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PubMed1998

Loss of the NF2 gene and merlin occur by the tumorlet stage of schwannoma development in neurofibromatosis 2.

Loss of the neurofibromatosis 2 (NF2) gene-encoded protein merlin is a universal finding in sporadic and NF2-associated schwannomas. Certain NF2 patients may develop numerous minute Schwann cell tumorlets of the spinal nerve roots in addition to larger, frank schwannomas and thereby provide an opportunity to investigate the timing of NF2 gene/merlin loss in Schwann cell tumorigenesis. We studied an NF2 patient with a germline NF2 gene frameshift mutation who had many Schwann cell tumorlets and schwannomas. Loss of heterozygosity studies of DNA from microdissected specimens showed allelic loss of the NF2 region of chromosome 22q in tumorlets as well as schwannomas. Immunohistochemistry further demonstrated loss of merlin expression in tumorlets as well as schwannomas, with intact expression in adjacent nerve. Thus, loss of both NF2 alleles and merlin occur early in Schwann cell tumorigenesis, before the tumorlet stage. The study of tumorlets and schwannomas in such patients may also provide an opportunity to elucidate mechanisms responsible for the subsequent growth of Schwann cell lesions into symptomatic tumors.

Adult↗
PubMed1998

Clinical manifestations of mutations in the neurofibromatosis type 2 gene in vestibular schwannomas (acoustic neuromas).

Vestibular schwannomas (acoustic neuromas) continue to cause significant facial nerve and hearing morbidity, despite marked improvement in diagnosis and treatment. Mutation of a tumor-suppressor gene on human chromosome 22 has been found to be associated with vestibular schwannoma formation. The central hypothesis of this study is that specific mutations in the neurofibromatosis type 2 (NF2) gene may produce specific clinical characteristics or phenotypic expressions. The purposes of this investigation are: 1. to determine what proportion of vestibular schwannomas from patients with spontaneous unilateral and familial bilateral schwannomas have mutations present within the NF2 gene; 2. to determine whether specific types of mutations are associated with a specific clinical manifestation of this disease; and 3. to further define the relationship between newly discovered mutations within the NF2 tumor-suppressor gene and possible clinical applications of this knowledge to advance diagnosis and treatment of patients with NF2 and spontaneous vestibular schwannomas. DNA from 61 schwannomas (29 unilateral vestibular schwannomas and 32 from patients with bilateral vestibular schwannomas [NF2]) were examined, and 33 unique mutations were identified. Significant differences were found in the frequency, distribution, and type of mutation between the NF2 schwannomas and the spontaneous vestibular schwannomas. Three clinical subtypes of NF2 were identified. In tumors from 28 patients, no mutations were identified. Of the 33 mutations identified in the NF2 gene, 30 were likely to result in loss of tumor-suppressor function from protein truncation; however, three milder mutations termed missense mutations were associated with milder clinical manifestations of the disease and had a slower estimated growth rate. Variable clinical presentation in patients whose tumors had severe or truncating types of mutations suggest that factors in addition to the mutation class are likely to be responsible for a portion of the clinical expression of disease. New diagnostic options are now available for NF2 that will improve the likelihood of hearing and facial nerve preservation and ultimately have significant impact on the management of vestibular schwannomas.

Adult↗
PubMed1996

Intramedullary spinal cord tumors in neurofibromatosis.

Neurofibromatosis (NF) describes the most commonly inherited disorders affecting the nervous system. These autosomal dominant, neurocutaneous syndromes are associated with multiple tumors of the nervous system, including neurofibromas, schwannomas, meningiomas, and intracranial gliomas. Spinal cord involvement in NF is typically from extramedullary growth of spinal nerve root tumors. Intramedullary spinal cord tumors in NF have been reported as scattered, single cases in literature. However, this association has not been clearly defined as have other nervous system neoplasms that are typically linked with NF. We present a series of nine patients with NF with intramedullary spinal cord tumors who were managed at our institution from 1984 to 1994. The patients' ages ranged from 4 to 31 years. There were seven male patients and two female patients. Three patients had NF-1 (von Recklinghausen's), five patients had NF-2, and one patient had NF, type uncertain. There were three cervicomedullary tumors, two cervical tumors, three cervicothoracic tumors, and one thoracic tumor. A histological examination revealed five ependymomas, three astrocytomas, and one intramedullary schwannoma. Two patients with malignant intramedullary spinal ocrd tumors have died with progressive disease. One other patient has required a subsequent operation for recurrent tumor. The other six patients are doing well, and their prognosis is expected to be related to their systemic disease. We conclude that there is a clinical entity of intramedullary spinal cord tumors associated with NF.

