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Total colonic aganglionosis and Hirschsprung’s disease: a review

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Abstract

Total colonic aganglionosis is a relatively uncommon form of Hirschsprung’s disease (HSCR). It occurs in approximately 2–13 % of HSCR cases and involves the entire colon which is aganglionic but may extend proximally into varying lengths of small bowel. As a result, it should be separated into Total colonic aganglionosis (TCA) [defined as aganglionosis extending from the anus to at least the ileocaecal valve but no more than 50 cm small bowel proximal to the ileocaecal valve] and total colonic and small bowel aganglionosis (TCSA) which may involve very long segments of small bowel aganglionosis. Clinically, TCA appears to represent a different spectrum of disease in terms of presentation and difficulties which may be experienced in diagnosis suggesting a different pathophysiology from the more common forms of HSCR. It is therefore not yet clear whether TCA merely represents a long form of HSCR or a different expression of the disease. A number of differences exist between TCA and other forms of HSCR which require explanation if its ubiquitous clinical features are to be understood. In addition to the usual explanations for the aganglionosis of HSCR, there is some evidence suggesting that in place of being purely congenital, it may represent certain different pathophysiologic mechanisms, some of which may continue to be active after birth. This study reviews what is known about the clinical, radiological and histopathologic differences between TCA and the more frequently encountered recto-sigmoid (or short-segment; S-HSCR) and correlates them with what is currently known about the genetic and molecular biologic background to find possible pathogenetic mechanisms.

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References

  1. Meijers JH, van der Sanden MP, Tibboel D, van der Kamp AW, Luider TM, Molenaar JC (1992) Colonization characteristics of enteric neural crest cells: embryological aspects of Hirschsprung’s disease. J Pediatr Surg 27:811–814

    Article  CAS  PubMed  Google Scholar 

  2. Amiel J, Lyonnet S (2001) Hirschsprung disease, associated syndromes, and genetics: a review. J Med Genet 38(11):729–739

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Moore SW (2006) The contribution of associated congenital anomalies in understanding Hirschsprungs disease. Pediatr Surg Int 22:305–315

    Article  CAS  PubMed  Google Scholar 

  4. Kaiser G, Bettex M (1982) Disorders and congenital malformations associated with Hirschsprungs disease. In: Holschneider AM (ed) Hirschsprung’s disease. Hipokrates-Verlag, Stuttgart, pp 49–53

    Google Scholar 

  5. Zuelzer WW, Wilson JL (1948) Functional intestinal obstruction on a congenital neurogenic basis in infancy. Am J Dis Child 75:40–64

    CAS  PubMed  Google Scholar 

  6. Cass D, Myers N (1987) Total colonic aganglionosis: 30 years experience. Pediatr Surg Int 2:68–75

    Google Scholar 

  7. Moore SW (1993) A study of the etiology of post-surgical obstruction in patients with Hirschsprungs disease. Doctoral Thesis University of Cape Town. pp 1–375

  8. Moore SW, Zaahl M (2009) Clinical and genetic differences in Total colonic aganglionosis (TCA) in Hirschsprungs disease. J Pediatr Surg 44(10):1899–1903

    Article  PubMed  Google Scholar 

  9. Davies MR, Cywes S, Rode H (1981) The manometric evaluation of the rectosphincteric reflex in total colonic aganglionosis. J Pediatr Surg 16:660–663

    Article  CAS  PubMed  Google Scholar 

  10. Festen C, Severijnen RS, vd Staak F, Rieu PN (1988) Total Colonic Aganglionosis: treatment and follow-up. Z Kinderchir 44:153–155

    Google Scholar 

  11. Bodian M, Carter CO, Ward BCH (1951) Hirschsprungs disease. Lancet 1:302–309

    Article  CAS  PubMed  Google Scholar 

  12. Louw JH (1971) Total colonic aganglionosis. Can J Surg 21:397–405

    Google Scholar 

  13. Freeman NV (1971) Long segment Hirschsprungs disease. Proc Roy Soc Med 64:30–32

    Google Scholar 

  14. Martin LW (1972) Surgical Management of total colonic aganglionosis. Ann Surg 176:343–346

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Ieiri S, Suita S, Nakatsuji T, Akiyoshi J, Taguchi T (2008) Total colonic aganglionosis with or without small bowel involvement: a 30-year retrospective nationwide survey in Japan. J Pediatr Surg 43:2226–2230

