Mark Lebwohl MD1
1Sol and Clara Kest Professor and Chairman, Department of Dermatology, Mount Sinai School of Medicine
The author has served as an investigator, consultant, or speaker for the following companies: Abbott Laboratories, Inc., Allergen, Inc., Amgen, Inc., Biogen, Inc., Centocor, Inc., Connetics Corporation, Fujisawa Healthcare, Inc., Galderma Laboratories, L.P., Genentech, Inc., Leo Pharmaceuticals, and Warner-Chilcott Pharmaceuticals.
The FDA has not approved the following drugs for specific uses described in this chapter: infliximab and TNF-α blockers for the treatment of sarcoidosis and Wegener granulomatosis; rituximab for the treatment of lymphomatoid granulomatosis; and calcipotriene for the treatment of morphea.
The cutaneous manifestations of systemic diseases are so numerous and varied that a single chapter could not cover them all, even in a cursory way. Instead, this chapter reviews key cutaneous manifestations of systemic diseases that should be recognized by most physicians, and it highlights recent developments in the diagnosis and management of such disorders. For fuller discussions of specific diseases, including their cutaneous manifestations, readers are referred to the chapters devoted to these conditions.
In many of the disorders presented in this chapter, workup and therapy of the underlying systemic condition are essential to a favorable outcome. A finding of cutaneous sarcoidosis, for example, should prompt a search for systemic sarcoidosis. In other conditions—for example, recessive dystrophic epidermolysis bullosa—treatment of the skin disorder is key to the management of the systemic disease.
Cardiopulmonary and Vascular Diseases
The cutaneous manifestations of sarcoidosis are as varied as its systemic manifestations [see 14:V Chronic Diffuse Infiltrative Lung Disease]. Papules around the eyes or nose are most characteristic. The term lupus pernio refers to noncaseating granulomas that result in translucent, violaceous plaques of the ears, cheeks, and nose [see Figure 1]. Involvement of underlying bone can occur. Diagnosis is made by skin biopsy. Treatment with intralesional corticosteroids is traditional, and oral antimalarials and methotrexate have been used with success. More recently, infliximab has been successfully used for the treatment of sarcoidosis.1 Other tumor necrosis factor-α (TNF-α) blockers such as etanercept have been used to successfully treat arthritis and skin lesions associated with sarcoidosis.2 Infliximab has also been used to treat lupus pernio.3
Figure 1. Lupus Pernio in Sarcoidosis
Characteristic facial lesions of sarcoidosis, called lupus pernio, are shown.
There has been an increase in the use of interferon for the treatment of hepatitis C and multiple sclerosis, and a number of reports of sarcoidosis have been attributed to this treatment. Infliximab therapy has been found to effect a response in these cases.4
In some patients with sarcoidosis, erythema nodosum, characterized by deep, tender erythematous nodules, occurs on the lower extremities. Lupus pernio is associated with a more chronic course of sarcoidosis, whereas erythema nodosum indicates a more acute and benign disease.5
Wegener granulomatosis is associated with both distinctive and nonspecific mucocutaneous signs. Palpable purpura is one of the most common skin findings, but ulcers, papules, nodules, and bullae have also been described. In addition to upper and lower pulmonary symptoms [see 14:IV Focal and Multifocal Lung Disease], saddle-nose deformity, nasal ulcerations, and septal perforation should suggest the diagnosis of Wegener granulomatosis. Definitive diagnosis is made by demonstrating a necrotizing granulomatous vasculitis in a patient with upper and lower respiratory tract disease and glomerulonephritis. Cytoplasmic antineutrophil cytoplasmic autoantibodies (c-ANCA) are often present. Standard therapy is with cyclophosphamide and corticosteroids. TNF-α blockers have proved to be effective for some patients with refractory Wegener granulomatosis.6
Lymphomatoid granulomatosis is a rare, destructive, angiocentric disorder that results from Epstein-Barr virus-associated B cell lymphoproliferative disease.7 This condition can be associated with skin lesions. Typically, patients develop erythematous papules or nodules that may or may not ulcerate.8 This disorder is clinically distinguishable from Wegener granulomatosis by the absence of upper respiratory tract involvement. Diagnosis is established by demonstrating a granulomatous necrotizing infiltrate with atypical lymphoid cells around blood vessels. Lymphomatoid granulomatosis is usually fatal; however, rituximab has been used successfully to treat this condition.9
Churg-Strauss syndrome, or allergic granulomatous angiitis, most commonly presents as asthma and eosinophilia; however, related skin lesions develop in up to 40% of patients. Symmetrical, palpable purpura and petechiae of the lower extremities are the most common findings; these lesions show a leukocytoclastic vasculitis on skin biopsy. Cutaneous nodules caused by extravascular necrotizing granulomas and papules of the elbows also occur.10 One of the clues to the diagnosis of this disorder is the presence of perinuclear antineutrophil cytoplasmic antibodies (p-ANCA).11
Xanthomas are cutaneous manifestations of hyperlipoproteinemias. Several types of xanthomas occur with different lipid abnormalities. Xanthelasmas of the eyelids [see Figure 2] are the most common manifestations of familial hypercholesterolemia; however, in at least half the people who have eyelid lesions, plasma lipid levels are normal. Planar xanthomas are flat yellow plaques that can involve the palms, soles, neck, and chest. They can occur in patients with primary biliary cirrhosis or multiple myeloma. Tuberous xanthomas are large yellow or red nodules that appear on the extensor surfaces of joints, such as on the elbows and hands, but are not attached to underlying tendons. They can occur in patients with elevated triglyceride or cholesterol levels. In contrast, tendinous xanthomas, which can appear in patients with familial hypercholesterolemia, are fixed to underlying tendons of the elbows, ankles, knees, and hands. Eruptive xanthomas occur when plasma triglyceride levels suddenly become elevated. Skin lesions consist of small yellow papules that often resolve with lowering of triglyceride levels.
Figure 2. Xanthelasma and Arcus Senilis in Hypercholesterolemia
Xanthelasma and arcus senilis are shown in a patient with hypercholesterolemia.
