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Background: Unilateral sporadic vestibular schwannomas (USVS) are caused by inactivating somatic mutations of both alleles of the neurofibromatosis 2 (NF2) tumor suppressor gene. Unilateral sporadic vestibular schwannomas have a widely-varying growth patterns whose causes are poorly understood. Objective: We examined the relationships between an index of USVS growth, and genetic abnormalities and pathological growth indices. Subjects and Methods: Single-strand conformational polymorphism analysis and heteroduplex methods were used to screen for mutations in all 17 exons of the NF2 gene in USVS from 63 patients. Loss of heterozygosity (LOH) analyses were also carried out. An index of USVS growth (clinical growth index, CGI) was calculated as maximum tumor diameter divided by duration of symptoms. The immunohistochemical growthindices were based on monoclonal antibodies to Ki-67 and another tumor cell proliferation marker (platelet-derived growth factor (PDGF)). Results: CGI was highly variable and did not significantly decrease with increasing age at diagnosis. Either somatic NF2 mutations or LOH was found in 88% of tumors. PDGF and Ki-67 increased significantly with increasing age at diagnosis, and PDGF was lower in tumors with LOH than in those without LOH. In multiple linear regression analysis, CGI was significantly higher in people with higher PDGF, after accounting for age at diagnosis and LOH. Conclusion: An index of USVS growth increases with increasing PDGF, after accounting for age and LOH.

Purpose: Four sets of clinical diagnostic criteria have been proposed for neurofibromatosis 2, but all have low sensitivity at the time of initial clinical assessment for the disease among patients with a negative family history who do not present with bilateral vestibular schwannomas. We have empirically developed and tested an improved set of diagnostic criteria that uses current understanding of the natural history and genetic characteristics of neurofibromatosis 2 to increase sensitivity while maintaining very high specificity. Methods: We used data from the UK Neurofibromatosis 2 Registry and Kaplan-Meier curves to estimate frequencies of clinical features at various ages among patients with or without unequivocal neurofibromatosis 2. On the basis of this analysis, we developed the Baser criteria, a new diagnostic system that incorporates genetic testing and gives more weight to the most characteristic features and to those that occur before 30 years of age. Results: In an independent validation subset of patients with unequivocal neurofibromatosis 2, the Baser criteria increased diagnostic sensitivity to 79% (9–15% greater than previous sets of criteria) while maintaining 100% specificity at the age at onset of the first characteristic sign of neurofibromatosis 2. Conclusion: The Baser criteria permit early diagnosis in a greater proportion of patients with neurofibromatosis 2 than previous sets of diagnostic criteria.

Purpose Optic pathway gliomas (OPGs) are the most common CNS tumor in neurofibromatosis 1 (NF1) patients. We evaluated the long-term risk of second tumors in NF1-related OPGs after radiotherapy. Patients and Methods We reviewed 80 NF1 OPG patients from two NF1 clinics to evaluate the long-term risk of developing subsequent nervous system tumors, with or without radiotherapy. Results Fifty-eight patients were assessable for second tumors. Nine (50%) of 18 patients who received radiotherapy after their OPGs developed 12 second tumors in 308 person-years of follow-up after radiotherapy. Eight (20%) of 40 patients who were not treated with radiotherapy developed nine tumors in 721 person-years of follow-up after diagnosis of their OPGs. The relative risk of second nervous system tumor after radiotherapy was 3.04 (95% CI, 1.29 to 7.15). Conclusion There is a significantly increased risk of second nervous system tumors in those NF1 patients who received radiotherapy for their OPGs, especially when treated in childhood. Thus radiotherapy should only be used if absolutely essential in children with NF1.

Objective: To screen for NF2 mutations in people with meningiomas. Methods: Lymphocyte or tumour DNA was analysed from 46 individuals from 36 families who presented with a meningioma at age ⩽15 years without vestibular schwannoma (VS), or who had multiple meningiomas in adulthood before the diagnosis of VS. Results: Eight of 13 people with meningioma and other features of neurofibromatosis 2 (NF2) had an identified constitutional NF2 mutation in blood DNA, but none of the other subjects had identified constitutional NF2 mutations. Conclusions: Constitutional NF2 mutations are the most likely cause of meningioma in children and in people with a meningioma plus other non-VS features of NF2. Mosaic NF2 may be the cause of about 8% of multiple meningiomas in sporadic adult cases, but there are other causes in the majority of other such patients and in multiple meningioma in families.

Neurofibromatosis 2 (NF2) is an autosomal dominant disease that is characterized by tumors on the vestibular branch of the VIII cranial nerve, but other types of nervous system tumors usually occur as well. Genotype-phenotype correlations are well documented for overall NF2 disease severity but have not been definitively evaluated for specific types of non–VIII nerve tumors. We evaluated genotype-phenotype correlations for various types of non–VIII nerve tumors in 406 patients from the population-based United Kingdom NF2 registry, using regression models with the additional covariates of current age and type of treatment center (specialty or nonspecialty). The models also permitted consideration of intrafamilial correlation. We found statistically significant genotype-phenotype correlations for intracranial meningiomas, spinal tumors, and peripheral nerve tumors. People with constitutional NF2 missense mutations, splice-site mutations, large deletions, or somatic mosaicism had significantly fewer tumors than did people with constitutional nonsense or frameshift NF2 mutations. In addition, there were significant intrafamilial correlations for intracranial meningiomas and spinal tumors, after adjustment for the type of constitutional NF2 mutation. The type of constitutional NF2 mutation is an important determinant of the number of NF2-associated intracranial meningiomas, spinal tumors, and peripheral nerve tumors.

