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Hirschsprung’s Disease

  • Prem PuriEmail author
  • Christian Tomuschat
  • Hiroki Nakamura
Living reference work entry

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Abstract

Hirschsprung’s disease (HSCR) is a relatively common cause of intestinal obstruction in the newborn. It is characterized by the absence of ganglion cells in the distal bowel beginning at the internal sphincter and extending proximally for varying distances. The absence of ganglion cells in HSCR has been attributed to a failure of migration of neural crest-derived cells. The earlier the arrest of migration, the longer the aganglionic segment of bowel. 80–90% of patients with HSCR produce clinical symptoms and are diagnosed in the neonatal period. Delayed passage of meconium is the cardinal symptom in over 90% of affected neonates. About one-third of babies with HSCR present with enterocolitis which remains the most common cause of morbidity and mortality in the disease. This chapter describes in-depth the etiopathogenesis, pathophysiology, diagnosis, and management of Hirschsprung’s disease. The progress in understanding of normal gut development and motility has led to an expanding field of research into developing novel therapies for HSCR. During the last decade, there has been an increasing focus on the development of novel stem cell-based therapies for the treatment of HSCR. Research is ongoing to determine the optimal source of stem cells to generate a new enteric nervous system in the aganglionic bowel and also to determine the best way to deliver stem cells to the affected bowel.

Keywords

Hirschsprung’s disease Aganglionosis Enterocolitis Children Constipation Hypoganglionosis Rectal biopsy 

