GASTROENTEROLOGY 2003;124:1595–1614
Skin Signs of Gastrointestinal Disease
IRWIN M. BRAVERMAN
Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut
wo reference points are used in this survey of the
T skin signs associated with gastrointestinal diseases:
major signs and symptoms that confront the clinician on
a daily basis and specific disorders that present with a
variety of signs and symptoms related to gastrointestinal
disease. The cutaneous signs and the manner in which
they evolve are described in detail where appropriate for
easier identification. There is often an association be-
tween involvement of the skin and joints in clinical
medicine, and this is especially true in gastrointestinal
disorders. For that reason the skin and the joints are
discussed together when they are important for diagno-
sis.
Gastrointestinal Hemorrhage
In some patients with gastrointestinal hemor-
rhage, the astute clinician makes the underlying diagno-
sis by finding characteristic skin lesions, even though the
site of the bleeding still may not be pinpointed.
Hereditary hemorrhagic telangiectasia (HHT, Rendu-
Osler-Weber disease) is perhaps the most well-known
dermatologic entity associated with melena, but the di-
agnostic lesions may be missed if the patient is anemic.
Hence, all patients with melena and anemia should be
examined carefully for telangiectasia after adequate blood
replacement. For instance, a 65-year-old black man had
been admitted 4 times in 4 years to the Yale-New Haven
Hospital for anemia and melena. During the fourth
hospitalization, tiny red spots were seen on the patient’s
lips after he had been given a transfusion (Figure 1).
Gastroscopy revealed identical telangiectases on the gas-
tric mucosa.
In HHT, the vascular lesions develop primarily on the
lips (Figure 2), nasal mucosa, tongue, palms, and palate;
but they also can be found under the nails, on the soles
of the feet, and even on the tympanic membrane. The
true lesion of HHT, usually dark red, tends to be slightly
elevated with an ill-defined border and one or more legs
radiating from an eccentrically placed punctum. This is
shown easily by stretching the lip (Figure 2). Although
some lesions in HHT can be flat with sharp borders, the
majority conform to the earlier description.
Nose bleeds occur in 95% of patients by age 20 years;
it is uncommon for them to appear after this age.1
Visible telangiectases appear on the skin and mucous
membranes 5–20 years after the epistaxes begin and the
disease usually declares itself by age 40.2 Gastrointestinal
bleeding develops in the fourth and fifth decades and is
present in 20% to 45% of patients.3
Multiple pulmonary arteriovenous fistulae and malfor-
mations (AVM) are present in approximately 20% of
patients and frequently produce coin lesions on chest
radiographs. Clubbing, cyanosis, and polycythemia can
be associated with extensive fistula formation; and these
signs may be the sole or major manifestations of HHT.6
Cerebral abscesses and paradoxic emboli with stroke are
common complications of pulmonary AVM and may be
one of the presenting manifestations of the disease.4,5
AVM also can be present in the colon and stomach. In
the liver, the vascular malformations are surrounded by
broad fibrous septa, a picture that has been misinter-
preted as cirrhosis by some investigators.5,6 Rarely, these
vascular fistulae may be accompanied by significant left-
to-right shunting with resulting high output failure.7
von Willebrand’s disease may coexist with HHT.8
Patients with von Willebrand’s disease who have recur-
rent bleeding, especially from the gastrointestinal tract,
ought to be examined for the presence of telangiectases of
HHT. Similarly, in a patient with melena and apparent
absence of telangiectases, the presence of AVM or cere-
bral abscesses should prompt one to consider the presence
of HHT.
HHT is inherited as an autosomal-dominant disease.
Family history is positive in about 80% of cases and
prevalence is estimated to range from 1:40,000 to
1:100,000.9 The gene for Osler’s disease has been located
on chromosome 9q3 and has been shown to be a muta-
tion of endoglin, a transforming growth factor ␤– bind-
ing protein of endothelial cells.13
Abbreviations used in this paper: AVM, arteriovenous fistulae and
malformations; HHT, hereditary hemorrhagic telangiectasia.
© 2003 by the American Gastroenterological Association
0016-5085/03/$30.00
doi:10.1016/S0016-5085(03)00327-5
1596 IRWIN M. BRAVERMAN
Figure 1. Telangiectases appeared after the patient had been given a
transfusion.
Cavernous hemangiomas in the skin may be associated
with similar lesions in the bowel that are responsible for
the gastrointestinal bleeding. In some cases the cutane-
ous cavernous hemangiomas are blue, soft, and compress-
ible and have been labeled blue rubber-bleb nevi.
The main complication of Kaposi’s hemorrhagic sar-
coma is gastrointestinal bleeding. Usually, the cause of
the melena is readily apparent because cutaneous lesions
are present. However, in the patient shown in Figure 3,
gastrointestinal bleeding had been present for 1–2 years
before the pathognomonic skin lesions developed. The
lesions of Kaposi’s sarcoma can arise anywhere in the
alimentary canal, and often can be seen in the mouth
(Figure 4). Kaposi’s sarcoma needs to be considered in
men of Italian or Eastern European Jewish backgrounds
who are older than 65 years, as well as in those with
acquired immune deficiency syndrome.
Necrotizing angiitis of the small blood vessels (hyper-
sensitivity angiitis, leukocytoclastic vasculitis) involves
Figure 2. HHT. Telangiectases composed of branching vessels that
can be made more visible by stretching the lip.
GASTROENTEROLOGY Vol. 124, No. 6
Figure 3. Kaposi sarcoma. Characteristic plaques on sole. Typical
nodules on legs and ankle.
the gastrointestinal tract and produces melena, diarrhea,
cramps, and intussusception. The characteristic accom-
panying skin lesion is a palpable purpuric spot that
occasionally may ulcerate (Figure 5). The eruption can be
florid or subtle. Its extent or severity cannot be correlated
with the intensity of the visceral involvement. Gastroin-
testinal bleeding is a major feature of this immune
complex disorder in children, in whom it is called Schoen-
lein-Henoch purpura.
Major gastrointestinal bleeding is also one of the most
important complications of pseudoxanthoma elasti-
cum.10 The diagnostic yellow papules are found on the
neck and in the flexures (Figure 6). The abnormal pro-
Figure 4. Kaposi sarcoma. Involvement in the mouth.
May 2003
Figure 5. Leukocytoclastic vasculitis. Palpable purpura producing
oval lesions and polycyclic lesions through confluence.
liferation of elastic tissue responsible for the cutaneous
lesions also develops in the retina and produces angioid
streaks. Hemorrhage occurs through mucosal vessels in
which microaneurysms have formed secondary to abnor-
malities of the elastic tissue in the vascular wall.
Chronic blood loss can be produced by neurofibroma-
tosis when it affects the gastrointestinal tract.
Gastrointestinal Polyposis
Gardner’s syndrome is a dominantly transmitted
disease characterized by premalignant colonic and rectal
polyps and associated with cutaneous, osseous, and dental
Figure 6. Pseudoxanthoma elasticum. Yellow papules and plaques
on the neck simulating plucked chicken skin.
SKIN SIGNS 1597
lesions.11 The most frequent cutaneous signs are large
disfiguring sebaceous cysts found primarily on the face;
they also may appear on the trunk, scrotum, and extrem-
ities. Banal fibromas and desmoids, which are locally
invasive fibrous tissue neoplasms that may arise in scars,
also may be present.
Disfiguring cutaneous lumps also can be produced by
the osseous lesions: osteomatosis of the cranium, maxilla,
mandible, and sinuses. Osteomatosis may be detectable
only by radiograph examination. The dental abnormali-
ties include odontomas, supernumerary and unerupted
teeth, and dentigerous cysts. The long bones are affected
much less frequently.
The sebaceous cysts develop at birth or in early child-
hood. They do not continue to increase in size indefi-
nitely. Fortunately, the cysts are evident for many years
before the polyps develop. Half of the affected individ-
uals will have polyps by the age of 20, when malignant
degeneration begins to develop. Polyposis is rare in chil-
dren. About 50% of persons with Gardner’s syndrome
develop carcinomatous polyps of the colon.11 However,
duodenal, ileal, and gastric polyps also may develop in
Gardner’s syndrome. In a few patients, carcinomas have
developed in polyps arising in the duodenum and in the
area of the ampulla of Vater.
