Cutaneous Signs of 10 Unusual Systemic Diseases
The above image shows the classic presentation of systemic sclerosis (SSc), also known as systemic scleroderma: thickened skin, a pinched nose, taut skin, and numerous telangiectasias.
Cutaneous manifestations of systemic disease may be the initial complaint that causes patients to seek out a healthcare provider. Clinicians must maintain a high index of suspicion for an underlying systemic disorder when patients present with unexplained dermatologic complaints. Can you identify and treat the following relatively uncommon conditions?
Cutaneous Signs of 10 Unusual Systemic Diseases
Nephrogenic Systemic Fibrosis
The above image shows nephrogenic systemic fibrosis (NSF), or nephrogenic fibrosing dermopathy, on the leg of an affected patient.
NSF is a fibrotic disease of the skin and internal organs that develops in patients with renal insufficiency after exposure to gadolinium-based contrast agents (GBCAs). Most patients with NSF are undergoing hemodialysis or peritoneal dialysis or have had a renal transplantation.
The condition is similar to, yet distinct from, scleroderma, scleromyxedema, and eosinophilic fasciitis. The exact mechanism of action has not been established, but it may involve a circulating fibrocyte that is stimulated by gadolinium.[1,2] A study of patients with end-stage renal disease found the overall incidence of NSF to be 4.3 cases per 1000 patient-years; each radiologic study that uses gadolinium carries a 2.4% risk for NSF.[3] Disease onset may be insidious, potentially taking place months to years after the initial insult, or it may be rapid, occurring over the course of days to weeks. Patients may report pain and pruritus. On physical examination, patients have indurated, thickened, shiny, and hardened skin with brawny hyperpigmentation.
Cutaneous Signs of 10 Unusual Systemic Diseases
Distinct papules and subcutaneous nodules may be present in patients with NSF, and the skin may develop a woody texture. In some patients, the skin may resemble the texture of an orange (ie, peau d'orange), as seen in this abdominal image. The lesions are typically symmetrical, with the ankles and thighs most commonly involved, followed by the wrists and upper arms. The trunk and especially the face are less commonly involved. Radiographs may show calcifications of the soft tissue. Laboratory studies are typically aimed at ruling out other potential causes of these cutaneous manifestations; commonly, the only abnormal findings are elevated blood urea nitrogen (BUN) and creatinine levels.
Cutaneous Signs of 10 Unusual Systemic Diseases
Formal diagnosis of NSF is usually made with a deep skin biopsy, which may show thickened collagen bundles with surrounding clefts, mucin deposition, and proliferation of fibroblasts and elastic fibers.[4] The histology slide shown here reveals increased fibroblast-like cells in the dermis reaching into the fascia. The overall NSF disease course is chronic and progressive, with minimal chance for recovery in the absence of improved renal function. No consistently successful treatment options exist, but extracorporeal photopheresis may be the most promising therapy, and research is ongoing. Overall mortality rates have been reported to be 48% and 20% for patients with and without cutaneous manifestations, respectively.[5] Complications from excessive fibrosis (eg, reduced mobility, restricted ventilation) are the most common causes of death. In recent years, new guideline recommendations (including limiting GBCAs and delaying the use of these agents in patients with acute renal failure) have helped to vastly reduce the number of cases of NSF.[6]
Cutaneous Signs of 10 Unusual Systemic Diseases
Systemic Sclerosis
The above image shows telangiectasias and perioral radial furrows in a patient with SSc.
SSc is a systemic connective tissue disease characterized by vasomotor instability, fibrosis, and immunologic disturbances, as well as by atrophy of the skin, subcutaneous tissue, muscles, and internal organs. The exact pathophysiology of SSc is incompletely understood but involves excessive collagen deposition through a combination of genetic, environmental, vascular, immunologic, and microchimeric factors. SSc is a rare disease, with an annual prevalence of 50-300 cases per 1 million people.[7] Initial presentations are protean, with patients reporting pruritus, Raynaud phenomenon, dysphagia, dyspnea, palpitations, nonproductive cough, fatigue, atypical chest pain, joint pain or swelling, weakness, and muscle aches.