Kawasaki disease, also called mucocutaneous lymph node syndrome [see 15:VIII Systemic Vasculitis Syndromes], is a disorder in children that can be complicated by coronary artery occlusion and myocardial infarction, coronary artery aneurysms, ECG abnormalities, cardiac arrhythmias, or myocarditis.12 It has been suggested that a toxin secreted by Staphylococcus aureus is responsible for this disease, but proof of the precise cause remains elusive.13 Diagnosis is based on clinical criteria that include fever, conjunctivitis, lymphadenopathy, and rash. In addition to a generalized erythematous eruption, abnormalities of the oral mucosa, as well as swelling and erythema of the hands and feet, may develop. Striking desquamation of the palms and soles ultimately occurs. Perianal and scrotal erythema and scaling are common as well. Thrombocytosis is a late finding, with platelet counts increasing to more than one million over 2 weeks after the onset of the disease. Approximately 15% to 25% of untreated children develop coronary artery aneurysms that may lead to sudden death.14Treatment with intravenous immunoglobulin reduces the frequency of coronary artery abnormalities.15
Pseudoxanthoma elasticum (PXE) is an autosomal recessively inherited disorder of elastic tissue caused by mutations in the ABCC6 transporter protein.16 PXE is associated with a wide array of systemic manifestations. Angioid streaks, the ocular hallmark of PXE, are breaks in the Bruch membrane. Retinal bleeding and vision loss commonly occur. Calcification of the internal elastic laminae of arteries can result in bleeding or occlusion of these vessels. As a result, patients develop intermittent claudication on walking and occlusive coronary artery disease at an early age. Cardiac valvular abnormalities have also been described.17 Skin lesions consist of yellow xanthomalike macules, papules, or redundant folds of skin in flexural areas, particularly the neck and axillae [see Figure 3]. Some patients may have systemic manifestations of PXE without clinically apparent skin lesions.18 Diagnosis is established by biopsy of scar or normal-appearing flexural skin.19 There is no therapy for the skin lesions associated with PXE.
Figure 3. Xanthomalike Papules in Pseudoxanthoma Elasticum
Xanthomalike papules are characteristic of pseudoxanthoma elasticum. The neck and axillae are the most common sites of involvement.
The two cutaneous manifestations of rheumatic fever are erythema marginatum and subcutaneous nodules. Erythema marginatum is a transient faint annular erythematous rash that often develops over joints [see Figure 4]. The subcutaneous nodules that appear with rheumatic fever are nontender, freely movable nodules measuring approximately 1 cm in diameter; they occur on the extensor surfaces of elbows, hands, or feet.
Figure 4. Erythema Marginatum in Rheumatic Fever
Transient annular erythematous rashes (erythema marginatum) typically occur in patients with rheumatic fever.
YELLOW NAIL SYNDROME
Yellow nail syndrome is caused by an abnormality of lymphatics [see Figure 5]. Affected patients develop lymphedema, usually of the legs, and pleural effusions. Pulmonary symptoms such as recurrent bronchitis are also common. Diagnosis is made by finding evidence of abnormal lymphatic function associated with yellow nails without other causes of nail pathology. Increased microvascular permeability with leakage of proteins may play a role in the development of the yellow nail syndrome.20
Figure 5. Yellow Nail Syndrome
Yellow nails are a sign of underlying disease of the lymphatics in patients with yellow nail syndrome.
There are numerous cutaneous manifestations of diabetes mellitus [see 9:II Diabetes Mellitus]. Acanthosis nigricans can occur in patients with diabetes and other endocrinopathies, such as Cushing syndrome, acromegaly, polycystic ovary syndrome, and thyroid disease. Insulin resistance is an underlying factor in several of the aforementioned endocrinopathies; it also may play a role in the development of acanthosis nigricans. Skin lesions consist of brown velvety patches in intertriginous areas, especially the neck and axillae [see Figure 6], and occur more commonly in obese patients with diabetes.21 Acanthosis nigricans has also been associated with internal malignancies, particularly gastric adenocarcinoma or other gastrointestinal adenocarcinomas.
Figure 6. Acanthosis Nigricans
Acanthosis nigricans, a dark velvety acanthosis that can occur in patients with diabetes mellitus and other endocrine disorders, often appears on the neck.
Necrobiosis lipoidica is a specific cutaneous manifestation of diabetes. Lesions consist of chronic atrophic patches with enlarging erythematous borders. The legs are most commonly affected. The centers of the lesions appear yellow because of subcutaneous fat that is visible through the atrophic dermis and epidermis. Occasionally, the lesions ulcerate. Necrobiosis lipoidica is often associated with diabetic nephropathy or retinopathy.22
Scleredema, another manifestation of diabetes, consists of induration of the skin of the back and posterior neck in obese patients with type 2 (non-insulin-dependent) diabetes. Scleredema may improve if diabetes is controlled.23 Less commonly, scleredema occurs in nondiabetic patients after streptococcal pharyngitis; in such patients, the disease is self-limited, resolving within 2 years of onset. High-dose corticosteroids,24 radiation,25 and ultraviolet-A1 irradiation (UVA1)26 have all been used to treat scleredema.
Diabetic bullae, neuropathic ulcers, and so-called waxy skin and stiff joints occur in patients with diabetes. In the last condition mentioned, scleroderma-like induration of the skin over the dorsal aspect of the hands prevents full flexion or extension of the proximal interphalangeal joints.
Diabetic patients are prone to a number of infections, including erythrasma, a corynebacterial infection resulting in asymptomatic reddish-brown patches in intertriginous sites, especially the groin and axillae. Patients are also prone to staphylococcal infections and frequently develop furuncles and carbuncles. Candidal infections are another risk, particularly when blood glucose levels are poorly controlled.
Graves disease consists of a triad of exophthalmos, hyperthyroidism, and pretibial myxedema [see 3:I Thyroid]. Pretibial myxedema presents as skin-colored nodules and plaques that extend from the pretibial area down to the dorsa of the feet. Lesions often develop after treatment of hyperthyroidism, although they can occur at any stage in the evolution of Graves disease.
Onycholysis, the separation of the nail plate from the nail bed, occurs in many patients with hyperthyroidism. Other autoimmune skin diseases, such as vitiligo and alopecia areata, are increased in patients with Graves disease. Manifestations of thyroid disease include the stigmata of hypothyroidism. Patients can develop alopecia; specifically, they can lose the lateral third of the eyebrows. Edematous thickening of the lips, tongue, and nose occur as well.
Patients with any of a number of gastrointestinal diseases may present with cutaneous manifestations; similarly, patients with certain cutaneous diseases can develop gastrointestinal complications.
