7.3 Skin Signs of Systemic Disease, Porphyrias, Nutritional Deficiency & Paraneoplastic Dermatoses
Key Takeaways
- Porphyria cutanea tarda, due to reduced uroporphyrinogen decarboxylase activity, causes skin fragility, blisters, milia, and hypertrichosis on sun-exposed skin and is treated with phlebotomy or low-dose hydroxychloroquine.
- Erythropoietic protoporphyria, usually caused by FECH mutations, presents in childhood with burning pain on sun exposure without blisters, and afamelanotide implants are approved in the EU for adults.
- Malignant acanthosis nigricans and tripe palms, especially with sudden onset and mucosal involvement, are associated with gastric adenocarcinoma and other internal cancers.
- Acrodermatitis enteropathica, caused by SLC39A4 mutations or acquired zinc deficiency, produces periorificial and acral dermatitis, alopecia, and diarrhoea.
- Necrolytic migratory erythema, with migrating erosive plaques around the groin and mouth, weight loss, and diabetes, is the classic sign of a glucagonoma.
Last updated: September 2026
7.3 Skin Signs of Systemic Disease, Porphyrias, Nutritional Deficiency & Paraneoplastic Dermatoses
Examination questions often show a skin sign and ask for the underlying disease, or the next investigation. The tables below group the most important links.
Endocrine and Metabolic Disease
| Condition | Skin Signs |
|---|---|
| Diabetes mellitus | Acanthosis nigricans (insulin resistance), diabetic dermopathy (shin spots), necrobiosis lipoidica, bullosis diabeticorum, scleroedema, eruptive xanthomas, neuropathic foot ulcers, candidiasis and other infections, waxy skin with limited joint mobility |
| Hyperthyroidism (Graves) | Warm moist skin, diffuse hair thinning, onycholysis, pretibial myxoedema, thyroid acropachy |
| Hypothyroidism | Dry, cold, rough skin, carotenaemia (yellow tint), loss of the outer eyebrows, coarse brittle hair, generalised myxoedema |
| Cushing syndrome | Thin skin, wide purple striae, easy bruising, acne, hirsutism, plethora |
| Addison disease | Diffuse hyperpigmentation, most marked in palmar creases, scars, and mucosa |
| Acromegaly | Thick, oily skin; cutis verticis gyrata; skin tags |
Kidney Disease
- Chronic kidney disease-associated pruritus, sometimes severe. Difelikefalin (a peripheral kappa-opioid agonist) is approved in the EU for moderate-to-severe pruritus in adults on haemodialysis.
- Half-and-half nails, uraemic xerosis, and pigmentation.
- Acquired perforating dermatosis: itchy keratotic papules in diabetic and dialysis patients.
- Calciphylaxis (see the deposition disorders section).
- Nephrogenic systemic fibrosis: skin thickening after gadolinium contrast in severe kidney failure.
- Pseudoporphyria: PCT-like blisters with normal porphyrins, caused by dialysis or drugs (naproxen, furosemide, tetracyclines).
Liver and Gastrointestinal Disease
- Liver disease: jaundice, spider naevi, palmar erythema, Terry nails, cholestatic pruritus, xanthomas (primary biliary cholangitis). Hepatitis C is linked to porphyria cutanea tarda, lichen planus, and cryoglobulinaemic vasculitis. Wilson disease causes azure lunulae.
- Inflammatory bowel disease: erythema nodosum (parallels bowel activity), pyoderma gangrenosum (independent course), oral aphthae, pyostomatitis vegetans (ulcerative colitis), perianal fistulae and skin tags, metastatic Crohn disease, and Sweet syndrome.
- Coeliac disease: dermatitis herpetiformis.
Inherited Syndromes with Skin Markers
| Syndrome (Gene) | Skin Markers | Internal Risk |
|---|---|---|
| Peutz-Jeghers (STK11) | Lip and buccal lentigines | GI hamartomas; GI, breast, and pancreatic cancer |
| Hereditary haemorrhagic telangiectasia (ENG, ACVRL1) | Telangiectasias of lips, tongue, fingertips; recurrent epistaxis | Arteriovenous malformations in lung, brain, liver |
| Gardner syndrome (APC) | Epidermoid cysts, osteomas, desmoid tumours | Colorectal cancer |
| Muir-Torre syndrome (mismatch repair genes, for example MSH2) | Sebaceous adenomas and carcinomas, keratoacanthomas | Colorectal, endometrial, and other cancers (Lynch syndrome) |
| Cowden syndrome (PTEN) | Trichilemmomas, acral keratoses, oral papillomas | Breast, thyroid, and endometrial cancer |
| Birt-Hogg-Dubé (FLCN) | Fibrofolliculomas on the face | Renal tumours, lung cysts, pneumothorax |
| Hereditary leiomyomatosis and renal cell cancer (FH) | Painful cutaneous leiomyomas | Uterine fibroids, aggressive renal cancer |
Nutritional Deficiencies
| Deficiency | Skin Signs | Causes |
|---|---|---|
| Zinc | Acrodermatitis enteropathica: sharply defined erosive, crusted dermatitis around the mouth, nose, and anus and on the hands and feet; alopecia; diarrhoea; irritability | Inherited (SLC39A4, zinc transporter; signs at weaning) or acquired (parenteral nutrition, malabsorption, alcoholism, bariatric surgery, premature breastfed infants) |
| Niacin (B3): pellagra | Photodistributed dermatitis including the Casal necklace; the "3 Ds": dermatitis, diarrhoea, dementia (and death) | Alcoholism, isoniazid, carcinoid syndrome (tryptophan diversion), Hartnup disease |
| Vitamin C: scurvy | Perifollicular haemorrhages, corkscrew hairs, bleeding swollen gums, poor wound healing | Restricted diets, alcoholism, older adults living alone |
| Vitamin A | Follicular hyperkeratosis (phrynoderma), night blindness | Malabsorption, restrictive diets |
| Protein-energy (kwashiorkor) | "Flaky paint" dermatosis, hair colour change (flag sign), oedema | Famine, severe illness |
| Iron | Koilonychia, angular cheilitis, diffuse hair loss, pruritus | Blood loss, poor intake |
| Biotin, essential fatty acids | Periorificial dermatitis, alopecia | Parenteral nutrition, raw egg-white diets (biotin) |
The Porphyrias
Porphyrias are defects of haem synthesis. Accumulated porphyrins absorb light in the Soret band (about 400–410 nm), which is visible light, and generate reactive oxygen species. Ordinary sunscreens that block only UV do not protect.