Adolescent↗
PubMed1997

Spine update. The management of scoliosis in neurofibromatosis.

When evaluating patients with neurofibromatosis and scoliosis, a careful search for the evidence of dystrophic changes should done, because prognosis and management depend highly on the presence of these changes. Preoperative imaging studies including computed tomography or magnetic resonance imaging are recommended, especially in cases of dystrophic scoliosis, to detect unrecognized intraspinal lesions. The radiographic findings and the response to treatment in patients with nondystrophic scoliosis are similar to those in patients with idiopathic scoliosis, and the same decision-making process for idiopathic scoliosis is applicable. Careful follow-up evaluation is mandatory, however, because of the tendency for extraordinary progression to occur with growth. Brace treatment of the short, angulated, dystrophic curves is ineffective; early and aggressive surgical intervention is strongly recommended. In most cases, dystrophic curvatures are best treated with combined anterior and posterior spinal arthrodesis. The fusion area should be generous, and the entire structural area of the deformity both anteriorly and posteriorly should be fused.

Adolescent↗
PubMed2004

Recent advances in neurofibromatosis type 1.

PURPOSE OF REVIEW: The past decade, since the identification of the neurofibromatosis type 1 (NF1) gene, has witnessed great advances in our understanding of the role of the NF1 gene in the molecular pathogenesis of NF1-associated clinical abnormalities. The purpose of this review is to highlight recent advances in defining the molecular etiology of nervous system tumors and learning disabilities. RECENT FINDINGS: Neurofibromas and optic pathway gliomas result from NF1 inactivation in Schwann cells and astrocytes, respectively, but other cellular factors contribute to tumorigenesis. In addition, malignant progression of plexiform neurofibromas to malignant peripheral nerve sheath tumors requires additional genetic changes, including increased expression of growth factor receptors, molecules that are involved in tumor invasion and metastasis, and inactivation of critical cell cycle regulators. In addition, specific types of NF1 gene mutation may be associated with an increased risk for malignancy in individuals with NF1. SUMMARY: Research over the past few years has resulted in a detailed understanding of the molecular genetics of benign and malignant tumors affecting individuals with NF1 as well as the development of refined small animal models for these tumors. In addition, clinical studies have begun to define specific subpopulations of patients at risk for cancer and have identified targeted therapies for NF1-associated tumors, based on basic science research advances.

Adult↗
PubMedDate not supplied

Presymptomatic diagnosis for children of sporadic neurofibromatosis 2 patients: a method based on tumor analysis.

PURPOSE: To provide presymptomatic diagnosis for children of sporadic neurofibromatosis 2 patients in whom no NF2-mutations were found by screening their blood-DNA. METHODS: Tumors of four patients were analyzed for NF2 allele losses and mutations. RESULTS: Nonsense NF2 mutations and NF2 allele losses were found in all tumors. None of these alterations was found in any of eight children examined, suggesting that these children did not inherit the disease. CONCLUSIONS: Finding two genetic alterations of a tumor suppressor gene in associated tumors is useful for presymptomatic diagnosis. Identification of the lost allele in tumors alone also enables exclusion of disease transmission in 50% of cases.

Adult↗
PubMed2004

Serial analysis of gene expression in neurofibromatosis type 2-associated vestibular schwannoma.