The carcinoid syndrome is characterized by episodic flushing that can be associated with abdominal pain, diarrhea, and wheezing. Ninety percent of carcinoid tumors originate in the gastrointestinal tract; however, bronchial carcinoids occur occasionally. Less common cutaneous manifestations of carcinoid tumors include sclerodermatous changes. Cutaneous metastases present as deep nodules; hyperkeratosis may occur; and the patient may experience pigmentation changes similar to those seen in pellagra.
INFLAMMATORY BOWEL DISEASE
There are several specific and nonspecific cutaneous manifestations of inflammatory bowel disease [see 4:IV Inflammatory Bowel Diseases]. In both Crohn disease and ulcerative colitis, disease can progress to a hypercoagulable stage, causing venous and arterial thromboses that can lead to loss of digits and limbs. Aphthous stomatitis is another nonspecific manifestation of inflammatory bowel disease [see Figure 7]. In patients with Crohn disease, the lesions may appear as noncaseating granulomas, whereas in patients with ulcerative colitis, they may be indistinguishable from canker sores.
Figure 7. Aphthous Stomatitis in Ulcerative Colitis
Aphthous stomatitis is a common finding in patients with ulcerative colitis.
Pyoderma gangrenosum occurs in patients with Crohn disease and ulcerative colitis and has also been reported in patients with chronic active hepatitis, rheumatoid arthritis, and a number of myeloproliferative disorders. The lesions are distinguishable from other ulcers by the presence of craterlike holes, pustules, and purulent drainage [see Figure 8]. Pyoderma gangrenosum may occur at sites of trauma. Treatment with intralesionally injected or systemic corticosteroids may be required. Immunosuppressive agents such as cyclosporine have proved to be dramatically effective; in refractory cases, thalidomide has been shown to be beneficial.27 Infliximab has proved to be highly effective in the treatment of refractory pyoderma gangrenosum.28
Figure 8. Pyoderma Gangrenosum
Pyoderma gangrenosum is characterized by ulcers that begin with craterlike holes draining pus.
Erythema nodosum is a septal panniculitis that is associated with a number of conditions, including Crohn disease, ulcerative colitis, Behçet syndrome, sarcoidosis, infection, and the ingestion of estrogens and other drugs. Other manifestations of Crohn disease include inguinal abscesses and sinuses and anal fistulas.
METASTATIC CROHN DISEASE
The term metastatic Crohn disease refers to histologically proven noncaseating granulomas that are remote from the gastrointestinal tract in patients with Crohn disease. The clinical presentation can be quite variable, and the diagnosis of this disorder is frequently missed. In some cases, patients present with marked swelling of the scrotum or vulva.
CUTANEOUS CONDITIONS WITH GASTROINTESTINAL COMPLICATIONS
Cowden disease is an autosomal dominant disorder in which gastrointestinal polyps develop along with numerous skin lesions. This disease has been attributed to mutations of the tumor suppressor gene PTEN.29 Wartlike papules known as trichilemmomas occur, particularly around the nose, mouth, and ears but also on the hands and feet [see Figure 9]. Small papules can also develop on the gingival mucosa, creating a cobblestone appearance. Hemangiomas and lipomas can occur.30 A distinctive nodule of the scalp known as Cowden fibroma has been described. Up to 50% of women with Cowden disease develop breast cancer, a finding that has been associated independently with the PTEN mutation.31 Thyroid carcinomas, thyroid adenomas, and thyroid goiters can occur as well.
Figure 9. Trichilemmomas in Cowden Disease
The patient's nose and cheeks are covered with small papules called trichilemmomas, which represent the cutaneous hallmark of Cowden disease.
Dermatitis herpetiformis is an immunobullous disease that is associated with a gluten-sensitive enteropathy [see 2:IX Vesiculobullous Diseases]. Skin lesions begin as vesicles that are so pruritic that they are quickly broken by scratching, leaving only excoriations and crusts [see Figure 10]. Like patients with celiac disease who are not on a gluten-free diet, patients with dermatitis herpetiformis have an increased risk of gastrointestinal lymphoma.32
Figure 10. Lesions of Herpetiformis
The primary lesions of herpetiformis are vesicles that quickly break to form crusts and erosions.
In Peutz-Jegher syndrome, patients develop hamartomatous polyps of the small intestine that are associated with pigmented macules of the lips and oral mucosa [see 2:X Malignant Cutaneous Tumors]. Also, pigmented macules can develop on the palms, fingers, soles, and toes and in areas around the mouth, nose, and rectum. The disease is inherited as an autosomal dominant trait, and a significant proportion of cases are associated with mutations in the serine/threonine protein kinase I1/LKB1 (STKI1/LKB1) gene, although mutations in this gene do not account for all cases.33
Recessive Dystrophic Epidermolysis Bullosa
Recessive dystrophic epidermolysis bullosa is a congenital bullous disease with recurrent blistering and scarring, particularly on the hands and feet [see 2:IX Vesiculobullous Diseases]. The scarring results in pseudosyndactyly, giving rise to mittenlike hands. Ingestion of coarse food can result in mucosal bullae of the esophagus, which heal with scarring and stricture formation. Dysphagia is a frequent complaint. Scarring of the esophagus can lead to squamous cell carcinoma, which is a leading cause of death in this disorder.34 Gastroenterologists and dermatologists must play key roles in the management of these patients. Liquid and pureed diets and appropriate skin care are essential to the survival of patients with this debilitating disorder. Prenatal diagnosis can be made by sampling DNA from the chorionic villus.35 All forms of dystrophic epidermolysis bullosa have been attributed to mutations in the type VII collagen gene.36 Recently, through the use of a self-inactivating minimal lentivirus-based vector, the type VII collagen gene has been delivered and type VII collagen expressed in immunodeficient mice, suggesting the possibility that, in the future, gene therapy may be available to successfully treat this devastating disorder.37
There are several forms of local and systemic amyloidosis [see 12:XV Chronic Lymphoid Leukemias and Plasma Cell Disorders]. In a form associated with multiple myeloma, amyloid fibrils consisting of immunoglobulin light chains are deposited in the skin. Shiny translucent papules develop, particularly on the eyelids. Because of amyloid deposits in blood vessels, spontaneous bleeding occurs. Minimal trauma results in petechiae and purpura. Macroglossia also occurs in some patients with myeloma-associated amyloidosis and in some with primary systemic amyloidosis. The systemic manifestations of myeloma-associated and primary systemic amyloidosis are quite varied. Hepatomegaly develops in 50% of patients. Amyloid can affect the heart, resulting in heart failure or myocardial infarction. Survival of patients who undergo heart transplantations for cardiac amyloidosis is lower than survival after cardiac transplantation for other indications.38Amyloidosis of the gastrointestinal tract can result in malabsorption and protein-losing enteropathy. Treatment with thalidomide (up to 400 mg daily) and intermittent dexamethasone is rapidly effective in some patients, but side effects are frequent.39
Mastocytosis is caused by the infiltration of mast cells into the skin and other organs [see 4:XI Diseases Producing Malabsorption and Maldigestion]. Urticaria pigmentosa refers to the skin lesions that occur in most patients with mastocytosis. Reddish-brown macules and papules resembling nevi are characteristic [see Figure 11]. Stroking of individual lesions results in urticarial wheals—a phenomenon known as the Darier sign. Pruritus, flushing, abdominal pain, nausea, vomiting, and diarrhea are common complaints.
