Schwannomatosis: a genetic and epidemiological study

Evans, D. Gareth; Bowers, Naomi L.; Tobi, Simon; Hartley, Claire; Wallace, Andrew; King, Andrew T.; Lloyd, Simon; Rutherford, Scott A.; Hammerbeck-Ward, Charlotte; Pathmanaban, Omar; Freeman, Simon; Ealing, John; Kellett, Mark; Laitt, Roger; Thomas, Owen; Halliday, Dorothy; Ferner, Robin E; Taylor, Amy; Duff, Chris; Harkness, Elaine F.; Smith, Miriam J.

doi:10.1136/jnnp-2018-318538

Cited by 123 publications

(135 citation statements)

References 23 publications

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“…Similarly, those with multiple non-vestibular schwannomas, without other NF2 features, may well have mosaic NF2. In the current report, three of 13 cases in this category have developed a VS and 10 further cases have not 15 . About 50% of apparent schwannomatosis cases who do not have an LZTR1 or SMARCB1 variant have mosaic NF2 15 .…”

Section: Discussionsupporting

confidence: 45%

“…In one study, amongst 3013 patients treated with radiotherapy before the age of 16, mostly for enlarged tonsils 27 , seventy (2.3%) of the patients developed neural tumours, with seven developing multiple schwannomas or meningiomas. This is far higher than the birth incidence of NF2 and schwannomatosis combined 15 . More recently, three of 33 sporadic adults meeting NF2 criteria in Israel had received cranial radiotherapy in childhood and none had an identifiable NF2 variant on blood analysis 28 .…”

Section: Discussionmentioning

confidence: 76%

“…Nonetheless, the present study represents by far the largest assessment of diagnostic criteria based on close to 3000 patients with molecular analysis. It includes potentially all of the identified NF2 cases in England through the four designated highly specialised commissioned centres 15 and includes referrals for molecular testing of all those with a >1% chance of harbouring an NF2 pathogenic variant in the last 8 years 19 . Although the molecular confirmation of NF2 appears very low, this is most likely to be attributable to mosaicism, as most evaluable cases (90%) with two tumours had an identical NF2 variant detected in each tumour.…”

Section: Discussionmentioning

confidence: 99%

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Identifying the deficiencies of current diagnostic criteria for neurofibromatosis 2 using databases of 2777 individuals with molecular testing

Evans

King

Bowers

et al. 2019

Genetics in Medicine

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We have evaluated deficiencies in existing diagnostic criteria for neurofibromatosis 2 (NF2). Methods: Two large databases of individuals fulfilling NF2 criteria (n=1361) and those tested for NF2 variants with criteria short of diagnosis (n=1416) were interrogated. We assessed the proportions meeting each diagnostic criterion with constitutional or mosaic NF2 variants and the specificity with regard to refuted diagnosis. Results: There was no evidence for usefulness of old criteria 'glioma' or 'neurofibroma'. 'Ependymoma' had 100% specificity and high levels of confirmed NF2 diagnosis (67.7%). Those with bilateral vestibular schwannoma (VS) alone aged ≥60 years had the lowest confirmation rate (6.6%) and reduced specificity (80%). Siblings as a firstdegree-relative, without an affected parent, had 0% specificity. All three individuals with a unilateral VS and an affected sibling were proven not to have NF2. The biggest overlap was with LZTR1-associated schwannomatosis. In this category, seven individuals with a unilateral VS plus ≥2 non-dermal schwannomas reduced specificity to 67%. Conclusion: The present study has confirmed important deficiencies in NF2 diagnostic criteria. The term 'glioma' should be dropped and replaced by 'ependymoma'. Similarly 'neurofibroma' should be removed. Dropping 'sibling' from first-degreerelatives should be considered and testing of LZTR1 should be recommended for unilateral VS.

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Section: Discussionsupporting

confidence: 45%

Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

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Identifying the deficiencies of current diagnostic criteria for neurofibromatosis 2 using databases of 2777 individuals with molecular testing

Evans

King

Bowers

et al. 2019

Genetics in Medicine

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“…This protein binds to the N-terminal domain of CUL3 via the BTB-BACK domain and to substrates via the KELCH domain (15). Mutations in LZTR1 are also identified in Noonan syndrome (18)(19)(20) and schwannomatosis (21)(22)(23)(24). Noonan syndrome is the most common RASopathy caused by mutations in genes involved in the RAS/MAPK signaling pathway, whereas schwannomatosis is a rare neurofibromatosis.…”

