Materiały źródłowe

• #1 Hirschsprung Disease: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/178493-overview

  Hirschsprung disease is a developmental disorder characterized by the absence of ganglia in the distal colon, resulting in a functional obstruction. […] Although this condition was described by Ruysch in 1691 and popularized by Hirschsprung in 1886, the pathophysiology was not clearly determined until the middle of the 20th century, when Whitehouse and Kernohan reported aganglionosis of the distal colon as the cause of obstruction in a case series. […] In patients with Hirschsprung disease, both myenteric and submucosal plexuses are absent. The anus is invariably affected, and aganglionosis continues proximally for a variable distance. In the absence of ENS reflexes, control of the intestinal smooth muscle is overwhelmingly extrinsic. The activity of both the cholinergic system and the adrenergic system is 2-3 times that of normal intestine. The cholinergic (excitatory) system is thought to predominate over the adrenergic (inhibitory) system, leading to an increase in smooth muscle tone. With the loss of the intrinsic enteric relaxing impulses, the increased muscle tone is unopposed. This phenomenon leads to an imbalance of smooth muscle contractility, uncoordinated peristalsis, and a functional obstruction.

• #2 Hirschsprung disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/hirschsprung-disease/

  Hirschsprung disease is an intestinal disorder characterized by the absence of nerves in parts of the intestine. This condition occurs when the nerves in the intestine (enteric nerves) do not form properly during development before birth (embryonic development). […] Enteric nerves trigger the muscle contractions that move stool through the intestine. Without these nerves in parts of the intestine, the material cannot be pushed through, causing severe constipation or complete blockage of the intestine in people with Hirschsprung disease. […] Isolated Hirschsprung disease can result from mutations in one of several genes, including the RET, EDNRB, and EDN3 genes. However, the genetics of this condition appear complex and are not completely understood. […] Mutations in the RET gene are the most common known genetic cause of Hirschsprung disease. The RET gene provides instructions for producing a protein that is involved in signaling within cells. This protein appears to be essential for the normal development of several kinds of nerve cells, including nerves in the intestine.

• #3 Hirschsprung Disease: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/178493-overview

  Hirschsprung disease is a developmental disorder characterized by the absence of ganglia in the distal colon, resulting in a functional obstruction. […] Although this condition was described by Ruysch in 1691 and popularized by Hirschsprung in 1886, the pathophysiology was not clearly determined until the middle of the 20th century, when Whitehouse and Kernohan reported aganglionosis of the distal colon as the cause of obstruction in a case series. […] In patients with Hirschsprung disease, both myenteric and submucosal plexuses are absent. The anus is invariably affected, and aganglionosis continues proximally for a variable distance. In the absence of ENS reflexes, control of the intestinal smooth muscle is overwhelmingly extrinsic. The activity of both the cholinergic system and the adrenergic system is 2-3 times that of normal intestine. The cholinergic (excitatory) system is thought to predominate over the adrenergic (inhibitory) system, leading to an increase in smooth muscle tone. With the loss of the intrinsic enteric relaxing impulses, the increased muscle tone is unopposed. This phenomenon leads to an imbalance of smooth muscle contractility, uncoordinated peristalsis, and a functional obstruction.

• #4

  https://www.jci.org/articles/view/83178

  Hirschsprungs disease (HSCR) causes functional intestinal obstruction due to the absence of the enteric nervous system (ENS) in the distal bowel and is usually diagnosed shortly after birth or during childhood. […] In this issue of the JCI, Soret and colleagues identify a new mechanism that causes HSCR-like disease in mice and involves deposition of excess collagen VI in the intestine by migrating ENS precursors as they colonize fetal bowel. Remarkably, their findings may explain some of the so-called missing heritability of HSCR and suggest a mechanism for increased HSCR incidence in children with Down syndrome (trisomy 21). […] HSCR is a complex genetic disease that has a global incidence of 1 in 5,000 human births and is characterized by the absence of neural ganglia in the distal gut, from the anus up to a variable length of the intestines.

• #5 Hirschsprung Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK562142/

  Hirschsprung disease (HD) is a congenital disorder characterized by the absence of ganglion cells (GC) at the Meissner’s plexus (submucosa) and Auerbach’s plexus (muscularis) of the terminal rectum that extends in a variable distance proximally. […] In Hirschsprung disease, there is a disruption of the migration process and differentiation of neural crest cells at the level of the enteric nervous system, which is under the control of the RET gene and its ligands. This disturbance causes a total absence of GC in the nerve plexuses. It leads to the overactivity of the intestine with the persistent release of acetylcholine. Subsequently, there is a continuous contraction of the narrowed (affected) colonic segment and progressive secondary dilatation of the healthy proximal colon. […] Disturbed rostrocaudal migration of the neural crest cells (NCC) along a variable length of the intestine is responsible for HD. GC first migrates to the myenteric plexus and then to the submucosal plexus. […] Animal models have also highlighted an arrest or delay in the migration of NCCs as the factor behind the pathogenesis of HD.

• #6 Hirschsprung’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Hirschsprung%27s_disease

  Hirschsprung’s disease (HD or HSCR) is a birth defect in which nerves are missing from parts of the intestine. […] The disorder may occur by itself or in association with other genetic disorders such as Down syndrome. About half of isolated cases are linked to a specific genetic mutation, and about 20% occur within families. Some of these occur in an autosomal dominant manner. The cause of the remaining cases is unclear. […] The most accepted theory of the cause of Hirschsprung is a defect in the craniocaudal migration of neuroblasts originating from the neural crest that occurs during the first 12 weeks of gestation. Defects in the differentiation of neuroblasts into ganglion cells and accelerated ganglion cell destruction within the intestine may also contribute to the disorder. […] This lack of ganglion cells in the myenteric and submucosal plexus is well documented in Hirschsprung’s disease.

• #7 The Developmental Etiology and Pathogenesis of Hirschsprung disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3691347/

  Proper neural crest cell migration, proliferation, differentiation, survival, and apoptosis all contribute to a functional ENS. Perturbation in any of these processes can lead to a Hirschsprung disease phenotype. […] Many genes which play a critical functional role in neural crest cell development have been implicated in HSCR, including the proto-oncogene RET, endothelin signaling genes, and transcription factors. […] Although over a dozen genes have been identified that contribute to the etiology of HSCR, these pathways only account for about half of the known cases. […] The ENS is derived from migratory neural crest cells which originate at the vagal (somites 17) and sacral (caudal to somite 24) regions of the embryonic axis. […] During migration, chains of interconnected neural crest cells at the leading edge of the population are referred to as the wavefront.

• #8 Pediatric Hirschsprung Disease: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/929733-overview

  Hirschsprung disease results from the absence of enteric neurons within the myenteric and submucosal plexus of the rectum and/or colon. […] Enteric neurons are derived from the neural crest and migrate caudally with the vagal nerve fibers along the intestine. […] Arrest in migration leads to an aganglionic segment. This results in clinical Hirschsprung disease. […] Mutations in the Ret proto-oncogene have been associated with multiple endocrine neoplasia (MEN) 2A or MEN 2B and familial Hirschsprung disease. […] Other genes associated with Hirschsprung disease include the glial cell-derived neurotrophic factor gene, the endothelin-B receptor gene, and the endothelin-3 gene. […] Hirschsprung’s disease genes and the development of the enteric nervous system.

• #9 The Developmental Etiology and Pathogenesis of Hirschsprung disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3691347/

  Proper neural crest cell migration, proliferation, differentiation, survival, and apoptosis all contribute to a functional ENS. Perturbation in any of these processes can lead to a Hirschsprung disease phenotype. […] Many genes which play a critical functional role in neural crest cell development have been implicated in HSCR, including the proto-oncogene RET, endothelin signaling genes, and transcription factors. […] Although over a dozen genes have been identified that contribute to the etiology of HSCR, these pathways only account for about half of the known cases. […] The ENS is derived from migratory neural crest cells which originate at the vagal (somites 17) and sacral (caudal to somite 24) regions of the embryonic axis. […] During migration, chains of interconnected neural crest cells at the leading edge of the population are referred to as the wavefront.

• #10 Congenital aganglionic megacolon (Hirschsprung disease) – UpToDate

  https://www.uptodate.com/contents/congenital-aganglionic-megacolon-hirschsprung-disease

  Hirschsprung disease (HD) is a motor disorder of the colon, which is caused by the failure of neural crest cells (precursors of enteric ganglion cells) to migrate completely during intestinal development during fetal life. The resulting aganglionic segment of the colon fails to relax, causing a functional obstruction. […] The most accepted theory of the cause of HD is that there is a defect in the craniocaudal migration of neuroblasts originating from the neural crest, a process that begins at four weeks of gestation and ends at week 7 with the arrival of neural crest-derived cells at the distal end of the colon. In HD, the cells fail to reach the distal colon, rendering that segment aganglionic and therefore with abnormal motor function, resulting in HD. Defects in the differentiation of neuroblasts into ganglion cells and ganglion cell destruction within the intestine may also contribute to the disorder.

• #11 Pathophysiology of Hirschsprung’s Disease and its Diagnosis

  https://www.jcmedu.org/jcmedu-articles/pathophysiology-of-hirschsprungs-disease-and-its-diagnosis-96460.html

  Hirschsprungs Disease (HD or HSCR) is a birth defect in which nerves in parts of the intestine are missing. […] The most accepted theory for the cause of Hirschsprungs is a defect in the craniocaudal migration of neural crest-derived neuroblasts that occurs during the first 12 weeks of pregnancy. Defects in the differentiation of neuroblasts into ganglion cells and accelerated destruction of ganglion cells in the gut may also contribute to the disorder. […] This lack of ganglion cells in the myenteric and submucosal plexus is well documented in Hirschsprungs disease. In Hirschsprungs disease, the segment lacking neurons (aganglionic) narrows, causing the normal proximal part of the intestine to distend with feces. […] The absence of ganglion cells results in persistent overstimulation of the nerves in the affected area, leading to contraction.

• #12 Hirschsprung Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK562142/

  Hirschsprung disease (HD) is a congenital disorder characterized by the absence of ganglion cells (GC) at the Meissner’s plexus (submucosa) and Auerbach’s plexus (muscularis) of the terminal rectum that extends in a variable distance proximally. […] In Hirschsprung disease, there is a disruption of the migration process and differentiation of neural crest cells at the level of the enteric nervous system, which is under the control of the RET gene and its ligands. This disturbance causes a total absence of GC in the nerve plexuses. It leads to the overactivity of the intestine with the persistent release of acetylcholine. Subsequently, there is a continuous contraction of the narrowed (affected) colonic segment and progressive secondary dilatation of the healthy proximal colon. […] Disturbed rostrocaudal migration of the neural crest cells (NCC) along a variable length of the intestine is responsible for HD. GC first migrates to the myenteric plexus and then to the submucosal plexus. […] Animal models have also highlighted an arrest or delay in the migration of NCCs as the factor behind the pathogenesis of HD.

• #13 Hirschsprung’s Disease.

  https://www.e-jyms.org/DOIx.php?id=10.12701/yujm.2007.24.1.11

  Hirschsprung’s disease is one of the most common causes of intestinal obstruction in neonates and infants. The underlying pathology of this disease is the absence of the ganglion cells in both the myenteric (Auerbach’s) plexus and the submucosal (Meissner’s) plexus. […] the cause of the absence of the ganglion cells has not been identified. Hirschsprung’s disease can be successfully treated with the Swenson, the Duhamel, and the Soave operations even though the pathogenesis is unknown. […] With the recent progress of molecular biology and genetics, a more detailed approach to the pathogenesis of Hirschsprung’s disease can be undertaken.

• #14 Hirschsprung’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Hirschsprung%27s_disease

  Hirschsprung’s disease (HD or HSCR) is a birth defect in which nerves are missing from parts of the intestine. […] The disorder may occur by itself or in association with other genetic disorders such as Down syndrome. About half of isolated cases are linked to a specific genetic mutation, and about 20% occur within families. Some of these occur in an autosomal dominant manner. The cause of the remaining cases is unclear. […] The most accepted theory of the cause of Hirschsprung is a defect in the craniocaudal migration of neuroblasts originating from the neural crest that occurs during the first 12 weeks of gestation. Defects in the differentiation of neuroblasts into ganglion cells and accelerated ganglion cell destruction within the intestine may also contribute to the disorder. […] This lack of ganglion cells in the myenteric and submucosal plexus is well documented in Hirschsprung’s disease.

