Association of Genetic Predisposition With Solitary Schwannoma or Meningioma in Children and Young Adults

Abstract

IMPORTANCE Meningiomas and schwannomas are usually sporadic, isolated tumors occurring in adults older than 60 years and are rare in children and young adults. Multiple schwannomas and/or meningiomas are more frequently associated with a tumor suppressor syndrome and, accordingly, trigger genetic testing, whereas solitary tumors do not. Nevertheless, apparently sporadic tumors in young patients may herald a genetic syndrome.OBJECTIVE To determine the frequency of the known heritable meningioma-or schwannoma-predisposing mutations in children and young adults presenting with a solitary meningioma or schwannoma. DESIGN, SETTING, AND PARTICIPANTSUsing the database of the Manchester Centre for Genomic Medicine, this cohort study analyzed lymphocyte DNA from young individuals prospectively referred to the clinic for genetic testing between January 1, 1990, and December 31, 2016, on presentation with a single meningioma (n = 42) or schwannoma (n = 135) before age 25 years. Sequencing data were also examined from an additional 39 patients with neurofibromatosis type 2 who were retrospectively identified as having a solitary tumor before age 25 years. Patients with schwannoma were screened for NF2, SMARCB1, and LZTR1 gene mutations, while patients with meningioma were screened for NF2, SMARCB1, SMARCE1, and SUFU. MAIN OUTCOMES AND MEASURESThe type of underlying genetic mutation, or lack of a predisposing mutation, was associated with the presenting tumor type and subsequent development of additional tumors or other features of known schwannoma-and meningioma-predisposing syndromes.RESULTS In 2 cohorts of patients who presented with an isolated meningioma (n = 42; median [range] age, 11 [1-24] years; 22 female) or schwannoma (n = 135; median [range] age, 18 [0.2-24] years; 60 female) before age 25 years, 16 of 42 patients (38%) had a predisposing mutation to meningioma and 27 of 135 patients (20%) to schwannoma, respectively. In the solitary meningioma cohort, 34 of 63 patients (54%) had a constitutional mutation in a known meningioma predisposition gene. Twenty-five of 63 patients (40%) had a constitutional NF2 mutation, and 9 (14%) had a constitutional SMARCE1 mutation. In the cohort of those who developed a solitary schwannoma before age 25 years, 44 of 153 patients (29%) had an identifiable genetic predisposition. Twenty-four patients (55%) with a spinal schwannoma had a constitutional mutation, while only 20 (18%) with a cranial schwannoma had a constitutional predisposition (P < .001). Of 109 cranial schwannomas, 106 (97.2%) were vestibular. Four of 106 people (3.8%) with a cranial schwannoma had an LZTR1 mutation (3 were vestibular schwannomas and 1 was a nonvestibular schwannoma), and 9 (8.5%) had an NF2 mutation.CONCLUSIONS AND RELEVANCE A significant proportion of young people with an apparently sporadic solitary meningioma or schwannoma had a causative predisposition mutation. This finding has important clinical implications because of the risk of additional tumors and the possibility of familial disease. Young...

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

“…In addition to ruling out NF2 as a cause of familial unilateral VS, we have also excluded germline‐definite pathogenic variants in LZTR1 and SMARCB1. LZTR1 is a plausible gene to cause familial unilateral VS, as we found germline pathogenic variants in 3/106 (2.7%) patients with young‐onset isolated sporadic VS . There has also been a further case report of a unilateral sporadic VS due to an LZTR1 variant .…”

“…In addition to ruling out NF2 as a cause of familial unilateral VS, we have also excluded germline-definite pathogenic variants in LZTR1 and SMARCB1. LZTR1 is a plausible gene to cause familial unilateral VS, as we found germline pathogenic variants in 3/106 (2.7%) patients with young-onset isolated sporadic VS. 5 There has also been a further case report of a unilateral sporadic VS due to an LZTR1 variant. 12 It can also be confused with NF2, as patients with a germline pathogenic LZTR1 mutation usually develop multiple other non-intradermal schwannomas in addition to a unilateral VS. 4 As such, the likelihood of an LZTR1 variant causing just unilateral VS and no other schwannomas in more than one family member appears unlikely.…”

“…VSs are usually solitary tumors; however about 4% to 6% are associated with neurofibromatosis type 2 (NF2), an autosomal‐dominant monogenic condition caused by pathogenic variants in the NF2 gene on chromosome 22q . Rarely, schwannomatosis caused by pathogenic variants in the LZTR1 gene can cause isolated VS, or VS that can be misdiagnosed as NF2. A previous report in this journal over 20 years ago suggested that familial occurrence of unilateral VS occurred more frequently than by chance, and this might be due to germline variants in the NF2 gene .…”

“…The natural question occurs as to whether this familial occurrence could be caused by hypomorphic (less disease causing) variants in the NF2 gene. Although NF2 usually presents with bilateral VS at initial presentation, it may frequently present with a unilateral VS either with other NF2 features or as an isolated tumor . Furthermore, LZTR1 pathogenic variants can also present with apparently isolated VS at young ages .…”

“…Although NF2 usually presents with bilateral VS at initial presentation, it may frequently present with a unilateral VS either with other NF2 features or as an isolated tumor. 3,5,[7][8][9] Furthermore, LZTR1 pathogenic variants can also present with apparently isolated VS at young ages. 5 We therefore reviewed our laboratory testing of patients referred with an apparently isolated VS with a close relative diagnosed with the same problem.…”