Introduction
Disorders of elastic tissue
332
Increased elastic tissue 333
Elastoma (elastic nevus) 333
Linear focal elastosis 335
Focal dermal elastosis 335
Elastoderma 335
Elastofibroma 335
Elastosis perforans serpiginosa 335
Pseudoxanthoma elasticum 337
Acquired pseudoxanthoma elasticum 338
Elastic globes 339
Solar elastotic syndromes 339
Solar elastosis (actinic elastosis) 341
Nodular elastosis with cysts and comedones 342
Elastotic nodules of the ears 343
Collagenous and elastotic plaques of
the hands 343
Erythema ab igne 343
Decreased elastic tissue 344
Nevus anelasticus (papular elastorrhexis) 344
Perifollicular elastolysis 345
Anetoderma 345
Cutis laxa 346
Elastolysis of the earlobes 348
Williams–Beuren syndrome 348
Papillary-dermal elastolysis
(fibroelastolytic papulosis) 348
Mid-dermal elastolysis 348
Menkes’ syndrome 349
12
Fragile X syndrome 349
Wrinkly skin syndrome 349
Granulomatous diseases 349
‘Granulomatous slack skin’ 349
Myxedema 350
Acrokeratoelastoidosis 350
Variable or minor elastic
tissue changes 350
Leprechaunism (Donohue syndrome) 350
Syndromes of premature aging 350
Wrinkles 350
Scar tissue 350
Marfan’s syndrome 350
332 SECTION 4  •  the dermis and subcutis
INTRODUCTION
Normal elastic tissue
Elastic fibers are the important resilient component of mammalian
connective tissue, and their presence is necessary for the proper struc-
ture and function of the cardiovascular, pulmonary, and intestinal
systems.1,2 Their structural role is to endow tissues with elastic recoil
and resilience.3 They constitute less than 4% of the dry weight of the
skin, forming a complex and extensive network in the dermis which
imparts elasticity to the skin.4
Structure and composition
Mature elastic fibers are composed of structural glycoproteins, which
contribute to the formation of 10–12  nm microfibrils, and elastin, a
fibrous protein with a molecular weight of 72 000 kDa.4 Elastin forms
an amorphous core to the elastic fibers and this is surrounded by the
microfibrils. Approximately 90% of the mature elastic fiber is elastin.
It has a high concentration of alanine and valine, but less hydroxypro-
line than is present in collagen. Elastin-producing cells secrete tropo-
elastin, a 70 kDa precursor of elastin, which becomes highly crosslinked
by the action of lysyl oxidase to form mature elastin.5 It is the product
of a single copy gene, located in the chromosomal locus 7q11.2, in the
human genome.6 Mutations in this gene cause the Williams–Beuren
syndrome and some cases of cutis laxa. The microfibrils consist of
several distinct proteins including fibrillin; abnormalities of the micro-
fibrils occur in Marfan’s syndrome (see p. 350). The fibrillin-1 gene
(FBN1), identified in 1991, is located on chromosome 15q21.1.5
There is a second fibrillin gene on chromosome 5 (FBN2), mutations
of which cause congenital contractural arachnodactyly.7
A new family of extracellular matrix proteins, the fibulins, is being
characterized progressively. Fibulins 1, 2, 3, 4, and 5 have been identi-
fied. The latter, fibulin-5, appears to be deficient in the autosomal
recessive form of cutis laxa.8,9 Fibulin-5 is essential for dermal elastic
fiber assembly.10 The various fibulins are localized to different parts
of the elastic fiber with fibulin-1 in the amorphous core and fibulin-2
in the fibrillin-containing elastin-associated microfibrils. Fibulin-2 is
increased in solar elastosis.11 Fibulin-4 is also essential for elastic-fiber
formation, since its absence abolishes normal elastogenesis and leads
to irregular elastin aggregates.3 Its absence has also been found in a
rare form of autosomal recessive cutis laxa.12
The papillary dermis contains fine fibers which run perpendicular
to the dermoepidermal junction and connect the basal lamina to the
underlying dermal elastic tissue.13 These oxytalan fibers, as they are
called, consist of microfibrils without a core of elastin.14 They branch
to form a horizontal plexus in the upper reticular dermis, where
they are known as elaunin fibers. They contain a small amount
of elastin. The mature elastic fibers with their full composition of
elastin are found below this in the reticular dermis. These three types
of fibers probably correspond to consecutive stages of normal
elastogenesis.14
Formation of elastic fibers
The formation of elastic fibers by fibroblasts, and in some circum-
stances by smooth muscle cells and chondroblasts, entails several dif-
ferent steps which are still poorly understood. Theoretically, these
stages would include the expression of genes coding for elastin polypep-
tides, various intracellular processes, secretion of the precursor compo-
nents, and extracellular modifications leading to the assembly of the
fibers.4 Fibulin-5 plays an important role in this assembly by acting as
an adaptor molecule between elastin and the matrix scaffold.15
Elastin is secreted in the form of a precursor, tropoelastin. This is
ultimately crosslinked with desmosine to form stable elastin.16 The
formation of desmosine requires the copper-dependent enzyme lysyl
oxidase.16 Defects in this enzyme can result from a spectrum of muta-
tions in the ATPase gene (ATP7A), as seen in Menkes’ syndrome (see
p. 349). Impaired elastinogenesis can also result from other altered
transport mechanisms important to elastic fiber assembly.7 One such
example is a deficiency in elastin binding protein (EBP), which trans-
ports tropoelastin from its site of synthesis in the cell to the cell
membrane. Costello syndrome (see p. 347) results from a functional
deficiency in EBP.
A congenital disorder of glycosylation involving a defect in the bio-
synthesis of N- and O-glycans has been reported in several patients
with cutis laxa, indicating the role these glycans play in the stability
of various extracellular matrix proteins; they may be involved in the
glycosylation of fibulin-5.17
Degrading of elastic tissue
Very few enzymes can degrade crosslinked elastin.18 One of these is
elastase, which is found in the pancreas and in neutrophils, macro-
phages, platelets, certain bacteria, and cultured human fibroblasts.16,18
Elastases exhibit a broad specificity. They are found in all classes of
proteinases. Elastase activity is present in neutrophil elastase, cathep-
sin G, proteinase 3, and matrix metalloproteinases 2 and 9 (gelatinases
A and B).19 MMP12 (metalloelastase) is another matrix metallopro-
teinase which also has an important role in the degradation of elastic
fibers.3 The exact role of elastase in normal skin is uncertain; it plays
a part in the elastolysis seen in anetoderma and in acquired cutis laxa
associated with inflammatory skin lesions. Elastase inhibitors also exist;
these include α1-antitrypsin, α2-macroglobulin, and lysozyme.20 There
are two factors, vitronectin and delay-accelerating factor, which appear
to prevent damage to elastic fibers by complement.21 Further work is
needed to clarify the role of these substances.
Age-related changes
There is evidence of continuing synthesis of elastic fibers throughout
life, but after the age of 50 the new fibers are loosely rather than
closely assembled.22 With age, there is some loss of the superficial
dermal fibers and a slow, progressive degradation of mature fibers.16,23
This is accompanied by changes in collagen and extracellular matrix.24,25
Ultrastructural changes include the formation of cystic spaces and
lacunae, imparting a porous look to the fibers;26,27 they may fragment
or develop a fuzzy, indistinct border.26 The changes are quite distinct
from those seen in solar elastosis.
Another age-related change is the deposition on elastic fibers of
terminal complement complexes and vitronectin. This latter substance
is a multifunctional glycoprotein that is hypothetically involved in the
prevention of tissue damage in proximity to local complement
activation.28
Staining of elastic tissue
Elastic tissue can be demonstrated in hematoxylin and eosin-stained
sections if appropriate modifications, as described by O’Brien, are
made.29 Notwithstanding this method, the commonly used stains for
elastic tissue are the orcein, aldehyde–fuchsin, Verhoeff, and Weigert
methods. However, the superficial fine elastic fibers do not stain with
most of these methods, although they will with a modified orcein
stain16 and the Luna stain, which incorporates aldehyde–fuchsin and
Weigert’s iron hematoxylin.30 The Luna stain also demonstrates a fibril-
lary component in solar elastosis. Elastic fibers stain a brilliant purple
against a pale lavender background with this stain.30 Miller’s modifica-
tion of Weigert’s resorcin–fuchsin has been suggested as the best
method for demonstrating new elastic fibers.31
A monoclonal antibody, HB8, has been described as a stain for
elastic fibers.32 It has no advantages over the modified orcein, Luna, or
Miller stains.
 DISORDERS OF ELASTIC TISSUE  •  CHAPTER 12 333

Table 12.1  Summary of the major disorders of elastic tissue

Diagnosis
Elastoma
Linear focal elastosis
Focal dermal elastosis
Elastoderma
Elastofibroma
Elastosis perforans serpiginosa
Pseudoxanthoma elasticum (PXE)
Elastic globes
Solar elastosis
Nodular elastosis
Elastotic nodules of the ears
Collagenous and elastotic plaques
Erythema ab igne
Nevus anelasticus (papular
elastorrhexis)
Perifollicular elastolysis
Anetoderma
Papillary-dermal elastolysis
(fibroelastolytic papulosis)
Mid-dermal elastolysis
Cutis laxa
Menkes’ syndrome
‘Granulomatous slack skin’
Clinical features
Solitary or multiple; papules and disks; sometimes
osteopoikilosis; linear variant reported
Palpable stria-like yellow lines; lumbosacral region
Late onset, PXE-like lesions
Localized lax, wrinkled skin
Deep scapular region; older age
Hyperkeratotic papules on face and neck
Yellowish papules and plaques; angioid streaks
Asymptomatic
Thickened, furrowed skin
Usually periorbital with cysts and comedones
Asymptomatic papules on the ear
Waxy, linear plaques at juncture of palmar and dorsal skin
Follows repeated heat exposure
Papular lesions on lower trunk; early onset, no inflammation
Common; face and back; often associated acne vulgaris
Well-circumscribed areas of soft, wrinkled skin; may have
preceding inflammation or be secondary to some other
disease
Papules and cobblestone plaques on neck and upper trunk,
resembling PXE
Widespread patches of fine wrinkling; additional perifollicular
papules in some cases; may have preceding inflammatory
phase
Widespread, large folds of pendulous skin; often involves
internal organs; congenital or acquired
Copper storage disease; brittle, ‘steel wool’ hair; vascular
and neurological changes
Pendulous skin in flexural areas; T-cell lymphoma
Pathology
Increased, thick, branching elastic fibers
Numerous elongated wavy fibers, some with
‘paintbrush’ ends
Increase in normal elastic fibers; no PXE changes
Increased, pleomorphic elastic tissue in upper dermis
Proliferation of collagen and elastic tissue
Papillary accumulation and transepidermal elimination
of elastic tissue
Fragmented and calcified elastic fibers in mid dermis;
may perforate
Basophilic cytoid bodies in the upper dermis
Accumulation of curled basophilic elastic fibers and
elastic masses in upper dermis
Comedones and usually solar elastosis
Clumped masses of elastotic material
Thick collagen, some perpendicular; admixed granular,
elastotic material; basophilic elastotic masses
Elastotic material in dermis
A ‘minus nevus’ with reduced, fragmented elastic
tissue in reticular dermis
Loss of elastic tissue around follicles
Loss of elastic fibers, particularly in mid dermis
Loss of elastic tissue in papillary dermis; no
calcification of remaining fibers
Loss of elastic tissue from mid dermis
Fragmentation and loss of elastic fibers
Pili torti, often with monilethrix and trichorrhexis nodosa
Lymphoid cells; granulomas with multinucleate giant
cells; absence of elastic fibers

Categorization of elastic tissue disorders

A simple classification of disorders of cutaneous elastic tissue divides
them into those in which the elastic tissue is increased and those in
which it is reduced.33 The solar elastotic syndromes are best considered
as a discrete group. Minor alterations in elastic tissue may occur in the
various collagen disorders, in line with the observation that alterations
in one component of the connective tissue matrix may influence the
structure and function of others.34 This group will not be considered
in great detail here.
Although not categorized separately in this chapter, it should be
remembered that elastic fibers are the most important structure to
undergo transepidermal elimination. This can occur in elastosis perfo-
rans serpiginosa, perforating folliculitis, perforating pseudoxanthoma
elasticum, solar elastosis, keratoacanthoma, healing wounds, and
hypertrophic discoid lupus erythematosus.
The clinical and pathological features of the major disorders of
elastic tissue are summarized in Table 12.1. The genetic abnormalities
in the various disorders are listed in Table 12.2.
INCREASED ELASTIC TISSUE
Very little is known about the mechanisms which lead to an increase
in dermal elastic tissue. Besides the conditions to be considered below,
a mild increase in elastic tissue has been reported in osteogenesis
imperfecta,35 chronic acidosis,36 amyotrophic lateral sclerosis37 and
some stages of radiation dermatitis.38,39 The solar elastotic syndromes
are also characterized by increased elastic tissue and they will be con-
sidered after this section.
ELASTOMA (ELASTIC NEVUS)
Elastoma (elastic nevus, juvenile elastoma,40 nevus elasticus, connec-
tive tissue nevus of Lewandowsky type41) is a variant of connective
tissue nevus (see p. 317) in which the predominant abnormality is an
increase in dermal elastic tissue.42 The lesions may be solitary or mul-
tiple40,43 and in the latter circumstance they are often associated with
334 SECTION 4  •  the dermis and subcutis

Table 12.2  Genetic abnormalities in disorders of elastic tissue

Disease
Buschke–Ollendorff syndrome
(elastomas)
Pseudoxanthoma elasticum
Cutis laxa (dominant)
Williams–Beuren syndrome
Cutis laxa (recessive)
Cutis laxa (X-linked recessive)
Cutis laxa (acquired)
Costello syndrome
Mid-dermal elastolysis
Wrinkly skin syndrome
Marfan’s syndrome
Menkes’ syndrome
Fragile X syndrome
Genetic abnormality (mutations
unless stated)
Loss of function mutations in LEMD3
(MAN1) on chromosome 12q14
ABCC6 gene on chromosome 16p13.1
ELN (elastin) gene on chromosome 7q11.2
Deletion of ELN and contiguous genes on
chromosome 7q11.2
FBLN5 (fibulin-5) gene on chromosome 14
FBLN4 (fibulin-4) gene
Disorders of glycosylation
Allelic to Menkes’ syndrome (see below)
FBLN5 and ELN mutations may predispose A
to some cases
Unknown; functional deficiency of elastin-
binding protein
HRAS gene on chromosome 11p15.5
One family with Keutel syndrome had this
change. Defect in MGP (matrix Gla
protein) gene
Deletions of 2q32 reported, but not
subsequently accepted. Defect in
N-protein glycosylation likely
Fibrillin-1 (FBN1) gene of 15q21.1
ATP7A gene on chromosome Xq12–q13
FMR1 gene on chromosome Xq27.3

multiple small foci of sclerosis of bone (osteopoikilosis). This associa-
tion is known as the Buschke–Ollendorff syndrome44,45 and the cutane-
ous lesions as dermatofibrosis lenticularis disseminata. In several
instances, the cutaneous lesions have shown abnormalities in collagen
rather than elastic tissue (collagenomas)46–48 and for this reason derma-
tofibrosis lenticularis disseminata is not entirely synonymous with the
term ‘elastoma’.43
The Buschke–Ollendorff syndrome (OMIM 166700) is inherited as
an autosomal dominant trait with variable expressivity.44 While most
individuals with this syndrome have both skin manifestations and
osteopoikilosis, some family members have only cutaneous lesions or
only bony lesions, but not both.46,49–52 The genetic defect in the
Buschke–Ollendorff syndrome has now been determined. It involves
loss-of-function mutations in the LEMD3 gene (also called MAN1),
which encodes an inner nuclear membrane protein that influences
Smad signaling.53,54 Melorheostosis (OMIM 155950) appears to be
allelic with this syndrome and the concurrence of the two diseases
has been reported.54–56 The cutaneous lesions (elastomas) may be
widely distributed flesh-colored or yellowish papules or localized,
asymmetrically distributed plaques on the lower trunk or extremities.57
These localized lesions are thought to represent type 2 segmental
manifestations of an autosomal dominant trait.58 A large, multilo­
bulated, exophytic variant has been reported.59 They develop at an
early age. The nail–patella syndrome, another disorder of connective
tissue, has been reported in a family with the Buschke–Ollendorff
syndrome.60
Studies of the desmosine content of elastomas indicate a 3–7-fold
increase in elastin.61 There appears to be an abnormality of elastogen-
esis with faulty aggregation of elastin units associated with the overall
increase in elastin.
B
Fig. 12.1  Elastoma. (A) There is increased elastic tissue in much of the dermis,
but excluding either end. (Orcein) (B) There are coarse irregular clumps of elastic
tissue within the reticular dermis. (Verhoeff–van Gieson)
Histopathology
Examination of hematoxylin and eosin-stained sections usually shows
a normal dermis,44 although sometimes there is an increase in its thick-
ness. The epidermis may have a slight wavy pattern. Elastic tissue
stains show an accumulation of broad, branching and interlacing elastic
fibers in the mid and lower dermis (Fig. 12.1).47 The papillary dermis is
unaffected. Sometimes the elastic fibers encase the collagen in a mar-
ble-vein configuration.40,62 Clumped elastic fibers have been reported;63
they are a regular feature in linear focal elastosis.64 A morphometric
analysis shows a 4–5-fold increase in elastic fibers compared to normal
skin; the diameter of the fibers is also increased.65
Uncommon changes include an increase in acid mucopolysaccha-
rides,47 slight thickening of collagen bundles, or a well-developed vas-
cular component.66 Two cases have been reported with facial plaques
and increased dermal elastic tissue;67,68 in one, there was also perifol-
licular mucin.68
Electron microscopy
Ultrastructural findings have been variable.61,69 Usually there are
branched elastic fibers of variable diameter, without fragmentation.
Elastic microfibrils may be replaced by granular or lucent material.40,70
Collagen fibers are sometimes increased in diameter69 and some fibro-
blasts may have dilated rough endoplasmic reticulum.61 In linear focal
elastosis, sequential maturation of elastic fibers can be seen, suggesting
active elastogenesis.71

LINEAR FOCAL ELASTOSIS
Linear focal elastosis (elastotic striae) is a distinctive acquired lesion
composed of palpable, stria-like, yellow lines that typically occur in the
lumbosacral region,64,71–77 but other sites, such as the face78 and legs79
may be affected. There is a predilection for males. It occurs at all ages,
but predominantly in the elderly.80 This condition, which has been
likened to a keloid of elastic fibers, may be an unusual form of striae
distensae (see p. 319),75 but its pathogenesis is currently unknown.80
Histopathology
Numerous elongated, wavy elastic fibers are present in the mid dermis.
At their ends, some fibers are split into a ‘paintbrush formation’.74
Fragmented fibers are also present. The elastic fibers have been
reported as thickened75 or thinned. Clumped elastic fibers are some-
times seen.80
FOCAL DERMAL ELASTOSIS
Focal dermal elastosis is a distinct entity of late onset, characterized
by a pseudoxanthoma elasticum-like eruption.81–84 The elastin content
of the skin is significantly increased.85
Histopathology
There is an increase in normal-appearing elastic fibers in the mid and
deep dermis.81 There are no changes of pseudoxanthoma elasticum.
ELASTODERMA
Elastoderma, an exceedingly rare condition, is an acquired, localized
laxity of skin resembling cutis laxa with lax, extensible, wrinkled
skin.86–88 The lesions are not indurated. The clinical presentation differs,
therefore, from elastoma (elastic nevus).
Histopathology
Elastoderma has an excessive accumulation of pleomorphic elastic
tissue within the dermis, particularly the upper dermis. On routine H
& E sections, there are numerous eosinophilic irregular fibers in the
papillary and reticular dermis. On elastic tissue stains, there are masses
of thin, intertwined fibers.86 The fibers are not calcified.88
ELASTOFIBROMA
Elastofibroma (elastofibroma dorsi) is a relatively rare, slowly growing
proliferation of collagen and abnormal elastic fibers with a predilec-
tion for the subscapular fascia of older individuals, particularly
females.84,89–92 It is rarely found at other sites. Most elastofibromas are
unilateral and asymptomatic. Multiple elastofibromas are rare.93 Nearly
two-thirds of the 300 or more cases so far reported have been from
southern Japan.94 Although an association with pseudoxanthoma elas-
ticum has been recorded, there is no abnormality in the ABCC6 gene.95
The pathogenesis is unknown, but they may represent a reaction to
prolonged mechanical stress, possibly involving disturbed elastic fibril-
logenesis by periosteal-derived cells.96 Cytogenetic studies have found
evidence of chromosomal instability and/or clonal changes suggesting
a neoplastic process.97 Elastofibromas are gray-white or tan in color and
measure 5–10  cm in diameter. Subclinical elastofibromas have been
found at autopsy.98
Histopathology
Elastofibromas are non-encapsulated lesions which blend with the sur-
rounding fat and connective tissue.90 They are hypocellular and com-
DISORDERS OF ELASTIC TISSUE  •  CHAPTER 12 335
posed of swollen collagen bundles admixed with numerous, irregular,
lightly eosinophilic fibers and some mature fat (Fig. 12.2). The fibers,
which account for almost 50% of the tissue, stain black with the Ver-
hoeff elastic stain. Some fibers are branched while others show a ser-
rated edge.
The elastic fibers contain elastin but not fibrillin-1. No staining for
actin or desmin was observed in one study.95 The cells express CD34.97
Electron microscopy
Electron microscopy confirms the presence of abnormal elastic fibers,
which result from a proliferation of elastic fibrils around the original
elastic fibers.98 Large (‘active’) fibroblasts89 and cells with the features
of myofibroblasts99 have both been described.
ELASTOSIS PERFORANS SERPIGINOSA
Elastosis perforans serpiginosa (also known as perforating elastosis –
OMIM 130100) presents as small papules, either grouped or in a
circinate or serpiginous arrangement, on the neck, upper extremities,
upper trunk, or face.100–106 Rarely, the lesions are generalized.84,107,108
There is a predilection for males, with the onset usually in the second
decade. Familial cases have been reported.109–111 An autosomal domi-
nant mode of inheritance with variable expressivity of the trait has
been suggested.112 In up to a third of cases there is an associated sys-
temic condition or connective tissue disorder: these include Down
syndrome,108,113–116 osteogenesis imperfecta,117 cutis laxa,118 Ehlers–
Danlos syndrome, Marfan’s syndrome, acrogeria, scleroderma,119,120
an abnormal 47,XYY karyotype,121 diabetes mellitus,122 perforating
folliculitis,123 and chronic renal failure.124
Similar cutaneous lesions have been reported in patients with
Wilson’s disease and cystinuria receiving long-term penicillamine
therapy.118,125–129 In these patients, a local copper depletion or a direct
effect of penicillamine on elastin synthesis may be responsible for the
formation of the abnormal elastic fibers, which are then eliminated
transepidermally.125,130 Elastic tissue damage appears to occur in other
organs as well, a feature generally lacking in the usual idiopathic form
of the disease.130,131 The nature of the defect in the idiopathic form is
unknown, but it is possible that perforating elastosis is the final
common pathway for more than one abnormality of elastic fibers.101,132
This theory is compatible with the finding of a 67 kDa elastin receptor
in keratinocytes immediately surrounding the elastic materials being
eliminated in lesions of elastosis perforans serpiginosa.133,134 The elastin
receptor may be involved in the interaction between keratinocytes and
elastin.133,134
Various therapies have been used including liquid nitrogen cryo-
therapy, isotretinoin, and imiquimod.135
Histopathology100–103
In fully developed lesions there is a localized area of hyperplastic
epidermis, associated with a channel through which the basophilic
nuclear debris and brightly eosinophilic fragmented elastic fibers are
being eliminated (Fig. 12.3). A keratinous plug usually overlies this
channel, which may take the form of a dilated infundibular structure
or a more oblique canal coursing through hyperplastic epidermis, fol-
licular epithelium or the acrosyringium (Figs 12.4, 12.5). When the canal
is oblique, sections may only show a surface plug of keratinous debris
and a localized area of hyperplastic epidermis which in its lower
portion forms a bulbous protrusion into the dermis. This appears to
envelop an area of the papillary dermis containing basophilic debris
and some refractile eosinophilic elastic fibers.
Elastic tissue stains show increased numbers of coarse elastic fibers
in the papillary dermis. Some of these appear to overlap the basal
epidermal cells. In the region of their transepidermal elimination,
the elastic fibers lose their staining properties as they enter the canal
336 SECTION 4  •  the dermis and subcutis

