Medullary thyroid carcinoma in a child with a new RET mutation and a RET polymorphism.

We report a 12 year old boy with an isolated medullary thyroid carcinoma (MTC). A mutation analysis of the RET-proto-oncogene in this boy showed an in frame insertion-deletion mutation (insTTCTdelG) at codon 666 of the RET proto-oncogene. This RET mutation has not been reported previously. The boy's mother and his 82-year-old maternal grandfather showed the same mutation. None of the two ever showed symptoms of MTC. The mother underwent a preventive total thyroidectomy and pathological examination showed C-cell hyperplasia and early MTC. Further genetic analysis showed that the boy inherited a well-known coding polymorphism in exon 11 (G691S) from his father. Therefore the boy is a compound heterozygote for the insertion-deletion mutation at codon 666 and the G691S polymorphism in the RET gene. We hypothesize that the insTTCTdelG mutation at codon 666 is associated with low penetrance for MTC and that the young age of MTC in the reported child results most likely from the additive effects of both mutations (insTTCTdelG and G691S).