C618R mutation in exon 10 of the RET proto-oncogene in a kindred with multiple endocrine neoplasia type 2A and Hirschsprung's disease.

The cosegregation of multiple endocrine neoplasia (MEN) type 2A with Hirschsprung's disease (HSCR), two diseases associated with mutation of the RET proto-oncogene, is infrequent. A 30-yr-old man was referred for screening of MEN 2A. Surgery for HSCR was performed at 4 yr of age. Basal and pentagastrin-stimulated calcitonin levels were abnormal. Histological examination of the thyroid confirmed bilateral medullary thyroid carcinoma. Screening of family members revealed six subjects with medullary thyroid carcinoma or abnormal pentagastrin-stimulated calcitonin test; one had an unilateral pheochromocytoma and two were affected with HSCR. DNA sequence analysis showed a heterozygote C618R mutation in exon 10 of the RET proto-oncogene in the proband and his mother, as well as in second-degree relatives with MEN 2A phenotype or HSCR. In this study, we report on a novel kindred with MEN 2A and HSCR phenotype associated with a point mutation (C618R) in one of the cysteine codons at the extracellular domain of the RET proto-oncogene.