Endocrine Abstracts

Introduction: Multiple endocrine neoplasia type 2 (MEN2) and medullary thyroid carcinoma (MTC) are autosomal-dominant inherited diseases caused by germline mutations within the RET protooncogene. Until now, genetic testing for mutations of exon 10, 11, 13, 14, 15 and 16 was recommended for these patients (familial and sporadic cases) to identify disease-causing mutations. Because of a strong genotype–phenotype correlation in these diseases, early genetic testing of relatives of the affected gene carrier is important to detect asymptomatic gene carriers to plan thyroid management e.g. total thyroidectomy.

According to ‘Consensus Guidelines for Diagnosis and Therapy of MEN1 Type 1 and Type 2’ we started to expand genetic testing for RET mutations within the remaining 15 exons of the RET protooncogene in 100 unrelated apparently sporadic index cases tested negative for exon 10, 11, 13, 14, 15 and 16. Thus, we want to get knowledge about the frequency and localisation of mutations within other regions of the gene to improve genetic testing strategy if necessary.

Methods: Genomic DNA was extracted from peripheral blood leukocytes, followed by PCR amplification and direct sequencing of exons including corresponding exon–intron boundaries.

Results: Until now additional analysis of six exons revealed two novel heterozygous germline mutations in exon 8: p.Ala513Gly and p.Arg552Gln. In addition, we detected a RET mutation p.Thr338Ile known from a study of Hirschsprung’s disease.

Conclusion: So far, we detected three RET mutations in three out of 100 apparently sporadic patients tested negative for exon 10, 11, 13, 14, 15 and 16.

Our data indicate by now that genetic counseling and genetic testing for RET mutations should include rare mutations and be done in familial and apparently sporadic MTC/MEN2 index cases to confirm the diagnosis and define asymptomatic gene carriers for early therapy.