A C
Fig. 12.2  Elastofibroma dorsi. (A) Coarse elastic fibers are admixed with collagen and adipose tissue. (B) The fibers have an irregular outline. (H & E) (C) An elastic
tissue stain confirms the irregular outline. (Verhoeff–van Gieson)

Fig. 12.3  Elastosis perforans serpiginosa. Debris is entering a channel
within the epidermis. (H & E)
and become brightly eosinophilic. They will stain with the Giemsa
method. A few foreign body giant cells and inflammatory cells
are often present in the dermis adjacent to the channel. In older
lesions, there is focal dermal scarring and usually an absence of elastic
fibers.
IgM, C3, and C4 were demonstrated on the abnormal elastic fibers
in the papillary dermis in one of two cases studied by
immunofluorescence.136
In penicillamine-related cases, there is an increased number of
thickened elastic fibers in the reticular dermis and less hyperplasia of
elastic fibers in the papillary dermis, except in the areas of active
transepidermal elimination.137 The elastic fibers are irregular in outline
with buds and serrations. This may be discerned in hematoxylin and
eosin-stained preparations, but it is well shown by elastic tissue stains
(Fig. 12.6)138 or in Epon-embedded thin sections stained with toluidine
blue.130
Electron microscopy
Ultrastructural examination of the dermis in penicillamine-related
cases shows that the elastic fibers have a normal core and an irregular
coat with thorn-like protrusions at regular intervals, the so-called
‘lumpy bumpy’ or ‘bramble-bush’ fibers.137–140 Collagen fibers are also
abnormal with extreme variations in thickness.140,141 Electron micros-
copy of idiopathic cases has shown increased numbers of large elastic

A B
Fig. 12.4  (A) Elastosis perforans serpiginosa. (B) Debris and elastic fibers are being enveloped by a bulbous protrusion of the epidermis. (H & E)
Fig. 12.5  Elastosis perforans serpiginosa. Another case with a less obvious
epidermal channel. (H & E)
DISORDERS OF ELASTIC TISSUE  •  CHAPTER 12 337
fibers which are convoluted and branching.142 Fine filaments, similar to
those in embryonic elastic fibers, are present on the surface of the
fibers.142,143
PSEUDOXANTHOMA ELASTICUM
Pseudoxanthoma elasticum (OMIM 264800) is an inherited disorder
of connective tissue in which calcification of elastic fibers occurs in
certain areas of the skin, eyes, and cardiovascular system.144–149 Muta-
tions in the ABCC6 gene on chromosome 16p13.1 are responsible for
this condition. Over 60 different mutations of this gene have been
reported.150,151 Its incidence ranges from 1 : 70 000 to 1 : 100 000 live
births.152 Skin changes are usually evident by the second decade and
consist of closely set yellowish papules with a predilection for flexural
creases, particularly in the neck and axillae and less commonly in the
groins, periumbilical area, and the cubital and popliteal fossae.145–147,153,154
Oral lesions may occur.148 The skin becomes wrinkled and thickened
and eventually may become lax and redundant, resembling cutis
laxa.155–158 Mental (chin) creases are common.159,160 The calcium content
of affected skin may be up to several hundred times normal.161 Calci-
fication occurring in the breast may lead to problems in the interpreta-
tion of mammograms.162 Eye changes include angioid streaks and a
degenerative choroidoretinitis which may lead to blindness. Angioid
streaks can occur in the absence of pseudoxanthoma elasticum.163
338 SECTION 4  •  the dermis and subcutis
A Patients purported to have coexisting elastosis perforans serpiginosa
B the elastic fibers.171
Fig. 12.6  (A) Elastosis perforans serpiginosa due to penicillamine
therapy. (H & E) (B) The elastic fibers have a serrated appearance. (Verhoeff–
van Gieson)
Calcification of elastic fibers in arteries and intimal and endocardial
fibroelastosis develop. The vascular changes may lead to hypertension,
sudden cardiac death,164 cerebrovascular accidents, and gastrointestinal
hemorrhage.165–167 Gastric bleeding may be increased in pregnancy, but
most pregnancies in this condition are uncomplicated.168
Pseudoxanthoma elasticum has been associated with certain hemo-
globinopathies such as β-thalassemia and sickle cell disease.152,169 Neph-
rolithiasis is another rare association.170 Its occurrence is interesting as
the ABCC6 gene encodes a transmembrane transporter protein
ABCC6 (MRP6), a member of the ATP-binding cassette (ABC) super-
family.171 This protein is strongly expressed in the liver and kidney,
with a possible role in phosphocalcic metabolism.170 Hyperphosphata-
sia has been reported in several cases.172 The administration of vitamin
D3 results in further deposition of calcium salts.173 Oral phosphate
binders have been used in a small number of cases, with clinical
improvement of skin lesions in half.174 Urinary glycosaminoglycan
levels are elevated early in the disease.175 Polymyositis and lupus ery-
thematosus are other associations, possibly due to chance.176,177
Characterization of the gene mutations responsible for this condi-
tion have led to a change in our understanding of its inheritance. Previ-
ously it was believed that there were two variants with autosomal
dominant inheritance and two with autosomal recessive inheritance.
The clinical presentations and severity of these variants appeared to
differ.178–181 It was acknowledged that the interpretation of the genetic
studies that resulted in these views was made difficult by the limited
phenotypic expression of the disease in some individuals.182 It is now
believed that fewer than 2% of cases, if any, are autosomal dominant.
In one study of 142 subjects, all cases were autosomal recessive in
their mode of inheritance.183 Consanguinity was high. Homozygous
patients had typical clinical appearances, including angioid streaks in
the eye, although the severity of the disease varied.183 All 67 subjects
that were heterozygous for the gene showed no cutaneous features of
pseudoxanthoma elasticum, but few had skin biopsies.183 Heterozy-
gotes may uncommonly experience severe ophthalmological complica-
tions.123 Whether they may have cardiovascular complications remains
to be determined. Another study showed histological changes in
dermal elastic fibers in heterozygotes but the authors still concluded
that the relevance of performing a skin biopsy to detect heterozygous
carriers remains to be determined.171
and pseudoxanthoma elasticum have been reported; they are now
regarded as having perforating pseudoxanthoma elasticum.184–187 In
such a case, associated with Moya Moya vasculopathy, amino acid
substitutions were found in a region close to the ABCC6 gene site.187
Many of these patients have so-called ‘acquired pseudoxanthoma elas-
ticum’ (see below).
The factors that lead to the calcification of initially normal elastic
fibers in pseudoxanthoma elasticum are not known.188 The role of
ABCC6 has not been delineated, and its substrate has not been identi-
fied.171 Polyanionic material is deposited in association with the calci-
fied material. Cultured fibroblasts from patients with this condition
release a proteolytic substance and it has been postulated that this may
cause selective damage to elastin, leading to calcification.189 Fibrillin
appears to be abnormal in only isolated cases (unlike the findings in
Marfan’s syndrome).190 Decreased deposition of fibrillin-2 has been
reported in pseudoxanthoma elasticum.191 These isolated findings have
been replaced with a viewpoint that several structural proteins with
an affinity for calcium (vitronectin, fibronectin, and bone sialoprotein)
are increased in this condition and responsible for the calcification of
There has been one report of spontaneous resolution and repair of
elastic tissue calcification.192 There is one report of the successful treat-
ment of this condition with oral tocopherol acetate and ascorbic acid,
both antioxidants.193 It took 2 years of treatment for the papules to
disappear.193
Acquired pseudoxanthoma elasticum
Acquired pseudoxanthoma elasticum refers to an etiologically and
clinically diverse group of patients with late onset of the disease, no
family history, absence of vascular and retinal stigmata, and identical
dermal histology.149,194,195 The term ‘perforating calcific elastosis’ has
been suggested for some of these cases.196,197 Included in this group are
individuals exposed to calcium salts, including farmers exposed to
Norwegian saltpeter (calcium and ammonium nitrate),198,199 and obese,
usually multiparous black women who develop reticulated and atro-
phic plaques and some discrete papules around the umbilicus186,196,200
or lower chest.201 Perforation is common in this latter group.202 Patients
with chronic renal failure on dialysis have also been reported with this
acquired variant.194,203,204
Pseudoxanthoma elasticum-like fibers have been found in other
skin diseases in the absence of other signs of this disease,205,206 and as
an acquired localized disorder.207 These changes have been seen par-
ticularly in disorders of the subcutis such as lipodermatosclerosis,
morphea profunda, erythema nodosum, but also in granuloma annu-
lare, lichen sclerosus, tumefactive lipedema, and a basal cell
carcinoma.205,206
 DISORDERS OF ELASTIC TISSUE  •  CHAPTER 12 339

Pseudo-pseudoxanthoma elasticum refers to the development of the

systemic changes of pseudoxanthoma elasticum in patients on long-
term penicillamine therapy for Wilson’s disease. However, it has also
been used for the cases referred to above as acquired pseudoxanthoma
elasticum.208 A spectrum of elastic tissue disorders, particularly elasto-
sis perforans serpiginosa (see above), occurs with penicillamine
therapy.209,210

Histopathology147
There are short, curled, frayed, basophilic elastic fibers in the reticular
dermis, particularly in the upper and mid parts (Figs 12.7, 12.8). The
papillary dermis is spared except at sites of transepidermal elimination
(perforation). The elastic fibers in affected skin are stained black with
the von Kossa method (Fig. 12.9). They stain with the Verhoeff method
and there is intense blue staining with phosphotungstic acid hematoxy-
lin (PTAH). Calcinosis cutis211 and osteoma cutis157,158 are rare compli- A
cations. There is a good correlation between the severity of the clinical
change and the histology.183
If perforation is present, there is a focal central erosion or tunnel
with surrounding pseudoepitheliomatous hyperplasia or prominent
acanthosis (Fig. 12.10). Basophilic elastic fibers are extruded through
this defect. Sometimes foreign body giant cells, histiocytes, and a few
chronic inflammatory cells are present when there is perforation or
traumatic ulceration.212,213 The giant cells may then engulf some elastic
fibers.
In the acquired localized forms the changes can be found in the
dermis and/or the septa of the subcutaneous fat.206
Electron microscopy
Calcification occurs initially in the central zones of the elastic fibers.214
There is also some calcification of intercellular spaces and occasionally
also of collagen fibers; the latter change may be reversible.172,201 There
is continuing elastogenesis with some normal elastic fibers.172 Twisted
collagen fibrils and thready material,215 which has been found to contain B
fibrinogen, collagenous protein, and glycoprotein, are also present.216
This indicates that the abnormality is not limited to the elastic fibers.

ELASTIC GLOBES
Elastic globes are small basophilic bodies, found in the upper dermis
of clinically normal skin, which stain positively for elastic fibers
(Fig. 12.11). They are considered with the other dermal cytoid bodies
on page 387. Numerous elastic globes have been reported in a
patient with epidermolysis bullosa whose skin was wrinkled217 and in
a patient with the cartilage–hair hypoplasia syndrome whose skin was
hyperextensible.218
As the globes contain D-aspartyl residue-containing peptide, it has
been postulated that they result from UV-induced skin damage.219

SOLAR ELASTOTIC SYNDROMES

The term ‘solar elastosis’ refers to the accumulation of abnormal elastic
tissue in the dermis in response to long-term sun exposure. Photoaging
is a process distinct from the changes taking place due to chronological
aging, although photoaging does increase in severity with chronological
aging.220–223 The effects of both are cumulative.224 A review of photoag-
ing was published in 2007.225 Another review looking at treatment
options was published in 2008.226 The cosmetic effects of photodamage
are assuming increasing importance in society. There are many differ-
ent clinical patterns of solar elastosis, some of which form distinct
clinicopathological entities.227,228 Other clinical patterns are histologi-
cally indistinguishable from one another and they are usually grouped
together under the umbrella term ‘solar elastosis’.
C
Fig. 12.7  (A) Pseudoxanthoma elasticum. (B) Note the short, curled elastic
fibers in the reticular dermis. (C) They are basophilic. (H & E)
The following entities are regarded as solar elastotic syndromes:
• solar elastosis
• nodular elastosis with cysts and comedones
• elastotic nodules of the ears
• collagenous and elastotic plaques of the hands.
Colloid milium can also be regarded as a solar elastotic syndrome, as
it appears that the colloid substance derives, at least in major part,
340 SECTION 4  •  the dermis and subcutis

Fig. 12.8  Pseudoxanthoma elasticum. The elastic fibers are short and curled.
(Verhoeff–van Gieson)

B
Fig. 12.10  (A) Perforating pseudoxanthoma elasticum. (B) The elastic
fibers which are about to undergo transepithelial elimination are short, curled and
frayed. Clumped elastic fibers are also present. (Verhoeff–van Gieson)

from elastic fibers through actinic degeneration.229 Colloid degenera-

A
B protected skin.233
Fig. 12.9  Pseudoxanthoma elasticum. (A) Calcium salts are deposited on
the abnormal elastic fibers. (von Kossa) (B) Larger deposits of dystrophic
calcification may occur. (H & E)
tion (paracolloid, colloid milium-like solar elastosis) has overlapping
features histologically with both colloid milium and solar elastosis.
These topics are considered with the cutaneous deposits in Chapter
14 (pp. 384 and 385).
Solar elastotic skin is more susceptible than normal skin to chronic
infections with Staphylococcus aureus and several other bacteria. This
results from a decline in the adaptive capabilities of the immune
system.230 Uncommonly, this results in a chronic suppurative process,
variants of which have been reported as ‘coral reef granuloma’ and
blastomycosis-like pyoderma (see p. 553). Actinic comedonal plaque,
in which fibrous tissue and comedones are present with some residual
elastosis at the periphery, can be the end-stage picture of this inflam-
matory process.
Another secondary change that may occur in sun-damaged skin is
the formation of actinic granulomas in which there is a granulomatous
response to solar elastotic material and its resorption by macrophages
and giant cells (elastophagocytosis, elastoclasis).231,232 Actinic granulo-
mas present clinically as one or more annular lesions with an atrophic
center and an elevated border. They are considered with the granulo-
matous tissue reaction (see p. 188). Elastophagocytosis has also been
reported in association with various inflammatory processes in sun-
Ultraviolet light is usually incriminated in the etiology of the degen-
erative changes.234 Human studies have demonstrated that small
amounts of UVA or solar-simulated UV are capable of producing

A
B
Fig. 12.11  Elastic globes. (A) There are multiple, round, and ovoid deposits in
the papillary dermis. Solar elastosis is also present. (H & E) (B) An elastic tissue
stain of the same case. (Verhoeff–van Gieson)
cutaneous photodamage.235,236 Long-term exposure to PUVA (psoralens
and ultraviolet A) is associated with persistent increases in actinic
degeneration and pigmentary abnormalities on both sun-exposed and
sun-protected sites.237 However, it has been suggested that infrared
radiation may also contribute, as changes characteristic of solar elasto-
sis are seen in erythema ab igne.238 Although not usually regarded as
one of the elastotic syndromes, this condition will be considered in
this section because of its similar histological appearances. Two further
causes of heightened elastosis are cigarette smoking239–241 and photo-
sensitivity resulting from the therapeutic use of hydroxyurea.242 The
degree of aging in photoprotected skin correlates significantly with
patient age and a history of cigarette smoking.243
SOLAR ELASTOSIS (ACTINIC ELASTOSIS)
The usual clinical appearance of solar elastosis is thickened, dry,
coarsely wrinkled skin with loss of skin tone.244 Sometimes there is a
yellowish hue. There may be some telangiectasia and pigmentary
changes (poikilodermatous changes) in severe cases.245,246 The best rec-
ognized clinical variant is cutis rhomboidalis in which there is thick-
ened, deeply fissured skin on the back of the neck. Other clinical
patterns include citrine skin,247 Dubreuilh’s and other elastomas,248 and
solar elastotic bands of the forearm.249,250 Elastotic bands are character-
ized by cordlike plaques across the flexor surfaces of the forearms.251
The author has seen a similar, but much milder phenomenon on the
DISORDERS OF ELASTIC TISSUE  •  CHAPTER 12 341
face of a colleague with severe solar damage. Bullous lesions are
extremely rare.252,253
The origin of the elastotic material has been the subject of much
debate. It has been attributed to the degradation of collagen or elastic
fibers or both.254,255 Alternatively, it has been suggested by others that
the material results from the actinic stimulation of fibroblasts.256 More
recent work indicates that the elastotic material is primarily derived
from elastic fibers.257,258 The increased elastin appears to result from
transcriptional activation of the elastin gene.259,260 In contrast, various
studies have clearly shown that in unexposed skin, elastin content
decreases with age (−44%) between 50 and 70 years of age. Interest-
ingly, the elastin content of moderately sun-exposed areas does not
change during aging, which may be the result of age-induced reduction
and sun-dependent increase in elastin.261 In addition to the increased
production of elastin in sun-exposed skin, there is reduced human
leukocyte elastase activity, possibly a consequence of increased lyso-
zyme production which protects elastin from proteolysis.261 In con-
trast, neutrophil elastase is increased following experimental radiation
to sun-protected skin.262 Clusterin, a glycoprotein, is markedly increased
in solar elastosis. Its role is not completely elucidated.263 A small
amount of type I and VI collagen and procollagen type III are present,
but the significance of this finding remains uncertain.257 DNA photo-
damage and UV-generated reactive oxygen species are the initial
molecular events that lead to most of the typical histological and clini-
cal manifestations of chronic photodamage of the skin.264 Photoaging
results in the accumulation of glycosaminoglycans on the elastotic
material in the upper dermis and not between collagen and elastic
fibers as in normal skin.265,266 Fibrillin is also increased.258 Collagen VII
is reduced and this may contribute to the formation of wrinkles by
weakening the bond between the dermis and the epidermis.267 D-aspar-
tyl residues are increased in chronological and photo-induced aging.219
Matrix metalloproteinase-7 and -12 are increased in photodamaged
skin; they may contribute to remodeling of elastotic areas.268,269 Metal-
loproteinase-1 may be responsible for the degeneration and reduction
in collagen.270–272 Fibulin-2, which belongs to a novel family of extracel-
lular matrix protein, is significantly increased in actinically damaged
skin.11 Other consequences of photoaging are mutations in p53 and the
partial loss of the ability of epidermal cells to differentiate normally.273
The changes are qualitatively quite different from those seen in chron-
ological aging,274,275 contrary to the assertion of some.276
Various therapies have been used in recent times to improve the
clinical appearance of photoaged skin.226 One such technique, derm-
abrasion, produces clinical improvement by the synthesis of type I
collagen.277 Another technique, the prolonged application of topical
tretinoin (retinoic acid), produces epidermal thickening,225,278–281 hyper-
granulosis, an increase in epidermal Langerhans cells,231 the deposition
of collagen in the papillary dermis,282 and, sometimes, an increase in
fine elastic fibers in the papillary dermis.283 Carbon dioxide laser resur-
facing, and the intradermal injection of crosslinked hyaluronic acid
may also be used.226,284 These changes may result in an improved clinical
appearance,285,286 although this has not occurred in all studies.287 Imiqui-
mod, tacrolimus ointment, topical 5-aminolevulinic acid, and topical
estrogen creams have all been used successfully in the treatment of
photoaging.288–291 Over-the-counter preparations have had variable
results.292 The prolonged use of sunscreens results in a significant
reduction in the amount of solar elastosis and other harmful effects;293,294
it is the single most cost-effective therapy.225,266
Histopathology
In mild actinic damage there is a proliferation of elastic fibers in the
papillary dermis. These are normal or slightly increased in thickness.
In established cases the papillary and upper reticular dermis is replaced
by accumulations of thickened, curled, and serpiginous fibers forming
tangled masses which are basophilic in hematoxylin and eosin-stained
342 SECTION 4  •  the dermis and subcutis
Fig. 12.12  Solar elastosis with amorphous and fibrillary material in the upper
dermis. (H & E)
Fig. 12.13  Solar elastosis. Curled elastotic fibers are insinuating between basal
keratinocytes. This represents the early stages of the transepidermal elimination of
these damaged fibers. (H & E)
sections (Fig. 12.12).22 Sometimes there are amorphous masses of elas-
totic material in which the outline of fibers is lost except at the
periphery. These masses are thought to form from the tangled fibers,
as transitions can be seen on electron microscopy. A thin grenz zone
of normal-appearing collagen is present in the subepidermal zone.295
This may have lost its network of fine vertical fibers. Collagen is
reduced in amount in the reticular dermis. Telangiectases may be
seen.266 In a study of Korean skin with chronic photodamage, there
was a gradual decrease in the number and size of dermal vessels over
several decades of sun exposure.296 Transepidermal elimination of elas-
totic material can occur.297 This process is not uncommon following
cryotherapy to severely damaged skin, which seems to trigger it in
some individuals (Fig. 12.13). The elastotic material stains black with
the Verhoeff stain (Fig. 12.14). Sometimes the homogeneous deposits
are less well stained. Melanocytes and Merkel cells are both increased
in number.298,299
Biopsies from individuals with chronic sunlight exposure, some of
whom had persistent erythema, have been described as showing a
‘perivenular histiocytic-lymphocytic infiltrate in which numerous mast
cells, often in close apposition to fibroblasts, were observed’: this
condition has been termed ‘chronic heliodermatitis’.300 In normal-
appearing sun-exposed skin there are more mast cells, macrophages,
Fig. 12.14  Perforating solar elastosis. The elastic fibers being eliminated are
thick, curled, and serpiginous in morphology. (Verhoeff–van Gieson)
CD4+, CD45RO+ T cells and CD1a+ dendritic cells than sun-protected
skin.301
Epidermal changes also occur in severely damaged skin. The stratum
corneum may be compact and laminated or gelatinous; it sometimes
contains vesicles full of proteinaceous material.302 In the malpighian
layer, cell heterogeneity, vacuolization, and dysplasia may be found.302
In bullous solar elastosis there is a well-defined, horizontally ori-
ented cleft, lined by fibrin, in the middle of a dermis showing marked
solar elastosis.253 Red cell extravasation in the region of the cleft is not
uncommon.
Electron microscopy
A spectrum of ultrastructural changes is found which parallels the
clinical degree of damage.22,303,304 In mild cases, the elastic fibers in the
papillary dermis are increased in number. The microfibrillar dense
zones become irregular in outline, more electron dense, and many
times larger. In severe cases the elastin matrix becomes granular and
develops lucent areas around the microfibrillar dense zones.22 Some
fibers become disrupted and show a moth-eaten appearance or become
transformed into finely granular bodies.22 Similar ultrastructural find-
ings have been reported in chronic radiodermatitis.305 Deformed col-
lagen fibers, of various diameters, are found in the papillary dermis.306
Following PUVA therapy, the elastic fiber changes include a break-
down of the microfibrils and subsequent fragmentation of the elastic
fibers.307 Melanocytes show degenerative changes with the develop-
ment of large intracytoplasmic vacuoles.298
Scanning electron microscopy of solar elastosis shows some normal
fibers, some thick damaged cylindrical fibers, and large masses of mark-
edly changed fibers, which probably correspond to the amorphous
deposits seen in severe cases.308
NODULAR ELASTOSIS WITH CYSTS
AND COMEDONES
The solar degenerative condition, nodular elastosis with cysts and
comedones, is also known as the Favre–Racouchot syndrome.309 It
occurs as thickened yellowish plaques studded with cysts and open
comedones.310–312 It involves the head and neck, but particularly the
skin around the eyes. Lesions may extend to the temporal and zygo-
matic areas. A case involving the shoulder region has been reported.313
Rare cases are unilateral.314 There is a predilection for older males who
have a history of prolonged solar exposure. Smoking may act in con-
junction with solar damage to potentiate the development of this
 DISORDERS OF ELASTIC TISSUE  •  CHAPTER 12 343

condition.315,316 A case precipitated by radiation therapy and success-

fully treated with low-dose isotretinoin has been reported.317 Another
case was provoked by ultraviolet (UVA1 and UVB) radiation.318

Histopathology310,311
In addition to the marked solar elastosis, there are dilated follicles
and comedones which contain keratinous debris in the lumen. The
sebaceous glands are often atrophic. A recent study of patients without
much solar exposure showed multiple comedones without significant
solar elastosis, suggesting that the two processes might be
independent.319

ELASTOTIC NODULES OF THE EARS

Elastotic nodules are small, usually asymptomatic, pale papules and A
nodules found predominantly on the anterior crus of the antihelix in
response to actinic damage.320–322 They are often bilateral. There is a
marked predilection for elderly white males. Rare cases develop on
the helix, where they may be painful, simulating chondrodermatitis
nodularis helicis. They may be diagnosed clinically as basal cell carci-
noma, amyloid, or even small gouty tophi.

