LECTURE
Newer skin signs of systemic disease
William D. James
Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA(Received for publication on May 7, 2001)

Abstract. The skin is a well-known re¯ection of internal disease states. It provides the astute clinician
with clues that lead to the diagnosis of systemic illness. While skin disease is rarely life-threatening,
serious morbidity and mortality may be avoided by early recognition of subtle cutaneous signs signaling
internal problems. The recent literature was reviewed to glean new ®ndings that either added new
associations to older syndromes or described completely new diseases. While entire books are written
regarding the ``Skin Signs of Internal Disease'', this article focuses only on the newest of such ®ndings.
(Keio J Med 50 (3): 188±191, September 2001)
Key words: internal medicine, scleromyxedema, hepatitis C, dermatology

Hepatitis C-related Conditions
The incidence of hepatitis C infection is risingworldwide. There have been many conditions associated with this life-threatening liver disorder, including
necrolytic acral erythema, mixed cryoglobulinemia,
porphyria cutanea tarda, lichen planus, pruritus, periarteritis nodosa and the red ®nger syndrome.1 The ®rst
three are most dramatically linked to hepatitis C, while
the latter four are characteristic enough to suggest theneed for hepatitis serology upon diagnosis.
Necrolytic acral erythema was ®rst described by El
Darouti and El Ela in 1996.2 Seven patients with predominantly lower extremity tender well-de®ned velvety
or scaly surfaced red plaques were reported. Since then,an eighth patient has been documented.3 Five werewomen and their ages ranged from 12 to 58. The hands
were also affected in many by this distinctive change.
Biopsy revealed a pallor of the super®cial acanthotic,
hyperkeratotic epidermis which may lead to blistering,both clinically and histopathologically. These microscopic ®ndings suggest a nutritional de®ciency or the
glucagonoma syndrome. However, as necrolytic acral
erythema has acral predominance and spares the periora®cial skin, investigation for hepatitis C infection
should be done. Herein lies the importance; the chance
to diagnose a communicable disease with potential di-sastrous long-term sequelae. Treatment with interferon
can alleviate both the systemic illness and the cutaneous eruption.
Mixed cryoglobulinemia and porphyria cutanea
tarda are highly indicative of hepatitis C infection while
lichen planus, pruritus and periarteritis nodosa arevariably associated with this infection. Studies fromdifferent countries with widely varying backgroundrates of infection in the populace continue to suggest agenerally low but real risk above the norm for the latter
three conditions.1 Hepatitis C serologies are a part of
the workup for the etiology of all of these diseases.
The red ®nger syndrome has recently been de®ned
as chronic striking well-de®ned painless distal erythemaof the ®ngers and toes with multiple telangiectasias.4±6First thought to be a sign of HIV infection, it has become more closely associated with hepatitis C infection,
similar to the manner in which porphyria cutanea tarda
was ®nally appreciated to be more closely associatedwith hepatitis C rather than HIV disease. The red ®nger
syndrome is also seen in connective tissue disease
patients, particularly those with dermatomyositis andlupus erythematosus.
Connective Tissue Diseases
Two recent articles regarding signs of connective tissue disease are highlighted. Five patients, four girls andPresented at the 1203rd Meeting of The Keio Medical Society in Tokyo, April 10, 2001.
Reprint requests to: Dr. William D. James, Program Director of the Residency Program, Director of Clinical Services, and Vice Chairman,
Department of Dermatology, University of Pennsylvania Health System, 2 Maloney Building, 3600 Spruce Street, Philadelphia, PA 19104-4283,USA188

Keio J Med 2001; 50 (3): 188±191

a boy, were reported with juvenile dermatomyositis(DM) and striking gingival telangiectasias.7 All had
prominent nail fold telangiectasias. Additionally, otheroral ®ndings of DM were noted, including edema,erythema, ulcers and white plaques. These oral ®ndings
join the shawl sign, the Samitz sign (cuticular fraying),mechanic's hands, and ulcerations as newer signs ofDM. These complement the heliotype swelling of theperiocular tissues, nail fold telangiecetiasis, Gottron
papules and the Gottron sign as indicators of this disease with a plethora of skin signs.
Tumid lupus erythematosus was described over 70years ago but it has attracted little attention over theyears.8 After only a small number of case reports andsmall case series Kuhn et al. reported 40 patients withthis disease.9 The de®nition they use includes smooth
red-violet patches, papules, or plaques (Fig. 1) of theface, neck, upper trunk, and arms (sun-exposed sites)
which on biopsy reveal super®cial and deep perivascular lymphohistocytic in®ltrates with abundant mucininterstitially. These patients generally noted the onsetof the eruption in the summer (70%) between the agesof 30 and 50. Interestingly, men and women wereequally represented. While some patients also exhibited
discoid lupus erythematosus lesions, associated systemic lupus erythematosus was rare. The skin disease
clears regularly with antimalarial treatment with noscarring. If one adheres to their disease de®nition,reticulated erythematous mucinosis and plaque-likeerythematous mucinosis would be included under thedesignation tumid erythematosus. The lumping together of these disorders is reasonable.
Vascular Processes
Four cases of a new disease process called diffuse
dermal angiomatosis have been described.10±12 Threeof the four have had painful ulcerations of the thighwithin violaceous, hyperpigmented thickened plaques.
Severe peripheral vascular disease and exertional pain
were present in these three patients. On biopsy, a dermal proliferation of endothelial cells was present. All ofthese three patients' ulcers healed after revascularization. A fourth case involved the upper extremity of arenal dialysis patient with an arteriovenous access.
Again revascularization led to disease remission. It isfelt that this process is a subtype of reactive angioendothelomatosis.
Reactive erythemas have been the subject of newreports. Pustular vasculitis of the dorsal hands wasde®ned by Strutton, et al. in 1995 as ulcerative lesions
with a pustular border that involved the dorsal radialaspect of the hands of six women.13 Some had associated fever and leukocytosis, but none had leukemia
or in¯ammatory bowel disease. They reported that189

