A genetic study of type 2 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity.
TL;DR: In this article, a clinical and genetic study of type 2 neurofibromatosis (NF2) has been carried out in the United Kingdom and the results show 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.
Abstract: 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.
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TL;DR: The deduced product has homology with proteins at the plasma membrane and cytoskeleton Interface, a previously unknown site of action of tumour suppressor genes in humans.
Abstract: Neurofibromatosis type 2 (NF2) is a monogenic dominantly inherited disease predisposing carriers to develop nervous system tumours. To identify the genetic defect, the region between two flanking polymorphic markers on chromosome 22 was cloned and several genes identified. One is the site of germ-line mutations in NF2 patients and of somatic mutations in NF2-related tumours. Its deduced product has homology with proteins at the plasma membrane and cytoskeleton interface, a previously unknown site of action of tumour suppressor genes in humans.
1,279 citations
TL;DR: A candidate gene for the NF2 tumor suppressor that has suffered nonoverlapping deletions in DNA from two independent NF2 families and alterations in meningiomas from two unrelated NF2 patients is identified.
1,268 citations
TL;DR: The diagnostic criteria for neurofibromatosis 1 and neurof fibromaatosis 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 are determined.
Abstract: 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.
1,150 citations
TL;DR: Estimates for NF1, NF2, FAP, and VHL are in line with previous estimates, and the first estimates of birth incidence and de novo mutation rate for Gorlin syndrome are provided.
Abstract: Autosomal dominantly inherited tumor-prone syndromes are a substantial health problem and are amenable to epidemiologic studies by combining cancer surveillance registries with a genetic register (GR)-based approach. Knowledge of the frequency of the conditions provides a basis for appropriate health-resources allocations. GRs for five tumor-prone syndromes were established in the Manchester region of North West England in 1989 and 1990. Mapping birth dates of affected individuals from families onto regional birth rates has allowed an estimate of birth incidence, disease prevalence, and de novo mutation rates. Disease prevalence in order of frequency were for neurofibromatosis type 1 (NF1): 1 in 4,560; familial adenomatous polyposis (FAP): 1 in 18,976; nevoid basal cell carcinoma [Gorlin syndrome (GS)]: 1 in 30,827; neurofibromatosis type 2 (NF2) 1 in 56,161; and von Hippel Lindau (VHL) 1 in 91,111. Best estimates for birth incidence were: 1 in 2,699; 1 in 8,619; 1 in 14,963, 1 in 33,000; and 1 in 42,987, respectively. The proportions due to de novo mutation were: 42% (NF1); 16% (FAP); 26% (GS); 56% (NF2); and 21% (VHL). Estimates for NF1, NF2, FAP, and VHL are in line with previous estimates, and we provide the first estimates of birth incidence and de novo mutation rate for GS.
704 citations
TL;DR: Current knowledge of meningioma epidemiology and new directions for research efforts in this field are highlighted, with the increased emphasis on research dedicated to the study of brain tumors coupled with the advent of new tools in genetic and molecular epidemiology making the current era an ideal time to advance knowledge.
Abstract: Meningiomas are the most frequently reported primary intracranial neoplasms, accounting for approximately 25% of all such lesions diagnosed in the United States. Few studies have examined the risk factors associated with a diagnosis of meningioma with two categories of exposure, hormones (both endogenous and exogenous) and radiation, most strongly associated with meningioma risk. Limited data are also available on long-term outcomes for meningioma patients, although it is clear that the disease is associated with significant morbidity and mortality. Recent legislation passed in the United States (The Benign Brain Tumor Cancer Registries Amendment Act [H.R. 5204]) mandates registration of benign brain tumors such as meningioma. This will increase the focus on this disease over the coming years as well as likely increase the reported prevalence of the disease. The increased emphasis on research dedicated to the study of brain tumors coupled with the advent of new tools in genetic and molecular epidemiology make the current era an ideal time to advance knowledge for intracranial meningioma. This review highlights current knowledge of meningioma epidemiology and new directions for research efforts in this field.
601 citations
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TL;DR: A large number of the patients diagnosed with neurofibromatosis are women, and the prognosis is poor for the vast majority of the women diagnosed with the disease.