Figure 11. Urticaria Pigmentosa
Multiple brown macules resembling nevi occur in patients with urticaria pigmentosa.
Most patients with mastocytosis have an indolent form of the disease, even when mast cells have infiltrated the bone marrow.40 Malignant or aggressive systemic mast cell disease can involve the spleen, liver, and lymph nodes in addition to the skin and bone marrow. Histologically, infiltrates contain atypical nonmetachromatic mast cells that are monoclonal in some patients.41 Children with urticaria pigmentosa usually have a better prognosis than adults with the disease.42
The diagnosis of mastocytosis is made by the demonstration of mast cells on skin biopsy. Because mast cells easily degranulate, making them difficult to identify, biopsies should be performed with a minimum of tissue manipulation.
The porphyrias result from defective hemoglobin synthesis, leading to excess porphyrins in the blood and in body tissues [see 9:VII The Porphyrias].
Congenital Erythropoietic Porphyria
Congenital erythropoietic porphyria is a rare autosomal recessive disorder that has been attributed to mutations in the gene for uroporphyrinogen III synthase.43 This condition is characterized by severe photosensitivity. Vesicles and bullae develop after sun exposure; these lesions heal with scar formation. Erythrodontia (red-stained teeth) is a characteristic feature [see Figure 12]. Digit, ear, and nose loss is common in patients who manage to survive to adulthood [see Figure 13]. Hypertrichosis is another frequent complication. Formation of gallstones, splenomegaly, and hemolytic anemia are also associated with this condition.
Figure 12. Erythrodontia in Congenital Erythopoietic Porphyria
A reddish pigmentation (erythrodontia) occurs when porphyrins are deposited in the teeth in congenital erythropoietic porphyria.
Figure 13. Skin Changes in Congenital Erythropoietic Porphyria
Skin changes in congenital erythropoietic porphyria can be severe; scarring and loss of digits are common in older patients.
Porphyria Cutanea Tarda
Porphyria cutanea tarda is characterized by photosensitivity, vesicle formation (especially on the dorsa of the hands) [see Figure 14], and hypertrichosis. The condition may be associated with ingestion of alcohol or medications such as estrogens. Diagnosis of the porphyrias can be established by elevated urinary porphyrin levels. Examination of the urine with a Wood lamp will often reveal pink-red fluorescence attributable to the high level of urinary porphyrins. Porphyria cutanea tarda can be associated with hepatitis C. Phlebotomy is effective therapy.
Figure 14. Vesicles and Bullae in Porphyria Cutanea Tarda
Cruting and scarring follow the appearance of vesicles and bullae in porphyria cutanea tarda.
AIDS may result in cutaneous infections and neoplasms that are often dramatic in their extent and severity. This section focuses on selected cutaneous manifestations of infections and other diseases associated with AIDS. (For a more comprehensive discussion of disorders associated with HIV infection, see 7:XXXIII HIV and AIDS and other chapters devoted to specific conditions.)
Banal viral infections, such as molluscum contagiosum, that are ordinarily self-limited and easily curable have become widespread, chronic, and enormous problems in patients with AIDS. These umbilicated white papules, ordinarily only a few millimeters in diameter, can reach diameters of 1 to 2 cm in patients with AIDS. Similarly, condyloma acuminatum, caused by human papillomavirus (HPV) infection, is often difficult to treat in patients with AIDS.
Herpes simplex virus infections become chronic and erosive, forming large, nonhealing ulcers [see 7:XXVI Herpesvirus Infections]. Acyclovir-resistant strains of herpes simplex virus have been reported in some patients with AIDS44; these patients require other antiviral agents, such as foscarnet. Mutations in thymidine kinase and DNA polymerase genes of herpes simplex viruses can render them resistant to acyclovir and foscarnet.45 Topical cidofovir gel has been reported to be beneficial for herpes infections in patients infected with HIV.46
Herpes zoster infections are a common sign of HIV infection. In the non-HIV-infected host, herpes zoster is characterized by grouped vesicles in a dermatomal distribution. The eruption is self-limited, resolving within 1 to 2 weeks. In contrast, herpes zoster infection can develop into a disseminated vesicular eruption in patients with AIDS; and in some AIDS patients, chronic herpetic lesions develop and last for months.
Fungal infections are common in patients with HIV infection. Monilial infections include oral thrush and candidiasis of the groin. Several fungal infections that rarely cause widespread infection in patients with normal immune systems (e.g., cryptococcosis, histoplasmosis, aspergillosis, and sporotrichosis) have emerged as serious pathogens in patients with AIDS.
Bacterial infections are more frequent and severe in patients with AIDS than in patients with normal immune systems. Bacillary angiomatosis, caused by Bartonella henselae, presents as purple papules and nodules that can be mistaken for Kaposi sarcoma (see below). Chronic fever and chills can occur, as can bone lesions. Epidemiologic evidence suggests that cats may be the source of human infection.47Diagnosis by serologic testing has been commonly used, but in the future, polymerase chain reaction may offer a rapid and convenient way of establishing this diagnosis.48 The condition resolves upon treatment with oral antibiotics [see 7:XI Infections Due to Brucella, Francisella, Yersinia pestis, and Bartonella].
