RARE DISEASE
Hirschsprung disease
Hirschsprung disease
Hirschsprung disease
Synonyms: Aganglionic megacolon, Colonic aganglionosis, Congenital intestinal aganglionosis, HSCR
Synonyms: Aganglionic megacolon, Colonic aganglionosis, Congenital intestinal aganglionosis, HSCR
Synonyms: Aganglionic megacolon, Colonic aganglionosis, Congenital intestinal aganglionosis, HSCR
Drug discovery
3
drugs
With orphan designations
Overview
Hirschsprung disease (HSCR) is a congenital disorder caused by the absence of ganglion cells in the distal colon, leading to functional obstruction and impaired peristalsis. It occurs in ~1 in 5,000 live births, with male predominance (3–4:1), and is associated with genetic conditions like Down syndrome (5–10% of cases) [1][9][14]. Diagnosis involves rectal biopsy and imaging. Treatment requires surgical resection of the aganglionic bowel segment, typically via pull-through procedures, with favorable long-term outcomes in most patients [1][7][12][15].
Burden
Acute complications: Enterocolitis (10–30% of cases), intestinal perforation, and sepsis [5][13][15].
Chronic morbidity: Persistent constipation (20–40%), fecal incontinence (5–10%), and growth delays [1][12][15].
Economic impact: Extended hospitalizations, need for reoperations (up to 10% of cases), and lifelong multidisciplinary care [1][12][13].
Therapies
Primary surgery: Laparoscopic or transanal pull-through (Swenson, Soave, Duhamel techniques) to excise aganglionic bowel [1][12][19].
Staged repair: Colostomy/ileostomy followed by delayed pull-through in complex cases (e.g., enterocolitis, long-segment disease) [3][7][13].
Adjuvant care: Preoperative rectal irrigation, antibiotics for enterocolitis, and postoperative bowel management protocols [3][7][11].
Categories: rare gastroenterological diseases, rare genetic diseases, rare transplant-related disorders
Research Papers
1,808 drug discovery papers about Hirschsprung disease, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,808 drug discovery papers about Hirschsprung disease, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-13 | Ex vivo fluorescence confocal microscopy combined with rapid immunofluorescence for intraoperative intestinal mapping in near-total intestinal aganglionosis: a pediatric proof-of-concept case report.
In Hirschsprung disease (HD), intraoperative identification of ganglionated bowel remains central to surgical planning, particularly in extensive or near-total intestinal aganglionosis (nTIA), where bowel preservation is critical. Frozen-section histopathology remains the intraoperative standard. Ex-vivo fluorescence confocal microscopy (FCM) provides microscopic assessment of fresh tissue, while rapid immunofluorescence (rIF) has the potential to add targeted visualization of enteric neural structures. We describe a single pediatric proof-of-concept case in which FCM combined with selected rIF was integrated into intraoperative intestinal mapping. A full-term newborn, diagnosed at birth with nTIA, underwent tube stoma formation at 40 cm from the Treitz ligament without bowel resection. At 4-years, surgery was scheduled to remove aganglionic segments and lengthen the remaining bowel. During surgery the small bowel segment proximal to the ostomy measured 70 cm. Twenty-four full-thickness biopsies were collected every 20 cm from sigmoid colon to presumed ganglionic areas at stoma level. All samples underwent FCM for morphological assessment of fresh tissue. rIF was applied to four selected samples, two from presumed ganglionated bowel and two from presumed aganglionic bowel, as an adjunct to enhance visualization of S100B-positive neural and glial structures. Fresh tissue was incubated for 30 min with a primary anti-S100B antibody followed by an Alexa Fluor 647-conjugated secondary antibody, then rinsed and counterstained with acridine orange. Under fluorescence laser visualization ganglion cells were identified in functional segments while hypertrophic nerve fibers were detected in aganglionic regions. Surgical planning relied on integrated intraoperative assessment, with final confirmation by conventional histopathology. The simultaneous application of a longitudinal intestinal lengthening (LILT) ensured maximization of functional bowel. This single-case experience demonstrates the technical feasibility of integrating ex vivo FCM and rIF into intraoperative intestinal mapping for complex Hirschsprung disease. The approach should be regarded as exploratory and complementary to established histopathological assessment.
2026-08-02 | RNA methylation and the potential role of folate supplementation in preventing Hirschsprung disease.
To determine whether folate supplementation may reduce the incidence of Hirschsprung disease (HSCR) by regulating the methylation level of growth arrest-specific 5 (GAS5). The m6A methylation deficiency model and folate supplementation model were created using the m6A inhibitor 3-Deazaadenosine (DAZ) and folate, respectively. The effects of folate on the morphology, mortality, and number of HuC/D positive neurons in zebrafish were observed. The methylation level and proliferation ability of mouse enteric neural crest stem cells (ENCSCs) were detected by m6A ELISA and EdU assay respectively. Human HSCR cases and control tissues were collected. The expression level of GAS5 in intestinal tissues was detected by qRT-PCR. M6A ELISA, actinomycin D, and MeRIP qRT-PCR were used to detect the effect of folate on m6A methylation levels, GAS5 stability, and the content of m6A-modified GAS5 in N2a cells. The RIP assay was used to detect the content of GAS5 bound to YTH N6-methyladenosine RNA binding protein F2 (YTHDF2) under different folate concentrations. Supplementation of folate can ameliorate the decreased ENCSC proliferation ability caused by low m6A methylation level, reduce embryonic mortality of zebrafish and increase the number of HuC/D positive neurons at 96 hpf. Furthermore, folate may reduce the expression of the demethylase alkB homologue 5 (ALKBH5), weaken ALKBH5's demethylation effect on GAS5, promote the degradation of GAS5 by YTHDF2, and subsequently reduce the expression of GAS5. Additional folate supplementation during early embryonic development may serve as a strategy for preventing HSCR.
2026-07-17 | Thymic Stromal Lymphopoietin-Driven B-Cell Hyperactivation Impairs Intestinal Epithelial Homeostasis Predisposing to Enterocolitis in Hirschsprung Disease.
