Cutting-edge regenerative therapy for Hirschsprung disease and its allied disorders.

Hirschsprung disease (HSCR) and its associated disorders (AD-HSCR) often result in severe hypoperistalsis caused by enteric neuropathy, mesenchymopathy, and myopathy. Notably, HSCR involving the small intestine, isolated hypoganglionosis, chronic idiopathic intestinal pseudo-obstruction, and megacystis-microcolon-intestinal hypoperistalsis syndrome carry a poor prognosis. Ultimately, small-bowel transplantation (SBTx) is necessary for refractory cases, but it is highly invasive and outcomes are less than optimal, despite advances in surgical techniques and management. Thus, regenerative therapy has come to light as a potential form of treatment involving regeneration of the enteric nervous system, mesenchyme, and smooth muscle in affected areas. We review the cutting-edge regenerative therapeutic approaches for managing HSCR and AD-HSCR, including the use of enteric nervous system progenitor cells, embryonic stem cells, induced pluripotent stem cells, and mesenchymal stem cells as cell sources, the recipient intestine's microenvironment, and transplantation methods. Perspectives on the future of these treatments are also discussed.

Thyroid Hormone in the Pathogenesis of Congenital Intestinal Dysganglionosis.

INTRODUCTION: The objective of this study is to investigate the role of thyroid hormone (TH) in the pathogenesis of intestinal dysganglionosis (ID). METHODS: A zebrafish model of congenital hypothyroidism (CH) was created by exposing the larvae to the 6-propyl-2-thiouracil (PTU). The enteric neurons were labeled with anti-HuC/D antibodies. The number of enteric neurons was counted. The larval intestine was dissociated and stained with anti-p75 and anti-α4 integrin antibodies. Mitosis and apoptosis of the p75+ α4 integrin+ enteric neural crest cells (ENCCs) were studied using flow cytometry. Intestinal motility was studied by analyzing the transit of fluorescent tracers. RESULTS: PTU (25 mg/L) significantly reduced TH production at 6- and 9-days post fertilization without changing the body length, body weight, and intestinal length of the larvae. Furthermore, PTU inhibited mitosis of ENCCs and reduced the number of enteric neurons throughout the larval zebrafish intestine. Importantly, PTU inhibited intestinal transit of fluorescent tracers. Finally, thyroxine supplementation restored ENCC mitosis, increased the number of enteric neurons, and recovered intestinal motility in the PTU-treated larvae. CONCLUSIONS: PTU inhibited TH production, reduced the number of enteric neurons, impaired intestinal motility, and impeded ENCC mitosis in zebrafish, suggesting a possible role of CH in the pathogenesis of ID.

Retinoic acid receptor beta variant-related colonic hypoganglionosis.

Retinoic acid receptor beta (RARB) variants are heavily linked to pathologies of neural crest cell migration. The purpose of this report is to present a 23-month-old male with the previously described R387C RARB gain-of-function variant whose gastrointestinal issues and long-term constipation lead to the discovery of colonic hypoganglionosis. This case further delineates the pattern of malformation associated with RARB variants. The findings are also consistent with the known etiology of aganglionic colon due to failed neural crest cell migration.

Acquired isolated hypoganglionosis as a distinct entity: results from a nationwide survey.

PURPOSE: Acquired isolated hypoganglionosis (A-IH) is a late-onset intestinal pseudo-obstruction disorder and shows different pathophysiological findings from congenital isolated hypoganglionosis (C-IH). In this study, we retrospectively examined five cases of A-IH and investigated the features of A-IH. METHODS: Five cases of A-IH were extracted from a nationwide retrospective cohort study in 10 years, from which totally 355 cases of Allied Disorders of Hirschsprung's Disease (ADHD) were collected. RESULTS: Ages of onset were between 13 and 17 years in three cases, and 4 years and 4 months in ones. Initial symptoms were abdominal distension and/or chronic constipation in 4 cases, whereas one exhibited intestinal perforation. Affected lesions varied from case to case, extending various length of intestinal tracts. All cases underwent multiple operations (average: 4.6 times), such as enterostomy, resection of dilated intestines, and/or pull-through. Pathological findings showed the decreased numbers of ganglion cells and degeneration of ganglion cells, whereas the size of the plexus was normal. Currently, all cases were alive and almost all eat regular food without requiring parenteral feeding. CONCLUSION: A-IH is rare, but distinct entity characterized by different clinical courses and pathological findings from those of C-IH. The outcome is considered to be favorable after a resection of affected intestine.

