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Abstract

Background

Missense mutations in five exons of the RET proto-oncogene have been found to cosegregate with the inherited cancer syndrome, multiple endocrine neoplasia type 2A (MEN2A). Sequence abnormalities involving c804 in exon 14 occur rarely and to date have been found in five kindreds. Initial reports linked the c804 mutation to a mild C-cell disease phenotype with low penetrance and an indolent course, and questioned the appropriateness of aggressive strategies such as prophylactic thyroidectomy in early childhood. The purpose of this study is to report the clinical correlates of five additional MEN2A kindreds that harbour the c804 RET mutation, with the intention of clarifying therapeutic recommendations in asymptomatic carriers.

Methods

Thirty-eight members from five distinct kindreds at risk for the c804 mutation underwent genetic analysis using genomic DNA and direct DNA sequencing. Operative and pathology reports were reviewed. Detection of C-cell hyperplasia (CCH) or medullary thyroid carcinoma (MTC) was accomplished biochemically by baseline or pentagastrin-stimulated calcitonin determinations.

Results

Twenty-three gene carriers were identified. The predisposing c804 missense mutation in each case resulted in a TTG, ATG or CTG substitution. Of the 23 patients testing genetically positive, 14 proceeded to thyroidectomy. At operation, MTC was found in seven patients (age 6–56 years), CCH in six patients (age 13–40 years) and normal thyroid histology was present in a single patient (age 27 years). One of the seven patients with MTC died from widespread metastases at age 12 years. Nine of the 23 gene carriers delayed operative intervention. Four of the nine patients have undergone biochemical testing. Three of the four patients have a raised calcitonin level and a single patient remains clinically and biochemically negative at age 40 years.

Conclusion

Penetrance of the c804 mutation is highly variable. In contrast to initial reports, however, MTC associated with sequence abnormalities at this site has aggressive potential. Therefore, prophylactic thyroidectomy remains a reasonable approach in children testing genetically positive. © 2000 British Journal of Surgery Society Ltd