MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A IN TWO FAMILIES WITH THE FAMILIAL MEDULLARY THYROID CARCINOMA-ASSOCIATED G533C MUTATION OF THE RET PROTO-ONCOGENE

Peppa M.¹, Pikounis V.¹, Kamakari S.², Peros G.³, Economopoulos T.¹, Hadjidakis D.¹, Raptis A.S.⁴

¹Endocrine Unit, Second Department of Internal MedicinePropaedeutic, Research Institute and Diabetes Center, Athens University Medical School, "Attikon" University Hospital, Athens, Greece, ²BioGenomica, Center for Genetic Research and Analysis, Athens, Greece, ³Fourth Department of Surgery, Athens University Medical School, "Attikon" University Hospital, Athens, Greece, ⁴Hellenic National Diabetes Center 'Attikon" University Hospital, Athens, Greece

Background: Multiple endocrine neoplasia type 2 is an autosomal dominant hereditary disorder, associated with germ line gain-of-function mutations of the RET protooncogene. This is characterised by the combined occurrence of tumours in multiple endocrine and non-endocrine glands, giving rise to three distinct subtypes namely MEN2A, MEN2B and Familial Medullary Thyroid Carcinoma (FMTC).

Aim:To identify mutations of the RET-proto-oncogene and characterize clinical characteristics in two families with MEN2A phenotype.

Patients and Methods: We studied 2 unrelated female index patients, 35 and 45 yrs old, with MEN2A syndrome consisting of pheochromocytoma -which was the presenting feature- and medullary carcinoma (MTC). Eleven family members were also included in the study. DNA extraction, polymerase chain reaction (PCR) and sequencing of the RET gene (exons 8, 10, 11, and 13-16), were performed according to standard procedures.

Results: Direct sequencing of exon 8 revealed a G to T transversion at nucleotide 1597 (Genbank accession no: NM_020630) in heterozygote state, which causes a substitution of glycine to cysteine residue at codon 533 (G533C) in the cysteine-rich domain of RET protein. The mutation was found in both index patients and in 5 family members, two of whom underwent total thyroidectomy showing MTC on histology report.

Conclusions: These data indicate that the G533C mutation of the RET proto-oncogene which has been considered to be only FMTC associated, is possibly involved in the pathogenesis of MEN2A. This mutation should be tested especially in the case of the negative screening for the classical mutations. Furthermore, patients harbouring this mutat ion should be considered as having MEN2A phenotype and screened annually for pheochromocytoma or other components of the syndrome.