Cutaneous markers of systemic disease

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Meet the patient

A 68-year-old man, previously well, returns saying his trunk has "broken out in moles" over six weeks. He has lost 8 kg. On examination his axillae and the backs of his hands are velvety and dark, his palms feel rugose like damp suede, and dozens of stuck-on seborrhoeic keratoses cover his trunk. None of this is benign ageing. The sudden tempo, the weight loss, and the triad of acanthosis nigricans plus tripe palms plus an explosive crop of seborrhoeic keratoses (the sign of Leser-Trélat) make this paraneoplastic until you prove otherwise — book the oesophagogastroduodenoscopy for gastric adenocarcinoma today.[10]

The trap on every ward round: a benign-looking skin sign in a thin, older adult who is losing weight is not benign. Tempo and weight loss are the two levers that flip a common finding into a malignancy search. Hold that thought through every section below.[1]

Overview — why this topic pays out

A cutaneous marker of systemic disease is any skin, nail, hair, or mucosal finding that raises the probability of an internal disorder — endocrine, gut, liver, kidney, blood, rheumatological, neurological, infectious, or neoplastic. Some markers are pathognomonic — their presence alone makes the diagnosis (the Kayser-Fleischer ring in Wilson disease; adenoma sebaceum in tuberous sclerosis). Most are specific but not absolute (dermatitis herpetiformis in coeliac disease). A few are non-specific pointers that send you down a differential (erythema nodosum).[1]

The reason examiners love this topic is that the skin is examined without a machine, without a needle, and in seconds. A trained eye reads insulin resistance from the axillae, coeliac disease from the elbows, occult gastric cancer from the palms, and Wilson disease from the cornea before any blood result returns. The corollary — and the trap — is that every marker must be read as a sentence, not a word: morphology, distribution, tempo, age, and weight-loss history together decide which system to chase, and how fast.[1]

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The spine — cluster by organ system, then chase the mechanism

File every marker by the organ system it points to, because that is how the investigation branches. A second axis — mechanism — separates markers driven by a shared metabolic, immune, or genetic process (skin and viscera diseased together) from paraneoplastic markers driven by tumour-derived growth factors.[2]

The working framework — six buckets

Epidemiology — the age-and-weight-loss pivot

Markers span every age. Genodermatoses (café-au-lait macules, ash-leaf spots, incontinentia pigmenti) declare themselves in infancy. Atopic and infectious markers own childhood and young adulthood. Metabolic, hepatic, and paraneoplastic markers become steadily more likely as the patient ages. The single pivot that should make you sit up is age over 50 with unexplained weight loss: here a new, fast-moving cutaneous sign carries a real probability of malignancy, and the threshold to investigate is low.[2]

A few markers carry a signature risk profile worth memorising. Acanthosis nigricans is common in obesity, type 2 diabetes, and the metabolic syndrome — but the same lesion in a thin, non-diabetic older adult is malignant until proven otherwise. Porphyria cutanea tarda is switched on by hepatitis C, haemochromatosis, alcohol, oestrogens, and HIV. Dermatitis herpetiformis tracks coeliac disease, peaking in northern European populations with an HLA-DQ2/DQ8 backbone. Sweet syndrome and acquired ichthyosis in an adult each carry about a one-in-five chance of an underlying tumour and earn a directed search.[1]

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Pathophysiology — five mechanisms, one skin

The skin mirrors internal disease through a small set of recurring mechanisms. Learn the mechanism and you can predict which system a marker belongs to.[1]

Shared hormonal and metabolic signalling. Insulin resistance drives acanthosis nigricans: hyperinsulinaemia docks onto insulin-like growth factor 1 and epidermal growth factor receptors on keratinocytes and fibroblasts, and the squamous epithelium proliferates into a velvet-like thickening of flexural skin. The same insulin/IGF axis sits behind acrochordons (skin tags) and, controversially, the hirsutism of polycystic ovary syndrome.[2] Hyperglycaemia and microangiopathy drive necrobiosis lipoidica and granuloma annulare through collagen degeneration and a palisading granulomatous reaction in the dermis; thyroid-stimulating immunoglobulins drive pretibial myxoedema through fibroblast activation and glycosaminoglycan deposition.[1]

