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Hirschsprung's disease: a search for etiology
1Children's Research Centre, Our Lady's Hospital for Sick Children, Dublin, Ireland.
Seminars in Pediatric Surgery
|August 27, 1998
Summary
Hirschsprung's disease (HD) involves aganglionosis, possibly due to neural crest cell migration failure or altered microenvironments affecting neuronal development and survival. Genetic factors and immunological mechanisms also contribute to HD etiology.
Area of Science:
- Developmental biology
- Gastroenterology
- Genetics
Background:
- Hirschsprung's disease (HD) is characterized by the absence of ganglion cells in the distal bowel.
- The traditional hypothesis attributes HD to failed neural crest cell migration.
- Emerging evidence suggests post-migration failures, including differentiation issues and microenvironmental influences, contribute to HD pathogenesis.
Purpose of the Study:
- To review current understanding and recent advancements in the etiology of Hirschsprung's disease.
- To explore alternative hypotheses beyond failed neural crest cell migration.
- To highlight the roles of microenvironmental factors, smooth muscle cells, immunological mechanisms, and genetic predispositions in HD.
Main Methods:
- Review of existing literature and experimental findings on Hirschsprung's disease.
- Analysis of mouse models of intestinal aganglionosis.
- Examination of extracellular matrix protein distributions, smooth muscle cell interactions, neurotrophic factor levels, and immunological markers in HD.
- Genetic analysis of susceptibility genes in familial and sporadic HD cases.
Main Results:
- Extracellular matrices are crucial for enteric neurogenesis, and their altered distribution is observed in HD.
- Smooth muscle cells of aganglionic colon create an unfavorable microenvironment for neuronal development, with decreased neurotrophic factors.
- Increased MHC class II antigens and ICAM-1 suggest immunological involvement in HD etiology.
- Genetic factors, particularly mutations in the RET gene, are significant contributors to HD.
Conclusions:
- The etiology of Hirschsprung's disease is multifactorial, involving failed migration, differentiation defects, unfavorable microenvironments, immunological factors, and genetic mutations.
- Understanding these complex interactions is crucial for advancing HD research and potential therapeutic strategies.
- Further research is needed to fully elucidate the precise mechanisms underlying Hirschsprung's disease.