Cutaneous Signs of 10 Unusual Systemic Diseases
The above image shows contraction flexures of the fingers in SSc, with autoamputation of the distal phalanges due to ischemia.
The American College of Rheumatology and the European League Against Rheumatism (ACR/EULAR) jointly published SSc reclassification criteria in 2013 that are more sensitive and specific than the 1980 ACR criteria, as well as simpler to use.[8,9] Whereas the previous SSc classification involved one major criterion (proximal scleroderma) and two minor criteria (sclerodactyly, erosions, atrophy of the fingertips, bilateral lung fibrosis), the new classification scores weighted criteria, with a total score of 9 or more indicating definitive SSc.[8] Bilateral skin thickening of the fingers that extends proximal to the metacarpophalangeal joints represents a score of 9, which makes this finding alone sufficient for the diagnosis. The other seven weighted features in the new classification criteria are skin thickening of the fingers, fingertip lesions, Raynaud phenomenon, abnormal nail fold capillaries, telangiectasia, pulmonary arterial hypertension/interstitial lung disease, and the presence of SSc-related autoantibodies.[8]
Cutaneous Signs of 10 Unusual Systemic Diseases
The three distinct phases of cutaneous involvement in SSc are edematous, indurative, and atrophic. Other skin findings that may be present include generalized skin fibrosis of the chest and limbs, areas of hyperpigmentation and hypopigmentation (shown; lower legs), atrophy of the ala nasi and lips, telangiectasias, and nail fold capillary dilatation. Arterial fibrosis can lead to ulcers or autoamputations, as seen in the previous slide.
Histologic findings on skin biopsy include a loss of rete ridges, atrophy of epidermal skin appendages, and broad hyalinized collagen fibers in the reticular dermis. Mononuclear cells, mostly T cells, may form a perivascular infiltrate in the deep dermis and subcutaneous tissue. Patients with pruritus may respond to camphor, menthol, topical emollients, psoralen ultraviolet A (UVA) treatment, and UVA1 phototherapy. Immunomodulation is not consistently helpful. Mortality is typically related to kidney and lung changes.
Cutaneous Signs of 10 Unusual Systemic Diseases
Sarcoidosis
The above image demonstrates the formation of erythema nodosum in sarcoidosis.
Sarcoidosis is a disease characterized by noncaseating epithelioid granulomas that may affect any organ system; however, sarcoidosis usually starts in the lungs, skin, and intrathoracic lymph nodes.[10,11] The exact pathophysiology is incompletely understood but is thought to be secondary to antigenic stimulation from infectious, environmental, or autoimmune sources. The overall estimated US prevalence is 1-40 cases per 100,000 people,[12] with black individuals disproportionately affected (about 13-fold) relative to white persons (about 35.5-36.4 cases per 100,000 annually vs about 2.8 cases per 100,000 annually, respectively).[13] Patients most commonly report fever, fatigue, weight loss, dyspnea, dry cough, chest pain, and/or lymphadenopathy. Cutaneous involvement may have a variety of presentations and occurs in approximately 25% of patients[14] (granulomatous skin lesions: 9-37%[15]). Patients may develop erythema nodosum, lupus pernio, subcutaneous nodules, plaques, or lesions that are maculopapular, nodular, angiolupoid, ichthyosiform, lichenoid, psoriasiform, or ulcerative.
Cutaneous Signs of 10 Unusual Systemic Diseases
Maculopapular sarcoidosis is the most common type of cutaneous sarcoidosis; the lesions are usually asymptomatic and resolve without scarring. Lupus pernio is characterized by red to purple, indurated plaques and nodules that typically affect the nose (shown), cheeks, ears, and lips.
Plaque sarcoidosis is characterized by round to oval, red-brown to purple, infiltrated plaques that may have atrophic centers and a symmetrical distribution. Patients may also develop infiltration of existing scars that then become red or purple and tender.
Subcutaneous nodular sarcoidosis, also called Darier-Roussy sarcoidosis, is characterized by subcutaneous nodules that are typically nontender, firm, oval, and flesh colored or violaceous; they are found on the extremities or trunk.