the biopsies were Sweet-like, however leukocytoclastic
vasculitis was clearly evident in all lesions. A rapid response to steroids was characteristic and left no residual
scarring. I have seen several such patients with identicalclinical lesions limited to the dorsal hands (Fig. 2).
None of the biopsies revealed vasculitis and I consider
this to be a subset of Sweet syndrome.14 Thus far no
associated disease has been seen with this distinctive
eruption.
Rheumatoid neutrophilitic dermatitis is anotherrecently de®ned in¯ammatory disorder.15 It is characterized as chronic erythematous plaques affecting primarily the trunk with ®brotic nodules of the extremities(Fig. 3). It affects patients with longstanding rheumatoid arthritis. Biopsies revealed a neutrophilic in®ltrateof the dermis with intact neutrophils in®ltrated between
collagen bundles. There was no vasculitis or leukocytoclasis. This disorder is in clear contrast to Sweet syndrome and other neutrophilic reactive processes such aspyoderma gangrenosum, vasculitis and erythema elevatum diutinum.
Renal Disease
Scleromyxedema is a well-known, well-de®ned disorder consisting of in®ltrated papules and plaques of
the head and neck, trunk, and at times the limbs. In 90
percent of patients, a circulating paraprotein is present.
The mucinous in®ltrate may involve the viscera. Cooper, et al. reported a new subset of scleromyxedema,that was associated with renal dialysis.16 They haveseen 15 patients with primarily extremity papules andplaques which were thickened and hyperpigmented.
Some patients had localized solitary lesions whileothers had diffuse thickening of the skin with ¯exion
contractures. None had an associated paraprotein,
or visceral involvement, and only some had trunkallesions. All 15 patients, who were aged 31 to 74 years
and mostly men, were receiving or had received renal
dialysis. My experience with four such patients mirrors
their report (Fig. 4).
Tumor-related Conditions
Birt, Hogg and Dube in 1977 reported 15 patients in
one family who had multiple small skin-colored domeshaped papules, which on biopsy revealed perfollicular®brosis and epithelial proliferation.17 Many subsequentpatients with multiple familial ®brofolliculomas havebeen documented (Fig. 5). A triad of these lesions
associated with acorchordons and trichodiscomas was
originally thought to exist, but my experience and thatof others point out that the latter two papules are also
®brofolliculomas if sectioned horizontally.18,19
The recently appreciated fact is that this skin disease190James WD: Newer skin signs of systemic disease

Fig. 1 Reticulate erythematous patch in a man with lupus erythematosus.

Fig. 4 Hyperpigmented sclerotic plaque of scleromyxedema in a
renal dialysis patient.

Fig. 2Pustular erosive lesion on the dorsal radial aspect of the hand.

Fig. 5 Form Fibrofolliculomas in a patient with Birt-Hogg-Dubesyndrome.

Fig. 3 Erythematous, edematous ®xed plaques of rheumatoid neutrophilic dermatitis.

may have internal associations. Familial renal cell carcinomas, recurrent pneumothorax secondary to pulmonary cysts, and possibly colonic polyposis and carcinoma are well documented.19 I have seen two patientswith Birt-Hogg-Dube syndrome and neural derived
tumors, a neurothekioma and a meningioma. It is now
appreciated that a chest X-ray, an abdominal CT scanand ultrasound, and a colonoscopy should be done in
all newly diagnosed patients and their family members.
Generally, the pulmonary symptoms predate the onsetof the papules (late teens vs. early thirties), and therenal and colonic abnormalities frequently occur laterin life after the papules become apparent.19

Keio J Med 2001; 50 (3): 188±191

Finally, an acral variant of acquired cutis laxa has
been de®ned over the past 10 years. Four patients witheasily deformed ®nger pads that lack elasticity and resiliency, have been reported.20±22 Two of them, as in acase I recently observed, had associated amyloidosis
and myeloma. While generalized acquired cutis laxa is awell-known complication of these associated diseases,
this acral variant has only recently been recognized.
Continued vigilance is needed when assessing ourdermatology patients, so we do not miss recognizing
men and women who come for skin care but are manifesting treatable internal disease.
References
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