Histopathology321
There is marked elastotic degeneration of the dermis with the forma-
tion of irregular, coarse elastotic fibers and larger clumped masses of
elastotic material (Figs 12.15, 12.16). These changes are best seen with
the Verhoeff elastic stain. The overlying epidermis shows mild to
moderate orthokeratosis and some irregular acanthosis. There is mild
telangiectasia of vessels in the papillary dermis, and some new collagen
is often present in this area.

COLLAGENOUS AND ELASTOTIC PLAQUES

OF THE HANDS
Also known as ‘degenerative collagenous plaques of the hands’, ‘kera-
toelastoidosis marginalis’, and ‘digital papular calcific elastosis’,323 col-
lagenous and elastotic plaques of the hands is a slowly progressive,
degenerative condition found predominantly in older males.324–327 There
are waxy, linear plaques at the juncture of palmar and dorsal skin of
the hands. The condition particularly involves the medial aspect of the
thumbs and the lateral (radial) aspect of the adjacent index finger. In
this respect the lesions resemble in part those seen in the genoderma-
tosis acrokeratoelastoidosis (see p. 261).324 Physical trauma of a repeti-
tive nature and prolonged actinic exposure may play a role in the
etiology of collagenous and elastotic plaques of the hand.326,328

Histopathology
The most noticeable changes are in the dermis where there are numer-
ous thick collagen bundles having a haphazard arrangement, but with
a proportion running perpendicular to the surface (Fig. 12.17).329 There
B
is often a slight basophilic tint to the dermis; elastotic fibers can be
seen in the lower papillary dermis and intimately admixed with the Fig. 12.15  (A) Elastotic nodule of the ear. (B) Clumped masses of elastotic
material are present in the mid dermis. (H & E)
collagen bundles in the reticular dermis. Basophilic elastotic masses
are found in the upper dermis.323 The dermis shows reduced cellularity
The overlying epidermis may show mild hyperkeratosis and thicken-
with large areas devoid of fibroblasts.327 Sweat ducts may be mildly
ing of the granular layer. In some cases there is slight acanthosis, while
dilated in the mid dermis and compressed in other areas.
in others there may be loss of the rete pattern.
In elastic tissue stains, the elastotic material in the lower papillary
dermis is confirmed (Fig. 12.18). In the reticular dermis, granular and
elastotic material can be seen in an intimate relationship within some ERYTHEMA AB IGNE
of the larger collagen bundles.324 In some cases, there are focal deposits
of calcification in the dermis. The changes are distinct from those of Erythema ab igne refers to the development of persistent areas of
solar elastosis. reticular erythema, with or without pigmentation, at the sites of
344 SECTION 4  •  the dermis and subcutis
Fig. 12.16  Elastotic nodule of the ear. There are clumped masses of
elastotic material. (Verhoeff–van Gieson)
repeated exposure to heat, usually from open hearths.330,331 Other cases
have included frequent hot bathing,332 a laptop computer placed on
the thighs,333 and a heating pad.334 The lower legs are usually involved.
Erythema ab igne is now seen only rarely.335 Keratoses and, rarely,
squamous cell carcinomas may develop in lesions of long standing.336
Histopathology330,337
There is thinning of the epidermis with effacement of the rete ridges
and some basal vacuolar changes. Areas of epithelial atypia, resembling
that seen in actinic keratoses, are sometimes present. There is usually
prominent elastotic material in the mid dermis.338 A few large histio-
cytes may be present. A small amount of hemosiderin and melanin
may be present in the upper dermis.330
DECREASED ELASTIC TISSUE
There are several distinct levels in the biosynthesis of elastic fibers at
which errors can be introduced. These can lead to reduced production
of elastic fibers or to the appearance of abnormal ones. Breakdown of
fibers (elastolysis) is another mechanism which can lead to a reduction
in the elastic tissue content of the dermis. This probably results from
increased elastase activity.
B
Fig. 12.17  (A) Collagenous and elastotic plaque. (B) The collagen
bundles in the upper dermis have a characteristic haphazard arrangement with
some bundles arranged vertically. Elastotic material is admixed. (H & E)
The reduction in dermal elastic tissue can be generalized, as in cutis
laxa, or localized, as in anetoderma and blepharochalasis. Cases with
features intermediate between these two types or with fine wrinkling
of the skin occur. Sometimes the reduction in elastic fibers is subclini-
cal or overshadowed by other features. This is the case in various
granulomatous inflammatory disorders.
Skin atrophy, associated with a decrease in elastic fibers, has been
reported at the site of thiocolchicoside injections.339
NEVUS ANELASTICUS (PAPULAR ELASTORRHEXIS)
Nevus anelasticus is the term suggested by Staricco and Mehregan66
for several cases reported in the earlier literature characterized by an
absence or definite reduction and/or fragmentation of elastic fibers in
cutaneous lesions of early onset.340 Further cases have been reported
in which multiple papular lesions have developed, particularly on the
trunk.340–343 The term papular elastorrhexis has been used for such
cases; it has been regarded by some as a distinct variant of connective
tissue nevus,344 and not synonymous with nevus anelasticus. The author
has been criticized in a recent paper for not separating cases of papular
elastorrhexis from nevus anelasticus.345 However, another recent paper
by Ryder and Antaya has suggested that nevus anelasticus, papular
elastorrhexis, and eruptive collagenoma are the same entity; their

Fig. 12.18  Collagenous and elastotic plaque. Elastic tissue is reduced
between the thickened vertical collagen. There are curled fibers in the papillary
dermis. (Verhoeff–van Gieson)
preference for a name for this composite entity was papular elastor-
rhexis.346 The lesions are not perifollicular in distribution. Separation
from the non-inflammatory type of anetoderma may be difficult (see
below).
Histopathology
Sections show a localized reduction in elastic fibers, with normal col-
lagen.341 The elastic fibers may show intense fragmentation in some
cases.340 Fibers in the papillary dermis may be normal. There is no
inflammation in nevus anelasticus, but mild dermal inflammation has
been reported in papular elastorrhexis.347 However this is a tenuous
feature to use in separating these conditions as various elastic tissue
diseases may have (mild) inflammatory stages.
PERIFOLLICULAR ELASTOLYSIS
Perifollicular elastolysis is a not uncommon condition of the face and
upper back in which 1–3  mm gray or white, finely wrinkled lesions
develop in association with a central hair follicle.348,349 Balloon-like
bulging of larger lesions may develop.348 The disorder is significantly
associated with acne vulgaris.349,350 An elastase-producing strain of
DISORDERS OF ELASTIC TISSUE  •  CHAPTER 12 345
Fig. 12.19  Perifollicular elastolysis. There is absence of elastic tissue around
the pilosebaceous follicle. A few thin fibers are present near the edge of the
photomicrograph. (Verhoeff–van Gieson)
Staphylococcus epidermidis was found in the hair follicles located
within lesions in one report.348
Histopathology348
There is an almost complete loss of elastic fibers confined to the
immediate vicinity of hair follicles (Fig. 12.19). There is no
inflammation.
ANETODERMA
Anetoderma (macular atrophy) is a rare cutaneous disorder in which
multiple, oval lesions with a wrinkled surface develop progressively
over many years.351,352 Individual lesions may bulge outwards or be
slightly depressed. They usually herniate inwards with finger tip pres-
sure. There is a predilection for the upper trunk and upper arms, but
the neck and thighs may also be involved. Facial involvement may lead
to chalazodermia.351 Onset of the lesions is in late adolescence and
early adult life. Childhood cases have been reported.353 Familial cases
are quite rare.354–359
The onset of lesions may be preceded by an inflammatory stage
with erythematous macules and papules (Jadassohn–Pellizzari type)
or there may be no identifiable precursor inflammatory lesions
(Schweninger–Buzzi type).352 These two types have been classified as
primary anetodermas. As an inflammatory infiltrate may be present
even in cases with no clinical inflammatory features, this classification
is outdated.360 Patients with primary anetoderma frequently have at
least one prothrombotic abnormality, the most common being the
presence of antiphospholipid antibodies.360–363 Secondary anetoder-
mas351,352 develop during the course of other diseases such as syphilis,
leprosy, sarcoidosis, granuloma annulare,364 tuberculosis, varicella,365
HIV infection,366,367 folliculitis,368 angular cheilitis,369 Lyme disease,370
acrodermatitis chronica atrophicans,351 lupus erythematosus,351 amyloi-
dosis, lymphocytoma cutis,371 cutaneous B-cell lymphoma,372,373 mycosis
fungoides,374 juvenile xanthogranuloma,375,376 immunocytoma,377 or
following penicillamine therapy378 or hepatitis B immunization.379
Patches of anetoderma may develop in extremely premature infants,380
usually at the sites of attachment of gel electrocardiographic elec-
trodes.381,382 Anetoderma-like changes have been reported in a patient
with the clinical features of atrophoderma. The term ‘atrophoderma
elastolytica discreta’ was used for these lesions.383 The association with
urticaria pigmentosa may be coincidental.384 Rarely, secondary aneto-
derma overlies a pilomatrixoma.385,386 The lesions of secondary aneto-
346 SECTION 4  •  the dermis and subcutis
derma do not always correspond with those of the primary disease
process.
A variety of ocular and skeletal defects have been reported in indi-
viduals with anetoderma. They have been chronicled in a review of
the extensive European literature on this condition.351
Theoretically, anetoderma could result from increased degradation
or reduced synthesis of elastic tissue.387 It has been suggested that all
cases have an inflammatory pathogenesis, which would tend to indicate
that an elastolytic process is operative.21,388 Increased expression of
various metalloproteinases has been reported; they play an important
role in the degradation of elastic fibers in anetodermic skin.19,389 The
concentration of elastin, as measured by the desmosine content of
the skin, is markedly reduced.387 Immunological abnormalities, the
most common of which is a positive antinuclear factor, have been
documented.390–392
Histopathology388
If a biopsy is taken from a clinically inflammatory lesion, the dermis
will show a moderately heavy perivascular and even interstitial infil-
trate, predominantly of lymphocytes. Plasma cells and eosinophils are
occasionally present. Neutrophils have been noted sometimes in very
early lesions.388
In established lesions, most reports have noted an essentially
normal appearance in hematoxylin and eosin-stained sections.
However, in one large series, a perivascular infiltrate of lymphocytes
was found in all cases.388 There was a predominance of helper T cells.393
The authors of that account did not attempt to reconcile their findings
with earlier reports in which inflammatory cells were noted to be
absent.352,387,388
Scattered macrophages and giant cells, some showing elastophago-
cytosis, may also be present.394 Non-caseating granulomas were present
in one case, in association with Takayasu’s arteritis.395
Elastic tissue stains show a normal complement of fibers in the early
inflammatory lesions. In established lesions, elastic fibers are sparse in
the superficial dermis and almost completely absent in the mid dermis
(Fig. 12.20).
Direct immunofluorescence in some cases of primary anetoderma
shows a pattern of immune deposits similar to that of lupus erythe-
matosus.396 There are no other manifestations of the latter disease in
these cases.
Fig. 12.20  Anetoderma. There is a heavy infiltrate of lymphocytes in the mid
dermis. Beneath this the elastic fibers have almost completely disappeared. Five
years after this biopsy was taken the patient developed cutaneous lupus
erythematosus. (Verhoeff–van Gieson)
Electron microscopy
The elastic fibers which remain are fragmented and irregular in appear-
ance but the collagen is normal.387,397 Occasionally, macrophages can be
seen enveloping the fragmented fibers.398
CUTIS LAXA
The term ‘cutis laxa’ encompasses a group of rare disorders of elastic
tissue in which the skin hangs in loose folds, giving the appearance of
premature aging.347,399 In many cases, there is a more generalized loss
of elastic fibers involving the lungs, gastrointestinal tract and aorta,
leading to emphysema, hernias, diverticula, and aneurysms.400–403 It is
an etiologically heterogeneous disorder.
Congenital and acquired forms exist. Congenital cutis laxa is geneti-
cally heterogeneous: there are several different autosomal recessive
forms of the disease (OMIM 219100), one of which is associated with
growth retardation.404–408 These cases were reported in the earlier lit-
erature and may be examples of the De Barsy syndrome (see below).
There is an autosomal dominant form (OMIM 123700) which is less
severe.409 One of the dominant forms is allelic to the Williams–Beuren
syndrome and is related to mutations in the elastin (ELN) gene.410 The
X-linked recessive variant (OMIM 304150),411 in which there is a
deficiency of lysyl oxidase, is now regarded as a variant of Menkes’
syndrome (OMIM 309400);410,412,413 the two are allelic.410 It is caused
by mutations in the ATP7A gene.414 The congenital forms are associ-
ated with a characteristic facies, with a hooked nose and a long upper
lip (‘blood-hound’ facies).415 Congenital cutis laxa has been reported
in a young male with the Kabuki make-up syndrome.416,417 It has also
been reported in a newborn with congenital hypothyroidism due to
isolated thyrotropin deficiency.418
More than 50 cases of acquired cutis laxa have been described.
The changes may be generalized or localized.419–424 Localized cases may
be acral or cephalic in distribution.425 Acquired cutis laxa may be of
insidious onset426 or develop after a prior inflammatory lesion of
the skin427 which may take the form of erythema, erythema multi-
forme, urticaria,428,429 a vesicular eruption, including dermatitis herpeti-
formis,430 or Sweet’s syndrome.431 Several cases have followed an
allergic reaction to penicillin,432,433 while others have been associated
with isoniazid therapy,434 mastocytosis,435 myelomatosis,436–439 cutaneous
lymphoma,440,441 rheumatoid arthritis,442 systemic lupus erythemato-
sus,443 or the nephrotic syndrome.399 In a case associated with
celiac disease, deposits of IgA were present on the dermal elastic
fibers.444 Cutis laxa may occur as a manifestation of pseudoxanthoma
elasticum. Late-onset cutis laxa also occurs in hereditary gelsolin
amyloidosis (type V – familial amyloidosis of the Finnish type
(OMIM 105120)) caused by a G654A or G654T gelsolin gene muta-
tion on chromosome 9q34.445,446 Gelsolin amyloid is deposited in
dermal nerves, blood vessels, and appendages, and often encircles
elastic fibers in the lower dermis leading to fragmentation and loss of
fibers.445
The congenital cases result from a defect in the synthesis or assem-
bly of the components of the elastic fiber. All patients with the auto-
somal dominant form of cutis laxa who have had genetic sequencing
studies performed have had mutations in the ELN gene localized to
chromosome 7q11.2.447 Its product, tropoelastin, is the most abundant
component of elastic fibers.414,448 Mutations in the ELN gene not only
cause cutis laxa448 but also cause subvalvular aortic stenosis,449 which
may occur as an isolated disease or as part of the Williams–Beuren
syndrome (Williams syndrome), a microdeletional syndrome that
involves the deletion of one complete copy of ELN (see below).414,450
The De Barsy syndrome appears to be another subgroup of cutis laxa
that may involve a defect in elastin production with increased degrada-
tion.451 This syndrome is also characterized by progeroid features and
mental retardation.452

The molecular defects underlying the recessive forms of cutis laxa
have recently been discovered.8,9 Mutations in the fibulin-5 gene
(FBLN5) were the first identified.410 Mutations in this gene are also
responsible for age-related macular degeneration, the leading cause of
irreversible visual loss in the Western world.453 A missense mutation
in the fibulin-4 (FBLN4) gene has also resulted in cutis laxa.12 A con-
genital disorder of glycosylation involving a defect in the biosynthesis
of N- and O-glycans has also been found in patients with cutis laxa.17
Other rare syndromes associated with cutis laxa in which the mecha-
nism of the decrease in fibers is not known include the Barber–Say
syndrome (OMIM 209885), characterized by a dysmorphic face and
hypertrichosis,454 the SCARF syndrome (OMIM 312830), with
skeletal abnormalities,455 and geroderma osteodysplasticum (OMIM
231070).456 It has been suggested recently that the elastic tissue abnor-
mality in geroderma osteodysplasticum has overlap features between
cutis laxa and wrinkly skin syndrome (OMIM 278250).457
In those acquired cases associated with severe dermal inflammation,
it has been suggested that granulocytic elastase may be responsible for
the degradation of the elastic fibers. Cultured fibroblasts from one case
showed increased elastase activity.429 One report suggested that several
factors, including high levels of cathepsin G, low lysyl oxidase activity,
and a reduction in circulating proteinase inhibitor(s), could all contrib-
ute to the loss of elastin.458 Collagenase and gelatinase A and B expres-
sion is up-regulated at the transcriptional level in cutis laxa.459 This
may explain the collagen abnormalities (see below) that are sometimes
A B
Fig. 12.21  (A) Cutis laxa. (B) There is an almost complete absence of elastic fibers. (Orcein)
DISORDERS OF ELASTIC TISSUE  •  CHAPTER 12 347
found.460 A more recent paper has described missense alleles in both
the elastin and fibulin-5 genes in a patient with acquired cutis laxa
with inflammatory destruction of elastic fibers, suggesting an underly-
ing genetic susceptibility in some patients with acquired cutis laxa.461
Localized areas of loose skin may develop in cutaneous lesions of
sarcoidosis, syphilis, and neurofibromatosis.426 Loose skin localized to
the hands, feet, and neck, and deep palmar and plantar creases are
seen in Costello syndrome (OMIM 218040) in which there are also
characteristic facies, mental retardation, growth disorders, and, some-
times, hypertrophic cardiomyopathy.462–464 Acanthosis nigricans may
also be present.465 There is an increased susceptibility to bladder
cancers and rhabdomyosarcoma. It results from a functional deficiency
in elastin-binding protein (EBP).7,462 Mutations in the HRAS gene on
chromosome 11p15.5 account for the majority of cases of Costello
syndrome but other candidate genes have been mentioned
sporadically.
Reduced elastic fibers were present in one case of the ‘Michelin-tire’
syndrome (see p. 846).466
Histopathology467
The fine elastic fibers in the papillary dermis are lost and there is a
decrease in fibers elsewhere in the dermis (Fig. 12.21). Remaining fibers
are often shortened and they vary greatly in diameter. The borders are
sometimes indistinct and hazy. Fragmentation of fibers may be noted.
348 SECTION 4  •  the dermis and subcutis
Giant cells are rarely present, phagocytosing elastic fibers. A variable
inflammatory reaction is present in the acquired cases with an associ-
ated clinical inflammatory component.428 In several cases, the inflam-
matory infiltrate has been quite heavy, with neutrophils, eosinophils,
and lymphocytes in the superficial and deep dermis.433 Deposits of
immunoglobulins have been demonstrated on elastic fibers in the
dermis in several cases.439,444
Shortening and rupture of elastic fibers are seen in Costello syn-
drome. There are decreased amounts of elastin.463
Electron microscopy399
The elastic tissue varies in content, appearance, and the proportion
and manner by which elastin and the microfibrillar component associ-
ate.468,469 The microfibrils are reduced in the papillary dermis.470 There
is some fragmentation of elastic fibers with accumulation of granular
material.436 Fragmented fibers are sometimes surrounded by fibroblasts
or macrophages. Abnormalities of collagen structure have been noted
in a few reports,468,471 but specifically excluded in others.436 An unusual
case of acquired cutis laxa, associated with the cutaneous and systemic
deposition of a fibrillar protein, has been reported.472
Elastolysis of the earlobes
Elastolysis of the earlobes may represent a variant of cutis laxa con-
fined to the earlobes.473 This is supported by cases with associated
facial involvement.429,473 Blepharochalasis is a similar condition that
presents with recurrent bouts of painless edema of the eyelids and
periorbital region resulting in degradation of elastic fibers and their
subsequent loss from the dermis.443,474 The floppy eyelid syndrome is
morphologically similar.475
WILLIAMS–BEUREN SYNDROME
Williams–Beuren syndrome (OMIM 194050), also known as Williams’
syndrome, is a multisystem, congenital disorder characterized by cra-
niofacial, neurobehavioral, cardiovascular, and metabolic changes.450,476
It results from a microdeletion in the q11.23 region of chromosome
7, involving the elastin gene and up to 26 other genes such as the
LIMK1 gene.477 It is therefore a contiguous gene syndrome. Genes on
other chromosomes have also been implicated. Its prevalence is
approximately 1 in 10 000 births. Despite a moderate reduction in
elastin deposition in the skin, the clinical changes are relatively mild
with increased softness and mobility of the skin.476
Histopathology
The overall appearance of the skin in H & E sections is normal. Mor-
phometric analyses of elastic fibers have demonstrated a marked
reduction in elastic fiber diameter and volume compared with healthy
controls.65
A recent study of 10 cases showed the presence of disorganized
pre-elastic (oxytalan and elaunin) fibers in the papillary dermis and
disorganized mature elastic fibers in the reticular dermis.478 Fibers were
shortened and rarefied.478
PAPILLARY-DERMAL ELASTOLYSIS
(FIBROELASTOLYTIC PAPULOSIS)
Papillary-dermal elastolysis is a rare disorder of elastic tissue character-
ized by clinical lesions resembling pseudoxanthoma elasticum, with
small papules and cobblestone plaques on the neck and upper trunk.25,479
Reported cases have occurred exclusively in females, but if the merged
entity (see below) is accepted, both sexes may be involved.480 Similar
histopathological changes were present in a case presenting as a small,
hyperpigmented plaque.481 It has been suggested recently that this
condition is part of the spectrum of white fibrous papulosis of the neck
(see p. 317), for which the term ‘fibroelastolytic papulosis of the neck’
has been suggested.480 The pathogenesis of these two merged entities
is unknown; it is possibly related to intrinsic aging.480,482
The coexistence of papillary-dermal elastolysis and linear focal
dermal elastosis in the same patient has been reported.483
Histopathology
There is a complete loss of elastic fibers in the papillary dermis. The
remaining fibers are not calcified or fragmented; that is, there are no
histopathological features of pseudoxanthoma elasticum. Elastophago-
cytosis was present in one case, suggesting that this may be the mecha-
nism for the loss of elastic fibers.484 Immunohistochemical studies have
demonstrated a disappearance of both elastin and fibrillin-1 from the
papillary dermis, suggesting that this condition is more than an age-
related state.485,486
MID-DERMAL ELASTOLYSIS
Mid-dermal elastolysis, first described by Shelley and Wood in 1977,487
is characterized by widespread patches of fine wrinkling due to a loss
of elastic fibers from the mid dermis.487–492 The clinical features can be
quite subtle.493 A few cases have shown a second clinical feature with
looseness of the skin around hair follicles.494 Other cases have had
flesh-colored papules in a perifollicular distribution.495 A third clinical
pattern with a prominent reticular appearance has been reported.496 It
may represent the end stage of granuloma annulare.496 Most cases have
involved the upper extremities, neck, and trunk of women. It may
represent a variant of anetoderma.
In nearly 50% of cases, erythema, urticaria, or burning precedes or
coincides with the development of the lesions, suggesting that an
inflammatory process may be involved in the pathogenesis. In some
cases, the condition appears to be photoinduced or photoaggra-
vated.495,497,498 The onset has followed augmentation mammoplasty with
silicone implants,499 granuloma annulare,500,501 and lupus erythemato-
sus.502 Lesions may remain stable for many years. Mid-dermal elastoly-
sis has been reported in one family with the Keutel syndrome (OMIM
245150), a rare autosomal recessive syndrome, characterized by abnor-
mal cartilage calcification and due to mutations in the matrix Gla
protein (MGP) gene.503
There is some similarity to the cases reported from South Africa
and South America, in young children, in whom wrinkling developed
after a preceding inflammatory stage.504–506
An immunohistochemical study has shown enhanced expression of
CD34+ and CD68+ cells and of matrix metalloproteinase-1 (MMP-
1).507 Another study confirmed the increase in CD68+ cells, but found
that MMP-9 was present in epidermal keratinocytes and in large cells
in lesional dermis.495 This study of 11 patients concluded that the onset
of the disease is strongly associated with UV exposure, which may
induce fibroblast-like cells to express MMP-9 that in turn could be
involved in the degradation of elastic fibers.495 MMP-9 was also impli-
cated in another study, in the destruction of the elastic fibers in this
condition.193
Histopathology
Sections stained with hematoxylin and eosin may appear normal,
although in the early inflammatory stage a mild infiltrate of lympho-
cytes is present around vessels and, to a lesser extent, in interstitial
areas.494,508 Spindle-shaped cells and large multinucleated cells with
angulated outline are scattered between collagen bundles in the mid

