SAT-509 - Characterizing Paraganglioma/Pheochromocytoma in Less Common Genes: A Single Institution Experience of Caring for Patients with SDHA, SDHC, SDHAF2, TMEM127, FH and MAX

Background: Paraganglioma/pheochromocytoma (PPGL) can be caused by pathogenic variants (PVs) in multiple genes, including less common genes such as SDHA, SDHC, SDHAF2, TMEM127, FH, and MAX. Little is known about the presentation and management of PPGL in these genes. Here, we aim to characterize a single institution’s cohort of rare gene-related PPGLs.

Methods: Patients seen in the cancer genetics clinic with a PV in one of the following genes: SDHA, SDHC, SDHAF2, TMEM127, FH, and MAX were queried. The inclusion period for query was between September 1, 2016 and August 31st, 2025. Additional PPGL cases seen in endocrinology with rare gene PVs were also included. Demographic, tumor, and genetic factors were abstracted.

Results: A total of 211 PVs were identified in 210 individuals; one person carried PVs in both SDHA and FH. Most PVs occurred in FH (n=116, 55.0%), followed by SDHA (n=73, 34.6%). Nine individuals in this cohort (4.2%) had a diagnosis of PPGL: five with SDHA PV, and two each with SDHC and SDHAF2 PVs. An additional three PPGL cases were identified through the endocrinology database (two with MAX PVs and one with a TMEM127 PV), yielding 12 PPGL cases with rare germline PVs. All carried unique PVs and were considered unrelated.
Among the 12 individuals with PPGL, tumor onset ranged from 20 to 63 years. In two cases, a tumor was detected during surveillance initiated after cascade testing based on a PV identified in a relative. Five individuals (41.7%) had head and neck paragangliomas—mostly carotid body tumors (2 SDHC, 1 SDHA, 2 SDHAF2). Five pheochromocytomas were diagnosed (2 SDHA, 2 MAX, 1 TMEM127), including two bilateral tumors (both MAX PVs). Three individuals reported a family history of PPGL, while most had no affected relatives.
All tumors were treated surgically except for one glomus vagale, which was managed with stereotactic radiation. No cases required additional treatment. At least half of the individuals (n=6) continued recommended hereditary PPGL surveillance; available records do not clarify the surveillance status of the remainder.

Conclusion: Identifying germline PVs in rare hereditary PPGL genes has become increasingly common with broad multigene panel testing. In our cohort, the occurrence of PPGL varied substantially across the less common genes, and no FH-related PPGLs were observed (0/116). Overall, our findings align with reported associations for SDHAF2, MAX, and TMEM127, but further study is needed to clarify PPGL penetrance in other rare genes such as FH and SDHA. Improved characterization of gene-specific risks will help refine surveillance strategies and optimize clinical management for affected individuals.

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