Pediatric Surgery International

, Volume 31, Issue 8, pp 695–700 | Cite as

Familial hirschsprung’s disease: a systematic review

  • Danielle Mc Laughlin
  • Prem PuriEmail author
Original Article



Hirschsprung’s disease (HSCR) is a multi-genetic disorder with complex inheritance patterns. Population risk is 1 in 5000 but is reported to be increased in families of patients with HSCR. Appropriate counseling of affected families could be assisted by data from a large volume of patients. It was the aim of this study to systematically analyse the patterns of familial HSCR in the published literature.


Pubmed ® database was searched using the terms “Hirschsprung’s disease” and “familial” for studies published between 1980 and 2015 on cohorts of index patients with HSCR reporting on familial recurrence. Studies giving rates of familial HSCR together with the total number of HSCR cases at that centre were included.


In 4331 index cases of HSCR, an overall rate of 7.6 % familial recurrence was found. In total colonic aganglionosis, 20 % of cases were familial. Recurrence of HSCR within families predominantly occurred in siblings (62 %) and was reported between parent and offspring in 22 % and in other relatives in 16 %. Multiple generations were affected in 15 % of families.


Familial recurrence of HSCR occurs frequently and should be discussed with families of diagnosed patients. Genetic counseling should be offered in these families and in particular for those patients with long segment and total colonic aganglionosis.


Hirschsprung’s Disease Familial Total colonic aganglionosis 


  1. 1.
    Heanue TA, Pachnis V (2007) Enteric nervous system development and Hirschsprung’s disease: advances in genetic and stem cell studies. Nat Rev Neurosci 8(6):466–479. doi: 10.1038/nrn2137 PubMedCrossRefGoogle Scholar
  2. 2.
    Langer JC (2012) Laparoscopic and transanal pull-through for Hirschsprung disease. Semin Pediatr Surg 21(4):283–290. doi: 10.1053/j.sempedsurg.2012.07.002 PubMedCrossRefGoogle Scholar
  3. 3.
    Menezes M, Corbally M, Puri P (2006) Long-term results of bowel function after treatment for Hirschsprung’s disease: a 29-year review. Pediatr Surg Int 22(12):987–990. doi: 10.1007/s00383-006-1783-8 PubMedCrossRefGoogle Scholar
  4. 4.
    Laughlin DM, Friedmacher F, Puri P (2012) Total colonic aganglionosis: a systematic review and meta-analysis of long-term clinical outcome. Pediatr Surg Int 28(8):773–779. doi: 10.1007/s00383-012-3117-3 PubMedCrossRefGoogle Scholar
  5. 5.
    Alves MM, Sribudiani Y, Brouwer RW, Amiel J, Antinolo G, Borrego S, Ceccherini I, Chakravarti A, Fernandez RM, Garcia-Barcelo MM, Griseri P, Lyonnet S, Tam PK, van Ijcken WF, Eggen BJ, te Meerman GJ, Hofstra RM (2013) Contribution of rare and common variants determine complex diseases-Hirschsprung disease as a model. Dev Biol 382(1):320–329. doi: 10.1016/j.ydbio.2013.05.019 PubMedCrossRefGoogle Scholar
  6. 6.
    Amiel J, Sproat-Emison E, Garcia-Barcelo M, Lantieri F, Burzynski G, Borrego S, Pelet A, Arnold S, Miao X, Griseri P, Brooks AS, Antinolo G, de Pontual L, Clement-Ziza M, Munnich A, Kashuk C, West K, Wong KK, Lyonnet S, Chakravarti A, Tam PK, Ceccherini I, Hofstra RM, Fernandez R, Hirschsprung Disease C (2008) Hirschsprung disease, associated syndromes and genetics: a review. J Med Genet 45(1):1–14. doi: 10.1136/jmg.2007.053959 PubMedCrossRefGoogle Scholar
  7. 7.