Scabies and other pruritic eruptions
Scabies, a severely pruritic eruption, has a predilection for the buttocks, the genitals, the periumbilical area, and the webs between the fingers. Norwegian scabies, a thickly crusted psoriasislike form of the parasitic disease, has been described in patients with Down syndrome and in other immunosuppressed persons. In recent years, Norwegian scabies has been reported most commonly in patients with AIDS. The scales of Norwegian scabies contain thousands of mites that are easily seen with the microscope. Burrows form linear lesions up to 1 cm long. The causative mite, Sarcoptes scabiei, can be identified by microscopic examination of scrapings from the burrows.
Eosinophilic pustular folliculitis and papular eruption of AIDS are pruritic rashes that affect patients with HIV infection. It has been suggested that pruritic papular eruption in patients with HIV infection may represent a reaction to arthropod bites.49 Both eosinophilic pustular folliculitis and papular eruption of AIDS are characterized by severe itching, and skin-colored papules and excoriations are common in both. Patients with eosinophilic pustular folliculitis can develop pustules and erythematous papules. Both conditions respond to treatment with ultraviolet B.
Kaposi sarcoma, a slowly progressive vascular neoplasm, was originally described in elderly Italian and Jewish men [see 2:X Malignant Cutaneous Tumors]. Subsequently, a more rapidly progressive form of the disorder was described in immunosuppressed patients with lymphomas and in kidney transplant patients on immunosuppressive drugs. An aggressive form has been described in patients with AIDS [see Figure 15]. Classic Kaposi sarcoma typically affects the lower extremities and only gradually progresses to other sites. In contrast, AIDS-related Kaposi sarcoma can occur on any surface of the body, including mucous membranes. Human herpesvirus type 8 has been implicated in both classic and AIDS-related Kaposi sarcoma.50 Treatments include radiation therapy, cryotherapy, and intralesional injection with vinblastine; systemic chemotherapy can also be effective. In patients with AIDS, Kaposi sarcoma is best treated with antiretroviral regimens.
Figure 15. Kaposi Sarcoma
Kaposi sarcoma is the most common malignancy of AIDS patients. It often presents as purple patches, plaques, or papules. Purple macules on the foot can be seen in patients with classic Kaposi sarcoma but are seen here in a patient with AIDS-related Kaposi sarcoma.
Oral Hairy Leukoplakia
Oral hairy leukoplakia, another condition that has been described in HIV-infected patients, consists of linear white papules on the lateral surfaces of the tongue that result in the so-called hairy appearance. Oral hairy leukoplakia can be distinguished from oral thrush in that the lesions cannot be rubbed off, as they can be in thrush.
Thanks to the development of effective antiretroviral therapy, the frequency of opportunistic infections in patients with HIV infection has diminished markedly.
OTHER IMMUNODEFICIENT STATES
Other inherited or acquired immunodeficiency states share a number of clinical features. Susceptibility to monilial infections or bacterial infections is increased in disorders such as chronic granulomatous disease and chemotherapy-induced neutropenia. Oral ulcers similarly occur in cyclic neutropenia and in chemotherapy-induced immunosuppression.
Some immunosuppressive drugs have characteristic cutaneous effects. Corticosteroids, when used long-term, cause vascular fragility, resulting in steroid purpura. They can also cause cutaneous atrophy, formation of striae, and acneiform eruptions. Cyclosporine is associated with hypertrichosis. Aphthous stomatitis is a characteristic effect of numerous immunosuppressive drugs, particularly agents that suppress bone marrow function. Chronic immunosuppression can lead to the development of lymphoma and nonmelanoma skin cancer. Avoidance of excessive exposure to sunlight may prevent development of the latter.
Cutaneous manifestations can be major features of a number of systemic infections; for example, patients with overwhelming septicemia can develop disseminated intravascular coagulation (DIC), which results in cutaneous infarcts and hemorrhage into the skin. Key cutaneous features of selected systemic infections follow.
The cutaneous manifestations of infective endocarditis include petechiae, splinter hemorrhages (linear red streaks under the nail), Osler nodes (tender purpuric nodules on the finger pads and toes), and Janeway lesions (nontender purpuric macules of the palms and soles). Skin lesions are caused by either septic emboli or vasculitis. Treatment of the underlying infection results in resolution of the cutaneous manifestations [see 7:XVIII Infective Endocarditis].
STAPHYLOCOCCAL TOXIC-SHOCK SYNDROME
Staphylococcal toxic-shock syndrome was first recognized in menstruating women who used superabsorbent tampons [see 7:I Infections Due to Gram-Positive Cocci]. It is caused by an exotoxin produced by certain strains of S. aureus.51 Staphylococcal infections in bone, soft tissue, and other sites have been implicated. Patients develop diffuse sunburnlike erythema, with swelling of the hands and feet, followed by desquamation of the palms and soles. Erythema of mucous membranes, fever, and hypotension also occur. Gastrointestinal symptoms, impaired renal function, elevated liver function values, thrombocytopenia, and myositis can develop.
STAPHYLOCOCCAL SCALDED SKIN SYNDROME
Staphylococcal scalded skin syndrome (SSSS) is caused by a circulating exfoliative toxin produced by S. aureus phage group 11. Generalized bulla formation with large areas of desquamation is characteristic of the disorder. Along with tenderness, erythema, and exfoliation of skin, patients have fever. The source of the staphylococcal infection is not always apparent; occasionally, the infection arises in a wound or in an occult abscess. Because the staphylococcal infection is usually remote from the affected skin, culture of the skin does not grow S. aureus.
SSSS must be differentiated from toxic epidermal necrolysis. Toxic epidermal necrolysis commonly affects adults and involves mucous membranes; SSSS usually affects children and spares mucous membranes. In addition, toxic epidermal necrolysis can last for several weeks and has a high mortality, whereas SSSS lasts a few days and usually has a good outcome. Histologically, SSSS shows bulla formation in the upper epidermis, and the bulla cavity contains free-floating, normal-appearing, acantholytic cells. In toxic epidermal necrolysis, bulla formation occurs at the basal layer of the epidermis, and the epidermal cells are necrotic. Treatment with antibiotics effective against S. aureus eliminates the underlying cause of SSSS.
Necrotizing fasciitis is caused by a mixed anaerobic infection of an ulcer or a surgical or traumatic wound. The affected skin is erythematous, warm, and tender and develops hemorrhagic bullae that rupture to form rapidly enlarging areas of gangrene that extend down to the fascia. Surgical debridement is essential for this life-threatening infection.52
Acute meningococcemia can occur either in epidemics or in isolated cases [see 7:III Infections Due to Neisseria]. Fever, headache, and a hemorrhagic rash develop. If untreated, patients develop DIC, with extensive hemorrhage, hypotension, and ultimately death. The causative organism, Neisseria meningitidis, is usually identified in cerebrospinal fluid but can also be identified by smear or cultures of skin lesions or by blood cultures. Treatment with antibiotics and supportive care are essential aspects of therapy.
