Neurocutaneous Syndromes
A Step 1 high-yield tour of the phakomatoses (NF1, NF2, tuberous sclerosis, Sturge-Weber, VHL, plus ataxia-telangiectasia), pairing each signature skin lesion with its CNS/visceral tumor, its gene/protein/mechanism, and the tested next-best-step. Includes a genetics table, four vignettes, morphology buzzwords, and accurate memory anchors.
Overview: the phakomatoses
Neurocutaneous syndromes (phakomatoses) are inherited or mosaic disorders in which ectodermal/neuroectodermal tissues — plus some mesodermal, vascular structures — form hamartomas and neoplasms, so the skin and CNS are affected together. Most of the inherited forms inactivate a tumor-suppressor gene by a two-hit mechanism (germline mutation + somatic second hit). Boards test a classic set: NF1, NF2, tuberous sclerosis (TSC), Sturge-Weber, and von Hippel-Lindau (VHL), with ataxia-telangiectasia a frequent add-on.
The exam links one signature skin lesion to one signature CNS/visceral tumor. Strategy: recognize the cutaneous marker first (usually the earliest sign), then anticipate the internal lesion and the correct screening / next step.
Inheritance anchors: NF1, NF2, TSC, VHL are autosomal dominant; Sturge-Weber is sporadic (somatic mosaic GNAQ, not inherited); ataxia-telangiectasia is autosomal recessive.
- NF1 — NF1 gene, chr 17, AD; product neurofibromin, a Ras-GTPase–activating protein (tumor suppressor); loss → unchecked Ras signaling.
- NF2 — NF2 gene, chr 22, AD; product merlin (schwannomin). NF-2 → chr 22 → bilateral vestibular (acoustic) schwannomas.
- Tuberous sclerosis — TSC1 (hamartin, chr 9) or TSC2 (tuberin, chr 16), AD; loss of the hamartin–tuberin complex disinhibits mTOR.
- Sturge-Weber — somatic activating mutation in GNAQ; mosaic, not inherited.
- VHL — VHL gene, chr 3p, AD; pVHL is the substrate-recognition component of an E3 ubiquitin ligase complex that degrades HIF-1α → loss ↑ VEGF/EPO.
- Ataxia-telangiectasia — ATM gene, chr 11, AR; defective sensing/repair of double-strand DNA breaks.
Side-by-side comparison
| Syndrome | Gene (chr), inherit. | Skin buzzword | CNS / eye | Systemic |
|---|---|---|---|---|
| NF1 | NF1 (17), AD | ≥6 café-au-lait, axillary/inguinal freckling, cutaneous + plexiform neurofibromas | Optic glioma, Lisch nodules (iris hamartoma) | Pheochromocytoma, scoliosis, MPNST |
| NF2 | NF2 (22), AD | Sparse skin schwannomas | Bilateral vestibular schwannoma, meningioma, ependymoma | Juvenile cataract |
| TSC | TSC1/2 (9/16), AD | Ash-leaf macule, shagreen patch, facial angiofibroma, periungual fibroma | Cortical tubers, SEGA, retinal hamartoma | Cardiac rhabdomyoma, renal angiomyolipoma, seizures |
| Sturge-Weber | GNAQ, sporadic | Port-wine stain (V1±V2) | Leptomeningeal angioma, tram-track Ca²⁺ | Glaucoma, seizures |
| VHL | VHL (3p), AD | (few skin signs) | Retinal + CNS hemangioblastoma | Clear-cell RCC, pheochromocytoma, pancreatic cysts |
Stem: A 7-year-old has 8 flat, uniformly light-brown macules >5 mm, freckling in both axillae, and several soft dome-shaped papules that invaginate on pressure ("buttonhole" sign). Slit-lamp shows pigmented iris hamartomas.
- Dx: Neurofibromatosis type 1 — ≥6 café-au-lait macules + axillary freckling (Crowe sign) + neurofibromas + Lisch nodules.
- Buzzwords: café-au-lait (>5 mm prepubertal, >15 mm postpubertal), smooth "coast of California" borders (vs jagged "coast of Maine" in McCune-Albright).
- Next best step / traps:
- Baseline ophthalmology exam for optic pathway glioma.
- A neurofibroma that turns painful, hard, or rapidly enlarging → suspect malignant peripheral nerve sheath tumor (MPNST) → MRI + biopsy.
