THE RELATIONSHIP BETWEEN SPECIFIC RET PROTOONCOGENE MUTATIONS AND DISEASE PHENOTYPE IN MULTIPLE ENDOCRINE NEOPLASIA TYPE-2 - INTERNATIONAL RET MUTATION CONSORTIUM ANALYSIS

Objective.-Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant disorder. The 3 recognized subtypes include MEN 2A, characte rized by medullary thyroid carcinoma (MTC), pheochromocytoma (pheo), a nd hyperparathyroidism (HPT); MEN 2B, by MTC, pheo, and characteristic stigmata; and familial MTC (FMTC), by the presence of MTC only. The p urpose of this study was to establish the relationship between specifi c mutations and the presence of certain disease features in MEN 2 whic h could help in clinical decision making. Design.-Correlative survey s tudy of 477 MEN 2 families. Setting.-Eighteen tertiary referral center s worldwide. Patients.-A total of 477 independent MEN 2 families. Main Outcome Measures.-Association between the position and type of germli ne mutation in the RET proto-oncogene and the presence or absence of M TC, pheo, HPT, and/or other features in a family. Results.-There is a statistically significant association between the presence of any muta tion at a specific position (codon 634) and the presence of pheo and H PT. The presence of a specific mutation, CGC at codon 634, has yet to be associated with FMTC, Conversely, mutations at codons 768 and 804 a re thus far seen only with FMTC, while codon 918 mutation is MEN 2B-sp ecific. Rare families with both MEN 2 and Hirschsprung disease were fo und to have MEN 2-specific codon mutations. Patients with Hirschsprung disease presenting with such mutations should be monitored for the po ssible development of MEN 2 tumors. Conclusions.-This consortium analy sis suggests that genotype-phenotype correlations do exist and, if mad e reliably absolute, could prove useful in the future in clinical mana gement with respect to screening, surveillance, and prophylaxis, as we ll as provide insight into the genetic effects of particular mutations .