Hirschsprung-associated enterocolitis develops independently of NOD2 variants.
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.
Lacher
Martin
M
Department of Pediatric Surgery, Research Laboratories, University of Munich, D-80337 Munich, Germany. martin.lacher@lmu.de
Fitze
Guido
G
Helmbrecht
Johanna
J
Schroepf
Sebastian
S
Berger
Michael
M
Lohse
Peter
P
Koletzko
Sibylle
S
Ballauff
Antje
A
Grote
Veit
V
Goedeke
Jan
J
von Schweinitz
Dietrich
D
Kappler
Roland
R
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
C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein