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At least 19 recordsLinked to original sources
PubMed1996

A point mutation associated with a severe phenotype of neurofibromatosis 2.

Neurofibromatosis 2 (NF2) is an autosomal dominant disease characterized by bilateral vestibular schwannomas and other nonmalignant tumors of the brain, spinal cord, and peripheral nerves. Although the average age of onset of NF2 is 20 years, some individuals may become symptomatic in childhood. We studied 5 unrelated NF2 patients who became symptomatic before age 13. All 5 had multiple tumors in addition to vestibular schwannoma, and none had a positive family history. Sequence analysis of the NF2 gene revealed identical nonsense mutation of exon 6 in 3 patients. Because this mutation destroys a restriction enzyme recognition site, genomic DNA from the 2 other children was directly tested for this change and identical alterations were detected. Although the work of our laboratory and others has not, in general, detected identical mutations in unrelated patients, this mutation seems to occur particularly frequently in the pediatric population and thus may be associated with an especially severe phenotype. Restriction analysis in children with NF2 may be a cost effective way of identifying their mutation. Further work is needed to characterize the effects of this change on the NF2 protein product and its relationship to this severe phenotype.

Adolescent↗
PubMed2000

The parental origin of new mutations in neurofibromatosis 2.

Neurofibromatosis 2 (NF2) is an autosomal dominant disorder characterized by schwannomas and meningiomas that develop after inactivation of both copies of the NF2 gene. Approximately half of all patients with NF2 have unaffected parents and the disease results from new mutations at the NF2 locus. Loss of heterozygosity (LOH) in tumor specimens due to deletions covering the normal NF2 allele can be used to infer the haplotypes surrounding underlying mutations and determine the allelic origin of new mutations. We studied 71 sporadic NF2 patients using both LOH and pedigree analysis and compared the parental origin of the new mutation with the underlying molecular change. In the 45 informative individuals, 31 mutations (69%) were of paternal and 14 (31%) were of maternal origin (P=0.016). Comparison with corresponding constitutional mutations revealed no correlation between parental origin and the type or location of the mutations. However, in 4 of 6 patients with somatic mosaicism the NF2 mutation was of maternal origin. A slight parent of origin effect on severity of disease was found. Further clinical and molecular studies are needed to determine the basis of these unexpected observations.

Adolescent↗
PubMed1994

Mutational analysis of patients with neurofibromatosis 2.

Neurofibromatosis 2 (NF2) is a genetic disorder characterized by the development of multiple nervous-system tumors in young adulthood. The NF2 gene has recently been isolated and found to encode a new member of the protein 4.1 family of cytoskeletal associated proteins, which we have named merlin. To define the molecular basis of NF2 in affected individuals, we have used SSCP analysis to scan the exons of the NF2 gene from 33 unrelated patients with NF2. Twenty unique SSCP variants were seen in 21 patients; 10 of these individuals were known to be the only affected person in their kindred, while 7 had at least one other known affected relative. In all cases in which family members were available, the SSCP variant segregated with the disease; comparison of sporadic cases with their parents confirmed the de novo variants. DNA sequence analysis revealed that 19 of the 20 variants observed are predicted to lead to a truncated protein due to frameshift, creation of a stop codon, or interference with normal RNA splicing. A single patient carried a 3-bp deletion removing a phenylalanine residue. We conclude that the majority of NF2 patients carry an inactivating mutation of the NF2 gene and that neutral polymorphism in the gene is rare.

Base Sequence↗
PubMed1997

The ocular presentation of neurofibromatosis 2.

Neurofibromatosis 2 (NF2) is an inherited disorder characterised primarily by bilateral vestibular schwannomas and other central nervous system tumours. Individuals with NF2 also have early onset cortical and posterior subcapsular or capsular cataract and other ocular abnormalities, such as retinal hamartomas. Although their diagnostic significance is rarely appreciated, the ocular manifestations are often the first sign of disease. We describe 5 cases that illustrate the diverse ocular manifestations of NF2.

Adolescent↗
PubMed2005

Vestibular evoked myogenic potentials in neurofibromatosis 2.