Scarlet fever begins with pharyngitis caused by group A Streptococcus [see 7:I Infections Due to Gram-Positive Cocci]. A generalized rash develops 1 to 2 days after onset of the pharyngitis. The rash is characterized by pinpoint erythematous papules that may be easier to palpate than to see. Other characteristic lesions include a white strawberry tongue and linear petechial macules occurring in body folds (Pastia lines). As the rash fades, desquamation of the palms and soles appears. Treatment with penicillin results in rapid resolution of all symptoms.
Vibrio vulnificus infection arises from minor trauma sustained while swimming in lakes or the ocean or while cleaning seafood. Cellulitis occurs, with lymphangitis and bacteremia. In patients with hepatic cirrhosis, infection can occur after eating raw oysters. These patients develop hemorrhagic bullae, with leukopenia and DIC.53 Treatment with antibiotics is necessary; management of complications may require intensive supportive care.
Lyme disease is caused by the spirochete Borrelia burgdorferi and is transmitted primarily by the tick Ixodes scapularis [see 7:XVII Infections Due to Rickettsia, Ehrlichia, and Coxiella]. The characteristic skin lesion, erythema chronicum migrans, begins as an erythematous macule or papule at the site of the tick bite. Over days and weeks, the erythematous lesion expands to form a red ring, often with central clearing. If left untreated, lesions last weeks or months. Hematogenous dissemination of spirochetes occurs after several weeks, resulting in multiple annular patches of erythema chronicum migrans [see Figure 16]. Systemic complications include an acute arthritis involving one or a few large joints a few weeks after the onset of symptoms. A chronic erosive arthritis develops in approximately 10% of patients. Neurologic symptoms, including Bell palsy, can occur, as can cardiac complications, including heart failure and cardiac conduction abnormalities.
Figure 16. Erythema Chronicum Migrans in Lyme Disease
Several weeks after primary infection with Lyme disease, hematogenous dissemination of spirochetes results in multiple patches of erythema chronicum migrans.
Lyme disease can be prevented by the removal of ticks within 18 hours of attachment. Once symptoms have developed, oral antibiotics are effective at destroying B. burgdorferi. A vaccine containing a genetically engineered protein from the surface of the bacteria was found to prevent infection in most vaccinated people54; however, for a number of reasons, including lack of demand, the vaccine has been discontinued.55
ROCKY MOUNTAIN SPOTTED FEVER
Rocky Mountain spotted fever (RMSF) is a tick-borne illness caused by Rickettsia rickettsii [see 7:XVII Infections Due to Rickettsia, Ehrlichia, and Coxiella]. It is characterized by the sudden onset of fevers, chills, and headache. Approximately 4 days later, a characteristic erythematous rash develops on the wrists and ankles and becomes purpuric. The rash then spreads centrally to involve the extremities, trunk, and face.
Because the mortality of RMSF is high, patients should be treated immediately with intravenous chloramphenicol or tetracycline if RMSF is suspected. Diagnosis can then be established by skin biopsy: immunofluorescence with antibodies against R. rickettsii shows the organism in the walls of cutaneous blood vessels. Serologic tests, such as the Weil-Felix reaction, can confirm the diagnosis after the acute phase of the illness.
BASAL CELL NEVUS SYNDROME
The basal cell nevus syndrome is an autosomal dominant disorder attributed to mutational inactivation of the PTCH gene56 in which patients develop basal cell carcinomas at an early age [see 2:X Malignant Cutaneous Tumors]. Multiple skeletal abnormalities are associated with the syndrome, and affected individuals may also develop jaw cysts. Lamellar calcification of the falx cerebri occurs, as well as other neurologic abnormalities, including medulloblastomas.
EPIDERMAL NEVUS SYNDROME
The epidermal nevus syndrome is characterized by systemic manifestations, such as seizures, mental retardation, blindness, and skeletal abnormalities in association with large epidermal nevi. The nevi consist of long pigmented streaks that are linear or whirled and involve large areas of the body [see Figure 17].
Figure 17. Epidermal Nevus Syndrome
The epidermal nevus syndrome is characterized by linear or whirled streaks of pigmentation that involve large areas of the body.
Incontinentia pigmenti is an inherited syndrome that affects the skin and nervous system. Mutations in the NEMO gene, an essential component of the nuclear factor-κB signaling cascade, account for 85% of cases.57 The inheritance pattern is X-linked dominant and is lethal in male fetuses. The first skin manifestations begin within weeks after birth, occasionally occurring in utero, and consist of linear patterns of vesiculobullous lesions. Within weeks, these lesions evolve into verrucous papules and, eventually, into pigmented whirls. Apart from neurologic symptoms, patients may have ocular abnormalities, scarring alopecia, and skeletal malformations.
Hypomelanosis of Ito
Hypomelanosis of Ito, also called incontinentia pigmenti achromians, consists of whirls of hypopigmentation that are associated with neurologic symptoms in 50% of patients. Skin lesions are present at birth or develop in early childhood. In addition to seizures and mental retardation, skeletal and ocular abnormalities occur.
Neurofibromatosis is a common autosomal dominant disorder involving the skin and nervous system [see 2:XI Benign Cutaneous Tumors]. Skin lesions include cutaneous neurofibromas, which are soft, skin-colored nodules that are often pedunculated [see Figure 18]. Café au lait macules are flat, evenly pigmented patches up to several centimeters in diameter. Six or more café au lait macules greater than 1.5 cm in diameter are found in most patients with neurofibromatosis type 1 (also called von Recklinghausen disease). Plexiform neuromas are larger, deeper tumors that are associated with hypertrophy of bony and soft tissues. In a small proportion of tumors, neurofibrosarcomas will arise. On skin biopsy, café au lait macules are found to contain macromelanosomes—giant granules of pigment in melanocytes and keratinocytes. Axillary and inguinal freckling also appear as pigmented macules that resemble small café au lait spots in intertriginous sites. Lisch nodules—pigmented iris hamartomas—are also found in most patients with neurofibromatosis.
