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ABSTRACT

  • Neurofibromatosis 2 (NF2) is an autosomal dominant disorder that affects approximately 1 in 40,000 individuals. It is characterized by the development of bilateral vestibular schwannomas and other histologically benign intracranial, spinal, and peripheral nerve tumors. The only nontumorous manifestations of NF2 are cataract and retinal hamartoma. NF2 is fully penetrant by age 60 years, and half of all cases represent new mutations.

  • Syndromes related to NF2 include sporadic unilateral vestibular schwannoma, mosaic inactivation of the NF2 gene, schwannomatosis, and multiple meningiomas. NF2 is genetically and clinically distinct from von Recklinghausen disease or neurofibromatosis 1.

  • Positional cloning identified the gene for NF2 on chromosome 22q. It spans 110 kb with 16 constitutive exons and 1 alternatively spliced exon. The NF2 protein product is a member of the protein 4.1 family of cytoskeleton-associated proteins. These proteins play a critical role in maintaining membrane stability and cell shape by connecting integral membrane proteins to the spectrin–actin lattice of the cytoskeleton.

  • A large number of germ-line mutations have been detected in NF2 patients, with the majority predicted to result in gross protein truncation. Detection of somatic alterations in NF2-related tumors has supported the hypothesis that the NF2 gene acts as a true tumor suppressor in both schwannomas and meningiomas. NF2 also appears to play a role in the development of mesothelioma, although this tumor is not seen in patients with NF2.

  • Diagnosis of NF2 is currently dependent on clinical criteria, although genetic diagnosis may soon be feasible. Treatment of NF2-related tumors remains largely surgical. Advances in hearing augmentation, such as auditory brainstem implants, may improve the quality of life for many patients.

CLINICAL ASPECTS

Historical Notes and Nomenclature

In 1822, J.H. Wishart made a case report of an unfortunate 21-year-old man who was found at autopsy to have multiple dural-based tumors, hydrocephalus, and multiple tumors at the skull base, a classic description of what is now recognized as neuro-fibromatosis 2 (NF2).1 Seventy years after Wishart's observations, Fredrich Daniel von Recklinghausen published his famous monograph on neurofibromatosis 1 (NF1),2 and in several sub-sequent publications the presence of skin and spinal cord tumors in both NF1 and NF2 blurred the distinctions between the disorders. In 1902, Henneberg and Koch recognized a clinically distinct form of NF, which lacked skin alterations typical of von Recklinghausen disease and included “acoustic neuromas.”3 They referred to this distinct disorder as “central neurofibromatosis” in contrast to the peripheral features of von Recklinghausen disease. In 1915, Bassoe and Nuzum described a patient with bilateral cerebellopontine angle tumors and other central nervous system tumors.4 In 1930, a family with 38 members who had bilateral cerebellopontine angle tumors transmitted in an autosomal dominant fashion was reported, emphasizing the genetic nature of this disorder.5 Several subsequent works confirmed that the form of neurofibromatosis (NF) characterized by bilateral cerebellopontine angle tumors is a disorder distinct from the more common or peripheral form ...

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