HYPOTHESIS: The genesis, morphology, and growth characteristics of vestibular schwannomas are determined by genetic alterations which vary gene transcript expression and this transcript expression can be qualitatively and quantitatively evaluated using the SAGE technique. By use of such technique, gene products with tumorigenic potential may be identified, providing insight and targets for future study. BACKGROUND: Serial analysis of gene expression (SAGE) is a powerful new technique that allows detailed qualitative and quantitative evaluation of cellular gene transcript expression. Tissue in limited quantity (5 x 10 to 2 x 10 cells) may be analyzed by a modified version of SAGE called microSAGE. Application of SAGE or microSAGE to study vestibular schwannoma gene expression has not been previously reported. METHODS: Fresh, vestibular schwannoma specimen from an individual with the diagnosis of neurofibromatosis type 2 was attained intraoperatively and maintained in a sealed container at -80degreesC until the time of analysis. The tissue was processed according to the microSAGE protocol, using 180 mg of vestibular schwannoma as starting material. RESULTS: The protocol resulted in the generation and sequencing of a tag library involving 458 tags representing 277 different gene products, including many transcripts known to be expressed in vestibular schwannomas. Several gene products with tumorigenic potential were identified. CONCLUSIONS: These data demonstrate that microSAGE is a useful technique to study vestibular schwannoma gene expression. Future studies will include building more comprehensive libraries and comparing libraries from various vestibular schwannoma phenotypes to identify useful diagnostic or prognostic markers, and targets for therapeutic intervention.

Adult↗
PubMed2003

Neurofibromatosis 2.

PURPOSE OF REVIEW: Recent clinical and molecular research on neurofibromatosis 2 (NF2) is reviewed, and the implications for clinical practice and research are discussed. RECENT FINDINGS: NF2 patients who are treated in specialty centers have a significantly lower risk of mortality than those who are treated in non-specialty centers. Vestibular schwannoma growth rates in NF2 are generally higher in younger people but are highly variable, even among multiple NF2 patients of similar ages in the same family. Radiation therapy is best reserved for NF2 patients who have particularly aggressive tumors, those who are poor surgical risks, those who refuse surgery, or those who are elderly. In-vivo studies have demonstrated that leptomeningeal cell activation of in mice results in leptomeningeal hyperplasia and meningioma formation. In-vitro studies have identified molecules that interact with the product (merlin or schwannomin), some of which (e.g., CD44 and paxillin) may play critical roles in merlin growth regulation. SUMMARY: NF2 patients should be referred to specialty treatment centers for optimal care. Clinical management of multiple patients in NF2 families cannot be based on the expectation of similar vestibular schwannoma growth rates, even when other clinical aspects of disease severity are similar. The availability of accurate mouse models of human NF2-associated tumors and the identification of molecules involved in merlin growth regulation now provide an opportunity to design targeted treatments for schwannomas and meningiomas.

Animals↗
PubMed2005

Modeling neurofibromatosis type 1 tumors in the mouse for therapeutic intervention.

Von Recklinghausen's neurofibromatosis is a dominantly inherited cancer syndrome. Its gene encodes neurofibromin, a protein with ras GTPase-activating function (rasGAP) and, therefore, all NF1-associated pathology is thought to originate from selective deregulation of the ras pathway. We have constructed a variety of mouse models for NF1 that permit recapitulation of the most common tumors seen in patients. In addition, these mouse models offer insights into tumor origin and into paracrine interactions. Given the molecular and pathological fidelity of the mouse tumors to the human counterparts, it is hoped that these mouse strains will serve as effective tools for therapeutic discovery.

Animals↗
PubMed2005

Is osseous dysplasia a primary feature of neurofibromatosis 1 (NF1)?

Characteristic skeletal lesions are a cardinal feature of the autosomal dominant condition, neurofibromatosis 1 (NF1). The most frequently involved skeletal sites are the sphenoid wing, vertebrae, and tibia. Osseous lesions may range in severity in NF1 but are often progressive. They may lead to serious clinical consequences and be resistant to treatment. The skeletal lesions of NF1 are usually considered to be 'dysplasias', i.e. primary defects of bone, although there is no direct evidence supporting this interpretation. Moreover, it is difficult to understand why a generalized dysplasia of bone would produce focal lesions that show such a striking predisposition to only a few bones. We review the clinical and pathological features of NF1 skeletal lesions and propose that they result from an abnormal response of NF1 halpoinsufficient bone to abnormal mechanical forces rather than from a primary osseous dysplasia.

