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Original Investigation
September 2017

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

Author Affiliations
  • 1Department of Neurosurgery, Manchester Centre for Clinical Neuroscience, Salford Royal National Health Service Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Manchester, England
  • 2Children's Brain Tumour Research Network, Royal Manchester Children's Hospital, Centre for Paediatric, Teenage, and Young Adult Cancer, University of Manchester, Manchester, England
  • 3Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, England
  • 4Manchester Centre for Genomic Medicine, St Mary’s Hospital, Central Manchester University Hospitals National Health Service Foundation Trust and Manchester Academic Health Science Centre, Manchester, England
  • 6Division of Molecular and Clinical Cancer Sciences, School of Medical Science, Faculty of Biology, Medicine, and Health, Manchester Academic Health Science Centre, Manchester, England
  • 7Institut für Klinische Chemie und Laboratoriumsdiagnostik, Universitätsklinikum Jena, Jena, Germany
  • 8Adult Genetics Unit, South Australia Pathology at the Women’s and Children’s Hospital, and University Department of Paediatrics, University of Adelaide, Adelaide, Australia
JAMA Neurol. 2017;74(9):1123-1129. doi:10.1001/jamaneurol.2017.1406
Key Points

Question  What proportion of apparently solitary schwannomas or meningiomas presenting in children and young people is caused by a heritable predisposing mutation?

Findings  In this study involving 2 cohorts of 177 patients who presented with isolated meningioma or schwannoma before age 25 years, 16 of 42 patients had a predisposing mutation to meningioma and 27 of 135 patients to schwannoma.

Meaning  Genetic testing for young people with a solitary meningioma or schwannoma may be useful for predicting their likelihood of developing additional tumors.

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 Participants  Using 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 Measures  The 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 patients presenting with a solitary meningioma or schwannoma should be referred for genetic testing.

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