OR08-05 Case Series Of French Canadian Patients With Paragangliomas Carrying The c.397C>T SDHC Mutation: Insights On SDHC Phenotype And Outcomes

Abstract

Abstract Disclosure: S. Parisien-La Salle: None. D. Nadine: None. Z. El-Haffaf: None. A. Lacroix: None. A. Gimenez-Roqueplo: None. I. Bourdeau: None. Introduction: Germline SDHC pathogenic variants in pheochromocytomas and paragangliomas (PGLs) (PPGLs) are rare with a prevalence of 1-2% (1). The associated phenotype of patients with SDHC mutated PPGLs remains unclear. Objective: Describe the phenotype and outcomes of our cohort of patients with PGL carrying the recurrent SDHC c.397C>T (p.Arg133Ter) mutation due to a likely French Canadian founder effect (2). Methods: We retrospectively reviewed the charts of patients with SDHC related PPGLs from 2005-2022 to analyse their phenotype and outcomes. Results: In our genotyped PPGL cohort, 35% (84/240) of patients had an identified germline pathogenic/likely pathogenic variant in a known PPGL susceptibility gene. Of these, 27.4% (23/84) had a mutation in the SDHC gene. The SDHC c.397C>T mutation was identified in 87% (20/23) of SDHC patients, all being French Canadians. In the SDHC c.397C>T group, mean age at diagnosis was 46.3 years old. Sixty-five percent (13/20) presented with head and neck PGLs (HNPGL) and 35% (7/20) with thoraco-abdominal PGLs (TAPGLs), with 2 being intracardiac and one retrocardiac PGLs. There were no pheochromocytomas. Fifteen percent (3/20) had metastatic disease and 20% (4/20) had multiple tumors. One patient also presented with a GIST. TAPGLs were functional in 85.7% (6/7) of cases (mostly norepinephine/normetanephrine) and HNPGLs were biochemically active in 38.5% (5/13) of cases (mostly dopamine). In these 20 SDHC c.397C>T mutated patients with PGLs, 12 underwent curative surgery and were considered in remission. The PGL recurrence rate was of 25% (3/12) during a mean follow-up time of 11.4 years. The other 3 patients were not of French Canadian origin and had pathogenic variants that had previously been described: SDHC c.487T>C (p.Ser163Pro), SDHC c.380 A>G (p.His127Arg) and SDHC c.1A>G (p.Met1Val). Conclusion: The SDHC c.397C>T mutation is very prevalent in patients with PGLs who are of French Canadian descent due to a likely founder effect. Compared to other SDHC cohorts, SDHC c.397C>T PGLs showed a lower rate of metastasis and associated tumors, but a higher rate of multiple PGLs. Although this may indicate a possibly less aggressive phenotype, the recurrence rate was high at 25%, thus requiring close monitoring and lifelong follow-up. Bibliography: 1. Toledo RA, Burnichon N, Cascon A, Benn DE, Bayley JP, Welander J, et al. Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas. Nat Rev Endocrinol. 2017;13(4):233-47.2. Bourdeau I, Grunenwald S, Burnichon N, Khalifa E, Dumas N, Binet MC, et al. A SDHC Founder Mutation Causes Paragangliomas (PGLs) in the French Canadians: New Insights on the SDHC-Related PGL. J Clin Endocrinol Metab. 2016;101(12):4710-8. Presentation: Friday, June 16, 2023