Skip to main content
SpringerLink
Log in

Genetische Grundlagen des Morbus Hirschsprung

Genetic bases of Hirschsprung’s disease

  • Schwerpunkt: Gastrointestinale Motilitätsstörungen
  • Published:
Der Pathologe Aims and scope Submit manuscript

Zusammenfassung

Der M. Hirschsprung ist eine Neurocristopathie infolge fehlender oder malfunktionaler intramuraler intestinaler Ganglienzellen. Der aganglionäre Anteil ist nach rostral sehr variabel. Der M. Hirschsprung kann in Typ 1 (kurzes Segment) und Typ 2 (langes Segment) eingeteilt werden. Er tritt isoliert auf den Gastrointestinaltrakt beschränkt oder bei 12% der Patienten syndromal als Begleiterscheinung zahlreicher anderer, genetisch bedingter Krankheiten auf. Die Populationshäufigkeit beträgt 1/5000 mit 4- bis 5-fach höherer Beteiligung des männlichen Geschlechts. Zahlreiche Gene und nichtcodierende polymorphe DNA-Sequenzvarianten spielen eine ätiologische Rolle. Das wichtigste identifizierte Gen ist das RET-Gen. Suszeptibilitätsloci auf 3p21, 9q31 und 19q12 interagieren mit dem RET-Locus. Mit GALNACT-2 und RASGEF1A sind 2 neue Gene „downstream“ (in 3’-Richtung) von RET identifiziert worden. Eine vor kurzem beschriebene, häufige, nichtkodierende RET-Variante RET+3 ist signifikant mit einer Suszeptibilität für M. Hirschsprung assoziiert und trägt im Vergleich zu selteneren Allelen ein 20-fach erhöhtes Hirschsprung-Risiko.

Abstract

Hirschsprung’s disease constitutes a neural crest stem cell disorder (neurocristopathy) which is caused by absent or malfunctional intestinal intramural ganglion cells. The rostral extension of the aganglionic segment is variable. Hirschsprung’s disease can be classified into type 1 (short segment) and type 2 (long segment) forms. It is limited to the gastrointestinal tract, but may occur in the syndromal context of manifold genetic diseases in 12% of patients. The prevalence is 1:5,000 with a distinct male predominance of 4–5:1. Numerous genes and non-coding polymorphous DNA sequence variants are involved in the pathogenesis of Hirschsprung’s disease. The most important gene is RET. Susceptibility loci on 3p21, 9q31 and 19q12 interact with this gene. Downstream of RET, two new genes, GALNACT-2 and RASGEF1A, have also been identified. A recently described, frequent, non-coding RET variant, RET+3, is significantly associated with susceptibility to Hirschsprung’s disease and carries a 20-fold increased risk of contracting the disease compared to rarer alleles.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2
Abb. 3
Abb. 4

Literatur

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

    Article  PubMed  Google Scholar 

  2. Andrew A (1971) The origin of intramural ganglia. IV. The origin of enteric ganglia: a critical review and discussion of the present state of the problem. J Anat 108: 169–184

    PubMed  Google Scholar 

  3. Angrist M, Kauffman E, Slaugenhaupt SA et al. (1993) A gene for Hirschsprung disease (megacolon) in the pericentromeric region of human chromosome 10. Nat Genet 4: 351–356

    Article  PubMed  Google Scholar 

  4. Attié T, Pelet A, Edery P et al. (1995) Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease. Hum Mol Genet 4: 1381–1386

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  6. Bielschowsky M, Schofield GC (1962) Studies on megacolon in piebald mice. Aust J Exp Biol Med Sci 40: 395–403

    PubMed  Google Scholar 

  7. Bodian M, Carter CO (1963) Family study of Hirschsprung’s disease. Ann Hum Genet 29: 261–277

    Google Scholar 

  8. Bolande R (1973) The neurocristopathies: A unifying concept of disease arising in neural crest maldevelopment. Hum Pathol 5: 409–429

    Article  Google Scholar 

  9. Bolk S, Pelet A, Hofstra RMW et al. (2000) 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 USA 97: 268–273

    Article  PubMed  Google Scholar 

  10. Burzynski GM, Nolte IM, Osinga J et al. (2004) Localizing a putative mutation as the major contributor to the development of sporadic Hirschsprung disease to the RET genomic sequence between the promoter region and exon 2. Eur J Hum Genet 12: 604–612

    Article  PubMed  Google Scholar 

  11. Chakravarti A, Lyonnet S (2001) Hirschsprung disease. In: CR Scriver et al. (eds) The Metabolic and Molecular Bases of Inherited Disease. 8th edn. McGraw-Hill, New York, pp 6231-6255

  12. DeLellis R, Heitz Ph U, Lloyd R, Eng C (2004) Pathology and genetics of tumours of endocrine organs. WHO Classification of Tumours, IARC, Lyon, France

  13. Emison ES, McCallion AS, Kashuk CS et al. (2005) A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease. Nature 434: 857–863

    Article  PubMed  Google Scholar 

  14. Fitze G, Appelt, H, König IR et al. (2003) Functional haplotypes of the RET proto-oncogene promoter are associated with Hirschsprung disease (HSCR). Hum Mol Genet 12: 3207–3214

    Article  PubMed  Google Scholar 

  15. Gabriel SB, Salomon R, Pelet A et al. (2002) Segregation at three loci explains familial and population risk in Hirschsprung disease. Nat Genet 31: 89–93

    PubMed  Google Scholar 

  16. Hosoda K, Hammer RE, Richardson JA et al. (1994) Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. Cell 79: 1267–1276

