Neurofibromatosis Type 2

Neurofibromatosis type 2 (NF2-related schwannomatosis) is an autosomal dominant tumour predisposition syndrome with an incidence of about 1 in 25,000 to 33,000. It is caused by loss of function of NF2 (22q12.2), encoding merlin (schwannomin), a tumour suppressor.

About 50% are de novo, and about one third of de novo cases are mosaic. Penetrance is about 95% by age 60.

Genotype phenotype correlation:

• Truncating variants cause severe disease (Wishart type, early onset and rapid growth).
• Missense and splice variants cause milder disease (Gardner type).

• Bilateral vestibular schwannomas (over 90%; hallmark), presenting at about 18 to 24 years with hearing loss, tinnitus and imbalance, or earlier in childhood with other manifestations
• Other cranial and peripheral nerve schwannomas (trigeminal, facial, lower cranial nerves; cutaneous and subcutaneous schwannomas)
• Meningiomas (50 to 75%; intracranial and spinal, multiple, may cause seizures, mass effect, optic nerve sheath compression)
• Spinal tumours: intramedullary ependymomas (about 20 to 50%) and spinal schwannomas, causing weakness, sensory loss, and myelopathy
• Eye: juvenile posterior subcapsular cataract (60 to 80%; may be the first sign), retinal hamartoma, epiretinal membranes, and amblyopia
• Mononeuropathy: facial palsy, foot drop (in childhood presentations), and hand weakness; neuropathy from nerve compression

• Revised diagnostic criteria (2022): definite diagnosis with bilateral vestibular schwannomas, or a first degree relative with NF2 plus unilateral vestibular schwannoma or two other NF2-related lesions, or two or more NF2-related lesions with a pathogenic NF2 variant.
• Investigation: MRI of internal auditory canals (thin section with gadolinium), whole brain and whole spine; audiometry and brainstem evoked potentials; ophthalmological assessment; and NF2 genetic testing (including multiple tissue testing for mosaicism).
• Surveillance MRI annually of the brain and spine.

• Specialised multidisciplinary care in a national NF2 centre.
• Vestibular schwannoma: watchful waiting for small tumours; stereotactic radiosurgery for growing tumours; microsurgery when needed with preservation of hearing as the key goal.
• Bevacizumab 7.5 mg/kg IV every 3 weeks (or 5 mg/kg every 2 weeks) for progressive tumours in patients where surgery would cause deafness or risk, with improvement in hearing in about 40% and tumour shrinkage in about 40%. Monitor blood pressure, proteinuria, wound healing, and bleeding.
• Hearing rehabilitation: hearing aids and CROS, cochlear implant (if cochlear nerve is preserved), and auditory brainstem implant for those with bilateral deafness. Early sign language and lip reading training before total hearing loss.
• Meningiomas: observation, surgical resection or radiosurgery for growth or symptoms; radiotherapy for patients with NF2 has a higher secondary malignancy risk.
• Spinal ependymoma: observation unless symptomatic, then surgery.
• Cataract surgery when vision is affected.
• Pain: gabapentin or pregabalin for neuropathic pain.
• Genetic counselling: 50% risk to offspring (higher in the setting of germline mosaicism for those with mosaic parents); prenatal and preimplantation testing.