Case Report: Rare pheochromocytoma in a patient with Li–Fraumeni syndrome: a 3-event, 4-hit model of pathogenesis

Li–Fraumeni syndrome (LFS) is a rare autosomal dominant hereditary cancer predisposition syndrome caused by germline TP53 pathogenic variants. Despite numerous studies of associated cancers with this syndrome, cases of pheochromocytoma have not been well documented. We present a patient from an LFS family who developed a right adrenal mass with a clinical presentation consistent with a pheochromocytoma. Genetic studies of this tumor identified a germline TP53 pathogenic variant (c.818G>A; p.Arg273His) with somatic loss of the wild-type allele (loss of heterozygosity, LOH). In addition, a likely somatic NF1 pathogenic variant was found with concomitant LOH. There were no reported cases of pheochromocytoma in the family history. In addition, several bile duct adenomas (BDAs) were discovered and biopsied intraoperatively. Sequence analysis of one BDA revealed a likely somatic FGFR2::FKR pathogenic fusion and the identical germline TP53 pathogenic variant. In contrast to the pheochromocytoma, the BDA showed no evidence of a second TP53 alteration that might suggest that TP53 had played a role in its pathogenesis. This case highlights the rare presentation of pheochromocytoma in LFS and provides a molecular hypothesis of how this tumor may have developed.