There have been no definitive skin markers identified
for recognizing familial polyposis, except perhaps for a
reticulated perineal hyperpigmentation observed in one
of our patients (Figure 7) and also described by Hol-
länder.12 In some cases mandibular osteomatosis can be
present. The association of multiple sebaceous cysts and
premalignant polyposis of the colon—termed Oldfield’s
syndrome—is yet another recognized disorder.13 The prag-
matic approach had been to study any patient with a
family history of extensive facial sebaceous cysts for
evidence of colonic polyposis.
Figure 7. Reticulated pigmentation on perineum of woman with
familial polyposis. Reprinted with permission.31
1598 IRWIN M. BRAVERMAN
A retinal lesion diagnostic for this group of disorders
has been discovered. Bilateral congenital hypertrophy of
the retinal pigment epithelium is present in up to 90%
of affected persons with Gardner’s syndrome and familial
polyposis and has been linked directly to the mutations
in the APC gene. In general, more than 4 such retinal
lesions have to be present for them to be a significant
sign (Figure 8).14 Unilateral sporadic congenital hyper-
trophy of the retinal pigment epithelium also occurs, but
it is not an indicator of familial polyposis. In addition,
bilateral retinal hyperpigmented lesions that have a
grouped appearance (bear tracks) also are not indicators
of this disorder.15 Congenital hypertrophy of the retinal
pigment epithelium is produced when the mutation in
the APC gene occurs after exon 9 in the coding sequence,
but is not present when it occurs before exon 9. The
range of phenotypic expression of this retinal lesion in
different individuals is believed to result from different
allelic manifestations of APC mutations.
Different clusters of APC mutations may account for
the variation in phenotypic expression of extracolonic
manifestations of Gardner’s syndrome and familial pol-
yposis. For example, some cases of Turcot’s syndrome
(intestinal polyposis associated with malignant brain tu-
mors) are associated with mutations in the APC gene.16
Peutz-Jeghers syndrome is a dominantly transmitted
disorder characterized by distinctive pigmentation and
intestinal polyps.17,18 In at least 90% of the cases, the
small intestine is involved, but in 50% of the patients,
the stomach, colon, and rectum also are affected. Poly-
posis of the nasal mucosa, bladder, bronchus, and appen-
dix also may occur. The pigmented spots, noted at birth
or in early childhood, are flat and irregular and vary in
size from 1 to 12 mm. They are black, brown, or blue;
the intensity of the color may be light or dark. The sites
of predilection are the vermilion borders of the lips and
Figure 8. Congenital hypertrophy of the retinal pigment epithelium.
Two oval black lesions are present. Reprinted with permission.16
GASTROENTEROLOGY Vol. 124, No. 6
Figure 9. Peutz-Jeghers syndrome. Typical perioral pigmentation.
the oral mucosa (Figure 9); the skin of the perioral,
perianal, and periorbital areas; the dorsal aspects of the
fingers and toes, especially over the joints; and the palms
and soles. Pigmented spots also may develop on the
elbows. The facial pigmentation can fade and eventually
disappear with age, but the pigmentation on the buccal
mucosa, tongue, and palate remains. This mucosal pig-
mentation is indistinguishable from that often seen in
black individuals and in patients with adrenal insuffi-
ciency. Pigmented papillomas on the buccal mucosa are
an uncommon manifestation.19 Less common sites of
increased pigmentation are the palms and the rectal
mucosa. Dark linear bands on the nails, identical to those
produced by junctional nevi in the nail matrix, have been
observed.20 Clubbing is a minor feature of the disease.
Although the complete syndrome exhibits pigmenta-
tion and polyposis, either feature can exist alone. The
prevalence of patients with only pigmented spots is not
known and probably varies from pedigree to pedigree. In
one family, 10 individuals (half the family members)
ranging in age from 8 to 46 years had only pigmented
macules.21 An identical pattern of pigmentation without
any systemic disease has been called the Laugier-Hun-
ziker syndrome. Although the pigmentation appears at
any time after puberty, there are no compelling data to
indicate that this syndrome is different from Peutz-
Jeghers syndrome without systemic involvement.22
Approximately 6% of patients with Peutz-Jeghers
syndrome appear to be at risk for developing gastroin-
testinal cancer. In these patients, the mucosa of the
stomach, duodenum, colon, and, less commonly, the
ileum often is described as showing micropolyposis when
gross polyps are not present. The gastrointestinal cancers
have arisen from areas of micropolyposis.23 In addition,
Giardiello et al.24 pointed out that these patients are at
increased risk for cancers of the pancreas, breast, lung,
ovary, endometrium, and endocervix.
May 2003
Cronkhite and Canada25 and Johnson et al.26 described
3 middle-aged women who abruptly developed abdom-
inal cramping, diarrhea, and weight loss, in association
with loss of hair from the scalp, eyebrows, trunk, axillae,
and pubic area (Cronkhite-Canada syndrome). Diarrhea
was sometimes accompanied by melena. Hyperpigmen-
tation was present on the hands, arms, and face, and in
body folds and palmar creases. One of the women devel-
oped buccal pigmentation. In some, the nails were shed
and in others, dystrophic changes or onycholysis devel-
oped. Benign adenomatous polyposis of the stomach,
ileum, colon, and rectum was present. In most cases,
histologic examinations revealed juvenile polyps with
cystic dilatation of glands with prominent inflammation,
but in the remainder a mixture of juvenile and adeno-
matous polyps was present. Significant malabsorption
could not be shown by laboratory tests. There have been
over 120 cases reported in the world literature, with 80
cases originating in Japan.27 Loss of taste for salty or
sweet substances has been a common symptom in Japa-
nese patients. In 25% dry mouth was present. The
mortality rate from this disorder is about 25%. The
disease may be relentless with death in less than 2 years,
and sometimes, within months. Malignant transforma-
tion of a polyp or a carcinoma in the colon and rectum
has developed in about 10% of patients.27 In those cases
with improvement, whether spontaneous or induced by
steroids or antiplasmin drugs, the nail dystrophies and
hair loss improved as the gastrointestinal symptoms im-
proved. The serum proteins and electrolyte levels also
returned toward normal as did the loss of taste and dry
mouth.27 Polyps decreased in size. However, the etiology
of this disorder still remains a mystery.
In Torre’s syndrome, multiple low-grade carcinomas,
primarily of the gastrointestinal and genitourinary tracts,
arise over intervals of up to 30 years in association with
multiple cutaneous sebaceous gland neoplasms.28 This
entity is believed to be inherited in an autosomal-dom-
inant fashion. The majority of patients begin to develop
their malignancies in the fourth and fifth decades and
have a positive family history for multiple low-grade
carcinomas in the same sites. The sebaceous gland tu-
mors are found chiefly on the trunk, and less often on the
face, and include adenomas, carcinomas, and, less fre-
quently, basal cell tumors with sebaceous differentiation.
Clinically they present as yellowish or violaceous nodules
that may have an ulcerated surface. These tumors tend to
remain localized in the skin without any significantly
aggressive local growth.
In the majority of patients, the value of this skin sign
is not so much an early warning system for the first
SKIN SIGNS 1599
gastrointestinal cancer as it is an alert to anticipate the
possible development of additional gastrointestinal neo-
plasms. Because sebaceous gland tumors are rare, their
appearance should prompt the physician to consider the
possibility of undiagnosed Torre’s syndrome in an oth-
erwise healthy person. The biologic course and times of
appearance of the multiple low-grade gastrointestinal
cancers in this entity are identical to those seen in the
cancer family syndrome. Lynch et al.29 have presented
evidence that Torre’s syndrome may in fact represent the
full phenotypic expression of the gene responsible for the
cancer family syndrome.
Disturbances in Gastrointestinal
Motility
Although these gastrointestinal disturbances can
occur in systemic scleroderma without cutaneous sclero-
sis, usually there are other telltale signs in the skin;
cuticular telangiectasia, telangiectatic mats, and vascular
spots resembling those of HHT. The appearance of these
telangiectases in association with Raynaud’s phenome-
non are as indicative of scleroderma as is sclerosis of the
skin. These signs should be looked for in patients with
unexplained dysphagia or malabsorption. The telangiec-
tatic mat is a pink-to-red, well-marginated macule that
ranges in size from 1 to 6 mm and occurs most often on
the face, palms, and dorsa of the hands. These lesions also
can be found on the lips, tongue, palate, and buccal
mucosa. The distinctive feature of these spots is their
square, rectangular, polyangular, oval, or arciform shape
(Figures 10 and 11). They may look like flattened cherry
angiomas. Closely packed fine vessels can sometimes be
seen in these macules when they are very large. Ninety
percent of patients with the calcinosis, Raynaud’s phe-
nomenon, sclerodactyly, and telangiectasia (CRST) vari-
Figure 10. CRST syndrome. Telangiectatic mats on lips and tongue.