    Moore SW (2012) Chromosomal and related mendelian syndromes associated with hirschsprung’s disease. Pediatr Surg Int 28(11):1045–1058PubMedCrossRefGoogle Scholar
  8. 8.
    Puffenberger EG, Hosoda K, Washington SS, Nakao K, deWit D, Yanagisawa M, Chakravart A (1994) A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung’s disease. Cell 79(7):1257–1266PubMedCrossRefGoogle Scholar
  9. 9.
    Verdy M, Weber AM, Roy CC, Morin CL, Cadotte M, Brochu P (1982) Hirschsprung’s disease in a family with multiple endocrine neoplasia type 2. J Pediatr Gastroenterol Nutr 1(4):603–607PubMedCrossRefGoogle Scholar
  10. 10.
    Garcia-Barcelo M, Sham MH, Lee WS, Lui VC, Chen BL, Wong KK, Wong JS, Tam PK (2004) Highly recurrent RET mutations and novel mutations in genes of the receptor tyrosine kinase and endothelin receptor B pathways in Chinese patients with sporadic Hirschsprung disease. Clin Chem 50(1):93–100. doi: 10.1373/clinchem.2003.022061 PubMedCrossRefGoogle Scholar
  11. 11.
    Levitt MA, Hamrick MC, Eradi B, Bischoff A, Hall J, Pena A (2013) Transanal, full-thickness, Swenson-like approach for Hirschsprung disease. J Pediatr Surg 48(11):2289–2295. doi: 10.1016/j.jpedsurg.2013.03.002 PubMedCrossRefGoogle Scholar
  12. 12.
    Engum SA, Petrites M, Rescorla FJ, Grosfeld JL, Morrison AM, Engles D (1993) Familial Hirschsprung’s disease: 20 cases in 12 kindreds. J Pediatr Surg 28(10):1286–1290PubMedCrossRefGoogle Scholar
  13. 13.
    Decker RA, Peacock ML (1998) Occurrence of MEN 2a in familial Hirschsprung’s disease: a new indication for genetic testing of the RET proto-oncogene. J Pediatr Surg 33(2):207–214PubMedCrossRefGoogle Scholar
  14. 14.
    Coyle D, Friedmacher F, Puri P (2014) The association between Hirschsprung’s disease and multiple endocrine neoplasia type 2a: a systematic review. Pediatr Surg Int 30(8):751–756. doi: 10.1007/s00383-014-3538-2 PubMedCrossRefGoogle Scholar
  15. 15.
    Bourdelat D, Vrsansky P, Pages R, Duhamel B (1997) Duhamel operation 40 years after: a multicentric study. Eur J pediatr surg 7(2):70–76. doi: 10.1055/s-2008-1071057 PubMedCrossRefGoogle Scholar
  16. 16.
    Vrsansky P, Bourdelat D, Pages R (1998) Principal modifications of the Duhamel procedure in the treatment of Hirschsprung’s disease. Analysis based on results of an international retrospective study of 2,430 patients. Pediatr Surg Int 13(2–3):125–132PubMedCrossRefGoogle Scholar
  17. 17.
    Kleinhaus S, Boley SJ, Sheran M, Sieber WK (1979) Hirschsprung’s disease—a survey of the members of the surgical section of the American Academy of Pediatrics. J Pediatr Surg 14(5):588–597PubMedCrossRefGoogle Scholar
  18. 18.
    Carter CO, Evans K, Hickman V (1981) Children of those treated surgically for Hirschsprung’s disease. J Med Genet 18(2):87–90PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Badner JA, Sieber WK, Garver KL, Chakravarti A (1990) A genetic study of Hirschsprung disease. Am J Hum Genet 46(3):568–580PubMedCentralPubMedGoogle Scholar
  20. 20.
