Genetics & Epidemiology

• Inheritance: Autosomal dominant; ~50% are de novo mutations
• Gene: NF1 on chromosome 17q11.2
• Protein: Neurofibromin — a tumor suppressor that functions as a RAS-GTPase-activating protein (GAP); loss of function → unregulated RAS signaling → cell proliferation
• Prevalence: ~1 in 3,000 — most common phakomatosis
• Penetrance: Nearly 100% by age 5, but variable expressivity

Diagnostic Criteria (NIH — ≥2 Required)

• ≥6 café-au-lait macules (>5 mm prepubertal; >15 mm postpubertal)
• ≥2 neurofibromas of any type OR 1 plexiform neurofibroma
• Axillary or inguinal freckling (Crowe sign)
• Optic pathway glioma (typically pilocytic astrocytoma)
• ≥2 Lisch nodules (iris hamartomas — seen on slit-lamp exam)
• Distinctive osseous lesion: sphenoid wing dysplasia, thinning of long bone cortex ± pseudoarthrosis
• First-degree relative with NF1 by above criteria

Updated 2021 Criteria Additions

• Pathogenic NF1 variant (heterozygous) identified on genetic testing
• Choroidal abnormalities (≥2 identified by optical coherence tomography/near-infrared reflectance imaging)

Associated Tumors

Neurological Complications

• Learning disability / ADHD: most common neurological complication (~50–60%); intellectual disability in ~5%
• Seizures: ~6–10% of patients
• UBOs (unidentified bright objects): T2/FLAIR hyperintensities in basal ganglia, cerebellum, brainstem; non-progressive; typically resolve by adulthood; do NOT enhance and are NOT tumors
• Cerebrovascular: moyamoya-like vasculopathy, cerebral aneurysms, arterial stenosis
• Hypertension: renal artery stenosis or pheochromocytoma
• Sphenoid wing dysplasia: pulsating exophthalmos

Genetics & Epidemiology

• Inheritance: Autosomal dominant; ~50% de novo
• Gene: NF2 on chromosome 22q12.2
• Protein: Merlin (schwannomin) — a cytoskeletal tumor suppressor linking cell membrane to actin cytoskeleton
• Prevalence: ~1 in 25,000–33,000 (much rarer than NF1)
• Presentation: Typically in late teens to early 20s with hearing loss or tinnitus

Clinical Features

• Bilateral vestibular schwannomas: hallmark and pathognomonic finding; present in >95% of NF2 patients
• Meningiomas: ~50% of NF2 patients; often multiple; may be intracranial or spinal
• Ependymomas: spinal ependymomas most common; intramedullary
• Schwannomas: other cranial nerves (especially CN V, VII), spinal nerve roots, peripheral nerves
• Posterior subcapsular cataracts: juvenile cataracts in ~60–80%; may be earliest sign
• NO café-au-lait macules, NO Lisch nodules (distinguish from NF1)

MISME Mnemonic

• Multiple
• Inherited
• Schwannomas
• Meningiomas
• Ependymomas

Diagnostic Criteria (Manchester Criteria)

• Definite NF2: Bilateral vestibular schwannomas (VS) on imaging, OR
• First-degree relative with NF2 + unilateral VS at age <30, OR
• First-degree relative with NF2 + any 2 of: meningioma, schwannoma, glioma, posterior subcapsular cataract

Presentation & Complications

• Hearing loss: progressive unilateral then bilateral sensorineural hearing loss (most common presenting symptom)
• Tinnitus: often precedes hearing loss
• Facial weakness/numbness: tumor growth compressing CN V and VII
• Imbalance: vestibular dysfunction from VS
• Myelopathy: from spinal schwannomas, ependymomas, or meningiomas

Genetics

• Inheritance: Autosomal dominant; ~2/3 are de novo mutations
• TSC1: chromosome 9q34 → hamartin
• TSC2: chromosome 16p13.3 → tuberin
• TSC2 mutations tend to cause more severe disease than TSC1
• Hamartin and tuberin form a complex that inhibits the mTOR pathway → loss of function → unregulated mTOR signaling → cell growth and proliferation
• Prevalence: ~1 in 6,000

Classic Triad (Vogt Triad)

• Seizures + intellectual disability + facial angiofibromas (“adenoma sebaceum”)
• Full triad present in only ~30% of patients
• Seizures are the most common neurological manifestation (~80–90%); often infantile spasms in the first year of life

Skin Manifestations

CNS Manifestations

Systemic Manifestations

• Cardiac rhabdomyomas: most common cardiac tumor in children; often multiple; may cause arrhythmias; tend to regress spontaneously; may be first prenatal finding
• Renal angiomyolipomas (AML): ~80% of TSC patients; fat-containing benign tumors; risk of hemorrhage if >4 cm; treat with mTOR inhibitors or embolization
• Renal cysts: when TSC2 is contiguously deleted with PKD1 gene → TSC + polycystic kidney disease
• Lymphangioleiomyomatosis (LAM): cystic lung disease predominantly in women; progressive dyspnea; can cause pneumothorax
• Retinal hamartomas: “mulberry lesion” or flat, translucent lesion; usually asymptomatic