Hirschsprung-associated enterocolitis, a lethal complication of Hirschsprung's disease-a prevalent congenital disorder with high morbidity-has a poorly understood pathogenesis. We investigated how aberrant immune-stromal crosstalk drives mucosal injury in Hirschsprung's disease. Integrated single-cell RNA sequencing, spatial transcriptomics, bulk RNA sequencing, and proteomics were performed using human Hirschsprung's disease tissues. Validation was conducted using murine Hirschsprung-associated enterocolitis (Ednrb-/-) models, flow cytometry, multiplex immunohistochemistry, in vitro B-cell stimulation, epithelial coculture, rescue experiments with the thymic stromal lymphopoietin inhibitor baicalein, and ex vivo intestinal organoid assays. We identified significant expansion and hyperactivation of B cells that colocalized with epithelial barrier defects in Hirschsprung's disease segments. Multiomics analysis revealed an activated phenotype in these naive and memory B cells, characterized by the upregulation of B lymphocyte kinase, B cell linker, and proliferating cell nuclear antigen, which may contribute to impaired epithelial homeostasis. Crucially, we identified profibrotic thymic stromal lymphopoietin+ fibroblasts enriched in Hirschsprung's disease. Spatial mapping and in vitro assays demonstrated that thymic stromal lymphopoietin potently activated B cells, synergizing with classical stimuli to enhance proliferation. Activated B cells, in turn, secreted proinflammatory factors, such as, ICAM1 and CCL5, which induced epithelial apoptosis, suppressed proliferation, and disrupted tight junctions-effects that were amplified by thymic stromal lymphopoietin costimulation. Activated B cells and epithelial dysfunction were conserved in Hirschsprung-associated enterocolitis (Ednrb-/-) mouse models. Coculture and ex vivo organoid experiments confirmed that thymic stromal lymphopoietin-activated B cells directly destabilized epithelial homeostasis; crucially, baicalein treatment rescued epithelial proliferation, attenuated apoptosis, and reduced inflammation-associated gene expression. Our study reveals a novel pathogenic mechanism whereby thymic stromal lymphopoietin instigates pathogenic B-cell hyperactivation, thereby disrupting epithelial integrity and increasing susceptibility to Hirschsprung-associated enterocolitis. Inhibition of thymic stromal lymphopoietin signaling with baicalein ameliorates epithelial injury, highlighting this axis as a promising therapeutic target for Hirschsprung-associated enterocolitis prevention in patients with Hirschsprung's disease.
2026-07-16 | 12-HHT is associated with epithelial barrier enhancement and reduced inflammatory responses in colon organoids of normoganglionosis in Hirschsprung's disease.
Hirschsprung-associated enterocolitis remains a major postoperative complication of Hirschsprung's disease (HD), and impaired epithelial barrier integrity has been proposed as a contributing factor. In this study, we investigated whether 12-hydroxyheptadecatrienoic acid (12-HHT), an endogenous leukotriene B4 receptor 2 (BLT2) agonist, is associated with epithelial barrier enhancement and reduced inflammatory responses in patient-derived colonic organoids. Normoganglionic specimens from rectal/rectosigmoid HD at pull-through (HD-N; n = 8) and transverse colon specimens from anorectal malformation (ARM) at colostomy closure (n = 10) were used to generate colonic organoids. Epithelia were isolated using ethylenediaminetetraacetic acid and subsequently embedded in Matrigel. Baseline expression of TJP1, TJP2, F11R (encoding junctional adhesion molecule-A), JAM2, CLDN1, CLDN3, CLDN4) and LTB4R2 (encoding BLT2) was assessed by qPCR and immunoblotting. Organoids were then treated with 12-HHT (0.4, 2, or 10 μM) for 7 days, followed by qPCR. Additional experiments assessed cytokine expression (IL1B, IL6) and TJPs after 24 h with tumor necrosis factor-α (TNF-α, 100 ng/mL) plus phosphate buffered saline or 12-HHT. Barrier function was evaluated using FITC-dextran influx assays. HD-N and ARM organoids exhibited similar growth efficiencies. Baseline expression for F11R, JAM2, CLDN1, CLDN3, CLDN4, and LTB4R2 was significantly lower in HD-N than in ARM. TJPs were upregulated by 12-HHT at 2 and 10 μM in both groups, with stronger effects in ARM. In HD-N organoids, 10 μM 12-HHT suppressed TNF-α-induced IL1B and IL6 elevation mitigated tight junction proteins (TJPs) downregulation more effectively than 2 μM. 12-HHT attenuated TNF-α-induced FITC-dextran influx in HD-N organoids. 12-HHT is associated with epithelial barrier enhancement and reduced inflammatory responses in HD-N organoids.
2026-07-15 | Optimized chemogenetic ablation and regeneration of enteric nervous system neurons in zebrafish.
The enteric nervous system (ENS) is the intrinsic nervous system of the gut and regulates essential functions, including motility. ENS loss is associated with gastrointestinal disorders such as Hirschsprung disease. Restoring missing neurons by stimulating neuronal regeneration presents a promising therapeutic approach for ENS disorders. To study ENS regeneration, we developed a targeted chemogenetic neuron ablation model in zebrafish using the Gal4/UAS-NTR 2.0 system. Spatially and temporally controlled neuronal death was confirmed by morphological changes, neuron loss quantification, and TUNEL assay. We observed an acute immune response that normalizes at 1 day post-treatment (dpt). We found complete restoration of ENS neuron numbers to control levels by 9 dpt, with recovery of gut motility. We identify neuronal subtype-specific differences in regenerative capacity and/or timing of cell replacement. Our study establishes a robust platform for dissecting the cellular-molecular mechanisms of ENS regeneration to develop potential treatment approaches for ENS-related disorders.
cell therapies
2026-07-21 | Extracellular vesicles in perinatal conditions: A minimally invasive approach to regenerative medicine.
