Hirschsprung’s Disease

  • Prem Puri
  • Florian Friedmacher


Hirschsprung’s disease (HD) is a relatively common cause of intestinal obstruction in newborn infants. It is characterized by the absence of ganglion cells in the distal bowel, which begins at the level of the internal anal sphincter and extends proximally for varying distances. The absence of ganglion cells has been attributed to the failure of migration of neural crest cells.


Hirschsprung disease Aetiology and pathogenesis Surgery Outcomes 


  1. 1.
    Ruysch F. Observationum anatomico-chirurgicarum centuria. Amsterdam; 1691.Google Scholar
  2. 2.
    Jacobi A. On some important causes of constipation in infants. Am J Obstet Gynecol. 1869;2:96–113.Google Scholar
  3. 3.
    Hirschsprung H. Stuhlträgheit Neugeborener in Folge von Dilatation und Hypertrophie des Colons. Jahrb f Kinderheilkunde. 1888;27:1–7.Google Scholar
  4. 4.
    Tittel K. Über eine angeborene Missbildung des Dickdarms. Wien Klin Wochenschr. 1901;14:903–7.Google Scholar
  5. 5.
    Ehrenpreis T. Megacolon in the newborn: a clinical and roentgenological study with special regard to the pathogenesis. Acta Chir Scand Suppl. 1946;112:94.Google Scholar
  6. 6.
    Whitehouse FR, Kernohan JW. Myenteric plexuses in congenital megacolon: study of 11 cases. Arch Intern Med. 1948;82:75–111.CrossRefGoogle Scholar
  7. 7.
    Swenson O, Bill AH. Resection of rectum and rectosigmoid with preservation of the sphincter for benign spastic lesions producing megacolon. Surgery. 1948;24:212–20.PubMedGoogle Scholar
  8. 8.
    Puri P. Hirschsprung’s disease. In: Puri P, editor. Newborn Surgery. London: Hodder Arnold; 2011. p. 554–65.CrossRefGoogle Scholar
  9. 9.
    Haricharan RN, Georgeson KE. Hirschsprung disease. Semin Pediatr Surg. 2008;17:266–75.CrossRefPubMedGoogle Scholar
  10. 10.
    Kleinhaus S, et al. Hirschsprung’s disease: a survey of the members of the Surgical Section of the American Academy of Pediatrics. J Pediatr Surg. 1979;14:588–97.CrossRefPubMedGoogle Scholar
  11. 11.
    Sherman JO, et al. A 40-year multinational retrospective study of 880 Swenson procedures. J Pediatr Surg. 1989;24:833–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Suita S, et al. Hirschsprung’s disease in Japan: analysis of 3852 patients based on a nationwide survey in 30 years. J Pediatr Surg. 2005;40:197–201.CrossRefPubMedGoogle Scholar
  13. 13.
    Senyuz OF, et al. Total intestinal aganglionosis with involvement of the stomach. Pediatr Surg Int. 1988;3:74–5.CrossRefGoogle Scholar
  14. 14.
    Sharif K, et al. New perspective for the management of near-total or total intestinal aganglionosis in infants. J Pediatr Surg. 2003;38:25–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Meier-Ruge W. Ultrashort segment Hirschsprung disease: an objective picture of the disease substantiated by biopsy. Z Kinderchir. 1985;40:146–50.PubMedGoogle Scholar
  16. 16.
    Meier-Ruge WA, et al. Diagnosis and therapy of ultrashort Hirschsprung’s disease. Eur J Pediatr Surg. 2004;14:392–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Neilson IR, Yazbeck S. Ultrashort Hirschsprung’s disease: myth or reality. J Pediatr Surg. 1990;25:1135–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Haney PJ, Hill JL, Sun CCJ. Zonal colonic aganglionosis. Pediatr Radiol. 1982;12:258–61.CrossRefPubMedGoogle Scholar
  19. 19.
    MacIver AG, Whitehead R. Zonal colonic aganglionosis, a variant of Hirschsprung’s disease. Arch Dis Child. 1972;47:233–7.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Seldenrijk CA, et al. Zonal aganglionosis: an enzyme and immunohistochemical study of two cases. Virchows Arch A Pathol Anat Histopathol. 1986;410:75–81.CrossRefPubMedGoogle Scholar
  21. 21.
    Kapur RP, et al. Hypothesis: pathogenesis of skip areas in long-segment Hirschsprung’s disease. Pediatr Pathol Lab Med. 1995;15:23–37.CrossRefPubMedGoogle Scholar
  22. 22.