• #15 Congenital aganglionic megacolon (Hirschsprung disease) – UpToDate

  https://www.uptodate.com/contents/congenital-aganglionic-megacolon-hirschsprung-disease

  Hirschsprung disease (HD) is a motor disorder of the colon, which is caused by the failure of neural crest cells (precursors of enteric ganglion cells) to migrate completely during intestinal development during fetal life. The resulting aganglionic segment of the colon fails to relax, causing a functional obstruction. […] The most accepted theory of the cause of HD is that there is a defect in the craniocaudal migration of neuroblasts originating from the neural crest, a process that begins at four weeks of gestation and ends at week 7 with the arrival of neural crest-derived cells at the distal end of the colon. In HD, the cells fail to reach the distal colon, rendering that segment aganglionic and therefore with abnormal motor function, resulting in HD. Defects in the differentiation of neuroblasts into ganglion cells and ganglion cell destruction within the intestine may also contribute to the disorder.

• #16 Hirschsprung Disease: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/178493-overview

  One possible etiology of Hirschsprung disease is the arrest of aboral neuroblast migration. Alternatively, although normal cell migration may occur, neuroblasts may be subject to apoptosis, failure of proliferation, or improper differentiation within the affected distal intestinal segment. Fibronectin, laminin, neural cell adhesion molecule (NCAM), and neurotrophic factors present in the intestinal stroma are necessary for normal enteric ganglion development, whereas their absence or dysfunction may also have a role in the etiology of Hirschsprung disease. […] Investigators have also identified several genes whose improper expression results in a Hirschsprung disease phenotype. Genome-wide association studies (GWAS) in Europeans and Asians have identified three common disease-susceptibility variants at the RET, SEMA3, and NRG1 loci.

• #17 Pathophysiology of Hirschsprung’s Disease and its Diagnosis

  https://www.jcmedu.org/jcmedu-articles/pathophysiology-of-hirschsprungs-disease-and-its-diagnosis-96460.html

  Hirschsprungs Disease (HD or HSCR) is a birth defect in which nerves in parts of the intestine are missing. […] The most accepted theory for the cause of Hirschsprungs is a defect in the craniocaudal migration of neural crest-derived neuroblasts that occurs during the first 12 weeks of pregnancy. Defects in the differentiation of neuroblasts into ganglion cells and accelerated destruction of ganglion cells in the gut may also contribute to the disorder. […] This lack of ganglion cells in the myenteric and submucosal plexus is well documented in Hirschsprungs disease. In Hirschsprungs disease, the segment lacking neurons (aganglionic) narrows, causing the normal proximal part of the intestine to distend with feces. […] The absence of ganglion cells results in persistent overstimulation of the nerves in the affected area, leading to contraction.

• #18 Stem cell-based therapy for hirschsprung disease, do we have the guts to treat? | Gene Therapy

  https://www.nature.com/articles/s41434-021-00268-4

  Hirschsprung disease (HSCR) is a congenital anomaly of the colon that results from failure of enteric nervous system formation, leading to a constricted dysfunctional segment of the colon with variable lengths, and necessitating surgical intervention. […] The underlying pathophysiology includes a defect in neural crest cells migration, proliferation and differentiation, which are partially explained by identified genetic and epigenetic alterations. […] The primary pathology in HSCR is the failure of proper ENS formation, leading to a constricted dysfunctional segment of the bowel that causes fecal obstruction. This defect often arises from genetic defects in the pathways responsible for ENCC migration, proliferation, differentiation and survival. […] Nevertheless, studied cases revealed single, multiple or even no detected genetic defects, as well as the involvement of environmental factors, affirming the diseases complex and multifactorial nature.

• #19 Hirschsprung’s Disease: Pathogenesis and Overview | SpringerLink

  https://link.springer.com/chapter/10.1007/978-981-13-3606-5_2

  Surgical options using various techniques of pull-through surgery have been performed in clinical practice as a consensus therapy for years, whereas the pathogenesis of Hirschsprungs disease (HD) remains unclear. […] The remaining 80% of sporadic cases highlights the need to understand the etiology and pathogenic mechanism of HD. There are two major theories that explain the pathogenesis of HD in children. One is nongenetic pathogeneses and the other is genetic. The nongenetic factors include the abnormalities in migration of neural crest cells (NCCs), microenvironment surrounding the NCCs, cell adhesion molecules, neurotrophic factors, immunologic response in utero, epithelial-derived signal, and autophagy. These abnormalities may be responsible for the innervation deficiency due to incomplete colonization of enteric NCCs in the gut.

• #20 The Developmental Etiology and Pathogenesis of Hirschsprung disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3691347/

  Proper neural crest cell migration, proliferation, differentiation, survival, and apoptosis all contribute to a functional ENS. Perturbation in any of these processes can lead to a Hirschsprung disease phenotype. […] Many genes which play a critical functional role in neural crest cell development have been implicated in HSCR, including the proto-oncogene RET, endothelin signaling genes, and transcription factors. […] Although over a dozen genes have been identified that contribute to the etiology of HSCR, these pathways only account for about half of the known cases. […] The ENS is derived from migratory neural crest cells which originate at the vagal (somites 17) and sacral (caudal to somite 24) regions of the embryonic axis. […] During migration, chains of interconnected neural crest cells at the leading edge of the population are referred to as the wavefront.

• #21 The Developmental Etiology and Pathogenesis of Hirschsprung disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3691347/

  Proper neural crest cell migration, proliferation, differentiation, survival, and apoptosis all contribute to a functional ENS. Perturbation in any of these processes can lead to a Hirschsprung disease phenotype. […] Many genes which play a critical functional role in neural crest cell development have been implicated in HSCR, including the proto-oncogene RET, endothelin signaling genes, and transcription factors. […] Although over a dozen genes have been identified that contribute to the etiology of HSCR, these pathways only account for about half of the known cases. […] The ENS is derived from migratory neural crest cells which originate at the vagal (somites 17) and sacral (caudal to somite 24) regions of the embryonic axis. […] During migration, chains of interconnected neural crest cells at the leading edge of the population are referred to as the wavefront.

• #22 Hirschsprung’s Disease—Recent Understanding of Embryonic Aspects, Etiopathogenesis and Future Treatment Avenues

  https://www.mdpi.com/1648-9144/56/11/611

  Hirschsprung’s disease is a neurocristopathy, caused by defective migration, proliferation, differentiation and survival of neural crest cells, leading to gut aganglionosis. […] The most prominent etiopathogenetic factor in the development of HSCR is the NC disorder, this condition falls into the category of neurocristopathies. […] The understanding of HSCR etiopathogenesis was obscure until 1948. […] With the advancements in molecular biology, HSCR was among the first conditions in which the genetic aspects were documented. […] Multiple genes have been implicated in the failure of NCCs to effectively populate the gut and develop normally into the ENS. […] Some of the most thoroughly studied and significant genes whose disruptive expression contributes to the development of HSCR are RET and GDNF.

• #23 Hirschsprung disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/hirschsprung-disease/

  Hirschsprung disease is an intestinal disorder characterized by the absence of nerves in parts of the intestine. This condition occurs when the nerves in the intestine (enteric nerves) do not form properly during development before birth (embryonic development). […] Enteric nerves trigger the muscle contractions that move stool through the intestine. Without these nerves in parts of the intestine, the material cannot be pushed through, causing severe constipation or complete blockage of the intestine in people with Hirschsprung disease. […] Isolated Hirschsprung disease can result from mutations in one of several genes, including the RET, EDNRB, and EDN3 genes. However, the genetics of this condition appear complex and are not completely understood. […] Mutations in the RET gene are the most common known genetic cause of Hirschsprung disease. The RET gene provides instructions for producing a protein that is involved in signaling within cells. This protein appears to be essential for the normal development of several kinds of nerve cells, including nerves in the intestine.

• #24 Hirschsprung disease — Knowledge Hub

  https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/hirschsprung-disease/

  Sporadic, short-segment Hirschsprung disease is believed to have an oligogenic mechanism of inheritance and can be associated with single-gene variants, variants in non-coding regions, copy number variants (CNVs) and chromosomal anomalies. Incomplete penetrance and the presence of genetic modifiers are both recognised. […] Around 40%50% of familial cases and 10%20% of sporadic cases will be found to have a loss-of-function variant in the RET pathway. Variants have most commonly been described in the RET gene, but also in SOX10, PHOX2B, L1CAM, KIF1BP, EDNRB, EDN3, ZEB2. […] In non-syndromic Hirschsprung disease where a RET pathogenic variant is identified, inheritance is autosomal dominant with incomplete penetrance (50%70%).

• #25 Hirschsprung disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/hirschsprung-disease/

  Hirschsprung disease is an intestinal disorder characterized by the absence of nerves in parts of the intestine. This condition occurs when the nerves in the intestine (enteric nerves) do not form properly during development before birth (embryonic development). […] Enteric nerves trigger the muscle contractions that move stool through the intestine. Without these nerves in parts of the intestine, the material cannot be pushed through, causing severe constipation or complete blockage of the intestine in people with Hirschsprung disease. […] Isolated Hirschsprung disease can result from mutations in one of several genes, including the RET, EDNRB, and EDN3 genes. However, the genetics of this condition appear complex and are not completely understood. […] Mutations in the RET gene are the most common known genetic cause of Hirschsprung disease. The RET gene provides instructions for producing a protein that is involved in signaling within cells. This protein appears to be essential for the normal development of several kinds of nerve cells, including nerves in the intestine.

• #26 Hirschsprung disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/hirschsprung-disease/

  Mutations in the RET gene that cause Hirschsprung disease result in a nonfunctional version of the RET protein that cannot transmit signals within cells. Without RET protein signaling, enteric nerves do not develop properly. Absence of these nerves leads to the intestinal problems characteristic of Hirschsprung disease. […] Changes in either the EDNRB gene or the EDN3 gene disrupt the normal functioning of the endothelin receptor type B or the endothelin 3 protein, preventing them from transmitting signals important for the development of enteric nerves. As a result, these nerves do not form normally during embryonic development. A lack of enteric nerves prevents stool from being moved through the intestine, leading to severe constipation and intestinal blockage.

• #27 Hirschsprung’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Hirschsprung%27s_disease

  The absence of ganglion cells results in a persistent overstimulation of nerves in the affected region, resulting in contraction. […] The RET proto-oncogene accounts for the highest proportion of both familial and sporadic cases, with a wide range of mutations scattered along its entire coding region. […] RET is a gene that codes for proteins that assist cells of the neural crest in their movement through the digestive tract during the development of the embryo. Those neural crest cells eventually form bundles of nerve cells called ganglions. EDNRB codes for proteins that connect these nerve cells to the digestive tract. Thus, mutations in these two genes could directly lead to the absence of certain nerve fibers in the colon. Research suggests that several genes are associated with Hirschsprung’s disease.

• #28 Stem cell-based therapy for hirschsprung disease, do we have the guts to treat? | Gene Therapy

  https://www.nature.com/articles/s41434-021-00268-4

  To date, around 21 genes were pinpointed in HSCR that code for proteins involved in NCC functions and ENS development pathways. […] The RET proto-oncogene (OMIM 164761) was found to be the major contributor to the disease phenotype, with more than 200 RET loss-of-function mutations linked to ~20% of the sporadic as well as up to half of the familial forms of the disease. […] Epigenetic modifications were also investigated in the context of ENS development and HSCR pathogenesis. […] The susceptibility of the distal colon in HSCR in particular is not fully understood. However, the fact that NCC migration is rostrocaudal indicates a failure of maintenance of the progenitor pool. […] The GDNF/RET signaling system is composed of Glial cell-derived neurotrophic factor (GDNF) that is secreted by the gut mesoderm and interacts with the tyrosine kinase RET receptor and GDNF family receptor 1 (GFR1) receptor that are present in the ENCC.

• #29 Stem cell-based therapy for hirschsprung disease, do we have the guts to treat? | Gene Therapy

  https://www.nature.com/articles/s41434-021-00268-4

  GDNF/RET signaling plays a role in chemotaxis of ENCC to migrate distally. Moreover, it promotes proliferation by acting as a mitogenic factor to ensure an adequate ENCC pool. […] In subsequent phases, GDNF/RET promotes neuronal differentiation. […] ET3/EDNRB pathway is comprised of Endothelin-3 (ET3) that is secreted by the gut mesoderm to bind to EDNRB protein in the ENCC. This signaling pathway maintains ENCC progenitors in an undifferentiated state, allowing them to migrate and fully colonize the gut.

• #30 Hirschsprung’s disease: clinical dysmorphology, genes, micro-RNAs, and future perspectives | Pediatric Research

  https://www.nature.com/articles/pr2016202

  The endothelins are vasoactive molecules, which make a family of 21 amino acid isopeptides (EDN1, EDN2, and EDN3) with each molecule containing two intra-chain disulphide bonds encoded by a separate gene. […] The final action is the constriction or relaxation of the smooth muscles of the blood vessels, raising or lowering the blood pressure, among other functions. […] SOX10 is crucial for their survival. […] Mutations in SOX10 that result in the loss of the transactivating domain or that disrupt protein-protein interactions with PAX3 result in Waardenburg syndrome types 2 (WS2) without HSCR. […] The role of SOX10 during enteric nervous system development.