Branching vessels are not seen in these lesions.
1600 IRWIN M. BRAVERMAN GASTROENTEROLOGY Vol. 124, No. 6

Figure 11. CRST syndrome. Telangiectatic mats have discrete bor-

ders and varying shapes.
Figure 12. Dermatomyositis. Cuticular erythema with discrete linear
telangiectases and flat-topped papules over joints (Gottron’s sign).

ant of scleroderma will have such lesions, but 10% have

telangiectasia indistinguishable from and in the identical erythematosus and dermatomyositis, there is usually an
distribution as those seen in HHT. However, bleeding associated periungual erythema (Figure 12), but in
does not occur from them and there is no family history scleroderma the dilated vessels develop on normally col-
of similar lesions. Stress is placed on these fine distinc- ored skin. Although these dilated vessels have been stud-
tions between the telangiectases of scleroderma and those ied extensively by capillary microscopy, their detection is
of HHT because of their extremely important diagnostic easy with the naked eye. Cuticular telangiectasia occurs
significance. When the red telangiectatic mat of sclero- in at least two thirds of the patients with 1 of the 3
derma is stretched, it becomes fainter and pink; radiating connective tissue diseases, in 5% of the patients with
legs are not present. rheumatoid arthritis, and in an occasional patient with
Aperistalsis of the esophagus has been correlated with leukocytoclastic angiitis. Only twice has the author
the presence of Raynaud’s phenomenon both in otherwise found such lesions in a healthy person without evidence
healthy individuals and in those with other collagen of an underlying disorder. Large numbers of telangiec-
disorders.30 tatic vessels may develop on the periungual tissue of
Dysphagia caused by dysfunction of skeletal muscle in every nail, or only a few may appear at the base of 1 or
the pharynx and upper third of the esophagus is a feature 2 nails; however, the significance is the same. This sign
of dermatomyositis. This disorder is recognized by the is particularly helpful in diagnosing connective tissue
typical distribution of its rash. Patients have a diffuse diseases with gastrointestinal signs and symptoms before
erythematous to violaceous color with or without slight
scale over sun-exposed areas on the upper chest and back,
as well as along the hairline of the scalp and over the
knees and elbows. Violaceous flat-topped papules de-
velop over the dorsal interphalangeal joints in about one
third of the patients with dermatomyositis. The papules
may evolve into atrophic hypopigmented macules, and
the fine wiry telangiectasia, which may have been diffi-
cult to see in the papules, becomes obvious. These early
and late lesions, designated Gottron’s sign, are pathogno-
monic of dermatomyositis (Figure 12).
A pathognomonic sign of connective tissue disease,
such as lupus erythematosus, dermatomyositis, and
scleroderma, is cuticular telangiectasia (Figure 13). Lin-
ear wiry vessels that are perpendicular to the base of the
nail overlie the posterior nail fold. They are usually Figure 13. Scleroderma. Linear telangiectasia is present on the nail-
bright red, but they appear black if thrombosed. In lupus fold without erythema.
May 2003
the other diagnostic features of lupus erythematosus,
dermatomyositis, and scleroderma develop.31
The Paterson-Brown-Kelly-Plummer-Vinson syn-
drome also is associated with dysphagia. This disorder
seems to be more prevalent in Great Britain than in the
United States.32,33 This disease almost exclusively affects
women and is characterized by angular stomatitis, atro-
phic tongue, and brittle nails that are sometimes spoon
shaped (koilonychia). Iron deficiency with or without
anemia is present in most patients. From those who are
normal, one can usually elicit a previous history of iron
deficiency and anemia that has been corrected. Dysphagia
is believed to be caused by spasm that is secondary to
iron deficiency. Radiologically, a postcricoid esophageal
web (a fold of normal mucosa) appears with swallowing.
When the disorder continues for a long time, carcinoma
may develop in the postcricoid area. Administration of
iron relieves the dysphagia, causes the web to disappear,
and cures the mucocutaneous lesions.
Specific Disorders
Epidermolysis Bullosa
Epidermolysis bullosa is a genetically determined
group of bullous diseases in which minor trauma to the
skin results in massive blisters (Figure 14). The skin
heals with scarring. In some children, the esophagus
behaves in an identical way. Dysphagia secondary to
strictures eventually results. The anal mucosa also may
react to injury in the same fashion as the skin.34 Twenty-
one patients have developed squamous cell carcinomas,
usually with metastases, in the areas of scarring. In 5, the
cancers arose on the tongue and in the pharynx, esoph-
agus, stomach, or perianal area. In the rest, the carcino-
mas arose in areas of skin involvement.35
Figure 14. Epidermolysis bullosa. Characteristic appearance of bul-
lae. Reprinted with permission.31
SKIN SIGNS 1601
Figure 15. Urticaria pigmentosa. Reddish-brown freckle-like lesions
are characteristic of the adult form of mastocytosis.
Mastocytosis
Patients with urticaria pigmentosa (cutaneous or
systemic mastocytosis) seek medical attention because of
urticaria. The itchy hives often develop after a hot bath,
vigorous rubbing with a towel, or pressure against the
skin. Close inspection reveals brown to reddish-brown
freckle-like macules on an urticarial base. The lesions are
composed of increased numbers of mast cells in the
dermis underlying a hyperpigmented epidermis (Figure
15). When stroked or subjected to heat, the mast cells
degranulate and release histamine, thereby producing
localized urticaria and pruritus (Darier’s sign).
Urticaria pigmentosa in children is almost always a
purely cutaneous disease and usually resolves spontane-
ously. The eruption in children is composed of light
brown, yellow-brown, or red-brown macules and pap-
ules. Solitary mastocytomas as large as 6 cm may de-
velop.
Thirty percent to 50% of adult patients with urticaria
pigmentosa have some evidence of systemic involve-
ment.36 Collections of mast cells may be found in the
bones, gastrointestinal tract, lungs, liver, spleen, and
bone marrow. Involvement of the gastrointestinal tract
can be detected by barium studies. Degranulation of the
enormous pool of mast cells can be produced in some
patients by ingestion of codeine or alcohol or by injection
of polymyxin B, with the resultant symptoms of head-
ache, flushing, palpitations, diarrhea, and pruritus. The
liver and spleen may become enlarged. The accumulation
of mast cells in the bones may produce either osteoscle-
rotic or osteolytic shadows on radiographs that fre-
quently are misdiagnosed as bone cancer when the un-
derlying illness is not recognized.
Uncommonly, myelodysplastic states may occur and
progress to chronic myelocytic or chronic myelomono-
1602 IRWIN M. BRAVERMAN
cytic leukemias.37 Secondary acute leukemias of any type
may develop. Mast cell leukemias are very rare. In child-
hood mastocytosis, malignancies do occur, but are rare.
Acanthosis Nigricans
Acanthosis nigricans, which is probably the most
well-known cutaneous marker of internal malignancy,
occurs more commonly in a variety of situations unre-
lated to neoplasia: as a congenital or familial lesion; in
association with puberty, endocrine disease, and excessive
weight gain; and with a number of congenital anoma-
lies.38 The terms benign and malignant acanthosis nigricans
refer to the associated disorders and not to the dermato-
sis, which never undergoes malignant change. Other
terms applied to this entity include juvenile, benign, and
pseudoacanthosis nigricans,when it is not accompanied by
cancer.
The clinical and histologic features of acanthosis nigri-
cans are identical in all the disorders with which it is
associated. Acanthosis nigricans chiefly affects the flex-
ures: neck, axillae, groin, and antecubital spaces (Figure
16). With extensive involvement, lesions can be found on
the areolae, around the umbilicus, and in the perineal
area. It may take the form of extensive papillomatous
changes on the gums, buccal mucosa, tongue, palate, and
lips with papillary masses, presumed to be part of the
same process, shown by radiograph in the lower pharynx
and esophagus.39 Hyperkeratosis of the palms and of the
skin over the elbows, knees, and interphalangeal joints
can occur as well. When the palms are affected, the skin
not only becomes somewhat thickened, but the dermato-
glyphics over the entire surface become so exaggerated
that they produce a honeycomb or rugose appearance
(Figure 17).