    Bjornland K, Diseth TH, Emblem R (1998) Long-term functional, manometric, and endosonographic evaluation of patients operated upon with the Duhamel technique. Pediatr Surg Int 13(1):24–28PubMedCrossRefGoogle Scholar
  21. 21.
    Cilley RE, Statter MB, Hirschl RB, Coran AG (1994) Definitive treatment of Hirschsprung’s disease in the newborn with a one-stage procedure. Surgery 115(5):551–556PubMedGoogle Scholar
  22. 22.
    De Lagausie P, Carricaburu E, Ferkadji L, Huaut O, Aigrain Y (2004) Laparoscopic Duhamel procedure: management of 55 cases. Pediatr Endosurg Innov Tech 8(2):119–122. doi: 10.1089/1092641041360913 CrossRefGoogle Scholar
  23. 23.
    Fitze G, Appelt H, König IR, Görgens H, Stein U, Walther W, Gossen M, Schreiber M, Ziegler A, Roesner D, Schackert HK (2003) Functional haplotypes of the RET proto-oncogene promoter are associated with Hirschsprung disease (HSCR). Hum Mol Genet 12(24):3207–3214PubMedCrossRefGoogle Scholar
  24. 24.
    Fortuna RS, Weber TR, Tracy TF Jr, Silen ML, Cradock TV (1996) Critical analysis of the operative treatment of Hirschsprung’s disease. Arch Surg 131(5):520–524PubMedCrossRefGoogle Scholar
  25. 25.
    Jakobson-Setton A, Weissmann-Brenner A, Achiron R, Kuint J, Gindes L (2015) Retrospective analysis of prenatal ultrasound of children with Hirschsprung disease. Prenat Diagn 35(7):699–702. doi: 10.1002/pd.4595 PubMedCrossRefGoogle Scholar
  26. 26.
    Jung PM (1995) Hirschsprung’s disease: one surgeon’s experience in one institution. J Pediatr Surg 30(5):646–651PubMedCrossRefGoogle Scholar
  27. 27.
    Klein MD, Coran AG, Wesley JR, Drongowski RA (1984) Hirschsprung’s disease in the newborn. J Pediatr Surg 19(4):370–374PubMedCrossRefGoogle Scholar
  28. 28.
    Koh CE, Yong TL, Fenton EJ (2008) Hirschsprung’s disease: a regional experience. ANZ J Surg 78(11):1023–1027. doi: 10.1111/j.1445-2197.2008.04724.x PubMedCrossRefGoogle Scholar
  29. 29.
    Lee CC, Lien R, Chiang MC, Yang PH, Chu SM, Fu JH, Lai JY (2012) Clinical impacts of delayed diagnosis of Hirschsprung’s disease in newborn infants. Pediatr Neonatol 53(2):133–137. doi: 10.1016/j.pedneo.2012.01.011 PubMedCrossRefGoogle Scholar
  30. 30.
    Luis LA, Encinas JL, Avila LF, Andrés AM, Burgos L, Fernández A, Queizán A, Olivares P, López-Santamaría M, Burgos E, Hernández F, Lassaletta L, Tovar JA (2006) Hirschsprung disease: lessons learned from the last 100 cases. Cir Pediatr 19(3):177–181PubMedGoogle Scholar
  31. 31.
    Marty TL, Seo T, Matlak ME, Sullivan JJ, Black RE, Johnson DG (1995) Gastrointestinal function after surgical correction of Hirschsprung’s disease: long-term follow-up in 135 patients. J Pediatr Surg 30(5):655–658PubMedCrossRefGoogle Scholar
  32. 32.
    Moore SW, Zaahl M (2010) Familial associations in medullary thyroid carcinoma with Hirschsprung disease: the role of the RET-C620 “Janus” genetic variation. J Pediatr Surg 45(2):393–396. doi: 10.1016/j.jpedsurg.2009.10.080 PubMedCrossRefGoogle Scholar
  33. 33.