Immune cross-reactivity. When the same antigen lives in skin and viscera, one immune response produces both the rash and the organ disease. Dermatitis herpetiformis is the cutaneous face of coeliac disease: IgA anti-epidermal transglutaminase deposits at the dermal papillae to make intensely itchy vesicles, while the same process flattens the duodenal villi. Psoriasis shares a T-helper-17/interleukin-23 axis with psoriatic arthritis and the metabolic syndrome. Lichen planus shares immune mechanisms with chronic hepatitis C in a subset of patients.[1]

Oestrogen and vascular effects. The spider naevi, palmar erythema, and gynaecomastia of chronic liver disease reflect a liver that can no longer clear circulating oestrogens and vasoactive substances — capillaries proliferate and dilate in sun-exposed and palmar skin.[1]

Tumour-derived growth factors — the paraneoplastic mechanism. This is the mechanism examiners reward most. Tumours — gastric adenocarcinoma above all — secrete transforming growth factor-alpha, epidermal growth factor, and IGF-1 that act on the epidermis to produce acanthosis nigricans, the sign of Leser-Trélat (an explosive eruption of seborrhoeic keratoses), tripe palms (velvety palmar thickening), and erythema gyratum repens (concentric advancing rings). A glucagonoma secretes glucagon — with zinc and amino-acid deficiency implicated — to produce necrolytic migratory erythema; resect the tumour and the eruption melts away. The tumour-directed immune response in dermatomyositis is the paraneoplastic variant of the same idea.[10]

Embryological and genetic links. Skin, nervous system, eye, and much of the viscera share ectodermal and neural-crest origin, so the genodermatoses declare themselves as constellations of pigmentary or hamartomatous lesions with neurological, endocrine, and neolithic risk — café-au-lait macules and Lisch nodules in neurofibromatosis type 1; ash-leaf macules, angiofibromas (adenoma sebaceum), shagreen patches, and periungual fibromas in tuberous sclerosis; and the lentiginoses of LEOPARD, Carney, and Peutz-Jeghers syndromes.[14]

The catalogue by organ system

This is the heart of the topic. For each marker you want three things locked down: morphology, distribution, and the systemic disease it signals. Group them by the organ the bedside workup should target.[1]

Endocrine markers

Striae and the Cushingoid habitus. Purple, broad (more than one centimetre) abdominal striae, a moon face, buffalo hump, central obesity, and easy bruising are the cutaneous face of Cushing syndrome — endogenous hypercortisolism or exogenous steroids. Thin, silvery striae distensae are a normal variant of rapid growth or pregnancy and mean nothing. Acne, hirsutism, and acanthosis nigricans complete the metabolic picture in insulin resistance and polycystic ovary syndrome.[1]

Gastrointestinal and hepatic markers

The gut–skin axis is the richest single source of examination stems. Several markers here are essentially diagnostic of their systemic counterpart.[1]

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Wilson disease and the Kayser-Fleischer ring. A brown-green copper deposit at the periphery of Descemet membrane, best seen at the slit lamp, is essentially pathognomonic for Wilson disease in a patient with neurological or hepatic involvement. It is the prototype of a sign that lives in the skin's neighbourhood — the eye — yet signals a metabolic liver disease, and it fades with chelation (penicillamine, trientine, zinc).[13]

Other GI and hepatic markers. Mucocutaneous pigmentation of the lips, buccal mucosa, and digits is the hallmark of Peutz-Jeghers syndrome (STK11 mutation; hamartomatous polyps; raised GI, breast, and ovarian cancer risk). Acrodermatitis enteropathica — a periorificial and acral dermatitis with diarrhoea — signals zinc deficiency, classically in total parenteral nutrition given without zinc or in chronic diarrhoea. Jaundice is the visible endpoint of hyperbilirubinaemia from any hepatic, biliary, or haemolytic cause. Pruritus ani and fistulae point to Crohn disease; glossitis and angular cheilitis point to B12 or iron deficiency.[1]

Rheumatological markers

Connective tissue diseases produce some of the most distinctive patterns in medicine, and the rash is often the presenting feature.[1]

