Current Gastroenterology Reports

, Volume 9, Issue 3, pp 245–253 | Cite as

Symptomatology, pathophysiology, diagnostic work-up, and treatment of Hirschsprung disease in infancy and childhood

  • Fleur de Lorijn
  • Guy E. Boeckxstaens
  • Marc A. Benninga
Open Access


In the majority of infants and children with constipation, no obvious cause can be identified. A rare cause of constipation is Hirschsprung disease (HD). HD is characterized by the absence of ganglion cells from the anorectum for a variable length up to the duodenum. The extent of the aganglionic segment varies, but in most patients the lesion does not extend beyond the rectum and sigmoid colon. This review focuses on the passage of meconium, the recognition of HD, and new insights in its pathophysiology and genetics. The authors also provide a summary of the diagnostic evaluation and treatment of HD in infancy and childhood.


Enteric Nervous System Internal Anal Sphincter Anorectal Manometry Contrast Enema Functional Constipation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References and Recommended Reading

  1. 1.
    Weaver LT, Lucas A: Development of bowel habit in preterm infants. Arch Dis Child 1993, 68:317–320.PubMedGoogle Scholar
  2. 2.
    Verma A, Dhanireddy R: Time of first stool in extremely low birth weight (< or = 1000 grams) infants. J Pediatr 1993, 122:62–69.Google Scholar
  3. 3.
    MClain CR Jr: Amniopraphy studies of the gastrointestinal motility of the human fetus. Am J Obstet Gynecol 1963, 86:1079–1087.PubMedGoogle Scholar
  4. 4.
    Dumont RC, Rudolph CD: Development of gastrointestinal motility in the infant and child. Gastroenterol Clin North Am 1994, 23:655–671.PubMedGoogle Scholar
  5. 5.
    Sarna SK: Physiology and pathophysiology of colonic motor activity (2). Dig Dis Sci 1991, 36:998–1018.PubMedCrossRefGoogle Scholar
  6. 6.
    Kenny SE, Vanderwinden JM, Rintala RJ, et al.: Delayed maturation of the interstitial cells of Cajal: a new diagnosis for transient neonatal pseudoobstruction. Report of two cases. J Pediatr Surg 1998, 33:94–98.PubMedCrossRefGoogle Scholar
  7. 7.
    Huizinga JD: Physiology and pathophysiology of the interstitial cell of Cajal: from bench to bedside. II. Gastric motility: lessons from mutant mice on slow waves and innervation. Am J Physiol Gastrointest Liver Physiol 2001, 281:G1129–G1134.PubMedGoogle Scholar
  8. 8.
    Huizinga JD, Thuneberg L, Kluppel M, et al.: W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature 1995, 373:347–349.PubMedCrossRefGoogle Scholar
  9. 9.
    Dimmitt RA,. Moss RL: Meconium diseases in infants with very low birth weight. Semin Pediatr Surg 2000, 9:79–83.PubMedGoogle Scholar
  10. 10.
    Hyman PE, Milla PJ, Benninga MA, et al.: Childhood functional gastrointestinal disorders: neonate/toddler. Gastroenterology 2006, 130:1519–1526.PubMedCrossRefGoogle Scholar
  11. 11.
    Benninga MA, Voskuijl WP, Taminiau JA. Childhood constipation: is there new light in the tunnel? J Pediatr Gastroenterol Nutr 2004, 39:448–464.PubMedCrossRefGoogle Scholar
  12. 12.
    Scharli AF, Kiesewetter WB: Defecation and continence: some new concepts. Dis Colon Rectum 1970, 13:81–107.PubMedCrossRefGoogle Scholar
  13. 13.
    Puri P: Hirschsprung’s disease: clinical generalities. In Hirschsprung’s Disease and Allied Disorders. Edited by Holschneider AM, Puri P. Frankfurt, Germany: Springer; 2000:129–135.Google Scholar
  14. 14.
    de Lorijn F, Reitsma JB, Voskuijl WP, et al.: Diagnosis of Hirschsprung’s disease: a prospective, comparative accuracy study of common tests. J Pediatr 2005, 1146:787–792Google Scholar
  15. 15.