In acanthosis nigricans, the skin is thrown up into
folds and a papillomatous appearance is produced micro-
Figure 16. Acanthosis nigricans.
GASTROENTEROLOGY Vol. 124, No. 6
Figure 17. Acanthosis nigricans involving the palms. A honeycomb
appearance is produced by the thickened skin.
scopically. Hyperpigmentation varies from brown to
black. In its mildest form, acanthosis nigricans looks like
exaggerated skin lines and often is thought by patients
and their families to be dirty skin. As the dermatosis
becomes more severe, a verrucose, velvety, and at times
shaggy appearance develops, and gross papillomas can be
found. When acanthosis nigricans is associated with can-
cer, it may spread as the neoplasm disseminates and may
regress temporarily when the malignancy is resected.
Acanthosis nigricans associated with cancer is a disease
of adults. In 80% to 90% of all instances, the cancer is
abdominal; in 60%, the cancer arises in the stomach.
Other associated carcinomas have included those of the
uterus, liver, esophagus, pancreas, prostate, ovary, kid-
ney, colon, and rectum. Almost all cancers accompanying
this dermatosis have been adenocarcinomas. Uncom-
monly, there have been associated instances of choriocar-
cinoma, non-Hodgkin’s lymphoma, and Hodgkin’s dis-
ease. In about 60% of cases, the dermatosis and the
cancer appeared at the same time.40 When the dermatosis
preceded the cancer, the interval was 1–3 years, and
when it appeared after the cancer, the interval was as
long as 2 years and usually was associated with metasta-
ses. The tumors associated with acanthosis nigricans are
highly malignant, and the average survival after the
cancer is discovered or resected is 12 months. How is
acanthosis nigricans in an adult evaluated? In the major-
ity of cases (approximately 75%), one will find a signif-
icantly obese individual who has been fat since puberty
and who has had acanthosis nigricans since that time.
About 25% of adults have an endocrine abnormality,
usually pituitary-based such as Cushing’s disease, acro-
megaly, Stein-Leventhal syndrome, or insulin-resistant
diabetes.38 Cancer is the cause in less than 1% of those
with acanthosis nigricans. Special concern must be given
May 2003
to nonobese adults who develop acanthosis nigricans, for
they are the ones in whom a malignancy is almost always
present.
Intestinal Bypass Syndromes
Intestinal bypass procedures for the treatment of
morbid obesity have been followed by rheumatic syn-
dromes in as many as 23% of the cases.40 Arthritis,
arthralgias, and cutaneous lesions of leukocytoclastic vas-
culitis have developed. The latter consisted of erythem-
atous papules, vesicopustules, and erythema nodosum–
like lesions that arose on the extremities, trunk, and face.
The antigenic stimulus for this immune complex syn-
drome is thought to be bacterial in origin, secondary to
bacterial overgrowth in the excluded loop of bowel.
Degos’ Disease
The cutaneous features of Degos’ disease (malig-
nant atrophic papulosis) are distinctive and unique. In
addition to the skin, the gastrointestinal tract is the
system most frequently involved. Gastrointestinal signs
and symptoms include nausea, vomiting, ileus, melena,
severe pain in all areas of the abdomen, and, rarely,
diarrhea with malabsorption.
The basic pathologic process is an endovasculitis char-
acterized by endothelial cell swelling and proliferation,
sometimes in association with fibrinoid necrosis within
the intima. Fibrous tissue is deposited between the in-
tima and internal elastic lamina, and thrombosis of the
vessel eventually occurs. All these changes happen in the
absence of significant inflammation or necrosis in the
media or adventitia of the vessels.42 These pathologic
findings in no way resemble those of necrotizing angiitis.
The histologic appearance of a fully evolved lesion is
remarkable. The epidermis is only 2 or 3 cell layers thick,
and it overlies a wedge-shaped area of acellular homoge-
neous-appearing collagen. Lesions ulcerate only rarely.
The eruption of Degos’ disease evolves as crops of ery-
thematous papules that undergo umbilication and pro-
duce doughnut-shaped lesions with porcelain-white cen-
ters and slightly elevated red borders. Eventually they
flatten out to produce brilliant white spots with a sur-
rounding ring of erythema composed of fine palisading
telangiectases (Figure 18). Evolution of the lesions can
occur within a week. These spots can be as large as 10
mm, and it is not unusual for several lesions to coalesce
and form a clover-leaf–like pattern. Individuals may have
hundreds of these spots on the skin.
Identical histologic and clinical lesions frequently
form in the walls of the gastrointestinal tract, and mul-
tiple minute perforations eventually develop to produce
a fatal peritonitis. In 3 series, 15 of 30 patients died in
SKIN SIGNS 1603
Figure 18. Degos’ disease. Typical lesions. Telangiectasia on periph-
ery of porcelain white macules. Reprinted with permission.31
this fashion.43– 45a At the time these cases were reported,
10 of the remaining patients were alive, and 3 of these
had abdominal pain. Three patients died from involve-
ment of the central nervous system. Neurologic involve-
ment produces dysphasia, headache, numbness of ex-
tremities, ataxia, and diplopia. The cerebral cortex has
been involved by white plaques similar to those in the
skin and gastrointestinal tract. The heart, kidneys, peri-
cardium, pleura, bladder, conjunctivae and retinas, and
oral and labial mucosae have also been affected in some
patients.
Degos’ disease occurs about 3 times more frequently in
men than in women. Over 100 patients with Degos’
disease had been described since the initial reports by
Köhlmeier in 194145b and Degos et al. in 1942.45c Four
instances of familial disease have been recorded.46 Indi-
viduals have lived for as long as 9 years before dying, but
the average duration of the disease is 2 years. In about
three quarters of the cases, the disease has begun in
patients 14 –36 years old; the oldest recorded patient was
57 years old. Some of the patients who were alive at the
time of their case reports had been living with their
illness for 3– 6 years.
There may be a benign form of Degos’ disease that is
limited to the skin.46 The author has followed-up a
patient who has not had evidence of systemic involve-
ment for 10 years. Reports of long-term observations will
be crucial in evaluating this possibility.
The etiology and pathogenesis are still unknown de-
spite extensive histochemical, ultrastructural, immuno-
logic, and coagulation studies in the past 20 years.47 In
2 cases, increased adhesiveness and aggregation of plate-
lets have been shown with successful treatment of skin
lesions and cessation of new lesion development with
dipyridamole and aspirin.47,48 One case was reported49 to
be associated with the presence of antiphospholipid and
1604 IRWIN M. BRAVERMAN
antiendothelial cell antibodies49 but subsequently, in a
larger series of 15 cases, none of the patients had detect-
able levels of antiphospholipid and antiendothelial cell
antibodies.50 In a recent case of our own, state-of-the-art
tests for platelet adhesiveness and aggregation failed to
disclose any abnormalities. Despite these negative col-
lective findings, the histopathology strongly suggests
that an aberration in the coagulation process is still the
best lead for developing an understanding of this disease.
Familial Mediterranean Fever
Familial Mediterranean fever, a variety of hered-
itofamilial amyloidosis, is transmitted as an autosomal-
recessive disorder. Outside the United States, familial
Mediterranean fever occurs almost exclusively in Sephar-
dic Jews, Armenians, and, to a lesser degree, in Levantine
Arabs. Familial Mediterranean fever has been described
under a variety of names: benign or familial paroxysmal
peritonitis, periodic disease, and familial paroxysmal poly-
serositis. The disease is 1.5 times more frequent in men
than in women and develops by 20 years of age in
60%–90% of predisposed individuals.51
The disease is characterized by recurrent episodes of
acute abdominal pain, skin lesions, and joint involve-
ment. The symptoms and clinical and radiologic signs of
peritonitis are mimicked exactly. At laparotomy, a nor-
mal or hyperemic peritoneum, sometimes with a small
amount of cloudy fluid, is found in the abdominal cavity.
The fluid is sterile on bacteriologic culture and is com-
posed chiefly of neutrophils.
Joint involvement usually is manifested as an asym-
metric monoarthritis. However, polyarthralgias and
polyarthritis can occur. The knee, ankle, hip, and shoul-
der are affected most frequently. The arthritis is charac-
terized by effusion, heat, tenderness, and loss of mobility.
Usually the attack of arthritis abates within 1 week, but
it sometimes persists for weeks or months. Despite swell-
ing and immobility for long periods, the joint returns to
its normal state; chronic disability does not result. His-
tologic examination of the synovium during an attack
shows the same acute inflammation seen in the histologic
sections of the peritoneum: acute vasodilatation, edema,
and perivascular collections of neutrophils.
