NF2-Related Schwannomatosis

Clinical characteristics: NF2-related schwannomatosis (NF2) is characterized by bilateral vestibular schwannomas with associated symptoms of tinnitus, hearing loss, and balance dysfunction. The average age of onset is 18 to 24 years. Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years. Affected individuals may also develop schwannomas of other cranial and peripheral nerves, meningiomas, ependymomas, and (very rarely) low-grade astrocytomas. Because NF2 is considered an adult-onset disease, it may be underrecognized in children, in whom skin tumors and ocular findings (retinal hamartoma, thickened optic nerves, cortical wedge cataracts, third cranial nerve palsy) may be the first manifestations. Mononeuropathy that occurs in childhood is an increasingly recognized finding; it frequently presents as a persistent facial palsy or hand/foot drop.

Diagnosis/testing: The diagnosis of NF2 is established in a proband with bilateral vestibular schwannomas, an identical NF2 pathogenic variant identified in two or more anatomically distinct NF2-related tumors, or a combination of clinical and molecular criteria that fulfill the consensus diagnostic criteria.

Management: Targeted therapy: The VEGF antibody bevacizumab for rapidly growing vestibular schwannomas; bevacizumab has also shown some clinical benefit in some individuals with ependymoma.

Supportive care: Treatment of vestibular schwannoma is primarily surgical; stereotactic radiosurgery, most commonly with the gamma knife, may be an alternative to surgery. Individuals with vestibular tumors need to be aware of insidious problems with balance and underwater disorientation, which can result in drowning. Cervical spine MRI prior to cranial surgery; lumbosacral MRI prior to regional analgesia. Treatment for hearing loss includes referral to an audiologist, lipreading and sign language instruction, and possibly hearing aids and/or cochlear or brain stem implants. Surgical treatment for infantile cataracts and patching as needed. Management through rehabilitation medicine, physical therapy, and/or occupational therapy should be considered for hand or foot drop due to mono- or polyneuropathy. Surgical removal as needed for cutaneous schwannomas that are causing disfigurement and/or pain.

Surveillance: For affected or at-risk individuals, annual neurologic examination by a provider with experience in NF2; annual brain MRI beginning at approximately age ten to 12 years and continuing until at least the fourth decade of life; annual hearing evaluation, including BAER testing; annual complete ophthalmology examination.

Agents/circumstances to avoid: Radiation therapy of NF2-associated tumors, especially in childhood, when malignancy risks are likely to be substantially higher.

Evaluation of relatives at risk: Early identification of relatives who inherited the family-specific NF2 pathogenic variant allows for appropriate surveillance, resulting in earlier detection and treatment of disease manifestations.

Genetic counseling: NF2 is inherited in an autosomal dominant manner. Approximately 50% of individuals diagnosed with NF2 have an affected parent. Approximately 50% of individuals diagnosed with NF2 have the disorder as the result of a de novo NF2 pathogenic variant. As many as 25% to 50% of individuals with a de novo NF2 pathogenic variant have somatic mosaicism for the variant. The possibility that a parent has NF2 can be excluded if the proband is shown to be mosaic. Each child of an individual with NF2 has up to a 50% chance of inheriting the pathogenic variant: offspring of an individual with a germline pathogenic variant have a 50% chance of inheriting the variant, while offspring of an individual who has mosaic NF2 may have a less than 50% risk of inheriting the variant. Once the NF2 pathogenic variant has been identified in the family, prenatal and preimplantation genetic testing are possible.