    Martin LW, et al. Hirschsprung’s disease with skip area (segmental aganglionosis). J Pediatr Surg. 1979;14:686–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Sprinz H, Cohen A, Heaton LD. Hirschsprung’s disease with skip area. Ann Surg. 1961;153:143–8.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    O’Donnell AM, Puri P. Skip segment Hirschsprung’s disease: a systematic review. Pediatr Surg Int. 2010;26:1065–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Orr JD, Scobie WG. Presentation and incidence of Hirschsprung’s disease. BMJ. 1983;287:1671–1.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Passarge E. Genetics of Hirschsprung’s disease: evidence for heterogeneous etiology and a study of 63 families. N Engl J Med. 1967;276:138–43.CrossRefPubMedGoogle Scholar
  27. 27.
    Spouge D, Baird PA. Hirschsprung disease in a large birth cohort. Teratology. 1985;32:171–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Torfs C (1998) An epidemiological study of Hirschsprung’s disease in a multiracial Californian population. Paper presented at the Third International Meeting: Hirschsprung’s disease and related neurocristopathies, Evian, France.Google Scholar
  29. 29.
    Emison ES, et al. A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk. Nature. 2005;434:857–63.CrossRefPubMedGoogle Scholar
  30. 30.
    Badner JA, et al. A genetic study of Hirschsprung’s disease. Am J Hum Genet. 1990;46:568–80.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Ikeda K, Goto S. Diagnosis and treatment of Hirschsprung’s disease in Japan. An analysis of 1628 patients. Ann Surg. 1984;199:400–5.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Paran TS, Rolle U, Puri P. Enteric nervous system and developmental abnormalities in childhood. Pediatr Surg Int. 2006;22:945–59.CrossRefPubMedGoogle Scholar
  33. 33.
    Gershon MD. Functional anatomy of the enteric nervous system. In: Holschneider AM, Puri P, editors. Hirschsprung’s disease and allied disorders. Heidelberg: Springer; 2008. p. 21–49.CrossRefGoogle Scholar
  34. 34.
    Gershon MD, Chalazonitis A, Rothman TP. From neural crest to bowel: development of the enteric nervous system. J Neurobiol. 1993;24:199–214.CrossRefPubMedGoogle Scholar
  35. 35.
    Puri P, Rolle U. Development of the enteric nervous system. In: Holschneider AM, Puri P, editors. Hirschsprung’s disease and allied disorders. Heidelberg: Springer; 2008. p. 13–20.CrossRefGoogle Scholar
  36. 36.
    Puri P, Ohshiro K, Wester T. Hirschsprung’s disease: a search for etiology. Semin Pediatr Surg. 1998;7:140–7.CrossRefPubMedGoogle Scholar
  37. 37.
    Rolle U, Nemeth L, Puri P. Nitrergic innervation of the normal gut and in motility disorders of childhood. J Pediatr Surg. 2002;37:551–67.CrossRefPubMedGoogle Scholar
  38. 38.
    Burns AJ, et al. Development of the enteric nervous system and its role in intestinal motility during fetal and early postnatal stages. Semin Pediatr Surg. 2009;18:196–205.CrossRefPubMedGoogle Scholar
  39. 39.
    Burns AJ, Le Douarin NM. The sacral neural crest contributes neurons and glia to the post-umbilical gut: spatiotemporal analysis of the development of the enteric nervous system. Development. 1998;125:4335–47.PubMedGoogle Scholar
  40. 40.
    Le Douarin NM, Teillet MA. Migration of neural crest cells to wall of digestive tract in avian embryo. J Embryol Exp Morphol. 1973;30:31–48.PubMedGoogle Scholar
  41. 41.
    Puri P, Shinkai T. Pathogenesis of Hirschsprung’s disease and its variants: recent progress. Semin Pediatr Surg. 2004;13:18–24.CrossRefPubMedGoogle Scholar
  42. 42.
    Furness JB, Costa M. Structure of the enteric nervous system. In: Furness JB, editor. The enteric nervous system. Oxford: Blackwell; 2006. p. 1–28.Google Scholar
  43. 43.
    Tam PK, Garcia-Barcelo M. Genetic basis of Hirschsprung’s disease. Pediatr Surg Int. 2009;25:543–58.CrossRefPubMedGoogle Scholar
  44. 44.