• #31 Stem cell-based therapy for hirschsprung disease, do we have the guts to treat? | Gene Therapy

  https://www.nature.com/articles/s41434-021-00268-4

  GDNF/RET signaling plays a role in chemotaxis of ENCC to migrate distally. Moreover, it promotes proliferation by acting as a mitogenic factor to ensure an adequate ENCC pool. […] In subsequent phases, GDNF/RET promotes neuronal differentiation. […] ET3/EDNRB pathway is comprised of Endothelin-3 (ET3) that is secreted by the gut mesoderm to bind to EDNRB protein in the ENCC. This signaling pathway maintains ENCC progenitors in an undifferentiated state, allowing them to migrate and fully colonize the gut.

• #32 Hirschsprung disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/hirschsprung-disease/

  Mutations in the RET gene that cause Hirschsprung disease result in a nonfunctional version of the RET protein that cannot transmit signals within cells. Without RET protein signaling, enteric nerves do not develop properly. Absence of these nerves leads to the intestinal problems characteristic of Hirschsprung disease. […] Changes in either the EDNRB gene or the EDN3 gene disrupt the normal functioning of the endothelin receptor type B or the endothelin 3 protein, preventing them from transmitting signals important for the development of enteric nerves. As a result, these nerves do not form normally during embryonic development. A lack of enteric nerves prevents stool from being moved through the intestine, leading to severe constipation and intestinal blockage.

• #33 Hirschsprung’s disease: clinical dysmorphology, genes, micro-RNAs, and future perspectives | Pediatric Research

  https://www.nature.com/articles/pr2016202

  The endothelins are vasoactive molecules, which make a family of 21 amino acid isopeptides (EDN1, EDN2, and EDN3) with each molecule containing two intra-chain disulphide bonds encoded by a separate gene. […] The final action is the constriction or relaxation of the smooth muscles of the blood vessels, raising or lowering the blood pressure, among other functions. […] SOX10 is crucial for their survival. […] Mutations in SOX10 that result in the loss of the transactivating domain or that disrupt protein-protein interactions with PAX3 result in Waardenburg syndrome types 2 (WS2) without HSCR. […] The role of SOX10 during enteric nervous system development.

• #34 Congenital aganglionic megacolon (Hirschsprung disease) – UpToDate

  https://www.uptodate.com/contents/congenital-aganglionic-megacolon-hirschsprung-disease

  Mutations in several genes have been identified in patients with HD. HD is a genetically complex disorder caused by variants in multiple rare genes with low penetrance and variable expression. Thus, individuals with multiple pathogenic variants have substantially increased risk compared with those with fewer pathogenic variants. For nonsyndromic forms, long-segment disease tends to be transmitted by autosomal dominant inheritance and short-segment disease often reflects autosomal recessive or multifactorial inheritance.

• #35 Hirschsprung disease — Knowledge Hub

  https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/hirschsprung-disease/

  Sporadic, short-segment Hirschsprung disease is believed to have an oligogenic mechanism of inheritance and can be associated with single-gene variants, variants in non-coding regions, copy number variants (CNVs) and chromosomal anomalies. Incomplete penetrance and the presence of genetic modifiers are both recognised. […] Around 40%50% of familial cases and 10%20% of sporadic cases will be found to have a loss-of-function variant in the RET pathway. Variants have most commonly been described in the RET gene, but also in SOX10, PHOX2B, L1CAM, KIF1BP, EDNRB, EDN3, ZEB2. […] In non-syndromic Hirschsprung disease where a RET pathogenic variant is identified, inheritance is autosomal dominant with incomplete penetrance (50%70%).

• #36 “Too much guts and not enough brains”: (epi)genetic mechanisms and future therapies of Hirschsprung disease — a review | Clinical Epigenetics | Full Text

  https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0718-x

  Hirschsprung disease is a neurocristopathy, characterized by aganglionosis in the distal bowel. It is caused by failure of the enteric nervous system progenitors to migrate, proliferate, and differentiate in the gut. […] Hence, alterations in expression of genes specific for the enteric nervous system may contribute to the pathogenesis of Hirschsprungs disease. Several epigenetic mechanisms contribute to regulate gene expression, such as modifications of DNA and RNA, histone modifications, and microRNAs. […] The genetic background of HSCR is complex. […] The ganglion cells of the enteric nervous system (ENS) are entirely derived from the neural crest which is a transient, multipotent cell population originating from the neural tube. […] Several genes are associated with ENS development, thereby also in the pathogenesis of HSCR disease. RET is identified as the main HSCR gene as the RET mutation is found in 50% of familial and 1520% of sporadic HSCR cases.

• #37 “Too much guts and not enough brains”: (epi)genetic mechanisms and future therapies of Hirschsprung disease — a review | Clinical Epigenetics | Full Text

  https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0718-x

  Both DNMT3B and MeCP2 expression are decreased in neural stem cells obtained from HSCR patients, which result in a decrease of global DNA methylation. This may contribute to an aberrant expression pattern of HSCR-associated genes. […] Several HSCR-associated genes are regulated by the methylation degree of their promoter areas. One of these genes is RET, and it has been suggested that the level of RET expression determines the length of the aganglionic segment. […] Thus, aberrant methylation patterns resulting in epigenetic inactivation or overactivation of HSCR-associated genes are implicated in the development of HSCR. […] The role of histone modifications is of critical importance in CNS development. ENS development may be regulated by the same mechanisms, and if that is the case, then HSCR pathogenesis could be linked to histone modifications. […] Histone modifications enhance or silence transcription of specific genomic regions and may also apply to HSCR-associated genes such as RET. […] In HSCR patients with aberrant epigenetic patterns, these could be potentially corrected pharmacologically.

• #38 “Too much guts and not enough brains”: (epi)genetic mechanisms and future therapies of Hirschsprung disease — a review | Clinical Epigenetics | Full Text

  https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0718-x

  Both DNMT3B and MeCP2 expression are decreased in neural stem cells obtained from HSCR patients, which result in a decrease of global DNA methylation. This may contribute to an aberrant expression pattern of HSCR-associated genes. […] Several HSCR-associated genes are regulated by the methylation degree of their promoter areas. One of these genes is RET, and it has been suggested that the level of RET expression determines the length of the aganglionic segment. […] Thus, aberrant methylation patterns resulting in epigenetic inactivation or overactivation of HSCR-associated genes are implicated in the development of HSCR. […] The role of histone modifications is of critical importance in CNS development. ENS development may be regulated by the same mechanisms, and if that is the case, then HSCR pathogenesis could be linked to histone modifications. […] Histone modifications enhance or silence transcription of specific genomic regions and may also apply to HSCR-associated genes such as RET. […] In HSCR patients with aberrant epigenetic patterns, these could be potentially corrected pharmacologically.

• #39 “Too much guts and not enough brains”: (epi)genetic mechanisms and future therapies of Hirschsprung disease — a review | Clinical Epigenetics | Full Text

  https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0718-x

  Both DNMT3B and MeCP2 expression are decreased in neural stem cells obtained from HSCR patients, which result in a decrease of global DNA methylation. This may contribute to an aberrant expression pattern of HSCR-associated genes. […] Several HSCR-associated genes are regulated by the methylation degree of their promoter areas. One of these genes is RET, and it has been suggested that the level of RET expression determines the length of the aganglionic segment. […] Thus, aberrant methylation patterns resulting in epigenetic inactivation or overactivation of HSCR-associated genes are implicated in the development of HSCR. […] The role of histone modifications is of critical importance in CNS development. ENS development may be regulated by the same mechanisms, and if that is the case, then HSCR pathogenesis could be linked to histone modifications. […] Histone modifications enhance or silence transcription of specific genomic regions and may also apply to HSCR-associated genes such as RET. […] In HSCR patients with aberrant epigenetic patterns, these could be potentially corrected pharmacologically.

• #40

  https://www.jci.org/articles/view/83178

  The composition of the extracellular matrix (ECM) is another important factor that can influence gut colonization by eNCCs and might thus contribute to HSCR pathogenesis. […] Our data thus unveil a clinically relevant pathogenic mechanism for HSCR that involves cell-autonomous changes in ECM composition surrounding eNCCs. […] This cumulative work suggests that the ECM of the gut wall is a major player in ENS formation. Targeting this previously overlooked aspect of ENS development could have clinical relevance for the cell-based therapies currently being developed for treatment of enteric neuropathies. […] Our previous analysis of the TashT line showed that, among several pathways and processes affected, the mutant eNCCs were notably found to impose major changes on the composition of their own ECM, including increased collagen VI levels. With the Holstein line, we now demonstrate that the single alteration of collagen VI levels in the ECM surrounding eNCCs is enough by itself to cause aganglionosis. […] Therefore, combined with the fact that the genes encoding the key subunits for collagen VI assembly are located on human Chr.21q, this allows us to propose a possible molecular explanation for the strong association between Down syndrome and HSCR.

• #41

  https://www.jci.org/articles/view/83178

  Hirschsprungs disease (HSCR) causes functional intestinal obstruction due to the absence of the enteric nervous system (ENS) in the distal bowel and is usually diagnosed shortly after birth or during childhood. […] In this issue of the JCI, Soret and colleagues identify a new mechanism that causes HSCR-like disease in mice and involves deposition of excess collagen VI in the intestine by migrating ENS precursors as they colonize fetal bowel. Remarkably, their findings may explain some of the so-called missing heritability of HSCR and suggest a mechanism for increased HSCR incidence in children with Down syndrome (trisomy 21). […] HSCR is a complex genetic disease that has a global incidence of 1 in 5,000 human births and is characterized by the absence of neural ganglia in the distal gut, from the anus up to a variable length of the intestines.

• #42

  https://www.jci.org/articles/view/85003

  Hirschsprungs disease (HSCR) is a severe congenital anomaly of the enteric nervous system (ENS) characterized by functional intestinal obstruction due to a lack of intrinsic innervation in the distal bowel. […] Increased collagen VI levels during development mainly result in slower migration of eNCCs. […] Importantly, for a majority of patients in a HSCR cohort, the myenteric ganglia from the ganglionated region are also specifically surrounded by abundant collagen VI microfibrils, an outcome accentuated by Down syndrome. […] The hypothesis that increased collagen VI production by migrating ENCDCs in children with Down syndrome underlies increased HSCR risk is provocative and interesting. […] Soret et al. next hypothesized that their observations in mice may be relevant for human HSCR and could explain the increased HSCR occurrence in children with Down syndrome. […] Remarkably, collagen VI was more abundant in tissue surrounding myenteric ganglia of children with HSCR compared with that in control specimens (2-fold higher) and present at even higher levels surrounding myenteric ganglia of children with Down syndrome and HSCR (3-fold higher).

• #43 A collagen VI–dependent pathogenic mechanism for Hirschsprung’s disease – Archive ouverte HAL

  https://hal.science/hal-04166667/

  Hirschsprung’s disease (HSCR) is a severe congenital anomaly of the enteric nervous system (ENS) characterized by functional intestinal obstruction due to a lack of intrinsic innervation in the distal bowel. Distal innervation deficiency results from incomplete colonization of the bowel by enteric neural crest cells (eNCCs), the ENS precursors. […] This insertion induces eNCC-specific upregulation of Col6a4 expression that increases total collagen VI protein levels in the extracellular matrix (ECM) surrounding both the developing and the postnatal ENS. Increased collagen VI levels during development mainly result in slower migration of eNCCs. This appears to be due to the fact that collagen VI is a poor substratum for supporting eNCC migration and can even interfere with the migration-promoting effects of fibronectin.

• #44

  https://www.jci.org/articles/view/85003

  Hirschsprungs disease (HSCR) is a severe congenital anomaly of the enteric nervous system (ENS) characterized by functional intestinal obstruction due to a lack of intrinsic innervation in the distal bowel. […] Increased collagen VI levels during development mainly result in slower migration of eNCCs. […] Importantly, for a majority of patients in a HSCR cohort, the myenteric ganglia from the ganglionated region are also specifically surrounded by abundant collagen VI microfibrils, an outcome accentuated by Down syndrome. […] The hypothesis that increased collagen VI production by migrating ENCDCs in children with Down syndrome underlies increased HSCR risk is provocative and interesting. […] Soret et al. next hypothesized that their observations in mice may be relevant for human HSCR and could explain the increased HSCR occurrence in children with Down syndrome. […] Remarkably, collagen VI was more abundant in tissue surrounding myenteric ganglia of children with HSCR compared with that in control specimens (2-fold higher) and present at even higher levels surrounding myenteric ganglia of children with Down syndrome and HSCR (3-fold higher).

