A novel case of multiple endocrine neoplasia type 2A associated with two de novo mutations of the RET protooncogene

We report a novel case of multiple endocrine neoplasia type 2A (MEN 2A) ass ociated with two mutations of the protooncogene RET. One affects codon 634 and causes a cysteine to arginine substitution; the second at codon 640 cau ses an alanine to glycine substitution in the transmembrane region. The two mutations were present on the same RET allele and were detected in germlin e and tumor DNA. Both mutations were de novo, i.e. they were not found in t he DNA of the parents or relatives. Immunohistochemical and RT-PCR analysis showed that the pheochromocytoma expressed calcitonin as well as both RET alleles. A cell line established from the tumor and propagated in culture s ustained the expression of RET and calcitonin, as did the original pheochro mocytoma. Because the patient presented with medullary thyroid carcinoma an d pheuchromocytoma without parathyroid gland involvement, we speculate that this clinical picture could be correlated with the two RET mutations and t o the unusual calcitonin production. This is the first report of a MEN 2A c ase due to two mutations of the RET gene and associated with a calcitonin-p roducing pheochromocytoma.