    Badner JA, Sieber WK, Garver KL, Chakravarti A. A genetic study of Hirschsprung’s disease. Am J Hum Genet 1990, 46:568–80.PubMedGoogle Scholar
  16. 16.
    Ikeda K, Goto S: Diagnosis and treatment of Hirschsprung’s disease in Japan. An analysis of 1628 patients. Ann Surg 1984, 199:400–405.PubMedCrossRefGoogle Scholar
  17. 17.
    Kleinhaus S, Boley SJ, Sheran M, Sieber WK: Hirschsprung’s disease — a survey of the members of the Surgical Section of the American Academy of Pediatrics. J Pediatr Surg 1979, 14:588–597.PubMedGoogle Scholar
  18. 18.
    Plaza-Menacho I, Burzynski GM, de Groot JW, et al.: Current concepts in RET-related genetics, signaling and therapeutics. Trends Genet 2006, 22:627–36.PubMedCrossRefGoogle Scholar
  19. 19.
    Brooks AS, Oostra BA, Hofstra RM: Studying the genetics of Hirschsprung’s disease: unraveling an oligogenic disorder. Clin Genet 2005, 67:6–14.PubMedCrossRefGoogle Scholar
  20. 20.
    Edery P, Lyonnet S, Mulligan LM, et al.: Mutations of the RET proto-oncogene in Hirschsprung’s disease. Nature 1994, 367:378–380.PubMedCrossRefGoogle Scholar
  21. 21.
    Romeo G, Ronchetto P, Luo Y, et al.: Point mutations affecting the tyrosine kinase domain of the RET protooncogene in Hirschsprung’s disease. Nature 1994, 367:377–378.PubMedCrossRefGoogle Scholar
  22. 22.
    Iwashita T, Kurokawa K, Qiao S, et al.: Functional analysis of ret with Hirschsprung mutations affecting its kinase domain. Gastroenterology 2001, 121:24–33.PubMedCrossRefGoogle Scholar
  23. 23.
    Eng C: Seminars in medicine of the Beth Israel Hospital, Boston. The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung’s disease. N Engl J Med 1996, 335:943–951.PubMedCrossRefGoogle Scholar
  24. 24.
    Borrello MG, Smith DP, Pasini B, et al.: RET activation by germline MEN2A and MEN2B mutations. Oncogene 1995, 11:2419–2427.PubMedGoogle Scholar
  25. 25.
    Amiel J, Lyonnet S: Hirschsprung’s disease, associated syndromes, and genetics: a review. J Med Genet 2001, 38:729–739.PubMedCrossRefGoogle Scholar
  26. 26.
    Taraviras S, Pachnis V: Development of the mammalian enteric nervous system. Curr Opin Genet Dev 1999, 9:321–327.PubMedCrossRefGoogle Scholar
  27. 27.
    Bates MD: Development of the enteric nervous system. Clin Perinatol 2002, 29:97–114.PubMedCrossRefGoogle Scholar
  28. 28.
    Gershon MD, Ratcliffe EM: Developmental biology of the enteric nervous system: pathogenesis of Hirschsprung’s disease and other congenital dysmotilities. Semin Pediatr Surg 2004, 13:224–235.PubMedCrossRefGoogle Scholar
  29. 29.
    Chitkara DK, Di Lorenzo C. From the bench to the ‘crib’-side: implications of scientific advances to paediatric neurogastroenterology and motility. Neurogastroenterol Motil 2006, 18:251–262.PubMedCrossRefGoogle Scholar
  30. 30.
    Scharli AF: Pathophysiology of Classical Hirschsprung’s disease. In Hirschsprung’s Disease and Allied Disorders. Edited by Holschneider AM, Puri P. Frankfurt, Germany: Springer; 2000:109–125.Google Scholar
  31. 31.
    Farouk R, Bartolo DC: The anorectum. In An Illustrated Guide to Gastrointestinal Motility. Edited by Kumar D, Wingate D. New York: John Wiley; 1993:449–470.Google Scholar
  32. 32.
