Molecular Analysis of the NF2 Tumor-Suppressor Gene in Schwannomatosis

Jacoby, Lee B.; Jones, Deborah; Davis, Kevin; Kronn, David; Short, M. Priscilla; Gusella, James F.; MacCollin, Mia

doi:10.1086/301633

Cited by 166 publications

(133 citation statements)

References 29 publications

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“…The other 5 patients were excluded although they fulfilled the research criteria 17 for schwannomatosis for the following reasons: blood samples of 2 patients under 30 years of age were not available, and 3 patients under 45 years of age had not undergone cranial MR imaging. Of the 65 patients with schwannomatosis, 51 had highquality cranial MR images.…”

Section: Results Patient Groupsmentioning

confidence: 99%

“…Detecting the mutations of the NF2 gene in a single tumor cannot help to differentiate schwannomatosis from NF2, because mutations of the NF2 gene are also common in tumors of patients with schwannomatosis. 17,34 Mutations of the NF2 gene in schwannomatosis are believed to be caused by a "four-hit mechanism;" 14,34 types of mutations in different tumors should be random. Plotkin et al 30 suggested detecting NF2 mutations in 2 or more separate tumors of patients with schwannomatosis.…”

Section: Discussionmentioning

confidence: 99%

“…In 1997, the first research criteria for schwannomatosis were proposed. 17 Patients with 2 or more pathologically confirmed schwannomas and who lacked radiographic evidence of vestibular schwannoma on an imaging study performed after the age of 18 years were now diagnosed with schwannomatosis. It was not until 2003 that the NF2 locus was excluded as the cause of familial schwannomatosis.…”

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Clinical features of spinal schwannomas in 65 patients with schwannomatosis compared with 831 with solitary schwannomas and 102 with neurofibromatosis Type 2: a retrospective study at a single institution

Zhao

Zhang

et al. 2016

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OBJECT The aim of this study was to evaluate the clinical features of spinal schwannomas in patients with schwannomatosis and compare them with a large cohort of patients with solitary schwannomas and neurofibromatosis Type 2 (NF2). METHODS The study was a retrospective review of 831 patients with solitary schwannomas, 65 with schwannomatosis, and 102 with NF2. The clinical, radiographic, and pathological data were extracted with specific attention to the age at onset, location of tumors, initial symptoms, family history, and treatment outcome. RESULTS The male-to-female ratio of patients with schwannomatosis (72.3% vs 27.7%) was significantly higher than that of patients with solitary schwannomas (53.3% vs 46.7%) and NF2 (54.0% vs 46.0%), respectively (chi-square test, p = 0.012). The mean age at the first spinal schwannoma operation of patients with NF2 (24.7 ± 10.2 years) was significantly younger than that of patients with solitary schwannomas (44.8 ± 13.2 years) and schwannomatosis (44.4 ± 14.1 years; 1-way ANOVA, p < 0.001). The initial symptoms were similar among the 3 groups, with pain being the most common. The distribution of spinal tumors among the 3 groups was significantly different. The peak locations of spinal schwannomas in patients with solitary schwannomas were at C1–3 and T12–L3; in schwannomatosis, the peak location was at T12-L5. A preferred spinal location was not evident for intradural-extramedullary tumors in NF2. Only a slight prominence in the lumbar area could be observed. The patients in the 3 groups obtained similar benefits from the operation; the recovery rates in the patients with solitary schwannomas, NF2, and schwannomatosis were 50.1%, 38.0%, and 53.9%, respectively. The prognosis varied among spinal schwannomas in the patients with schwannomatosis. Up until the last date of follow-up, most patients with schwannomatosis (81.5%) had undergone a single spinal operation, but 12 patients (18.5%) had undergone multiple spinal operations. Patients with nonsegmental schwannomatosis or those with early onset disease seemed to have a poor prognosis; they were more likely to undergo multiple spinal operations. Small cauda equina nodules were common in patients with schwannomatosis (46.7%) and NF2 (86.9%); these small schwannomas appeared to have relatively static behavior. Two patients suspicious for schwannomatosis were diagnosed with NF2 with the detection of constitutional NF2 mutations; 1 had unilateral vestibular schwannoma, and the other had suspicious bilateral trigeminal schwannomas. CONCLUSIONS The clinical features of spinal schwannomas vary among patients with solitary schwannomas, NF2, and schwannomatosis. Spinal schwannomas of patients with NF2 appear to be more aggressive than those in patients with solitary schwannomas and schwannomatosis. Spinal schwannomas of schwannomatosis predominate in the lumbar area, and most of them can be treated successfully with surgery. The prognosis varies among spinal schwannomas of schwannomatosis; some patients may need multiple operations due to newly developed schwannomas. Sometimes, it is difficult to differentiate schwannomatosis from NF2 based on clinical manifestations. It is prudent to perform close follow-up examinations in patients with undetermined schwannomatosis and their offspring.

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Section: Results Patient Groupsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Clinical features of spinal schwannomas in 65 patients with schwannomatosis compared with 831 with solitary schwannomas and 102 with neurofibromatosis Type 2: a retrospective study at a single institution

Zhao

Zhang

et al. 2016

SPI

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“…Therefore, the hallmark of schwannomatosis is different somatic variants in multiple tumors from the same patient. 2 Schwannomatosis is a genetic condition, but for poorly understood reasons its occurrence does not follow common inheritance patterns. The majority of cases are sporadic with 15-25% of cases being inherited from an affected parent.…”

Section: Introductionmentioning

confidence: 99%

Expanding the mutational spectrum of LZTR1 in schwannomatosis

et al. 2014

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Schwannomatosis is characterized by the development of multiple non-vestibular, non-intradermal schwannomas. Constitutional inactivating variants in two genes, SMARCB1 and, very recently, LZTR1, have been reported. We performed exome sequencing of 13 schwannomatosis patients from 11 families without SMARCB1 deleterious variants. We identified four individuals with heterozygous loss-of-function variants in LZTR1. Sequencing of the germline of 60 additional patients identified 18 additional heterozygous variants in LZTR1. We identified LZTR1 variants in 43% and 30% of familial (three of the seven families) and sporadic patients, respectively. In addition, we tested LZTR1 protein immunostaining in 22 tumors from nine unrelated patients with and without LZTR1 deleterious variants. Tumors from individuals with LZTR1 variants lost the protein expression in at least a subset of tumor cells, consistent with a tumor suppressor mechanism. In conclusion, our study demonstrates that molecular analysis of LZTR1 may contribute to the molecular characterization of schwannomatosis patients, in addition to NF2 mutational analysis and the detection of chromosome 22 losses in tumor tissue. It will be especially useful in differentiating schwannomatosis from mosaic Neurofibromatosis type 2 (NF2). However, the role of LZTR1 in the pathogenesis of schwannomatosis needs further elucidation.

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“…In the late 1990s the suggestion was made that schwannomatosis should be classified as a separate condition [21]. The first clinical diagnos tic criteria were formulated in 1997 by Jacoby et al [12]. Contemporary diagnostic clinical criteria for schwannomatosis were established in 2005 during a meeting under the patronage of the National Neu rofibromatosis Foundation [20].…”

Section: Discussionmentioning

confidence: 99%