Medullary thyroid cancer and pheochromocytoma in MEN2A: are there parent of origin effects on disease expression?

There are no data on the impact of parent-of-origin effects on the expression of multiple endocrine neoplasia type 2A (MEN2A). The present study aimed to explore effects of parent-of-origin and offspring gender in MEN2A. In total, 224 carriers harbored heterozygous RET (REarranged during Transfection) p.Cys634 missense variants, for 169 of whom information on parent-of-origin gender was available. Altogether, offspring from affected fathers harbored more often node metastases from medullary thyroid cancer (45 vs. 19%; P = 0.006) and bilateral pheochromocytoma (24 vs. 10%; P = 0.021) than offspring from affected mothers. The former also also tended to be older at most recent follow-up (medians of 21 vs. 14 years; P = 0.056) and tended to have more often pheochromocytoma (33 vs. 19 yrs.; P = 0.051) and primary hyperparathyroidism (13 vs. 4%; P = 0.090) than the latter. Daughters from affected fathers harbored more often node metastases (39 vs. 15%; P = 0.043) than daughters from affected mothers. This difference decreased in male offspring when sons from affected fathers were compared with sons from affected mothers (52 vs. 40%; P = 0.111). There was also a slight deficit of male offspring: 1.1 sons each per affected mother and father vs. 1.2 daughters per affected mother and 1.4 daughters per affected father. These data suggest a parent-of-origin effect in MEN2A, warranting international collaborative research.

Automated summary

This study found parent-of-origin and offspring gender effects on the risk and disease phenotype in MEN2A, suggesting a more significant association between fathers and sons in disease inheritance and manifestation.