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

Management Highlights

• Selumetinib (MEK1/2 inhibitor) — FDA-approved April 2020 for pediatric (≥2 yr) inoperable symptomatic plexiform neurofibromas in NF1
• Annual ophthalmologic exam in children (screen for optic pathway glioma)
• Blood pressure monitoring (renal artery stenosis, pheochromocytoma)
• MRI for suspected MPNST: rapid growth, pain, new neurologic deficit

Genetics & Epidemiology

• 2022 nomenclature update: NF2 has been reclassified as “NF2-related schwannomatosis” under the broader schwannomatosis umbrella (per international consensus)
• 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 diagnostic hallmark; present in >95% of NF2 patients. Note: mosaic/segmental NF2 cases may NOT have bilateral VS (unilateral VS or other features only)
• Meningiomas: ~50% of NF2 patients; often multiple; may be intracranial or spinal
• Ependymomas: spinal ependymomas most common; intramedullary; often multiple; cervical/cervicomedullary spinal cord predilection
• 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

Management Highlights

• Bevacizumab (anti-VEGF) — used for growing vestibular schwannomas with hearing preservation in NF2-related schwannomatosis
• Microsurgical resection or stereotactic radiosurgery for symptomatic VS (with hearing-preservation considerations)
• Annual brain and spine MRI surveillance for new schwannomas, meningiomas, ependymomas
• Audiology and ophthalmologic monitoring

Overview

• Distinct from NF2-related schwannomatosis; characterized by multiple peripheral schwannomas, often painful — SMARCB1- or LZTR1-related
• Pain is the dominant clinical feature (often disproportionate to tumor size)
• Bilateral vestibular schwannomas are uncommon and favor NF2-related schwannomatosis; however, unilateral vestibular schwannoma can occur, especially in LZTR1-related schwannomatosis, so its presence does not exclude non-NF2 schwannomatosis. Intracranial meningiomas are uncommon.

Genetics

• SMARCB1-related schwannomatosis: SMARCB1 gene at 22q11.23
• LZTR1-related schwannomatosis: LZTR1 gene at 22q11.21
• Both loci are on chromosome 22q in close proximity to the NF2 gene — this proximity confounds molecular testing and can mimic mosaic NF2
• Autosomal dominant with reduced penetrance; ~15–25% of familial schwannomatosis is SMARCB1, smaller fraction LZTR1

Management

• Pain control (often multimodal — neuropathic pain agents, surgical resection of symptomatic tumors)
• Genetic counseling and testing to distinguish from mosaic NF2-related schwannomatosis

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 / contiguous gene syndrome: TSC2 and PKD1 are adjacent on 16p13.3; a contiguous deletion produces severe early-onset polycystic kidney disease alongside TSC
• Lymphangioleiomyomatosis (LAM): cystic lung disease predominantly in women; progressive dyspnea; can cause pneumothorax
• Retinal hamartomas: “mulberry lesion” or flat, translucent lesion; usually asymptomatic

TAND — TSC-Associated Neuropsychiatric Disorders

• TAND is the current consensus term (2012/2021 international TSC consensus) for the neuropsychiatric spectrum in TSC
• Includes autism spectrum disorder, ADHD, anxiety, mood disorders, intellectual disability, and academic/behavioral difficulties
• Routine TAND screening recommended at every clinical encounter and annually

Management Highlights

• Vigabatrin is first-line for infantile spasms in TSC (preferred over ACTH in this population per AAN/CNS guidelines); risk of irreversible peripheral visual field constriction — requires baseline and serial ophthalmologic monitoring
• Everolimus — FDA-approved for SEGA, renal AML, and TSC-associated refractory focal seizures (2018, EXIST-3)
• Surgical resection for SEGA causing obstructive hydrocephalus when mTOR therapy is not feasible
• Epilepsy surgery (focal resection, hemispherectomy, VNS, RNS) for medically refractory seizures
• Annual brain MRI through young adulthood; renal imaging; echocardiogram in infants; dermatologic surveillance

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 > spinal > retinal > brainstem (brainstem less common than retinal)
• 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

Management Highlights

• Belzutifan (HIF-2α inhibitor) — FDA-approved August 2021 for VHL-associated RCC, CNS hemangioblastomas, and pancreatic neuroendocrine tumors not requiring immediate surgery
• Surgical resection for symptomatic or growing hemangioblastomas; stereotactic radiosurgery for non-resectable lesions
• Nephron-sparing surgery for RCC (often multifocal and bilateral)
• Annual ophthalmologic exam, brain/spine MRI, abdominal imaging, plasma/urine metanephrines

Genetics & Pathogenesis

• NOT inherited — caused by a somatic mosaic activating mutation in GNAQ gene (9q21.2). Specifically a recurrent somatic activating mutation p.R183Q in GNAQ (mosaic; not heritable)
• 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

Management Highlights

• Low-dose aspirin is commonly used to reduce stroke-like episodes and may reduce seizure burden in Sturge-Weber
• Early antiseizure therapy for seizures; hemispherectomy considered for refractory epilepsy with diffuse unilateral involvement
• Annual ophthalmologic surveillance for glaucoma (lifelong)
• Pulsed-dye laser therapy for port-wine stain

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