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Hirschsprung disease — integrating basic science and clinical medicine to improve outcomes

Key Points

  • Hirschsprung disease is a potentially fatal birth defect in which the enteric nervous system (ENS) is missing from the distal bowel

  • Hirschsprung disease is a non-Mendelian, multigenic, partially penetrant, genetic disease

  • Surgery to bypass the aganglionic bowel is life-saving, but not curative

  • Enterocolitis occurs commonly even after surgery and can be life-threatening

  • Non-genetic factors affect ENS development, suggesting some cases of Hirschsprung disease might be preventable

  • Regenerative medicine strategies such as stem cell therapy could provide new treatment options

Abstract

Hirschsprung disease is defined by the absence of enteric neurons at the end of the bowel. The enteric nervous system (ENS) is the intrinsic nervous system of the bowel and regulates most aspects of bowel function. When the ENS is missing, there are no neurally mediated propulsive motility patterns, and the bowel remains contracted, causing functional obstruction. Symptoms of Hirschsprung disease include constipation, vomiting, abdominal distension and growth failure. Untreated disease usually causes death in childhood because bloodstream bacterial infections occur in the context of bowel inflammation (enterocolitis) or bowel perforation. Current treatment is surgical resection of the bowel to remove or bypass regions where the ENS is missing, but many children have problems after surgery. Although the anatomy of Hirschsprung disease is simple, many clinical features remain enigmatic, and diagnosis and management remain challenging. For example, the age of presentation and the type of symptoms that occur vary dramatically among patients, even though every affected child has missing neurons in the distal bowel at birth. In this Review, basic science discoveries are linked to clinical manifestations of Hirschsprung disease, including partial penetrance, enterocolitis and genetics. Insights into disease mechanisms that might lead to new prevention, diagnostic and treatment strategies are described.

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Figure 1: The enteric nervous system.
Figure 2: The enteric nervous system and Hirschsprung disease.
Figure 3: Enteric nervous system precursors must fully colonize the fetal bowel to prevent Hirschsprung disease.
Figure 4: Optimal Hirschsprung disease risk assessment should incorporate genetic and clinical criteria.
Figure 5: Decision analysis for rectal biopsy.
Figure 6: Mechanisms underlying Hirschsprung-disease-associated enterocolitis.
Figure 7: Current and future Hirschsprung disease evaluation and management.

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Acknowledgements

R.O.H. is supported by the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research (1008525), the Children's Discovery Institute at Washington University School of Medicine (MD-11-2013-269), FDA (R01FD005133), Penn Medicine Neuroscience Center, March of Dimes 6-FY15-235, PennCHOP Microbiome Program (FP00021900), NIH Common Fund (1OT2OD023859-01), Canadian Institutes of Health Research (201610PJT), and by generous support from the Irma and Norman Braman Endowment, The Suzi and Scott Lustgarten Center Endowment and The Children's Hospital of Philadelphia Research Institute.

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Heuckeroth, R. Hirschsprung disease — integrating basic science and clinical medicine to improve outcomes. Nat Rev Gastroenterol Hepatol 15, 152–167 (2018). https://doi.org/10.1038/nrgastro.2017.149

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