hirschsprung disease


Summary: Congenital MEGACOLON resulting from the absence of ganglion cells (aganglionosis) in a distal segment of the LARGE INTESTINE. The aganglionic segment is permanently contracted thus causing dilatation proximal to it. In most cases, the aganglionic segment is within the RECTUM and SIGMOID COLON.

Top Publications

  1. Alves M, Burzynski G, Delalande J, Osinga J, van der Goot A, Dolga A, et al. KBP interacts with SCG10, linking Goldberg-Shprintzen syndrome to microtubule dynamics and neuronal differentiation. Hum Mol Genet. 2010;19:3642-51 pubmed publisher
    ..Thus, our data indicate that KBP is involved in neuronal differentiation and that the central and enteric nervous system defects seen in GOSHS are likely caused by microtubule-related defects. ..
  2. Tsai Y, Murakami N, Gariepy C. Postnatal intestinal engraftment of prospectively selected enteric neural crest stem cells in a rat model of Hirschsprung disease. Neurogastroenterol Motil. 2011;23:362-9 pubmed publisher
    ..selected enteric neural crest stem cells (eNCSCs) to engraft and differentiate in the postnatal gut in the Hirschsprung disease (HD, ednrb(sl/sl)) rat...
  3. Emison E, Garcia Barcelo M, Grice E, Lantieri F, Amiel J, Burzynski G, et al. Differential contributions of rare and common, coding and noncoding Ret mutations to multifactorial Hirschsprung disease liability. Am J Hum Genet. 2010;87:60-74 pubmed publisher
    The major gene for Hirschsprung disease (HSCR) encodes the receptor tyrosine kinase RET...
  4. Pini Prato A, Rossi V, Avanzini S, Mattioli G, Disma N, Jasonni V. Hirschsprung's disease: what about mortality?. Pediatr Surg Int. 2011;27:473-8 pubmed publisher
    ..Postoperatively, close follow-up appointments are recommended. Families should be acknowledged and educated for prompt recognition and treatment of severe life-threatening complications. ..
  5. Zhu J, Garcia Barcelo M, Tam P, Lui V. HOXB5 cooperates with NKX2-1 in the transcription of human RET. PLoS ONE. 2011;6:e20815 pubmed publisher
    ..Therefore, defects in cis- or trans-regulation of RET by HOXB5 could lead to reduction of RET expression and contribute to the manifestation of the HSCR phenotype. ..
  6. Luzón Toro B, Torroglosa A, Núñez Torres R, Enguix Riego M, Fernández R, De Agustin J, et al. Comprehensive analysis of NRG1 common and rare variants in Hirschsprung patients. PLoS ONE. 2012;7:e36524 pubmed publisher
    b>Hirschsprung disease (HSCR, OMIM 142623) is a developmental disorder characterized by the absence of ganglion cells along variable lengths of the distal gastrointestinal tract, which results in tonic contraction of the aganglionic gut ..
  7. Stanchina L, Van de Putte T, Goossens M, Huylebroeck D, Bondurand N. Genetic interaction between Sox10 and Zfhx1b during enteric nervous system development. Dev Biol. 2010;341:416-28 pubmed publisher
    The involvement of SOX10 and ZFHX1B in Waardenburg-Hirschsprung disease (hypopigmentation, deafness, and absence of enteric ganglia) and Mowat-Wilson syndrome (mental retardation, facial dysmorphy and variable congenital malformations ..
  8. de la Torre L, Langer J. Transanal endorectal pull-through for Hirschsprung disease: technique, controversies, pearls, pitfalls, and an organized approach to the management of postoperative obstructive symptoms. Semin Pediatr Surg. 2010;19:96-106 pubmed publisher
    ..emerged in the late 1990s as the most recent step in the evolution of the surgical correction of Hirschsprung disease. This operation provides the advantages of a minimal access approach with shorter hospital stay, shorter ..
  9. Moore S, Zaahl M. Intronic RET gene variants in Down syndrome-associated Hirschsprung disease in an African population. J Pediatr Surg. 2012;47:299-302 pubmed publisher
    Clinical association between Hirschsprung disease (HD) and Down syndrome (DS) is well established. RET promoter and intron 1 variations have been shown to interfere with RET function, increasing the risk of HD pathogenesis...

