial hypertriglyceridemia increased hepatic production
o VLDLs occurs. rupti e anthomas are common. Depend
ing on the cause o this lipid pattern the ris o atherosclerotic
disease may ary.
Familial hypercholesterolemia
amilial hypercholesterolemia ( ) has an LP A ( rederic
son type a) lipid pro le. t is caused by mutations in multiple
genes most o ten the LDL receptor. ne in persons carry
527

26
Errors in Metabolism
Fig. 26-22 Eruptive xanthomas in lipoprotein lipase deficiency.
Fig. 26-23 Xanthomas in homozygous familial hypercholesterolemia.
a mutation in this gene and they present with planar tendon
or tuberous anthomas rom age . Their LDL cholesterol
is two to three times normal and they ha e a two old to three
old increase in cardio ascular disease. These persons are
termed hetero ygotes. two hetero ygotes marry one
in our children will be homo ygous recessi e or the LDL
receptor and will present in childhood (teens or early twenties)
with anthomas LDL cholesterol our to si times normal and
cardio ascular disease and aortic stenosis. omo ygous
patients may ha e large anthelasmas ( anthomatous pseudo
spectacles) and anthomas o the interdigital web spaces and
the gluteal cle t ( ig. ).
SECONDARY HYPERLIPOPROTEINEMIA
Obstructive liver disease (xanthomatous
biliary cirrhosis)
This type o hyperlipoproteinemia shows an increase in serum
phospholipid and cholesterol le els gi ing a type lipopro
tein pattern. anthomatous biliary cirrhosis is caused by
the presence o lipoprotein which is secreted by the li er
in cholestasis. Lipoprotein has the ability to carry large
uantities o ree cholesterol and phospholipids. The triglyc
erides are not ele ated and the plasma is clear showing no
chylomicrons.
The anthomatous lesions are plane anthomas with lesions
on the ace e or sur aces o the e tremities and trun . Striate
528
tahir99 - UnitedVRG
palmar and plantar lesions and anthelasmas are also seen.
Tuberous anthomas may occur. Pruritus is e tremely se ere.
epatomegaly and aundice are present. Cholestyramine can
help in allaying pruritus.
Alagille syndrome is a congenital disorder characteri ed by
intrahepatic bile ductular atresia patent e trahepatic bile
ducts a characteristic acies (prominent orehead deep set
eyes straight nose and small pointed chin) cardiac murmur
ertebral and ocular abnormalities low intelligence and
hypogonadism. t is an autosomal dominant inherited condi
tion. There is persistent cholestasis early in li e with pruritus
and hyperbilirubinemia. Lipid le els increase by age years
and planar or papular anthomas may occur. Alagille syn
drome is a treatable condition with cholestyramine and at
soluble itamins leading to long term impro ement.
Pancreatitis
yperlipidemia in the hyperchylomicronemic syndromes
(types and V) may cause pancreatitis; it may be recurrent
and pancreatic necrosis and death may occur. Alternati ely
pancreatitis (perhaps initiated by ethanol) may cause type or
V hyperlipoproteinemia by inducing insulin de ciency and a
relati e lac o lipoprotein lipase acti ity. A triglyceride le el
o mg dL is re uired or pancreatitis to occur in the
setting o hypertriglyceridemia. The amylase may be normal
but the lipase will be ele ated.
Medication-induced hyperlipoproteinemia
strogens by decreasing lipoprotein lipase acti ity and
increasing VLDL synthesis may cause LP or LP pat
terns. rupti e anthomas may occur. ral prednisone may
induce insulin resistance and cause LP or LP patterns to
de elop. ral retinoids indomethacin protease inhibitors
or V and olan apine may also cause erupti e anthomas
through hypertriglyceridemia.
Cerebrotendinous xanthomatosis
Cerebrotendinous anthomatosis is a rare autosomal recessi e
disease caused by an accumulation o cholestanol in plasma
lipoproteins brain and anthomatous tissue. The underlying
abnormality is a mutation in the sterol hydro ylase gene
(C P ) in the mitochondria leading to incomplete o ida
tion o cholesterol to bile acids. As a result cholestanol an
intermediate accumulates in tendons brain heart lungs and
the lens o the eye. The disorder is characteri ed by prominent
tendinous anthomas especially o the Achilles tendons (not
present in all patients) macroglossia progressi e neurologic
dys unction in many orms in antile diarrhea de elopmental
cataracts and atherosclerotic coronary artery disease. Plasma
cholestanol is ele ated and can e ceed more than times
normal le els. Patients with cerebrotendinous anthomatosis
are treated with chenodeo ycholic acid and early treatment
can pre ent the progressi e neurologic impairment.
Sitosterolemia (phytosterolemia)
n sitosterolemia a rare autosomal recessi e disorder plasma
plant sterols are e tremely ele ated (> times normal). This
disorder is caused by mutations in the genes encoding the
ABCG and ABCG transporters which are e pressed only in
the intestine and li er. n the intestine they pump plant sterols
and cholesterol out o intestinal cells bac into the lumen o
the gut limiting sterol and cholesterol absorption. n the li er
they pump plant sterols into the bile aiding in their e cretion.
Absence o either o these genes results in increased absorp
tion and decreased e cretion o plant sterols leading to their
accumulation in the body. Patients de elop tendinous antho
mas anthelasma and tuberous intertriginous and palmar
anthomas. The diagnosis o sitosterolemia should be consid
ered in any child or adolescent with anthomas and a low LDL
cholesterol (< ). t can also present as dietary responsi e
hypercholesterolemia in in ancy. Phytosterolemia can also
mimic amilial hypercholesterolemia in the adult because
most patients also ha e type a hyperlipoproteinemia and
accelerated atherosclerosis due to the enhanced absorption o
cholesterol. Treatment is dietary restriction o plant sterols
cholesterol and some shell sh (clam oysters scallops) whose
sterols are also hyperabsorbed. n addition bile se uestrants
(chenodeo ycholic acid) can be used. etimibe an inhibitor
o PC L ( iemann Pic C li e ) inhibits absorption o
plant sterols and can be e ecti e in reducing plasma sterol
le els.
Verruciform xanthoma
Verruci orm anthoma (V ) is an uncommon lesion that
occurs as a reddish orange or paler hyper eratotic pla ue or
papillomatous growth with a pebbly or errucous sur ace. The
most common site is the oral mucosa. V has also been
reported on other mucosal sur aces genitalia lower e tremi
ties ( ig. ) and elsewhere. n the e ternal genitalia in
men the lesions re uently resemble condylomata acuminata
and are not associated with any other condition. Disorders
with damage o the papillary dermis ha e been associated
with V including recessi e dystrophic epidermolysis bullosa
lymphedema and GV D. Similarly ul ar V ha e been
associated with lichen sclerosus lichen planus Paget s disease
and radiodermatitis. Additionally V has been reported in a
patient with psoriatic lesions undergoing P VA therapy and
in psoriasi orm s in lesions in an V positi e patient. isto
logically there is acanthosis without atypia para eratosis and
anthoma cells in the papillary dermis. pidermal ne us li e
lesions in C LD syndrome (congenital hemidysplasia with
ichthyosi orm erythroderma and limb de ects) ha e histologic
characteristics o V . n a small percentage o V patients a
mutation in the SD L gene ( β hydro ysteroid dehydroge
nase) has been ound. This gene is also mutated in C LD
syndrome e plaining why it and V share the same histology.
n one child a genital V responded to topical imi uimod
treatment.
Fig. 26-24 Verruciform xanthoma.
Familial α-lipoprotein deficiency
(hypoalphalipoproteinemia, Tangier disease)
Tangier disease is caused by mutations in the cell membrane
Secondary hyperlipoproteinemia
protein ABCA which mediates the secretion o e cess cho
lesterol rom cells into the DL metabolic pathway. This
results in a pro ound de ciency o DL and accumulation o
cholesterol in tissue macrophages. The characteristic clinical
nding is enlarged yellow tonsils rom accumulation o lipid
in this locali ed area. anthomas do not occur but there is
di use accumulation o cholesterol esters in the s in as well
as in the intestines thymus bone marrow lymph nodes and
spleen. Peripheral neuropathy splenomegaly (with thrombo
cytopenia) and premature coronary artery disease are other
eatures o Tangier disease.
Björkhem I: Cerebrotendinous xanthomatosis. Curr Opin Lipidol 2013;
24:283.
Blankenship DW, et al: Verruciform xanthoma of the upper extremity in
the absence of chronic skin disease or syndrome: a case report and
review of the literature. J Cutan Pathol 2013; 40:745.
Boyd AS, Roffwarg D: Cutaneous verrucous xanthoma in a bone marrow
transplant recipient with recessive dystrophic epidermolysis bullosa.
Pediatr Dermatol 2013; 30:480.
Broeshart JH, et al: Normolipemic plane xanthoma associated with
adenocarcinoma and severe itch. J Am Acad Dermatol 2003; 49:119.
Brown CA, et al: Tuberous and tendinous xanthomata secondary to
ritonavir-associated hyperlipidemia. J Am Acad Dermatol 2005; 52:S86.
Burnside NJ, et al: Type III hyperlipoproteinemia with xanthomas and
multiple myeloma. J Am Acad Dermatol 2005; 53:S281.
Chung HG, et al: CD 30 (Ki-1)–positive large-cell cutaneous T-cell
lymphoma with secondary xanthomatous changes after radiation
therapy. J Am Acad Dermatol 2003; 48:S28.
D’Acunto C, et al: Xanthelasma palpebrarum: a new adverse reaction to
intradermal fillers? Br J Dermatol 2013; 168:437.
Dey A, et al: Cardiovascular profile of xanthelasma palpebrarum.
Biomed Res Int 2013; 2013:932863.
Erkan E: Rebuttal to “ezetimibe treatment should be considered for
patients with sitosterolemia.” Pediatr Nephrol 2014; 29:1471.
Fite C, et al: Vulvar verruciform xanthoma. Arch Dermatol 2011;
147:1087.
Fujimoto N, et al: Ultraviolet irradiation may generate plane xanthomas
on mycosis fungoides. Br J Dermatol 2013; 168:213.
Fujimoto N, et al: Verruciform xanthoma results from epidermal
apoptosis with galectin-7 overexpression. J Eur Acad Dermatol
Venereol 2013; 27:922.
Garcia MA, et al: Alagille syndrome: cutaneous manifestations in 38
children. Pediatr Dermatol 2005; 22:11.
Geyer AS, et al: Eruptive xanthomas associated with protease inhibitor
therapy. Arch Dermatol 2004; 140:617.
Girish MP, Gupta MD: Xanthomatous pseudospectacles in familial
hypercholesterolemia. N Engl J Med 2005; 352:2424.
Gregorious S, et al: Treatment of mycosis fungoides with bexarotene
results in remission of diffuse plane xanthomas. J Cutan Med Surg
2013; 17:52.
Guo Y, et al: Successful treatment of verruciform xanthomas with
imiquimod. J Am Acad Dermatol 2013; 69:e184.
Helm TN, et al: Verruciform xanthomas with porokeratosis-like
features but no clinically apparent lymphedema. J Cutan Pathol
2012; 39:887.
Huang HY, et al: Normolipemic papuloeruptive xanthomatosis in a child.
Pediatr Dermatol 2009; 26:360.
Joshi R, Ovhal A: Verruciform xanthoma: report of five cases. Indian J
Dermatol 2012; 57:479.
Kose R: Treatment of large xanthelasma palpebrarums with full-
thickness skin grafts obtained by blepharoplasty. J Cutan Med Surg
2013; 17:197.
Kulkarni ML, et al: Cerebrotendinous xanthomatosis: an early diagnosis
by biochemical tests. Indian J Pediatr 2014; 81:840.
Kwiterovich PO: Diagnosis and management of familial
dyslipoproteinemias. Curr Cardiol Rep 2013; 15:371.
Lee HY, et al: Outcomes of surgical management of xanthelasma
palpebrarum. Arch Plast Surg 2013; 40:380.
529
 Li SG: Images in clinical medicine. Familial hypercholesterolemia. N Neefjes J, van der Kant R: Stuck in traffic: an emerging theme in
26 Engl J Med 2009; 360:1885.
Mehra S, et al: A novel somatic mutation of the 3β-hydroxysteroid
diseases of the nervous system. Trends Neurosci 2014; 37:66.
Stern G, et al: Niemann-Pick’s and Gaucher’s diseases. Parkinsonism
dehydrogenase gene in sporadic cutaneous verruciform xanthoma. Relat Disord 2014; 2051:S143.
Arch Dermatol 2005; 141:1263. Texeira VB, et al: Generalized lichen nitidus in a boy with Niemann-Pick
Errors in Metabolism

Mignarri A, et al: A suspicion index for early diagnosis and treatment of disease type B. An Bras Dermatol 2013; 88:977.
cerebrotendinous xanthomatosis. J Inherit Metab Dis 2014; 37:421.
Park JH, et al: Sitosterolemia presenting with severe
hypercholesterolemia and intertriginous xanthomas in a breastfed
infant: case report and brief review. J Clin Endocrinol Metab 2014; GAUCHER’S DISEASE
99:1512.
Park JS, et al: Hepatic ABC transporters and triglyceride metabolism. Although rare Gaucher s disease is the most common lyso
Curr Opin Lipidol 2012; 23:196. somal storage disease. t is an autosomal recessi e disorder
Rhyne J, et al: Multiple splice defects in ABCA1 cause low HDL-C in a caused by insu cient acti ity o the lysosomal en yme acid
family with hypoalphalipoproteinemia and premature coronary disease.
β glucosidase (glucocerebrosidase GBA glucosylceramidase).
BMC Med Genet 2009; 10:1.
Robinson MR, Meehan SA: Verruciform xanthoma. Cutis 2013; 91:272.
The disease occurs most re uently among Ash ena i Jews.
Rosmaninho A, et al: Diffuse plane xanthomatosis associated with Appro imately in carry the de ecti e gene. Lysosomal
monoclonal gammopathy. An Bras Dermatol 2011; 86:S50. accumulation o glucosylceramide the substrate o GBA in
Ryu DJ, et al: Verruciform xanthoma of the palatal gingiva: a report of macrophages causes the disease mani estations. n rare cases
two cases. J Korean Assoc Oral Maxillofac Surg 2013; 39:292. Gaucher s disease is caused by mutations in the prosaposin
Shirdel A, et al: Diffuse normolipaemic plane xanthomatosis associated gene which encodes the saposin C acti ator protein that is
with adult T-cell lymphoma/leukaemia. J Eur Acad Dermatol Venereol necessary or optimal acti ity o β glucosidase. Gaucher cells
2008; 22:1252. are identi ed histologically as large macrophages μm
Sinnott BP, Mazzone T: Tuberous xanthomas associated with olanzapine in diameter with one nucleus or a ew small nuclei and pale
therapy and hypertriglyceridemia in the setting of a rare apolipoprotein
cytoplasm that stains aintly or at but is PAS positi e.
E mutation. Endocr Pract 2006; 12:183.
Sopena J, et al: Disseminated verruciform xanthoma. Br J Dermatol Gaucher s disease occurs at any age but three types are
2004; 151:717. recogni ed type (adult orm) without neurologic in ol e
Szalat R, et al: Pathogenesis and treatment of xanthomatosis ment; type the in antile orm with acute early neurologic
associated with monoclonal gammopathy. Blood 2011; 118:3777. mani estations; and type the u enile chronic neuropathic
Teixeira V, et al: Verruciform xanthomas: report of two cases. Dermatol orm. Some type patients ha e congenital ichthyosis that
Online J 2012; 18:10. precedes neurologic mani estations and some are born with
Tsuang W: Hypertriglyceridemic pancreatitis: presentation and a collodion membrane. pidermal ultrastructural and bio
management. Am J Gastroenterol 2009; 104:984. chemical abnormalities occur in all type patients. epato
Tsubakio-Yamamoto K, et al: Current therapy for patients with
splenomegaly osteopenia osteoporosis o the long bones
sitosterolemia: effect of ezetimibe on plant sterol metabolism. J
Atheroscler Thromb 2010; 17:891.
pingueculae o the sclera and a distincti e bron e coloration
Zhao Y, et al: 1064-nm Q-switched Nd:YAG laser in an effective and o the s in rom melanin characteri e the adult type. A deeper
safe approach to treat xanthelasma palpebrarum in Asian population. pigmentation may e tend rom the nees to the eet ( ig.
J Eur Acad Dermatol Venereol 2014; Jun 9. [Epub ahead of print.] ). This is o ten caused by hemosiderin and may be accom
panied by thrombocytopenia and splenomegaly.
The diagnosis is con rmed by D A testing or the a ected
NIEMANN-PICK DISEASE gene.
Therapy or Gaucher s disease now consists o en yme
iemann Pic disease is a rare autosomal recessi e condition replacement therapy ( RT) with intra enous mannose
that has three recogni ed subtypes. The disorder was origi terminated glucocerebrosidase. nly type and type patients
nally described in Ash ena i Jews. Type A and type B are both are treated; RT does not bene t type patients. RT is e ec
caused by mutations in the acid sphingomyelinase gene ti e in pre enting isceral disease in all type and type
(SMPD ). Type A is more se ere presents in in ancy with patients and re erses and pre ents most symptoms in type
neuro isceral disease and is o ten atal. Type B is purely is patients. Bone marrow transplantation per ormed be ore
ceral (nonneurologic) and sur i al into adulthood is charac neurologic de cits occur has a high mortality rate ( )
teristic. S in lesions in patients with iemann Pic disease
types A and B include anthomas (s in colored to tan papules)
and yellow brown induration o the s in. istologically
oamy histiocytes are ound which on electron microscopy
ha e characteristic cytoplasmic inclusions. iemann Pic
disease type C is caused by mutations in the PC and PC
genes which are in ol ed in endosomal lysosomal cholesterol
tra c ing. Type C is a neuro isceral disease with a ariable
age o onset and neurodegenerati e course. Patients may
present rom the perinatal period to adulthood. Cholestatic
aundice is characteristic. arly onset disease is o ten associ
ated with se ere neurologic disease and death be ore age .
Patients with late in antile and u enile orms ha e neurologic
disease. Patients with the adult orm o type C may demon
strate isceral in ol ement and psychiatric and cogniti e dis
orders. Death occurs be ore age .
Grasko Y, et al: A novel missense SMPD I gene mutation, T460P, and
clinical findings in a patient with Niemann-Pick disease type B
presenting to a lipid disorders clinic. Ann Clin Biochem 2014; 51(Pt
5):615. Fig. 26-25 Pigmentation of the lower leg/Dr. Gaucher’s disease.
530

tahir99 - UnitedVRG
but when success ul it has halted neurologic progression. RT
is success ul in treating some o the mani estations o the adult
orm (Gaucher s disease type ) but is limited by cost. Sub
strate reduction therapy using the glycolipid synthesis inhibi
tor butyldeo yno irimycin (miglustat) is also a ailable.
The intense study o Gaucher s disease has led to two inter
esting ndings. ore than o adult patients with Gau
cher s disease ha e monoclonal gammopathy and about
o these patients ha e an associated myelodysplasia (myeloma
or lymphoma). ore than o adult Gaucher s disease
patients will de elop myeloma. etero ygous carriers o GBA
mutations are re uently ound in patients with Par inson s
disease. Par inson s disease is associated with certain patho
genic ariant GBA mutations.
Grabowski GA: Phenotype, diagnosis, and treatment of Gaucher’s
disease. Lancet 2008; 372:1263.
Grosbois B, et al: Gaucher disease and monoclonal gammopathy: a
report of 17 cases and impact of therapy. Blood Cells Mol Dis 2009;
43:138.
Hughes DA: Enzyme, substrate, and myeloma in Gaucher disease. Am
J Hematol 2009; 84:199.
Mignot C, et al: Gaucher disease. Handb Clin Neurol 2013;113:1709.
Rosenbaum H, et al: Hypercoagulability, Parkinsonism, and Gaucher
disease. Semin Thromb Hemost 2013; 39:928.
LIPOID PROTEINOSIS
Also nown as rbach Wiethe disease and hyalinosis cutis et
mucosae lipoid proteinosis is a rare autosomal recessi e con
dition that usually presents in in ancy with a hoarse cry or
oice. ucosal lesions include yellowish white in ltrati e
deposits on the inner sur ace o the lips undersur ace o the
tongue auces and u ula. nability to protrude the woody
tongue because o renulum shortening is characteristic. ero
stomia may occur. n childhood beaded eyelid papules are
seen. eitis and hyaline deposits on and in the eye may
de elop. Wa y yellow papules and nodules with generali ed
s in thic ening occur ( ig. ). echanical riction leads to
hyper eratosis o the hands elbows nees buttoc s and
a illae. Acral hyper eratotic papules occur in about
Fig. 26-26 Papules of the eyelid in lipoid proteinosis. (Courtesy of Dr.
Eric Krause.)
o patients and ha e been described as errucous. n act in
some patients these lesions are induced by human papilloma
irus ( PV). n one patient with lipoid proteinosis epidermo
dysplasia erruci ormis was diagnosed. inor trauma leads
to bullae that heal with poc li e or acneli e scars especially
Lipoid proteinosis
on the ace ( ig. ). This may be related to the increased
ris or bacterial s in in ections in these patients. Scalp in ol e
ment may lead to mild loss o hair. eurologic se uelae
include epilepsy dystonia and cogniti e impairments.
Distincti e histologic eatures include e treme dilation o
the blood essels thic ening o the essel walls progressi e
hyalini ation o sweat glands and in ltration o the dermis
and subcutaneous tissue with e tracellular hyaline deposits.
ormal s in and mucous membranes also show changes o
endothelial proli eration o the subpapillary essels and a
homogeneous thic ening o the walls o the deeper essels.
Type V collagen and laminin are increased around blood
essels.
Lipoid proteinosis is caused by mutations in the e tracel
lular matri protein . This protein binds to heparin sul ate
proteoglycans which are also the binding substances or PV
perhaps e plaining the re uency o PV in ection. Di eren
tiation rom erythropoietic protoporphyria may be di cult
especially histologically.
umerous patients with lipoid proteinosis ha e been treated
with systemic retinoids with positi e results. A dose o about
. mg g o acitretin is well tolerated and e ecti e. oarse
ness impro es in most patients palmar and plantar hyper
eratosis is reduced and patients may note reduction in s in
blisters. ral ulcerations impro e. arlier treatment (be ore
age ) was associated with a better response. istologically
the epidermis is less thic but the hyaline deposition is
unchanged. Although death rom respiratory obstruction
occasionally occurs in in ancy the disease is otherwise com
patible with a normal li e span.
Bakry OA, et al: Two Egyptian cases of lipoid proteinosis successfully
treated with acitretin. J Dermatol Case Rep 2014; 1:29.
Dertlioğlu SB, et al: Demographic, clinical, and radiologic signs and
treatment responses of lipoid proteinosis patients: a 10-case series
from Şanlıurfa. Int J Dermatol 2014; 53:516.
O’Blenes C, et al: Epidermodysplasia verruciformis in lipoid proteinosis:
case report and discussion of pathophysiology. Pediatr Dermatol 2013;
Mar 28. [Epub ahead of print.]
Fig. 26-27 Acneiform
scarring in lipoid
proteinosis.
531

26 ANGIOKERATOMA CORPORIS DIFFUSUM
(FABRY DISEASE)
abry disease ( D) is a rare lin ed lysosomal storage disease.
Errors in Metabolism
t is caused by mutations in the α galactosidase A gene ( L )
leading to a de ciency in α galactosidase A. This results in the
inability to cataboli e glycosphingolipids and globotriaosyl
ceramide accumulates in lysosomes in many tissues including
endothelial cells erector pili muscles dorsal root ganglion
ner es and isceral organs. ales are a ected more se erely
and earlier. emale hetero ygotes (carriers o the de ecti e
gene) can ha e a broad spectrum o disease rom asymptom
atic to disease as se ere as males depending on which
chromosome is inacti ated in which organs. This can ma e
con rming the diagnosis o D in a emale with limited cuta
neous and isceral disease uite di cult.
S in lesions are common and in about one uarter o male
patients a dermatologist ma es the diagnosis. The most char
acteristic s in lesions are widespread punctate telangiectatic
ascular papules that on rst inspection suggest purpura but
are actually angio eratomas. Some show hyper eratotic tops
but these are less prominent than in other orms o angio era
toma. Angio eratomas occur in o male and o emale
patients with D. The a erage age o onset in males is about
age and in emales about years later. Lesions can be
present as early as age year. Lesions tend to occur in the
bathing trun area rom the umbilicus to the genitalia
where they may be present in large numbers. Smaller macular
angiomas are seen especially on the pro imal limbs palms
and soles around the nail olds o the digits and on the er
milion border o the lips ( ig. ). Telangiectasias occur in
about o men presenting about age and in women
about age . Vascular tortuosities o the upper eyelid are seen
in o D patients with showing microaneurysms.
The ophthalmologist should e amine or these lesions when
screening or the characteristic corneal opacities. The ascular
lesions can be treated with intense pulsed light or arious
ascular lasers.
ther s in mani estations o D include lower limb edema
and lymphedema. Leg ulceration can occur. air growth is
scanty. ypohidrosis is reported by or more o male and
about one third o emale patients starting in their twenties.
Fig. 26-28 Fabry disease.
532
tahir99 - UnitedVRG
Anhidrosis occurs in o male patients. eat intolerance
can occur. About
plain o hyperhidrosis.
o emale and o male patients com
Visceral disease is common especially o the idneys
cardio ascular system ner ous system and G tract. nly
one organ may be in ol ed. Proteinuria ollowed by renal
ailure may begin as early as the second decade and
typically presents around age . Cardio ascular e ents
(myocardial in arction arrhythmia angina congesti e heart
ailure) typically appear at about age contributing to pre
mature mortality. About o men and women ha e a
cerebro ascular accident (stro e) at about age . About
o cryptogenic stro es are caused by undiagnosed
D. Abdominal pain nausea omiting and diarrhea can all
occur.
europathic pain is the most common initial presentation
a ecting about two thirds o D patients. t may begin in child
hood but its nonspeci c nature and the lac o physical nd
ings delay the diagnosis usually by more than a decade until
other stigmata appear. Thermohypesthesia is o ten present.
The acroparesthesia or burning pain a ects primarily the
longest ner es and is se erest on the hands and eet. t may
be transient or may last or hours. Treatment is as or neuropa
thy with tricyclics gabapentin capsaicin and anticon ul
sants. About o D patients de elop carpal tunnel
syndrome. Cramps and asciculation may be the presenting
neurologic symptoms. emale patients may be misdiagnosed
as ha ing multiple sclerosis.
Distincti e whorl li e opacities o the cornea occur in
o patients and de elop characteristic spo eli e cataracts
in the posterior capsular location. Telangiectasias may be
present on the con uncti a and in the eye.
The diagnosis o D may be con rmed by nding dimin
ished le els o α galactosidase A in leu ocytes serum bro
blasts or amniotic uid cells. Less than en yme acti ity
is usually detected in a ected males. n emales the diagnosis
re uires the identi cation o a genetic mutation in the L
gene. This can be uite di cult i an a ected male relati e is
not identi ed since hundreds o L mutations ha e thus ar
been described that cause D.
istologically there is dilation o capillaries in the papillary
dermis resulting in endothelium lined lacunae lled with
blood and surrounded by acanthotic and hyper eratotic epi
dermis. lectron microscopy re eals characteristic electron
dense bodies in endothelial cells pericytes erector pili muscles
and broblasts. They are also present in normal s in o a ected
adults and children.
n yme replacement therapy is sa e and can re erse sub
strate storage in the lyso yme. RT leads to a reduction in
neuropathic pain relie o G symptoms and stabili ation o
cardiomyopathy; le t entricular mass decreases. Stro e and
ascular coronary disease still occur but perhaps at a lower
rate. arly treatment may be more e ecti e in pre enting pro
gression o D.
Although widespread angio eratomas are typical o
D patients with other rare autosomal recessi e lysosomal
storage diseases such as galactosialidosis aspartylglycos
aminuria G gangliosidosis (β galactosidase de ciency
which may also mani est e tensi e dermal melanocytosis)
and α acetylgalactosaminidase de ciency ( an a i disease)
ha e been reported to ha e abry li e angio eratomas. Also
se eral patients with no detectable en yme de ciency ha e
been reported including a amily with autosomal dominant
inherited abry li e angio eratomas associated with arterio
enous mal ormations. t should be emphasi ed that there are
many normal patients who ha e widespread small petechia
li e lesions that erupt in adulthood a ariant o cherry
angiomas.

FUCOSIDOSIS
Angio eratomas identical to those o abry disease occur in
types and o this rare lysosomal storage disease. ucosi
dosis can be distinguished clinically by the re uent presence
o acial dysmorphism se ere mental retardation wea ness
spasticity and sei ures. The most se erely a ected patients
die in childhood (type ) without the de elopment o typical
angio eratomas. Patients with type disease ha e se ere
spondyloepiphyseal dysplasia and normal intelligence. The
adolescent type patient can also ha e angio eratomas.
ucosidosis is autosomal recessi e and is caused by a de
ciency in α L ucosidase usually detected in leu ocytes.
SIALIDOSIS
Sialidosis (mucolipidosis type ) is an autosomal recessi e
lysosomal storage disease caused by mutations in the sialidase
gene EU . Two types are described the se erest o which is
the in antile orm (type ) in which the children die within
the rst years o li e. Type sialidosis is less se ere and is
characteri ed by mental retardation myoclonus cerebellar
ata ia hypotonia s eletal abnormalities and acial dysmor
phism. Angio eratoma can occur.
β-MANNOSIDASE DEFICIENCY
This rare autosomal recessi e lysosomal storage disease o
glycoprotein metabolism is caused by a de ciency o β
mannosidase that results in the accumulation o a characteris
tic disaccharide in the lysosomes which may also be ound in
the urine. n addition to the abry li e angio eratomas mental
retardation hearing loss aggressi e beha ior peripheral neu
ropathy recurrent in ections epilepsy coarse acies and s el
etal abnormalities are o ten present.
Böttcher T, et al: Fabry disease: underestimated in the differential
diagnosis of multiple sclerosis. PLoS One 2013; 8:e71894.
Canafoglia L, et al: Expanding sialidosis spectrum by genome-wide
screening. J Am Acad Neurol 2014; 82:2003.
Ferraz MJ, et al: Gaucher disease and Fabry disease: new markers and
insights in pathophysiology for two distinct glycosphingolipidoses.
Biochem Biophys Acta 2014; 1841:811.
Juan P, et al: Fabry disease: multidisciplinary evaluation after 10 years
of treatment with agalsidase beta. JIMD Rep 2014; 16:7.
Kanitakis J, et al: Fucosidosis with angiokeratoma:
immunohistochemical and electron microscopic study of a new case
and literature review. J Cutan Pathol 2005; 32:506.
Mahmud HM: Fabry’ s disease: a comprehensive review on
pathogenesis, diagnosis and treatment. J Pak Med Assoc 2014;
64:189.
Michaud L: Vascular tortuosities of the upper eyelid: a new clinical
finding in Fabry patient screening. J Ophthamol 2013; 2013:207573.
Molho-Pessach V, et al: Angiokeratoma corporis diffusum in human
beta-mannosidosis: report of a new case and a novel mutation. J Am
Acad Dermatol 2007; 57:407.
Morais P, et al: Angiokeratomas of Fabry successfully treated with
intense pulsed light. J Cosmet Laser Ther 2008; 10:218.
Nakai K, et al: Multiple leg ulcers in a patient with Fabry disease. J Eur
Acad Dermatol Venereol 2008; 22:382.
Nance CS, et al: Later-onset Fabry disease: an adult variant presenting
with the cramp-fasciculation syndrome. Arch Neurol 2006; 63:453.
Rombach SM, et al: Natural course of Fabry disease and the
effectiveness of enzyme replacement therapy: a systematic review and
meta-analysis. J Inherit Metab Dis 2014; 37:341.
Toyooka K: Fabry disease. Handb Clin Neurol 2013; 113:1437.
Tsukadaira A, et al: Diagnosis of fucosidosis through a skin rash. Intern
Med 2005; 44:907.
Van der Tol L, et al: A systematic review on screening for Fabry disease:
prevalence of individuals with genetic variants of unknown significance.
J Med Genet 2014; 51:1.
Necrobiosis lipoidica/necrobiosis lipoidica diabeticorum
SKIN DISORDERS IN DIABETES MELLITUS
S in lesions are common in diabetic patients with two thirds
or more ha ing at least one s in nding. erosis appears to be
particularly common a ecting o those with type dia
betes. eratosis pilaris is also common a ecting more than
o diabetic patients. ther speci c cutaneous ndings o
diabetes are discussed ne t.
NECROBIOSIS LIPOIDICA/NECROBIOSIS
LIPOIDICA DIABETICORUM
ecrobiosis lipoidica ( L) is characteri ed by well
circumscribed rm depressed wa y yellow brown pla ues
usually o the anterior shin. Although L can occur in persons
without diabetes mellitus o cases o L occur in insulin
dependent (type ) diabetic patients and occur in persons
at ris or the de elopment o diabetes (who ha e glucose
intolerance or a amily history o diabetes). L occurs in the
setting o diabetes it is called necrobiosis lipoidica diabetico
rum ( LD). Women are a ected three times more o ten than
men; the condition usually appears between ages and but
may occur in children or elderly people as well. The a erage
age o onset is or all diabetic patients but years on
a erage in insulin dependent patients and in non insulin
dependent patients. Although L is reported to a ect only
. o diabetic patients the pre alence was much higher
(> ) in series o patients with type diabetes. n L
precedes the onset o ran diabetes by an a erage o years.
Control o the diabetes does not in uence the course o the L.
The earliest changes are small sharply bordered ele ated
red papules that may be capped by a slight scale and that do
not disappear under diascopic pressure. Later the lesions
de elop into irregularly round or o al lesions with well
de ned borders and a smooth glistening (gla ed) sur ace. The
center becomes depressed and sul ur yellow so that a rm
yellowish lesion orms surrounded at times by a iolet red or
pin border. n the yellow portion numerous telangiectases
and ectatic eins are e ident. lceration occurs in one third o
LD patients. n an unusual case the pla ues were studded
with e ophytic nodules resembling tuberous anthomas. This
patient had mar ed hyperlipidemia perhaps contributing to
the morphology. Rarely s uamous cell carcinoma may occur
in chronic ulcers.
The most common location o the lesions is the shins ( ig.
). uch less o ten lesions will appear on the orearms
and rarely lesions ha e been reported on the trun ace scalp
palms and soles.
istologically well de eloped lesions o L demonstrate
a super cial deep and interstitial in ammatory process
that in ol es the whole reticular dermis and o ten the pan
niculus. Because the dermis is rm punch biopsy specimens
appear rectangular rather than tapered. The in ammatory
cells include lymphocytes histiocytes multinucleate giant
cells and plasma cells. At low magni cation there are layered
palisaded granulomas with pale pin degenerated collagen
alternating with amphophilic staining histiocytes. n contrast
to granuloma annulare mucin is not increased in the centers
o the granulomas and there is no normal dermis in L
lesions. Between granulomas in granuloma annulare the col
lagen pattern is relati ely normal although in ammatory cells
533
 Fig. 26-29 Necrobiosis
26 lipoidica diabeticorum.
Errors in Metabolism
may be present. n L the o erlying epidermis tends to be
thinned with loss o the normal rete ridge pattern.
Treatment o LD a ter control o the diabetes is achie ed
is not completely satis actory. Pioglita one treatment may be
bene cial. nitial therapy is superpotent topical corticosteroids
with occlusion. Topical calcineurin inhibitors can also be e ec
ti e. ntralesional in ections o triamcinolone suspension into
the in ammatory papules and acti e ad ancing edges can be
uite e ecti e. n ection into the yellow center is o little bene t
and may result in ulceration. t had been proposed that LD
is caused by the microangiopathy o diabetes. or this reason
agents designed to impro e circulation ha e been used at
times with success. These include low dose aspirin nicotin
amide pento i ylline and dipyridamole. The blood ow in
lesions o LD is normal howe er suggesting that this is
better considered as an in ammatory dermatosis. Photother
apy including P VA and VA has been e ecti e in select
patients. ral immunomodulatory therapy should be consid
ered in patients unresponsi e to topical treatment. Antima
larial treatment and thalidomide are nonimmunosuppressi e
options that would not alter blood sugar control. Systemic
anti in ammatories reported to be e ecti e in select cases
include systemic corticosteroids mycophenolate mo etil
( ) and cyclosporin A. T inhibitors (speci cally in i
imab and etanercept) ha e been e ecti e in re ractory cases
either systemically or by intralesional in ection. owe er
patients being treated with T inhibitors or other conditions
ha e de eloped LD similar to the parado o patients who
ta e T inhibitors de eloping psoriasis. yperbaric o ygen
may be used or patients with chronic ulceration. n se ere
cases with persistent ulceration e cision and s in gra ting
ha e been e ecti e although the LD may recur in or at the
edges o the gra ts. Despite initial reports o success photody
namic therapy only impro es about one third o treated
patients. Pancreas idney transplantation led to resolution in
one case but the patient also recei ed prednisone and
tacrolimus orally.
Chatterjee N, et al: An observational study of cutaneous manifestations
in diabetes mellitus in a tertiary care hospital of eastern India. Indian J
Endocrinol Metab 2014; 18:217.
Chung CG, et al: Necrobiosis lipoidica occurring in a patient with
rheumatoid arthritis on concurrent tumor necrosis factor-α inhibitor. Int
J Dermatol 2014; Apr 2. [Epub ahead of print.]
534
tahir99 - UnitedVRG
Franklin C, et al: Ulcerated necrobiosis lipoidica as a rare cause for
chronic leg ulcers: case report series of ten patients. Int Wound J
2013; Oct 7. [Epub ahead of print.]
Grillo E, et al: Necrobiosis lipoidica. Aust Fam Physician 2014;
43:129.
Kato M, et al: Necrobiosis lipoidica with infiltration of Th17 cells into
vascular lesions. J Dermatol 2014; 41:459.
Kurdi AT: Bullosis diabeticorum. Lancet 2013; 382:e31.
Murao K: Photodynamic therapy for necrobiosis lipoidica is an
unpredictable option: three cases with different results. Int J Dermatol
2013; 52:1567.
Murphy-Chutorian B, et al: Dermatologic manifestations of diabetes
mellitus: a review. Endocrinol Metab Clin North Am 2013; 42:869.
Quondamatteo F: Skin and diabetes mellitus: what do we know? Cell
Tissue Res 2014; 355:1.
Reid SD, et al: Update on necrobiosis lipoidica: a review of etiology,
diagnosis, and treatment options. J Am Acad Dermatol 2013;
69:783.
Salazar-Nievas M, et al: Cutaneous indurated plaque on the abdomen
associated with diabetes mellitus. Aust Fam Physician 2013; 42:876.
Schilling WH, et al: Cutaneous stigmata associated with insulin
resistance and increased cardiovascular risk. Int J Dermatol 2014;
53:1062.
Shenavandeh S, et al: Diabetic muscle infarction and diabetic
dermopathy two manifestations of uncontrolled prolong diabetes
mellitus presenting with severe leg pain and leg skin lesions. J
Diabetes Metab Disord 2014; 13:38.
Uva L, et al: Squamous cell carcinoma arising in ulcerated necrobiosis
lipoidica diabeticorum. Int Wound J 2013; Dec 26. [Epub ahead of
print.]
OTHER DIABETIC DERMADROMES
n addition to necrobiosis lipoidica there are many cutaneous
signs in this common endocrinopathy.
Diabetic dermopathy (shin spots)
Dull red papules that progress to small well circumscribed
round atrophic hyperpigmented lesions on the shins are a
common cutaneous sign o diabetes occurring in up to o
diabetic patients. The lesions are twice as common in men;
o diabetic men o er age ha e diabetic dermopathy.
Lesions begin on the lower e tremities as crops o our or e
dull red macules . cm in diameter. As the lesions resol e
they become shallow depressed and hyperpigmented scars.
Although shin spots occur indi idually in people who do not
ha e diabetes i our or more are present the speci city is
high or diabetes.
Diabetic bullae
onin ammatory spontaneous painless blistering most
o ten in acral locations is characteristic o diabetic bullae ( ig.
). Lesions tend to in ol e the lower legs and to be cm
or more in diameter. The incidence is . per year. n one
series o diabetic patients ( . ) de eloped diabetic
bullae o er a year period. n many cases lesions heal spon
taneously in wee s usually without scarring. owe er
lesions may be complicated at times by chronic ulceration.
Aggressi e and cautious management with dressings and dia
betic oot care is re uired. inor amputations may be needed.
Lesions appear a ter periods o relati e hypoglycemia perhaps
e plaining the clinical resemblance o diabetic bullae to pres
sure bullae.
Lesions are subepidermal. lectron microscopic studies
show separation at the lamina lucida le el. D is negati e.
There is a reduced threshold to suction induced blistering in
 Fig. 26-30 Bullous
eruption of diabetes.
Fig. 26-31 Carotenemia, yellow palm shown next to normal palm.
insulin dependent (type ) diabetic patients. Treatment is
obser ation diabetic control aspiration o the bulla to pre ent
e pansion by hydrostatic pressure and aggressi e wound
management to optimi e healing and pre ent in ection.
Carotenosis
Carotenosis is a yellowish discoloration o the s in especially
o the palms and soles ( ig. ) which is sometimes seen
in diabetic patients.
Limited joint mobility and waxy skin
Limited oint mobility (LJ ) and wa y s in are important not
only because o the pre alence o these conditions in
diabetic patients with long standing disease but also because
they are associated with micro ascular complications such as
nephropathy and retinopathy. Joint symptoms begin with
limitation o oint mobility in the th nger at the metacarpo
phalangeal and pro imal oints and progress radially to the
other ngers. The condition is bilateral symmetric and pain
less. Dupuytren s contractures and palmar brosis may be
associated. n ol ement o the eet also occurs and is thought
to contribute to the de elopment o chronic ulcerations.
Such open sores on the neuropathic micro ascularly compro
Citrullinemia
mised in ection prone diabetic oot pose a constant threat to
li e and limb.
Other associated conditions
in patients with diabetes
Various abnormalities associated with diabetes are erysipelas
li e erythema o the legs or eet; sweating disturbances; par
esthesias o the legs; mal per orans ulcerations; a predisposition
to certain in ections such as mucormycosis group B strepto
coccal in ections nonclostridial gas gangrene and malignant
e ternal otitis resulting rom Pseu omonas; disseminated gran
uloma annulare; erupti e anthomas; clear cell syringomas;
rubeosis o the ace; lipoatrophy or lipohypertrophy at sites o
insulin in ection; ac uired per orating disorders; acanthosis
nigricans; s in tags; and nger pebbling. Pruritus is common
in adult diabetic patients typically o the central trun . t is
associated with e idence o diabetic neuropathy and probably
represents a orm o neuropathic pruritus. Treatment is similar
to that or neuropathy starting with gabapentin.
Bello F, et al: Two cases of bullosis diabeticorum following long-
distance journeys by road: a report of two cases. Case Rep Endocrinol
2012; 2012:367218.
Kurdi AT: Bullosis diabeticorum. Lancet 2013; 382:e31.
Lopez PR, et al: Bullosis diabeticorum associated with a prediabetic
state. South Med J 2009; 102:643
Sehgal VN, et al: Noninsulin-dependent, type II diabetes mellitus-related
dermatoses. Part II. Skinmed 2011; 9:302.
Silverberg NB, Lee-Wong M: Generalized yellow discoloration of the skin.
The diagnosis: carotenemia. Cutis 2014; 93:E11.
Weerasuriya T, et al: Bullosis diabeticorum following carpal tunnel
decompression. BMJ Case Rep 2012; 2012.
Zhang AJ, et al: Bullosis diabeticorum: case report and review. N Z Med
J 2013; 126:91.
OTHER METABOLIC DISORDERS
CITRULLINEMIA
Citrullinemia occurs in two orms. Type is caused by a de
ciency o the en yme argininosuccinic acid synthetase ( SS
gene). This en yme con erts citrulline and aspartic acid to
argininosuccinic acid as a part o the urea cycle. Low plasma
arginine le els result and the hypothesis is that since eratin
is arginine dermatitis may occur. eonates who present
with se ere de ciencies and hyperammonemic crises may
de elop erosi e erythematous scaling patches and pla ues
prominent in the perioral lower abdominal diaper and
buttoc regions. This eruption clears with arginine supple
mentation. Short sparse hair may also be present. Citrul
linemia type is caused by a de ect in the SCL gene and
is seen primarily in ast Asia usually presenting in adoles
cence or adulthood.
n carbamoyl phosphate synthetase de ciency low plasma
arginine le els may also occur and similar cutaneous ndings
ha e been reported in this second metabolic de ect o the urea
cycle.
Diets high in arginine will heal the s in lesions.
Engel K, et al: Mutations and polymorphisms in the human
argininosuccinate synthetase (ASS1) gene. Hum Mutat 2009;
30:300.
535
 Fiermonte G, et al: An adult with type 2 citrullinemia presenting in
26
Europe. N Engl J Med 2008; 358:1408.
HARTNUP DISEASE
Errors in Metabolism
artnup disease is an inborn error o tryptophan e cretion
named a ter the artnup amily in whom it was rst noted.
t is the second most common inherited aminoaciduria a ter
phenyl etonuria. The characteristic ndings are a pellagrali e
dermatitis ollowing e posure to sunlight intermittent cere
bellar ata ia psychosis and constant aminoaciduria.
The dermatitis occurs on e posed parts o the s in chie y
the ace nec hands and legs. The erythematous scaly patches
are up into a hot red e udati e state a ter e posure to sun
light ollowed by hyperpigmentation. Stomatitis and ul itis
also occur. The disease becomes milder with increasing age.
Rarely an acrodermatitis enteropathica li e eruption with
normal inc le els may occur in patients with artnup disease.
artnup disease is an autosomal recessi e trait. Large
amounts o neutral amino acids including tryptophan
are present in the urine establishing the diagnosis. artnup
disease is caused by mutations in the SLC gene. The
SLC A en yme transports neutral amino acids across
the apical membrane o epithelial cells in the gut and idneys.
The s in lesions respond to niacinamide but the neurologic
disease may not impro e.
Orbak Z, et al: Hartnup disease masked by kwashiorkor. J Health Popul
Nutr 2010; 28:413.
Sander CS, et al: Severe exfoliative erythema of malnutrition in a child
with coexisting coeliac and Hartnup’ s disease. Clin Exp Dermatol
2009; 34:178.
PROLIDASE DEFICIENCY
Prolidase de ciency (PD) is an autosomal recessi e inherited
inborn error o metabolism caused by mutations in the PEPD
gene. Prolidase clea es dipeptides containing C terminal
proline or hydro yproline. When this en yme is de cient the
normal recycling o proline residues obtained rom collagen
degradation is impaired. A buildup o iminodipeptides results
with disturbances in connecti e tissue metabolism and e cre
tion o large amounts o iminodipeptides in the urine. Clini
cally o patients ha e some dermatologic mani estations.
The most important cutaneous signs which almost always
appear be ore the a ected person is years old are s in
ragility; ulceration and scarring o the lower e tremities; pho
tosensiti ity and telangiectasia; poliosis; scaly erythematous
maculopapular and purpuric lesions; and thic ening o the
s in with lymphedema o the legs. Some o these signs result
rom de ecti e collagen metabolism in the dermis and around
dermal essels. Systemic signs and symptoms include mental
de ciency splenomegaly and recurrent in ections. An unusual
acial appearance is noted at times with low hairline rontal
bossing and saddle nose. About o patients with pro
lidase de ciency meet American Rheumatology Association
(ARA) criteria or the diagnosis o systemic lupus erythema
tosus (SL ). Antinuclear antibodies (A As) e tractable
nuclear antigen ( A) and anti dsD A may be positi e; C
and C are low; and cytopenias are present. Because C has
a high proline content a relati e de ciency o unctional C
may e plain the high re uency o lupus erythematosus (L )
in these patients.
Prolidase de ciency is con rmed by determining prolidase
acti ity in erythrocytes leu ocytes or broblasts in culture or
by se uence analysis o the PEPD gene. n long standing ulcer
ations s uamous cell carcinomas may occur.
536
tahir99 - UnitedVRG
Butbaul Aviel Y, et al: Prolidase deficiency associated with systemic
lupus erythematosus (SLE): single site experience and literature review.
Pediatr Rheumatol 2012; 10:18.
Dunn R, Dolianitis C: Prolidase deficiency: the use of topical proline for
treatment of leg ulcers. Australas J Dermatol 2008; 49:237.
Fimiani M, et al: Squamous cell carcinoma of the leg in a patient with
prolidase deficiency. Br J Dermatol 1999; 140:362.
PHENYLKETONURIA
Phenyl etonuria (P ) is an autosomal recessi e disorder o
phenylalanine metabolism caused by a de ciency in the
en yme phenylalanine hydro ylase. Phenylalanine is not
metaboli ed to tyrosine. P is the most common orm o
inherited aminoaciduria a ecting in li e births in the
nited States. t is characteri ed by mental de ciency; epilep
tic sei ures; pigmentary dilution o s in hair and eyes; pseu
doscleroderma; and dermatitis ( ig. ). t is most common
in white persons.
A ected children are blue eyed with blond hair and air
s in. They are usually e tremely sensiti e to light and about
ha e an ec ematous dermatitis. t is clinically similar to
atopic dermatitis with a predilection or the e ures. The
dermatitis is worst in the youngest patients may impro e with
dietary treatment and has been e acerbated by phenylalanine
challenge in a carrier o the recessi e gene. ndurations o the
thighs and buttoc s are present early in in ancy and increase
with time. A ter many years the lesions so ten and become
atrophic.
Blood le els o phenylalanine are high. The presence o phe
nylpyru ic acid in the urine is demonstrated by a characteris
tic deep green color when a ew drops o erric chloride
solution are added. Green diapers occur in histidinemia as
well as in P .
n de eloped countries uni ersal screening or P is prac
ticed so dietary therapy with phenylalanine restriction is insti
tuted. Sapropterin dihydrochloride may also be gi en. This
pre ents the mani estations o the disease. compliance is
poor the mani estations including ec ema may de elop at
any age ollowed by impro ement o the s in with reinstitu
tion o the diet.
Al-Mayouf SM, Al-Owain MA: Progressive sclerodermatous skin changes
in a child with phenylketonuria. Pediatr Dermatol 2006; 23:136.
Belloso LM, et al: Cutaneous findings in a 51-year-old man with
phenylketonuria. J Am Acad Dermatol 2003; 49:S190.
Longo N, et al: Single-dose, subcutaneous recombinant phenylalanine
ammonia lyase conjugated with polyethylene glycol in adult patients
Fig. 26-32 Light-skinned, light-haired phenylketonuria patient with
dermatitis. (Courtesy of Dr. Jeff Miller.)
 with phenylketonuria: an open-label, multicenter, Phase 1 dose-
escalation trial. Lancet 2014; 384:37.
Somaraju UR, Merrin M: Sapropterin dihydrochloride for phenylketonuria.
Cochrane Database Syst Rev 2012; 12:CD008005.
ALKAPTONURIA AND OCHRONOSIS
Al aptonuria inherited as an autosomal recessi e trait is
caused by the lac o renal and hepatic homogentisic acid
o idase the en yme necessary or the catabolism o homogen
tisic acid ( GA) a product o tyrosine and phenylalanine
metabolism. cess GA is e creted in the urine and depos
ited in connecti e tissues throughout the body especially the
cartilage. The urine is dar and becomes blac on standing.
en with al aptonuria outnumber women by . al e replacement may be necessary. itisinone can greatly
or many years the dar urine may be the only indication
o the presence o al aptonuria. n the meantime large
amounts o GA accumulate in the body tissues. By the third
decade o li e the deposition o pigment becomes apparent.
The early sign is the pigmentation o the sclera ( sler s sign;
ig. ) and the cartilage o the ears ( ig. ). Later the
cartilage o the nose and tendons especially those on the
hands becomes discolored.
Blue or mottled brown macules appear on the s in. The
bluish macules ha e a predilection or the ngers ears nose
genital regions apices o the a illae and buccal and aginal
mucosae. Palmoplantar pigmentation may occur and may be
accentuated along the thenar and hypothenar eminences as
pigmented pitted papules. The transgradience o the inde
ngers is also a ected closely resembling degenerati e col
lagenous pla ues the hand and acro eratoelastoidosis. The
apocrine sweat glands are rich in ochronotic pigment granules
and the intradermal in ection o epinephrine into the s in o
the a illary ault will yield brown blac sweat droplets in the
ollicular ori ces. The cerumen is o ten blac . istologically
Fig. 26-33 Osler’s sign.
Fig. 26-34 Ochronotic pigmentation of ear cartilage.
there are large irregular ochre bodies within the reticular
dermis. These represent degenerated elastic bers with depo
sition o ochronotic pigment and stain blac with crystal iolet
or methylene blue.
chronotic arthropathy rst in ol es the a ial spine oints
Alkaptonuria and ochronosis
ollowed by the nees shoulders and hips. Radiographs show
a characteristic appearance o early calci cation o the inter
ertebral dis and later narrowing o the inter ertebral spaces
with e entual dis collapse. Tendon rupture may occur. eart
disease results rom GA deposition in the aortic and mitral
al es. Renal disease is caused by GA stones in the urinary
system and can progress to renal ailure.
There is no e ecti e treatment or al aptonuria. Dietary
restriction o tyrosine and phenylalanine is recommended but
may not pre ent progression o disease. Joint and cardiac
reduce GA e cretion but does not appear to be e ecti e once
oint disease is present. n mouse models howe er nitisinone
treatment rom birth pre ented tissue deposition o the GA
and de elopment o oint disease suggesting early treatment
might lead to stabili ation o disease. Tyrosine eratopathy
can result rom nitisinone treatment. Li e span is generally
una ected.
Exogenous ochronosis
Topically applied phenolic intermediates such as hydro ui
none carbolic acid (phenol) picric acid and resorcinol
may produce e ogenous ochronosis ( ig. ). en o er
the counter hydro uinone can produce ochronosis i used
regularly or a long period. ydro uinone speci cally inhibits
the en yme homogentisic acid o idase locally resulting in
accumulation o this substance on the collagen bers in tissues
where hydro uinone is applied. All s in types can be a ected
but ethnic groups with the highest pre alence o melasma and
hydro uinone use are primarily reported A rican Americans
A ricans and Asians. Since most patients use the hydro uinone
to treat melasma ndings o melasma may o erlay the s in
ndings o e ogenous ochronosis. The typical ndings are
gray brown or blue blac macules usually o er the ygomatic
regions. Ca iarli e hyperchromic pinpoint papules may occur
which on dermoscopy can be seen associated with ollicular
openings. Con ettili e depigmentation ( rom the hydro ui
none) may be admi ed with the hyperpigmentation. istologi
cally e ogenous ochronosis and al aptonuria ha e identical
changes on s in biopsy ( ig. ). Treatment is less than sat
is actory. Stopping the application o hydro uinone may lead
Fig. 26-35 Exogenous ochronosis.
537