• #45

  https://www.jci.org/articles/view/83178

  The composition of the extracellular matrix (ECM) is another important factor that can influence gut colonization by eNCCs and might thus contribute to HSCR pathogenesis. […] Our data thus unveil a clinically relevant pathogenic mechanism for HSCR that involves cell-autonomous changes in ECM composition surrounding eNCCs. […] This cumulative work suggests that the ECM of the gut wall is a major player in ENS formation. Targeting this previously overlooked aspect of ENS development could have clinical relevance for the cell-based therapies currently being developed for treatment of enteric neuropathies. […] Our previous analysis of the TashT line showed that, among several pathways and processes affected, the mutant eNCCs were notably found to impose major changes on the composition of their own ECM, including increased collagen VI levels. With the Holstein line, we now demonstrate that the single alteration of collagen VI levels in the ECM surrounding eNCCs is enough by itself to cause aganglionosis. […] Therefore, combined with the fact that the genes encoding the key subunits for collagen VI assembly are located on human Chr.21q, this allows us to propose a possible molecular explanation for the strong association between Down syndrome and HSCR.

• #46 A collagen VI–dependent pathogenic mechanism for Hirschsprung’s disease – Archive ouverte HAL

  https://hal.science/hal-04166667/

  Collectively, our data thus unveil a clinically relevant pathogenic mechanism for HSCR that involves cell-autonomous changes in ECM composition surrounding eNCCs. Moreover, as COL6A1 and COL6A2 are on human Chr.21q, this mechanism is highly relevant to the predisposition of patients with Down syndrome to HSCR.

• #47 Hirschsprung Disease: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/178493-overview

  Hirschsprung disease is a developmental disorder characterized by the absence of ganglia in the distal colon, resulting in a functional obstruction. […] Although this condition was described by Ruysch in 1691 and popularized by Hirschsprung in 1886, the pathophysiology was not clearly determined until the middle of the 20th century, when Whitehouse and Kernohan reported aganglionosis of the distal colon as the cause of obstruction in a case series. […] In patients with Hirschsprung disease, both myenteric and submucosal plexuses are absent. The anus is invariably affected, and aganglionosis continues proximally for a variable distance. In the absence of ENS reflexes, control of the intestinal smooth muscle is overwhelmingly extrinsic. The activity of both the cholinergic system and the adrenergic system is 2-3 times that of normal intestine. The cholinergic (excitatory) system is thought to predominate over the adrenergic (inhibitory) system, leading to an increase in smooth muscle tone. With the loss of the intrinsic enteric relaxing impulses, the increased muscle tone is unopposed. This phenomenon leads to an imbalance of smooth muscle contractility, uncoordinated peristalsis, and a functional obstruction.

• #48 Hirschsprung’s disease – Pathophysiology – TeachMePaediatrics

  https://teachmepaediatrics.com/surgery/abdominal/hirschsprungs-disease/

  Hischsprungs disease is where ganglionic cells of the myenteric and submucosal plexuses in the bowel aren’t present proximally from the anus to a variable length along the large intestine. The most common accepted aetiology of this disease is due to the arrest of the neuroblast, derived from neural crest cell migration in fetal development between week 8 to 12. It is also accepted that sometimes normal cell migration occurs but the neuroblast fails to properly develop due to apoptosis, improper differentiation, or failure in proliferation. The aganglionic segment remains in a tonic state leading to failure in peristalsis and bowel movements. Faeces in the rectum fail to trigger relaxation of the internal anal sphincter, due to aganglionosis. The accumulation of faeces in the rectosigmoid region is responsible for the functional obstruction, which is the cause of many of the symptoms. Increased intraluminal pressure can lead to decreased blood flow and deterioration in the mucosal layer. This stasis can lead to bacterial proliferation and the subsequent complication of Hirschsprungs enterocolitis, which has a mortality rate of 25-30%. If not recognised early this can lead to sepsis and death. […] The strongest association with Hirschsprungs, is the Receptor tyrosine kinase (RET) gene, a proto-oncogene on chromosome 10q11. HD is strongly associated with chromosomal abnormalities, with 10-15% HD cases associated with trisomy 21 (Down Syndrome).

• #49 Hirschsprung’s disease – Pathophysiology – TeachMePaediatrics

  https://teachmepaediatrics.com/surgery/abdominal/hirschsprungs-disease/

  Hischsprungs disease is where ganglionic cells of the myenteric and submucosal plexuses in the bowel aren’t present proximally from the anus to a variable length along the large intestine. The most common accepted aetiology of this disease is due to the arrest of the neuroblast, derived from neural crest cell migration in fetal development between week 8 to 12. It is also accepted that sometimes normal cell migration occurs but the neuroblast fails to properly develop due to apoptosis, improper differentiation, or failure in proliferation. The aganglionic segment remains in a tonic state leading to failure in peristalsis and bowel movements. Faeces in the rectum fail to trigger relaxation of the internal anal sphincter, due to aganglionosis. The accumulation of faeces in the rectosigmoid region is responsible for the functional obstruction, which is the cause of many of the symptoms. Increased intraluminal pressure can lead to decreased blood flow and deterioration in the mucosal layer. This stasis can lead to bacterial proliferation and the subsequent complication of Hirschsprungs enterocolitis, which has a mortality rate of 25-30%. If not recognised early this can lead to sepsis and death. […] The strongest association with Hirschsprungs, is the Receptor tyrosine kinase (RET) gene, a proto-oncogene on chromosome 10q11. HD is strongly associated with chromosomal abnormalities, with 10-15% HD cases associated with trisomy 21 (Down Syndrome).

• #50 Hirschsprung Disease: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/178493-overview

  Hirschsprung disease is a developmental disorder characterized by the absence of ganglia in the distal colon, resulting in a functional obstruction. […] Although this condition was described by Ruysch in 1691 and popularized by Hirschsprung in 1886, the pathophysiology was not clearly determined until the middle of the 20th century, when Whitehouse and Kernohan reported aganglionosis of the distal colon as the cause of obstruction in a case series. […] In patients with Hirschsprung disease, both myenteric and submucosal plexuses are absent. The anus is invariably affected, and aganglionosis continues proximally for a variable distance. In the absence of ENS reflexes, control of the intestinal smooth muscle is overwhelmingly extrinsic. The activity of both the cholinergic system and the adrenergic system is 2-3 times that of normal intestine. The cholinergic (excitatory) system is thought to predominate over the adrenergic (inhibitory) system, leading to an increase in smooth muscle tone. With the loss of the intrinsic enteric relaxing impulses, the increased muscle tone is unopposed. This phenomenon leads to an imbalance of smooth muscle contractility, uncoordinated peristalsis, and a functional obstruction.

• #51 Hirschsprung Disease: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/178493-overview

  Hirschsprung disease is a developmental disorder characterized by the absence of ganglia in the distal colon, resulting in a functional obstruction. […] Although this condition was described by Ruysch in 1691 and popularized by Hirschsprung in 1886, the pathophysiology was not clearly determined until the middle of the 20th century, when Whitehouse and Kernohan reported aganglionosis of the distal colon as the cause of obstruction in a case series. […] In patients with Hirschsprung disease, both myenteric and submucosal plexuses are absent. The anus is invariably affected, and aganglionosis continues proximally for a variable distance. In the absence of ENS reflexes, control of the intestinal smooth muscle is overwhelmingly extrinsic. The activity of both the cholinergic system and the adrenergic system is 2-3 times that of normal intestine. The cholinergic (excitatory) system is thought to predominate over the adrenergic (inhibitory) system, leading to an increase in smooth muscle tone. With the loss of the intrinsic enteric relaxing impulses, the increased muscle tone is unopposed. This phenomenon leads to an imbalance of smooth muscle contractility, uncoordinated peristalsis, and a functional obstruction.

• #52 Hirschsprung Disease: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/178493-overview

  Hirschsprung disease is a developmental disorder characterized by the absence of ganglia in the distal colon, resulting in a functional obstruction. […] Although this condition was described by Ruysch in 1691 and popularized by Hirschsprung in 1886, the pathophysiology was not clearly determined until the middle of the 20th century, when Whitehouse and Kernohan reported aganglionosis of the distal colon as the cause of obstruction in a case series. […] In patients with Hirschsprung disease, both myenteric and submucosal plexuses are absent. The anus is invariably affected, and aganglionosis continues proximally for a variable distance. In the absence of ENS reflexes, control of the intestinal smooth muscle is overwhelmingly extrinsic. The activity of both the cholinergic system and the adrenergic system is 2-3 times that of normal intestine. The cholinergic (excitatory) system is thought to predominate over the adrenergic (inhibitory) system, leading to an increase in smooth muscle tone. With the loss of the intrinsic enteric relaxing impulses, the increased muscle tone is unopposed. This phenomenon leads to an imbalance of smooth muscle contractility, uncoordinated peristalsis, and a functional obstruction.

• #53 Hirschsprung Disease: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/178493-overview

  Hirschsprung disease is a developmental disorder characterized by the absence of ganglia in the distal colon, resulting in a functional obstruction. […] Although this condition was described by Ruysch in 1691 and popularized by Hirschsprung in 1886, the pathophysiology was not clearly determined until the middle of the 20th century, when Whitehouse and Kernohan reported aganglionosis of the distal colon as the cause of obstruction in a case series. […] In patients with Hirschsprung disease, both myenteric and submucosal plexuses are absent. The anus is invariably affected, and aganglionosis continues proximally for a variable distance. In the absence of ENS reflexes, control of the intestinal smooth muscle is overwhelmingly extrinsic. The activity of both the cholinergic system and the adrenergic system is 2-3 times that of normal intestine. The cholinergic (excitatory) system is thought to predominate over the adrenergic (inhibitory) system, leading to an increase in smooth muscle tone. With the loss of the intrinsic enteric relaxing impulses, the increased muscle tone is unopposed. This phenomenon leads to an imbalance of smooth muscle contractility, uncoordinated peristalsis, and a functional obstruction.

• #54 Hirschsprung’s disease – Pathophysiology – TeachMePaediatrics

  https://teachmepaediatrics.com/surgery/abdominal/hirschsprungs-disease/

  Hischsprungs disease is where ganglionic cells of the myenteric and submucosal plexuses in the bowel aren’t present proximally from the anus to a variable length along the large intestine. The most common accepted aetiology of this disease is due to the arrest of the neuroblast, derived from neural crest cell migration in fetal development between week 8 to 12. It is also accepted that sometimes normal cell migration occurs but the neuroblast fails to properly develop due to apoptosis, improper differentiation, or failure in proliferation. The aganglionic segment remains in a tonic state leading to failure in peristalsis and bowel movements. Faeces in the rectum fail to trigger relaxation of the internal anal sphincter, due to aganglionosis. The accumulation of faeces in the rectosigmoid region is responsible for the functional obstruction, which is the cause of many of the symptoms. Increased intraluminal pressure can lead to decreased blood flow and deterioration in the mucosal layer. This stasis can lead to bacterial proliferation and the subsequent complication of Hirschsprungs enterocolitis, which has a mortality rate of 25-30%. If not recognised early this can lead to sepsis and death. […] The strongest association with Hirschsprungs, is the Receptor tyrosine kinase (RET) gene, a proto-oncogene on chromosome 10q11. HD is strongly associated with chromosomal abnormalities, with 10-15% HD cases associated with trisomy 21 (Down Syndrome).

• #55 Diagnosis and pathophysiology of Hirschsprung’s disease – Pelviperineology A Multidisciplinary Pelvic Floor Journal

  https://pelviperineology.org/articles/diagnosis-and-pathophysiology-of-hirschsprungs-disease/doi/PPj.2021.40.02.006

  Hirschsprungs Disease (HD) is relatively common in children. Surgical treatment is aimed at removing the aganglionic section of the gut and repairing the intestinal tract. […] The absence of enteric ganglion cells of the myenteric and submucosal plexus along variable portions of the gastrointestinal tract results in HD, which is characterized by sustained contraction of the aganglionic bowel segment, leading to intestinal obstruction and distension of proximal segments (megacolon). […] The gold standard for an HD diagnosis is a rectal biopsy. […] In HD, apart from the absence of RAIR, there is no information about the function of the external anal sphincter (EAS), puborectalis muscle (PRM), and levator plates (LP). This information can be useful for improving the accuracy of the preoperative diagnosis, as well as for choosing the optimal method of surgical treatment. […] The present study has shown that the aganglionic rectum does not have neural connections with anorectal sphincters. Therefore, an increase in rectal pressure does not induce relaxation of the IAS, a contraction of the PRM, external anal sphincter, and levator plates.

• #56 Hirschsprung’s disease – Pathophysiology – TeachMePaediatrics

  https://teachmepaediatrics.com/surgery/abdominal/hirschsprungs-disease/

  Hischsprungs disease is where ganglionic cells of the myenteric and submucosal plexuses in the bowel aren’t present proximally from the anus to a variable length along the large intestine. The most common accepted aetiology of this disease is due to the arrest of the neuroblast, derived from neural crest cell migration in fetal development between week 8 to 12. It is also accepted that sometimes normal cell migration occurs but the neuroblast fails to properly develop due to apoptosis, improper differentiation, or failure in proliferation. The aganglionic segment remains in a tonic state leading to failure in peristalsis and bowel movements. Faeces in the rectum fail to trigger relaxation of the internal anal sphincter, due to aganglionosis. The accumulation of faeces in the rectosigmoid region is responsible for the functional obstruction, which is the cause of many of the symptoms. Increased intraluminal pressure can lead to decreased blood flow and deterioration in the mucosal layer. This stasis can lead to bacterial proliferation and the subsequent complication of Hirschsprungs enterocolitis, which has a mortality rate of 25-30%. If not recognised early this can lead to sepsis and death. […] The strongest association with Hirschsprungs, is the Receptor tyrosine kinase (RET) gene, a proto-oncogene on chromosome 10q11. HD is strongly associated with chromosomal abnormalities, with 10-15% HD cases associated with trisomy 21 (Down Syndrome).