Biomechanical Phenomena↗
PubMed1997

Neurofibromatosis 1 and 2.

Neurofibromatosis (NF) 1 and 2 are multisystem disorders associated with a variety of neoplastic and non-neoplastic manifestations that typically progress in severity during the lifetime of the affected patient. The importance of appropriately diagnosing these disorders stems from the fact that the natural history of an associated neoplasm, such as a peripheral nerve tumor or an optic glioma, may be significantly different depending on whether or not the lesion arises in a person with NF. In addition, the indications for therapeutic intervention, hierarchy of treatment options and long-term management goals may differ substantially for patients with NF-related versus sporadic tumors. Finally, recognition of the diagnosis comprises an essential step for providing appropriate multidisciplinary evaluation and counseling to affected patients and their families. This article addresses the principal manifestations of these disorders and provides a contemporary review of the diagnostic and therapeutic issues that arise in children with NF1 and NF2.

Humans↗
PubMed1999

Mouse models of tumor development in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a prevalent familial cancer syndrome resulting from germ line mutations in the NF1 tumor suppressor gene. Hallmark features of the disease are the development of benign peripheral nerve sheath tumors (neurofibromas), which can progress to malignancy. Unlike humans, mice that are heterozygous for a mutation in Nf1 do not develop neurofibromas. However, as described here, chimeric mice composed in part of Nf1-/- cells do, which demonstrates that loss of the wild-type Nf1 allele is rate-limiting in tumor formation. In addition, mice that carry linked germ line mutations in Nf1 and p53 develop malignant peripheral nerve sheath tumors (MPNSTs), which supports a cooperative and causal role for p53 mutations in MPNST development. These two mouse models provide the means to address fundamental aspects of disease development and to test therapeutic strategies.

Animals↗
PubMed1999

Mouse tumor model for neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder characterized by increased incidence of benign and malignant tumors of neural crest origin. Mutations that activate the protooncogene ras, such as loss of Nf1, cooperate with inactivating mutations at the p53 tumor suppressor gene during malignant transformation. One hundred percent of mice harboring null Nf1 and p53 alleles in cis synergize to develop soft tissue sarcomas between 3 and 7 months of age. These sarcomas exhibit loss of heterozygosity at both gene loci and express phenotypic traits characteristic of neural crest derivatives and human NF1 malignancies.

Animals↗
PubMed2007

Refractive errors in neurofibromatosis type 1 and type 2.

OBJECTIVE: To document the prevalence of refractive errors in patients with neurofibromatosis type 1 (NF1) and type 2 (NF2) and to compare it with that of age- and sex-matched controls. METHODS: 82 patients with NF1, 21 patients with NF2 and 103 age- and sex-matched controls were evaluated in this prospective observational case-control study. Cycloplegic autorefraction and dilated fundus examination were performed. Myopia was defined as the spherical equivalent refraction of at least -0.50 diopters (D), hyperopia as the spherical equivalent refraction of at least 2.0 D and astigmatism as the cylinder of at least 1.0 D. Main outcome measures were refractive error, IQ, years of education, height, weight and body mass index (BMI). RESULTS: The prevalence of myopia was 23.1% in patients with NF1, 23.8% in patients with NF2 and 16.5% in age- and sex-matched controls. These differences were significant (p<0.03, p<0.03), and adjusting for intelligence, education, height, weight and BMI increased the significance of this finding (p<0.001, p<0.001). The prevalences of astigmatism and hyperopia were similar in both groups. CONCLUSION: A high prevalence of myopia seems to be an additional feature of NF1 and NF2.

Case-Control Studies↗
PubMed2005

Methodological issues in longitudinal studies: vestibular schwannoma growth rates in neurofibromatosis 2.