    Moore SW, Rode H, Millar AJ, Albertyn R, Cywes S (1991) Familial aspects of Hirschsprung’s disease. Eur J Pediatr Surg 1(2):97–101PubMedCrossRefGoogle Scholar
  34. 34.
    More K, Rao S, McMichael J, Minutillo C (2014) Growth and developmental outcomes of infants with Hirschsprung disease presenting in the neonatal period: a retrospective study. J Pediatr 165(1):73–77. doi: 10.1016/j.jpeds.2014.02.062 PubMedCrossRefGoogle Scholar
  35. 35.
    Mir E, Karaca I, Günsar C, Sencan A, Fesçekoglu O (2001) Primary Duhamel-Martin operations in neonates and infants. Pediatr Int 43(4):405–408PubMedCrossRefGoogle Scholar
  36. 36.
    Murthi GV, Raine PA (2003) Preoperative enterocolitis is associated with poorer long-term bowel function after Soave-Boley endorectal pull-through for Hirschsprung’s disease. J Pediatr Surg 38(1):69–72PubMedCrossRefGoogle Scholar
  37. 37.
    Neuvonen MI, Kyrklund K, Lindahl HG, Koivusalo AI, Rintala RJ, Pakarinen MP (2015) A population-based, complete follow-up of 146 consecutive patients after transanal mucosectomy for Hirschsprung disease. J Pediatr Surg. doi: 10.1016/j.jpedsurg.2015.02.006
  38. 38.
    Orr JD, Scobie WG (1983) Presentation and incidence of Hirschsprung’s disease. Br Med J (Clin Res Ed) 287(6406):1671CrossRefGoogle Scholar
  39. 39.
    Pini Prato A, Gentilino V, Giunta C, Avanzini S, Parodi S, Mattioli G, Martucciello G, Jasonni V (2008) Hirschsprung’s disease: 13 years’ experience in 112 patients from a single institution. Pediatr Surg Int 24(2):175–182PubMedCrossRefGoogle Scholar
  40. 40.
    Reding R, de Ville de Goyet J, Gosseye S, Clapuyt P, Sokal E, Buts JP, Gibbs P, Otte JB (1997) Hirschsprung’s disease: a 20-year experience. J Pediatr Surg 32(8):1221–1225CrossRefGoogle Scholar
  41. 41.
    Ruiz-Ferrer M, Torroglosa A, Luzón-Toro B, Fernández RM, Antiñolo G, Mulligan LM, Borrego S (2011) Novel mutations at RET ligand genes preventing receptor activation are associated to Hirschsprung’s disease. J Mol Med. 89(5):471–480. doi: 10.1007/s00109-010-0714-2 PubMedCrossRefGoogle Scholar
  42. 42.
    Russell MB, Russell CA, Fenger K, Niebuhr E (1994) Familial occurrence of Hirschsprung’s disease. Clin Genet 45(5):231–235PubMedCrossRefGoogle Scholar
  43. 43.
    Ryan ET, Ecker JL, Christakis NA, Folkman J (1992) Hirschsprung’s disease: associated abnormalities and demography. J Pediatr Surg 27(1):76–81CrossRefGoogle Scholar
  44. 44.
    Sarioglu A, Tanyel FC, Büyükpamukçu N, Hiçsönmez A (1997) Hirschsprung-associated congenital anomalies. Eur J Pediatr Surg 7(6):331–337PubMedCrossRefGoogle Scholar
  45. 45.
    Shinall MC Jr, Koehler E, Shyr Y, Lovvorn HN 3rd (2008) Comparing cost and complications of primary and staged surgical repair of neonatally diagnosed Hirschsprung’s disease. J Pediatr Surg 43(12):2220–2225. doi: 10.1016/j.jpedsurg.2008.08.048 PubMedCrossRefGoogle Scholar
  46. 46.