• #57 Hirschsprung’s disease – Pathophysiology – TeachMePaediatrics

  https://teachmepaediatrics.com/surgery/abdominal/hirschsprungs-disease/

  Hischsprungs disease is where ganglionic cells of the myenteric and submucosal plexuses in the bowel aren’t present proximally from the anus to a variable length along the large intestine. The most common accepted aetiology of this disease is due to the arrest of the neuroblast, derived from neural crest cell migration in fetal development between week 8 to 12. It is also accepted that sometimes normal cell migration occurs but the neuroblast fails to properly develop due to apoptosis, improper differentiation, or failure in proliferation. The aganglionic segment remains in a tonic state leading to failure in peristalsis and bowel movements. Faeces in the rectum fail to trigger relaxation of the internal anal sphincter, due to aganglionosis. The accumulation of faeces in the rectosigmoid region is responsible for the functional obstruction, which is the cause of many of the symptoms. Increased intraluminal pressure can lead to decreased blood flow and deterioration in the mucosal layer. This stasis can lead to bacterial proliferation and the subsequent complication of Hirschsprungs enterocolitis, which has a mortality rate of 25-30%. If not recognised early this can lead to sepsis and death. […] The strongest association with Hirschsprungs, is the Receptor tyrosine kinase (RET) gene, a proto-oncogene on chromosome 10q11. HD is strongly associated with chromosomal abnormalities, with 10-15% HD cases associated with trisomy 21 (Down Syndrome).

• #58 Hirschsprung disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/hirschsprung-disease/

  Hirschsprung disease is an intestinal disorder characterized by the absence of nerves in parts of the intestine. This condition occurs when the nerves in the intestine (enteric nerves) do not form properly during development before birth (embryonic development). […] Enteric nerves trigger the muscle contractions that move stool through the intestine. Without these nerves in parts of the intestine, the material cannot be pushed through, causing severe constipation or complete blockage of the intestine in people with Hirschsprung disease. […] Isolated Hirschsprung disease can result from mutations in one of several genes, including the RET, EDNRB, and EDN3 genes. However, the genetics of this condition appear complex and are not completely understood. […] Mutations in the RET gene are the most common known genetic cause of Hirschsprung disease. The RET gene provides instructions for producing a protein that is involved in signaling within cells. This protein appears to be essential for the normal development of several kinds of nerve cells, including nerves in the intestine.

• #59 Stem cell-based therapy for hirschsprung disease, do we have the guts to treat? | Gene Therapy

  https://www.nature.com/articles/s41434-021-00268-4

  To date, around 21 genes were pinpointed in HSCR that code for proteins involved in NCC functions and ENS development pathways. […] The RET proto-oncogene (OMIM 164761) was found to be the major contributor to the disease phenotype, with more than 200 RET loss-of-function mutations linked to ~20% of the sporadic as well as up to half of the familial forms of the disease. […] Epigenetic modifications were also investigated in the context of ENS development and HSCR pathogenesis. […] The susceptibility of the distal colon in HSCR in particular is not fully understood. However, the fact that NCC migration is rostrocaudal indicates a failure of maintenance of the progenitor pool. […] The GDNF/RET signaling system is composed of Glial cell-derived neurotrophic factor (GDNF) that is secreted by the gut mesoderm and interacts with the tyrosine kinase RET receptor and GDNF family receptor 1 (GFR1) receptor that are present in the ENCC.

• #60 Stem cell-based therapy for hirschsprung disease, do we have the guts to treat? | Gene Therapy

  https://www.nature.com/articles/s41434-021-00268-4

  GDNF/RET signaling plays a role in chemotaxis of ENCC to migrate distally. Moreover, it promotes proliferation by acting as a mitogenic factor to ensure an adequate ENCC pool. […] In subsequent phases, GDNF/RET promotes neuronal differentiation. […] ET3/EDNRB pathway is comprised of Endothelin-3 (ET3) that is secreted by the gut mesoderm to bind to EDNRB protein in the ENCC. This signaling pathway maintains ENCC progenitors in an undifferentiated state, allowing them to migrate and fully colonize the gut.

• #61 Hirschsprung disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/hirschsprung-disease/

  Mutations in the RET gene that cause Hirschsprung disease result in a nonfunctional version of the RET protein that cannot transmit signals within cells. Without RET protein signaling, enteric nerves do not develop properly. Absence of these nerves leads to the intestinal problems characteristic of Hirschsprung disease. […] Changes in either the EDNRB gene or the EDN3 gene disrupt the normal functioning of the endothelin receptor type B or the endothelin 3 protein, preventing them from transmitting signals important for the development of enteric nerves. As a result, these nerves do not form normally during embryonic development. A lack of enteric nerves prevents stool from being moved through the intestine, leading to severe constipation and intestinal blockage.

• #62 Stem cell-based therapy for hirschsprung disease, do we have the guts to treat? | Gene Therapy

  https://www.nature.com/articles/s41434-021-00268-4

  To date, around 21 genes were pinpointed in HSCR that code for proteins involved in NCC functions and ENS development pathways. […] The RET proto-oncogene (OMIM 164761) was found to be the major contributor to the disease phenotype, with more than 200 RET loss-of-function mutations linked to ~20% of the sporadic as well as up to half of the familial forms of the disease. […] Epigenetic modifications were also investigated in the context of ENS development and HSCR pathogenesis. […] The susceptibility of the distal colon in HSCR in particular is not fully understood. However, the fact that NCC migration is rostrocaudal indicates a failure of maintenance of the progenitor pool. […] The GDNF/RET signaling system is composed of Glial cell-derived neurotrophic factor (GDNF) that is secreted by the gut mesoderm and interacts with the tyrosine kinase RET receptor and GDNF family receptor 1 (GFR1) receptor that are present in the ENCC.

• #63 The Hirschsprung’s–multiple endocrine neoplasia connection | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-the-hirschsprung39smultiple-endocrine-neoplasia-connection-S1807593222023985

  The presence of a HSCRMEN2 association raises the question of which HSCR patients are at greatest risk and should therefore be further investigated by RET gene analysis. […] The most frequently identified mutation responsible for MEN2A involves the substitution of the cysteine amino acid at position 634 (Cys634Arg or C634R) by the amino acid arginine. […] The cosegregation of HSCR and MEN2 is particularly interesting as it involves both a switch off and a switch on of the gene in the same patient. […] It is therefore fairly clear that RET gene screening is of considerable value in familial screening, and offering RET testing is considered best practice for the clinical management of patients at risk of MEN2A and MEN2B.

• #64 The Hirschsprung’s–multiple endocrine neoplasia connection | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-the-hirschsprung39smultiple-endocrine-neoplasia-connection-S1807593222023985

  The presence of a HSCRMEN2 association raises the question of which HSCR patients are at greatest risk and should therefore be further investigated by RET gene analysis. […] The most frequently identified mutation responsible for MEN2A involves the substitution of the cysteine amino acid at position 634 (Cys634Arg or C634R) by the amino acid arginine. […] The cosegregation of HSCR and MEN2 is particularly interesting as it involves both a switch off and a switch on of the gene in the same patient. […] It is therefore fairly clear that RET gene screening is of considerable value in familial screening, and offering RET testing is considered best practice for the clinical management of patients at risk of MEN2A and MEN2B.

• #65 The Developmental Etiology and Pathogenesis of Hirschsprung disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3691347/

  Different populations of ENCCs exhibit different migration behaviors depending on their position along the migratory trail. […] Many genes contribute to normal enteric neural crest cell migration and the formation of a functional enteric nervous system, and mutations in any of these genes may cause an HSCR phenotype. […] Endothelin signaling is also necessary for normal ENCC migration and may help maintain a permissive NCC environment. […] The EDN3-EDNRB signaling pathway is not only involved with regulating ENCC migration, but also plays a role in maintaining the enteric progenitors in a proliferative state. […] The balance between retinoic acid synthesis and catabolism is critical to regulate the precise spatiotemporal domains of retinoid signaling during embryogenesis. […] Although these studies suggest a role for retinoid signaling in the pathogenesis of colonic aganglionosis, the HSCR phenotype in the Rbp4/ mice is only observed in response to a vitamin A deficient diet, creating a somewhat artificial situation.

• #66 The Developmental Etiology and Pathogenesis of Hirschsprung disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3691347/

  Different populations of ENCCs exhibit different migration behaviors depending on their position along the migratory trail. […] Many genes contribute to normal enteric neural crest cell migration and the formation of a functional enteric nervous system, and mutations in any of these genes may cause an HSCR phenotype. […] Endothelin signaling is also necessary for normal ENCC migration and may help maintain a permissive NCC environment. […] The EDN3-EDNRB signaling pathway is not only involved with regulating ENCC migration, but also plays a role in maintaining the enteric progenitors in a proliferative state. […] The balance between retinoic acid synthesis and catabolism is critical to regulate the precise spatiotemporal domains of retinoid signaling during embryogenesis. […] Although these studies suggest a role for retinoid signaling in the pathogenesis of colonic aganglionosis, the HSCR phenotype in the Rbp4/ mice is only observed in response to a vitamin A deficient diet, creating a somewhat artificial situation.

• #67 Stem cell-based therapy for hirschsprung disease, do we have the guts to treat? | Gene Therapy

  https://www.nature.com/articles/s41434-021-00268-4

  GDNF/RET signaling plays a role in chemotaxis of ENCC to migrate distally. Moreover, it promotes proliferation by acting as a mitogenic factor to ensure an adequate ENCC pool. […] In subsequent phases, GDNF/RET promotes neuronal differentiation. […] ET3/EDNRB pathway is comprised of Endothelin-3 (ET3) that is secreted by the gut mesoderm to bind to EDNRB protein in the ENCC. This signaling pathway maintains ENCC progenitors in an undifferentiated state, allowing them to migrate and fully colonize the gut.

• #68 Hirschsprung disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/hirschsprung-disease/

  Mutations in the RET gene that cause Hirschsprung disease result in a nonfunctional version of the RET protein that cannot transmit signals within cells. Without RET protein signaling, enteric nerves do not develop properly. Absence of these nerves leads to the intestinal problems characteristic of Hirschsprung disease. […] Changes in either the EDNRB gene or the EDN3 gene disrupt the normal functioning of the endothelin receptor type B or the endothelin 3 protein, preventing them from transmitting signals important for the development of enteric nerves. As a result, these nerves do not form normally during embryonic development. A lack of enteric nerves prevents stool from being moved through the intestine, leading to severe constipation and intestinal blockage.

• #69 Hirschsprung’s disease: clinical dysmorphology, genes, micro-RNAs, and future perspectives | Pediatric Research

  https://www.nature.com/articles/pr2016202

  The complex genetic etiology, which entangles HSCR, is intriguing and linked with mutations in the genes that encode mostly signaling molecules crucial for the proper development of the ENS. […] The most important genes and pathways that have been investigated include: Glial cell-derived pathway genes (RET, GDNF, NTN, SOX10, PHOX2b), Endothelin pathway genes (EDN3, EDNRB, SOX10), and TGF signaling pathway genes (ZFHX1B). […] The mechanism behind these interactions is not yet fully known, but Ret and Ednrb might interact by activating common downstream signaling molecules. […] The complex process of how ENS development leads to adequate function of the gastrointestinal tract is far from being understood. […] EDNRB and SOX10 are components of signaling cascades that are critical to the development of the ENS together with RET-GDNF signaling.

• #70 Hirschsprung’s disease: clinical dysmorphology, genes, micro-RNAs, and future perspectives | Pediatric Research

  https://www.nature.com/articles/pr2016202

  The complex genetic etiology, which entangles HSCR, is intriguing and linked with mutations in the genes that encode mostly signaling molecules crucial for the proper development of the ENS. […] The most important genes and pathways that have been investigated include: Glial cell-derived pathway genes (RET, GDNF, NTN, SOX10, PHOX2b), Endothelin pathway genes (EDN3, EDNRB, SOX10), and TGF signaling pathway genes (ZFHX1B). […] The mechanism behind these interactions is not yet fully known, but Ret and Ednrb might interact by activating common downstream signaling molecules. […] The complex process of how ENS development leads to adequate function of the gastrointestinal tract is far from being understood. […] EDNRB and SOX10 are components of signaling cascades that are critical to the development of the ENS together with RET-GDNF signaling.

