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

The germline nonsense SDHC c.397C>T (p.Arg133Ter) variant, a founder variant likely originating from France, is accompanied by loss of SDHB protein expression on tumour immunohistochemistry.

The germline pathogenic SDHC c.397C>T (p.Arg133Ter) variant is found in more than 40% of mutation-positive paragangliomas in French-Canadian patients, supporting a founder effect. This international case series gathered 45 adults carrying this variant and managed between 2010 and 2024 at four university hospitals, two in Québec, one in the northeastern United States and one in France; 46.7% were women and the mean age at diagnosis was 49.7 years. Forty-four patients (97.8%) had a paraganglioma and one (2.2%) a pheochromocytoma, the most frequent sites being head and neck (26/44, 59.1%), then thoracic including mediastinal (12/44, 27.3%, half of them in or near cardiac structures), and lastly abdominal (6/44, 13.6%). Multiple tumours were present in 15.6% of patients (7/45) and metastatic disease in 11.1% (5/45), while four patients (15.4%) recurred after surgical resection over a mean follow-up of 7.9 years; loss of SDHB protein expression was confirmed in all available samples.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

What changes practice is the share of thoracic and mediastinal sites, more than a quarter of paragangliomas and often adjacent to the heart: a surveillance protocol limited to the neck and abdomen misses a substantial proportion of tumours in these carriers. Conversely, the 11.1% metastatic and 15.4% recurrence rates come from a series of patients ascertained through their tumours at referral centres, and cannot be used as the risk to quote to an asymptomatic relative identified by cascade testing. The founder effect, however, is directly actionable: in a family of Québec origin, targeted testing for this variant can precede full panel analysis.

Analysis by Dr Thibaut Benquey