Psoriasis and psoriatic arthritis. Well-demarcated erythematous plaques with silvery scale on extensor surfaces and the scalp, plus nail changes (pitting, onycholysis, oil-drop salmon patches, subungual hyperkeratosis), make psoriasis. Add nail involvement, dactylitis, enthesitis, or an asymmetrical large-joint arthritis and you have psoriatic arthritis — which affects up to 30 percent of patients with psoriasis and changes management to NSAIDs, DMARDs, and IL-17, IL-23, or TNF-alpha biologics.[1]

Dermatomyositis. The pathognomonic signs are Gottron papules (violaceous papules over the metacarpophalangeal and interphalangeal joints) and the heliotrope rash (violaceous discoloration of the upper eyelids, often with oedema). Supporting clues are a V-sign and shawl-sign poikilodermatous erythema in sun-exposed distributions, mechanic's hands (hyperkeratotic, fissured lateral fingers), and periungual telangiectasia with a ragged cuticle. In the adult form, 15 to 25 percent harbour an occult malignancy — ovarian, lung, gastric or colorectal, breast, and (especially in Asian populations) nasopharyngeal — and a structured malignancy workup is mandatory at diagnosis.[3]

Systemic lupus erythematosus. The malar (butterfly) rash is the classic facial erythema that spares the nasolabial folds — the single discriminator that separates it from seborrhoeic dermatitis and rosacea, which fill those folds. Discoid lupus makes scarring coin-shaped plaques with follicular plugging on the scalp, face, and ears; only a minority progress to systemic disease. Other SLE markers are photosensitivity, oral ulcers, alopecia, livedo reticularis, and vasculitic lesions. The 2019 EULAR/ACR classification needs an ANA entry criterion plus weighted clinical and immunological criteria (anti-dsDNA, anti-Sm, antiphospholipid, low complement).[1]

Livedo reticularis and antiphospholipid syndrome. A persistent, net-like cyanotic discoloration of the limbs is livedo reticularis; pair it with thrombosis (DVT, arterial thrombosis, stroke) or recurrent miscarriage and it signals the antiphospholipid syndrome. Livedo also features in Sneddon syndrome (livedo plus stroke) and in cholesterol embolisation after vascular instrumentation.[1]

Systemic sclerosis and CREST. The combination of Raynaud phenomenon (often years ahead of everything else), sclerodactyly (tight, shiny digits), facial thickening with a beak-like nose and microstomia, calcinosis cutis, and mat telangiectasia defines systemic sclerosis. The limited cutaneous form is the CREST syndrome (Calcinosis, Raynaud, Esophageal dysmotility, Sclerodactyly, Telangiectasia), tied to the anti-centromere antibody; diffuse cutaneous disease carries anti-Scl-70 (anti-topoisomerase I) and a higher risk of pulmonary fibrosis and renal crisis.[12]

Renal markers

Half-and-half (Lindsay) nails — a proximal pale or white half and a distal pink or brown half occupying roughly 20 to 60 percent of the nail — show up in about a quarter of chronic kidney disease patients and are a classic long-case finding. Uraemic frost (white crystalline urea on the skin in advanced uraemia) is now rare with dialysis but remains a named sign. Calciphylaxis (calcific uraemic arteriolopathy) is a devastating small-vessel vasculopathy of dialysis-dependent CKD: exquisitely painful, retiform purpuric plaques that progress to necrotic ulcers, with high mortality and a need for urgent wound care, calcium-phosphate control, and sodium thiosulphate. Acquired ichthyosis and intractable pruritus with excoriations round out advanced CKD.[1]

Haematological markers

Sweet syndrome (acute febrile neutrophilic dermatosis) announces itself with the abrupt onset of tender, erythematous plaques and nodules — often on the upper limbs and face — plus fever, arthralgia, and a neutrophil leucocytosis; histology shows a dense dermal neutrophil infiltrate. About a fifth of cases are malignancy-associated, most often with acute myeloid leukaemia and myelodysplasia; it also follows solid tumours, inflammatory bowel disease, and drugs (G-CSF). Sweet syndrome melts away with systemic corticosteroids.[6]

