Neurofibromatosis Type 2 

Central neurofibromatosis, or neurofibromatosis type 2 (NF2), is a multisystem genetic disorder associated with bilateral vestibular schwannomas, spinal cord schwannomas, meningiomas, gliomas, and juvenile cataracts, with a paucity of cutaneous features (which are seen more consistently in neurofibromatosis type 1 [NF1]). (See the image below.)

Although quite variable in its age of onset and severity of symptoms in affected individuals, NF2 is associated with significant morbidity and decreased life span. Furthermore, diagnosis in childhood is often difficult because of the absence of central nervous system (CNS) involvement at a young age. (See Prognosis, Clinical, and Workup.)

Complications of NF2 may include the following (See Clinical, Workup, and Treatment):

• Unilateral or, frequently, bilateral vestibular schwannomas leading to tinnitus, hearing loss, and/or problems with balance
• Meningiomas, gliomas, ependymomas, and other cerebral, cerebellar, or spinal cord lesions that may result in neurologic deficits, seizures, and/or hydrocephalus
• Peripheral nerve schwannomas, mixed tumors, and, occasionally, neurofibromas
• Peripheral neuropathies
• Visually significant juvenile cataracts

NF2 is inherited as an autosomal dominant condition, although half of affected individuals have NF2 as a result of a new (de novo) gene mutation. The manifestations of NF2 result from mutations in (or, rarely, deletion of) the NF2 gene, located on the long arm of chromosome 22. Affected individuals need only 1 mutated or deleted NF2 gene to exhibit signs of the condition.

The NF2 gene product known as merlin serves as a tumor suppressor; decreased function or production of this protein results in a predisposition to develop a variety of tumors of the central and peripheral nervous systems.

Increasing evidence indicates that merlin is involved in a number of cellular pathways and works in concert with other proteins to promote cellular adhesion and responses via the growth factor receptor.^[1] Understanding these interactions may eventually lead to more effective targeted treatment strategies, since the benign nature of NF2 lesions makes tumors frequently less responsive to chemotherapy or radiation therapy.

Numerous mutations in the NF2 gene have been identified, most of which are predicted to result in production of a truncated protein with loss of its usual function.

The estimated incidence of neurofibromatosis type 2 (NF2) is 1 in 37,000 per year, with about half of affected individuals representing first cases in the family as a result of new, dominant mutations.

Although the genetic change causing NF2 is present at conception, the clinical manifestations occur over many years. The typical age of onset of symptoms is in the late teens to early 20s, but the age range covers the entire life span. Some evidence indicates that age of onset of clinical symptoms is lower in maternally transmitted NF2. While NF2 is quite variable in severity from person to person, family studies have shown some intrafamilial consistency in age of onset. Somatic mosaicism for the NF2 mutation in sporadic cases may also complicate the clinical picture, resulting in underdiagnosis or late diagnosis.

The prognosis of neurofibromatosis type 2 (NF2) depends on a number of factors, including age of symptom onset, degree of hearing deficit, and number and location of various tumors. Although age of onset is relatively similar within families, the age range can vary from 2-70 years. While the tumors themselves are relatively indolent and do not undergo malignant transformation, studies performed in the late 1980s and early 1990s showed clearly that significant rates of mortality and morbidity are associated with the diagnosis of NF2.

One such study suggested that the survival from the time of actual diagnosis averages 15 years; however, this may be changing for the better with improved diagnosis, surgical techniques, surveillance, screening, and recognition of mild disease (due in part to increased physician awareness and availability of molecular diagnostic options).

Morbidity and mortality

Vestibular schwannomas are the most common and well-recognized feature of NF2 leading to significant morbidity. Symptoms of tinnitus, gradual hearing loss, and even vestibular dysfunction are frequently the initial signs of NF2. Although unilateral hearing loss is the number 1 presenting symptom, bilateral deafness would be expected to eventually occur in most affected individuals. Untreated vestibular schwannomas can extend locally and may result in brainstem compression, hydrocephalus, and, occasionally, facial nerve palsy.

Dumbbell-shaped spinal cord schwannomas are quite common in NF2 and result in significant morbidity; they present a great therapeutic challenge. Spinal cord ependymomas, astrocytomas, and meningiomas also occur, but less frequently. Intracranial meningiomas, on the other hand, are a frequent finding; they may be asymptomatic, or they may cause a variety of symptoms and CNS deficits.

Nonvestibular schwannomas occur in more than half of patients and are often diagnosed in patients with an earlier age at diagnosis of NF2. Cranial nerves III and V are most commonly involved, but the rare occurrence of jugular foramen schwannomas potentially impacting the glossopharyngeal, vagus, and/or spinal accessory nerves may lead to dysphagia, esophageal dysmotility, hoarseness, or aspiration.

On the other hand, nonvestibular schwannomas in patients with NF2 tend to be more indolent and to grow slowly over time. This can complicate treatment decision making, since options include surgery, radiation therapy, and watchful waiting.^[2]

Posterior subcapsular, or juvenile, cataracts can predate CNS symptomatology. These cataracts may progress over time, leading to decreased visual acuity. A fair percentage of affected individuals are found to have retinal hamartomas or epiretinal membranes that may or may not be visually significant.

Sensory motor polyneuropathy is seen in some individuals with NF2 who may or may not have identifiable tumors along the length of the peripheral nerve(s) of interest.

Patients and at-risk family members should be made aware of specific symptoms, such as tinnitus, hearing deficits, focal weakness, sensory changes, or balance problems, that might suggest tumor growth and should prompt immediate medical attention.

Patients with vestibular schwannomas should be cautioned about diving and underwater activities, because of increased risks for disorientation and potential for drowning.

Patients and their families may be referred to neurofibromatosis (NF)-specific regional and national support groups for continuous updates on advances in treatment, as well as for emotional support. Neurofibromatosis, Inc., for example, can be reached at the toll-free number 1-800-942-6825.

The Children's Tumor Foundation has a toll-free number (1-800-323-7938) for information and to sign up for their newsletter.

The NF2 Review, located in Los Angeles, CA, can be reached at 1-213-483-4431 and not only has an NF2-specific newsletter, but also has a particular research interest in NF2, with a team of specialists working on auditory brainstem implants (ABIs) and the newest surgical approaches to vestibular schwannomas.

Online resources include the NIH Web site and an NF2 person-to-person support group known as the NF2 crew.