Some of the cutaneous lesions associated with an at-
tack are unique. Sharply demarcated red patches that are
hot, tender, and edematous and that occur on the calves,
around the ankles, and on the dorsa of the feet are the
lesions seen most frequently. This eruption has been
called erysipelas-like erythema. It may be the sole manifes-
tation of an attack, or it may accompany the arthritis.
Sohar et al.51 noted that the erysipelas-like erythema and
GASTROENTEROLOGY Vol. 124, No. 6
brief synovial attacks involving the legs were sometimes
precipitated by prolonged standing, walking, or minor
trauma to the extremity.
Urticaria, rather than painful erythematous lesions,
can arise during attacks of familial Mediterranean fever.
Subcutaneous nodules also have been observed in acute
episodes, and histologic examination of these lumps is
said to show only a nonspecific panniculitis. Azizi and
Fisher52 have shown that the histologic findings in the
erysipelas-like erythema are identical to those found in
peritoneal and synovial tissues during a biopsy examina-
tion during an attack: acute inflammation manifested by
vasodilatation, edema, and perivascular collection of neu-
trophils. The histologic basis of the urticaria is unknown.
In some patients, purpura has been a manifestation dur-
ing an attack, but its etiology and pathogenesis are also
unknown.
Acrodermatitis Enteropathica
Acrodermatitis enteropathica, although uncom-
mon, is distinctive. Over 180 cases have been reported in
the literature.53 This illness usually appears from 2 weeks
to 20 months after birth, but at least 3 individuals have
developed the disease as late as 4 and 7.5 years. It often
develops after weaning. Three individuals were not di-
agnosed until adulthood; however, careful inquiry re-
vealed that the disease was present in a mild fashion in
these latter 3 patients since early childhood. Boys and
girls are affected equally by this disorder. In many in-
stances, the disease probably was transmitted recessively
because siblings, but never parents, were affected.54 The
cause of the disorder is zinc deficiency related to poor
intestinal absorption.
The cutaneous lesions involve both the periorificial
areas—mouth, nose, eyes, ears, and perineum—and the
extensor surfaces of the major joints, fingers, and toes
(Figures 19 and 20). The scalp is also affected frequently.
The tongue and the buccal mucosa also can be involved.
Most times, but not always, the basic lesion is a vesi-
cobullous eruption arising from an erythematous base.
The blisters quickly collapse, and discrete plaques with
varying amounts of scale develop at these sites. Exuda-
tion sometimes is present. When the fingers and toes are
involved, there is marked erythema and swelling of the
paronychial tissues, and the nails are grooved transversely
and often lifted up by subungual thickening. The tongue
and the buccal mucosa may be covered with white
patches. Alopecia results when the scalp is affected.
The clinical picture mimics either severe candidiasis or
pustular psoriasis, depending on the areas that are af-
fected. Candida albicans has been isolated from the skin
May 2003 SKIN SIGNS 1605

and mucosal lesions in 20% of the cases, but this isola-

tion is believed to represent a secondary infection and not
a primary etiologic factor. Discrete, bright red, scaly
plaques in the periorificial areas are markers of this
disease.
In one of our patients, the disease flared during each of
4 pregnancies because of an induced zinc deficiency.
Remissions occurred each time postpartum.
Kelly et al.55 showed histologic abnormalities of the
duodenal mucosa that resembled those of sprue in 3
children: loss of villous architecture with flattening of
villi accompanied by inflammatory cells in the lamina
propria. Diiodohydroxyquin and human milk only par-
tially reversed the bowel abnormalities; zinc restored
them completely to normal.
Syndromes of zinc deficiency mimicking acrodermati-
tis enteropathica formerly were seen in individuals re-
ceiving long-term parenteral nutrition (hyperalimenta-
tion) that typically did not contain zinc56 –58; chronic
alcoholics with poor nutrition57; patients who have had
small intestinal bypass procedures for treatment of obe-
sity57; and individuals suffering from anorexia nervosa.59
Zinc deficiency with the cutaneous manifestations of
acrodermatitis also can develop as a complication of Figure 20. Acrodermatitis enteropathica. Perineal involvement in the
12-week-old infant shown in Figure 19.
regional enteritis.60 In addition to the typical cutaneous
lesions found in acrodermatitis, several other types may
be seen in zinc deficiency: generalized and localized
eczema craquelé, lesions resembling the migratory necro- with production of microvesicles and some acantholysis
lytic erythema seen with glucagonoma, and angular sto- as found in acrodermatitis enteropathica.58
matitis.57 Apathy, depression, and irritability may ac-
company these cutaneous changes. Essential fatty acid Inflammatory Diseases of the
deficiencies can produce a similar picture.58 Histologic Bowel
examination of the cutaneous lesions produced in these Ulcerative Colitis
syndromes shows extensive necrosis of the midepidermis Skin lesions are found in 6% to 34% of patients
with ulcerative colitis; the recorded prevalence depends
on the observer compiling the series.61– 63 One of the
most common lesions is aphthous stomatitis. Aphthous
ulcers, indistinguishable from the ordinary variety, fre-
quently develop with acute exacerbations of the illness.
Erythema nodosum develops in 3%–10% of the cases
and appears almost always during the acute phase of the
disease.
Fernandez-Herlihy64 studied the significance of arthri-
tis with ulcerative colitis in a series of 555 patients.
Typical rheumatoid arthritis and spondylitis developed
in 46 patients, but in only 6 individuals did joint disease
precede the onset of the bowel disorder. The develop-
ment of rheumatoid arthritis is related to the chronicity
of the underlying colitis and can be accompanied by
Figure 19. Acrodermatitis enteropathica in a 12-week-old infant. Typ- iritis, uveitis, and episcleritis. On the other hand, ar-
ical periorificial eruption. thralgias and acute toxic arthritis are related to the
1606 IRWIN M. BRAVERMAN
activity of the disease in the same way as erythema
nodosum and pyoderma gangrenosum.
Pyoderma gangrenosum, a term applied to ulcers having
undermined necrotic bluish margins, occurs in 1%–10%
of patients with active ulcerative colitis.62,65 Pyoderma
gangrenosum usually begins as a frank pustule, pustular
nodule, or, rarely, as an erythematous nodule that
quickly ulcerates and spreads to encompass areas as large
as 9 –12 inches (Figure 21). Individual ulcerations also
may coalesce to form larger lesions. No area of the body
has been spared by this process.66 In a few patients,
pyoderma gangrenosum has developed before the ulcer-
ative colitis has appeared. Although conventional medi-
cal wisdom has stated that pyoderma gangrenosum de-
velops almost exclusively during periods of disease
activity and can be used as an indication for colectomy,
pyoderma gangrenosum does not always parallel disease
activity,67 but may arise during periods of remission, and
even after colectomy, by as long as 12 years (Figure 22).
Other types of pustular reactions can be seen in ulcer-
ative colitis. They have the same significance to disease
activity as classic pyoderma gangrenosum, but they do
not always evolve into giant necrotic ulcerations. The
inflammatory response in these reactions is probably less
violent than in classic pyoderma gangrenosum and there-
fore less apt to produce extensive ulceration. The histol-
ogy of these reactions when studied is indistinguishable
from that found in pyoderma gangrenosum. A descrip-
tion of these pustular eruptions, which in my view
represent variants of pyoderma gangrenosum, follows.
Ricketts et al.68 reported that in some of their patients
with ulcerative colitis, erythematous and papulopustular
nodules arose, but then resolved without undergoing
ulceration. In some of the patients, vesicular eruptions on
an erythematous base later appeared in the same sites,
but these lesions also subsided without ulcerating.
Figure 21. Pyoderma gangrenosum. Fully developed lesion with pus-
tular undermined necrotic border.
