Digestive Diseases and Sciences

, Volume 56, Issue 6, pp 1818–1827 | Cite as

Novel Classification and Pathogenetic Analysis of Hypoganglionosis and Adult-Onset Hirschsprung’s Disease

  • Mi Young Do
  • Seung-Jae MyungEmail author
  • Hyo-Jin Park
  • Jun-Won Chung
  • In-Wha Kim
  • Sun Mi Lee
  • Chang Sik Yu
  • Hye Kyung Lee
  • Jong-Keuk Lee
  • Young Soo Park
  • Se Jin Jang
  • Hye Jin Kim
  • Byong Duk Ye
  • Jeong-Sik Byeon
  • Suk-Kyun Yang
  • Jin-Ho Kim
Original Article


Background and Aims

Researchers have not clearly described the clinical and pathogenetic features of hypoganglionosis and adult-onset Hirschsprung’s disease, which cause pseudo-obstruction or intractable constipation. We conducted this study to explore these features of hypoganglionosis and adult-onset Hirschsprung’s disease in Korean patients.


We enrolled 24 patients pathologically confirmed as having hypoganglionosis and 11 as having adult-onset Hirschsprung’s disease. We recruited 26 subjects who had undergone operation for nonobstructive colon cancer and 45 healthy volunteers as controls. We described their clinical features, investigated ganglion cells and interstitial cells of Cajal (ICC), and analyzed RET, EDNRB, EDN3, and SOX10 genes.


We classified hypoganglionosis patients into two groups: type I (focal type, n = 13), with focally narrowed transition zone (TZ); and type II (diffuse type, n = 11), without transition zone. Hypoganglionosis patients had significantly fewer ganglion cells than the controls, and those cells were scarcer in the transition zone than in the proximal dilated area (P < 0.05). The ICC numbers in both diseases were significantly lower than in controls; however, they were similar between transition zone and the proximal dilated area in hypoganglionosis. In adult-onset Hirschsprung’s disease, two significant intronic RET polymorphic variants, IVS14-24G>A and IVS19+47T>C, were significantly associated with adult-onset Hirschsprung’s disease (P = 0.0122 and 0.0295, respectively), but not with hypoganglionosis.


Hypoganglionosis and adult-onset Hirschsprung’s disease have different pathophysiologic characteristics, although their clinical presentations are similar. We suggest that there are two subgroups of hypoganglionosis: those with or without a focally narrowed transition zone with a profoundly diminished number of ganglion cells.


Hypoganglionosis Adult-onset Hirschsprung’s disease Pseudo-obstruction Intractable constipation Ganglion cell Interstitial cells of Cajal 



The authors thank Ms. Hyun Suk Song for her assistance with data collection. This work was supported by a grant (2008-0261) from the Asan Institute for Life Sciences and the Korean Society of Neurogastroenterology and Motility (2009).

Conflict of interest

None of the authors has any conflict of interest to declare.

Supplementary material

10620_2010_1522_MOESM1_ESM.pdf (60 kb)
Supplementary material 1 (PDF 60 kb)