Cutaneous Signs of 10 Unusual Systemic Diseases
The classic histologic findings of sarcoid lesions are noncaseating granulomas (shown), which are usually in the superficial dermis. Treatment typically involves oral corticosteroids, but topical or intralesional corticosteroids may be used for limited cutaneous lesions. Other potential therapies for cutaneous lesions include methotrexate, antimalarial agents, cyclosporine, allopurinol, psoralen UVA treatment, thalidomide, pentoxifylline, melatonin, and tumor necrosis factor (TNF)-alpha antagonists. Radiation has been used to treat resistant cutaneous lesions. The overall disease course is variable, with a mortality rate of less than 5%, typically due to cardiac or pulmonary fibrosis.[16] More than half of patients with sarcoidosis have remission within 3 years of diagnosis, and two thirds of patients have remission within 10 years of diagnosis.[17]
Cutaneous Signs of 10 Unusual Systemic Diseases
Mixed Connective Tissue Disease
The above image demonstrates Raynaud phenomenon in mixed connective tissue disease (MCTD).
MCTD is generally considered to be a distinct and rare disorder with features of SSc, systemic lupus erythematosus (SLE), and polymyositis.[18,19] Although the exact pathogenesis is incompletely understood, MCTD is an autoimmune disorder; anti–U1-ribonucleoprotein (RNP) complex antibodies are a specific marker for the disease.[18] Patients usually report Raynaud phenomenon, headaches, fatigue, myalgias, arthralgias, and skin changes. The typical skin findings are sausage-shaped fingers, swollen hands without sclerodactyly, abnormal capillaries in the nail fold, and palpable purpura; rarely, peripheral gangrene or leg ulcers occur. MCTD may develop into SSc that spreads to the face, scalp, trunk, and extremities.
Cutaneous Signs of 10 Unusual Systemic Diseases
Immunologic studies may be helpful in diagnosing MCTD. Indirect immunofluorescence of skin lesions reveals epidermal nuclear immunoglobulin G (IgG) staining (shown), which may be related to high titers of U1-RNP antibodies. Histologic findings are nonspecific. Treatment for cutaneous manifestations of MCTD is typically limited to topical corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs). Plasmapheresis may aid in the removal of circulating immune complexes and thereby improve visceral circulation;[20] this therapy may also benefit patients with concurrent MCTD and antiphospholipid syndrome (APS).[21] Mortality is typically the result of pulmonary hypertension, nephritis, myocarditis, or widespread vasculitis.[22]
Cutaneous Signs of 10 Unusual Systemic Diseases
Dermatomyositis
Gottron papules (shown), seen in dermatomyositis, are elevated, violaceous papules and plaques typically found over bony prominences.
Dermatomyositis is an idiopathic inflammatory myopathy with associated cutaneous findings.[23] The estimated incidence of dermatomyositis is 1-10 cases per million people.[24,25] Patients may report pruritic skin lesions; a scaly, pruritic scalp; proximal muscle weakness; fatigue; arthralgias; dyspnea; dysphagia; arrhythmias; and dysphonia. In up to 40% of patients, skin disease may be the only manifestation.[26,27] The classic physical examination findings are the heliotrope rash, shawl sign, periungual erythema and telangiectases, and Gottron papules.[23,28]
The periorbital heliotrope rash is a violaceous to dusky, erythematous rash with or without edema, in a symmetrical distribution. The shawl (or V-) sign, which is diffuse, flat, and erythematous, spreads over the back and shoulders or forms a "V" shape that occupies the posterior neck and back or the neck and upper chest; the severity increases with exposure to UV light. Patients with dermatomyositis have a significantly greater risk than does the general population for developing cancer, with the risk being highest for cancer of the lymphatic/hematopoietic system, lung, ovary, colon, bladder, breast, cervix, pancreas, and esophagus.[29]
Cutaneous Signs of 10 Unusual Systemic Diseases
Other potential skin findings in dermatomyositis include malar erythema, poikiloderma in a photosensitive distribution (shown), violaceous erythema on the extensor surfaces, panniculitis, and calcinosis cutis. Scalp involvement is common, with an erythematous to violaceous, psoriasiform dermatitis. Skin biopsy samples reveal an interface dermatitis that is identical to SLE, with excessive mucin and vacuolar dermatitis. Treatment for skin involvement involves avoiding sun exposure and using sunscreens, topical corticosteroids, antimalarial agents, methotrexate, and/or mycophenolate mofetil. Dermatomyositis may spontaneously remit in up to 20% of patients, but about 15% of patients will have a fulminant course with eventual death.[30] The overall prognosis typically depends on the severity of the myopathy.