References

  1. Angrist M, Bolk S, Thiel B, Puffenberger EG, Hofstra RM, Buys CH, et al. Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease. Hum Mol Genet. 1995;4(5):821–30.PubMedGoogle Scholar
  2. Attie T, Pelet A, Edery P, Eng C, Mulligan LM, Amiel J, et al. Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease. Hum Mol Genet. 1995;4(8):1381–6.PubMedGoogle Scholar
  3. Badner JA, Sieber WK, Garver KL, Chakravarti A. A genetic study of Hirschsprung disease. Am J Hum Genet. 1990;46(3):568–80.PubMedPubMedCentralGoogle Scholar
  4. Baker SS, Kozielski R. Calretinin and pathologic diagnosis of Hirschsprung disease: has the time come to abandon the acetylcholinesterase stain? J Pediatr Gastroenterol Nutr. 2014;58(5):544–5.PubMedGoogle Scholar
  5. Bealer JF, Natuzzi ES, Flake AW, Adzick NS, Harrison MR. Effect of nitric oxide on the colonic smooth muscle of patients with Hirschsprung’s disease. J Pediatr Surg. 1994;29(8):1025–9.PubMedGoogle Scholar
  6. Bergeron KF, Silversides DW, Pilon N. The developmental genetics of Hirschsprung’s disease. Clin Genet. 2013;83(1):15–22.PubMedGoogle Scholar
  7. Burkardt DD, Graham JM Jr, Short SS, Frykman PK. Advances in Hirschsprung disease genetics and treatment strategies: an update for the primary care pediatrician. Clin Pediatr. 2014;53(1):71–81.Google Scholar
  8. Burns AJ, Roberts RR, Bornstein JC, Young HM. Development of the enteric nervous system and its role in intestinal motility during fetal and early postnatal stages. Semin Pediatr Surg. 2009;18(4):196–205.PubMedGoogle Scholar
  9. Covault J, Sanes JR. Distribution of N-CAM in synaptic and extrasynaptic portions of developing and adult skeletal muscle. J Cell Biol. 1986;102(3):716–30.PubMedGoogle Scholar
  10. Coyle D, Puri P. Hirschsprung’s disease in children with Mowat–Wilson syndrome. Pediatr Surg Int. 2015;31(8):711–7.PubMedGoogle Scholar
  11. Coyle D, Friedmacher F, Puri P. The association between Hirschsprung’s disease and multiple endocrine neoplasia type 2a: a systematic review. Pediatr Surg Int. 2014;30(8):751–6.PubMedGoogle Scholar
  12. Croaker GD, Shi E, Simpson E, Cartmill T, Cass DT. Congenital central hypoventilation syndrome and Hirschsprung’s disease. Arch Dis Child. 1998;78(4):316–22.PubMedPubMedCentralGoogle Scholar
  13. de Arruda Lourencao PL, Takegawa BK, Ortolan EV, Terra SA, Rodrigues MA. A useful panel for the diagnosis of Hirschsprung disease in rectal biopsies: calretinin immunostaining and acetylcholinesterase histochemistry. Ann Diagn Pathol. 2013;17(4):352–6.PubMedGoogle Scholar
  14. Duess JW, Puri P. Syndromic Hirschsprung’s disease and associated congenital heart disease: a systematic review. Pediatr Surg Int. 2015;31(8):781–5.PubMedGoogle Scholar
  15. Duess JW, Hofmann AD, Puri P. Prevalence of Hirschsprung’s disease in premature infants: a systematic review. Pediatr Surg Int. 2014;30(8):791–5.PubMedGoogle Scholar
  16. Edery P, Lyonnet S, Mulligan LM, Pelet A, Dow E, Abel L, et al. Mutations of the RET proto-oncogene in Hirschsprung’s disease. Nature. 1994;367(6461):378–80.PubMedGoogle Scholar
  17. Elhalaby EA, Coran AG, Blane CE, Hirschl RB, Teitelbaum DH. Enterocolitis associated with Hirschsprung’s disease: a clinical–radiological characterization based on 168 patients. J Pediatr Surg. 1995;30(1):76–83.PubMedGoogle Scholar
  18. Fiori MG. Domenico Battini and his description of congenital megacolon: a detailed case report one century before Hirschsprung. J Peripher Nerv Syst. 1998;3(3):197–206.PubMedGoogle Scholar
  19. Friedmacher F, Puri P. Hirschsprung’s disease associated with Down syndrome: a meta-analysis of incidence, functional outcomes and mortality. Pediatr Surg Int. 2013;29(9):937–46.PubMedGoogle Scholar
  20. Georgeson KE, Robertson DJ. Laparoscopic-assisted approaches for the definitive surgery for Hirschsprung’s disease. Semin Pediatr Surg. 2004;13(4):256–62.PubMedGoogle Scholar
  21. Georgeson KE, Fuenfer MM, Hardin WD. Primary laparoscopic pull-through for Hirschsprung’s disease in infants and children. J Pediatr Surg 1995;30(7):1017-21; discussion 21–2.Google Scholar
  22. Gershon M. Functional anatomy of the enteric nervous system. In: Holshneider A, Puri P, editors. Hirschsprung’s disease and allied disorders. Heidelberg: Springer; 2008. p. 21–49.Google Scholar
  23. Granstrom AL, Danielson J, Husberg B, Nordenskjold A, Wester T. Adult outcomes after surgery for Hirschsprung’s disease: evaluation of bowel function and quality of life. J Pediatr Surg. 2015;50(11):1865–9.PubMedGoogle Scholar
  24. Heanue TA, Pachnis V. Enteric nervous system development and Hirschsprung’s disease: advances in genetic and stem cell studies. Nat Rev Neurosci. 2007;8(6):466–79.PubMedGoogle Scholar
