Cutaneous Signs of Systemic Disease
A board-focused tour of the skin findings that betray internal disease — metabolic/endocrine markers, paraneoplastic dermatoses, neutrophilic and IBD-associated eruptions, connective-tissue and vascular signs, and neurocutaneous syndromes — pairing each classic morphology buzzword and immunofluorescence/biopsy clue with the next-best diagnostic step it demands.
The skin as a diagnostic window
The skin externalizes internal disease through four board-favored mechanisms: metabolic/deposition (insulin resistance drives IGF-1–mediated keratinocyte growth in acanthosis nigricans; lipid deposits form xanthomas), paraneoplastic signaling (tumor-secreted growth factors such as TGF-α, or immune cross-reactivity), shared autoimmunity (celiac disease → dermatitis herpetiformis), and vascular deposition of immune complexes or emboli.
Exams reward two moves: (1) recognize the classic morphology + distribution from a photo or buzzword, then (2) choose the next best step — usually the internal workup the skin sign demands (e.g., abrupt acanthosis nigricans → upper endoscopy for gastric adenocarcinoma).
Timing is the tell: an abrupt, extensive, or atypical eruption in an adult flags malignancy, whereas an indolent, symmetric lesion favors benign metabolic disease. Throughout, pair the lesion with its confirmatory biopsy/immunofluorescence finding and its systemic association.
- Acanthosis nigricans: velvety hyperpigmented plaques in axillae/neck/groin → insulin resistance (obesity, T2DM, PCOS). Abrupt + extensive with tripe palms and mucosal lesions → gastric adenocarcinoma.
- Necrobiosis lipoidica: yellow-brown atrophic plaques with telangiectasias on the shins, may ulcerate → diabetes.
- Diabetic dermopathy: brown atrophic "shin spots" — the most common cutaneous sign of diabetes.
- Eruptive xanthomas: crops of yellow papules on extensors/buttocks → hypertriglyceridemia (chylomicrons/VLDL).
- Tendinous xanthomas + xanthelasma + corneal arcus → familial hypercholesterolemia (LDL-receptor defect).
- Pretibial myxedema (non-pitting, orange-peel) + exophthalmos + acropachy → Graves; vitiligo signals autoimmune thyroid/T1DM/Addison/pernicious anemia.
- Necrolytic migratory erythema: migratory erosive erythema + glossitis + weight loss → glucagonoma (check glucagon, glucose, zinc).
Paraneoplastic dermatoses
| Cutaneous sign | Morphology / buzzword | Associated malignancy |
|---|---|---|
| Malignant acanthosis nigricans | Sudden, extensive velvety plaques; tripe palms | Gastric adenocarcinoma |
| Sign of Leser-Trélat | Explosive eruption of seborrheic keratoses | GI adenocarcinoma |
| Necrolytic migratory erythema | Migratory erosions, angular cheilitis | Glucagonoma |
| Sweet syndrome | Tender "juicy" red plaques, fever, neutrophilia | AML |
| Erythema gyratum repens | "Wood-grain" concentric bands, migrates fast | Lung cancer |
| Dermatomyositis | Heliotrope rash, Gottron papules | Ovarian, lung, GI |
| Acquired ichthyosis | Diffuse fish-scale scaling in an adult | Hodgkin lymphoma |
| Hypertrichosis lanuginosa acquisita | Fine "malignant down" lanugo hair | Lung, colon |
Stem: A 30-year-old man has intensely pruritic, grouped vesicles and excoriations symmetrically over the elbows, knees, buttocks, and scalp. He reports intermittent bloating and loose stools; ferritin is low.
- Diagnosis: Dermatitis herpetiformis — the cutaneous expression of celiac disease.
- Confirm: skin biopsy with direct immunofluorescence = granular IgA deposits at the dermal papillae tips; serology anti-tissue-transglutaminase (tTG) IgA and anti-endomysial antibodies.
- Next best step / management: lifelong gluten-free diet (treats gut and skin; lowers enteropathy-associated T-cell lymphoma risk). Add dapsone for rapid itch relief — but check G6PD first (hemolysis).
Board traps: lesions are herpetiform (grouped) but not herpetic/viral; GI symptoms may be absent; select IgA (not IgG) serology and biopsy perilesional skin for DIF.
- Pyoderma gangrenosum: rapidly enlarging painful ulcer with violaceous, undermined borders; shows pathergy (worsens with trauma/debridement) → IBD, rheumatoid arthritis, hematologic malignancy/IgA gammopathy. Diagnosis of exclusion; treat with immunosuppression (systemic steroids), NOT aggressive surgical debridement.