    Stebbing JF, Brading AF, Mortensen NJ: Nitric oxide and the rectoanal inhibitory reflex: retrograde neuronal tracing reveals a descending nitrergic rectoanal pathway in a guinea-pig model. Br J Surg 1996, 83:493–498.PubMedCrossRefGoogle Scholar
  33. 33.
    Rattan S, Chakder S: Role of nitric oxide as a mediator of internal anal sphincter relaxation. Am J Physiol 1992, 262:G107–G12.PubMedGoogle Scholar
  34. 34.
    Ward SM, Morris G, Reese L, et al.: Interstitial cells of Cajal mediate enteric inhibitory neurotransmission in the lower esophageal and pyloric sphincters. Gastroenterology 1998, 115:314–329.PubMedCrossRefGoogle Scholar
  35. 35.
    Burns AJ, Lomax AE, Torihashi S, et al.: Interstitial cells of Cajal mediate inhibitory neurotransmission in the stomach. Proc Natl Acad Sci U S A 1996, 93:1200–1213.CrossRefGoogle Scholar
  36. 36.
    de Lorijn F, de Jonge WJ, Wedel T, et al.: Interstitial cells of cajal are involved in the rectoanal inhibitory. Gut 2005, 54:1107–1113PubMedCrossRefGoogle Scholar
  37. 37.
    de Lorijn F, Kremer LC, Reitsma JB, Benninga MA: Diagnostic tests in Hirschsprung’s disease: a systematic review. J Pediatr Gastroenterol Nutr 2006, 42:496–505.PubMedCrossRefGoogle Scholar
  38. 38.
    Emir H, Akman M, Sarimurat N, et al.: Anorectal manometry during the neonatal period: its specificity in the diagnosis of Hirschsprung’s disease. Eur J Pediatr Surg 1999, 9:101–103.PubMedGoogle Scholar
  39. 39.
    Osatakul S, Patrapinyokul S, Osatakul N: The diagnostic value of anorectal manometry as a screening test for Hirschsprung’s disease. J Med Assoc Thai 1999, 82:1100–1105.PubMedGoogle Scholar
  40. 40.
    De Campo JF, Mayne V, Boldt DW, De Campo M: Radiological findings in total aganglionosis coli. Pediatr Radiol 1984, 14:205–209.PubMedCrossRefGoogle Scholar
  41. 41.
    Athow AC, Filipe MI, Drake DP: Problems and advantages of acetylcholinesterase histochemistry of rectal suction biopsies in the diagnosis of Hirschsprung’s disease. J Pediatr Surg 1990, 25:520–526.PubMedCrossRefGoogle Scholar
  42. 42.
    Smith SD, Tagge EP, Hannakan C, Rowe MI: Characterization of neonatal multisystem organ failure in the surgical newborn. J Pediatr Surg 1991, 26:494–497.PubMedCrossRefGoogle Scholar
  43. 43.
    Seth R, Heyman MB: Management of constipation and encopresis in infants and children. Gastroenterol Clin North Am 1994, 23:621–636.PubMedGoogle Scholar
  44. 44.
    Blake NS: Diagnosis of Hirschsprung’s disease and allied disorders. In Hirschsprung’s Disease and Allied Disorders. Edited by Holschneider AM, Puri P. Frankfurt, Germany: Springer; 2000:223–290.Google Scholar
  45. 45.
    Doig CM: Hirschsprung’s disease: a review. Int J Colorectal Dis 1991, 6:52–62.CrossRefGoogle Scholar
  46. 46.
    Taxman TL, Yulish BS, Rothstein FC: How useful is the barium enema in the diagnosis of infantile Hirschsprung’s disease? Am J Dis Child 1986, 140:881–884.PubMedGoogle Scholar
  47. 47.
    Das NL, Hingsbergen EA: Case 22: total colonic aganglionosis—long-segment Hirschsprung disease. Radiology 2000, 215:391–394.Google Scholar
  48. 48.
    Proctor ML, Traubici J, Langer JC, et al.: Correlation between radiographic transition zone and level of aganglionosis in Hirschsprung’s disease: Implications for surgical approach. J Pediatr Surg 2003, 38:775–778.PubMedCrossRefGoogle Scholar
  49. 49.