26
Errors in Metabolism
Fig. 26-36 Large, ochre bodies in the dermis in exogenous
ochronosis.
to impro ement. switched lasers has shown early promis
ing but inconsistent impro ement.
Aquaron R: Alkaptonuria: a very rare metabolic disorder. Indian J
Biochem Biophys 2013; 50:339.
Bellew SG, et al: Treatment of exogenous ochronosis with a Q-switched
alexandrite (755 mm) laser. Dermatol Surg 2004; 30:555.
Gil I, et al: Dermoscopic and reflectance confocal microscopic features
of exogenous ochronosis. Arch Dermatol 2010; 146:1021.
Introne WJ, et al: A 3-year randomized therapeutic trial of nitisinone in
alkaptonuria. Mol Genet Metab 2011; 103:307.
Khaled A, et al: Endogenous ochronosis: case report and a systematic
review of the literature. Int J Dermatol 2011; 50:262.
Liu WC, et al: Exogenous ochronosis in a Chinese patient: use of
dermoscopy aids early diagnosis and selection of biopsy site.
Singapore Med J 2014; 55:e1.
Mishra SN, et al: Diagnostic utility of dermatoscopy in hydroquinone-
induced exogenous ochronosis. Int J Dermatol 2013; 52:413.
Moche MJ, et al: Cutaneous annular sarcoidosis developing on a
background of exogenous ochronosis: a report of two cases and
review of the literature. Clin Exp Dermatol 2009; 35:399.
Preston AJ, et al: Ochronotic osteoarthropathy in a mouse model of
alkaptonuria, and its inhibition by nitisinone. Ann Rheum Dis 2014;
73:284.
Ranganath LR, et al: Natural history of alkaptonuria revisited analyses
based on scoring systems. J Inherit Metab Dis 2011; 34:1141.
Ranganath LR, et al: Recent advances in management of alkaptonuria.
J Clin Pathol 2013; 66:367.
Singh A, Ramesh V: Exogenous ochronosis. Indian J Med Res 2014;
139:327.
Tan SK: Exogenous ochronosis in ethnic Chinese Asians: a
clinicopathological study, diagnosis and treatment. J Eur Acad
Dermatol Venereol 2011; 25:842.
Thomas M, et al: Acral pigmentation in alkaptonuria resembling
degenerative collagenous plaques of the hands: a report of five cases.
J Am Acad Dermatol 2010; 65:e45.
Turgay E, et al: Endogenous ochronosis. Clin Exp Dermatol 2009;
34:e865.
Zaraa I, et al: Endogenous ochronosis with a fatal outcome. J Cutan
Med Surg 2012; 16:357.
WILSON’S DISEASE
(HEPATOLENTICULAR DEGENERATION)
Wilson s disease is an autosomal recessi e derangement o
copper transport. The disease is caused by dys unction
o a copper transporting en yme P type adenosine triphos
phatase (ATP B) which is re uired to e crete copper into the
bile. This leads to accumulation o copper in the li er brain
cornea and idney. A ected persons de elop hepatomegaly
splenomegaly and neuropsychiatric changes. Slurred speech
538
tahir99 - UnitedVRG
a s uea y oice sali ation dysphagia tremors incoordina
tion and spasticity may all occur. There is progressi e atal
hepatic and central ner ous system degeneration.
A ure lunulae ( s y blue moons ) o the nails occur in
o patients and the smo y greenish brown ayser leischer
rings de elop at the edges o the corneas. yperpigmentation
de elops on the lower e tremities in most patients. A ague
greenish discoloration o the s in on the ace nec and geni
talia may also be present. An idiopathic blistering eruption
that ceased with treatment o Wilson s disease has been
reported. S in changes o cirrhosis ( ascular spiders and
palmar erythema) may occur. Low ceruloplasmin le el in the
serum leads to the suspected diagnosis along with ele ated
hour urinary copper e cretion and ele ated ree serum
copper. Ten percent o carriers or Wilson s disease ha e a low
ceruloplasmin le el so additional tests should be per ormed
to con rm the diagnosis.
The treatment is a low copper diet o ten with agents that
bind copper and enhance its e cretion rom the body.
D Penicillamine or g day orally remo es copper by chelat
ing it. Potential side e ects include pemphigus cutis la a
and elastosis per orans serpiginosa which has been reported
repeatedly in Wilson patients recei ing penicillamine. Trien
tine another copper chelator enhances copper e cretion. t has
less to icity but is somewhat less e ecti e than D penicillamine.
inc supplementation leads to increased metallothionein in the
gut and li er. This leads to more copper e cretion in the stool.
inc can be gi en at the same time as D penicillamine. Treat
ment must be continued or li e.
Harada M: Pathogenesis and management of Wilson disease. Hepatol
Res 2014; 44:395.
TYROSINEMIA II (RICHNER-HANHART SYNDROME)
Tyrosinemia is an autosomal recessi e syndrome resulting
rom a de ciency o hepatic tyrosine aminotrans erase an
important en yme in the degradation o tyrosine and phenyl
alanine. t is caused by mutations in the gene. The diag
nosis is con rmed by identi ying ele ated le els o serum
tyrosine. Clinical eatures are mild to se ere eratitis and
hyper eratotic erosi e lesions o palms and soles o ten with
mild mental retardation. Photophobia and tearing usually
occur as the eratitis begins and ultimately neo asculari a
tion is seen. Pain ul palmar and plantar hyper eratosis may be
the only mani estation. The ngertips and the hypothenar and
thenar eminences are primarily a ected on the palms. nitially
only the soles may be a ected with hyper eratosis mainly
o er the tips o the digits and on weight bearing sur aces. n
any child presenting with palmoplantar eratoderma the
diagnosis o tyrosinemia type must be considered. A low
tyrosine low phenylalanine diet may impro e or pre ent the
eye and s in lesions but it may or may not bene t established
mental retardation.
Meissner T, et al: Richner-Hanhart syndrome detected by expanded
newborn screening. Pediatr Dermatol 2008; 25:378.
Pasternack SM, et al: Identification of two new mutations in the TAT
gene in a Danish family with tyrosinaemia type II. Br J Dermatol 2009;
160:704.
Valikhami M, et al: Oculocutaneous tyrosinaemia or tyrosinaemia type
2: a case report. J Eur Acad Dermatol Venereol 2006; 20:591.
HURLER SYNDROME
(MUCOPOLYSACCHARIDOSIS I)
urler syndrome or gargoylism is an autosomal recessi e
lysosomal storage disease o mucopolysaccharide metabolism.
A de ciency o α iduronidase is the causati e de ect. This
en yme is responsible or the brea down o heparan sul ate
and dermatan sul ate. All patients ha e undetectable en yme
acti ity by current assays yet there is signi cant polymor
phism in the se erity and age o onset. n general cases are

Lafora’s disease
di ided into se ere mucopolysaccharidosis ( PS urler
syndrome) and attenuated PS ( urler Scheie syndrome
Scheie syndrome).
urler syndrome is characteri ed by mental retardation
hepatosplenomegaly umbilical and inguinal hernia genital
in antilism corneal opacities and s in abnormalities. Patients
with urler syndrome ha e acial dysmorphism with a broad
saddle nose thic lips and a large tongue. The s in is thic
ened with ridges and groo es especially on the upper hal
o the body. ine lanugo hair is pro usely distributed all o er
the body. Large coarse hair is prominent especially on the
e tremities. Dermal melanocytosis characteri ed by e tensi e Fig. 26-37 Hunter syndrome papules.
blue pigmentation with both a dorsal and a entral distribu
tion indistinct borders and a persistent or progressi e course
occurs in some patients with lysosomal storage disease includ Fig. 26-38 PAS-stained
ing patients with urler syndrome unter syndrome and inclusions in Lafora’s
G gangliosidosis type . The s eletal system is de ormed disease.
with hydrocephalus yphosis and gibbus (cat bac shape).
The hands are broad and ha e clawli e ngers. The oints are
distorted.
The diagnosis o PS is made by demonstrating ele ated
urinary glycosaminoglycan le els and de cient en yme acti
ity in broblasts leu ocytes serum or blood spots. Prenatal
diagnosis is possible. ematopoietic stem cell transplantation
( SCT) is the most e ecti e treatment or urler syndrome.
t can pre ent mental deterioration i per ormed early enough
(be ore age and be ore de elopmental uotients all below
). Cardiac and oint complications are not pre ented by
SCT. RT with recombinant human α iduronidase (Aldura
yme) is an option in patients who are not candidates or
SCT.
Ashrafi MR, et al: Extensive mongolian spots: a clinical sign merits
special attention. Pediatr Neurol 2006; 34:143.
Behera B, et al: Hurler syndrome with a tuft of hair. Indian J Dermatol
Venereol Leprol 2006; 72:147.
Muenzer J, et al: Mucopolysaccharidosis I: management and treatment
guidelines. Pediatrics 2009; 123:19.

HUNTER SYNDROME
(MUCOPOLYSACCHARIDOSIS II)
unter syndrome is lin ed recessi e lysosomal storage
disease caused by de ciency o the en yme iduronate
sul atase. The pebbly lesions o PS in the s in o the upper
bac nec chest pro imal arms or thighs represent the only
diagnostic s in changes o the mucopolysaccharidoses. The
lesions are rm esh colored to white papules and nodules
which coalesce into a cobblestone or reticular pattern ( ig.
). They generally occur at about age . istologically
the lesions demonstrate increased dermal mucin and meta
chromatic granules in the cytoplasm o dermal broblasts and
at times in eccrine sweat glands and epidermal eratinocytes.
Additionally the dermal melanocytosis pre iously described
or urler syndrome may occur in unter syndrome.
Dermatan sul ate and heparan sul ate are e creted in the
urine in large amounts and the diagnosis o unter syndrome
can be con rmed by absent iduronate sul atase in leu o
cytes. SCT and RT can be use ul in appropriately e aluated
patients.
Ito K, et al: The effect of haematopoietic stem cell transplant on
papules with “pebbly” appearance in Hunter’s syndrome. Br J
Dermatol 2004; 151:207.
Jones SA, et al: Mortality and cause of death in mucopolysaccharidosis
type II: a historical review based on data from the Hunter Outcome
Survey (HOS). J Inherit Metab Dis 2009; 32:534.
Ochiai T, et al: Significance of extensive mongolian spots in Hunter’s
syndrome. Br J Dermatol 2003; 148:1173.
Sakata S, et al: Skin rash with the histological absence of
metachromatic granules as the presenting feature of Hunter syndrome
in a 6-year-old boy. Br J Dermatol 2008; 159:249.
LAFORA’S DISEASE
La ora s disease is an autosomal recessi e orm o progressi e
myoclonic and tonic clonic epilepsy beginning at puberty. t
is characteri ed by myoclonic er s ollowed by progressi e
ata ia dysphagia dysarthria dementia and death in early
adulthood. Diagnosis is established in the proper clinical
setting by demonstration o characteristic PAS positi e cyto
plasmic inclusion bodies in the eccrine ducts a illary apocrine
myoepithelial cells ( ig. ) and peripheral ner es. The
best site to biopsy is the a illa. ther conditions in which
similar polyglucosan inclusions can be seen include normal
aging (amyloid bodies) double athetosis syndrome amyo
trophic lateral sclerosis and glycogen storage disease type V.
539
 Cutaneous mani estations are rare in La ora s disease. Papu
26 lonodular lesions on the ears and indurated thic ened pla ues
on the arms ha e been reported. Large amounts o acid muco
polysaccharides were demonstrated histologically in these
lesions. The disease is caused by mutations o either the
Errors in Metabolism
EPM gene ( o cases) or the L C gene which
encodes ubi uitin ligase. The products o these two genes
orm a comple critical to the regulation o neuronal unction.
This e plains how mutations in either gene lead to the same
phenotype.
Karimipour D, et al: Lafora’s disease. J Am Acad Dermatol 1999;
41:790.
Kecmanović M, et al: Lafora disease: severe phenotype associated with
homozygous deletion of the NHLRC1 gene. J Neurol Sci 2013;
325:170.
CADASIL SYNDROME
Cerebral autosomal dominant arteriopathy with subcortical
in arcts and leu oencephalopathy (CADAS L) is a neuro as
cular disease o young and middle age people. t is the most
common heritable cause o stro e and ascular dementia in
adults. t is caused by mutations in the gene or TC a The gene de ect results in impaired degradation o ery long
transmembrane protein. Children ha e cogniti e impairment;
young adults ha e depression and migraine with aura; and
patients in their orties and ties e perience apathy mood
disturbances and motor disability. ecuti e dys unction
in the late thirties to ties is ollowed by dementia in the
si ties and se enties. There is deposition o a granular osmo
philic material (G ) in the media o arterial walls seen
on electron microscopy. This may be demonstrated by a spe
ci c immunostain. The diagnosis should be con rmed by
genetic testing which will identi y most but not all patients
with CADAS L. ltrastructural e amination o s in biopsy is
restricted to patients with negati e genetic screening and ea
tures highly suggesti e o CADAS L or when genetic testing
is not a ailable.
Chabriat H, et al: CADASIL. Lancet Neurol 2009; 8:643.
Lee YC, et al: The remarkably variable expressivity of CADASIL: report
of a minimally symptomatic man at an advanced age. J Neurol 2009;
256:1026.
Moreton FC, et al: Changing clinical patterns and increasing prevalence
in CADASIL. Acta Neurol Scand 2014; 130:197.
Morroni M, et al: Role of electron microscopy in the diagnosis of
CADASIL syndrome: a study of 32 patients. PLoS One 2013; 8:e65482.
Ratzinger G, et al: CADASIL: an unusual manifestation with prominent
cutaneous involvement. Br J Dermatol 2005; 152:246.
Rumbaugh JA, et al: CADASIL. J Am Acad Dermatol 2000; 43:1128.
Walsh JS, et al: CADASIL. J Am Acad Dermatol 2000; 43:1125.
FARBER DISEASE
Also nown as arber lipogranulomatosis arber disease is
characteri ed by periarticular nodules; oint swelling and
de ormation (usually the initial presentation); a wea hoarse
cry ( rom laryngeal in ol ement); pulmonary ailure; and
motor and mental retardation. t is caused by de ciency o
lysosomal acid ceramidase resulting rom mutations in the
S gene. Progressi e accumulation o ceramide in a ected
tissues results in the complications.
The rubbery subcutaneous nodules ha e a distinct yellowish
hue and are cm in diameter. They are usually located o er
the oints lumbar spine scalp and weight bearing areas. is
tologically these are granulomas. arber disease presents with
a highly ariable spectrum with the most se erely a ected
children dying by age years and mildly a ected children
reaching their teens. There is no correlation between the
540
tahir99 - UnitedVRG
genotype or the residual ceramidase le el and the phenotype.
n more mildly a ected cases that ha e not been diagnosed in
in ancy the periarticular swellings and predominant oint
disease in about one third o patients leads to the incorrect
diagnosis o u enile idiopathic arthritis. An animal model has
allowed treatment strategies to be tested.
Kostik MM, et al: Farber lipogranulomatosis with predominant joint
involvement mimicking juvenile idiopathic arthritis. J Inherit Metab Dis
2013; 36:1079.
Sands MS, et al: Farber disease: understanding a fatal childhood
disorder and dissecting ceramide biology. EMBO Mol Med 2013;
5:799.
Schuchman E: A132: Farber disease explains subset of juvenile
idiopathic arthritis. Arthritis Rheumatol 2014; 66:S173.
ADRENOLEUKODYSTROPHY
(SCHILDER’S DISEASE)
Adrenoleu odystrophy ( ALD) is an lin ed disorder in
which cerebral white matter becomes progressi ely demye
linated and serious adrenocortical insu ciency usually
occurs. ALD is caused by mutations in the CD gene.
chain atty acids (> carbons). S in hyperpigmentation o ten
calls attention to the adrenal disease (Addison s) and mental
deterioration indicates the e en gra er diagnosis o ALD. A
mild ichthyotic appearance to the s in o the trun and legs
and sparse hair with trichorrhe is nodosa li e eatures may
occur. Although males are most se erely a ected emale het
ero ygote carriers can in adulthood de elop Addison s
disease and chronic myelopathy and peripheral neuropathy
o ten with ecal incontinence. S in biopsies may show char
acteristic acuoli ation o eccrine secretory coils (duct cells
being spared) and biopsies o the s in and con uncti a may
show diagnostic cle ts in Schwann cells surrounding myelin
ated a ons. Loren o s oil and pioglita one are potential ther
apies. Bone marrow transplantation may bene t a small
subset o ALD patients.
Berger J, et al: Pathophysiology of X-linked adrenoleukodystrophy.
Biochimie 2014; 98:135.
Chen X, et al: Adult cerebral adrenoleukodystrophy and Addison’s
disease in a female carrier. Gene 2014; 544:248.
Engelen M, et al: X-linked adrenoleukodystrophy in women: a cross-
sectional cohort study. Brain 2014; 137:693.
Morató L, et al: Pioglitazone halts axonal degeneration in a mouse
model of X-linked adrenoleukodystrophy. Brain 2013; 136:2432.
Sassa T, et al: Lorenzo’s oil inhibits ELOVL1 and lowers the level of
sphingomyelin with a saturated very long-chain fatty acid. J Lipid Res
2014; 55:524.
GOUT
Classic gout presents as an acute monoarthritis usually o the
great toe or nee in a middle age to elderly man with hyper
uricemia. n such patients with chronic disease usually present
or more than years monosodium urate monohydrate may
be deposited in the dermal or subcutaneous tissues orming
papules or nodules called tophi ( ig. ). Rarely tophi may
be the initial presentation o gout e en with normal serum
uric acid le els. Gouty tophi ary rom pinhead to pea si ed
or rarely e en baseball si ed. Tophi are typically ound on the
pinna or outer heli o the ears and o er the distal interpha
langeal articulations. Tophi are o a yellow or cream color.
er time tophi tend to brea down and discharge sodium
urate crystals a terward healing and perhaps brea ing down
again. Atypical presentations o gout include nasal bridge
 Fig. 26-40 Lesch-
Nyhan syndrome.

Lesch-Nyhan syndrome
Fig. 26-39 Gouty tophus.

tophi gouty panniculitis (in ammatory subcutaneous nodules LESCH-NYHAN SYNDROME

mimic ing other orms o panniculitis possibly with normal
serum uric acid) and nger pad tophi. When urate crystal
deposition occurs in the dermis the lesions ha e been described
as pustular or intradermal tophi.
The diagnosis o gout is eri ed histologically by nding the
characteristic long needle shaped crystals o monosodium
urate. Because routine processing dissol es these deposits
ation in absolute ethanol or ree ing is optimal or their
demonstration but this is rarely done because most specimens
are submitted in ormalin. Rather μ unstained sections
rom ormalin ed specimens can demonstrate characteristic
crystals under polari ed light. Atypical gout occurs as a poly
articular chronic arthritis o ten o the hands. t occurs e ually
in women and men and there may be tophi re uently o erly
ing eberden nodes at presentation. Another ris group is
organ transplant patients o whom de elop gout. Treat
ment with certain medications has been associated with the
appearance o tophi. These include diuretics methotre ate
cyclosporine and etanercept. Treatment with allopurinol can
result in disappearance o the tophi.
Also nown as u enile gout Lesch yhan syndrome is a rare
lin ed recessi e inherited disorder characteri ed by child
hood hyperuricemia gout tophi ( ig. ) choreoathetosis
progressi e mental retardation and sel mutilation. The cuta
neous lesions are distincti e. assi e sel mutilation o lips
with the teeth occurs. The ngers are also se erely chewed.
The ears and nose are occasionally mutilated. An early diag
nostic clue is orange crystals in the diaper. The blood uric acid
is increased and allopurinol mg day is gi en. There
is a mar ed de ciency in an en yme o purine metabolism
hypo anthine guanine phosphoribosyltrans erase ( GPRT).
Forbess LJ, et al: The broad spectrum of urate crystal deposition:
unusual presentations of gouty tophi. Semin Arthritis Rheum 2012;
42:146.
Meseguer-Yebra C, et al: Joint destruction and presence of small
papules on the palms and soles. Clin Exp Dermatol 2012; 37:450.
Weaver J, et al: Simple non-staining method to demonstrate urate
crystals in formalin-fixed, paraffin-embedded skin biopsies. J Cutan
Pathol 2009; 36:560.

Bonus images for this chapter can be found online at expertconsult.inkling.com

eFig. 26-1 Vulvar amyloidosis.
eFig. 26-2 Macular amyloidosis. (Courtesy of
Dr. Lawrence Lieblich.)
eFig. 26-3 Porphia cutanea tarda.
eFig. 26-4 Osteoma cutis. (Courtesy of Dr. Curt
Samlaska.)
eFig. 26-5 Tuberous xanthomas.
eFig. 26-6 Tendinous xanthomas.
eFig. 26-7 Eruptive xanthomas.
eFig. 26-8 Eruptive xanthomas.
eFig. 26-9 Xanthelasma.
eFig. 26-10 Interdigital xanthomas in
homozygous familial hypercholesterolemia.
eFig. 26-11 Zebra bodies in Fabry disease.
eFig. 26-12 Necrobiosis lipoidica diabeticorum.
eFig. 26-13 Gouty tophus. (Courtesy of Dr.
James Fitzpatrick.)

541
 eFig. 26-1 Vulvar eFig. 26-4 Osteoma
amyloidosis. cutis. (Courtesy of Dr.
Curt Samlaska.)

Lesch-Nyhan syndrome
eFig. 26-5 Tuberous xanthomas.

eFig. 26-6 Tendinous

xanthomas.

eFig. 26-2 Macular amyloidosis. (Courtesy of Dr. Lawrence Lieblich.)

eFig. 26-3 Porphia cutanea tarda.

eFig. 26-7 Eruptive xanthomas.

541.e1

tahir99 - UnitedVRG
26
Errors in Metabolism

eFig. 26-8 Eruptive xanthomas.

eFig. 26-11 Zebra bodies in Fabry disease.

eFig. 26-12
Necrobiosis lipoidica
diabeticorum.

eFig. 26-9 Xanthelasma.

eFig. 26-10 Interdigital

xanthomas in
homozygous familial
hypercholesterolemia.

eFig. 26-13 Gouty tophus.

541.e2
 Bonus images for this chapter can be found online at
expertconsult.inkling.com
27 Genodermatoses and Congenital Anomalies
Genetic disorders are o ten grouped into three categories
chromosomal single gene and polygenetic. Chromosomal
disorders can be numerical such as trisomy and monosomy
or structural resulting rom translocations or deletions. ost
genodermatoses show single gene or mendelian inheritance
(autosomal dominant autosomal recessi e or lin ed reces
si e genes). Polygenetic syndromes o ten in ol e comple
interactions o genes.
Autosomal dominant conditions re uire only a single gene
to produce a gi en phenotype. sually the patient has one
a ected parent or is a ected by a new mutation. The disease
is transmitted rom generation to generation. Autosomal
recessi e traits re uire a homo ygous state to produce the
abnormality. The pedigree will o ten re eal parental consan
guinity. Parents will be clinically una ected but o ten ha e
a ected relati es. lin ed conditions occur when the mutant
gene is carried on the chromosome. a disease is lin ed
recessi e the loss is e ident in males ( ) who do not ha e
a second chromosome to e press the normal allele. There
ore lin ed recessi e traits occur almost e clusi ely in
males. They cannot transmit the disease to sons (who inherit
their chromosome) but all their daughters will be carriers.
Carrier emales who are hetero ygous (ha ing one normal and
one abnormal chromosome) occasionally show some e i
dence o the disease. This occurs as a result o lyoni ation the
physiologic segmental inacti ation o one o the chromo
somes. lin ed dominant disease states are usually lethal in
males. Sur i al is possible in emales who retain a normal
allele. Because the mutation is lethal in many a ected cell
lines emales typically demonstrate loss o normal tissue in
the a ected segments (narrow Blasch o segments loss o
digits microphthalmia loss o teeth). lin ed dominant traits
result in pedigrees in which more than one emale is a ected
but no males e press the disease. Rarely males may sur i e
especially i they ha e line elter syndrome ( ).
osaicism is the presence o two or more genetically distinct
cell lines in a single indi idual. t may occur as a result o
physiologic inacti ation o one chromosome (lyoni ation) or
as the result o post ygotic somatic mutation. osaicism o ten
presents in a linear and whorled pattern along the lines o
Blasch o. n mosaic states genes that are detrimental to a cell
population during etal de elopment (e.g. incontinentia pig
menti) typically result in thin segments because they are o er
grown by the ad acent normal tissue. Con ersely genes that
con er a growth ad antage during etal de elopment (e.g.
mutated tumor suppressor gene in segmental neuro broma
tosis) may result in broad pla ue type lesions that ha e grown
beyond the boundaries o a typical Blasch o segment.
n autosomal dominant conditions a normal allele remains
but is not enough to pre ent disease. Loss o hetero ygosity
(L ) is the segmental loss o this remaining normal
allele. L may gi e rise to segments o the body with an
e aggerated presentation o the syndrome. The a ected area
542
tahir99 - UnitedVRG
corresponds to a Blasch o segment or pla ue. The orehead
pla ue o tuberous sclerosis is related to a mutation in a tumor
suppressor gene. The loss o the tumor suppressor gene
imparts a growth ad antage and loss o hetero ygosity lea es
no suppressor gene product in the segment. As a result the
a ected segment grows beyond its Blasch o boundaries
orming a broad pla ue.
When a patient presents with segmental distribution o a
disorder it is critical to determine i the disorder is a result o
mosaicism or L . n L the abnormal allele is present
throughout the body including gonadal tissue. n a patient
who presents with segmental neuro bromatosis but has Lisch
nodules or a illary rec ling L rather than mosaicism is
li ely to account or the segmental presentation. The ris o
passing the gene to a child is about . A geneticist should
be in ol ed during discussions o ris o transmission because
the mechanisms may be comple . Patients with mosaicism
based on post ygotic somatic gene mutation may ha e gonadal
mosaicism and may be capable o passing on the gene. Gonadal
mosaicism is more li ely when more than one segment is
present on di erent regions o the body. Be ore gastrulation
when a ca ity orms in the embryo e ery cell is pluripotent
and can gi e rise to an entire organism or it can contribute to
multiple sites o the body. At gastrulation cells become dedi
cated to produce speci c segments o the body. Blasch o seg
ments in di erent regions suggest a mutation that occurred
be ore gastrulation when the in ol ed cell lines could contrib
ute to di erent parts o the body including the gonads. Poly
genetic disorders such as psoriasis may also present with
limited and linear orms that may relate to segmental L or
post ygotic mutation.
nline endelian nheritance in an ( .org) contains
a comprehensi e database o nown genetic disorders and has
a search unction that allows the clinician to match clinical
mani estations with possible diagnoses. Pub ed s clinical
uery unction can also be used to match mani estations with
syndromes and Genetest.org lists sources or genetic testing.
Happle R: Superimposed segmental manifestation of polygenic skin
disorders. J Am Acad Dermatol 2007; 57(4):690–699.
X-LINKED, MOSAIC, AND RELATED DISORDERS
INCONTINENTIA PIGMENTI
Also nown as Bloch Sul berger disease incontinentia pig
menti is an lin ed dominant condition characteri ed by
whorled pigmentation on the trun preceded by esicular and
errucous changes. t appears in girls during the rst wee s
a ter birth ( ig. ). ost lesions are e ident by the time the
in ant is wee s old. A esicular phase is present in o
cases. This rst stage begins in most indi iduals be ore wee s
o age and is replaced by errucous lesions a ter se eral wee s

Fig. 27-1 Early incontinentia pigmenti.
to months in two thirds o patients. Although these usually
resol e by year o age lesions may persist or many years. n
the third or pigmentary phase pigmented macules in strea s
sprays splatters and whorls ollow the lines o Blasch o. The
pigmentary stage may last or many years and then ade away
lea ing no se uelae. A ourth stage may be seen in some adult
women mani esting subtle aint hypochromic or atrophic
linear lesions most o ten on the e tremities.
istologically the esicular stage is characteri ed by spon
giosis with eosinophils. As the lesions mature clusters o dys
eratotic cells appear within the epidermis. Dys eratotic cells
predominate in the errucous stage and pigment incontinence
(dermal melanophages) predominates in hyperpigmented
lesions.
ther cutaneous changes include patchy alopecia at the
erte o the scalp atrophic changes simulating acrodermatitis
chronica atrophicans on the hands onychodystrophy late
subungual tumors that resemble subungual eratoacanthoma
and may ha e underlying lytic bone lesions and palmoplantar
hyperhidrosis. tracutaneous mani estations occur in
o patients. ost re uently in ol ed are the teeth (up to ) patients are edentulous. Both genders are e ually a ected and
bones ( ) central ner ous system (C S; ) and eyes
( ). mmune dys unction with de ecti e neutrophil chemo
ta is and ele ated g has been reported. osinophilia is
common. ncontinentia pigmenti is an important cause o neo
natal sei ures and encephalopathy.
Dental abnormalities usually mani est by the time the indi
idual is years old. Dental de ects include delayed eruption
partial anodontia ( ) microdontia and cone or peg shaped
teeth ( ). The most common C S ndings are sei ures
( ) mental retardation ( ) spastic paralysis ( ) micro
cephaly destructi e encephalopathy and motor impairment.
The eye changes include strabismus cataracts retinal detach
ments optic atrophy blue sclerae and e udati e chorioretini
tis. S eletal abnormalities include syndactyly s ull de ormities
dwar sm spina bi da club oot (talipes) supernumerary ribs
hemiatrophy and shortening o the legs and arms.
ncontinentia pigmenti is caused by a mutation in the nuclear
actor κB ( EMO gene on the chromosome locali ed to
. The gene is generally lethal in male etuses although
males with line elter syndrome ( ) may sur i e.
osaicism may also account or some cases in males. EMO
mutations also cause lin ed ectodermal dysplasia with
immunode ciency characteri ed by alopecia hypohidrosis
dental anomalies and de ects in humoral immunity. steope
trosis and lymphedema may be present.
ncontinentia pigmenti achromians di ers in that it is a
negati e image with hypopigmentation (see section a ter
ne t). t has autosomal dominant inheritance no esicular or
errucous stages and a higher incidence o C S abnormali
ties. Patients with linear and whorled ne oid hypermelanosis
lac the esicular and errucous phases.
lin ed reticulate pigmentation disorder with systemic
Naegeli-Franceschetti-Jadassohn syndrome
mani estations is a rare lin ed recessi e genodermatosis
that mimics stage incontinentia pigmenti. n males cutane
ous in ol ement is characteri ed by reticulate hyperpigmen
tation o the s in characteristic acies and se ere systemic
in ol ement. n the carrier emales mani estations are limited
to the s in.
endelian susceptibility to mycobacterial disease is a rare
syndrome predisposing to in ection with wea ly irulent
mycobacteria such as M cobacterium bovis bacille Calmette
Gu rin (BCG) and en ironmental nontuberculous mycobac
teria. The causati e mutations in EMO selecti ely a ect the
CD dependent induction o interleu in ( L ) in mono
nuclear cells.
se o ruby lasers to treat pigmented lesions in in ants and
young children may worsen the condition. sually the end
stage o strea s o incontinentia pigmenti starts to ade at age
years and by adulthood there may be minimal residual
pigmentation.
NAEGELI-FRANCESCHETTI-
JADASSOHN SYNDROME
Also nown as the chromatophore ne us o aegeli aegeli
ranceschetti Jadassohn syndrome di ers rom incontinentia
pigmenti in that the pigmentation is reticular with no preced
ing in ammatory changes esiculation or errucous lesions.
Vasomotor changes and hypohidrosis are present. There is
reticulate pigmentation in ol ing the nec e ural s in and
perioral and periorbital areas. Di use eratoderma and punc
ti orm accentuation o the palms and soles may occur. Derma
toglyphics are abnormal producing atrophic or absent ridges
on ngerprints. Congenital malalignment o the great toenails
may be ound. Dental abnormalities are common and many
the syndrome appears to be transmitted as an autosomal dom
inant trait related to mutations in eratin causing increased
susceptibility to tumor necrosis actor (T ) α induced apop
tosis. The syndrome is allelic to dermatopathia pigmentosa
reticularis.
Bustamante J, et al: Genetic lessons learned from X-linked mendelian
susceptibility to mycobacterial diseases. Ann NY Acad Sci 2011;
1246:92–101.
Fusco F, et al: Incontinentia pigmenti: report on data from
2000 to 2013. Orphanet J Rare Dis 2014; 9:93.
Itin PH, et al: Spontaneous fading of reticular pigmentation in Naegeli-
Franceschetti-Jadassohn syndrome. Dermatology 2010;
221(2):135–136.
Mahmoud BH, et al: Controversies over subungual tumors in
incontinentia pigmenti. Dermatol Surg 2014; 40:1157–1159.
Marques GF, et al: Incontinentia pigmenti or Bloch-Sulzberger
syndrome: a rare X-linked genodermatosis. An Bras Dermatol 2014;
89:486–489.
Minić S, et al: Systematic review of central nervous system
anomalies in incontinentia pigmenti. Orphanet J Rare Dis 2013;
8:25.
Okita M, et al: NEMO gene rearrangement (exon 4-10 deletion) and
genotype-phenotype relationship in Japanese patients with
incontinentia pigmenti and review of published work in Japanese
patients. J Dermatol 2013; 40(4):272–276.
Poziomczyk CS, et al: ncontinentia pigmenti. An Bras Dermatol 2014;
89:26–36.
Zhang Y, et al: Incontinentia pigmenti (Bloch-Siemens syndrome). Eur J
Pediatr 2013; 172(8):1137–1138.
543
 Fig. 27-2 Incontinentia
27 pigmenti achromians.
Genodermatoses and Congenital Anomalies
INCONTINENTIA PIGMENTI ACHROMIANS
(HYPOMELANOSIS OF ITO)
ncontinentia pigmenti achromians ( PA) is characteri ed by
arious patterns o bilateral or unilateral hypopigmentation
ollowing the lines o Blasch o ( ig. ). The lesions suggest
the negati e image o incontinentia pigmenti and usually
de elop by the rst year o li e. The emale male ratio is about
. . Three uarters o a ected indi iduals ha e associated
anomalies o the C S eyes hair teeth s in nails musculo
s eletal system or internal organs including polycystic idney
disease. Patients may mani est psychomotor or mental impair
ment autism microcephaly coarse acies and dysmorphic
ears. Some patients ha e had associated Sturge Weber
syndrome li e leptomeningeal angiomatosis.
ore than hal o PA patients ha e chromosomal abnor
malities with most demonstrating mosaicism or aneuploidy
or unbalanced translocations. Se eral patients ha e demon
strated trisomy mosaicism. o in ammatory changes or
esiculation are ound be ore the de elopment o the hypopig
mentation. There is no treatment but e entual repigmentation
is the rule.
Baxter LL, et al: The etiology and molecular genetics of human
pigmentation disorders. Wiley Interdiscip Rev Dev Biol 2013;
2(3):379–392.
LINEAR AND WHORLED NEVOID HYPERMELANOSIS
This disorder o pigmentation de elops within a ew wee s o
birth and progresses or years be ore stabili ing. There is
linear and whorled hyperpigmentation ollowing the lines o
Blasch o without preceding bullae or errucous lesions.
Sparing o mucous membranes eyes palms and soles is
noted. Congenital anomalies such as mental retardation cere
bral palsy atrial septal de ects de trocardia auricular atresia
hemiatrophy and patent ductus arteriosus may be present.
Bilateral giant cerebral aneurysms ha e been reported. There
is no se ual predilection. Biopsy o pigmented areas demon
strates increased pigmentation o the basal layer and promi
nence o melanocytes without incontinence o pigment.
544
tahir99 - UnitedVRG
Fig. 27-3
Chondrodysplasia
punctata.
ost cases appear to be sporadic although amilial cases
ha e been reported. Sporadic orms ha e been attributed to
mosaicism. Because o con usion with other pigmented disor
ders such as incontinentia pigmenti early linear epidermal
ne i hypomelanosis o to and ne us depigmentosus it is
li ely that linear and whorled ne oid hypermelanosis may be
more common than pre iously appreciated.
Cohen J 3rd, et al: Analysis of 36 cases of Blaschkoid dyspigmentation:
reading between the lines of Blaschko. Pediatr Dermatol 2014;
31:471–476.
Mehta V, et al: Linear and whorled nevoid hypermelanosis. Int J
Dermatol 2011; 50(4):491.
Metta AK, et al: Linear and whorled nevoid hypermelanosis in three
successive generations. Indian J Dermatol Venereol Leprol 2011;
77(3):403.
CHONDRODYSPLASIA PUNCTATA
A ariant o the original Conradi nermann syndrome or
chondrodystrophia calci cans congenita chondrodysplasia
punctata is characteri ed by ichthyosis o the s in similar to
that o the collodion baby ollowed by hyper eratotic whirl
and swirl patterns on erythematous s in. n addition to red
dening the wa y shiny s in has hyper eratotic scales o a
peculiar crushed eggshell con guration ( ig. ). As the
child grows ollicular atrophoderma and pseudopelade
de elop. sually the ichthyosis clears within the rst year o
li e but may lea e behind hyperpigmentation similar to that
seen in incontinentia pigmenti. An additional eature is minor
nail de ects such as platonychia and onychoschi ia.
There are our orms o chondrodysplasia punctata classi
ed by their inheritance patterns. The Conradi nermann
type is associated with autosomal dominant inheritance acial
dysmorphia with a low nasal bridge short stature mild
disease cataracts and ew s in lesions. The rhi omelic orm
has autosomal recessi e inheritance mar ed shortening o the
e tremities cataracts ichthyosis and nasal hypoplasia; the
patient dies in in ancy. The lin ed recessi e type has been
described as part o contiguous gene deletion syndromes
with short stature telebrachydactyly and nasal hypoplasia.
The lin ed dominant orm ( apple syndrome Conradi
nermann apple syndrome or CDP ) is lethal in males.
 apple syndrome ( lin ed dominant chondrodysplasia
punctata) has ichthyosi orm erythroderma along the lines o
Blasch o cataracts asymmetric limb shortening and calci ed
stippling o the epiphyses o long bones. ollicular atropho
derma replaces the erythroderma a ter the rst year.
The s eletal de ects re ealed on radiographic e aluation
include irregular calci ed stippling o the cartilaginous epiph
yses in the long bones costal cartilages and ertebral diaphy
sis. The stippling occurs in the etus and persists until age or
years. The humeri and emurs may be shortened and oint
dysplasia may occur. istologic e aluation o the ichthyotic
lesions re eals a thinned granular cell layer calci cation o
eratotic ollicular plugs and ocal hyperpigmentation o
basal eratinocytes. The eratotic ollicular plugs and calcium
deposits are characteristic o chondrodysplasia punctata and
help ul in establishing the diagnosis in newborns. Various
types are related to de ects in pero isomal metabolism plas
malogen and cholesterol biosynthesis. lin ed recessi e
chondrodysplasia punctata (CDP ) is caused by a de ect in
arylsul atase located on p . . There may be an association
between the rhi omelic ariety and maternal autoimmunity
and connecti e tissue disease.
Aubourg P, et al: Peroxisomal disorders. Handb Clin Neurol 2013;
113:1593–609.
Kanungo S, et al: Sterol metabolism disorders and neurodevelopment:
an update. Dev Disabil Res Rev 2013; 17(3):197–210.
Lambrecht C, et al: Conradi-Hünermann-Happle syndrome: a novel
heterozygous missense mutation, c.204G>T (p.W68C). Pediatr
Dermatol 2014; 31:493–496.
KLINEFELTER SYNDROME
line elter syndrome the most common se chromosome dis
order consists o hypogonadism gynecomastia eunuchoid
ism small or absent testicles and ele ated gonadotropins. The
patient may ha e a low rontal hairline sparse body hair with
only a ew hairs in the a illary and pubic areas scanty or
absent acial hair in men and shortening o the th digit o
both hands.
Thrombophlebitis and recurrent or chronic leg ulcerations
may be a presenting mani estation; these may be more common
than pre iously reported. The cause o the hypercoagulable
state is belie ed to be an increase in plasminogen acti ator
inhibitor le els. Patients are at an increased ris o lupus
erythematosus and a ariety o cancers especially male breast
cancer hematologic malignancies and sarcomas (retinoblas
toma and rhabdomyosarcoma).
any o these patients are tall; some are obese. Dull mental
ity is common and psychiatric disorders occur in about one
third o patients. line elter syndrome is most re uently asso
ciated with an se chromosome pattern although other
ariations occur as the number o chromosomes increases.
Androgen therapy may result in impro ements in appearance
and unction.
XXYY GENOTYPE
The genotype is considered to be a ariant o line elter
syndrome. n addition to the changes seen in line elter as
cular changes occur in patients such as cutaneous angi
omas acrocyanosis and peripheral ascular disease leading
to stasis dermatitis. ypertelorism clinodactyly pes planus
and dental abnormalities are common. Systemic mani esta
tions include asthma cardiac de ects radioulnar synostosis
inguinal hernia cryptorchidism C S de ects attention de cit
disorder autism and sei ures.
TURNER SYNDROME
Turner syndrome also nown as gonadal dysgenesis is char
acteri ed by a webbed nec low posterior hairline margin
Noonan syndrome
increased carrying angle at the elbow (cubitus algus) con
genital lymphedema and a triangular mouth. Patients may
demonstrate alopecia o the rontal area on the scalp oil
onychia cutis la a cutis hyperelastica mental retardation
short stature in antilism impaired se ual de elopment
primary amenorrhea numerous melanocytic ne i angio era
tomas and an increased ris o melanoma pilomatricoma and
thyroid disease. Coarctation o the aorta is re uently ound.
There may be an increased incidence o alopecia areata and
halo ne i in these patients.
Patients with Turner syndrome ha e only chromosomes
rather than the normal . An chromosome is missing
resulting in an genotype. osaicism structural abnormali
ties o the chromosome or a partial de ciency o one se
chromosome may account or a number o the ariations in
gonadal dysgenesis. Se eral genetic loci ha e been implicated
including the short stature homeobo gene. Loss o long arm
material ( ) can result in short stature and o arian ailure
but deletions distal to do not appear to a ect stature.
Loss o the short arm ( p) produces the ull phenotype.
Patients with ery distal p deletions usually ha e normal
o arian unction.
o speci c treatment is a ailable or Turner syndrome.
uman growth hormone (hG ) has been used to treat the
short stature. A re iew o the Cochrane Central Register o
Controlled Trials determined that hG increases short term
growth but ew data e ist regarding its e ects on nal height.
ultiple pterygium syndrome ( scobar syndrome) is a rare
autosomal recessi e disorder characteri ed by multiple con
genital oint contractures and multiple s in webs that may
mimic Turner syndrome.
Castelo-Branco C: Management of Turner syndrome in adult life and
beyond. Maturitas 2014; 79:471–475.
Güven A, et al: Multiple pterygium syndrome: mimicking the findings of
Turner syndrome. J Pediatr Endocrinol Metab 2011;
24(11-12):1089–1093.
NOONAN SYNDROME
oonan syndrome is an autosomal dominant disease associ
ated with a webbed nec that mimics Turner syndrome. ales
and emales are e ually a ected and the chromosome number
is normal. The other ma or eatures are a characteristic
acies with hypertelorism prominent ears short stature unde
scended testicles low posterior nec hairline cardio ascular
abnormalities (e.g. pulmonary stenosis) and cubitus algus.
rom to o patients ha e dermatologic ndings
lymphedema short curly hair dystrophic nails tendency
toward eloid ormation so t elastic s in eratosis pilaris
atrophicans (ulerythema o eyebrows) multiple granular cell
tumors and abnormal dermatoglyphics. The oonan syn
drome gene P P encodes the nonreceptor protein tyro
sine phosphatase S P in ol ed in the RAS AP pathway.
Growth hormone can help patients achie e more normal
stature.
oonan syndrome is grouped among the RASopathies
o erlapping neurode elopmental syndromes resulting rom
germline mutations in genes that participate in the rat
sarcoma mitogen acti ated protein inase (RAS AP )
pathway (P P SOS S or S and S OC ).
Patients with oonan syndrome may ha e SOS mutations
associated with normal cognition and stature mutations
545
 entailing a high ris o hypertrophic cardiomyopathy speci c
27 P P mutations predisposing to u enile myelomonocytic
leu emia or S OC mutation (p.Ser Gly) associated with
loose anagen syndrome. Certain characteristics in early child
hood suggest the diagnosis o a RASopathy including con
Genodermatoses and Congenital Anomalies
genital heart de ects se ere eeding di culties and delay o
de elopmental milestones together with hair and s in anoma
lies. eeding di culties and de elopmental motor delay are
the most common eatures with the cardio aciocutaneous syn
drome and Costello syndrome. Thin hair is common among
S OC and mutation positi e in ants. Ca au lait spots
are ound in patients with LS and P P mutations whereas
eratosis pilaris is more common in those with SOS S OC
and mutations. any patients with the RASopathies
appear to ha e an increased ris o lupus erythematosus.
Legius syndrome is classi ed as a RASopathy but is discussed
later with the di erential diagnosis o neuro bromatosis
which is traditionally classi ed as a pha omatosis.
MULTIPLE LENTIGINES (LEOPARD) SYNDROME
The L PARD syndrome multiple lentigines electrocardio
graphic conduction abnormalities ocular hypertelorism pul
monary stenosis abnormal genitalia retardation o growth
and sensorineural dea ness is also nown as multiple
lentigines syndrome cardiocutaneous syndrome lentiginosis
pro usa syndrome or progressi e cardiomyopathic lentigino
sis. The lentigines are small dar brown polygonal and irreg
ularly shaped macules usually measuring mm in diameter.
ndi idual lesions may be larger e en up to . cm. ela
noma has been described in these patients so atypical lesions
should be biopsied.
The L PARD syndrome shares many clinical eatures with
oonan syndrome. These are allelic disorders; patients with
both syndromes demonstrate mutations in the oonan syn
drome gene P P Although the R in L PARD indi
cates growth retardation some patients with the syndrome
also e hibit mild mental retardation or speech di culties.
any cases appear sporadically; howe er inheritance as an
autosomal dominant genetic trait has also been reported.
COSTELLO SYNDROME
Costello syndrome is characteri ed by growth retardation;
ailure to thri e in in ancy; coarse acies; redundant s in on
the nec palms soles and ngers; acanthosis nigricans; and
nasal papillomata. Ventricular dilation is obser ed in more
than o cases. ydrocephalus brain atrophy Chiari mal
ormation and syringomyelia may occur. ild to moderate
mental de ciency is re uently disco ered and most patients
e hibit a characteristic sociable and riendly personality.
CARDIOFACIOCUTANEOUS SYNDROME
Cardio aciocutaneous (C C) syndrome is characteri ed by a
distincti e acial appearance heart de ects and mental retar
dation. acial characteristics include high orehead with bitem
poral constriction downslanting palpebral ssures hypoplastic
supraorbital ridges a depressed nasal bridge and posteriorly
angulated ears with prominent helices. The heart de ects
include pulmonic stenosis atrial septal de ect and hypertro
phic cardiomyopathy. Patients may ha e ectodermal abnor
malities including sparse brea able hair hyper eratotic s in
lesions and a generali ed ichthyosis li e condition. ost cases
occur sporadically but autosomal dominant transmission has
546
tahir99 - UnitedVRG
been reported. Various subtypes relate to di erent genes
in the RAS
M P
AP pathway including
mutations.
S and
The most re uent dermatologic ndings in C C patients
in ol e the hair which may be sparse curly ne or thic
woolly or brittle. n more than hal o the reported cases the
patient had dry scaly or hyper eratotic ichthyotic s in.
ther cutaneous ndings include sparse or absent eyebrows
and eyelashes low posterior hairline patchy alopecia scant
body hair ollicular hyper eratosis eratosis pilaris eratosis
pilaris atrophicans aciei palmoplantar eratoderma sebor
rheic dermatitis ec ema lymphedema hemangiomas ca au
lait spots pigmented ne i hyperpigmented macules or stripes
cutis marmorata and sacral dimples. ail dystrophy oil
onychia and dysplastic teeth ha e also been reported.
The di erential diagnosis includes oonan syndrome
Pallister illian mosaic aneuploid syndrome (mosaic tetra
somy p trisomy p) and Costello syndrome. The di culty
o ten arises in assessing the acial eatures which are similar
in all these syndromes. clusion o P P mutations in C C
syndrome and Costello syndrome con rms distinct genetic
etiologies.
EPIDERMAL NEVUS SYNDROMES
mportant clues to the diagnosis o speci c epidermal ne us
syndromes include linear lesions with ne us sebaceus ( S) in
Schimmelpenning syndrome S and papular ne us spilus in
phacomatosis pigmento eratotica so t white hair in angora
hair ne us syndrome (Schauder syndrome) breast hypoplasia
in Bec er ne us syndrome mosaic R C mutation in bro
blast growth actor receptor epidermal ne us ( ) syndrome
(characteri ed by so t el ety and C S abnormalities) and
acral strawberry papillomatous lesions on tips o ngers or
toes in C LD syndrome. ther syndromes include ne us
trichilemmocysticus (cysts in blasch oid distribution) didy
mosis aplasticosebacea ( S with aplasia cutis congenita)
SCALP syndrome ( S C S mal ormations aplasia cutis
limbal dermoid and pigmented ne us) Gorbello syndrome
(systemati ed linear el ety with bone de ects) VADA
syndrome (ne us epidermicus errucosus with angiodyspla
sia and aneurysms) and CL V syndrome (congenital lipo
matous o ergrowth ascular mal ormations and with
nonprogressi e proportionate o ergrowth).
Aoki Y, et al: Ras/MAPK syndromes and childhood hemato-oncological
diseases. Int J Hematol 2013; 97(1):30–36.
Balsera AM, et al: Distinct mechanism of formation of the 48, XXYY
karyotype. Mol Cytogenet 2013; 6(1):25.
Cirstea IC, et al: Diverging gain-of-function mechanisms of two novel
KRAS mutations associated with Noonan and cardio-facio-cutaneous
syndromes. Hum Mol Genet 2013; 22(2):262–270.
Dillon S, et al: Klinefelter’s syndrome (47,XXY) among men with
systemic lupus erythematosus. Acta Paediatr 2011;
100(6):819–823.
Hafner C, et al: Keratinocytic epidermal nevi are associated with mosaic
RAS mutations. J Med Genet 2012; 49(4):249–253.
Hafner C, et al: Mosaic RASopathies. Cell Cycle 2013;
12(1):43–50.
Laura FS: Epidermal nevus syndrome. Handb Clin Neurol 2013;
111:349–368.
Martínez-Quintana E, et al: LEOPARD syndrome: clinical features and
gene mutations. Mol Syndromol 2012; 3(4):145–157.
Myers A, et al: Perinatal features of the RASopathies: Noonan
syndrome, cardiofaciocutaneous syndrome and Costello syndrome.
Am J Med Genet A 2014; 164:2814–2821.
Niemeyer CM: RAS diseases in children. Haematologica 2014;
99:1653–1662.
Rauen KA: The RASopathies. Annu Rev Genomics Hum Genet 2013;
14:355–369.
 Rogol AD, et al: Considerations for androgen therapy in children and lagenoma) oral papillomatosis ( ig. ) gingi al hyperplasia
adolescents with Klinefelter syndrome (47, XXY). Pediatr Endocrinol ash lea hypomelanotic macules ( ig. ) s in bromas and
Rev 2010; 8(Suppl 1):145–150. ca au lait spots.
Tumurkhuu M, et al: A novel SOS1 mutation in Costello/CFC syndrome Adenoma sebaceum lesions (angio bromas) are mm
affects signaling in both RAS and PI3K pathways. J Recept Signal
yellowish red translucent discrete wa y papules that are

