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American Family Physician Oct 2006Hirschsprung's disease (congenital megacolon) is caused by the failed migration of colonic ganglion cells during gestation. Varying lengths of the distal colon are... (Review)
Review
Hirschsprung's disease (congenital megacolon) is caused by the failed migration of colonic ganglion cells during gestation. Varying lengths of the distal colon are unable to relax, causing functional colonic obstruction. Hirschsprung's disease most commonly involves the rectosigmoid region of the colon but can affect the entire colon and, rarely, the small intestine. The disease usually presents in infancy, although some patients present with persistent, severe constipation later in life. Symptoms in infants include difficult bowel movements, poor feeding, poor weight gain, and progressive abdominal distention. Early diagnosis is important to prevent complications (e.g., enterocolitis, colonic rupture). A rectal suction biopsy can detect hypertrophic nerve trunks and the absence of ganglion cells in the colonic submucosa, confirming the diagnosis. Up to one third of patients develop Hirschsprung's-associated enterocolitis, a significant cause of mortality. Patients should be monitored closely for enterocolitis for years after surgical treatment of Hirschsprung's disease. With proper treatment, most patients will not have long-term adverse effects and can live normally.
Topics: Enterocolitis; Evidence-Based Medicine; Hirschsprung Disease; Humans; Infant, Newborn
PubMed: 17087425
DOI: No ID Found -
Orphanet Journal of Rare Diseases Jun 2020Hirschsprung's disease (HSCR) is a serious congenital bowel disorder with a prevalence of 1/5000. Currently, there is a lack of systematically developed guidelines to... (Review)
Review
BACKGROUND
Hirschsprung's disease (HSCR) is a serious congenital bowel disorder with a prevalence of 1/5000. Currently, there is a lack of systematically developed guidelines to assist clinical decision-making regarding diagnostics and management.
AIMS
This guideline aims to cover the diagnostics and management of rectosigmoid HSCR up to adulthood. It aims to describe the preferred approach of ERNICA, the European Reference Network for rare inherited and congenital digestive disorders.
METHODS
Recommendations within key topics covering the care pathway for rectosigmoid HSCR were developed by an international workgroup of experts from 8 European countries within ERNICA European Reference Network from the disciplines of surgery, medicine, histopathology, microbiology, genetics, and patient organization representatives. Recommendation statements were based on a comprehensive review of the available literature and expert consensus. AGREE II and GRADE approaches were used during development. Evidence levels and levels of agreement are noted.
RESULTS
Thirty-three statements within 9 key areas were generated. Most recommendations were based on expert opinion.
CONCLUSION
In rare or low-prevalence diseases such as HSCR, there remains limited availability of high-quality clinical evidence. Consensus-based guidelines for care are presented.
Topics: Adult; Consensus; Europe; Hirschsprung Disease; Humans; Prevalence
PubMed: 32586397
DOI: 10.1186/s13023-020-01362-3 -
Medicina (Kaunas, Lithuania) Nov 2020Hirschsprung's disease is a neurocristopathy, caused by defective migration, proliferation, differentiation and survival of neural crest cells, leading to gut... (Review)
Review
Hirschsprung's disease is a neurocristopathy, caused by defective migration, proliferation, differentiation and survival of neural crest cells, leading to gut aganglionosis. It usually manifests rapidly after birth, affecting 1 in 5000 live births around the globe. In recent decades, there has been a significant improvement in the understanding of its genetics and the association with other congenital anomalies, which share the pathomechanism of improper development of the neural crest. Apart from that, several cell populations which do not originate from the neural crest, but contribute to the development of Hirschsprung's disease, have also been described, namely mast cells and interstitial cells of Cajal. From the diagnostic perspective, researchers also focused on "Variants of Hirschsprung's disease", which can mimic the clinical signs of the disease, but are in fact different entities, with distinct prognosis and treatment approaches. The treatment of Hirschsprung's disease is usually surgical resection of the aganglionic part of the intestine, however, as many as 30-50% of patients experience persisting symptoms. Considering this fact, this review article also outlines future hopes and perspectives in Hirschsprung's disease management, which has the potential to benefit from the advancements in the fields of cell-based therapy and tissue engineering.
