Somatic NF2 mutation in a vestibular schwannoma arising in a patient with neurofibromatosis type 1

Misa Shogaku¹Hiroshi Yamada^1*Seiji Yamada²Ryota Fujinami¹Shigeki Yamada¹Motoki Tanikawa¹Yusuke Okuno¹Mitsuhito Mase¹

• ¹Nagoya Shiritsu Daigaku, Nagoya, Japan
• ²Fujita Ika Daigaku Igakubu Daigakuin Igaku Kenkyuka, Toyoake, Japan

Background: Neurofibromatosis type 1 (NF1) and vestibular schwannoma are genetically and clinically distinct entities, with vestibular schwannomas classically associated with neurofibromatosis type 2. The occurrence of a vestibular schwannoma in a patient with NF1 is rare, and its underlying molecular mechanism remains unclear. Case Presentation: We report a 51-year-old man clinically diagnosed with neurofibromatosis type 1 who developed a unilateral vestibular schwannoma presenting with progressive hearing loss and neurological symptoms. Histopathological examination following surgical resection confirmed the diagnosis of vestibular schwannoma, and genetic analyses were subsequently performed on the schwannoma, a cutaneous neurofibroma, and peripheral blood from the same patient. Genetic Findings: Whole-exome sequencing revealed a pathogenic germline NF1 mutation shared across all analyzed samples. In contrast, the vestibular schwannoma harbored a somatic NF2 mutation accompanied by loss of chromosome 22, while these alterations were absent in the neurofibroma and blood samples. Conclusion: This case demonstrates that a vestibular schwannoma arising in a patient with neurofibromatosis type 1 can be driven by secondary somatic NF2 alterations accompanied by loss of chromosome 22. Comprehensive multi-tissue genetic analysis enabled direct distinction between germline and tumor-specific events, highlighting the critical role of tumor-specific somatic alterations beyond the germline background.