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Nature Reviews. Disease Primers Oct 2023Hirschsprung disease (HSCR) is a rare congenital intestinal disease that occurs in 1 in 5,000 live births. HSCR is characterized by the absence of ganglion cells in the... (Review)
Review
Hirschsprung disease (HSCR) is a rare congenital intestinal disease that occurs in 1 in 5,000 live births. HSCR is characterized by the absence of ganglion cells in the myenteric and submucosal plexuses of the intestine. Most patients present during the neonatal period with the first meconium passage delayed beyond 24 h, abdominal distension and vomiting. Syndromes associated with HSCR include trisomy 21, Mowat-Wilson syndrome, congenital central hypoventilation syndrome, Shah-Waardenburg syndrome and cartilage-hair hypoplasia. Multiple putative genes are involved in familial and isolated HSCR, of which the most common are the RET proto-oncogene and EDNRB. Diagnosis consists of visualization of a transition zone on contrast enema and confirmation via rectal biopsy. HSCR is typically managed by surgical removal of the aganglionic bowel and reconstruction of the intestinal tract by connecting the normally innervated bowel down to the anus while preserving normal sphincter function. Several procedures, namely Swenson, Soave and Duhamel procedures, can be undertaken and may include a laparoscopically assisted approach. Short-term and long-term comorbidities include persistent obstructive symptoms, enterocolitis and soiling. Continued research and innovation to better understand disease mechanisms holds promise for developing novel techniques for diagnosis and therapy, and improving outcomes in patients.
Topics: Infant, Newborn; Humans; Hirschsprung Disease; Down Syndrome; Waardenburg Syndrome; Anal Canal; Intellectual Disability
PubMed: 37828049
DOI: 10.1038/s41572-023-00465-y -
Pediatric and Developmental Pathology :... 2020Diagnosis or exclusion of Hirschsprung disease (HSCR) is a frequent exercise in any pediatric hospital. Although HSCR may present at different ages and with varied... (Review)
Review
Diagnosis or exclusion of Hirschsprung disease (HSCR) is a frequent exercise in any pediatric hospital. Although HSCR may present at different ages and with varied clinical findings, the most common presentation is a neonate with severe constipation or signs of intestinal obstruction. A variety of diagnostic tests including contrast enema and anorectal manometry may be used as diagnostic screens, but diagnosis ultimately rests upon histopathological evaluation of a rectal biopsy. For the experienced pathologist, conventional hematoxylin-and-eosin-stained sections often suffice to exclude HSCR or establish the diagnosis. However, ancillary diagnostic tests such as acetylcholinesterase histochemistry or calretinin immunohistochemistry are complementary and extremely helpful in some cases. In this Perspectives article, we review the clinical and pathological features of HSCR, highlight those that are found in most patients, and discuss how to address particularly challenging aspects of the diagnostic workup.
Topics: Adolescent; Biomarkers; Biopsy; Child; Child, Preschool; Colon; Diagnostic Techniques, Digestive System; Hirschsprung Disease; Humans; Immunohistochemistry; Infant; Infant, Newborn; Predictive Value of Tests; Rectum; Staining and Labeling
PubMed: 31791203
DOI: 10.1177/1093526619892351 -
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 -
Current Opinion in Gastroenterology Jan 2021To provide the definition, causes, and current recommendations for workup and treatment of acute infectious colitis in adults, a common medical problem of diverse cause. (Review)
Review
PURPOSE OF REVIEW
To provide the definition, causes, and current recommendations for workup and treatment of acute infectious colitis in adults, a common medical problem of diverse cause.
RECENT FINDINGS
The management of acute colitis in adults depend upon establishment of cause. Most forms of infectious colitis are treatable with antimicrobials. Multiplex polymerase chain reaction (PCR) followed by guided culture on PCR-positive pathogens can often confirm active infection while standard culture methods provide isolates for antibiotic susceptibility testing, subtyping, and Whole Genome Sequencing.
SUMMARY
Patients with colitis may be suffering from a range of etiologies including infectious colitis, neutropenic colitis, drug-induced colitis, and inflammatory bowel disease. The present review was prepared to provide an approach to prompt diagnosis and management of acute colitis to prevent severe complications (e.g. dehydration and malnutrition, or toxic megacolon) and provide recommendations for antimicrobial therapy.