Neurofibromatosis 2 (NF2), an autosomal dominant disorder that is characterised by tumours of cells of neural crest origin, is caused by inactivating mutations of the NF2 gene on chromosome 22q12.1,2 Bilateral vestibular schwannomas are the most frequent manifestation of the disease, but other central and peripheral nervous system schwannomas, cerebral meningiomas, and ocular abnormalities are also common.3–5 The birth incidence of NF2 is 1 in 33 000 to 1 in 40 000.6 Constitutional NF2 mutations have been found in 30-60% of NF2 patients, and genotype-phenotype correlations have been substantiated.7–12 Half of NF2 patients are new mutations,6 in whom constitutional NF2 mutations can occur either in parental germline cells (prezygotic) or in cells after fertilisation (postzygotic). Postzygotic mutations can result in mosaicism, defined as the presence of a mutation, deletion, or chromosomal abnormality in a group or population of cells.13 Owing to the rarity of NF2, most previous reports of mosaicism in NF2 have been limited in scope,14–16 although a recent study estimated that 25% of NF2 patients with new mutations are mosaic.17 In this study, we describe mutational analysis of 27 mosaic cases of NF2 and the results of genetic testing in their children. NF2 patients were identified through the United Kingdom NF2 registry in the Department of Medical Genetics, St Mary’s Hospital, Manchester. Patients are ascertained by contacting neurosurgeons, otolaryngologists, neurologists, paediatricians, dermatologists, and geneticists throughout the United Kingdom, augmented in the North West Region by the Regional Cancer Registry. There were 297 people from unrelated families who were screened for constitutional NF2 mutations; 256 had bilateral vestibular schwannomas and 41 met other Manchester clinical diagnostic criteria for NF2.3,18 Of these 297 families, 68 families had affected patients in more than one generation, but the …

Background: Four sets of clinical diagnostic criteria for neurofibromatosis 2 (NF2) have been developed by groups of expert clinicians, but sensitivity has never been formally assessed. The sets of criteria differ for people without bilateral vestibular schwannomas, which are pathognomonic for NF2. Objective: To empirically evaluate the four existing sets of clinical diagnostic criteria for NF2. Methods: The study was based on 163 of 403 people in the United Kingdom NF2 registry (41%) who presented without bilateral vestibular schwannomas. The authors applied the sets of criteria to each person at initial assessment and at the most recent clinical evaluation (mean ± SE length of follow-up, 13 ± 1 years). Results: In people with “definite NF2” and a negative family history of NF2, the 1987 US NIH and 1991 NIH criteria each identify 78% of people at the most recent clinical evaluation but 0% at initial assessment. The National Neurofibromatosis Foundation (NNFF) criteria and the Manchester criteria each identify higher proportions at both time points (NNFF criteria, 91% and 10%; Manchester criteria, 93% and 14%), but the proportions at initial assessment are still low. Conclusions: None of the existing sets of criteria are adequate at initial assessment for diagnosing people who present without bilateral vestibular schwannomas as having NF2, particularly people with a negative family history of NF2. The authors recommend that a single, revised set of diagnostic criteria be devised to replace all of the existing sets of criteria.

Measuring correlation in clinical traits among relatives is important to our understanding of the causes of variable expressivity in Mendelian diseases. Random effects models are widely used to estimate intrafamilial correlations, but such models have limitations. We incorporated survival techniques into a random effects model so that it can be used to estimate intrafamilial correlations in continuous variables with right censoring, such as age at onset. We also describe a negative-binomial gamma mixture model to determine intrafamilial correlations of discrete (e.g., count) data. We demonstrate the utility of these methods by analyzing intrafamilial correlations among patients with neurofibromatosis 2 (NF2), an autosomal-dominant disease caused by mutations of the NF2 tumor-suppressor gene. We estimated intrafamilial correlations in age at first symptom of NF2, age at onset of hearing loss, and number of intracranial meningiomas in 390 NF2 nonprobands from 153 unrelated families. A significant intrafamilial correlation was observed for each of the three features: age at onset (0.35; 95% confidence interval (CI) 0.23-0.47), age at onset of hearing loss (0.51; 95% CI, 0.35-0.64), and number of meninginomas (0.29; 95% CI, 0.15-0.43). Significant correlations were also observed for age at first symptom within NF2 families with truncating mutations (0.41; 95% CI, 0.06-0.68) or splice-site mutations (0.29; 95% CI, 0.03-0.51), for age at onset of hearing loss within families with missense mutations (0.67; 95% CI, 0.18-0.89), and for number of meningiomas within families with splice-site mutations (0.39; 95% CI, 0.13-0.66). Our findings are consistent with effects of both allelic and nonallelic familial factors on the clinical variability of NF2.

