Accelerated MEN2A in homozygous RET carriers in the context of consanguinity

Abstract

Abstract Background Homozygous mutations, 2 identical gene versions (alleles), 1 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-30s and early 40s. 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, whereas homozygotes developed node-positive medullary thyroid cancer in their mid-40s, 6 years earlier than heterozygotes in their early 50s. Conclusion These results, limited in scope and size and modulated by extent of consanguinity, are consistent with moderate dose–response effects accelerating MEN2A development.