    Caniano DA, et al. Total intestinal aganglionosis. J Pediatr Surg. 1985;20:456–60.CrossRefPubMedGoogle Scholar
  45. 45.
    Nemeth L, et al. Three-dimensional morphology of gut innervation in total intestinal aganglionosis using whole-mount preparation. J Pediatr Surg. 2001;36:291–4.CrossRefPubMedGoogle Scholar
  46. 46.
    Jannot AS, et al. Male and female differential reproductive rate could explain parental transmission asymmetry of mutation origin in Hirschsprung disease. Eur J Hum Genet. 2012;20:917–20.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Caniano DA, Teitelbaum DH, Qualman SJ. Management of Hirschsprung’s disease in children with trisomy 21. Am J Surg. 1990;159:402–4.CrossRefPubMedGoogle Scholar
  48. 48.
    Goldberg E. An epidemiological study of Hirschsprung’s disease. Int J Epidemiol. 1985;13:479–85.CrossRefGoogle Scholar
  49. 49.
    Moore SW. Down syndrome and the enteric nervous system. Pediatr Surg Int. 2008;24:873–83.CrossRefPubMedGoogle Scholar
  50. 50.
    Quinn FMJ, Surana R, Puri P. The influence of trisomy 21 on outcome in children with Hirschsprung’s disease. J Pediatr Surg. 1994;29:781–3.CrossRefPubMedGoogle Scholar
  51. 51.
    Arnold S, et al. Interaction between a chromosome 10 RET enhancer and chromosome 21 in the Down syndrome-Hirschsprung disease association. Hum Mutat. 2009;30:771–5.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Moore SW, Zaahl MG. Intronic RET gene variants in Down syndrome-associated Hirschsprung disease in an African population. J Pediatr Surg. 2012;47:299–302.CrossRefPubMedGoogle Scholar
  53. 53.
    Amiel J, et al. Hirschsprung disease, associated syndromes and genetics: a review. J Med Genet. 2008;45:1–14.CrossRefPubMedGoogle Scholar
  54. 54.
    Wallace AS, Anderson RB. Genetic interactions and modifier genes in Hirschsprung’s disease. World J Gastroenterol. 2011;17:4937–44.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Amiel J, et al. Heterozygous endothelin receptor B (EDNRB) mutations in isolated Hirschsprung disease. Hum Mol Genet. 1996;5:355–7.CrossRefPubMedGoogle Scholar
  56. 56.
    Angrist M, et al. Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient. Nat Genet. 1996;14:341–4.CrossRefPubMedGoogle Scholar
  57. 57.
    Attié T, et al. Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease. Hum Mol Genet. 1995;4:1381–6.CrossRefPubMedGoogle Scholar
  58. 58.
    Bidaud C, et al. Endothelin-3 gene mutations in isolated and syndromic Hirschsprung disease. Eur J Hum Genet. 1997;5:247–51.PubMedGoogle Scholar
  59. 59.
    Brooks AS, et al. Homozygous nonsense mutations in KIAA1279 are associated with malformations of the central and enteric nervous systems. Am J Hum Genet. 2005;77:120–6.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Carter TC, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Doray B, et al. Mutation of the RET ligand, neurturin, supports multigenic inheritance in Hirschsprung disease. Hum Mol Genet. 1998;7:1449–52.CrossRefPubMedGoogle Scholar
  62. 62.
    Garavelli L, et al. Hirschsprung disease, mental retardation, characteristic facial features, and mutation in the gene ZFHX1B (SIP1): confirmation of the Mowat-Wilson syndrome. Am J Med Genet A. 2003;116A:385–8.CrossRefPubMedGoogle Scholar
  63. 63.
    Garcia-Barcelo M, et al. Association study of PHOX2B as a candidate gene for Hirschsprung’s disease. Gut. 2003;52:563–7.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Garcia-Barcelo MM, et al. Evaluation of the NK2 homeobox 1 gene (NKX2–1) as a Hirschsprung’s disease locus. Ann Hum Genet. 2008;72:170–7.CrossRefPubMedGoogle Scholar
  65. 65.
    Garcia-Barcelo MM, et al. Correlation between genetic variations in Hox clusters and Hirschsprung’s disease. Ann Hum Genet. 2007;71:526–36.CrossRefPubMedGoogle Scholar
  66. 66.