    Benninga MA: Constipation and faecal incontinence in childhood [thesis]. Baarn: Bosch en Keuning; 1994.Google Scholar
  50. 50.
    Nurko S: Gastrointestinal manometry, methodology and indications. In Pediatric Gastrointestinal Disease. Edited by Walker W, Durie PR, Hamilton JR, et al.: Philadelphia: BC Decker; 2000:1485–1510.Google Scholar
  51. 51.
    Benninga MA, Omari TI, Haslam RR, et al.: Characterization of anorectal pressure and the anorectal inhibitory reflex in healthy preterm and term infants. J Pediatr 2001, 139:233–237.PubMedCrossRefGoogle Scholar
  52. 52.
    de Lorijn F, Omari TI, Kok JH, et al.: Maturation of the rectoanal inhibitory reflex in very premature infants. J Pediatr 2003, 143:630–633.PubMedCrossRefGoogle Scholar
  53. 53.
    Meunier P, Marechal JM, de Beaujeu MJ: Rectoanal pressures and rectal sensitivity studies in chronic childhood constipation. Gastroenterology 1979, 77:330–336.PubMedGoogle Scholar
  54. 54.
    Meier-Ruge W, Lutterbeck PM, Herzog B, et al.: Acetylcholinesterase activity in suction biopsies of the rectum in the diagnosis of Hirschsprung’s disease. J Pediatr Sur 1972, 7:11–17.CrossRefGoogle Scholar
  55. 55.
    Kurer MH, Lawson JO, Pambakian H: Suction biopsy in Hirschsprung’s disease. Arch Dis Child 1986, 61:83–84.PubMedGoogle Scholar
  56. 56.
    Ghosh A, Griffiths DM: Rectal biopsy in the investigation of constipation. Arch Dis Child 1998, 79:266–268.PubMedCrossRefGoogle Scholar
  57. 57.
    Sherman JO, Snyder ME, Weitzman JJ, et al.: A 40-year multinational retrospective study of 880 Swenson procedures. J Pediatr Surg 1989, 24:833–838.PubMedCrossRefGoogle Scholar
  58. 58.
    Georgeson KE, Fuenfer MM, Hardin WD: Primary laparoscopic pull-through for Hirschsprung’s disease in infants and children. J Pediatr Surg 1995, 30:1017–1021.PubMedCrossRefGoogle Scholar
  59. 59.
    El-Sawaf MI, Drongowski RA, Chamberlain JN, et al.: Are the long-term results of the transanal pull-through equal to those of the transabdominal pull-through? A comparison of the 2 approaches for Hirschsprung disease. J Pediatr Surg 2007, 42:41–47PubMedCrossRefGoogle Scholar
  60. 60.
    Geerdes BP, Hazebroek FWJ: Pediatric disorders of the distal gastrointestinal tract, surgical aspects. In Integrated Medical and Surgical Gastroenterology. Edited by Lanschot JJB, Gouma DJ, Jansen PLM, et al.: Stuttgart, Germany: Thieme Medical Publishers; 2004:644–653.Google Scholar
  61. 61.
    Marty TL, Seo T, Matlak ME, et al.: Gastrointestinal function after surgical correction of Hirschsprung’s disease: long-term follow-up in 135 patients. J Pediatr Surg 1995, 30:655–658.PubMedCrossRefGoogle Scholar
  62. 62.
    Teitelbaum DH, Caniano DA, Qualman SJ: The pathophysiology of Hirschsprung’s-associated enterocolitis: importance of histologic correlates. J Pediatr Surg 1989, 24:1271–1277.PubMedCrossRefGoogle Scholar
  63. 63.
    Puri P, Wester T: Enterocolitis complicating Hirschsprung’s Disease. In Hirschsprung’s Disease and Allied Disorders. Edited by Holschneider AM, Puri P. Frankfurt, Germany: Springer; 2000;165–173.Google Scholar
  64. 64.
    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, 31:1496–1502.PubMedCrossRefGoogle Scholar
  65. 65.
