Clinical features and outcomes of MEN2A with RET codon 634 pathogenic variants

RET

Germline pathogenic RET codon 634 variants: p.C634R compared with other p.C634X

Germline pathogenic RET codon 634 variants carry a high risk of early-onset medullary thyroid carcinoma, and the p.C634R variant has been suspected of conferring a more aggressive phenotype. This single-centre retrospective cohort from the MTCCoRe registry compares 60 p.C634R carriers with 75 carriers of other p.C634X variants, seen at least once between May 2012 and May 2024. The p.C634R variant is associated with higher penetrance of pheochromocytoma (67% vs 37%, p < 0.001) and primary hyperparathyroidism (30% vs 15%, p = 0.036). Medullary thyroid carcinoma prevalence (87% vs 80%), median age at initial thyroidectomy (18 vs 20 years), tumour characteristics and disease-free, overall and distant metastasis-free survival do not differ significantly between groups.

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

For the thyroid, the study does not justify managing p.C634R differently from other codon 634 variants. The excess of pheochromocytoma and hyperparathyroidism in p.C634R carriers does, however, argue for particularly rigorous adrenal and parathyroid surveillance, to be confirmed in a multicentre series since all 135 patients come from a single centre.

Analysis by Dr Thibaut Benquey