We searched PubMed using the search term “neurofibromatosis type 2” or “NF2” in combination with the terms “nervous system”, “schwannoma”, “meningioma”, “ependymoma”, or “cataract”. We also searched the reference lists of reports identified by this search strategy and selected those we judged relevant. We have used mainly reports published between December, 1998, and December, 2008, but have included relevant landmark publications before December, 1998. Pertinent articles not identified
SeminarNeurofibromatosis type 2
Introduction
Neurofibromatosis type 2 is a multiple neoplasia syndrome that results from a mutation in the NF2 tumour suppressor gene on chromosome 22q12. The disorder occurs in one in 25 000 livebirths and is inherited as an autosomal dominant trait. It has wide phenotypic variability and nearly 100% penetrance by 60 years of age.1, 2 Improvements in diagnosis and treatment have led to a rise in the diagnostic prevalence from one in 210 000 in 1992, to one in 100 000 people in 2005.1, 2
Patients are predisposed to development of lesions of the nervous system, eyes, and skin (figure 1, table 1). Bilateral vestibular nerve schwannomas are the distinctive feature of neurofibromatosis type 2, but affected people can develop schwannomas in other cranial, spinal, and peripheral nerves. Other nervous system tumours associated with the disorder include meningiomas, ependymomas, astrocytomas, and rarely, neurofibromas. Peripheral neuropathies can develop independently of compressive tumours. Ocular abnormal findings include cataracts, epiretinal membranes, and retinal hamartomas. Cutaneous tumours—usually schwannomas—are a frequent finding.
The multiple, progressive, and protean features associated with neurofibromatosis type 2 present substantial management challenges. Patients should be managed in specialty centres with a skilled multidisciplinary team, consisting of a neurosurgeon, otolaryngologist, neurologist, geneticist, ophthalmologist, pathologist, radiologist, audiologist, and experienced nursing staff.20, 21 Optimum management includes screening of populations at risk, early diagnosis, close surveillance, and development of treatment frameworks on the basis of the natural history of each associated feature (Panel 1, Panel 2).
Section snippets
Molecular biology
The NF2 tumour suppressor gene was identified in 1993. It has 17 exons that encode for a 69 kDa protein product called merlin (moesin-ezrin-radixin-like protein) or schwannomin.22, 23 Consistent with Knudson's two-hit hypothesis of tumorigenesis, tumour formation initiates when both alleles of this gene are inactivated.24 Patients either inherit a germline mutation of one affected allele from a parent or acquire a de novo mutation of an allele at the postzygotic stage of embryogenesis.
Diagnosis and clinical presentation
Diagnosis is based on clinical criteria; the presence of a constitutional NF2 mutation is not part of present diagnostic criteria. The Manchester diagnostic criteria21—which are the most widely used—include patients without a family history of this disorder or bilateral vestibular schwannoma but who have multiple other related lesions (table 2).3, 46, 47 Because more than half of patients do not have a positive family history and might present with clinical features other than vestibular
Genetics and clinical phenotypes
Th neurofibromatoses consist of three distinct diseases—neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis. Neurofibromatosis type 2 (formerly central neurofibromatosis or bilateral acoustic neurofibromatosis) was first described in 1822 in a deaf patient with tumours in the skull, dura mater, and brain.52 For several decades, it became inextricably intertwined with neurofibromatosis type 1 (formerly von Recklinghausen's disease or peripheral neurofibromatosis), which is
Vestibular schwannomas
Bilateral vestibular schwannomas are the distinctive feature of neurofibromatosis type 2 and are identified in 90–95% of patients (table 1).3, 4, 5 Sporadic vestibular schwannomas more frequently originate within the inferior vestibular portion of cranial nerve VIII (vestibulocochlear nerve), but in this disorder this predilection is not present.76, 77, 78 Although more than 99% of vestibular schwannomas in neurofibromatosis type 2 are benign, they remain a substantial cause of morbidity
Ocular manifestations
Lens opacities are an important diagnostic marker. 60–81% of neurofibromatosis type 2 patients have cataracts (table 1).3, 4, 5, 15 Only cataracts identified in patients younger than 50 years can be regarded as specific to the disorder; including opacities located in the posterior subcapsular or capsular, and peripheral cortical region of the lens (figure 6).131, 132 Small size and peripheral location of cortical wedge opacities necessitates a careful ophthalmological examination after maximum
Cutaneous manifestations
Skin tumours are present in 59–68% of patients with this disorder and include skin plaques, subcutaneous tumours, and intradermal tumours (table 1).3, 4, 19 They have a raised frequency in severely affected patients and are often multiple (mean skin tumours; 7·1).3, 4, 19 No predilection to site has been substantiated. Most skin tumours are schwannomas, although histologically confirmed neurofibromas or mixed tumours have been occasionally identified.19, 129
Skin plaques are well circumscribed,
Disease progression and survival
Average age at symptom onset in neurofibromatosis type 2 is 20 years but diagnosis is delayed on average for 7 years.3, 4, 5, 139 Although the range of disease progression is highly variable, most patients are rendered deaf and many will eventually need wheelchair assistance. Early age at symptom onset and the presence of intracranial meningiomas at diagnosis—both cardinal markers of increased disease severity—are associated with a heightened risk of early mortality.20 In 1992, although mean
Conclusion
Increased understanding of the clinical manifestations of neurofibromatosis type 2 in conjunction with improved precision of genetic tests and imaging studies have improved early diagnosis of patients. Further insight into the molecular pathogenesis and natural history of lesions in this disorder along with advances in treatment and restorative modalities will lead to improved management of these patients.
Search strategy and selection criteria
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