    Nah SA, de Coppi P, Kiely EM, Curry JI, Drake DP, Cross K, Spitz L, Eaton S, Pierro A (2012) Duhamel pull-through for Hirschsprung disease: a comparison of open and laparoscopic techniques. J Pediatr Surg 47(2):308–312. doi: 10.1016/j.jpedsurg.2011.11.025 PubMedCrossRefGoogle Scholar
  47. 47.
    Shono K, Hutson JM (1994) The treatment and postoperative complications of Hirschsprung’s disease. Pediatr Surg Int 9(5–6):362–365CrossRefGoogle Scholar
  48. 48.
    Svensson PJ, Molander ML, Eng C, Anvret M, Nordenskjöld A (1998) Low frequency of RET mutations in Hirschsprung disease in Sweden. Clin Genet 54(1):39–44PubMedCrossRefGoogle Scholar
  49. 49.
    Virtanen VB, Pukkala E, Kivisaari R, Salo PP, Koivusalo A, Arola J, Miettinen PJ, Rintala RJ, Perola M, Pakarinen MP (2013) Thyroid cancer and co-occurring RET mutations in Hirschsprung disease. Endocr Relat Cancer 20(4):595–602. doi: 10.1530/ERC-13-0082 PubMedCrossRefGoogle Scholar
  50. 50.
    Wang JS, Lee HC, Huang FY, Chang PY, Sheu JC (2004) Unexpected mortality in pediatric patients with postoperative Hirschsprung’s disease. Pediatr Surg Int 20(7):525–528PubMedCrossRefGoogle Scholar
  51. 51.
    Weber TR, Fortuna RS, Silen ML, Dillon PA (1999) Reoperation for Hirschsprung’s disease. J Pediatr Surg 34(1):153-156; discussion 156-7 PubMedCrossRefGoogle Scholar
  52. 52.
    Yanchar NL, Soucy P (1999) Long-term outcome after Hirschsprung’s disease: patients’ perspectives. J Pediatr Surg 34(7):1152–1160PubMedCrossRefGoogle Scholar
  53. 53.
    Ziad F, Katchy KC, Al Ramadan S, Alexander S, Kumar S (2006) Clinicopathological features in 102 cases of Hirschsprung disease. Ann Saudi Med. 26(3):200–204PubMedGoogle Scholar
  54. 54.
    Anupama B, Zheng S, Xiao X (2007) Ten-year experience in the management of total colonic aganglionosis. J Pediatr Surg. 42(10):1671–1676PubMedCrossRefGoogle Scholar
  55. 55.
    Azzis O, Fremond B, Dabadie A, Jouan J, Bracq H, Babut JM (1996) Total colonic form of Hirschsprung disease: treatment and long-term follow-up in 16 cases. Chirurgie 121(3):225–229PubMedGoogle Scholar
  56. 56.
    Barrena S, Andres AM, Burgos L, Luis AL, Hernandez F, Martinez L, Lopez-Santamaria M, Lassaletta L, Tovar JA (2008) Long-term results of the treatment of total colonic aganglionosis with two different techniques. Eur J Pediatr Surg 18(6):375–379PubMedCrossRefGoogle Scholar
  57. 57.
    Bickler SW, Harrison MW, Campbell TJ, Campbell JR (1992) Long-segment Hirschsprung’s disease. Arch Surg 127(9):1047–1050; discussion 1050–1041 PubMedCrossRefGoogle Scholar
  58. 58.
    Cass DT, Myers N (1987) Total colonic aganglionosis: 30 years’ experience. Pediatr Surg Int 2:68–75Google Scholar
  59. 59.
    Choe EK, Moon SB, Kim HY, Lee SC, Park KW, Jung SE (2008) Outcomes of surgical management of total colonic aganglionosis. World J Surg 32(1):62–68PubMedCrossRefGoogle Scholar
  60. 60.
    Dykes EH, Guiney EJ (1989) Total colonic aganglionosis. J Pediatr Gastroenterol Nutr 8(1):129–132PubMedCrossRefGoogle Scholar
  61. 61.
