Description

• Neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) are neurocutaneous syndromes (phakomatoses). Although they share a name and both are autosomal dominant disorders, they are two distinct conditions with genes on different chromosomes.
• NF2 is an autosomal dominant inherited tumor predisposition syndrome that predisposes affected individuals to tumors of the CNS, most commonly bilateral vestibular schwannomas, leading to hearing loss and possible deafness. NF2 also predisposes patients to intracranial and spinal meningiomas.
• Synonym(s): bilateral acoustic neurofibromatosis; formerly central NF

Epidemiology

Incidence
Birth incidence: 1/33,000 to 40,000

Prevalence
1/60,000

Etiology and Pathophysiology

Protein product of affected gene is called “merlin” or “schwannomin”:

• Merlin is a cell membrane–related protein.
• Merlin is the NF2 tumor suppressor, a negative regulator of mammalian target of rapamycin complex 1 (mTORC1) (1).
• Involved in interaction between actin (within the cytoskeleton) and the cell membrane; suppresses tumorigenesis through contact-mediated growth inhibition

Genetics

• Online Mendelian Inheritance in Man 101000
• Caused by a mutation in the NF2 gene on chromosome 22q12; autosomal dominant inheritance
• Penetrance is close to 100%.
• 50% of affected patients have a new mutation.
• 25–30% of those with no family history (simplex cases) are mosaic for disease-causing mutations.
• If there are other close family members with NF2, the affected parent has a 50% chance of transmitting the mutation to each of his or her offspring.
• Historically, two forms of disease have been described: Wishart (more aggressive, onset during late teens or early 20s) and Gardner (less aggressive and older age of onset); however, many different causative mutations have been characterized.
• Genotype–phenotype correlation:
  • Mild NF2 phenotype (older age of onset, fewer tumors) associated with mosaicism, missense mutations, certain splice-site mutations, and certain large deletions
  • Severe NF2 phenotype usually caused by protein-truncating mutations (frame-shift or nonsense mutations)
  • Changes in the 5′ half of the gene have a higher risk of meningioma than do changes in the 3′ half.

Risk Factors

• Having an affected first-degree relative is a diagnostic criterion.
• Increased risk of mortality associated with younger age at diagnosis of NF2, intracranial meningiomas, and nonmosaic NF2 mutation
• Splice-site mutations had lower mortality rate than truncating mutations.
• Mortality rate has improved since 1980.

General Prevention

Genetic counseling

Commonly Associated Conditions

• Bilateral vestibular schwannomas may be associated with tinnitus and partial hearing loss or deafness.
• Tumors
  • Schwannomas of the other cranial nerves (24–51%)
  • Schwannomas of spinal and/or peripheral nerves
  • Intracranial meningiomas (including optic nerve meningiomas) and intraspinal meningiomas. Meningiomas in NF2 are more often anaplastic than are sporadic meningiomas and occur at an earlier age; lifetime risk ~75%
  • Low-grade CNS malignancies (ependymomas); rarely astrocytomas
  • Intramedullary or extramedullary spinal tumors (63–90%)
  • “Neurofibromatosis” is a misnomer because neurofibromata are relatively infrequent.
• Neurologic
  • Bilateral vestibular schwannomas may be associated with balance dysfunction, headache, or seizures.
  • Peripheral neuropathy in up to 66% of adults; generalized polyneuropathy in 3–10%
  • May have mononeuropathy in childhood, presenting as facial palsy, squint (CN III paralysis), foot drop, or hand drop
• Ophthalmologic
  • Reduced visual acuity
  • Cataracts (60–85%) may be the first sign of NF2 (but are rarely symptomatic), epiretinal membranes (12–40%), retinal hamartomas (6–22%).
• Dermatologic: 70% of patients have skin tumors, but only 10% have >10 tumors.