Although apparently the same condition as Hirschsprung's disease (HSCR), total colonic aganglionosis (TCA) patients (2%-14% congenital aganglionosis) display clinical, histopathologic, and genetic differences that may account for altered clinical presentations.
Clinical, radiologic, and histologic features of 22 TCA patients of 114 HSCR cases (including 16 kindreds) were retrospectively evaluated by chart review. With ethical permission, DNA mutation analysis of the RET and EDNRB genes was carried out. Polymerase Chain Reaction (PCR) products were screened for genetic variation of by Hetroduplex Single Strand conformation polymorphism (HEX/SSCP) analysis and compared with 60 normal population control samples (20/ethnic groups). The SSCP variants were validated with automated sequencing techniques showing conformational variants in acrylamide gel.
Of the 22 patients, 12 (55%) presented within the first 28 days of extrauterine life, but 10 presented later with 3 (14%) presenting more than 6 months of age. The TCA patients evaluated differed clinically, radiologically, and histologically, and misdiagnosis occurred in 23% (5/22). Seven patients (32%) were familial-the remainder being nonrelated. Histologic features varied, and difficulties in diagnosis occurred in 5 (24%), with unclear histologic condition delaying diagnosis in one and a mistaken aganglionic level, requiring repeat surgery in two. RET variations were detected in 82% (18/22)of TCA as opposed to 33% short segment (S-HSCR) with multiple genetic RET variations in 5 (28%). Genetic variations included exon 2 SNPs but less than in S-HSCR. One had an isolated RET A4 variation with no other abnormalities. Intronic RET variations occurred in intron 6 (2 patients) (IVS6+56delG) and intron 16 (2 patients) (IVS16-38delG). A cysteine radical mutation (C620R) (2 patients) was related to Multiple Endocrine Neoplasia Type 2 (MEN2) in the family. In contrast to S-HSCR, genetic variations in TCA aggregated to the important tyrosine kinase (intracellular) region in 5 patients suggesting a possible pathogenetic link. EDNRB variations occurred in 7 patients (32%) all within exon 4 of the gene.
Total colonic aganglionosis differs clinically from other HSCR phenotypes and may lead to misdiagnosis. Potential disease-related RET gene mutations include exon 17-21 genetic variations that suggest the possibility of disrupted downstream signaling pathways from vital gene recruitment sites as possible TCA contributing factors.