Figure 18. Neurofibramatosis
Axillary freckling, café au lait spots, and neurofibromas are evident in a patient with neurofibromatosis type 1.
Several variants of neurofibromatosis exist, including segmental neurofibromatosis, in which patients develop a segmental distribution of café au lait spots and cutaneous neurofibromas, and neurofibromatosis type 2, which consists of acoustic neuromas, schwannomas, and meningiomas without Lisch nodules and with fewer café au lait macules than appear in type 1. Patients with neurofibromatosis type 2 may have some cutaneous neurofibromas as well. Neurofibromatosis types 1 and 2 are caused by different genetic defects. Neurofibromatosis type 1 is caused by mutations in the NF1 gene for neurofibromin on chromosome 17.58 Neurofibromatosis type 2 has been attributed to inactivating mutations in the NF2 tumor suppressor gene whose product, merlin, plays a number of roles in tumorigenesis.59
Sneddon syndrome is a disease of the skin and nervous system caused by occlusion of small to medium-sized arteries in persons younger than 45 years. The skin lesions resemble livedo reticularis and have been called livedo racemosa. Transient ischemic attacks or strokes are common. Definitive diagnosis is made by demonstrating characteristic vascular changes on skin biopsy of patients with associated neurologic findings.
Tuberous sclerosis is an autosomal dominant disease that affects the skin and nervous system. Mutations that inactivate the TSC1 or TSC2tumor suppressor genes affect the respective gene products, hamartin and tuberin, leading to tuberous sclerosis.60 Affected patients can develop seizures, mental retardation, and brain lesions called tubers, which can be seen on CT scans. Adenoma sebaceum, the most characteristic cutaneous manifestation of tuberous sclerosis, consists of skin-colored papules of the face [see Figure 19a]. Other skin lesions are hypopigmented macules referred to as ash-leaf macules [see Figure 19b], smaller hypopigmented lesions called confetti macules, periungual and subungual fibromas (skin-colored nodules that arise around the fingers and toenails) [see Figure 19c], and the shagreen patch (a skin-colored plaque made of thick dermal connective tissue).
Figure 19a. Tuberous Sclerosis: Adenoma Sebaceum
Several of the characteristic cutaneous findings of tuberous sclerosis are shown: adenoma sebaceum (shown here); ash-leaf macule (see Figure 19b); and periungual fibromas (see Figure 19c).
Figure 19b. Tuberous Sclerosis: Ash-leaf Macule
Several of the characteristic cutaneous findings of tuberous sclerosis are shown: adenoma sebaceum (see Figure 19a); ash-leaf macule (shown here); and periungual fibromas (see Figure 19c).
Figure 19c. Tuberous Sclerosis: Periungual Fibromas
Several of the characteristic cutaneous findings of tuberous sclerosis are shown: adenoma sebaceum (I>see Figure 19a); ash-leaf macule (see Figure 19b); and periungual fibromas (shown here).
Fabry disease is caused by an abnormality of α-galactosidase A, resulting in deposition of glycosphingolipids in body tissues. The disorder is inherited as an X-linked recessive trait. A variety of different mutations in the gene for α-galactosidase A have been found in unrelated families with Fabry disease.61 Affected males often complain of severe pain in the extremities, with burning of the palms and soles. Episodes of pain are transient, but patients complain of persistent paresthesias in the hands and feet.
Skin lesions consist of angiokeratomas, which are pinpoint red or purple papules that resemble cherry hemangiomas [see Figure 20]. Angiokeratomas are most commonly found in the periumbilical area but can also occur on the palms, soles, trunk, extremities, and mucous membranes. In adults, glycosphingolipids become deposited in blood vessels and organs, affecting the heart, heart valves, coronary arteries, and kidneys. Replacement therapy with recombinant human α-galactosidase A can improve cutaneous, gastrointestinal, neurologic, and psychiatric symptoms; it has been shown to be safe and can eliminate substrate storage of glycosphingolipids, but questions remain regarding optimal dosing.62
Figure 20. Angiokeratomas in Fabry Disease
Angiokeratomas are particularly common in the periumbilical area of patients with Fabry disease.
Polyarteritis nodosa is an inflammatory condition that affects muscular arteries [see 15:VIII Systemic Vasculitis Syndromes]. Aneurysms form in many arteries, including those leading to the kidneys and subcutaneous tissue. Diagnosis of the systemic form of polyarteritis can be made by demonstrating aneurysms of the renal arteries on renal arteriograms.
A localized cutaneous form of polyarteritis nodosa most commonly presents as painful nodules of the lower extremities.63 In mild cases, patients may only have livedo reticularis; but in severe cases, skin lesions can ulcerate. A polyneuropathy may be associated with the disorder. Patients with classic polyarteritis and microaneurysms have an increased incidence of hepatitis B antigenemia; in contrast to patients with other vasculitides, they usually do not have antineutrophil cytoplasmic antibodies.64
Perforating disorders include several conditions characterized by extrusion of dermal material through the epidermis. These lesions often develop in association with renal failure and diabetes mellitus.65 Skin lesions are characterized by hyperkeratotic papules with central white craters that histologically can be shown to contain dermal material. Reactive perforating collagenosis, perforating folliculitis, and Kyrle disease are all examples of perforating disorders associated with renal failure.
Calciphylaxis, also known as calcific uremic arteriolopathy, is a condition of patients with renal failure in which localized areas of skin become necrotic as a result of vascular calcification. Calciphylaxis begins with painful purpuric patches that may be reticulated, resembling livedo reticularis. These patches progress to indurated plaques that may ulcerate, becoming necrotic [see Figure 21]. Calciphylaxis often eventuates in amputation or death. Parathyroidectomy may result in healing of affected skin without amputation.66
Figure 21. Calciphylaxis
Calcification of arteries in patients with renal failure results in calciphylaxis. Affected skin forms a black, necrotic eschar.
The best-known cutaneous manifestations of dermatomyositis, an inflammatory disorder of muscle and skin, are Gottron papules and heliotrope erythema. Gottron papules are erythematous scaling macules and papules that occur on the dorsa of the knuckles [see Figure 22]. Heliotrope erythema consists of periorbital erythema and edema. Scalp lesions, which can be associated with alopecia, have been described.67 The lesions are often misdiagnosed as seborrheic dermatitis or psoriasis.
Figure 22. Gottron Papules in Dermatomyositis
Erythematous scaling papules on the dorsal aspects of the knuckles (Gottron papules) are a sign of dermatomyositis.