    Garcia-Barcelo MM, et al. Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung’s disease. Proc Natl Acad Sci U S A. 2009;106:2694–9.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Herbarth B, et al. Mutation of the Sry-related Sox10 gene in dominant megacolon, a mouse model for human Hirschsprung disease. Proc Natl Acad Sci U S A. 1998;95:5161–5.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Hofstra RM, et al. A loss-of-function mutation in the endothelin-converting enzyme 1 (ECE-1) associated with Hirschsprung disease, cardiac defects, and autonomic dysfunction. Am J Hum Genet. 1999;64:304–8.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Hofstra RMW, et al. RET and GDNF gene scanning in Hirschsprung patients using two dual denaturing gel systems. Hum Mutat. 2000;15:418–29.CrossRefPubMedGoogle Scholar
  70. 70.
    Ivanchuk SM, et al. De novo mutation of GDNF, ligand for the RET/GDNFR-alpha receptor complex, in Hirschsprung disease. Hum Mol Genet. 1996;5:2023–6.CrossRefPubMedGoogle Scholar
  71. 71.
    Jiang Q, et al. Copy number variants in candidate genes are genetic modifiers of Hirschsprung disease. PLoS One. 2011;6:e21219.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Kusafuka T, Wang YP, Puri P. Novel mutations of the endothelin-B receptor gene in isolated patients with Hirschsprung’s disease. Hum Mol Genet. 1996;5:347–9.CrossRefPubMedGoogle Scholar
  73. 73.
    Lui VC, et al. Perturbation of hoxb5 signaling in vagal neural crests down-regulates ret. leading to intestinal hypoganglionosis in mice. Gastroenterology. 2008;134:1104–15.CrossRefPubMedGoogle Scholar
  74. 74.
    Myers SM, et al. Investigation of germline GFR alpha-1 mutations in Hirschsprung disease. J Med Genet. 1999;36:217–20.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Pasini B, et al. Loss of function effect of RET mutations causing Hirschsprung disease. Nat Genet. 1995;10:35–40.CrossRefPubMedGoogle Scholar
  76. 76.
    Pingault V, et al. Human homology and candidate genes for the dominant megacolon locus: a mouse model of Hirschsprung disease. Genomics. 1997;39:86–9.CrossRefPubMedGoogle Scholar
  77. 77.
    Puffenberger EG, et al. A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung’s disease. Cell. 1994;79:1257–66.CrossRefPubMedGoogle Scholar
  78. 78.
    Rosenfeld JA, et al. Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations. Genet Med. 2009;11:797–805.CrossRefPubMedGoogle Scholar
  79. 79.
    Southard-Smith EM, Kos L, Pavan WJ. Sox10 mutation disrupts neural crest development in Dom Hirschsprung mouse model. Nat Genet. 1998;18:60–4.CrossRefPubMedGoogle Scholar
  80. 80.
    Stanchina L, et al. Genetic interaction between Sox10 and Zfhx1b during enteric nervous system development. Dev Biol. 2010;341:416–28.CrossRefPubMedGoogle Scholar
  81. 81.
    Svensson PJ, et al. A heterozygous frameshift mutation in the endothelin-3 (EDN-3) gene in isolated Hirschsprung’s disease. Pediatr Res. 1999;45:714–7.CrossRefPubMedGoogle Scholar
  82. 82.
    Tang CS, et al. Genome-wide copy number analysis uncovers a new HSCR Gene: NRG3. PLoS Genet. 2012;8:e1002687.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Tang CS, et al. Mutations in the NRG1 gene are associated with Hirschsprung disease. Hum Genet. 2012;131:67–76.CrossRefPubMedGoogle Scholar
  84. 84.
    Tang CSM, et al. Fine mapping of the NRG1 Hirschsprung’s disease locus. PLoS One. 2011;6:e16181.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Wakamatsu N, et al. Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease. Nat Genet. 2001;27:369–70.CrossRefPubMedGoogle Scholar
  86. 86.
    Wallace AS, et al. L1cam acts as a modifier gene during enteric nervous system development. Neurobiol Dis. 2010;40:622–33.CrossRefPubMedGoogle Scholar
  87. 87.
    Wallace AS, et al. L1cam acts as a modifier gene for members of the endothelin signalling pathway during enteric nervous system development. Neurogastroenterol Motil. 2011;23:e510–22.CrossRefPubMedGoogle Scholar
  88. 88.