Genetics

• Inheritance: Autosomal dominant
• Gene: VHL on chromosome 3p25.3
• Protein: pVHL — tumor suppressor that targets HIF (hypoxia-inducible factor) for degradation
• Loss of pVHL → constitutive HIF activation → overproduction of VEGF, PDGF, EPO → vascular tumor proliferation and angiogenesis
• Prevalence: ~1 in 36,000

Major Manifestations

VHL Classification

Hemangioblastoma Specifics

• WHO grade I, benign, highly vascular
• Classic imaging: cystic mass with enhancing mural nodule
• Location in VHL: cerebellar (most common) > spinal cord > brainstem > retina
• Secondary polycythemia: hemangioblastomas can secrete erythropoietin (EPO) → elevated hematocrit
• VHL-associated hemangioblastomas: typically multiple and recurrent (vs. sporadic hemangioblastoma: single)
• Sporadic hemangioblastomas are the most common primary intra-axial posterior fossa tumor in adults

Genetics & Pathogenesis

• NOT inherited — caused by a somatic mosaic activating mutation in GNAQ gene (9q21.2)
• GNAQ encodes Gαq protein involved in endothelin signaling → constitutive activation of downstream pathways → vascular malformation
• Mutation occurs during embryonic development → affects structures derived from the cephalic neural crest
• Sporadic — recurrence risk for siblings is negligible

Clinical Features

• Port-wine stain (nevus flammeus):
  • Facial capillary malformation in V1 (ophthalmic) distribution — forehead and upper eyelid involvement is key
  • May extend to V2 and V3 distribution
  • Present at birth; does NOT blanch with pressure
  • NOT all port-wine stains indicate Sturge-Weber (only ~5–10% of V1 port-wine stains are associated with leptomeningeal angiomatosis)
• Leptomeningeal angiomatosis:
  • Ipsilateral to the facial port-wine stain
  • Pial vascular malformation → venous stasis and chronic ischemia of underlying cortex
  • “Tram-track” calcifications: gyriform cortical calcifications on CT, ipsilateral to the port-wine stain (represent calcified cortex beneath the angioma)
• Seizures:
  • Most common neurologic manifestation (~75–90%)
  • Typically focal, contralateral to the angioma; onset usually in the first year of life
  • May become refractory; hemispherectomy considered in severe cases
• Contralateral hemiparesis: progressive; due to chronic cortical ischemia
• Intellectual disability: ~50–60%; correlates with seizure severity and extent of angioma
• Glaucoma: ipsilateral; due to elevated episcleral venous pressure from conjunctival/episcleral vascular malformation; present in 30–70%
• Stroke-like episodes: may occur, resembling migrainous infarcts

Imaging

• CT: “Tram-track” gyriform cortical calcifications (classic finding); cortical atrophy
• MRI with contrast: leptomeningeal enhancement ipsilateral to the port-wine stain; cortical atrophy; enlarged choroid plexus (ipsilateral)
• SWI/GRE: demonstrates calcification and venous abnormalities

Genetics

• Inheritance: Autosomal recessive (the only AR phakomatosis)
• Gene: ATM (ataxia telangiectasia mutated) on chromosome 11q22.3
• Protein: ATM kinase — critical for DNA double-strand break repair and cell-cycle checkpoint regulation
• Prevalence: ~1 in 40,000–100,000

Clinical Features

• Progressive cerebellar ataxia:
  • Earliest neurological sign; onset age 1–4 years (initially gait ataxia, then limb ataxia)
  • Progressive — most patients wheelchair-bound by age 10–12
  • Due to progressive cerebellar Purkinje cell degeneration
• Oculocutaneous telangiectasias:
  • Appear by age 3–6 years (later than ataxia)
  • Bulbar conjunctivae (most prominent), ears, flexor surfaces of arms, face
• Oculomotor apraxia: inability to generate voluntary saccades; compensatory head thrusting
• Immunodeficiency:
  • IgA deficiency (most common), IgG2 subclass deficiency, low IgE
  • T-cell dysfunction (thymic hypoplasia)
  • → Recurrent sinopulmonary infections (leading cause of morbidity)
• Cancer predisposition:
  • Defective DNA repair → increased sensitivity to ionizing radiation
  • ~25–30% lifetime cancer risk; lymphoma and leukemia most common
  • Carriers (heterozygotes) have increased breast cancer risk
• Other: choreoathetosis, peripheral neuropathy (later), endocrine dysfunction (growth failure, insulin resistance)

Laboratory Findings

• Elevated alpha-fetoprotein (AFP): found in >95% of patients; important diagnostic clue
• Low immunoglobulins: IgA, IgG2, IgE
• Elevated CEA (less specific)
• Chromosomal instability: spontaneous chromosomal breaks, translocations (especially involving chromosomes 7 and 14 at TCR and Ig gene loci)
• Radiation sensitivity: in vitro lymphocyte testing shows increased sensitivity to ionizing radiation