Pyoderma gangrenosum straddles haematology and gastroenterology, linking to IBD and the myelodysplastic syndromes (and, in the syndrome of pyoderma gangrenosum, acne, and suppurative hidradenitis — PASH). Thrombophlebitis migrans (Trousseau syndrome) — recurrent, migratory superficial thromboses in odd sites — is a hypercoagulable flag for pancreatic cancer and other mucin-producing adenocarcinomas. Generalised pruritus without a primary skin disease is a classic marker of polycythaemia vera (often aquagenic, flaring after a warm bath), Hodgkin and non-Hodgkin lymphoma, and iron-deficiency anaemia. Pallor, bruising, and petechiae reflect anaemia and thrombocytopenia from marrow failure or infiltration.[1]

The paraneoplastic markers — read these as a cancer screen

This group, more than any other, is why a dermatology or general medicine examiner will test your skin knowledge. Each marker carries a strong, specific malignancy association, and recognising it can be the first and only clue to an otherwise occult tumour. There is no place for humour here — these are rashes that buy or cost a patient a curative resection.[10]

The paraneoplastic face-off — name the marker, name the tumour, name the discriminator. Each of these is a growth-factor-driven epidermal signal; what tells them apart at the bedside is morphology.[10]

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Neurological and genodermatosis markers

Because skin and nervous system share embryological origin, the neurocutaneous syndromes (phakomatoses) and genodermatoses present as constellations of cutaneous markers that signal neurological, endocrine, and neoplastic risk.[1]

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Incontinentia pigmenti deserves its own line. A female infant with blaschkoid vesicles that progress to verrucous and then whorled hyperpigmentation has an X-linked dominant disorder (NEMO/IKBKG mutation, usually lethal in males) with dental, ocular, and neurological anomalies — refer for genetics, ophthalmology, and dental surveillance.[15]

The hands — a whole examination in 30 seconds

You can examine the hands in seconds and pull out a disproportionate amount of information. Each nail sign has a tight association list, which is exactly why examiners love them.[1]

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Distinguishing the mimics

A rash that looks like one marker may be another, and the cost of error is a missed malignancy, a missed coeliac, or the wrong treatment. Three face-offs recur in examinations.[1]

Pyoderma gangrenosum versus Sweet syndrome versus ecthyma gangrenosum. All three throw up erythematous nodules or plaques that ulcerate. Pyoderma gangrenosum is a painful ulcer with undermined, violaceous edges and pathergy (it worsens with debridement), and it links to IBD, arthritis, and myelodysplasia. Sweet syndrome makes tender, non-ulcerated plaques with fever and a dermal neutrophil infiltrate, and it links to AML, IBD, and drugs. Ecthyma gangrenosum is a rapidly progressive necrotic ulcer of Pseudomonas septicaemia in a neutropenic, immunocompromised patient — an emergency, not an inflammatory dermatosis. Biopsy and culture settle it: PG and Sweet are sterile and neutrophilic; ecthyma is infected.[1]

Malar rash (SLE) versus rosacea versus seborrhoeic dermatitis versus heliotrope (dermatomyositis). The SLE malar or butterfly rash spares the nasolabial folds, is photosensitive, and is not greasy. Rosacea fills the nasolabial folds, shows telangiectasia, papules, pustules, and flushing, and does not scar. Seborrhoeic dermatitis is greasy and scaly, sitting in the nasolabial folds, eyebrows, and chest. The heliotrope rash of dermatomyositis is periorbital — the eyelids — violaceous and oedematous: a different distribution entirely.[1]

Erythema nodosum versus erythema multiforme versus nodular vasculitis. Erythema nodosum is a panniculitis — tender subcutaneous nodules on the shins that do not ulcerate and resolve with bruising. Erythema multiforme is an epidermal and dermal process with target lesions (three concentric zones) on extensor surfaces and mucosa, often triggered by HSV or drugs. Nodular vasculitis (erythema induratum) ulcerates and involves the calves posteriorly, often with TB in the background.[1]

Bedside assessment — turn the catalogue into an engine

The structured skin exam turns a list into a diagnostic engine. Start with morphology and distribution, then move to the sites of highest yield: the face (malar rash, heliotrope, spider naevi, facial flushing, oral mucosa, Kayser-Fleischer ring at the slit lamp), the hands (clubbing, palmar erythema, Gottron papules, tripe palms, koilonychia, nail signs, periungual telangiectasia, xanthomas), the trunk (striae, spider naevi, café-au-lait, ichthyosis, scalp and nails for psoriasis), and the lower legs (necrobiosis lipoidica, pretibial myxoedema, erythema nodosum, eczema, half-and-half nails, livedo). Two manoeuvres earn marks: the Schamroth window test for clubbing (the diamond-shaped window between opposing nailbeds vanishes) and diascopy of a lesion to see whether it blanches (erythema) or stays purpuric (vasculitis).[1]

