Neurofibromatosis Type 2 Molecular Basis of Disease

The development of bilateral vestibular schwannomas is a hallmark of neurofibromatosis type 2 (NF2). Other commonly associated tumors include schwannomas of other central, spinal, and peripheral nerves and meningiomas (reviewed in References 1 and 35 to 38). This is a life-threatening disorder due to the location of the tumors, along with the propensity for development of multiple tumors. Most patients become completely deaf and can have poor balance and vision, and weakness. The mean age of onset is 18 to 24 years and the mean age of death is 36 years. The age at onset of symptoms and age at diagnosis are predictors of vestibular schwannoma growth rates and risk of death (Reference 39 and references therein). Ependymomas and astrocytomas occur less frequently and are usually indolent central nervous system tumors. Patients affected with NF2 are at minimal increased risk for malignancy. Juvenile posterior subcapsular cataract is a common nontumor manifestation. The disorder may be underdiagnosed in children who present with ocular and skin manifestations. Early diagnosis improves management, which is primarily surgical and radiological. Modifications to the criteria for a diagnosis of NF2,initially established by the 1987/1991 National Institute of Health Consensus Conference, have been proposed to increase the specificity.40 A consensus statement on management of the NF2 patient and family was recently published.41

NF2 is caused by haploinsufficiency for the tumor suppressor merlin (also known as schwannomin), the protein product of the NF2 gene (Table 21-1). About one half of patients are the first case of NF2 in the family. These sporadic cases result from de novo mutation of the NF2 gene, a significant fraction of which are postzygotic mutations that result in mosaicism. The majority of constitutional germline mutations are private, predict the truncation of merlin, and are distributed throughout the gene (see Clinical Utility of Testing below). In NF2 patients, a vestibular schwannoma develops from a progenitor Schwann cell that carries a somatic inactivating mutation in the single remaining NF2 gene. Merlin is a protein of the cytoskeleton whose normal function remains to be determined, although it is known to associate with transmembrane proteins important in adhesion, proteins involved in signaling pathways, and cytoskeletal proteins (reviewed in Reference 42).

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