    Moore SW, Millar AJ, Cywes S: Long-term clinical, manometric, and histological evaluation of obstructive symptoms in the postoperative Hirschsprung’s patient. J Pediatr Surg 1994, 29:106–111.PubMedCrossRefGoogle Scholar
  66. 66.
    Hartman EE, Oort FJ, Aronson DC, et al.: Critical factors affecting quality of life of adult patients with anorectal malformations or Hirschsprung’s disease. Am J Gastroenterol 2004, 99:907–913.PubMedCrossRefGoogle Scholar
  67. 67.
    Attie T, Pelet A, Edery P, et al.: Diversity of RET protooncogene mutations in familial and sporadic Hirschsprung disease. Hum Mol Genet 1995, 4:1381–1386.PubMedCrossRefGoogle Scholar
  68. 68.
    Ivanchuk SM, Myers SM, Eng C, Mulligan LM: De novo mutation of GDNF, ligand for the RET/GDNFR-alpha receptor complex, in Hirschsprung’s disease. Hum Mol Genet 1996, 5:2023–2026.PubMedCrossRefGoogle Scholar
  69. 69.
    Doray B, Salomon R, Amiel J, et al.: Mutation of the RET ligand, neurturin, supports multigenic inheritance in Hirschsprung disease. Hum Mol Genet 1998, 7:1449–1452.PubMedCrossRefGoogle Scholar
  70. 70.
    Carrasquillo MM, McCallion AS, Puffenberger EG, et al.: Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease. Nat Genet 2002, 32:237–244.PubMedCrossRefGoogle Scholar
  71. 71.
    Bidaud C, Salomon R, Van Camp G, et al.: Endothelin-3 gene mutations in isolated and syndromic Hirschsprung disease. Eur J Hum Genet 1997, 5:247–251.PubMedGoogle Scholar
  72. 72.
    Pingault V, Bondurand N, Kuhlbrodt K, et al.: SOX10 mutations in patients with Waardenburg-Hirschsprung disease. Nat Genet 1998, 18:171–173.PubMedCrossRefGoogle Scholar
  73. 73.
    Hofstra RM, Valdenaire O, Arch E, 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, 64:304–308.PubMedCrossRefGoogle Scholar
  74. 74.
    Wakamatsu N, Yamada Y, Yamada K, et al.: Mutations in SIP1, encoding Smad interacting protein-1, cause a form of Hirschsprung disease. Nat Genet 2001, 27:369–370.PubMedCrossRefGoogle Scholar
  75. 75.
    Dastot-Le Moal F, Wilson M, et al.: ZFHX1B mutations in patients with Mowat-Wilson syndrome. Hum Mutat 2007 28:313–321.PubMedCrossRefGoogle Scholar
  76. 76.
    Brooks AS, Bertoli-Avella AM, Burzynski GM, et al.: Homozygous nonsense mutations in KIAA1279 are associated with malformations of the central and enteric nervous systems. Am J Hum Genet 2005, 77:120–126.PubMedCrossRefGoogle Scholar
  77. 77.
    Amiel J, Laudier B, Attie-Bitach T, et al.: Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet 2003, 33:459–461.PubMedCrossRefGoogle Scholar
  78. 78.
    Gabriel SB, Salomon R, Pelet A, et al.: Segregation at three loci explains familial and population risk in Hirschsprung disease. Nat Genet 2002, 31:89–93.PubMedGoogle Scholar
  79. 79.
    Bolk S, Pelet A, Hofstra RM, Angrist M, et al.: A human model for multigenic inheritance: phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus. Proc Natl Acad Sci U S A, 2004, 97:268–273.CrossRefGoogle Scholar
  80. 80.
    Brooks AS, Leegwater PA, Burzynski GM, et al.: A novel susceptibility locus for Hirschsprung’s disease maps to 4q31.3-q32.3. J Med Genet 2006, 43:e35.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Fleur de Lorijn
  • Guy E. Boeckxstaens
  • Marc A. Benninga
    • 1
  1. 1.Gastroenterology and NutritionEmma Children’s Hospital AMC / Academic Medical CenterAmsterdamThe Netherlands

Personalised recommendations