MUTATIONAL ANALYSIS OF MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A ASSOCIATED WITH HIRSCHSPRUNGS-DISEASE

Background. The clinical association of multiple endocrine neoplasia t ype 2A (MEN 2A) and Hirschsprung's disease (HD), although rare, has be en previously observed. Recently, germline mutations in the RET proto- oncogene, a transmembrane receptor with tyrosine kinase activity, have been detected in patients with familial HD. RET is also the predispos ition gene for the inherited cancer syndrome MEN 2A. Methods. We descr ibe a DNA sequence variation within the coding region of RET in two la rge unrelated kindreds with MEN 2A (with 83 and 42 persons affected) i n which HD cosegregated with MEN 2A in seven patients. Mutational anal ysis was performed with a highly sensitive polymerase chain reaction-b ased denaturing gradient gel electrophoresis technique followed by dir ect sequencing of mutants. Results. genetic analysis by denaturing gra dient gel electrophoresis detected mutant bands in RET exon 10 in pati ents with MEN 2A from both kindreds. Direct DNA sequencing of mutants revealed a thymine-to-adenine base change in codon 618, resulting in a cysteine-to-serine substitution. The identical mutation was present i n all seven children with HD. Of these children five underwent thyroid ectomy for C-cell abnormalities; one 3-year-old child is awaiting thyr oid surgery, and the remaining patient died at age of 12 weeks. Conclu sions. The RET codon 618 Ser mutation could predispose patients with M EN 2A to HD. RET may assume a critical role in embryologic enteric ner ve migration and tumorigenesis of cells from neural crest lineage.