  1. 1.
    De Giorgio R, Sarnelli G, Corinaldesi R, et al. Advances in our understanding of the pathology of chronic intestinal pseudo-obstruction. Gut. 2004;53:1549–1552.PubMedCrossRefGoogle Scholar
  2. 2.
    De Giorgio R, Camilleri M. Human enteric neuropathies: morphology and molecular pathology. Neurogastroenterol Motil. 2004;16:515–531.PubMedCrossRefGoogle Scholar
  3. 3.
    Lesser PB, El-Nahas AM, Lukl P, et al. Adult-onset Hirschsprung’s disease. JAMA. 1979;242:747–748.PubMedCrossRefGoogle Scholar
  4. 4.
    Todd IP. Adult Hirschsprung’s disease. Br J Surg. 1977;64:311–312.PubMedCrossRefGoogle Scholar
  5. 5.
    Martucciello G, Pini Prato A, Puri P, 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;40:1527–1531.PubMedCrossRefGoogle Scholar
  6. 6.
    Yu CS, Kim HC, Hong HK, et al. Evaluation of myenteric ganglion cells and interstitial cells of Cajal in patients with chronic idiopathic constipation. Int J Colorectal Dis. 2002;17:253–258.PubMedCrossRefGoogle Scholar
  7. 7.
    Kim HJ, Kim AY, Lee CW, et al. Hirschsprung disease and hypoganglionosis in adults: radiologic findings and differentiation. Radiology. 2008;247:428–434.PubMedCrossRefGoogle Scholar
  8. 8.
    Choi JS, Lim JS, Kim H, et al. Colonic pseudoobstruction: CT findings. Am J Roentgenol. 2008;190:1521–1526.CrossRefGoogle Scholar
  9. 9.
    Burns AJ. Disorders of interstitial cells of Cajal. J Pediatr Gastroenterol Nutr. 2007;45:S103–S106.PubMedCrossRefGoogle Scholar
  10. 10.
    Wedel T, Spiegler J, Soellner S, et al. Enteric nerves and interstitial cells of Cajal are altered in patients with slow-transit constipation and megacolon. Gastroenterology. 2002;123:1459–1467.PubMedCrossRefGoogle Scholar
  11. 11.
    Lee JI, Park H, Kamm MA, et al. Decreased density of interstitial cells of Cajal and neuronal cells in patients with slow-transit constipation and acquired megacolon. J Gastroenterol Hepatol. 2005;20:1292–1298.PubMedCrossRefGoogle Scholar
  12. 12.
    Vanderwinden JM, Rumessen JJ, Liu H, et al. Interstitial cells of Cajal in human colon and in Hirschsprung’s disease. Gastroenterology. 1996;111:901–910.PubMedCrossRefGoogle Scholar
  13. 13.
    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;33:1209–1214.PubMedCrossRefGoogle Scholar
  14. 14.
    Iwashita T, Kruger GM, Pardal R, Kiel MJ, Morrison SJ. Hirschsprung disease is linked to defects in neural crest stem cell function. Science. 2003;301:972–976.PubMedCrossRefGoogle Scholar
  15. 15.
    Fitze G, Cramer J, Ziegler A, et al. Association between c135G/A genotype and RET proto-oncogene germline mutations and phenotype of Hirschsprung’s disease. Lancet. 2002;359:1200–1205.PubMedCrossRefGoogle Scholar
  16. 16.
    Metcalf AM, Phillips SF, Zinsmeister AR, et al. Simplified assessment of segmental colonic transit. Gastroenterology. 1987;92:40–47.PubMedGoogle Scholar
  17. 17.
    Jung HY, Park JS, Park YJ, Kim YJ, Kim K, Koh IS. HapAnalyzer:minimum haplotype analysis system for association studies. Genomics Inform. 2004;2:107–109.Google Scholar
  18. 18.
    Taguchi T, Masumoto K, Ieiri S, et al. New classification of hypoganglionosis: congenital and acquired hypoganglionosis. J Pediatr Surg. 2006;41:2046–2051.PubMedCrossRefGoogle Scholar
  19. 19.
    Scharli AF, Sossai R. Hypoganglionosis. Semin Pediatr Surg. 1998;7:187–191.PubMedGoogle Scholar
  20. 20.
    Munakata K, Fukuzawa M, Nemoto N. Histologic criteria for the diagnosis of allied diseases of Hirschsprung’s disease in adults. Eur J Pediatr Surg. 2002;12:186–191.PubMedCrossRefGoogle Scholar
  21. 21.
    Bruder E, Meier-Ruge WA. Hypoganglionosis as a cause of chronic constipation. Pathologe. 2007;28:131–136.PubMedCrossRefGoogle Scholar
  22. 22.
    Riemann JF, Schmidt H, Zimmermann W. The fine structure of colonic submucosal nerves in patients with chronic laxative abuse. Scan J Gastroenterol. 1980;15:761–768.CrossRefGoogle Scholar
  23. 23.
    Reifferscheid P, Oehmichen M, Schweizer P, et al. Erworbene segmentare Hypoganglionosen. Z Kinderchir. 1978;23:49–52.Google Scholar
  24. 24.
    Schmidt A, Dreissler W. Zum sekundaren Gagnlienzellverlust des Dick-und Dunndarms nach rezidivierendem Ileus and Peritonitis beim Saugling. Z Kinderchir. 1988;43:54–55.PubMedGoogle Scholar
  25. 25.
    Schweizer P, Peiffer J, Oehmichen M, et al. Pathogenese sekundarer neuronaler Veranderungen im Darm. Z Kinderchir. 1980;31:197–204.Google Scholar
  26. 26.
    Sangkhathat S, Kusafuka T, Chengkriwate P, Patrapinyokul S, Sangthong B, Fukuzawa M. Mutations and polymorphisms of Hirschsprung disease candidate genes in Thai patients. J Hum Genet. 2006;51:1126–1132.PubMedCrossRefGoogle Scholar
  27. 27.
    Sanders KM, Ordög T, Koh SD, et al. Development and plasticity of interstitial cells of Cajal. Neurogastroenterol Motil. 1999;11:311–338.PubMedCrossRefGoogle Scholar
  28. 28.
    Vanderwinden JM, Rumessen JJ. Interstitial cells of Cajal in human gut and gastrointestinal disease. Microsc Res Tech. 1999;47:344–360.PubMedCrossRefGoogle Scholar
  29. 29.
    Young HM, Torihashi S, Ciampoli D, et al. Identification of neurons that express stem cell factor in the mouse small intestine. Gastroenterology. 1998;115:898–908.PubMedCrossRefGoogle Scholar
  30. 30.
    Wu JJ, Rothman TP, Gershon MD. Development of the interstitial cell of Cajal: origin, kit dependence and neuronal and nonneuronal sources of kit ligand. J Neurosci Res. 2000;59:384–401.PubMedCrossRefGoogle Scholar
  31. 31.
    Torihashi S, Ward SM, Sanders KM. Development of c-Kit-positive cells and the onset of electrical rhythmicity in murine small intestine. Gastroenterology. 1997;112:144–155.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Mi Young Do
    • 1
  • Seung-Jae Myung
    • 1
    Email author
  • Hyo-Jin Park
    • 2
  • Jun-Won Chung
    • 3
  • In-Wha Kim
    • 4
  • Sun Mi Lee
    • 4
  • Chang Sik Yu
    • 5
  • Hye Kyung Lee
    • 6
  • Jong-Keuk Lee
    • 4
  • Young Soo Park
    • 7
  • Se Jin Jang
    • 7
  • Hye Jin Kim
    • 8
  • Byong Duk Ye
    • 1
  • Jeong-Sik Byeon
    • 1
  • Suk-Kyun Yang
    • 1
  • Jin-Ho Kim
    • 1
  1. 1.Department of Internal Medicine, Asan Digestive Disease Research Institute, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulKorea
  2. 2.Department of Internal MedicineYonsei University College of MedicineSeoulKorea
  3. 3.Department of Internal MedicineGachon Graduate School of MedicineIncheonKorea
  4. 4.Asan Institute for Life SciencesAsan Medical CenterSeoulKorea
  5. 5.Colorectal Clinic, Department of Surgery, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulKorea
  6. 6.Department of Pharmacology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulKorea
  7. 7.Department of Pathology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulKorea
  8. 8.Department of Radiology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulKorea

Personalised recommendations