- Erythema nodosum: tender red shin nodules; a septal panniculitis that never ulcerates and heals like a bruise (contusiform) → strep, sarcoidosis (Löfgren = EN + bilateral hilar adenopathy + arthralgia), IBD, TB, cocci/histo, drugs (OCP, sulfonamides), pregnancy.
- Sweet syndrome: abrupt tender edematous "juicy" plaques + fever + neutrophilia; biopsy = dense dermal neutrophils → infection, AML, drugs (G-CSF); dramatic response to steroids.
- Other IBD clues: aphthous stomatitis, pyostomatitis vegetans, perianal fistulae/skin tags (Crohn).
Stem: A 52-year-old woman has a violaceous rash on the upper eyelids (heliotrope), scaly pink papules over the knuckles (Gottron papules), a photodistributed "shawl sign," and proximal weakness — she struggles to rise from a chair and comb her hair.
- Diagnosis: Dermatomyositis. Support: ↑CK/aldolase; antibodies — anti-Mi-2 (classic skin), anti-Jo-1 (antisynthetase → ILD, mechanic's hands), anti-TIF1-γ / anti-NXP-2 (malignancy risk).
- Key association: paraneoplastic — ovarian, lung, GI, nasopharyngeal cancers.
- Next best step: age- and risk-appropriate malignancy screening (transvaginal US/CA-125 ± CT chest/abd/pelvis) plus PFTs/HRCT for interstitial lung disease.
Buzzword discriminator: Gottron papules sit directly over the knuckles (MCP/IP joints), whereas the SLE hand rash characteristically spares the skin over the knuckles and instead involves the skin between them (over the dorsal phalanges).
Neurocutaneous syndromes
| Syndrome | Skin findings | Gene / inheritance | Systemic tumors / features |
|---|---|---|---|
| NF1 | ≥6 café-au-lait macules, axillary/inguinal freckling (Crowe sign), neurofibromas | NF1 (neurofibromin), Ch17, AD | Optic glioma, pheochromocytoma; Lisch nodules (iris hamartomas) |
| NF2 | Few/no skin lesions | NF2 (merlin), Ch22, AD | Bilateral vestibular schwannomas, meningiomas |
| Tuberous sclerosis | Ash-leaf macules, shagreen patch, facial angiofibromas, periungual fibromas | TSC1/TSC2, AD | Cardiac rhabdomyoma, renal angiomyolipoma, SEGA, seizures |
| Sturge-Weber | Port-wine stain (V1 trigeminal) | GNAQ, sporadic | Leptomeningeal angioma, seizures, glaucoma |
| von Hippel-Lindau | Cutaneous rare | VHL, Ch3, AD | Retinal/CNS hemangioblastoma, RCC, pheochromocytoma |
Diagnose neurofibromatosis type 1 when ≥2 of the NIH criteria are present — "CAFÉ SPOT":
- C — Café-au-lait macules (≥6; >5 mm prepubertal, >15 mm postpubertal)
- A — Axillary/inguinal freckling (Crowe sign)
- F — Fibromas: ≥2 neurofibromas or 1 plexiform
- É — Eye: ≥2 Lisch nodules (iris hamartomas)
- S — Skeletal: sphenoid dysplasia / long-bone cortical thinning
- P — Positive family history (first-degree relative)
- O — Optic glioma
- T — Two of the above are required to diagnose
Pearl: café-au-lait macules are also seen in McCune-Albright (large, unilateral, "coast of Maine" jagged borders + precocious puberty + polyostotic fibrous dysplasia) — versus NF1's small, smooth "coast of California" borders.
- Palpable purpura (non-blanching papules, dependent/lower legs) = small-vessel leukocytoclastic vasculitis → IgA vasculitis/HSP (IgA immune complexes, post-URI, kids, + arthralgia/abdominal pain/nephritis), cryoglobulinemia (HCV), drugs, ANCA vasculitis.
- Livedo reticularis / retiform purpura (net-like violaceous mottling) → antiphospholipid syndrome, polyarteritis nodosa (HBV), cholesterol emboli (post-catheterization, eosinophilia, blue toes).
- Infective endocarditis: Osler nodes (painful pulp nodules — "O = Ouch"), Janeway lesions (painless palms/soles), splinter hemorrhages, Roth spots.
- SLE: photosensitive malar rash sparing the nasolabial folds; scarring discoid plaques.
- Systemic sclerosis: sclerodactyly, Raynaud, CREST/limited (calcinosis, telangiectasia; anti-centromere) vs diffuse (anti-Scl-70/topoisomerase I).
- Erythema migrans: expanding targetoid "bull's-eye" patch → Lyme (Borrelia).
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