Objective. —Neurofibromatosis 1 and neurofibromatosis 2 are autosomal dominant genetic disorders in which affected individuals develop both benign and malignant tumors at an increased frequency. Since the original National Institutes of Health Consensus Development Conference in 1987, there has been significant progress toward a more complete understanding of the molecular bases for neurofibromatosis 1 and neurofibromatosis 2. Our objective was to determine the diagnostic criteria for neurofibromatosis 1 and neurofibromatosis 2, recommendations for the care of patients and their families at diagnosis and during routine follow-up, and the role of DNA diagnostic testing in the evaluation of these disorders. Data Sources. —Published reports from 1966 through 1996 obtained by MEDLINE search and studies presented at national and international meetings. Study Selection. —All studies were reviewed and analyzed by consensus from multiple authors. Data Extraction. —Peer-reviewed published data were critically evaluated by independent extraction by multiple authors. Data Synthesis. —The main results of the review were qualitative and were reviewed by neurofibromatosis clinical directors worldwide through an Internet Web site. Conclusions. —On the basis of the information presented in this review, we propose a comprehensive approach to the diagnosis and treatment of individuals with neurofibromatosis 1 and neurofibromatosis 2.

https://jamanetwork.com/journals/jama/articlepdf/417288/jama_278_1_042.pdf

The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2.

Objective:To determine the incidence of vestibular schwannoma (VS) in sporadic, neurofibromatosis type 2 (NF2) germ-line and mosaic form in a 10-year period.Study Design:Review of all incident cases of VS presenting to the four main neurosurgical centers for a population of 4.1 million from 1990 to

Incidence of Vestibular Schwannoma and Neurofibromatosis 2 in the North West of England over a 10-year Period: Higher Incidence than Previously Thought

Neurofibromatosis 2 (NF2) is an autosomal dominant disease predisposing to multiple tumors of the central and peripheral nervous system. Bilateral vestibular schwannomas are the hallmark of the disease. To define the clinical spectrum of the disease, we performed gadolinium-enhanced magnetic resonance imaging of the brain and spine as well as neurological, dermatological, and ocular examinations in 48 patients with NF2 diagnosed with the National Institutes of Health diagnostic criteria. Patients were ascertained from patient workshops and publications and from referral as a result of vestibular schwannoma surgery. Vestibular schwannomas were found in 46 patients (96%, 43 bilateral and 3 unilateral), spinal tumors were found in 43 (90%), posterior subcapsular cataracts were found in 30 (63%), meningiomas were found in 28 (58%), and trigeminal schwannomas were found in 14 (29%). The presenting symptoms included hearing loss or tinnitus in 15 patients (31%), multiple or nonspecific symptoms in 15 (31%), skin tumors in 12 (25%), and ocular symptoms in 6 (13%). When the complete spine was imaged, spinal tumors were more common in patients with NF2 than has previously been reported. This is a noteworthy finding, because spinal tumors are a major cause of NF2 morbidity and mortality.

The neuroimaging and clinical spectrum of neurofibromatosis 2.

Modifier genes convert "simple" Mendelian disorders to complex traits.

A consensus conference on neurofibromatosis 2 (NF2) was held in 2002 at the request of the United Kingdom (UK) Neurofibromatosis Association, with particular emphasis on vestibular schwannoma (VS) surgery. NF2 patients should be managed at specialty treatment centres, whose staff has extensive experience with the disease. All NF2 patients and their families should have access to genetic testing because presymptomatic diagnosis improves the clinical management of the disease. Some clinical manifestations of NF2, such as ocular abnormalities, can be detected in infancy; therefore, clinical screening for at-risk members of NF2 families can start at birth, with the first magnetic resonance (MRI) scan at 10-12 years of age. Minimal interference, maintenance of quality of life, and conservation of function or auditory rehabilitation are the cornerstones of NF2 management, and the decision points to achieve these goals for patients with different clinical presentations are discussed.

Management of the patient and family with neurofibromatosis 2: a consensus conference statement.

Neurofibromatosis type 2 (NF2) is a monogenic dominantly inherited disease that predisposes to the development of tumors of the nervous system, particularly meningiomas and schwannomas. The gene which, when altered, causes NF2, is localized on chromosome 22 and has recently been identified. The NF2 gene is also the site of somatic mutation in tumors, suggesting that it might have a tumor suppressor activity. We here report a screening method for the detection of point mutations in NF2 which takes advantage of denaturing gradient gel electrophoresis (DGGE). This method efficiently screens 95% of the coding sequence and 90% of intron/exon junctions. When applied to 91 unrelated NF2 patients, it enabled the identification of 32 germ-line mutations. Since mutations are found in only one third of the patients, it is expected that mutations or deletions affecting the promoter and/or intronic regions of the NF2 gene occur frequently. The characterized mutations are preferentially located within the 5' half of the gene. Most of them are predicted to lead to the synthesis of a truncated protein. A search for genotype/phenotype correlations showed that, at least in this series of patients, mild manifestations of the disease were associated with mutations which preserve the C-terminal end of the protein.

Stephan Pulst

Papers

Screening for germ-line mutations in the NF2 gene.