The association between dermatomyositis and malignancy has been established68,69; one epidemiologic study indicates patients with dermatomyositis are at particular risk for ovarian and lung cancer.69
Classifications of dermatomyositis include a juvenile variant characterized by calcification of skin or muscle. A vasculitic form in children is complicated by cutaneous infarcts and ulceration and by gastrointestinal vasculitis with abdominal pain, bleeding, or perforation. The vasculitic form carries a poor prognosis, with many of the patients dying of this disease.
SCLERODERMA AND SCLERODERMA-LIKE DISEASES
The sclerodermas include a number of distinct syndromes sharing a common feature, induration of the skin [see 15:V Scleroderma and Related Diseases].
Progressive Systemic Sclerosis and CREST Syndrome
Progressive systemic sclerosis, also known as systemic scleroderma, is a frequently fatal disease in which patients present with Raynaud phenomenon and sclerodactyly (induration of the skin of the digits) [see Figure 23]. Cutaneous induration can become widespread. Involvement of the face can lead to a characteristic appearance with pursed lips and bound-down skin of the nose that creates a beaklike appearance. Patients with antibodies to Scl-70 have a poor prognosis, often succumbing to renal disease and malignant hypertension. Pulmonary fibrosis can occur. Patients with anticentromere antibodies have a more slowly progressive variant of scleroderma known as the CREST syndrome, which is characterized by cutaneous calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia. With time, pulmonary hypertension and right-sided heart failure develop.
Figure 23. Sclerodactyly in Systemic Sclerosis
Sclerodactyly with a nonhealing digital ulcer commonly occurs in progressive systemic sclerosis.
Morphea, also called localized scleroderma, is characterized by sharply demarcated patches of indurated skin that can become generalized. It is distinguished from progressive systemic sclerosis by the absence of Raynaud phenomenon, sclerodactyly, or the systemic complications of scleroderma. There have been innovations in the treatment of both progressive systemic sclerosis and morphea. Exposure to psoralen and longwave ultraviolet light (PUVA) has been reported to improve progressive systemic sclerosis and morphea dramatically,70 and exposure to UVA1 (the longer UVA spectrum, from 340 to 400 nm) has been reported to benefit patients with localized scleroderma.71 Anecdotal evidence suggests that topical calcipotriene is an effective treatment for morphea.72 Further studies must be done to confirm the efficacy of these treatments. Anecdotal reports have indicated that minocycline may benefit patients with progressive systemic sclerosis, but controlled trials are needed.73
Graft versus Host Disease
As organ transplantation becomes more common, another scleroderma-like illness, graft versus host disease, increases in frequency, particularly after bone marrow transplantation [see 5:X Transfusion Therapy and 5:XI Hematopoietic Stem Cell Transplantation]. There are two stages of graft versus host disease. The first, acute graft versus host disease, develops 10 to 40 days after transplantation and consists of an erythematous macular and papular rash that is often associated with fever, hepatomegaly, lymphadenopathy, or gastrointestinal symptoms. Chronic graft versus host disease usually develops 3 months after transplantation but can occur later; it consists of purple papules resembling lichen planus [see Figure 24]. Sclerodermatous skin changes with telangiectasia, reticulated hyperpigmentation, and alopecia are most characteristic. Both cyclosporine and PUVA have proved to be useful in the prevention and treatment of graft versus host disease.74,75 Infliximab has been used very successfully to treat acute graft versus host disease.76
Figure 24. Chronic Lichenoid Versus Graft Host Reaction
Flat-topped papules are seen in this chronic lichenoid graft versus host reaction.
Scleroderma-like hardening of the skin also occurs in eosinophilic fasciitis. Puckering of the skin on the extremities typically develops and is associated with pain. In contrast to progressive systemic sclerosis, Raynaud phenomenon does not occur. Definitive diagnosis requires biopsy of skin and fascia overlying the affected muscle. In some cases of eosinophilic fasciitis, hematologic abnormalities develop, including aplastic anemia, thrombocytopenia, Hodgkin disease, and leukemias.77
SYSTEMIC LUPUS ERYTHEMATOSUS
There are many cutaneous manifestations of systemic lupus erythematosus (SLE), including nonspecific manifestations such as Raynaud phenomenon, photosensitivity, alopecia, and mucosal ulcers. More specific cutaneous manifestations of SLE include so-called discoid lupus (characterized by round scarred skin lesions with central hypopigmentation and a rim of hyperpigmentation) and malar erythema [see 15:IV Systemic Lupus Erythematosus]. As we learn more about lupus, the spectrum of skin diseases associated with this disorder continues to expand. Subacute cutaneous lupus, a variant characterized serologically by anti-Ro and anti-La antibodies, is associated with annular or psoriasiform skin lesions [see Figure 25].
Figure 25. Subacute Cutaneous Lupus Erythematosus
Annular scaling erythematous patches are characteristic of subacute cutaneous lupus erythematosus.
Anticardiolipin Antibody Syndrome
The anticardiolipin antibody syndrome, which can occur in patients with SLE, has been described in patients who suffer repeated episodes of phlebitis, arterial thromboses, and repeated miscarriages. Cutaneous infarcts are common manifestations, and livedo reticularis can occur. Patients may have false positive serologies for syphilis and have a circulating lupus anticoagulant. Circulating antiphospholipid antibodies are the serologic hallmark of this syndrome; however, many asymptomatic persons have antiphospholipid antibodies,78 and antiphospholipid antibody tests can have false negative results. In some patients, a battery of tests may be needed to establish diagnosis; the dilute Russell viper venom time, an assay for circulating lupus anticoagulant, has been found to be among the more sensitive tests.79
Livedo vasculitis, another disorder that has been associated with lupus, is characterized by painful recurrent ulcers over the lower legs and ankles. The ulcers heal, leaving white sclerotic scars. Affected patients often have livedo reticularis. This condition, also known as atrophie blanche, has been attributed to thrombotic processes rather than immune complex deposition or leukocytoclastic vasculitis.80
Neonatal lupus is a distinct syndrome of annular, erythematous macules and papules occurring on the face of newborn infants. The disorder has been attributed to transplacental passage of anti-Ro and occasionally anti-La antibodies. Mothers are often asymptomatic, but some may have lupus or SjF6gren syndrome. Congenital heart block is the most serious complication of this disorder.81
Editors: Dale, David C.; Federman, Daniel D.