    Emslie J, Krishnamoorthy M, Applebaum H (1997) Long-term follow-up of patients treated with ileoendorectal pull-through and right colon onlay patch for total colonic aganglionosis. J Pediatr Surg 32(11):1542–1544PubMedCrossRefGoogle Scholar
  62. 62.
    Escobar MA, Grosfeld JL, West KW, Scherer LR, Rouse TM, Engum SA, Rescorla FJ (2005) Long-term outcomes in total colonic aganglionosis: a 32-year experience. J Pediatr Surg 40(6):955–961PubMedCrossRefGoogle Scholar
  63. 63.
    Festen C, Severijnen R, Vanderstaak F, Rieu P (1989) Total colonic aganglionosis - treatment and follow-up. Zeitschrift Fur Kinderchirurgie 44(3):153–155PubMedGoogle Scholar
  64. 64.
    Galifer RB, Frapier JM, Bosc O, Massip A, Rieu D, Couture A, Veyrac C, Barneon G (1987) Total colonic aganglionosis without ileal involvement - an analysis of 6 cases. Chirur Pediatr 28(3):137–144Google Scholar
  65. 65.
    Hernández F, Rivas S, Avila LF, Díaz M, Leal N, Martínez L, Murcia J, Olivares P, Mariño JM, López M, Lassaletta L, Tovar JA (2003) Extensive aganglionosis. Treatment and long term results. Cir Pediatr 16(2):54–57PubMedGoogle Scholar
  66. 66.
    Hoehner JC, Ein SH, Shandling B, Kim PCW (1998) Long-term morbidity in total colonic aganglionosis. J Pediatr Surg 33(7):961–965PubMedCrossRefGoogle Scholar
  67. 67.
    Menezes M, Pini Prato A, Jasonni V, Puri P (2008) Long-term clinical outcome in patients with total colonic aganglionosis: a 31-year review. J Pediatr Surg 43(9):1696–1699. doi: 10.1016/j.jpedsurg.2008.01.072 PubMedCrossRefGoogle Scholar
  68. 68.
    N-fekete C, Ricour C, Martelli H, Jacob SL, Pellerin D (1986) Total colonic aganglionosis (with or without ileal involvement) - a review of 27 cases. J Pediatr Surg 21(3):251–254PubMedCrossRefGoogle Scholar
  69. 69.
    Raboei EH (2008) Long-term outcome of total colonic aganglionosis. Eur J Pediatr Surg 18(5):300–302. doi: 10.1055/s-2008-1038495 PubMedCrossRefGoogle Scholar
  70. 70.
    Shen C, Song Z, Zheng S, Xiao X (2009) A comparison of the effectiveness of the Soave and Martin procedures for the treatment of total colonic aganglionosis. J Pediatr Surg 44(12):2355–2358. doi: 10.1016/j.jpedsurg.2009.07.056 PubMedCrossRefGoogle Scholar
  71. 71.
    Travassos DV, van der Zee DC (2011) Is complete resection of the aganglionic bowel in extensive total aganglionosis up to the middle ileum always necessary? J Pediatr Surg 46(11):2054–2059PubMedCrossRefGoogle Scholar
  72. 72.
    Tsuji H, Spitz L, Kiely EM, Drake DP, Pierro A (1999) Management and long-term follow-up of infants with total colonic aganglionosis. J Pediatr Surg 34(1):158–161PubMedCrossRefGoogle Scholar
  73. 73.
    Yeh YT, Tsai HL, Chen CY, Wang JB, Chin TW, Wei CF, Liu CS (2014) Surgical outcomes of total colonic aganglionosis in children: a 26-year experience in a single institute. J Chin Med Assoc 77(10):519–523. doi: 10.1016/j.jcma.2014.05.012 PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.National Children’s Research CentreOur Lady’s Children’s HospitalDublin 12Ireland

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