More Information


  1. Borrego S, Ruiz Ferrer M, Fernandez R, Antinolo G. Hirschsprung's disease as a model of complex genetic etiology. Histol Histopathol. 2013;28:1117-36 pubmed publisher
    b>Hirschsprung disease (HSCR), or aganglionic megacolon, is a developmental disorder characterised by the absence of ganglion cells along variable length of the distal gastrointestinal tract, leading to the most common form of functional ..
  2. Jiang Q, Ho Y, Hao L, Nichols Berrios C, Chakravarti A. Copy number variants in candidate genes are genetic modifiers of Hirschsprung disease. PLoS ONE. 2011;6:e21219 pubmed publisher
    b>Hirschsprung disease (HSCR) is a neurocristopathy characterized by absence of intramural ganglion cells along variable lengths of the gastrointestinal tract...
  3. Laranjeira C, Pachnis V. Enteric nervous system development: Recent progress and future challenges. Auton Neurosci. 2009;151:61-9 pubmed publisher
    ..The present review will focus on recent progress on understanding the development of the mammalian enteric nervous system and highlight interesting directions of future research. ..
  4. Sribudiani Y, Metzger M, Osinga J, Rey A, Burns A, Thapar N, et al. Variants in RET associated with Hirschsprung's disease affect binding of transcription factors and gene expression. Gastroenterology. 2011;140:572-582.e2 pubmed publisher
    ..Binding of the transcription factors NXF, ARNT2, and SIM2 to RET depend on the RET polymorphism of Enh2 and affect RET expression and the development of Hirschsprung's disease. ..
  5. Zhou R, Niwa S, Homma N, Takei Y, Hirokawa N. KIF26A is an unconventional kinesin and regulates GDNF-Ret signaling in enteric neuronal development. Cell. 2009;139:802-13 pubmed publisher
    ..We therefore propose that the unconventional kinesin KIF26A plays a key role in enteric nervous system development by repressing a cell growth signaling pathway. ..
  6. Tang C, Tang W, So M, Miao X, Leung B, Yip B, et al. Fine mapping of the NRG1 Hirschsprung's disease locus. PLoS ONE. 2011;6:e16181 pubmed publisher
    ..This indicates that the effects of NRG1 common variants are likely to depend on other alleles or epigenetic factors present in the patients and would account for the variability in the genetic predisposition to HSCR. ..
  7. Nishiyama C, Uesaka T, Manabe T, Yonekura Y, Nagasawa T, Newgreen D, et al. Trans-mesenteric neural crest cells are the principal source of the colonic enteric nervous system. Nat Neurosci. 2012;15:1211-8 pubmed publisher
    ..and evidence suggests that impaired trans-mesenteric migration of ENCCs may underlie the pathogenesis of Hirschsprung disease (intestinal aganglionosis)...
  8. Ruiz Ferrer M, Torroglosa A, Núñez Torres R, De Agustin J, Antinolo G, Borrego S. Expression of PROKR1 and PROKR2 in human enteric neural precursor cells and identification of sequence variants suggest a role in HSCR. PLoS ONE. 2011;6:e23475 pubmed publisher
  9. Núñez Torres R, Fernandez R, Acosta M, Enguix Riego M, Marbà M, Carlos de Agustín J, et al. Comprehensive analysis of RET common and rare variants in a series of Spanish Hirschsprung patients confirms a synergistic effect of both kinds of events. BMC Med Genet. 2011;12:138 pubmed publisher
    RET is the major gene associated to Hirschsprung disease (HSCR) with differential contributions of its rare and common, coding and noncoding mutations to the multifactorial nature of this pathology...
  10. Carter T, Kay D, Browne M, Liu A, Romitti P, Kuehn D, et al. Hirschsprung's disease and variants in genes that regulate enteric neural crest cell proliferation, migration and differentiation. J Hum Genet. 2012;57:485-93 pubmed publisher
    ..The findings for HOXB5 and PHOX2B provide supportive evidence that genes regulating ENCC proliferation, migration and differentiation could be risk factors for HSCR. ..