dermis in these early lesions.495 They did not stain for CD68 or factor
XIIIa in one study.495 Phagocytosis of elastic fibers has been present in
some cases,491,509 but specifically excluded in others.494,497 This may, of
course, be related to the age of the lesion biopsied. Two cases of mid-
dermal elastophagocytosis, presenting as persistent reticulate ery-
thema, have been reported.510
There is one report of a patient with mid-dermal elastolysis in which
the initial erythematous and urticarial plaques revealed a neutrophilic
infiltrate in the papillary and mid dermis and a normal pattern of
elastic fibers.511 In addition to the neutrophils there was leukocytoclas-
tic debris, some endothelial swelling of vessels, and a few admixed
lymphocytes, histiocytes, and eosinophils.511
Stains for elastic tissue show an absence of fibers in the mid dermis.
Elastic tissue is usually preserved around appendages, even in the clini-
cal subset with perifollicular involvement.512 There is no involvement
of the papillary dermis or the lower reticular dermis.494
Electron microscopy
Degeneration of elastic fibers has been recorded. Engulfment of elastic
fibers by macrophages can be seen in those cases that have histological
evidence of elastophagocytosis.484,508
MENKES’ SYNDROME
Menkes’ kinky hair syndrome (OMIM 309400) is a rare multisystem
disorder of elastic tissue transmitted as an X-linked recessive trait.513–515
The defective gene (ATP7A) has been localized to chromosome Xq12–
q13.516,517 Characteristically the hair is white, sparse, brittle, and kinky.
It looks and feels like steel wool. Pili torti and, occasionally, monile-
thrix are present. Neurodegenerative changes, vascular insufficiency,
hypothermia, and susceptibility to infections are other manifestations
of this syndrome.38,515 Mild forms occur.518
The finding of reduced serum copper levels led to the view that
Menkes’ syndrome was a simple copper deficiency state akin to that
seen in copper-deficient sheep.519,520 It is now thought to be due to a
spectrum of mutations in the copper-transporting ATPase gene,
ATP7A.7 There is reduced activity of the copper-dependent enzyme
lysyl oxidase in fibroblasts derived from the skin of patients with this
syndrome.521 This enzyme is necessary for the crosslinking of elastin.4
It has been suggested that this syndrome should be reclassified with
Ehlers–Danlos syndrome type IX, in which a disorder of lysyl oxidase
also occurs (see p. 328).
Histopathology
There are various hair shaft abnormalities which include pili torti,
monilethrix, and trichorrhexis nodosa.515 The internal elastic lamina of
vessels is fragmented and there is intimal proliferation. Dermal elastic
tissue appears to be unaffected.
Electron microscopy
The elastic fibers in the reticular dermis show a paucity of the cen­
tral amorphous component while retaining normal microfibrillary
material.516
FRAGILE X SYNDROME
Fragile X syndrome (OMIM 300624), a rare X-linked form of mental
retardation, is associated with a characteristic facies and connective
tissue abnormalities which are clinically reminiscent of cutis laxa and
the Ehlers–Danlos syndromes.522,523 Most cases result from an increase
in length of a stretch of CGG triplet repeats in the FMR1 gene situ-
ated on the long arm of the X chromosome (Xq27.3).524–526 Rarely, the
DISORDERS OF ELASTIC TISSUE  •  CHAPTER 12 349
condition results from the deletion of all or part of this gene.525,527
Attention deficit hyperactivity disorder is a frequent behavioral
problem in young boys with fragile X syndrome.528
Histopathology522
There is a reduction in dermal elastic tissue. The fibers are fragmented
and curled and lack arborization. There is a reduction in stromal acid
mucopolysaccharides.
WRINKLY SKIN SYNDROME
Wrinkly skin syndrome (OMIM 278250) is a rare autosomal recessive
disorder characterized by wrinkled skin with poor elasticity over the
abdomen and on the dorsum of the hands and feet.529,530 It has some
features overlapping with cutis laxa type II.531 A recent study was
unable to distinguish between wrinkly skin syndrome and cutis laxa
with growth and developmental delay (OMIM 219200).457 Increased
palmar and plantar creases, a prominent venous pattern on the chest,
microcephaly, and musculoskeletal abnormalities form part of the
syndrome. There is overlap between wrinkly skin syndrome and gero-
derma osteodysplasticum (OMIM 231070).457,532
The genetic defect in this syndrome has not been characterized but
one case has been associated with deletion of 2q32.529 A defect in
N-protein glycosylation seems to be the likely mechanism of this
disease.457
Histopathology
There is an irregular pattern of elastic fiber distribution. Oxytalan
fibers are absent from the papillary dermis. Thickened and frag-
mented fibers are present in the mid dermis while there is a paucity
of elastic fibers in the deep dermis; those present are in fragmented
clumps.529
GRANULOMATOUS DISEASES
Rarely, anetoderma develops as a complication of sarcoidosis, leprosy,
or tuberculosis. Reduced numbers of elastic fibers, not necessarily
leading to clinical manifestations, may occur in the course of several
other granulomatous disorders. These include the closely related con-
ditions of elastolytic giant cell granuloma, actinic granuloma, atypical
necrobiosis lipoidica of the face and scalp, and Miescher’s granu-
loma.533,534 Elastic tissue is reduced in active lesions of granuloma annu-
lare. Multinucleate giant cells and macrophages appear to be responsible
for the digestion of the elastic fibers.533 These conditions are discussed
further in Chapter 7 (pp. 169–194).
‘GRANULOMATOUS SLACK SKIN’
Granulomatous slack skin, a rare form of cutaneous T-cell lymphoma,
is characterized by progressively pendulous skin folds in flexural areas
and an abnormal cutaneous infiltrate.535–540 A unique t(3;9)(q12;p24)
translocation has been reported in one patient.541 The distinctive clini-
cal appearance results from elastolysis, apparently mediated by giant
cells in the infiltrate (see p. 980).
Histopathology535
There is permeation of the entire dermis and subcutis by a heavy
infiltrate of lymphocytes admixed with tuberculoid granulomas and
giant cells with up to 30 nuclei. Foam cells may also be present.537
There is almost complete absence of elastic tissue in the dermis, and
elastic fibers may be seen within the giant cells. Loss of elastic fibers
350 SECTION 4  •  the dermis and subcutis
and subcutaneous granulomas are not present in the granulomatous
form of mycosis fungoides which otherwise resembles this condition
on histopathology (see p. 977).535
MYXEDEMA
Elastic fibers are significantly reduced in the dermis in hypothyroid
myxedema and in pretibial myxedema.542 Ultrastructural examination
shows wide variability of elastic fiber diameter and a decrease in
microfibrils.542
ACROKERATOELASTOIDOSIS
Acrokeratoelastoidosis (OMIM 101850) is a genodermatosis (see
p. 261) in which the dermal elastic fibers are usually fragmented and
decreased in number. Sometimes they are normal.327,543 The epidermal
changes are clinically more significant than the elastic tissue changes,
although pathogenetically the elastorrhexis is probably the primary
event and the accompanying keratoderma could be secondary to
chronic trauma.544–548 The term focal acral hyperkeratosis has been
proposed for a clinically identical disorder, but where changes in elastic
fibers cannot be demonstrated.543
VARIABLE OR MINOR ELASTIC
TISSUE CHANGES
LEPRECHAUNISM (DONOHUE SYNDROME)
Leprechaunism, also known as Donohue syndrome (OMIM 246200),
is a rare disorder with characteristic facies, phallic enlargement, and a
deficiency of subcutaneous fat stores.549 Cutaneous changes include
hypertrichosis, acanthosis nigricans, wrinkled loose skin, and promi-
nent rugal folds around the body orifices.549
It is due to mutations in the insulin receptor gene on chromosome
19p13.2
Histopathology
Loss and fragmentation of elastic fibers and decreased collagen were
noted in one report of this condition.550 In contrast, in a recent study
it was noted that the elastic fibers were thick and extended into the
widened septa of the subcutaneous fat.549
SYNDROMES OF PREMATURE AGING
The elastic tissue changes in the premature aging conditions are variable.
They may be increased in Werner’s syndrome (see p. 328) with granular
and filamentous ultrastructural changes.551 Elastosis perforans has been
reported in acrogeria (see p. 329).552 At other times there may be loss of
elastic fibers in association with dermal atrophy or sclerosis.553
WRINKLES
Although of great cosmetic importance, wrinkles are of little derma-
topathological interest. In general, wrinkles are bilateral and increased
with aging and sun damage. One case of unilateral wrinkles has been
reported.554 Wrinkles are an important component of ‘smoker’s face’,
resulting from prolonged cigarette smoking.239,555–558 Wrinkles may
result from a reduction in collagen VII in photodamaged skin, with a
consequent weakening of the bond between the dermis and epider-
mis.267 Estrogen therapy appears to reduce the incidence of wrinkles.559
The use of bovine collagen injections theoretically poses the risk of
the transmission of bovine spongiform encephalopathy.560
Histopathology561–564
It has been stated that wrinkles are a ‘con­figurational change’ with no
distinguishing histological features.561 In contrast, it has been reported
that the dermis in a deep wrinkle shows substantially fewer elastotic
changes than the surrounding areas and that the superficial elastic
fibers appear slightly thickened and the overlying epidermis
depressed.563,564 Increased elastosis is found in biopsies from ‘smoker’s
face’. It appears to result from degradation of existing fibers, and not
from the synthesis of new elastic material.557
A study involving 157 skin biopsies has demonstrated numerous
modifications in different structures of the skin: hypertrophied elas-
totic tissue on the flanks of the wrinkle and reduced or absent elastic
fibers under the wrinkle, atrophy of the dermal collagen under the
wrinkle, and a marked decrease in chrondroitin sulfates and oxytalan
fibers in the papillary dermis.565
Electron microscopy
Electron-dense inclusions have been noted in elastic fibers in the upper
dermis of the wrinkled areas; these are thought to represent the earli-
est changes of solar elastosis.563,564 More severe changes are present in
the surrounding dermis.
SCAR TISSUE
There have been conflicting reports on the status of elastic fibers in
scar tissue. If appropriate stains are used, fine elastic fibers can be
demonstrated in scars that have been present for over 3 months.31 They
increase progressively over time, but they are always thinner than in
normal skin.
MARFAN’S SYNDROME
Marfan’s syndrome (OMIM 154700) is a rare, autosomal dominant
defect of connective tissue, with ocular, skeletal, and cardiovascular
manifestations.566 There is a wide range of overlapping phenotypes.567
Marfan’s syndrome has a prevalence of 1 in 5000–10 000 individuals;
up to 30% of cases represent new mutations. Cutaneous manifesta-
tions are of little clinical importance; they include striae distensae and
elastosis perforans serpiginosa.568 Defects in the crosslinking and com-
position of collagen have been described, but abnormalities in elastic
tissue (a mutation in the fibrillin-1 – FBN1 – gene on chromosome
15q21.1) are the dominant feature.6,569 Defects in the fibrillin-2 gene
(FBN2) cause a phenotypically related disorder.5 These various disor-
ders have been called the microfibrillopathies.5
A recent study of 1013 probands with this syndrome and FBN1
mutations has attempted a genotype–phenotype correlation.567
Although no set of features was pathognomonic for a particular subtype
of FBN1 mutation, the occurrence of specific organ involvement dif-
fered significantly in some instances.567 Skin involvement (found in
approximately one-half of the cases) correlated with PTC mutations
(premature termination codons) in the FBN1 gene.567
Histopathology
The striae distensae show the usual features of this lesion (see p. 319)
with regeneration of elastic fibers.570 The lesions of elastosis per­
forans serpiginosa resemble those already described for this entity
(see p. 335).
Clinically normal skin shows no detectable abnormality, although
one study suggested that the elastic fibers looked a little tortuous and
 DISORDERS OF ELASTIC TISSUE  •  CHAPTER 12 351

fragmented.568 In some cases, thinning of the dermis, resulting from a References

diminished quantity of collagen due to thinner collagen bundles, has
been noted. The complete reference list can be found on the companion Expert
Consult Web site at http://www.expertconsultbook.com and/or the
Electron microscopy accompanying volume of references.
Electron microscopy shows an increase in fine elastic fibers, possibly
resulting from incomplete fusion of elastic fibers.568 Degenerative
changes in elastic fibers have been observed in the lung.571

References
Introduction
1. Sandberg LB, Soskel NT, Wolt TB. Structure of the elastic fiber: an
overview. J Invest Dermatol 1982; 79 (Suppl 1): 128s–132s.
2. Davidson JM, Crystal RG. The molecular aspects of elastin gene
expression. J Invest Dermatol 1982; 79 (Suppl 1): 133s–137s.
3. Kielty CM. Elastic fibres in health and disease. Expert Rev Mol
Med 2006; 8: 1–23.
4. Uitto J, Rhyanen L, Abraham PA, Perejda AJ. Elastin in diseases. J
Invest Dermatol 1982; 79 (Suppl 1): 160s–168s.
5. Robinson PN, Godfrey M. The molecular genetics of Marfan
syndrome and related microfibrillopathies. J Med Genet 2000; 37:
9–25.
6. Christiano AM, Uitto J. Molecular pathology of the elastic fibers. J
Invest Dermatol 1994; 103: 53s–57s.
7. Urbán Z, Boyd CD. Elastic-fiber pathologies: primary defects in
assembly – and secondary disorders in transport and delivery. Am J
Hum Genet 2000; 67: 4–7.
8. Hu Q, Loeys BL, Coucke PJ et al. Fibulin-5 mutations:
mechanisms of impaired elastic fiber formation in recessive cutis
laxa. Hum Mol Genet 2006; 15: 3379–3386.
9. Markova D, Zou Y, Ringpfeil F et al. Genetic heterogeneity of cutis
laxa: a heterozygous tandem duplication within the fibulin-5
(FBLN5) gene. Am J Hum Genet 2003; 72: 998–1004.
10. Zheng Q, Choi J, Rouleau L et al. Normal wound healing in mice
deficient for fibulin-5, an elastin binding protein essential for
dermal elastic fiber assembly. J Invest Dermatol 2006; 126:
2707–2714.
11. Hunzelmann N, Nischt R, Brenneisen P et al. Increased deposition
of fibulin-2 in solar elastosis and its colocalization with elastic
fibres. Br J Dermatol 2001; 145: 217–222.
12. Hucthagowder V, Sausgruber N, Kim KH et al. Fibulin-4: a novel
gene for an autosomal recessive cutis laxa syndrome. Am J Hum
Genet 2006; 78: 1075–1080.
13. Tsuji T. Elastic fibers in the dermal papilla. Scanning and
transmission electron microscopic studies. Br J Dermatol 1980;
102: 413–417.
14. Cotta-Pereira G, Rodrigo FG, Bittencourt-Sampaio S. Oxytalan,
elaunin, and elastic fibers in the human skin. J Invest Dermatol
1976; 66: 143–148.
15. Zheng Q, Davis EC, Richardson JA et al. Molecular analysis of
fibulin-5 function during de novo synthesis of elastic fibers. Mol
Cell Biol 2007; 27: 1083–1095.
16. Frances C, Robert L. Elastin and elastic fibers in normal and
pathologic skin. Int J Dermatol 1984; 23: 166–179.
17. Wopereis S, Morava É, Grünewald S et al. A combined defect in
the biosynthesis of N- and O-glycans in patients with cutis laxa and
neurological involvement: the biochemial characteristics. Biochim
Biophys Acta 2005; 1741: 156–164.
18. Werb Z, Banda MJ, McKerrow JH, Sandhaus RA. Elastases and
elastin degradation. J Invest Dermatol 1982; 79 (Suppl 1):
154s–159s.
19. Venencie PY, Bonnefoy A, Gogly B et al. Increased expression of
gelatinases A and B by skin explants from patients with
anetoderma. Br J Dermatol 1997; 137: 517–525.
20. Park PW, Biedermann K, Mecham L et al. Lysozyme binds to
elastin and protects elastin from elastase-mediated degradation. J
Invest Dermatol 1996; 106: 1075–1080.
21. Werth VP, Ivanov IE, Nussenzweig V. Decay-accelerating factor in
human skin is associated with elastic fibers. J Invest Dermatol
1988; 91: 511–516.
22. Braverman IM, Fonferko E. Studies in cutaneous aging: 1. The
elastic fiber network. J Invest Dermatol 1982; 78: 434–443.
DISORDERS OF ELASTIC TISSUE  •  CHAPTER 12 351.e1
23. Takema Y, Yorimoto Y, Kawai M, Imokawa G. Age-related changes
in the elastic properties and thickness of human facial skin. Br J
Dermatol 1994; 131: 641–648.
24. West MD. The cellular and molecular biology of skin aging. Arch
Dermatol 1994; 130: 87–95.
25. Rongioletti F, Rebora A. Fibroelastolytic patterns of intrinsic skin
aging: pseudoxanthoma-elasticum-like papillary dermal elastolysis
and white fibrous papulosis of the neck. Dermatology 1995; 191:
19–24.
26. Tsuji T, Hamada T. Age-related changes in human dermal elastic
fibres. Br J Dermatol 1981; 105: 57–63.
27. Herzberg AJ, Dinehart SM. Chronologic aging in black skin. Am J
Dermatopathol 1989; 11: 319–328.
28. Dahlback K, Lofberg H, Alumets J, Dahlback B.
Immunohistochemical demonstration of age-related deposition of
vitronectin (S-protein of complement) and terminal complement
complex on dermal elastic fibers. J Invest Dermatol 1989; 92:
727–733.
29. O’Brien JP, Regan W. Actinically degenerate elastic tissue is the
likely antigenic basis of actinic granuloma of the skin and of
temporal arteritis. J Am Acad Dermatol 1999; 40: 214–222.
30. Kligman LH. Luna’s technique. A beautiful stain for elastin. Am J
Dermatopathol 1981; 3: 199–201.
31. Roten SV, Bhat S, Bhawan J. Elastic fibers in scar tissue. J Cutan
Pathol 1996; 23: 37–42.
32. Dawson JF, Brochier J, Schmitt D et al. Elastic fibres: histological
correlation with orcein and a new monoclonal antibody, HB8. Br J
Dermatol 1984; 110: 539–546.
33. Reed RJ, Clark WH, Mihm MC. The cutaneous elastoses. Hum
Pathol 1973; 4: 187–199.
34. Holbrook KA, Byers PH. Structural abnormalities in the dermal
collagen and elastic matrix from the skin of patients with inherited
connective tissue disorders. J Invest Dermatol 1982; 79 (Suppl 1):
7s–16s.
Increased elastic tissue
35. Stadil P. Histopathology of the corium in osteogenesis imperfecta.
Danish Med Bull 1961; 8: 131–134.
36. Olmstead EG, Lunseth JH. Skin manifestations of chronic acidosis.
Arch Dermatol 1958; 77: 304–313.
37. Fullmer HM, Siedler HD, Krooth RS, Kurland LT. A cutaneous
disorder of connective tissue in amyotrophic lateral sclerosis. A
histochemical study. Neurology 1960; 10: 717–724.
38. Bader L. Disorders of elastic tissue: a review. Pathology 1973; 5:
269–289.
39. Fisher ER, Wechsler HL. The so-called collagen diseases and
elastoses of skin. In: Helwig EB, Mostofi FK, eds. The skin. New
York: Robert E Krieger, 1980; 366.
40. Ledoux-Corbusier M, Achten G, de Dobbeleer G. Juvenile
elastoma (Weidman). An ultrastructural study. J Cutan Pathol 1981;
8: 219–227.
41. Raque CJ, Wood MG. Connective-tissue nevus. Arch Dermatol
1970; 102: 390–396.
42. Uitto J, Santa Cruz DJ, Eisen AZ. Connective tissue nevi of the
skin. J Am Acad Dermatol 1980; 3: 441–461.
43. Verbov J. Buschke–Ollendorff syndrome (disseminated
dermatofibrosis with osteopoikilosis). Br J Dermatol 1977; 96:
87–90.
44. Atherton DJ, Wells RS. Juvenile elastoma and osteopoikilosis (the
Buschke–Ollendorf syndrome). Clin Exp Dermatol 1982; 7:
109–113.
45. Reinhardt LA, Rountree CB, Wilkin JK. Buschke–Ollendorff
syndrome. Cutis 1983; 31: 94–96.
46. Schorr WF, Optiz JM, Reyes CN. The connective tissue nevus–
osteopoikilosis syndrome. Arch Dermatol 1972; 106: 208–214.
351.e2 SECTION 4  •  the dermis and subcutis
47. Morrison JGL, Wilson Jones E, MacDonald DM. Juvenile elastoma
and osteopoikilosis (the Buschke–Ollendorff syndrome). Br J
Dermatol 1977; 97: 417–422.
48. Piette-Brion B, Lowy-Motulsky M, Ledoux-Corbusier M, Achten
G. Dermatofibromas, elastomas and deafness: a new case of
Buschke–Ollendorff syndrome? Dermatologica 1984; 168:
255–258.
49. Verbov J, Graham R. Buschke–Ollendorff syndrome – disseminated
dermatofibrosis with osteopoikilosis. Clin Exp Dermatol 1986; 11:
17–26.
50. Woodrow SL, Pope FM, Handfield-Jones SE. The Buschke–
Ollendorff syndrome presenting as familial elastic tissue naevi. Br J
Dermatol 2001; 144: 890–893.
51. Foo CCI, Kumarasinghe SPW. Juvenile elastoma: A forme fruste of
the Buschke-Ollendorff syndrome? Australas J Dermatol 2005; 46:
250–252.
52. Kawamura A, Ochiai T, Tan-Kinoshita M, Suzuki H. Buschke-
Ollendorff syndrome: three generations in a Japanese family.
Pediatr Dermatol 2005; 22: 133–137.
53. Couto AR, Bruges-Armas J, Peach CA et al. A novel LEMD3
mutation common to patients with osteopoikilosis with and without
melorheostosis. Calcif Tissue Int 2007; 81: 81–84.
54. Hellemans J, Preobrazhenska O, Willaert A et al. Loss-of-function
mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff
syndrome and melorheostosis. Nat Genet 2004; 36: 1213–1218.
55. Mumm S, Wenkert D, Zhang X et al. Deactivating germline
mutations in LEMD3 cause osteopoikilosis and Buschke-Ollendorff
syndrome, but not sporadic melorheostosis. J Bone Miner Res
2007; 22: 243–250.
56. Hellemans J, Debeer P, Wright M et al. Germline LEMD3
mutations are rare in sporadic patients with isolated melorheostosis.
Hum Mutat 2006; 27: 290–296.
57. Huilgol SC, Griffiths WAD, Black MM. Familial juvenile elastoma.
Australas J Dermatol 1994; 35: 87–90.
58. Ehrig T, Cockerell CJ. Buschke-Ollendorff syndrome: Report of a
case and interpretation of the clinical phenotype as a type 2
segmental manifestation of an autosomal dominant skin disease. J
Am Acad Dermatol 2003; 49: 1163–1166.
59. Fork HE, Sanchez RL, Wagner RF Jr, Raimer SS. A new type of
connective tissue nevus: isolated exophytic elastoma. J Cutan
Pathol 1991; 18: 457–463.
60. Drouin CA, Grenon H. The association of Buschke-Ollendorf
syndrome and nail-patella syndrome. J Am Acad Dermatol 2002;
46: 621–625.
61. Uitto J, Santa Cruz DJ, Starcher BC et al. Biochemical and
ultrastructural demonstration of elastin accumulation in the skin
lesions of the Buschke–Ollendorff syndrome. J Invest Dermatol
1981; 76: 284–287.
62. Cole GW, Barr RJ. An elastic tissue defect in dermatofibrosis
lenticularis disseminata. Arch Dermatol 1982; 118: 44–46.
63. Danielsen L, Midtgaard K, Christensen HE. Osteopoikilosis
associated with dermatofibrosis lenticularis disseminata. Arch
Dermatol 1969; 100: 465–470.
64. Moiin A, Hashimoto K. Linear focal elastosis in a young 89. Madri JA, Dise CA, LiVolsi VA et al. Elastofibroma dorsi: an
black man: a new presentation. J Am Acad Dermatol 1994; 30:
874–877.
65. Ghomrasseni S, Dridi M, Bonnefoix M et al. Morphometric
analysis of elastic skin fibres from patients with: cutis laxa,
anetoderma, pseudoxanthoma elasticum, and Buschke-Ollendorff
and Williams-Beuren syndromes. J Eur Acad Dermatol Venereol
2001; 15: 305–311.
66. Staricco RG, Mehregan AH. Nevus elasticus and nevus elasticus
vascularis. Arch Dermatol 1961; 84: 943–947.
67. Sosis AC, Johnson WC. Connective tissue naevus. Dermatologica
1972; 144: 57–62.
68. Becke RFA, Musso LA. An unusual epithelial–connective tissue
naevus with perifollicular mucinosis. Australas J Dermatol 1978;
19: 118–120.
69. Danielsen L, Kobayasi T, Jacobsen GK. Ultrastructural changes in
disseminated connective tissue nevi. Acta Derm Venereol 1977; 57:
93–101.
70. Reymond JL, Stoebner P, Beani JC, Amblard P. Buschke–Ollendorf
syndrome. An electron microscopic study. Dermatologica 1983;
166: 64–68.
71. Hagari Y, Mihara M, Morimura T, Shimao S. Linear focal elastosis.
An ultrastructural study. Arch Dermatol 1991; 127: 1365–1368.
72. Burket JM, Zelickson AS, Padila RS. Linear focal elastosis
(elastotic striae). J Am Acad Dermatol 1989; 20: 633–636.
73. Kirkegaard L, Goldsmith SM, Solomon AR. Linear focal elastosis.
J Cutan Pathol 1996; 23: 53 (abstract).
74. Breier F, Trautinger F, Jurecka W, Hönigsmann H. Linear focal
elastosis (elastotic striae): increased number of elastic fibres
determined by a video measuring system. Br J Dermatol 1997; 137:
955–957.
75. Hashimoto K. Linear focal elastosis: Keloidal repair of striae
distensae. J Am Acad Dermatol 1998; 39: 309–313.
76. Tamada Y, Yokochi K, Ikeya T et al. Linear focal elastosis: A
review of three cases in young Japanese men. J Am Acad Dermatol
1997; 36: 301–303.
77. Choi SW, Lee JH, Woo HJ et al. Two cases of linear focal
elastosis: different histopathologic findings. Int J Dermatol 2000;
39: 207–209.
78. Inaloz HS, Kirtak N, Karakok M, Ozgoztasi O. Facial linear focal
elastosis: a case report. Int J Dermatol 2003; 42: 558–560.
79. Ramlogan D, Tan BB, Garrido M. Linear focal elastosis. Br J
Dermatol 2001; 145: 188–190.
80. Péč J, Chromej I. Linear focal elastosis: what’s new? J Eur Acad
Dermatol Venereol 2004; 18: 247–249.
81. Tajima S, Shimizu K, Izumi T et al. Late-onset focal dermal
elastosis: clinical and histological features. Br J Dermatol 1995;
133: 303–305.
82. Limas C. Late onset focal dermal elastosis. A distinct
clinicopathologic entity? Am J Dermatopathol 1999; 21: 381–383.
83. Kossard S. Pseudoxanthoma-like late-onset focal dermal elastosis.
Australas J Dermatol 2005; 46: 47–50.
84. Lewis KG, Bercovitch L, Dill SW, Robinson-Botsom L. Acquired
disorders of elatic tissue: Part 1. Increased elastic tissue and solar
elastotic syndromes. J Am Acad Dermatol 2004; 51: 1–21.
85. Tajima S, Tanaka N, Ohnishi Y et al. Analysis of elastin
metabolism in patients with late-onset focal dermal elastosis. Acta
Derm Venereol 1999; 79: 285–287.
86. Yen A, Wen J, Grau M et al. Elastoderma. J Am Acad Dermatol
1995; 33: 389–392.
87. Kornberg RL. Elastoderma. J Am Acad Dermatol 1996; 34: 1093.
88. Trench Vieira AC, Trench Vieira W, Michalany N et al.
Elastoderma of the neck in a teenage boy. J Am Acad Dermatol
2005; 53: S147–S149.
immunochemical study of collagen content. Hum Pathol 1981; 12:
186–190.
90. Enzinger FM, Weiss SW. Soft tissue tumours. St Louis: Mosby,
1983; 33–37.
91. Schwarz T, Oppolzer G, Duschet P et al. Ulcerating elastofibroma
dorsi. J Am Acad Dermatol 1989; 21: 1142–1144.
92. Cota C, Solivetti F, Kovacs D et al. Elastofibroma dorsi: histologic
and echographic considerations. Int J Dermatol 2006; 45:
1100–1103.
93. Shimizu S, Yasui C, Tateno M et al. Multiple elastofibromas. J Am
Acad Dermatol 2004; 50: 126–129.