To evaluate clinical and molecular predictors of the risk of mortality in people with neurofibromatosis 2 (NF2), we analyzed the mortality experience of 368 patients from 261 families in the United Kingdom NF2 registry, using the Cox proportional-hazards model and the jackknife method. Age at diagnosis, intracranial meningiomas, and type of treatment center were informative predictors of the risk of mortality. In Cox models, the relative risk of mortality increased 1.13-fold per year decrease in age at diagnosis (95% confidence interval [CI] 1.08-1.18) and was 2.51-fold greater in people with meningiomas compared with those without meningiomas (95% CI 1.38-4.57). The relative risk of mortality in patients treated at specialty centers was 0.34 compared with those treated at nonspecialty centers (95% CI 0.12-0.98). In a separate model, the relative risk of mortality in people with constitutional NF2 missense mutations was very low compared with those with other types of mutations (nonsense or frameshift mutations, splice-site mutations, and large deletions), but the CI could not be well quantified because there was only one death among people with missense mutations. We conclude that age at diagnosis, the strongest single predictor of the risk of mortality, is a useful index for patient counseling and clinical management (as are intracranial meningiomas). To ensure optimal care, we recommend that people with NF2 be referred to specialty treatment centers.

Editor—We have previously reported on a large clinical study of patients with neurofibromatosis 2 (NF2)1and described the usefulness of audiological screening in early detection of VS in NF2.2 Although DNA diagnosis is possible by linkage analysis and by detecting the NF2 family specific mutation, this is not possible in all cases. Only 40% of sporadic patients (new mutations) have an identifiable NF2 mutation3 and as 50% of NF2 patients have no family history,4 up to 30% of those at risk of NF2 will not be able to have a DNA presymptomatic test. While it is possible to calculate residual risks of NF2 from age at onset of symptoms curves,5 a more useful measure would be the level of risk reduction from a normal cranial MRI scan. A database recording information on affected subjects with NF2 was set up in Manchester in 1989. Patients were actively sought across the UK from paediatricians, neurosurgeons, ENT surgeons, geneticists, and dermatologists. We have used this database to determine the age at which MRI detects asymptomatic tumours in subjects with NF2 and the value of audiological screening. We have also created life curves for risk reduction in subjects at 50% risk of NF2. Patient details from hospital notes and proformas have been entered into a database at St Mary's Hospital Manchester since 1989. A total of 344 patients fulfilling our published criteria for NF2 are recorded (table 1).1 3 5 Information on all known tumours, age at presentation and diagnosis, and many different symptoms are included. We have analysed details of patients who have been detected as having VS on a screening MRI scan without any known central nervous system pathology, signs, or symptoms. It has been our practice to carry out a baseline MRI …

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.

(2000). Advances in Neurofibromatosis 2 (NF2): A Workshop Report. Journal of Neurogenetics: Vol. 14, No. 2, pp. 63-106.

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.

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 as2 other intracranial tumors andor = 4 spinal tumors, and the severe phenotype as eitheror = 2 other intracranial tumors of4 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.

Mutations in the neurofibromatosis 2 (NF2) tumor suppressor gene on chromosome 22q12 cause a clinically variable autosomal dominant syndrome characterized by bilateral vestibular schwannomas (VSs), other nervous system tumors, and early onset lenticular cataracts. We studied three pairs of monozygotic (MZ) twins with NF2, all with bilateral VSs, to separate genetic from nongenetic causes of clinical variability. The evaluation included gadolinium-enhanced high-resolution magnetic resonance imaging of the head and spine, neuro-ophthalmic examination with slit lamp, physical examination, and zygosity testing with microsatellite markers. Each MZ pair was concordant for general phenotypic subtype (mild or severe) and often for the affected organ systems. However, the MZ pairs were discordant for some features of disease presentation or progression. For example, all three pairs were discordant for presence or type of associated cranial tumors. We hypothesize that phenotypic differences between NF2 MZ twins are at least partly due to stochastic processes, such as the loss of the second NF2 allele or alleles of other genes.

Purpose To evaluate the ocular abnormalities in patients with clinically diagnosed neurofibromatosis 2 and asymptomatic gene carriers. Methods Probands were ascertained through a surgical otolaryngology practice. In a cross-sectional study, we examined 49 patients with neurofibromatosis 2, 30 offspring of patients, and, as a comparison group, 18 parents and siblings of patients with sporadic neurofibromatosis 2. The examination included a complete neuro-ophthalmic assessment, physical examination, and, for patients and first-degree relatives at risk, cranial and spinal magnetic resonance imaging with gadolinium enhancement, if not previously performed. Results The most common ocular abnormalities were posterior subcapsular or capsular, cortical, or mixed lens opacities in 33 (67%) of 49 patients with neurofibromatosis 2 and retinal hamartomas in 11 (22%). We used segregation analysis to determine the mutation carrier status of six at-risk offspring who were 30 years old or younger in two multigeneration families. Three asymptomatic mutation carriers had cataracts, whereas those who were predicted not to carry the mutation did not have cataracts. Asymptomatic mutation carriers may have developmental abnormalities of the eye that are detectable in childhood or adolescence, a finding that may assist in early diagnosis of the disease. Conclusions A variety of ocular abnormalities are present in neurofibromatosis 2, including cataracts, retinal hamartomas, and ocular motor deficits. Many of these are developmental or acquired early in life and may assist in presymptomatic diagnosis. For screening at-risk relatives of patients with neurofibromatosis 2, the types of cataract that are most suggestive of neurofibromatosis 2 are plaque-like posterior subcapsular or capsular cataract and cortical cataract with onset under the age of 30 years.