Tuberous sclerosis (epiloia, Bourneville disease)

Transduct Res 2013; 33(2):124–128.
distributed symmetrically principally o er the chee s nose
and orehead. They ha e also been reported in patients with
multiple endocrine neoplasia ( ) and the Birt ogg
PHAKOMATOSES Dube syndrome. These lesions are present in o patients
older than years persist inde nitely and may increase in
The pha omatoses are the arious inherited disorders o the number.
C S associated with congenital retinal tumors and cutaneous Shagreen pla ue is named a ter a type o leather tanned to
in ol ement. These include tuberous sclerosis on Rec ling produce nobs on the sur ace resembling shar s in. Patches
hausen s disease (neuro bromatosis) on ippel Lindau o this type o nobby s in arying rom to cm in diam
disease (angiomatosis retinae) ata ia telangiectasia ne oid eter are ound on the trun most o ten on the lumbosacral
basal cell carcinoma syndrome ne us sebaceus and Sturge area. These are connecti e tissue ne i composed almost e clu
Weber syndrome. si ely o collagen occur in o patients and de elop in the
rst decade o li e.
oenen tumors (periungual angio bromas) occur in o
patients ( ig. ). The tumors are small digitate protruding
TUBEROUS SCLEROSIS asymptomatic and periungual subungual. They appear at
(EPILOIA, BOURNEVILLE DISEASE) puberty. Similar lesions may occur on the gingi a. ails may
also demonstrate longitudinal groo es long leu onychia and
Tuberous sclerosis described by Desiree agloire Bourne ille short red strea s.
in is also called epiloia (epi epilepsy; loi low intelligence; Congenital white lea shaped macules also called hypomel
a adenoma sebaceum). This classic triad o adenoma seba anotic macules are ound in o patients with tuberous
ceum ( ig. ) mental de ciency and epilepsy howe er is sclerosis ranging in number rom to . ccasional patients
present in only a minority o patients. ther associated ea may not de elop the macules until years o age. These may
tures include periungual bromas shagreen pla ues (col be shaped li e an ash lea but linear and con etti type white

Fig. 27-4 Angiofibromas (adenoma sebaceum).

Fig. 27-6 Ash-leaf macules.

Fig. 27-5 Shagreen patch. Fig. 27-7 Periungual fibromas.

547
 macules may also be present. Wood s light e amination should
27 be per ormed when e aluating a patient or tuberous sclerosis.
ocal poliosis (locali ed tu ts o white hair) may be present at
birth. Solitary ash lea macules can occur in the general popu
lation and may be con used with other hypopigmented
Genodermatoses and Congenital Anomalies
macules such as ne us depigmentosus.
ental de ciency usually appreciated early in li e is present
in o patients arying widely in its mani estations.
pilepsy also occurs is ariable in its se erity and usually also
presents early in li e. Between and o patients ha e
sei ures or nonspeci c electroencephalographic abnormali
ties. amartomatous proli erations o glial and neuronal tissue
produce potatoli e nodules in the corte . ray e aluation will
re eal these once calci ed but computed tomography (CT)
cranial ultrasonography and magnetic resonance imaging
( R ) may de ne these lesions as early as wee s o age and
thus are use ul in ma ing an early diagnosis. These brain
tumors may progress to gliomas. Subependymal nodules
( candle drippings ) are similar lesions in the entricular
walls. Astrocytomas may also occur. orehead pla ues may
be a mar er or more serious intracranial in ol ement.
Retinal tumors (pha omas) occur which are optic ner e or
retinal ner e hamartomas. Various ophthalmologic ndings
such as pigmentary changes nystagmus and angioid strea s
occur in o patients. Renal hamartomas (angiomyolipo
mas in cystic disease in broadenomas or mi ed
tumors) and cardiac tumors (rhabdomyomas in ) may also
occur. n the amilial ariety o tuberous sclerosis
patients ha e angiomyolipomas which o ten are bilateral and
cause renal ailure. Women o childbearing age may present
with pulmonary lymphangioleiomyomatosis with progressi e
respiratory ailure or spontaneous pneumothora . ewer e i
dence suggests that the ma ority o adult women with tuber
ous sclerosis de elop at least some pulmonary mani estations
o the disease. The condition is characteri ed by di use pro
li eration o smooth muscle cells and cystic degeneration o the
pulmonary parenchyma associated with the peri ascular epi
thelioid cells ( P C cells) implicated in arious P Comas.
Almost hal o patients with epiloia ha e bony abnormalities
such as bone cysts and sclerosis which can be seen on ray
e aluation. i e or more pits in the enamel o permanent teeth
are a mar er or this disease.
Tuberous sclerosis is a common inherited autosomal domi
nant disease with highly ariable penetrance. Pre alence
estimates range rom in to in . p to
cases may result rom spontaneous mutations. There are two
genes the mutations o which produce indistinguishable
phenotypes SC and p . SC SC and SC
are tumor suppressor genes. SC encodes or tuberin a puta
ti e guanosine triphosphatase (GTPase) acti ating protein or
rap and rab . SC encodes or hamartin a no el protein
with no signi cant homology to tuberin or any other erte
brate protein. amartin and tuberin associate physically in
i o suggesting that they unction in the same comple rather
than in separate pathways. This interaction o tuberin and
hamartin e plains the indistinguishable phenotypes caused by
mutations in either gene. amartomas re uently demonstrate
loss o the remaining normal allele (loss o hetero ygosity).
Diagnosis
The ash lea macules are usually present at birth in tuberous
sclerosis patients and are most easily seen with Wood s light.
ray e amination ails to show calci ed intracranial nodules
ultrasonography CT or R should be per ormed. undu
scopic e amination hand and oot ray e aluation and renal
ultrasonography are o ten rewarding in a patient with ew
548
tahir99 - UnitedVRG
clinical ndings; up to o asymptomatic parents ha e
been identi ed using these tests.
ultiple periungual bromas are highly correlated with the
syndrome but solitary bromas may occur in una ected indi
iduals. olecular analysis or SC and SC may be the
only way to identi y mildly a ected indi iduals.
Treatment
Adenoma sebaceum can be treated by sha ing dermabrasion
or laser therapy. Lesions are li ely to recur re uiring repeat
treatment. Cranial irradiation o astrocytomas should be
a oided because this may result in the subse uent de elop
ment o glioblastomas. Topical and systemic mammalian target
o rapamycin (mT R) inhibitors o er a nonsurgical alternati e
to treatment o angio bromas. erolimus was the rst mT R
inhibitor appro ed in the nited States and urope as a treat
ment or subependymal giant cell astrocytomas. Clinical e i
dence also supports the use o mT R inhibitors including
sirolimus in a ariety o tuberous sclerosis comple associated
disease mani estations including acial angio bromas renal
angiomyolipoma and epilepsy.
Cudzilo CJ, et al: Lymphangioleiomyomatosis screening in women with
tuberous sclerosis. Chest 2013; 144(2):578–585.
Curatolo P, et al: mTOR inhibitors in tuberous sclerosis complex. Curr
Neuropharmacol 2012; 10(4):404–415.
o Liebman JJ, et al: Koenen tumors in tuberous sclerosis: a review and
clinical considerations for treatment. Ann Plast Surg 2014; 73:721–722.
Teng JM, et al: Dermatologic and dental aspects of the 2012
International Tuberous Sclerosis Complex Consensus Statements.
JAMA Dermatol 2014; 150:1095–1101.
Tu J, et al: Topical rapamycin for angiofibromas in paediatric patients
with tuberous sclerosis: follow-up of a pilot study and promising future
directions. Australas J Dermatol 2014; 55(1):63–69.
NEUROFIBROMATOSIS
(VON RECKLINGHAUSEN’S DISEASE)
euro bromatosis is an autosomal dominant inherited syn
drome mani ested by de elopmental changes in the ner ous
system bones and s in. n type neuro bromatosis (
on Rec linghausen s disease) which includes more than
o o cases patients ha e many neuro bromas ( ig. ) ca au
lait spots a illary rec les ( ig. ) giant pigmented hairy
ne i sacral hypertrichosis cutis erticis gyrata and macro
glossia. euro bromas o the areolae occur in more than
o women with . Lisch nodules are ound in the irides o
about one uarter o patients under years o age and in
o adult patients. Type neuro bromatosis ( ) central or
acoustic neuro bromatosis is distinguished by bilateral acous
tic neuromas usually in the absence o cutaneous lesions
although neuro bromas and schwannomas may occur. Type
(mi ed) and type ( ariant) orms resemble type but ha e
cutaneous neuro bromas. Patients with these types are at
greater ris or de eloping optic gliomas neurilemmomas
and meningiomas. These orms are inherited as autosomal
dominant traits. Segmental neuro bromatosis may arise rom
post ygotic somatic mutation or L ( ig. ).
euro bromas are so t tumors that can be pushed down
into the panniculus by light pressure with the nger ( but
tonholing ) and spring bac when released. istologically
these are well circumscribed but rarely encapsulated spindle
cell proli erations with an amphophilic my oid stroma and
many mast cells. The spindle cells ha e a wa y appearance.
euro bromas result rom proli eration o all supporting ele
ments o the ner e bers including Schwann perineurial
 Fig. 27-8 Fig. 27-10 A and
Neurofibromatosis B, Segmental
type 1. neurofibromatosis.

Neurofibromatosis (von Recklinghausen’s disease)

A

Fig. 27-9 Axillary

freckling.

Fig. 27-11 Plexiform

neurofibroma.

endoneurial and mast cells and blood essels. A on stains

demonstrate indi idual a ons spread randomly throughout
the tumor in contrast to a schwannoma where a ner e trun
is compressed at one edge o the tumor but no a ons are
present within its bul .
Subcutaneous ple i orm neuro bromas are irtually pathog
nomonic o and are o ten a mani estation o L . n
palpation these resemble a bag o worms. The o erlying
s in is usually hyperpigmented and may resemble a giant ca
au lait macule ( ig. ). istologically they demonstrate
numerous elongated encapsulated neuro bromas o ten
embedded in di use neuro broma that in ol es the dermis
and subcutaneous at.
The ca au lait macule is a uni ormly pigmented smooth
edged light brown macule. ost o ten these macules are
549
 present at birth and almost always present by year o age.
27 The nding o si or more o these lesions measuring at least
. cm in diameter is diagnostic usually indicating . n
children the minimum diameter or a signi cant lesion is
. cm. istologically basilar hyperpigmentation is noted
Genodermatoses and Congenital Anomalies
and giant melanosomes may be seen. A illary rec ling
(Crowe s sign) may occur e tending to the nec and in ol ing
the inguinal genital and perineal areas.
any organ systems may be in ol ed. Acromegaly cretin
ism hyperparathyroidism my edema pheochromocytoma
(< ) or precocious puberty may be present. Bone changes
(usually erosi e) may produce lordosis yphosis and pseu
doarthrosis as well as spina bi da dislocations and atrau
matic ractures. euromas o spinal ner es may cause arious
paralyses. Patients with are our times more li ely to
de elop malignancies than the general population. Cutaneous
neuro bromas rarely de elop into malignant peripheral
ner e sheath tumors. A growing or hardening lesion is an
indication or biopsy. An increased incidence o breast carci
noma Wilms tumor rhabdomyosarcomas gastrointestinal
(G ) malignancies and chronic myelogenous leu emia (C L)
has also been reported. Children with are times
more li ely to de elop malignant myeloid disorders than age
matched controls and the ris or C L may be higher or
those with anthogranulomas.
ental retardation dementia epilepsy and a ariety o
intracranial malignancies may occur. ypertelorism heralds
a se ere e pression o neuro bromatosis with brain in ol e
ment. Di use interstitial lung disease occurs in o be dictated by ndings on clinical e aluation. t concluded that
patients.
Appro imately o cases o represent new muta
tions. The gene or is in the pericentric region o chromo
some . and codes or neuro bromin a protein that
negati ely regulates signals transduced by Ras proteins. There
is a high rate o spontaneous post ygotic mutation o this
gene. Both alleles must be a ected or the indi idual to grow
a neuro broma. n patients with the syndrome there is germ
line loss o one allele and each neuro broma that de elops
represents a late spontaneous mutation noc ing out the
remaining allele. arly post ygotic mutation a ecting the
second allele in etal li e results in L a ecting an entire
Blasch o segment. The gene or is on the long arm o
chromosome and encodes or merlin (schwanno
min) a protein that lin s the actin cytos eleton to cell sur ace
glycoproteins and unctions as a negati e growth regulator.
Germline loss o unction mutations in the SP ED gene ha e
been associated with an li e phenotype with pigmen
tary changes but no neuro bromas (Legius syndrome) which
is grouped with the RASopathies.
Diagnosis
The diagnosis o re uires two or more o the ollowing
criteria to be ul lled
. Si or more ca au lait macules with a greatest diameter
o more than mm in prepubertal indi iduals and a
greatest diameter o more than mm in postpubertal
indi iduals
. Two or more neuro bromas o any type or one ple i orm
neuro broma
. rec ling in the a illary or inguinal regions
. ptic gliomas
. Two or more Lisch nodules
. Distincti e osseous lesion such as a sphenoid dysplasia
or thinning o the long bone corte with or without
pseudarthrosis
550
tahir99 - UnitedVRG
. irst degree relati e (parent sibling or o spring) with
the disease
A diagnosis o re uires either o the ollowing
. Bilateral eighth cranial ner e masses as demonstrated on
CT or R
. irst degree relati e with and either unilateral
eighth ner e mass or two o the ollowing a
neuro broma meningioma glioma schwannoma and
u enile posterior subcapsular lenticular opacity
Although not listed in the pre ious criteria the presence
o ne us anemicus anthogranuloma and glomus tumors is
strongly associated with a diagnosis o and the pre a
lence is high during the rst years o li e when other diag
nostic criteria may be absent. e us anemicus is usually ound
on the nec and upper chest whereas the anthogranulomas
tend to be cephalic or genital.
Screening and monitoring for complications
n one study o asymptomatic patients with who
underwent cerebral imaging optic gliomas were detected
suggesting that screening R or CT may be o alue and
uorine uorodeo yglucose positron emission tomogra
phy (P T) has shown some alue in discriminating between
benign and malignant tumors. The ational nstitutes o
ealth ( ) consensus panel concluded that studies should
laboratory tests in asymptomatic patients are unli ely to be o
alue. n the ma ority o patients with imaging studies
should only be per ormed as indicated by signs or symptoms.
patients in contrast o ten re uire imaging studies.
Screening studies should include an audiogram and brainstem
auditory e o ed responses. R is the best imaging procedure
or patients with e idence o hearing impairments or abnor
mal e o ed responses. Tests o estibular unction may be
use ul because eighth cranial ner e tumors de elop on the
estibular di ision. A screening R should be per ormed by
puberty. ther tests should be per ormed as dictated by signs
and symptoms. Pediatric patients with ha e a worse
prognosis with demonstrating hearing loss isual
impairment and abnormal ambulation.
Trials o targeted therapy to reduce the growth o cutaneous
neuro bromas are ongoing and are li ely to result in better
treatment options or se erely a ected patients.
Blakeley J: Development of drug treatments for neurofibromatosis type
2–associated vestibular schwannoma. Curr Opin Otolaryngol Head
Neck Surg 2012; 20(5):372–379.
Ferner RE, et al: Neurofibromatosis type 1 (NF1): diagnosis and
management. Handb Clin Neurol 2013; 115:939–955.
Ferrari F, et al: Juvenile xanthogranuloma and nevus anemicus in the
diagnosis of neurofibromatosis type I. JAMA Dermatol 2014;
150:42–46.
Gutmann DH, et al: Optimizing biologically targeted clinical trials for
neurofibromatosis. Expert Opin Investig Drugs 2013; 22(4):443–462.
Harrison B, Sammer D: Glomus tumors and neurofibromatosis: A newly
recognized association. Plast Reconstr Surg Glob Open 2014; 2:e214.
Madanikia SA, et al: Increased risk of breast cancer in women with NF1.
Am J Med Genet 2012; 158A(12):3056–3060.
Millan MJ: An epigenetic framework for neurodevelopmental disorders:
from pathogenesis to potential therapy. Neuropharmacology 2013;
68:2–82.
Pasmant E, et al: Neurofibromatosis type 1: from genotype to
phenotype. J Med Genet 2012; 49(8):483–489.
Pećina-Šlaus N: Merlin, the NF2 gene product. Pathol Oncol Res 2013;
19(3):365–373.
Ponti G, et al: Cancer-associated genodermatoses: skin neoplasms as
clues to hereditary tumor syndromes. Crit Rev Oncol Hematol 2013;
85(3):239–256.

Fig. 27-12 Proteus syndrome.
Treglia G, et al: Usefulness of whole-body fluorine-18-
fluorodeoxyglucose positron emission tomography in patients with
neurofibromatosis type 1: a systematic review. Radiol Res Pract 2012;
2012:431029.
Vranceanu AM, et al: Quality of life among adult patients with
neurofibromatosis 1, neurofibromatosis 2 and schwannomatosis: a
systematic review of the literature. J Neurooncol 2013;
114(3):257–262.
PROTEUS SYNDROME
Although not a pha omatosis Proteus syndrome may be con
used with neuro bromatosis. This rare sporadic disease is
named a ter the Gree god Proteus who could change shape.
The syndrome has protean mani estations that include dispro
portionate asymmetric and distorting segmental o ergrowth;
cerebri orm plantar hyperplasia ( ig. ); epidermal ne i;
patchy dermal hypoplasia; macrocephaly; hyperostosis; mus
cular hypoplasia; hypertrophy o long bones; ascular mal or
mations o the capillary enous or lymphatic types; lipomas
lipohypoplasia; atty o ergrowth; bullous lung alterations;
intellectual disability; sei ures; brain mal ormations; and deep
ein thrombosis. Germline mutations o P E cause the P E
hamartoma tumor syndrome which includes arious pheno
types (Cowden Bannayan Riley Ru alcaba Proteus Proteus
li e and Lhermitte Duclos syndromes).
Joseph erric nown as the lephant an li ely had
Proteus syndrome rather than neuro bromatosis. Proteus syn
drome is belie ed to be caused by a somatic mutation that is
lethal in the nonmosaic state. Patients with a greater number
o cutaneous lesions also ha e the most e tracutaneous abnor
malities. The ndings o both o ergrowth (pleioproteus com
ponent) and hypoplasia (elattoproteus component) in the
same patient may be a mani estation o genetic twin spotting
(didymosis) o ere pression and de ciency o a gene product.
Linear lesions with P E mutations are now classi ed as seg
mental Cowden syndrome.
Cohen MM Jr: Proteus syndrome review: molecular, clinical, and
pathologic features. Clin Genet 2014; 85(2):111–119.
Lindhurst MJ, et al: AKT1 gene mutation levels are correlated with
the type of dermatologic lesions in patients with Proteus syndrome.
J Invest Dermatol 2014; 134(2):543–546.
VON HIPPEL–LINDAU SYNDROME
Von ippel Lindau syndrome is an autosomal dominant dis
order consisting o retinal angiomas cerebellar medullary
angioblastic tumors pancreatic cysts and renal tumors and
cysts. sually the s in is not in ol ed although angiomas
may occur in the occipitocer ical region or may be general
i ed. The syndrome is associated with a germline mutation o
a tumor suppressor gene on the short arm o chromosome .
rom to o cerebellar hemangioblastomas produce
Ataxia-telangiectasia
erythropoietin and are accompanied by a secondary polycy
themia. cular lesions may lead to retinal detachment. Ten
percent o hypernephromas and ewer than o renal cysts
also produce erythropoietin. Pheochromocytoma has been
associated in se eral indreds with on ippel Lindau
disease.
Patiroglu T, et al: Cerebellar hemangioblastoma associated with diffuse
neonatal hemangiomatosis in an infant. Childs Nerv Syst 2012;
28(10):1801–1805.
ATAXIA-TELANGIECTASIA
Also nown as Louis Bar syndrome ata ia telangiectasia con
sists o cerebellar ata ia oculocutaneous telangiectasia and
sinopulmonary in ection. t is amilial and is usually rst
noted when the child begins to wal . There is aw wardness
and a swaying gait which results in the child needing to use
a wheelchair by about years o age. Choreic and athetoid
mo ements and pseudopalsy o the eyes are other eatures.
ine telangiectases appear on the e posed sur aces o the con
uncti a at about age . ystagmus is present. Telangiectases
also appear later on the butter y area o the ace inside the
heli and o er the bac s o the ears in the roo o the mouth
in the nec lace area in the e ures and o er the dorsa o the
hands and eet. ther stigmata are ca au lait patches
hypopigmented macules melanocytic ne i hypertrichosis
seborrheic dermatitis premature graying and sparsity o the
hair and progeroid eatures.
The s in tends to be dry and coarse and o er time becomes
tight and inelastic as in scleroderma. Atrophic granuloma
tous scarring pla ues may occur. arly death rom bronchiec
tasis occurs in more than hal these patients most o whom
ha e recurrent sinus and lung in ections that begin between
and years o age.
Patients may ha e a mar ed gA de ciency with decreased
lymphocytes and a small to absent thymus. The most
common types o malignancy are lymphomas usually o the
B cell type and leu emias. t has been shown that homo y
gous patients also ha e a higher ris o breast cancer
times higher than age matched controls. etero ygous carri
ers share the de ecti e repair o radiation induced damage
and there is a three old to e old higher ris or de elop
ment o neoplasms especially breast cancer in hetero ygotes
under age . The o aries and testicles do not de elop nor
mally. There is de cient thymus de elopment with absence
o assall s corpuscles and a lac o T helper cells. Suppres
sor T cells are normal. n o cases gA is absent or de
cient; in absent or de cient g is seen; and in gG
is ery low.
Ata ia telangiectasia is transmitted as an autosomal reces
si e trait and hetero ygotes although they lac clinical nd
ings are cancer prone. The gene has been designated M
(ata ia telangiectasia mutated gene) and is a member o a
amily o phosphatidylinositol inase li e en ymes in ol ed
in cell cycle control meiotic recombination telomere length
monitoring and D A damage response. A ected cells are
hypersensiti e to ioni ing radiation and are de ecti e at the
G S chec point a ter radiation damage. They are abnormally
resistant to inhibition o D A synthesis by ioni ing radiation.
The M gene is located on chromosome . . Transloca
tions are common in these patients particularly or chromo
somes and . A high pre alence o M gene mutations
551
 has also been ound in a di erse array o sporadic lymphop
27 roli erati e disorders.
arly diagnosis can be di cult and the most re uent mis
diagnosis is cerebral palsy. Persistently ele ated le els o
alpha etoprotein (A P) and carcinoembryonic antigen occur;
Genodermatoses and Congenital Anomalies
these may be use ul in early diagnosis. n culture ata ia
telangiectasia broblasts are three times more sensiti e to
illing by ioni ing radiation but not ultra iolet light. alu
ations or ele ated A P and radiosensiti ity o broblasts
used to be the standard or diagnosis o this disorder
but immunoblotting the AT protein e pression is now
possible.
Greenberger S, et al: Dermatologic manifestations of ataxia-
telangiectasia syndrome. J Am Acad Dermatol 2013; 68(6):932–936.
Knoch J, et al: Rare hereditary diseases with defects in DNA-repair. Eur
J Dermatol 2012; 22(4):443–455.
EPIDERMOLYSIS BULLOSA
pidermolysis bullosa ( B) is a group o rare genetic disorders
that ha e in common the ormation o blisters in response to
minor physical in ury. Treatment consists o pre ention o
trauma decompression o large blisters and treatment o
in ection. B ac uisita is an autoimmune disease and is dis
cussed in Chapter . The inherited types o B are classi ed
as listed in Bo .
nternal in ol ement may occur in se eral o these subtypes
o B. sophageal and laryngeal complications are seen pri
marily in recessi e dystrophic B but may be present in unc
tional B ( erlit ). Pyloric atresia is reported to occur in
unctional B. cular lesions may be se ere in dystrophic B
and mild lesions ha e been reported in simple and unctional
disease.
Clinical ndings and routine histologic eatures o erlap
and accurate diagnosis depends on genetic mutation mapping
electron microscopy ( ) studies or immuno uorescent
mapping. The latter two can identi y the le el o the epidermal
separation and also may de ne other de ects such as absence
o anchoring brils or hypoplasia o hemidesmosomes. n
recessi e dystrophic B re eals that the clea age is below
the basal lamina and that anchoring brils are diminished or
absent.
mmuno uorescent mapping may de ne the le el o the
split without resorting to . By staining biopsy specimens
or normal components o the basement membrane one
(B ) such as bullous pemphigoid antigen laminin type V
collagen or LDA antigen the le el o the split may be deter
mined by whether the antigen locali es at the roo or base o
the blister. n simple types all these components will be at
the base; in dystrophic types all will be at the roo ; and in
unctional types bullous pemphigoid antigen will be on the
roo whereas type V collagen and LDA will be at the base.
has been ound to be absent or diminished in dystrophic
B. The speci c eratin abnormalities along with the abnormal
genes ha e been identi ed or many o these disorders. Supra
basal orms o B simple are caused by de ects in transgluta
minase pla ophilin desmopla in and pla oglobin. Basal
orms o B simple are caused by de ects in genes encoding
or eratins and plectin e ophilin and bullous pem
phigoid antigen . n generali ed types o unctional B there
are de ecti e genes encoding or laminin collagen V
α β integrin and α integrin. n locali ed types o unctional
B there are de ecti e genes encoding or laminin colla
gen V and α β integrin. Sublamina densa dystrophic
orms result rom mutations in type V collagen gene COL
indler syndrome represents a mi ed orm related to de ects
in indlin ( ermitin amily homolog ).
552
tahir99 - UnitedVRG
Box 27-1 Inherited types of epidermolysis bullosa (EB)
Intraepidermal
• EB simplex, generalized intermediate, normal keratins 5 and
14 staining, KRT5 or KRT14 mutation (specify type)
• EB simplex, localized, normal keratins 5 and 14 staining,
KRT5 or KRT14 mutation (specify type)
• EB, generalized severe, normal keratins 5 and 14 staining,
KRT5 or KRT14 mutation (specify type)
• EB simplex (Ogna)
• EB simplex–migratory circinate
• EB simplex with mottled pigmentation, normal keratin 5
staining, KRT5 mutation (specify type)
• EB with muscular dystrophy
• EB with pyloric atresia
• EB superficialis
• Acantholytic EB simplex, DSP or JUP mutations (specify type)
• Acral peeling skin syndrome
• Skin fragility syndromes
• Skin fragility–wooly hair syndrome (desmoplakin deficiency)
• Skin fragility–plakoglobin deficiency
• Skin fragility–ectodermal dysplasia syndrome (plakophilin
deficiency)
• EB simplex autosomal recessive–BP230 deficiency
• EB simplex autosomal recessive–exophilin 5 deficiency
• EB simplex autosomal recessive–K14
Junctional (intralamina lucida)
• Junction EB (JEB), generalized severe, laminin-332 absent,
LAMA3, LAMB3, or LAMC2 mutations (specify type)
• Junction EB (JEB), generalized intermediate, laminin-332 or
collage XVII reduced staining, LAMA3, LAMB3, LAMC2, or
COL17A1 mutations (specify type)
• JEB localized
• JEB with pyloric atresia (α6β4-integrin)
• JEB, late onset (collagen XVII)
• JEB with respiratory and renal involvement (α3-integrin
subunit)
• JEB inversa
Dermolytic or dystrophic (sublamina densa)
Dominant forms
• Dystrophic EB, generalized, normal collagen VII staining,
COL7A1 mutation (specify type)
• EB pruriginosa
• Pretibial EB
• Bullous dermolysis of the newborn
Recessive forms
• Generalized severe, collagen VII absent, COL7A1 mutations
(specify type)
• Generalized intermediate, collagen VII reduced staining,
COL7A1 mutations (specify type)
• Bullous dermolysis of the newborn, granular intraepidermal
collagen VII staining, COL7A1 mutations (specify type)
• Localized (various types, including EB pruriginosa and
pretibial EB)
Intraepidermal forms
Epidermolysis bullosa simplex,
generalized intermediate
.
The generali ed type o B simple ( BS) dominantly inher
ited with complete penetrance occurs in in births. t
is characteri ed by the de elopment o esicles bullae and
milia o er the oints o the hands elbows nees and eet ( ig.
) as well as other sites sub ect to repeated trauma. The
child is a ected at birth or shortly therea ter with impro e
ment within the rst ew months but with disease recurring
when the child begins crawling or later in childhood. The
blistering is worse during the summer and impro es during
the winter. The lesions are sparse and do not lead to se ere
atrophy. i ols y s sign is negati e. sually the mucous
membranes and nails are not in ol ed. BS is usually milder
than other orms o B.
nherited as an autosomal dominant trait BS is a disease
in which eratin gene mutations cause the production o
de ecti e intermediate laments which lead to epidermal
basal cell ragility and subse uent blistering. Gene mutations
produce abnormalities in eratins and eratins e pressed
in the basal cell layer. Patients hetero ygous or abnormal
eratin ha e blistering limited to the hands and eet but
homo ygotes ha e more se ere and widespread blistering o
the s in and mucous membranes. Separation occurs through
the basal cell layer. Rubbing s in with an eraser may lead to
a subclinical lesion that demonstrates the split histologically.
Localized epidermolysis bullosa simplex
Recurrent bullous eruption o the hands and eet is autosomal
dominantly determined and appears in a chronic orm in
in ancy or at times later in li e. The Weber Coc ayne designa
tion has been dropped in recent classi cation schemes. The
lesions e acerbate during hot weather and when the patient is
sub ected to prolonged wal ing or marching as in military
ser ice. yperhidrosis may be an associated nding. n local
i ed BS the bullae are intraepidermal and suprabasal and
healing occurs without scarring.
Application o aluminum chloride he ahydrate in anhy
drous ethanol (Drysol) on the normal s in o hands and eet
twice a day has been shown to reduce blistering in this orm
o B. A ter wee s o daily therapy the patient can be
switched to wee ly or twice wee ly applications.
Epidermolysis bullosa simplex, generalized severe
n this autosomal dominant ariant o BS acti e blisters with
circinate con guration occur in in ancy. ilia may de elop
but there is no scarring. The oral mucosa is in ol ed. ails are
shed but may regrow sometimes with dystrophy. Blistering
Fig. 27-13 Epidermolysis bullosa simplex.
lessens with age. yper eratosis o the palms and soles may
occur. istologically the split is through the basal layer and
tono laments are clumped on . Point mutations ha e been
shown in eratin and genes.
Epidermolysis bullosa
Epidermolysis bullosa simplex (Ogna)
Generali ed bruising and hemorrhagic blisters occur. BS is
transmitted as an autosomal dominant trait. At birth there are
small acral traumatic sanguineous blisters. The basal erati
nocytes in this syndrome do not stain with antiplectin
antibodies.
Epidermolysis bullosa simplex
with mottled pigmentation
ne Swedish amily has been reported with autosomal domi
nant BS with congenital scattered hyperpigmented and
hypopigmented macules that ade slowly a ter birth. The
remaining eatures are similar to those o generali ed BS.
ltrastructural studies show acuoli ation o the basal cell
layer.
Epidermolysis bullosa simplex
with muscular dystrophy
A orm o BS is associated with late onset neuromuscular
disease and is inherited as an autosomal recessi e trait. Wide
spread blistering at birth is associated with scarring milia
atrophy nail dystrophy dental anomalies laryngeal webs
and urethral strictures. Progressi e muscular dystrophy with
wea ness and wasting begins in childhood or later. This
disease is caused by a mutation in the plectin gene with
a ected patients ha ing absent plectin in their s in and
muscles.
Junctional forms
Junctional epidermolysis bullosa, generalized severe
n unctional B a rare type that has autosomal recessi e trans
mission se ere generali ed blistering may be present at birth
and e tensi e denudation may pro e atal within a ew
months. There is generali ed blistering ( ig. ) with rela
ti e sparing o the hands and characteristic perioral and
Fig. 27-14 Junctional epidermolysis bullosa.
553
 perinasal hypertrophic granulation tissue. entually the
27 lesions heal without scarring or milia ormation but erosions
may persist or years. Dysplastic teeth are common. Laryngeal
and bronchial lesions may cause respiratory distress and e en
death. Additional systemic complications include G tract
Genodermatoses and Congenital Anomalies

gallbladder corneal and aginal disease. Patients who sur i e

in ancy ha e growth retardation and o ten moderate to se ere
re ractory anemia. Separation occurs in the lamina lucida as
shown by .
erlit unctional B is caused by mutations in three genes
L M L M or L MC which code or polypeptide sub
units o laminin . n addition to good wound care and control
o in ection epidermal autographs o cultured eratinocytes
isolated rom clinically unin ol ed s in and grown on colla
gen sponges may be use ul or chronic acial erosions. Com
plete reepitheliali ation can be achie ed o er months.
Fig. 27-15 Epidermolysis bullosa, dominant dystrophic.
Junctional epidermolysis bullosa with pyloric atresia
Fig. 27-16 Bart
This rare autosomal recessi e inherited orm o unctional B syndrome.
presents at birth with se ere mucocutaneous ragility and
gastric outlet obstruction. en i the pyloric atresia is repaired
the neonates may die rom the se erity o their s in disease.
they sur i e the neonatal period the blistering diminishes.
Persistent scarring o the urinary tract may occur howe er
with stenosis o the ureteral esicular unction re uiring
numerous urologic procedures. This syndrome is usually
caused by a genetic mutation in either the α or β integrin
genes ( and ). This α β integrin comple is
uni uely e pressed on epithelial sur aces.

Dermolytic or dystrophic forms

The cause o dystrophic B in both autosomal dominant and
autosomal recessi e inherited orms is mutation in the COL
gene encoding or type V collagen. The anchoring brils in
these patients are de ecti e or de cient. Presumably because
o antigen e posure anti type V collagen anti BP and
anti BP autoantibodies may be detected.