Topics: Hirschsprung Disease; Humans
PubMed: 33202966
DOI: 10.3390/medicina56110611 -
Pediatric Surgery International May 2017Patients with Hirschsprung disease are at risk for Hirschsprung-associated enterocolitis (HAEC), an inflammatory disorder of the bowel that represents the leading cause... (Review)
Review
BACKGROUND
Patients with Hirschsprung disease are at risk for Hirschsprung-associated enterocolitis (HAEC), an inflammatory disorder of the bowel that represents the leading cause of serious morbidity and death in these patients. The diagnosis of HAEC is made based on clinical signs and symptoms which are often non-specific, making it difficult to establish a definitive diagnosis in many patients. The purpose of this guideline is to present a rational, expert-based approach to the diagnosis and management of HAEC.
METHODS
The American Pediatric Surgical Association Board of Governors established a Hirschsprung Disease Interest Group. Group discussions, literature review, and expert consensus were then used to summarize the current state of knowledge regarding diagnosis, management, and prevention of Hirschsprung-associated enterocolitis (HAEC).
RESULTS
Guidelines for the diagnosis of HAEC and its clinical grade, utilizing clinical history, physical examination findings, and radiographic findings, are presented. Treatment guidelines, including patient disposition, diet, antibiotics, rectal irrigations and surgery, are presented.
CONCLUSIONS
Clear, standardized definitions of Hirschsprung-associated enterocolitis and its treatment are lacking in the literature. This guideline serves as a first step toward standardization of diagnosis and management.
LEVEL OF EVIDENCE
V.
Topics: Anti-Bacterial Agents; Enterocolitis; Female; Hirschsprung Disease; Humans; Intestines; Male; Physical Examination; Practice Guidelines as Topic; Therapeutic Irrigation
PubMed: 28154902
DOI: 10.1007/s00383-017-4065-8 -
American Journal of Physiology.... Jul 2013The enteric nervous system (ENS) provides the intrinsic innervation of the bowel and is the most neurochemically diverse branch of the peripheral nervous system,... (Review)
Review
The enteric nervous system (ENS) provides the intrinsic innervation of the bowel and is the most neurochemically diverse branch of the peripheral nervous system, consisting of two layers of ganglia and fibers encircling the gastrointestinal tract. The ENS is vital for life and is capable of autonomous regulation of motility and secretion. Developmental studies in model organisms and genetic studies of the most common congenital disease of the ENS, Hirschsprung disease, have provided a detailed understanding of ENS development. The ENS originates in the neural crest, mostly from the vagal levels of the neuraxis, which invades, proliferates, and migrates within the intestinal wall until the entire bowel is colonized with enteric neural crest-derived cells (ENCDCs). After initial migration, the ENS develops further by responding to guidance factors and morphogens that pattern the bowel concentrically, differentiating into glia and neuronal subtypes and wiring together to form a functional nervous system. Molecules controlling this process, including glial cell line-derived neurotrophic factor and its receptor RET, endothelin (ET)-3 and its receptor endothelin receptor type B, and transcription factors such as SOX10 and PHOX2B, are required for ENS development in humans. Important areas of active investigation include mechanisms that guide ENCDC migration, the role and signals downstream of endothelin receptor type B, and control of differentiation, neurochemical coding, and axonal targeting. Recent work also focuses on disease treatment by exploring the natural role of ENS stem cells and investigating potential therapeutic uses. Disease prevention may also be possible by modifying the fetal microenvironment to reduce the penetrance of Hirschsprung disease-causing mutations.
