Endocrine Abstracts (2006) 11 P513

A rare RET gene mutation is found in two apparently unrelated Greek kindreds with familial medullary thyroid carcinoma

N Mytakidis1, M Zachariou1, T Anagnostopoulos2, E Vassiliou1, D Thomas1, A Tertipi1, T Rampias3, I Konstantopoulou3, P Natsis1, D Yannoukakos2 & P Kaldrymidis1

1Department of Endocrinology, Metaxa Hospital, Piraeus, Greece; 2Molecular Diagnostics Laboratory, I/R-RP, National Center for Scientific Research “Demokritos” Athens, Greece; 3BioGenomica, Center for Genetic Research & Analysis, Athens, Greece.

Familial medullary thyroid carcinoma (FMTC) is caused by germ-line mutations in the RET proto-oncogene. These mutations concern mainly exons 10 and 11, whereas mutations in exons 13–16 are rare. Mutations in exon 8 have been reported in the literature only twice.

We performed direct analysis of exons 7–19 and 21 of RET gene in two apparently unrelated Greek index-patients with FMTC, presenting negative initial screening for mutations in exons 10–16. We have found the same exon 8 mutation in both. Informed consent was obtained from all members of both families. The mutation was detected in heterozygosis, in seven MTC patients as well as in twenty-four asymptomatic relatives of both families. An additional MTC patient was found to be homozygous for the mutation, due to parental consanguinity. The same point mutation has been reported only once in the literature in another family with different country of origin. It is the first time that a biallelic carrier of this mutation is described.

It is most likely that this mutation causes FMTC, as no other mutation was found, the mutation co-segregates with FMTC, and family members without the mutation are clinically unaffected. The mutation shows wide clinical heterogeneity, as patients’ ages at diagnosis ranged from 23 to 88 years. Because of the rarity of this point mutation, there are no specific recommendations regarding the age of malignant progression and therefore, appropriate timing for prophylactic surgery. Since the earliest age at diagnosis of MTC reported up to date for this mutation is 21, we recommended pentagastrin stimulation test in all carriers of the mutation and total thyroidectomy (with or without lymph-node dissection of the central neck compartment) in all adults. Two of them were operated recently, a 35-year-old male presenting C-cell hyperplasia and a 25-year-old female presenting a microscopic MTC focus.