Objective:
Schwannomas are benign nerve sheath tumors that can arise from cranial, spinal, or peripheral nerves. In 2022 the nomenclature for tumor predisposition syndromes leading to schwannoma formation was revised to identify syndromes based on the underlying pathogenic genetic variant (PV) rather than clinical features. The three most commonly implicated PVs are NF2, SMARCB1, and LZTR1 [1]. We report the case of a 46-year-old man referred to our clinic following thoracic spine surgery for two pathologically confirmed WHO Grade 1 schwannomas. Genetic counseling and testing revealed a germline POT1 mutation (c.360_363delCAAG). POT1 is a well-established tumor suppressor gene implicated in melanoma and sarcoma predisposition but has not previously been associated with schwannomatosis. Both Ambry Genetics and Invitae/LabCorp databases contained only one prior report of this specific variant. Next-generation sequencing of both tumor tissue specimens revealed pathogenic frameshift mutations in both POT1 and NF2, consistent with the “four-hit mechanism” proposed by Sestini et al. To our knowledge, this is the first published report describing germline POT1-associated schwannomatosis. This case broadens the genetic landscape of schwannoma predisposition syndromes and highlights the importance of comprehensive germline and somatic testing in patients with multiple schwannomas.
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