title: Hirschsprung-associated enterocolitis develops independently of NOD2 variants.
abstract: BACKGROUD/PURPOSE: Hirschsprung-associated enterocolitis (HAEC) represents a cause for significant pre- and postoperative morbidity and mortality in Hirschsprung disease (HD). Although multiple studies on HAEC have been performed and several mechanisms have been presumed, the pathogenesis of this condition remains unclear. As changes in colonic mucosal defense are key factors suggested in both Crohn's disease (CD) and HAEC pathogenesis, the aim of the current study was to investigate genetic alterations in the most important susceptibility gene for Crohn's enterocolitis (NOD2) to see whether carriers of polymorphisms within the NOD2 gene are predisposed to the development of HAEC.
  
  
  METHODS
  Genotyping for the NOD2 variants in exon 4 (p.Arg702Trp [rs2066844]), exon 8 (p.Gly908Arg [rs2066845]), and exon 11 (p.1007fs [rs2066847]) was performed in 52 white children with HD (41 boys, 11 girls), 152 healthy controls, and 152 children with CD (onset of disease <17 years; mean, 11.8 years). Seventeen patients with HD (32.7%) were carriers of a RET germline mutation, 35 children (67.3%) had short segment disease, and 17 (32.7%) had long segment disease.
  
  
  RESULTS
  Ten children (19.2%) with HD were heterozygous carriers of at least one NOD2 variant vs 17 (11.2%) in the healthy control group and 69 (45.4%) in the CD cohort. Hirschsprung-associated enterocolitis was observed in 7 children (13.5%), with 4 having short segment HD and 3 with long segment HD; but none of them were carriers of NOD2 variants.
  
  
  CONCLUSIONS
  Our study shows that NOD2 variants described to be causatively associated with CD do not predispose to the development of HAEC. As data on the molecular basis of HAEC are limited, the distinct mechanisms involved in the pathogenesis of this complication remain unclear.
authors.affiliation: Department of Pediatric Surgery, Research Laboratories, University of Munich, D-80337 Munich, Germany. martin.lacher@lmu.de
authors.forename: Martin
authors.initials: M
authors.lastname: Lacher
authors.forename: Guido
authors.initials: G
authors.lastname: Fitze
authors.forename: Johanna
authors.initials: J
authors.lastname: Helmbrecht
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schroepf
authors.forename: Michael
authors.initials: M
authors.lastname: Berger
authors.forename: Peter
authors.initials: P
authors.lastname: Lohse
authors.forename: Sibylle
authors.initials: S
authors.lastname: Koletzko
authors.forename: Antje
authors.initials: A
authors.lastname: Ballauff
authors.forename: Veit
authors.initials: V
authors.lastname: Grote
authors.forename: Jan
authors.initials: J
authors.lastname: Goedeke
authors.forename: Dietrich
authors.initials: D
authors.lastname: von Schweinitz
authors.forename: Roland
authors.initials: R
authors.lastname: Kappler
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004760:Enterocolitis / Q000209:etiology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D006579:Heterozygote; D006627:Hirschsprung Disease / Q000150:complications / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D011110:Polymorphism, Genetic
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein