Cutaneous Manifestations of Systemic Disease (Clinical)

Endocrine and metabolic clues

Acanthosis nigricans. Velvety, hyperpigmented, thickened plaques on the posterior neck, axillae, and groin. The usual driver is insulin resistance: high insulin levels stimulate IGF-1 receptors on keratinocytes and fibroblasts. Associations include obesity, type 2 diabetes, PCOS (HAIR-AN syndrome), Cushing syndrome, acromegaly, and drugs such as niacin and glucocorticoids. Screen with HbA1c or fasting glucose and treat the cause with weight loss and metformin.

Malignant acanthosis nigricans appears abruptly and extensively in a thin, older patient with weight loss, often involving the oral mucosa and palms (tripe palms). Tumor-derived TGF-α drives it, and gastric adenocarcinoma is the classic cause: perform upper endoscopy and CT. A sudden eruption of seborrheic keratoses (sign of Leser-Trélat) carries the same warning.

Diabetes. Necrobiosis lipoidica produces yellow-brown, shiny, atrophic plaques with telangiectasias and a red-violet rim on both anterior shins, and minor trauma can ulcerate them. It is most closely tied to diabetes (classically type 1, more often women) and shows palisaded granulomas around degenerated collagen. Potent topical or intralesional corticosteroids to the active border are first-line; tight glycemic control does not reliably change its course. The most common diabetic skin finding is diabetic dermopathy (small brown atrophic shin macules).

Xanthomas. Eruptive xanthomas are crops of 1–5 mm yellow papules with red halos on the buttocks and extensor limbs that appear when triglycerides are usually above 1,000 mg/dL, a level that also threatens acute pancreatitis. Causes include uncontrolled diabetes, lipoprotein lipase deficiency, alcohol, oral estrogen, and retinoids, and the lesions fade as triglycerides fall. Tendon xanthomas (Achilles, knuckles) indicate familial hypercholesterolemia, palmar crease xanthomas indicate dysbetalipoproteinemia (apoE2), and about half of patients with xanthelasma have normal lipids.

Thyroid dermopathy. Pretibial myxedema belongs to Graves disease, not hypothyroidism: nonpitting, waxy plaques with a peau d'orange surface on the shins and dorsal feet, produced when TSH-receptor antibodies stimulate fibroblasts to deposit glycosaminoglycans. It nearly always accompanies ophthalmopathy and may occur with acropachy (clubbing with periosteal new bone). Potent topical steroids under occlusion help; restoring euthyroidism does not reverse it.

Gastrointestinal and rheumatologic clues

Pyoderma gangrenosum. This neutrophilic dermatosis begins as a painful pustule that rapidly breaks down into an ulcer with a violaceous, undermined border and a purulent base, usually on the legs or around a stoma, and heals with cribriform scars. About half of patients have inflammatory bowel disease, rheumatoid arthritis, a myeloid disorder (AML, myelodysplastic syndrome, myeloproliferative neoplasm), or an IgA monoclonal gammopathy. It is a diagnosis of exclusion: biopsy the edge and culture tissue to rule out infection, vasculitis, and malignancy.

Pathergy: debridement, grafting, and even needle sticks enlarge the ulcer, so surgical debridement is contraindicated. Treat with systemic corticosteroids or cyclosporine, a TNF inhibitor such as infliximab when IBD coexists, topical or intralesional steroids or tacrolimus for small lesions, and gentle moist wound care.

Erythema nodosum. Tender red shin nodules from septal panniculitis that heal without ulceration or scarring. In IBD (Crohn disease more than ulcerative colitis) it rises and falls with bowel activity, whereas pyoderma gangrenosum may run an independent course. Other causes are sarcoidosis (Löfgren syndrome), streptococcal pharyngitis, tuberculosis, pregnancy, and oral contraceptives.

Managing cutaneous lupus. All forms are photosensitive: strict sun protection, topical or intralesional corticosteroids, and hydroxychloroquine for widespread or refractory disease. Smoking worsens discoid lupus and blunts the antimalarial response, and a drug-induced SCLE clears after the drug is stopped.

Maternal anti-Ro/SSA crosses the placenta and can cause neonatal lupus: an annular periorbital rash and congenital complete heart block. Pregnant women with anti-Ro need serial fetal echocardiography from about 16 to 26 weeks.

