A novel double mutation val648ile and val804leu or ret proto-oncogene in multiple endocrine neoplasia type 2

AIM: We report the case of a woman with MEN2A presenting a double mutation in RET protooncogene. METHODS: RET mutational analysis was performed by Sanger sequencing of DNA. RESULTS: The proband was compound heterozygote for the RET germline mutations Val648Ile and Val804Leu, mapping on exons 11 and 14 respectively. Genetic analysis of family members showed the presence of the Val648Ile mutation in all except one daughter, who carried the Val804Leu mutation. However, all of them did not show any clinical, biochemical or histological sign of neoplastic disease either in thyroid or adrenal gland. Furthermore, a daughter and the proband's sister who underwent a prophylactic thyroidectomy did not present pathological evidence of C cell disease. CONCLUSIONS: We suppose that the combined effect of the two mutations may have induced the development of pheochromocytoma in our patient. Thus, in the presence of single RET-induced mild MTC phenotype, the search for additional genetic anomalies may lead to discover rare but potentially more aggressive double mutation genotypes.