Neurofibromatosis 2 (NF2) is characterized by bilateral vestibular neurofibromas. Although the facial nerve, the cochlear nerve, and the superior division of the vestibular nerve can be evaluated before surgery, whether the inferior division of the vestibular nerve is affected remains undetermined without an operation. A total of 7 patients with NF2 (2 men and 5 women) underwent pure tone audiometry, caloric testing, vestibular evoked myogenic potential (VEMP) testing, and magnetic resonance imaging. Audiometry revealed mean hearing levels of less than 26 dB for 1 ear, 26 to 70 dB for 8 ears, 71 to 90 dB for 3 ears, and more than 90 dB for 2 ears. Caloric testing revealed an absent response in 71% of the 14 ears. Seven ears underwent VEMP testing, and only 1 ear (14%) displayed absent VEMPs. Magnetic resonance imaging depicted space-occupying lesions in all 14 auditory canals: small tumors in 3 ears, medium tumors in 7 ears, and large tumors in 4 ears. The tumor size of NF2 is related to the caloric response, but is unrelated to the mean hearing level or VEMPs. In conclusion, NF2 originates from the superior vestibular nerve more often than the inferior vestibular nerve. It more often infiltrates the cochlear nerve than the inferior vestibular nerve.

Adolescent↗
PubMed1996

The neuroimaging and clinical spectrum of neurofibromatosis 2.

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.

Adolescent↗
PubMed2000

Focal amyotrophy in neurofibromatosis 2.

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterised by bilateral vestibular schwannomas and other CNS tumours including meningiomas and spinal schwannomas. Occasionally, peripheral neuropathy occurs in these patients but this is the first report of focal amyotrophy. Clinical, electrophysiological, and imaging data from four NF2 patients seen at a specialist neurofibromatosis clinic over a 4 year period are described in whom symptomatic focal amyotrophy preceded the diagnosis of NF2. Two presented with wasting and weakness of a single muscle group, several years before NF2 was diagnosed. In one patient a mononeuritis multiplex was the presenting feature of NF2, and in one patient focal wasting and weakness developed after the diagnosis of NF2 was made. In none of the four cases could a focal peripheral nerve or root neurofibroma be identified despite extensive imaging with MRI, and the limitations of neuroimaging for identifying a structural cause in patients with NF2 with a focal peripheral nerve lesion is discussed. It is likely that NF2 may affect peripheral nerve structures in a manner distinct from a compressive schwannoma.

Adolescent↗
PubMed1990

NIH conference. Neurofibromatosis 1 (Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis). An update.

The neurofibromatoses comprise at least two autosomal dominant disorders affecting an estimated 100,000 Americans with clinical manifestations that may require care from every type of clinician. Neurofibromatosis 1 and neurofibromatosis 2 have in common the occurrence of many neurofibromas but are distinctly different clinical disorders. The disease genes are on different chromosomes. Magnetic resonance imaging, particularly with gadolinium enhancement, has generally supplanted other techniques for visualizing brain, spinal, and other neural tumors in both disorders. The technique has rekindled the controversy over the nature and frequency of optic pathway tumors in patients with neurofibromatosis 1 and has revealed, throughout the brains of young patients, bright lesions that have uncertain clinical consequences and unknown pathologic bases. In patients with neurofibromatosis 2, small acoustic neuromas can be seen, leading to the possibility of excision with preservation of hearing and facial nerve function. Abnormal hearing may occur to excess in patients with neurofibromatosis 1, but acoustic neuroma has never been documented. In patients with neurofibromatosis 2, a battery of audiologic tests has a high positive predictive power. Lisch nodules or iris hamartomas, probably a universal sign in adults with the neurofibromatosis 1 gene, cause no problem with vision. Posterior capsular lens opacity in patients with neurofibromatosis 2 is a helpful diagnostic sign and a potential source of additional handicap in persons at risk for impaired hearing. Progress in the clinical delineation of the disorders has been matched with considerable research into the still obscure pathogenesis of the disorders. Such rapid advances may necessitate reconsideration of the conclusions of the National Institutes of Health Consensus Development Conference on Neurofibromatosis, especially those on the categories of persons in which a neurofibromatosis should be considered and the need for caution in recommending surgery. Watchful waiting may often be the best management for acoustic neuromas in neurofibromatosis 2.

Chromosome Aberrations↗
PubMed1997

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

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.

Genes, Neurofibromatosis 1↗
PubMed2000

A clinical study of vestibular schwannomas in type 2 neurofibromatosis.