    Article  PubMed  Google Scholar 

  16. Gordon H, Louw JH, Torrington M, Cywes S (1966) A genetical study of Hirschsprungs disease. S Afr Med J 40:720–721

    CAS  PubMed  Google Scholar 

  17. Kleinhaus S, Boley SJ, Sheran M, Sieber WK (1979) Hirschsprungs disease: a survey of the Surgical section of the American Academy of Pediatrics. J Pediatr Surg 14:588–597

    Article  CAS  PubMed  Google Scholar 

  18. Moore SW, Rode H, Millar AJ, Albertyn R, Cywes S (1991) Familial aspects of Hirschsprungs disease. Eur J Pediatr Surg 1:97–107

    Article  CAS  PubMed  Google Scholar 

  19. Nemeth L, Yoneda A, Kader M, Devaney D, Puri P (2001) Three-dimensional morphology of gut innervation in total intestinal aganglionosis using whole-mount preparation. J Pediatr Surg 36:291–295

    Article  CAS  PubMed  Google Scholar 

  20. Caniano DA, Ormsbee HS III, Polito W, Sun CC, Barone FC, Hill JL (1985) Total intestinal aganglionosis. J Pediatr Surg 20:456–460

    Article  CAS  PubMed  Google Scholar 

  21. Hoehner JC, Ein SH, Shandling B, Kim PC (1998) Long-term morbidity in total colonic aganglionosis. J Pediatr Surg 33:961–965

    Article  CAS  PubMed  Google Scholar 

  22. Senyuz OF, Buyukunal C, Danismend N, Erdogan E, Ozbay G, Soylet Y (1989) Extensive intestinal aganglionosis. J Pediatr Surg 24:453–456

    Article  CAS  PubMed  Google Scholar 

  23. Sharif K, Beath SV, Kelly DA, McKiernan P, van Mourik I, Mirza D, Mayer AD, Buckels JA, de Ville GJ (2003) New perspective for the management of near-total or total intestinal aganglionosis in infants. J Pediatr Surg 38:25–28

    Article  CAS  PubMed  Google Scholar 

  24. Ikeda K, Goto S (1986) Total colonic aganglionosis with or without small bowel involvement: an analysis of 137 patients. J Pediatr Surg 21:319–322

    Article  CAS  PubMed  Google Scholar 

  25. 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 40:955–961

    Article  PubMed  Google Scholar 

  26. Anupama B, Zheng S, Xiao X (2007) Ten-year experience in the management of total colonic aganglionosis. J Pediatr Surg 42:1671–1676

    Article  PubMed  Google Scholar 

  27. Lefebvre MP, Leape LL, Pohl DA, Safaii H, Grand RJ (1984) Total colonic aganglionosis initially diagnosed in an adolescent. Gastroenterology 87:1364–1366

    CAS  PubMed  Google Scholar 

  28. Lall A, Agarwala S, Bhatnagar V, Gupta AK, Mitra DK (1999) Total colonic aganglionosis: diagnosis and management in a 12-year-old boy. J Pediatr Surg 4:1413–1414

    Article  Google Scholar 

  29. Myers MB, Bradburn D, Vela R, Payzant A, Karlin S (1966) Total aganglionic colon in an adult: first reported case. Ann Surg 163:97–102

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. DeLorijn F, Reitsma JB, Voskuijl WP, Aronson DC, Ten Kate FJ, Smets AM, Taminiau JA, Benninga MA (2005) Diagnosis of Hirschsprung’s disease: a prospective, comparative accuracy study of common tests. J Pediatr 146:787–792

    Article  Google Scholar 

  31. Jamieson DH, Dundas SE, Belushi SA, Cooper M, Blair GK (2004) Does the transition zone reliably delineate aganglionic bowel in Hirschsprung’s disease? Pediatr Radiol 34:811–815

    Article  PubMed  Google Scholar 

  32. Stranzinger E, DiPietro MA, Teitelbaum DH, Strouse PJ (2008) Imaging of total colonic Hirschsprung disease. Pediatr Radiol 38:1162–1170

    Article  PubMed  Google Scholar 

  33. Berdon WE, Koontz P, Baker DH (1964) The Diagnosis of colonic and terminal ileal aganglionosis. Am J Roentgenol Radium Ther Nucl Med 91:680–689

    CAS  PubMed  Google Scholar 

  34. Hayakawa K, Hamanaka Y, Suzuki M, Nakatsu M, Nishimura K, Tanaka M, Yamamoto E, Mukaihara S, Hojo M, Shimizu T, Takasu K, Shimotake T (2003) Radiological findings in total colon aganglionosis and allied disorders. Radiat Med 21:128–134

