Genodermatoses
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Direct answer
Cutaneous stigmata that announce a multisystem single-gene syndrome — this is what the genodermatoses are, and NEET-PG tests the same short list relentlessly. Neurofibromatosis 1 (NF1 gene, chromosome 17) is diagnosed by two or more of: six or more café-au-lait macules, axillary or inguinal freckling, two or more neurofibromas or one plexiform type, optic pathway glioma, two or more Lisch iris hamartomas, sphenoid wing dysplasia, or an affected first-degree relative. Tuberous sclerosis (TSC1 hamartin/TSC2 tuberin) shows hypomelanotic ash-leaf macules, facial angiofibromas, shagreen patch, periungual Koenen fibromas, with seizures and SEGA. Xeroderma pigmentosum (nucleotide excision repair defect) means freckling before age two, photophobia, and skin cancers in childhood. Gorlin syndrome (PTCH1) combines basal cell carcinomas with jaw keratocysts and palmar pits, and Darier disease (ATP2A2) greasy crusted papules with nail V-nicking and palmar pits.
What you must remember
- NF1 diagnostic anchors: café-au-lait macules (six or more; 5 mm pre-pubertal, 15 mm post-pubertal), Crowe's axillary freckling, cutaneous and plexiform neurofibromas, Lisch nodules on slit-lamp, optic glioma, skeletal lesions; chromosome 17 (NF2, with bilateral vestibular schwannomas, is chromosome 22).
- NF1 complications to counsel: plexiform neurofibroma may transform to malignant peripheral nerve sheath tumour — new pain, rapid growth or neurological deficit demands urgent imaging; learning disability and hypertension (renal artery stenosis) are the quiet associations.
- Tuberous sclerosis quartet: ash-leaf hypomelanosis (Wood's lamp), facial angiofibromas (adenoma sebaceum), shagreen patch (lumbosacral connective-tissue naevus), Koenen periungual fibromas — plus seizures, intellectual disability, SEGA, cardiac rhabdomyoma and renal angiomyolipoma; the "Ash-leaf spot first" rule: in an infant with infantile spasms, Wood's lamp the skin.
- Xeroderma pigmentosum: autosomal recessive nucleotide excision repair failure (XP-A through XP-G); acute blistering sunburns, freckling before two years, poikiloderma, then BCC, SCC and melanoma in childhood — strict total photoprotection; De Sanctis-Cacchione variant adds neurodegeneration.
- Gorlin (basal cell naevus) syndrome: PTCH1/hedgehog pathway — multiple BCCs from adolescence, odontogenic keratocysts of the jaw, palmar/plantar pits, calcified falx cerebri, bifid ribs, medulloblastoma risk in childhood; avoid radiation therapy (it induces BCCs).
- Darier disease (keratosis follicularis): ATP2A2 (SERCA2) — crusted, greasy, malodorous papules in seborrhoeic and flexural areas in a butterfly distribution, heat-exacerbated; nail sign is V-shaped distal nicking plus subungual hyperkeratosis; histology: suprabasilar acantholysis with corps ronds and grains.
- Hailey-Hailey disease (familial benign chronic pemphigus): ATP2C1 — flexural, crusted, fissured plaques ("railroad-track" fissuring), histology like a "dilapidated brick wall"; the ATP2A2/ATP2C1 calcium-pump pairing with Darier is a favourite.
- Incontinentia pigmenti (Bloch-Sulzberger): X-linked dominant (IKBKG/NEMO), male-lethal; four stages — vesicular (birth, Blaschkoid blisters with eosinophilia), verrucous, hyperpigmented whorled swirls, then atrophic streaks with hair loss; pegged/conical teeth, nail dystrophy, seizures and retinal detachment — paediatric ophthalmology referral is mandatory.
- Vascular-collagen set to finish: pseudoxanthoma elasticum (ABCC6) — "plucked chicken" yellow papules on neck and flexures with angioid streaks (Bruch membrane) and GI bleeding; dyskeratosis congenita — reticulate pigmentation, nail dystrophy, leukoplakia, then marrow failure (short-telomere disease); acrodermatitis enteropathica — periorificial and acral dermatitis with diarrhoea and alopecia from zinc malabsorption, responding to zinc supplementation.
Reading the skin as the syndrome's front page
A 3-month-old girl is admitted with linear blisters along the left arm and trunk, blood eosinophilia, and a mother whose own "birthmarks" fade in summer. The linearity follows Blaschko's lines; the mother's whorled pigmentation is the third stage of the same disease. You stage incontinentia pigmenti, photograph the blisters, and book dental (pegged teeth), ophthalmological (retinal) and neurodevelopment follow-up. The cutaneous stage is self-limiting; the retinal and dental sequelae are not.
Contrast the developmental clinic's 2-year-old with infantile spasms: the Wood's lamp reveals ash-leaf hypomelanosis on the trunk. The skin finding converts a seizure work-up into a targeted one — brain imaging for tubers and SEGA, echocardiography for rhabdomyoma, renal ultrasound for angiomyolipoma, and genetics confirming TSC1/TSC2. In both children, nobody needed the skin to be "cured" — they needed the skin to be read.
Where the exam plants its one-liners
The guaranteed formats are the criteria-count (how many café-au-lait macules, at what size, at what age), the chromosome pair (NF1 = 17, NF2 = 22), the gene-product pair (TSC1 hamartin, TSC2 tuberin), the XP repair mechanism (nucleotide excision), and the Darier nail sign (V-nicking). Incontinentia pigmenti appears as the staged, Blaschko-linear, male-lethal stem with eosinophilia; PXE through angioid streaks; dyskeratosis congenita through the pigmentation-nail-leukoplakia-marrow tetrad. The Darier-Hailey-Hailey calcium-pump pair (ATP2A2 ER, ATP2C1 Golgi) separates prepared candidates from lucky ones.
Frequently asked questions
What are the diagnostic criteria for neurofibromatosis 1?
Two or more of: six-plus café-au-lait macules, axillary/inguinal freckling, two-plus neurofibromas or a plexiform neurofibroma, optic glioma, two-plus Lisch nodules, sphenoid dysplasia, or an affected parent.
Which gene defect underlies xeroderma pigmentosum?
Nucleotide excision repair failure — unrepaired UV-induced pyrimidine dimers lead to early freckling, poikiloderma and childhood skin cancers.
What are the four cutaneous stages of incontinentia pigmenti?
Vesicular, verrucous, whorled hyperpigmentation along Blaschko's lines, and finally hypopigmented atrophic streaks — an X-linked dominant, male-lethal IKBKG/NEMO disorder.
Which skin sign should be sought in an infant with infantile spasms?
Hypomelanotic ash-leaf macules of tuberous sclerosis, best revealed by Wood's lamp examination — the fastest clue to the syndrome.
How do Darier and Hailey-Hailey diseases differ genetically?
Darier (ATP2A2, ER calcium pump) shows keratotic papules with V-nicked nails; Hailey-Hailey (ATP2C1, Golgi calcium pump) shows flexural fissured plaques with a dilapidated-brick-wall histology.