Abstract: Neurofibromatosis is of great importance not only to the thousands of affected patients and their physicians but also to researchers concerned with genetics, melanin synthesis, neural-crest embryol...
1,219 citations
TL;DR: A human genomic clone is isolated that detects novel restriction fragments specific to individuals with myotonic dystrophy, strongly supporting earlier results which indicated that most cases are descended from one original mutation.
Abstract: Myotonic dystrophy is the commonest adult form of muscular dystrophy, with an estimated incidence of 1 per 7,500, although this is likely to be an underestimate because of the difficulty of detecting minimally affected individuals. It is a multisystem autosomal dominant disorder of unknown biochemical basis. No case of new mutation has been proven. We have isolated a human genomic clone that detects novel restriction fragments specific to individuals with myotonic dystrophy. A two-allele EcoRI polymorphism is seen in normal individuals, but in most affected individuals one of the normal alleles is replaced by a larger fragment, which varies in length both between unrelated affected individuals and within families. The unstable nature of this region may explain the characteristic variation in severity and age at onset of the disease. A second polymorphism at this locus is in almost complete linkage disequilibrium with myotonic dystrophy, strongly supporting our earlier results which indicated that most cases are descended from one original mutation.
721 citations
TL;DR: A population-based study in south-east Wales identified 135 patients with von Recklinghausen neurofibromatosis and found that the disease is disfiguring but not a major cause of morbidity, and the management of the disease relates to its complications.
Abstract: A population-based study in south-east Wales (population 668,100) identified 135 patients with von Recklinghausen neurofibromatosis (prevalence 20/10(5]. In addition to multiple cafe-au-lait spots and/or dermal neurofibromas, freckling was present in the axilla (67%), groin (44%) or submammary areas (29% of adult females). Although not a criterion for diagnosis, Lisch nodules were almost invariably present in the iris (93% of patients overall; 96% of those aged greater than or equal to 20 yrs). The complications of von Recklinghausen neurofibromatosis in this cohort (n = 135 unless stated) were plexiform neurofibromas (40/125), severe mental retardation (1), epilepsy (6), optic glioma (2), spinal neurofibroma (2), aqueduct stenosis (2), meningioangiomatosis (1), scoliosis requiring surgery (6), pseudoarthrosis (3), delayed puberty (2), visceral and endocrine tumours (6), and congenital glaucoma (1). There were no cases of acoustic neuroma. Considering all living family members aged greater than or equal to 18 yrs, together with their deceased relatives, the frequency of CNS and malignant tumours related to the disease was 4.4-5.2%. Uncomplicated von Recklinghausen neurofibromatosis is disfiguring but not a major cause of morbidity. The management of the disease relates to its complications which can be divided into three categories: those which occur in childhood and cause lifelong morbidity (moderate-severe mental handicap, facial plexiform neurofibromas, orthopaedic), those which can occur at any time but are 'treatable' (benign disorders of the nervous system, visceral and endocrine tumours, renal artery stenosis), and malignant or CNS tumours. The combined frequency for each category based on this survey was 12%, 16% and 4.4-5.2%, respectively.
632 citations
Journal Article•
TL;DR: This paper will first examine the evidence concerning genomic imprinting which has been accumulated over the past few years and then explore how it may relate to human development and human diseases.
Abstract: This paper will first examine the evidence concerning genomic imprinting which has been accumulated over the past few years and then explore how it may relate to human development and human diseases
616 citations
TL;DR: Linkage analysis of 15 Utah kindreds demonstrated that a gene responsible for von Recklinghausen neurofibromatosis is located near the centromere on chromosome 17, indicating that a significant proportion of NF cases are due to mutations at a single locus.
Abstract: Linkage analysis of 15 Utah kindreds demonstrated that a gene responsible for von Recklinghausen neurofibromatosis (NF) is located near the centromere on chromosome 17. The families also gave no evidence for heterogeneity, indicating that a significant proportion of NF cases are due to mutations at a single locus. Further genetic analysis can now refine this localization and may lead to the eventual identification and cloning of the defective gene responsible for this disorder.
605 citations