    Article  PubMed  Google Scholar 

  17. Hüther W (1954) Die Hirschsprung’sche Krankheit als Folge einer Entwicklungsstörung der intramuralen Ganglien. Beitr Pathol Anat Allg Pathol 114: 161–191

    Google Scholar 

  18. Iwashita T, Murakami H, Asai N, Takahashi M (1996) Mechanism of Ret dysfunction by Hirschsprung mutations affecting its extracellular domain. Hum Mol Genet 5: 1577–1580

    Article  PubMed  Google Scholar 

  19. Iwashita T, Kruger GM, Pardal R et al. (2002) Hirschsprung disease is linked to defects in neural crest stem cell function. Science 301: 972–976

    Article  Google Scholar 

  20. Jain S, Watson MA, DeBenedetti MK, Hiraki Y, Moley JF, Milbrandt J (2004) Expression profiles provide insights into early malignant potential and skeletal abnormalities in multiple endocrine neoplasia type 2B syndrome tumors. Cancer Res 64: 3907–3913

    Article  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  22. Lyonnet S, Bolino A, Pelt A et al. (1993) A gene for Hirschsprung disease maps to the proximal long arm of chromosome 10. Nat Genet 4: 346–350

    Article  PubMed  Google Scholar 

  23. Madsen CM (1964) Hirschsprung’s disease. Munksgaard, Copenhagen

  24. McCabe L, Griffin LD, Kinzer A et al. (1990) Overo lethal white foal syndrome: equine model of aganglionic megacolon (Hirschsprung disease). Am J Med Genet 36: 336–340

    Article  PubMed  Google Scholar 

  25. McCallion AS, Stames E, Conlon RA, Chakravarti A (2003) Phenotype variation in two-locus mouse models of Hirschsprung disease: Tissue-specific interaction between Ret and Ednrb. Proc Natl Acad Sci USA 100: 1826–1831

    Article  PubMed  Google Scholar 

  26. McKusick VA (2006) Online Mendelian inheritance in man, OMIM (TM) McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, Maryland) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, Maryland, 2000) (http://www.ncbi.nlm.nih.gov/Omim/)

  27. Okamoto E, Ueda T (1967) Embryogenesis of intramural ganglion of the gut and its relation to Hirschsprung’s disease. J Pediatr Surg 2: 437–443

    Article  Google Scholar 

  28. Omenn GS, McKusick VA (1979) The association of Waardenburg syndrome and Hirschsprung megacolon. Am J Med Genet 3: 217–223

    Article  PubMed  Google Scholar 

  29. Passarge E (1967a) The genetics of Hirschsprung’s disease: evidence for heterogeneous etiology and a study of sixty-three families. N Engl J Med 276: 138–143

    PubMed  Google Scholar 

  30. Passarge E (1967b) Quelques considerations etiologiques et génétiques sur la maladie de Hirschsprung. Médecine et Hygiène 25: 240–241

    Google Scholar 

  31. Passarge E (1972) Genetic heterogeneity and recurrence risk of congenital intestinal aganglionosis. Birth Defects Orig Art Ser VIII(2): 63–67

    Google Scholar 

  32. Passarge E (2002) Dissecting Hirschsprung disease. Nat Genet 31: 11–12

    PubMed  Google Scholar 

  33. Passarge E (2003) Gastrointestinal tract: Molecular genetics of Hirschsprung disease. Nature Encyclopedia of the Human Genome 2: 578–583

    Google Scholar 

  34. Passarge E (2007) Hirschsprung disease genetic dissection of a complex disorder. In: Mayo O, Leach C (eds) Fifty years of human genetics. A celebration of the life and work of George Robert Fraser. Wakefield, Adelaide, South Australia

  35. Romeo G, Ronchetto P, Luo Y et al. (1994) Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung’s disease. Nature 367: 377–378

    Article  PubMed  Google Scholar 

  36. Shah KN, Dalal SJ, Desai MP et al. (1981) White forelock, pigmentary disorder of irides, and long segment Hirschsprung disease: possible variant of Waardenburg syndrome. J Pediatr 99: 432–435

    Article  PubMed  Google Scholar 

  37. Smith VV, Eng C, Milla PJ (1999) Intestinal ganglioneuromatosis and multiple endocrine neoplasia type 2B: Implications for treatment. Gut 45: 143–146

    PubMed  Google Scholar 

  38. Yin M, King SK, Hutson JM, Chow CW (2006) Multiple endocrine neoplasia type 2B diagnosed on suction rectal biopsy in infancy: a report of 2 cases. Pediatr Dev Pathol 9: 56–60

    Article  PubMed  Google Scholar 

Download references

Interessenkonflikt

Es besteht kein Interessenkonflikt. Der korrespondierende Autor versichert, dass keine Verbindungen mit einer Firma, deren Produkt in dem Artikel genannt ist, oder einer Firma, die ein Konkurrenzprodukt vertreibt, bestehen. Die Präsentation des Themas ist unabhängig und die Darstellung der Inhalte produktneutral.

Author information

Authors and Affiliations

  1. Institut für Humangenetik, Universitätsklinikum Essen, 45122, Essen, Deutschland

    E. Passarge

  2. Institut für Pathologie, Universitätsspital Basel, Basel, Schweiz

    E. Bruder

Authors
  1. E. Passarge
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Bruder
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. Passarge.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Passarge, E., Bruder, E. Genetische Grundlagen des Morbus Hirschsprung. Pathologe 28, 113–118 (2007). https://doi.org/10.1007/s00292-007-0899-5

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00292-007-0899-5

Schlüsselwörter

Keywords

Search

Navigation