SDHC c.397C>T-related pheochromocytomas and paragangliomas: insights from an international study

The SDHC c.397C>T (p.Arg133Ter) germline pathogenic variant is present in over 40% of mutation-positive paragangliomas in French-Canadian patients, supporting a founder effect. We aimed to characterize pheochromocytomas and paragangliomas (PPGLs) associated with this variant in a large international cohort of European descent. We conducted an international case series of adults with PPGLs carrying the SDHC c.397C>T germline pathogenic variant, treated between 2010 and 2024 at four university hospitals: two in the province of Québec (Canada), one in the Northeastern United States, and one in France. Among the 45 patients confirmed with PPGLs harboring the SDHC c.397C>T pathogenic variant, 46.7% were women, and the mean age at diagnosis was 49.7 years. Forty-four patients (97.8%) had paragangliomas, and one (2.2%) had a pheochromocytoma. The most common paraganglioma sites were the head and neck (26/44, 59.1%), followed by the thoracic (including mediastinal) region (12/44, 27.3%; half located in or near cardiac structures), and finally the abdominal region (6/44, 13.6%). Multiple tumors were present in 15.6% (7/45) of cases, and metastatic disease was identified in 11.1% (5/45). Following surgical resection, four patients (15.4%) experienced recurrence during a mean follow-up of 7.9 years. Loss of SDHB protein expression was confirmed in all available immunohistochemistry samples. The SDHC c.397C>T founder pathogenic variant, likely originating from France, is common in the province of Québec, with probable migration to New England (USA), and appears enriched for thoracic (including mediastinal) paragangliomas. Although based on a limited series, affected patients remain at risk of recurrence and metastasis and should be followed up closely.