94. Ohtake N, Setoyama M, Kanzaki T. Elastofibroma dorsi.
Dermatology 1998; 197: 74–77.
95. Naouri M, Michenet P, Chassaing N, Martin L.
Immunohistochemical characterization of elastofibroma and
exclusion of ABCC6 as a predisposing gene. Br J Dermatol 2007;
156: 755–758.
96. Kumaratilake JS, Krishnan R, Lomax-Smith J, Cleary EG.
Elastofibroma: disturbed elastic fibrillogenesis by periosteal-derived
cells? Hum Pathol 1991; 22: 1017–1029.
97. Hisaoka M, Hashimoto H. Elastofibroma: clonal fibrous
proliferation with predominant CD34-positive cells. Virchows Arch
2006; 448: 195–199.
98. Jarvi OH, Lansimies PH. Subclinical elastofibromas in the scapular
region in an autopsy series. Acta Path Microbiol Scand (A) 1975;
83: 87–108.
99. Ramos CV, Gillespie W, Narconis RJ. Elastofibroma. A
pseudotumor of myofibroblasts. Arch Pathol Lab Med 1978; 102:
538–540.
100. Mehregan AH. Elastosis perforans serpiginosa. A review of the
literature and report of 11 cases. Arch Dermatol 1968; 97:
381–393.
101. Patterson JW. The perforating disorders. J Am Acad Dermatol
1984; 10: 561–581.
102. Woo TY, Rasmussen JE. Disorders of transepidermal elimination.
Part 1. Int J Dermatol 1985; 24: 267–279.
103. White CR. The dermatopathology of perforating disorders. Semin
Dermatol 1986; 5: 359–366.
104. Weidman AI, Allyn B. Elastosis perforans serpiginosa. Two cases
involving the ear. Arch Dermatol 1971; 103: 324–327.
105. Abdullah A, Colloby PS, Foulds IS, Whitcroft I. Localized
idiopathic elastosis perforans serpiginosa effectively treated by the
Coherent Ultrapulse 5000c Aesthetic Laser. Int J Dermatol 2000;
39: 719–720.
106. Vearrier D, Buka RL, Roberts B et al. What is standard of care in
the evaluation of elastosis perforans serpiginosa? a survey of
pediatric dermatologists. Pediatr Dermatol 2006; 23: 219–224.
107. Pedro SD, Garcia RL. Disseminate elastosis perforans serpiginosa.
Arch Dermatol 1974; 109: 84–85.
108. Rasmussen JE. Disseminated elastosis perforans serpiginosa in four
mongoloids. Br J Dermatol 1972; 86: 9–13.
109. Woerdeman MJ, Bour DJH, Bijlsma JB. Elastosis perforans
serpiginosa. Report of a family with a chromosomal investigation.
Arch Dermatol 1965; 92: 559–560.
110. Ayala F, Donofrio P. Elastosis perforans serpiginosa. Report of a
family. Dermatologica 1983; 166: 32–37.
111. Rios-Buceta L, Amigo-Echenagusia A, Sols-Candelas M et al.
Elastosis perforans serpiginosa with simultaneous onset in two
sisters. Int J Dermatol 1993; 32: 879–881.
112. Langeveld-Wildschut EG, Toonstra J, van Vloten WA, Beemer FA.
Familial elastosis perforans serpiginosa. Arch Dermatol 1993; 129:
205–207.
113. Crotty G, Bell M, Estes SA, Kitzmiller KW. Cytologic features of
elastosis perforans serpiginosa (EPS) associated with Down’s
syndrome. J Am Acad Dermatol 1983; 8: 255–256.
114. Siragusa M, Romano C, Cavallari V, Schepis C. Localized elastosis
perforans serpiginosa in a boy with Down syndrome. Pediatr
Dermatol 1997; 14: 244–246.
115. De Pasquale R, Nasca MR, Musumeci ML, Micali G. Elastosis
perforans serpiginosa in an adult with Down’s syndrome: report of
a case with symmetrical localized involvement. J Eur Acad
Dermatol Venereol 2002; 16: 387–389.
116. Mehta RK, Burrows NP, Rowland Payne CME et al. Elastosis
perforans serpiginosa and associated disorders. Clin Exp Dermatol
2001; 26: 521–524.
DISORDERS OF ELASTIC TISSUE  •  CHAPTER 12 351.e3
117. Carey TD. Elastosis perforans serpiginosa. Arch Dermatol 1977;
113: 1444–1445.
118. Hill VA, Seymour CA, Mortimer PS. Penicillamine-induced
elastosis perforans serpiginosa and cutis laxa in Wilson’s disease.
Br J Dermatol 2000; 142; 560–561.
119. Barr RJ, Siegel JM, Graham JH. Elastosis perforans serpiginosa
associated with morphea. An example of ‘perforating morphea’. J
Am Acad Dermatol 1980; 3: 19–22.
120. May NC, Lester RS. Elastosis perforans serpiginosa associated with
systemic sclerosis. J Am Acad Dermatol 1982; 6: 945.
121. Armstrong DKB, Walsh MY, Allen GE. Elastosis perforans
serpiginosa associated with unilateral atrophoderma of Pasini and
Pierini in an individual with 47, XYY karyotype. Br J Dermatol
1997; 137: 158–160.
122. Wong KC, Fryer JA, Li M, Crosland G. Acquired perforating
dermatosis in diabetes mellitus: an unusual case. Australas J
Dermatol 1999; 40: 108–110.
123. Martin L, Maître F, Bonicel P et al. Heterozygosity for a single
mutation in the ABCC6 gene may closely mimic PXE.
Consequences of this phenotype overlap for the definition of PXE.
Arch Dermatol 2008; 144: 301–306.
124. Schamroth JM, Kellen P, Grieve TP. Elastosis perforans serpiginosa
in a patient with renal disease. Arch Dermatol 1986; 122: 82–84.
125. Pass F, Goldfischer S, Sternlieb I, Scheinberg IH. Elastosis
perforans serpiginosa during penicillamine therapy for Wilson
disease. Arch Dermatol 1973; 108: 713–715.
126. Rosenblum GA. Liquid nitrogen cryotherapy in a case of elastosis
perforans serpiginosa. J Am Acad Dermatol 1983; 8: 718–721.
127. Goldstein JB, McNutt NS, Hambrick GW Jr, Hsu A. Penicillamine
dermatopathy with lymphangiectases. A clinical, immunohistologic,
and ultrastructural study. Arch Dermatol 1989; 125: 92–97.
128. Levy RS, Fisher M, Alter JN. Penicillamine: review and cutaneous
manifestations. J Am Acad Dermatol 1983; 8: 548–558.
129. Van Joost T, Vuzevski VD, ten Kate FJW et al. Elastosis perforans
serpiginosa: clinical, histomorphological and immunological
studies. J Cutan Pathol 1988; 15: 92–97.
130. Price RG, Prentice RSA. Penicillamine-induced elastosis perforans
serpiginosa. Tip of the iceberg? Am J Dermatopathol 1986; 8:
314–320.
131. Eide J. Elastosis perforans serpiginosa with widespread arterial
lesions: a case report. Acta Derm Venereol 1977; 57: 533–537.
132. Rapini RP, Hebert AA, Drucker CR. Acquired perforating
dermatosis. Evidence for combined transepidermal elimination of
both collagen and elastic fibers. Arch Dermatol 1989; 125:
1074–1078.
133. Fujimoto N, Tajima S, Ishibashi A. Elastin peptides induce
migration and terminal differentiation of cultured keratinocytes via
67 kDa elastin receptor in vitro: 67 kDa elastin receptor is
expressed in the keratinocytes eliminating elastic materials in
elastosis perforans serpiginosa. J Invest Dermatol 2000; 115:
633–639.
134. Fujimoto N, Akagi A, Tajima S et al. Expression of the 67-kDa
elastin receptor in perforating skin disorders. Br J Dermatol 2002;
146: 74–79.
135. Kelly SC, Purcell SM. Imiquimod therapy for elastosis perforans
serpiginosa. Arch Dermatol 2006; 142: 829–830.
136. Bergman R, Friedman-Birnbaum R, Hazaz B. A direct
immunofluorescence study in elastosis perforans serpiginosa. Br J
Dermatol 1985; 113: 573–579.
137. Bardach H, Gebhart W, Niebauer G. ‘Lumpy-bumpy’ elastic fibers
in the skin and lungs of a patient with penicillamine-induced
elastosis perforans serpiginosa. J Cutan Pathol 1979; 6: 243–252.
138. Gebhart W, Bardach H. The ‘lumpy-bumpy’ elastic fiber. A marker
for long-term administration of penicillamine. Am J Dermatopathol
1981; 3: 33–39.
351.e4 SECTION 4  •  the dermis and subcutis
139. Kirsch N, Hukill PB. Elastosis perforans serpiginosa induced by
penicillamine. Electron microscopic observations. Arch Dermatol
1977; 113: 630–635.
140. Hashimoto K, McEvoy B, Belcher R. Ultrastructure of
penicillamine-induced skin lesions. J Am Acad Dermatol 1981; 4:
300–315.
141. Reymond JL, Stoebner P, Zambelli P et al. Penicillamine induced
elastosis perforans serpiginosa: an ultrastructural study of two
cases. J Cutan Pathol 1982; 9: 352–357.
142. Meves C, Vogel A. Electron microscopical studies in elastosis
perforans serpiginosa. Dermatologica 1973; 145: 210–221.
143. Volpin D, Pasquali-Ronchetti I, Castellani I et al. Ultrastructural
and biochemical studies on a case of elastosis perforans
serpiginosa. Dermatologica 1978; 156: 209–223.
144. Hacker SM, Ramos-Caro FA, Beers BB, Flowers FP. Juvenile
pseudoxanthoma elasticum: recognition and management. Pediatr
Dermatol 1993; 10: 19–25.
145. Neldner KH. Pseudoxanthoma elasticum. Int J Dermatol 1988; 27:
98–100.
146. Woo TY, Rasmussen JE. Disorders of transepidermal elimination.
Part 2. Int J Dermatol 1985; 24: 337–348.
147. Goodman RM, Smith EW, Paton D et al. Pseudoxanthoma
elasticum: a clinical and histopathological study. Medicine
(Baltimore) 1963; 42: 297–334.
148. Danielsen L, Kobayasi T. Pseudoxanthoma elasticum. An
ultrastructural study of oral lesions. Acta Derm Venereol 1974; 54:
173–176.
149. Lebwohl M, Neldner K, Pope FM et al. Classification of
pseudoxanthoma elasticum: report of a consensus conference. J Am
Acad Dermatol 1994; 30: 103–107.
150. Bercovitch L, Terry P. Pseudoxanthoma elasticum. J Am Acad
Dermatol 2004; 51: S13–S14.
151. Chassaing N, Martin L, Calvas P et al. Pseudoxanthoma Acad Dermatol 2000; 42: 685–687.
elasticum: a clinical, pathophysiological and genetic update
including 11 novel ABCC6 mutations. J Med Genet 2005; 42:
881–892.
152. van Meurs T, van Hagen JM, van de Scheur MR et al. Classic
pseudoxanthoma elasticum in a patient with sickle cell disease. J
Am Acad Dermatol 2007; 56: 170–171.
153. Larralde M, Markan PA, Peruffo ML et al. Yellowish papules on
flexural areas of a child. Pediatr Dermatol 2002; 19: 557–559.
154. Egawa Y, Tanioka M, Araki E et al. Red-brown macules on the
abdomen. Clin Exp Dermatol 2008; 33: 219–220.
155. Rongioletti F, Bertamino R, Rebora A. Generalized
pseudoxanthoma elasticum with deficiency of vitamin K-dependent
clotting factors. J Am Acad Dermatol 1989; 21: 1150–1152.
156. Uenishi T, Uchiyama M, Sugiura H, Danno K. Pseudoxanthoma
elasticum with generalized cutaneous laxity. Arch Dermatol 1997;
133: 664–666.
157. Choi GS, Kang D-S, Chung JJ, Lee M-G. Osteoma cutis coexisting
with cutis laxa-like pseudoxanthoma elasticum. J Am Acad
Dermatol 2000; 43: 337–339.
158. Bahadir S, Çobanoğlu Ü, Şiviloglu Ç et al. Cutis laxa-like
pseudoxanthoma elasticum with ossification. Int J Dermatol 2004;
43: 375–378.
159. Lebwohl M, Lebwohl E, Bercovitch L. Prominent mental (chin)
crease: A new sign of pseudoxanthoma elasticum. J Am Acad
Dermatol 2003; 48: 620–622.
160. Galadari H, Lebwohl M. Pseudoxanthoma elasticum: Temporary
treatment of chin folds and lines with injectable collagen. J Am
Acad Dermatol 2003; 49: S265–S266.
161. Reeve EB, Neldner KH, Subryan V, Gordon SG. Development and
calcification of skin lesions in thirty-nine patients with
pseudoxanthoma elasticum. Clin Exp Dermatol 1979; 4: 291–301.
162. Bercovitch L, Schepps B, Koelliker S et al. Mammographic
findings in pseudoxanthoma elasticum. J Am Acad Dermatol 2003;
48: 359–366.
163. Brown SJ, Talks SJ, Needham SJ, Taylor AEM. Pseudoxanthoma
elasticum: biopsy of clinically normal skin in the investigation of
patients with angioid streaks. Br J Dermatol 2007; 157: 748–751.
164. Nolte KB. Sudden cardiac death owing to pseudoxanthoma
elasticum: a case report. Hum Pathol 2000; 31: 1002–1004.
165. Mendelsohn G, Bulkley BH, Hutchins GM. Cardiovascular
manifestations of pseudoxanthoma elasticum. Arch Pathol Lab Med
1978; 102: 298–302.
166. Dymock RB. Pseudoxanthoma elasticum: report of a case with
reno-vascular hypertension. Australas J Dermatol 1979; 20: 82–84.
167. Akhtar M, Brody H. Elastic tissue in pseudoxanthoma elasticum.
Ultrastructural study of endocardial lesions. Arch Pathol 1975; 99:
667–671.
168. Bercovitch L, Leroux T, Terry S, Weinstock MA. Pregnancy and
obstetrical outcomes in pseudoxanthoma elasticum. Br J Dermatol
2004; 151: 1011–1018.
169. Baccarani-Contri M, Bacchelli B, Boraldi F et al. Characterization
of pseudoxanthoma elasticum-like lesions in the skin of patients
with β-thalassemia. J Am Acad Dermatol 2001; 44: 33–39.
170. Fabre B, Bayle P, Bazex J et al. Pseudoxanthoma elasticum and
nephrolithiasis. J Eur Acad Dermatol Venereol 2005; 19: 212–215.
171. Martin L, Chassaing N, Delaite D et al. Histological skin changes
in heterozygote carriers of mutations in ABCC6, the gene causing
pseudoxanthoma elasticum. J Eur Acad Dermatol Venereol 2007;
21: 368–373.
172. Eng AM, Bryant J. Clinical pathologic observations in
pseudoxanthoma elasticum. Int J Dermatol 1975; 14: 586–605.
173. Hamamoto Y, Nagai K, Yasui H, Muto M. Hyperreactivity of
pseudoxanthoma elasticum-affected dermis to vitamin D3. J Am
174. Sherer DW, Singer G, Uribarri J et al. Oral phosphate binders in
the treatment of pseudoxanthoma elasticum. J Am Acad Dermatol
2005; 53: 610–615.
175. Rodríguez-Cuartero A, García-Vera E. Pseudoxanthoma elasticum:
a study of urinary glycosaminoglycan levels in two cases. Br J
Dermatol 1997; 137: 473–474.
176. Horner KL, Kalus A, Hornung RL. Pseudoxanthoma elasticum and
polymyositis in a child. J Am Acad Dermatol 2006; 54: S61–S62.
177. Le Scanff J, Sève P, Dalle S et al. Coexisting pseudoxanthoma
elasticum and lupus erythematosus: Report of two cases. Int J
Dermatol 2007; 46: 622–624.
178. Pope FM. Historical evidence for the genetic heterogeneity of
pseudoxanthoma elasticum. Br J Dermatol 1975; 92: 493–509.
179. Uitto J, Boyd CD, Lebwohl MG et al. International Centennial
Meeting on Pseudoxanthoma Elasticum: progress in PXE research.
J Invest Dermatol 1998; 110: 840–842.
180. Sherer DW, Sapadin AN, Lebwohl MG. Pseudoxanthoma
elasticum: an update. Dermatology 1999; 199: 3–7.
181. Macmillan DC. Pseudoxanthoma elasticum and a coagulation
defect. Br J Dermatol 1971; 84: 182.
182. Sherer DW, Bercovitch L, Lebwohl M. Pseudoxanthoma elasticum:
Significance of limited phenotypic expression in parents of affected
offspring. J Am Acad Dermatol 2001; 44: 534–537.
183. Christen-Zäch S, Huber M, Struk B et al. Pseudoxanthoma
elasticum: evaluation of diagnostic criteria based on molecular
data. Br J Dermatol 2006; 155: 89–93.
184. Schutt DA. Pseudoxanthoma elasticum and elastosis perforans
serpiginosa. Arch Dermatol 1965; 91: 151–152.
185. Lund HZ, Gilbert CF. Perforating pseudoxanthoma elasticum. Its
distinction from elastosis perforans serpiginosa. Arch Pathol Lab
Med 1976; 100: 544–546.

