Objective: To describe a genotype-phenotype correlation in MEN2 families with germline mutations of codons 790/791 and discuss options for the therapeutic management of gene carriers.
Summary background data: Heredity of MEN2 syndromes is caused by a heterozygous germline mutation in the protooncogene. Rare mutations of codons 790/791 associated with incomplete penetrant MEN2A/FMTC phenotype were reported in five families, contraindicating the prophylactic thyroidectomy for the genetically affected children.
Methods: Forty-five patients with a putative sporadic MTC were screened for germline mutations by direct DNA sequencing. Family members of identified index cases underwent genetic analysis. Gene carriers were examined clinically and biochemically, and all gene carriers underwent prophylactic thyroidectomy.
Results: Five index patients were identified, four of whom harbored mutations in codons 790/791 and one in codon 634. In the kindreds, four L790F carriers and one Y791F carrier were detected. The thyroid gland histology of L790F carriers revealed medullary thyroid carcinoma in two patients (aged 29 and 50 years) and C-cell hyperplasia in two additional patients (aged 9 and 16 years). The Y791F carrier had a normal histology.
Conclusions: Codon 790/791 mutations had diverse penetrance. Whereas prophylactic thyroidectomy in children is a justifiable approach for codon 790 mutation carriers, the indication for thyroidectomy should depend on the clinical course of codon 791 carriers.