Cutaneous Signs of 10 Unusual Systemic Diseases
Pretibial Myxedema
Pretibial myxedema, or thyroid dermopathy, is a rare disorder characterized by localized skin lesions caused by the deposition of hyaluronic acid in the dermis and subcutaneous tissue. On physical examination, the lesions are bilateral, firm, nonpitting, asymmetrical plaques or nodules with a shiny pink to purple-brown color (shown).
Pretibial myxedema is usually a component of thyroid disease and is nearly always associated with Graves disease, although it has also been seen in patients with Hashimoto thyroiditis, primary hypothyroidism, and euthyroidism. The overall incidence of pretibial myxedema is generally reported to be less than 5% of patients with Graves disease.[31] Patients frequently report the development of nonpitting edema on the anterior or lateral aspects of the legs.
Cutaneous Signs of 10 Unusual Systemic Diseases
Hair follicles may be prominent in patients with pretibial myxedema, giving the skin a peau d'orange texture. Overlying hyperhidrosis and hypertrichosis may also be present. Although the lesions in pretibial myxedema typically appear on the legs, they may also be found on the thighs, shoulders, hands, and forehead, and they often occur in areas of recent or previous trauma. Skin biopsy results typically show deposition of mucin in the reticular dermis with attenuation of collagen fibers (shown). The lesions are generally only of cosmetic concern, but topical corticosteroids and compression stockings may be prescribed. Although the lesions may persist for several years, they typically regress spontaneously. In patients with mild disease that does not require treatment, about 50% will have complete remission after several years.[32]
Cutaneous Signs of 10 Unusual Systemic Diseases
Pyoderma Gangrenosum
The above image demonstrates the classic form of pyoderma gangrenosum.
Pyoderma gangrenosum is a rare ulcerative cutaneous condition that is often associated with other medical disorders, with an estimated 50-70% of cases occurring in patients who also have inflammatory bowel disease (eg, ulcerative colitis, Crohn disease), a rheumatologic condition (eg, polyarthritis), or a hematologic malignancy (eg, leukemia).[33] Its etiology is not well understood, but dysregulation of neutrophil chemotaxis is believed to be involved. The global incidence of pyoderma gangrenosum is about 3-10 cases per million people each year.[33,34] Patients will usually report an initial lesion as a small red papule or pustule that changes into a larger, ulcerative lesion. Frequently associated symptoms include pain, arthralgias, and malaise.
The two main variants of pyoderma gangrenosum are the classic and atypical forms. The classic form is characterized by a deep ulceration with a violaceous border that overhangs the ulcer bed; these lesions are most often found on the legs.
Cutaneous Signs of 10 Unusual Systemic Diseases
The lesions of the atypical form of pyoderma gangrenosum have a vesiculopustular component along the borders and are usually more superficial than those seen in the classic form. Atypical pyoderma gangrenosum is most commonly found on the dorsal surface of the hands (shown, with ruptured bullae), the extensor parts of the forearms, and the face.
The histologic features of pyoderma gangrenosum are nonspecific: neutrophilic infiltration, hemorrhage, and necrosis. No specific therapy for this condition is effective in all patients.[34] Topical options include corticosteroids, cromolyn sodium solution, nitrogen mustard, and 5-aminosalicylic acid. Systemic therapies include corticosteroids, cyclosporine, chemotherapeutics, TNF-alpha inhibitors, nicotine, and intravenous Ig. The overall prognosis is very good, but many patients suffer relapses. Mortality from pyoderma gangrenosum is rare and is usually related to an underlying condition.