    Zhu J, et al. HOXB5 cooperates with NKX2–1 in the transcription of human RET. PLoS One. 2011;6:e20815.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Edery P, et al. Mutations of the RET proto-oncogene in Hirschsprung’s disease. Nature. 1994;367:378–80.CrossRefPubMedGoogle Scholar
  90. 90.
    Romeo G, et al. Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung’s disease. Nature. 1994;367:377–8.CrossRefPubMedGoogle Scholar
  91. 91.
    Sancandi M, et al. Incidence of RET mutations in patients with Hirschsprung’s disease. J Pediatr Surg. 2000;35:139–42.CrossRefPubMedGoogle Scholar
  92. 92.
    Emison ES, 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.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Alves MMM, et al. Mutations in SCG10 are not involved in Hirschsprung’s disease. PLoS One. 2010;5:e15144.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Kusafuka T, Wang YP, Puri P. Mutation analysis of the RET, the endothelin-B receptor, and the endothelin-3 genes in sporadic cases of Hirschsprung’s disease. J Pediatr Surg. 1997;32:501–4.CrossRefPubMedGoogle Scholar
  95. 95.
    Dasgupta R, Langer JC. Hirschsprung disease. Curr Probl Surg. 2004;41:942–88.CrossRefPubMedGoogle Scholar
  96. 96.
    Kakita Y, et al. Selective demonstration of mural nerves in ganglionic and aganglionic colon by immunohistochemistry for glucose transporter-1: prominent extrinsic nerve pattern staining in Hirschsprung disease. Arch Pathol Lab Med. 2000;124:1314–9.PubMedGoogle Scholar
  97. 97.
    Kobayashi H, Obriain DS, Puri P. Nerve growth factor receptor immunostaining suggests an extrinsic origin for hypertrophic nerves in Hirschsprung’s disease. Gut. 1994;35:1605–7.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Payette RF, et al. Origin and morphology of nerve fibers in the aganglionic colon of the lethal spotted (ls/ls) Mutant Mouse. J Comp Neurol. 1987;257:237–52.CrossRefPubMedGoogle Scholar
  99. 99.
    Tam PKH, Boyd GP. Origin, course, and endings of abnormal enteric nerve fibers in Hirschsprung’s disease defined by whole-mount immunohistochemistry. J Pediatr Surg. 1990;25:457–61.CrossRefPubMedGoogle Scholar
  100. 100.
    Watanabe Y, et al. Spatial distribution and pattern of extrinsic nerve strands in the aganglionic segment of congenital aganglionosis: stereoscopic analysis in spotting lethal rats. J Pediatr Surg. 1995;30:1471–6.CrossRefPubMedGoogle Scholar
  101. 101.
    Weinberg AG. Hirschsprung’s disease: a pathologist’s view. Perspect Pediatr Pathol. 1975;2:207–39.PubMedGoogle Scholar
  102. 102.
    Frigo GM, et al. Some observations on intrinsic nervous mechanism in Hirschsprung’s disease. Gut. 1973;14:35–40.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Vizi ES, et al. Characteristics of cholinergic neuroeffector transmission of ganglionic and aganglionic colon in Hirschsprung’s disease. Gut. 1990;31:1046–50.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Boston VE, Cywes S, Davies MRQ. Serum and erythrocyte acetylcholinesterase activity in Hirschsprung’s disease. J Pediatr Surg. 1978;13:407–10.CrossRefPubMedGoogle Scholar
  105. 105.
    Imamura K, et al. Pathophysiology of aganglionic colon segment: experimental study on aganglionosis produced by a new method in rat. J Pediatr Surg. 1975;10:865–73.CrossRefPubMedGoogle Scholar
  106. 106.
    Sato A, et al. Pathophysiology of aganglionic colon and anorectum: an experimental study on aganglionosis produced by a new method in the rat. J Pediatr Surg. 1978;13:399–435.CrossRefPubMedGoogle Scholar
  107. 107.
    Garrett JR, Howard ER, Nixon HH. Autonomic nerves in rectum and colon in Hirschsprung’s disease: a cholinesterase and catecholamine histochemical study. Arch Dis Child. 1969;44:406–17.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Nirasawa Y, et al. Hirschsprung’s disease: catecholamine content, alpha-adrenoceptors, and the effect of electrical stimulation in aganglionic colon. J Pediatr Surg. 1986;21:136–42.CrossRefPubMedGoogle Scholar
  109. 109.
    Touloukian RJ, Aghajanian G, Roth RH. Adrenergic hyperactivity of aganglionic colon. J Pediatr Surg. 1973;8:191–5.CrossRefPubMedGoogle Scholar
  110. 110.
