The developmental genetics of Hirschsprung's disease

Authors

  • K-F Bergeron,

    1. Molecular Genetics of Development Laboratory, Department of Biological Sciences and BioMed Research Center, University of Quebec at Montreal (UQAM), Quebec, Canada
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  • DW Silversides,

    1. Department of Veterinary Biomedicine, Centre de recherche en reproduction animale (CRRA), Faculty of Veterinary Medicine, University of Montreal, Quebec, Canada
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  • N Pilon

    Corresponding author
    • Molecular Genetics of Development Laboratory, Department of Biological Sciences and BioMed Research Center, University of Quebec at Montreal (UQAM), Quebec, Canada
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  • The authors declare no conflict of interest.

Corresponding author: Nicolas Pilon, Department of Biological Sciences and BioMed Research Center, Faculty of Sciences, University of Quebec at Montreal (UQAM), 141 President-Kennedy Ave, Montreal, PQ, Canada H2X 3Y7.

Tel.: +1 514 987 3000x3342;

fax: +1 514 987 4647;

e-mail: pilon.nicolas@uqam.ca

Abstract

Hirschsprung's disease (HSCR), also known as aganglionic megacolon, derives from a congenital malformation of the enteric nervous system (ENS). It displays an incidence of 1 in 5000 live births with a 4:1 male to female sex ratio. Clinical signs include severe constipation and distended bowel due to a non-motile colon. If left untreated, aganglionic megacolon is lethal. This severe congenital condition is caused by the absence of colonic neural ganglia and thus lack of intrinsic innervation of the colon due in turn to improper colonization of the developing intestines by ENS progenitor cells. These progenitor cells are derived from a transient stem cell population called neural crest cells (NCC). The genetics of HSCR is complex and can involve mutations in multiple genes. However, it is estimated that mutations in known genes account for less than half of the cases of HSCR observed clinically. The male sex bias is currently unexplained. The objective of this review is to provide an overview of the pathophysiology and genetics of HSCR, within the context of our current knowledge of NCC development, sex chromosome genetics and laboratory models.

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