Neurofibromatosis type 2

Karen S Dixit MD (Dr. Dixit of Feinberg School of Medicine at Northwestern University in Chicago, Illinois, has no relevant financial relationships to disclose.)
Jeffrey J Raizer MD (Dr. Raizer, Medical Director of Neuro-Oncology at Feinberg School of Medicine at Northwestern University, received honorariums from Agenus, BMS, Genentech, Novartis, and Stemline for service on advisory boards; honorariums from Genetech and Merck for speaking engagements; and stock options from Aurasense for service on their advisory board.)
Edward J Dropcho MD, editor. (Dr. Dropcho of Indiana University Medical Center has no relevant financial relationships to disclose.)
Originally released March 21, 1995; last updated December 13, 2015; expires December 13, 2018

This article includes discussion of neurofibromatosis type 2, acoustic neurofibromatosis, central neurofibromatosis, and NF2. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Neurofibromatosis type 2, one of the disorders in the family of phakomatoses, is an autosomal dominant disease of neuroectodermal dysplasia. Neurofibromatosis type 2 shares certain clinical features, including dermatologic findings, with neurofibromatosis type 1, but can be distinguished in part by its relative rarity and its known association with vestibular schwannomas. Since the discovery of the underlying causative gene, research has focused on the genetic mechanisms underlying tumorigenesis and improving treatment for affected patients. In this article, the authors review the clinical features of neurofibromatosis 2, highlight progress in our understanding of the function of the neurofibromatosis type 2 gene, and offer current management strategies for clinical sequelae associated with this condition.

Key points

 

• Neurofibromatosis type 2 is an autosomal dominant disorder caused by mutations of the neurofibromatosis type 2 gene, a tumor suppressor gene located on chromosome 22, whose normal protein product is Merlin/Schwannomin.

 

• The average age of onset for neurofibromatosis type 2 is 22 years old, but patients may also present in childhood. 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 8), 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 neurofibromatosis type 2 patients sometimes display cutaneous features (eg, pigmented skin lesions called “cafe au lait” spots) typical of neurofibromatosis type 1, these skin findings are typically less common and less numerous than in neurofibromatosis type 1 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.

Historical note and terminology

Neurofibromatosis type 2 is one of a spectrum of overlapping clinical disorders known as the neurofibromatoses (Korf 1990). Neurofibromatosis type 2 has also been called central or acoustic neurofibromatosis because of its characteristic involvement of the central nervous system with tumors, especially meningiomas and acoustic neuromas that are now termed vestibular schwannomas (Eldridge 1990). It is much less common than neurofibromatosis type 1, with which, historically, it was often confused (Short et al 1994). It accounts for 5% to 10% of all cases of neurofibromatosis (Eldridge 1990). Neurofibromatosis type 2 is now well characterized clinically as an autosomal dominant disorder with genetic origins on the long arm of chromosome 22, distinct from neurofibromatosis type 1 (Rouleau et al 1987; Wertelecki et al 1988).

Wishart reported the first patient with probable neurofibromatosis type 2 who had multiple intracranial tumors and no recorded cutaneous features (Wishart 1820). Harvey 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 (Cushing 1917). However, from the time of von Recklinghausen's report in 1865 until recently, neurofibromatosis type 1 and neurofibromatosis type 2 were frequently classified as the same disease and referred to as von Recklinghausen disease or multiple neurofibromatosis (Short et al 1994). The perception that neurofibromatosis type 1 and neurofibromatosis type 2 were 1 disease arose because café au lait spots and peripheral nerve tumors can occur in either condition (Short et al 1994). Following the recognition of the autosomal dominant inheritance pattern of acoustic neuromas, these tumors were considered 1 of the complications of neurofibromatosis type 1 (Huson 1994).

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 (Gardiner and Frazier 1930). The subclassification was not adopted at that time, however. 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 (Short et al 1994).

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 (Young et al 1970). This subclassification was more widely accepted by the 1980s (Kanter et al 1980; Riccardi 1981), and the natural history of neurofibromatosis type 2, with its greater morbidity and mortality in the majority of affected individuals, was recognized (Huson and Thrush 1985; Martuza and Eldridge 1988). Moreover, the absence of acoustic neuromas in neurofibromatosis type 1 was also appreciated (Riccardi 1982). 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 (Neurofibromatosis Conference Statement 1988). The mapping of the neurofibromatosis type 2 gene to chromosome 22 confirmed the impression of neurofibromatosis type 2 as a distinct entity (Rouleau et al 1987). 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.

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