Topics: Animals; Body Patterning; Enteric Nervous System; Gastrointestinal Tract; Gene Expression Regulation, Developmental; Hirschsprung Disease; Humans; Neural Crest
PubMed: 23639815
DOI: 10.1152/ajpgi.00452.2012 -
Translational Research : the Journal of... Jul 2013The enteric nervous system is the part of the autonomic nervous system that directly controls the gastrointestinal tract. Derived from a multipotent, migratory cell... (Review)
Review
The enteric nervous system is the part of the autonomic nervous system that directly controls the gastrointestinal tract. Derived from a multipotent, migratory cell population called the neural crest, a complete enteric nervous system is necessary for proper gut function. Disorders that arise as a consequence of defective neural crest cell development are termed neurocristopathies. One such disorder is Hirschsprung disease (HSCR), also known as congenital megacolon or intestinal aganglionosis. HSCR occurs in 1/5000 live births and typically presents with the inability to pass meconium, along with abdominal distension and discomfort that usually requires surgical resection of the aganglionic bowel. This disorder is characterized by a congenital absence of neurons in a portion of the intestinal tract, usually the distal colon, because of a disruption of normal neural crest cell migration, proliferation, differentiation, survival, and/or apoptosis. The inheritance of HSCR disease is complex, often non-Mendelian, and characterized by variable penetrance. Extensive research has identified a number of key genes that regulate neural crest cell development in the pathogenesis of HSCR including RET, GDNF, GFRα1, NRTN, EDNRB, ET3, ZFHX1B, PHOX2b, SOX10, and SHH. However, mutations in these genes account for only ∼50% of the known cases of HSCR. Thus, other genetic mutations and combinations of genetic mutations and modifiers likely contribute to the etiology and pathogenesis of HSCR. The aims of this review are to summarize the HSCR phenotype, diagnosis, and treatment options; to discuss the major genetic causes and the mechanisms by which they disrupt normal enteric neural crest cell development; and to explore new pathways that may contribute to HSCR pathogenesis.
Topics: Animals; Cell Movement; Enteric Nervous System; Gastrointestinal Tract; Hirschsprung Disease; Humans; Mutation; Neural Crest
PubMed: 23528997
DOI: 10.1016/j.trsl.2013.03.001 -
Archives of Pathology & Laboratory... May 2022Intestinal neuronal dysplasia type B (IND B) is a complex entity involving the enteric nervous system, clinically manifested with constipation in infancy. Diagnosis has...
CONTEXT.—
Intestinal neuronal dysplasia type B (IND B) is a complex entity involving the enteric nervous system, clinically manifested with constipation in infancy. Diagnosis has been established by histopathologic analysis of rectal biopsies. However, the criteria for the diagnosis have been questioned and modified, hindering diagnostic practice.
OBJECTIVE.—
To analyze the applicability of PTEN immunohistochemistry in the diagnosis of IND B and to compare with control cases and cases of Hirschsprung disease (HD).
DESIGN.—
PTEN immunohistochemical expression was analyzed in colorectal samples from 29 cases of IND B and compared with 4 control cases and 6 cases of HD. The pattern of PTEN immunoexpression was analyzed in glial cells of the submucosal and myenteric nerve plexuses and in neural fibrils of the muscularis propria using a scoring system.
RESULTS.—
Marked reduction or absence of PTEN expression was observed in glial cells of the submucosal nerve plexuses in all cases of the IND B group and in the myenteric nerve plexuses in 28 of 29 cases (96.5%). Lack of PTEN expression was detected in neural fibrils within the muscularis propria in 21 of 29 cases (72%) of the IND B group. PTEN expression was positive in the same neural structures of the control and HD groups.
CONCLUSIONS.—
PTEN immunohistochemistry may be a valuable tool in the diagnostic evaluation of IND B. Lack of or reduction of PTEN expression in neural fibrils within the muscularis propria suggests that involvement of the neuromuscular junction may be a key event in the pathogenesis of the motility disturbance occurring in IND B.
Topics: Humans; Immunohistochemistry; Enteric Nervous System; Myenteric Plexus; Hirschsprung Disease; Constipation; PTEN Phosphohydrolase
PubMed: 35943858
DOI: 10.5858/arpa.2021-0424-OA -
The EMBO Journal Jan 2023Hirschsprung disease (HSCR), one of several neurocristopathies in children, is characterized by nerve loss in the large intestine and is mainly treated by surgery, which...
Hirschsprung disease (HSCR), one of several neurocristopathies in children, is characterized by nerve loss in the large intestine and is mainly treated by surgery, which causes severe complications. Enteric neural crest-derived cell (ENCC) transplantation is a potential therapeutic strategy; however, so far with poor efficacy. Here, we assessed whether and how fecal microbiota transplantation (FMT) could improve ENCC transplantation in a rat model of hypoganglionosis; a condition similar to HSCR, with less intestinal innervation. We found that the hypoganglionosis intestinal microenvironment negatively influenced the ENCC functional phenotype in vitro and in vivo. Combining 16S rDNA sequencing and targeted mass spectrometry revealed microbial dysbiosis and reduced short-chain fatty acid (SCFA) production in the hypoganglionic gut. FMT increased the abundance of Bacteroides and Clostridium, SCFA production, and improved outcomes following ENCC transplantation. SCFAs alone stimulated ENCC proliferation, migration, and supported ENCC transplantation. Transcriptome-wide mRNA sequencing identified MAPK signaling as the top differentially regulated pathway in response to SCFA exposure, and inhibition of MEK1/2 signaling abrogated the SCFA-mediated effects on ENCC. This study demonstrates that FMT improves cell therapy for hypoganglionosis via short-chain fatty acid metabolism-induced MEK1/2 signaling.