    PubMed  Google Scholar 

  35. Solari V, Piotrowska AP, Puri P (2003) Histopathological differences between recto-sigmoid Hirschsprung’s disease and total colonic aganglionosis. Pediatr Surg Int 19:349–354

    Article  CAS  PubMed  Google Scholar 

  36. Knowles CH, De Giorgio R, Kapur RP, Bruder E, Farrugia G, Geboes K et al (2009) Gastrointestinal neuromuscular pathology: guidelines for histological techniques and reporting on behalf of the Gastro 2009 International Working Group. Acta Neuropathol 118(2):271–301

    Article  PubMed  Google Scholar 

  37. Rabah R (2010) Total colonic aganglionosis: case report, practical diagnostic approach and pitfalls. Arch Pathol Lab Med 134:1467–1473

    PubMed  Google Scholar 

  38. Kapur RP (2009) 1Practical pathology and genetics of Hirschsprung’s disease. Semin Pediatr Surg 8:212–223

    Article  Google Scholar 

  39. Wang H, Zhang Y, Liu W, Wu R, Chen X, Gu L, Wei B, Gao Y (2009) Interstitial cells of Cajal reduce in number in recto-sigmoid Hirschsprung’s disease and total colonic aganglionosis. Neurosci Lett 451:208–211

    Article  CAS  PubMed  Google Scholar 

  40. Horigome F, Seki T, Kobayashi H, Ozaki T, Yamataka A (2007) Developmental anomalies of the enteric nervous system in normoganglionic segments of bowel from rats with total colonic aganglionosis. Pediatr Surg Int 23:991–995

    Article  PubMed  Google Scholar 

  41. Badner JA, Sieber WK, Garver KL, Chakravarti A (1990) A genetic study of Hirschsprung disease. Am J Hum Genet 46:568–580

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Solari V, Ennis S, Yoneda A, Wong L, Messineo A, Hollwarth ME, Green A, Puri P (2003) Mutation analysis of the RET gene in total intestinal aganglionosis by wave DNA fragment analysis system. J Pediatr Surg 38(3):497–501

    Article  CAS  PubMed  Google Scholar 

  43. Hofstra RM, Wu Y, Stulp RP, Elfferich P, Osinga J, Maas SM, Siderius L, Brooks AS, vd Ende JJ, Heydendael VM, Severijnen RS, Bax KM, Meijers C, Buys CH (2005) RET and GDNF gene scanning in Hirschsprung patients using two dual denaturing gel systems. Hum Mutat 15(5):418–429

    Article  Google Scholar 

  44. Lantieri F, Griseri P, Puppo F, Campus R, Martucciello G, Ravazzolo R, Devoto M, Ceccherini I (2006) Haplotypes of the human RET proto-oncogene associated with Hirschsprung disease in the Italian population derive from a single ancestral combination of alleles. Ann Hum Genet 70:12–26

    Article  CAS  PubMed  Google Scholar 

  45. Derrick EH, St George-Grambauer BM (1957) Megacolon in mice. J Path Bacteriol 73:569–571

    Article  Google Scholar 

  46. Lane PW (1966) Association of megacolon with 2 recessive spotting genes in the mouse. J Hered 57:29–31

    CAS  PubMed  Google Scholar 

  47. Nagahama M, Ozaki T, Hama K (1985) A study of the myenteric plexus of the congenital aganglionosis rat (spotting lethal). Anat Embryol (Berl) 171:285–296

    Article  CAS  Google Scholar 

  48. Nagahama M, Semba R, Tsuzuki M, Ozaki T (2001) Distribution of peripheral nerve terminals in the small and large intestine of congenital aganglionosis rats (Hirschsprung’s disease rats). Pathol Int 51:145–157

    Article  CAS  PubMed  Google Scholar 

  49. Gariepy CE, Williams SC, Richardson JA, Hammer RE, Yanagisawa M (1998) Transgenic expression of the endothelin-B receptor prevents congenital intestinal aganglionosis in a rat model of Hirschsprung disease. J Clin Invest 102:1092–1101

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Kapur RP (1999) Early death of neural crest cells is responsible for total enteric aganglionosis in Sox10(Dom)/Sox10(Dom) mouse embryos. Pediatr Dev Pathol 2:559–569

    Article  CAS  PubMed  Google Scholar 

  51. Stanchina L, Baral V, Robert F, Pingault V, Lemort N, Pachnis V, Goossens M, Bondurand N (2006) Interactions between Sox10, Edn3 and Ednrb during enteric nervous system and melanocyte development. Dev Biol 295(1):232–249