Dominant dystrophic epidermolysis bullosa

n the e tensor sur aces o the e tremities esicles and bullae
appear; these are most pronounced o er the oints especially
o er the toes ngers nuc les an les and elbows ( ig.
Spontaneous esh colored scarli e (albopapuloid) lesions
may appear on the trun o ten in adolescence with no pre i
ous trauma. The nails may be thic ened. sually i ols y s
sign is present and re uently the accumulated uid in a bulla
can be mo ed under the s in se eral centimeters away
rom the original site. ealing usually occurs with scarring
and atrophy. ilia are o ten present on the rims o the ears
dorsal sur aces o the hands and e tensor sur aces o the arms
and legs.
The mucous membranes are re uently in ol ed. Bullae
esicles and erosions are encountered on the buccal mucosa
tongue palate esophagus pharyn and laryn . The latter
in ol ement is mani ested by persistent hoarseness in some o
these patients. There may be angular contractures at the gin
gi olabial sulcus and dysphagia rom pharyngeal scarring.
Scarring on the tip o the tongue is typical. The teeth are
normal. sually the con uncti a is not in ol ed.
ther changes include nail dystrophy partial alopecia o the
scalp absence o body hair dwar sm and the ormation o
contractures and clawli e hands with atrophy o the phalan
geal bones and pseudosyndactylism. The albopapuloid type
( ormerly Pasini type) is now recogni ed as a more se ere
554
). e pression o dominant dystrophic B. The type ormerly
nown as Coc ayne Touraine is more limited in e tent and
se erity and no albopapuloid lesions are seen.
pidermolysis bullosa pruriginosa is characteri ed by
e treme pruritus licheni ed pla ue prurigoli e lesions and
iolaceous linear scarring. Pretibial B is characteri ed by
recurrent blistering and scarring pla ues in the pretibial area.
ail dystrophy is common. Both B pruriginosa and pretibial
B can be inherited in either dominant or recessi e ashion.
istologically a nonin ammatory subepidermal bulla is
generally present. n clea age occurs beneath the basal
lamina and anchoring brils are rudimentary and reduced in
number. n blistered areas these are not demonstrable.
Autologous meshed split thic ness s in gra ts and alloge
neic cultured eratinocytes may be used in treating nonheal
ing s in de ects. n many patients with dominant dystrophic
B blistering reduces o er time and only nail dystrophy may
be present in adulthood.
Bart syndrome
Bart described congenital locali ed de ects o the s in ( ig.
) mechanoblisters and nail de ormities with autosomal

tahir99 - UnitedVRG
dominant inheritance. Although the clinical and histologic
picture o this syndrome is one o a mildly scarring mechano
bullous dermatosis with a a orable prognosis associations
with mandibulo acial dysostosis renal aplasia and congenital
abnormalities o the lower e tremities ha e been reported.
Bart syndrome is not a distinct entity but rather a clinical
ariant o other orms o B mostly dominant dystrophic B
based on identi cation o a de ect in the COL gene (chro
mosome p) encoding or type V collagen.
Transient bullous dermolysis of the newborn
n ashimoto et al. reported a newborn who de eloped
blisters rom e ery minor trauma. Separation was below the
basal lamina with degeneration o collagen and anchoring
brils. There was rapid healing by months o age. ails were
not damaged and there was no scarring. The authors consid
ered the ollowing as criteria or this entity
. Vesiculobullous lesions present at birth or induced by
riction
. Spontaneous reco ery at a ew months o age
. o dystrophic scars
. Subepidermal blisters beginning in the dermal papillae
. ltrastructurally obser ed collagenolysis and damaged
anchoring brils
. normous dilation o rough endoplasmic reticulum with
stellate bodies o eratinocytes in their acuoles
The cause was shown in one amily to be a trans ersion
mutation in the COL gene encoding or type V collagen
and it is there ore allelic with other ariants o dominant or
recessi e dystrophic B. The mechanism or the transient
nature o reduced amounts o type V collagen along the
dermoepidermal unction remains to be de ned.
Acrokeratotic poikiloderma
(Kindler syndrome, Weary-Kindler syndrome)
n indler reported a combination o poi iloderma con
genitale and traumatic blistering o the eet rom minor trauma.
The disorder shares some clinical eatures with dominant dys
trophic B but in the largest reported amilial cluster inheri
tance ollowed an autosomal recessi e pattern. Characteristic
eatures include s in ragility with blistering congenital acral
bullae generali ed poi iloderma with prominent atrophy
photosensiti ity acral eratoses se ere periodontal disease
and phimosis. Some patients de elop intestinal dys unction or
ulcerati e colitis. Pseudoainhum and sclerotic bands were
reported in one case. The principal histologic change is absence
o elastic bers in the papillary dermis and ragmented bers
in the middermis. ltrastructural studies ha e shown replica
tion o the lamina densa. Acro eratotic poi iloderma is caused
by loss o unction mutations in ermitin amily homolog an
actin cytos eleton associated protein encoded by the gene
E M which plays a role in eratinocyte adhesion migra
tion and proli eration. The protein is mainly e pressed in
basal eratinocytes. t binds to ermitin amily homolog as
well as β and β integrins.
Ectodermal dysplasia/skin fragility syndrome
(McGrath syndrome)
This syndrome includes trauma induced s in ragility and
de ects o the hair nails and sweat glands. Trauma induced
blisters or s in tearing are noted on the pressure points espe
cially a ter prolonged standing or wal ing. Desmosomes in the
Epidermolysis bullosa
Fig. 27-17 Epidermolysis bullosa, recessive dystrophic type.
lower epidermis are small and reduced in number. The disor
der is caused by mutations in the pla ophilin gene P P
gene map locus .
Recessive dystrophic epidermolysis bullosa,
generalized severe
All orms o recessi e dystrophic B result rom mutations in
the gene encoding type V collagen COL Generali ed
recessi e dystrophic B in its mildest orm has blisters limited
primarily to the hands eet elbows and nees and limited
complications. The se erer ariety characteristically begins at
birth with generali ed cutaneous and mucosal blistering.
Digital usion with encasement o the ngers and toes in scar
tissues orming a mittenli e de ormity ( ig. ) is char
acteristic o the se ere orm o recessi e dystrophic B occur
ring in up to o patients by age . Dental complications
may be se ere including rampant dental caries and microsto
mia. sophageal stricture may be present. Anemia and growth
retardation are re uently seen in the se erest cases and pro
gressi e nutritional de ciency can result in atal cardiomyopa
thy. atal systemic amyloidosis (AA type) has also been
reported. There is a high ris o de eloping cutaneous
s uamous cell carcinomas (SCCs) with up to o patients
a ected by age . These SCCs may be multiple and can
metastasi e and cause death. Both pretibial B and B prurigi
nosa may e hibit recessi e inheritance.
Although gene therapy is promising treatment remains
primarily palliati e. Gentle wound care and proper nutrition
are critical. Debilitating oral lesions produce pain scarring
and microstomia. Aggressi e dental inter ention is recom
mended. utritional support is o critical importance. Auto
logous meshed split thic ness s in gra ts and allogeneic
cultured eratinocytes ha e been use ul in treating nonhealing
cutaneous de ects or may be used or closure a ter remo al o
large cutaneous malignancies. A single in ection o allogeneic
broblasts at the margins can accelerate early healing o
chronic recessi e dystrophic B erosions. amily education
and re erral to D BRA (Dystrophic pidermolysis Bullosa
Research Association o America West th Street Room
ew or www.debra.org) are strongly
recommended.
Abdul-Wahab A, et al: Gene therapies for inherited skin disorders. Semin
Cutan Med Surg 2014; 33:83–90.
Chu MB, et al: Speedy simple technique for subungual blister
evacuation in epidermolysis bullosa. J Am Acad Dermatol 2013;
69(1):e7–e8.
555
 Fine JD, et al: Inherited epidermolysis bullosa: updated
27 recommendations on diagnosis and classification. J Am Acad
Dermatol 2014; 70:1103–1126.
Fortuna G, et al: The largest family of the Americas with dominant
dystrophic epidermolysis bullosa pruriginosa: a 18-year longitudinal
Genodermatoses and Congenital Anomalies
genotype-phenotype study. J Dermatol Sci 2013; 71(3):217–221.
Gonzalez ME: Evaluation and treatment of the newborn with
epidermolysis bullosa. Semin Perinatol 2013; 37(1):32–39.
Mahto A, et al: Late-onset pretibial recessive dystrophic epidermolysis
bullosa. Clin Exp Dermatol 2013; 38(6):630–632.
Murrell DF: The pitfalls of skin biopsies to diagnose epidermolysis
bullosa. Pediatr Dermatol 2013; 30(2):273–275.
Yang CS, et al: An incompletely penetrant novel mutation in COL7A1
causes epidermolysis bullosa pruriginosa and dominant dystrophic
epidermolysis bullosa phenotypes in an extended kindred. Pediatr
Dermatol 2012; 29(6):725–731.
FAMILIAL BENIGN CHRONIC PEMPHIGUS
(HAILEY-HAILEY DISEASE)
n ailey and ailey described a amilial disease char
acteri ed by persistently recurrent bullous and esicular
dermatitis o the sides o the nec a illae and e ures. The
eruption may remain locali ed or may become widespread.
sually intact blisters are not e ident. nstead the lesions
appear as macerated pla ues with a reticulated pattern o s
suring ( ig. ). Lesions may become thic ly crusted and
may resemble impetigo. Sometimes the center becomes dry
and crusted and an acti ely in ammatory border spreads
peripherally producing circinate and gurate patterns. The
onset is usually in the late teens or early twenties. The condi
tion is typically worse during the summer. Lesions tend to
recur at sites o prior in ol ement. There may be tenderness
and enlargement o the regional lymph glands caused by sec
ondary bacterial in ection. Longitudinal leu onychia may
occur. n ol ement o the esophagus mouth and labia ma ora
is rare.
ailey ailey disease is inherited in an autosomal dominant
manner and o patients e press new mutations. The
disease is caused by a genetic de ect in a calcium adenosine
triphosphatase P C on chromosome .
n predisposed persons with ailey ailey disease s in
trauma bacterial or ungal in ection and dermatoses may
trigger lesions. Sunburn may also e acerbate the disease.
Widespread bullous lesions may occur in response to drug
eruptions and may be misdiagnosed as to ic epidermal necrol
ysis. The histopathologic picture is uni ue. There is acanthosis
and ull thic ness acantholysis resembling a dilapidated bric
Fig. 27-18 Hailey-Hailey disease.
556
tahir99 - UnitedVRG
wall. A red band o dys eratosis is present surrounding the
nucleus with no e idence o the blue or clear bands that occur
in Darier s disease.
The treatment o ailey ailey disease is di cult. any
patients impro e with the use o systemic antibiotics e ecti e
against Staph lococcus aureus topical clindamycin anti ungal
agents or mupirocin. Corticosteroids administered topically
systemically or both ha e shown response. Cyclosporine
methotre ate oral retinoids topical calcineurin inhibitors
topical calcitriol tacalcitol botulinum to in photodynamic
therapy (PDT) narrow band ultra iolet B therapy ( B VB)
ale acept terbina ne minocycline niacinamide and dapsone
ha e been used in se ere cases. Dermabrasion and carbon
dio ide (C ) laser apori ation ha e been e ecti e in re rac
tory disease as the epidermis heals rom unin ol ed adne al
structures. Gra ting and electron beam therapy ha e been
help ul in the most se ere orms o ailey ailey disease.
D’Errico A, et al: Hailey-Hailey disease treated with methotrexate. J
Dermatol Case Rep 2012; 6(2):49–51.
Hamada T, et al: Successful therapeutic use of targeted narrow-band
ultraviolet B therapy for refractory Hailey-Hailey disease. Acta Derm
Venereol 2013; 93(1):110–111.
Vanderbeck KA, et al: Combined therapeutic use of oral alitretinoin and
narrowband ultraviolet-B therapy in the treatment of Hailey-Hailey
disease. Dermatol Reports 2014; 6:5604.
Varada S, et al: Remission of refractory benign familial chronic
pemphigus (Hailey-Hailey disease) with the addition of systemic
cyclosporine. J Cutan Med Surg 2014; 18:1–4.
DISORDERS OF CORNIFICATION (ICHTHYOSES
AND ICHTHYOSIFORM SYNDROMES)
chthyosis is not one disease but a group o diseases in which
the homeostatic mechanism o epidermal cell inetics or di
erentiation is altered resulting in the clinical appearance o
scale. Because these disorders mani est as abnormal di eren
tiation o the epidermis the term disorders o corni cation is
pre erred to ichthyosis.
Treatment
A systematic re iew o the literature on treatment o eratin
i ing disorders other than ichthyosis ulgaris concluded that
e idence is strongest to support the use o urea pro
pylene glycol lactic acid calcipotriol (limited to a wee ly
dose o g) and topical liaro ole (which bloc s retinoic acid
metabolism). ral liaro ole was not superior to oral acitretin.
Symptomatic treatment with α hydro y acids such as lactic
acid or ammonium lactate lotion is help ul but patients
with atopic dermatitis and ichthyosis ulgaris may nd that
these products sting. ther compounds with hydrating and
eratolytic properties are also bene cial. Creams containing
urea are e ecti e humectants. Response to topical reti
noids has been ariable. Widespread use o topical salicylic
acid in children may lead to salicylism and salicylic acid prod
ucts are best reser ed or thic er locali ed areas when
urea has ailed. Baths may help by hydrating the horny layer
but the water must be sealed in with an e aporation barrier
such as white petrolatum. Topical calcipotriene ointment has
pro ed e ecti e in a ariety o ichthyoses and topical ma a
calcitol a itamin D analogue has been used success ully in
mosaic type bullous congenital ichthyosi orm erythroderma.
Application o a solution o propylene glycol in water
under an occlusi e suit remo es the scales. Propylene glycol
can produce renal ailure and cardiac to icity when gi en
systemically but ew reports o ad erse e ects ha e been
noted with topical use. any patients bene t rom the use o
a sauna suit e en without the use o propylene glycol so the
ris bene t ratio o adding the propylene glycol to the regimen
should be e aluated care ully. Topical ta arotene and other
topical retinoids can be help ul to treat ectropion.
Ichthyosis vulgaris
chthyosis ulgaris is autosomal dominant inherited and is
characteri ed by onset in early childhood usually between
and months with ne scales that appear pasted on o er
the entire body. Varying degrees o dryness o the s in may
be e ident. The scales are coarser on the lower e tremities than
on the trun . The e tensor sur aces o the e tremities are most
prominently in ol ed and the a illary and gluteal olds are
usually not a ected. Although the antecubital and popliteal
ossae are usually spared by ichthyosis ulgaris atopic changes
may be present because these disorders are re uently associ
ated. Accentuated s in mar ings and hyper eratosis o the
palms are common eatures and eratosis pilaris is re uently
associated. The scalp is in ol ed with only slight scaling.
eratotic lesions may be ound on the palmar creases ( erato
sis punctata). Atopy mani ested as hay e er ec ema asthma
or urticaria is o ten present. The course is a orable with
limited ndings by the time the patient is an adult.
istologically there is compact eosinophilic ortho eratosis.
The granular layer is reduced or absent and eratohyalin gran
ules may appear spongy or ragmented on . The spinous
layer is o normal thic ness. ilaggrin is reduced in in ol ed
epidermis and pro laggrin messenger R A is unstable in
eratinocytes. This is a retention hyper eratosis with a normal
rate o epidermal turno er. The di erential diagnosis includes
se ere erosis lin ed ichthyosis and ac uired ichthyosis.
X-linked ichthyosis
lin ed ichthyosis is transmitted only to males by hetero y
gous mothers as an lin ed recessi e trait. This condition
results rom a de ciency o steroid sul atase (arylsul atase C)
and occurs in male births. nset is usually be ore
age months. Cesarean birth is typical with ailure in progres
sion o labor because o a placental sul atase de ciency. Scales
are dar large and prominent on the anterior nec e tensor
sur aces o the e tremities ( ig. ) and the trun . The sides
o the nec are in ariably in ol ed gi ing the child an
unwashed loo . The elbow and nee e ures are relati ely
spared as are the ace and scalp; the palms and soles are
almost always spared.
The condition may be con used with ichthyosis ulgaris
but typically has dar er scales and demonstrates dramatic
clearing during the summer months. A diagnosis o lin ed
Fig. 27-19 X-linked ichthyosis.
ichthyosis is li ely i the abdomen is more in ol ed than the
bac and i the ichthyosis e tends down the entire dorsum o
the leg. eratosis pilaris is not present and the incidence o
atopy is not increased. Corneal opacities (which do not a ect
ision) are seen by slit lamp e amination on the posterior
Disorders of cornification (ichthyoses and ichthyosiform syndromes)
capsule or Descemet s membrane in about o a ected
males and emale carriers. Another e tracutaneous eature is
a incidence o cryptorchidism and an independently
increased ris o testicular cancer. nli e ichthyosis ulgaris
lin ed ichthyosis does not impro e with age but gradually
worsens in both e tent and se erity.
There is usually a deletion at p . and steroid sul atase
is lac ing in broblasts leu ocytes and eratinocytes. The
diagnosis can be con rmed by lipoprotein electrophoresis
because the increase in cholesterol sul ate ma es the low
density lipoproteins (LDLs) migrate much more rapidly and
cholesterol sul ate is ele ated in serum erythrocyte mem
branes and eratin. The reduced en yme acti ity can be
assessed in broblasts eratinocytes leu ocytes and prena
tally in amniocytes.
Multiple sulfatase deficiency
Patients with multiple sul atase de ciency display an o erlap
o steroid sul atase de ciency mucopolysaccharidosis and
metachromatic leu odystrophy. The scaling is sometimes
milder than lin ed recessi e ichthyosis. There may be de el
opmental delay spastic uadriparesis and coarse acial ea
tures. istologic e amination shows hyper eratosis with a
normal granular cell layer. This autosomal recessi e disorder
is caused by a lac o or de ciency in all nown sul atases.
Autosomal recessive ichthyosis
Biochemical and genetic studies ha e helped to de ne the
speci c ichthyotic subtypes. Clinical eatures o ten o erlap
and in the past the se erity o the disease determined the
classi cation. denti cation o speci c de ects such as trans
glutaminase (TG ) and pro laggrin laggrin are impor
tant to de ne each disorder and are the basis or classi cation
o ichthyotic disorders.
Lamellar ichthyosis
Lamellar ichthyosis is present at birth or becomes apparent
soon a ter and almost always in ol es the entire cutaneous
sur ace. sually a collodion li e membrane encases the
baby at birth then des uamates o er the rst wee s o li e
( ig. ). The ensuing ichthyosis is characteri ed by large
( mm) grayish brown scales which are stri ingly uad
rilateral ree at the edges and adherent in the center
( ig. ). n se ere cases the scales may be so thic that they
are li e armor plate. oderate hyper eratosis o the palms
and soles is re uently present. The ollicles in most cases ha e
a crateri orm appearance. ctropion is usually present and is
a help ul diagnostic sign.
Lamellar ichthyosis is inherited as an autosomal recessi e
trait. About hal the patients ha e decreased or absent TG
acti ity. LO E and LO mutations can produce a
similar appearance. Lamellar ichthyosis type has been asso
ciated with mutations in the C gene.
n addition to the topical agents recommended or the treat
ment o other ichthyoses ta arotene (Ta orac) and oral reti
noids can impro e symptoms. The ad erse e ects o prolonged
retinoid therapy ma e their use or long term maintenance
therapy di cult.
557

27
Genodermatoses and Congenital Anomalies
Fig. 27-20 Collodion baby.
Fig. 27-21 Lamellar ichthyosis.
Nonbullous congenital ichthyosiform erythroderma
ost in ants with nonbullous congenital ichthyosi orm eryth
roderma are born enclosed in a constricting parchmentli e or
collodion li e membrane. They also ha e ectropion o the
eyelids which has led to con usion with lamellar ichthyosis
and at one time the term lamellar ichthyosis was used or
almost all patients with nonbullous autosomal recessi e ich
thyoses. Because mutations in M LO E or LO
can lead to either congenital ichthyosi orm erythroderma or
lamellar ichthyoses the entities are separated largely on the
basis o the clinical phenotype.
Within hours o birth ssuring and peeling begin and
large eratinous lamellae are cast o in days coincident
with rapid impro ement. As the membrane is shed underly
ing redness and scaling are apparent ( ig. ). Generali ed
in ol ement is the rule including the ace palms soles and
e ures. Cicatricial alopecia nail dystrophy and some ectro
pion are common. Scales may be large and plateli e on the
legs but are li ely to be ne on the trun ace and scalp. The
558
tahir99 - UnitedVRG
Fig. 27-22 Nonbullous
congenital
ichthyosiform
erythroderma.
condition has been ound in association with neutral lipid
storage disease.
istologically para eratosis and in ammation are seen more
re uently in congenital ichthyosi orm erythroderma than in
lamellar ichthyoses. The stratum corneum is usually thic er in
lamellar ichthyoses and is usually not para eratotic.
Harlequin fetus
arle uin etus is a se ere disorder that a ects the s in in
utero causing thic horny armorli e plates co ering the
entire sur ace. The ears are rudimentary or absent and
eclabium and ectropion are se ere. The child is o ten stillborn
or dies soon a ter deli ery. With aggressi e management
howe er there ha e been long term sur i ors who de elop
eatures o congenital ichthyosi orm erythroderma or lamellar
ichthyosis. Absent or abnormal lamellar granules a lac o
e tracellular lipid lamellae and lipid droplets in the stratum
corneum ha e been reported. Abnormalities o pro laggrin
and eratin ( ) and e pression ha e been reported.
Recessi e inheritance has been a ored supported by reports
o consanguinity. Some reports suggest a dominant mutation
with parental mosaicism.
Epidermolytic ichthyosis
An autosomal dominant inherited disorder also nown as
bullous congenital ichthyosi orm erythroderma or epidermo
lytic hyper eratosis ( ) epidermolytic ichthyosis is usually
mani ested by blisters at or shortly a ter birth. Later thic
ened horny warty or spineli e ridged scales predominate
( ig. ). They are particularly prominent at the e ures.
There is remar able heterogeneity particularly in regard to
the degree o hyper eratosis e tent o body sur ace in ol e
ment presence or absence o erythroderma and palm and sole
in ol ement. An association with hypocalcemic itamin D
resistant ric ets has been reported. pidermal ne i o the
epidermolytic type are mosaic e pressions o epidermolytic
ichthyosis.
pidermolytic ichthyosis is caused by mutations in
the genes or and . eratin distribution patterns in

Fig. 27-23 Epidermolytic hyperkeratosis. (Courtesy of Dr. Shyam
Verma.)
eratinocytes are abnormal suggesting an altered assembly
process o corni ed cell en elopes. A recessi e orm related to
mutation has been described.
istologically the lesional s in demonstrates compact
hyper eratosis. The granular layer is greatly thic ened and
contains coarse blue and red eratohyaline granules. pider
mal cells detach in the granular cell layer and may appear
acuolated. re eals the ormation o perinuclear haloes.
These ndings allow prenatal diagnosis by etal s in biopsy.
pidermolytic ichthyosis has been described as an incidental
nding in normal s in s in ad acent to benign and malignant
epidermal tumors and normal oral mucosa.
Short intensi e therapy with high dose itamin A
o A uasol A daily or wee s produces modest clinical
impro ement. thers ha e tried administering systemic reti
noids with similar results; howe er the patient s blistering
may worsen despite clinical impro ement o the scales. Deci
sions regarding systemic retinoid therapy must there ore be
made on a case by case basis. Application o . retinoic acid
(Retin A cream) has been used success ully. Pyogenic in ec
tion is a common problem and appropriate antibiotics should
be administered. A water solution o glycerin and
lactic acid applied to wet s in can result in clinical impro e
ment. The disease tends to become less se ere with age.
Ichthyosis bullosa of Siemens
nce classi ed as a subtype o epidermolytic ichthyosis
( ) this condition is characteri ed by a lac o erythema
relati ely mild hyper eratosis usually limited to the e ures
and super cial molting or peeling o the s in (the mauser
ung phenomenon). chthyosis bullosa o Siemens is caused
by mutations in the gene or eratin e.
Acquired ichthyosis
chthyosis clinically similar to ichthyosis ulgaris may de elop
in patients with se eral systemic diseases. Ac uired ichthyosis
has been reported with odg in disease and may be a
presenting symptom. t has also occurred in non odg in
lymphoma mycosis ungoides multiple myeloma and carci
nomatosis. n hypothyroidism patients may de elop ne
scaling o the trun and e tremities as well as carotenemia
and di use alopecia. Characteristic ichthyosi orm lesions may
de elop in patients with sarcoidosis particularly o er the
lower e tremities. Biopsy o the lesion will o ten show granu
lomas. chthyosi orm changes ha e also been reported in
patients with ansen s disease nutritional de ciency ac uired
immunode ciency syndrome (A DS) human T cell lympho
Disorders of cornification (ichthyoses and ichthyosiform syndromes)
tropic irus in ection lupus erythematosus and dermatomyo
sitis. Drug induced ichthyosis may occur with nicotinic acid
statins triparanol and butyrophenones.
Abdul-Wahab A, et al: Gene therapies for inherited skin disorders. Semin
Cutan Med Surg 2014; 33:83–90.
Craiglow BG, et al: Topical tazarotene for the treatment of ectropion in
ichthyosis. JAMA Dermatol 2013; 149(5):598–600.
Digiovanna JJ, et al: Systemic retinoids in the management of
ichthyoses and related skin types. Dermatol Ther 2013;
26(1):26–38.
Dufresne H, et al: Importance of therapeutic patient education in
ichthyosis: results of a prospective single reference center study.
Orphanet J Rare Dis 2013; 8(1):113.
Dyer JA, et al: Care of the newborn with ichthyosis. Dermatol Ther
2013; 26(1):1–15.
Fleckman P, et al: Topical treatment of ichthyoses. Dermatol Ther 2013;
26(1):16–25.
Hernández-Martin A, et al: A systematic review of clinical trials of
treatments for the congenital ichthyoses, excluding ichthyosis vulgaris.
J Am Acad Dermatol 2013; 69(4):544–549.
Lai-Cheong JE, et al: Pathogenesis-based therapies in ichthyoses.
Dermatol Ther 2013; 26(1):46–54.
Madan RK, Levitt J: A review of toxicity from topical salicylic acid
preparations. J Am Acad Dermatol 2014; 70:788–792.
Pan M, et al: Urea: a comprehensive review of the clinical literature.
Dermatol Online J 2013; 19:20392.
Prado R, et al: Collodion baby: an update with a focus on practical
management. J Am Acad Dermatol 2012; 67(6):1362–1374.
Richard G, et al: Management of ichthyosis and related conditions,
gene-based diagnosis and emerging gene-based therapy. Dermatol
Ther 2013; 26(1):55–68.
Restrictive dermopathy
Restricti e dermopathy is a rare lethal autosomal recessi e
inherited laminopathy characteri ed by abnormal acies tight
s in sparse or absent eyelashes and secondary oint changes.
Virtually all cases are associated with polyhydramnios
reduced etal mo ements and premature deli ery. n ants
e hibit a ed acial e pression with blurring o the groo e
between nose and chee sometimes described as an Asiatic
porcelain doll appearance. Patients also e hibit micrognathia
mouth in the O position rigid and tense s in with erosions
and denudations and multiple oint contractures. Some
patients ha e wide cranial sutures small pinched nose low set
ears microstomia roc er bottom eet scaly s in and respira
tory insu ciency. Pulmonary hypoplasia microcolon essel
transposition natal teeth ectropion submucous cle t palate
hypospadias urethral duplication dysplasia o cla icles
adrenal hypoplasia and an enlarged placenta with short
umbilical cord may be noted.
istopathologic eatures include hyper eratosis para era
tosis abnormal eratohyaline granules and e acement o the
rete ridge pattern. The dermis is attenuated with collagen
bers parallel to the epidermis resembling a scar or tendon.
lastic bers are absent. The subcutis demonstrates hypoplas
tic eccrine and sebaceous glands. The disease is usually caused
by mutations in MPS E causing loss o unction o the
encoded inc metalloproteinase ST and resulting in accu
mulation o prelamin A at the nuclear periphery. Dominant
and progeroid orms may be related to L A mutations.
Starke S, et al: Progeroid laminopathy with restrictive dermopathy–like
features caused by an isodisomic LMNA mutation p.R435C. Aging
(Albany NY) 2013; 5(6):445–459.
559
 Fig. 27-24 Ichthyosis
27 linearis circumflexa.
Genodermatoses and Congenital Anomalies
Ichthyosis linearis circumflexa
chthyosis linearis circum e a is an inherited autosomal reces
si e disorder o corni cation in which migratory annular and
polycyclic patches occur ( ig. ). t may rst appear as
se ere congenital generali ed e oliati e erythroderma. Later
lesions predominate on the trun and e tremities and appear
as a polycyclic serpiginous eruption characteri ed by con
stantly changing patterns. n about wee the lesions attain
their ma imum diameter and in olute lea ing no atrophy
scarring or pigmentation. The lesions may clear almost com
pletely during the summer. ost patients are ound to ha e
bamboo hair (trichorrhe is in aginata). The association o ich
thyosi orm dermatitis hair abnormality and atopic diathesis
is called etherton syndrome. Because o coe istent atopic
dermatitis the scalp ace and eyebrow regions are erythema
tous and scaly. airs may racture below the sur ace o the
scalp so that the patient appears bald. utations in SP
which encodes the serine protease inhibitor a al type
protein ha e been identi ed in etherton syndrome and
result in unopposed alli rein related peptidase ( L ) and
L acti ities and o eracti ity o elastase ( LA ).
istologic e amination shows hyper eratosis para erato
sis and acanthosis. The granular layer is typically absent.
Acitretin has been e ecti e in some patients but should be
a oided in erythrodermic neonates; long term use is limited
by to icity. Topical tacrolimus has also been reported as e ec
ti e but in one report three patients treated twice with .
tacrolimus ointment were ound to ha e signi cant tacrolimus
blood le els. Although none o these patients de eloped signs
or symptoms o to ic e ects monitoring o blood le els is
ad ised i tacrolimus is used in this setting. B VB has been
reported as e ecti e.
Hovnanian A: Netherton syndrome: skin inflammation and allergy by
loss of protease inhibition. Cell Tissue Res 2013; 351(2):289–300.
Maatouk I, et al: Narrowband ultraviolet B phototherapy associated with
improvement in Netherton syndrome. Clin Exp Dermatol 2012;
37(4):364–366.
Neutral lipid storage disease
Dor man Chanarin syndrome is a rare autosomal recessi e
disorder characteri ed by an ichthyosi orm eruption myopa
560
tahir99 - UnitedVRG
thy and acuolated leu ocytes. Lipid acuoles are present in
all circulating granulocytes and monocytes as well as in
dermal broblasts Schwann cells smooth muscle cells and
sweat gland cells. ther organ systems such as the C S li er
muscles ears and eyes may also ha e deposits. Associated
cutaneous disorders include poi iloderma atrophicans ascu
lare and bullous congenital ichthyosi orm erythroderma.
eutral lipid storage disease is caused by a regulatory de ect
that alters the rates o synthesis and degradation o the ma or
cellular phospholipids particularly triacylglycerol deri ed
diacylglycerol. ndings show electron lucent globular
inclusions in lamellar structures. Dietary inter ention with
modulation o dietary ats has been shown to aid in control
ling the disease. ibrates ha e also been used.
Van de Weijer T, et al: Effects of bezafibrate treatment in a patient and a
carrier with mutations in the PNPLA2 gene, causing neutral lipid
storage disease with myopathy. Circ Res 2013; 112(5):e51–e54.
Ichthyosis follicularis (ichthyosis follicularis,
alopecia, and photophobia syndrome)
chthyosis ollicularis is characteri ed by noncicatricial uni er
sal alopecia se ere photophobia and generali ed cutaneous
ollicular pro ections that are esh colored and spiny. There is
erosis o nonspiny s in and absence o sebaceous glands has
been noted histologically. epatosplenomegaly undescended
testicles nail dystrophy inguinal hernia short stature sei
ures psychomotor de elopmental delay digital anomalies
and ptosis ha e been reported. ales outnumber emales .
The main considerations in the di erential diagnosis are
eratitis ichthyosis dea ness ( D) syndrome and eratosis
ollicularis spinulosa decal ans ( SD). chthyosis ollicularis
results rom mutations in the M PS gene impairing choles
terol homeostasis. Patients can be treated with topical erato
lytics and emollients. A partial response to acitretin therapy
has been noted in some patients. ntensi e lubrication o the
ocular sur ace is essential. Cardiopulmonary complications
remain the ma or cause o death.
Mégarbané H, et al: Ichthyosis follicularis, alopecia, and photophobia
(IFAP) syndrome. Orphanet J Rare Dis 2011; 6:29.
Sjögren-Larsson syndrome
S gren Larsson syndrome is characteri ed by ichthyosis spastic
paralysis oligophrenia mental retardation and a degenerati e
retinitis. The ichthyosis is usually generali ed with minimal or
no in ol ement o the scalp hair or nails. There is a e ural and
lower abdominal accentuation. The central ace is spared ectro
pion is unusual and palms and soles are in ol ed. ongolian
spots may be present. Beginning by age or years there is
spastic paralysis consisting o a sti aw ward mo ement o the
e tremities. Gluten sensiti ity has been reported. re eals
prominent Golgi apparatus and increased numbers o mitochon
dria in eratinocytes. sually a se ere mental de ciency is
present. The epilepsy is o the grand mal type. This syndrome is
o autosomal recessi e inheritance locali ed to chromosome
p . . These patients ha e a broblast and leu ocyte de
ciency in atty aldehyde dehydrogenase.
Dutra LA, et al: Sjogren-Larsson syndrome. Adv Exp Med Biol 2012;
724:344–350.
Refsum syndrome
Re sum syndrome (heredopathia atactica polyneuriti ormis)
is an autosomal recessi e inherited ichthyosis with atypical
retinitis pigmentosa hypertrophic peripheral neuropathy cer Fig. 27-25 KID syndrome.
ebellar ata ia ner e dea ness and arious electrocardiographic
changes. The ichthyosis resembles ichthyosis ulgaris. t may
be generali ed or locali ed to the palms and soles. t is o
delayed onset and shows lipid acuoles in the basal layer. The

Disorders of cornification (ichthyoses and ichthyosiform syndromes)

epidermal cell turno er rate is increased. Biochemically the
disease is a pero isomal disorder characteri ed by e cessi e
accumulation o phytanic acid pristanic acid and picolinic
acid in atty tissues myelin sheaths heart idneys and retinal
tissues.
Re sum syndrome is caused by a de ciency o phytanolyl
pristanoyl CoA hydro ilase. n most patients mutations in the
P gene ha e been identi ed and a second locus has been
ound on chromosome with mutations in PE (a
gene also associated with rhi omelic chondrodysplasia punc
tata type ) and P . Dietary restriction o phytanic acid
containing egetables can lead to an impro ement o neurologic
symptoms but does not a ect retinal changes. n ortunately
in many patients dietary restriction is not su cient to pre ent
acute attac s or stabili e the progressi e course. The acids are
locali ed within ery low density lipoprotein (VLDL) LDL
and high density lipoprotein ( DL) particles and may be
remo ed by e tracorporeal LDL apheresis.
Braverman NE, et al: Peroxisome biogenesis disorders: biological,
clinical and pathophysiological perspectives. Dev Disabil Res Rev
2013; 17(3):187–196.

Fig. 27-26 CHILD

Rud syndrome syndrome, left hand
has a bony defect.
Rud syndrome is characteri ed by ichthyosis hypogonadism
small stature mental retardation acanthosis nigricans epi
lepsy macrocytic anemia and rarely retinitis pigmentosa.
ost indreds ha e shown autosomal recessi e inheritance
and may be atypical ariants o well described disorders such
as S gren Larsson syndrome or Re sum syndrome rather
than representing a distinct inherited disorder. Some patients
ha e lin ed steroid sul atase de ciency.
Happle R: Rud syndrome does not exist. Eur J Dermatol 2012; 22(1):7.

Keratitis-ichthyosis-deafness syndrome
The eratitis ichthyosis dea ness ( D or Senter) syndrome is
characteri ed by asculari ation o the cornea an e tensi e
congenital ichthyosi orm eruption neurosensory dea ness
reticulated hyper eratosis o the palms and soles hypotricho
sis partial anhidrosis nail dystrophy and tight heel cords.
Distincti e leathery errucoid pla ues in ol e the central
portion o the ace and ears. These changes with absent eye
brows and eyelashes and urrows about the mouth and chin
gi e the children a uni ue acies ( ig. ). ccasionally
hairs may demonstrate bright and dar bands on polari ed
microscopy as seen in trichothiodystrophy. Chronic mucocu Sakabe J, et al: Connexin 26 (GJB2) mutations in keratitis-ichthyosis-
taneous candidiasis and superin ection o s in lesions is deafness syndrome presenting with squamous cell carcinoma. J
common. Benign trichilemmal tumors and SCC occur in Dermatol 2012; 39(9):814–815.
appro imately o patients.
Some indreds lac dea ness. The disorder is related to mis
sense mutations in the gene that encodes conne in CHILD syndrome: congenital hemidysplasia with
(C ). ost cases are sporadic. ichthyosiform erythroderma and limb defects
sotretinoin treatment may e acerbate and promote corneal
asculari ation. Treatment with acitretin has been reported to Present at birth congenital hemidysplasia with ichthyosi orm
clear the hyper eratotic ichthyotic lesions with minimal e ect erythroderma and limb de ects (C LD) syndrome is charac
on the cornea or hearing. Cyclosporin A eyedrops ha e been teri ed by unilateral in ammatory epidermal ne i and ipsilat
used to treat corneal neo asculari ation. eral limb hypoplasia or limb de ects ( ig. ). eatures may
Coggshall K, et al: Keratitis, ichthyosis, and deafness syndrome: a ary widely rom complete absence o an e tremity to de ects
review of infectious and neoplastic complications. J Am Acad Dermatol o internal organs in ol ing the musculos eletal cardio ascu
2013; 69(1):127–134. lar or central ner ous system. Biopsy may demonstrate
561
 abnormal lamellar granules in the upper stratum spinosum.
27 The condition is belie ed to be lin ed dominant and is lethal
in hemi ygous males. Sur i al in males has been reported as
a result o mosaicism. n emales lyoni ation may produce
cutaneous patterns ollowing the lines o Blasch o similar to
Genodermatoses and Congenital Anomalies
incontinentia pigmenti or lin ed dominant chondrodyspla
sia. The pathogenesis is related to mutations in the SD L
gene that is locali ed at and in ol ed in cholesterol
metabolism. When unilateral epidermal ne i show eatures o
erruci orm anthoma C LD syndrome should be sus
pected. The C LD ne us is distinguished by ptychotropism
( e ural in ol ement) wa y yellowish scaling laterali ation
showing both di use and linear in ol ement and the pres
ence o oamy macrophages in the dermal papillae.
Raychaudhury T, et al: A novel X-chromosomal microdeletion
encompassing congenital hemidysplasia with ichthyosiform
erythroderma and limb defects. Pediatr Dermatol 2013; 30(2):250–252.
Erythrokeratodermia variabilis
rythro eratodermia ariabilis also called erythro erato
dermia gurata ariabilis and endes da Costa type eryth
ro eratodermia is a rare autosomal dominant disorder
characteri ed by erythematous patches and hyper eratotic
pla ues o sparse but generali ed distribution. The erythema
tous patches may assume bi arre geographic con gurations
that are sharply demarcated ( ig. ). er time they
change shape or si e or in olute completely. The eratotic
pla ues are reddish brown o ten polycyclic and ed in loca
tion. The e tensor sur aces o the limbs buttoc s a illae
groins and ace are most o ten in ol ed. Appro imately
o patients display a palmoplantar eratoderma associated
with peeling. air nails and mucous membranes are spared.
The onset o erythro eratodermia ariabilis is shortly a ter
birth or rarely at birth or in early adult li e. There may be
some impro ement with age particularly a ter menopause.
acerbations ha e been seen during pregnancy. The gurate
erythematous component may be accentuated by e posure to
heat cold or wind. motional upsets may also be a actor.
The gene has been mapped to p p the gene
coding or a gap unction protein α (conne in ). istologi
Fig. 27-27
Erythrokeratoderma
variabilis.
562
tahir99 - UnitedVRG
cally there is hyper eratosis and para eratosis and a dimin
ished granular layer. Acanthosis may occur. ltrastructurally
epidermal eratinosomes are diminished.
Systemic retinoids such as acitretin or isotretinoin alone or
combined with psoralens and ultra iolet A ( VA) therapy can
restore the de cient eratinosomes and partially clear the
hyper eratotic pla ues. rythro eratodermia ariabilis o ten
relapses when therapy is discontinued. rea salicylic acid
and lactic acid ha e pro ed use ul or the hyper eratotic
pla ues.
Scott CA, et al: Connexins in epidermal homeostasis and skin disease.
Biochim Biophys Acta 2012; 1818(8):1952–1961.
Yüksek J, et al: Erythrokeratodermia variabilis: successful treatment with
retinoid plus psoralen and ultraviolet A therapy. J Dermatol 2011;
38(7):725–727.
Progressive symmetric erythrokeratodermia
Progressi e symmetric erythro eratodermia (erythro erato
dermia progressi a symmetrica) is a rare autosomal dominant
inherited disorder that mani ests soon a ter birth with ery
thematous hyper eratotic pla ues that are symmetrically dis
tributed on the e tremities buttoc s and ace sparing the
trun . Palmoplantar eratoderma may be present. The lesions
may regress at puberty. ccipital alopecia oligodontia and
se ere caries ha e been reported. ne indred with Vohwin
el syndrome demonstrated an insertion mutation in the loric
rin gene but other patients ha e shown no e idence o
or LO mutations. Topical treatments including erato
lytics corticosteroids and retinoids ha e had ariable success.
Wei S, et al: Evidence for the absence of mutations at GJB3, GJB4 and
LOR in progressive symmetrical erythrokeratodermia. Clin Exp
Dermatol 2011; 36(4):399–405.
PITYRIASIS ROTUNDA
Pityriasis rotunda (pityriasis circinata) mani ests as per ectly
circular scaly patches on the torso and pro imal portions o
the e tremities ( ig. ). The scale is adherent and resem
bles that o ichthyosis ulgaris. There is a strong ethnic pre
disposition with a preponderance o reports in blac persons
Japanese oreans and talians. Some cases are associated
with systemic illnesses especially in dar er s inned patients.
Associated illnesses include tuberculosis other pulmonary
Fig. 27-28 Pityriasis
rotunda.
disorders li er disease malnutrition leu emia lymphoma
and carcinoma o the esophagus or stomach. amilial cases
with autosomal dominant transmission ha e also been
described.
Two orms o pityriasis rotunda occur. Type is ound in
blac or Asian persons usually has ewer than hyperpig
mented lesions is non amilial and may be associated with
systemic disease. Type disease occurs in white persons has
larger numbers o hypopigmented lesions is o ten amilial
and usually is not associated with internal disease.
The di erential diagnosis includes tinea ersicolor tinea
corporis erythrasma ansen s disease ed drug eruptions
and pityriasis alba. Some patients note a seasonal impro e
ment during the summer and some respond to emollients
during the winter months. Low le els o steroid sul atase ha e
been identi ed and the pro laggrin terminal domain is
absent in some patients. Topical and systemic retinoids ha e
been used success ully but pityriasis rotunda o ten is unre
sponsi e unless the patient has an underlying systemic illness
that can be treated.
Yoneda K, et al: The profilaggrin N-terminal domain is absent in
pityriasis rotunda. Br J Dermatol 2012; 166(1):227–229.
Zur RL, et al: Pityriasis rotunda diagnosed in Canada: case
presentation and review of the literature. J Cutan Med Surg 2013;
17(0):1–3.
POROKERATOSIS
Poro eratosis comprises a heterogeneous group o disorders
that are inherited in an autosomal dominant ashion. cept
or the punctate type they are characteri ed by distinct
clinical ndings o a eratotic ridge with a central groo e that
corresponds to the cornoid lamella on histology ( ig. ).
The groo e may be accentuated by the application o gentian
iolet ollowed by remo al with alcohol. The dye remains
in the groo e. Po idone iodine has been similarly used.
mmunosuppression V e posure and radiation therapy
may e acerbate poro eratosis and promote the de elopment
o s in cancers within the lesions. The linear type has the
greatest ris o malignant trans ormation. Segmental orms
ha e been reported in a blasch oid distribution and a ter radi
ation therapy.
Topical uorouracil ( ) can be e ecti e in destroying
indi idual lesions; it may need to be applied under occlusion
but may result in scarring. n disseminated super cial actinic
poro eratosis (DSAP) where the ris o malignant trans or
Fig. 27-29 Porokeratosis with keratotic ridge. (Courtesy of Dr. Curt
Samlaska.)
mation is ery low the ris s o treatment with must be
weighed against the generally indolent course o the lesions.
PDT has been used with incubation under a heating pad to
promote porphyrin con ersion. Sun protection emollients
and obser ation or signs o malignant degeneration may be
Porokeratosis
the most suitable course o action or many patients with
DSAP. ther agents that ha e been shown to be e ecti e
or some patients with DSAP include topical imi uimod
itamin D analogs diclo enac gel and topical retinoids
including ta arotene. Salicylic acid and α hydro yl acids
may ma e the lesions less noticeable. ral retinoids ha e
shown e cacy but the lesions re uently recur a ter treat
ment and long term treatment with these agents is impracti
cal. Combinations o oral retinoids and topical ha e been
e ecti e or re ractory DSAP and poro eratosis plantaris pal
maris et disseminata but the side e ects o treatment may be
considerable. Destructi e modalities must e tend into the
dermis and produce scarring in order to pre ent recurrence.
Destructi e modalities employed include cryotherapy electro
desiccation and curettage C laser ablation switched ruby
laser ractional photothermolysis ashlamp pumped pulsed
dye laser re uency doubled neodymium doped yttrium
aluminum garnet ( d AG) laser dermabrasion and gren
ray radiotherapy.
Plaque-type porokeratosis (Mibelli)
Pla ue type poro eratosis is a chronic progressi e disease
characteri ed by the ormation o slightly atrophic patches
surrounded by an ele ated warty border. The lesion begins
as a small eratotic papule which spreads peripherally and
becomes depressed centrally. entually it becomes a circi
nate or serpiginous well de ned pla ue surrounded by a
eratotic wall or collar. This wall is grayish or brownish and
re uently is surmounted by a tiny groo e or linear ridge
running along its summit. The enclosed central portion o the
pla ue consists o dry smooth atrophic s in; the lanugo hairs
generally are absent when the patches occur in hairy areas.
Linear or osteri orm distribution o the lesions may also
occur. the nail matri is in ol ed nail dystrophy may
de elop. Lesions may appear during chemotherapy or malig
nancy a ter renal transplantation while on psoralen plus
VA (P VA) treatment and in areas o chronic sun damage
or chemical e posure such as ben ylhydrochlorothia ide.
Sites o predilection are the sur aces o the hands and ngers
as well as the eet and an les. The disease also occurs on the
ace and scalp (where it produces bald patches) on the buccal
mucosa (where the ridge becomes macerated by moisture and
appears as a mil y white raised cord) and on the glans penis
(where it causes erosi e balanitis).
istologically the principal diagnostic changes are in the
area o the cornoid lamella. This area demonstrates a column
o para eratotic eratin e tending at about a degree angle
rom a ocus o dys eratotic cells in the malpighian layer. The
column trails behind the ocus o dys eratosis as the ocus
e pands peripherally. The granular cell layer is absent beneath
the para eratotic column. The central portion o the lesion
may demonstrate atrophy with loss o the rete ridge pattern
lichenoid dermatitis or psoriasi orm hyperplasia.
Disseminated superficial actinic porokeratosis
Disseminated super cial actinic poro eratosis (DSAP) is char
acteri ed by numerous super cial circinate eratotic brown
ish red macules ound on sun e posed s in ( ig. ). t is
more common in women. The distribution o the lesions on
563
27
Genodermatoses and Congenital Anomalies
Fig. 27-30 Disseminated superficial actinic porokeratosis.
Fig. 27-31 Linear
porokeratosis with
squamous cell
carcinoma.
the sun e posed areas indicates that actinic radiation is an
important actor in the pathogenesis and new lesions ha e
been induced by e posure at commercial tanning salons. ac
erbations occur in up to two thirds o patients during summer.
mmunosuppression is also well documented as e acerbating
the disease. DSAP has been seen in patients with A DS cir
rhosis and Crohn s disease. rgan transplant patients may
de elop DSAP. mpro ement o the immunosuppression may
lead to resolution o the lesions. Gene loci ha e been locali ed
to chromosomes . . and . . suggesting
that DSAP is a genetically heterogeneous disorder.
Linear porokeratosis
Linear poro eratosis may be segmental or generali ed. t may
be identi ed during the newborn period and when ound in
the segmental pattern may ollow the lines o Blasch o. lcer
ations and erosions in ol ing the ace or e tremities may
delay the correct diagnosis and linear poro eratosis should be
included in the di erential diagnosis o ulcerati e lesions in
the neonatal period. This orm o poro eratosis has the highest
ris o de eloping cutaneous malignancies including SCC
( ig. ) Bowen s disease and basal cell carcinoma.
564
tahir99 - UnitedVRG
Fig. 27-32 Porokeratotic eccrine ostial and dermal duct nevus.
Porokeratosis palmaris, plantaris, et disseminata
n this distincti e orm o poro eratosis lesions rst appear
on the palms or soles or more o ten both. nset is re uently
noted when patients are in their twenties. Slowly the lesions
may e tend o er the entire body. n poro eratotic eccrine
ostial and dermal duct ne us the presentation clinically
appears as a ne us comedonicus o the palm or sole ( ig.
) but histologic analysis re eals multiple coronoid
lamella li e para eratotic columns. n poro eratosis punctata
palmaris et plantaris or punctate poro eratosis lesions are
limited to the hands and eet.
Porokeratotic eccrine ostial and dermal duct nevus
This is a related condition that a ects the eccrine ostia and
typically presents with olar eratosis resembling music bo
spines.
Zhang SQ, et al: Exome sequencing identifies MVK mutations in
disseminated superficial actinic porokeratosis. Nat Genet 2012;
44(10):1156–1160.
DARIER’S DISEASE (KERATOSIS FOLLICULARIS,
DARIER-WHITE DISEASE)
Darier s disease is an autosomal dominant inherited s in dis
order characteri ed by brown eratotic papules that tend to
coalesce into patches in a seborrheic distribution. arly lesions
are small rm papules almost the color o normal s in. ach
papule becomes co ered with a greasy gray brown crust that
ts into a small conca ity in the summit o the papule. As the
lesions age their color dar ens. er years the papules grow
and may use to orm malodorous papillomatous egetating
growths.
The nec shoulders ace e tremities ront o the chest and
midline o the bac are sites o predilection or the disease. A
re uent site or the earliest lesions is behind the ears. As the
eruption spreads the entire trun buttoc s genitals and
other parts o the s in may be in ol ed. sually the eruption
is symmetric and widespread but stri ing unilateral or seg
mental in ol ement may also occur. Cases with segmental
distribution probably represent post ygotic mutations.
Vegetations appear chie y in the a illae gluteal crease and
groin and behind the ears. The scalp is generally co ered with
greasy crusts. Lesions on the ace are o ten prominent about

Fig. 27-33 Darier’s disease. (Courtesy of Dr. Lawrence Lieblich).
the nose. The lips may be crusted ssured swollen and
super cially ulcerated and there may be a patchy eratosis
with super cial erosions on the dorsum o the tongue. Small
white papules or pebbling may be present on the gingi a and
palate. n ol ement o the oropharyn esophagus hypophar
yn laryn and anorectal mucosa has been reported. Punctate
eratoses are re uently noted on the palms and soles. A
general horny thic ening o the palms and soles may be
present because o innumerable closely set small papules. n
the dorsa o the hands and on the shins the at errucous
papules may resemble errucae planae. The nails show sub
ungual hyper eratosis ragility and splintering with longitu
dinal alternating white and red strea s and triangular nic ing
o the ree edges ( ig. ). sophageal in ol ement has
been described.
Darier s disease is usually worse in the summer. t may
begin a ter se ere sunburn and in some patients the lesions
may be reproduced with suberythema doses o VB light.
Lithium carbonate has been shown to induce Darier s disease
in some indi iduals. Disseminated cutaneous herpes simple
may be a complication o the disease.
Abnormal dissolution o desmosomal pla ue proteins is
seen speci cally desmopla in and pla oglobin and des
moglein. Acantholysis occurs as a result o de ciency in the
tono lament desmosome attachment. Calcium ion (Ca +)
dependent cell cell adhesion molecules (epithelial cadherins)
are greatly reduced on the acantholytic cells o patients with
Darier s disease. The Darier gene P has been locali ed
to . and codes or the second iso orm o a calcium
ATPase o the sarcoplasmic endoplasmic reticulum (S RCA )
pump which transports Ca + rom the cytosol into the endo
plasmic reticulum. nhibition o S RCA impairs tra c ing o
Acrokeratosis verruciformis
desmopla in to the cell sur ace contributing to acantholysis.
Histology
Darier s disease is characteri ed by acantholytic dys eratosis
with o erlying hyper eratosis. Round acantholytic dys era
totic cells (corps ronds) typically demonstrate a pale or blue
halo surrounding the nucleus. Grains are at deeply baso
philic dys eratotic cells seen most re uently in the stratum
granulosum and stratum corneum. ormation o a suprabasal
cle t (lacuna) is noted and may in ol e hair ollicles as well as
the sur ace epidermis. Dermal papillae co ered by a single
layer o basal cells pro ect as illi into the acantholytic space.
Treatment
During ares topical antibacterial agents oral antibiotics and
short term application o a corticosteroid may be o bene t.
or locali ed disease topical retinoids may be e ecti e but
papules o ten occur at the periphery o the treated region.
Topical diclo enac sodium has also been used. ral retinoids
are the drugs o choice or most se ere cases. Cyclosporine
may control se ere ares and topical sunscreens and ascorbic
acid can pre ent disease ares in some patients. or hypertro
phic lesions dermabrasion laser apori ation or e cision and
gra ting can be considered. PDT using topical aminole ulinic
acid produces an initial in ammatory response that lasts
wee s. n some patients with Darier s disease this is ollowed
by sustained impro ement. Because o the initial in amma
tory response it is only appropriate or patients who ha e
ailed most other options.
Anuset D, et al: Efficacy of oral alitretinoin for the treatment of
Darier disease: a case report. J Am Acad Dermatol 2014;
71:e46–48.
Letulé V, et al: Treatment of Darier disease with oral alitretinoin. Clin Exp
Dermatol 2013; 38(5):523–525.
Millán-Parrilla F et al: Improvement of Darier disease with diclofenac
sodium 3% gel. J Am Acad Dermatol 2014; 70:e89–90.
Stewart LC, et al: Vulval Darier’s disease treated successfully with
ciclosporin. J Obstet Gynaecol 2008; 28(1):108–109.
ACROKERATOSIS VERRUCIFORMIS
This rare autosomal dominant genodermatosis is character
i ed by numerous at errucous papules occurring on the
bac s o the hands insteps nees and elbows. The papules
are closely grouped and resemble warts e cept that they are
atter and more locali ed. The errucous lesions are identical
to those in Darier s disease and some but not all cases o
acro eratosis erruci ormis o op are caused by mutations
in the P gene.
istologically hyper eratosis thic ening o the granular
layer acanthosis and church spire papillomatosis characteri e
the disease. A ailable treatments are li uid nitrogen therapy
sha e e cision and C laser ablation. Recurrence is common.
Acitretin has been used success ully.
DeFelice T, et al: Acrokeratosis verruciformis. Dermatol Online J 2012;
18(12):12.
Serarslan G, et al: Acitretin treatment in acrokeratosis verruciformis of
Hopf. J Dermatolog Treat 2007; 18(2):123–125.
565

