RISK AND PENETRANCE OF PRIMARY HYPERPARATHYROIDISM IN MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A FAMILIES WITH MUTATIONS AT CODON-634 OF THE RET PROTOONCOGENE

Germline mutations of the RET proto-oncogene are responsible for multi ple endocrine neoplasia type 2, including multiple endocrine type 2A ( MEN 2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma. T he relationship between specific mutations and syndromic features has been established. In particular, the risk for pheochromocytoma and hyp erparathyroidism (HPT) in MEN 2A patients is clearly associated with t he presence of the RET mutation at a specific position, i.e. at codon 634. Also, a correlation between a specific mutation, C634R, and the d evelopment of HPT has been suggested but is still controversial. To fu rther investigate the relationship between specific mutations of codon 634 and the development of HPT, we studied a population of 188 indivi duals, carrying mutations at codon 634, namely C634R (65 patients belo nging to 10 families), C634Y (80 patients belonging to 11 families), o r the less frequent codon 634 mutations [i.e. C634S, C634F, C634G, or C634W (43 patients belonging to 9 families)]. In this series of patien ts, we defined an overall HPT prevalence of 19.1% and found that this prevalence did not vary significantly, with respect to the nature of t he mutation. However, irrespective of the particular mutation, the pre valence of HPT showed a high interfamilial variability. The statistica l model that best fitted with the observed data was in favor of the he terogeneity of the risk for HPT, with 40% of the families showing an H PT risk of 34% and 60% of the families showing an HPT risk of 9%. In a ddition, our study clearly demonstrated that HPT could he an early com ponent 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.