Pediatric Surgery International

, Volume 34, Issue 11, pp 1127–1137 | Cite as

Advances in understanding the association between Down syndrome and Hirschsprung disease (DS–HSCR)

  • S. W. MooreEmail author
Review Article


The clinical association between Trisomy 21 (Down syndrome) and aganglionosis (Hirschsprung disease; DS–HSCR) is well-established, being of the order of 5% and remains the most common congenital association with Hirschsprung disease. However, little consensus exists as to the possible etiologic and genetic factors influencing this association. Recent research has identified a number of levels at which development of the enteric nervous system is potentially affected in Trisomy 21. These include a decreased central pool of available neuroblasts for migration into the enteric nervous system, abnormal neuroblast type, poor synaptic nerve function and early germline gene-related influences on the migrating neuroblasts due to genetic mutations of a number of important developmental genes, and possible somatic mutations resulting from alterations in the local tissue microenvironment. In this paper, we review available evidence for this association. In addition, we provide evidence of both germline and somatic gene mutations suggesting causation. Although the picture is complex, recent associations between specific RET proto-oncogene variations have been shown to be significant in Down syndrome patients with Hirschsprung disease, as they probably interfere with vital RET functions in the development of the autonomic and enteric nervous systems, increasing the risk of disturbed normal function. In addition, we explore potential role of other facilitatory influence of other susceptibility genes as well as potential other chromosome 21 gene actions and the microenvironment on the Down syndrome gastro-intestinal tract. The various ways in which trisomy of chromosome influences the enteric nervous system are becoming clearer. The sum of these effects influences the outcome of surgery in Down syndrome patients with Hirschsprung Disease.


Hirschsprung disease Trisomy 21 Down syndrome Chromosome 21 Genetics Treatment 


Compliance with ethical standards

Conflict of interest

I have no potential conflicts of interest. Grant support for this research was from the Medical Research Council of South Africa Self initiated research (SIR) grant and the National Research Foundation of South Africa (Incentive grant for rated researchers).

Research involving human participants

This is a review article, but there is some reporting on research involving human participants from published reports. This article does not contain any studies with animals performed by any of the authors.’

Informed consent

All patients within our reported study had a signed informed consent as indicated in the relevant publication.


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© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Paediatric Surgery, Faculty of Medicine and Health SciencesUniversity of StellenboschCape TownSouth Africa

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