Neurocutaneous Syndromes (Phakomatoses)

What You'll Learn

NF1 (neurofibromin, 17q11.2) — most common phakomatosis; 2021 revised criteria require ≥2 features (café-au-lait macules, neurofibromas, axillary/inguinal freckling, optic pathway glioma, Lisch nodules or ≥2 choroidal abnormalities on OCT/near-infrared imaging, distinctive osseous lesion, pathogenic heterozygous NF1 variant, or first-degree relative with NF1). For isolated pigmentary findings, consider Legius syndrome (SPRED1); avoid diagnosing NF1 from pigmentary criteria alone without a non-pigmentary criterion or an affected parent meeting criteria.
NF2-related schwannomatosis (merlin/schwannomin, 22q12.2; "NF2" remains accepted board shorthand under 2022 nomenclature) — hallmark is bilateral vestibular schwannomas; also meningiomas, ependymomas, posterior subcapsular cataracts. Mosaic/segmental NF2-related schwannomatosis may lack bilateral vestibular schwannomas.
TSC (hamartin 9q34 / tuberin 16p13.3) — cortical tubers, subependymal nodules, SEGA; seizures most common neurologic feature; mTOR inhibitors (everolimus) for SEGA
VHL (VHL gene, 3p25.3) — hemangioblastomas (cerebellar > spinal > retinal), clear cell renal cell carcinoma, pheochromocytoma
Sturge-Weber — somatic mosaic GNAQ mutation (NOT inherited); port-wine stain (V1), leptomeningeal angiomatosis, “tram-track” calcifications, seizures, glaucoma
Ataxia-telangiectasia (AR, ATM gene, 11q22.3) — progressive cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency, elevated AFP, DNA repair defect
Distinguish inheritance patterns: NF1, NF2, TSC, VHL are autosomal dominant; ataxia-telangiectasia is autosomal recessive; Sturge-Weber is sporadic (somatic)

HighYield Pearls

NF1 (17q11, neurofibromin / Ras-GAP, AD) — 2021 revised criteria: diagnose with ≥2 of — ≥6 café-au-lait macules (≥5 mm prepubertal / ≥15 mm postpubertal), axillary/inguinal freckling, Lisch nodules or ≥2 choroidal abnormalities on OCT/near-infrared imaging, ≥2 neurofibromas or 1 plexiform, optic pathway glioma, sphenoid wing dysplasia or tibial pseudoarthrosis, pathogenic heterozygous NF1 variant, or first-degree relative meeting criteria. For isolated pigmentary findings, consider Legius syndrome (SPRED1) — don’t diagnose NF1 from pigmentary criteria alone without a non-pigmentary criterion or an affected parent meeting criteria.
NF2-related schwannomatosis (22q12, merlin, AD; "NF2" remains accepted board shorthand under 2022 nomenclature): bilateral vestibular schwannomas are the diagnostic hallmark; also meningiomas, ependymomas, juvenile posterior subcapsular cataracts; NO Lisch nodules. Mosaic/segmental NF2-related schwannomatosis may lack bilateral VS.
TSC (TSC1 hamartin 9q34 / TSC2 tuberin 16p13, AD) → mTOR upregulation: cortical tubers + subependymal nodules + SEGA; cardiac rhabdomyoma (infant), renal AMLs, facial angiofibromas, ash-leaf macules, shagreen patch, ungual fibromas.
Sturge-Weber (encephalotrigeminal angiomatosis): somatic mosaic GNAQ mutation (NOT inherited); port-wine stain in V1 forehead/eyelid ± V2/V3 + ipsilateral leptomeningeal angiomatosis + “tram-track” gyriform cortical calcifications + glaucoma + refractory focal seizures ± hemiparesis/hemianopia.
VHL (3p25, pVHL → HIF dysregulation, AD): hemangioblastomas (cerebellum > spinal > retina), clear cell RCC (leading cause of death), pheochromocytoma, pancreatic cysts/NETs, endolymphatic sac tumors.
Ataxia-telangiectasia (ATM, 11q22, AR): progressive cerebellar ataxia + oculocutaneous telangiectasias + IgA deficiency + elevated AFP + radiosensitivity — avoid therapeutic ionizing radiation and radiomimetics (e.g., bleomycin).
Incontinentia pigmenti (IKBKG/NEMO, Xq28): X-linked dominant, lethal in males; skin lesions evolve in 4 stages along Blaschko lines (vesicular → verrucous → hyperpigmented → hypopigmented/atrophic) + seizures, stroke, CNS hemorrhage, dental anomalies.
PHACE(S): segmental facial hemangioma + posterior fossa malformation (often Dandy-Walker variant) + arterial anomalies (Moyamoya-like) + cardiac/coarctation + eye anomalies (± sternal cleft); predominantly female.
Screening & targeted therapy: NF1 — annual pediatric ophtho for optic pathway glioma; selumetinib (MEK inhibitor) for inoperable symptomatic plexiform neurofibromas. TSC — vigabatrin first-line for infantile spasms; everolimus (mTOR inhibitor) for SEGA, renal AML, refractory focal seizures. VHL — annual ophtho, brain/spine MRI, abdominal imaging, plasma metanephrines; belzutifan (HIF-2α inhibitor) for VHL-associated RCC, hemangioblastomas, pancreatic NETs. NF2 — bevacizumab for growing VS with hearing preservation.