A patient with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and severe hypoganglionosis associated with a novel SOX10 mutation.

In this report, we present the case of a female infant with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease (PCWH) associated with a novel frameshift mutation (c.842dupT) in exon 5, the last exon of SOX10. She had severe hypoganglionosis in the small intestine and entire colon, and suffered from frequent enterocolitis. The persistence of ganglion cells made both the diagnosis and treatment difficult in the neonatal period. She also showed hypopigmentation of the irises, hair and skin, bilateral sensorineural deafness with hypoplastic inner year, severe demyelinating neuropathy with hypotonia, and diffuse brain hypomyelination. The p.Ser282GlnfsTer12 mutation presumably escapes from nonsense-mediated decay and may generate a dominant-negative effect. We suggest that hypoganglionosis can be a variant intestinal manifestation associated with PCWH and that hypoganglionosis and aganglionosis may share the same pathoetiological mechanism mediated by SOX10 mutations.

Japanese clinical practice guidelines for allied disorders of Hirschsprung's disease, 2017.

BACKGROUND: Despite the presence of ganglion cells in the rectum, some patients have symptoms similar to those of Hirschsprung's disease. A consensus has yet to be established regarding the terminology for these diseases. We defined this group of diseases as "allied disorders of Hirschsprung's disease" and compiled these guidelines to facilitate accurate clinician diagnosis and provide appropriate treatment strategies for each disease. METHODS: These guidelines were developed using the methodologies in the Medical Information Network Distribution System (MINDS). Of seven allied disorders, isolated hypoganglionosis; megacystis-microcolon-intestinal hypoperistalsis syndrome; and chronic idiopathic intestinal pseudo-obstruction were selected as targets of clinical questions (CQ). In a comprehensive search of the Japanese- and English-language articles in PubMed and Ichu-Shi Web, 836 pieces of evidence related to the CQ were extracted from 288 articles; these pieces of evidence were summarized in an evidence table. RESULTS: We herein outline the newly established Japanese clinical practice guidelines for allied disorders of Hirschsprung's disease. Given that the target diseases are rare and intractable, most evidence was drawn from case reports and case series. In the CQ, the diagnosis, medication, nutritional support, surgical therapy, and prognosis for each disease are given. We emphasize the importance of full-thickness intestinal biopsy specimens for the histopathological evaluation of enteric ganglia. Considering the practicality of the guidelines, the recommendations for each CQ were created with protracted discussions among specialists. CONCLUSIONS: Clinical practice recommendations for allied disorders of Hirschprung's disease are given for each CQ, along with an assessment of the current evidence. We hope that the information will be helpful in daily practice and future studies.

Genetics of enteric neuropathies.

Abnormal development or disturbed functioning of the enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal tract, is associated with the development of neuropathic gastrointestinal motility disorders. Here, we review the underlying molecular basis of these disorders and hypothesize that many of them have a common defective biological mechanism. Genetic burden and environmental components affecting this common mechanism are ultimately responsible for disease severity and symptom heterogeneity. We believe that they act together as the fulcrum in a seesaw balanced with harmful and protective factors, and are responsible for a continuum of symptoms ranging from neuronal hyperplasia to absence of neurons.

Advances in understanding functional variations in the Hirschsprung disease spectrum (variant Hirschsprung disease).

Hirschsprung disease (HSCR) is a fairly well understood congenital, genetically based functional obstruction due to the congenital absence of ganglion cells in the distal bowel. However, although over 90% of Hirschsprung cases conform to the normally accepted histological diagnostic criteria, it has become increasingly clear that in addition to HSCR, there is a group of functional disturbances relating to a number of other congenital neurodysplastic conditions causing some degree of gastrointestinal tract malfunction. Although these represent a variety of possibly separate conditions of the enteric nervous system, this spectrum it would appear to be also influenced by similar developmental processes. The term "variant Hirschsprung" is commonly used to describe these conditions, but ganglion cells are mostly present if abnormal in number and distribution. These conditions are a problem group being amongst the most difficult to diagnose and treat with possible practical and legal consequences. The problem appears to be possibly one of definition which has proven difficult in the relative paucity of normal values, especially when correlated to age and gestation. It is the purpose of this paper to review the current position on these conditions and to explore possible shared common pathogenetic and genetic mechanisms. This article explores those conditions where a similar pathogenetic mechanisms to HSCR can be demonstrated (e.g. hypoganglionosis) as well as other neural features, which appear to represent separate conditions possibly linked to certain syndromes.

Guidelines for the management of postoperative obstructive symptoms in children with Hirschsprung disease.

Although most children with Hirschsprung disease ultimately do well, many experience a variety of ongoing problems after pull-through surgery. The most common include obstructive symptoms, soiling, enterocolitis and failure to thrive. The purpose of this guideline is to present a rational approach to the management of postoperative obstructive symptoms in children with Hirschsprung disease. The American Pediatric Surgical Association Board of Governors established a Hirschsprung Disease Interest Group. Group discussions, literature review and expert consensus were then used to summarize the current state of knowledge regarding causes, methods of diagnosis, and treatment approaches to children with obstructive symptoms following pull-through for Hirschsprung disease. Causes of obstructive symptoms post-pull-through include mechanical obstruction; persistent or acquired aganglionosis, hypoganglionosis, or transition zone pull-through; internal sphincter achalasia; disordered motility in the proximal intestine that contains ganglion cells; or functional megacolon caused by stool-holding behavior. An algorithm for the diagnosis and management of obstructive symptoms after a pull-through for Hirschsprung disease is presented. A stepwise, logical approach to the diagnosis and management of patients experiencing obstructive symptoms following pull-through for Hirschsprung disease can facilitate treatment. Level of evidence V.

Early jejunostomy creation in cases of isolated hypoganglionosis: verification of our own experience based on a national survey.

PURPOSE: Isolated hypoganglionosis (IH) is a rare disease, with few well-established therapeutic strategies. This study aims to verify our preliminary therapeutic strategies developed to date in a comparison with data obtained from a nationwide survey of congenital-type IH. METHODS: Of the 90 registered IH cases assessed in a survey of Japanese pediatric surgical departments, 40 patients who had initially undergone jejunostomy (JE) and 41 treated with ileostomy (IL) were analyzed. Thirteen patients with JE sites located less than 50 cm from the ligament of Treitz were defined as having undergone upper jejunostomy (UJE). Postsurgical plain abdominal X-ray findings and survival rates, estimated using the Kaplan-Meier method, were used to evaluate improvements following stoma creation. RESULTS: Improvements in bowel obstruction were observed in significantly more UJE patients (9/13) than non-UJE patients [20/63 (22 JE and 41 IL cases); p = 0.01]. Furthermore, the JE patients demonstrated a significantly higher survival rate than the IL patients (p = 0.01). Following the completion of the 10-year follow-up period, three JE patients died after undergoing massive bowel resection. CONCLUSIONS: To manage IH successfully, patients should undergo JE less than 50 cm from the ligament of Treitz during the neonatal period. Properly managing the distal intestines is important for achieving long-term survival.

Paneth-like cells disruption and intestinal dysbiosis in the development of enterocolitis in an iatrogenic rectosigmoid hypoganglionosis rat model.

Background: Hypoganglionosis resembles Hirschsprung disease (HSCR) which is characterized by severe constipation. Enterocolitis due to hypoganglionosis or Hirschsprung-associated enterocolitis (HAEC) is a life-threatening complication of both diseases. This study investigated the role of Paneth-like cells (PLCs) and gut microbiota in the development of enterocolitis in an iatrogenic rectosigmoid hypoganglionosis rat model. Methods: The rectosigmoid serosa of male Sprague-Dawley rats were exposed to 0.1% benzalkonium chloride (BAC). The rats were then sacrificed after 1, 3, 5, 8, and 12 weeks. A sham group was sacrificed on Week 12. With hematoxylin-eosin staining, the ganglionic cells were quantified, the degree of enterocolitis was analyzed, and the PLCs was identified. Intestinal barrier function was assessed for the anti-peripherin, occludin, and acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) ratio. qRT-PCR was used as reference for the evaluation of antimicrobial peptide (AMP) of PLCs using cryptdins, secretory Phospholipase A2, and lysozyme levels. 16S rRNA high-throughput sequencing on fecal samples was performed to analyze the changes in the intestinal microbiota diversity in each group. Results: After 1 week of intervention, the ganglion cells were fewer in all sacrificial 0.1% BAC groups at varying times than those in the sham group. Occludin and peripherin were decreased, while the AChE/BChE ratio was increased. At Week 5 postintervention, the number of α-defensins-positive PLCs increased in the sigmoid colon tissues from BAC-treated rats. Conversely, PLCs-produced AMP decreased from Week 5 to Week 12. The sham group demonstrated increased Lactobacillus and decreased Bacteroides, while the 0.1% BAC group exhibited reciprocal changes, indicating dysbiosis. Enterocolitis occurred from Week 1 postintervention. Conclusion: Application with BAC influences the disruption of PLCs in Week 5 postintervention, and dysbiosis exacerbate the occurrence of enterocolitis. Further research on Paneth cells involvement in HAEC development is warranted.

Chronic intestinal pseudo-obstruction due to adult-onset acquired isolated hypoganglionosis with muscular atrophy in the small intestine: a case report and review of literature.

BACKGROUND: Chronic intestinal pseudo-obstruction (CIPO) is a rare intestinal disorder characterized by impaired propulsion of the digestive tract and associated with symptoms of intestinal obstruction, despite the absence of obstructive lesions. CIPO includes several diseases. However, definitive diagnosis of its etiology is difficult only with symptoms or imaging findings. CASE PRESENTATION: A 56-year-old man was referred to our hospital due to a 3-year history of continuous abdominal distention. Imaging, including computed tomography of the abdomen, and endoscopy revealed marked dilatation of the entire small intestine without any obstruction point. Therefore, he was diagnosed with CIPO. Since medical therapy didn't improve his symptoms, enterostomy and percutaneous endoscopic gastro-jejunostomy were performed. These procedures improved abdominal symptoms. However, he required home central venous nutrition due to dehydration. The pathological findings of full-thickness biopsies of the small intestine taken during surgery revealed decreased number and degeneration of ganglion cells in the normal plexus. These findings led to a final diagnosis of CIPO due to acquired isolated hypoganglionosis (AIHG). CONCLUSIONS: Here, we report the case of a patient with CIPO secondary to adult-onset AIHG of the small intestine. Since AIHG cannot be solely diagnosed using clinical findings, biopsy is important for its diagnosis.

A Rare Case Presentation on Total Colonic Aganglionosis in a Female Infant of Indian Origin.

Total colonic aganglionosis, also called total colonic Hirschsprung's disease, is a known congenital disorder caused by the migration of abnormal embryonic neuroblasts. RET, NRG1, and L1CAM genes are reported as pathological gene variants associated with the incidence of different variants of Hirschsprung's disease. Major clinical presentations are well documented as inefficiency to pass stools, vomiting, fever, persistent crying, and other features of intestinal obstruction. We present here the case of a two-day-old female infant of Indian origin and its diagnostic, clinical, and case management data.

A case report of segmental hypoganlionosis of the ileum in an adult.

Intestinal hypoganglionosis in adults is quite uncommon, and hypoganglionosis of the ileum has not been documented to date. The majority of studies on this disorder are single case reports and brief case series. We describe a 30-year-old male patient with bowel obstruction and intestinal hypoganglionosis of the ileum and we review the literature on the disorder.

Adult-onset megacolon with focal hypoganglionosis: A detailed phenotyping and prospective cohort study.

BACKGROUND: In this prospective cohort study, we evaluated features of "adult-onset megacolon with focal hypoganglionosis." METHODS: We assessed the radiologic, endoscopic, and histopathologic phenotyping and treatment outcomes of 29 patients between 2017 and 2020. Data from community controls, consisting of 19,948 adults undergoing health screenings, were analyzed to identify risk factors. Experts reviewed clinical features and pathological specimens according to the London Classification for gastrointestinal neuromuscular pathology. KEY RESULTS: The median age of the patients with adult-onset megacolon with focal hypoganglionosis at symptom onset was 59 years (range, 32.0-74.9 years), with mean symptom onset only 1 year before diagnosis. All patients had focal stenotic regions with proximal bowel dilatation (mean diameter, 78.8 mm; 95% confidence interval [CI], 72-86). The comparison with community controls showed no obvious risk factors. Ten patients underwent surgery, and all exhibited significant hypoganglionosis: 5.4 myenteric ganglion cells/cm (interquartile range [IQR], 3.7-16.4) in the stenotic regions compared to 278 cells/cm (IQR, 190-338) in the proximal and 95 cells/cm (IQR, 45-213) in the distal colon. Hypoganglionosis was associated with CD3+ T cells along the myenteric plexus. Colectomy was associated with significant symptom improvement compared to medical treatment [change in the Global Bowel Satisfaction score, -5.4 points (surgery) vs. -0.3 points (medical treatment); p < 0.001]. CONCLUSIONS AND INFERENCES: Adult-onset megacolon with focal hypoganglionosis has distinct features characterized by hypoganglionosis due to inflammation. Bowel resection appears to benefit these patients.

Diagnostic challenges of hypoganglionosis based on immunohistochemical method.

Background: Hypoganglionosis resembles Hirschsprung's disease as in both diseases, patients may present with severe constipation or pseudo-obstruction. To date, diagnosis of hypoganglionosis is still difficult to be established due to lack of international consensus regarding diagnostic criteria. This study aims to evaluate the use of immunohistochemistry to provide objective support for our initial subjective impression of hypoganglionosis as well as to describe the morphological features of this study. Methods: This is a cross-sectional study. Three resected intestinal samples from patients with hypoganglionosis at Kyushu University Hospital, Fukuoka, Japan were included in this study. One healthy intestinal sample was used as control. All specimens were immunohistochemically stained with anti-S-100 protein, anti-α-smooth muscle actin (α-SMA), and anti-c-kit protein antibodies. Results: (I) S-100 immunostaining: hypoplasia of the myenteric ganglia and marked reduction of intramuscular nerve fibers were observed in several segments of the intestine. (II) α-SMA immunostaining: the pattern of the muscular layers was almost normal in all segments; however, some areas showed hypotrophy of the circular muscle (CM) layers and hypertrophy of the longitudinal muscle (LM) layers. (III) C-kit immunostaining: a decreased in the number of interstitial cells of Cajal (ICCs) was observed in almost all segments of the resected intestine, even around the myenteric plexus. Conclusions: Each segment of intestine in hypoganglionosis had different numbers of ICCs, sizes, and distributions of ganglions, as well as patterns of musculature, which may range from severely abnormal to nearly normal. Further investigations regarding the definition, etiology, diagnosis, and treatment of this disease should be performed to improve the prognosis of this disease.

Historical Cohort Study of Congenital Isolated Hypoganglionosis of the Intestine: Determining the Best Surgical Interventions.

No standard diagnostic method or surgical treatment for congenital isolated hypoganglionosis (CIHG) has been established. This study aimed to analyze the clinical outcomes of patients with CIHG and identify the best surgical interventions provided thus far. Data on surgical interventions in 19 patients were collected between 1992 and 2020, including the type of enterostomy, type of revision, and length of the intestines. Ganglion cells in the myenteric plexus were enumerated using Hu C/D staining. The ratio of the length of the small intestine to its height was defined as the intestinal ratio (IR). The outcomes were assessed using the stoma output, growth parameters including the body mass index (BMI), and parenteral nutrition (PN) dependency. All patients required a diverting enterostomy. The IR ranged from 0.51 to 1.75 after multiple non-transplant surgeries. The stoma types were tube-stoma, end-stoma, Santulli-type, and Bishop-Koop (BK)-type. Patients with Santulli- or BK-type stomas had better BMIs and less PN dependency in terms of volume than those with end-stomas or tube-stomas. Two patients with BK-type stomas were off PN, and three who underwent an intestinal transplantation (Itx) achieved enteral autonomy. The management of CIHG involves a precise diagnosis using Hu C/D staining, neonatal enterostomy, and stoma revision using the adjusted IR and Itx if other treatments do not enable enteral autonomy.

Colonic pseudo-obstruction in a patient with dyssynergic defecation: A case report.

Introduction and importance: Colonic pseudo-obstruction (CPO) is characterized by massive colonic dilatation of the large intestine without mechanical obstruction. In this study, we report our surgical experience in treating refractory CPO with increased anal sphincter tone, suggested as type IV dyssynergia. CASE PRESENTATION: A 48-year-old man with intellectual disability, depression, heart failure, and end-stage renal disease presented with acute exacerbation of CPO. He had a history of chronic constipation and abdominal distension. Colonic dilatation and defecation difficulty persisted despite medication and repeated colonoscopic decompression. Anal manometry results indicated type IV dyssynergia with increased rectal pressure. Hartmann's operation was performed to resect the redundant megacolon and to avoid increased anal sphincter pressure during defecation. Hypoganglionosis was observed in the resected colon, which could worsen the chronic process of CPO. CLINICAL DISCUSSION: Meticulous evaluation and careful management are required to treat CPO patients because the pathophysiology of CPO has not yet been clearly identified. Proper surgical treatment is needed for patients with refractory CPO. CONCLUSION: CPO requires meticulous evaluation and careful management owing to the risk of bowel perforation. Precise evaluation to identify other factors affecting defecation problems accompanied by CPO is required to make appropriate treatment decisions.

Rare case of adult intestinal hypoganglionosis and review of the literature.

Intestinal hypoganglionosis is a rare condition in adults. We report a case of intestinal hypoganglionosis in the mid-distal transverse colon to splenic flexure in a 65-year-old female patient presenting with altered bowel habit and abdominal distension, and reviewed the current literature on this topic. Our patient had a medical history of neurofibromatosis type 1. A preoperative computed tomography (CT) scan demonstrated a grossly dilated transverse colon without obstruction. A laparotomy for subtotal colectomy was performed, with histopathology demonstrating intestinal hypoganglionosis.

Adults Hirschsprung's disease, a call for awareness. A Case Report and review of the literature.

Hirschsprung's disease (HD) is an uncommon condition in adulthood; the term adult HD denotes diagnosis after the age of ten. Patients suffer from constipation for many years before the diagnosis is established. They have very characteristic radiologic findings; however, the diagnosis is confirmed with full thickness biopsies. We describe the case of a 19-year-old Caucasian female patient from Southeast Missouri with a history of chronic constipation who was referred to the General Surgery Department by her primary care provider (PCP) due to massive colonic and rectal dilation in an abdominal CT scan. After rectal biopsies were performed the diagnosis of Hirschsprung's disease was confirmed. She was referred to a tertiary center where she underwent a colo-anal pull through procedure. She has been doing well for three years. Diagnosis of this condition can be very challenging, hence the need for clinical suspicion, good quality biopsies and inter-specialty communication among PCPs, gastroenterologists, surgeons and pathologists. Surgery aiming to remove or bypass the aganglionic colonic or rectal segment is the standard of care; quality of life can be significantly improved after surgery.