Extracellular vesicles (EVs) are lipid bilayer-delimited nanoparticles released by cells to act as mediators of intercellular communication during organ development, injury, and repair. EVs carry cargo (bioactive proteins, lipids, and nucleic acids) that reflects the status of the parent cell and is transferred to recipient cells to regulate biological processes, such as inflammation, immune responses, and tissue regeneration. These properties have made EVs promising tools for investigating disease pathogenesis, improving diagnostic and prognostic accuracy, and developing cell-free regenerative therapies for conditions characterized by dysregulation of multiple biological pathways. EVs are particularly relevant in diseases that affect the pediatric population where pathogenesis often remains poorly understood, access to affected tissues is limited, and treatment options are frequently inadequate. This review summarizes current evidence on EV applications in fetal and neonatal disorders, including necrotizing enterocolitis, congenital diaphragmatic hernia, and bronchopulmonary dysplasia, and highlights emerging data in biliary atresia, spina bifida, short bowel syndrome, and Hirschsprung's disease. In this age group, human milk and amniotic fluid represent particularly attractive biologically accessible sources of EVs, combining therapeutic potential with feasibility of clinical application. Building on robust preclinical evidence, the field is now advancing toward clinical translation, but several aspects still need to be addressed such as cargo heterogeneity, scalability of production, dosing, biodistribution, safety, and regulatory standardization. Herein, we discuss the translational challenges and future directions that will shape the clinical application of EVs in perinatal conditions.
2026-07-17 | Sacral Neuromodulation in Pediatric Gastrointestinal Motility Disorders: An Exploratory Prospective Cohort Analysis of Clinical Outcomes Based on Different Approaches.
To evaluate the efficacy and safety of minimally invasive sacral neuromodulation (SNM) and noninvasive enteral neuromodulation (ENM) in children with refractory gastrointestinal motility disorders (GMD). This prospective exploratory trial enrolled pediatric patients with GMD between 2019 and 2024 at a single tertiary referral center. Children with inflammatory bowel disease or mechanical causes of GMD were excluded. Participants received either SNM through an implanted device or ENM through surface electrodes. Stimulation was delivered at 14 Hz, 210 μs pulse width, with individualized intensity (median 1.0 mA for SNM; 6.0 mA for ENM). Primary outcomes were abdominal pain, fecal incontinence, defecation frequency, and stool consistency. Treatment success was defined as clinically significant improvement in at least two of these four domains. Quality of life was assessed at baseline and 12 weeks. Safety outcomes were monitored over a 12-month follow-up. Of 70 eligible patients, 48 completed the study (18 SNM; 30 ENM). Diagnoses included Hirschsprung disease, functional constipation, and congenital neuronal malformations. Severe comorbidities were more frequent in the SNM group (45%) than the ENM group (3%; p = 0.0018). Treatment success was observed in 80% (24/30) of the ENM cohort and 83% (15/18) of SNM cohort. No significant differences were found between groups for individual outcomes. No major complications occurred. Minor adverse events were comparable (ENM 27%; SNM 17%). Both SNM and ENM are effective and safe options for treating pediatric GMD and may be considered within a multimodal therapeutic approach. This trial is registered at clinicaltrials.gov (ID NCT04713085, title "Sacral Neuromodulation in Children and Adolescents"). Web link: https://clinicaltrials.gov/study/NCT04713085.
2026-07-03 | Endoscopic-Assisted Division of Septal Formation After Duhamel Procedure for Hirschsprung Disease: Two Case Reports.
The management of septal formation after the Duhamel procedure in Hirschsprung disease remains unclear. We report two cases treated with an endoscopic-assisted approach. Case 1 is a 5-year-old girl with Hirschsprung disease who underwent the Duhamel procedure. Persistent constipation led to a contrast enema, confirming septal formation. Transanal endoscopic-assisted division with an endoscopic linear stapler improved symptoms initially. However, constipation and enterocolitis with bleeding recurred 5 months later, requiring redo surgery. Case 2 is a 21-year-old female with a history of Hirschsprung disease, treated with the Duhamel procedure. She had three episodes of severe abdominal pain and enterocolitis in the past month. Colonoscopy revealed a septal formation with proximal intestinal dilatation. Endoscopic-assisted division resulted in complete resolution of symptoms. No complications occurred. Septal formation may cause an obstruction contributing to constipation and enterocolitis. Early recognition and division of the septum are recommended in patients with severe constipation or enterocolitis after the Duhamel procedure.
2026-04-17 | Electrode Placement and Continence Outcomes in Pediatric Hirschsprung's Disease: Rectal Versus Surface Stimulation After Trans-Anal Pull-Through Surgeries.
To compare the outcome of rectal and surface electrode stimulation, when performed concomitantly with routine anal sphincter (AS) exercises and bio-feedback training, in children who have received corrective surgery to address Hirschsprung disease (HD). Sixty-seven patients (pediatric) who underwent corrective surgery due to HD were randomly assigned to Group A (rectal electrode, n=34) or Group B (surface electrode, n=33). The two groups were given the same protocols of AS and bio-feedback training. The Pediatric Quality of Life Inventory (PedsQL), Bowel Function Score (BFS), Pediatric Incontinence and Constipation Scoring System Scale (PICSS) were measured at baseline, post intervention and follow-up. There were significant improvements in both groups over time across all outcomes. PedsQL increased (d=0.42-1.28, η²p up to 0.37), BFS improved notably (d=1.21, η²p=0.35), and PICSS decreased (d up to 1.15, η²p=0.33). The greatest gains occurred from baseline to follow-up, with smaller but significant changes from post-treatment to follow-up, indicating sustained effects. Electrical stimulation with rectal electrodes, combined with AS exercises and bio-feedback training, is a major way of improving bowel functioning, continence and quality of life in Hirschsprung child. Such results highlight the promise of multimodal rehabilitation and should be supported by additional multicenter studies.