  11. Jennings L, Yu M, Rand C, Kravis N, Berry Kravis E, Patwari P, et al. Variable human phenotype associated with novel deletions of the PHOX2B gene. Pediatr Pulmonol. 2012;47:153-61 pubmed publisher
    ..The case with PHOX2B partial exon 3 deletion had a CCHS-compatible phenotype (hypoventilation, Hirschsprung disease)...
  12. Tang C, Ngan E, Tang W, So M, Cheng G, Miao X, et al. Mutations in the NRG1 gene are associated with Hirschsprung disease. Hum Genet. 2012;131:67-76 pubmed publisher
    b>Hirschsprung disease (HSCR, congenital colon aganglionosis) is a relatively common complex genetic condition caused by abnormal development of the enteric nervous system (ENS)...
  13. Fernández R, Bleda M, Núñez Torres R, Medina I, Luzón Toro B, Garcia Alonso L, et al. Four new loci associations discovered by pathway-based and network analyses of the genome-wide variability profile of Hirschsprung's disease. Orphanet J Rare Dis. 2012;7:103 pubmed publisher
    ..This approach, based on the study of functionally-related gene sets, requires of lower sample sizes and opens new opportunities for the study of rare diseases. ..
  14. Mostafa R, Moustafa Y, Hamdy H. Interstitial cells of Cajal, the Maestro in health and disease. World J Gastroenterol. 2010;16:3239-48 pubmed
    ..This mini review describes what is known about the physiologic function and role of ICCs in GI system motility and in a variety of GI system motility disorders. ..
  15. Tang C, Cheng G, So M, Yip B, Miao X, Wong E, et al. Genome-wide copy number analysis uncovers a new HSCR gene: NRG3. PLoS Genet. 2012;8:e1002687 pubmed publisher
    b>Hirschsprung disease (HSCR) is a congenital disorder characterized by aganglionosis of the distal intestine...
  16. Puri P, Gosemann J. Variants of Hirschsprung disease. Semin Pediatr Surg. 2012;21:310-8 pubmed publisher
    Variants of Hirschsprung disease are conditions that clinically resemble Hirschsprung disease, despite the presence of ganglion cells in rectal suction biopsies...
  17. Tomycz N, Haynes R, Schmidt E, Ackerson K, Kinney H. Novel neuropathologic findings in the Haddad syndrome. Acta Neuropathol. 2010;119:261-9 pubmed publisher
    ..This study implicates novel brain findings in Haddad syndrome mimicking those in murine Phox2b null mutants. This case suggests that abnormalities occur in CCHS in a network of sites critical to chemoreception...
  18. Hotta R, Natarajan D, Burns A, Thapar N. Stem cells for GI motility disorders. Curr Opin Pharmacol. 2011;11:617-23 pubmed publisher
    ..Although definitive cell replenishment therapies for gut motility disorders appear to be an exciting and realistic prospect, even in the short-term, a number of challenges remain to be addressed before definitive clinical application. ..
  19. Barlow A, Dixon J, Dixon M, Trainor P. Balancing neural crest cell intrinsic processes with those of the microenvironment in Tcof1 haploinsufficient mice enables complete enteric nervous system formation. Hum Mol Genet. 2012;21:1782-93 pubmed publisher
    ..In fact, these deficiencies can be overcome by balancing NCC intrinsic processes of proliferation and differentiation with extrinsic influences of the gut microenvironment. ..
  20. Sánchez Mejías A, Watanabe Y, M Fernández R, Lopez Alonso M, Antinolo G, Bondurand N, et al. Involvement of SOX10 in the pathogenesis of Hirschsprung disease: report of a truncating mutation in an isolated patient. J Mol Med (Berl). 2010;88:507-14 pubmed publisher
    ..the myenteric and submucosal plexus of the gastrointestinal tract, also known as aganglionic megacolon or Hirschsprung disease (HSCR)...
  21. Shen C, Song Z, Zheng S, Xiao X. A comparison of the effectiveness of the Soave and Martin procedures for the treatment of total colonic aganglionosis. J Pediatr Surg. 2009;44:2355-8 pubmed publisher
    ..Although each procedure has advantages and disadvantages, the Soave procedure is promising for the treatment of TCA, especially with regard to postoperative complications. A long-term follow-up study is needed. ..