Three questions reframe any cutaneous sign toward the systemic: How fast did it appear? — an eruption over weeks in an older adult, especially with weight loss, is paraneoplastic until proven otherwise. Is it where a benign cause would put it? — acanthosis in the obese diabetic's axilla is benign; acanthosis on a thin patient's palms with a tripe texture is malignant. What else is on examination? — a single finding is a clue; a constellation is a diagnosis. Raynaud plus sclerodactyly plus telangiectasia is CREST. Spider naevi plus palmar erythema plus Terry nails plus gynaecomastia is cirrhosis.[1]

Investigations — the triggered workup

The marker triggers a specific, narrow investigation — not a blanket set of bloods and imaging. Each marker owns its own workup.[1]

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Skin biopsy and direct immunofluorescence confirm the diagnosis when the picture is unclear: punch perilesional skin (not the ulcer itself) for routine histology and a separate sample for direct immunofluorescence. The fluorescence patterns are diagnostic: granular IgA at the dermal papillae in dermatitis herpetiformis; linear IgG and C3 along the basement membrane in bullous pemphigoid; linear IgA along the basement membrane in linear IgA disease; intercellular fish-net IgG and C3 in pemphigus vulgaris. Necrobiotic granulomas in the dermis support necrobiosis lipoidica and granuloma annulare; a dense dermal neutrophil infiltrate supports Sweet syndrome.[5]

Management — treat the disease, not the skin

The cutaneous marker is treated by treating the underlying disease; skin-directed therapy is adjunctive. There are, however, a few situations in which the marker is itself the emergency.[1]

Where the marker demands urgent action. Sweet syndrome with high fever is treated with systemic corticosteroids (prednisolone 0.5 to 1 mg/kg/day) once infection is excluded — untreated it causes real morbidity and may be the opening shot of an acute leukaemia that needs haematology within days. Calciphylaxis in a dialysis patient is a dermatology-nephrology emergency with high short-term mortality: urgent wound care, correction of the calcium-phosphate product, and intravenous sodium thiosulphate. Pyoderma gangrenosum is managed with systemic immunosuppression (high-dose prednisolone, ciclosporin, or a biologic such as infliximab or ustekinumab) and an explicit ban on surgical debridement, which triggers pathergy and catastrophic widening of the ulcer.[11]

Definitive, disease-specific management.[1]

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Special populations

Pregnancy. Palmar erythema and spider naevi are physiological in pregnancy (oestrogen), so a single palmar sign in a young pregnant woman is not cirrhosis. Melasma (chloasma), linea nigra, and striae gravidarum are hormonal. Pruritic urticarial papules and plaques of pregnancy (PUPPP) and intrahepatic cholestasis of pregnancy (pruritus without primary skin lesions, raised bile acids, foetal risk) are the dermatoses to separate from systemic disease. Cushingoid striae from hypercortisolism must be distinguished from the common, physiological striae of pregnancy.[1]

Children. Genodermatoses dominate — café-au-lait and axillary freckling (NF1), hypopigmented ash-leaf macules and facial angiofibromas (tuberous sclerosis), incontinentia pigmenti along Blaschko lines in female infants. Kawasaki disease (strawberry tongue, polymorphous rash, desquamation of fingers and toes, coronary artery aneurysms) and atopic dermatitis are common; juvenile dermatomyositis carries a lower malignancy rate than the adult form and a calcinosis-heavy phenotype.[1]

The elderly. The malignancy pivot owns this group. A new acanthosis, Leser-Trélat, tripe palms, erythema gyratum repens, acquired ichthyosis, or unexplained generalised pruritus in an older adult earns a focused malignancy search — OGD for the gastric markers, CT CAP, age-appropriate screening, and targeted tests such as mammography and colonoscopy. Senile purpura (Bateman purpura) on the dorsal forearms, from dermal atrophy and vascular fragility, is benign and must not be mistaken for a vasculitic or thrombocytopenic process.[1]

The immunocompromised. HIV lays down a sequence of cutaneous markers that mirror the falling CD4 count — florid seborrhoeic dermatitis, recalcitrant psoriasis, extensive molluscum contagiosum, oral hairy leukoplakia (EBV), Kaposi sarcoma (HHV-8), chronic herpes simplex, and bacillary angiomatosis — and these markers track progression to AIDS.[16]

Pitfalls — the harm is in getting the attribution wrong

The complications are mostly the complications of missing the systemic disease behind the marker. Miss an occult gastric cancer behind a tripe palms or a sign of Leser-Trélat, an ovarian cancer behind a dermatomyositis, or a glucagonoma behind a necrolytic migratory erythema, and a resectable tumour becomes an advanced one. The mirror error is over-attribution — labelling a benign acanthosis as malignant, or a physiological palmar erythema as cirrhosis — which drives unnecessary, invasive tests. Tempo, weight loss, distribution, and age resolve most of these.[1]

The classic procedural pitfall is surgical debridement of pyoderma gangrenosum. PG worsens with trauma — the pathergy phenomenon — and debridement produces catastrophic, rapidly enlarging ulcers. The rule: never debride a painful ulcer with undermined violaceous edges in a patient with IBD or a haematological disorder until PG is excluded.[11] A second pitfall is treating the skin and not the disease — potent topical steroids will not control dermatitis herpetiformis (it is driven by dietary gluten), and glycaemic optimisation alone rarely reverses necrobiosis lipoidica; the skin disease needs its own management alongside the systemic one.

A third pitfall is confusing the marker's natural history with treatment failure. Necrobiosis lipoidica can progress despite excellent glycaemic control (the link to hyperglycaemia is not straightforward). The sign of Leser-Trélat can precede detectable malignancy by months, so a negative initial malignancy screen in a high-risk picture earns a repeat search, not reassurance. And Terry nails and half-and-half nails can occur in healthy older adults — a single nail sign without systemic corroboration is not a diagnosis.[1]

Prognosis and disposition

Prognosis tracks the underlying disease. Paraneoplastic markers (acanthosis, Leser-Trélat, tripe palms, erythema gyratum repens) usually regress with successful treatment of the tumour and reappear at recurrence — their behaviour is itself a tumour marker. Necrolytic migratory erythema resolves within weeks of glucagonoma resection. Dermatitis herpetiformis clears on a strict gluten-free diet and flags the long-term coeliac risks (enteropathy-associated T-cell lymphoma, osteoporosis, other autoimmune disease) that the diet also reduces. Dermatomyositis prognosis is dominated by the malignancy and by interstitial lung disease (especially anti-MDA5 and anti-synthetase antibodies). Calciphylaxis carries a one-year mortality that may exceed 40 percent.[1]

Most cutaneous markers are managed outpatient by the specialty that owns the systemic disease — gastroenterology for coeliac, IBD, and PCT; endocrinology for diabetes and thyroid; rheumatology for the connective tissue diseases; haemato-oncology for Sweet syndrome and AML. Admission is for the emergencies: severe Sweet with high fever, calciphylaxis, a large pyoderma gangrenosum, or systemic decompensation of the underlying disease (acute liver failure in Wilson, thyroid storm in Graves with pretibial myxoedema).[1]

Evidence and guidelines

The evidence base is large case series and consensus guidelines rather than randomised trials — these are uncommon diseases. The 2019 EULAR/ACR classification criteria for SLE (ANA entry criterion plus additive weighted criteria) have largely superseded the older 1997 ACR and 2012 SLICC criteria. The 2017 EULAR/ACR classification for idiopathic inflammatory myopathies (including dermatomyositis) standardised the clinical, histological, and myositis-specific antibody definitions and stratifies malignancy risk — anti-TIF1-gamma and anti-NXP2 carry the highest malignancy risk in adult dermatomyositis.[3]

The ACR/EULAR classification criteria for systemic sclerosis (2013) weight skin thickening, fingertip changes, telangiectasia, abnormal nailfold capillaries, pulmonary arterial hypertension and interstitial lung disease, and SSc-related autoantibodies (anti-centromere, anti-topoisomerase I, anti-RNA polymerase III). The Sydney classification and revised international criteria for coeliac disease underpin serology-first diagnosis with biopsy confirmation; a non-biopsy diagnosis (high-titre tTG-IgA plus anti-endomysial antibody in symptomatic children) is now accepted in paediatric guidance in several regions. The 2008 ACR/EULAR classification for antiphospholipid syndrome (updated 2023) defines the clinical and laboratory criteria (lupus anticoagulant, anticardiolipin, anti-beta-2-glycoprotein I).[12]

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Exam pearls and high-yield minutiae

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Ward-round test

1. A 58-year-old thin man has a three-month history of rapidly progressive velvety darkening of the axillae and palms, 8 kg weight loss, and new 'moles' over the trunk. What is the most important next investigation?

Upper gastrointestinal endoscopy to screen for gastric adenocarcinoma. The combination of rapidly progressive acanthosis nigricans with tripe palms and the explosive new seborrhoeic keratoses of the sign of Leser-Trélat is the classical triad of paraneoplastic acanthosis nigricans from gastric adenocarcinoma, driven by tumour-derived TGF-alpha and EGF. Add a CT chest, abdomen, and pelvis. The marker may regress once the tumour is resected.[10]

2. A 45-year-old woman has six months of a violaceous rash over her knuckles and upper eyelids, proximal muscle weakness, and a new facial rash. What must you do at diagnosis?

Screen for occult malignancy. The Gottron papules over the metacarpophalangeal joints and the heliotrope rash on the upper eyelids make the diagnosis of dermatomyositis; 15 to 25 percent of adults with dermatomyositis harbour an occult malignancy — ovarian, lung, gastric or colorectal, breast, and (especially in Asian populations) nasopharyngeal. Order CT of the chest, abdomen, and pelvis, mammography, age-appropriate endoscopy, ovarian imaging, and myositis-specific antibodies (anti-TIF1-gamma marks the malignancy-associated form). Treat the myositis with systemic corticosteroids and a steroid-sparing agent.[3]

3. A 30-year-old man has intensely itchy vesicles on his elbows, knees, and buttocks. Name the diagnosis, the serology, the immunofluorescence pattern, and the two limbs of treatment.

This is dermatitis herpetiformis, the cutaneous counterpart of coeliac disease. Serology is tTG-IgA (with total IgA to exclude deficiency); direct immunofluorescence of perilesional skin shows granular IgA at the dermal papillae. Treat with a strict lifelong gluten-free diet (resolves the rash and the enteropathy) plus dapsone for itch while the diet takes effect — check G6PD and monitor the full blood count.[5]

4. A 24-year-old woman has new parkinsonism, a low-grade hepatitis, and a brown-green ring at the corneal periphery on slit-lamp examination. What is the ring, what is the diagnosis, and what is the first-line treatment?

The ring is the Kayser-Fleischer ring — copper deposited at the periphery of Descemet membrane. The diagnosis is Wilson disease. Confirm with serum and 24-hour urinary copper and a low caeruloplasmin; image the brain if neurology is prominent. First-line treatment is chelation with penicillamine or trientine, with oral zinc for maintenance or pre-symptomatic disease. The ring fades as copper is cleared.[13]

5. A 70-year-old smoker has concentric, slowly advancing 'wood-grain' rings on his trunk with desquamation and weight loss. Name the marker, the target malignancy, and the next investigation.

This is erythema gyratum repens — one of the most specific paraneoplastic markers in dermatology, malignancy-associated in about 80 percent of cases, with lung cancer the leading target (then breast, GI, bladder, prostate). The next investigation is chest imaging with CT of the chest, abdomen, and pelvis, and a directed search for the primary tumour. Treat the tumour and the eruption often regresses.[7]

References

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13. [13]Arora N, Bhat P, Goel R, et al. Kayser-Fleischer ring QJM, 2020.PMID 31432083
14. [14]Bauer AJ, Stratakis CA. The lentiginoses: cutaneous markers of systemic disease and a window to new aspects of tumourigenesis J Med Genet, 2005.PMID 15958502
15. [15]Cohen BA. Incontinentia pigmenti Neurol Clin, 1987.PMID 3306331
16. [16]Ameen M. Cutaneous markers of HIV infection and progression Curr HIV Res, 2010.PMID 20636278