Cutaneous Signs of 10 Unusual Systemic Diseases
HIV-Associated Lipodystrophy
The above image shows lipoatrophy-associated loss of subcutaneous facial tissue.
Lipodystrophy (generally some combination of lipohypertrophy and lipoatrophy) may develop in 11-83% of patients[35] infected with the human immunodeficiency virus (HIV) who are being treated with antiretroviral therapy (ART).[35,36] The pathogenesis is not understood, but patients are at increased risk for hyperlipidemia, atherosclerosis, and diabetes mellitus. Patients with lipohypertrophy typically have an enlarged dorsocervical fat pad, circumferential expansion of the neck, breast enlargement, and abdominal visceral fat accumulation, whereas those with lipoatrophy usually demonstrate fat wasting with loss of subcutaneous tissue in the face, arms, legs, and buttocks.
Tesamorelin, a synthetic analogue of human growth hormone-releasing hormone, has been approved by the US Food and Drug Administration for abdominal fat reduction in HIV-infected patients with lipodystrophy.[37,38]
Surgical removal of fat or implantation of synthetic filler material may be used for cosmetic remediation,[38] while withdrawal of thymidine analogues may reverse lipoatrophy. Treatment of the underlying metabolic derangements is necessary.
Cutaneous Signs of 10 Unusual Systemic Diseases
Hirsutism
Hirsutism (shown) is a condition characterized by excessive growth of thick, dark hair in a masculine pattern in women.[39] The etiology is either increased levels of androgen or increased hair follicle sensitivity to androgen. Common conditions that can lead to the development of hirsutism include polycystic ovarian syndrome, adrenal hyperplasia, Cushing syndrome, obesity, hyperinsulinemia, hyperprolactinemia, and hypothyroidism. The estimated prevalence is 10% of women of reproductive age.[39] Common sites of excessive hair growth include the face, chest, areolae, linea alba, upper back, lower back, buttocks, inner thighs, and external genitalia. The diagnosis of hirsutism is typically made by evaluating the patient for familial and drug-induced causes and obtaining laboratory tests for androgen excess. Treatment involves control of any underlying conditions, removal of any offending medications, and either hair removal or hair bleaching.
Cutaneous Signs of 10 Unusual Systemic Diseases
Acanthosis Nigricans
Acanthosis nigricans is a skin disorder that is mainly associated with obesity/insulin resistance, endocrine disorders, malignancies, and certain drugs; it causes the development of hyperpigmented, velvety skin lesions (shown).[40-43] Nonmalignant systemic diseases in which acanthosis nigricans can arise include acromegaly, dermatomyositis, Hashimoto thyroiditis, SLE, lipoatrophic diabetes mellitus, Werner syndrome, and phenylketonuria.[43] The pathophysiology is believed to be related to stimulation of epidermal keratinocytes and dermal fibroblast proliferation.[43] The malignant form is rare and is most commonly associated with gastrointestinal tract adenocarcinomas (90%), particularly gastric cancer.[41,42]
Patients with acanthosis nigricans typically report asymptomatic areas of skin darkening and thickening; the macular lesions are usually symmetrical, progress to palpable plaques, and may occur at any site, although most are found in the axillary (shown), groin, posterior neck, and intertriginous areas.[40-42]
Cutaneous Signs of 10 Unusual Systemic Diseases
The diagnosis of acanthosis nigricans is typically made clinically.[41-43] The most common cause is insulin resistance associated with obesity. Skin biopsy is useful if the clinical circumstances are not revealing. Histologic findings typically reveal hyperkeratosis, papillomatosis, and hyperpigmentation (shown).[43] There is no specific treatment for acanthosis nigricans, but correction of the underlying disease may reduce or eliminate the hyperkeratotic lesions.[40-43] The prognosis is related to the underlying disease, but patients with skin lesions from malignant disease typically have more advanced disease and very poor outcomes, with an estimated average survival rate of 2 years.[41]
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