Abstract
We report a 39-year-old man who developed neuroblastoma, renal cell cancer, and multifocal gastrointestinal stromal tumor (GIST) in the stomach over the last 3 decades attributable to SDHA. He had no family history of cancer and no other symptoms or signs of a phakomatosis. Immunohistochemistry (IHC) on his GIST demonstrated succinate dehydrogenase (SDH)-deficiency, with strong c-KIT and DOG-1 expression. Tumor profiling testing to guide tyrosine kinase inhibitor choice revealed no oncogenic KIT/PDGFRA somatic alteration but two loss of function pathogenic variants in SDHA. Germline genetic testing confirmed one of the two SDHA variants was constitutional. The GIST, neuroblastoma, and renal carcinoma each had second SDHA alterations, providing a unifying genetic diagnosis for patient and his family. Strikingly, the GIST and neuroblastoma and shared the same second somatic SDHA variant, and were not otherwise clonally related tumors, supporting segmental mosaicism of a second SDHA variant. To our knowledge this is the first report of a cancer syndrome caused by the combination of a germline and second allele mosaic mutation. Our report provides a basis for studies of mosaicism in patients with autosomal dominant germline cancer predisposition who have an unusually severe or unusual cancer spectrum.