Endocrine Abstracts

MEN2B is the most aggressive form of MEN2. Consequently, the new American Thyroid Association guidelines recommend prophylactic thyroidectomy early in the first year of life. Ninety-seven percentage of MEN2B cases result from a germline methionine to threonine mutation at codon 918 (M918T) of the RET proto-oncogene. In addition, an exceedingly rare alanine to phenylalanine mutation at codon 883 (A883F) has been reported in 4 unrelated adults. In each case metastatic MTC and the clinical features of MEN2B occurred in the presence of a de novo A883F germline mutation. We describe the first MEN2B family with the A883F mutation and report the results of prophylactic thyroidectomy. The 29-year-old female proband presented with symptomatic, metastatic MTC and features of MEN2B. Her 8-year-old son, who inherited the A883F mutation, also had classical features of MEN2B. Unexpectedly, his basal calcitonin was within the normal range. Remarkably, prophylactic thyroidectomy revealed only C-cell hyperplasia (CCH). The ATA guidance for prophylactic thyroidectomy in MEN2B is based solely on data from individuals with the common M918T mutation and the specific finding that virtually all infants have CCH and MTC by 1 year of age. The finding of only CCH in an 8-year-old with MEN2B suggests the A883F mutation results in a much less aggressive form of MTC. Accordingly, the A883F mutant has a lower in vitro transforming ability than the common MEN2B mutant M918T or even the C634R mutant that causes MEN2A. This unique family provides new insight into the molecular pathology of MTC with important implications for management of MEN2B. The finding of CCH alone in an 8-year-old with MEN2B resulting from an A883F mutation suggests that prophylactic thyroidectomy may be delayed in such families until 5 years of age when surgical complication rates approach those of adults.