🔍 Quick ReferenceSkin / clinical · Imaging · Genes / pathology / tumors

Skin / clinical signs

Café-au-lait macules + axillary/inguinal freckling + Lisch nodules → NF1
Young adult with bilateral hearing loss / tinnitus ± juvenile posterior subcapsular cataracts → NF2
Ash-leaf macules + shagreen patch + facial angiofibromas (“adenoma sebaceum”) + periungual (Koenen) fibromas + confetti macules → TSC
Port-wine stain in V1 (forehead/upper eyelid) distribution → Sturge-Weber
Oculocutaneous (bulbar conjunctival) telangiectasias + progressive cerebellar ataxia in a child → Ataxia-telangiectasia
Blaschko-line vesicular → verrucous → hyperpigmented streaks (female infant) → Incontinentia pigmenti
Plexiform neurofibroma → NF1 (pathognomonic; ~10% MPNST risk)
Episodic flushing + headache + hypertension → VHL pheochromocytoma
Large segmental facial hemangioma in an infant girl → PHACE(S)

Imaging signs

Bilateral vestibular schwannomas on MRI → NF2 (pathognomonic)
Cortical tubers + subependymal nodules (“candle-dripping”) + SEGA at foramen of Monro → TSC
“Tram-track” gyriform cortical calcifications + cortical atrophy + ipsilateral choroid plexus enlargement + leptomeningeal enhancement → Sturge-Weber
Cerebellar or spinal cystic mass with enhancing mural nodule (± spinal syrinx) → VHL hemangioblastoma
Sphenoid wing dysplasia + optic pathway glioma → NF1
FASI / unidentified bright objects (UBOs) in basal ganglia, cerebellum, brainstem → NF1 (non-enhancing, not tumors)
Posterior fossa malformation (Dandy-Walker variant) + Moyamoya-like arteriopathy + facial hemangioma → PHACE(S)
Cardiac rhabdomyoma on prenatal/infant echo → TSC

Genes / pathology / tumors

NF1 gene (17q11) → neurofibromin (Ras-GAP) → NF1
NF2 gene (22q12) → merlin / schwannomin → NF2
TSC1 (hamartin, 9q34) / TSC2 (tuberin, 16p13) → mTOR upregulation; cardiac rhabdomyoma; renal AML → TSC
Somatic mosaic GNAQ p.R183Q (9q21) → Sturge-Weber (not heritable)
VHL (3p25) → pVHL / HIF; hemangioblastoma + clear cell RCC + pheochromocytoma + EPO-driven polycythemia → VHL
ATM (11q22) → DNA double-strand break repair; low IgA, elevated AFP, radiosensitivity → Ataxia-telangiectasia
IKBKG / NEMO (Xq28) → Incontinentia pigmenti
SMARCB1 / LZTR1 (22q11) → Schwannomatosis (non-NF2; painful peripheral schwannomas; bilateral VS favor NF2-related schwannomatosis, but unilateral VS can occur in LZTR1-related schwannomatosis)
PTEN (10q23) → Lhermitte-Duclos (dysplastic gangliocytoma of cerebellum) → Cowden syndrome

Overview — Phakomatoses at a Glance

Disease	Inheritance	Gene / Protein	Chromosome	Key Features
NF1	AD	NF1 / neurofibromin	17q11.2	Café-au-lait macules, neurofibromas, optic gliomas, Lisch nodules
NF2	AD	NF2 / merlin (schwannomin)	22q12.2	Bilateral vestibular schwannomas, meningiomas, ependymomas
TSC	AD	TSC1 / hamartin; TSC2 / tuberin	9q34; 16p13.3	Cortical tubers, SEGA, angiofibromas, cardiac rhabdomyomas
VHL	AD	VHL / pVHL	3p25.3	Hemangioblastomas, renal cell carcinoma, pheochromocytoma
Sturge-Weber	Sporadic (somatic)	GNAQ (somatic mosaic)	9q21.2	Port-wine stain (V1), leptomeningeal angiomatosis, seizures, glaucoma
Ataxia-Telangiectasia	AR	ATM	11q22.3	Cerebellar ataxia, telangiectasias, immunodeficiency, elevated AFP

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