All 13 patients with neurofibromatosis 2 (NF2) who presented over a period of 17 years at the Institute of Neurological Sciences, Glasgow were reviewed and compared to patients with sporadic vestibular schwannomas. The NF2 patients presented at a younger age than those with sporadic vestibular schwannomas. A significant number had normal pure tone audiograms and a small number also had normal auditory brainstem responses at presentation. Vestibular schwannomas in NF2 patients grow more often and more rapidly than sporadic unilateral ones. They are more liable to infiltrate the cochlear and facial nerves making hearing and facial nerve preservation more difficult to achieve. Because the relatives of these patients often have normal audiograms and normal auditory brain stem responses in the presence of a schwannoma, our recommended method of screening of relatives of NF2 patients is magnetic resonance image scanning with Gd-DTPA enhancement.

Adolescent↗
PubMed1997

[Bilateral acoustic neurinomas (neurofibromatosis 2)].

Type 2 neurofibromatosis is a rare genetic condition, with an autosomal (dominant) inheritance and a prevalence of 1/50.000 inhabitants, characterized by bilateral acoustic neuromas. We present here a 16-year-old patient with a greater growth of the right-sided neuroma. A review of the literature, regarding incidence, clinical presentation, diagnostic clues and treatment is also included.

Adolescent↗
PubMed1989

[Neurofibromatosis 2 (bilateral acoustic neurofibromatosis)].

We report a personal series of 28 patients with neurofibromatosis 2 (NF-2), emphasizing the differences from classical NF-1. The hallmark of NF-2 is bilateral acoustic neuromas with initial symptoms usually occurring in the second or third decade. The natural history may lead to bilateral deafness, but hearing loss may also be a complication of surgery. NF-2 is frequently accompanied by additional intracranial tumors (particularly multiple meningiomas). Half of our patients had a spinal space-occupying lesion. NF-2 is inherited as an autosomal dominant trait, and many patients appear to represent new mutations.

Adolescent↗
PubMed1996

Identification of NF2 germ-line mutations and comparison with neurofibromatosis 2 phenotypes.

Neurofibromatosis 2 (NF2) is an autosomal inherited disorder that predisposes carriers to nervous system tumors. To examine genotype-phenotype correlations in NF2, we performed mutation analyses and gadolinium-enhanced magnetic resonance imaging of the head and full spine in 59 unrelated NF2 patients. In patients with vestibular schwannomas (VSs) or identified NF2 mutations, the mild phenotype was defined as < 2 other intracranial tumors and < or = 4 spinal tumors, and the severe phenotype as either > or = 2 other intracranial tumors of > 4 spinal tumors. Nineteen mutations were found in 20 (34%) of the patients and were distributed in 12 of the 17 exons of the NF2 gene, including intron-exon boundaries. Seven mutations were frameshift, six were nonsense, four were splice site, two were missense, and one was a 3-bp in frame deletion. The nonsense mutations included one codon 57 and two codon 262 C-->T transition in CpG dinucleotides. The frameshift and nonsense NF2 mutations occurred primarily in patients with severe phenotypes. The two missense mutations occurred in patients with mild phenotypes, and three of the four splice site mutations occurred in families with both mild and severe phenotypes. Truncating NF2 mutations are usually associated with severe phenotypes, but the association of some mutations with mild and severe phenotypes indicates that NF2 expression is influenced by stochastic, epigenetic, or environmental factors.

DNA Mutational Analysis↗
PubMed1998

[Fluorescein angiography of retinal changes in patients with neurofibromatosis 2].

BACKGROUND: Neurofibromatosis 2 (NF2) is a rare autosomal dominant disorder (prevalence 1:37.000) associated with changes in tumor suppressor genes. Intraocular manifestations have been reported as subcapsular cataract, retinal hamartomas, epiretinal membranes, keratopathy in facial palsy, and tumors of the nerves I-V are typical ocular manifestations of NF2. PATIENTS AND MATERIALS: We prospectively examined 7 patients who met the diagnostic criteria of NF2 with regard to retinal changes using fluorescence angiography and red-free fundus photography. RESULTS: In four patients, we found window defects of the pigment epithelium in the macular or paramacular areas. In one patient we observed a combined pigment epithelial and astrocytic hamartoma. A choked papilla was found in two patients. CONCLUSIONS: Presumably, retinal changes in NF2 occur more frequently than has been assumed previously. Our results confirm that in NF2 patients more attention should be paid to abnormalities of the optic disk, the retina and the choroid.