Section: Introductionmentioning

confidence: 99%

LZTR1 inactivation promotes MAPK/ ERK pathway activation in glioblastoma by stabilizing oncoprotein RIT1

Wang

Zhang

et al. 2020

Preprint

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Large-scale sequencing studies on glioblastoma have identified numerous genetic alterations.Leucine-zipper-like transcription regulator 1 (LZTR1) is inactivated by non-synonymous mutations and copy number losses, suggesting that it is a tumor suppressor in glioblastoma.However, how LZTR1 mutations contribute to glioblastoma pathogenesis remains poorly understood. Here, we revealed that LZTR1, as an adaptor of the CUL3 E3 ubiquitin ligase complex, recognizes and triggers ubiquitin-dependent degradation of oncoprotein RIT1, a RAS-like GTPase. Wild-type LZTR1 suppresses glioblastoma cell proliferation and migration by inactivating the MAPK/ERK signaling pathway in a RIT1-dependent manner. However, the effects were abrogated by the glioblastoma-associated LZTR1 mutations. Our findings revealed the underlying molecular mechanism of LZTR1 mutations-driven glioblastoma, and provide novel therapeutic target for LZTR1 mutations-driven glioblastoma.

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“…NF1 has a birth incidence of 1 in 2,699 to 1 in 3,000 and a prevalence of 1 in 4,560 (Evans et al, ). For NF2, the birth incidence is 1 in 27,956 and prevalence is 1 in 50,000, and schwannomatosis has a birth incidence of 1 in 68,956 and a prevalence of 1 in 126,000 (Evans et al, ).…”

Section: Introductionmentioning

confidence: 99%

From process to progress—2017 International Conference on Neurofibromatosis 1, Neurofibromatosis 2 and Schwannomatosis

Ferner

Elgersma

Evans

et al. 2019

American J of Med Genetics Pt A

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The neurofibromatoses are inherited, tumor suppressor disorders that are characterized by multiple, benign peripheral nerve sheath tumors and other nervous system tumors. Each disease is associated with a distinct genetic mutation and with a different pathogenesis and clinical course. Neurofibromatosis 1 (NF1) is common and epitomized by multiple neurofibromas with widespread complications. NF2 and schwannomatosis are rare diseases that are typified by multiple schwannomas that are particularly painful in people with schwannomatosis. Since 1985, the Children's Tumor Foundation (formerly the National Neurofibromatosis Foundation) has hosted an international Neurofibromatosis Conference, bringing together international participants who are focused on NF research and clinical care. The 2017 Conference, held in Washington, DC, was among the largest gatherings of NF researchers to date and included presentations from clinicians and basic scientists, highlighting new data regarding the molecular and cellular mechanisms underlying each of these diseases as well as results from clinical studies and clinical trials. This article summarizes the findings presented at the meeting and represents the current state-of-the art for NF research. the neurofibromatoses-neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis. The neurofibromatoses are inherited tumor predisposition diseases linked to mutations in distinct genes.NF1 has a birth incidence of 1 in 2,699 to 1 in 3,000 and a prevalence of 1 in 4,560 (Evans et al., 2010). For NF2, the birth incidence is 1 in 27,956 and prevalence is 1 in 50,000, and schwannomatosis has a birth incidence of 1 in 68,956 and a prevalence of 1 in 126,000 (Evans et al., 2018).In the early 1990s, the focus of neurofibromatosis research was on identifying the molecular pathways underpinning the pathophysiology of these disorders. However, recent advances in molecular biology, the development of animal models, and novel imaging techniques have been matched by an increased understanding of the clinical manifestations and natural history of these conditions. The advent of targeted disease therapy has highlighted the interdependence of the scientist and clinician and the importance of animal models in screening potential new treatments.

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Schwannomatosis: a genetic and epidemiological study

Abstract: Within the highly ascertained North-West England population, schwannomatosis has less than half the birth incidence and prevalence of NF2.

Cited by 123 publications

References 23 publications

Identifying the deficiencies of current diagnostic criteria for neurofibromatosis 2 using databases of 2777 individuals with molecular testing

Identifying the deficiencies of current diagnostic criteria for neurofibromatosis 2 using databases of 2777 individuals with molecular testing

LZTR1 inactivation promotes MAPK/ ERK pathway activation in glioblastoma by stabilizing oncoprotein RIT1

From process to progress—2017 International Conference on Neurofibromatosis 1, Neurofibromatosis 2 and Schwannomatosis

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