Topics: Rats; Animals; Fecal Microbiota Transplantation; Hirschsprung Disease; Signal Transduction; Fatty Acids, Volatile; Cell- and Tissue-Based Therapy
PubMed: 36382711
DOI: 10.15252/embj.2022111139 -
Gastroenterology Nov 2020Hirschsprung disease (HSCR) is a life-threatening birth defect in which the distal colon is devoid of enteric neural ganglia. HSCR is treated by surgical removal of...
BACKGROUND & AIMS
Hirschsprung disease (HSCR) is a life-threatening birth defect in which the distal colon is devoid of enteric neural ganglia. HSCR is treated by surgical removal of aganglionic bowel, but many children continue to have severe problems after surgery. We studied whether administration of glial cell derived neurotrophic factor (GDNF) induces enteric nervous system regeneration in mouse models of HSCR.
METHODS
We performed studies with four mouse models of HSCR: Holstein (Hol, a model for trisomy 21-associated HSCR), TashT (TashT, a model for male-biased HSCR), Piebald-lethal (Ednrb, a model for EDNRB mutation-associated HSCR), and Ret (with aganglionosis induced by mycophenolate). Mice were given rectal enemas containing GDNF or saline (control) from postnatal days 4 through 8. We measured survival times of mice, and colon tissues were analyzed by histology, immunofluorescence, and immunoblots. Neural ganglia regeneration and structure, bowel motility, epithelial permeability, muscle thickness, and neutrophil infiltration were studied in colon tissues and in mice. Stool samples were collected, and microbiomes were analyzed by 16S rRNA gene sequencing. Time-lapse imaging and genetic cell-lineage tracing were used to identify a source of GDNF-targeted neural progenitors. Human aganglionic colon explants from children with HSCR were cultured with GDNF and evaluated for neurogenesis.
RESULTS
GDNF significantly prolonged mean survival times of Hol mice, Ednrb mice, and male TashT mice, compared with control mice, but not Ret mice (which had mycophenolate toxicity). Mice given GDNF developed neurons and glia in distal bowel tissues that were aganglionic in control mice, had a significant increase in colon motility, and had significant decreases in epithelial permeability, muscle thickness, and neutrophil density. We observed dysbiosis in fecal samples from Hol mice compared with feces from wild-type mice; fecal microbiomes of mice given GDNF were similar to those of wild-type mice except for Bacteroides. Exogenous luminal GDNF penetrated aganglionic colon epithelium of Hol mice, inducing production of endogenous GDNF, and new enteric neurons and glia appeared to arise from Schwann cells within extrinsic nerves. GDNF application to cultured explants of human aganglionic bowel induced proliferation of Schwann cells and formation of new neurons.
CONCLUSIONS
GDNF prolonged survival, induced enteric neurogenesis, and improved colon structure and function in 3 mouse models of HSCR. Application of GDNF to cultured explants of aganglionic bowel from children with HSCR induced proliferation of Schwann cells and formation of new neurons. GDNF might be developed for treatment of HSCR.
Topics: Animals; Colon; Disease Models, Animal; Dysbiosis; Enteric Nervous System; Gastrointestinal Microbiome; Gastrointestinal Motility; Glial Cell Line-Derived Neurotrophic Factor; Hirschsprung Disease; Humans; Intestinal Absorption; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Nerve Regeneration; Neural Stem Cells; Neurogenesis; Permeability; Recovery of Function; Schwann Cells; Tissue Culture Techniques
PubMed: 32687927
DOI: 10.1053/j.gastro.2020.07.018 -
Arquivos de Neuro-psiquiatria Jan 2015
Topics: Facies; Hirschsprung Disease; Humans; Intellectual Disability; Microcephaly
PubMed: 25608118
DOI: 10.1590/0004-282X20140224