2025-12-01 | Unlocking the Neurogenic Potential of Enteric Glial Cells for Hirschsprung Disease Therapy
sponsorship: This study was funded by the National Health and Medical Research Council Medical Research Future Fund and National Stem Cell Foundation Australia. Klaas Van Mechelen was funded by a PhD Fellowship Fundamental Research (11K8523N) and Travel Grant (V465223N) from the Research Foundation Flanders (FWO) and received support from the KU Leuven Global PhD fellowship. Pieter Vanden Berghe is supported by a REACH grant (Reach Hirschsprung Foundation) . Marlene M. Hao was funded by an ARC fellowship (DE190101209) and the National Health and Medical Research Council (2021360) . Lincon A. Stamp was funded by NSCFA, and National Health and Medical Research Council Medical Research Future Fund grants (2009049, 2032801) . (National Health and Medical Research Council Medical Research Future Fund|2009049, National Health and Medical Research Council Medical Research Future Fund|2032801, National Stem Cell Foundation Australia|11K8523N, National Stem Cell Foundation Australia|V465223N, Research Foundation Flanders (FWO), KU Leuven Global PhD fellowship, ARC fellowship|DE190101209, National Health and Medical Research Council|2021360, REACH grant (Reach Hirschsprung Foundation), NSCFA, National Health and Medical Research Council Medical Research Future Fund|2009049, National Health and Medical Research Council Medical Research Future Fund|2032801)
proteins
2026-07-06 | Combinatorial multiomic analysis from a pedigree of Sox10Dom Hirschsprung mice identifies multiple high confidence candidate modifiers of Enteric Nervous System development.
Hirschsprung disease (HSCR) is characterized by absence of enteric ganglia (aganglionosis) along variable lengths of the distal intestine. This disorder results from deficient colonization of fetal intestine by enteric neural crest-derived cells (ENCDCs). HSCR exhibits complex, multifactorial inheritance with penetrance and severity varying widely even within families. SOX10 is among causal genes that predispose to aganglionosis. Yet, how gene interactions influence severity of HSCR aganglionosis is not understood. Prior mapping of aganglionosis modifiers was achieved in a standard F1-intercross utilizing the Sox10Dom HSCR mouse model. Here we deploy a novel strategy of genotyping an extended pedigree pedigree of Sox10Dom mice on a mixed genetic background. GWAS in this pedigree points to novel aganglionosis modifier intervals with replication and refinement of prior modifier regions. Complementary omics analysis of the developing Enteric Nervous System (ENS) enabled identification of multiple high-priority candidate genes within these modifier intervals based on gene expression, chromatin accessibility, and presence of conserved SOX10 binding motifs. We implemented a prioritization pipeline for ranking potential modifiers that generated candidate lists including several well-known for effects on ENS development as well as multiple novel genes. Among the novel genes, Dach1 ranked as a top priority candidate gene for modifying migration of ENCDCs and thus influencing aganglionosis severity. The results identify genome intervals with intrinsic genes that are logical candidates for modifying Sox10Dom aganglionosis severity. We also note that several human orthologs to aganglionosis modifier candidate genes are within linkage disequilibrium blocks containing genetic variants associated with human gut motility disorders, which offers opportunity for gaining biological insight into human HSCR severity.
2026-07-03 | Endogenous peptide derived from c-Cbl-associated protein counteracts its inhibitory effect on enteric neural crest cell colonization in Hirschsprung disease.
Hirschsprung disease (HSCR) is a congenital malformation characterized by the absence of the enteric nervous system (ENS) in the distal colon, resulting from defective colonization of enteric neural crest cells (ENCCs). The underlying pathogenesis of HSCR remains incompletely understood. Here, we report that c-Cbl-associated protein (CAP), also known as sorbin and SH3 domain-containing protein 1 (SORBS1), is upregulated in the aganglionic colon tissues of children with HSCR. Functional studies revealed that CAP overexpression suppresses ENCC colonization by binding the lipid raft protein flotillin-1 through its sorbin homology (SoHo) domain, followed by recruitment of the focal adhesion protein vinculin via its SH3 domain. Using mass spectrometry, we identified an endogenous CAP-derived peptide, termed PDCAP, in aganglionic colon tissues. ELISA further revealed reduced PDCAP levels in the diseased colon tissues of HSCR children. Mechanistically, PDCAP exerts a protective role by competing with its precursor protein, CAP, for binding to flotillin-1, thereby reversing CAP-mediated inhibition of ENCC colonization. This protective function was further validated in Caplsl/lsl;Nestin-Cre as well as Ednrb-/- mouse models of either sex, where PDCAP promoted ENCC colonization and ENS development. Collectively, our findings establish PDCAP as a functional antagonist of its precursor CAP, providing a rationale for exploring peptide-mediated interventions in HSCR.Significance Statement This study identifies a novel pathogenic mechanism in Hirschsprung disease (HSCR), showing that upregulated c-Cbl-associated protein (CAP) suppresses enteric neural crest cell (ENCC) colonization through interactions with flotillin-1 and vinculin. We further characterize an endogenous peptide derived from c-Cbl-associated protein (PDCAP) that competitively binds flotillin-1 and thereby counteracts CAP-mediated inhibition of ENCC colonization. By demonstrating the protective role of PDCAP in promoting ENCC colonization and enteric nervous system (ENS) development, our findings suggest a potential biological strategy to support ENS formation and provide a new direction for future therapeutic exploration.
2026-04-30 | Updated European Reference Network for rare Inherited and Congenital Digestive and Gastrointestinal Anomalies guidelines for the management of rectosigmoid Hirschsprung's disease 2025.
