RET proto-oncogene in Sardinia: V804M is the most frequent mutation and may be associated with FMTC/MEN-2A phenotype

OBJECTIVE: Genetic screening of RET proto-oncogene is a powerful tool for the early identification of familial cases of medullary thyroid carcinoma (MTC), comprising isolated familial thyroid medullary carcinoma (FMTC) and multiple endocrine neoplasia syndromes 2A (MEN-2A) and 2B (MEN-2B). We report the results obtained by RET mutation analysis of subjects living in Sardinia, an Italian island whose inhabitants display a peculiar genetic background due to geographic isolation and low immigration rate for several centuries. DESIGN: Retrospective study reporting data on 67 patients referred during the last 5 years for RET analysis because affected by MTC or first degree relatives of MTC patients. MAIN OUTCOME: Only three mutations were identified affecting codons 620 (exon 10), 634 (exon 11), and 804 (exon 14); surprisingly, the most prevalent mutation found was V804M (overall prevalence: 59%). This finding is quite different from previous studies carried out in other Caucasian and non-Caucasian populations, in which the frequency of the V804M mutation is consistently reported less than 5%. The phenotype associated to V804M mutation was mostly FMTC (16/17 cases = 94.1%), but in one case (5.9%) primary hyperparathyroidism was found, suggesting a MEN-2A. CONCLUSIONS: These results underline the importance of the genetic background in the distribution of RET mutations and should be taken into consideration when performing genetic evaluation of MTC patients

A novel germline mutation of MEN 1 gene in a patient with acromegaly and multiple endocrine tumors

Germline mutations of the MEN 1 gene are responsible for multiple endocrine neoplasia type 1 (MEN 1), a dominantly inherited cancer syndrome characterized by tumors of the parathyroids, gastro-intestinal endocrine tissue, anterior pituitary and other endocrine tissues. We report on a 55-yr old woman, presentingwith active acromegaly (due to GH-secreting microadenoma), associated to bilateral adrenal adenomatosis and Hürthle-cell thyroid neoplasia. No evidence of hyperparathyroidism or gastrinsecreting tumor was found. Peripheral blood genomic DNA was extracted, amplified by PCR, purified and analyzed by direct sequencing. The analysis revealed a heterozygous mutation in exon 4 of the MEN 1 gene: a G to A missense mutation at codon 229 (CGC→CAC), which changes arginine to histidine. This mutation causes loss of the HhaI restriction site and can thus be employed for a rapid familiar screening. This case represents a newly recognized germline mutation of the MEN 1 gene