Neurofibromatosis Types 1, 2, and Schwannomatosis: Genetics and Management

Neurofibromatoses are autosomal dominant tumor predisposition syndromes:

NF1 (von Recklinghausen)

• Gene: NF1 (17q11.2) — neurofibromin (RAS GTPase activator).
• Incidence: 1:3,000.
• Diagnostic criteria (NIH): ≥2 of: 6+ café-au-lait macules (>5mm prepubertal, >15mm post), axillary/inguinal freckling, 2+ neurofibromas or 1 plexiform, optic glioma, 2+ Lisch nodules, osseous lesion (sphenoid dysplasia), 1st-degree relative with NF1.
• Complications: MPNST (malignant transformation), scoliosis, vasculopathy, learning disabilities.

NF2

• Gene: NF2 (22q12.2) — merlin (cytoskeletal linker).
• Incidence: 1:25,000.
• Hallmark: Bilateral vestibular schwannomas (hearing loss, tinnitus, imbalance).
• Also: Meningiomas, ependymomas, schwannomas, cataracts, peripheral neuropathy.

Schwannomatosis

• Genes: SMARCB1 (22q11.23), LZTR1 — chromatin remodeling.
• Features: Multiple schwannomas (spinal, peripheral) without vestibular tumors; chronic pain dominant; no café-au-lait spots.

Management

• Annual multidisciplinary surveillance (neurology, genetics, ophthalmology, orthopedics, oncology).
• Surgery for symptomatic/compressive tumors; MEK inhibitors (selumetinib) for inoperable plexiform NF1.
• Genetic counseling; prenatal/preimplantation testing available.

No cure, but lifespan near-normal with monitoring (except MPNST).