Advances in understanding the association between Down syndrome and Hirschsprung disease (DS–HSCR)
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.
KeywordsHirschsprung 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.’
All patients within our reported study had a signed informed consent as indicated in the relevant publication.
- 1.World Health Association (2018) WHO’s Human Genomics in Global Health initiative- Downs syndrome. http://www.who.int/genomics/public/geneticdiseases/en/index1.html
- 19.Friedmacher F, Puri P (2013) Hirschsprung’s disease associated with Down syndrome: a meta-analysis of incidence, functional outcomes and mortality. PediatrSurgInt 29:937–946Google Scholar
- 23.Li JC, Busch L, Kuhnel W (2000) Immunohistochemical study on gastroenteric nervous system in trisomy 16 mice:an animal model of Down syndrome. World JGastroenterol 6:793–799Google Scholar
- 31.Karlsen AS, Pakkenberg B (2011) Total numbers of neurons and glial cells in cortex and basal ganglia of aged brains with Down syndrome—a stereological study. CerebCortex 21:2519–2524Google Scholar
- 49.Jiang Q, Arnold S, Heanue T, Kilambi KP, Doan B, Kapoor A, Ling AY, Sosa MX, Guy M, Jiang Q, Burzynski G, West K, Bessling S, Griseri P, Amiel J, Fernandez RM, Verheij JB, Hofstra RM, Borrego S, Lyonnet S, Ceccherini I, Gray JJ, Pachnis V, McCallion AS, Chakravarti A et al (2015) Functional loss of semaphorin 3C and/or semaphorin 3D and their epistatic interaction with ret are critical to Hirschsprung disease liability. Am J Hum Genet 96:581–596CrossRefGoogle Scholar
- 54.Sanchez-Mejias A, Fernandez RM, Lopez-Alonso M, Antinolo G, Borrego S (2010) New roles of EDNRB and EDN3 in the pathogenesis of Hirschsprung disease. GenetMed 12:39–43Google Scholar
- 60.Baumann J (2007) Down syndrome cell adhesion molecule—a common determinant of brain and heart wiring. PediatrRes 62:1Google Scholar
- 61.de Andrade GB, Kunzelman L, Merrill MM, Fuerst PG (2014) Developmentally dynamic colocalization patterns of DSCAM with adhesion and synaptic proteins in the mouse retina. MolVis 20:1422–1433Google Scholar
- 62.Cheng W (2018) ATP50 on human chromosome 21 as a potntial link between Hirschsprung disease and Down syndrome. poster 15 5th International symposium on development of the enteric nervous system.Boston, USA April 8–11 2018Google Scholar
- 64.Moore SW, Zaahl MG (2014) Tissue specific somatic mutations and aganglionosis in Hirschsprung’s disease. J PediatrSurg 49:258–261Google Scholar
- 82.Moore SW, Zaahl M (2006) Immunomodulatory genes, enterocolitis and Hirschsprungs disease (HSCR). Abstract 013: British Association of Paediatric Surgeons Stockholm 19–21 July, 2006Google Scholar
- 83.Korenberg JR, Kawashima H, Pulst SM, Ikeuchi T, Ogasawara N, Yamamoto K et al (1990) Molecular definition of a region of chromosome 21 that causes features of the Down syndrome phenotype. AmJ Hum Genet 47:236–246Google Scholar
- 88.Moore SW (2017) Genetic impact on the treatment & management of Hirschsprung disease. J PediatrSurg 52:218–222 :.PM:28003043Google Scholar
- 92.Pini PA, Rossi V, Avanzini S, Mattioli G, Disma N, Jasonni V (2011) Hirschsprung’s disease: what about mortality? PediatrSurgInt 27:473–478Google Scholar