The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2: International RET Mutation Consortium Analysis

Different subtypes of multiple endocrine neoplasia type 2 (MEN-2) appear to be linked to specific gene mutations in the RET oncogene. MEN-2 is characterized by tumors in various glands, including the thyroid and adrenals. It has three subtypes depending on the organs affected by tumors: MEN-2A, MEN-2B and familial medullary thyroid cancer (FMTC). Researchers performed genetic testing on 477 families worldwide who had a family history of MEN-2. A gene mutation at position 634 in the RET oncogene was associated with MEN-2A, while a mutation at position 918 was specific for MEN-2B and mutations at 768 and 804 were specific for FMTC.
Objective.--Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant disorder. The 3 recognized subtypes include MEN 2A, characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (pheo), and hyperpara-thyroidism (HPT); MEN 2B, by MTC, pheo, and characteristic stigmata; and familial MTC (FMTC), by the presence of MTC only. The purpose of this study was to establish the relationship between specific mutations and the presence of certain disease features in MEN 2 which could help in clinical decision making. Design.--Correlative survey study of 477 MEN 2 families. Setting.--Eighteen tertiary referral centers worldwide. Patient$.--A total of 477 independent MEN 2 families. Main Outcome Measures.--Association between the position and type of germline mutation in the RET proto-oncogene and the presence or absence of MTC, pheo, HPT, and/or other features in a family. Results.--There is a statistically significant association between the presence of any mutation at a specific position (codon 634) and the presence of pheo and HPT. The presence of a specific mutation, CGC at codon 634, has yet to be associated with FMTC. Conversely, mutations at codons 768 and 804 are thus far seen only with FMTC, while codon 918 mutation is MEN 2B--specific. Rare families with both MEN 2 and Hirschsprung disease were found to have MEN 2--specific codon mutations. Patients with Hirschsprung disease presenting with such mutations should be monitored for the possible development of MEN 2 tumors. Conclusions.--This consortium analysis suggests that genotype-phenotype correlations do exist and, if made reliably absolute, could prove useful in the future in clinical management with respect to screening, surveillance, and prophylaxis, as well as provide insight into the genetic effects of particular mutations. JAMA. 1996;276:1575-1579