Objective Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder leading to various tumors of the CNS, with vestibular schwannomas being the hallmark of the disease. We have observed multiple asymptomatic spinal lesions in patients who have a single symptomatic spinal tumor. Accordingly, we studied the frequency, multiplicity, and variety of spinal tumors in all patients with NF2 to determine what is characteristic of the disease. Subjects and methods MR images of the entire spinal canal were made in 73 patients aged 4-69 years with NF2. The number, location, morphology, signal characteristics, and contrast medium uptake of the spinal tumors as seen on MR images were recorded and analyzed. Histopathologic proof of 22 spinal tumors was obtained in 19 patients. Results Spinal tumors were found on MR images in 89% of the patients studied. No location in any part of the spine was preferred. MR imaging showed intramedullary tumors in 24 patients (33%) (three ependymomas pathologically proven). Extradural and intradural extramedullary tumors were found on MR imaging in the cervical spine of 36 patients, the thoracic spine of 40 patients, and the lumbar spine of 49 patients. These tumors were meningiomas, schwannomas, or neurofibromas, three categories that could not be differentiated on the basis of the neuroradiologic findings, with ten schwannomas, seven meningiomas, and two neurofibromas pathologically proven. Extradural extramedullary tumors were found on MR imaging in the cervical spine of 12 patients, the thoracic spine of five patients, and the lumbar spine of 18 patients. A syrinx associated with a tumor was found in two patients. In 19 patients the variety of tumor types was confirmed by histologic examination. Conclusion Patients with NF2 frequently have spinal tumors, which are often multiple and of various histologic types. The presence of multiple and different pathologic types of spinal tumors is highly suggestive of NF2.

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.

Schwannomas are common tumors of the nervous system and are frequently found in patients with neurofibromatosis (NF) 2. Although loss of heterozygosity in NF2 tumors suggests that the NF2 gene functions as a tumor suppressor gene, the NF2 gene shows amino acid sequence homology to structural proteins in one of which dominantly acting mutations have been described. We performed a mutational analysis in 30 vestibular schwannomas and examined the effect of mutations on the NF2 protein. We detected 18 mutations in 30 vestibular schwannomas of which seven contained loss or mutation of both NF2 alleles. Most mutations were predicted to result in a truncated protein. Mutational hot spots were not identified. Immunocytochemical studies using antibodies to the NF2 protein showed complete absence of staining in tumor Schwann cells, whereas staining was observed in normal vestibular nerve. These data indicate that loss of NF2 protein function is a necessary step in schwannoma pathogenesis and that the NF2 gene functions as a recessive tumor suppressor gene.

Background Neurofibromatosis type 1 (NF1) affects 1 in 2500 people, and 15% of these may develop an optic pathway glioma (OPG). OPGs behave differently in NF1, and, given their frequency, surveillance is important. However, this is difficult because of the additional complications these patients may have, such as learning difficulties. Management is also different given that NF1 results from loss of function of tumour suppressor gene. A genotype–phenotype correlation may help to determine who is at risk of developing these tumours, aid focused screening, and shed light on response to treatments. Methods As part of a long-term follow-up study of patients with NF1 OPGs, the authors assessed genotype–phenotype correlation. Fluorescein in situ hybridisation was performed to identify large deletions, and then a full gene screen for mutations, by denaturing high-performance liquid chromatography. Results 80 patients with NF1 OPGs were identified, and molecular analyses were performed in a subset of 29. A clustering of pathogenic changes in the 5′ tertile of the gene was found. The authors combined these results with those for another two NF1 OPG cohorts and collectively found the same trend. When compared with a control population of NF1 patients without an OPG, the OR of a mutation being present in the 5′ tertile was 6.05 (p=0.003) in the NF1 OPG combined cohorts. Conclusion It is possible that genotype is a significant determinant of the risk of development of OPGs in NF1.

Objective: Using highly informative microsatellite markers flanking the neurofibromatosis type 2 gene, we determined the frequency of chromosome 22 allele loss in vestibular schwannomas. Design: Peripheral lymphocyte/vestibular schwannoma DNA pairs were analyzed with five different microsatellite markers on chromosome 22. Patients: Samples were taken from 32 patients (17 females and 15 males). Twenty-seven tumors occurred sporadically, and five were from patients with neurofibromatosis type 2. Results: Using the microsatellite markers D22S351, CRYB2, D22S268, D22S304, and interleukin type 2Rβ, we found loss of heterozygosity for at least two markers in 12 tumors. Ten tumors showed loss of heterozygosity for markers flanking the neurofibromatosis type 2 gene. Although microsatellite markers require little DNA for analysis and are highly informative, allele patterns may be difficult to interpret in some cases. Conclusions: Loss of heterozygosity of chromosome 22 alleles was a frequent event in vestibular schwannomas. In 10 tumors, heterozygosity was lost for centromeric and telomeric markers indicating likely monosomy 22. However, 63% of tumors did not reveal a detectable chromosomal loss. Unless a second vestibular schwannoma locus exists, these tumors likely harbor point mutations in the neurofibromatosis type 2 gene or deletions below the level of resolution of the markers used in this study. (Arch Otolaryngol Head Neck Surg. 1993;119:1285-1288)