    Hiramoto Y, Kiesewet WB. Response of colonic muscle to drugs: in-vitro study of Hirschsprung’s disease. J Pediatr Surg. 1974;9:13–20.CrossRefPubMedGoogle Scholar
  111. 111.
    Wright PG, Shepherd JJ. Some observations on response of normal human sigmoid colon to drugs in vitro. Gut. 1966;7:41–51.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Bult H, et al. Nitric oxide as an inhibitory nonadrenergic noncholinergic neurotransmitter. Nature. 1990;345:346–7.CrossRefPubMedGoogle Scholar
  113. 113.
    Dawson TM, et al. Nitric oxide synthase and neuronal NADPH diaphorase are identical in brain and peripheral tissues. Proc Natl Acad Sci U S A. 1991;88:7797–801.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Hope BT, et al. Neuronal NADPH diaphorase is a nitric oxide synthase. Proc Natl Acad Sci U S A. 1991;88:2811–4.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Bealer JF, et al. Nitric oxide synthase is deficient in the aganglionic colon of patients with Hirschsprung’s disease. Pediatrics. 1994;93:647–51.PubMedGoogle Scholar
  116. 116.
    Guo RS, et al. The distribution and co-localization of nitric oxide synthase and vasoactive intestinal polypeptide in nerves of the colons with Hirschsprung’s disease. Virchows Arch. 1997;430:53–61.CrossRefPubMedGoogle Scholar
  117. 117.
    Kobayashi H, Obriain DS, Puri P. Lack of expression of NADPH diaphorase and neural cell adhesion molecule (NCAM) in colonic muscle of patients with Hirschsprung’s disease. J Pediatr Surg. 1994;29:301–4.CrossRefPubMedGoogle Scholar
  118. 118.
    Larsson LT, et al. Lack of neuronal nitric oxide synthase in nerve fibers of aganglionic intestine: a clue to Hirschsprung’s disease. J Pediatr Gastroenterol Nutr. 1995;20:49–53.CrossRefPubMedGoogle Scholar
  119. 119.
    Vanderwinden JM, et al. Interstitial cells of Cajal in human colon and in Hirschsprung’s disease. Gastroenterology. 1996;111:901–10.CrossRefPubMedGoogle Scholar
  120. 120.
    Kusafuka T, Puri P. Altered mRNA expression of the neuronal nitric oxide synthase gene in Hirschsprung’s disease. J Pediatr Surg. 1997;32:1054–8.CrossRefPubMedGoogle Scholar
  121. 121.
    Bealer JF, et al. Effect of nitric oxide on the colonic smooth muscle of patients with Hirschsprung’s disease. J Pediatr Surg. 1994;29:1025–9.CrossRefPubMedGoogle Scholar
  122. 122.
    Mostafa RM, Moustafa YM, Hamdy H. Interstitial cells of Cajal, the Maestro in health and disease. World J Gastroenterol. 2010;16:3239–48.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Yamataka A, et al. A lack of intestinal pacemaker (C-Kit) in aganglionic bowel of patients with Hirschsprung’s disease. J Pediatr Surg. 1995;30:441–4.CrossRefPubMedGoogle Scholar
  124. 124.
    Yamataka A, et al. Intestinal pacemaker C-KIT+ cells and synapses in allied Hirschsprung’s disorders. J Pediatr Surg. 1997;32:1069–74.CrossRefPubMedGoogle Scholar
  125. 125.
    Horisawa M, Watanabe Y, Torihashi S. Distribution of c-kit immunopositive cells in normal human colon and in Hirschsprung’s disease. J Pediatr Surg. 1998;33:1209–14.CrossRefPubMedGoogle Scholar
  126. 126.
    Rolle U, et al. Altered distribution of interstitial cells of Cajal in Hirschsprung disease. Arch Pathol Lab Med. 2002;126:928–33.PubMedGoogle Scholar
  127. 127.
    Nemeth L, Maddur S, Puri P. Immunolocalization of the gap junction protein Connexin43 in the interstitial cells of Cajal in the normal and Hirschsprung’s disease bowel. J Pediatr Surg. 2000;35:823–8.CrossRefPubMedGoogle Scholar
  128. 128.
    Piotrowska AP, Solari V, Puri P. Distribution of Ca2+−activated K channels, SK2 and SK3, in the normal and Hirschsprung’s disease bowel. J Pediatr Surg. 2003;38:978–83.CrossRefPubMedGoogle Scholar
  129. 129.