27
Genodermatoses and Congenital Anomalies
Fig. 27-34 Pachyonychia congenita.
PACHYONYCHIA CONGENITA
n Jadassohn and Lewandows y described a rare o ten
amilial anomaly o the nails that they named pachyonychia
congenita. t is characteri ed by thic ened nail beds o all
ngers and toes palmar and plantar hyper eratosis blistering
under the callosities palmar and plantar hyperhidrosis spiny
ollicular eratoses and benign leu o eratosis o the mucous
membranes. The nail plates are e tremely hard and are rmly
attached to the nail beds. The nail bed is lled with yellow
horny eratotic debris which may cause the nail to pro ect
upward at the ree edge ( ig. ). Paronychial in ammation
is re uently present. Delayed onset o pachyonychia in young
adulthood has been described as has acro osteolysis.
n the e tensor sur aces o the e tremities buttoc s and
lumbar regions spineli e ollicular eratotic papules are
ound. Remo al o these central cores lea es a slightly bleed
ing ca ity. The eruption on the outer aspects o the upper and
lower e tremities is also ollicular resembling eratosis pilaris.
This latter condition is not constant and disappears at times.
Pain ul riction blisters may de elop on the plantar aspects
o the toes or heels or along the edges o the eet and cases
ha e been misdiagnosed as epidermolysis bullosa. n a study
o patients the triad o toenail thic ening plantar erato
derma and plantar pain was reported by o patients by
age . Leu o eratosis o the tongue and oral mucosa as well
as occasional laryngeal in ol ement with hoarseness may
occur. This oral leu o eratosis resembles an oral white sponge
ne us histologically and is not predisposed to the de elop
ment o malignancy.
Pachyonychia congenita is di ided into our types. Type
(Jadassohn Lewandows y syndrome) is the most common as
pre iously described. Type (Jac son Sertoli syndrome) has
the same eatures as type with the additional eatures o
natal teeth and steatocystoma multiple . Patients with type
syndrome typically ha e less se ere palmoplantar erato
derma and oral lesions may be absent. Type (Scha ter
Branauer syndrome) is similar to type with the addition o
leu o eratosis o the corneas. Pachyonychia congenita tarda
was suggested as the name or late onset disease (type V).
Type V disease has been described with hyperpigmentation
around the nec waist a illae thighs e ures o the nees
buttoc s and abdomen. Pigmentary incontinence and amyloid
deposition are seen in biopsy specimens.
Pachyonychia congenita is usually inherited as an autoso
mal dominant trait although recessi e orms ha e been
reported. There is a genetic mutation o eratin a or in
type disease and o eratin b or in type disease. There
is a higher li elihood o oral leu o eratosis with
566
tahir99 - UnitedVRG
Fig. 27-35
Dyskeratosis
congenita. (Courtesy
of Dr. Lawrence
Lieblich.)
mutations and natal teeth and cysts are strongly associated
with mutation. omo ygous dominant missense muta
tion in has been associated with se ere pachyonychia
congenita and alopecia. utant speci c small inhibitory R As
(siR As) and hedgehog signaling may be important in disease
e pression.
A ulsion o the nails brings about only temporary relie .
Vigorous curettage o the matri and nail bed is the simplest
and most e ecti e therapy. Destruction o the nail matri with
phenol may be partially e ecti e but recurrence o nail bed
hyper eratosis is common. The eratoderma is di cult to
treat but topical lactic acid ammonium lactate salicylic acid
or urea may be o some bene t. sotretinoin has been reported
to clear the eratotic papules and the oral leu o eratosis but
not the palms or soles. Acitretin has been shown to be e ecti e
in treating the late onset orm.
Eliason MJ, et al: A review of the clinical phenotype of 254 patients with
genetically confirmed pachyonychia congenita. J Am Acad Dermatol
2012; 67(4):680–686.
Irvine AD: Double trouble: homozygous dominant mutations and hair
loss in pachyonychia congenita. J Invest Dermatol 2012;
132(7):1757–1759.
O’Toole EA, et al: Pachyonychia congenita cornered: report on the 11th
Annual International Pachyonychia Congenita Consortium meeting. Br
J Dermatol 2014; 171:974–977.
Wilson NJ, et al: Homozygous dominant missense mutation in keratin
17 leads to alopecia in addition to severe pachyonychia congenita. J
Invest Dermatol 2012; 132(7):1921–1924.
DYSKERATOSIS CONGENITA
(ZINSSER-COLE-ENGMAN SYNDROME)
Dys eratosis congenita is a rare congenital syndrome
characteri ed by cutaneous poi iloderma nail dystrophy
and premalignant leu opla ia. Atrophy and telangiectasia are
accompanied by tan gray mottled hyperpigmented and
hypopigmented macules or reticulated patches ( ig. ).
These lesions are located typically on the upper torso nec
and ace although the e tremities may also be in ol ed.
The nails may be thin and dystrophic although only ridging
and longitudinal ssuring may be seen in mild cases. This is
the rst component o the syndrome to appear becoming
apparent between ages and . The other cutaneous lesions
generally ollow within years. Leu opla ia occurs mostly
on the buccal mucosa where e tensi e in ol ement with er
rucous thic ening may be present. The anus agina con unc
ti a and urethral meatus can be in ol ed. alignant neoplasms
o the s in mouth nasopharyn esophagus rectum and
cer i may occur in sites o leu opla ia. ther mani estations
o dys eratosis congenita include hyperhidrosis o the palms
and soles bullous con uncti itis gingi al disorders dental
caries hypodontia thin tooth enamel periodontitis dysphagia
resulting rom esophageal strictures and di erticula s eletal
abnormalities aplastic anemia mental de ciency and hyper
splenism. n many cases a anconi type o anemia de elops
beginning with leu openia and thrombocytopenia and pro
gressing to se ere pancytopenia. Pulmonary complications
include interstitial brosis and Pneumoc stis jiroveci ( ormerly
P carinii) pneumonia.
Patients with dys eratosis congenita ha e short telomeres
related to mutations in genes that encode components o the
telomerase comple . These include dys erin E C E
P and OP The genetic de ect or the lin ed orm is
located on and associated with the D C gene or dys
erin a protein implicated in both telomerase unction and
ribosomal R A processing. The presence o short leu ocyte
telomeres can be help ul diagnostically. Autosomal dominant
inheritance is o ten associated with mutations in hTR h E C
in ol ed in the R A component o telomerase. Some autoso
mal dominant cases ha e anemia and reticulated pigmenta
tion ollowing the lines o Blasch o. interest some patients
with idiopathic aplastic anemia or myelodysplastic syndrome
without s in ndings demonstrate h E C mutations. Autoso
mal recessi e inheritance o dys eratosis congenita has also
been reported.
Granulocyte colony stimulating actor and erythropoietin
may pro ide short term bene ts in treating bone marrow
ailure. Bone marrow transplantation or hematopoietic stem
cell transplantation with nonmyeloablati e conditioning
a ords the best outcomes.
oyeraal reidarsson syndrome is characteri ed by intra
uterine growth retardation cerebellar hypoplasia mental
retardation microcephaly progressi e combined immunode
ciency and aplastic anemia. The syndrome is genetically het
erogeneous. Some patients demonstrate D C gene mutations
and are there ore allelic to dys eratosis congenita.
Ballew BJ, et al: Updates on the biology and management of
dyskeratosis congenita and related telomere biology disorders. Expert
Rev Hematol 2013; 6(3):327–337.
Fernández García MS, Teruya-Feldstein J: The diagnosis and treatment of
dyskeratosis congenita: a review. J Blood Med 2014; 5:157–167.
Gramatges MM, et al: Short telomeres: from dyskeratosis congenita to
sporadic aplastic anemia and malignancy. Transl Res 2013; Jun 1.
doi:pii: S1931-5244(13)00146-1. 10.1016/j.trsl.2013.05.003. [Epub
ahead of print.] PMID: 23732052.
Keeling B, et al: Dyskeratosis congenita. Dermatol Online J 2014; 20:9.
FANCONI SYNDROME
Also nown as amilial pancytopenia or amilial panmyelo
phthisis anconi syndrome may be associated with di use
pigmentation o the s in (hypopigmentation hyperpigmenta
tion and ca au lait macules) absence o the thumbs aplasia
o the radius se ere hypoplastic anemia thrombocytopenia
retinal hemorrhage strabismus generali ed hyperre e ia
and testicular hypoplasia. The syndrome is associated with
increased ris o myelomonocytic leu emia SCC and hepatic
tumors. o hypersensiti ity to V light rays or chemical
agents is present. uman papilloma irus D A is o ten ound
in the SCCs. Both cutaneous and pulmonary mani estations o
associated Sweet syndrome ha e been reported. Some patients
mani est short stature ailure to thri e absent thumbs short
palpebral ssures and typical s in abnormalities but no
hematologic abnormalities.
anconi syndrome is inherited in an autosomal recessi e
manner. Analysis has shown e complementation groups
Ectodermal dysplasia
( A A A B A C A D and A ) and there ore e associ
ated genes. The genes play an important role in hematopoiesis
and abnormal gene e pression has been shown to increase
apoptosis. A A has been locali ed to . and A D to
p . . Chromosome patterns are re uently abnormal.
Chatham-Stephens K, et al: Metachronous manifestations of Sweet’s
syndrome in a neutropenic patient with Fanconi anemia. Pediatr Blood
Cancer 2008; 51(1):128–130.
Dokal I, et al: Inherited aplastic anaemias/bone marrow failure
syndromes. Blood Rev 2008; 22(3):141–153.
ECTODERMAL DYSPLASIA
The ectodermal dysplasias are a clinically and genetically het
erogenous group o genodermatoses in which the cardinal
eatures are the abnormal absent incomplete or delayed
de elopment during embryogenesis o one or more o the
epidermal or mucosal appendages (hair sebaceous glands
nails teeth or mucosal glands). Some patients with ectoder
mal dysplasia also ha e eatures o mucous membrane pem
phigoid with mucosal anti B BP autoantibodies and
se ere bilateral cicatri ing con uncti itis with blindness. Cra
nio acial reconstruction and dental implants can impro e
uality o li e or patients with ectodermal dysplasia but the
ailure rate o dental implants is high in this population.
Hypohidrotic ectodermal dysplasia
(anhidrotic ectodermal dysplasia,
Christ-Siemens-Touraine syndrome)
The classic triad o this disorder consists o hypotrichosis
anodontia and hypohidrosis or anhidrosis. ebrile sei ures
may occur in childhood. Biopsy con rms that eccrine glands
are absent or rudimentary. Prenatal s in biopsy may be
diagnostic.
Patients with the disorder ha e acies suggesti e o congeni
tal syphilis. The chee bones are high and wide whereas the
lower hal o the ace is narrow. The supraorbital ridges are
prominent and the nasal bridge is depressed orming a saddle
nose. The tip o the nose is small and upturned and the nos
trils are large and conspicuous. The eyebrows are scanty and
the eyes slant upward. The lips are thic ened with the upper
lip particularly protrusi e. At the buccal commissures there
may be radiating urrows (pseudorhagades) and on the chee s
there may be telangiectases. Sebaceous gland hyperplasia may
be noted on the chee s and orehead. Absence o mammary
glands and nipples has been reported.
Generali ed hypotrichosis is present with thin sparse hair
on the scalp. The s in is so t thin dry and smooth. There is
partial or total anodontia and nails may be thinned brittle
and ridged. The teeth may be conical in shape. ental retarda
tion has been reported but may be a conse uence o hyper
thermic episodes in childhood.
The inheritance pattern is almost always lin ed recessi e.
Three genes ectodysplasin ED DA receptor ED
and DAR associated death domain ED DD ha e been
described. All are in ol ed in nuclear actor ( ) κB acti a
tion. emale carriers may ha e segmental e pression that can
be demonstrated with a starch iodide test or sweating. Both
autosomal recessi e and dominant modes o inheritance ha e
567
 Fig. 27-37 AEC
27 syndrome with scalp
dermatitis.
Genodermatoses and Congenital Anomalies

Fig. 27-36 Hidrotic ectodermal dysplasia.

Fig. 27-38 Ectrodactyly
in EEC syndrome.
been described. The gene or autosomal dominant hypohi
drotic ectodermal dysplasia has been mapped to .
lin ed anhidrotic ectodermal dysplasia with immunode
ciency is caused by mutations in the gene encoding κB
modulator EMO or inhibitor o κB inase ( γ). Stop
codon mutations are associated with a se ere phenotype with
associated osteopetrosis and lymphedema. Patients may dem
onstrate an impaired antibody response to polysaccharides
hypogammaglobulinemia hyper g syndrome impaired
natural iller cell cytoto icity and arious associated autoim
mune diseases.

Hidrotic ectodermal dysplasia

The hidrotic type o congenital ectodermal dysplasia is o ten
re erred to as Clouston syndrome. nheritance is autosomal
dominant. ccrine sweat glands unction normally and acial
eatures are normal. Alopecia nail dystrophy palmoplantar
hyper eratosis ( ig. ) and eye changes such as cataracts
and strabismus are seen. Some patients ha e eatures resem
bling pachyonychia congenita. Widespread poromas and pal
moplantar syringo broadenomas ha e been described. The
de ecti e gene has been identi ed as encoding the gap
unction protein conne in on the pericentromeric region o
chromosome ( . ).
AEC syndrome (Hay-Wells syndrome)
An yloblepharon ( usion or partial usion o the lids) ectoder
mal de ects and cle t lip and or palate constitute the A C
syndrome. t has an autosomal dominant pattern o inheritance.
An yloblepharon may be present at birth. Sparse hair dental
de ects cle t palate and lip dystrophic nails hypospadias
syndactyly absent lacrimal puncta stenotic auditory canals
and short stature may be present. An erosi e scalp dermatitis
is more li ely to be obser ed in A C than in other ectodermal
disorders and occurs at an early age. The scalp dermatitis is
o ten e tensi e and di cult to treat and it persists or recurs
( ig. ). Low re uency ultrasound has been success ul in
treating scalp wounds unresponsi e to other measures. A C
syndrome is associated with mutations in the p gene.
EEC syndrome
ctodermal dysplasia ectrodactyly and cle t lip palate are
de ning eatures o C syndrome. The C patient lac s
568
scalp dermatitis but has mild hypohidrosis and ectrodactyly
(congenital absence o all or part o a digit) is a prominent
eature ( ig. ). olliculitis with scarring may be noted
during puberty and ocular eratitis can be a prominent
eature. As with the A C syndrome C syndrome is associ
ated with mutations in the p gene.
Rapp-Hodgkin ectodermal dysplasia syndrome
Characteristic eatures o Rapp odg in ectodermal dysplasia
syndrome include anomalies o hair (pili torti pili canaliculi
alopecia erosi e olliculitis thinning o eyebrows lashes)
cle t lip palate onychodysplasia dental caries hypodontia
cranio acial abnormality ( ig. ) hypohidrosis otitis
media (hearing de cits) and hypospadias. t is usually inher
ited in an autosomal dominant manner. The syndrome is
allelic to A C and C with p mutations demonstrated in
all three syndromes.
Ectodermal dysplasia with corkscrew hairs
Abramo its Ac erman et al. described this disorder in
patients rom se en amilies li ing on argarita sland north
east o Vene uela. Salient eatures include cor screw hairs
(e aggerated pili torti) scalp eloids ollicular plugging

tahir99 - UnitedVRG
 Fig. 27-39 Rapp-
Hodgkin syndrome.
eratosis pilaris erosis ec ema palmoplantar eratodermia
syndactyly onychodysplasia and con uncti al neo ascular
i ation. Typical acies ante erted pinnae malar hypoplasia
cle t lip palate and dental abnormalities may also be ound.
nheritance is autosomal recessi e. Anhidrosis and hypohidro
sis are not eatures.
Odonto-tricho-ungual-digital-palmar syndrome
irst described by endo a et al. the salient clinical eatures
are natal teeth trichodystrophy prominent interdigital olds
simianli e hands with trans erse palmar creases and ungual
digital dystrophy inherited as an autosomal dominant trait.
ypoplasia o the rst metacarpal and metatarsal bones and
distal phalanges o the toes may also occur.
Lenz-Majewski syndrome
Len a ews i syndrome is characteri ed by hyperostosis
craniodiaphyseal dysplasia dwar sm cutis la a pro imal
symphalangism syndactyly brachydactyly mental retarda
tion enamel hypoplasia and hypertelorism.
CHIME syndrome
The C syndrome a rare neuroectodermal disorder com
prises colobomas o the eye heart de ects ichthyosi orm der
matosis mental retardation and ear de ects. ther eatures
may include acial anomalies epidermal ne i de elopmental
delay in antile macrostomia recurrent in ections acute lym
phoblastic leu emia and duplicated renal collecting system.
The inheritance is belie ed to be autosomal recessi e related
to mutations in the glycosylphosphatidylinositol gene P L
Lelis syndrome
The Lelis syndrome is a orm o ectodermal dysplasia with
acanthosis nigricans palmoplantar hyper eratosis hypotri
Pachydermoperiostosis (idiopathic hypertrophic osteoarthropathy, Touraine-Solente-Gole syndrome)
Fig. 27-40 Pachydermoperiostosis.
chosis hypohidrosis nail dystrophy early loss o adult teeth
and mental retardation.
Nectinopathies
Cle t lip palate ectodermal dysplasia and ectodermal
dysplasia syndactyly syndrome are caused by recessi e muta
tions in the P L and P L genes respecti ely. These
genes encode nectins and which act in cooperation with
cadherins to promote cellular adhesion.
Brancati F, et al: Nectinopathies: an emerging group of ectodermal
dysplasia syndromes. G Ital Dermatol Venereol 2013; 148(1):59–64.
Felipe AF, et al: Corneal changes in ectrodactyly–ectodermal dysplasia–
cleft lip and palate syndrome: case series and literature review. Int
Ophthalmol 2012; 32(5):475–480.
Kawai T, et al: Diagnosis and treatment in anhidrotic ectodermal
dysplasia with immunodeficiency. Allergol Int 2012; 61(2):207–217.
Knaudt B, et al: Skin symptoms in four ectodermal dysplasia syndromes
including two case reports of Rapp-Hodgkin syndrome. Eur J Dermatol
2012; 22(5):605–613.
Ng BG, et al: Mutations in the glycosylphosphatidylinositol gene PIGL
cause CHIME syndrome. Am J Hum Genet 2012; 90(4):685–688.
PACHYDERMOPERIOSTOSIS (IDIOPATHIC
HYPERTROPHIC OSTEOARTHROPATHY,
TOURAINE-SOLENTE-GOLE SYNDROME)
Pachydermoperiostosis is characteri ed by thic ening o the
s in in olds and accentuation o creases on the ace and scalp
clubbing o the ngers and periostosis o the long bones. The
changes are especially prominent on the orehead where the
hori ontal lines are deepened and the s in becomes shiny ( ig.
). The eyelids particularly the upper lids are thic ened.
Li ewise there is thic ening o the ears and lips and the
tongue is enlarged. The scalp may be thic ened and may show
cutis erticis gyrata (pachydermie orticelle). The e tremities
especially the elbows nees and hands are enlarged and
spade shaped. The ngers become club shaped. The palms are
rough and the thenar and hypothenar eminences are enlarged.
yperhidrosis is common. yper eratotic linear lesions o the
palms and soles may be present. These lines are rippled
resembling sand o the wind blown desert. o ements o
the muscles may be pain ul. An association with gynecomastia
and osteoporosis has been described.
There are inherited and ac uired orms o pachydermoperi
ostosis. The ac uired orm may occur with chronic pulmonary
569
 mediastinal and cardiac diseases that are associated with
27 chronic hypo ia in peripheral tissues. Some cases ha e been
associated with bronchogenic carcinoma. When such an asso
ciation occurs enlargement o the orehead hands and ngers
may antedate recognition o the tumor or may de elop a ter
Genodermatoses and Congenital Anomalies
the tumor is identi ed as present. Bronchogenic carcinoma
associated pachydermoperiostosis occurs almost e clusi ely in
men o er age whereas inherited Touraine Solente Gole
syndrome usually occurs as an autosomal dominant disorder
with onset in late adolescence. t is not associated with malig
nant disease. ore prominent signs are seen in males. Autoso
mal recessi e inheritance with cle t palate and congenital heart
de ects has been described. rontal rhytidectomy has been
used to treat associated leonine acies and bone mani estations
ha e shown some response to oral bisphosphonate therapy
and arthroscopic syno ectomy. P D gene mutations a ect
ing hydro yprostaglandin dehydrogenase ( PGD ) and
mutations in the prostaglandin transporter gene SLCO
ha e been described.
CUTIS VERTICIS GYRATA
Cutis erticis gyrata is characteri ed by olds and urrows on
the scalp usually in an anteroposterior direction. ost re
uently the erte is in ol ed but other areas may ha e the
distincti e urrowing. There may be olds. The hair itsel
is normal.
Cutis erticis gyrata has been reported primarily in males
with a male emale ratio o . nset is usually at puberty
with more than o patients de eloping it be ore age .
The condition may be amilial when it occurs as a component
o pachydermoperiostosis. t has been reported to result rom
de elopmental anomalies in ammation trauma tumors
ne i amyloidosis syphilis my edema hlers Danlos syn
drome Turner syndrome line elter syndrome ragile syn
drome emura enib and the insulin resistance syndrome.
Biopsy ndings can be normal or may show thic collagen
bundles and hypertrophy o adne al structures.
Cutis erticis gyrata is re uently ound in patients with
mental retardation sei ures and schi ophrenia. Rarely a
cerebri orm intradermal ne us may be mista en or this dis
order. n se erely in ol ed cases e cision with gra ting or
scalp reduction may be indicated. Surgical e cision has been
used success ully to impro e acial in ol ement.
George L, et al: Frontal rhytidectomy as surgical treatment for
pachydermoperiostosis: a case report. J Dermatolog Treat 2008;
19(1):61–63.
Harding JJ, et al: Cutis verticis gyrata in association with vemurafenib
and whole-brain radiotherapy. J Clin Oncol 2014; 32:e54–56.
Sasaki T, et al: Identification of mutations in the prostaglandin
transporter gene SLCO2A1 and its phenotype-genotype correlation in
Japanese patients with pachydermoperiostosis. J Dermatol Sci 2012;
68(1):36–44.
Taha HM, Orlando A: Butterfly-shape scalp excision: a single stage
surgical technique for cutis verticis gyrata. J Plast Reconstr Aesthet
Surg 2014; 67:1747–1749.
APLASIA CUTIS CONGENITA
Aplasia cutis congenita has a predilection or the midline o
the erte o the scalp. t presents with locali ed absence o
s in and is rarely associated with ull thic ness de ects o the
cranium. An association with thyroid disease and thyroid
medications has been noted. Rarely multiple symmetric
de ects may occur in the s in o the lower e tremities. Distal
radial epiphyseal dysplasia has been associated with locali ed
aplasia cutis congenita.
570
tahir99 - UnitedVRG
The hair collar sign re ers to a ring o long dar hair
encircling the lesion. t is o ten seen with membranous aplasia
cutis which may represent a orme ruste o a neural tube
de ect. Bullous aplasia cutis congenita demonstrates a bro
ascular or edematous stroma similar to that seen in encepha
loceles and meningoceles suggesting it may also be related to
a neural tube de ect. ocal preauricular dermal dysplasia is a
orm o aplasia cutis congenita not typically associated with
any e tracutaneous anomalies. The SCALP syndrome is a
ne us sebaceus syndrome with C S mal ormations aplasia
cutis congenita limbal dermoid and a giant congenital pig
mented melanocytic ne us with neurocutaneous melanosis.
ADAMS-OLIVER SYNDROME
eatures o Adams li er syndrome include se ere aplasia
cutis congenita o the scalp which may in ol e both s in and
s ull ossi cation de ects limb de ects (brachydactyly syndac
tyly o toes two and three and hypoplastic toenails) e tensi e
cutis marmorata telangiectatica congenita cryptorchidism
and cardiac abnormalities including dilated cardiomyopathy
and heart bloc . ther associations include hemangiomas ret
rognathia and micrognathia strabismus and atrial septal
de ect. Adams li er is a rare autosomal dominant inherited
neuroectodermal syndrome.
Atasoy HI, et al: Unique variant of Adams-Oliver syndrome with dilated
cardiomyopathy and heart block. Pediatr Int 2013; 55(4):508–512.
Bakry O, et al: Adams-Oliver syndrome: a case with isolated aplasia
cutis congenita and skeletal defects. J Dermatol Case Rep 2012;
6(1):25–28.
Lam J, et al: SCALP syndrome: sebaceous nevus syndrome, CNS
malformations, aplasia cutis congenita, limbal dermoid, and pigmented
nevus (giant congenital melanocytic nevus) with neurocutaneous
melanosis: a distinct syndromic entity. J Am Acad Dermatol 2008;
58(5):884–888.
FOCAL DERMAL HYPOPLASIA (GOLTZ SYNDROME)
Golt syndrome is an lin ed dominant disorder character
i ed by mal ormations a ecting the s in eyes C S and s el
eton. Golt syndrome is related to de ects in PO C a
regulator o Wnt signaling. The large ma ority o patients with
Golt syndrome ha e been emale with lethality in most male
o spring. emales are protected by chromosome mosa
icism identical to the situation in incontinentia pigmenti.
Reddish tan atrophic o ten linear or cribri orm patches are
re uently present on the buttoc s a illae and thighs ( ig.
). Later lipocytes accumulate in the lesions in a ne oid
ashion resulting in yellowish brown nodules. The lesions are
stri ingly linear and o ten serpiginous ollowing lines o
Blasch o. They are o ten narrower than typical Blasch o seg
ments suggesting that the genetic de ect is lethal in many o
the a ected cells during de elopment. Telangiectases are o ten
present and segmental presentations ha e been described.
Papillomas may occur around the ori ces o the mouth anus
and ul a. They may be misdiagnosed as condylomata acu
minata. An early in ammatory esicular stage has been
described along with cle t lip and palate. About o
patients ha e s eletal de ects. Bone changes most o ten in ol e
the e tremities where there may be syndactyly oligodactyly
and adactyly ( ig. ). Scoliosis spina bi da and hypopla
sia o the cla icle ha e also been reported. rom to
o patients ha e ocular or dental abnormalities with coloboma
being the most common ocular de ect.
Van Allen yhre syndrome appears to represent a se ere
orm o Golt syndrome with split oot and split hand anoma
lies. DAS syndrome (microphthalmia dermal aplasia and
 Fig. 27-41 Goltz
syndrome.
Fig. 27-42 Goltz
syndrome.
sclerocornea) is also an lin ed phenotype but distinct rom
Golt syndrome. t has been mapped to p . . Patients ha e
bilateral microphthalmia with blepharophimosis and linear
dermal aplasia o ten in ol ing the ace.
Treatment o atrophic erythematous patches has been suc
cess ul using a ashlamp pumped pulsed dye laser.
Asano M, et al: A case of almost unilateral focal dermal hypoplasia
resulting from a novel mutation in the PORCN gene. Acta Derm
Venereol 2013; 93(1):120–121.
Stevenson DA, et al: Goltz syndrome and PORCN mosaicism. Int J
Dermatol 2014; 12:1481–1484.
WERNER SYNDROME (ADULT PROGERIA)
Werner syndrome is an autosomal recessi e premature aging
syndrome characteri ed by many metabolic and structural
abnormalities in ol ing the s in hair eyes muscles atty
tissues bones blood essels and carbohydrate metabolism.
Cells demonstrate genomic instability. Because most o these
signs are not ully mani ested be ore age the diagnosis is
usually made in middle age. These patients usually die be ore
age rom malignant disease or ascular accidents.
Fig. 27-43 Progeria.
Progeria (Hutchinson-Gilford syndrome)
The most characteristic ndings are premature aging and
arrest o growth at puberty senile cataracts de eloping in the
late twenties and thirties premature balding and graying and
scleroderma li e lesions o the s in. A characteristic change is
the loss o subcutaneous tissue and wasting o muscles espe
cially the e tremities so that the legs become spindly and the
trun becomes stoc y. steoporosis and aseptic necrosis are
re uently ound in the small bones o the hands. The s in
changes include poi iloderma scleroderma atrophy hyper
eratoses and leg ulcers. The s in has a di use dar gray or
blac ish pigmentation. A high pitched oice and hypogonad
ism in both genders are distincti e in Werner syndrome.
Pain ul callosities with ulcerations may occur around the
malleoli Achilles tendons heels and toes. The hair thins on
the eyebrows a illae and pubis. The s in o er the chee bones
becomes taut producing proptosis and bea ing o the nose.
Cataracts de elop early and the ocal cords become thic
ened leading to a wea high pitched oice. Premature arte
riosclerosis and se ual impotence are re uently obser ed.
Diabetes is common and areas o calcinosis circumscripta
occur. Gene e pression mimics normal aging.
A high rate o malignancy is associated with Werner syn
drome including a old increase in melanoma. Thyroid
adenocarcinoma hepatoma meningioma leu emia carci
noma o the breast brosarcoma and a ariety o sarcomas
ha e been reported. istologic changes in the s in may include
atrophy o the epidermis and brosis o the dermis.
Werner syndrome is molecularly heterogeneous. The Werner
protein con ers adhesi e properties to macromolecular pro
teins and is re uired or genomic stability. t belongs to the
Rec amily o D A helicases and appears to play a role in
telomere maintenance homologous recombination and D A
repair. utant L A encoding nuclear lamin A C is associ
ated with atypical Werner syndrome with a se erer pheno
type. utations in L A also cause utchinson Gil ord
progeria mery Drei uss muscular dystrophy and dilated
cardiomyopathy.
PROGERIA (HUTCHINSON-GILFORD SYNDROME)
Progeria or utchinson Gil ord syndrome is characteri ed
by accelerated aging dwar sm alopecia generali ed atrophy
o the s in and muscles enlarged head with prominent scalp
eins and a high incidence o generali ed atherosclerosis
usually atal by the second decade o li e. The large bald head
and lac o eyebrows and eyelashes are distincti e ( ig. ).
The s in is wrin led pigmented and atrophic. The nails are
thin and atrophic. ost patients lac subcutaneous at which
571
 Fig. 27-44 Xeroderma
27 pigmentosum.
(Courtesy of Dr. Ken
Kraemer.)
Genodermatoses and Congenital Anomalies
produces the appearance o premature senility. There are
usually sclerodermatous pla ues on the e tremities. The intel
ligence remains intact. Arteriosclerosis anginal attac s and
hemiplegia may occur ollowed by death rom coronary heart
disease at an early age. utations in L A and mosaicism
ha e been identi ed. Treatment is symptomatic mainly
control o diabetes mellitus and treatment o leg ulcerations.
Coppedè F: The epidemiology of premature aging and associated
comorbidities. Clin Interv Aging 2013; 8:1023–1032.
Goto M, et al: Werner syndrome: a changing pattern of clinical
manifestations in Japan (1917–2008). Biosci Trends 2013; 7(1):13–22.
Kalinowski A, et al: Interfacial binding and aggregation of lamin A tail
domains associated with Hutchinson-Gilford progeria syndrome.
Biophys Chem 2014; 195:43–48.
Lauper JM, et al: Spectrum and risk of neoplasia in Werner syndrome: a
systematic review. PLoS One 2013; 8(4):e59709.
XERODERMA PIGMENTOSUM
eroderma pigmentosum is an autosomal recessi e disorder
characteri ed by de ecti e D A thymidine dimer e cision
repair e treme sun sensiti ity rec ling and s in cancer. Sun
sensiti ity and lentigines are early s in ndings ( ig. ) logic disturbance with a shortened li e span. Dermal bro
with median onset be ore age years. S in cancers o ten
appear be ore age and an increase in internal cancer has
been noted as well. data suggest a old increase in
s in cancer be ore age . n a study o patients had
basal cell carcinoma or SCC and melanoma was noted in . The D A helicases unwind D A and are important in D A
ost o the tumors occur on the head and nec . cular abnor
malities were ound in and included ectropion corneal
opacity and neoplasms. Progressi e neurologic degeneration
is seen in about o patients. eroderma pigmentosum
patients in complementation group C remain ree o neuro
logic problems. Complementation groups are de ned by cor
rection o e cision repair when broblasts rom patients in
di erent groups are used. A ariant type with normal e ci
sion repair has also been described. Retinoids can pre ent the
appearance o new cancers but side e ects are signi cant and
a rebound in the number o cancers occurs when the drug is
stopped suggesting that the tumors are merely suppressed.
Photoprotection remains essential or management. ndi id
ual tumors may be e cised or destroyed with cryotherapy.
Some may be treated with topical imi uimod or . Topical
application o recombinant liposomal encapsulated T
endonuclease V repairs V induced cyclobutane pyrimidine
dimers and is a promising orm o therapy. Gene therapy is
also being pursued. Guidelines or e aluation and manage
ment rom the P Society can be ound at www. ps.org. A
572
tahir99 - UnitedVRG
publication rom the ational nstitutes o ealth can be
ound at www.cc.nih.go ccc patient education pepubs
p .pd .
eroderma pigmentosum Coc ayne syndrome and tricho
thiodystrophy are all associated with de ects in nucleotide
e cision repair ( R). Global genome R repairs D A
lesions throughout the genome pre enting the accumulation
o mutations. Transcription coupled R pre ents cell death
caused by stalled transcription by rapidly identi ying and
repairing de ects in the transcribed strand o D A. S in
tumors in eroderma pigmentosum patients ha e sunlight
induced mutations in S p and P C genes. utations
in the P gene gi e rise to the complementation group G
orm o eroderma pigmentosum as well as early onset Coc
ayne syndrome. Prenatal diagnosis is possible with cultured
chorionic illus cells or amniocytes.
The De Sanctis Cacchione syndrome consists o eroderma
pigmentosum with mental de ciency dwar sm and gonadal
hypoplasia. t occurs most o ten in patients in complementa
tion group D. utations in the E CC gene which also cause
Coc ayne syndrome type B ha e been demonstrated as well.
COCKAYNE SYNDROME
Coc ayne syndrome is an autosomal recessi e syndrome with
sun sensiti ity and neurologic degeneration related to muta
tions in e genes (CS CS P PD and P ) encoding
or proteins in ol ed in the transcription coupled subpathway
o nucleotide e cision D A repair. t di ers rom eroderma
pigmentosum in the lac o rec ling and s in cancer and in
the presence o dwar sm bea ed nose loss o subcutaneous
tissue dea ness basal ganglia calci cation ailure o brain
growth and retinopathy.
Coc ayne described the syndrome as dwar sm with retinal
atrophy and dea ness. Dermatologic eatures include photo
dermatitis with telangiectasia atrophy and scarring. The
hands and eet are large and cyanotic. icrocephaly sun en
eyes se ere e ion contractures dorsal yphosis cryptorchi
dism cataracts growth retardation mental retardation hypo
thalamic and cerebellar dys unction and retinitis pigmentosa
with optic atrophy may be seen. There is progressi e neuro
blasts and lymphoblastoid cell lines as well as cultured
amniotic uid cells rom an a ected etus demonstrate
impaired colony orming ability and decreased D A and
R A synthesis a ter V light e posure ( nm).
replication D A repair and R A transcription. utations in
P or PD D A helicase can result in eroderma pigmen
tosum Coc ayne syndrome or trichothiodystrophy. The
Coc ayne syndrome complementation group A (CSA) and
CSB genes responsible or the syndrome are associated with
R A polymerase. CSB protein plays a role in transcription as
well as global R. Coc ayne syndrome has also been associ
ated with mutations in P
XERODERMA PIGMENTOSUM/COCKAYNE
SYNDROME COMPLEX
Some patients ha e s in eatures o eroderma pigmentosum
and neurologic eatures o Coc ayne syndrome. Patients in
complementation groups B D and G ha e presented with the
comple . utations in the associated genes may gi e rise to
clinical mani estations o eroderma pigmentosum Coc ayne
syndrome or the eroderma pigmentosum Coc ayne syn
drome comple .

TRICHOTHIODYSTROPHY
Trichothiodystrophy is an autosomal recessi e disorder char
acteri ed by photosensiti ity ichthyosis brittle hair intellec
tual impairment decreased ertility and short stature (P B DS).
A re iew o patients noted a wide spectrum o clinical
eatures that aried rom patients with only hair in ol ement
to those with pro ound de elopmental de ects. Common ea
tures included intellectual impairment ( ) short stature
( ) ichthyosis ( ) ocular abnormalities ( ) in ections
( ) and photosensiti ity ( ). ore than hal the patients
had abnormal characteristics at birth and patients died
be ore age .
Tay syndrome is similar to trichothiodystrophy but lac s
photosensiti ity. Abnormalities in R o V damaged
D A are present in about o Tay patients. The V sensi
ti ity and de ecti e R are similar to those o eroderma
pigmentosum patients but these patients do not e perience
an increased incidence o s in cancer. Two o the three
described complementation groups match eroderma pig
mentosum groups B and D with the PD gene accounting or
most photosensiti e trichothiodystrophy. A combined ero
derma pigmentosum trichothiodystrophy comple has been
described. Patients with trichothiodystrophy without ero
derma pigmentosum do not ha e an increase in s in cancer
ormation.
The hair with sul ur reduced to o the normal alue
has distincti e eatures under polari ing and light microscopy
and scanning . With light microscopy eratin orientation
alternates in a Z pattern. With polari ing microscopy the hair
shows alternating bright and dar regions that gi e a stri ing
striped or tiger tail appearance but the pattern may not be
e ident at birth and a similar pattern o bright and dar bands
has been described in the eratitis ichthyosis dea ness syn
drome. airs demonstrate heterogeneous de ciency in sul ur
with the greatest loss in areas o trichoschisis (clean ractures).
Trichorrhe is nodosa li e ractures may also be seen. n addi
tion the hair is e tremely attened and olds o er itsel li e a
thic ribbon. The hair sha t outline is irregular and slightly
undulating and the melanin granules are distributed in a
wa y pattern. With scanning the sur ace shows mar ed
ridging and uting and the cuticle scales may be absent or
greatly reduced.
Aamann MD, et al: Cockayne Syndrome group B protein stimulates
NEIL2 DNA glycosylase activity. Mech Ageing Dev 2014; 135:1–14.
DiGiovanna JJ, et al: Shining a light on xeroderma pigmentosum. J
Invest Dermatol 2012; 132(3 Pt 2):785–796.
Ferrando J, et al: Further insights in trichothiodistrophy: a clinical,
microscopic, and ultrastructural study of 20 cases and literature review.
Int J Trichology 2012; 4(3):158–163.
Grossberg AL: Update on pediatric photosensitivity disorders. Curr Opin
Pediatr 2013; 25(4):474–479.
Lanzafame M, et al: From laboratory tests to functional characterisation
of Cockayne syndrome. Mech Ageing Dev 2013; 134(5-6):171–179.
Lehmann AR, et al: Xeroderma pigmentosum. Orphanet J Rare Dis
2011; 6:70.
Niedernhofer LJ, et al: Xeroderma pigmentosum and other diseases of
human premature aging and DNA repair: molecules to patients. Mech
Ageing Dev 2011; 132(6-7):340–347.
BLOOM SYNDROME
(BLOOM-TORRE-MACHACEK SYNDROME)
Bloom syndrome is transmitted as an autosomal recessi e
trait chie y among Jewish persons o astern uropean origin.
t is characteri ed by photosensiti e telangiectatic erythema in
the butter y area o the ace and dwar sm. Telangiectatic
Fig. 27-45 Bloom
syndrome.
Rothmund-Thomson syndrome (poikiloderma congenitale)
erythematous patches resembling lupus erythematosus
de elop in the rst years o li e ( ig. ). Bullous crusted
lesions may be present on the lips. acerbation o s in lesions
occurs during the summer. ther changes that may be
noted are ca au lait spots ichthyosis acanthosis nigricans
syndactyly irregular dentition lens opacities prominent ears
hypospadias and cryptorchidism. The stunted growth is char
acteri ed by normal body proportions no endocrine abnor
malities (e cept diabetes mellitus) and low birth weight at ull
term. Dolichocephaly and narrow delicate acies are present.
mmune unctions are abnormal and G and respiratory in ec
tions o ten occur. Cancer o all cell types and sites is increased
in re uency. Leu emia lymphoma adenocarcinoma o the
sigmoid colon and oral and esophageal SCC as well as other
malignancies ha e been associated with Bloom syndrome.
About one uarter o patients under age de elop a neo
plasm. Regular use o a broad spectrum sunscreen as well as
photoprotection is recommended. Testing or Bloom syn
drome should be per ormed in children with consanguineous
parents and dysmorphic eatures because growth hormone
treatment is contraindicated in these patients.
The gene mutated in Bloom syndrome LM codes or a
Rec D A helicase. BL is locali ed to the nuclear bodies
and the nucleolus and is critical or genomic stability. BL
interacts with WR the D A helicase mutated in Werner
syndrome and is part o a large BRCA containing comple
containing D A repair actors. BL e pression is highest
during the S and G phases o the cell cycle. BL associates
with telomeres and ribosomal D A. BL interacts directly
with AT the protein product o the gene mutated in ata ia
telangiectasia and together they recogni e abnormal D A
structures.
Park CJ, et al: Solution structure of the RecQ C-terminal domain of
human Bloom syndrome protein. J Biomol NMR 2014; 58(2):141–147.
Renes JS, et al: Bloom syndrome in short children born small for
gestational age: a challenging diagnosis. J Clin Endocrinol Metab
2013; 98(10):3932–3938.
Thomas ER, et al: Surveillance and treatment of malignancy in Bloom
syndrome. Clin Oncol (R Coll Radiol) 2008; 20(5):375–379.
ROTHMUND-THOMSON SYNDROME
(POIKILODERMA CONGENITALE)
Rothmund Thomson syndrome is a rare autosomal recessi e
disorder. Poi iloderma begins at months o age with
573
 Fig. 27-46 Rothmund-
27
Thomson syndrome.
Genodermatoses and Congenital Anomalies
tense pin edematous patches on the chee s hands eet and
buttoc s sparing the chest bac and abdomen (acute phase).
Sensiti ity to sunlight may be mani ested by the de elopment
o bullae or intense erythema a ter brie sun e posure. This is
ollowed by ne reticulated or punctate atrophy associated
with telangiectasia and reticulated pigmentation (chronic
phase) ( ig. ). Characteristically the arms and legs are
a ected with sparing o the antecubital and popliteal ossae.
The s in lesions are characteristic. therwise patients with
Rothmund Thomson syndrome may ha e a broad range o
noncutaneous lesions. Short stature (two thirds o patients)
small hands with radial ray de ects saddle nose absence or
sparseness o eyebrows and eyelashes ( ) alopecia o
the scalp ( ) and numerous bone de ects ( ) are o ten
obser ed. ypogonadism dystrophic nails and de ecti e
dentition are seen in a signi cant proportion o patients (
). Cataracts occur in a small percentage o patients in child
hood or young adult li e and glomerulonephritis has been
reported. Associated cutaneous neoplasms include SCC
Bowen s disease basal cell carcinoma and melanoma but the
ris or osteosarcoma o bone is particularly high (> ). The
syndrome is related to biallelic mutations o the EC L gene.
Thus at least a subset o patients with Rothmund Thomson
syndrome has abnormal D A helicase acti ity as do patients
with Werner and Bloom syndromes.
Canger EM, et al: Oral findings of Rothmund-Thomson syndrome. Case
Rep Dent 2013; 2013:935716.
Manavi S, Mahajan VK: Rothmund-Thomson syndrome. Indian Dermatol
Online J 2014; 5:518–519.
HEREDITARY SCLEROSING POIKILODERMA AND
MANDIBULOACRAL DYSPLASIA
ereditary sclerosing poi iloderma is an autosomal dominant
condition. The s in changes consist o generali ed poi ilo
derma appearing in childhood (but not at birth) with hyper
eratotic and sclerotic cutaneous bands e tending across the
antecubital spaces a illary aults and popliteal ossae. n
addition the palms and soles may show sclerosis resembling
shiny scotch grain leather. Aortic stenosis clubbing o the
ngers and locali ed calcinosis o the s in ha e also been
noted. There is no treatment. The cases described by Weary
were subse uently reported later in li e as mandibuloacral
dysplasia a rare autosomal recessi e syndrome characteri ed
by mandibular hypoplasia delayed cranial suture closure
dysplastic cla icles abbre iated club shaped terminal phalan
ges myopathy lipodystrophy acro osteolysis atrophy o the
s in o the hands and eet and typical acial changes. an
dibuloacral dysplasia must be distinguished rom progeria
and Werner syndrome.
A distinct subtype has been described in two generations o
a South A rican amily. The characteristics included poi ilo
derma tendon contracture and pulmonary brosis with
apparent autosomal dominant inheritance. Sparse ne hairs
are present on the scalp ace and body.
574
tahir99 - UnitedVRG
Khumalo NP, et al: Poikiloderma, tendon contracture and pulmonary
fibrosis: a new autosomal dominant syndrome? Br J Dermatol 2006;
155(5):1057–1061.
Lombardi F, et al: Compound heterozygosity for mutations in LMNA in a
patient with a myopathic and lipodystrophic mandibuloacral dysplasia
type A phenotype. J Clin Endocrinol Metab 2007; 92(11):4467–4471.
SCLEROATROPHIC SYNDROME OF HURIEZ
urie syndrome a ery rare autosomal dominant disorder
is characteri ed by the ollowing
. Scleroatrophy o the hands with sclerodactyly
. Ridging clubbing or hypoplasia o the nails
. Lamellar eratoderma o the hands and to a lesser
e tent the soles
Patients with urie syndrome may also ha e multiple telan
giectasias o the lips and ace and e ion contractures o
the little nger. Aggressi e SCCs occur in the scleroatrophic
s in including that o the palms and soles ( li etime ris
mortality in a ected persons). A ected patients ha e
reduced Langerhans cells in a ected s in but normal dermal
dendritic cells.
FRANCESCHETTI-KLEIN SYNDROME
(MANDIBULOFACIAL DYSOSTOSIS)
This syndrome includes palpebral antimongoloid ssures
hypoplasia o the acial bones macrostomia aulted palate
mal ormations o both the e ternal and internal ear buccal
auricular stula abnormal de elopment o the nec with
stretching o the chee s accessory acial ssures and s eletal
de ormities. Patients who ha e the complete syndrome usually
die in in ancy but patients with the aborti e type may li e to
an old age. ranceschetti lein syndrome is allelic to the
Treacher Collins syndrome and caused by the Treacher
Collins ranceschetti CO gene.
TREACHER COLLINS SYNDROME
Treacher Collins syndrome includes mid ace hypoplasia
with micrognathia microtia conducti e hearing loss and
cle t palate. t is inherited as an autosomal dominant trait and
caused by mutations in the CO gene which encodes a
protein called treacle.
OCULOAURICULOFRONTONASAL SYNDROME
This syndrome is sporadic in nature although autosomal
recessi e inheritance has been suggested by some authors.
eatures include hemi acial microsomia microtia ocular
hypertelorism upper palpebral colobomata preauricular tags
lateral ace cle ting and nasal cle ting.
POPLITEAL PTERYGIUM SYNDROME
Pterygia or s in olds may e tend rom the thigh down to
the heel and thus pre ent e tension or rotation o the legs.
Crural pterygia cryptorchidism bi d scrotum agenesis o the
labia ma ora cle t lip and palate adhesions between the
eyelids syndactyly and talipes e uino arus may be present.
Autosomal dominant inheritance has been described and
popliteal pterygium syndrome is allelic to the an der Woude
syndrome.
VAN DER WOUDE SYNDROME
The an der Woude syndrome is an autosomal dominant cra
nio acial disorder characteri ed by hypodontia pits o the
lower lip and cle t palate. t is associated with mutations in
the gene. ther reported associations include natal teeth
an yloglossia syndactyly e uino arus oot de ormity and
congenital heart disease. Lower lip pits may be ound in other
congenital disorders such as popliteal pterygium syndrome
and occasionally in oro aciodigital syndrome type (oral
renula and cle ts hypoplasia o alae nasi and digital asym
metry). Surgical correction is the treatment o choice.
APERT SYNDROME (ACROCEPHALOSYNDACTYLY)
Apert syndrome is autosomal dominant inherited and is char
acteri ed by craniosynostosis and usion o the digits (syn
dactyly). Patients present with synostosis o the eet hands
carpi tarsi cer ical ertebrae and s ull. The acial eatures
are distorted and the second third and ourth ngers are
used into a bony mass with a single nail. eurologic de ects
may be caused in part by brain compression by the abnormal
s ull. culocutaneous albinism and se ere acne ulgaris ha e
been reported with Apert syndrome although some o the
acnei orm lesions actually represent ollicular hamartomas.
utations in the broblast growth actor receptor
gene are responsible or Apert Crou on and P ei er
syndromes.
PFEIFFER SYNDROME
P ei er syndrome is autosomal dominant inherited and
consists o osteochondrodysplasia and craniosynostosis. Type
patients ha e normal intelligence and generally a good
outcome. Types and are associated with se ere neurologic
compromise a poor prognosis and sporadic occurrence.
Respiratory compromise may occur as a result o tracheal ste
nosis and brous cartilaginous rings.
CROUZON SYNDROME
Crou on syndrome includes craniosynostosis and acanthosis
nigricans. t is associated with mutations in the gene.
The crou onodermos eletal syndrome with choanal atresia
and hydrocephalus is caused by mutations in a gene
associated with achondroplastic dwar sm.
CARPENTER SYNDROME
Carpenter syndrome is an acrocephalopolysyndactyly syn
drome with an autosomal recessi e pattern o inheritance.
Patients present with craniosynostosis and acral de ormities
that include syndactyly.
WHISTLING FACE SYNDROME
n this rare disorder also nown as craniocarpotarsal syn
drome reeman Sheldon syndrome Windmill Vane and
syndrome and distal arthrogryposis type the child appears
to be whistling all the time. This con guration is the result o
microstomia deep set eyes attened mid ace coloboma con
tracted oint muscles o the ngers and hands and alterations
o the nostrils. lnar de iation o the ngers yphoscoliosis
and talipes e uino arus may be present. Brain anomalies ha e
Other syndromes that include hair abnormalities
also been reported. Autosomal dominant autosomal reces
si e and sporadic ariants ha e been reported. Prenatal diag
nosis can be made on ultrasound. Surgical inter ention may
be re uired or some patients.
Herman TE, et al: Crouzono-dermo-skeletal syndrome, Crouzon
syndrome with acanthosis nigricans syndrome. J Perinatol 2014;
34(2):164–165.
Raposo-Amaral CE, et al: Patient-reported quality of life in highest-
functioning Apert and Crouzon syndromes: a comparative study. Plast
Reconstr Surg 2014; 133(2):182e–191e.
Roscioli T, et al: Genotype and clinical care correlations in
craniosynostosis: findings from a cohort of 630 Australian and New
Zealand patients. Am J Med Genet C Semin Med Genet 2013;
163(4):259–270.
OTHER SYNDROMES THAT INCLUDE
HAIR ABNORMALITIES
Hallerman-Streiff syndrome
allerman Strei syndrome includes characteristic bird
acies congenital cataracts microphthalmia mandibular
hypoplasia hypotrichosis and dental abnormalities. The nose
is thin sharp and hoo ed and the chin is absent. The hair is
di usely sparse and brittle. Baldness may occur rontally or at
the scalp margins but sutural alopecia hair loss ollowing
the lines o the cranial sutures is characteristic o this syn
drome. The small ace is in sharp contrast with a dispropor
tionately large appearing head. The lips are thin; some o the
teeth may be absent while others are dystrophic resulting in
malocclusion. ystagmus strabismus and other ocular abnor
malities occur. Cle t palate and syndactyly may be present
representing o erlap with oculodentodigital dysplasia associ
ated with gene mutation.
Polyostotic fibrous dysplasia
(Albright’s disease)
Polyostotic brous dysplasia may present as slowly progres
si e li elong unilateral hair loss (scalp pubic a illary and
palpebral). Sic le cell disease is o ten characteri ed by scanti
ness o body and acial hair.
Cronkhite-Canada syndrome
Cron hite Canada syndrome is characteri ed by alopecia s in
pigmentation onychodystrophy malabsorption and general
i ed G polyposis.
Marinesco-Sjögren syndrome
arinesco S gren syndrome consists o cerebellar ata ia
mental retardation congenital cataracts inability to chew
ood thin brittle ngernails and sparse hair. The dystrophic
hairs do not ha e the normal layers (corte cuticle medulla)
and o the hair sha ts show narrow bands o abnormal
incomplete eratini ation. There is an autosomal recessi e
type o inheritance in this syndrome and the gene has been
mapped to chromosome .
575
 Generalized trichoepitheliomas
27 Generali ed trichoepitheliomas alopecia and myasthenia
gra is may be a ariant o the generali ed hair ollicle hamar
toma syndrome. There is a report o a locali ed ariant o this
Genodermatoses and Congenital Anomalies
syndrome. istologically there is replacement o the hair ol
licles by trichoepithelioma li e epithelial proli erations associ
ated with hyperplastic sebaceous glands.
Crow-Fukase (POEMS) syndrome
This ac uired syndrome is characteri ed by polyneuropathy
organomegaly endocrinopathy protein and s in changes
(P S) such as di use hyperpigmentation dependent
edema s in thic ening hyperhidrosis and hypertrichosis.
Cartilage-hair hypoplasia (McKusick-type
metaphyseal chondrodysplasia)
Cartilage hair hypoplasia encompasses short limbed dwar
ism and abnormally ne and sparse hair in children. These
children are especially susceptible to iral in ections and
recurrent respiratory in ections. A high incidence o non
odg in lymphoma leu emia SCC and basal cell carcinoma
has been reported. A unctional de ect o small lymphocytes
with impaired cell mediated immunity may occur ( ig. ).
ost patients are anergic to s in test panels and ha e increased
numbers o natural iller cells. The ma or mutation in ol es
the M P gene which encodes a component o mitochondrial
R A processing endoribonuclease.
Cartilage hair hypoplasia has been associated with
menn syndrome a ariant o se ere combined immunode
ciency disease (SC D) which includes erythroderma eosino
philia and susceptibility to arious pathogens. utations
in recombination acti ating genes and or
Artemis ha e been associated with menn syndrome. Artemis
de ciency causes inability to repair D A double strand brea s
and is one o the causes o radiosensiti e SC D.
Trichorhinophalangeal syndrome
This genetic disorder consists o ne and sparse scalp hair thin
nails pear shaped broad nose and cone shaped epiphyses o
the middle phalanges o some ngers and toes. Supernumer
ary teeth ha e been reported. There is an autosomal dominant
Fig. 27-47 Noninfectious granuloma in cartilage-hair hypoplasia.
(Courtesy of Drs. James Treat and Albert Yan.)
576
tahir99 - UnitedVRG
and also a recessi e inheritance type. Trichorhinophalangeal
syndrome can result rom single base pair mutations or dele
tion o the PS gene which encodes a GATA inc nger
transcription actor located on chromosomal band . .
Type (Langer Giedion syndrome) includes mental retarda
tion and multiple e ostoses and is a contiguous gene syn
drome caused by a one copy deletion in the chromosome
region spanning the genes PS and E Type
resembles a se ere orm o type with short stature.
Papillon-Lefèvre syndrome
Papillon Le re syndrome is characteri ed by hyper eratosis
palmaris et plantaris periodontosis and sparsity o the hair.
yperhidrosis and other signs and symptoms begin early in
li e. nheritance o this disease is o an autosomal recessi e type.
Klippel-Feil syndrome
lippel eil syndrome consists o a low posterior scalp hairline
e tending onto the shoulders with a short nec limiting mo e
ment o the nec and suggesti e o webbing. The cer ical er
tebrae are used. This syndrome is caused by aulty segmentation
o the mesodermal somites between the third and se enth
wee s in utero. Strabismus nystagmus cle t palate bi d u ula
and high palate are other eatures. ar abnormalities include
microtia e ternal ear canal stenosis and chronic ear in amma
tion. lippel eil syndrome occurs mostly in girls.
McKusick syndrome
eatures o c usic syndrome include short limbed dwar
ism and ne sparse hypoplastic and dysmorphic hair.
Atrichia with papules
This rare autosomal recessi e disorder is characteri ed by loss
o hair beginning shortly a ter birth and the de elopment o
cutaneous cystic papules. utations in the hairless gene ha e
been identi ed in both humans and mice but a similar phe
notype has also been reported with a normal hairless gene but
with itamin D resistant ric ets type A and mutations in the
itamin D receptor gene. The cyst epithelium demonstrates
eratins and suggesting deri ation rom the ollicular
bulge and the presence o stem cells. Both the hairless gene
and the itamin D receptor gene produce inc nger proteins
and may ha e o erlapping unctions.
Bansal M, et al: Atrichia with papular lesions. Int J Trichology 2011;
3(2):112–114.
Candamourty R, et al: Trichorhinophalangeal syndrome type 1: a
case report with literature review. J Nat Sci Biol Med 2012;
3(2):209–211.
David D, et al: Co-segregation of trichorhinophalangeal syndrome
with a t(8;13)(q23.3;q21.31) familial translocation that appears to
increase TRPS1 gene expression. Hum Genet 2013;
132(11):1287–1299.
Min BJ, et al: An interstitial, apparently-balanced chromosomal insertion
in the etiology of Langer-Giedion syndrome in an Asian family. Eur J
Med Genet 2013; 56(10):561–565.
Nickles K, et al: Long-term results after treatment of periodontitis in
patients with Papillon-Lefèvre syndrome: success and failure. J Clin
Periodontol 2013; 40(8):789–798.
Wang S, et al: Atrichia with papular lesions in a Chinese family caused
by novel compound heterozygous mutations and literature review.
Dermatology 2013; 226(1):68–74.