To revise the 2018 European Reference Network for rare Inherited and Congenital Digestive and Gastrointestinal Anomalies (ERNICA) clinical guideline for the management of rectosigmoid Hirschsprung's disease (HSCR) based on new evidence and evolving clinical priorities, ensuring continued relevance, trustworthiness, and consistency in care. The update followed a structured five-step process: identifying new evidence (2018-2024), prioritizing recommendations using the Update Priority Tool, and revising selected topics using the Grading of Recommendations Assessment, Development and Evaluation-Evidence to Decision (GRADE EtD) framework. A multidisciplinary panel of pediatric surgeons, patient representatives, and methodologists from 12 countries oversaw the process. Revised recommendations were developed through evidence review and consensus meetings. Ten prioritized clinical topics were revised. Key updates include refined recommendations on histopathological staining in diagnosis, preoperative screening for renal anomalies and malnutrition, postoperative anastomotic calibration, individualized dietary guidance, sexual and fertility health during follow-up, transition to adult care, and the role of botulinum toxin in managing Hirschsprung's-associated enterocolitis (HAEC). Routine preventive anal dilatations were no longer recommended. The guideline highlights the importance of structured, multidisciplinary, and patient-centered care throughout the lifespan and identifies several research gaps, including nutrition, transition of care, fertility, and HAEC definitions. This updated guideline reflects current evidence and expert consensus, supporting equitable, patient-centered HSCR care. Implementation will be supported via the European Pediatric Surgical Audit (EPSA), and future updates will be informed by registry data and ongoing research.
2026-03-12 | Dual roles of GDNF in enteric glial cell plasticity: direct transdifferentiation via the CaMKII/NeuroD1 pathway and cooperative regulation in a neural stem cell-inducing medium.
Hirschsprung disease (HSCR) is a congenital condition featuring aganglionosis in the distal colon, causing functional obstruction. While EGF and bFGF are well-characterized neurogenic factors, the precise mechanistic role of GDNF in modulating enteric glial cell plasticity remains incompletely understood. EGCs were identified via proteomic profiling and immunofluorescence in Ednrb⁻/⁻ mice modeling HSCR. EGC/PK060399egfr and primary EGCs were induced with neural stem cell-inducing medium (NSC-Med). Morphological changes, EdU assay, immunofluorescence, RT‒qPCR, and Western blotting were employed to assess the expression of stemness- and neuron-associated markers. Metabolomic and transcriptomic analyses were performed to evaluate metabolic remodeling and signaling pathways. Following treatment with NSC-Med, immunofluorescence analysis revealed that neurospheres expressed high proportions of Nestin-positive (97.09%), Sox2-positive (50.11%), and p75NTR-positive (77.87%) cells. Metabolomic profiling revealed a significant enhancement of the Warburg effect in the NSC-Med group. Western blot analysis further revealed elevated expression of PKM2, along with significant increases in both extracellular and intracellular lactate levels following NSC-Med treatment. NSC-Med treatment significantly enhanced proliferation, as demonstrated by a 2.3-fold increase in EdU incorporation (P < 0.05). Transcriptomic analysis revealed the activation of the calcium signaling pathway in the GDNF group. Western blotting revealed a significant increase in CaMKII phosphorylation, and treatment with the calcium chelator BAPTA-AM attenuated GDNF-induced NeuroD1 upregulation. NSC-Med promotes stem cell-associated features and gene expression in enteric glial cells. GDNF-a key component of NSC-Med-activates a neurogenic cascade via the calcium signaling pathway (CaMKII-NeuroD1 axis), which offers a potential targeted molecular strategy for HSCR therapy.
2026-02-27 | Surgical Complications in Hirschsprung Disease and the Impact of Botulinum Toxin Injection on Hirschsprung-Associated Enterocolitis.
Background: Hirschsprung disease (HD) is associated with substantial postoperative morbidity, particularly due to Hirschsprung-associated enterocolitis (HAEC), despite definitive surgical treatment. Postoperative outcomes may vary according to the length of the aganglionic segment and the surgical technique used, and optimal management of recurrent HAEC remains a significant clinical challenge. Methods: The medical records of patients who underwent corrective surgery for HD between 2011 and 2023 were retrospectively reviewed. Demographic characteristics, disease segment length, surgical technique, postoperative complications, and HAEC episodes were recorded. HAEC diagnosis and follow-up assessments were conducted in accordance with the Delphi criteria. Patients with recurrent HAEC and obstructive symptoms refractory to standard conservative management were evaluated for botulinum toxin injection (BTI). Results: A total of 72 patients were included in the study. The majority of the patients were male (83.3%), with a mean age at diagnosis of 11 months. The Duhamel procedure was the most frequently performed surgical technique. Although the rate of anastomotic leakage was greater in patients who underwent the Swenson procedure compared with the Duhamel group, this difference did not reach statistical significance when the appropriate statistical methods were used because the small sample size. No significant difference in the incidence of HAEC was observed among the different surgical techniques. BTI was administered to 13 patients, and regression of enterocolitis episodes according to the Delphi criteria was observed in 11 patients (84.6%). Most postoperative complications are observed in patients with long-segment Hirschsprung disease. Conclusions: Postoperative complications and HAEC remain major clinical challenges in the management of Hirschsprung disease, particularly in patients with long-segment involvement. Although the surgical technique may influence certain complication rates, HAEC appears to be a multifactorial condition. Botulinum toxin injection may serve as a supportive treatment option in selected patients with refractory HAEC; however, prospective controlled studies are needed to further clarify its role.
gene therapies
2026-07-06 | BxbI-mediated insertion of a 77kb human RET sensitive haplotype into the mouse genome to generate a humanized model of Hirschsprung disease
Abstract Hirschsprung disease (HSCR) is a complex developmental disorder of the enteric nervous system, primarily driven by regulatory variants within enhancer elements of the RET gene. To investigate how these variants lead to aganglionosis, we developed a humanized mouse model by inserting an intact 77kb human RET genomic locus into the Rosa26 safe-harbor locus. Utilizing “big DNA” synthetic biology and Bxb1-mediated recombination, we integrated the complete human locus including all exons, introns, and upstream regulatory elements which we validated via nanopore and short-read sequencing. Functional analysis confirmed in vivo human RET expression; however, our initial HSCR-associated “sensitive” haplotype expressed at only 21% of wild-type levels. This significant reduction proved insufficient to rescue the viability when endogenous mouse Ret was deleted. We identified that this deficiency is partially driven by five risk SNPs within established enhancers. Specifically, using CRISPR/Cas9 to restore a conserved So×10 binding site (converting a sensitive SNP to a protective one) increased RET expression by 1.9-fold and restored transcription factor binding. This study provides a robust framework for modeling human-specific regulatory disorders and demonstrates the critical impact of non-coding variation on disease pathogenesis.