186. Schwartz RA, Richfield DF. Pseudoxanthoma elasticum with
transepidermal elimination. Arch Dermatol 1978; 114: 279–280.
187. Meyer S, Zanardo L, Kaminski WE et al. Elastosis perforans
serpiginosa-like pseudoxanthoma elasticum in a child with severe
Moya Moya disease. Br J Dermatol 2005; 153: 431–434.
188. Walker ER, Frederickson RG, Mayes MD. The mineralization of
elastic fibers and alterations of extracellular matrix in
pseudoxanthoma elasticum. Ultrastructure, immunocytochemistry,
and x-ray analysis. Arch Dermatol 1989; 125: 70–76.
189. Gordon SG, Overland M, Foley J. Evidence for increased protease
activity secreted from cultured fibroblasts from patients with
pseudoxanthoma elasticum. Connect Tissue Res 1978; 6: 61–68.
190. Godfrey M, Cisler J, Geerts M-L et al. Fibrillin
immunofluorescence in pseudoxanthoma elasticum. J Am Acad
Dermatol 1995; 32: 589–594.
191. Truter S, Sapadin A, Rosenbaum J et al. Role of fibrillin-2 in
pseudoxanthoma elasticum. J Invest Dermatol 1996; 106: 894
(abstract).
192. Martinez-Hernandez A, Huffer WE, Neldner K et al. Resolution
and repair of elastic tissue calcification in pseudoxanthoma
elasticum. Arch Pathol Lab Med 1978; 102: 303–305.
193. Takata T, Ikeda M, Kodama H, Kitagawa N. Treatment of
pseudoxanthoma elasticum with tocopherol acetate and ascorbic
acid. Pediatr Dermatol 2007; 24: 424–425.
194. Nickoloff BJ, Noodleman FR, Abel EA. Perforating
pseudoxanthoma elasticum associated with chronic renal failure
and hemodialysis. Arch Dermatol 1985; 121: 1321–1322.
195. Dupre A, Bonafe JL, Christol B. Chequered localized
pseudoxanthoma elasticum: a variety of Christensen’s exogenous
pseudoxanthoma elasticum? Acta Derm Venereol 1979; 59:
539–541.
196. Hicks J, Carpenter CL, Reed RJ. Periumbilical perforating
pseudoxanthoma elasticum. Arch Dermatol 1979; 115: 300–303.
197. Caldas Lopes L, Lobo L, Bajanca R. Perforating calcific elastosis. J
Eur Acad Dermatol Venereol 2003; 17: 206–207.
198. Christensen OB. An exogenous variety of pseudoxanthoma
elasticum in old farmers. Acta Derm Venereol 1978; 58:
319–321.
199. Nielsen AO, Christensen OB, Hentzer B et al. Salpeter-induced
dermal changes electron-microscopically indistinguishable from
pseudoxanthoma elasticum. Acta Derm Venereol 1978; 58:
323–327.
200. Kazakis AM, Parish WR. Periumbilical perforating
pseudoxanthoma elasticum. J Am Acad Dermatol 1988; 19:
384–388.
201. Neldner KH, Martinez-Hernandez A. Localized acquired cutaneous
pseudoxanthoma elasticum. J Am Acad Dermatol 1979; 1:
523–530.
202. Pruzan D, Rabbin PE, Heilman ER. Periumbilical perforating
pseudoxanthoma elasticum. J Am Acad Dermatol 1992; 26:
642–644.
203. Nikko AP, Dunningan M, Cockerell CJ. Calciphylaxis with
histologic changes of pseudoxanthoma elasticum. Am J
Dermatopathol 1996; 18: 396–399.
204. Sapadin AN, Lebwohl MG, Teich SA et al. Periumbilical
pseudoxanthoma elasticum associated with chronic renal failure
and angioid streaks – apparent regression with hemodialysis. J Am
Acad Dermatol 1998; 39: 338–344.
205. Bowen AR, Götting C, LeBoit PE, McCalmont TH.
Pseudoxanthoma elasticum-like fibers in the inflamed skin of
patients without pseudoxanthoma elasticum. J Cutan Pathol 2007;
34: 777–781.
206. Taylor NE, Foster WC, Wick MR, Patterson JW. Tumefactive
lipedema with pseudoxanthoma elasticum-like microscopic
changes. J Cutan Pathol 2004; 31: 205–209.
DISORDERS OF ELASTIC TISSUE  •  CHAPTER 12 351.e5
207. Lalla S, Kavanagh GM. Acquired pseudoxanthoma elasticum of the
elbow flexures. Br J Dermatol 2004; 151: 242–244.
208. Sueki H, Amemiya M, Watanabe H et al. Spontaneous resolution in
a case of pseudo-pseudoxanthoma elasticum. Br J Dermatol 2001;
144: 213–215.
209. Choi H-J, Lee D-K, Chang S-E et al. An iatrogenic dermatosis with
ulceration. Clin Exp Dermatol 2005; 30: 463–464.
210. Poon E, Mason GH, Oh C. Clinical and histological spectrum of
elastotic changes induced by penicillamine. Australas J Dermatol
2002; 43: 147–151.
211. Buka R, Wei H, Sapadin A et al. Pseudoxanthoma elasticum and
calcinosis cutis. J Am Acad Dermatol 2000; 43: 312–315.
212. Heyl T. Pseudoxanthoma elasticum with granulomatous skin
lesions. Arch Dermatol 1967; 96: 528–531.
213. Loche F, Raynal H, Bazex J. Acne-like eruption induced by
pseudoxanthoma elasticum: effectiveness of liquid nitrogen
cryotherapy. Eur J Dermatol 1998; 1: 63–65.
214. McKee PH, Cameron CHS, Archer DB, Logan WC. A study of
four cases of pseudoxanthoma elasticum. J Cutan Pathol 1977; 4:
146–153.
215. Danielsen L, Kobayasi T. Pseudoxanthoma elasticum. An
ultrastructural study of scar tissue. Acta Derm Venereol 1974; 54:
121–128.
216. Yamamura T, Sano S. Ultrastructural and histochemical analysis of
thready material in pseudoxanthoma elasticum. J Cutan Pathol
1984; 11: 282–291.
217. Nakayama H, Hashimoto K, Kambe N, Eng A. Elastic globes:
electron microscopic and immunohistochemical observations. J
Cutan Pathol 1988; 15: 98–103.
218. Brennan TE, Pearson RW. Abnormal elastic tissue in cartilage–hair
hypoplasia. Arch Dermatol 1988; 124: 1411–1414.
219. Miura Y, Fujimoto N, Komatsu T et al. Immunohistochemical study
of chronological and photo-induced aging skins using the antibody
raised against D-aspartyl residue-containing peptide. J Cutan Pathol
2004; 31: 51–56.
Solar elastotic syndromes
220. Gilchrest BA. A review of skin ageing and its medical therapy. Br J
Dermatol 1996; 135: 867–875.
221. Malvy DJ-M, Guinot C, Preziosi P et al. Epidemiologic
determinants of skin photoaging: Baseline data of the SU.VI.MAX.
cohort. J Am Acad Dermatol 2000; 42: 47–55.
222. Yaar M, Gilchrest BA. Ageing and photoageing of keratinocytes
and melanocytes. Clin Exp Dermatol 2001; 26: 583–591.
223. Guinot C, Malvy DJ-M, Ambroisine L et al. Relative contribution
of intrinsic vs extrinsic factors to skin aging as determined by a
validated skin age score. Arch Dermatol 2002; 138: 1454–1460.
224. Fisher GJ, Kang S, Varani J et al. Mechanisms of photoaging and
chronological skin aging. Arch Dermatol 2002; 138: 1462–1470.
225. Yaar M, Gilchrest BA. Photoageing: mechanism, prevention and
therapy. Br J Dermatol 2007; 157: 874–887.
226. Fisher GJ, Varani J, Voorhees JJ. Looking older. Fibroblast collapse
and therapeutic implications. Arch Dermatol 2008; 144: 666–672.
227. Salasche SJ, Clemons DE. Cutaneous manifestations of chronic
solar exposure. J Assoc Milit Dermatol 1985; 11: 3–10.
228. Calderone DC, Fenske NA. The clinical spectrum of actinic
elastosis. J Am Acad Dermatol 1995; 32: 1016–1024.
229. Hashimoto K, Black M. Colloid milium: a final degeneration
product of actinic elastoid. J Cutan Pathol 1985; 12: 147–156.
230. Sunderkötter C, Kalden H, Luger TA. Aging and the skin immune
system. Arch Dermatol 1997; 133: 1256–1262.
231. O’Brien JP, Regan W. Actinically degenerate elastic tissue is the
likely antigenic basis of actinic granuloma of the skin and of
temporal arteritis. J Am Acad Dermatol 1999; 40: 214–222.
351.e6 SECTION 4  •  the dermis and subcutis
232. Garg A, Kundu RV, Plotkin O, Aronson IK. Annular elastolytic
giant cell granuloma heralding onset and recurrence of acute
myelogenous leukemia. Arch Dermatol 2006; 142: 532–533.
233. Barnhill RL, Goldenhersh MA. Elastophagocytosis: a non-specific
reaction pattern associated with inflammatory processes in sun-
protected skin. J Cutan Pathol 1989; 16: 199–202.
234. Cockerell EG, Freeman RG, Knox JM. Changes after prolonged
exposure to sunlight. Arch Dermatol 1961; 84: 467–472.
235. Lowe NJ, Meyers DP, Wieder JM et al. Low doses of repetitive
ultraviolet A induce morphologic changes in human skin. J Invest
Dermatol 1995; 105: 739–743.
236. Lavker RM, Gerberick GF, Veres D et al. Cumulative effects from
repeated exposures to suberythemal doses of UVB and UVA in
human skin. J Am Acad Dermatol 1995; 32: 53–62.
237. Stern RS. Actinic degeneration and pigmentary change in
association with psoralen and UVA treatment: A 20-year
prospective study. J Am Acad Dermatol 2003; 48: 61–67.
238. O’Brien JP. Solar and radiant damage to elastic tissue as a cause of
internal vascular damage. Australas J Dermatol 1980; 21: 1–8.
239. Boyd AS, Stasko T, King LE Jr et al. Cigarette smoking-associated
elastotic changes in the skin. J Am Acad Dermatol 1999; 41:
23–26.
240. Knuutinen A, Kallioinen M, Vähäkangas K, Oikarinen A. Smoking
and skin: a study of the physical qualities and histology of skin in
smokers and non-smokers. Acta Derm Venereol 2002; 82: 36–40.
241. Doshi DN, Hanneman KK, Cooper KD. Smoking and skin aging in
identical twins. Arch Dermatol 2007; 143: 1543–1546.
242. Vélez A, López-Rubio F, Moreno J-C. Chronic hydroxyurea-
induced dermatomyositis-like eruption with severe dermal elastosis.
Clin Exp Dermatol 1998; 23: 94–95.
243. Helfrich YR, Yu L, Ofori A et al. Effect of smoking on aging of
photoprotected skin. Evidence gathered using a new photonumeric
scale. Arch Dermatol 2007; 143: 397–402.
244. Castanet J, Ortonne J-P. Pigmentary changes in aged and photoaged
skin. Arch Dermatol 1997; 133: 1296–1299.
245. Kocsard E. Senile elastosis: central phenomenon of aging of
exposed skin. Geriatrics Digest 1970; 7: 10–18.
246. Taylor CR, Stern RS, Leyden JJ, Gilchrest BA. Photoaging/
photodamage and photoprotection. J Am Acad Dermatol 1990; 22:
1–15.
247. Ma W, Wlaschek M, Tantcheva-Poór I et al. Chronological ageing
and photoageing of the fibroblasts and the dermal connective tissue.
Clin Exp Dermatol 2001; 26: 592–599.
248. Degos R, Touraine R, Civatte J, Belaich S. Elastome en nappe du
nez. Bull Soc Franc Derm Syph 1966; 73: 123–124.
249. Raimer SS, Sanchez RL, Hubler WR Jr, Dodson RF. Solar elastotic
bands of the forearm: an unusual clinical presentation of actinic
elastosis. J Am Acad Dermatol 1986; 15: 650–656.
250. Gambichler T, Altmeyer P, Stücker M. Cerebriform elastoma: An
unusual presentation of actinic elastosis. J Am Acad Dermatol
2005; 52: 1106–1108.
251. Kiyohara T, Kumakiri M, Kouraba S. Solar elastotic bands in a
Japanese man. J Am Acad Dermatol 2003; 49: 1193–1195.
252. Williams BT, Barr RJ, Dutta B. Bullous solar elastosis. J Am Acad
Dermatol 1996; 34: 856–858.
253. Lugo A, Montalvo L, González JR, Sánchez JL. Bullous solar
elastosis. Am J Dermatopathol 2005; 27: 34–35.
254. Mitchell RE. Chronic solar dermatosis: a light and electron
microscopic study of the dermis. J Invest Dermatol 1967; 48:
203–220.
255. Stevanovic DV. Elastotic degeneration. A light and electron
microscopic study. Br J Dermatol 1976; 94: 23–29.
256. Bouissou H, Pieraggi M-T, Julian M, Savit T. The elastic tissue of
the skin. A comparison of spontaneous and actinic (solar) aging. Int
J Dermatol 1988; 27: 327–335.
257. Chen VL, Fleischmajer R, Schwartz E et al. Immunochemistry of
elastotic material in sun-damaged skin. J Invest Dermatol 1986; 87:
334–337.
258. Sellheyer K. Pathogenesis of solar elastosis: synthesis or
degradation? J Cutan Pathol 2003; 30: 123–127.
259. Bernstein EF, Chen YQ, Tamai K et al. Enhanced elastin and
fibrillin gene expression in chronically photodamaged skin. J Invest
Dermatol 1994; 103: 182–186.
260. Miyachi Y, Ishikawa O. Dermal connective tissue metabolism in
photoageing. Australas J Dermatol 1998; 39: 19–23.
261. Seite S, Zucchi H, Septier D et al. Elastin changes during
chronological and photo-ageing: the important role of lysozyme. J
Eur Acad Dermatol Venereol 2006; 20: 980–987.
262. Rijken F, Kiekens RCM, Bruijnzeel PLB. Skin-infiltrating
neutrophils following exposure to solar-simulated radiation could
play an important role in photoageing of human skin. Br J
Dermatol 2005; 152: 321–328.
263. Janig E, Haslbeck M, Aigelsreiter A et al. Clusterin associates with
altered elastic fibers in human photoaged skin and prevents elastin
from ultraviolet-induced aggregation in vitro. Am J Pathol 2007;
171: 1474–1482.
264. Trautinger F. Mechanisms of photodamage of the skin and its
functional consequences for skin ageing. Clin Exp Dermatol 2001;
26: 573–577.
265. Bernstein EF, Underhill CB, Hahn PJ et al. Chronic sun exposure
alters both the content and distribution of dermal
glycosaminoglycans. Br J Dermatol 1996; 135: 255–262.
266. Rabe JH, Mamelak AJ, McElgunn PJS et al. Photoaging:
Mechanisms and repair. J Am Acad Dermatol 2006; 55: 1–19.
267. Craven NM, Watson REB, Jones CJP et al. Clinical features of
photodamaged human skin are associated with a reduction in
collagen VII. Br J Dermatol 1997; 137: 344–350.
268. Saarialho-Kere U, Kerkelä E, Jeskanen L et al. Accumulation of
matrilysin (MMP-7) and macrophage metalloelastase (MMP-12) in
actinic damage. J Invest Dermatol 1999; 113: 664–672.
269. Fisher GJ, Datta SC, Talwar HS et al. Molecular basis of sun-
induced premature skin ageing and retinoid antagonism. Nature
1996; 379: 335–339.
270. Fisher GJ, Wang ZQ, Datta SC et al. Pathophysiology of premature
skin aging induced by ultraviolet light. N Engl J Med 1997; 337:
1419–1428.
271. Varani J, Warner RL, Gharaee-Kermani M et al. Vitamin A
antagonizes decreased cell growth and elevated collagen-degrading
matrix metalloproteinases and stimulates collagen accumulation in
naturally aged human skin. J Invest Dermatol 2000; 114: 480–486.
272. Hase T, Shinta K, Murase T et al. Histological increase in
inflammatory infiltrate in sun-exposed skin of female subjects: the
possible involvement of matrix metalloproteinase-1 produced by
inflammatory infiltrate on collagen degradation. Br J Dermatol
2000; 142: 267–273.
273. Yaar M, Gilchrest BA. Aging versus photoaging: postulated
mechanisms and effectors. J Invest Dermatol (Symposium
Proceedings) 1998; 3: 47–51.
274. Bhawan J, Andersen W, Lee J et al. Photoaging versus intrinsic
aging: a morphologic assessment of facial skin. J Cutan Pathol
1995; 22: 154–159.
275. Warren R, Gartstein V, Kligman AM et al. Age, sunlight, and facial
skin: a histologic and quantitative study. J Am Acad Dermatol
1991; 25: 751–760.
276. Montagna W, Carlisle K. Structural changes in aging human skin. J
Invest Dermatol 1979; 73: 47–53.
277. Nelson BR, Majmudar G, Griffiths CEM et al. Clinical
improvement following dermabrasion of photoaged skin correlates
with synthesis of collagen 1. Arch Dermatol 1994; 130: 1136–1142.