KERATOSIS PILARIS
eratosis pilaris may be limited in mild cases to the posterior
upper arms and mani ests as a horny plug in each hair ollicle.
The thighs are the ne t most common site but lesions may
occur on the ace orearms buttoc s trun and legs. acial
in ol ement may be mista en or acne ulgaris and may lea e
small pitted scars e en when the condition does not scar
elsewhere. Variants o eratosis pilaris with more prominent
scarring are included under the heading o eratosis pilaris
atrophicans.
The indi idual lesions are small acuminate ollicular
papules. They may or may not be erythematous. Sometimes
the eratotic plugs are the most prominent eature o the erup
tion whereas at other times most o the lesions are punctate
erythematous papules. ccasionally in ammatory acnei orm
pustules and papules may appear.
orcible remo al o one o the plugs lea es a minute cup
shaped depression at the ape o the papule which is soon
lled by new eratotic material. The lesions tend to be arranged
in poorly de ned groups dotting the otherwise normal s in
in a airly regular pattern. They are prone to appear in erotic
or atopic patients. Autosomal dominant inheritance has been
described.
ther conditions associated with eratosis pilaris are ichthyo
sis ollicularis atrichia with papular lesions mucoepidermal
dysplasia cardio aciocutaneous syndrome ( eratosis pilaris
curly hair sparse hair with pulmonary al e stenosis hypertro
phic cardiomyopathy or atrial septal de ect) ectodermal dys
plasia with cor screw hairs and D syndrome. eratosis
pilaris rubra has prominent erythema and widespread areas o
s in in ol ement but no atrophy or hyperpigmentation.
Treatment is di cult but some patients respond to topical
retinoids. Ammonium lactate can produce some smooth
ing o the lesions but seldom results in impro ement o the
erythema. Topical calcipotriene is e ecti e in some patients.
Pulsed dye laser has been used or erythematous ariants.
ERYTHROMELANOSIS FOLLICULARIS
FACIEI ET COLLI
Patients with this condition present with well demarcated ery
thema ollicular papules and hyperpigmentation. tching and
photosensiti ity may be prominent.
FOLLICULAR ATROPHODERMA
ollicular atrophoderma consists o ollicular indentations
without hairs notably occurring on e tensor sur aces o the
hands legs and arms. Scrotal ( ssured) tongue may also be
ound. t has been described repeatedly in association with
other genetically determined abnormalities including
lin ed dominant chondrodysplasia punctata Ba e syndrome
( ollicular atrophoderma type) and eratosis palmoplantaris
disseminata. Ba e (Ba e Dupr Christol) syndrome is char
acteri ed by congenital hypotrichosis ollicular atropho
derma multiple milia hypohidrosis and basal cell carcinomas.
Both trichorrhe is nodosa and pili bi urcati ha e been
described in patients with the syndrome.
KERATOSIS PILARIS ATROPHICANS
eratosis pilaris atrophicans is seen in three syndromes era
tosis pilaris atrophicans aciei atrophodermia ermiculata
and eratosis pilaris ollicularis spinulosa decal ans. eratosis
pilaris atrophicans has been reported as being associated with
woolly hair and oonan syndrome. erlap between the
three entities may occur.
Response to therapy is o ten limited but some success has
Keratosis pilaris atrophicans
been noted with eratolytics and retinoids. Pulsed dye laser
therapy has led to impro ement in erythema but not s in
roughness.
Keratosis pilaris atrophicans faciei
and ulerythema ophryogenes
eratosis pilaris atrophicans aciei is characteri ed by persis
tent erythema and small horny ollicular papules with onset
during childhood. n in olution these lea e pitted scars and
atrophy with resulting alopecia. The disorder in ol es the
eyebrows rom which it may rarely spread to the neighboring
s in and e en to the scalp. The term ulerythema ophryogenes
is used to describe cases with in ol ement limited to the
lateral third o the eyebrows.
Lesions may also begin on the chee s or temples rather than
the eyebrows. The ollicles become reddened ( ig. ) then
de elop papules and nally ollicular atrophy. n eratosis
pilaris atrophicans aciei the ollicular in ol ement e tends to
the chee s and orehead.
istologically ollicular hyper eratosis o the upper third
o the hair ollicle is seen. A small depressed scar orms when
the lesion heals. t may occur with atopy or woolly hair and
may be seen in oonan syndrome and the cardio aciocutane
ous syndrome. Transmission is autosomal dominant.
Atrophodermia vermiculata
Atrophodermia ermiculata is also nown as atrophoderma
ermiculata atrophodermia ulerythematosa olliculitis ulery
thematosa reticulata and honeycomb atrophy. t is character
i ed by symmetric in ol ement o the ace by numerous small
closely crowded areas o atrophy separated by narrow ridges
producing a cribri orm or honeycomb sur ace. This worm
eaten ( ermiculate) appearance results rom atrophy o the
ollicles and surrounding s in. ach atrophic area is an abrupt
pitli e depression mm in diameter. Among the ridges a
ew milia may be seen.
Fig. 27-48 Ulerythema ophryogenes.
577
 The s in co ering the ridges is e en with the normal s in
27 but contrasts with it by being somewhat wa y rmer and
apparently stretched. The cause o the disease is undeter
mined but amilial occurrence has been noted and it may be
associated with other diseases such as congenital heart bloc
Genodermatoses and Congenital Anomalies
other cardiac anomalies neuro bromatosis oligophrenia or
Down syndrome.
istologically the epidermis is slightly atrophic with
diminution in si e o the interpapillary pro ections. n the
dermis the capillaries are dilated and the essels ha e a mod
erate lymphocytic peri ascular in ltration. ollicles may be
enlarged tortuous dilated and hyper eratotic.
Rombo syndrome
Rombo syndrome is a rare disorder characteri ed by atropho
dermia ermiculata cyanosis o the hands and eet milia
telangiectases hypotrichosis multiple basal cell carcinomas
and trichoepitheliomas. The associated ermicular atropho
derma produces a coarse grainy s in te ture. Rombo
syndrome is inherited in an autosomal dominant manner. t
must be distinguished rom Ba e syndrome Rasmussen syn
drome (milia trichoepithelioma cylindroma) and multiple
trichoepitheliomas.
Keratosis follicularis spinulosa decalvans
(Siemens-1 syndrome)
n eratosis ollicularis spinulosa decal ans eratosis pilaris
begins on the ace and progresses to in ol e the scalp limbs
and trun . There is hyper eratosis o the palms and soles.
Cicatricial alopecia o the scalp and eyebrows is characteristic.
Atopy photophobia and corneal abnormalities are re uently
associated. Dea ness physical and mental retardation recur
rent in ections nail abnormalities acne eloidalis nuchae
tu ted hair olliculitis and aminoaciduria ha e also been pur
ported associations. The disorder is genetically heterogeneous.
Although inheritance in large indreds has been lin ed
recessi e lin ed dominant and autosomal dominant inheri
tance ha e also been suggested. n one lin ed orm the
de ecti e genetic site is on p . p . in the region o the
gene or spermidine spermine ( ) acetyltrans erase.
Alcántara González J, et al: Keratosis pilaris rubra and keratosis pilaris
atrophicans faciei treated with pulsed dye laser: report of 10 cases. J
Eur Acad Dermatol Venereol 2011; 25(6):710–714.
Janjua SA, et al: Keratosis follicularis spinulosa decalvans associated
with acne keloidalis nuchae and tufted hair folliculitis. Am J Clin
Dermatol 2008; 9(2):137–140.
Marqueling AL, et al: Keratosis pilaris rubra: a common but
underrecognized condition. Arch Dermatol 2006; 142(12):1611–1616.
H SYNDROME
The syndrome is an inherited syndrome characteri ed
by hyperpigmentation hypertrichosis and indurated patches
o s in in ol ing the lower two thirds o the body with
hearing loss hypogonadism hepatosplenomegaly short
stature cardiac anomalies and scrotal masses. The patients
e hibit growth hormone de ciency and hypergonadotropic
hypogonadism with a oospermia. Biopsies o in ol ed s in
578
tahir99 - UnitedVRG
demonstrate acanthosis with dermal and subcutaneous in l
tration by histiocytes plasma cells and mast cells.
Molho-Pessach V, et al: The H syndrome: a genodermatosis
characterized by indurated, hyperpigmented, and hypertrichotic skin
with systemic manifestations. J Am Acad Dermatol 2008l; 59(1):79–85.
MELAS SYNDROME
The LAS syndrome (mitochondrial myopathy encepha
lopathy lactic acidosis stro eli e episodes) is a rare neurode
generati e mitochondrial disorder inherited in the maternal
line. Caution is re uired during anesthesia or procedures
because se ere acidosis neurologic deterioration and cardio
respiratory compromise may occur with a single dose o pro
po ol. Di use erythema with reticular pigmentation may
occur. o the s in may re eal abnormal mitochondria.
Hämäläinen RH, et al: Tissue- and cell-type-specific manifestations of
heteroplasmic mtDNA 3243A>G mutation in human induced
pluripotent stem cell–derived disease model. Proc Natl Acad Sci USA
2013; 110(38):E3622–3630.
Kubota Y, et al: Skin manifestations of a patient with MELAS syndrome.
J Am Acad Dermatol 1999; 41:469–473.
Potestio CP, Check JH, et al: Improvement in symptoms of the syndrome
of mitochondrial encephalopathy, lactic acidosis, and stroke-like
symptoms (MELAS) following treatment with sympathomimetic
amines–possible implications for improving fecundity in women of
advanced reproductive age. Clin Exp Obstet Gynecol 2014;
41:343–345.
Bonus images for this chapter can be found online at
expertconsult.inkling.com
eFig. 27-1 Late pigmentary incontinentia pigmenti.
eFig. 27-2 Angiofibromas.
eFig. 27-3 Oral papillomas in tuberous sclerosis.
eFig. 27-4 Periungual fibromas.
eFig. 27-5 Café au lait macules.
eFig. 27-6 Proteus syndrome. (Courtesy of Dr. Michelle Maroon.)
eFig. 27-7 Ataxia-telangiectasia.
eFig. 27-8 Epidermolysis bullosa simplex.
eFig. 27-9 Junctional epidermolysis bullosa.
eFig. 27-10 Benign familial pemphigus.
eFig. 27-11 Hailey-Hailey disease.
eFig. 27-12 X-linked ichthyosis.
eFig. 27-13 Porokeratosis.
eFig. 27-14 Darier’s disease.(Courtesy of Dr. Lawrence Lieblich.)
eFig. 27-15 Pachyonychia congenita.
eFig. 27-16 Pachyonychia congenita.
eFig. 27-17 Pachyonychia congenita.
eFig. 27-18 Pachyonychia congenita.
eFig. 27-19 Hypohidrotic ectodermal dysplasia. (Courtesy of James
Fitzpatrick, MD.)
eFig. 27-20 Cutis verticis gyrata.
eFig. 27-21 Goltz syndrome.
eFig. 27-22 Sclerodermatous legs in progeria.
eFig. 27-23 Ocular squamous cell carcinoma in xeroderma
pigmentosum.
eFig. 27-24 Rothmund-Thomson syndrome.
 H syndrome
eFig. 27-1 Late pigmentation in incontinentia pigmenti.

eFig. 27-4 Periungual fibromas.

eFig. 27-2 Angiofibromas.

eFig. 27-3 Oral papillomas in tuberous sclerosis. eFig. 27-5 Café au lait macules.

578.e1
 eFig. 27-6 Proteus
27 syndrome. (Courtesy
of Dr. Michelle
Maroon.)
Genodermatoses and Congenital Anomalies

eFig. 27-9 Junctional epidermolysis bullosa.

eFig. 27-10 Benign

familial pemphigus.

eFig. 27-7
Ataxia-telangiectasia.

eFig. 27-11 Hailey-

Hailey disease.

eFig. 27-8
Epidermolysis bullosa
simplex.

578.e2

tahir99 - UnitedVRG
 eFig. 27-12 X-linked eFig. 27-14 Darier’s
ichthyosis. disease. (Courtesy of
Dr. Lawrence
Lieblich.)

H syndrome
eFig. 27-15
Pachyonychia
congenita.

eFig. 27-13 Porokeratosis.

eFig. 27-16 Pachyonychia congenita.

578.e3
27
Genodermatoses and Congenital Anomalies

eFig. 27-17 Pachyonychia congenita. eFig. 27-20 Cutis verticis gyrata.

eFig. 27-18
Pachyonychia
congenita.

eFig. 27-21 Goltz syndrome.

eFig. 27-19 Hypohidrotic ectodermal dysplasia.

eFig. 27-22 Sclerodermatous legs in progeria.

578.e4

tahir99 - UnitedVRG
 eFig. 27-24 Rothmund-
Thomson syndrome.

H syndrome
eFig. 27-23 Ocular squamous cell carcinoma in xeroderma
pigmentosum.

578.e5
 Bonus images for this chapter can be found online at
Dermal and Subcutaneous Tumors
n this chapter proli erations deri ed rom ascular endothe
lial cells broblasts myo broblasts smooth muscle cells
Schwann cells and lipocytes are re iewed. Also discussed are
se eral neoplasms o cells in ading or aberrantly present in
the dermis such as metastatic cancer endometriosis and
meningioma.
CUTANEOUS VASCULAR ANOMALIES
Di erentiation between in antile hemangiomas and ascular
mal ormations is help ul when planning therapy because
in antile hemangiomas in olute spontaneously while ascular
mal ormations are persistent. Blie et al. reported si indreds
in which in antile hemangiomas and ascular mal ormations
occurred in arious amily members in an autosomal domi
nant manner lin ing the two disorders.
Garzon MC, et al: Vascular malformations. Part I. J Am Acad Dermatol
2007; 56(3):353–370.
Garzon MC, et al: Vascular malformations. Part II. Associated
syndromes. J Am Acad Dermatol 2007; 56(4):541–564.
Kumar S, et al: Management strategy for facial venous malformations.
Natl J Maxillofac Surg 2014; 5(1):93–96.
Hamartomas
amartomas are characteri ed by an abnormal arrangement
o tissues normally present in a gi en site. This is in contrast
to a ne us which has an increase in tissue normally present
at a gi en site but in an orderly normal arrangement.
Phakomatosis pigmentovascularis
Patients with a combination o ascular mal ormations and
melanocytic or epidermal ne i are grouped into this disorder
and these are mani estations o genetic twin spotting. The
re ised classi cation includes only our types pha omatosis
cesio ammea (blue ne us dermal melanosis and ne us am
meus) pha omatosis spilorosa (ne us spilus and a pale pin
ascular spot) pha omatosis cesiomarmorata (blue spots and
cutis marmorata telangiectatica congenita) and unclassi able
cases not corresponding to the pre ious patterns. Associated
systemic ndings may include intracranial and isceral ascu
lar anomalies ocular abnormalities choroidal melanoma and
hemihypertrophy o the limbs. Pha omatosis cesio ammea is
the most common type ( ) and hal o patients with this
type ha e serious mani estations such as lippel Trenaunay
Par es Weber syndrome or Sturge Weber syndrome. Bilateral
dea ness and malignant hypertension ha e also been described.
Some authors ha e suggested that particularly e tensi e and
aberrant mongolian spots may be a mar er or more se ere
systemic in ol ement. Pha omatosis spilorosa has been asso
ciated with multiple granular cell tumors. ost patients are
tahir99 - UnitedVRG
expertconsult.inkling.com
28
Asian. Phacomatosis pigmento eratotica is now classi ed
separately as a syndrome that includes pigmented and epider
mal ne i but it has been described with connecti e tissue
ne us and pinhead si ed angioma li e lesions superimposed
on a spec led lentiginous ne us.
Arnold AW, et al: Phacomatosis melanorosea without extracutaneous
features: an unusual type of phacomatosis pigmentovascularis. Eur J
Dermatol 2012; 22(4):473–475.
Eccrine angiomatous hamartoma
ccrine angiomatous hamartoma usually appears as a solitary
nodular lesion on the acral areas o the e tremities particu
larly the palms and soles but identical lesions also occur on
areas o the body that normally ha e ew eccrine glands. This
lesion appears at birth or in early childhood and is o ten asso
ciated with pain and hyperhidrosis. The lesion is a dome
shaped tender bluish nodule. ypertrichosis may be present.
When it is stro ed or pinched drops or beaded rings o per
spiration may be seen.
istologically there is a combination o lobules o mature
eccrine glands and ducts with thin walled blood essels.
cessi e mucin at smooth muscle ner e in ltration and
terminal hairs may be present. The lesion has been associated
with spindle cell hemangioma arterio enous mal ormation
(AV ) and errucous hemangioma. cision may be neces
sary because o pain.
Halder C, et al: Eccrine angiomatous hamartoma: late onset facial
presentation. Indian J Dermatol 2014; 59(4):403–405.
Shin J, et al: Eccrine angiomatous hamartoma: a review of ten cases.
Ann Dermatol 2013; 25(2):208–212.
Malformations
al ormations are abnormal structures that result rom an
aberration in embryonic de elopment or trauma. The abnor
mality may be caused by an anatomic mal ormation or a
unctional alteration (as in ne us anemicus). Anatomic mal or
mations are subdi ided according to the type o essel in ol ed
capillary enous arterial lymphatic or combined. The term
capillary mal ormation is sometimes used as a synonym or
ne us ammeus but it is best used as a term encompassing a
ariety o entities including salmon patch ne us anemicus
and cutis marmorata telangiectatica congenita.
Di use capillary mal ormation with o ergrowth has been
characteri ed as a distinct syndrome that di ers rom lippel
Trenaunay Par es Weber syndrome ( TPW) by prominent
subcutaneous eins rather than persistent embryologic essels
and other ascular mal ormations. TPW re uires enous
and lymphatic as well as capillary mal ormation. Cutis
marmorata telangiectatica congenita is di erentiated by retic
ulated atrophy and limb hypoplasia; the macrocephaly capil
lary mal ormation syndrome by hypotonia hydrocephalus
579
 de elopmental delay and digital syndactyly and CL V S Fig. 28-1 Cutis
28 (congenital lipomatous asymmetric o ergrowth o the trun
lymphatic capillary enous and combined type vascular
marmorata
telangiectatica
mal ormations epidermal ne i s eletal and spinal anomalies) congenitale. (Courtesy
syndrome by o ergrowth with triangular eet dysmorphic of Brooke Army
Dermal and Subcutaneous Tumors

toes and truncal lymphatic enous and capillary mal orma Medical Center
tions. The macrocephaly capillary mal ormation syndrome Teaching File.)
o ten demonstrates a reticulated capillary mal ormation and
may include syndactyly and as well as asymmetry. The
P C associated segmental o ergrowth syndromes include
megalencephaly capillary mal ormation ( CAP) syndrome
hemimegalencephaly) and segmental body o ergrowth syn
dromes including CL V S syndrome.
Happle R: What is a capillary malformation? J Am Acad Dermatol 2008;
59(6):1077–1079.
Lee MS, et al: Diffuse capillary malformation with overgrowth: a clinical
subtype of vascular anomalies with overgrowth. J Am Acad Dermatol
2013; 69:589–594.

Nevus anemicus
e us anemicus is a congenital disorder characteri ed by
macules o arying si e and shape that are paler than the sur
rounding s in and cannot be made red by trauma cold or
heat. The ne us resembles itiligo but there is a normal
amount o melanin. Wood s light does not accentuate it and
diascopy causes it to merge into the surrounding blanched
s in. The patches are usually well de ned with irregular
edges. t may occur on the nec and trun o young children
with neuro bromatosis when other eatures ha e not yet
de eloped. e us anemicus can also be ound in tuberous
sclerosis or as one component o pha omatosis pigmento as
cularis. n ne us anemicus the triple response o Lewis lac s
a are but outside the ne us a are does de elop a ter rubbing
the s in. The underlying de ect is an increased sensiti ity o
the blood essels to catecholamines. n biopsy and with con
ocal microscopy lesional s in resembles normal s in.
Nevus oligemicus
e us oligemicus presents as a patch o li id s in that is cooler
than the normal s in as a result o decreased blood ow. Vaso
constriction o deep essels is thought to be the underlying
de ect.
Ferrari F, et al: Juvenile xanthogranuloma and nevus anemicus in the
diagnosis of neurofibromatosis type 1. JAMA Dermatol 2014;
150(1):42–46.
Marque M, et al: Nevus anemicus in neurofibromatosis type 1: a
potential new diagnostic criterion. J Am Acad Dermatol 2013;
69(5):768–775.
Cutis marmorata telangiectatica congenita
(congenital phlebectasia, van Lohuizen syndrome)
Cutis marmorata telangiectatica congenita is characteri ed by
the presence o a purplish reticulated ascular networ with
a segmental distribution usually in ol ing the e tremities
( ig. ). The mottling is pronounced and is made more
distinct by crying igorous acti ity and cold. At birth it may
resemble a port wine stain and lesions usually impro e by
years o age but may remain stable. The condition occurs
sporadically and there is a emale preponderance. The seg
mental distribution suggests mosaicism and occasional amil
ial occurrence could be e plained by paradominant inheritance
where hetero ygous indi iduals are phenotypically normal
and the mutation is transmitted unpercei ed only becoming
mani est when a post ygotic mutation gi es rise to loss o
hetero ygosity.
580
Associated anomalies occur in more than hal o patients.
Common anomalies include aricosities ne us ammeus
ulceration macrocephaly and hypoplasia and hypertrophy o
so t tissue and bone. nusual associations include generali ed
congenital bromatosis premature o arian ailure Chiari
mal ormation and rectal and genital anomalies. These lesions
are associated with pha omatosis pigmento ascularis and the
Adams li er syndrome (limb abnormalities scalp de ects
s ull ossi cation de ects). igh copper le els and increased
elastolysis ha e been described.
The di erential diagnosis includes residual ascular lesions
rom neonatal lupus and Boc enheimer syndrome. Boc en
heimer syndrome appears in childhood and shows progres
si e de elopment o large enous ectasias in ol ing one limb.
o treatment is re uired or cutis marmorata telangiectatica
congenita. any o the lesions will become less noticeable
with time.
Memarzadeh A, et al: Limb length discrepancy in cutis marmorata
telangiectatica congenita: an audit of assessment and management in
a multidisciplinary setting. Br J Dermatol 2014; 170(3):681–686.
Pleimes M, et al: Characteristic congenital reticular erythema: cutis
marmorata telangiectatica congenita. J Pediatr 2013; 163(2):604–
604.e1.
Nevus flammeus (port wine stain)
e us ammeus nuchae ( stor bite ) is a congenital capillary
mal ormation present in o newborns. t may persist in at
least o the population. t usually is a pin red macule situ
ated on the posterior midline between the occipital protuber
ance and the tip o the spine o the th cer ical ertebra. The
long a is is usually up and down. A similar appearing midline
ne us ammeus (salmon patch ne us simple or angel s

Fig. 28-2 Port wine stain. (Courtesy Dr. Debarbrata Bandyopadhyay.)
iss ) on the glabellar region or on one upper eyelid is present
in appro imately o newborns. t tends to ade during
childhood and is rarely associated with Bec with Wiedemann
or CAP syndrome.
ther port wine stains occur in an estimated chil
dren. The stains are present at birth and ary in color rom
pin to dar or bluish red. The lesions are usually unilateral
and located on the ace and nec ( ig. ) although they may
be widespread and in ol e as much as hal the body. The most
common site is a unilateral distribution on the ace. The
mucous membrane o the mouth may be in ol ed. Although
the sur ace o a ne us ammeus is usually smooth small as
cular nodular outgrowths or warty e crescences may de elop
o er time. These lesions o ten become more bluish or purple
with age. Se eral reports document multiple basal cell carci
nomas occurring in adult li e o er sites o long standing ne us
ammeus. Rarely ne us ammeus may appear as an ac uired
condition usually with onset a ter trauma.
e us ammeus in the area supplied by the ophthalmic
di ision o the trigeminal cranial ner e is a component o the
Sturge Weber syndrome (encephalotrigeminal angiomatosis)
but the leptomeningeal component is present in only o cooled laser treatment at wa elengths o
patients with all or most o the V branch o the trigeminal
ner e in ol ed. Leptomeningeal angiomatosis may clinically
mani est as epilepsy mental retardation hemiplegia hemi
sensory de ects and homonymous hemianopsia. Characteris
tic calci cations are present in the outer layers o the cerebral
corte ; these consist o double contoured tram trac s that
ollow the brain con olutions. cular abnormalities such
as glaucoma buphthalmos (in antile glaucoma related to
abnormal de elopment o angle ormed by cornea and iris)
retinal detachment and blindness a ect appro imately
o patients. These may be present without leptomeningeal
in ol ement. The syndrome results rom the persistence o the
primiti e embryonal ascular ple us that de elops during
the si th etal wee around the cephalic neural tube and in the
region destined to become acial s in. ormally the ple us
tahir99 - UnitedVRG
regresses during the ninth wee but in the Sturge Weber syn
drome it persists. ibronectin gene e pression is increased in
lesional broblasts.
ergrowth o so t tissue and underlying bone may occur
in an a ected e tremity gi ing rise to the lippel Trenaunay
Cutaneous vascular anomalies
Par es Weber syndrome. The lippel Trenaunay syndrome is
characteri ed by port wine mal ormations and the Par es
Weber syndrome by deep AV s.
Port wine stains are components o many rare congenital
disorders. ccasionally ne us ammeus may be a mani esta
tion o pha omatosis pigmento ascularis. The Bec with
Wiedemann syndrome may comprise acial port wine stain
macroglossia omphalocele isceral hyperplasia occasionally
hemihypertrophy and hypoglycemia. Cobb syndrome (cuta
neous meningospinal angiomatosis) is a non amilial disorder
characteri ed by a port wine hemangioma or other ascular
mal ormation in a dermatome supplied by a segment o the
spinal cord containing a enous mal ormation or AV .
yphoscoliosis is common and multiple neurologic gastroin
testinal (G ) urologic and s eletal abnormalities may also be
present. Proteus syndrome is characteri ed by ascular mal
ormations that include ne us ammeus hemihypertrophy
macrodactyly errucous epidermal ne us so t tissue subcu
taneous masses and cerebri orm o ergrowth o the plantar
sur ace. Roberts syndrome consists o a acial port wine stain
and hypomelia hypotrichosis growth retardation and cle t
lip. The Wyburn ason syndrome consists o unilateral retinal
AV associated with ipsilateral port wine stain near the
a ected eye. This may be present in association with Sturge
Weber syndrome. The TAR syndrome is de ned by congenital
thrombocytopenia bilateral absence or hypoplasia o the
radius and port wine stain. Coats disease mani ests with
retinal telangiectasia and ipsilateral acial port wine stain. The
capillary mal ormation arterio enous mal ormation (C
AV ) syndrome is an autosomal dominant disorder caused
by hetero ygous S mutations and resulting in multi ocal
capillary mal ormations and high ris or ast ow lesions.
Lesional s in in ne us ammeus demonstrates o ere pres
sion o ascular endothelial growth actor (V G ) and its
receptor (V G R ). ccasional amilial segregation o port
wine stains has been noted and a large associated gene locus
CMC has been identi ed on chromosome . S a gene
encoding p RasGAP is ound within this region and het
ero ygous inacti ating S mutations ha e been ound in
a ected amilies. Somatic mutations in ha e been
described in Sturge Weber syndrome and port wine stains.
istologically port wine stains demonstrate dilation o cap
illaries in the subpapillary networ . Laser therapy has been
used with satis actory results but a number o treatments are
re uired and recurrence is common. The ashlamp pulsed
dye laser has the best record o sa ety and e cacy. Typically
a pulse duration o . ms is used. A study o cryogen spray
ersus nm
both with mm spot si e in a range o J cm demon
strated better blanching at nm. n another study purple
lesions responded best to nm at . ms whereas red and
pin lesions showed similar results with either nm at
. ms or nm or ms. n this study nm at . ms
was less e ecti e than the other settings. ptical thermal
models predict that or essel diameters o and μm
e ecti e pulse durations should be appro imately . and
ms respecti ely. Cryospray cooling and uence can be
aried to produce optimal results. or dar er s inned patients
multiple pulse stac ing with multiple cryogen spurts pro ides
better epidermal protection. ntense pulsed light has been
e ecti e in some patients resistant to multiple pulsed dye laser
treatments. Long pulse pulsed ale andrite lasers wor best or
hypertrophic purple lesions whereas pulsed dye lasers wor
581
 best or at pin lesions. The ariable pulse pulsed dye laser
28 may be e ecti e in lesions re ractory to standard pulse dye
laser treatment. A re uency doubled ( nm) neodymium
doped yttrium aluminum garnet ( d AG) laser that allows
or shorter pulse widths large spot si es and high uences
Dermal and Subcutaneous Tumors
resulted in up to impro ement in color at month a ter
a single treatment. ther studied modalities include nm
diode and nm d AG lasers as well as intense pulse
light systems. Photodynamic therapy and use o antiangio
genic agents a ter laser irradiation show promise.
Cerrati EW, et al: Surgical treatment of head and neck port-wine stains
by means of a staged zonal approach. Plast Reconstr Surg 2014;
134(5):1003–1012.
Jagtap S, et al: Sturge-Weber syndrome: clinical spectrum, disease
course, and outcome of 30 patients. J Child Neurol 2013;
28(6):725–731.
Laquer VT, et al: Microarray analysis of port wine stains before and after
pulsed dye laser treatment. Lasers Surg Med 2013; 45(2):67–75.
Lian CG, et al: Novel genetic mutations in a sporadic port-wine stain.
JAMA Dermatol 2014; 150(12):1336–1340.
Ortiz AE, et al: Port-wine stain laser treatments and novel approaches.
Facial Plast Surg 2012; 28(6):611–620.
Reddy KK, et al: Treatment of port-wine stains with a short pulse width
532-nm Nd:YAG laser. J Drugs Dermatol 2013; 12(1):66–71.
Shirley MD, et al: Sturge-Weber syndrome and port-wine stains caused
by somatic mutation in GNAQ. N Engl J Med 2013;
368(21):1971–1979.
Deep venous malformations including cavernous
venous malformation
Ca ernous enous mal ormations present as rounded bright
red or deep purple spongy nodules. They occur chie y on the
n
head and nec and may in ol e both the s in and the mucous
membranes. There is usually a deep component with a con
U
nection to the enous circulation. Calci ed phleboliths and
locali ed hyperhidrosis may occasionally be present but the
-
lesions are generally asymptomatic. The deep components are
not amenable to laser therapy. Results o surgical resection are
generally poor. Compression may be help ul. Customi ed
9
snug tting garments are pre erable to elastic bandages.
Se eral syndromes are associated with enous mal orma
ri 9
tions. The Bannayan Riley Ru alcaba syndrome is described
later in this chapter. a ucci syndrome also nown as dys
chondroplasia with hemangiomata is characteri ed by mul
tiple ascular mal ormations with dyschondroplasia. The
h
dyschondroplasia is mani ested by une en bone growth as a
result o the de ects o ossi cation with enchondromatosis
t a
that results in multiple and re uent ractures in the period o
bone growth. During the prepubertal years cm nodules
appear on the small bones o the hand or oot. Later larger
nodules the enchondromas appear on the long bones. uch
later similar lesions appear on the trun . Sarcomatous degen
eration occurs in o patients. The distribution o the
lesions is mostly unilateral. ultiple enous mal ormations o
the s in and mucous membranes are present in this nonhe
reditary mesodermal dysplasia disorder. Lymphangiomas
may also occur. Pigmentary changes such as itiligo and ca
au lait macules ha e been noted. n llier disease the enchon
dromatosis is present without the cutaneous abnormalities.
uman enchondromatosis has been associated with abnor
malities in parathyroid hormone related protein (PT rP) its
receptor and the ndian hedgehog gene. PT rP delays
di erentiation o proli erating chondrocytes whereas
promotes proli eration.
The blue rubber bleb ne us syndrome is characteri ed by
cutaneous and G enous mal ormations. The s in lesions
ha e a cyanotic bluish appearance with a so t ele ated nip
pleli e center but deeper lesions may also occur. They can be
582
Fig. 28-3 Blue rubber
bleb nevus syndrome.
G
R
emptied by rm pressure lea ing them accid. The lesions are
V
located predominantly on the trun and arms. octurnal pain
may occur and is a characteristic symptom. Gastrointestinal
d
hemangiomas are ound throughout the G tract ( ig. )
but are numerous in the small intestine. Rupture o a lesion
ti e
may produce melena. ccasionally other organs may e press
enous mal ormations and symptomatic central ner ous
system (C S) lesions ha e been described. This syndrome
generally occurs as a sporadic condition. t may be present as
an autosomal dominant amilial trait. Treatment o bleeding
or pain ul lesions is destruction or e cision. inimally in a
si e surgical techni ues are well suited to the treatment o
numerous lesions. or patients who continue to ha e bleeding
episodes that re uire blood trans usions octreotide a soma
tostatin analog nown to decrease splanchnic blood ow may
be e ecti e. ε Aminocaproic acid has also been used.
Gorham s disease (Gorham s sign) is characteri ed by cuta
neous and osseous enous and lymphatic mal ormations
associated with massi e osteolysis or disappearing bones.
Although multiple areas o the s eletal system may be
in ol ed usually only a single bone is destroyed. The bone is
completely or partially replaced with brous tissue. The cuta
neous mal ormation may be the initial sign o the disease
which typically appears in young children usually in areas
ad acent to in ol ed bones.
Sinusoidal hemangioma is a ascular mal ormation that
usually presents in adults as a bluish purple nodule less than
cm in diameter on the trun or breasts. ultiple lesions may
occur and a acial location has also been reported. istologi
cally it appears as a lobular circumscribed mass with dilated
interconnected ascular channels lled with blood.
A amilial condition o multiple cutaneous and mucosal
enous mal ormations with abnormal enous channels and
decreased or absent smooth muscle was shown to result rom
an acti ating mutation in the receptor tyrosine inase E
endothelial gene. t is located on chromosome p and is the
result o a single amino acid substitution in the inase domain
o the E receptor.
Cerebral ca ernomas are ascular mal ormations that may
be inherited in an autosomal dominant manner. The gene
CCM has been mapped to chromosome . Cutaneous mal
ormations are sometimes present including hyper eratotic
cutaneous capillary enous mal ormations.
Venous mal ormation (V ) should be distinguished rom
glomu enous mal ormation (G glomangioma). V s are
usually sporadic whereas G s are re uently inherited. V
is lin ed to chromosome p ; G is lin ed to p and loss
o unction mutations in glomulin. G can be pin at initial
presentation but e ol es to blue blac with a cobblestone
appearance and minimal hyper eratosis. n ol ement o
an e tremity is typical and the G s are o ten pain ul i com
pressed. V is an isolated mucosal or subcutaneous blue
lesion that may in ol e muscle. The lesion o ten shrin s with
e ternal pressure and is typically pain ul in the morning due
to congestion. ncreased pain may be noted at puberty during
menstruation with pregnancy or with oral contracepti es.
V may be associated with intra ascular coagulopathy.
Sclerotherapy is more e ecti e in V than in G . thanol
amine oleate has been reported as a no el sclerotherapy agent.
Both so t tissue in ury and neuropathy ha e been reported
a ter arious orms o emboli ation or sclerotherapy. Absence
o deeper tissue in ol ement noted with magnetic resonance
imaging ( R ) is associated with a higher rate o s in necrosis
and alcohol emboli ation.
Fayad LM, et al: Venous malformations: MR imaging features that
predict skin burns after percutaneous alcohol embolization
procedures. Skeletal Radiol 2008; 37(10):895–901.
Klippel-Trenaunay syndrome (hemangiectatic
hypertrophy, angio-osteohypertrophy syndrome)
lippel Trenaunay syndrome ( TS) is characteri ed as a triad
o ne us ammeus enous and lymphatic mal ormations and
so t tissue hypertrophy o the a ected e tremity ( ig. ).
The lower limb is a ected in appro imately o patients.
When there is an associated arterio enous (AV) stula Par es
Weber is appended to the diagnosis.
The earliest and most common presenting sign is a ne us
ammeus that is con ned to the s in o an e tremity. The port
wine stain o ten stops abruptly at the midline with a sharp
linear border but it may be patchy and e tend o er the but
toc s and trun and may occasionally be seen with a bilateral
or generali ed distribution. Varicose eins may be present.
The deeper V in this sporadic syndrome may be con ned to
the s in but it o ten e tends to muscle and bone. Venous
Fig. 28-4 Klippel-
Trenaunay syndrome.
tahir99 - UnitedVRG
thromboembolism has been reported with an incidence as
high as . n other patients the deep enous system is
hypoplastic.
The in ol ed limb is usually larger and longer than normal.
ther less re uent eatures include intermittent claudication
Cutaneous vascular anomalies
enous ulcers increased s in temperature di use hair loss
hypertrichosis lymphedema altered sweating lacrimation or
sali ation. Gait abnormalities are common. emihypertrophy
o the ace; cutaneous lymphangioma; aricose pulmonary
bladder and colonic eins; and recurrent pulmonary emboli
ha e been reported. ntradural spinal cord AV s epidural
hemangioma and epidural angiomyolipoma ha e been
reported to occur at the same segmental le el as cutaneous
lesions o TS. Clinical e aluation consists o color duple
ultrasonography to e aluate the patency o the deep enous
system R or isuali ation o hypertrophic muscle and
bone arteriography when an AV stula is suspected and con
entional radiography o both e tremities. arly enography
may be per ormed i the deep enous system is not hypoplas
tic to determine whether there are de ects that might be ame
nable to surgical correction. Thic slice dynamic magnetic
resonance pro ection angiography ( RPA) and intra arterial
digital subtraction angiography can be used to detect AV
shunting in Par es Weber syndrome. utations associated
with the angiogenic actor VG ha e been described in TS.
A balanced translocation in ol ing chromosomes . and
has also been reported.
lashlamp pumped pulsed dye laser treatments may be
used or the ne us ammeus component. The aricosities and
mal ormations may respond to micro oam sclerosis endo e
nous thermal ablation or surgical stripping. dema is managed
through ele ation graded compression pumps tted gar
ments and diuretics. Surgery may be per ormed to correct the
ine uality in limb length to relie e deep enous obstruction
or to correct an associated AV stula. S in ulcers ha e
responded to sunitinib. The lippel Trenaunay Support Group
website can be ound at www. t.org.
Lacerda Lda S, et al: Differential diagnoses of overgrowth syndromes:
the most important clinical and radiological disease manifestations.
Radiol Res Pract 2014; 2014:947451.
Nguyen S, et al: Skin ulcers in Klippel-Trenaunay syndrome respond to
sunitinib. Transl Res 2008; 151(4):194–196.
Redondo P, et al: Microfoam treatment of Klippel-Trenaunay syndrome
and vascular malformations. J Am Acad Dermatol 2008;
59(2):355–356.
Arteriovenous fistulas
An arterio enous stula is a route rom artery to ein bypass
ing the capillary bed. AV stulas may be congenital or ac uired.
Congenital AV stulas occur mostly on the e tremities and
may be recogni ed or at least suspected in the presence o
aricose eins ulcerations hemangiomas and ne us am
meus. They may occur internally as a component o sler
Weber Rendu disease (hereditary hemorrhagic telangiectasia).
Ac uired AV stulas are usually the result o trauma ( ig.
) but may be created intentionally or hemodialysis access.
The s in o er AV stulas is warmer hair may grow aster
and the a ected limb may be larger than the other; thrills and
bruits may be discerned in some cases. Changes may result
rom stasis a ascular steal syndrome edema a ascular
mass increased sweating or paresthesias. At times reddish
purple nodules or a pla ue may be present with a clinical
resemblance to aposi sarcoma; this has been called pseudo
aposi sarcoma (Stewart Blue arb syndrome). t may occur
because o congenital mal ormations in which case a unilat
eral purplish discoloration o the s in o er or distal to the AV
anomaly begins to appear in the second or third decade o li e.
583