We previously reported an outbreak of acute respiratory illness associated with eosinophilia in a group of rubber workers who performed a thermoinjection process in which synthetic rubber was heated and then injected onto metal molds. This study was conducted to determine if persistent respiratory health effects were associated with this work area and to explore the possible allergic etiology of this syndrome. A survey was performed 1 mo after a major improvement in area ventilation and consisted of baseline, cross-shift, and cross-week spirometry; diffusing capacity; serum immunoglobulin E (IgE), total eosinophil count; and skin patch testing. Baseline lung function, cross-shift, and cross-week spirometry were not significantly worse in the exposed group as compared to the control group. However, either eosinophilia (greater than 450/mm3) or elevated serum IgE (greater than 470 ng/ml) were present in 44% of exposed workers vs. 11% of the control group (p = .003). Nine months later, neither eosinophilia nor elevated IgE were associated with employment in this work area. We conclude that employment in the thermoinjection process was associated with eosinophilia and elevated IgE, which suggests sensitization to one of the components of the rubber, although no effect on pulmonary function could be demonstrated.

Diagnostic criteria for schwannomatosis have been proposed in a recent consensus statement. These criteria permit schwannomatosis to be distinguished from neurofibromatosis type 2 (NF2) in most patients, but there is some clinical overlap between the two diseases. In this study, the authors use data from the population-based United Kingdom NF2 Registry to recommend modifications that increase the specificity of the schwannomatosis diagnostic criteria.

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.

Chromosome 22q loss of heterozygosity (LOH) is the most common allelic loss in benign meningioma and is thought to be the earliest initiating event in meningioma formation. We used published data and logistic regression to evaluate the association of 22q LOH with age at diagnosis in 318 transitional, fibroblastic, and meningothelial meningiomas. After adjustment for anatomical location, the odds ratio of 22q LOH per year of age was >1 in each histological type of meningioma, and was significantly >1 in transitional and fibroblastic meningioma. This finding is compatible with involvement of the neurofibromatosis 2 tumour suppressor gene, NF2, on chromosome 22q in the high incidence of benign meningioma in the elderly.

Neurofibromatosis type 2 (NF2) is an autosomal dominant condition characterised by vestibular schwannomas, schwannomas of other cranial nerves, meningiomas, and other low grade brain malignancies.1 The severity of NF2 is variable, with some patients having early onset disease and more rapidly growing tumours that occur in greater numbers. The NF2 gene is on chromosome 22q12.2,3 The protein product (termed merlin or schwannomin) is a cell cytoskeleton associating protein. Genotype−phenotype correlations have been demonstrated, with missense mutations and large deletions causing mild disease, and nonsense or frameshift mutations causing severe disease.4,5 The current mutation screening techniques of single strand conformation polymorphism analysis (SSCP), protein truncation test, and denaturing gradient gel electrophoresis detect 33–65% of mutations, although adding a deletion strategy increases the proportion to 80%.6 However, deletion testing and chromosome analysis are rarely reported in studies of NF2 mutations. In this study, we present five NF2 patients for whom chromosome analysis, usually following routine molecular screening, revealed the underlying genetic aberration. ### Case 1 A 20 year old female was referred with a large diffuse goitre commencing early in puberty, moderate learning difficulties, and bilateral sensorineural hearing loss, which resembles the phenotype of Pendred’s syndrome. She was born after a normal pregnancy and delivery. Her physical and mental development during early infancy was not remarkable, but developmental delay became apparent in the second year of life. Growth parameters were within the normal range. She began to walk at the age of 3 years. Six months later, audiometric tests showed no hearing impairment although chronic otitis media was diagnosed on one side. According to the parents, her communication had been improving with age, but her speech remained dysarthric and her articulation was very poor. In primary school, she had sub-average grades in all subjects. Her affect was good and …

