Accelerated MEN2A in homozygous RET carriers in the context of consanguinity.

This article focuses on the clinical impact of homozygous mutations in the RET proto-oncogene on the development of multiple endocrine neoplasia type 2A (MEN2A), a genetic syndrome characterized by medullary thyroid cancer (MTC), pheochromocytoma, and primary hyperparathyroidism. Through a systematic literature analysis of five RET mutation families with both homozygous and heterozygous carriers, the study found that homozygous individuals from consanguineous families, particularly those with first-degree cousin parents, tend to develop node-positive MTC and pheochromocytoma significantly earlier—by approximately 23 to 27 years—than heterozygous relatives. The age difference was less pronounced in families carrying the founder mutation p.Leu666delinsAsnSer, where homozygotes developed MTC about six years earlier than heterozygotes. These findings, though limited by small sample sizes and varying degrees of consanguinity, suggest a moderate dose–response effect of RET homozygosity accelerating MEN2A onset and progression.