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

Emerging data suggests that the distinct phenotype of HAEC in children with HD may be the result of the complex interplay between host genetics, immune response and environmental triggers. Data suggest that approximately 20-30 percent of patients with HD develop HAEC. Thus, well-designed, multi-disciplinary investigations of genetic, immune and microbial etiologies of HAEC, with sufficient power to detect differences in disease phenotype are critically needed.

The Hirschsprung Disease clinical phenotype of HAEC:

Hirschsprung disease (HD; also known as congenital aganglionic megacolon) affects 1 in 5000 live births [2]. Surgical repair (excision of the aganglionic colon and pull through of the normally ganglionated intestine to the anal canal) is typically performed in infants with HD during the first few months of life [3, 4]. A subgroup of these children with HD will also develop Hirschsprung associated enterocolitis (HAEC), a potentially severe infection of the small bowel and colon[5]. Children who develop HAEC can present with fever, abdominal distention, explosive diarrhea, vomiting, lethargy, and if not diagnosed and treated promptly, can lead to life threatening sepsis and death. HAEC may occur pre- or post-surgery in HD patients. There have been widely varying reports of HAEC incidence ranging from 15-50% pre-surgery to 2-30% post-surgery. A lack of clear definition of HAEC criteria is at least partially responsible for this significant variation in reported incidence[6, 7]. A standardized definition of HAEC was recently developed and published in 2009[1]. The HAEC score consists of the most important clinical diagnostic criteria for HAEC identified from a group of international experts using the Delphi method. Preliminary validation with case scenarios was achieved and the HAEC score can now be used as a standardized and reproducible outcome measure for future studies on children with Hirschsprung disease. Now it is possible to perform rigorous studies of the genetic, immune, and microbial differences in HD patients who develop HAEC compared with those children with HD that have not developed HAEC.

Genetic variation: Currently there are 10 different genes identified (RET, GDNF, NTN, EDNRB, ET3, ECE-1, SOX10, ZFHX1B, PHOX2B, NGR1) in individuals affected with either isolated or syndromic Hirschsprung disease. The RET gene plays a critical role in ENS development and mutations in the RET gene have been found in 7-35% of sporadic cases and approximately 50% of familial cases. EDNRB and ET3 each account for approximately 5% of patients with HD and also are responsible for Shah-Waardenberg Syndrome. Mutations in each of the remaining 7 genes have been found in a small number of isolated and syndromic HD patients[8].

The RET tyrosine kinase signaling pathway plays a major role in ENS migration, along with its ligands GDNF and NTN. The EDNRB G-protein coupled receptor together with its ligand ET3 and endothelin cleavage enzyme ECE-1 forms a separate signaling pathway important in ENS development. The RET and EDNRB signaling pathways appear interact with an additive effect through an as yet to be described mechanism. PHOX2B is a transcriptional regulator of the RET gene and SOX10 appears to be a transcriptional regulator of both RET and EDNRB genes. The complex regulation of the genes in each pathway, combined with the cross-signaling between pathways and the effects on ENS migration is the subject of ongoing investigations[8, 9].