• #71 “Too much guts and not enough brains”: (epi)genetic mechanisms and future therapies of Hirschsprung disease — a review | Clinical Epigenetics | Full Text

  https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0718-x

  Hirschsprung disease is a neurocristopathy, characterized by aganglionosis in the distal bowel. It is caused by failure of the enteric nervous system progenitors to migrate, proliferate, and differentiate in the gut. […] Hence, alterations in expression of genes specific for the enteric nervous system may contribute to the pathogenesis of Hirschsprungs disease. Several epigenetic mechanisms contribute to regulate gene expression, such as modifications of DNA and RNA, histone modifications, and microRNAs. […] The genetic background of HSCR is complex. […] The ganglion cells of the enteric nervous system (ENS) are entirely derived from the neural crest which is a transient, multipotent cell population originating from the neural tube. […] Several genes are associated with ENS development, thereby also in the pathogenesis of HSCR disease. RET is identified as the main HSCR gene as the RET mutation is found in 50% of familial and 1520% of sporadic HSCR cases.

• #72 The Developmental Etiology and Pathogenesis of Hirschsprung disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3691347/

  Different populations of ENCCs exhibit different migration behaviors depending on their position along the migratory trail. […] Many genes contribute to normal enteric neural crest cell migration and the formation of a functional enteric nervous system, and mutations in any of these genes may cause an HSCR phenotype. […] Endothelin signaling is also necessary for normal ENCC migration and may help maintain a permissive NCC environment. […] The EDN3-EDNRB signaling pathway is not only involved with regulating ENCC migration, but also plays a role in maintaining the enteric progenitors in a proliferative state. […] The balance between retinoic acid synthesis and catabolism is critical to regulate the precise spatiotemporal domains of retinoid signaling during embryogenesis. […] Although these studies suggest a role for retinoid signaling in the pathogenesis of colonic aganglionosis, the HSCR phenotype in the Rbp4/ mice is only observed in response to a vitamin A deficient diet, creating a somewhat artificial situation.

• #73 The Developmental Etiology and Pathogenesis of Hirschsprung disease

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3691347/

  Proper neural crest cell migration, proliferation, differentiation, survival, and apoptosis all contribute to a functional ENS. Perturbation in any of these processes can lead to a Hirschsprung disease phenotype. […] Many genes which play a critical functional role in neural crest cell development have been implicated in HSCR, including the proto-oncogene RET, endothelin signaling genes, and transcription factors. […] Although over a dozen genes have been identified that contribute to the etiology of HSCR, these pathways only account for about half of the known cases. […] The ENS is derived from migratory neural crest cells which originate at the vagal (somites 17) and sacral (caudal to somite 24) regions of the embryonic axis. […] During migration, chains of interconnected neural crest cells at the leading edge of the population are referred to as the wavefront.

• #74 Hirschsprung’s disease: clinical dysmorphology, genes, micro-RNAs, and future perspectives | Pediatric Research

  https://www.nature.com/articles/pr2016202

  The complex genetic etiology, which entangles HSCR, is intriguing and linked with mutations in the genes that encode mostly signaling molecules crucial for the proper development of the ENS. […] The most important genes and pathways that have been investigated include: Glial cell-derived pathway genes (RET, GDNF, NTN, SOX10, PHOX2b), Endothelin pathway genes (EDN3, EDNRB, SOX10), and TGF signaling pathway genes (ZFHX1B). […] The mechanism behind these interactions is not yet fully known, but Ret and Ednrb might interact by activating common downstream signaling molecules. […] The complex process of how ENS development leads to adequate function of the gastrointestinal tract is far from being understood. […] EDNRB and SOX10 are components of signaling cascades that are critical to the development of the ENS together with RET-GDNF signaling.

• #75 Hirschsprung Disease: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/178493-overview

  One possible etiology of Hirschsprung disease is the arrest of aboral neuroblast migration. Alternatively, although normal cell migration may occur, neuroblasts may be subject to apoptosis, failure of proliferation, or improper differentiation within the affected distal intestinal segment. Fibronectin, laminin, neural cell adhesion molecule (NCAM), and neurotrophic factors present in the intestinal stroma are necessary for normal enteric ganglion development, whereas their absence or dysfunction may also have a role in the etiology of Hirschsprung disease. […] Investigators have also identified several genes whose improper expression results in a Hirschsprung disease phenotype. Genome-wide association studies (GWAS) in Europeans and Asians have identified three common disease-susceptibility variants at the RET, SEMA3, and NRG1 loci.

• #76 Hirschsprung disease: current perspectives | OAS

  https://www.dovepress.com/hirschsprung-disease-current-perspectives-peer-reviewed-fulltext-article-OAS

  The reason for the incomplete migration and development of ganglion cells is as yet not fully understood. […] HSCR is known to be a congenitally determined, sex-modified multifactorial condition, which arises largely from a multigenetic malfunction of ENS development. […] The best example to date lies in the additional susceptibility gene for semaphorin 3A, which results in signaling pathway dysfunction in conjunction with a variant in Ret, leading to malfunction and disease. […] It has long been recognized as presenting particular problems in diagnosis and management. […] It is not yet clear whether TCA merely represents a long form of HSCR or a different expression of the disease, but its nature suggests a different pathophysiology from the more common forms of HSCR. […] Genetic factors are known to be implicated in HSCR pathogenesis. However, the pattern of inheritance remains unclear, and variable Mendelian inheritance with autosomal dominant, recessive, and multigenic patterns being reported.

• #77 Hirschsprung Disease: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/178493-overview

  One possible etiology of Hirschsprung disease is the arrest of aboral neuroblast migration. Alternatively, although normal cell migration may occur, neuroblasts may be subject to apoptosis, failure of proliferation, or improper differentiation within the affected distal intestinal segment. Fibronectin, laminin, neural cell adhesion molecule (NCAM), and neurotrophic factors present in the intestinal stroma are necessary for normal enteric ganglion development, whereas their absence or dysfunction may also have a role in the etiology of Hirschsprung disease. […] Investigators have also identified several genes whose improper expression results in a Hirschsprung disease phenotype. Genome-wide association studies (GWAS) in Europeans and Asians have identified three common disease-susceptibility variants at the RET, SEMA3, and NRG1 loci.

• #78 Hirschsprung’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Hirschsprung%27s_disease

  Hirschsprung’s disease (HD or HSCR) is a birth defect in which nerves are missing from parts of the intestine. […] The disorder may occur by itself or in association with other genetic disorders such as Down syndrome. About half of isolated cases are linked to a specific genetic mutation, and about 20% occur within families. Some of these occur in an autosomal dominant manner. The cause of the remaining cases is unclear. […] The most accepted theory of the cause of Hirschsprung is a defect in the craniocaudal migration of neuroblasts originating from the neural crest that occurs during the first 12 weeks of gestation. Defects in the differentiation of neuroblasts into ganglion cells and accelerated ganglion cell destruction within the intestine may also contribute to the disorder. […] This lack of ganglion cells in the myenteric and submucosal plexus is well documented in Hirschsprung’s disease.

• #79 Hirschsprung’s disease – Pathophysiology – TeachMePaediatrics

  https://teachmepaediatrics.com/surgery/abdominal/hirschsprungs-disease/

  Hischsprungs disease is where ganglionic cells of the myenteric and submucosal plexuses in the bowel aren’t present proximally from the anus to a variable length along the large intestine. The most common accepted aetiology of this disease is due to the arrest of the neuroblast, derived from neural crest cell migration in fetal development between week 8 to 12. It is also accepted that sometimes normal cell migration occurs but the neuroblast fails to properly develop due to apoptosis, improper differentiation, or failure in proliferation. The aganglionic segment remains in a tonic state leading to failure in peristalsis and bowel movements. Faeces in the rectum fail to trigger relaxation of the internal anal sphincter, due to aganglionosis. The accumulation of faeces in the rectosigmoid region is responsible for the functional obstruction, which is the cause of many of the symptoms. Increased intraluminal pressure can lead to decreased blood flow and deterioration in the mucosal layer. This stasis can lead to bacterial proliferation and the subsequent complication of Hirschsprungs enterocolitis, which has a mortality rate of 25-30%. If not recognised early this can lead to sepsis and death. […] The strongest association with Hirschsprungs, is the Receptor tyrosine kinase (RET) gene, a proto-oncogene on chromosome 10q11. HD is strongly associated with chromosomal abnormalities, with 10-15% HD cases associated with trisomy 21 (Down Syndrome).

• #80 A collagen VI–dependent pathogenic mechanism for Hirschsprung’s disease – Inserm – Institut national de la santé et de la recherche médicale

  https://inserm.hal.science/hal-04166667v1

  Collectively, our data thus unveil a clinically relevant pathogenic mechanism for HSCR that involves cell-autonomous changes in ECM composition surrounding eNCCs. […] Moreover, as COL6A1 and COL6A2 are on human Chr.21q, this mechanism is highly relevant to the predisposition of patients with Down syndrome to HSCR.

• #81 A collagen VI–dependent pathogenic mechanism for Hirschsprung’s disease – Inserm – Institut national de la santé et de la recherche médicale

  https://inserm.hal.science/hal-04166667v1

  Hirschsprung’s disease (HSCR) is a severe congenital anomaly of the enteric nervous system (ENS) characterized by functional intestinal obstruction due to a lack of intrinsic innervation in the distal bowel. […] Distal innervation deficiency results from incomplete colonization of the bowel by enteric neural crest cells (eNCCs), the ENS precursors. […] This insertion induces eNCC-specific upregulation of Col6a4 expression that increases total collagen VI protein levels in the extracellular matrix (ECM) surrounding both the developing and the postnatal ENS. […] Increased collagen VI levels during development mainly result in slower migration of eNCCs. […] Importantly, for a majority of patients in a HSCR cohort, the myenteric ganglia from the ganglionated region are also specifically surrounded by abundant collagen VI microfibrils, an outcome accentuated by Down syndrome.

• #82 A collagen VI–dependent pathogenic mechanism for Hirschsprung’s disease – Inserm – Institut national de la santé et de la recherche médicale

  https://inserm.hal.science/hal-04166667v1

  Hirschsprung’s disease (HSCR) is a severe congenital anomaly of the enteric nervous system (ENS) characterized by functional intestinal obstruction due to a lack of intrinsic innervation in the distal bowel. […] Distal innervation deficiency results from incomplete colonization of the bowel by enteric neural crest cells (eNCCs), the ENS precursors. […] This insertion induces eNCC-specific upregulation of Col6a4 expression that increases total collagen VI protein levels in the extracellular matrix (ECM) surrounding both the developing and the postnatal ENS. […] Increased collagen VI levels during development mainly result in slower migration of eNCCs. […] Importantly, for a majority of patients in a HSCR cohort, the myenteric ganglia from the ganglionated region are also specifically surrounded by abundant collagen VI microfibrils, an outcome accentuated by Down syndrome.

• #83

  https://www.jci.org/articles/view/85003

  Hirschsprungs disease (HSCR) is a severe congenital anomaly of the enteric nervous system (ENS) characterized by functional intestinal obstruction due to a lack of intrinsic innervation in the distal bowel. […] Increased collagen VI levels during development mainly result in slower migration of eNCCs. […] Importantly, for a majority of patients in a HSCR cohort, the myenteric ganglia from the ganglionated region are also specifically surrounded by abundant collagen VI microfibrils, an outcome accentuated by Down syndrome. […] The hypothesis that increased collagen VI production by migrating ENCDCs in children with Down syndrome underlies increased HSCR risk is provocative and interesting. […] Soret et al. next hypothesized that their observations in mice may be relevant for human HSCR and could explain the increased HSCR occurrence in children with Down syndrome. […] Remarkably, collagen VI was more abundant in tissue surrounding myenteric ganglia of children with HSCR compared with that in control specimens (2-fold higher) and present at even higher levels surrounding myenteric ganglia of children with Down syndrome and HSCR (3-fold higher).

• #84 A collagen VI–dependent pathogenic mechanism for Hirschsprung’s disease – Inserm – Institut national de la santé et de la recherche médicale

  https://inserm.hal.science/hal-04166667v1

  Collectively, our data thus unveil a clinically relevant pathogenic mechanism for HSCR that involves cell-autonomous changes in ECM composition surrounding eNCCs. […] Moreover, as COL6A1 and COL6A2 are on human Chr.21q, this mechanism is highly relevant to the predisposition of patients with Down syndrome to HSCR.

