MG-100 Review of a large family with schwannomatosis identifies an expanded phenotype

Abstract

Background Schwannomatosis and atypical teratoid rhabdoid tumour syndrome (ATRT) are autosomal dominant disorders associated with mutations in the SMARCB1 gene on chromosome 22q, but with different age at onset and tumour predisposition. Missense mutations in the first and last exons of SMARCB1 typically cause multiple, benign schwannomas of the peripheral and spinal nerves (average age 28.3y), whereas, large deletion and frameshift mutations in exons 2–8 typically cause malignant rhabdoid tumours (before age 3y). Recently, families with both types of tumours have been described including a Newfoundland and Labrador (NL) family identified through a proband with ‘glioma’ and her brother with multiple spinal cord schwannomas. Objectives We were interested in determining the age-at-onset, type and number of tumours for NL family members in order to develop a clinical screening program. Design/method We obtained family history, and reviewed clinical records and genetic test results for 18 consenting members of this family with ‘schwannomatosis’ and a SMARCB1 missense mutation in exon 9. Results Seven family members had from 1–26 peripheral schwannomas, four had multiple spinal schwannomas, one had an ocular schwannoma, the proband (who died at 52y) had a high grade glioma with rhabdoid features, a five year old had an ATRT, and two obligate carriers in their 70s had no identified tumours. Conclusions The spectrum of tumours and age at onset was broader than expected. We recommend a complete clinical examination and, for adults, full-body MRI at diagnosis, annual clinical review, and repeat imaging to review any new pain, ‘lumps’ or dysfunction.