Vascular and granulomatous clues

Livedo reticularis. A violaceous, lacy network produced by sluggish flow in the dermal venous plexus. Mottling in the cold that clears with warming is physiologic. Persistent, irregular, broken-ring livedo (livedo racemosa) points to antiphospholipid syndrome, where it is the most common skin sign, and also to SLE, Sneddon syndrome (livedo racemosa with strokes), cholesterol emboli after arterial catheterization (blue toes, eosinophilia, AKI), polyarteritis nodosa, and cryoglobulinemia. Test for lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein I antibodies, confirmed at least 12 weeks apart.

Palpable purpura. Raised, nonblanching purpura on the legs and buttocks reflects leukocytoclastic vasculitis of dermal postcapillary venules. Causes include drugs (β-lactams, sulfonamides, often 7–10 days after starting), infection (hepatitis C with mixed cryoglobulinemia, endocarditis), IgA vasculitis, ANCA-associated vasculitis, connective tissue disease, and malignancy. Flat petechiae point instead to thrombocytopenia or other platelet problems.

Lupus pernio. Despite its name, this is cutaneous sarcoidosis: chronic, indurated, violaceous plaques on the nose, cheeks, ears, and lips, most often in Black women, with noncaseating granulomas on biopsy. It signals chronic, severe disease with pulmonary fibrosis and sinonasal involvement. Erythema nodosum in Löfgren syndrome (bilateral hilar adenopathy, ankle arthritis, fever) marks acute sarcoidosis that usually remits.

Paraneoplastic dermatoses

Sweet syndrome. Also called acute febrile neutrophilic dermatosis: sudden fever with tender, edematous plaques on the face, neck, arms, and dorsal hands, peripheral neutrophilia, and a dense dermal neutrophilic infiltrate without vasculitis. Most cases follow infection or accompany IBD or pregnancy, G-CSF can trigger it, and about 20% are associated with malignancy, most often AML or MDS; malignancy-associated cases may lack neutrophilia, so check a CBC with smear. Systemic corticosteroids produce a rapid response.

Glucagonoma. Necrolytic migratory erythema is a migrating eruption of annular plaques with erosions and crusted edges on the groin, perineum, buttocks, and perioral skin, with glossitis and angular cheilitis. New diabetes, weight loss, anemia, venous thrombosis, diarrhea, and depression accompany it, and the rash reflects hypoaminoacidemia and zinc deficiency. Serum glucagon is markedly elevated; resection, octreotide, and amino acid and zinc replacement improve the skin.

Carcinoid syndrome. The liver clears serotonin released by a midgut neuroendocrine tumor, so symptoms appear once liver metastases release it into the systemic circulation; bronchial tumors bypass this requirement. Flushing of the face and upper trunk is episodic and dry, provoked by alcohol or stress, and accompanied by diarrhea, bronchospasm, and right-sided valve disease. Chronic flushing leaves telangiectasias, and diversion of tryptophan can cause pellagra. Confirm with 24-hour urine 5-HIAA and treat with octreotide or lanreotide.

Paraneoplastic pemphigus. Intractable, painful stomatitis with hemorrhagic lip crusting is the hallmark, joined by conjunctivitis and a polymorphous eruption of blisters, lichenoid papules, and target-like lesions that, unlike pemphigus vulgaris, involves the palms and soles. Antibodies target plakins (envoplakin, periplakin) and desmogleins. Bronchiolitis obliterans is a frequent cause of death; treat the neoplasm along with immunosuppression.

Renal disease and generalized pruritus

Calciphylaxis. Calcific uremic arteriolopathy affects patients with end-stage renal disease, usually on dialysis. Exquisitely painful retiform purpura progresses to black necrotic eschars on fatty areas such as the thighs, abdomen, and buttocks, as calcified arterioles thrombose. Risk factors include a high calcium-phosphate product, hyperparathyroidism, warfarin (which inhibits the vitamin K–dependent calcification inhibitor matrix Gla protein), obesity, and calcium-based binders. Management combines IV sodium thiosulfate, pain control, wound care, intensified dialysis, non-calcium binders, cinacalcet or parathyroidectomy, and stopping warfarin; mortality from sepsis is high.

Itch without a rash. When pruritus is generalized and the skin shows only excoriations or lichenification, look for a systemic cause. Dry skin (xerosis) is the most common cause in older adults.