2026-05-11 | FDA-approved RET protein-tyrosine kinase inhibitors in the management of RET-driven thyroid and lung cancer.
RET is a transmembrane receptor protein-tyrosine kinase that is required for the (i) survival and maturation of the enteric nervous system, the autonomic nervous system, and sensory neurons, (ii) renal development, and (iii) spermatogenesis. RET activation by its glial-cell derived neurotrophic factor (GDNF) ligands differs from that of all other receptor protein-tyrosine kinases because of the requirement for additional GDNF family receptor-α co-receptors (GFRα1/2/3/4, GFRAL). Activating RET-point mutations occur in multiple endocrine neoplasia syndromes (MEN2A, MEN2B) and in isolated medullary thyroid cancer. RET-fusion proteins, commonly KIF5B-RET, occur in NSCLC. More than three dozen fusion partners of RET have been described in papillary thyroid cancer. Several multikinase blockers targeting RET have been approved by the FDA for the treatment of cancer: (i) vandetanib for medullary thyroid carcinoma and (ii) cabozantinib, lenvatinib, and sorafenib for differentiated thyroid cancer. Pralsetinib is a specific RET blocker that is FDA-approved for the treatment of medullary thyroid cancer, RET-fusion positive thyroid cancer and NSCLC. Selpercatinib is FDA-approved for the management of RET-mutant medullary thyroid cancer, RET-fusion-positive thyroid cancer, and other RET-fusion-positive solid tumors. The RET signaling pathway participates in the pathogenesis of cancer, particularly in thyroid and lung cancer. Currently, the number of new cases of thyroid cancer bearing RET mutations or RET-fusion proteins is about 13,000 per year and the number of cases of RET-driven NSCLC range from about 2000-4000 per year in the United States. Inactivating RET mutations result in Hirschsprung disease, a congenital disorder leading to aganglionosis of the gastrointestinal tract.
2026-04-27 | Hirschsprung Disease: Pathophysiology, Clinical Manifestations, Diagnostic Evaluation, and Nursing Management
Hirschsprung disease (HD), also known as congenital aganglionic megacolon, is a developmental disorder of the enteric nervous system characterized by the congenital absence of parasympathetic ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexuses of the distal colon and rectum. This absence results in functional intestinal obstruction and extreme proximal colonic dilatation. The recto-sigmoid colon is the most frequently affected segment. HD has a well-established predilection for the male sex. Clinical presentation varies significantly by age of onset: neonates typically exhibit delayed meconium passage, abdominal distention, and bilious vomiting, while older children present with chronic constipation, failure to thrive, and progressive abdominal distention. Diagnosis is confirmed through a combination of contrast enema studies, anorectal manometry, and definitive rectal biopsy demonstrating the absence of ganglion cells. Surgical management includes initial colostomy for intestinal decompression, followed by definitive resection of the aganglionic segment with primary anastomosis. Nursing assessment, perioperative care, and family education are central pillars of comprehensive management.
2026-04-12 | Ostomy Complications: A Narrative Review for Emergency Clinicians.
An ostomy is a surgical opening between a hollow organ and the body surface. These are necessary for several conditions, but complications may arise following ostomy creation. This narrative review provides emergency clinicians with a focused overview of ostomy complications. An ostomy is a diverting measure for management of several conditions, including gastrointestinal malignancy, inflammatory bowel disease, bowel obstruction, perforation, and trauma, and in pediatric patients, other indications include bowel malformations, Hirschsprung's disease, and necrotizing enterocolitis. Ileostomies connect the small bowel to the skin surface and are typically on the right side of the abdomen with a smaller stoma, while colostomies connect the large bowel to the skin and are typically on the left side with a larger stoma. A number of complications may occur, most commonly within the first 5 years after ostomy creation. Early complications include high-output, stoma necrosis, stoma retraction, and skin irritation/dermatitis, while later complications include parastomal hernia, stomal prolapse, stomal stenosis, and bleeding. Surgical consultation is recommended for many of these complications. Emergent surgical intervention may be necessary in those with stoma necrosis and parastomal hernia with strangulated bowel, as well as those with obstruction. An understanding of ostomy complications can assist emergency clinicians.
2026-03-27 | Radiological phenotyping in patients with SOX10 pathogenic variants: insights into neck, brain and temporal bones abnormalities.
The SOX10 gene is essential for developing neural crest-derived tissues, including the temporal bone, peripheral and central nervous systems, and melanocytes. Pathogenic SOX10 variants are linked to a broad clinical spectrum, including Waardenburg syndrome (WS) in isolation, Kallmann syndrome (KS), as well as an entity characterised by the combination of peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease (PCWH). This study aims to characterise the full spectrum of abnormalities in the brain, temporal bone and neck regions, and their syndromic associations. 15 pediatric patients with genetically confirmed SOX10 germline pathogenic variants were included. All underwent MRI, and 9 also had CT of the temporal bone. Imaging and clinical data were systematically analysed by two pediatric neuroradiologists. Phenotypic analysis revealed bilateral temporal bone abnormalities in all patients, mainly characterised by a specific combination of semicircular canal (SCC) dysplasia/hypoplasia (with high prevalence of severely hypoplastic or absent posterior SCC) and a very reproducible form of cochlear hypoplasia called "flattened cochlea". Olfactory bulb agenesis or hypoplasia was identified in all patients but two. Other abnormalities include white matter changes suggestive of a hypomyelination pattern or deficient myelination in four and neck findings typically characterised by parotid gland aplasia/hypoplasia (15/15, 100%) or lacrimal gland aplasia/hypoplasia (13/15, 86%). Clinical phenotypes ranged from SNHL to WS type II or IV and PCWH. These results confirm the strong correlation between pathogenic SOX10 variants and characteristic temporal bone malformations, which, in association with other radiological abnormalities, represent highly specific diagnostic markers. The constellation of findings reflects the shared neural crest origin of the affected tissues and should always be investigated to support appropriate genetic testing. Early identification of these features via MRI can aid diagnosis, especially in children without classic syndromic signs, and support the patients' management.