Topics: Adult; Anti-Bacterial Agents; Bacterial Infections; Colitis; Humans; Inflammatory Bowel Diseases; Megacolon, Toxic
PubMed: 33105253
DOI: 10.1097/MOG.0000000000000693 -
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 -
Seminars in Pediatric Surgery Apr 2022The enteric nervous system (ENS) is a rich network of neurons and glial cells that comprise the gastrointestinal tract's intrinsic nervous system and are responsible for... (Review)
Review
The enteric nervous system (ENS) is a rich network of neurons and glial cells that comprise the gastrointestinal tract's intrinsic nervous system and are responsible for controlling numerous complex functions, including digestion, transit, secretion, barrier function, and maintenance of a healthy microbiome. Development of a functional ENS relies on the coordinated interaction between enteric neural crest-derived cells and their environment as the neural crest-derived cells migrate rostrocaudally along the embryonic gut mesenchyme. Congenital or acquired disruption of ENS development leads to various neurointestinal diseases. Hirschsprung disease is a congenital neurocristopathy, a disease of the neural crest. It is characterized by a variable length of distal colonic aganglionosis due to a failure in enteric neural crest-derived cell proliferation, migration, differentiation, and/or survival. In this review, we will review the science of Hirschsprung disease, targeting an audience of pediatric surgeons. We will discuss the basic biology of normal ENS development, as well as what goes awry in ENS development in Hirschsprung disease. We will review animal models that have been integral to studying this disease, as well as current hot topics and future research, including genetic risk profiling, stem cell therapy, non-invasive diagnostic techniques, single-cell sequencing techniques, and genotype-phenotype correlation.
Topics: Animals; Enteric Nervous System; Hirschsprung Disease; Humans; Neural Crest; Stem Cell Transplantation
PubMed: 35690468
DOI: 10.1016/j.sempedsurg.2022.151157 -
Cell Stem Cell Mar 2023The enteric nervous system (ENS) is derived from both the vagal and sacral component of the neural crest (NC). Here, we present the derivation of sacral ENS precursors...
The enteric nervous system (ENS) is derived from both the vagal and sacral component of the neural crest (NC). Here, we present the derivation of sacral ENS precursors from human PSCs via timed exposure to FGF, WNT, and GDF11, which enables posterior patterning and transition from posterior trunk to sacral NC identity, respectively. Using a SOX2::H2B-tdTomato/T::H2B-GFP dual reporter hPSC line, we demonstrate that both trunk and sacral NC emerge from a double-positive neuro-mesodermal progenitor (NMP). Vagal and sacral NC precursors yield distinct neuronal subtypes and migratory behaviors in vitro and in vivo. Remarkably, xenografting of both vagal and sacral NC lineages is required to rescue a mouse model of total aganglionosis, suggesting opportunities in the treatment of severe forms of Hirschsprung's disease.
Topics: Animals; Humans; Mice; Bone Morphogenetic Proteins; Disease Models, Animal; Growth Differentiation Factors; Heterografts; Hirschsprung Disease; Histones; Neural Crest
PubMed: 36868194
DOI: 10.1016/j.stem.2023.02.003 -
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 -
Pediatric Surgery International Feb 2023Hirschsprung's disease (HSCR) is a classical model of enteric neuropathy, occurring in approximately 2-2.8 in 10,000 newborns. It is the commonest form of congenital... (Review)
Review
Hirschsprung's disease (HSCR) is a classical model of enteric neuropathy, occurring in approximately 2-2.8 in 10,000 newborns. It is the commonest form of congenital bowel obstruction and is characterized by the absence of enteric ganglia in distal colon. Recent advances in genome-wide association analysis (GWAS) and next generation sequencing (NGS) studies have led to the discovery of a number of new HSCR candidate genes, thereby providing new insights into the genetic architecture and molecular mechanisms of the disease. Altogether, these findings indicated that genetic heterogeneity, variable penetrance and expressivity, and genetic interaction are the pervasive characteristics of HSCR genetics. In this review, we will provide an update on the genetic landscape of HSCR and discuss how the common and rare variants may act together to modulate the phenotypic manifestation. Translating the genetic findings to genetic risk prediction and to optimize clinical outcomes are undoubtedly the ultimate goals for genetic studies on HSCR. From this perspective, we will further discuss the major obstacles in the clinical translation of these latest genetic findings. Lastly, new measures to address these clinical challenges are suggested to advance precision medicine and to develop novel alternative therapies.
Topics: Infant, Newborn; Humans; Hirschsprung Disease; Genome-Wide Association Study
PubMed: 36749416
DOI: 10.1007/s00383-022-05358-x