STEPTRACKERNERVOUS SYSTEM + SKIN | PATHOLOGY + GENETICS | HIGH-YIELD REVIEW

Neurocutaneous Syndromes

Inherited disorders that mark the skin and seed the nervous system with tumors — mostly tumor-suppressor losses.

FOCUS ON
NF1 (chr 17): café-au-lait spots, neurofibromas, Lisch nodules, freckling, optic glioma, pheo. NF2 (chr 22): bilateral vestibular schwannomas, meningiomas, ependymomas. Tuberous sclerosis (TSC1/2 → mTOR): ash-leaf spots, angiofibromas, tubers, seizures, cardiac rhabdomyoma, renal angiomyolipoma. Sturge-Weber: port-wine stain + leptomeningeal angioma. VHL (chr 3): hemangioblastomas, RCC, pheo.
SYNDROME
GENE · INHERITANCE
FEATURES
CLUE
Neurofibromatosis type 1
NF1 (neurofibromin, RAS-GAP), chr 17; AD, full penetrance, variable expression
≥ 6 café-au-lait spots, cutaneous and plexiform neurofibromas, axillary/inguinal freckling, Lisch nodules, optic glioma, bone dysplasia, scoliosis, learning problems
Pheochromocytoma, MPNST, GIST, JMML
Neurofibromatosis type 2
NF2 (merlin), chr 22; AD
Bilateral vestibular schwannomas, meningiomas, ependymomas, juvenile cataracts
"NF2 — two ears"
Tuberous sclerosis — CNS
TSC1 (hamartin, chr 9) or TSC2 (tuberin, chr 16); loss → mTOR overactive; AD
Cortical tubers, subependymal nodules, SEGA; seizures (infantile spasms), intellectual disability, autism
Vigabatrin for infantile spasms · everolimus
Tuberous sclerosis — skin & organs
Hamartomas in many organs
Ash-leaf hypopigmented macules, shagreen patch, facial angiofibromas, periungual fibromas; cardiac rhabdomyoma, renal angiomyolipoma, lymphangioleiomyomatosis
Wood lamp shows ash-leaf spots
Sturge-Weber syndrome
Somatic mosaic GNAQ mutation (not inherited)
Port-wine stain (V1/V2) + ipsilateral leptomeningeal angioma → seizures, hemiparesis, intellectual disability; glaucoma; "tram-track" calcifications
Capillary malformation of the face
Von Hippel-Lindau
VHL, chr 3p; AD; HIF not degraded
Hemangioblastomas (cerebellum, retina, cord), bilateral clear cell RCC, pheochromocytoma, pancreatic cysts/NETs, endolymphatic sac tumors
Polycythemia from EPO
Ataxia-telangiectasia
ATM (DNA double-strand break repair); AR
Toddler-onset cerebellar ataxia, ocular and skin telangiectasias, IgA deficiency → sinopulmonary infections
↑ AFP · lymphoma/leukemia · radiation-sensitive
Hereditary hemorrhagic telangiectasia
ENG, ACVRL1 (or SMAD4); AD
Mucocutaneous telangiectasias, recurrent epistaxis, GI bleeding; AVMs in lung (paradoxical stroke, brain abscess), brain, liver
Osler-Weber-Rendu
Gorlin syndrome
PTCH1 (hedgehog pathway); AD
Multiple early basal cell carcinomas, jaw keratocysts, palmar pits, medulloblastoma, falx calcification
Basal cell nevus syndrome
Li-Fraumeni syndrome
Germline TP53; AD
Sarcomas, breast cancer, brain tumors, adrenocortical carcinoma, leukemia at young ages
"SBLA" cancers

Mechanism — tumor suppressors and their brakes

NF1
→
RAS stays onNeurofibromas, gliomas
TSC1/TSC2
→
mTOR stays onHamartomas
VHL
→
HIF stays onVascular tumors, EPO
PTCH1
→
Hedgehog stays onBCC, medulloblastoma

Inherited one bad copy; a second somatic hit in a single cell starts each tumor.

Syndromes at a glance

SYNDROME
CHR
SKIN
CNS
NF1
17
Café-au-lait, freckling
Optic glioma, neurofibromas
NF2
22
Few
Bilateral schwannomas, meningiomas
Tuberous sclerosis
9, 16
Ash-leaf, angiofibromas
Tubers, SEGA, seizures
Sturge-Weber
Somatic
Port-wine stain
Leptomeningeal angioma
VHL
3
—
Hemangioblastoma
Ataxia-telangiectasia
11
Telangiectasias
Cerebellar atrophy

How it's tested

COMMON CONFUSIONNF1 = many skin findings, few CNS tumors (optic glioma). NF2 = few skin findings, many CNS tumors (schwannomas, meningiomas).
THE TRAPA cardiac rhabdomyoma found on prenatal ultrasound is a tuberous sclerosis clue — and these tumors usually regress on their own.
YOUR APPROACHSkin sign → CNS lesion → other organs (heart, kidney, adrenal, lung) → gene and chromosome → pathway (RAS, mTOR, HIF, hedgehog).

If you see… think…

Café-au-lait spots, axillary freckles, iris hamartomas → NF1
NF1 with paroxysmal hypertension → pheochromocytoma
Rapidly growing painful plexiform neurofibroma → MPNST
Bilateral hearing loss in a young adult with meningiomas → NF2
Infantile spasms, ash-leaf spots, cardiac rhabdomyoma → tuberous sclerosis
Renal tumor with fat, smooth muscle and vessels → angiomyolipoma (TSC)
Facial port-wine stain, seizures, tram-track calcifications → Sturge-Weber
Retinal and cerebellar hemangioblastomas + RCC → von Hippel-Lindau
Toddler with ataxia, eye telangiectasias, recurrent sinusitis, ↑ AFP → ataxia-telangiectasia
Recurrent nosebleeds + lung AVM + brain abscess → HHT