other
2026-07-06 | Child health and education outcomes in children with Hirschsprung disease: a population-based data linkage study in England
Hirschsprung disease (HSCR) is a rare congenital intestinal condition that, despite lifesaving surgery, can result in a lower quality of life throughout childhood and into adulthood. There is a lack of population-level research on the reasons why children with HSCR are frequently hospitalised throughout childhood, or on school experiences. We used linked administrative data from health and education services (ECHILD) to create a cohort of births from 2002-2020. We evaluated admission and mortality rates, number of surgical procedures, and reasons for admissions for children with and without HSCR at ages 0-14. We assessed how many children had recorded Special Educational Needs by Year 1 of primary school (age 6). Of the 11,261,227 children in our cohort, 3227 (0.03%) had HSCR. 95.0% of children with HSCR were readmitted by age 4 compared with 40.2% of those without. Across ages and sexes, children with HSCR were frequently admitted for constipation, gastroenteritis, intestinal infections, abdominal pain, and nausea and vomiting. 44.0% of children with HSCR had recorded Special Educational Needs by age 6 compared with 17.9% of those without HSCR. Improvements to treatment success, including novel or complementary approaches, are required in order to improve quality of life for children with HSCR. Further research is needed to understand the impact of HSCR and its treatment at the transition from paediatric to adult services, and on child development, progress in school, and other psychosocial factors including mental health.
2026-06-27 | Maternal nonylphenol exposure induces offspring intestinal injury and enteric neuronal defects involving proinflammatory macrophage polarization.
Nonylphenol (NP), an environmental endocrine disruptor with estrogenic activity, has been reported to exert marked neurotoxic effects. Hirschsprung's disease (HSCR) is a congenital intestinal disease characterized by the absence of enteric neurons in the gut. However, it remains unclear whether maternal exposure to NP would induce HSCR-related intestinal lesions in the offspring. Sprague Dawley rat model of maternal NP exposure during pregnancy was established to explore the effects of prenatal NP exposure on the development of enteric nervous system in offspring. In vivo and in vitro experiments and clinical samples were conducted to explore the underlying mechanisms. Results showed that prenatal NP exposure inhibited proliferation, promoted apoptosis and decreased the number of enteric neurons in offsprings. Prenatal NP exposure promoted the pro-inflammatory polarization of macrophages. NP promoted the pro-inflammatory polarization of macrophages, whereas LINC00294 overexpression attenuated the expression of pro-inflammatory cytokines in NP-treated macrophages. Conditioned medium from NP-treated macrophages inhibited the proliferation and migration of SH-SY5Y cells and promoted apoptosis. LINC00294 overexpression and NF-κB inhibitor in macrophages significantly alleviated SH-SY5Y cells damage induced by NP. In conclusion, maternal NP exposure would induce HSCR-related intestinal injury and enteric neuronal defects in offspring, potentially through NP-mediated pro-inflammatory macrophage polarization via the LINC00294-mediated modulation of NF-κB signaling pathway. These findings deepen our understanding of NP toxicity and provide a theoretical basis for developing rational strategies to reduce its adverse effects on human health.
2026-06-15 | Redefining PHOX2B-Related Neurodevelopmental Disorders as Circuitopathies: A New Paradigm in Autonomic Network Medicine.
The paired-like homeobox transcription factor 2B (PHOX2B) is a master regulator whose mutations cause a spectrum of severe neurological and neurodevelopmental disorders, including Congenital central hypoventilation syndrome (CCHS), Hirschsprung disease, and neuroblastoma. For decades, a central paradox has challenged the field: how can PHOX2B's seemingly restricted expression in the brainstem account for the broad, multi-system clinical phenotypes observed in patients? Here, we elucidate how this paradox has been resolved by recent methodological advances. We synthesize evidence from multiple complementary methodologies, including single-cell transcriptomics, spatial transcriptomics, and viral circuit tracing, which have revealed a vastly expanded PHOX2B anatomical landscape. These advances uncover previously unrecognized expression in caudal midbrain and higher brainstem regions, supportive glial populations, and peripheral components, extending far beyond classical autonomic nuclei. Furthermore, while mapping evidence predominantly derives from murine models, insights from human disease models, such as pluripotent stem cell-derived brainstem organoids, suggest that PHOX2B orchestrates integrated neuro-glial networks rather than isolated functions. Consequently, we propose reconceptualizing CCHS and related conditions as a class of multi-system network disorders termed PHOX2B circuitopathies. This circuitopathy framework critically differentiates primary circuit disruptions from secondary systemic cascades (such as hypoxia-induced cognitive deficits), providing a cohesive mechanistic basis for the constellation of cardiovascular, metabolic, and neurobehavioral symptoms. Crucially, it advances the field beyond the reactive, symptomatic management predominantly outlined in current clinical guidelines. By shifting the focus toward proactive, precision drug discovery and circuit-targeted strategies, this paradigm establishes a roadmap for developing network-based biomarkers and exploring novel disease-modifying interventions beyond conventional ventilatory support.
2025-09-02 | Microenvironmental TFPI2 in Hirschsprung Disease: Mechanisms in ENCC Development.