278. Kossard S, Anderson P, Davies A, Cooper A. Histological
evaluation of the effect of 0.05% tretinoin in the treatment of
photodamaged skin. Australas J Dermatol 1993; 34: 89–95.
279. Weinstein GD, Nigra TP, Pochi PE et al. Topical tretinoin for
treatment of photodamaged skin. A multicenter study. Arch
Dermatol 1991; 127: 659–665.
280. Rosenthal DS, Roop DR, Huff CA et al. Changes in photo-aged
human skin following topical application of All-trans retinoic acid.
J Invest Dermatol 1990; 95: 510–515.
281. Bhawan J, Gonzalez-Serva A, Nehal K et al. Effects of tretinoin on
photodamaged skin. A histologic study. Arch Dermatol 1991; 127:
666–672.
282. Kang S, Fisher GJ, Voorhees JJ. Photoaging and topical tretinoin.
Therapy, pathogenesis, and prevention. Arch Dermatol 1997; 133:
1280–1284.
283. Ellis CN, Weiss JS, Hamilton TA et al. Sustained improvement
with prolonged topical tretinoin (retinoic acid) for photoaged skin.
J Am Acad Dermatol 1990; 23: 629–637.
284. Alexiades-Armenakas MR, Dover JS, Arndt KA. The spectrum of
laser skin resurfacing: Nonablative, fractional, and ablative laser
resurfacing. J Am Acad Dermatol 2008; 58: 719–737.
285. Uitto J. Understanding premature skin aging. N Engl J Med 1997;
337: 1463–1465.
286. Kafi R, Kwak HSR, Schumacher WE et al. Improvement of
naturally aged skin with vitamin A (Retinol). Arch Dermatol 2007;
143: 606–612.
287. Green C, Orchard G, Cerio R, Hawk JLM. A clinicopathological
study of the effects of topical retinyl propionate cream in skin
photoageing. Clin Exp Dermatol 1998; 23: 162–167.
288. Metcalf S, Crowson AN, Naylor M et al. Imiquimod as an
antiaging agent. J Am Acad Dermatol 2007; 56: 422–425.
289. Uetsu N, Okamoto H, Fujii K et al. Treatment of chronic actinic
dermatitis with tacrolimus ointment. J Am Acad Dermatol 2002;
47: 881–884.
290. Dover JS, Bhatia AC, Stewart B, Arndt KA. Topical
5-aminolevulinic acid combined with intense pulsed light in the
treatment of photoaging. Arch Dermatol 2005; 141: 1247–1252.
291. Hall G, Phillips TJ. Estrogen and skin: The effects of estrogen,
menopause, and hormone replacement therapy on the skin. J Am
Acad Dermatol 2005; 53: 555–568.
292. Chiu A, Kimball AB. Topical vitamins, minerals and botanical
ingredients as modulators of environmental and chronological skin
damage. Br J Dermatol 2003; 149: 681–691.
293. Boyd AS, Naylor M, Cameron GS et al. The effects of chronic
sunscreen use on the histologic changes of dermatoheliosis. J Am
Acad Dermatol 1995; 33: 941–946.
294. Phillips TJ, Bhawan J, Yaar M et al. Effect of daily versus
intermittent sunscreen application on solar simulated UV radiation-
induced skin response in humans. J Am Acad Dermatol 2000; 43:
610–618.
295. Lavker RM. Structural alterations in exposed and unexposed aged
skin. J Invest Dermatol 1979; 73: 59–66.
296. Chung JH, Yano K, Lee MK et al. Differential effects of
photoaging vs intrinsic aging on the vascularization of human skin.
Arch Dermatol 2002; 138: 1437–1442.
297. Goette DK. Transepidermal elimination of actinically damaged
connective tissue. Int J Dermatol 1984; 23: 669–672.
298. Toyoda M, Morohashi M. Morphological alterations of epidermal
melanocytes in photoageing: an ultrastructural and
cytomorphometric study. Br J Dermatol 1998; 139: 444–452.
299. Hartschuh W, Schulz T. Merkel cell hyperplasia in chronic
radiation-damaged skin: its possible relationship to fibroepithelioma
of Pinkus. J Cutan Pathol 1997; 24: 477–483.
300. Lavker RM, Kligman AM. Chronic heliodermatitis: a 324. Rahbari H. Acrokeratoelastoidosis and keratoelastoidosis marginalis
morphologic evaluation of chronic actinic dermal damage with
DISORDERS OF ELASTIC TISSUE  •  CHAPTER 12 351.e7
emphasis on the role of mast cells. J Invest Dermatol 1988; 90:
325–330.
301. Bosset S, Bonnet-Duquennoy M, Barré P et al. Photoaging shows
histological features of chronic skin inflammation without clinical
and molecular abnormalities. Br J Dermatol 2003; 149: 826–835.
302. Montagna W, Kirchner S, Carlisle K. Histology of sun-damaged
human skin. J Am Acad Dermatol 1989; 21: 907–918.
303. Ledoux-Corbusier M, Danis P. Pinguecula and actinic elastosis. An
ultrastructural study. J Cutan Pathol 1979; 6: 404–413.
304. Danielsen L, Kobayasi T. Degeneration of dermal elastic fibres in
relation to age and light-exposure. Preliminary report on electron
microscopic studies. Acta Derm Venereol 1972; 52: 1–10.
305. Ledoux-Corbusier M, Achten G. Elastosis in chronic
radiodermatitis. An ultrastructural study. Br J Dermatol 1974; 91:
287–295.
306. Bernstein EF, Chen YQ, Kopp JB et al. Long-term sun exposure
alters the collagen of the papillary dermis. J Am Acad Dermatol
1996; 34: 209–218.
307. Zelickson AS, Mottaz JH, Zelickson BD, Muller SA. Elastic tissue
changes in skin following PUVA therapy. J Am Acad Dermatol
1980; 3: 186–192.
308. Tsuji T. The surface structural alterations of elastic fibers and
elastotic material in solar elastosis: a scanning electron microscopic
study. J Cutan Pathol 1984; 11: 300–308.
309. Patterson WM, Fox MD, Schwartz RA. Favre-Racouchot disease.
Int J Dermatol 2004; 43: 167–169.
310. Cuce LC, Paschoal LHC, Curban GV. Cutaneous nodular
elastoidosis with cysts and comedones. Arch Dermatol 1964; 89:
798–802.
311. Helm F. Nodular cutaneous elastosis with cysts and comedones
(Favre–Racouchot syndrome). Arch Dermatol 1961; 84: 666–668.
312. Sharkey MJ, Keller RA, Grabski WJ et al. Favre–Racouchot
syndrome. A combined therapeutic approach. Arch Dermatol 1992;
128: 615–616.
313. Siragusa M, Maglioli E, Batolo D, Schepis C. An unusual location
of nodular elastosis with cysts and comedones (Favre–Racouchot’s
disease). Acta Derm Venereol 2000; 80: 452.
314. Mavilia L, Rossi R, Cannarozzo G et al. Unilateral nodular
elastosis with cysts and comedones (Favre-Racouchot syndrome):
report of two cases treated with a new combined therapeutic
approach. Dermatology 2002; 204: 251.
315. Keough GC, Laws RA, Elston DM. Favre–Racouchot syndrome: a
case for smokers’ comedones. Arch Dermatol 1997; 133: 796–797.
316. Rallis E, Karanikola E, Verros C. Successful treatment of Favre-
Racouchot disease with 0.05% tazarotene gel. Arch Dermatol 2007;
143: 810–812.
317. Breit S, Flaig MJ, Wolff H, Plewig G. Favre-Racouchot-like
disease after radiation therapy. J Am Acad Dermatol 2003; 49:
117–119.
318. Hedelund L, Wulf HC. Favre-Racouchot disease provoked by
UV-A1 and UV-B exposure. Arch Dermatol 2004; 140: 129–131.
319. Hassounah A, Pierard GE. Kerosis and comedos without prominent
elastosis in Favre–Racouchot disease. Am J Dermatopathol 1987;
9: 15–17.
320. Carter VH, Constantine VS, Poole WL. Elastotic nodules of the
antihelix. Arch Dermatol 1969; 100: 282–285.
321. Weedon D. Elastotic nodules of the ear. J Cutan Pathol 1981; 8:
429–433.
322. Kocsard E, Ofner F, Turner B. Elastotic nodules of the antihelix.
Arch Dermatol 1970; 101: 370.
323. Jordaan HF, Rossouw DJ. Digital papular calcific elastosis: a
histopathological, histochemical and ultrastructural study of 20
patients. J Cutan Pathol 1990; 17: 358–370.
– any relation? J Am Acad Dermatol 1981; 5: 348–350.
351.e8 SECTION 4  •  the dermis and subcutis
325. Burks JW, Wise LJ, Clark WH. Degenerative collagenous plaques
of the hands. Arch Dermatol 1960; 82: 362–366.
326. Kocsard E. Keratoelastoidosis marginalis of the hands.
Dermatologica 1964; 131: 169–175.
327. Abulafia J, Vignale RA. Degenerative collagenous plaques of the
hands and acrokeratoelastoidosis: pathogenesis and relationship
with knuckle pads. J Invest Dermatol 2000; 39: 424–432.
328. Todd D, Al-Aboosi M, Hameed O et al. The role of UV light in the
pathogenesis of digital papular calcific elastosis. Arch Dermatol
2001; 137: 379–381.
329. Ritchie EB, Williams HM. Degenerative collagenous plaques of the
hands. Arch Dermatol 1966; 93: 202–203.
330. Shahrad P, Marks R. The wages of warmth: changes in erythema ab
igne. Br J Dermatol 1977; 97: 179–186.
331. Milligan A, Graham-Brown RAC. Erythema ab igne affecting the
palms. Clin Exp Dermatol 1989; 14: 168–169.
332. Lin S-J, Hsu C-J, Chiu H-C. Erythema ab igne caused by frequent
hot bathing. Acta Derm Venereol 2002; 82: 478–479.
333. Bilic M, Adams BB. Erythema ab igne induced by a laptop
computer. J Am Acad Dermatol 2004; 50: 973–974.
334. Chatterjee S. Erythema ab igne from prolonged use of a heating
pad. Mayo Clin Proc 2005; 80: 1500.
335. Wilson NJE, Sharpe GR. Erythema ab igne in a child with atopic
eczema. Clin Exp Dermatol 1999; 24: 337–338.
336. Arrington JH III, Lockman DS. Thermal keratoses and squamous
cell carcinoma in situ associated with erythema ab igne. Arch
Dermatol 1979; 115: 1226–1228.
337. Finlayson GR, Sams WM Jr, Smith JG Jr. Erythema ab igne: a
histopathological study. J Invest Dermatol 1966; 46: 104–108.
338. Johnson WC, Butterworth T. Erythema ab igne elastosis. Arch
Dermatol 1971; 104: 128–131.
Decreased elastic tissue
339. Guarneri F, Guarneri C, Cannavò SP. Skin atrophy caused by
thiocolchicoside injections. Int J Dermatol 2006; 45: 1473–1474.
340. Bordas X, Ferrandiz C, Ribera M, Galofre E. Papular elastorrhexis:
a variety of nevus anelasticus? Arch Dermatol 1987; 123: 433–434.
341. Crivellato E. Disseminated nevus anelasticus. Int J Dermatol 1986;
25: 171–173.
342. Sears JK, Stone MS, Argenyi Z. Papular elastorrhexis: a variant of
connective tissue nevus. Case reports and review of the literature. J
Am Acad Dermatol 1988; 19: 409–414.
343. Schirren H, Schirren CG, Stolz W et al. Papular elastorrhexis: a
variant of dermatofibrosis lenticularis disseminata (Buschke–
Ollendorff syndrome)? Dermatology 1994; 189: 368–372.
344. Choonhakarn C, Jirarattanapochai K. Papular elastorrhexis: a
distinct variant of connective tissue nevi or an incomplete form of
Buschke-Ollendorff syndrome? Clin Exp Dermatol 2002; 27:
454–457.
345. del Pozo J, Martínez W, Sacristán F et al. Papular elastorrhexis, a
distinctive entity? Am J Dermatopathol 2008; 30: 188–190.
346. Ryder HF, Antaya RJ. Nevus anelasticus, papular elastorrhexis, 372. Kasper RC, Wood GS, Nihal M, LeBoit PE. Anetoderma arising in
and eruptive collagenoma: clinically similar entities with focal
absence of elastic fibers in childhood. Pediatr Dermatol 2005; 22:
153–157.
347. Lewis KG, Bercovitch L, Dill SW, Robinson-Botsom L. Acquired
disorders of elastic tissue: Part II. Decreased elastic tissue. J Am
Acad Dermatol 2004; 51: 165–185.
348. Varadi DP, Saqueton AC. Perifollicular elastolysis. Br J Dermatol
1970; 83: 143–150.
349. Taaffe A, Cunliffe WJ, Clayden AD. Perifollicular elastolysis – a
common condition. Br J Dermatol (Suppl) 1983; 24: 20.
350. Wilson BB, Dent CH, Cooper PH. Papular acne scars. A common
cutaneous finding. Arch Dermatol 1990; 126: 797–800.
351. Venencie PY, Winkelmann RK, Moore BA. Anetoderma. Clinical
findings, associations, and long-term follow-up evaluations. Arch
Dermatol 1984; 120: 1032–1039.
352. Miller WN, Ruggles CW, Rist TE. Anetoderma. Int J Dermatol
1979; 18: 43–45.
353. Yu H-J, Shin H, Kang M-S, Kim J-S. A case of primary
anetoderma in an infant. Br J Dermatol 2007; 157: 1267–1269.
354. Friedman SJ, Venencie PY, Bradley RR, Winkelmann RK. Familial
anetoderma. J Am Acad Dermatol 1987; 16: 341–345.
355. Aberer E, Weissenbacher G. Congenital anetoderma induced by
intrauterine infection? Arch Dermatol 1997; 133: 526–527.
356. Peterman A, Scheel M, Sams WM Jr, Pandya AG. Hereditary
anetoderma. J Am Acad Dermatol 1996; 35: 999–1000.
357. Zellman GL, Levy ML. Congenital anetoderma in twins. J Am
Acad Dermatol 1997; 36: 483–485.
358. Gerritsen MJP, de Rooij MJM, Sybrandy-Fleuren BAM, van de
Kerkhof PCM. Familial anetoderma. Dermatology 1999; 198:
321–322.
359. Thomas JE, Mehregan DR, Holland J, Mehregan DA. Familial
anetoderma. Int J Dermatol 2003; 42: 75–77.
360. Sparsa A, Piette JC, Wechsler B et al. Anetoderma and its
prothrombotic abnormalities. J Am Acad Dermatol 2003; 49:
1008–1012.
361. Romaní J, Pérez F, Llobet M et al. Anetoderma associated with
antiphospholipid antibodies: case report and review of the
literature. J Eur Acad Dermatol Venereol 2001; 15: 175–178.
362. de Souza EM, Daldon PEC, Cintra ML. Anetoderma associated
with primary antiphospholipid syndrome. J Am Acad Dermatol
2007; 56: 881–882.
363. Hodak E, Feureman H, David M. Primary anetoderma is a
cutaneous sign of antiphospholipid antibodies. J Am Acad
Dermatol 2008; 58: 351.
364. Özkan Ş, Fetil E, İzler F et al. Anetoderma secondary to
generalized granuloma annulare. J Am Acad Dermatol 2000; 42:
335–338.
365. Veraldi S, Schianchi R. Chickenpox, impetigo, and anetoderma.
Pediatr Dermatol 2006; 23: 305–306.
366. Ruiz-Rodriguez R, Longaker M, Berger TG. Anetoderma and
human immunodeficiency virus infection. Arch Dermatol 1992;
128: 661–662.
367. Lindstrom J, Smith KJ, Skelton HG et al. Increased anticardiolipin
antibodies associated with the development of anetoderma in HIV-1
disease. Int J Dermatol 1995; 34: 408–415.
368. Schepis C, Siragusa M. Secondary anetoderma in people with
Down’s syndrome. Acta Derm Venereol 1999; 79: 245.
369. Crone AM, James MP. Acquired linear anetoderma following
angular cheilitis. Br J Dermatol 1998; 138: 923–924.
370. Bauer J, Leitz G, Palmedo G, Hügel H. Anetoderma: Another facet
of Lyme disease? J Am Acad Dermatol 2003; 48: S86–S88.
371. Jubert C, Cosnes A, Wechsler J et al. Anetoderma may reveal
cutaneous plasmacytoma and benign cutaneous lymphoid
hyperplasia. Arch Dermatol 1995; 131: 365–366.
cutaneous B-cell lymphoproliferative disease. Am J Dermatopathol
2001; 23: 124–132.
373. Segurado MA, Guerra-Tapia A, Zarco C et al. Anetoderma
secondary to cutaneous B-cell lymphoma. Clin Exp Dermatol 2006;
31: 130–131.
374. Requena L, González-Guerra E, Angulo J et al. Anetodermic
mycosis fungoides: a new clinicopathological variant of mycosis
fungoides. Br J Dermatol 2008; 158: 157–162.
375. Ang P, Tay YK. Anetoderma in a patient with juvenile
xanthogranuloma. Br J Dermatol 1999; 140: 541–542.
376. Gamo R, Ortíz-Romero P, Sopena J et al. Anetoderma developing
in juvenile xanthogranuloma. Int J Dermatol 2005; 44: 503–506.

377. Child FJ, Woollons A, Price ML et al. Multiple cutaneous
immunocytoma with secondary anetoderma: a report of two cases.
Br J Dermatol 2000; 143: 165–170.
378. Davis W. Wilson’s disease and penicillamine-induced anetoderma.
Arch Dermatol 1977; 113: 976.
379. Daoud MS, Dicken CH. Anetoderma after hepatitis B immunization
in two siblings. J Am Acad Dermatol 1997; 36: 779–780.
380. Prizant TL, Lucky AW, Frieden IJ et al. Spontaneous atrophic
patches in extremely premature infants. Anetoderma of prematurity.
Arch Dermatol 1996; 132: 671–674.
381. Todd DJ. Anetoderma of prematurity. Arch Dermatol 1997; 133:
789.
382. Colditz PB, Dunster KR, Joy GJ, Robertson IM. Anetoderma of
prematurity in association with electrocardiographic electrodes. J
Am Acad Dermatol 1999; 41: 478–481.
383. Carrington PR, Altick JA, Sanusi ID. Atrophoderma elastolytica
discreta. Am J Dermatopathol 1996; 18: 212–217.
384. Carr RD. Urticaria pigmentosa associated with anetoderma. Acta
Derm Venereol 1971; 51: 120–122.
385. Shames BS, Nassif A, Bailey CS, Saltzstein SL. Secondary
anetoderma involving a pilomatricoma. Am J Dermatopathol 1994;
16: 557–560.
386. Kelly SE, Humphreys F, Aldridge RD. The phenomenon of
anetoderma occurring over pilomatricomas. J Am Acad Dermatol
1993; 28: 511.
387. Oikarinen AI, Palatsi R, Adomian GE et al. Anetoderma:
biochemical and ultrastructural demonstration of an elastin defect
in the skin of three patients. J Am Acad Dermatol 1984; 11: 64–72.
388. Venencie PY, Winkelmann RK. Histopathologic findings in
anetoderma. Arch Dermatol 1984; 120: 1040–1044.
389. Ghomrasseni S, Dridi M, Gogly B et al. Anetoderma. An altered
balance between metalloproteinases and tissue inhibitors of
metalloproteinases. Am J Dermatopathol 2002; 24: 118–129.
390. Hodak E, Shamai-Lubovitz O, David M et al. Immunologic
abnormalities associated with primary anetoderma. Arch Dermatol
1992; 128: 799–803.
391. Hodak E, Shamai-Lubovitz O, David M et al. Primary anetoderma
associated with a wide spectrum of autoimmune abnormalities. J
Am Acad Dermatol 1991; 25: 415–418.
392. Disdier P, Harlé J-R, Andrac L et al. Primary anetoderma
associated with the antiphospholipid syndrome. J Am Acad
Dermatol 1994; 30: 133–134.
393. Venencie PY, Winkelmann RK. Monoclonal antibody studies in the
skin lesions of patients with anetoderma. Arch Dermatol 1985; 121:
747–749.
394. Zaki I, Scerri L, Nelson H. Primary anetoderma: phagocytosis of
elastic fibres by macrophages. Clin Exp Dermatol 1994; 19:
388–390.
395. Taïeb A, Dufillot D, Pellegrin-Carloz B et al. Postgranulomatous
anetoderma associated with Takayasu’s arteritis in a child. Arch
Dermatol 1987; 123: 796–800.
396. Bergman R, Friedman-Birnbaum R, Hazaz B et al. An
immunofluorescence study of primary anetoderma. Clin Exp
Dermatol 1990; 15: 124–130.
397. Venencie PY, Winkelmann RK, Moore BA. Ultrastructural findings
in the skin lesions of patients with anetoderma. Acta Derm
Venereol 1984; 64: 112–120.
398. Kossard S, Kronman KR, Dicken CH, Schroeter AL. Inflammatory
macular atrophy: immunofluorescent and ultrastructural findings. J
Am Acad Dermatol 1979; 1: 325–334.
399. Tsuji T, Imajo Y, Sawabe M et al. Acquired cutis laxa concomitant
with nephrotic syndrome. Arch Dermatol 1987; 123: 1211–1216.
400. Schreiber MM, Tilley JC. Cutis laxa. Arch Dermatol 1961; 84:
266–272.
DISORDERS OF ELASTIC TISSUE  •  CHAPTER 12 351.e9
401. Ledoux-Corbusier M. Cutis laxa, congenital form with pulmonary
emphysema: an ultrastructural study. J Cutan Pathol 1983; 10:
340–349.
402. Mehregan AH, Lee SC, Nabai H. Cutis laxa (generalized
elastolysis). A report of four cases with autopsy findings. J Cutan
Pathol 1978; 5: 116–126.
403. Abdelmalek NF, Gerber TL, Menter A. Cardiocutaneous syndromes
and associations. J Am Acad Dermatol 2002; 46: 161–183.
404. Sakati NO, Nyhan WL. Congenital cutis laxa and osteoporosis. Am
J Dis Child 1983; 137: 452–454.
405. Agha A, Sakati NO, Higginbottom MC et al. Two forms of cutis
laxa presenting in the newborn period. Acta Paediatr Scand 1978;
67: 775–780.
406. Andiran N, Sarikayalar F, Saraçlar M, Çağlar M. Autosomal
recessive form of congenital cutis laxa: more than the clinical
appearance. Pediatr Dermatol 2002; 19: 412–414.
407. Nanda A, Lionel J, Al-Tawari AA, Anim JT. What syndrome is
this? [Autosomal recessive type II cutis laxa]. Pediatr Dermatol
2004; 21: 167–170.
408. Baldwin L, Kumrah L, Thoppuram P, Bhattacharji S. Congenital
cutis laxa (dermatochalasia) with cardiac valvular disease. Pediatr
Dermatol 2001; 18: 365–366.
409. Sarkar R, Kaur C, Kanwar AJ, Basu S. Cutis laxa in seven
members of a North-Indian family. Pediatr Dermatol 2002; 19:
229–231.
410. Claus S, Fischer J, Mégarbané H et al. A p.C217R mutation in
fibulin-5 from cutis laxa patients is associated with incomplete
extracellular matrix formation in a skin equivalent model. J Invest
Dermatol 2008; 128: 1442–1450.
411. Byers PH, Siegel RC, Holbrook KA et al. X-linked cutis laxa. N
Engl J Med 1980; 303: 61–65.
412. Brown FR III, Holbrook KA, Byers PH et al. Cutis laxa. Johns
Hopkins Med J 1982; 150: 148–153.
413. Ostlere LS, Pope FM, Holden CA. Cutis laxa complicating
Ehlers–Danlos syndrome type II. Clin Exp Dermatol 1996; 21:
135–137.
414. Rodriguez-Revenga L, Iranzo P, Badenas C et al. A novel elastin
gene mutation resulting in an autosomal dominant form of cutis
laxa. Arch Dermatol 2004; 140: 1135–1139.
415. George S, Jacob M, Pulimood S, Chandi SM. Cutis laxa. Clin Exp
Dermatol 1998; 23: 211–213.
416. Vaccaro M, Salpietro DC, Briuglia S et al. Cutis laxa in
Kabuki make-up syndrome. J Am Acad Dermatol 2005; 53:
S247–S251.
417. Salpietro DC, Guarneri F, Rigoli L et al. What syndrome is this?
[Kabuki make-up syndrome]. Pediatr Dermatol 2007; 24: 309–312.
418. Koklu E, Gunes T, Ozturk MA et al. Cutis laxa associated with
central hypothyroidism owing to isolated thyrotropin deficiency in
a newborn. Pediatr Dermatol 2007; 24: 525–528.
419. Fisher BK, Page E, Hanna W. Acral localized acquired cutis laxa. J
Am Acad Dermatol 1989; 21: 33–40.
420. Greenbaum SS, Krull EA, Rubin MG, Lee R. Localized acquired
cutis laxa in one of identical twins. Int J Dermatol 1989; 28:
402–406.
421. Ghigliotti G, Parodi A, Borgiani L et al. Acquired cutis laxa
confined to the face. J Am Acad Dermatol 1991; 24: 504–505.
422. Martin L, Requena L, Yus ES et al. Acrolocalized acquired cutis
laxa. Br J Dermatol 1996; 134: 973–976.
423. Perafán Riveros CJ, Bejarano Gavilán MF, Sayago França LF et al.
Acquired localized cutis laxa confined to the face: case report and
review of the literature. Int J Dermatol 2004; 43: 931–935.
424. Mataix J, Bañuls J, Lucas A et al. Prematurely aged appearance.
Clin Exp Dermatol 2006; 31: 833–834.
351.e10 SECTION 4  •  the dermis and subcutis
425. de Almeida HL Jr, Wolter M, de Farias MV, de Castro LAS. Elastic
tissue damage in cephalic aquired cutis laxa. J Cutan Pathol 2008;
35: 58–61.
426. Reed WB, Horowitz RE, Beighton P. Acquired cutis laxa. Primary
generalized elastolysis. Arch Dermatol 1971; 103: 661–669.
427. Nanko H, Jepsen LV, Zachariae H, Sogaard H. Acquired cutis laxa
(generalized elastolysis): light and electron microscopic studies.
Acta Derm Venereol 1979; 59: 315–324.
428. Chun SI, Yoon J. Acquired cutis laxa associated with chronic
urticaria. J Am Acad Dermatol 1995; 33: 896–899.
429. Bouloc A, Godeau G, Zeller J et al. Increased fibroblast elastase
activity in acquired cutis laxa. Dermatology 1999; 198: 346–350.
430. Lewis FM, Lewis-Jones S, Gipson M. Acquired cutis laxa with
dermatitis herpetiformis and sarcoidosis. J Am Acad Dermatol
1993; 29: 846–848.
431. Muster AJ, Bharati S, Herman JJ et al. Fatal cardiovascular disease
and cutis laxa following acute febrile neutrophilic dermatosis. J
Pediatr 1983; 102: 243–248.
432. Harris RB, Heaphy MR, Perry HO. Generalized elastolysis (cutis
laxa). Am J Med 1978; 65: 815–822.
433. Kerl H, Burg G, Hashimoto K. Fatal, penicillin-induced,
generalized postinflammatory elastolysis (cutis laxa). Am J
Dermatopathol 1983; 5: 267–276.
434. Koch SE, Williams ML. Acquired cutis laxa: case report and
review of disorders of elastolysis. Pediatr Dermatol 1985; 2:
282–288.
435. Mahajan VK, Sharma NL, Garg G. Cutis laxa acquisita associated
with cutaneous mastocytosis. Int J Dermatol 2006; 45: 949–951.
436. Hashimoto K, Kanzaki T. Cutis laxa. Ultrastructural and
biochemical studies. Arch Dermatol 1975; 111: 861–873.
437. Scott MA, Kauh YC, Luscombe HA. Acquired cutis laxa associated
with multiple myeloma. Arch Dermatol 1976; 112: 853–855.
438. Ting HC, Foo MH, Wang F. Acquired cutis laxa and multiple
myeloma. Br J Dermatol 1984; 110: 363–367.
439. Nikko A, Dunnigan M, Black A, Cockerell CJ. Acquired cutis laxa
associated with a plasma cell dyscrasia. Am J Dermatopathol 1996;
18: 533–537.
440. Machet MC, Machet L, Vaillant L et al. Acquired localized cutis
laxa due to cutaneous lymphoplasmacytoid lymphoma. Arch
Dermatol 1995; 131: 110–111.
441. Chartier S, Faucher L, Tousignant J, Rochette L. Acquired cutis
laxa associated with cutaneous angiocentric T-cell lymphoma. Int J
Dermatol 1997; 36: 772–776.
442. Rongioletti F, Cutolo M, Bondavalli P, Rebora A. Acral localized
acquired cutis laxa associated with rheumatoid arthritis. J Am Acad
Dermatol 2002; 46: 128–130.
443. Randle HW, Muller S. Generalized elastolysis associated with
systemic lupus erythematosus. J Am Acad Dermatol 1983; 8:
869–873.
444. García-Patos V, Pujol RM, Barnadas MA et al. Generalized
acquired cutis laxa associated with coeliac disease: evidence of
immunoglobulin A deposits on the dermal elastic fibres. Br J
Dermatol 1996; 135: 130–134.
445. Kiuru-Enari S, Keski-Oja J, Haltia M. Cutis laxa in hereditary
gelsolin amyloidosis. Br J Dermatol 2005; 152: 250–257.
446. Tanskanen M, Paetau A, Salonen O et al. Severe ataxia with
neuropathy in hereditary gelsolin amyloidosis: a case report.
Amyloid 2007; 14: 89–95.
447. Graul-Neumann LM, Hausser I, Essayie M et al. Highly variable
cutis laxa resulting from a dominant splicing mutation of the elastin
gene. Am J Med Genet 2008; 146A: 977–983.
448. Urban Z, Gao J, Pope FM, Davis EC. Autosomal dominant cutis
laxa with severe lung disease: synthesis and matrix deposition of
mutant tropoelastin. J Invest Dermatol 2005; 124: 1193–1199.
449. Szabo Z, Crepeau MW, Mitchell AL et al. Aortic aneurysmal
disease and cutis laxa caused by defects in the elastin gene. J Med
Genet 2006; 43: 255–258.
450. Uitto J. Elastic fibre abnormalities in skin disorders: what’s new? J
Eur Acad Dermatol Venereol 2001; 15: 303–304.
451. Guerra D, Fornieri C, Bacchelli B et al. The De Barsy syndrome. J
Cutan Pathol 2004; 31: 616–624.
452. Jukkola A, Kauppila S, Risteli L et al. New lethal disease involving
type I and III collagen defect resembling geroderma
osteodysplastica, De Barsy syndrome, and Ehlers-Danlos syndrome
IV. J Med Genet 1998; 35: 513–518.
453. Lotery AJ, Baas D, Ridley C et al. Reduced secretion of fibulin 5
in age-related macular degeneration and cutis laxa. Hum Mutat
2006; 27: 568–574.
454. Tenea D, Jacyk WK. What syndrome is this? [Barber-Say
syndrome]. Pediatr Dermatol 2006; 23: 183–184.
455. Koppe R, Kaplan P, Hunter A, MacMurray B. Ambiguous genitalia
associated with skeletal abnormalities, cutis laxa, craniostenosis,
psychomotor retardation, and facial abnormalities (SCARF
syndrome). Am J Med Genet 1989; 34: 305–312.
456. Boente Mdel C, Asial RA, Winik BC. Geroderma osteodysplastica.
Report of a new family. Pediatr Dermatol 2006; 23: 467–472.
457. Rajab A, Kornak U, Budde BS et al. Geroderma osteodysplasticum
hereditaria and wrinkly skin syndrome in 22 patients from Oman.
Am J Med Genet 2008; 146A: 965–976.
458. Fornieri C, Quaglino D, Lungarella G et al. Elastin production and
degradation in cutis laxa acquisita. J Invest Dermatol 1994; 103:
583–588.
459. Hatamochi A, Kuroda K, Shinkai H et al. Regulation of matrix
metalloproteinase (MMP) expression in cutis laxa fibroblasts:
upregulation of MMP-1, MMP-3 and MMP-9 genes but not of the
MMP-2 gene. Br J Dermatol 1998; 138: 757–762.
460. Hatamochi A, Mori K, Arakawa M et al. Collagenase gene
expression in cutis laxa fibroblasts is upregulated by transcriptional
activation of the promoter gene through a 12-O-tetradecanoyl-
phorbol-13-acetate (TPA)-responsive element. J Invest Dermatol
1996; 106: 631–636.
461. Hu Q, Reymond J-L, Pinel N et al. Inflammatory destruction of
elastic fibers in acquired cutis laxa is associated with missense
alleles in the elastin and fibulin-5 genes. J Invest Dermatol 2006;
126: 283–290.
462. Nguyen V, Buka RL, Roberts BJ, Eichenfield LF. Cutaneous
manifestations of Costello syndrome. Int J Dermatol 2007; 46:
72–76.
463. Hatamochi A, Nagayama H, Kuroda K et al. Costello syndrome
with decreased gene expression of elastin in cultured dermal
fibroblasts. Dermatology 2000; 201: 366–369.
464. Lin AE, Rauen KA, Gripp KW, Carey JC. Clarification of
previously reported Costello syndrome patients. Am J Med Genet
2008; 146A: 940–943.
465. Nasca MR, Strano L, Musumeci ML, Micali G. What syndrome is
this? [Costello syndrome). Pediatr Dermatol 2003; 20: 447–450.
466. Sato M, Ishikawa O, Miyachi Y et al. Michelin tyre syndrome: a
congenital disorder of elastic fibre formation? Br J Dermatol 1997;
136: 583–586.
467. Goltz RW, Hult A-M, Goldfarb M, Gorlin RJ. Cutis laxa. A
manifestation of generalized elastolysis. Arch Dermatol 1965; 92:
373–387.
468. Sephel GC, Byers PH, Holbrook KA, Davidson JM. Heterogeneity
of elastin expression in cutis laxa fibroblast strains. J Invest
Dermatol 1989; 93: 147–153.
469. Kitano Y, Nishida K, Okada N et al. Cutis laxa with ultrastructural
abnormalities of elastic fiber. J Am Acad Dermatol 1989; 21:
378–380.
470. Lebwohl MG, Schwartz E, Jacobs L et al. Abnormalities of fibrillin
in acquired cutis laxa. J Am Acad Dermatol 1994; 30: 950–954.

