There is no intervention involvement. The clinical data and biologic specimens collected during the study will serve as an invaluable resource for a wide spectrum of clinical and translational ancillary studies directly related to the aims and goals of the study.

A subgroup of children who have Hirschsprung Disease may or may not develop enterocolitis; therefore we will be identifying the bio-markers in children with or without associated enterocolitis.

Procedures include prospective data collection from medical records venipuncture and stool collection. 4 cc of blood will be drawn at the screening visit for genetic and immune testing. Additional 8.5 cc of blood will be drawn for CSMC patients for establishment of cell lines. 1. Stool sample collected at screening or follow-up if patient unable to provide at screening. DNA will be prepared from blood for Genome Wide Association Study and mutational analysis 2. Serological immune markers for inflammatory bowel disease (IBD) including ANCA, ASCA, OMPC, I2, and CBir1 and any newly identified markers. These tests will only be performed on patients who consent to the immune response sub-study. No additional blood sample required. 3. Collect and store fresh fecal specimens for future evaluation by molecular methodologies to determine relative proportions of enteric microflora.

Hirschsprung Disease

Enterocolitis

Cedars-Sinai Medical Center 8723 Alden Drive, Suite 240

Identification Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children With Hirschsprung Disease

Identification of Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children With Hirschsprung Disease

Rationale & hypothesis:
Currently there is no generally accepted pathogenic hypothesis for Hirschsprung Associated Enterocolitis. A number of hypotheses propose the role of host genetics, host immune responses, and environmental factors such as microbial triggers, including in particular, enteric flora, resulting in disease susceptibility and development. These factors (host immune/inflammatory cells, intestinal epithelia and microbial flora) and their interactions may also be important determinants of disease phenotype and disease progression. Therefore we hypothesize that there are identifiable immunologic, genetic, enteric flora profiles along with clinical risk factors that influence development of HAEC phenotype.

There is recent evidence that some HD patients who were thought to have refractory HAEC, actually developed IBD. Levin, DN et al. JPGN 2012. This aim is to explore the possibility that there may be similarities between the immune mechanisms involved in HAEC and IBD.

Data suggest that altered gut microbial populations may be partially responsible for the development of HAEC in susceptible HD patients. Most studies have focused on Clostridium difficile, because two groups reported increased frequency of C. diff. toxin positive stools in HD patients with HAEC compared with those without HAEC .[10, 11] Other groups subsequently reported very low frequencies of C. diff. toxin positivity in their patients with HAEC, thereby calling into question the role C. diff. plays in the pathogenesis of HAEC.[12] Other investigators have found E. coli, C. diff. and Cryptosporidium adherent to enterocytes on histological examinations of colon biopsies of patients with HAEC.[5] These findings indicate a breech in the protective mucus gel layer covering the luminal surface of the colon, leading to invasion of the epithelial barrier. Taken together, these studies suggest that the intestine-microbial interaction may be important in the pathogenesis of HAEC.

megacolon/tyrosine

Identification Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children With Hirschsprung Disease

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