Endocrine Abstracts

Familial medullary thyroid carcinoma (MTC), multiple endocrine neoplasia types 2A and 2B (MEN2A, 2B) and Hirschsprung disease (HSCR) are inherited neurocristopathies linked to germline mutations in the RET proto-oncogene. Activating germline RET mutations are presented in patients with FMTC, MEN2A and MEN2B, on the other hand, inactivating germline mutations in patients with HSCR. Nevertheless, there is an overlay in specific mutations in the exon 10 of the RET proto-oncogene. The aim of this study was to screen 6 exons (10,11,13,14,15 and 16) of the RET proto-oncogene by fluorescent sequencing method in three different groups of patients - 174 families with MTC (including MEN2A, 2B), 73 families with HSCR and 20 patients with only pheochromocytoma. In this report, we show that the point mutation Tyr791Phe in exon 13 of the RET proto-oncogene can cause different diseases derived from neural crest. We found Tyr791Phe mutation in 5 families with MTC (3%), 2 families with HSCR (3%) and 1 family with pheochromocytoma (5%). All these patients with the mutation have also a silent polymorphism Leu769 (T/G) in exon 13. In addition, in 2 families with MEN2 double germline mutations were detected: MEN2A family Tyr791Phe + Cys620Phe (exon 10) and MEN2B family Tyr791Phe + Met918Thr (exon 16). Tyr791Phe mutation had not been previously observed in HSCR patients. Detection of Tyr791Phe mutation in MEN2/MTC and HSCR families leads to a question whether this mutation has dual “Janus” character (gain-of-function as well as loss-of-function) as mutations described in exon 10 in HSCR/MEN2A patients. This study shows other character of this strange and frequently discussed Tyr791Phe mutation. On the basis of our genetic finding total thyroidectomy was recommended for all patients with Tyr791Phe mutation.

The work was supported by IGA MZ CR NR/7806-3, GACR 301/06/P425 and IGA MH CR NR/8519-3 and was approved by local Ethical committee.