    Article  CAS  PubMed  Google Scholar 

  52. Burns AJ, Pachnis V (2009) Development of the enteric nervous system: bringing together cells, signals and genes. Neurogastroenterol Motil 21:100–102

    Article  CAS  PubMed  Google Scholar 

  53. Thapar N (2009) New frontiers in the treatment of Hirschsprung disease. J Pediatr Gastroenterol Nutr 48(Suppl 2):S92–S94

    Article  PubMed  Google Scholar 

  54. Lane PW, Liu HM (1984) Association of megacolon with a new dominant spotting gene (Dom) in the mouse. J Hered 75:435–439

    CAS  PubMed  Google Scholar 

  55. Leffler A, Wedel T, Busch LC (1999) Congenital colonic hypoganglionosis in murine trisomy 16–an animal model for Down’s syndrome. Eur J Pediatr Surg 9(6):381–388

    Article  CAS  PubMed  Google Scholar 

  56. Moore SW (2012) Chromosomal and related Mendelian syndromes associated with Hirschsprung’s disease. Pediatr Surg Int 28:1045–1058

    Article  CAS  PubMed  Google Scholar 

  57. Luo Y, Barone V, Seri M, Bolino A, Bocciardi R, Ceccherini I, Pasini B, Tocco T, Lerone M, Cywes S, Moore S, Vanderwinden JM, Abramowicz MJ, Kristofferson U, Hamel B, Martucciello G, Romeo G (1994) Heterogeneity of mutations of the RET proto-oncogene in autosomal dominant HSCR. Eur J Hum Genet 2:272–280

    Google Scholar 

  58. Carrasquillo MM, McCallion AS, Puffenberger EG, Kaschuk CS, No N, Chakravarti A (2002) Genome-wide association study as well as the study of mouse models help to identify the interaction between RET and EDNRB pathways in Hirschsprung disease. Nature Genet 32:237–244

    Article  CAS  PubMed  Google Scholar 

  59. Martucciello G, Bicocci MP, Dodero P, Lerone M, Silengo-Cirillo M, Puliti A, Gimelli G (1992) Total colonic aganglionosis associated with intestitial deletion of the long arm of chromosome 10. Pediatr Surg Int 7(4):308–310

    Article  Google Scholar 

  60. Ceccherini I, Zhang AL, Matera I, Yang G, Devoto M, Romeo G, Cass DT (1995) Interstitial deletion of the endothelin-B receptor gene in the spotting lethal (sl) rat. Hum Mol Genet 4(11):2089–2096

    Article  CAS  PubMed  Google Scholar 

  61. Gariepy CE, Cass DT, Yanagisawa M (1996) Null mutation of endothelin receptor type B gene in spotting lethal rats causes aganglionic megacolon and white coat color. Proc Natl Acad Sci USA 93:867–872

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Ou-Yang MC, Yang SN, Hsu YM, Ou-Yang MH, Haung HC, Lee SY, Hsieh WS, Su YN, Liu CA (2007) Concomitant existence of total bowel aganglionosis and congenital central hypoventilation syndrome in a neonate with PHOX2B gene mutation. J Pediatr Surg 42:e9–e11

    Article  PubMed  Google Scholar 

  63. Inoue K, Shimotake T, Iwai N (2000) Mutational analysis of RET/GDNF/NTN genes in children with total colonic aganglionosis with small bowel involvement. Am J Med Genet 93:278–284

    Article  CAS  PubMed  Google Scholar 

  64. Jijiwa M, Fukuda T, Kawai K, Nakamura A, Kurokawa K, Murakumo Y, Ichihara M, Takahashi M (2004) A targeting mutation of tyrosine 1062 in Ret causes a marked decrease of enteric neurons and renal hypoplasia. Mol Cell Biol 24(18):8026–8036

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Stenqvist A, Lundgren TK, Smith MJ, Hermanson O, Castelo-Branco G, Pawson T, Ernfors P (2008) Subcellular receptor redistribution and enhanced microspike formation by a Ret receptor preferentially recruiting Dok. Neurosci Lett 435:11–16

    Article  CAS  PubMed  Google Scholar 

  66. Uesaka T, Nagashimada M, Yonemura S, Enomoto H (2008) Diminished Ret expression compromises neuronal survival in the colon and causes intestinal aganglionosis in mice. J Clin Invest 118:1890–1898

