Neurofibromatosis 2

Excerpt

Clinical characteristics: Neurofibromatosis 2 (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, 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 clinical findings that meet the consensus diagnostic criteria and/or by identification of a heterozygous pathogenic variant in NF2 on molecular genetic testing.

Management: Treatment of manifestations: 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. Treatment for hearing loss includes referral to an audiologist, lip-reading and sign language instruction, and possibly hearing aids and/or cochlear or brain stem implants.

Surveillance: For affected or at-risk individuals: annual MRI beginning at approximately age ten to 12 years and continuing until at least the fourth decade of life; hearing evaluation, including BAER testing; annual complete eye examination.

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

Evaluation of relatives at risk: Early identification of relatives who have 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 with NF2 have an affected parent, and 50% have NF2 as the result of a de novo pathogenic variant. However, 25% to 30% of simplex cases (i.e., single occurrence in a family) are mosaic for an NF2 pathogenic variant. If the proband has other affected family members, each child of the proband has a 50% chance of inheriting the pathogenic variant. Once the NF2 pathogenic variant has been identified in the family, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.