- New hypertension → screen for pheochromocytoma (plasma free metanephrines) or renal artery stenosis.
Stem: A 4-month-old has flurries of flexor spasms; EEG shows hypsarrhythmia. Wood-lamp exam reveals several hypopigmented "ash-leaf" macules, and an echo for a murmur shows an intracardiac mass.
- Dx: Tuberous sclerosis — infantile spasms + ash-leaf spots + cardiac rhabdomyoma (often regresses spontaneously).
- Buzzwords: ash-leaf macule (Wood lamp), shagreen patch (leathery orange-peel lumbosacral plaque), facial angiofibroma ("adenoma sebaceum"), Koenen periungual fibroma, renal angiomyolipoma.
- Next best step:
- Vigabatrin — first-line for TSC-associated infantile spasms (a key distinction from non-TSC spasms, where ACTH is first-line).
- Brain MRI for cortical tubers and subependymal giant cell astrocytoma (SEGA); a SEGA at the foramen of Monro causing hydrocephalus → everolimus (mTOR inhibitor) or resection.
Stem: A newborn has a flat, sharply demarcated dark-red patch over the forehead and upper eyelid that does not cross the midline. At 6 months he develops focal seizures; skull imaging shows curvilinear "tram-track" gyriform calcifications.
- Dx: Sturge-Weber syndrome — facial port-wine stain in V1 + ipsilateral leptomeningeal capillary-venous malformation; somatic GNAQ mutation.
- Buzzwords: port-wine stain / nevus flammeus (V1 > V2, respects midline), tram-track cortical calcification.
- Next best step:
- A V1 port-wine stain mandates brain MRI with contrast for the leptomeningeal angioma.
- Urgent ophthalmology to measure IOP — ipsilateral glaucoma is common and vision-threatening.
- The stain itself → pulsed-dye laser.
- Café-au-lait macule: uniformly tan, smooth "coast of California" border; ≥6 → NF1 (jagged "coast of Maine" = McCune-Albright).
- Neurofibroma: soft, pedunculated, "buttonhole" invagination; a plexiform neurofibroma is essentially pathognomonic for NF1.
- Ash-leaf macule: hypopigmented, best seen under Wood lamp; earliest TSC skin sign.
- Shagreen patch: flesh-colored orange-peel connective-tissue plaque over the lumbosacral back.
- Facial angiofibroma: red malar/nasolabial papules in a butterfly pattern.
- Port-wine stain: capillary malformation, unilateral, respects the midline; highest Sturge-Weber risk when it involves V1.
- Oculocutaneous telangiectasias: conjunctival + skin → ataxia-telangiectasia (+ ataxia, ↑ AFP, IgA deficiency, lymphoma/leukemia risk).
Stem: A 28-year-old with a family history of "brain and kidney tumors" presents with headache and gait ataxia. MRI shows a cystic cerebellar mass with an enhancing mural nodule. CBC reveals polycythemia.
- Dx: von Hippel-Lindau — cerebellar hemangioblastoma (paraneoplastic EPO → secondary polycythemia).
- Buzzwords: hemangioblastoma (cerebellum / retina / spinal cord), "mural nodule in a cyst," bilateral clear-cell RCC, pheochromocytoma.
- Next best step:
- Abdominal MRI/CT to screen for renal cell carcinoma (a leading cause of death).
- Plasma/urine metanephrines for pheochromocytoma before any surgery (avoid intra-op hypertensive crisis).
- Dilated retinal exam for retinal hemangioblastomas.
Chromosome anchors
- NF2 → chromosome 22 (two 2s) → bilateral vestibular schwannomas.
- VHL = 3 letters → chromosome 3 (3p).
- NF1 → chr 17; TSC1 → chr 9 (hamartin), TSC2 → chr 16 (tuberin).
Sturge-Weber = "STURGE"
- Sporadic · port-wine Stain · Tram-track calcification · Unilateral (V1, respects midline) · R intellectual disability · Glaucoma / GNAQ · Epilepsy.
Tuberous sclerosis — group by tissue
- Skin tetrad: ash-leaf macule · facial angiofibroma · shagreen patch · periungual (Koenen) fibroma.
- An "-oma" in every organ: cortical tuber & SEGA (brain) · cardiac rhabdomyoma · renal angiomyolipoma · pulmonary LAM.
- Pharm pearl: infantile spasms in TSC → vigabatrin first-line.
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