Fluorescein Angiography↗
PubMed1989

Distribution and immunoreactivity of cerebral micro-hamartomas in bilateral acoustic neurofibromatosis (neurofibromatosis 2).

Bilateral acoustic neurofibromatosis (neurofibromatosis 2, NF2) accounts for less than 10% of all cases of neurofibromatosis and manifests itself with bilateral acoustic schwannomas, multiple schwannomas of spinal nerve roots, meningiomas, glial tumors and hamartomatous CNS lesions. We have observed dysplastic foci of immature neuroectodermal cells in the cerebral cortex and basal ganglia of six patients afflicted with neurofibromatosis 2, ranging from occasional clusters of immature, dysplastic cells to numerous, confluent lesions. These cells, although often polymorphic and multinuclear did not show mitotic activity or a tendency for neoplastic transformation. To determine the histogenesis of these foci, extensive immunocytochemical reactions were carried out with antibodies to a variety of glial, neuronal and non-neural cell lineages. With the exception of S-100 protein, no immunoreactivity was detectable. S-100 was consistently expressed in these foci, irrespective of their size, location, and degree of polymorphism. On the basis of cytological appearance, distribution and immunoreactivity we tentatively designate these foci as glial micro-hamartomas. Although we did not systematically analyze the CNS of patients with von Recklinghausen neurofibromatosis (neurofibromatosis 1, NF1), the present study strongly suggests that these micro-hamartomas constitute a morphological hallmark of bilateral acoustic neurofibromatosis (NF2).

Adolescent↗
PubMedDate not supplied

CNS Young Investigator Award Lecture: molecular analysis of the neurofibromatosis 2 tumor suppressor.

Neurofibromatosis 2 (NF2), also known as bilateral acoustic neurofibromatosis or central neurofibromatosis, is a severe autosomal dominant disease characterized by the development of multiple nervous system tumors. The tumors of NF2, which include schwannomas, meningiomas and ependymomas, are histologically benign; however, their location and multiplicity led to great morbidity and mortality. These tumors commonly affect the general population in their isolated form, and have been found to undergo loss of chromosome 22 material in many studies; because of this the NF2 gene has been postulated to be a classic tumor suppressor. The NF2 gene has recently been isolated and found to encode a new member of the protein 4.1 family of cytoskeletal associated proteins which we have named merlin. To define the molecular basis of NF2 in germline and tumor specimens, we have used single-stranded conformation polymorphism (SSCP) analysis to scan the exons of the NF2 gene. We have located and characterized underlying causative mutation in 21 of 33 unrelated affected individuals studied, and 32 of 38 schwannomas. DNA sequence analysis revealed that over 90% of NF2 mutations are predicted to lead to a truncated protein due to frameshift, creation of a stop codon, or interference with normal RNA splicing. Current studies focus on relating the highly variable NF2 phenotype to its genotype, defining alternative NF2 related phenotypes, and elucidating the parental origin of new mutation in this disease.

Adolescent↗
PubMed1995

Retinal changes associated with neurofibromatosis 2.

INTRODUCTION: Neurofibromatosis (NF) is now known to be more than one disease. NF2, formerly classified as central neurofibromatosis, is characterized by bilateral vestibular schwannomas, previously termed "acoustic neuromas", and is much less common than NF1. Lens opacities at an early age have been described in approximately 85% of NF2 patients. PURPOSE: To determine the frequency of retinal abnormalities in NF2 patients. METHODS: We prospectively examined 15 consecutive patients who met the diagnostic criteria of NF2. RESULTS: We observed an epiretinal membrane in the macular or paramacular area in 12 of 15 patients, and a combined pigment epithelial and retinal hamartoma in the macula of one patient who also had an epiretinal membrane in the macula of the other eye. Additionally, 11 patients had central posterior cortical, subcapsular, or peripheral cortical lens opacities. CONCLUSIONS: Children or young patients with epiretinal membranes, combined pigment epithelial retinal hamartoma, and lens opacities that are not the result of other ocular disorders should have a neurologic evaluation and a careful family history for NF2.

Adolescent↗