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Jurvansuu JM, Goldman A (2008) Recent inventions on receptor tyrosine kinase RET modulation. Recent Pat Biotechnol 2:47–54

    Article  CAS  PubMed  Google Scholar 

  68. Kenny SE, Hofstra RM, Buys CHCM, Vaillant CR, Lloyd DA, Edgar DH (2000) Reduced endothelin-3 expression in sporadic Hirschsprung disease. Brit J Surg 87:580–585

    Article  CAS  PubMed  Google Scholar 

  69. Oue T, Puri P (1999) Altered endothelin-3 and endothelin-B receptor mRNA expression in Hirschsprung’s disease. J Pediatr Surg 34:1257–1260

    Article  CAS  PubMed  Google Scholar 

  70. Decker RA, Peacock ML, Watson P (1998) Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation. Hum Mol Genet 7(1):129–134

    Article  CAS  PubMed  Google Scholar 

  71. 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 45:393–396

    Article  PubMed  Google Scholar 

  72. Luzon-Toro B, Torroglosa A, Nunez-Torres R, Enguix-Riego MV, Fernandez RM, de Agustin JC, Antinolo G, Borrego S (2012) Comprehensive analysis of NRG1 common and rare variants in Hirschsprung patients. PLoS One 7:e36524

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Garcia-Barcelo MM, Tang CS, Ngan ES, Lui VC, Chen Y, So MT et al (2009) Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung’s disease. Proc Natl Acad Sci USA 106:2694–2699

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  74. Moore SW, Millar A, Rode H, Cywes S (1990) Intestinal atresia and Hirschsprungs disease. Pediatr Surg Int 5(3):182–189

    Article  Google Scholar 

  75. Gupta M, Beeram MR, Pohl JF, Custer MD (2005) Ileal atresia associated with Hirschsprung disease (total colonic aganglionosis). J Pediatr Surg 40(9):e5–e7

    Article  PubMed  Google Scholar 

  76. Michna BA, McWilliams NB, Krummel TM, Hartenberg MA, Salzberg AM (1988) Multifocal ganglioneuroblastoma coexistent with total colonic aganglionosis. J Pediatr Surg 23([1 Pt 2]):57–59

    Article  CAS  PubMed  Google Scholar 

  77. Cohen I, Gadd MA (1982) Hirschsprungs disease in a kindred : a possible clue to the genetics of the disease. J Pediatr Surg 17:632–634

    Article  CAS  PubMed  Google Scholar 

  78. Spouge D, Baird PA (1985) Hirschsprungs Disease in a large birth cohort. Teratology 32:171–177

    Article  CAS  PubMed  Google Scholar 

  79. Careskey JM, Weber TR, Grosfeld JL (1982) Total colonic aganglionosis. Analysis of 16 cases. Am J Surg 143:160–168

    Article  CAS  PubMed  Google Scholar 

  80. 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 34:158–161

    Article  CAS  PubMed  Google Scholar 

  81. Goto S, Gunter M, Scherer LR, Bloch T, Grosfeld JL (1986) Surgical treatment of total colonic aganglionosis: efficacy of aganglionic patch enteroplasty in the rat. J Pediatr Surg 21:601–607

    Article  CAS  PubMed  Google Scholar 

  82. 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 32:1542–1544

    Article  CAS  PubMed  Google Scholar 

  83. Menezes M, Pini Prato A, Jassoni V, Puri P (2009) Long-term clinical outcome in patients with total colonic aganglionosis: A 31 year review. J Pediatr Surg 43:1696–1699

    Article  Google Scholar 

  84. Ikawa H, Masuyama H, Hirabayashi T, Endo M, Yokoyama J (1997) More than 10 year’s follow-up to total colonic aganglionosis—severe iron deficiency anemia and growth retardation. J Pediatr Surg 32:25–27

    Article  CAS  PubMed  Google Scholar 

  85. Moore SW, Albertyn R, Cywes S (1996) Clinical outcome and long term quality of life after surgical correction of Hirschsprungs disease. J Pediatr Surg 31:1496–1502

    Article  CAS  PubMed  Google Scholar 

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I acknowledge the ongoing support obtained from the Medical Research Council of South Africa for this project.

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  1. Department of Paediatric Surgery, Faculty of Medicine, University of Stellenbosch, P.O. Box 19063, Tygerberg, 7505, South Africa

    S. W. Moore

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Moore, S.W. Total colonic aganglionosis and Hirschsprung’s disease: a review. Pediatr Surg Int 31, 1–9 (2015). https://doi.org/10.1007/s00383-014-3634-3

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