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PubMed2002

Predictors of vestibular schwannoma growth in patients with neurofibromatosis Type 2.

OBJECT: The results of two longitudinal studies of growth rates of vestibular schwannomas (VSs) in patients with neurofibromatosis Type 2 (NF2) differ as to whether VS growth rates decrease or increase with increasing patient age. The authors undertook this study to assess the relationship between VS growth rates and patient age and type of constitutional NF2 mutation; they also examined variability in VS growth rates among multiple patients in families with NF2. METHODS: Gadolinium-enhanced magnetic resonance images obtained in 18 patients with inherited NF2 from 11 unrelated families were retrospectively analyzed. The patients had been observed for a median of 4 years. Volumes of the VSs were measured using a two-component box model (intrameatal and extrameatal parts measured separately). Single-strand conformation polymorphism analysis and Southern blot analysis were used to identify constitutional NF2 mutations. Growth rates of the VSs were highly variable, but tended to decrease with increasing patient age both at onset of signs or symptoms of NF2 (r2 = 0.35, p = 0.026) and at diagnosis (r2 = 0.33, p = 0.012). The VS growth rates did not vary significantly with the type of constitutional NF2 mutation or the number of non-VS cerebral or spinal tumors. The VS growth rates were highly variable within families and did not correspond to clinical indices of NF2 disease severity, such as patient age at symptom onset and the number of non-VS cerebral and spinal tumors. CONCLUSIONS: The growth rates of VSs in patients with NF2 are highly variable, but tend to decrease with increasing patient age. Clinical treatment of multiple patients in families with NF2 cannot be based on the expectations of similar VS growth rates, even when other clinical aspects of disease severity are similar.

Adolescent↗
PubMed2002

Vestibular schwannoma growth in patients with neurofibromatosis Type 2: a longitudinal study.

OBJECT: The factors that determine the growth rates of vestibular schwannomas (VSs) in patients with neurofibromatosis Type 2 (NF2) are unknown. The authors undertook this study to determine if clinical factors or type of constitutional NF2 mutation were associated with VS growth rates in cases of NF2. METHODS: The authors reviewed serial gadolinium-enhanced magnetic resonance (MR) images of the head and full spine of 37 patients with sporadic NF2 who had been observed over periods ranging from 0.2 to 8 years (median 3.9 years) at a specialized referral clinic for NF2. A box model was used to calculate VS volumes so that tumor growth rates could be estimated. Temperature-gradient gel electrophoresis was used to screen for constitutional NF2 mutations. The VS growth rates tended to decrease with increasing patient age at onset of signs or symptoms (r2 = 0.23, p = 0.003) and at the time the baseline gadolinium-enhanced MR image was obtained (r2 = 0.38, p < 0.001). The authors did not find significant associations between VS growth rates and the number of non-VS cerebral or spinal tumors or different types of constitutional NF2 mutations. CONCLUSIONS: There is considerable variability in growth rates of VSs in patients with NF2, but they tend to be higher in patients who are younger at onset of signs or symptoms.

Adolescent↗
PubMed2006

Unilateral vestibular schwannoma with other neurofibromatosis type 2-related tumors: clinical and molecular study of a unique phenotype.

OBJECT: Although the manifestations of neurofibromatosis Type 2 (NF2) vary, the hallmark is bilateral vestibular schwannomas (VSs). The authors studied the clinical course and genetic basis of unilateral VSs associated with other NF2-related tumors. METHODS: Forty-four adults presenting with unilateral VSs and other NF2-related tumors were identified. A comprehensive review of patient records and cranial imaging was conducted. Molecular analysis of the NF2 locus was performed in available tumors and paired blood specimens. Patient age at symptomatic onset ranged from 11 to 63 years (mean 32 years). Twenty-two patients (50%) presented with eighth cranial nerve dysfunction. Twenty-six presented with multiple lesions. Thirty-eight harbored other intracranial tumors and 27 had spinal tumors, with most lesions situated ipsilateral to the VS. No patient had a relative with NF2, although two of 63 offspring had isolated NF2-related findings. A contralateral VS developed in four patients 3 to 46 years after the symptomatic onset of a unilateral VS, and two of these patients experienced rapid progression to total deafness. Results of a Kaplan-Meier analysis identified actuarial chances of developing contralateral VS: 2.9% (3-17 years after the VS symptomatic onset of unilateral VS), 11% (18-24 years), and 28.8% (25-40 years). Mosaicism for the NF2 gene mutation was proven in eight patients. CONCLUSIONS: The authors describe the clinical features of this unique phenotype--unilateral VS with other NF2-related tumors. Persons with this phenotype should undergo evaluation and monitoring similar to that conducted in patients with NF2, and the possibility of aggressive contralateral VS formation should be considered in their treatment. Molecular genetic analysis is best performed using resected tumor specimens and will enable future studies to determine the genetic risks of individuals with mosaicism.

