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Congenital gastrointestinal and neural anomalies
Research Guide
What is Congenital gastrointestinal and neural anomalies?
Congenital gastrointestinal and neural anomalies refer to developmental disorders such as Hirschsprung disease, characterized by the absence of enteric ganglia in variable lengths of the intestine due to defects in neural crest cell migration and differentiation, often linked to genetic mutations like those in the RET gene and GDNF signaling.
Hirschsprung disease represents the primary genetic cause of functional intestinal obstruction, occurring in 1/5000 live births and classified as a neurocristopathy with absent enteric ganglia. Amiel et al. (2007) in "Hirschsprung disease, associated syndromes and genetics: a review" detail its associations with syndromes and genetic factors including RET and SIP1 mutations. The field encompasses 25,911 papers on topics from neural crest cells to anorectal malformations, though 5-year growth data is unavailable.
Topic Hierarchy
Research Sub-Topics
Hirschsprung Disease Genetics
This sub-topic investigates genetic mutations like RET and EDNRB in Hirschsprung disease etiology. Researchers conduct genome-wide association studies and familial analyses.
Enteric Nervous System Development
This sub-topic explores neural crest cell migration and differentiation in gut innervation. Researchers use animal models to study developmental pathways and disruptions.
GDNF Signaling in Enteric Neurogenesis
This sub-topic examines GDNF-RET signaling cascades in enteric neuron survival and proliferation. Researchers analyze knockout models and therapeutic targeting.
Anorectal Malformations
This sub-topic covers embryology, surgical management, and associated neural anomalies in anorectal malformations. Researchers study long-term outcomes and comorbidities.
Stem Cell Therapy for Enteric Disorders
This sub-topic researches neural crest-derived stem cells for regenerating enteric neurons in Hirschsprung models. Researchers evaluate engraftment and functional integration.
Why It Matters
These anomalies cause severe intestinal obstruction in newborns, necessitating surgical interventions like pull-through procedures to restore bowel function. Amiel et al. (2007) in "Hirschsprung disease, associated syndromes and genetics: a review" report an incidence of 1/5000 live births, highlighting the need for genetic screening in families with history of the disorder or associated syndromes. Studies like Sánchez et al. (1996) in "Renal agenesis and the absence of enteric neurons in mice lacking GDNF" and Pichel et al. (1996) in "Defects in enteric innervation and kidney development in mice lacking GDNF" demonstrate GDNF's role in enteric nervous system and kidney development, informing therapies targeting GDNF signaling for preventing multi-organ defects. Tools such as the constipation scoring system by Agachan et al. (1996) aid in evaluating severity post-surgery.
Reading Guide
Where to Start
"Hirschsprung disease, associated syndromes and genetics: a review" by Amiel et al. (2007), as it provides a foundational overview of the disease definition, incidence, genetics, and syndromes in a single accessible review.
Key Papers Explained
Amiel et al. (2007) in "Hirschsprung disease, associated syndromes and genetics: a review" establishes the genetic framework including RET and SIP1, which is mechanistically supported by Sánchez et al. (1996) and Pichel et al. (1996) demonstrating GDNF knockout effects on enteric innervation in mice. Hulzinga et al. (1995) in "W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity" connects to motility defects via pacemaker cells. Agachan et al. (1996) and Rockwood et al. (2000) build clinically by offering validated scoring systems for constipation and incontinence outcomes.
Paper Timeline
Most-cited paper highlighted in red. Papers ordered chronologically.
Advanced Directions
Research continues on neural crest cell differentiation and stem cell applications for enteric neuron replacement, with genetics of RET/GDNF pathways central; no recent preprints or news available to indicate shifts.
Papers at a Glance
| # | Paper | Year | Venue | Citations | Open Access |
|---|---|---|---|---|---|
| 1 | Bowel Disorders | 2016 | Gastroenterology | 2.7K | ✓ |
| 2 | Functional Gastrointestinal Disorders: History, Pathophysiolog... | 2016 | Gastroenterology | 2.3K | ✕ |
| 3 | Global Prevalence of and Risk Factors for Irritable Bowel Synd... | 2012 | Clinical Gastroenterol... | 2.1K | ✕ |
| 4 | Worldwide Prevalence and Burden of Functional Gastrointestinal... | 2020 | Gastroenterology | 2.0K | ✓ |
| 5 | W/kit gene required for interstitial cells of Cajal and for in... | 1995 | Nature | 1.4K | ✕ |
| 6 | A constipation scoring system to simplify evaluation and manag... | 1996 | Diseases of the Colon ... | 1.2K | ✕ |
| 7 | Fecal incontinence quality of life scale | 2000 | Diseases of the Colon ... | 1.2K | ✕ |
| 8 | Renal agenesis and the absence of enteric neurons in mice lack... | 1996 | Nature | 1.2K | ✕ |
| 9 | Hirschsprung disease, associated syndromes and genetics: a review | 2007 | Journal of Medical Gen... | 1.2K | ✓ |
| 10 | Defects in enteric innervation and kidney development in mice ... | 1996 | Nature | 1.2K | ✕ |
Frequently Asked Questions
What is Hirschsprung disease?
Hirschsprung disease is a neurocristopathy characterized by the absence of enteric ganglia along a variable length of the intestine, leading to functional obstruction. Amiel et al. (2007) in "Hirschsprung disease, associated syndromes and genetics: a review" note its incidence at 1/5000 live births as the main genetic cause of such obstruction. It results from failed migration or differentiation of neural crest cells.
What genetic factors are involved in Hirschsprung disease?
Key genetic factors include mutations in RET, GDNF signaling, and SIP1. Amiel et al. (2007) review RET gene mutations and SIP1 mutations as central to the disorder's etiology. These mutations disrupt enteric nervous system development from neural crest cells.
How does GDNF deficiency affect enteric innervation?
GDNF deficiency leads to absence of enteric neurons and renal agenesis in mice models. Sánchez et al. (1996) in "Renal agenesis and the absence of enteric neurons in mice lacking GDNF" show this absence mimics Hirschsprung disease features. Pichel et al. (1996) in "Defects in enteric innervation and kidney development in mice lacking GDNF" confirm linked defects in innervation and kidney organogenesis.
What is the role of neural crest cells in these anomalies?
Neural crest cells fail to migrate and differentiate into enteric neurons, causing aganglionosis. Amiel et al. (2007) describe this as the core pathology in Hirschsprung disease. The process involves genetic regulation by RET and GDNF pathways.
What clinical tools assess outcomes in these patients?
The constipation scoring system by Agachan et al. (1996) correlates with physiologic findings to evaluate constipation severity. The Fecal Incontinence Quality of Life Scale by Rockwood et al. (2000) provides reliable measurement of incontinence impact. These tools standardize post-surgical management.
Open Research Questions
- ? How do specific RET gene mutations interact with modifier genes to determine the variable length of aganglionosis in Hirschsprung disease?
- ? What mechanisms link GDNF signaling disruptions to concomitant renal and enteric defects in congenital anomalies?
- ? Can stem cell therapies derived from neural crest cells restore enteric ganglia in Hirschsprung disease models?
- ? Which associated syndromes with SIP1 mutations most frequently co-occur with anorectal malformations and Hirschsprung disease?
- ? How does interstitial cells of Cajal dysfunction, as in W/kit gene defects, contribute to motility disorders beyond aganglionosis?
Recent Trends
The cluster includes 25,911 works on Hirschsprung disease genetics and neural crest cells, with Amiel et al. as a highly cited review at 1193 citations; no recent preprints or news in the last 12 months signal ongoing focus on established genetic models like RET and GDNF without reported growth rate.
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