Background: Schwannomas are benign tumours of the nervous system that are usually sporadic but also occur in the inherited disorder neurofibromatosis type 2 (NF2). The NF2 gene is a tumour suppressor on chromosome 22. Loss of expression of the NF2 protein product, merlin, is universal in both sporadic and NF2 related schwannomas. The GTPase signalling molecules RhoA and Rac1 regulate merlin function, but to date only mutation in the NF2 gene has been identified as a causal event in schwannoma formation. Methods: Comparative genomic hybridisation (CGH) was used to screen 76 vestibular schwannomas from 76 patients (66 sporadic and 10 NF2 related) to identify other chromosome regions that may harbour genes involved in the tumorigenesis. Results: The most common change was loss on chromosome 22, which was more frequent in sporadic than in NF2 related tumours. Importantly, eight tumours (10%) showed gain of copy number on chromosome 9q34. Each of the two NF2 patients who had received stereotactic radiotherapy had non-chromosome 22 changes, whereas only one of eight non-irradiated NF2 patients had any chromosome changes. Three tumours had gain on 17q, which has also been reported in malignant peripheral nerve sheath tumours that are associated with neurofibromatosis type 1. Other sites that were identified in three or fewer tumours were regions on chromosomes 10, 11, 13, 16, 19, 20, X, and Y. Conclusions: These findings should be verified using techniques that can detect smaller genetic changes, such as microarray-CGH.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with complete penetrance and extremely variable expression, and an incidence of approximately 1 in 4000 live births. Despite the high incidence of NF1, neither the natural history nor the genetic epidemiology of the disorder are well understood. People with NF1 have reduced reproductive fitness and life expectancy,1 but the cause of the high mutation rate at the NF1 locus is unknown. The most prominent clinical hallmarks of NF1 are cafe-au-lait (CAL) macules, neurofibromas, Lisch nodules of the iris, and axillary freckling.2 Other clinical manifestations are abnormalities of the cardiovascular, gastrointestinal, renal, and endocrine systems, facial and body disfigurement, cognitive deficit, and malignancies of the peripheral nerve sheath and central nervous system. About 25% of people with NF1 develop one or more of these clinical complications, which together cause significant morbidity and mortality.3 The tumours that occur in NF1 are dermal and plexiform neurofibromas, optic gliomas, malignant peripheral nerve sheath tumours (MPNSTs), pheochromocytomas, and rhabdomyosarcomas.1 Children with NF1 have an increased risk of developing myeloid disease, particularly juvenile chronic myeloid leukaemia. Some 30–40% of NF1 patients develop plexiform neurofibromas2–4 that become MPNSTs in 5–10% of cases,5–7 often in pre-existing plexiform neurofibromas. The NF1 gene on chromosome 17q11.2 spans more than 350 kb of genomic DNA and contains 60 exons.8 The 8457 bp open reading frame predicts a protein of 2818 amino acids with an estimated mass of 327 kDa.9,10 The NF1 gene product, neurofibromin, contains a 360 amino acid region with homology to the catalytic domain of the mammalian guanosine triphosphatase activating protein. Neurofibromin is a GTPase activating protein for members of the p21ras (Ras) protein family. Loss of neurofibromin function leads to downstream cell growth activation because neurofibromin negatively regulates …

Neurofibromatosis 2 (NF2) is an autosomal dominant disease that is caused by inactivating mutations of the NF2 tumour suppressor gene.1,2 Multiple central and peripheral nervous system tumours and ocular abnormalities are common in NF2; bilateral vestibular schwannomas are pathognomonic for the disease. Genotype-phenotype correlations are well established for NF2 associated tumours. In general, constitutional nonsense or frameshift NF2 mutations are associated with severe NF2 (that is, earlier onset of symptoms and more tumours), splice site mutations with variable disease severity, and missense mutations with mild disease. Genotype-phenotype correlations have not been reported for the non-tumour manifestations of NF2. The most common of these manifestations is presenile cataracts, which occur in about 60–80% of people with NF2.3–5 In animal models, lens fibre cells that are more differentiated express less Nf2 protein than the epithelial regions of the lens, suggesting that the Nf2 protein may play a role in lens epithelial cell migration or elongation.6 The purpose of this study was to determine if there were genotype-phenotype correlations for cataracts in NF2. The study was based on the United Kingdom NF2 registry in the Department of Medical Genetics, St Mary’s Hospital, Manchester. NF2 patients are ascertained by contacting neurosurgeons, otolaryngologists, neurologists, paediatricians, dermatologists, and geneticists throughout the United Kingdom, augmented in the North West Region by the Regional Cancer Registry. The study was subject to continuing ethics committee evaluation and patients consented to participation. Patients were screened for constitutional NF2 mutations using single strand conformational polymorphism analysis (SSCP) as previously described,7 and examined for cataracts using slitlamp biomicroscopy at the time of diagnosis of NF2. For this study, cataracts were defined as present or absent (that is, posterior subcapsular cataracts and cortical cataracts were aggregated). There were 255 people from 190 families (159 people with new …

Mutations of the neurofibromatosis 2 (NF2) tumor suppressor gene cause the inherited disorder NF2 and are also common in malignant mesothelioma, which is not a characteristic feature of NF2. The authors report an asbestos-exposed person with NF2 and malignant mesothelioma. Immunohistochemical analysis of the mesothelioma confirmed loss of expression of the NF2 protein, and comparative genomic hybridization revealed losses of chromosomes 14, 15, and 22, and gain of 7. The authors propose that a person with a constitutional mutation of an NF2 allele is more susceptible to mesothelioma.

Cross sectional studies have shown that 1-2% of patients with neurofibromatosis 1 (NF1) develop malignant peripheral nerve sheath tumours (MPNST). However, no population based longitudinal studies have assessed lifetime risk.NF1 patients with MPNST were ascertained from two sources for our north west England population of 4.1 million in the 13 year period 1984-1996: the North West Regional NF1 Register and review of notes of patients with MPNST in the North West Regional Cancer Registry.Twenty-one NF1 patients developed MPNST, equivalent to an annual incidence of 1.6 per 1000 and a lifetime risk of 8-13%. There were 37 patients with sporadic MPNST. The median age at diagnosis of MPNST in NF1 patients was 26 years, compared to 62 years in patients with sporadic MPNST (p0.001). In Kaplan-Meier analyses, the five year survival from diagnosis was 21% for NF1 patients with MPNST, compared to 42% for sporadic cases of MPNST (p=0.09). One NF1 patient developed two separate MPNST in the radiation field of a previous optic glioma.The lifetime risk of MPNST in NF1 is much higher than previously estimated and warrants careful surveillance and a low threshold for investigation.