Adolescent↗
PubMed1998

Neurofibromatosis: a common neurocutaneous disorder.

Neurofibromatosis (NF) type 1 (NF-1) is one of the most common of the neurocutaneous conditions, whereas NF type 2 (NF-2) accounts for an extremely small percentage of the total cases of NF. Indeed, most physicians will probably encounter at least one or two patients with NF-1 during the course of their practice. The manifestations can be varied and subtle; thus, the condition can sometimes be difficult to recognize. Nonetheless, the diagnosis of NF-1 is often clinically possible by the time the person is 10 years old. In this article, the diagnostic criteria for the most common types of NF are discussed, the common and some of the serious manifestations of both NF-1 and NF-2 are described, and suggestions for follow-up care are offered. Of importance, physicians must recognize that, although NF-1 and NF-2 share a common name, they are due to mutations in two different genes. Cure is not yet possible; thus, treatment is primarily symptomatic. A multi-disciplinary treatment team is often helpful, particularly for patients with complicated problems.

Chromosomes, Human, Pair 17↗
PubMed1999

Two independent mutations in a family with neurofibromatosis type 1 (NF1).

We report on two independent alterations of the NF1 gene in a three-generation kindred with neurofibromatosis type 1 (NF1). Using temperature gradient gel electrophoresis (TGGE) in a mutation analysis of exon 31 of the NF1 gene we detected the previously reported nonsense mutation R1947X. This C-to-T transition at codon 1947 in exon 31 is considered to represent a mutation "hot spot" of the NF1 gene due to 5mCpG deamination. All living family members together with their genomic DNA were included in this investigation. However, the mutation R1947X was absent from two undoubtedly affected siblings of the propositus. Another NF1 mutation (889-2A-->G) was identified in the two sibs by the protein truncation test (PTT). The novel splice site mutation 889-2A-->G results in a skip of NF1 exon 7 during splicing and protein truncation due to frameshift. The two NF1 alterations are linked to different paternal haplotypes. In our study of a three-generation kindred, R1947X represents a de novo mutation whereas 889-2A-->G is an inherited splice mutation. Implications for phenotype variation are discussed.

Chromosomes, Human, Pair 17↗
PubMed1999

Prenatal diagnosis of sporadic neurofibromatosis type 1 (NF1) by RNA and DNA analysis of a splicing mutation.

Neurofibromatosis type 1 (NF1) is one of the most common genetic disorders in humans with an incidence of 1 in 3500. Most of the NF1 mutations reported so far (over 240 mutations) are unique. Specific prenatal diagnosis can only be provided to familial cases by an indirect linkage analysis or to families with a previously identified mutation. Here we report the first prenatal diagnosis in sporadic NF1 by direct characterization of the mutation. We first identified the skipping of exon 10b of NF1 in the mRNA from a woman affected by NF1 and without familial history of the disease. The analysis of genomic DNA identified mutation IVS10b+1G-->A as the cause of the skipping of exon 10b. Chorionic villus sampling (CVS) was performed at 10 weeks of gestation and total RNA was directly extracted from the sample. After reverse transcription (RT) and polymerase chain reaction (PCR) of the cDNA, the skipping of exon 10b was not identified in the CVS upon agarose gel electrophoresis. The fetal origin of the CVS was confirmed via polymorphic markers and the absence of the IVS10b+1G-->A mutation was confirmed by genomic analysis.

Adult↗
PubMed1999

Epidemiology of neurofibromatosis type 1.

The prevalence of neurofibromatosis type 1 (NF1) is about 1/3,000. There are no known ethnic groups in which NF1 does not occur or is unusually common. The prevalence is somewhat higher in young children than in adults, a difference that probably results at least in part from the early death of some NF1 patients. NF1 is fully penetrant in adults, but many disease features increase in frequency or severity with age. The reproductive fitness of NF1 patients is reduced by about one-half. About half of all cases result from new mutations. The estimated rate of new NF1 mutations is unusually high, but the basis for this high mutation rate is not known. Am. J. Med. Genet. (Semin. Med. Genet.) 89:1-6, 1999.

Adult↗
PubMed1999

Hyperactive Ras as a therapeutic target in neurofibromatosis type 1.

The NF1 gene encodes neurofibromin, a GTPase-activating protein (GAP) for members of the p21(ras) (Ras) family, which negatively regulates Ras output by accelerating the conversion of active Ras. GTP to inactive Ras.GDP. Analysis of tumors from patients with neurofibromatosis type 1 (NF1) has shown biochemical evidence of hyperactive Ras as well as frequent loss of the normal NF1 allele, consistent with its role as a tumor suppressor gene. Taken together, these data suggest that novel therapeutics directed against components of the Ras signaling cascade might provide effective treatments for certain pathological complications of NF1. Here we summarize data that support a role for hyperactive Ras in NF1 disease, including Ras processing, activation, and down-regulation. We review targets for rational drug design, provide preliminary results, and discuss implications for future studies. Am. J. Med. Genet. (Semin. Med. Genet.) 89:14-22, 1999.