  22. Cornes B, Tang C, Leon T, Hui K, So M, Miao X, et al. Haplotype analysis reveals a possible founder effect of RET mutation R114H for Hirschsprung's disease in the Chinese population. PLoS ONE. 2010;5:e10918 pubmed publisher
    ..This suggests that RET(R114H) is a founder mutation for HSCR in the Chinese population. ..
  23. Heanue T, Pachnis V. Prospective identification and isolation of enteric nervous system progenitors using Sox2. Stem Cells. 2011;29:128-40 pubmed publisher
    ..Our studies will facilitate development of cell replacement strategies in animal models, critical to develop human cell replacement therapies for HSCR. ..
  24. Sánchez Mejías A, Núñez Torres R, Fernandez R, Antinolo G, Borrego S. Novel MLPA procedure using self-designed probes allows comprehensive analysis for CNVs of the genes involved in Hirschsprung disease. BMC Med Genet. 2010;11:71 pubmed publisher
    b>Hirschsprung disease is characterized by the absence of intramural ganglion cells in the enteric plexuses, due to a fail during enteric nervous system formation...
  25. Wang L, Fan Y, Zhou F, Li H, Zhang Y, Miao J, et al. Semaphorin 3A expression in the colon of Hirschsprung disease. Birth Defects Res A Clin Mol Teratol. 2011;91:842-7 pubmed publisher
    b>Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence of intrinsic ganglion cells in the nerve plexuses of the lower colon...
  26. Moore S, Zaahl M. Familial associations in medullary thyroid carcinoma with Hirschsprung disease: the role of the RET-C620 "Janus" genetic variation. J Pediatr Surg. 2010;45:393-6 pubmed publisher
    b>Hirschsprung disease (HSCR) is associated with the later development of multiple endocrine neoplasia (MEN2), because RET gene variations are associated with both conditions...
  27. Rangel S, de Blaauw I. Advances in pediatric colorectal surgical techniques. Semin Pediatr Surg. 2010;19:86-95 pubmed publisher
    ..the way that many of these conditions are managed, particularly in the areas of anorectal malformations and Hirschsprung disease. Furthermore, a more thorough understanding of the pathophysiology underlying encopresis and true fecal ..
  28. Wallace A, Schmidt C, Schachner M, Wegner M, Anderson R. L1cam acts as a modifier gene during enteric nervous system development. Neurobiol Dis. 2010;40:622-33 pubmed publisher
    ..Finally, we show that Sox10 can regulate the expression of L1cam. Thus, L1cam can act as a modifier gene for the HSCR associated gene, Sox10, and is likely to play a role in the etiology of Hirschsprung's disease. ..
  29. Leon T, Ngan E, Poon H, So M, Lui V, Tam P, et al. Transcriptional regulation of RET by Nkx2-1, Phox2b, Sox10, and Pax3. J Pediatr Surg. 2009;44:1904-12 pubmed publisher
    ..Mutations in RET regulatory regions are also associated with Hirschsprung disease (HSCR) (aganglionosis of the colon)...
  30. Núñez Torres R, Fernandez R, Lopez Alonso M, Antinolo G, Borrego S. A novel study of copy number variations in Hirschsprung disease using the multiple ligation-dependent probe amplification (MLPA) technique. BMC Med Genet. 2009;10:119 pubmed publisher
    b>Hirschsprung disease (HSCR) is a congenital malformation of the hindgut produced by a disruption in neural crest cell migration during embryonic development...
  31. Bergeron K, Silversides D, Pilon N. The developmental genetics of Hirschsprung's disease. Clin Genet. 2013;83:15-22 pubmed publisher
    ..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...
  32. Miao X, Leon T, Ngan E, So M, Yuan Z, Lui V, et al. Reduced RET expression in gut tissue of individuals carrying risk alleles of Hirschsprung's disease. Hum Mol Genet. 2010;19:1461-7 pubmed publisher
  33. Uesaka T, Enomoto H. Neural precursor death is central to the pathogenesis of intestinal aganglionosis in Ret hypomorphic mice. J Neurosci. 2010;30:5211-8 pubmed publisher
    ..Hypomorphic RET alleles cause intestinal aganglionosis [Hirschsprung disease (HSCR)], in which delayed migration and successive nonapoptotic ENCC death are considered to be major ..