28
Dermal and Subcutaneous Tumors
Fig. 28-5 Stasislike changes below acquired arteriovenous fistula.
This type accounts or o cases; the remainder are second
ary to stulas caused by trauma. atrogenic AV stulas such
as those produced to acilitate hemodialysis may also bring
about s in changes including reacti e angioendotheliomato
sis. istologically there is an increase in thic walled essels
lined by plump endothelial cells e tra asated erythrocytes
and deposits o hemosiderin. Proli erating endothelial cells
may occlude the lumen.
Cirsoid aneurysms (angioma arteriale racemosum) are
uncommon congenital AV stulas o the scalp or ace. They
may appear on the s in as a pulsating mass that may e tend
n
o er the nec and scalp and may penetrate into the cranium
or they may simply mani est as a solitary blue or red papule
U
in the midadult period. Abdominal AV stulas may be associ
ated with lower e tremity edema cyanosis pulsatile aricose
-
eins and scrotal edema.
Diagnosis o an AV stula is established by plethysmogra
phy thermography determination o o ygen saturation o
9
enous blood or arteriography.
Treatment o traumatically induced AV stulas by e cision
ri 9
is curati e. Because the congenital mal ormation ariety
consists o multiple small distal lesions surgical inter ention
is not easible in many patients. Color echo Doppler
ultrasonography guided sclerotherapy with polidocanol
h
micro oam has been used success ully in this setting. Sodium
tetradecyl sul ate and ethanolamine oleate ha e both been
t a
used as sclerosants in arious orms o AV mal ormation. Pres
sure and ele ation as supporti e measures may limit ulcer
ation in ection and other secondary complications.
Rutherford RB: Noninvasive evaluation for congenital arteriovenous
fistulas and malformations. Semin Vasc Surg 2012; 25(1):49–57.
Scruggs J, et al: Cutaneous manifestations of abdominal arteriovenous
fistulas. Cutis 2011; 87(6):284–286.
Prominent inferior labial artery
The arteries supplying the lips are normally tortuous to accom
modate the mo ements o the mouth. owell and reeman
reported a potentially troublesome arterial anomaly o the
lower lip characteri ed by the appearance o a pulsating
papule in the lower ermilion or cm rom the oral com
missure ormed by an especially tortuous segment o the in e
rior labial artery. A similar anomaly may in ol e the upper
lip. Caliber persistent labial artery may be misdiagnosed as
s uamous cell carcinoma and the biopsy may produce signi
cant bleeding. n the lip it is best to palpate or pulsation
prior to puncture.
584
Fig. 28-6 Superficial
lymphatic
malformation adjacent
to café au lait macule.
R G
V
d
Acral arteriolar ectasia
ti e
Paslin and eaton reported a man with purple serpiginous
ectatic arterioles on the bac s o his ngers which appeared
in the th decade o li e.
Howell JB, Freeman RG: The potential peril from caliber-persistent
arteries of the lips. J Am Acad Dermatol 2002; 46:256.
Paslin DA, Heaton CL: Acral arteriolar ectasia. Arch Dermatol 1972;
106:906.
Superficial lymphatic malformation
(lymphangioma circumscriptum)
The old term or super cial lymphatic mal ormation was
lymphangioma circumscriptum; howe er this is not a tumor
but rather a congenital mal ormation o the super cial lym
phatics. A super cial lymphatic mal ormation presents as
groups o deep seated esicleli e papules ( ig. ) resem
bling rog spawn at birth or shortly therea ter. The lesions are
usually yellowish but may be pin red or dar . When the
papules are punctured they e ude clear colorless lymph. The
papules are arranged irregularly in groups that may be
interconnected by sparsely scattered lymph cysts. The entire
process howe er as a rule is locali ed to one region. The sites
o predilection are the abdomen a illae genitalia and mouth
particularly the tongue. The scrotum is sub ect to multi ocal
lymphatic mal ormations presenting as clear thic walled
esicleli e lesions. At times the sur ace is errucous in which
case the color may be brownish and the lesions may be mis
ta en or warts. Lesions resembling molluscum contagiosum
ha e also been described.
re uently the lesions consist o a combination o blood and
lymph elements so that purple areas are sometimes seen scat
tered within the esicleli e papules. The lesions are also re
uently associated with a deep component that occupies the
subcutaneous tissues and muscles. er time these lymphatic
mal ormations show only slight changes.
As with angio eratomas lymphangiomas may be seen ad a
cent to ca au lait macules. This may represent a twin spotting
phenomenon. Ac uired lesions occur in the setting o chronic
lymphedema. Lesions occurring a ter radiation therapy
o erlap with atypical ascular lesion (AVL). A peculiar
penicillamine induced dermopathy may result rom damage
to the underlying supporting structures o the dermis and
allow dilation o lymph essels within areas o trauma such
as the dorsal hands and nees. Central acial in ol ement may
be seen in ariegate porphyria and sites o chronic high
potency steroid application may de elop lymphangiectasia.
cision and gra ting ulguration or coagulation is re
uently unsatis actory because o recurrences resulting rom
ascular connections between the sur ace lesions and deep
seated lymphatic cisterns. The deeper component should be
e aluated by R or other suitable radiologic imaging to
delineate the e tent o deep in ol ement be ore planned pro
cedures. Vapori ation with the carbon dio ide (C ) laser may
be success ul i deeper components are not present. Pulsed dye
laser intense pulse light systems sclerosants and electrosur
gical techni ues ha e also been reported as e ecti e. eloid
ormation has been described a ter laser apori ation o genital
lymphangiomas. Sclerotherapy has been reported as success
ul and radiotherapy has been used success ully in select
re ractory cases.
Emer J, et al: A case of lymphangioma circumscriptum successfully
treated with electrodessication following failure of pulsed dye laser.
Dermatol Online J 2013; 19(3):2.
Kupetsky EA, Pugliano-Mauro M: Lymphangioma circumscriptum: sodium
tetradecyl sulfate 0.1% versus hypertonic saline. Dermatol Surg 2014;
40(8):928–930.
Yang X, et al: Highly selective electrocoagulation therapy: an innovative
treatment for lymphangioma circumscriptum. Dermatol Surg 2014;
40(8):899–905.
Cystic lymphatic malformation
Cystic lymphatic mal ormations are deep seated typically mul
tilocular poorly de ned so t tissue masses that are painless
and co ered by normal s in. They are most common in the oral
ca ity and on the e tremities and ha e been described in a
ucci syndrome. Cystic hygromas are clinically better circum
scribed occurring usually in the nec ( ig. ) a illa or groin.
The posterior nec lesions may be associated with Turner syn
drome other chromosomal aneuploidy conditions hydrops
etalis or other congenital abnormalities. Cytogenic analysis
o children born with cystic hygromas is indicated because
aneuploidy may recur in subse uent pregnancies. Transab
dominal or trans aginal sonography can isuali e these lesions
Fig. 28-7 Cystic hygroma.
tahir99 - UnitedVRG
in utero. sually the lesions will recur a ter surgical treatment
because o their depth but in ection sclerotherapy with agents
such as (picibanil) may result in regression. Sildena l
has been reported as an e ecti e nonsurgical treatment in the
setting o pediatric orbital lymphangioma.
Cutaneous vascular anomalies
Gandhi NG, et al: Sildenafil for pediatric orbital lymphangioma. JAMA
Ophthalmol 2013; 131(9):1228–1230.
Guruprasad Y, et al: Cervical cystic hygroma. J Maxillofac Oral Surg
2012; 11(3):333–336.
Lymphangiomatosis
Di use or multi ocal dilated lymphatic channels in ol ing the
s in so t tissues bone and parenchymal organs are a rare
congenital condition. an e tremity is a ected the prognosis
is good; howe er when ital internal organs are in ol ed the
prognosis is poor. S in lesions are presenting signs in o
patients with thoracic lymphangiomatosis. These patients
ha e a high incidence o complications including chylothora
( ) pulmonary in ltrates ( ) bone lesions ( ) splenic
lesions ( ) cer ical in ol ement ( ) and disseminated
intra ascular coagulation ( ). Splenic lymphangiomatosis
has been associated with Proteus syndrome. Di use pulmo
nary lymphangiomatosis has been success ully treated with
be aci umab.
Gorham-Stout syndrome
Gorham Stout syndrome is characteri ed by lymphangioma
tosis and chylous e usions with osteolytic changes resulting
in anishing bones. Response to pegylated inter eron ( )
al a b was noted in a year old boy with systemic disease
Response to bisphosphonates has also been noted.
Al-Jamali J, et al: Gorham-Stout syndrome of the facial bones: a review
of pathogenesis and treatment modalities and report of a case with a
rare cutaneous manifestations. Oral Surg Oral Med Oral Pathol Oral
Radiol 2012; 114(6):e23–e29.
Aman J, et al: Successful treatment of diffuse pulmonary
lymphangiomatosis with bevacizumab. Ann Intern Med 2012;
156(11):839–840.
Nikolaou VS, et al: Vanishing bone disease (Gorham-Stout syndrome): a
review of a rare entity. World J Orthop 2014; 5(5):694–698.
Dilation of preexisting vessels
Spider angioma (vascular spider,
spider nevus, nevus araneus)
The lesion o spider angioma is suggesti e o a red spider.
The ascending central arteriole represents the body o the
spider and the radiating ne essels suggest the multiple legs.
These small telangiectases occur singly or se erally most re
uently on the ace and nec with decreasing re uency on
the upper trun and upper e tremities. n young children the
sites o predilection are the bac s o the hands and orearms
and the ace.
oung children and pregnant women show these lesions
most re uently. n pregnant women palmar erythema is
usually present with the ascular spiders. The presence o
ascular spiders in otherwise healthy children is common.
Vascular spiders also occur in patients with cirrhosis hepa
titis C malignant disease o the li er and other hepatic dys
unctions. The common denominator has been shown to be an
ele ated blood estrogen le el. le ations in V G and basic
broblastic growth actor are also signi cant predictors or
spider angiomas in cirrhotic patients. When ascular spiders
occur with palmar erythema and pallid nails with distal
585
 Fig. 28-8 Venous lake.
28
Dermal and Subcutaneous Tumors
hyperemic bands cirrhosis o the li er should be considered.
AV hemangioma has also been reported to be associated with
chronic li er disease.
The ascular spiders o childhood usually in olute without
treatment although se eral years may elapse be ore this
occurs. n pregnant women most lesions will in olute soon
a ter deli ery. acti e therapy will be per ormed either oblit
n
eration by electrodesiccation o the central punctum or laser
treatment can produce good results.
U
Venous lakes
-
Venous la es (phlebectases) are small dar blue slightly ele
ated blebs ( ig. ). They are easily compressed and are
9
located on the ace ears lips nec orearms and bac s o the
hands. These mani estations o chronic sun damage are
ri 9
e tremely dilated blood lled spaces lined with thin elon
gated endothelial cells and usually surrounded by prominent
solar elastosis. Venous la es may be treated by light electro
cautery laser ablation ulguration in rared coagulation intra
h
lesional in ection o polidocanol and cryotherapy.
a
Capillary aneurysms
t
These esh colored solitary lesions resembling an intradermal
ne us may suddenly grow larger and dar er and become
blue blac or blac as a result o thrombosis. Capillary aneu
rysms are surrounded by a one o erythema. The lesions may
be clinically indistinguishable rom malignant melanoma. is
tologically these are thrombotic dilated capillaries lying ust
below the epidermis. Sha e e cision in stages will e pose the
clot and eliminate the uncertainty.
Telangiectasia
Telangiectases are ne linear essels coursing on the sur ace
o the s in; collecti ely they are named telangiectasia. Telan
giectasia may occur in normal s in at any age in both genders
and anywhere on the s in and mucous membranes. ine tel
angiectases may be seen on the alae nasi o most adults. They
are prominent in areas o chronic actinic damage seen in air
s inned persons. Persons long e posed to wind cold or heat
are also sub ect to telangiectasia.
586
Telangiectases can be ound in such conditions as radioder
matitis eroderma pigmentosum lupus erythematosus (L )
dermatomyositis scleroderma and the CR ST syndrome
rosacea cirrhosis o the li er ac uired immunode ciency syn
drome (A DS) poi iloderma basal cell carcinoma necrobiosis
lipoidica diabeticorum sarcoid lupus ulgaris adenoma
sebaceum eloid angioma serpiginosum angio eratoma cor
poris di usum ata ia telangiectasia pregnancy sler Weber
Rendu disease and Bloom syndrome. These entities are
discussed in other sections with the disease states in which
they occur.
Altered capillary patterns on the ngernail olds (cuticular
telangiectases) are indicati e o collagen ascular disease such
as L scleroderma or dermatomyositis. Tortuous glomeru
loid loops are characteristic o L whereas dilated loops and
a ascular areas are typical o scleroderma and dermatomyo
sitis. Reticular telangiectatic erythema may occur o erlying
implantable cardio erter de brillators.
lectrodessication and laser ablation can be e ecti e. Pulsed
dye laser and other ascular lasers such as the nm
G
d AG laser are usually well tolerated and associated with
a low ris o scarring. Larger essels re uire a longer pulse
R
duration. Contact or cryospray cooling can reduce the inci
dence o complications. Pulse stac ing (multiple pulses o low
V
uences) has been used to reduce the incidence o side e ects
such as purpura hyperpigmentation hypopigmentation and
d
scar ormation.
ti e
Generalized essential telangiectasia
Generali ed essential telangiectasia (G T) is characteri ed by
the dilation o eins and capillaries o er a large segment o the
body without preceding or coe isting s in lesions. The telan
giectases may be distributed o er the entire body or locali ed
to some large area such as the legs arms and trun . The
lesions may be discrete or con uent. Distribution along the
course o the cutaneous ner es may occur. This type o telan
giectasia is rarely associated with systemic disease although
patients with a similar appearance may ha e autoimmune
disease. ne report documented G bleeding rom a water
melon stomach in a woman with G T.
ost re uently G T de elops in women in their orties
and ties. The initial onset is on the lower legs and then
spreads to the upper legs abdomen and arms. The dilations
persist inde nitely. Generally this is a sporadic condition
although it has been described in amilies as an autosomal
dominant trait in which case it has been termed hereditary
benign telangiectasia.
t has been reported that G T may be di erentiated rom
telangiectasia associated with systemic disease by assessing
al aline phosphatase acti ity. Telangiectatic essels in G T do
not ha e al aline phosphatase acti ity in the endothelium o
the terminal arteriole and the arterial portion o the capillary
loops.
ndi idual areas may be treated with laser ablation. igh
energy high re uency long pulse d AG laser and the
nm ashlamp pumped pulsed dye laser ha e been
reported to produce good results. Tetracycline etocona ole
and treatment o a chronic sinus in ection ha e led to in olu
tion in indi idual reports.
Universal angiomatosis
ni ersal angiomatosis called generali ed telangiectasia by
Bean is a bleeding disease that a ects the blood essels o the
s in and mucous membranes as well as other parts o the
body. Bean and Rather reported a year old boy who had
re uent nosebleeds and ear and upper respiratory in ections.

Fig. 28-9 Unilateral nevoid telangiectasia.
e had mottled s in with redness that blanched on pressure.
inely dilated blood essels were uni ersal suggesting the
term pin man. Some irregular white patches were also
present. Continual bleeding into the s in was e ident despite
normal coagulation o the blood. This type o angiomatosis
di ers rom generali ed telangiectasia because o its hemor
rhagic tendency especially epista is.
Unilateral nevoid telangiectasia
n unilateral ne oid telangiectasia ne threadli e telangiecta
ses de elop in a unilateral sometimes dermatomal distribu
tion ( ig. ). The areas most o ten in ol ed are the trigeminal
and C and C or ad acent areas with the right side in ol ed
slightly more o ten than the le t. n some cases the condition
is congenital but more o ten it is ac uired. ncreased estrogen
appears to play a role in the onset o ac uired cases (e.g.
pregnancy puberty in women adrenarche in men) and
hepatitis alcohol related cases ha e been reported. Lesions
ha e responded to pulse dye laser treatment.
Angiokeratomas
Angio eratomas are essentially telangiectases that ha e an
o erlying hyper eratotic sur ace. Angio eratoma corporis di
usum is discussed in Chapter .
Angiokeratoma circumscriptum
Angio eratoma circumscriptum is a mal ormation o dermal
and subcutaneous capillaries and eins and is ariably classi
ed as a capillary or enous mal ormation. The ascular mal
ormation is congenital. er time a errucous component
appears. The lesions are bluish red and well de ned and occur
mainly on the lower e tremities but also on the chest or
orearm. Linear segmental lesions ha e been described. Asso
ciated spinal lesions (Cobb syndrome) ha e been reported.
lippel Trenaunay syndrome has also been reported in asso
ciation with errucous ascular mal ormation. Super cial
ablati e therapy is typically ollowed by recurrence regard
less o whether ablation is per ormed by e cision laser cryo
therapy or electrocautery. n contrast ull thic ness e cision
is generally e ecti e and may be used in combination with
laser therapy.
Angiokeratoma of Mibelli
The lesions o angio eratoma o ibelli consist o mm red
ascular papules the sur aces o which become hyper eratotic
tahir99 - UnitedVRG
Cutaneous vascular anomalies
Fig. 28-10 Fordyce angiokeratomas.
o er time. The papules are dull red or purplish blac erru
cous and rounded and are usually situated on the dorsum o
the ngers and toes the elbows and the nees. re uently
these are called telangiectatic warts. The patient o ten has cold
cyanotic hands and eet. Autosomal dominant inheritance has
been described and an association with chilblains is common.
The condition is most re uently disco ered in prepubertal
children.
istologically hyper eratosis increased thic ness o the
granular layer and dilation o the subpapillary essels to orm
lacunae are the chie eatures.
The di erential diagnosis o angio eratomas o the dorsal
hands in children includes acral pseudolymphomatous angio
eratoma in children (APAC ). owe er APAC is
unilateral and sporadic in nature without associated cold sen
siti ity; histologic e amination re eals a dense nodular lym
phohistiocytic in ltrate with occasional plasma cells
eosinophils and multinucleated giant cells. t is a ariant o
pseudolymphoma and not primarily a ascular lesion. Similar
lesions may occur in adolescents and adults and the terms
acral angio eratoma li e pseudolymphoma and T cell rich
angiomatoid polypoid pseudolymphoma o the s in ha e
been used to describe these aried presentations.
Angio eratoma may be treated with electrocautery ulgura
tion C laser ablation long pulse ascular laser therapy or
cryotherapy with airly good results.
Angiokeratoma of the scrotum (Fordyce)
The angiomas are multiple small ascular papules that stud
the scrotum ( ig. ) and sometimes the ul a in middle
age and elderly indi iduals. There is o ten a di use redness o
the in ol ed area that may be a source o concern to the patient.
rethral or clitoral lesions may also be seen. n re uently the
eratotic part may be in oluntarily scratched o to produce
considerable bleeding. Rarely the lesions may bleed spontane
ously. istologically the many communicating lacunae in the
subpapillary layer are lined with endothelium and connected
underneath by dilated eins. Treatment is best accomplished
by sha e e cision cautery laser ablation or ulguration o
troublesome lesions. The primary therapy is reassurance.
Brown KR, et al: Superficial venous disease. Surg Clin North Am 2013;
93(4):963–982.
Dayrit JF, et al: T-cell-rich angiomatoid polypoid pseudolymphoma of
the skin: a clinicopathologic study of 17 cases and a proposed
nomenclature. J Cutan Pathol 2011; 38(6):475–482.
Turan H, et al: Acquired unilateral nevoid telangiectasia syndrome
accompanied by chronic hepatitis B virus infection. Acta
Dermatovenerol Croat 2013; 21(2):133–134.
587
 Fig. 28-11 Kimura’s
28 disease. (Courtesy of
Department of
Dermatology, Keio
University School of
Dermal and Subcutaneous Tumors
Medicine.)
Wang L, et al: Solitary angiokeratoma on palms and soles: a
clinicopathological analysis of 21 cases. J Dermatol 2013;
40(8):653–656.
Zeng Y, et al: Treatment of angiokeratoma of Mibelli alone or in
combination with pulsed dye laser and long-pulsed Nd:YAG laser.
Dermatol Ther 2014; 27(6):348–351.
Hyperplasias
Angiolymphoid hyperplasia with eosinophilia
Patients with angiolymphoid hyperplasia with eosinophilia
(AL ) usually present with pin to red brown dome shaped
dermal papules or nodules o the head or nec especially in
U
the retroauricular area and elsewhere on the scalp. AL may
also occur in the mouth and on the trun e tremities penis
-
and ul a. Grouped lesions merge to orm pla ues or grape
li e clusters. There is a emale preponderance and the a erage
age o onset is years. Symptoms can include pain or pruri
9
tus which may occur a ter trauma. An underlying AV shunt
is present as a result o damage to and repair o an artery or
ri 9
ein. istologically central thic walled essels with hobnail
endothelium are noted. Surrounding hyperplasia o smaller
essels and nodular lymphoid aggregates with eosinophils are
present.
h
Lesions do not spontaneously regress. Treatment with surgi
cal e cision is success ul in o cases. The lesions may recur
t a
i the underlying AV shunt is not e cised. ntralesional corti
costeroids pulsed dye laser therapy with con entional or
ultralong pulsed systems d AG laser cryotherapy pent
o i ylline indomethacin imi uimod and electrodesiccation
ha e been success ul in some patients. Di cult cases ha e
been controlled with al a b isotretinoin or inblastine
and partial responses to intralesional bleomycin ha e been
reported.
t is important to distinguish AL rom imura s disease
( ig. ). imura s disease is an in ammatory disorder that
presents as massi e subcutaneous swelling in the periauricu
lar and submandibular region in young Asian men. istologi
cally prominent germinal centers with eosinophils are present
in the subcutaneous tissue. Although blood essels are abun
dant changes are less prominent than in AL . Additionally
imura s disease is associated with allergic conditions such as
asthma rhinitis and ec ema and it is re uently accompanied
by lymphadenopathy peripheral blood eosinophilia and ele
ated g le el. Although clonal T cell gene rearrangement
has been reported in both AL and imura s disease het
eroduple polymerase chain reaction (PCR) has dispro ed
588
Fig. 28-12 Pyogenic
granuloma.
G
clonality in some cases positi e on con entional PCR. Coe is
tence o AL and peripheral T cell lymphoma has been
R
reported.
Akdeniz N, et al: Intralesional bleomycin for angiolymphoid hyperplasia.
V
Arch Dermatol 2007; 143(7):841–844.
Carlesimo M, et al: Angiolymphoid hyperplasia with eosinophilia treated
d
with isotretinoin. Eur J Dermatol 2007; 17(6):554–555.
Choi JE, et al: Successful treatment of Kimura’s disease with a 595-nm
ti e
ultra-long pulsed dye laser. Acta Derm Venereol 2008; 88(3):315–316.
Griauzde J, Srinivasan A: Imaging of vascular lesions of the head and
neck. Radiol Clin North Am 2015; 53(1):197–213.
Hoff SR, et al: Head and neck vascular lesions. Otolaryngol Clin North
n
Am 2015; 48(1):29–45.
Pyogenic granuloma
A pyogenic granuloma is a small erupti e usually solitary
sessile or pedunculated riable papule ( ig. ). The lesion
is common in children but may occur at any age. t occurs most
o ten on an e posed sur ace on the hands orearms or ace
or at sites o trauma. The lesion also occurs in the mouth
especially on the gingi a most o ten in pregnant women
(granuloma gra idarum). n the sole o the oot or nail bed
it may be mista en or a melanoma. Pyogenic granulomas
bleed easily on the slightest trauma and i cut o super cially
promptly recur. Recurring lesions may ha e one or many sat
ellite lesions.
Pyogenic granulomas may be seen in patients treated with
isotretinoin capecitabine emura enib or indina ir. sotreti
noin treatment o acne ulgaris can be complicated by numer
ous e uberant pyogenic granuloma li e lesions o the trun
or periungual lesions. Some data suggest that patients with
pyogenic granuloma ha e a statistically higher pre alence o
artonella seropositi ity compared with controls but a de nite
etiologic role has not been established.
istologically pyogenic granuloma is a lobular capillary
hemangioma with lobules separated by connecti e tissue
septa. With time the epidermis becomes thinned then eroded.
ea y secondary staphylococcal coloni ation is common.
ntra ascular pyogenic granuloma appears as a lobular capil
lary proli eration within a ein.
Treatment is by curettage or sha e e cision ollowed by
destruction o the base by ulguration or sil er nitrate. Sil er
nitrate alone may be su cient to treat smaller lesions. Topical
timolol imi uimod under occlusion and sclerotherapy with
monoethanolamine oleate or sodium tetra decyl sul ate ha e
been used success ully. At times a recalcitrant lesion may
re uire e cision or laser ablation. The drug induced ariety
will regress a ter lowering o the dose or discontinuation o Marks V, et al: Reflectance confocal microscopy features of angioma
the medication. Systemic corticosteroids ha e been used to serpiginosum. Arch Dermatol 2011; 147(7):878.
treat recurrent giant pyogenic granulomas.
Samatha Y, et al: Management of oral pyogenic granuloma with sodium
Benign neoplasms

Cutaneous vascular anomalies

tetra decyl sulphate: a case series. NY State Dent J 2013; 79(4):55–57.
Sammut SJ, et al: Pyogenic granuloma as a cutaneous adverse effect
of vemurafenib. N Engl J Med 2014; 371(13):1265–1267. Infantile hemangioma (strawberry hemangioma)
Intravascular papillary endothelial hyperplasia Strawberry (capillary) hemangiomas the most common
benign tumors o childhood are present at birth in one third
asson described this intra ascular papillary proli eration that o cases. The remainder appear shortly therea ter. Si ty percent
may mimic angiosarcoma. The lesions appear as red or pur are on the head and nec but they may occur anywhere. The
plish mm to cm papules or deep nodules on the head nec dome shaped lesion is dull to bright red and when in olution
or upper e tremities. The condition represents recanali ation begins strea s or islands o white appear in the lesion as it
o a thrombosed essel. istologic e amination re eals intra attens. The lesions ha e sharp borders; they are so t and
ascular papillary pro ections lined by endothelial cells. easily compressed ( ig. ). Generally they tend to grow
Thrombi may still be present and the papillary pro ections may o er the rst year or so remain stable or a period o months
ha e a brinous or hyaline core. igh resolution ultrasound and then slowly in olute spontaneously. The period o great
imaging may be use ul in establishing the diagnosis although est growth is the rst months. lceration occurs in almost
the diagnosis is usually made by biopsy. cision is curati e. o lesions usually by months o age. Appro imately
Kim TH, et al: Intravascular papillary endothelial hyperplasia (Masson’s resol e by the third year by age and by
tumour) in the vulva. Eur J Obstet Gynecol Reprod Biol 2013; years o age. The s in may appear normal a ter in olution but
169(2):413–414. more o ten atrophy telangiectasia or anetoderma type
redundancy is present.
Angioma serpiginosum The ma ority o these lesions occur sporadically but in
dreds with autosomal dominant inheritance o in antile hem
Angioma serpiginosum rst described by utchinson in angiomas and or ascular mal ormations ha e been described.
is characteri ed by minute copper colored to bright red angi Large segmental hemangiomas o the s in may be associated
omatous puncta that tend to become papular. These puncta with isceral hemangiomatosis in ol ing the li er G tract
occur in groups which enlarge through the constant ormula lung brain and mediastinum. acial segmental hemangiomas
tion o new points at the periphery whereas those at the center are associated with P AC syndrome; proposed by rieden
ade. n this manner linear arrays small rings or serpiginous et al. in P AC denotes the association o posterior ossa
patterns are ormed. o purpura is present but a netli e or brain mal ormations (primarily the Dandy Wal er mal orma
di use erythema orms the bac ground. n the areas undergo tion) hemangiomas arterial anomalies coarctation o the
ing in olution a delicate tracery o rings and lines a ne aorta and other cardiac de ects and eye abnormalities. When
des uamation and at times a semblance o atrophy are seen. sternal cle ting and abdominal raphae are present the desig
Slight licheni cation and scaling may be e ident in the papular nation P AC S is used. The hemangiomas re uently in ol e
lesions. The eruption predominates on the lower e tremities. more than one dermatome. lat lumbar hemangiomas are
Although it a ects both genders at all ages o cases occur o ten associated with occult spinal dysraphism. The acronym
in girls under . t is usually slowly progressi e and chronic L BAR syndrome has been used to describe the association
and although in olution may occur it is probably ne er com o lower body hemangioma urogenital anomalies myelopa
plete. Treatment with a pulsed dye laser will impro e or elimi thy bony de ormities anorectal mal ormations arterial anom
nate such lesions. Angioma serpiginosum ollowing Blasch o s alies and renal anomalies.
lines with associated esophageal papillomatosis has been
reported as an lin ed dominant condition with mild
Fig. 28-13 Infantile
eatures o Golt Gorlin syndrome including hair and nail
hemangioma.
dystrophy. The condition maps to p . .
Angioma serpiginosum must be di erentiated rom the
progressi e pigmentary disease o Schamberg. n the latter
pinpoint areas o purpura the so called cayenne pepper
spots orm macules that tend to coalesce and orm di usely
pigmented patches. The pigment is hemosiderin. Purpura
annularis telangiectodes ( a occhi) is o ten bilateral and is
characteri ed by acute outbrea s o telangiectatic points that
spread peripherally and orm small rings. n lichenoid purpu
ric and pigmentary dermatosis o Gougerot and Blum the
primary lesion is a minute lichenoid reddish brown papule
that is sometimes hemorrhagic. t has a tendency toward
central in olution and residual pigmentation.
n angioma serpiginosum the most important histologic
nding is dilated and tortuous capillaries in the dermal papil
lae and the upper dermis. o in ammatory in ltrate or
e tra asation o red blood cells is obser ed. The dilated capil
laries show no al aline phosphatase acti ity in contrast to
normal capillaries.
Blinkenberg EO, et al: Angioma serpiginosum with oesophageal
papillomatosis is an X-linked dominant condition that maps to
Xp11.3–Xq12. Eur J Hum Genet 2007; 15(5):543–547.
589

tahir99 - UnitedVRG
 ultiple hemangiomas usually mm in si e may
28 appear in the rst ew wee s to months o li e and in large
numbers. purely cutaneous they generally in olute without
se uelae and the term benign neonatal hemangiomatosis is
applied. owe er isceral lesions may be present in the C S
Dermal and Subcutaneous Tumors
lungs li er or other organs. When internal lesions are present
complications may occur such as G or C S bleeding high
output cardiac ailure obstructi e aundice and respiratory
ailure; this results in high mortality among untreated patients.
Preliminary screening includes stool guaiac test or occult
blood ( emoccult) and imaging o the li er. either o these
is positi e more e tensi e studies are indicated with special
attention to the thyroid and heart.
The pathogenesis o in antile hemangiomas is comple .
CD + stem cells within the hemangioma di erentiate into
mature blood essels that e press GL T a glucose trans
porter normally restricted to endothelial cells with blood
tissue barrier unction as in brain and placenta. The essels
proli erate then in olute. Some suggest the stem cells could
originate rom placental trophoblast. istologically straw
berry mar s are composed o primiti e endothelial cells
similar to those ound be ore the embryonic de elopment o
true enous channels. ltrastructurally they lac typical
Weibel Palade bodies but do ha e crystalloid inclusions
typical o embryonic endothelium and stain or GL T . They
also stain or c γ R Lewis antigen (Le ) and merosin.
oung hemangiomas show e idence o endothelial progenitor
cells that stain with CD and CD . n late stages the endo
thelium attens and the lumina are more apparent because o
increased blood ow. n time brosis becomes pronounced as
in olution progresses.
Simple obser ation may be appropriate or many heman
n
giomas allowing the lesions to regress spontaneously. The
so called Cyrano de ect a hemangioma that causes the
U
end o the nose to become bulbous may be success ully
approached surgically in many cases be ore the patient
-
begins school. Additionally surgical inter ention in small
pedunculated hemangiomas and eyelid tumors may also be
an e cellent option. Compressi e wraps may impro e
9
e tremity hemangiomas.
ndications or pharmacologic inter ention include se ere
ri 9
hemorrhage thrombocytopenia threatened cardio ascular
compromise rom high output cardiac ailure nasal or audi
tory canal obstruction hepatic hemangiomatosis s in ulcer
ation or threatened inter erence with ital unctions such as
h
eeding respiration passage o urine or stool limb unction
tissue destruction or ision. There is a ris o occlusion ambly
t a
opia astigmatism and myopia rom periorbital hemangiomas.
Additionally strong consideration should be gi en to treat
ment o hemangiomas that may lead to permanent dis gure
ment or long term psychological conse uences such as large
hemangiomas o the ear nose glabellar area or lips.
Beta bloc ers are used most re uently but systemic treat
ment can be complicated by bradycardia or hypoglycemia
and regular eedings are critical be ore and during treatment.
Rebound is common a ter discontinuation o β bloc ers and
longer courses are now usually employed. Some hemangio
mas respond to topical β bloc ers. ntralesional corticosteroid
treatment has been used but carries some ris o emboli ation
and occlusion o ocular essels. n ection regularly produces
pressures e ceeding the systemic arterial pressure leading to
possible emboli ation.
ral prednisone at a dose o mg g day has also been
used or in antile hemangioma. n the o patients who
respond well to treatment the enlarging hemangioma stops
growing in days. lcerations will heal within wee s.
The lesion will usually shrin i treatment is continued or
days. Laryngeal in ol ement and stridor i present are
590
usually dramatically relie ed by treatment. Repeated courses
o treatment may be underta en i rebound o growth occurs
on discontinuation o the steroidal agent. Some e perts recom
mend prolonged low dose oral corticosteroids o er a month
period to pre ent this rebound phenomenon. Treatment with
recombinant inter eron is rarely used because o the ris o
spastic diplegia. Topical imi uimod low re uency ultra
sound and selecti e arterial emboli ation ha e also been used.
Both d AG and potassium titanyl phosphate ( TP) lasers
ha e been used to deli er intralesional therapy.
Burne R, Taylor R: Monitoring propranolol treatment in periocular
infantile haemangioma. Eye (Lond) 2014; 28(11):1281–1285.
Chamlin SL, et al: Multicenter prospective study of ulcerated
hemangiomas. J Pediatr 2007; 151(6):684–689; 689.e1.
Hochman M: Infantile hemangiomas: current management. Facial Plast
Surg Clin North Am 2014; 22(4):509–521.
Hoff SR, et al: Head and neck vascular lesions. Otolaryngol Clin North
Am 2015; 48(1):29–45.
Iacobas I, et al: LUMBAR: association between cutaneous infantile
hemangiomas of the lower body and regional congenital anomalies.
G
J Pediatr 2010; 157(5):795–801.e1–e7.
McCuaig CC, et al: Therapy of ulcerated hemangiomas. J Cutan Med
Surg 2013; 17(4):233–242.
R
Pope E, et al: Oral versus high-dose pulse corticosteroids for
problematic infantile hemangiomas: a randomized, controlled trial.
Pediatrics 2007; 119(6):e1239–e1247.
V
Shehata N, et al: Late rebound of infantile hemangioma after cessation
of oral propranolol. Pediatr Dermatol 2013; 30(5):587–591.
d
Rapidly involuting congenital hemangioma
ti e
and noninvoluting congenital hemangioma
Rapidly in oluting congenital hemangioma (R C ) and non
in oluting congenital hemangioma ( C ) are rare GL T
negati e ascular tumors that present ully grown at birth and
either in olute rapidly or ail to in olute. Whereas smooth
muscle actin (S A) positi e cells are common in the walls o
in antile hemangiomas they are rare in R C . Children with
R C or C coe isting with in antile hemangioma ha e
been described as ha e children with partially in oluting con
genital hemangioma.
Cherry angiomas (senile angiomas,
de Morgan spots)
These round slightly ele ated ruby red papules . mm in
diameter are the most common ascular anomalies. t is a rare
year old person who does not ha e a ew and the number
increases with age. Probably e ery year old person has
some senile angiomas. ost are on the trun ; they are rarely
seen on the hands eet or ace. arly lesions may mimic pete
chiae. When lesions are surrounded by a purpuric halo amy
loidosis should be suspected. rupti e lesions ha e been
described a ter nitrogen mustard therapy. Light electrodesic
cation or laser ablation with intense pulsed light ( PL) and
long pulse d AG laser systems can be e ecti e. Sha e e ci
sion can also be per ormed but most patients accept reassur
ance and do not re uest remo al.
Fodor L, et al: A side-by-side prospective study of intense pulsed light
and Nd:YAG laser treatment for vascular lesions. Ann Plast Surg 2006;
56(2):164–170.
Ma HJ, et al: Eruptive cherry angiomas associated with vitiligo: provoked
by topical nitrogen mustard? J Dermatol 2006; 33(12):877–879.
Targetoid hemosiderotic hemangioma
n Santa Cru and Aronberg described a lesion character
i ed by a central brown or iolaceous papule surrounded by

Fig. 28-14 Targetoid hemosiderotic hemangioma.
an ecchymotic halo ( ig. ). The term hobnail hemangioma
has been proposed because many lesions are not targetoid.
These ac uired hemangiomas occur in the young to middle
age indi iduals and are present on the trun or e tremities.
They li ely represent trauma to a pree isting hemangioma
with thrombosis and subse uent recanali ation. istologi
cally a biphasic growth pattern is seen with central super
cial dilated ascular structures lined by prominent hobnail
endothelial cells and collagen dissecting narrow essels in
deeper parts o the lesion. The endothelial cells commonly
stain or CD but not CD . D staining suggests lymph
angiomatous proli eration.
Gutte RM, Joshi A: Targetoid hemosiderotic hemangioma. Indian
Dermatol Online J 2014; 5(4):559–560.
Glomeruloid hemangioma
Glomeruloid hemangioma is a distincti e benign ascular
neoplasm rst described in and reported in patients with
P S (Crow u ase) syndrome and Castleman s disease.
Some ha e also been associated with idiopathic thrombocyto
penic purpura and S gren syndrome. Similar lesions ha e
been reported in patients who are otherwise healthy.
The P S syndrome consists o polyneuropathy (se ere
sensorimotor) organomegaly (heart spleen idneys) endo
crinopathy component ( protein monoclonal gammopa
thy) and s in changes (hyperpigmentation hypertrichosis
thic ening sweating clubbed nails leu onychia angiomas).
Small rm red to iolaceous papules appear on the trun and
pro imal e tremities in appro imately one third o patients.
istologically the lesions may be micro enular hemangio
mas cherry angiomas multinucleated cell angiohistiocyto
mas or glomeruloid hemangiomas. The latter consist o ectatic
ascular structures containing aggregates o capillary loops
within a dilated lumen simulating the appearance o a renal
glomerulus. Se uestered degenerating red blood cells are a
characteristic nding. Two types o endothelial cell ha e been
noted within the lesions a capillary type endothelium with
large esicular nuclei open chromatin pattern and a large
amount o cytoplasm; and sinusoidal endothelium with small
basal nuclei dense chromatin and scant cytoplasm. Lesions
associated with P S syndrome demonstrate increased
e pression o V G and its receptor lt .
Jacobson-Dunlop E, et al: Glomeruloid hemangiomas in the absence of
POEMS syndrome. J Cutan Pathol 2012; 39(4):402–403.
tahir99 - UnitedVRG
Fig. 28-15 Tufted
angioma.
Cutaneous vascular anomalies
Microvenular hemangioma
The recently described micro enular hemangioma is an
ac uired benign ascular neoplasm that presents as an asymp
tomatic slowly growing . . cm reddish lesion on the
orearms or other sites o young to middle age adults. ulti
ple and erupti e ariants ha e been described. Dermoscopic
e amination re eals multiple well demarcated red globules.
onomorphous elongated blood essels with small lumina
in ol e the entire reticular dermis. n many areas the endo
thelial cells are surrounded by pericytes. The endothelial cells
are podoplanin (D ) negati e. GL T may be ocally posi
ti e. The main di erential diagnosis is aposi sarcoma. Along
with glomeruloid hemangioma micro enular hemangioma
may sometimes be present in P S syndrome.
Linos K, et al: Microvenular hemangioma presenting with numerous
bilateral macules, patches, and plaques: a case report and review of
the literature. Am J Dermatopathol 2013; 35(1):98–101.
Trindade F, et al: Microvenular hemangioma: an
immunohistochemical study of 9 cases. Am J Dermatopathol
2012; 34(8):810–812.
Tufted angioma (angioblastoma)
The tu ted angioma lesion usually de elops in in ancy or early
childhood on the nec and upper trun . Adult onset has also
been described. The lesions present as poorly de ned dull red
macules with a mottled appearance arying rom to cm in
diameter. Some show clusters o smaller angiomatous papules
superimposed on the main macular area ( ig. ) and asso
ciated hypertrichosis has been noted. The lesions are usually
sporadic although amilial cases ha e been reported. isto
logic e amination re eals small circumscribed angiomatous
tu ts and lobules scattered in the dermis in a so called can
nonball pattern. Tumors with eatures o both tu ted angioma
and aposi orm hemangioendothelioma ( ) ha e been
described and trans ormation between the tumors has also
been noted. mmunostaining can be help ul in distinguishing
these tumors. Tu ted angioma is characteri ed by a proli era
tion o CD + endothelial cells with ew actin positi e cells.
shows CD staining only in the luminal endothelial
cells. n in antile hemangiomas actin positi e cells outnumber
CD + cells.
ost lesions slowly e tend with time being progressi e but
benign in nature. ccasional spontaneous regression is docu
mented; howe er treatment with low dose aspirin pulsed
dye laser PL e cision high dose corticosteroids radiation
591
 incristine and propranolol has been success ul. Lesions asso
28 ciated with asabach erritt syndrome ha e also been treated
with emboli ation prednisone and incristine.
The term angioblastoma has also been used or a rare pedi
atric tumor o ten associated with destruction o regional struc
Dermal and Subcutaneous Tumors
tures including bone. Basic broblast growth actor has been
reported to be ele ated and some patients ha e responded to
treatment with al a b.
Fahrtash F, et al: Successful treatment of kaposiform
hemangioendothelioma and tufted angioma with vincristine. J Pediatr
Hematol Oncol 2010; 32(6):506–510.
Javvaji S, et al: Response of tufted angiomas to low-dose aspirin.
Pediatr Dermatol 2013; 30(1):124–127.
Sabharwal A, et al: Acquired tufted angioma of upper lip: case report
and review of the literature. Head Neck Pathol 2013; 7(3):291–294.
Wang L, et al: Congenital disseminated tufted angioma. J Cutan Pathol
2013; 40(4):405–408.
Yamamoto Y, et al: Successful treatment of tufted angioma with
propranolol. J Dermatol 2014; 41(12):1120–1122.
Kaposiform hemangioendothelioma
aposi orm hemangioendothelioma ( ) is an uncommon
ascular tumor that a ects in ants and young children. Rare
cases ha e been reported in adults. t was rst designated
in . Although it re uently occurs in the retroperito
neum may present as multinodular so t tissue masses
purpuric macules pla ues and multiple telangiectatic
papules. The lesions e tend locally and usually in ol e the
s in so t tissues and e en bone. The cutaneous ariant may
be associated with lymphangiomatosis. is locally aggres
si e and may be complicated by platelet trapping and con
sumpti e coagulopathy ( asabach erritt syndrome) but
distant metastases ha e not yet been reported. t has also been
reported in association with ilroy onne disease (primary
hereditary lymphedema).
istologically there are combined eatures o cellular in an
tile hemangioma and aposi sarcoma. Additionally in some
tumors lymphangiomatosis is seen sharply separated rom
the ascular lesion. There is a multilobular appearance that
closely resembles that o tu ted angioma but in lesions
are larger and less circumscribed and in ol e the deep so t
tissue and e en bone. Transition between these tumors has
been described. The transcription actor Pro has been
shown to induce proli eration and deep e tension in a mouse
model o the disease.
The prognosis depends on the depth and location o the
lesion. Signi cant morbidity and mortality may result rom
compression and in asion o surrounding structures. local
i ed to the s in lesions may be success ully e cised. owe er
because o their tendency or deep and in ltrati e growth this
is usually not possible. A response to β bloc ers has been
noted in only about one third o patients and a combination
o systemic corticosteroids and incristine either agent alone
or rapamycin is o ten necessary. Low dose radiation and
alcohol in ection ha e also been used or patients and
the combination o incristine aspirin and ticlopidine has
been gi en in the setting o asabach erritt syndrome.
Kasabach-Merritt syndrome
(hemangioma with thrombocytopenia)
asabach erritt syndrome ( S) is seen in in ants at an
a erage age o wee s. Be ore the onset o the acute e ent
the in ant will o ten ha e a reddish or bluish pla ue or tumor
on the limb or trun or in rare instances no isible lesion at
all. The lesions usually ha e an associated lymphatic compo
nent and most are s. S also occurs in tu ted angiomas
592
and multi ocal lymphangioendotheliomatosis lesions that
both demonstrate lymphatic di erentiation. S is rarely
reported in association with capillary hemangiomas or angio
sarcoma. Some patients with enous mal ormations will ha e
a chronic low grade consumpti e coagulopathy that occurs
throughout li e and this should not be con used with S.
n ants with S suddenly de elop a pain ul iolaceous
mass in association with purpura and thrombocytopenia. The
most stri ing sign is the bleeding tendency especially in
the hemangioma itsel or into the chest or abdominal ca ities.
The spleen may be enlarged. emoglobin platelets brinogen
and actors V and V are all reduced. Prothrombin time
and partial thromboplastin time are prolonged and brin split
products may be ele ated. Cases o microangiopathic hemo
lytic anemia ha e also been described. Repeated episodes o
bleeding may occur and although these may be spontaneous
bleeding can be precipitated by surgery directed either at the
hemangioma or elsewhere. The mortality may be as high as
with most deaths secondary to bleeding complications.
Because S may be a sel limited disorder e pectant
obser ation may be the best approach initially. Systemic cor
ticosteroids al a a incristine inblastine cyclophos
phamide actinomycin D emboli ation ε aminocaproic acid
antiplatelet agents irradiation e cision and compression
therapy ha e been used alone or in combination. Treatment
is o ten di cult howe er and some S patients respond
poorly to all attempted modalities.
Chiu YE, et al: Variable response to propranolol treatment of kaposiform
hemangioendothelioma, tufted angioma, and Kasabach-Merritt
phenomenon. Pediatr Blood Cancer 2012; 59(5):934–938.
Drolet BA, et al: Consensus-derived practice standards plan for
complicated kaposiform hemangioendothelioma. J Pediatr 2013;
163(1):285–291.
Fernandez-Pineda I, et al: Long-term outcome of vincristine-aspirin-
ticlopidine (VAT) therapy for vascular tumors associated with
Kasabach-Merritt phenomenon. Pediatr Blood Cancer 2013;
60(9):1478–1481.
Margolin JF, et al: Medical therapy for pediatric vascular anomalies.
Semin Plast Surg 2014; 28(2):79–86.
Shen W, et al: Treating kaposiform hemangioendothelioma with
Kasabach-Merritt phenomenon by intralesional injection of absolute
ethanol. J Craniofac Surg 2014; 25(6):2188–2191.
Multifocal lymphangioendotheliomatosis
Patients with multi ocal lymphangioendotheliomatosis
present at birth with hundreds o red brown pla ues as large
as se eral centimeters. Similar lesions may occur in the G tract
and are associated with se ere bleeding. Se ere thrombocyto
penic coagulopathy ( asabach erritt syndrome) occurs in
a ected children. Treatment with corticosteroids and or
al a results in little to no impro ement. The histology is
distincti e with delicate thin walled essels lined by hob
nailed endothelium with papillary tu ting. The endothelial
cells demonstrate a high proli erati e raction with i stain
ing and are reacti e with L V suggesting lymphatic
di erentiation.
Yeung J, et al: Multifocal lymphangioendotheliomatosis with
thrombocytopenia. J Am Acad Dermatol 2006; 54(5
Suppl):S214–S217.
Acquired progressive lymphangioma
(benign lymphangioendothelioma)
Wilson Jones introduced the term ac uired progressi e
lymphangioma in to designate a group o lymphangio
mas that occur anywhere in young indi iduals grow slowly
and present as bruiseli e lesions or erythematous macules.