| Porphyria (Enzyme) | Skin Features | Other Points |
|---|---|---|
| Porphyria cutanea tarda (PCT) (uroporphyrinogen decarboxylase, UROD) | Skin fragility, blisters, erosions, milia on the backs of the hands, hypertrichosis of the face, sclerodermoid plaques | The most common porphyria. Triggers: alcohol, iron overload (HFE mutations), oestrogens, hepatitis C, HIV. Raised urinary uroporphyrins; urine shows coral-pink fluorescence under Wood light. Treatment: phlebotomy to low-normal ferritin or low-dose hydroxychloroquine; remove triggers |
| Erythropoietic protoporphyria (EPP) (ferrochelatase, FECH) | Childhood burning, stinging pain within minutes of sun exposure, without blisters; later waxy thickening and fine scars on knuckles and nose | Raised free erythrocyte protoporphyrin; risk of gallstones and liver failure. Afamelanotide implant (EU-approved for adults) increases tolerance of light |
| Congenital erythropoietic porphyria (Günther) (UROS) | Severe blistering and mutilating scarring from infancy; erythrodontia (red-brown teeth that fluoresce); hypertrichosis | Haemolytic anaemia, splenomegaly |
| Variegate porphyria and hereditary coproporphyria | PCT-like blistering | Also acute neurovisceral attacks; avoid porphyrinogenic drugs |
| Acute intermittent porphyria | No skin signs | Acute attacks of abdominal pain, neuropathy, psychiatric features |
Paraneoplastic Dermatoses
A skin disease is probably paraneoplastic when it follows Curth criteria: it appears at the same time as the cancer, follows a parallel course (improves with treatment, returns with relapse), is uncommon in the general population, is linked to a specific tumour type, and has a statistical or genetic association.
| Dermatosis | Associated Malignancy |
|---|---|
| Malignant acanthosis nigricans (sudden, extensive, itchy, mucosal) and tripe palms | Gastric adenocarcinoma and other abdominal cancers; lung cancer with tripe palms alone |
| Sign of Leser-Trélat (sudden eruption of many seborrhoeic keratoses) | GI adenocarcinoma (the association is debated) |
| Acrokeratosis paraneoplastica (Bazex) | Psoriasiform plaques on ears, nose, fingers, and toes with nail dystrophy; squamous cell carcinoma of the upper aerodigestive tract |
| Erythema gyratum repens | Rapidly moving concentric "wood-grain" rings; lung cancer |
| Necrolytic migratory erythema | Migrating erosive plaques in the groin, buttocks, and around the mouth, glossitis, weight loss, diabetes; glucagonoma |
| Acquired hypertrichosis lanuginosa | Fine lanugo hair on the face and body; lung and colorectal cancer |
| Paraneoplastic pemphigus | Severe stomatitis; non-Hodgkin lymphoma, CLL, Castleman disease, thymoma |
| Dermatomyositis (especially anti-TIF1-gamma and anti-NXP2) | Ovarian, lung, gastric, breast, colorectal cancer |
| Sweet syndrome | Acute myeloid leukaemia and myelodysplasia |
| Trousseau sign (migratory thrombophlebitis) | Pancreatic and other adenocarcinomas |
| Multicentric reticulohistiocytosis | Destructive arthritis with papules around the nails ("coral beads"); various cancers |
Test Your Knowledge
A 62-year-old man develops rapidly spreading, itchy, velvety hyperpigmentation of the axillae and neck over 2 months, with thickened, ridged palms ("tripe palms") and mucosal involvement. He has lost 8 kg. Which investigation has the highest priority?
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D
Test Your Knowledge
An infant develops sharply demarcated, crusted, erosive dermatitis around the mouth and anus and on the hands and feet at weaning, together with hair loss and diarrhoea. What is the most likely diagnosis?
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B
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D
Test Your Knowledge
A 9-year-old girl cries with burning, stinging pain in her hands and face within minutes of going outside on sunny days, even through window glass. There are no blisters, but she has fine waxy scars over her knuckles. Which test and diagnosis fit best?
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B
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D
Test Your Knowledge
A 55-year-old woman has weight loss, new-onset diabetes, a sore red tongue, and migrating, erosive, crusted plaques in the groin, buttocks, and around the mouth. What is the most likely underlying tumour?
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B
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D