Accelerated MEN 2A in Homozygous RET Carriers in the Context of Consanguinity.

BACKGROUND: Homozygous mutations, two identical gene versions (alleles), one from each biological parent, are exceptional. Clinical descriptions of affected families, comprising few carriers only, are scattered throughout the literature, hindering evidence generation.

METHODS: Included in this literature analysis were 5 RET families with ≥1 homozygous carrier and ≥3 heterozygous carriers per family.

RESULTS: In consanguineous families with first-degree cousins, homozygotes presented with node-positive medullary thyroid cancer and pheochromocytoma in their mid-teens, whereas heterozygotes presented in their end-thirties and early forties. Homozygotes developed node-positive medullary thyroid cancer 27.4 years, and pheochromocytoma 23 years earlier than heterozygotes. These age differences were smaller in the 15 families carrying founder mutation p.Leu666delinsAsnSer, where homozygotes developed node-positive medullary thyroid cancer in their mid-forties, 6 years earlier than heterozygotes in their early fifties.

CONCLUSION: These results, limited in scope and size and modulated by extent of consanguinity, are consistent with moderate dose-response effects accelerating MEN2A development.