Four longitudinal studies of vestibular schwannoma (VS) growth rates in neurofibromatosis 2 (NF2) have yielded very different results on the relationship of VS growth rates to age. The studies had different patient eligibility criteria, indices of VS growth rates, VS volumetric methods, and sample sizes. We reanalysed data from two of the longitudinal studies and used data from the population based United Kingdom NF2 Registry to determine the most likely reason for the different results and the actual relationship of VS growth rates to age. We found that the eligibility criterion in one study caused selection bias for slower growing VS. The proper interpretation of the results from the four studies is that VS growth rates in NF2 are highly variable but tend to decrease with increasing age. Clinical trials for VS in NF2 should focus on younger patients because VS growth rates tend to decrease with increasing age, and because faster growing VS are more likely to be excised with increasing age than slower growing VS.

Age Factors↗
PubMed2007

Mitotic recombination as evidence of alternative pathogenesis of gastrointestinal stromal tumours in neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder resulting in the growth of a variety of tumours, and is inherited in an autosomal dominant pattern. Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours that commonly harbour oncogenic mutations in KIT or PDGFRA and are thought to arise from the interstitial cells of Cajal (ICC; the pacemaker cells of the gut). AIM: To characterise two patients with NF1 and GISTs. METHODS: Two patients were genotyped for germline mutations in NF1. GISTs from both patients were genotyped for somatic mutations in KIT and PDGFRA. Loss of heterozygosity (LOH) of NF1 in one GIST was assessed by genotyping seven microsatellite markers spanning 2.39 Mb of the NF1 locus in the tumour and in genomic DNA. The known germline mutation in NF1 was confirmed in GIST DNA by sequencing. The copy number of the mutated NF1 allele was determined by multiplex ligand-dependent probe amplification. RESULTS: GISTs from both patients were of wild type for mutations in KIT and PDGFRA. In the GIST with adequate DNA, all seven markers were informative and showed LOH at the NF1 locus; sequencing of NF1 from that GIST showed no wild-type sequence, suggesting that it was lost in the tumour. Multiplex ligand-dependent probe amplification analysis showed that two copies of all NF1 exons were present. CONCLUSIONS: This is the first evidence of mitotic recombination resulting in a reduction to homozygosity of a germline NF1 mutation in an NF1-associated GIST. We hypothesise that the LOH of NF1 and lack of KIT and PDGFRA mutations are evidence of an alternative pathogenesis in NF1-associated GISTs.

Adult↗
PubMed1992

Large de novo DNA deletion in a patient with sporadic neurofibromatosis 1, mental retardation, and dysmorphism.

A mildly dysmorphic, mentally retarded male with neurofibromatosis 1 (NF1) was found to have a de novo deletion of chromosome 17. The deletion occurred on the paternally derived chromosome 17 as shown by the absence of a D17S73 paternal allele. Densitometric analysis indicated that, in addition to the D17S73 locus, the patient has only one copy of four other adjacent loci. The deletion involved the loci D17S120, NF1, D17S57, D17S115, and D17S73 and was estimated to encompass more than 380 kb of DNA. The deletion of the entire paternal NF1 allele argues strongly that this disorder is not caused by the action of an abnormal NF1 protein. The extent of the deletion suggests that the mental retardation and dysmorphism of this patient may result from a deletion involving both the NF1 gene and contiguous genetic material.

Abnormalities, Multiple↗
PubMed1992

A genetic study of type 2 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity.

A clinical and genetic study of type 2 neurofibromatosis (NF2) has been carried out in the United Kingdom. Virtually complete ascertainment of cases in the north-west of England was achieved and suggests a population incidence of 1 in 33,000 to 40,000. In the UK as a whole, 150 cases have been identified and been used to study the clinical and genetic features of NF2. The autosomal dominant inheritance of NF2 was confirmed, 49% of cases were assessed as representing new mutations, and the mutation rate was estimated to be 6.5 x 10(-6). Evidence to support a maternal gene effect was found in that age at onset was 18.17 years in 36 maternally inherited cases and 24.5 in 20 paternally inherited cases (p = 0.027). The preponderance of maternally inherited cases was also significant (p = 0.03). Data are presented which suggest that there are two types of NF2, one with later onset and bilateral vestibular schwannomas as the only usual feature, and the other with earlier onset and multiple other tumours. A considerable number of cases did not fall easily into one or other group and other factors such as maternal effect on severity and anticipation need to be considered.

Adolescent↗