Genotype-specific development of MEN 2 constituent components in 683 RET carriers.

Abstract

The age-specific development of the 3 constituent components of multiple endocrine neoplasia type 2 (MEN 2) is incompletely characterized for many of the >30 causative rearranged during transfection (RET) mutations, which this genetic association study aimed to specify. Included in the study were 683 carriers of heterogeneous RET germline mutations: 53 carriers with 1 highest-risk mutation (codon 918); 240 carriers with 8 different high-risk mutations (codon 634); 176 carriers with 16 different intermediate-risk mutations (codon 609, 611, 618, 620 or 630); and 214 carriers with 6 different low-risk mutations (codon 768, 790, 804 or 891). There was a strong genotype-specific development of MEN 2 constituent components, with distinct age gradients from C cell disease to node-negative MTC, from node-negative to node-positive MTC, from node-positive MTC to pheochromocytoma, and from pheochromocytoma to primary hyperparathyroidism. Primary hyperparathyroidism was not observed among the 53 MEN 2B patients who carried highest-risk mutations (age range 0.5-50 yrs.), of whom no more than 12 (23%) and 3 (6%) carriers were older than age 30 yrs. and 35 yrs., respectively. The age-specific development of MTC differed significantly between the 4 RET risk categories, whereas the age-specific development of pheochromocytoma differed significantly only between the 2 strongest RET risk categories. No significant differences were noted in the development of primary hyperparathyroidism. These findings delineate age-specific disease manifestation corridors for the 3 constituent components of MEN 2 by RET genotype. These corridors are useful for initial risk assessment and organ-specific surveillance of newly identified RET carriers going forward.