• #85 Pediatric Hirschsprung Disease: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/929733-overview

  Hirschsprung disease results from the absence of enteric neurons within the myenteric and submucosal plexus of the rectum and/or colon. […] Enteric neurons are derived from the neural crest and migrate caudally with the vagal nerve fibers along the intestine. […] Arrest in migration leads to an aganglionic segment. This results in clinical Hirschsprung disease. […] Mutations in the Ret proto-oncogene have been associated with multiple endocrine neoplasia (MEN) 2A or MEN 2B and familial Hirschsprung disease. […] Other genes associated with Hirschsprung disease include the glial cell-derived neurotrophic factor gene, the endothelin-B receptor gene, and the endothelin-3 gene. […] Hirschsprung’s disease genes and the development of the enteric nervous system.

• #86 The Hirschsprung’s–multiple endocrine neoplasia connection | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-the-hirschsprung39smultiple-endocrine-neoplasia-connection-S1807593222023985

  The risk of patients with Hirschsprung’s disease later developing multiple endocrine neoplasia remains a matter of concern. […] The main susceptibility gene for Hirschsprung’s disease is the RET (rearranged during transfection) proto-oncogene tyrosine kinase which is situated at chromosome 10q11.2. […] It is generally accepted that aberrant RET protein synthesis, due to inactivating genetic variations, lead to the congenital malformation of the enteric nervous system (ENS) which we call Hirschsprung’s disease. […] The RET proto-oncogene [10q11.22] is the major gene involved in the pathogenesis of HSCR with causative loss-of-function mutations being identified in more than 70% of cases. […] Genetic mutation and/or variation may result in RET malfunction, which has been associated with at least four clinical conditions (HSCR, MEN type 2 syndromes (A and B) and familial medullary thyroid carcinoma (FMTC).

• #87 The Hirschsprung’s–multiple endocrine neoplasia connection | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-the-hirschsprung39smultiple-endocrine-neoplasia-connection-S1807593222023985

  The presence of a HSCRMEN2 association raises the question of which HSCR patients are at greatest risk and should therefore be further investigated by RET gene analysis. […] The most frequently identified mutation responsible for MEN2A involves the substitution of the cysteine amino acid at position 634 (Cys634Arg or C634R) by the amino acid arginine. […] The cosegregation of HSCR and MEN2 is particularly interesting as it involves both a switch off and a switch on of the gene in the same patient. […] It is therefore fairly clear that RET gene screening is of considerable value in familial screening, and offering RET testing is considered best practice for the clinical management of patients at risk of MEN2A and MEN2B.

• #88 The Hirschsprung’s–multiple endocrine neoplasia connection | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-the-hirschsprung39smultiple-endocrine-neoplasia-connection-S1807593222023985

  The presence of a HSCRMEN2 association raises the question of which HSCR patients are at greatest risk and should therefore be further investigated by RET gene analysis. […] The most frequently identified mutation responsible for MEN2A involves the substitution of the cysteine amino acid at position 634 (Cys634Arg or C634R) by the amino acid arginine. […] The cosegregation of HSCR and MEN2 is particularly interesting as it involves both a switch off and a switch on of the gene in the same patient. […] It is therefore fairly clear that RET gene screening is of considerable value in familial screening, and offering RET testing is considered best practice for the clinical management of patients at risk of MEN2A and MEN2B.

• #89 The Hirschsprung’s–multiple endocrine neoplasia connection | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-the-hirschsprung39smultiple-endocrine-neoplasia-connection-S1807593222023985

  The presence of a HSCRMEN2 association raises the question of which HSCR patients are at greatest risk and should therefore be further investigated by RET gene analysis. […] The most frequently identified mutation responsible for MEN2A involves the substitution of the cysteine amino acid at position 634 (Cys634Arg or C634R) by the amino acid arginine. […] The cosegregation of HSCR and MEN2 is particularly interesting as it involves both a switch off and a switch on of the gene in the same patient. […] It is therefore fairly clear that RET gene screening is of considerable value in familial screening, and offering RET testing is considered best practice for the clinical management of patients at risk of MEN2A and MEN2B.

• #90 Hirschsprung’s Disease—Recent Understanding of Embryonic Aspects, Etiopathogenesis and Future Treatment Avenues

  https://www.mdpi.com/1648-9144/56/11/611

  A mutation in these crucial genes makes it impossible for ENCCs to migrate and further develop in precise and timely manner. […] Although the genetics of HSCR pathogenesis is solidly understood, it elucidates roughly 50% of all cases. […] One such factor is the aforementioned retinoic acid signalling. […] The disruption of these two pathways at the same time thus has a synergic action. […] The study of HSCR in the context of these syndromes has greatly contributed to the understanding of its genetics. […] The most frequent and well-described individual anomalies in patients with HSCR are, in descending order, gastrointestinal, CNS, genitourinary, musculoskeletal, cardiovascular, craniofacial and integumentary anomalies. […] There is a high probability that the disturbances of ICCs are co-responsible for its development. […] The precise role of MCs in the HSCR pathogenesis in not yet understood.

• #91 Hirschsprung’s Disease—Recent Understanding of Embryonic Aspects, Etiopathogenesis and Future Treatment Avenues

  https://www.mdpi.com/1648-9144/56/11/611

  A mutation in these crucial genes makes it impossible for ENCCs to migrate and further develop in precise and timely manner. […] Although the genetics of HSCR pathogenesis is solidly understood, it elucidates roughly 50% of all cases. […] One such factor is the aforementioned retinoic acid signalling. […] The disruption of these two pathways at the same time thus has a synergic action. […] The study of HSCR in the context of these syndromes has greatly contributed to the understanding of its genetics. […] The most frequent and well-described individual anomalies in patients with HSCR are, in descending order, gastrointestinal, CNS, genitourinary, musculoskeletal, cardiovascular, craniofacial and integumentary anomalies. […] There is a high probability that the disturbances of ICCs are co-responsible for its development. […] The precise role of MCs in the HSCR pathogenesis in not yet understood.

• #92 Update on the Pathogenesis of the Hirschsprung-Associated Enterocolitis

  https://www.mdpi.com/1422-0067/24/5/4602

  Hirschsprung-associated enterocolitis (HAEC) is the leading cause of serious morbidity and mortality in patients with Hirschsprung disease (HSCR). […] One of the leading causes or risk factors for HAEC has been considered to be partial mechanical obstruction. […] However, HAEC also occurs in patients with enterostomy, and without any evidence of obstruction. Therefore, other factors must be involved. […] On the other hand, since the comprehensive review by Demehri, basic research on HAEC has made marked progress in terms of increasing the knowledge base, especially with respect to studies on genes, the microbiome, immunity, and other aspects. […] Taken together, the above studies have suggested that the pathogenesis of HAEC is closely associated with the underlying genes and the genetic background, although the specific mechanism(s) involved still require further study.

• #93 Update on the Pathogenesis of the Hirschsprung-Associated Enterocolitis

  https://www.mdpi.com/1422-0067/24/5/4602

  Hirschsprung-associated enterocolitis (HAEC) is the leading cause of serious morbidity and mortality in patients with Hirschsprung disease (HSCR). […] One of the leading causes or risk factors for HAEC has been considered to be partial mechanical obstruction. […] However, HAEC also occurs in patients with enterostomy, and without any evidence of obstruction. Therefore, other factors must be involved. […] On the other hand, since the comprehensive review by Demehri, basic research on HAEC has made marked progress in terms of increasing the knowledge base, especially with respect to studies on genes, the microbiome, immunity, and other aspects. […] Taken together, the above studies have suggested that the pathogenesis of HAEC is closely associated with the underlying genes and the genetic background, although the specific mechanism(s) involved still require further study.

• #94 Update on the Pathogenesis of the Hirschsprung-Associated Enterocolitis

  https://www.mdpi.com/1422-0067/24/5/4602

  The mucosal barrier serves as the first line of defense, protecting the healthy intestinal surface from adhesion and invasion by tubular microorganisms. […] Numerous studies have shown that structural defects and dysfunction of the intestinal mucosal barrier are responsible for the pathogenesis of HAEC. […] In conclusion, these studies have shown that dysfunction of GCs and reduced secretion of mucin lead to damage of the intestinal mucosal barrier, thereby leading to the development of HAEC. […] The abnormal ENS of HSCR leads to impaired intestinal motility, resulting in functional obstruction with subsequent stasis and overgrowth of pathogenic intestinal bacteria, destruction of the mucosal layer, invasion of the intestinal wall, dysfunction of the intestinal mucosal barrier, impaired immune response and consequent HAEC.

• #95 Update on the Pathogenesis of the Hirschsprung-Associated Enterocolitis

  https://www.mdpi.com/1422-0067/24/5/4602

  The mucosal barrier serves as the first line of defense, protecting the healthy intestinal surface from adhesion and invasion by tubular microorganisms. […] Numerous studies have shown that structural defects and dysfunction of the intestinal mucosal barrier are responsible for the pathogenesis of HAEC. […] In conclusion, these studies have shown that dysfunction of GCs and reduced secretion of mucin lead to damage of the intestinal mucosal barrier, thereby leading to the development of HAEC. […] The abnormal ENS of HSCR leads to impaired intestinal motility, resulting in functional obstruction with subsequent stasis and overgrowth of pathogenic intestinal bacteria, destruction of the mucosal layer, invasion of the intestinal wall, dysfunction of the intestinal mucosal barrier, impaired immune response and consequent HAEC.

• #96 Update on the Pathogenesis of the Hirschsprung-Associated Enterocolitis

  https://www.mdpi.com/1422-0067/24/5/4602

  The mucosal barrier serves as the first line of defense, protecting the healthy intestinal surface from adhesion and invasion by tubular microorganisms. […] Numerous studies have shown that structural defects and dysfunction of the intestinal mucosal barrier are responsible for the pathogenesis of HAEC. […] In conclusion, these studies have shown that dysfunction of GCs and reduced secretion of mucin lead to damage of the intestinal mucosal barrier, thereby leading to the development of HAEC. […] The abnormal ENS of HSCR leads to impaired intestinal motility, resulting in functional obstruction with subsequent stasis and overgrowth of pathogenic intestinal bacteria, destruction of the mucosal layer, invasion of the intestinal wall, dysfunction of the intestinal mucosal barrier, impaired immune response and consequent HAEC.

• #97 Update on the Pathogenesis of the Hirschsprung-Associated Enterocolitis

  https://www.mdpi.com/1422-0067/24/5/4602

  The mucosal barrier serves as the first line of defense, protecting the healthy intestinal surface from adhesion and invasion by tubular microorganisms. […] Numerous studies have shown that structural defects and dysfunction of the intestinal mucosal barrier are responsible for the pathogenesis of HAEC. […] In conclusion, these studies have shown that dysfunction of GCs and reduced secretion of mucin lead to damage of the intestinal mucosal barrier, thereby leading to the development of HAEC. […] The abnormal ENS of HSCR leads to impaired intestinal motility, resulting in functional obstruction with subsequent stasis and overgrowth of pathogenic intestinal bacteria, destruction of the mucosal layer, invasion of the intestinal wall, dysfunction of the intestinal mucosal barrier, impaired immune response and consequent HAEC.

• #98 Update on the Pathogenesis of the Hirschsprung-Associated Enterocolitis

  https://www.mdpi.com/1422-0067/24/5/4602

  This abnormal neurological function is considered to be an important cause of preoperative HAEC episodes. […] In conclusion, HAEC may be associated with reduced cholinergic innervation in the intestinal mucosa, a reduced density of NOS enteric neurons, abnormal receptor expression leading to abnormal neural development, reduced numbers of ICCs, and their phenotypic loss. […] The above studies collectively suggest the involvement of immune organs, immune cells, immunoglobulins, cytokines, inflammasomes, and exosomes in the development of HAEC, which, considered altogether, suggests that a close association exists between the immune system and HAEC. […] There are several hypotheses that have been proposed concerning the pathogenesis of HAEC and the mechanisms that interact with each other, so further research should be comprehensive.

• #99 Hirschsprung’s disease associated enterocolitis: A comprehensive review

  https://www.wjgnet.com/2219-2808/full/v12/i3/68.htm

  One of the initial studies implicating impaired mucosal defense in HSCR evaluated the role of secretory immunoglobulin A (sIgA). […] Other studies have suggested that the production and transport of intestinal mucins may be abnormal in HSCR and may have a potential role in the pathogenesis of HAEC. […] Emerging techniques, like next generation sequencing, have provided novel insight of the human intestinal microbiota, both in health and disease. […] However, most are limited to a small number of samples or differences in technique that demonstrate variation in results. Nevertheless, it seems evident that dysbiosis is part of the pathogenesis in HAEC.

• #100 Hirschsprung’s disease associated enterocolitis: A comprehensive review

  https://www.wjgnet.com/2219-2808/full/v12/i3/68.htm

  One of the initial studies implicating impaired mucosal defense in HSCR evaluated the role of secretory immunoglobulin A (sIgA). […] Other studies have suggested that the production and transport of intestinal mucins may be abnormal in HSCR and may have a potential role in the pathogenesis of HAEC. […] Emerging techniques, like next generation sequencing, have provided novel insight of the human intestinal microbiota, both in health and disease. […] However, most are limited to a small number of samples or differences in technique that demonstrate variation in results. Nevertheless, it seems evident that dysbiosis is part of the pathogenesis in HAEC.

