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  • Updated 03.22.2024
  • Released 03.21.1995
  • Expires For CME 03.22.2027

NF2-related schwannomatosis



NF2-related schwannomatosis is a tumor predisposition syndrome most commonly associated with the development of multiple schwannomas (classically bilateral vestibular schwannomas), meningiomas, and ependymomas. This disorder is caused by mutations in the neurofibromatosis 2 (NF2) gene, a tumor suppressor gene that encodes for merlin/schwannomin and is located on chromosome 22.

Key points

• NF2-related schwannomatosis is an autosomal dominant disorder caused by mutations of the neurofibromatosis 2 gene, a tumor suppressor gene located on chromosome 22, whose normal protein product is merlin/schwannomin.

• The average age of diagnosis for NF2-related schwannomatosis is in one’s 20s, but patients may also present across a spectrum of ages. The majority of affected children do not present with the vestibular or auditory complaints typical of adult patients.

• Classically, patients have bilateral vestibular schwannomas (CN VIII), which are frequently responsible for the initial presenting complaints (ie, hearing loss and tinnitus) in adult patients. Other associated sequelae include nervous system tumors (ie, meningiomas, schwannomas affecting other cranial nerves or spinal nerve roots, and gliomas), lens abnormalities, and peripheral neuropathy, among others.

• Although patients with NF2-related schwannomatosis sometimes display cutaneous features (eg, pigmented skin lesions called “cafe au lait” spots) typical of neurofibromatosis type 1 (NF1), these skin findings are typically less common and less numerous than in NF1 patients.

• Treatments currently target specific disease manifestations (ie, tumors, cataracts, neuropathy) rather than the underlying disease process. Genetic counseling is recommended to first-degree relatives of affected individuals.

• Treatment options include conservative management (observation), surgery, radiosurgery, and systemic therapy, with novel and repurposed targeted therapeutics, immunotherapy, adoptive T-cell therapy, tumor vaccines, as well as in vivo and ex vivo gene therapeutic strategies. A number of these approaches are undergoing continued investigation.

Historical note and terminology

NF2-related schwannomatosis has also been called central or acoustic neurofibromatosis because of its characteristic involvement of the central nervous system (CNS) with tumors, especially meningiomas and acoustic neuromas that are now termed vestibular schwannomas (37). It is much less common than NF1, with which, historically, it was often confused (114). This is less of an issue in contemporary times, as it is more broadly understood to be a distinct disease. NF2-related schwannomatosis is now well characterized clinically as an autosomal dominant disorder with genetic origins on the long arm of chromosome 22 (103; 133).

Wishart reported the first patient with probable neurofibromatosis type 2 who had multiple intracranial tumors and no recorded cutaneous features (134). Cushing reported a case of acoustic neuromas in 1917 and considered it to be a form of neurofibromatosis because the pathological changes were so similar to those seen in von Recklinghausen cases (31). However, since von Recklinghausen's report in 1865 and for many years later, NF1 and neurofibromatosis type 2 were frequently classified as the same disease and referred to as von Recklinghausen disease or multiple neurofibromatosis (114). The perception that NF1 and neurofibromatosis type 2 were one disease arose because café au lait spots and peripheral nerve tumors can occur in either condition (114). Following the recognition of the autosomal dominant inheritance pattern of acoustic neuromas, these tumors were considered one of the complications of NF1 (62).

Gardiner and Frazier reported a large family from Pennsylvania with neurofibromatosis type 2 and suggested that the bilateral acoustic neuromas represented a separate form of neurofibromatosis (53). However, the subclassification was not adopted at that time. A large study of neurofibromatosis in 1956 reported 5% of patients with what was called multiple neurofibromatosis, who had bilateral acoustic neuromas and, in retrospect, probably had neurofibromatosis type 2 (114).

A follow-up study of the Gardiner and Frazier family in 1970 again concluded that the condition was different from von Recklinghausen disease and suggested that it be called central neurofibromatosis (136). This subclassification was more widely accepted by the 1980s (69; 101), and the natural history of neurofibromatosis type 2, with its greater morbidity and mortality in the majority of affected individuals, was recognized (63; 79). Moreover, the absence of acoustic schwannomas in neurofibromatosis type 1 was also appreciated (102). The NIH Consensus Panel agreed in 1987 on clinical guidelines for diagnosis and nomenclature, recommending the name neurofibromatosis type 2 rather than central or acoustic neurofibromatosis (86). The mapping of the neurofibromatosis type 2 gene to chromosome 22 confirmed the impression of neurofibromatosis type 2 as a distinct entity (103). The most widely known clinical diagnostic criteria for neurofibromatosis type 2 are the Manchester criteria, first established in 1992. Research surrounding neurofibromatosis type 2 has been dominated by gene studies and the process in which these gene abnormalities impact disease course. This translational research has guided current research efforts in neurofibromatosis type 2 and has subsequent powerful clinical impact in future potential therapeutic options.

Updated nomenclature and diagnostic criteria were proposed for neurofibromatosis type 2. The current diagnostic criteria for neurofibromatosis type 2 and schwannomatosis classify patients primarily on the basis of their clinical features. Because the phenotype of neurofibromatosis type 2 and schwannomatosis spans a continuum without complete clinical delineation of these subtypes, the umbrella term “schwannomatosis” was introduced, and neurofibromatosis type 2 was proposed to be replaced by “NF2-related schwannomatosis” (95).

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