  34. Kenny S, Tam P, Garcia Barcelo M. Hirschsprung's disease. Semin Pediatr Surg. 2010;19:194-200 pubmed publisher
    ..This review aims to draw these strands together to explain the developmental and biological basis of HSCR, and how this knowledge may be used in the future to aid children with HSCR. ..
  35. Ruiz Ferrer M, Torroglosa A, Luzón Toro B, Fernandez R, Antinolo G, Mulligan L, et al. Novel mutations at RET ligand genes preventing receptor activation are associated to Hirschsprung's disease. J Mol Med (Berl). 2011;89:471-80 pubmed publisher
    b>Hirschsprung disease (HSCR) is a developmental disorder characterized by the absence of ganglion cells along variable lengths of the distal gastrointestinal tract...
  36. Tang C, Sribudiani Y, Miao X, de Vries A, Burzynski G, So M, et al. Fine mapping of the 9q31 Hirschsprung's disease locus. Hum Genet. 2010;127:675-83 pubmed publisher
    ..Our finding is supported by the role of IKBKAP in the development of the nervous system. ..
  37. Gershon M. Developmental determinants of the independence and complexity of the enteric nervous system. Trends Neurosci. 2010;33:446-56 pubmed publisher
    ..It is probable that highly prevalent disorders of gastrointestinal sensation and motility result from subtle defects in ENS development. ..
  38. Ohgami N, Ida Eto M, Shimotake T, Sakashita N, Sone M, Nakashima T, et al. c-Ret-mediated hearing loss in mice with Hirschsprung disease. Proc Natl Acad Sci U S A. 2010;107:13051-6 pubmed publisher
    A significantly increased risk for dominant sensorineural deafness in patients who have Hirschsprung disease (HSCR) caused by endothelin receptor type B and SOX10 has been reported...
  39. Sánchez Mejías A, Fernández R, Lopez Alonso M, Antinolo G, Borrego S. New roles of EDNRB and EDN3 in the pathogenesis of Hirschsprung disease. Genet Med. 2010;12:39-43 pubmed publisher
    b>Hirschsprung disease is characterized by the absence of intramural ganglion cells in the myenteric and submucosal plexuses within distal intestine, because of a fail in the enteric nervous system formations process...
  40. Liu C, Tang Q, Lou J, Luo C, Zhou X, Li D, et al. Association analysis of the RET proto-oncogene with Hirschsprung disease in the Han Chinese population of southeastern China. Biochem Genet. 2010;48:496-503 pubmed publisher
    b>Hirschsprung disease (HSCR) is a complex congenital disorder characterized by intestinal obstructions caused by the absence of the intestinal ganglion cells of the nerve plexuses in variable lengths of the digestive tract...
  41. Dang R, Torigoe D, Suzuki S, Kikkawa Y, Moritoh K, Sasaki N, et al. Genetic background strongly modifies the severity of symptoms of Hirschsprung disease, but not hearing loss in rats carrying Ednrb(sl) mutations. PLoS ONE. 2011;6:e24086 pubmed publisher
    b>Hirschsprung disease (HSCR) is thought to result as a consequence of multiple gene interactions that modulate the ability of enteric neural crest cells to populate the developing gut...
  42. Jain S, Knoten A, Hoshi M, Wang H, Vohra B, Heuckeroth R, et al. Organotypic specificity of key RET adaptor-docking sites in the pathogenesis of neurocristopathies and renal malformations in mice. J Clin Invest. 2010;120:778-90 pubmed publisher
    ..docking site for multiple adaptor proteins including Shc, caused distal colon aganglionosis reminiscent of Hirschsprung disease (HSCR)...
  43. Zhang D, Brinas I, Binder B, Landman K, Newgreen D. Neural crest regionalisation for enteric nervous system formation: implications for Hirschsprung's disease and stem cell therapy. Dev Biol. 2010;339:280-94 pubmed publisher
    ..This has important implications for proposed NC stem cell therapy for Hirschsprung's disease, since such cells may need to be optimised for positional identity. ..