• #101 Update on the Pathogenesis of the Hirschsprung-Associated Enterocolitis

  https://www.mdpi.com/1422-0067/24/5/4602

  This abnormal neurological function is considered to be an important cause of preoperative HAEC episodes. […] In conclusion, HAEC may be associated with reduced cholinergic innervation in the intestinal mucosa, a reduced density of NOS enteric neurons, abnormal receptor expression leading to abnormal neural development, reduced numbers of ICCs, and their phenotypic loss. […] The above studies collectively suggest the involvement of immune organs, immune cells, immunoglobulins, cytokines, inflammasomes, and exosomes in the development of HAEC, which, considered altogether, suggests that a close association exists between the immune system and HAEC. […] There are several hypotheses that have been proposed concerning the pathogenesis of HAEC and the mechanisms that interact with each other, so further research should be comprehensive.

• #102 Hirschsprung’s disease associated enterocolitis: A comprehensive review

  https://www.wjgnet.com/2219-2808/full/v12/i3/68.htm

  One of the initial studies implicating impaired mucosal defense in HSCR evaluated the role of secretory immunoglobulin A (sIgA). […] Other studies have suggested that the production and transport of intestinal mucins may be abnormal in HSCR and may have a potential role in the pathogenesis of HAEC. […] Emerging techniques, like next generation sequencing, have provided novel insight of the human intestinal microbiota, both in health and disease. […] However, most are limited to a small number of samples or differences in technique that demonstrate variation in results. Nevertheless, it seems evident that dysbiosis is part of the pathogenesis in HAEC.

• #103 Hirschsprung’s disease associated enterocolitis: A comprehensive review

  https://www.wjgnet.com/2219-2808/full/v12/i3/68.htm

  One of the initial studies implicating impaired mucosal defense in HSCR evaluated the role of secretory immunoglobulin A (sIgA). […] Other studies have suggested that the production and transport of intestinal mucins may be abnormal in HSCR and may have a potential role in the pathogenesis of HAEC. […] Emerging techniques, like next generation sequencing, have provided novel insight of the human intestinal microbiota, both in health and disease. […] However, most are limited to a small number of samples or differences in technique that demonstrate variation in results. Nevertheless, it seems evident that dysbiosis is part of the pathogenesis in HAEC.

• #104 Update on the Pathogenesis of the Hirschsprung-Associated Enterocolitis

  https://www.mdpi.com/1422-0067/24/5/4602

  This abnormal neurological function is considered to be an important cause of preoperative HAEC episodes. […] In conclusion, HAEC may be associated with reduced cholinergic innervation in the intestinal mucosa, a reduced density of NOS enteric neurons, abnormal receptor expression leading to abnormal neural development, reduced numbers of ICCs, and their phenotypic loss. […] The above studies collectively suggest the involvement of immune organs, immune cells, immunoglobulins, cytokines, inflammasomes, and exosomes in the development of HAEC, which, considered altogether, suggests that a close association exists between the immune system and HAEC. […] There are several hypotheses that have been proposed concerning the pathogenesis of HAEC and the mechanisms that interact with each other, so further research should be comprehensive.

• #105 New mutations associated with Hirschsprung disease | Anales de Pediatría

  https://www.analesdepediatria.org/en-new-mutations-associated-with-hirschsprung-articulo-S2341287920300065

  Describing mutations associated to HSCR, such as the ones found in this study, has a double implication. Firstly, it has a direct clinical implication: mutations associated to HSCR need to be known so that, when found in other patients, clinicians are aware that they are the cause of the disease and not an incidental finding, and know the exact location of the mutation in the gene, which allows knowing whether it is associated with syndromes or other diseases. […] Secondly, increasing the knowledge of the genetic basis of HSCR might contribute to an improved understanding of the pathogenesis of the disease in the future.

• #106 New mutations associated with Hirschsprung disease | Anales de Pediatría

  https://www.analesdepediatria.org/en-new-mutations-associated-with-hirschsprung-articulo-S2341287920300065

  Describing mutations associated to HSCR, such as the ones found in this study, has a double implication. Firstly, it has a direct clinical implication: mutations associated to HSCR need to be known so that, when found in other patients, clinicians are aware that they are the cause of the disease and not an incidental finding, and know the exact location of the mutation in the gene, which allows knowing whether it is associated with syndromes or other diseases. […] Secondly, increasing the knowledge of the genetic basis of HSCR might contribute to an improved understanding of the pathogenesis of the disease in the future.

• #107 “Too much guts and not enough brains”: (epi)genetic mechanisms and future therapies of Hirschsprung disease — a review | Clinical Epigenetics | Full Text

  https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0718-x

  Both DNMT3B and MeCP2 expression are decreased in neural stem cells obtained from HSCR patients, which result in a decrease of global DNA methylation. This may contribute to an aberrant expression pattern of HSCR-associated genes. […] Several HSCR-associated genes are regulated by the methylation degree of their promoter areas. One of these genes is RET, and it has been suggested that the level of RET expression determines the length of the aganglionic segment. […] Thus, aberrant methylation patterns resulting in epigenetic inactivation or overactivation of HSCR-associated genes are implicated in the development of HSCR. […] The role of histone modifications is of critical importance in CNS development. ENS development may be regulated by the same mechanisms, and if that is the case, then HSCR pathogenesis could be linked to histone modifications. […] Histone modifications enhance or silence transcription of specific genomic regions and may also apply to HSCR-associated genes such as RET. […] In HSCR patients with aberrant epigenetic patterns, these could be potentially corrected pharmacologically.

• #108 Stem cell-based therapy for hirschsprung disease, do we have the guts to treat? | Gene Therapy

  https://www.nature.com/articles/s41434-021-00268-4

  Hirschsprung disease (HSCR) is a congenital anomaly of the colon that results from failure of enteric nervous system formation, leading to a constricted dysfunctional segment of the colon with variable lengths, and necessitating surgical intervention. […] The underlying pathophysiology includes a defect in neural crest cells migration, proliferation and differentiation, which are partially explained by identified genetic and epigenetic alterations. […] The primary pathology in HSCR is the failure of proper ENS formation, leading to a constricted dysfunctional segment of the bowel that causes fecal obstruction. This defect often arises from genetic defects in the pathways responsible for ENCC migration, proliferation, differentiation and survival. […] Nevertheless, studied cases revealed single, multiple or even no detected genetic defects, as well as the involvement of environmental factors, affirming the diseases complex and multifactorial nature.

• #109

  https://www.jci.org/articles/view/83178

  The composition of the extracellular matrix (ECM) is another important factor that can influence gut colonization by eNCCs and might thus contribute to HSCR pathogenesis. […] Our data thus unveil a clinically relevant pathogenic mechanism for HSCR that involves cell-autonomous changes in ECM composition surrounding eNCCs. […] This cumulative work suggests that the ECM of the gut wall is a major player in ENS formation. Targeting this previously overlooked aspect of ENS development could have clinical relevance for the cell-based therapies currently being developed for treatment of enteric neuropathies. […] Our previous analysis of the TashT line showed that, among several pathways and processes affected, the mutant eNCCs were notably found to impose major changes on the composition of their own ECM, including increased collagen VI levels. With the Holstein line, we now demonstrate that the single alteration of collagen VI levels in the ECM surrounding eNCCs is enough by itself to cause aganglionosis. […] Therefore, combined with the fact that the genes encoding the key subunits for collagen VI assembly are located on human Chr.21q, this allows us to propose a possible molecular explanation for the strong association between Down syndrome and HSCR.

• #110 “Too much guts and not enough brains”: (epi)genetic mechanisms and future therapies of Hirschsprung disease — a review | Clinical Epigenetics | Full Text

  https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-019-0718-x

  Both DNMT3B and MeCP2 expression are decreased in neural stem cells obtained from HSCR patients, which result in a decrease of global DNA methylation. This may contribute to an aberrant expression pattern of HSCR-associated genes. […] Several HSCR-associated genes are regulated by the methylation degree of their promoter areas. One of these genes is RET, and it has been suggested that the level of RET expression determines the length of the aganglionic segment. […] Thus, aberrant methylation patterns resulting in epigenetic inactivation or overactivation of HSCR-associated genes are implicated in the development of HSCR. […] The role of histone modifications is of critical importance in CNS development. ENS development may be regulated by the same mechanisms, and if that is the case, then HSCR pathogenesis could be linked to histone modifications. […] Histone modifications enhance or silence transcription of specific genomic regions and may also apply to HSCR-associated genes such as RET. […] In HSCR patients with aberrant epigenetic patterns, these could be potentially corrected pharmacologically.

• #111 The potential effects and mechanism of echinacoside powder in the treatment of Hirschsprung’s Disease

  https://www.aimspress.com/article/doi/10.3934/mbe.2023636

  Possible complications, such as intestinal obstruction and inflammation of the intestinal tract, can have a detrimental effect on the prognosis after surgery for Hirschsprung disease. The aim of this study was to investigate the potential targets and mechanisms of action of echinacoside to improve the prognosis of Hirschsprung disease. […] Finally, we identified CA1, CA2, CA9, CA12, DNMT1, RIMS2, RPGRIP1L and ZEB2 as the core targets. Except for ZEB2, which is predominantly expressed in brain tissue, the remaining seven genes show tissue specificity and high expression in the gastrointestinal tract. […] This study may help us to further understand the pharmacological mechanisms of echinacoside and provide new guidance and ideas to guide the treatment of Hirschsprung disease.

• #112 Stem cell-based therapy for hirschsprung disease, do we have the guts to treat? | Gene Therapy

  https://www.nature.com/articles/s41434-021-00268-4

  Hirschsprung disease (HSCR) is a congenital anomaly of the colon that results from failure of enteric nervous system formation, leading to a constricted dysfunctional segment of the colon with variable lengths, and necessitating surgical intervention. […] The underlying pathophysiology includes a defect in neural crest cells migration, proliferation and differentiation, which are partially explained by identified genetic and epigenetic alterations. […] The primary pathology in HSCR is the failure of proper ENS formation, leading to a constricted dysfunctional segment of the bowel that causes fecal obstruction. This defect often arises from genetic defects in the pathways responsible for ENCC migration, proliferation, differentiation and survival. […] Nevertheless, studied cases revealed single, multiple or even no detected genetic defects, as well as the involvement of environmental factors, affirming the diseases complex and multifactorial nature.

• #113 Stem cell-based therapy for hirschsprung disease, do we have the guts to treat? | Gene Therapy

  https://www.nature.com/articles/s41434-021-00268-4

  Hirschsprung disease (HSCR) is a congenital anomaly of the colon that results from failure of enteric nervous system formation, leading to a constricted dysfunctional segment of the colon with variable lengths, and necessitating surgical intervention. […] The underlying pathophysiology includes a defect in neural crest cells migration, proliferation and differentiation, which are partially explained by identified genetic and epigenetic alterations. […] The primary pathology in HSCR is the failure of proper ENS formation, leading to a constricted dysfunctional segment of the bowel that causes fecal obstruction. This defect often arises from genetic defects in the pathways responsible for ENCC migration, proliferation, differentiation and survival. […] Nevertheless, studied cases revealed single, multiple or even no detected genetic defects, as well as the involvement of environmental factors, affirming the diseases complex and multifactorial nature.

• #114

  https://www.omim.org/entry/142623

  Isolated HSCR appears to be of complex nonmendelian inheritance with low sex-dependent penetrance and variable expression according to the length of the aganglionic segment, suggestive of the involvement of one or more genes with low penetrance. […] Lipson (1988) raised the question of hyperthermia in early gestation as a factor in Hirschsprung disease. Larsson et al. (1989) could not confirm a correlation between hyperthermia during pregnancy and Hirschsprung disease in the offspring. […] Carrasquillo et al. (2002) used a genomewide association study and a mouse model to identify interaction between the RET and EDNRB pathways in the pathogenesis of Hirschsprung disease. […] Torroglosa et al. (2014) compared the expression patterns of genes involved in human stem cell pluripotency between enteric precursors from controls and patients with Hirschsprung disease. The authors further evaluated the role of DNMT3B (602900) in the context of Hirschsprung disease by immunocytochemistry, global DNA methylation assays, and mutational screening. Seven differentially expressed genes were identified, and 3 missense mutations were found in DNMT3B that could potentially be pathogenic. These mutations were present in conjunction with RET mutations in patients with long-segment Hirschsprung disease.

• #115 Hirschsprung Disease: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/178493-overview

  The RET protooncogene has been implicated in several studies of Hirschsprung pathogenesis. […] These studies indicate the complexity of Hirschsprung pathogenesis. Ongoing studies of genetic and environmental factors will continue to elucidate this problematic disease in the future. […] Although enteric ganglion cells are the primary pathogenic entity in Hirschsprung disease, some studies suggest that other cell types may also be implicated.

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