    Soeda J, Obriain DS, Puri P. Mucosal neuroendocrine cell abnormalities in the colon of patients with Hirschsprung’s disease. J Pediatr Surg. 1992;27:823–7.CrossRefPubMedGoogle Scholar
  130. 130.
    Nemeth L, Rolle U, Puri P. Altered cytoskeleton in smooth muscle of aganglionic bowel. Arch Pathol Lab Med. 2002;126:692–6.PubMedGoogle Scholar
  131. 131.
    Covault J, Sanes JR. Distribution of N-CAM in synaptic and extrasynaptic portions of developing and adult skeletal muscle. J Cell Biol. 1986;102:716–30.CrossRefPubMedGoogle Scholar
  132. 132.
    Moore SE, Walsh FS. Specific regulation of N-CAM/D2-CAM cell adhesion molecule during skeletal muscle development. EMBO J. 1985;4:623–30.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Thiery JP, et al. Cell adhesion molecules in early chicken embryogenesis. Proc Natl Acad Sci U S A. 1982;79:6737–41.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Romanska HM, et al. Increased expression of muscular neural cell adhesion molecule in congenital aganglionosis. Gastroenterology. 1993;105:1104–9.CrossRefPubMedGoogle Scholar
  135. 135.
    Payette RF, et al. Accumulation of components of basal laminae: association with the failure of neural crest cells to colonize the presumptive aganglionic bowel of ls/ls mutant mice. Dev Biol. 1988;125:341–60.CrossRefPubMedGoogle Scholar
  136. 136.
    Tennyson VM, et al. Distribution of hyaluronic acid and chondroitin sulfate proteoglycans in the presumptive aganglionic terminal bowel of Ls/Ls fetal mice: an ultrastructural analysis. J Comp Neurol. 1990;291:345–62.CrossRefPubMedGoogle Scholar
  137. 137.
    Parikh DH, et al. Quantitative and qualitative analysis of the extracellular matrix protein, laminin, in Hirschsprung’s disease. J Pediatr Surg. 1992;27:991–6.CrossRefPubMedGoogle Scholar
  138. 138.
    Parikh DH, et al. Abnormalities in the distribution of laminin and collagen Type IV in Hirschsprung’s disease. Gastroenterology. 1992;102:1236–41.CrossRefPubMedGoogle Scholar
  139. 139.
    Parikh DH, et al. The extracellular matrix components, tenascin and fibronectin, in Hirschsprung’s disease: an immunohistochemical study. J Pediatr Surg. 1994;29:1302–6.CrossRefPubMedGoogle Scholar
  140. 140.
    Murphy F, Menezes M. Enterocolitis complicating Hirschsprung’s disease. In: Holschneider AM, Puri P, editors. Hirschsprung’s disease and allied disorders. Heidelberg: Springer; 2008. p. 133–43.CrossRefGoogle Scholar
  141. 141.
    Menezes M, et al. Long-term clinical outcome in patients with total colonic aganglionosis: a 31-year review. J Pediatr Surg. 2008;43:1696–9.CrossRefPubMedGoogle Scholar
  142. 142.
    Lake BD, et al. Hirschsprung’s disease: appraisal of histochemically demonstrated acetylcholinesterase activity in suction rectal biopsy specimens as an aid to diagnosis. Arch Pathol Lab Med. 1978;102:244–7.PubMedGoogle Scholar
  143. 143.
    Meier-Ruge W, Bruder E. Histopathological diagnosis and differential diagnosis of Hirschsprung’s disease. In: Holschneider AM, Puri P, editors. Hirschsprung’s disease and allied disorders. Heidelberg: Springer; 2008. p. 185–98.CrossRefGoogle Scholar
  144. 144.
    Meier-Ruge W, et al. Acetylcholinesterase activity in suction biopsies of rectum in diagnosis of Hirschsprung’s disease. J Pediatr Surg. 1972;7:11–7.CrossRefPubMedGoogle Scholar
  145. 145.
    Kobayashi H, et al. A new rapid acetylcholinesterase staining kit for diagnosing Hirschsprung’s disease. Pediatr Surg Int. 2007;23:505–8.CrossRefPubMedGoogle Scholar
  146. 146.
    Kobayashi H, et al. A rapid technique of acetylcholinesterase staining. Arch Pathol Lab Med. 1994;118:1127–9.PubMedGoogle Scholar
  147. 147.