  44. Jiang Q, Turner T, Sosa M, Rakha A, Arnold S, Chakravarti A. Rapid and efficient human mutation detection using a bench-top next-generation DNA sequencer. Hum Mutat. 2012;33:281-9 pubmed publisher
    ..detection by amplicon sequencing of three type 3 semaphorin genes SEMA3A, SEMA3C, and SEMA3D implicated in Hirschsprung disease (HSCR)...
  45. Ngan E, Garcia Barcelo M, Yip B, Poon H, Lau S, Kwok C, et al. Hedgehog/Notch-induced premature gliogenesis represents a new disease mechanism for Hirschsprung disease in mice and humans. J Clin Invest. 2011;121:3467-78 pubmed publisher
    ..Collectively, we defined PTCH1 and DLL3 as HSCR susceptibility genes and suggest that Hedgehog/Notch-induced premature gliogenesis may represent a new disease mechanism for HSCR. ..
  46. Cheung S, Tam Y, Chong H, Chan K, Mou W, Sihoe D, et al. An 18-year experience in total colonic aganglionosis: from staged operations to primary laparoscopic endorectal pull-through. J Pediatr Surg. 2009;44:2352-4 pubmed publisher
    ..5 years). Primary laparoscopic endorectal pull-through is feasible in TCA with limited small bowel involvement and has the advantage of a single-stage operation, avoiding a stoma and its related complications. ..
  47. Rabah R. Total colonic aganglionosis: case report, practical diagnostic approach and pitfalls. Arch Pathol Lab Med. 2010;134:1467-73 pubmed publisher
    b>Hirschsprung disease remains a challenging diagnosis for many pathologists...
  48. Wang L, Zhang Y, Fan Y, Li H, Zhou F, Miao J, et al. SEMA3A rs7804122 polymorphism is associated with Hirschsprung disease in the Northeastern region of China. Birth Defects Res A Clin Mol Teratol. 2012;94:91-5 pubmed publisher
    b>Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence of intrinsic ganglion cells in the nerve plexuses of the lower colon...
  49. Fu M, Sato Y, Lyons Warren A, Zhang B, KANE M, Napoli J, et al. Vitamin A facilitates enteric nervous system precursor migration by reducing Pten accumulation. Development. 2010;137:631-40 pubmed publisher
    b>Hirschsprung disease is a serious disorder of enteric nervous system (ENS) development caused by the failure of ENS precursor migration into the distal bowel...
  50. Best K, Glinianaia S, Bythell M, Rankin J. Hirschsprung's disease in the North of England: prevalence, associated anomalies, and survival. Birth Defects Res A Clin Mol Teratol. 2012;94:477-80 pubmed publisher
    ..This study confirmed a male predominance and an association with Down syndrome, but also found a temporal increase in Hirschsprung's disease prevalence. No cases were suspected prenatally, but half were diagnosed within 5 days of life. ..
  51. Walters L, Cantrell V, Weller K, Mosher J, Southard Smith E. Genetic background impacts developmental potential of enteric neural crest-derived progenitors in the Sox10Dom model of Hirschsprung disease. Hum Mol Genet. 2010;19:4353-72 pubmed publisher
    ..Developmental processes were investigated in congenic Sox10(Dom) mice, an established Hirschsprung disease (HSCR) model, on distinct inbred backgrounds, C57BL/6J (B6) and C3HeB/FeJ (C3Fe)...
  52. Yang J, Duan S, Zhong R, Yin J, Pu J, Ke J, et al. Exome sequencing identified NRG3 as a novel susceptible gene of Hirschsprung's disease in a Chinese population. Mol Neurobiol. 2013;47:957-66 pubmed publisher
    ..1329G>A (p.M443I) and two synonymous variants c.828G>A (p.T276T) and c.1365T>A (p.P455P) only in the cases. Our results indicated that NRG3 may be a susceptibility gene for HSCR in a Chinese population. ..
  53. Selfridge J, Song L, Brownstein D, Melton D. Mice with DNA repair gene Ercc1 deficiency in a neural crest lineage are a model for late-onset Hirschsprung disease. DNA Repair (Amst). 2010;9:653-60 pubmed publisher
    ..unrepaired endogenous DNA damage in the Ercc1-deficient colonic parasympathetic ganglia leads to the degeneration of this network and results in a colonic obstructive disorder that resembles late-onset Hirschsprung disease in man.