Drug Design↗
PubMed2000

Chromosome 17 loss-of-heterozygosity studies in benign and malignant tumors in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant condition characterized by benign tumor (neurofibroma) growth and increased risk of malignancy. Dermal neurofibromas, arising from superficial nerves, are primarily of cosmetic significance, whereas plexiform neurofibromas, typically larger and associated with deeply placed nerves, extend into contiguous tissues and may cause serious functional impairment. Malignant peripheral nerve sheath tumors (MPNSTs) seem to arise from plexiform neurofibromas. The NF1 gene, on chromosome segment 17q11.2, encodes a protein that has tumor suppressor function. Loss of heterozygosity (LOH) for NF1 has been reported in some neurofibromas and NF1 malignancies, but plexiform tumors have been poorly represented. Also, the studies did not always employ the same markers, preventing simple comparison of the frequency and extent of LOH among different tumor types. Our chromosome 17 LOH analysis in a cohort of three tumor types was positive for NF1 allele loss in 2/15 (13%) dermal neurofibromas, 4/10 (40%) plexiform neurofibromas, and 3/5 (60%) MPNSTs. Although the region of loss varied, the p arm (including TP53) was lost only in malignant tumors. The losses in the plexiform tumors all included sequences distal to NF1. No subtle TP53 mutations were found in any tumors. This study also reports the identification of both NF1 "hits" in plexiform tumors, further supporting the tumor suppressor role of the NF1 gene in this tumor type.

Adolescent↗
PubMed2000

Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2.

Hemizygosity for the NF2 gene in humans causes a syndromic susceptibility to schwannoma development. However, Nf2 hemizygous mice do not develop schwannomas but mainly osteosarcomas. In the tumors of both species, the second Nf2 allele is inactivated. We report that conditional homozygous Nf2 knockout mice with Cre-mediated excision of Nf2 exon 2 in Schwann cells showed characteristics of neurofibromatosis type 2. These included schwannomas, Schwann cell hyperplasia, cataract, and osseous metaplasia. Thus, the tumor suppressor function of Nf2, here revealed in murine Schwann cells, was concealed in hemizygous Nf2 mice because of insufficient rate of second allele inactivation in this cell compartment. The finding of this conserved function documents the relevance of the present approach to model the human disease.

Alleles↗
PubMedDate not supplied

[Neurofibromatosis type 2 (NF2)--classical example of a rare familial cancer syndrome].

Type 2 neurofibromatosis (NF2) is a dominantly inherited disorder characterized by a predisposition to multiple tumours of the nervous system. The incidence in the Caucasian population is estimated between one in 35,000 and one in 40,000 of live births. The NF2 gene was isolated and shown to have mutations in NF2 patients. It is considered to belong to tumour suppressor gene family. Direct NF2 gene analysis enables verification of tentative clinical diagnosis and makes genetic counselling possible.

Adult↗
PubMed2000

[Characterization of the neurofibromatosis type 1 gene and neurofibromin's role in cells].

Neurofibromatosis type 1(NF1), a pleiotrophic autosomal dominant disorder, was first described in 1882 by Friedrich Daniel von Recklinghausen. The cloning of the NF1 gene located at 17q11.2 revealed that the gene contains 60 exons and spans 350 kb of genomic DNA in 1990. The gene product of NF1 is neurofibromin. Neurofibromin is a major negative regulator of the Ras pathway in cells, which transmits mitogenic signals to the nucleus through the cascade of MAP kinase. Loss of neurofibromin in patients with NF1 leads to accumulation of activated Ras (bound to GTP), and thus increases downstream mitogenic signaling. Future understanding the neurofibromin's role will contribute to the development of agents and genetic therapies which modulate Ras-mediated signaling pathways.

Chromosomes, Human, Pair 17↗
PubMed2001

[From gene to disease; neurofibromatosis type 1].

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease characterised by café-au-lait spots, freckling in the axillary or inguinal region, dermal and plexiform neurofibromas and Lisch nodules. Complications are severe in one third of patients, and the clinical variability is pronounced, even within families. The NF1 gene has been localised to chromosome 17q11.2 and encodes the protein neurofibromin. The gene is proposed to be a tumour suppressor gene. Inactivation of neurofibromin leads to a disruption in cell growth regulation. Mutation analysis is possible but laborious, and therefore NF1 is generally a clinical diagnosis based on diagnostic criteria.