GASTROENTEROLOGY Vol. 124, No. 6
Figure 22. Ulcerative colitis. Ulcerating erythematous plaque. Re-
printed with permission.31
O’Loughlin and Perry69 described painful pustules
involving the skin and oral mucosa in 2 patients in
whom the colitis was flaring. The pustules on the skin
displayed several patterns: some were in clusters; some
arose from erythematous red plaques; and in others red
papules appeared first, became pustular, and subse-
quently sloughed to form small ulcers. Crops of these
pustules and papules arose during the time of disease
activity and disappeared after colectomy. The histologic
features were those of pyoderma gangrenosum. Johnson
and Wilson62 have described identical types of pustular
lesions that they called papulonecrotic lesions and ulcerating
erythematous plaques. The papulonecrotic lesions began as
scattered small red papules that became pustular and
subsequently necrotic. The ulcers persisted for several
weeks, leaving behind hyperpigmented scars after heal-
ing. The other lesions began as red plaques on the shins,
which broke down in several places to produce nonco-
alescing small ulcers that eventually healed over the
course of several weeks. Both types of lesions appeared
during periods of disease activity, disease inactivity, and
even 2 years after colectomy.
Figure 22 shows the ulcerating erythematous plaque
variety. This patient had a colectomy performed 2 years
earlier. He developed this lesion twice, and each time it
promptly disappeared after oral steroid therapy. The
histology in both cases was characteristic of pyoderma
gangrenosum. There was no evidence of necrotizing vas-
culitis.
Pyodermite végétante or pyoderma vegetans (Hallo-
peau) is most likely an exaggerated manifestation of the
pustular lesions found in ulcerative colitis. These lesions
have a predilection for the flexures, trunk, and upper
thighs. They also can occur on the lip, in the mouth, and
on the palate, where they are called pyostomatitis vegetans.
The palpebral conjunctivae also may be involved. They
begin as groups of pustules, rarely vesicles, or clear bullae
that break to form a hyperplastic or vegetating epithelial
May 2003 SKIN SIGNS 1607

surface over a boggy red base. The irregular surface of

these lesions displays small pustular summits. Fresh pus-
tules appear at the periphery of the vegetating plaques as
they slowly expand. Extensive plaques can cover the
trunk and abdomen. After months to years, the plaques
stop forming pustules, become dry, and resolve, leaving
behind hyperpigmented skin. Relapses may occur in the
same sites.70
These pustular lesions can arise in response to disease
activity, as well as appear during periods of disease
remission. They should be viewed as one of the extraco-
lonic manifestations of ulcerative colitis.
The lesions of pyoderma gangrenosum frequently are
sterile on bacteriologic culture. The histopathology of
fully developed pyoderma gangrenosum is nonspecific— Figure 23. Ulcerative colitis. Gangrene of fingertips secondary to
acute inflammation within the dermis and around ves- hypercoagulable state.
sels, with secondary ulceration of the epidermis. The
bulk of the inflammatory cells are neutrophils, but there
is no evidence of a necrotizing angiitis. Dantzig71 was 40%.73 Visceral venous thromboses are common. Studies
able to study 2 examples of pyoderma gangrenosum in its by Lee et al.74a indicate that ulcerative colitis, similar to
earliest phase. Both cases showed a dense infiltrate of disseminated malignancy, is associated with a hyperco-
large and small lymphocytes and other mononuclear cells agulable state, one facet of disseminated intravascular
in the mid- and lower dermis. There was dermal necrosis coagulation. Increased factor VIII activity, and thrombo-
associated with invasion and disruption of vascular walls cytosis (500,000 —1,000,000/mm3) were the most fre-
by lymphocytes, a histologic picture characteristic of quent abnormalities.
Although the thromboses in ulcerative colitis occur
cell-mediated hypersensitivity. As the necrosis evolves
chiefly in veins, Bargen and Barker74b described extensive
and the epidermis ulcerates, neutrophils would be ex-
arterial thromboses in one patient; and Kehoe and New-
pected to invade the area.
comer75 reported the case of a young man who developed
The skin of patients with ulcerative colitis may de-
superficial gangrene of the glans penis during an acute
velop pyoderma gangrenosum in response to trauma,
episode of colitis. These investigators also mentioned
especially after an intradermal injection (pathergic re-
that brachial artery occlusions have been observed in
sponse, pathergy) identical to that seen in Behçet’s dis-
other patients. Figure 23 shows 1 of 2 patients in the
ease.
author’s practice who developed gangrene of the fingers
Invariably, erythema nodosum and acute toxic arthri- and toes with acute episodes of ulcerative colitis.
tis are signs of disease activity and usually resolve after
the diseased bowel has been treated successfully medi- Crohn’s Disease
cally or surgically. Pyoderma gangrenosum is usually a Crohn’s disease can affect the small bowel (regional
sign of disease activity and, in those instances, it also enteritis), colon (granulomatous colitis), or small bowel
disappears after successful therapy of the colitis. and colon (ileocolitis). Perianal lesions, consisting of
The term pyoderma gangrenosum is applied properly only perianal and ischiorectal abscesses and sinuses, and fis-
to lesions that begin with pustules, or less commonly tulae-in-ano are found in 15%–50% of cases.76,77 Pain-
erythematous nodules, that break down to form spread- less anal fissures can be found in 50% to 60%.67 It is not
ing ulcers with necrotic undermined edges. In addition, unusual for fistulae to be the first manifestation of
the following diagnoses need to be excluded as a cause of Crohn’s disease, even though the inflammatory bowel
the necrotic ulcer: necrotizing vasculitis, mixed bacterial disease may have been mild or relatively asymptomatic.
infection-producing Meleney’s ulcer, iododerma or bro- Fistulae have been noted to precede clinically symptom-
moderma, deep fungal infection, spider bites, and facti- atic bowel disease by an average of 4 years (range, 1 mo
tial ulceration.72 to 22 yr). Although perianal abscesses and fistulae were
Thrombophlebitis develops in 1%–10% of patients believed to be an associated feature of ulcerative colitis in
with ulcerative colitis, but in patients examined by au- 10%–20% of cases, these observations were made before
topsy, the prevalence of venous thromboses is 30% to ulcerative colitis and granulomatous colitis were recog-
1608 IRWIN M. BRAVERMAN
nized to be separate entities.78 Perianal lesions are not a
manifestation of classic ulcerative colitis as it is currently
defined. Abdominal wall fistulae develop in 20% of
patients with Crohn’s disease—invariably postopera-
tively or in the scars from previous laparotomies. Fistulae
also can extend from the small bowel to the vagina,
rectum, and bladder.
In one large series, arthralgias and rheumatoid arthritis
developed in 9%–23%; conjunctivitis, episcleritis, and uve-
itis in 1%–13%; erythema nodosum in 4%–15%; and
pyoderma gangrenosum in 1%–1.6%. The highest preva-
lence occurred in patients with granulomatous colitis and
the lowest in those with regional enteritis. Clubbing, pal-
mar erythema, and phlebitis were found in 4% of 183
patients studied by McCallum and Kinmont.79
Perianal lesions often begin with anal or perianal
erythema that becomes edematous, producing a pur-
plish-red discoloration. In more advanced cases, inflam-
mation in the anal crypts of Morgagni produces red,
swollen, fleshy anal tags (Figure 24). These may progress
to fissure-in-ano and abscesses. The latter can break down
and extend to form large ulcers that cover the perineum,
thighs, scrotum, base of the penis, vulva, and anterior
abdominal wall. In most reported cases, the edges of the
ulcers were clean and not undermined and showed the
histologic sarcoid reaction of Crohn’s disease on biopsy
examination (granulomatous inflammation with nonca-
seating granulomas). In a minority of patients, the ulcers
Figure 24. Crohn’s disease. Red swollen fleshy nodules produced by
inflammation in the anal Morgagni’s crypts. Reprinted with permission.31
GASTROENTEROLOGY Vol. 124, No. 6
had the clinical appearance of pyoderma gangrenosum.
The skin around colostomies can develop identical ulcers
when the contiguous bowel is affected.
When the skin is involved at a site separated from the
gastrointestinal tract by normal tissue, the phenomenon
has been called metastatic Crohn’s disease. Histologi-
cally, a sarcoid reaction is present in the tissue. The
lesions take the form of ulcers, nodules, and areas of
erythema and can affect the flexural areas beneath the
breasts; the flexures of the groin and under the penis;
behind the ears and sites on the face, torso, and extrem-
ities.80 Rarely, the lesions may be multiple. The vulva
may be affected with edema, erythema, and ulcer-
ation.81,82
In addition to aphthous ulcers, which are common,
one also may find ulcerations of the buccal mucosa and
lips, which show the same characteristic granulomatous
changes. The ulcers develop hypertrophic granulation
tissue, which produces a cobblestone appearance. The
granulomatous inflammation has produced swellings on
the gingival margins and indurated polypoid tumors on
the buccal mucosa.83,84
Perianal lesions are more common in Crohn’s colitis
than in regional enteritis. Their development in regional
enteritis is believed to be caused by retrograde lymph
flow from the ileum to the perianal tissues. The presence
of such perianal lesions should make one consider the
possibility of Crohn’s disease even though bowel symp-
toms are absent or minimal. In the past, ischiorectal
abscess was synonymous with tuberculosis, in part be-
cause of the granulomatous inflammation. However, cur-
rently it should be regarded as a sign of Crohn’s disease
until proven otherwise. Ileocecal tuberculosis, which is
rare in the United States, ought to be considered when
pulmonary tuberculosis is present, or in areas where
milk-borne tuberculosis is common. A negative skin test
with tuberculin would exclude tuberculosis in such a
differential diagnosis.