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.

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.

Editor—Neurofibromatosis 2 (NF2) is a rare autosomal dominant disease that is characterised by benign nervous system tumours, skin lesions, and ocular abnormalities.1-3 Two studies have found that NF2 patients with a family history of the disease and with maternal inheritance have more severe disease than inherited cases with paternal inheritance. Kanter et al 4noted that patients with maternal inheritance had an earlier age at onset and Evans et al 5 found that patients with maternal inheritance had both an earlier age at onset and an earlier age at death. In both studies, the mean age at onset was 18 years with maternal inheritance and 24 years with paternal inheritance. These results require confirmation for several reasons. First, Parry et al 6 found identical mean ages at onset (22.8 years) in symptomatic NF2 patients with paternal or maternal inheritance. Second, these studies were based on relatively small numbers of patients. Kanter et al 4 studied 38 inherited cases, Evans et al 5 studied 56 inherited cases, and Parry et al 6 studied 36 inherited cases; 66% …

Neurofibromatosis type 2 is an often devastating autosomal dominant disorder which, until relatively recently, was confused with its more common namesake neurofibromatosis type 1. Subjects who inherit a mutated allele of the NF2 gene inevitably develop schwannomas, affecting particularly the superior vestibular branch of the 8th cranial nerve, usually bilaterally. Meningiomas and other benign central nervous system tumours such as ependymomas are other common features. Much of the morbidity from these tumours results from their treatment. It is now possible to identify the NF2 mutation in most families, although about 20% of apparently sporadic cases are actually mosaic for their mutation. As a classical tumour suppressor, inactivation of the NF2 gene product, merlin/schwannomin, leads to the development of both NF2 associated and sporadic tumours. Merlin/schwannomin associates with proteins at the cell cytoskeleton near the plasma membrane and it inhibits cell proliferation, adhesion, and migration. Keywords: NF2; vestibular schwannomma; meningioma; mosaic

In addition to schwannomas, patients with neurofibromatosis type 2 (NF2) frequently develop meningiomas and occasionally, ependymomas. Using DNA and protein analyses, we have shown NF2 gene mutations and lack of the gene product schwannomin in 29 schwannomas, 10 meningiomas, and in 7 ependymomas. We have raised antibodies (ABs) to peptides from the C-terminal (5990-AB) and N-terminal (5991-AB) domains of schwannomin. The ABs specifically detected a 65 kDa protein in a Schwann cell line and recognized schwannomin in the cytoplasm of Schwann cells (SCH), perineurial cells, and vestibular ganglion neurons. None of the 29 schwannomas were stained by the 5990-AB. Only 4 schwannomas were stained by the 5991-AB, indicating that most truncated schwannomins were unstable or not expressed in schwannomas. Seven of 10 meningiomas, including 3 tumors from NF2 patients, were not stained by either 5990-AB or 5991-AB. Only 2 of 7 ependymomas lacked schwannomin. Complete lack of schwannomin in these tumors supports a tumor suppressor function for schwannomin in some meningiomas and ependymomas. All tumors showed staining with an antibody to a C-terminal peptide of neurofibromin, confirming that full-length neurofibromin is present in these vestibular schwannomas, meningiomas, and ependymomas. The presence of schwannomin in some meningiomas and in the majority of ependymomas indicates that additional genes are likely to play a role in tumorigenesis of these tumors.

Neurofibromatosis 2 (NF2) is an autosomal dominant disorder that causes nervous system tumors and ocular abnormalities such as early-onset lenticular opacities. We assessed the clinical spectrum of NF2 at the time of presymptomatic DNA diagnosis in at-risk first-degree relatives. We studied five multigeneration NF2 families with short tandem repeat markers near the NF2 gene (NF2); gadolinium-enhanced high-resolution magnetic resonance imaging (GE-MRI); and ocular, dermatologic, and neurologic examinations. Eleven of 31 asymptomatic at-risk first-degree relatives were predicted by segregation analysis to be NF2 mutation carriers. Nine of the 11 NF2 mutation carriers were clinically evaluated. Four mutation carriers, including a 7-year-old, had vestibular schwannomas, early-onset cataracts, or both. However, five mutation carriers did not have clinical abnormalities, including a 38-year-old with normal cranial and spinal GE-MRIs and a normal ocular examination. These results indicate that clinical abnormalities can be present in young, but absent in middle-aged, presymptomatic NF2 mutation carriers. By identifying presymptomatic NF2 mutation carriers, DNA diagnosis of NF2 can improve genetic counseling and clinical management, and possibly reduce psychosocial difficulties in at-risk individuals.NEUROLOGY 1996;47: 1269-1277

Neurofibromatosis 2 (NF2) is a clinically variable autosomal dominant disorder, caused by mutations in the NF2 tumor suppressor gene on chromosome 22q12, that predisposes to nervous system tumors and ocular abnormalities. To assess intrafamilial phenotypic variability, we performed mutation analysis and clinical assessment on two multigeneration NF2 families with five patients and seven asymptomatic first-degree relatives of patients. One family had a point mutation of agCC --> ggCC at position 1447-2 at the exon 13/14 boundary predicted to lead to an altered splice acceptor sequence and exon deletion. The other family had an insertion of 2 base pairs (TC) at position 761 in exon 8, leading to a frameshift. Both mild and severe phenotypes occurred in each family, indicating that phenotypic variability in NF2 can be caused by factors other than NF2 mutations. Genetic counseling of NF2 families should include the possibility that presymptomatic NF2 mutation carriers can develop a different phenotype than previously diagnosed patients.