Fig. 28-16 Multiple glomangiomas.
Rarely the lesion is yellow or alopecic. The histologic appear
ance is that o delicate endothelium lined spaces dissecting
between collagen bundles. A similarity to the pla ue stage o
aposi sarcoma may be stri ing. Simple e cision is curati e.
Prednisone has caused some e tensi e lesions to regress.
Kim HS, et al: Acquired progressive lymphangioma. J Eur Acad
Dermatol Venereol 2007; 21(3):416–417.
Glomus tumor and glomangiomas
The solitary glomus or neuromyoarterial tumor is most re
uently a s in colored or slightly dus y blue rm nodule
mm in diameter. Subungual tumors show a bluish tinge
through the translucent nail plate. The tumor is usually
e tremely tender and paro ysmal pain occurs re uently.
Sensiti ity is li ely to be present constantly and when touched
the tumor responds with se ere radiating pain. owe er non
tender glomus tumors are encountered. The characteristic
location is subungual but tumor may occur on the ngers and
arms or elsewhere. Digital lesions are more common in
women and there is a male predominance o nondigital
lesions. There appears to be an association between glomus
tumor and neuro bromatosis. igh resolution R high
resolution ultrasonography ( ) and color duple
sonography may be used to de ne the limits o the tumor
be ore surgery is underta en. Progressi e growth may lead to
ulceration.
ultiple glomangiomas are usually nontender and are gen
erally widely distributed o er the body. These may be inher
ited as an autosomal dominant trait and can be congenital.
Clinically they may resemble lesions o blue rubber bleb ne us
( ig. ). When grouped in one area they may appear as a
con uent mass. ereditary multiple glomus tumors may rep
resent an autosomal dominant mosaic trait and may be con
genital. The glomus coccygeum is a normal structure that may
be seen in pilonidal sinus e cision specimens.
istologically glomus tumors contain numerous ascular
lumina lined by a single layer o attened endothelial cells.
Peripheral to the endothelial cells are layers o glomus cells.
Generally these are round and arranged in distinct rows
resembling strings o blac pearls. Rarely the cells ha e a
somewhat spindled morphology. ultiple glomangiomas
tend to ha e only one or two layers o glomus cells. Gloman
giomyomas ha e a prominent muscularis media in addition
to one or two layers o glomus cells. Both solitary and multiple
glomus tumors are related to the arterial segment o the cuta
neous glomus the Suc uet oyer canal. The glomus cells
tahir99 - UnitedVRG
are modi ed ascular smooth muscle cells and stain with
imentin rather than desmin. Smooth muscle actin is o ten
positi e.
Treatment o solitary glomus tumors is best carried out by
complete e cision which immediately produces relie rom
Cutaneous vascular anomalies
pain. The subungual tumors are most di cult to locate and
eradicate because they are usually small seldom more than a
ew millimeters in diameter.
Rare reports o glomangiosarcomas describe large deeply
located e tremity lesions that consist o sarcomatous areas
intermingled with areas o benign glomus tumor.
Ham KW, et al: Glomus tumors: symptom variations and magnetic
resonance imaging for diagnosis. Arch Plast Surg 2013; 40(4):392–396.
Harrison B, Sammer D: Glomus tumors and neurofibromatosis: a newly
recognized association. Plast Reconstr Surg Glob Open 2014;
2(9):e214.
Yanai T, et al: Immunohistochemical demonstration of cyclooxygenase-2
in glomus tumors. J Bone Joint Surg Am 2013; 95(8):725–728.
Hemangiopericytoma
True hemangiopericytomas are rare. The term is now reser ed
or lesions that demonstrate di erentiation toward pericytes
and cannot be otherwise classi ed. ost lesions ormerly clas
si ed as hemangiopericytomas are now classi ed as e amples
o solitary brous tumor or giant cell angio broma. Remaining
lesions can o ten be classi ed as glomangiopericytoma
myopericytoma or in antile myo bromatosis.
Clinically the typical lesion is a nontender bluish red tumor
that occurs on the s in or in the subcutaneous tissues on any
part o the body. The rm usually solitary nodule may be up
to cm in diameter. istologically the tumor is composed o
endothelium lined essels that are lled with blood and sur
rounded by cells with o al or spindle shaped nuclei (peri
cytes). The pericytes o ten orm a concentric peri ascular
pattern. Staghornli e ectatic spaces are o ten encountered.
Wide local e cision is the treatment o choice but radiation
therapy may produce e cellent palliation.
Lesions formerly classified as hemangiopericytomas
Various so t tissue tumors can present with a
hemangiopericytoma li e staghorn ascular pattern the most
common being solitary brous tumor. Solitary brous tumor
is usually CD + and has a wide distribution in the s in
mucosa and iscera. When e cision cannot be accomplished
targeted therapy including imatinib may be help ul. yo
bromas demonstrate nodular pale blue hypocellular ones
with surrounding hypercellular ones that contain staghorn
essels. Some e amples lac the hypocellular ones and
present only with a hemangiopericytoma li e pattern. yo
pericytoma is a rare mesenchymal neoplasm that typically
in ol es the e tremities. The tumor demonstrates concentric
peri ascular spindle cells with myoid di erentiation. Gloman
giopericytoma is a closely related tumor composed o peri as
cular spindle cells with myoid di erentiation; it combines
eatures o glomus tumors and a hemangiopericytoma li e
ascular pattern.
Stacchiotti S, et al: Targeted therapies in rare sarcomas: IMT, ASPS,
SFT, PEComa, and CCS. Hematol Oncol Clin North Am 2013;
27(5):1049–1061.
Watanabe K, et al. CD34-negative solitary fibrous tumour resistant to
imatinib. BMJ Case Rep 2013; Jul 5.
Proliferating angioendotheliomatosis
Diseases designated angioendotheliomatosis ha e historically
been di ided into two groups a reacti e in oluting type and
593
 Fig. 28-18 Spindle cell
28 hemangioendotheliomas.
(Courtesy of Dr. Timothy
Gardner.)
Dermal and Subcutaneous Tumors

Fig. 28-17 Diffuse dermal angiomatosis.

a malignant rapidly atal type. alignant angioendothelio

matosis has been shown to be intra ascular (angiotropic)
lymphoma rather than a true ascular lesion.
The reacti e type o angioendotheliomatosis is uncommon.
t occurs in patients who ha e subacute bacterial endocarditis
Chagas disease pulmonary tuberculosis cryoproteinemia
se ere atherosclerotic disease periodontal disease and anti
phospholipid antibodies as well as in patients with no iden
ti able underlying process. Patients present with red purple
patches pla ues nodules petechiae and ecchymoses usually
o the lower e tremities. Some may present with a li edoid
pattern or lesions resembling atrophie blanche. Di use dermal
angiomatosis is a ariant associated with ischemia or athero
sclerosis. The lesion occurs most o ten on the thigh breast
or pannus in areas o ascular insu ciency ( ig. ) and
may clear with re asculari ation. t has also been described
Spindle cell hemangioma
in association with an AV stula and with anticardiolipin (spindle cell hemangioendothelioma)
antibodies. Spindle cell hemangioma is a ascular tumor that was rst
istologically the essels in benign reacti e angio described in . The condition typically presents in a child or
endotheliomatosis are dilated and are lled with proli erating young adult who de elops blue nodules o rm consistency on
endothelial cells usually without atypia. Some cases demon a distal e tremity ( ig. ). sually multi ocal lesions occur
strate a proli eration o capillaries in the dermis with within an anatomic region. istologically a well circumscribed
di use lobular or mi ed patterns. ibrin microthrombi are dermal nodule will contain dilated ascular spaces with asci
common and some cases show amyloid deposits or positi e cles o spindle cells between them. Areas o the tumor will ha e
immunohistochemical staining or human herpes irus an open al eolar pattern resembling hemorrhagic lung tissue.
( V ) in lesional endothelial cell nuclei. The course in this Phleboliths are common. A thrombosed large ad acent essel
type is characteri ed by in olution o er years. Therapy or with recanali ation may be identi ed. The lesions appear to
the underlying condition has been considered as hastening represent benign ascular proli erations in response to trauma
in olution. to a larger essel. They may recur a ter e cision.
The malignant type o angioendotheliomatosis is actually
a large cell intra ascular lymphoma and is discussed in
Chapter . Low-grade malignancies
Kawaoka J, et al: Coexistence of diffuse reactive
angioendotheliomatosis and neutrophilic dermatosis heralding Epithelioid hemangioendothelioma
primary antiphospholipid syndrome. Acta Derm Venereol 2008;
88(4):402–403. pithelioid hemangioendothelioma usually presents as a soli
tary slow growing papule or nodule on a distal area o an
Hemangioendotheliomas e tremity and beha es as a low grade malignancy ( ig. ).
There is a male preponderance and onset is re uently be ore
emangioendotheliomas ( s) are a group o tumors that the indi idual is years o age. istologically there are two
span the spectrum rom benign to low grade malignancy. components dilated ascular channels and solid epithelioid
aposi orm s are associated with tu ted angiomas and and spindle cell elements with intracytoplasmic lumina. Wide
asabach erritt syndrome and are discussed with those enti e cision is recommended with e aluation o regional lymph
ties. Composite s may ha e epithelioid or reti orm eatures nodes which are the usual site o metastases. n the minority
and beha e as borderline malignant tumors. mmunoreacti o cases in which distant metastatic lesions de elop chemo
ity or Pro suggests lymphatic di erentiation. therapy radiation or both may be employed.
594

Fig. 28-19 Large, ulcerated epithelioid hemangioendothelioma.
Retiform hemangioendothelioma
Reti orm hemangioendothelioma is another orm o low grade
malignancy that presents as a slow growing e ophytic mass
dermal pla ue or subcutaneous nodule on the upper or lower
e tremities o young adults. istologically there are arbori
ing blood essels reminiscent o normal rete testis architecture.
V D A se uences ha e been reported in this tumor.
Wide e cision is recommended although local recurrences
are common. To date no widespread metastases ha e
occurred although regional lymph nodes may de elop tumor
in ltrates.
Epithelioid sarcomalike (pseudomyogenic)
hemangioendothelioma
The epithelioid sarcomali e ariant demonstrates sheets o
spindle epithelioid and rhabdomyoblastic cells. This ariant
also beha es as a low grade malignancy.
Endovascular papillary angioendothelioma
(Dabska tumor)
ndo ascular papillary angioendothelioma a rare low grade
angiosarcoma presents as a slow growing tumor on the head
nec or e tremity o in ants or young children. t shows mul
tiple ascular channels with papillary plugs o endothelial
cells surrounding central hyalini ed cores that pro ect into the
lumina sometimes orming a glomeruloid pattern. The entity
is contro ersial; similar histologic eatures ha e been obser ed
in other ascular tumors such as angiosarcoma reti orm
hemangioendothelioma and glomeruloid hemangioma. The
tumor may be a distinct entity or may demonstrate a histologic
pattern seen in other ascular tumors. Wide e cision and e ci
sion o the regional lymph nodes when in ol ed are usually
curati e.
Liau JY, et al: Composite hemangioendothelioma presenting as
a scalp nodule with alopecia. J Am Acad Dermatol 2013; 69(2):
e98–e99.
McNab PM, et al: Composite hemangioendothelioma and its
classification as a low-grade malignancy. Am J Dermatopathol 2013;
35(4):517–522.
Requena L, et al: Cutaneous epithelioid sarcomalike (pseudomyogenic)
hemangioendothelioma: a little-known low-grade cutaneous vascular
neoplasm. JAMA Dermatol 2013; 149(4):459–465.
tahir99 - UnitedVRG
Cutaneous vascular anomalies
Fig. 28-20 Kaposi sarcoma.
Malignant neoplasms
Kaposi sarcoma
orit aposi described this ascular neoplasm in and
called it multiple benign pigmented idiopathic hemorrhagic
sarcoma. Since his description the disease has been reported
in e separate clinical settings with di erent presentations
epidemiology and prognoses as ollows
. Classic aposi sarcoma ( S) an indolent disease seen
chie y in middle age men o Southern and astern
uropean origin
. A rican cutaneous S a locally aggressi e process
a ecting middle age A ricans in tropical A rica
. A rican lymphadenopathic S an aggressi e disease o
young patients primarily children under age
. aposi sarcoma in patients immunosuppressed by A DS
. Lymphoma or immunosuppressi e therapy
Clinical features
Classic Kaposi sarcoma
The early lesions appear most o ten on the toes or soles as
reddish iolaceous or bluish blac macules and patches that
spread and coalesce to orm nodules or pla ues ( ig. ).
These ha e a rubbery consistency. There may be brawny
edema o the a ected leg. acules or nodules may appear
usually much later on the arms and hands and rarely may
e tend to the ace ears trun genitalia or buccal ca ity espe
cially the so t palate. The course is slowly progressi e and may
lead to great enlargement o the lower e tremities as a result
o lymphedema. owe er there may be periods o remission
particularly in the early stages o the disease when nodules
may undergo spontaneous in olution. A ter in olution there
may be an atrophic and hyperpigmented scar.
African cutaneous Kaposi sarcoma
odular in ltrating ascular masses occur on the e tremities
mostly o men between ages and . This orm o S is
endemic in tropical A rica and has a locally aggressi e but
systemically indolent course.
African lymphadenopathic Kaposi sarcoma
Lymph node in ol ement with or without s in lesions may
occur in children under age . The course is aggressi e o ten
terminating atally within years o onset.
595
 AIDS-associated Kaposi sarcoma
28 Cutaneous lesions begin as one or se eral red to purple red
macules rapidly progressing to papules nodules and pla ues.
There is a predilection or the head nec trun and mucous
membranes. A ulminant progressi e course with nodal and
Dermal and Subcutaneous Tumors
systemic in ol ement is e pected. S may be the presenting
mani estation o human immunode ciency irus ( V)
in ection.
Immunosuppression-associated Kaposi sarcoma
The lesion s morphology resembles that o classic S; howe er
the site o presentation is more ariable.
Internal involvement
The G tract is the most re uent site o internal in ol ement
in classic S. The small intestine is probably the iscus most
o ten in ol ed. n addition the lungs heart li er con uncti a
adrenal glands and lymph nodes o the abdomen may be
a ected. S eletal changes are characteristic and diagnostic.
Bone in ol ement is always an indication o widespread
disease. Changes noted are rare action cysts and cortical
erosion.
A rican cutaneous S is re uently accompanied by massi e
edema o the legs and re uent bone in ol ement.
A rican lymphadenopathic S has been reported among
Bantu children who de elop massi e in ol ement o the
lymph nodes especially the cer ical nodes preceding the
appearance o s in lesions. The children also de elop lesions
on the eyelids and con uncti a rom which masses o hemor
rhagic tissue hang down. ye in ol ement is o ten associated
with swelling o the lacrimal parotid and submandibular
glands with a picture similar to i ulic syndrome.
n A DS associated S o patients ha e cutaneous
in ol ement alone whereas ha e isceral lesions only.
The most re uent sites o isceral in ol ement are the lungs
( ) G tract ( ) and lymph nodes ( ). Visceral in ol e
ment ultimately occurs in more than o patients with
A DS associated S. ther immunosuppressed patients with
S may ha e isceral in ol ement in a ariable percentage o
cases.
Epidemiology
aposi sarcoma is worldwide in distribution. n urope there
are oci o classic S in Galicia near the Polish Russian border
and e tending southward to Austria and taly. n ew or
City S has occurred mostly in elderly Galician Jewish and
southern talian men. n A rica S occurs largely south o the
Sahara Desert. ortheast Congo and Rwanda Burundi areas
ha e the highest pre alence and to a lesser e tent West and
South A rica.
The pre alence o A DS related S has decreased since the
s. ost cases are in men who ha e se with men ( S ).
Very ew reports ha e documented the e ceptional occurrence
o S in patients with A DS who ac uired their in ection rom
intra enous drug use or in aitians children or people with
hemophilia. Patients at ris or de eloping S associated with
other causes o immunosuppression include those with iatro
genic suppression rom oral prednisone or other chronic
immunosuppressi e therapies as may be gi en to transplant
patients. ndemic disease in southern urope is strongly asso
ciated with oral corticosteroid use and diabetes and is in ersely
associated with cigarette smo ing.
aposi sarcoma is associated with an increased ris o de el
oping second malignancies such as malignant lymphomas
( odg in disease T cell lymphoma non odg in lym
phoma) leu emia and myeloma. The ris o lymphoreticular
malignancy is about times greater in S patients than in the
general population.
596
Etiopathogenesis
aposi sarcoma is ormed by proli eration o abnormal ascu
lar endothelial cells. V is ound in S lesional tissue
irrespecti e o clinical type. Primary e usion lymphoma solid
lymphoma and Castleman s disease are other con rmed asso
ciations with V in ection.
Histology
istopathology o S aries considerably according to the
stage o the disease. arly lesions demonstrate irregularly
shaped ectatic essels with scattered lymphocytes and plasma
cells. The endothelial cells o the capillaries are large and pro
trude into the lumen resembling buds. Later lesions show
proli eration o essels around pree isting essels and adne al
structures. The pree isting structure may ut into the ascular
space orming a promontory sign. Dull pin globules e tra
asated erythrocytes and hemosiderin are present. odular
lesions are composed o spindle cells with erythrocytes that
appear to line up between spindle cells with no apparent as
cular space.
Treatment
All types o S are radiosensiti e. Radiation therapy has been
used with considerable success whether in small ractionated
doses in larger single doses to limited or e tended elds or
by electron beam radiation. Local e cision cryotherapy
alitretinoin gel (Panretin) locally in ected chemotherapy or
and laser ablation ha e been used or troublesome local
i ed lesions.
Vincristine solution . mg mL in ected intralesionally not
more than mL at one time and at inter als o wee s pro
duces in olution o tumors some or as long as months.
These studies indicate that ade uate control o S lesions may
be achie ed at least or periods o months. The de elop
ment o resistance to medication seems to be ine itable.
any other agents ha e been ound to be e ecti e; among
the best are inblastine and actinomycin D. The response
rate initially is high but recurrent lesions which are common
are generally less responsi e. Systemic therapy is usually
needed i more than new S lesions de elop in month or
i there is symptomatic lymphedema symptomatic pulmo
nary disease or symptomatic isceral in ol ement.
n the setting o V protease inhibitors ha e been shown
to ha e antiangiogenic e ects; howe er the results o non
nucleoside re erse transcriptase inhibitor based regimens are
not in erior to protease inhibitor based therapy in the pre en
tion o S. This suggests that regression o S is mediated by
an o erall impro ement in immune unction and not by the
e ects o speci c antiretro irals. Liposomal anthracyclines
and paclita el ha e been appro ed by the .S. ood and Drug
Administration ( DA) as rst line and second line monother
apy respecti ely or ad anced S.
Rapamycin (sirolimus) an inhibitor o the mammalian
target o rapamycin (mT R) is an e ecti e immunosuppres
sant or the pre ention o transplant re ection with bene ts as
a treatment or S. Dual inhibition o P α and mT R by
P appears promising.
Course
Classic S progresses slowly with rare lymph node or isceral
in ol ement. Death usually occurs years later rom unrelated
causes. A rican cutaneous S is aggressi e with early nodal
in ol ement and death rom S is e pected within years.
A DS related S although widespread is almost ne er
atal; almost all patients die o intercurrent in ection. The
course o the disease is ariable in patients who de elop
immunosuppression related S rom causes other than A DS.
Remo al o the immunosuppression may result in resolution
o the S without therapy. Among transplant patients a
change rom a calcineurin inhibitor to sirolimus o ten results
in regression o S lesions.
Chang Y, Moore P: Twenty years of KSHV. Viruses 2014;
6(11):4258–4264.
Donato V, et al: Radiation therapy in the treatment of HIV-related
Kaposi’s sarcoma. Anticancer Res 2013; 33(5):2153–2157.
La Ferla L, et al: Kaposi’s sarcoma in HIV-positive patients: the state of
art in the HAART-era. Eur Rev Med Pharmacol Sci 2013;
17(17):2354–2365.
Yaich S, et al: Sirolimus for the treatment of Kaposi sarcoma after renal
transplantation: a series of 10 cases. Transplant Proc 2012;
44(9):2824–2826.
Atypical vascular lesion
Atypical ascular lesion (AVL) occurs a ter mastectomy and
radiation. Staghornli e thin walled essels are present but
endothelial atypia is minimal. Lesions may represent a precur
sor to malignancy. M C ampli cation is noted in postirradia
tion angiosarcomas but not in primary cutaneous angiosarcoma
or in other radiation associated ascular proli erations such
as AVL.
Feller JK, et al: c-myc and cutaneous vascular neoplasms. Am J
Dermatopathol 2013; 35(3):364–369.
Angiosarcoma
Angiosarcomas o the s in occur in our clinical settings. irst
and most common are those that occur in the head and nec
o elderly people. The male emale ratio is . The lesion
o ten begins as a poorly de ned bluish macule that may be
mista en or a bruise. Distinguishing eatures are the re uent
occurrence o a peripheral erythematous ring satellite nodules
presence o intratumoral hemorrhage and the lesion s ten
dency to bleed spontaneously or a ter minimal trauma. The
tumor progressi ely enlarges asymmetrically o ten becomes
multicentric and de elops indurated bluish nodules and
pla ues. The sudden de elopment o thrombocytopenia may
herald metastatic disease or an enlarging primary tumor.
Solid sheets o atypical epithelioid cells may be present but
more o ten the pattern is that o subtle in ltration in the
dermis producing the appearance o crac s between collagen
bundles. The spaces are lined by hyperchromatic nuclei.
mmunopero idase staining or endothelial mar ers such as
CD CD and Ulex europeus lectin aids in the diagnosis and
most malignant ascular tumors are positi e or podoplanin
(D ).
arly diagnosis and complete surgical e cision ollowed by
moderate dose ery wide eld radiotherapy o er the best
prognosis or limited disease. Chemotherapy and radiation
therapy or e tensi e disease are o ten only palliati e espe
cially when dealing with scalp lesions and high grade lesions.
Do orubicin i os amide chemotherapy produces a modest
response rate. Paclita el is now o ten used as a rst line pallia
ti e systemic therapy achie ing an ob ecti e response rate o
. Sirolimus and both show promise or scalp and acial
angiosarcomas. Because o the multicentricity o lesions the
re uent occurrence on the ace or scalp and the rapid growth
with early metastasis death occurs in most patients within
years. A dramatic response was reported in a year old man
with recurrent angiosarcoma o the ace and scalp a ter com
bination treatment with al a a and cis retinoic acid.
The second classic clinical situation in which angiosarcoma
de elops is in chronic lymphedematous areas as occurs in the
upper arm a ter mastectomy the so called Stewart Tre es syn
drome ( ig. ). This tumor appears appro imately
years a ter surgery in an estimated . o patients. The
tahir99 - UnitedVRG
Fig. 28-21 Stewart-
Treves syndrome.
Fibrous tissue abnormalities
prognosis is poor or these patients with a mean sur i al o
months and year sur i al o . etastases to the
lungs are the most re uent cause o death. arly amputation
o ers the best hope.
A third setting includes tumors that de elop in pre iously
irradiated sites. the condition or which radiation therapy
was gi en was a benign one the a erage inter al between
radiation and de elopment o angiosarcoma is years. the
preceding illness was a malignant condition the inter al is
shortened to years. Again the prognosis is poor with sur
i al generally between months and years a ter diagnosis.
any patients with the Stewart Tre es syndrome recei ed
radiation and radiation may play a pathogenic role.
Angiosarcomas de elop in settings other than those pre i
ously described and this small miscellaneous subset com
prises the ourth category. An angiosarcoma producing
granulocyte colony stimulating actor was associated with
prominent peripheral leu ocytosis.
Dettenborn T, et al: Prognostic features in angiosarcoma of the head
and neck: a retrospective monocenter study. J Craniomaxillofac Surg
2014; 42(8):1623–1628.
Du W, et al: Vascular tumors have increased p70 S6-kinase activation
and are inhibited by topical rapamycin. Lab Invest 2013;
93(10):1115–1127.
Farid M, et al: Cutaneous versus non-cutaneous angiosarcoma:
clinicopathologic features and treatment outcomes in 60 patients at a
single Asian cancer centre. Oncology 2013; 85(3):182–190.
Hung J, et al: Sporadic versus radiation-associated angiosarcoma: a
comparative clinicopathologic and molecular analysis of 48 cases.
Sarcoma 2013; 2013:798403.
Patel AM, et al: The horizon for treating cutaneous vascular lesions.
Semin Cutan Med Surg 2012; 31(2):98–104.
Vora R, et al: Cutaneous angiosarcoma of head and neck. Indian J
Dermatol 2014; 59(6):632.
FIBROUS TISSUE ABNORMALITIES
Keloid
A eloid is a rm irregularly shaped brous hyperpig
mented pin or red e crescence. The growth usually arises as
the result o a cut laceration or burn or less o ten an acne
597
 pustule on the chest or upper bac and spreads beyond the
28 limits o the original in ury o ten sending out clawli e (cheloid)
prolongations. The o erlying epidermis is smooth glossy and
thinned rom pressure. The early growing lesion is red and
tender and has the consistency o rubber. t is o ten surrounded
Dermal and Subcutaneous Tumors
by an erythematous halo and the eloid may be telangiectatic.
Lesions may be tender pain ul and pruritic and may rarely
ulcerate or de elop draining sinus tracts.
eloids are o ten multiple. They may be as tiny as pinheads
or as large as an orange. Those that ollow burns and scalds
are large. Lesions are o ten linear re uently ha ing bulbous
e pansions at each end. The sur ace may be larger than the
base so that the edges are o erhanging. The most common
location is the sternal region but eloids also occur re uently
on the nec ears e tremities or trun and rarely on the ace
palms or soles. The earlobes are o ten in ol ed as a result o
ear piercing but in ol ement o the central ace is rare. eloids
are much more common and grow to larger dimensions in
blac persons than others.
Why certain indi iduals de elop eloids remains unsol ed.
Trauma is usually the immediate causati e actor but this
induces eloids only in those with a predisposition or their
de elopment. There is also a regional predisposition.
istologically a eloid is a dense and sharply de ned
nodular growth o myo broblasts and collagen with a whorl
li e arrangement resembling hypertrophic scar. Centrally
thic hyalini ed bundles o collagen are present and distin
guish eloids rom hypertrophic scars. lastic tissue is scanty
as in a scar. Through pressure the tumor causes thinning o
the normal papillary dermis and atrophy o ad acent append
ages which it pushes aside. ucopolysaccharides are
increased and o ten there are numerous mast cells.
eloids are usually distincti e. They may be distinguished
rom hypertrophic scars by their clawli e pro ections ( ig.
) which are absent in the hypertrophic scar; the e tension
o the eloid beyond the con nes o the original in ury; and
the presence o thic hyalini ed collagen bundles histologi
cally. re uently spontaneous impro ement o the hypertro
phic scar occurs o er months but not in the eloid. Atypical
lesions should be biopsied because carcinoma en cuirasse may
mimic eloid.
nitial treatment is usually by means o intralesional in ec
tion o triamcinolone suspension alone or in combination with
uorouracil ( ). sing a gauge needle on a mL
tuberculin Luer syringe triamcinolone suspension is in ected
into arious parts o the lesion; mg mL is generally used
or initial treatment although as the lesion so tens mg
mL may be su cient to produce in olution with less ris o
Fig. 28-22 Extensive keloids.
598
surrounding hypopigmentation and atrophy related to lym
phatic spread o the corticosteroid. n ections are repeated at
inter als o wee s as re uired. lattening and cessation
o itching are reliably achie ed by this approach and in some
cases may e en be achie ed with topical corticosteroids. The
lesions are ne er made narrower howe er and hyperpigmen
tation generally persists. can produce responses in re rac
tory eloids but is associated with a somewhat higher ris
o hyperpigmentation pain and ulceration a ter in ection.
Bleomycin is being in estigated alone and in combination
with triamcinolone. Trans orming growth actor (TG ) β is
nown to be in ol ed in eloid ormation and triamcinolone
acetonide induced decreases in cellular proli eration and col
lagen production are associated with a statistically signi cant
decrease in the le el o TG β in both normal and eloid
broblast cell lines. Anti TG β therapy loo s promising as
does nuclear actor ( ) κB inhibition and green tea polyphe
nol epigallocatechin gallate.
ther approaches to treatment include ashlamp pulsed
dye laser treatment which is also associated with reduced
e pression o TG β . Cryosurgery (including contact intral
esional needle cryoprobe and spray) intralesional etanercept
and calcium channel bloc ers ha e some demonstrated e
cacy in the treatment o eloids. ibroblasts deri ed rom the
central part o eloids grow aster than peripheral eloid and
non eloid broblasts. Verapamil has been shown to decrease
interleu in ( L ) and V G in these cultured cells and to
inhibit cell growth.
surgical remo al by e cision is easible and i narrowing
o the eloid is a itally important goal the eloid may
be e cised. A ter the e cision intralesional in ection o
triamcinolone or al a b may be combined with postop
erati e ray irradiation or topical application o imi uimod.
Silicone sheeting and pressure are other ad uncti e methods
used to limit recurrences. Results with these modalities
ha e been mi ed and a Cochrane re iew concluded that
the uality o e idence supporting silicone sheeting is gener
ally poor. eloids demonstrate an increased number o mast
cells and silicone gel sheet treatment has been shown to
reduce lesional mast cell numbers and decrease itching.
Banding at the base o the eloid with a suture ligature or
wee s has been used success ully to treat pedunculated
lesions.
Pierced ear eloids occur with considerable re uency.
When the eloid is young intralesional in ection o triamcino
lone is re uently su cient to control the problem. n old
eloids e cision o the lesion using lidocaine with triamcino
lone ollowed by in ections at wee inter als produces
good results. C laser e cision has also been success ul in old
mature eloids in this site.
Camacho-Martínez FM, et al: Results of a combination of bleomycin and
triamcinolone acetonide in the treatment of keloids and hypertrophic
scars. An Bras Dermatol 2013; 88(3):387–394.
Chopinaud M, et al: Intralesional cryosurgery to treat keloid scars:
results from a retrospective study. Dermatology 2014; 229(3):263–270.
Goldenberg G, et al: Use of intralesional cryosurgery as an innovative
therapy for keloid scars and a review of current treatments. J Clin
Aesthet Dermatol 2013; 6(7):23–26.
Huang C, et al: Pharmacological treatment for keloids. Expert Opin
Pharmacother 2013; 14(15):2087–2100.
Huang L, et al: A study of the combination of triamcinolone and
5-fluorouracil in modulating keloid fibroblasts in vitro. J Plast Reconstr
Aesthet Surg 2013; 66(9):e251–e259.
O’Brien L, et al: Silicone gel sheeting for preventing and treating
hypertrophic and keloid scars. Cochrane Database Syst Rev 2013;
9:CD003826.
Saha AK, et al: A comparative clinical study on role of 5-fluorouracil
versus triamcinolone in the treatment of keloids. Indian J Surg 2012;
74(4):326–329.
 Trisliana Perdanasari A, et al: Recent developments in the use of
intralesional injections in keloid treatment. Arch Plast Surg 2014;
41(6):620–629.
Dupuytren contracture
se ere. The association o Peyronie s disease with Dupuytren
contracture has been recogni ed.
n ection o al a b erapamil or collagenase has been
used. ntralesional triamcinolone suspension in ected or ionto
phoresed into the pla ues and nodules has shown mi ed

Fibrous tissue abnormalities

Dupuytren contracture is a bromatosis o the palmar aponeu
rosis. The lesion arises most re uently in men between ages
and as multiple rm nodules in the palm. sually three
to e nodules about cm in diameter de elop pro imal to
the ourth nger. Later the bromatosis produces contrac
tures which may be disabling. The condition occurs at times
with alcoholic cirrhosis diabetes mellitus muscular dystro
phy and chronic epilepsy. t is also associated with Peyronie s
disease plantar bromatosis and nuc le pads. n some cases
there is a amilial predisposition. The brous nodules are com
posed o myo broblasts that e press androgen receptors.
α Dihydrotestosterone induces an increase in Dupuytren
broblast proli eration. n contrast to deep bromatoses
which beha e more aggressi ely super cial bromatoses
lac β catenin and adenomatous polyposis coli (APC) gene
mutations.
arly disease may respond well to intralesional triamcino
lone or collagenase but surgical e cision o the in ol ed
palmar ascia may be the only way to liberate se erely con
tracted ngers. Androgen bloc ade represents a potential
a enue o pharmacologic therapy. As with eloids TG β
inhibition appears promising.
Plantar fibromatosis
The plantar analog o Dupuytren contracture plantar bro
matosis (Ledderhose s disease) occurs as slowly enlarging
nodules on the soles that ultimately cause di culty in
wal ing or e en weight bearing. The diagnosis is usually
made clinically but both biopsy and R can be used to
con rm the diagnosis. The usual surgical treatment is wide
e cision o the plantar ascia. Subtotal e cision is associated
with a high rate o recurrence. Although ad u ant radiother
apy is e ecti e in decreasing the recurrence rate it has a sig
ni cant complication rate with unctional impairment. As
with other orms o bromatosis intralesional in ection o tri
amcinolone acetonide or collagenase may represent nonsur
gical alternati es.
Baltzer H, et al: Cost-effectiveness in the management of
Dupuytren’s contracture: a Canadian cost-utility analysis of current
and future management strategies. Bone Joint J 2013;
95B(8):1094–1100.
Denkler K. Collagenase for recurrent Dupuytren contracture with skin
grafts. J Hand Surg Am 2013; 38(6):1264.
Dias JJ, et al: Patterns of recontracture after surgical correction of
Dupuytren disease. J Hand Surg Am 2013; 38(10):1987–1993.
Peimer CA, et al: Dupuytren contracture recurrence following treatment
with collagenase Clostridium histolyticum (CORDLESS study): 3-year
data. J Hand Surg Am 2013; 38(1):12–22.
Schulze SM, Tursi JP: Postapproval clinical experience in the treatment
of Dupuytren’s contracture with collagenase clostridium histolyticum
(CCH): the first 1000 days. Hand (NY) 2014; 9(4):447–458.
results. ral therapies include tocopherol ( itamin ) para
aminoben oate colchicine tamo i en and acetyl L carnitine
but data supporting oral therapy are wea . Surgical correction
tailored to the degree o de ormity is o ten success ul. tra
corporeal shoc wa e therapy may reduce penile pain but
may worsen cur ature.
Garaffa G, et al: Understanding the course of Peyronie’s disease. Int J
Clin Pract 2013; 67(8):781–788.
Lopes I, et al: Penile corporoplasty with Yachia’s technique for
Peyronie’s disease: single center experience with 117 patients. Urol
Ann 2013; 5(3):167–171.
Lipofibromatosis
Lipo bromatosis is a rare tumor o in ancy that typically pres
ents as a poorly demarcated slow growing so t tissue mass on
an e tremity. t is sometimes associated with other de ects
such as syndactyly cle t lip and palate trigonocephaly and
atrial septal de ect. istologically mature at is separated by
collagenous septa containing broblasts and myo broblasts.
A subtle honeycomb pattern o brosis may be noted at the
edge o the at lobule.
Boos MD, et al: Lipofibromatosis: an institutional and literature review of
an uncommon entity. Pediatr Dermatol 2014; 31:298–304.
Costa Dias S, et al: Lipofibromatosis of the knee in a 19-month-old
child. J Pediatr Surg 2012; 47(5):1028–1031.
Knuckle pads
nuc le pads (heloderma) are well de ned round pla ue
li e brous thic enings that de elop on the e tensor aspects
o the pro imal interphalangeal oints o the toes and ngers
( ig. ) including the thumbs. They de elop at any age
and grow to about mm in diameter o er a ew wee s or
months then persist permanently. They are esh colored or
Fig. 28-23 Knuckle
pads.

Peyronie’s disease
Plastic induration o the penis is a brous in ltration o the
interca ernous septum o the penis. This brosis results in the
ormation o nodules or pla ues. As a result o these pla ues
a brous chordee is produced and cur ature o the penis
occurs on erection sometimes so se ere as to ma e intromis
sion di cult or impossible. n some patients pain may be
599

tahir99 - UnitedVRG
 somewhat brown with normal or slightly hyper eratotic epi
28 dermis o erlying and adherent to them. They are a part o the
s in and are reely mo able o er underlying structures.
nuc le pads are sometimes associated with Dupuytren
contracture clubbing or camptodactylia (irreducible e ion
Dermal and Subcutaneous Tumors
contracture o one or more ngers). Some cases are amilial
and some are related to trauma or re uent nuc le crac ing.
Autosomal dominant associations o nuc le pads mi ed
hearing loss eratoderma and leu onychia ha e been
reported including Bart Pumphrey syndrome ( muta
tions). nuc le pads ha e also been associated with autosomal
dominant epidermolytic palmoplantar eratoderma with a
mutation in eratin .
istologically the lesions are bromas. They are di erenti
ated clinically rom the nodular type o neurodermatitis and
rom the small hemispherical pitted papules that may de elop
o er the nuc les a ter rostbite or in acrocyanosis and rom
rheumatic nodules. Treatment with intralesional in ection o
corticosteroids may be bene cial. As with eloids intralesional
may be bene cial.
Chen LH, et al: G59A mutation in the GJB2 gene in a Taiwanese family
with knuckle pads, palmoplantar keratoderma and sensorineural
hearing loss. Clin Exp Dermatol 2012; 37(3):300–301.
Du ZF, et al: A novel mutation within the 2B rod domain of keratin 9 in a
Chinese pedigree with epidermolytic palmoplantar keratoderma combined
with knuckle pads and camptodactyly. Eur J Dermatol 2011; 21(5):675–679.
Hyman CH, et al: Report of a family with idiopathic knuckle pads and
review of idiopathic and disease-associated knuckle pads. Dermatol
Online J 2013; 19(5):18177.
Pachydermodactyly
Pachydermodactyly represents a benign bromatosis o the
ngers. There is a ullness o the medial and lateral digit ust
pro imal to the pro imal interphalangeal oint. This asymp
tomatic process most o ten is rst noted in adolescence and
usually in ol es multiple ngers. t can be misdiagnosed as
u enile idiopathic arthritis. i e types ha e been described
classic locali ed transgrediens (abnormality e tends to
metacarpophalangeal areas) amilial and pachydermodac
tyly associated with tuberous sclerosis. Some cases may
result rom repetiti e ticli e obsessi e compulsi e beha iors.
ncreased collagen or mucin accounts or the swelling.
Patients with pachydermodactyly associated with repetiti e
tics respond to treatment or the obsessi e compulsi e
disorder.
El-Hallak M, et al: Pachydermodactyly mimicking juvenile idiopathic
arthritis. Arthritis Rheum 2013; 65(10):2736.
Desmoid tumor
Desmoid tumors occur as large deep seated well
circumscribed masses arising rom the muscular aponeurosis.
They most re uently occur on the abdominal wall especially
in women during or soon a ter pregnancy. Desmoid tumors
ha e been di ided into e types abdominal wall e tra
abdominal intra abdominal multiple and those occurring in
Gardner syndrome amilial adenomatous polyposis. They
recur locally and can ill i they in ade surround or compress
ital structures. The most dangerous desmoid tumors are
there ore those at the root o the nec and the intra abdominal
type. R will aid in the e aluation o so t tissue e tension
and recurrence a ter treatment. utations in the β catenin
gene correlate with local recurrence. Treatment may be with
wide local e cision radiotherapy or hormonal manipulation.
igh dose tamo i en in combination with sulindac has been
e ecti e. esenteric desmoid tumors ha e been treated with
600
antiangiogenic therapy with toremi ene and al a b. ma
tinib mesylate appears promising.
Devata S, et al: Desmoid tumors: a comprehensive review of the
evolving biology, unpredictable behavior, and myriad of management
options. Hematol Oncol Clin North Am 2013; 27(5):989–1005.
Collagenous fibroma (desmoplastic fibroblastoma)
This slow growing deep set benign brous tumor is usually
located in the deep subcutis ascia aponeurosis or s eletal
muscle o the e tremities limb girdles or head and nec
regions. t is characteri ed by hypocellularity and dense
bands o hyalini ed collagen that may in ltrate into s eletal
muscle. Despite this no tumors ha e been reported to metas
tasi e or recur a ter e cision. Chromosomal translocation ( ;
)( ; ) as well as trisomy ha e been reported. Tumor
cells stain or imentin and may stain or actin but ha e
been negati e or CD S protein eratin CD desmin
and β catenin.
Nishio J, et al: Translocation t(2;11) is characteristic of collagenous
fibroma (desmoplastic fibroblastoma). Cancer Genet 2011;
204(10):569–571.
Stacy RC, et al: Collagenous fibroma (desmoplastic fibroblastoma) of
the orbital rim. Ophthal Plast Reconstr Surg 2013; 29(4):e101–e104.
Aponeurotic fibroma
Aponeurotic broma has also been called u enile aponeu
rotic broma (calci ying broma). t is a tumorli e proli era
tion characteri ed by the appearance o slow growing
cystli e masses that occur on the limbs especially the hands
and eet. istologically the distincti e lesions are sharply
demarcated and composed o collagenous stroma showing
acid mucopolysaccharides in ltrated by plump mesenchymal
cells with o al nuclei. yalini ed areas are also present sug
gesting chondroid or osteoid metaplasia. An aid to the diag
nosis is stippled calci cation readily seen on radiographs.
Surgical e cision is the treatment o choice and can be guided
by R .
Schonauer F, et al: Calcifying aponeurotic fibroma of the distal phalanx.
J Plast Reconstr Aesthet Surg 2013; 66(2):e47–e49.
Infantile myofibromatosis
n antile myo bromatosis is the most common brous tumor
o in ancy. ighty percent o patients ha e solitary lesions
with hal o these occurring on the head and nec . About
are present at or soon a ter birth.
Congenital generali ed bromatosis is an uncommon condi
tion that presents at birth or soon a ter. t is characteri ed by
multiple rm dermal and subcutaneous nodules. S eletal
lesions primarily o the metaphyseal regions o the long
bones occur in o patients. only the s in and bones
de elop bromas the prognosis is e cellent with spontaneous
resolution o the lesions and with no complications e pected
in the rst years o li e. Some re er to this limited disease
as congenital multiple bromatosis. emales more re
uently contract the generali ed disease.
The bromas may in ol e the iscera including the G tract
breast lungs li er pancreas tongue serosal sur aces lymph
nodes or idney. Autosomal dominant inheritance has
been reported and mutations in PD and O C ha e
been described. istologically ascicles o spindle cells occur
in a whorled pattern. These nodules are composed o
myo broblasts.
 ortality in the more widespread subset is high; die
rom obstruction or compression o ital organs. Patients who
sur i e past months ha e spontaneous regression o their
disease. Some li e threatening cases ha e responded to low
dose chemotherapy.
Diffuse infantile fibromatosis
This process occurs within the rst years o li e and is usually
con ned to the muscles o the arms nec and shoulder area.
There is multicentric in ltration o muscle bers with bro
blasts resembling those in aponeurotic bromas. Calci cation
does not occur. Recurrence a ter e cision occurs in about one
third o patients.
Aggressive infantile fibromatosis
The clinical presentation o this locally recurring nonmetasta
si ing lesion in ol es single or multiple ast growing masses
that are present at birth or that occur within the rst year o
li e. n antile bromatosis may be seen in any location
although the arms legs and trun are the usual sites. isto
logically it is hypercellular and mimics malignancy.
Ferrari A, et al: Fibroblastic tumors of intermediate malignancy in
childhood. Expert Rev Anticancer Ther 2013; 13(2):225–236.
Lee J: Mutations in PDGFRB and NOTCH3 are the first genetic causes
identified for autosomal dominant infantile myofibromatosis. Clin Genet
2013; 84(4):340–341.
Ruparelia MS, et al: Infantile fibromatosis: a case report and
review of the literature. Br J Oral Maxillofac Surg 2011;
49(6):e30–e32.
Juvenile hyaline fibromatosis and infantile
systemic hyalinosis
Ju enile hyaline bromatosis and in antile systemic hyalinosis
are allelic autosomal recessi e conditions characteri ed by
multiple subcutaneous s in nodules hyaline deposition gin
gi al hypertrophy osteolytic bone lesions and oint contrac
tures. odular tumors o the scalp ace and e tremities
usually appear in early childhood. Pin con uent papules
may occur on the paranasal olds periauricular area ( ig.
) and perianal region. The gene has been mapped to
chromosome with at least di erent mutations in the
gene encoding capillary morphogenesis protein a trans
membrane protein induced during capillary morphogenesis
and that binds laminin and collagen V. istologically bro
blasts with ne intracytoplasmic eosinophilic granules are
embedded in a homogeneous eosinophilic dermal ground
substance. ltrastructurally the broblasts demonstrate
de ecti e synthesis o collagen deposited as brillogranular
material.
Denadai R, et al: Systemic hyalinosis: new terminology, severity grading
system, and surgical approach. J Pediatr 2012; 161(1):173; author
reply 173–174.
Infantile digital fibromatosis (infantile digital
myofibroblastoma, inclusion body fibroma)
n antile digital bromatosis is a rare neoplasm o in ancy and
childhood that usually occurs on the dorsal or lateral aspects
o the distal phalanges o the toes and ngers. The thumb and
great toe are usually spared. These asymptomatic rm red
smooth nodules occur during the rst year o li e in the
tahir99 - UnitedVRG
Fig. 28-24 Juvenile
hyaline fibromatosis.
Fibrous tissue abnormalities
rst month. Rare congenital lesions ha e been noted. The
lesions do not metastasi e but may in ltrate deeply. istologi
cally the epidermis is normal but the dermis is in ltrated
with proli erating myo broblasts and collagen bundles. osin
ophilic cytoplasmic inclusions in many o the broblasts are
characteristic. Treatment by surgical e cision has a high ris
o recurrence and conser ati e nonsurgical management is
o ten appropriate. Spontaneous regression is generally noted
but the lesion may cause unctional impairment and may in l
trate deeply be ore regression occurs. ohs micrographic
surgery has been per ormed success ully using both trichrome
staining and smooth muscle actin staining to demonstrate the
inclusion bodies within tumor cells.
Laskin WB, et al: Infantile digital fibroma/fibromatosis: a
clinicopathologic and immunohistochemical study of 69 tumors from
57 patients with long-term follow-up. Am J Surg Pathol 2009;
33(1):1–13.
Spingardi O, et al: Infantile digital fibromatosis: our experience and
long-term results. Chir Main 2011; 30(1):62–65.
Fibrous hamartoma of infancy
ibrous hamartoma o in ancy is a single dermal or subcutane
ous rm nodule o the upper trun that is present at birth or
shortly therea ter. erlying s in changes are uncommon but
may include increased hair alteration in pigmentation and
eccrine gland hyperplasia with hyperhidrosis. ost cases are
solitary but multiple tumors ha e been reported; o
lesions are noted within the rst year o li e and are
congenital. The male emale ratio is . . ost lesions occur
in the a illary region upper arm upper trun inguinal region
and e ternal genital area. An association with Williams syn
drome has been reported. Biopsy shows an organoid pattern
with di erent types o tissue organi ed in whorls or bands. n
early lesions lobules o mature at are interspersed between
my oid and brous areas. y oid ones ha e primiti e mes
enchymal cells with stellate nuclei. ibrosing areas demon
strate delicate collagen bundles and many elongated broblast
nuclei. The o erlying s in may demonstrate aborti e hair ol
licles and many eccrine units may be present. Comple chro
mosomal translocations ha e been reported. er time both
the my oid and the brosing areas de elop into cell poor
brous areas with thic collagen bundles. There is no recur
rence a ter e cision.
601
28
F-Eire P, et al: Cutaneous changes in fibrous hamartoma of infancy.
Indian J Dermatol 2013; 58(2):160.
Seguier-Lipszyc E, et al: Fibrous hamartoma of infancy. J Pediatr Surg
2011; 46(4):753–755.
Takahashi E, et al: Atrophic fibrous hamartoma of infancy with epidermal
Dermal and Subcutaneous Tumors
and adnexal changes. J Dermatol 2013; 40(3):212–214.
Fibromatosis colli
n bromatosis colli there is a brous tissue proli eration in l
trating the lower third o the sternocleidomastoid muscle at
birth. ine needle aspiration is use ul to con rm the diagnosis.
Spontaneous remission occurs within a ew months. ccasion
ally some patients are le t with a wrynec de ormity; howe er
this complication is amenable to surgery.
Lowry KC, et al: The presentation and management of fibromatosis
colli. Ear Nose Throat J 2010; 89(9):E4–E8.
Giant cell tumor of the tendon sheath
This giant cell tumor is most re uently attached to the tendons
o the ngers ( ig. ) hands and wrists and has a predilec
tion or the e or sur aces. t is rm cm in diameter and
does not spontaneously in olute. t recurs a ter e cision in
appro imately o cases. ibroma o the tendon sheath
represents a ariant o the giant cell tumor that lac s giant
Adams EL, et al: Giant cell tumor of the tendon sheath: experience with
65 cases. Eplasty 2012; 12:e50.
Garner HW, et al: Benign synovial tumors and proliferative processes.
Semin Musculoskelet Radiol 2013; 17(2):177–178.
Ainhum
Ainhum is also nown as dactylolysis spontanea ban o er
end and su hapa la. t is a disease a ecting the toes espe
cially the th toe characteri ed by a linear constriction around
the a ected digit that ultimately leads to the spontaneous
amputation o the distal part. t occurs chie y among blac
men in A rica. sually ainhum is unilateral but may be
bilateral.
The disease begins with a trans erse groo e in the s in on
the e or sur ace o the toe usually beneath the rst interpha
langeal articulation. The urrow is produced by a ringli e bro
sis and an induration o the dermis. t deepens and e tends
laterally around the toe until the two ends meet so that the
digit becomes constricted as i in a ligature. The constricted
part becomes swollen so t and a ter a time greatly distended.
lceration may result in a malodorous discharge with pain
and gangrene. The course o the disease is slow but in
years spontaneous amputation occurs generally at a oint.
The cause is un nown. The condition may result rom
chronic trauma and e posure to the elements by wal ing bare