Malabsorption Syndrome
Mucocutaneous abnormalities occur frequently in
malabsorption syndrome and have been the presenting
features of the disease in a significant number of persons.
In a series by Cooke et al.,85 stomatitis developed in 90%
of the patients with malabsorption. In the most severe
cases, the entire tongue and the buccal mucosa were
bright red with multiple ulcers. When the disease was
mild, the tips and edges of the tongue were smooth, red,
and sore. In pernicious anemia, the tongue is pale and
smooth. Acute glossitis can develop within 48 hours in
the malabsorption syndrome and can be accompanied by
May 2003
perianal soreness and dyspareunia. Folic acid and vitamin
B complex deficiencies are believed to be responsible for
the glossitis and stomatitis. Angular stomatitis was
found in half of their patients by Cooke et al.85
Vitamin K deficiency may produce purpura, petechiae,
melena, oral bleeding, hematuria, and even hemarthro-
ses. In some patients with malabsorption, hemorrhage
can be the first manifestation. In 17% of the patients in
the study by Cooke et al.,85 reversible clubbing occurred.
The findings in the series by Cooke et al.85 of 100
patients with sprue in Great Britain are comparable with
those reported by Green and Wollaeger86 in 124 indi-
viduals with sprue in the United States.
Dermatitis also can be the chief complaint of patients
with malabsorption; it has been reported in 10%–20% of
the cases.87 The rash is an erythematous scaling eruption
that has been reported variously as resembling seborrheic
dermatitis and psoriasis in some patients, and eczema,
asteatosis, and ichthyosis in others. The eczematous
patches often begin as a solitary lichenified or weeping
patch that becomes generalized and hyperpigmented.
The dermatitis and hyperpigmentation promptly clear
when the malabsorption has been treated successfully. In
the future, such cases should be reevaluated with regard
to possible zinc deficiency.
Increased pigmentation also may develop in the ab-
sence of dermatitis. The pigmentary patterns are of 3
types: melasmic (chloasmic)—a blotchy pigmentation on
the face and neck; addisonian—a distribution pattern,
including buccal pigmentation, similar to that of adrenal
insufficiency; and pellagroid—a purplish-brown color
that occurs over the exposed parts and extensor areas of
the limbs resembling pellagra, but is not associated with
cutaneous blisters or exudation. The pathogenesis of the
Addisonian hyperpigmentation in the malabsorption
syndrome is not known.
Purpura and hyperpigmentation also are characteristic
features of Whipple’s disease (intestinal lipodystrophy).
The pattern of the increased pigmentation is also Addi-
sonian, but buccal involvement is said not to occur.
Seronegative polyarthritis and arthralgias are prominent
features as well. Hair and nail growth can be abnormal in
celiac sprue. The scalp and facial hair may be shed and
remain sparse until malabsorption is corrected; the pubic
and axillary hair are similarly affected. Koilonychia is not
an unusual finding and responds to treatment with iron.
The nails also can become brittle and crack along their
free edges.
The precise factors responsible for the hair, nail, and
cutaneous abnormalities in celiac sprue are difficult to
delineate. Sometimes hypocalcemia appears to be the
SKIN SIGNS 1609
Figure 25. Dermatitis herpetiformis. Clusters of vesicles on erythem-
atous base.
major deficiency, and when it is corrected, the cutaneous
abnormalities disappear.88,89 At other times identical
dermatologic lesions occur in the presence of normal
levels of serum calcium and remit following a gluten-free
diet.89
Patients with intractable and hyperpigmented eczema
should be studied for malabsorption and hypocalcemia.
Shuster and Marks90 have emphasized 2 unsuspected
relationships between skin and gut: one concerns derma-
titis herpetiformis and celiac sprue; the other, termed
dermatogenic enteropathy, refers to the effect of an ex-
tensive dermatitis on the small intestine.
Dermatitis Herpetiformis
Dermatitis herpetiformis is a chronic, extremely
pruritic disease that is characterized by clusters of vesi-
cles distributed symmetrically over the extensor surfaces
of the knees and elbows, scalp, and back of the neck
(Figure 25).91 The face is affected infrequently and the
oral mucosa only rarely. The disease responds dramati-
cally to sulfones and sulfapyridine.
The illness may begin at any age, but it most fre-
quently appears in the second to fourth decades. Al-
though the disease appears to be lifelong in most indi-
viduals, it tends to become milder after it has been
present for about 10 years. Spontaneous remissions per-
sisting for several years or spontaneous cures have been
recorded.
The histology of the skin lesions in their earliest phase
is characterized by collections of neutrophils at the tips of
the dermal papillae (microabscesses), often in association
with separation of the papillary tips from overlying
epidermis.
Most patients with dermatitis herpetiformis diagnosed
on the basis of clinical and histologic features and their
1610 IRWIN M. BRAVERMAN
response to therapy have granular deposits of IgA iden-
tified by direct immunofluorescence in the dermal papil-
lae of their cutaneous lesions, in a 3–5-mm perilesional
zone, and sometimes in more distant normal skin. It is
now possible to make the diagnosis on formalin-fixed
tissue with the use of an avidin-biotin-peroxidase tech-
nique that is more convenient than direct immunofluo-
rescence on fresh tissue.92 Immunofluorescent markers of
IgA deposition are necessary for the diagnosis of derma-
titis herpetiformis.
Dermatitis herpetiformis is associated with mucosal
changes in the small bowel that are indistinguishable
from those of celiac sprue.93–95 The atrophic villous
pattern in dermatitis herpetiformis ranges from mild to
severe. It is more prominent in the proximal small bowel
than in the distal portion as observed in celiac sprue, but
the atrophy occurs in a spotty fashion as opposed to more
universal involvement in sprue. The differences in extent
and degree of mucosal involvement in dermatitis herpet-
iformis have been proposed as the reasons for the rarity of
clinical signs of malabsorption.94
Data from several series have shown that chemical
evidence of steatorrhea was present in 22 of 69 patients,
but in only 6 were there clinical signs and symptoms of
malabsorption.93,96,97 Katz and Strober98 found only 2 of
51 patients had symptoms of malabsorption. Dermatitis
herpetiformis preceded or followed malabsorption by as
long as 3 to 8 years. Ten percent to 33% of patients have
had abnormalities of D-xylose excretion, and anemia
secondary to iron and folate deficiencies. Abnormalities
in glucose, bicarbonate, and water absorption similar to
those found in sprue also have been present.93,96 –98
Sulfones produce remission in the skin lesions but
have no effect on the enteropathy. However, a gluten-free
diet in dermatitis herpetiformis will not only cause the
intestinal lesion to revert to normal as in sprue, but in
most patients it will induce a remission in the skin
lesions or significantly reduce the dose of sulfones nec-
essary to keep the skin clear.99,100 It requires 6 to 12
months to achieve these cutaneous effects with a gluten-
free diet. Return to a gluten-containing diet is followed
by a relapse of skin disease in 1 to 3 weeks. Some patients
with dermatitis herpetiformis do not respond to a glu-
ten-free diet.95,98 Curiously, IgA and C3 still can be
found in the normal skin of patients who have responded
to a gluten-free diet.98
The pathogenesis of dermatitis herpetiformis is be-
lieved to involve the deposition of IgA at the dermal-
epidermal junction of the skin with subsequent activa-
tion of complement by the alternative pathway.
Neutrophils are attracted to the site and the histologic
GASTROENTEROLOGY Vol. 124, No. 6
lesion is generated. However, the presence of IgA alone
is insufficient to initiate the formation of the lesions, and
other factors are necessary although they still are unde-
fined. It has been established that patch tests with an-
ionic I, Cl, Br, F, and SCN will initiate local lesions
within 24 to 48 hours. Oral potassium iodide also can
induce lesions and exacerbate the disease. It is not un-
derstood how the halogens bring this about. The signif-
icance of IgA deposition in the skin is likewise unclear.