  25. Hofmann AD, Duess JW, Puri P. Congenital anomalies of the kidney and urinary tract (CAKUT) associated with Hirschsprung’s disease: a systematic review. Pediatr Surg Int. 2014;30(8):757–61.PubMedGoogle Scholar
  26. Jakobson-Setton A, Weissmann-Brenner A, Achiron R, Kuint J, Gindes L. Retrospective analysis of prenatal ultrasound of children with Hirschsprung disease. Prenat Diagn. 2015;35(7):699–702.PubMedGoogle Scholar
  27. Kakita Y, Oshiro K, O’Briain DS, Puri P. 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(9):1314–9.PubMedGoogle Scholar
  28. Kapur RP, Reed RC, Finn LS, Patterson K, Johanson J, Rutledge JC. Calretinin immunohistochemistry versus acetylcholinesterase histochemistry in the evaluation of suction rectal biopsies for Hirschsprung disease. Pediatr Dev Pathol. 2009;12(1):6–15.PubMedGoogle Scholar
  29. Kenny SE, Tam PK, Garcia-Barcelo M. Hirschsprung’s disease. Semin Pediatr Surg. 2010;19(3):194–200.PubMedGoogle Scholar
  30. Kim AC, Langer JC, Pastor AC, Zhang L, Sloots CE, Hamilton NA, 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(6):1213–20.PubMedGoogle Scholar
  31. Kurahashi M, Nakano Y, Hennig GW, Ward SM, Sanders KM. Platelet-derived growth factor receptor alpha-positive cells in the tunica muscularis of human colon. J Cell Mol Med. 2012;16(7):1397–404.PubMedPubMedCentralGoogle Scholar
  32. Kusafuka T, Puri P. Altered mRNA expression of the neuronal nitric oxide synthase gene in Hirschsprung’s disease. J Pediatr Surg. 1997;32(7):1054–8.PubMedGoogle Scholar
  33. Mc Laughlin D, Puri P. Familial Hirschsprung’s disease: a systematic review. Pediatr Surg Int. 2015;31(8):695–700.PubMedGoogle Scholar
  34. Menezes M, Puri P. Long-term clinical outcome in patients with Hirschsprung’s disease and associated Down’s syndrome. J Pediatr Surg. 2005;40(5):810–2.PubMedGoogle Scholar
  35. Menezes M, Puri P. Long-term outcome of patients with enterocolitis complicating Hirschsprung’s disease. Pediatr Surg Int. 2006;22(4):316–8.PubMedGoogle Scholar
  36. 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(12):987–90.PubMedGoogle Scholar
  37. Menezes M, Pini Prato A, Jasonni V, Puri P. Long-term clinical outcome in patients with total colonic aganglionosis: a 31-year review. J Pediatr Surg. 2008;43(9):1696–9.PubMedGoogle Scholar
  38. Moore SW. Total colonic aganglionosis and Hirschsprung’s disease: a review. Pediatr Surg Int. 2015;31(1):1–9.PubMedGoogle Scholar
  39. Moore SW. Genetic impact on the treatment & management of Hirschsprung disease. J Pediatr Surg. 2017;52(2):218–22.PubMedGoogle Scholar
  40. Moore SE, Walsh FS. Specific regulation of N-CAM/D2-CAM cell adhesion molecule during skeletal muscle development. EMBO J. 1985;4(3):623–30.PubMedPubMedCentralGoogle Scholar
  41. Muise ED, Hardee S, Morotti RA, Cowles RA. A comparison of suction and full-thickness rectal biopsy in children. J Surg Res. 2016;201(1):149–55.PubMedGoogle Scholar
  42. 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(6):823–8.PubMedGoogle Scholar
  43. Nemeth L, Yoneda A, Kader M, Devaney D, Puri P. Three-dimensional morphology of gut innervation in total intestinal aganglionosis using whole-mount preparation. J Pediatr Surg. 2001;36(2):291–5.PubMedGoogle Scholar
  44. Nemeth L, Rolle U, Puri P. Altered cytoskeleton in smooth muscle of aganglionic bowel. Arch Pathol Lab Med. 2002;126(6):692–6.PubMedGoogle Scholar
  45. Nirasawa Y, Yokoyama J, Ikawa H, Morikawa Y, Katsumata K. Hirschsprung’s disease: catecholamine content, alpha-adrenoceptors, and the effect of electrical stimulation in aganglionic colon. J Pediatr Surg. 1986;21(2):136–42.PubMedGoogle Scholar
  46. O’Donnell AM, Coyle D, Puri P. Deficiency of platelet-derived growth factor receptor-alpha-positive cells in Hirschsprung’s disease colon. World J Gastroenterol. 2016;22(12):3335–40.PubMedPubMedCentralGoogle Scholar
  47. Orr JD, Scobie WG. Presentation and incidence of Hirschsprung’s disease. Br Med J. 1983;287(6406):1671.Google Scholar
  48. Passarge E. The genetics of Hirschsprung’s disease. Evidence for heterogeneous etiology and a study of sixty-three families. N Engl J Med. 1967;276(3):138–43.PubMedGoogle Scholar
  49. Passarge E. Dissecting Hirschsprung disease. Nat Genet. 2002;31(1):11–2.PubMedGoogle Scholar
  50. Puri P. Hirschsprung disease. In: Oldham K, Colombani P, Foglia R, editors. Surgery of infants and children: scientific principles and practice. New York: Lippincott-Raven; 1997. p. 1277–99.Google Scholar
  51. Puri P. Hirschsprung’s disease. In: Puri P, Hollwarth M, editors. Pediatric surgery. Heidelberg: Springer; 2006. p. 275–88.Google Scholar
  52. Puri P. Hirschsprung’s disease and variants. In: Puri P, Hollwarth M, editors. Pediatric surgery: diagnosis and management. Heidelberg: Springer; 2009. p. 453–62.Google Scholar