471. Marchase P, Holbrook K, Pinnell SR. A familial cutis laxa
syndrome with ultrastructural abnormalities of collagen and elastin.
J Invest Dermatol 1980; 75: 399–403.
472. Niemi K-M, Anton-Lamprecht I, Virtanen I et al. Fibrillar protein
deposits with tubular substructure in a systemic disease beginning
as cutis laxa. Arch Dermatol 1993; 129: 757–762.
473. Barker SM, Dicken CH. Elastolysis of the earlobes. J Am Acad
Dermatol 1986; 14: 145–147.
474. Dózsa A, Károlyi ZS, Degrell P. Bilateral blepharochalasis. J Eur
Acad Dermatol Venereol 2005; 19: 725–728.
475. Bilenchi R, Poggiali S, Pisani C et al. Floppy eyelid syndrome
associated with obstructive sleep apnoea. Br J Dermatol 2004; 151:
706.
476. Urbán Z, Peyrol S, Plauchu H et al. Elastin gene deletions in
Williams syndrome patients result in altered deposition of elastic
fibers in skin and a subclinical dermal phenotype. Pediatr Dermatol
2000; 17: 12–20.
477. Tam E, Young EJ, Morris CA et al. The common inversion of the
Williams-Beuren syndrome region at 7q11.23 does not cause
clinical symptoms. Am J Med Genet 2008; 146A: 1797–1806.
478. Dridi SM, Ghomrasseni S, Bonnet D et al. Skin elastic fibers in
Williams syndrome. Am J Med Genet 1999; 87: 134–138.
479. El-Charif MA, Mousawi AM, Rubeiz NG, Kibbi A-G.
Pseudoxanthoma elasticum-like papillary dermal elastolysis: a
report of two cases. J Cutan Pathol 1994; 21: 252–255.
480. Jagdeo J, Ng C, Ronchetti IP et al. Fibroelastolytic papulosis. J Am
Acad Dermatol 2004; 51: 958–964.
481. Ramos-Caro FA, Sevigny G, Mullins D. Solitary hyperpigmented
island in a sea of elastosis (anelastosis). Int J Dermatol 1998; 37:
699–700.
482. Lee HS, Song HJ, Hong WK et al. Pseudoxanthoma elasticum-like
papillary dermal elastolysis with solar elastosis. J Eur Acad
Dermatol Venereol 2008; 22: 368–369.
483. Akagi A, Tajima S, Kawada A, Ishibashi A. Coexistence of
pseudoxanthoma elasticum-like papillary dermal elastolysis and
linear focal dermal elastosis. J Am Acad Dermatol 2002; 47:
S189–S192.
484. Hashimoto K, Tye MJ. Upper dermal elastolysis: a comparative
study with mid-dermal elastolysis. J Cutan Pathol 1994; 21:
533–540.
485. Ohnishi Y, Tajima S, Ishibashi A et al. Pseudoxanthoma elasticum-
like papillary dermal elastolysis: report of four Japanese cases and
an immunohistochemical study of elastin and fibrillin-1. Br J
Dermatol 1998; 139: 141–144.
486. Tajima S, Ohnishi Y, Akagi A et al. Elastotic change in the
subpapillary and mid-dermal layers in pseudoxanthoma elasticum-
like papillary dermal elastolysis. Br J Dermatol 2000; 142:
586–588.
487. Shelley WB, Wood MG. Wrinkles due to idiopathic loss of
mid-dermal elastic tissue. Br J Dermatol 1977; 97: 441–445.
488. Brenner W, Gschnait F, Konrad K et al. Non-inflammatory dermal
elastolysis. Br J Dermatol 1978; 99: 335–338.
489. Rudolph RI. Mid dermal elastolysis. J Am Acad Dermatol 1990;
22: 203–206.
490. Rae V, Falanga V. Wrinkling due to middermal elastolysis. Report
of a case and review of the literature. Arch Dermatol 1989; 125:
950–951.
491. Ortel B, Rappersberger K, Konrad K. Middermal elastolysis in an
elderly man with evidence of elastic fiber phagocytosis. Arch
Dermatol 1992; 128: 88–90.
492. Kim JM, Su WPD. Mid dermal elastolysis with wrinkling. Report
of two cases and review of the literature. J Am Acad Dermatol
1992; 26: 169–173.
493. Martyn-Simmons CL, Burrows NP, Ostlere LS. A case of wrinkled
skin. Clin Exp Dermatol 2004; 29: 697–699.
DISORDERS OF ELASTIC TISSUE  •  CHAPTER 12 351.e11
494. Sterling JC, Coleman N, Pye RJ. Mid-dermal elastolysis. Br J
Dermatol 1994; 130: 502–506.
495. Patroi I, Annessi G, Girolomoni G. Mid-dermal elastolysis: A
clinical, histologic, and immunohistochemical study of 11 patients.
J Am Acad Dermatol 2003; 48: 846–851.
496. Martin LK, Kossard S, Murrell DF. Reticular variant of mid-dermal
elastolysis. Am J Dermatopathol 2008; 30: 287–290.
497. Snider RL, Lang PG, Maize JC. The clinical spectrum of mid-
dermal elastolysis and the role of UV light in its pathogenesis. J
Am Acad Dermatol 1993; 28: 938–942.
498. Harmon CB, Su WPD, Gagne EJ et al. Ultrastructural evaluation of
mid-dermal elastolysis. J Cutan Pathol 1994; 21: 233–238.
499. Kirsner RS, Falanga V. Features of an autoimmune process in
mid-dermal elastolysis. J Am Acad Dermatol 1992; 27: 832–834.
500. Yen A, Tschen J, Raimer SS. Mid-dermal elastolysis in an
adolescent subsequent to lesions resembling granuloma annulare. J
Am Acad Dermatol 1997; 37: 870–872.
501. Adams BB, Mutasim DF. Colocalization of granuloma annulare
and mid-dermal elastolysis. J Am Acad Dermatol 2003; 48:
S25–S27.
502. Boyd AS, King LE Jr. Middermal elastolysis in two patients with
lupus erythematosus. Am J Dermatopathol 2001; 23: 136–138.
503. Hur DJ, Raymond GV, Kahler SG et al. A novel MGP mutation in
a consanguineous family: review of the clinical and molecular
characteristics of Keutel syndrome. Am J Med Genet 2005; 135A:
36–40.
504. Marshall J, Heyl T, Weber HW. Post-inflammatory elastolysis and
cutis laxa. S Afr Med J 1966; 40: 1016–1022.
505. Verhagen AR, Woerdeman MJ. Post-inflammatory elastolysis and
cutis laxa. Br J Dermatol 1975; 92: 183–190.
506. Lewis PG, Hood AF, Barnett NK, Holbrook KA. Postinflammatory
elastolysis and cutis laxa. J Am Acad Dermatol 1990; 22: 40–48.
507. Gambichler T, Breuckmann F, Kreuter A et al.
Immunohistochemical investigation of mid-dermal elastolysis. Clin
Exp Dermatol 2004; 29: 192–195.
508. Neri I, Patrizi A, Fanti P et al. Mid-dermal elastolysis: a
pathological and ultrastructural study of five cases. J Cutan Pathol
1996; 23: 165–169.
509. Brod BA, Rabkin M, Rhodes AR, Jegasothy BV. Mid-dermal
elastolysis with inflammation. J Am Acad Dermatol 1992; 26:
882–884.
510. Bannister MJ, Rubel DM, Kossard S. Mid-dermal
elastophagocytosis presenting as a persistent reticulate erythema.
Australas J Dermatol 2001; 42: 50–54.
511. Lewis KG, Dill SW, Wilkel CS, Robinson-Botsom L. Mid-dermal
elastolysis preceded by acute neutrophilic dermatosis. J Cutan
Pathol 2004; 31: 72–76.
512. Maghraoui S, Grossin M, Crickx B et al. Mid dermal elastolysis.
Report of a case with a predominant perifollicular pattern. J Am
Acad Dermatol 1992; 26: 490–492.
513. Menkes JH, Alter M, Steigleder GK et al. A sex-linked recessive
disorder with retardation of growth, peculiar hair, and focal
cerebral and cerebellar degeneration. Pediatrics 1962; 29: 764–779.
514. Hockey A, Masters CL. Menkes’ kinky (steely) hair disease.
Australas J Dermatol 1977; 18: 77–80.
515. Hart DB. Menkes’ syndrome: an updated review. J Am Acad
Dermatol 1983; 9: 145–152.
516. Martins C, Gonçalves C, Moreno A et al. Menkes’ kinky hair
syndrome: ultrastructural cutaneous alterations of the elastic fibers.
Pediatr Dermatol 1997; 14: 347–350.
517. de Bie P, Muller P, Wijmenga C, Klomp LWJ. Molecular
pathogenesis of Wilson and Menkes disease: correlation of
mutations with molecular defects and disease phenotypes. J Med
Genet 2007; 44: 673–688.
351.e12 SECTION 4  •  the dermis and subcutis
518. Procopis P, Camakaris J, Danks DM. A mild form of Menkes’
steely hair syndrome. J Pediatr 1981; 98: 97–99.
519. Danks DM, Stevens BJ, Campbell PE et al. Menkes’ kinky hair
syndrome. Lancet 1972; 1: 1100–1102.
520. Oakes BW, Danks DM, Campbell PE. Human copper deficiency:
ultrastructural studies of the aorta and skin in a child with Menkes’
syndrome. Exp Mol Pathol 1976; 25: 82–98.
521. Royce PM, Camakaris J, Danks DM. Reduced lysyl oxidase
activity in skin fibroblasts from patients with Menkes’ syndrome.
Biochem J 1980; 192: 579–586.
522. Waldstein G, Mierau G, Ahmad R et al. Fragile X syndrome: skin
elastin abnormalities. Birth Defects 1987; 23: 103–114.
523. Thyagarajan B, Bower M, Berger M et al. A novel polymorphism
in the FMR1 gene. Implications for clinical testing of fragile X
syndrome. Arch Pathol Lab Med 2008; 132: 95–98.
524. Willemsen R, Olmer R, Otero YDD, Oostra BA. Twin sisters,
monozygotic with the fragile X mutation, but with a different
phenotype. J Med Genet 2000; 37: 603–604.
525. Moore SJ, Strain L, Cole GF et al. Fragile X syndrome with FMR1
and FMR2 deletion. J Med Genet 1999; 36: 565–566.
526. Nolin SL, Ding X-H, Houck GE et al. Fragile X full mutation
alleles composed of few alleles. Implications for CGG repeat
expansion. Am J Med Genet 2008; 146A: 60–65.
527. Coffee B, Ikeda M, Budimirovic DB et al. Mosaic FMR1 deletion
causes fragile X syndrome and can lead to molecular misdiagnosis:
a case report and review of the literature. Am J Med Genet 2008;
146A: 1358–1367.
528. Torrioli MG, Vernacotola S, Peruzzi L et al. A double-blind,
parallel, multicenter comparison of L-acetylcarnitine with placebo
on the attention deficit hyperactivity disorder in fragile X-syndrome
boys. Am J Med Genet 2008; 146A: 803–812.
529. Boente MDC, Winik BC, Asial RA. Wrinkly skin syndrome:
ultrastructural alterations of the elastic fibers. Pediatr Dermatol
1999; 16: 113–117.
530. Hamamy H, Masri A, Ajlouni K. Wrinkly skin syndrome. Clin Exp
Dermatol 2005; 30: 590–592.
531. Gupta N, Phadke SR. Cutis laxa type II and wrinkly skin
syndrome: distinct phenotypes. Pediatr Dermatol 2006; 23:
225–230.
532. Nanda A, Alsaleh QA, Al-Sabah H et al. Gerodermia
osteodysplastica/wrinkly skin syndrome: report of three patients
and brief review of the literature. Pediatr Dermatol 2008; 25:
66–71.
533. Yanagihara M, Kato F, Mori S. Extra and intracellular digestion of
elastic fibers by macrophages in annular elastolytic giant cell
granuloma. An ultrastructural study. J Cutan Pathol 1987; 14:
303–308.
534. Boneschi V, Brambilla L, Fossati S et al. Annular elastolytic giant
cell granuloma. Am J Dermatopathol 1988; 10: 224–228.
535. LeBoit PE, Zackheim HS, White CR Jr. Granulomatous variants of
cutaneous T-cell lymphoma. The histopathology of granulomatous
mycosis fungoides and granulomatous slack skin. Am J
Dermatopathol 1988; 12: 83–95.
536. Alessi E, Crosti C, Sala F. Unusual case of granulomatous
dermohypodermitis with giant cells and elastophagocytosis.
Dermatologica 1986; 172: 218–221.
537. Balus L, Bassetti F, Gentili G. Granulomatous slack skin. Arch
Dermatol 1985; 121: 250–252.
538. Convit J, Kerdel F, Goihman M et al. Progressive, atrophying,
chronic granulomatous dermohypodermitis. Arch Dermatol 1973;
107: 271–274.
539. LeBoit PE, Beckstead JH, Bond B et al. Granulomatous slack skin:
clonal rearrangement of the T-cell receptor β gene is evidence for
the lymphoproliferative nature of a cutaneous elastolytic disorder. J
Invest Dermatol 1987; 89: 183–186.
540. Belousova IE, Nikonova SM, Sima R, Kazakov DV.
Granulomatous slack skin with clonal T-cell receptor-γ gene
rearrangement in skin and lymph node. Br J Dermatol 2007; 157:
405–407.
541. Ikonomou IM, Aamot HV, Heim S et al. Granulomatous slack skin
with a translocation t(3;9)(q12;p24). Am J Surg Pathol 2007; 31:
803–806.
542. Matsuoka LY, Wortsman J, Uitto J et al. Altered skin elastic fibers
in hypothyroid myxedema and pretibial myxedema. Arch Intern
Med 1985; 145: 117–121.
543. Helbling I, Tucker SC, Chalmers RJG. Acquired crateriform
hyperkeratotic papules of the lower limbs: an unusual variant of
acrokeratoelastoidosis of Costa. Clin Exp Dermatol 2001; 26:
263–265.
544. Fiallo P, Pesce C, Brusasco A, Nunzi E. Acrokeratoelastoidosis of
Costa: a primary disease of the elastic tissue? J Cutan Pathol 1998;
25: 580–582.
545. Bogle MA, Hwang LY, Tschen JA. Acrokeratoelastoidosis. J Am
Acad Dermatol 2002; 47: 448–451.
546. Hu W, Cook TF, Vicki GJ, Glaser DA. Acrokeratoelastoidosis.
Pediatr Dermatol 2002; 19: 320–322.
547. Tsai S, Kageyama N, Warthan M, Cockerell CJ.
Acrokeratoelastoidosis. Int J Dermatol 2005; 44: 406–407.
548. Tajima S, Tanaka N, Ishibashi A, Suzuki K. A variant of
acrokeratoelastoidosis in systemic scleroderma: Report of 7 cases. J
Am Acad Dermatol 2002; 46: 767–770.
Variable or minor elastic tissue changes
549. Roth SI, Schedewie HK, Herzberg VK et al. Cutaneous
manifestations of leprechaunism. Arch Dermatol 1981; 117:
531–535.
550. Patterson JH, Watkins WL. Leprechaunism in a male infant. J
Pediatr 1962; 60: 730–739.
551. Bauer EA, Uitto J, Tan EML, Holbrook KA. Werner’s syndrome.
Evidence for preferential regional expression of a generalized
mesenchymal cell defect. Arch Dermatol 1988; 124: 90–101.
552. Venencie PY, Powell FC, Winkelmann RK. Acrogeria with
perforating elastoma and bony abnormalities. Acta Derm Venereol
1984; 64: 348–351.
553. Beauregard S, Gilchrest BA. Syndromes of premature aging.
Dermatol Clin 1987; 5: 109–121.
554. Shelley WB, Wood MG. Unilateral wrinkles. Manifestation of
unilateral elastic tissue defect. Arch Dermatol 1974; 110: 775–778.
555. Koh JS, Kang H, Choi SW, Kim HO. Cigarette smoking associated
with premature facial wrinkling: image analysis of facial skin
replicas. Int J Dermatol 2002; 41: 21–27.
556. Aizen E, Gilhar A. Smoking effect on skin wrinkling in the aged
population. Int J Dermatol 2001; 40: 431–433.
557. Just M, Ribera M, Monsó E et al. Effect of smoking on skin elastic
fibres: morphometric and immunohistochemical analysis. Br J
Dermatol 2007; 156: 85–91.
558. Chung JH, Lee SH, Youn CS et al. Cutaneous photodamage in
Koreans. Influence of sex, sun exposure, smoking, and skin color.
Arch Dermatol 2001; 137: 1043–1051.
559. Dunn LB, Damesyn M, Moore AA et al. Does estrogen prevent
skin aging? Arch Dermatol 1997; 133: 339–342.
560. Carruthers J, Carruthers A. Mad cows, prions, and wrinkles. Arch
Dermatol 2002; 138: 667–670.
561. Kligman AM, Zheng P, Lavker RM. The anatomy and pathogenesis
of wrinkles. Br J Dermatol 1985; 113: 37–42.
562. Wright ET, Shellow LR. The histopathology of wrinkles. Journal of
the Society of Cosmetic Chemists 1965; 24: 81.
563. Tsuji T. Ultrastructure of deep wrinkles in the elderly. J Cutan
Pathol 1987; 14: 158–164.

564. Tsuji T, Yorifuji T, Hayashi Y, Hamada T. Light and scanning
electron microscopic studies on wrinkles in aged persons’ skin. Br
J Dermatol 1986; 114: 329–335.
565. Contet-Audonneau JL, Jeanmaire C, Pauly G. A histological study
of human wrinkle structures: comparison between sun-exposed
areas of the face, with or without wrinkles, and sun-protected areas.
Br J Dermatol 1999; 140: 1038–1047.
566. Pyeritz RE, McKusick VA. The Marfan syndrome: diagnosis and
management. N Engl J Med 1979; 300: 772–777.
567. Faivre L, Collod-Beroud G, Loeys BL et al. Effect of mutation type
and location on clinical outcome in 1,013 probands with Marfan
syndrome or related phenotypes and FBN1 mutations: an
international study. Am J Hum Genet 2007; 81: 454–466.
DISORDERS OF ELASTIC TISSUE  •  CHAPTER 12 351.e13
568. Tsuji T. Marfan syndrome: demonstration of abnormal elastic fibers
in skin. J Cutan Pathol 1986; 13: 144–153.
569. Berteretche M-V, Hornebeck W, Pellat B et al. Histomorphometric
parameters and susceptibility to neutrophil elastase degradation of
skin elastic fibres from healthy individuals and patients with
Marfan syndrome, Ehlers–Danlos type IV, and pseudoxanthoma
elasticum. Br J Dermatol 1995; 133: 836–841.
570. Pinkus H, Keech MK, Mehregan AH. Histopathology of striae
distensae with special reference to striae and wound healing in the
Marfan syndrome. J Invest Dermatol 1966; 46: 283–292.
571. Sayers CP, Goltz RW, Mottaz J. Pulmonary elastic tissue in
generalized elastolysis (cutis laxa) and Marfan’s syndrome. A light
and electron microscopic study. J Invest Dermatol 1975; 65:
451–457.