Risk and Penetrance of Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 2A Families with Mutations at Codon 634 of theRETProto-Oncogene¹

Abstract

Germline mutations of the RET proto-oncogene are responsible for multiple endocrine neoplasia type 2, including multiple endocrine type 2A (MEN 2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma. The relationship between specific mutations and syndromic features has been established. In particular, the risk for pheochromocytoma and hyperparathyroidism (HPT) in MEN 2A patients is clearly associated with the presence of the RET mutation at a specific position, i.e. at codon 634. Also, a correlation between a specific mutation, C634R, and the development of HPT has been suggested but is still controversial. To further investigate the relationship between specific mutations of codon 634 and the development of HPT, we studied a population of 188 individuals, carrying mutations at codon 634, namely C634R (65 patients belonging to 10 families), C634Y (80 patients belonging to 11 families), or the less frequent codon 634 mutations [i.e. C634S, C634F, C634G, or C634W (43 patients belonging to 9 families)]. In this series of patients, we defined an overall HPT prevalence of 19.1% and found that this prevalence did not vary significantly, with respect to the nature of the mutation. However, irrespective of the particular mutation, the prevalence of HPT showed a high interfamilial variability. The statistical model that best fitted with the observed data was in favor of the heterogeneity of the risk for HPT, with 40% of the families showing an HPT risk of 34% and 60% of the families showing an HPT risk of 9%. In addition, our study clearly demonstrated that HPT could be an early component of the disease and provided the first estimate of age-specific and mutation-specific HPT penetrance in individuals with mutations of codon 634 of the RET proto-oncogene.

RET Cys634Arg mutation confers a more aggressive multiple endocrine neoplasia type 2A phenotype than Cys634Tyr mutation

“…Furthermore, the mutation-specific penetrance data in our study also showed higher penetrance of the C634R mutation than the C634Y mutation. Our data regarding HPT prevalence and age-related penetrance in C634R carriers agree with a previous report (24), which found higher HPT age-related penetrance in C634R carriers than in patients with any other amino acid exchange at codon 634; an individual comparison was not performed between specific amino acid substitutions at codon 634.…”

“…Taking into account the findings of previous studies (13,23,24), and our own findings, we hypothesise, in agreement with others (10), that specific amino acid substitutions could change the protein biochemistry altering its function; thus, the C634R mutation could confer a higher penetrance of the MEN2A phenotype and more aggressive behaviour of MTC than the C634Y mutation.…”

“…There is controversy regarding whether the C634R mutation confers a greater risk of developing parathyroid disease (4,7,9,24,25). Our investigation showed a significantly higher HPT prevalence in C634R carriers than in those with the C634Y mutation, despite the fact that more patients above the age of 40 years harboured the C634Y mutation and that the risk of developing HPT increases beyond this age.…”

Advances in risk-oriented surgery for multiple endocrine neoplasia type 2

“…Based on data from the French MEN2 registry, 5.6-9.1% of germline mutations (running in 8-13 of 143 families) occur de novo in the parental germline (Schuffenecker et al 1997), replenishing the pool of index patients that screening programs seek to deplete. These countervailing effects may make it unfeasible to diminish the percentage of index patients below the spontaneous mutation rate of 5.6-9.1%.…”

A Family Presenting with Catastrophic Features due to Pheochromocytoma Associated with Multiple Endocrine Neoplasia 2A

“…Accordingly, in the younger sister of the patient, tests for pheochromocytoma and follow-up observations based on serum concentrations of parathyroid hormone and calcium performed on a yearly basis are warranted. It has also been reported that mutations of codon 634 are associated with the development of pheochromocytoma before the age of 5-10 years [18]. In addition, this mutation corresponds to the high-risk phase II group with respect to the degree of malignancy of MTC [6].…”