Child↗
PubMedDate not supplied

Neurofibromatosis. Nosological considerations.

The neurofibromatosis (NF) represent a set of conditions having different clinical manifestations, prognosis and inheritance. It has been presented--on clinical grounds--seven types of NF, but for only two of these National Institute of Health Consensus Development Conference (NIHCDC) advent a set of diagnostic criteria. The genes responsible for NF1 and NF2 were mapped to the long arm of chromosome 17 (17q11.2) and respectively 22 (22q11.2), and their protein product (neurofibromin and respectively merlin or schwanomin) was identified. Recent studies are proved that NF1 and NF2 genes act as a tumour suppressor gene. Up to now, only a limited number of mutations in these genes have been characterized but even in these cases the genotype/fenotype correlation has not provided enough information to allow speculation on the etiologic role NF1 or NF2 mutations might play in the variant forms of NF. Further studies are required to elucidate the genes functions and mutation spectrum. This should provide a framework for the molecular classification and diagnosis and the development of new therapy for NF.

Chromosomes, Human, Pair 17↗
PubMedDate not supplied

[Neurofibromatosis type 2 as a result of a de novo mutation: a case report].

INTRODUCTION: Neurofibromatosis type 2 is a dominant autosomic hereditary disease which courses with distinct tumours of the central nervous system and scant cutaneous manifestations. The increased knowledge of the natural history and the genetics of NF 2 acquired over the past few years has shown that clinical onset possibly occurs during the paediatric age and an early diagnosis of these patients can be decisive in the final outcome. CLINICAL CASE: A 12 year old girl who visited the clinic because of a month old presentation of cervical tumour, otalgia and dysphonia. Exploration revealed signs of cranial nerve disorder and the magnetic resonance (MR) showed bilateral schwannomas of the eighth cranial nerves. The extension study showed ocular, auditory, troncoencephalic and cervical spinal cord disorders. The patient died three months after hospital admission. The genetic study showed a de novo mutation in the NF 2 gene (chromosome 22q12). DISCUSSION: The identification of the various mutations that cause NF 2 has enabled the early diagnosis of the patient s relatives. However, there are still patients who have not been confirmed genetically. Furthermore, de novo mutations are not predictable. NF 2 diagnosis is still clinical. In the last few years, two disease phenotypes have been defined: mild and moderate/serious, which is associated with an early onset and de novo mutations. The high incidence rate of cataracts and other associated tumours, such as those affecting paraspinal and cutaneous areas together with meningiomas, which up until now could have gone unnoticed, has also been observed. Clinical onset in the paediatric age is more frequent than was expected and shows distinct and subtle symptoms.

Adult↗
PubMed2002

[Otorhinolaryngological neurofibromatosis].

OBJECTIVE: To investigate the growth characteristic, clinical manifestation, diagnosis and treatment of neurofibromatosis (NF) in otorhinolaryngology. METHODS: Eleven cases of NF from 1989 to 2000 were analyzed retrospectively, among which, there were 5 and 2 cases occurring in nasal cavity and parapharynx (NF I), respectively, and 4 bilateral acoustic neuromas (NF II). RESULTS: NF I and NF II had long courses of 2-30 years, with common clinical features and unique characteristics. All patients with NF were operated on under general anesthesia. The NFs in the nasal cavity and sinus were resected through the paranasal approach and parapharyngeal NF through the lateral cervical approach. Unilateral acoustic neuromas were removed via the sigmoid sinus posterior suboccipital approach, one case bilateral acoustic neuromas was operated on in 2 stages. No death happened in this series. CONCLUSION: Surgical treatment is the best way for the treatment of NF. Radiotherapy can be considered in case of NF I with an extensive invasion, obscure border and recurrence.

Adult↗
PubMedDate not supplied

Molecular analysis of neurofibromatosis type 1 in Turkish families using polymorphic markers.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder characterized by multiple neurofibromas, café-au-lait spots, and Lisch nodules of iris. The NF1 gene is located on chromosome 17q11.2 and encodes an 11-13 kb mRNA containing 60 exons. The NF1 gene product neurofibromin is a large protein of 2818 amino acids which acts as a negative regulator in the ras signal transduction pathway. The disease has a high mutation rate and a wide range of expression. Because of the size and complexity of the gene, the variety of mutations and the need to identify the specific mutation in each family, indirect diagnosis using linked markers has an important part in genetic counseling. We analyzed 10 Turkish families with a total of 28 affected individuals and 34 non-affected relatives using polymorphic sequences, four intragenic and five flanking markers. Intragenic microsatellite markers were highly informative for all families. As a result, prenatal and presymptomatic diagnoses for familial cases are being made available.

Genes, Neurofibromatosis 1↗