    Martucciello G, et al. Controversies concerning diagnostic guidelines for anomalies of the enteric nervous system: a report from the fourth International Symposium on Hirschsprung’s disease and related neurocristopathies. J Pediatr Surg. 2005;40:1527–31.CrossRefPubMedGoogle Scholar
  148. 148.
    Montedonico S, et al. Histochemical staining of rectal suction biopsies as the first investigation in patients with chronic constipation. Pediatr Surg Int. 2008;24:785–92.CrossRefPubMedGoogle Scholar
  149. 149.
    Moore SW, Johnson G. Acetylcholinesterase in Hirschsprung’s disease. Pediatr Surg Int. 2005;21:255–63.CrossRefPubMedGoogle Scholar
  150. 150.
    Miyazaki E, Ohshiro K, Puri P. NADPH-diaphorase histochemical staining of suction rectal biopsies in the diagnosis of Hirschsprung’s disease and allied disorders. Pediatr Surg Int. 1998;13:464–7.CrossRefPubMedGoogle Scholar
  151. 151.
    Puri P. Hirschsprung’s disease. In: Puri P, Höllwarth M, editors. Pediatric surgery. Heidelberg: Springer; 2006. p. 275–88.CrossRefGoogle Scholar
  152. 152.
    De La Torre L, Langer JC. 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.CrossRefGoogle Scholar
  153. 153.
    Kim AC, et al. Endorectal pull-through for Hirschsprung’s disease-a multicenter, long-term comparison of results: transanal vs transabdominal approach. J Pediatr Surg. 2010;45:1213–20.CrossRefPubMedGoogle Scholar
  154. 154.
    Murphy F, Puri P. New insights into the pathogenesis of Hirschsprung’s associated enterocolitis. Pediatr Surg Int. 2005;21:773–9.CrossRefPubMedGoogle Scholar
  155. 155.
    Menezes M, Puri P. Long-term clinical outcome in patients with Hirschsprung’s disease and associated Down’s syndrome. J Pediatr Surg. 2005;40:810–2.CrossRefPubMedGoogle Scholar
  156. 156.
    Jarvi K, et al. Bowel function and gastrointestinal quality of life among adults operated for Hirschsprung’s disease during childhood: a population-based study. Ann Surg. 2010;252:977–81.CrossRefPubMedGoogle Scholar
  157. 157.
    Menezes M, Corbally M, Puri P. Long-term results of bowel function after treatment for Hirschsprung’s disease: a 29-year review. Pediatr Surg Int. 2006;22:987–90.CrossRefPubMedGoogle Scholar
  158. 158.
    Heij HA, et al. Long-term anorectal function after Duhamel operation for Hirschsprung’s disease. J Pediatr Surg. 1995;30:430–2.CrossRefPubMedGoogle Scholar
  159. 159.
    Marty TL, et al. Gastrointestinal function after surgical correction of Hirschsprung’s disease: long-term follow-up in 135 patients. J Pediatr Surg. 1995;30:655–8.CrossRefPubMedGoogle Scholar
  160. 160.
    Polley TZ Jr, Coran AG, Wesley JR. A ten-year experience with ninety-two cases of Hirschsprung’s disease. Including sixty-seven consecutive endorectal pull-through procedures. Ann Surg. 1985;202:349–55.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Levitt MA, et al. Hirschsprung disease and fecal incontinence: diagnostic and management strategies. J Pediatr Surg. 2009;44:271–7.CrossRefPubMedGoogle Scholar
  162. 162.
    Minkes RK, Langer JC. A prospective study of botulinum toxin for internal anal sphincter hypertonicity in children with Hirschsprung’s disease. J Pediatr Surg. 2000;35:1733–6.CrossRefPubMedGoogle Scholar
  163. 163.
    Friedmacher F, Puri P. Residual aganglionosis after pull-through operation for Hirschsprung’s disease: a systematic review and meta-analysis. Pediatr Surg Int. 2011;27:1053–7.CrossRefPubMedGoogle Scholar
  164. 164.
    Moore SW, Albertyn R, Cywes S. Clinical outcome and long-term quality of life after surgical correction of Hirschsprung’s disease. J Pediatr Surg. 1996;31:1496–502.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag London Ltd., part of Springer Nature 2018

Authors and Affiliations

  1. 1.National Children’s Research CentreOur Lady’s Children’s Hospital, CrumlinDublinIreland

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