  53. Puri P. Hirschsprung’s disease. In: Puri P, editor. Newborn surgery. 3rd ed. London: Hodder Arnold; 2011. p. 554–65.Google Scholar
  54. Raveenthiran V. Knowledge of ancient Hindu surgeons on Hirschsprung disease: evidence from Sushruta Samhita of circa 1200–600 BC. J Pediatr Surg. 2011;46(11):2204–8.PubMedGoogle Scholar
  55. Rivera LR, Poole DP, Thacker M, Furness JB. The involvement of nitric oxide synthase neurons in enteric neuropathies. Neurogastroenterol Motil. 2011;23(11):980–8.PubMedGoogle Scholar
  56. Rolle U, Nemeth L, Puri P. Nitrergic innervation of the normal gut and in motility disorders of childhood. J Pediatr Surg. 2002a;37(4):551–67.PubMedGoogle Scholar
  57. Rolle U, Piotrowska AP, Nemeth L, Puri P. Altered distribution of interstitial cells of Cajal in Hirschsprung disease. Arch Pathol Lab Med. 2002b;126(8):928–33.PubMedGoogle Scholar
  58. Ruttenstock E, Puri P. A meta-analysis of clinical outcome in patients with total intestinal aganglionosis. Pediatr Surg Int. 2009;25(10):833–9.PubMedGoogle Scholar
  59. Ruttenstock E, Puri P. Systematic review and meta-analysis of enterocolitis after one-stage transanal pull-through procedure for Hirschsprung’s disease. Pediatr Surg Int. 2010;26(11):1101–5.PubMedGoogle Scholar
  60. Senyuz OF, Buyukunal C, Danismend N, Erdogan E, Ozbay G, Soylet Y. Extensive intestinal aganglionosis. J Pediatr Surg. 1989;24(5):453–6.PubMedGoogle Scholar
  61. Skaba R. Historic milestones of Hirschsprung’s disease (commemorating the 90th anniversary of Professor Harald Hirschsprung’s death). J Pediatr Surg. 2007;42(1):249–51.PubMedGoogle Scholar
  62. Soret R, Mennetrey M, Bergeron KF, Dariel A, Neunlist M, Grunder F, et al. A collagen VI-dependent pathogenic mechanism for Hirschsprung’s disease. J Clin Invest. 2015;125(12):4483–96.PubMedPubMedCentralGoogle Scholar
  63. Spouge D, Baird PA. Hirschsprung disease in a large birth cohort. Teratology. 1985;32(2):171–7.PubMedGoogle Scholar
  64. Swenson O. Early history of the therapy of Hirschsprung’s disease: facts and personal observations over 50 years. J Pediatr Surg. 1996;31(8):1003–8.PubMedGoogle Scholar
  65. Swenson O. How the cause and cure of Hirschsprung’s disease were discovered. J Pediatr Surg. 1999;34(10):1580–1.PubMedGoogle Scholar
  66. Tam PK. Hirschsprung’s disease: a bridge for science and surgery. J Pediatr Surg. 2016;51(1):18–22.PubMedGoogle Scholar
  67. Tang CS, Tang WK, So MT, Miao XP, Leung BM, Yip BH, et al. Fine mapping of the NRG1 Hirschsprung’s disease locus. PLoS One. 2011;6(1):e16181.PubMedPubMedCentralGoogle Scholar
  68. Tennyson VM, Payette RF, Rothman TP, Gershon MD. 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(3):345–62.PubMedGoogle Scholar
  69. Thiery JP, Duband JL, Rutishauser U, Edelman GM. Cell adhesion molecules in early chicken embryogenesis. Proc Natl Acad Sci U S A. 1982;79(21):6737–41.PubMedPubMedCentralGoogle Scholar
  70. Tomuschat C, Puri P. RET gene is a major risk factor for Hirschsprung’s disease: a meta-analysis. Pediatr Surg Int. 2015;31(8):701–10.PubMedGoogle Scholar
  71. Tomuschat C, O’Donnell AM, Coyle D, Dreher N, Kelly D, Puri P. NOS-interacting protein (NOSIP) is increased in the colon of patients with Hirschsprung’s disease. J Pediatr Surg. 2017;52(5):772–777.PubMedGoogle Scholar
  72. Touloukian RJ, Aghajanian G, Roth RH. Adrenergic hyperactivity of the aganglionic colon. J Pediatr Surg. 1973;8(2):191–5.PubMedGoogle Scholar
  73. Vanderwinden JM, Rumessen JJ, Liu H, Descamps D, De Laet MH, Vanderhaeghen JJ. Interstitial cells of Cajal in human colon and in Hirschsprung’s disease. Gastroenterology. 1996;111(4):901–10.PubMedGoogle Scholar
  74. Wales JK. Presentation and incidence of Hirschsprung’s disease. Br Med J. 1984;288(6411):151.Google Scholar
  75. Weinberg AG. Hirschsprung’s disease – a pathologist’s view. Perspect Pediatr Pathol. 1975;2:207–39.PubMedGoogle Scholar
  76. Yamataka A, Ohshiro K, Kobayashi H, Fujiwara T, Sunagawa M, Miyano T. Intestinal pacemaker C-KIT+ cells and synapses in allied Hirschsprung’s disorders. J Pediatr Surg. 1997;32(7):1069–74.PubMedGoogle Scholar
  77. Ziegler MM, Ross AJ 3rd, Bishop HC. Total intestinal aganglionosis: a new technique for prolonged survival. J Pediatr Surg. 1987;22(1):82–3.PubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Prem Puri
    • 1
    • 2
    Email author
  • Christian Tomuschat
    • 1
  • Hiroki Nakamura
    • 1
  1. 1.National Children’s Research CentreOur Lady’s Children’s HospitalDublinIreland
  2. 2.School of Medicine and Medical Science and Conway Institute of Biomedical ResearchUniversity College DublinDublinIreland

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