Familial unilateral vestibular schwannoma is rarely caused by inherited variants in the NF2 gene

Abstract

Objectives/Hypothesis Unilateral vestibular schwannoma (VS) occurs with a lifetime risk of around 1 in 1,000 and is due to inactivation of the NF2 gene, either somatically or from a constitutional mutation. It has been postulated that familial occurrence of unilateral VS occurs more frequently than by chance, but no causal mechanism has been confirmed. Study Design Retrospective database analysis. Methods The likelihood of chance occurrence of unilateral VS, or occurring in the context of neurofibromatosis type 2 (NF2), was assessed using national UK audit data and data from the national NF2 database. Families with familial unilateral VS (occurrence in first‐ and second‐degree relatives) were assessed for constitutional NF2 and LZTR1 genetic variants, and where possible the tumor was also analyzed. Results Approximately 1,000 cases of unilateral VS occurred annually in the United Kingdom between 2013 and 2016. Of these, 2.5 may be expected to have a first‐degree relative who had previously developed a unilateral VS. The likelihood of this occurring in NF2 was considered to be as low as 0.05 annually. None of 28 families with familial unilateral VS had a constitutional NF2 intragenic variant, and in nine cases where the VS was analyzed, both mutational events in NF2 were identified and excluded from the germline. Only three variants of uncertain significance were found in LZTR1 . Conclusions Familial occurrence of unilateral VS is very unlikely to be due to a constitutional NF2 or definitely pathogenic LZTR1 variant. The occurrence of unilateral VS in two or more first‐degree relatives is likely due to chance. This phenomenon may well increase in clinical practice with increasing use of cranial magnetic resonance imaging in older patients. Level of Evidence 2b Laryngoscope , 129:967–973, 2019

Global Incidence of Sporadic Vestibular Schwannoma: A Systematic Review

“…Few population-based studies have reported the prevalence of sporadic VS in recent years. 3,7,16 To estimate the lifetime prevalence of sporadic VS in a clinical setting-that is, during routine clinical practice with modern neuroimaging capabilities, not through review of temporal bones at autopsy-the chance that a person sporadically develops a VS exceeds 1 in 500. 3 As the resolution of MRI continues to improve, the clinical prevalence will likely gradually approach historical temporal bone studies that have cited lifetime prevalence as high as 1 in 100 persons.…”

Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis

“…The role of mutation screening for NF2 in all patients with a unilateral vestibular schwannoma is less certain. Although these patients show an increased risk for the development of NF2, routine screening for germline mutations is not recommended except in patients younger than 30 years [ 65 , 66 ], but can undergo prenatal diagnosis and pre-implantation genetic diagnosis.…”

Pathogenic noncoding variants in the neurofibromatosis and schwannomatosis predisposition genes

“…An example of this is the variant in the splice donor site of intron 8, NC_000022.11 (NM_006767.3):c.791+1G>A, was recently detected in peripheral lymphocytes and tumor tissue of a patient presenting solely with unilateral vestibular schwannoma at age 14 (Gripp et al, 2017). A similar, more recent study in patients with unilateral vestibular schwannoma reported two VUS in LZTR1 , NM_006767.3:c.1230C>T and NM_006767.3:c.1687G>C, with the potential of affecting splicing, as predicted by in silico tools (Evans et al, 2019).…”