It has been proposed that the IgA is directed against
gluten protein or cross-reacting antigens, and that it
originates in the gastrointestinal tract.98 There is no
evidence that circulating immune complexes, which are
detectable in some patients,101,102 play a pathogenetic
role in this disease.
Other evidence links dermatitis herpetiformis to
sprue. Relatives of patients with dermatitis herpetiformis
have been shown to have a high prevalence of villous
atrophy assumed to be caused by celiac sprue.96 HLA-
B8/DRw3/DQw2 are present with increased frequency in
both sprue and dermatitis herpetiformis.98
Fry et al.103 and Doran et al.104 have reported that
absorption studies with D-xylose and folic acid yielded
false-positive results for malabsorption in patients with
extensive eczema and psoriasis. The abnormal results
from D-xylose testing have been attributed to decreased
renal clearance, not malabsorption. The reason for de-
creased renal clearance has not been studied. Low serum
folate levels are ascribed to increased use by the diseased
epidermis rather than to faulty absorption. Serum folate
and D-xylose levels, which are common screening tests
for malabsorption, cannot be used for this purpose in
patients with extensive skin disease. Correction of the
serum folate levels has not benefited the eruptions in
these patients.105
Diseases of the Pancreas
Pancreatitis
Acute hemorrhagic pancreatitis may be accompa-
nied by purpura in the left flank (Grey-Turner’s sign) or
in the periumbilical area (Cullen’s sign). Hematomas
dissect along fascial planes from the retroperitoneal site
of bleeding to the skin of the flank and periumbilical
area. Polyarthritis of the small joints of the hands, feet,
and elbows, in association with tender subcutaneous
nodules, fever, and eosinophilia, constitute a unique syn-
drome of pancreatic disease.106 Although most cases are
produced by a functioning acinar cell cancer of the
pancreas, identical signs and symptoms occur in acute
and chronic pancreatitis.107 The subcutaneous nodules
produced by fat necrosis often are tender and fluctuant
May 2003
with varying shades of erythema. Central necrosis with
leakage of oily material can occur. The lesions may be
multiple and located anywhere on the body. Markedly
elevated serum lipase and amylase levels are present.
Although fat necrosis may occur anywhere, the skin,
omentum, and perirenal and pelvic fat are affected pri-
marily. Tumor cells are not found in the areas of fat
necrosis, and it seems highly probable that the circulat-
ing increased levels of lipase, amylase, possibly trypsin,
and other unidentified factors from the pancreas are
responsible for this unique syndrome. The arthritis is
caused partly by fat necrosis in the periarticular tissue.
The tumor is assumed to be a functioning neoplasm
because of the presence of zymogen granules.108 Differ-
entiation from Weber-Christian disease (febrile nonsup-
purative panniculitis) is made by the presence of polyar-
thritis and a histologic picture of simple fat necrosis that
is different from the cytophagic histiocytic inflammation
seen in Weber-Christian disease. Fat necrosis does not
occur in erythema nodosum that is also simulated by this
entity.
Migratory Necrolytic Erythema
The islets of the pancreas are made up of a central
population of ␤ cells, the source of insulin, and a smaller
peripheral population of ␣ cells, source of glucagon. The
␣ cell– glucagon secreting tumors produce a well-defined
syndrome with a spectacular and unique eruption that
was defined in 1971. Since then, 95 proven or probable
examples have been recorded.109,110
Characteristically, the eruption is widespread, with
the severest areas of involvement being on the abdomen,
groin, perineum, thighs, and buttocks (Figure 26). The
legs, feet, and hands also can be affected, and most
patients have perioral lesions as well. The eruption waxes
and wanes in intensity, but there can be intervals of
Figure 26. Migratory necrolytic erythema in a patient with glu-
cagonoma. There are colarettes of scale around expanding borders.
SKIN SIGNS 1611
complete remission lasting for weeks or months. The
eruption begins with patches of intense erythema that
may be angular, annular, or highly irregular in outline.
Flaccid vesicles and bullae develop over the surface, but
their presence is sometimes difficult to appreciate be-
cause of their superficiality. They break quickly, leaving
denudation and crusts behind. The patches of erythema
extend with flaccid vesicles, bullae, or simply a collarette
of desquamating skin on the active margins. The centers
of the lesions heal, with hyperpigmentation sometimes
left behind. Circinate and polycyclic lesions frequently
develop from the merging patches of erythema. In a few
cases the rash has had the appearance of eczema craquelé
(erythema with fine fissuring). Usually individual lesions
run a course of 7–14 days, and typically one finds lesions
in all stages of development in a patient. The perioral
lesions also are characterized by patches of erythema with
crusting or peripheral scaling. In a number of individu-
als, pressure, friction, or trauma has initiated or aggra-
vated the eruption.
Histologically, there is marked intercellular edema in
the upper layers of the epidermis in association with
swelling of the epidermal cells themselves. In some in-
stances hydropic degeneration of the superficial epider-
mal cells can be found. There is marked edema in the
upper epidermis with accompanying epidermal cell
death that produces cleavage between the epidermis and
the stratum corneum, accounting for the development of
flaccid vesicles and bullae and the collarette of scale.
There is a minimal infiltrate of inflammatory cells in the
dermis.111,112 These histopathologic findings are very
similar to those found in acrodermatitis enteropathica,
acquired zinc deficiency, and pellagra.113
The eruption responds dramatically to oral diiodohy-
droxyquin, as does the rash of acrodermatitis entero-
pathica. However, unlike acrodermatitis enteropathica,
which is produced by zinc deficiency, the serum zinc
level in the glucagonoma syndrome is normal and the
eruption does not respond to zinc therapy.112
Besides the distinctive cutaneous findings, patients
with this syndrome have a glossitis (red, shiny, smooth
tongue), angular cheilitis, normocytic normochromic
anemia, weight loss, and low plasma amino acid levels.
In most of the individuals, mild diabetes mellitus and
diarrhea also have been present. With a few exceptions,
all of the patients thus far reported have had an ␣ cell
tumor of the pancreas accompanied by markedly elevated
serum glucagon levels. In 2 patients the glucagonomas
were found in the proximal duodenum and in the right
kidney. In approximately 50% of the patients at the time
of diagnosis, the tumors were metastatic to the liver and
1612 IRWIN M. BRAVERMAN
occasionally beyond to the nodes, spine, and adrenal
glands.110 In a few patients, resection of the tumor has
resulted in prompt resolution of the eruption, correction
of the anemia, restoration of normal glucagon levels in
the serum, and weight gain.112 The ␣ cell tumors in
general are slowly progressive neoplasms and the courses
in a representative group of 22 patients have ranged from
4 months to 13 years.112 In 5 patients described later, no
neoplasms were found.
Immunoreactive glucagon with a molecular weight of
3500 or 9000 daltons appears to be required for the
development of the clinical glucagonoma syndrome. Mo-
lecular species of immunoreactive glucagon greater than
9000 daltons may not be fully active biologically.114
Although the glucagonoma syndrome is associated with
a marked elevation of glucagon levels in the serum, the
hormone probably is not directly related to the patho-
genesis of the eruption. The rash waxes and wanes in the
presence of the tumor, and glucagon applied topically
and injected intradermally does not produce any reac-
tion.115,116
The mechanism underlying migratory necrolytic ery-
thema is not understood, but the hypotheses based on
limited evidence that have been proposed include an as
yet unidentified pancreatic peptide working alone or in
concert with glucagon; hypoaminoacidemia; and in-
creased epidermal levels of arachidonic acid and its me-
tabolites induced by glucagon that induces dermal in-
flammation after trauma.113,115–118
There have been reports of 5 patients with the classic
clinical and histologic findings of the glucagonoma syn-
drome who have not had a tumor.119 –122 These patients
had malabsorption syndromes, postnecrotic cirrhosis in
association with minimally active ulcerative colitis,
chronic pancreatitis, or elevated levels of a molecular
species of immunoreactive glucagon greater than 9000
daltons.
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Received December 16, 2002. Accepted February 20, 2003.
Address requests for reprints to: Irwin M. Braverman, M.D., Depart-
ment of Dermatology, Yale University School of Medicine, 333 Cedar
Street, New Haven, Connecticut 06520. Fax: (203) 785-7637.