We identified a missense mutation (T185 right arrow C, Phe62 right arrow Ser) in the neurofibromatosis 2 (NF2) gene in a family with mild and severe NF2 phenotypes.This mutation was previously reported in an unrelated family in which all affected individuals had mild phenotypes. These data demonstrate a lack of correlation between NF2 genotype and NF2 phenotype for this mutation.NEUROLOGY 1996;47: 544-546

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.

Vestibular schwannomas (VSs) are common benign tumors of Schwann cell origin and are frequently found in patients with neurofibromatosis type 2 (NF2). We analyzed 15 sporadic VSs for mutations in the NF2 gene. We detected mutations in three of the tumors, two of which contained loss of heterozygosity (LOH). One of the tumors contained a novel mutation, a 19-bp deletion in exon 4. The two other tumors contained an identical mutation, a complete exon 4 deletion. The exon 4 deletion represents the second most frequently reported mutation of the NF2 gene in VSs.

Bilateral acoustic neuromas are pathognomonic for neurofibromatosis 2. Patients with neurofibromatosis 2 present complex and challenging management problems, because growth or surgical removal of the acoustic neuroma may result in total hearing loss. Early diagnosis with gadolinium-enhanced magnetic resonance imaging and refinements in hearing preservation surgery have improved our ability to prevent total hearing loss. For patients with larger tumors or no useful hearing, the auditory brain-stem implant allows restoration of some auditory function when the tumor is removed. We describe our management strategy for patients with bilateral acoustic neuromas, and present case reports to show their diversity. We also discuss the newly identified neurofibromatosis 2 tumor suppressor gene. (Arch Otolaryngol Head Neck Surg. 1994;120:1307-1314)

Editor—Neurofibromatosis 2 (NF2) is an autosomal dominant disorder that is characterised by benign nervous system tumours (such as vestibular schwannomas (VSs), intracranial meningiomas, and spinal tumours) and other abnormalities.1Somatic mosaicism (the presence of a mutation, deletion, or chromosomal abnormality in a subpopulation of somatic cells) is thought to be relatively common in NF2, affecting perhaps 15% of sporadic cases.2 3 There can be considerable clinical variability in mosaics because somatic mutation can occur at different stages of the postzygotic cell lineage. Evans et al 2 reported the degree of mosaicism for five NF2 patients. Two patients with an estimated

We used a novel RNase cleavage assay (NIRCA) to screen for neurofibromatosis 2 (NF2) mutations in NF2 schwannomas. Mutations were found in tumors in 16 of 20 patients. Eleven patients (55%) had loss of heterozygosity or loss of one allele, indicating that the mutation was a germ-line mutation. The phenotypes of these patients were consistent with previous NF2 genotype-phenotype correlation studies: patients with nonsense mutations had severe phenotypes, whereas those with splice-site or missense mutations had milder and variable phenotypes. These results confirm the utility of NIRCA as a rapid and convenient method for screening for germ-line NF2 mutations.

Kaolin is one of several clays commercially exploited for its content of the nonfibrous, hydrated aluminum silicate kaolinite (Al2O3.2SiO2.2H2O). Industrial uses include the manufacture of adhesives, paper products, refractory materials, ceramics, and fillers for plastics, rubber, and paints. Inhalation of kaolin dust has been well documented to cause pneumoconiosis (Oldham, 1983; Kennedy, 1983; Sepulveda, 1983). Human (Hale,1956) and animal (Policard, 1954) studies provide evidence that kaolin itself is responsible for the lung disease rather than free silica present in the dust.

The catalytic activity of kaolin, an aluminum silicate, for generating hydroxyl radicals (.OH) from hydrogen peroxide (H2O2) was studied in a chemical system that measured .OH as evolution of methane (CH4) from dimethyl sulfoxide. In the presence of a reducing agent and 10 mM H2O2, hydrous and calcined kaolin generated mean +/- SE CH4 concentrations of 1634 +/- 328 and 1395 +/- 29 ppm, respectively. Surface modification with dipalmitoyl lecithin, the lipid of pulmonary surfactant, blocked generation of .OH in hydrous kaolin (38 +/- 38 ppm CH4) but not in calcined kaolin (875 +/- 262 ppm CH4). The catalytic activity of kaolin for producing .OH from H2O2 may be important in the pathogenesis of kaolin toxicity, and calcined kaolin may be more toxic than hydrous kaolin because the calcined form is resistant to surface modification by lipids of pulmonary surfactant.