Hirschsprung disease (HSCR) is a relatively common disorder in pediatric surgery, characterized by the absence of enteric ganglion cells due to defective colonization of enteric neural crest cells (ENCCs) in the intestine. This study aims to investigate alterations in the intestinal microenvironment, focusing on the tissue factor pathway inhibitor 2 (TFPI2) as a potential pathogenic factor. Transcriptomic datasets from HSCR patients and fetal mouse intestines were analyzed to identify candidate genes. TFPI2 expression was validated by qRT-PCR, immunohistochemistry, and Western blotting. Recombinant TFPI2 protein was applied to ENCC cultures to evaluate its effects on proliferation, apoptosis, and migration, using CCK-8, EdU, flow cytometry, Western blotting, and real-time cell observation. KEGG and GSEA analyses of transcriptomic data were conducted to explore potential mechanisms, and functional rescue was assessed using the PI3K-AKT pathway agonist IGF-1. TFPI2 was identified as a novel microenvironmental factor associated with HSCR. Its expression was significantly elevated in the aganglionic segments of HSCR patients and in the intestines of E14.5 fetal mice. TFPI2 inhibited ENCC proliferation and migration while promoting apoptosis, likely via downregulation of the PI3K-AKT signaling pathway. IGF-1 partially rescued TFPI2-induced effects on proliferation, migration, and apoptosis. This study identifies TFPI2 as a novel microenvironmental factor contributing to ENCC dysfunction in HSCR by inhibiting the PI3K-AKT signaling pathway. These findings provide new insights into the pathogenesis of HSCR and suggest that TFPI2 could be a potential therapeutic target.
2025-08-02 | circANKRD12/circTIMMDC1 synergistically regulates enteric neural crest cell migration via miR-181b-5p-PROX1-NOTCH1 axis in Hirschsprung's disease.
Circular RNAs (circRNAs) are implicated in Hirschsprung's disease (HSCR), a genetic disorder caused by defective migration and proliferation of enteric neural crest cells (ENCCs). Expression patterns of circANKRD12 and circTIMMDC1, and related molecules in the miR-181b-5p-PROX1-NOTCH1 axis were analyzed in human and mouse fetal intestines and HSCR patient tissues. Functional assays, including in vitro neural cell experiments, ex vivo ENCC explant, and in vivo zebrafish models, were conducted to assess the effects on neural cell behavior. circANKRD12 and circTIMMDC1 were significantly downregulated in HSCR patient tissues. Single-cell analysis confirmed PROX1, NOTCH1, and HES1 expression in ENCCs from human and mouse fetal intestines. Both circRNAs synergistically regulated PROX1 by sponging miR-181b-5p, activating the NOTCH1-HES1 signaling pathway, and enhancing neural cell migration. Knockdown of these circRNAs impaired ENCC proliferation and migration. Zebrafish lacking prox1a showed reduced enteric neurons. circANKRD12 and circTIMMDC1 synergistically modulate ENCC function via the miR-181b-5p-PROX1-NOTCH1 axis, providing insights into HSCR pathogenesis and potential therapies. The study identifies circANKRD12 and circTIMMDC1 as pathogenic circRNAs in HSCR, revealing their synergistic effects on regulating ENCC migration. The study reveals that prox1a (human PROX1 homolog) deficiency in zebrafish induces HSCR-like phenotypes. The study elucidates the detailed mechanistic insights into the circANKRD12/circTIMMDC1-miR-181b-5p-PROX1-NOTCH1 axis in ENCC migration. The study contributes to the development of diagnostic tools and therapies targeting the ceRNA network in HSCR, alongside improved prenatal screening methods for early detection.
small molecules
2026-08-13 | Ex vivo fluorescence confocal microscopy combined with rapid immunofluorescence for intraoperative intestinal mapping in near-total intestinal aganglionosis: a pediatric proof-of-concept case report.
In Hirschsprung disease (HD), intraoperative identification of ganglionated bowel remains central to surgical planning, particularly in extensive or near-total intestinal aganglionosis (nTIA), where bowel preservation is critical. Frozen-section histopathology remains the intraoperative standard. Ex-vivo fluorescence confocal microscopy (FCM) provides microscopic assessment of fresh tissue, while rapid immunofluorescence (rIF) has the potential to add targeted visualization of enteric neural structures. We describe a single pediatric proof-of-concept case in which FCM combined with selected rIF was integrated into intraoperative intestinal mapping. A full-term newborn, diagnosed at birth with nTIA, underwent tube stoma formation at 40 cm from the Treitz ligament without bowel resection. At 4-years, surgery was scheduled to remove aganglionic segments and lengthen the remaining bowel. During surgery the small bowel segment proximal to the ostomy measured 70 cm. Twenty-four full-thickness biopsies were collected every 20 cm from sigmoid colon to presumed ganglionic areas at stoma level. All samples underwent FCM for morphological assessment of fresh tissue. rIF was applied to four selected samples, two from presumed ganglionated bowel and two from presumed aganglionic bowel, as an adjunct to enhance visualization of S100B-positive neural and glial structures. Fresh tissue was incubated for 30 min with a primary anti-S100B antibody followed by an Alexa Fluor 647-conjugated secondary antibody, then rinsed and counterstained with acridine orange. Under fluorescence laser visualization ganglion cells were identified in functional segments while hypertrophic nerve fibers were detected in aganglionic regions. Surgical planning relied on integrated intraoperative assessment, with final confirmation by conventional histopathology. The simultaneous application of a longitudinal intestinal lengthening (LILT) ensured maximization of functional bowel. This single-case experience demonstrates the technical feasibility of integrating ex vivo FCM and rIF into intraoperative intestinal mapping for complex Hirschsprung disease. The approach should be regarded as exploratory and complementary to established histopathological assessment.
2026-08-02 | RNA methylation and the potential role of folate supplementation in preventing Hirschsprung disease.
To determine whether folate supplementation may reduce the incidence of Hirschsprung disease (HSCR) by regulating the methylation level of growth arrest-specific 5 (GAS5). The m6A methylation deficiency model and folate supplementation model were created using the m6A inhibitor 3-Deazaadenosine (DAZ) and folate, respectively. The effects of folate on the morphology, mortality, and number of HuC/D positive neurons in zebrafish were observed. The methylation level and proliferation ability of mouse enteric neural crest stem cells (ENCSCs) were detected by m6A ELISA and EdU assay respectively. Human HSCR cases and control tissues were collected. The expression level of GAS5 in intestinal tissues was detected by qRT-PCR. M6A ELISA, actinomycin D, and MeRIP qRT-PCR were used to detect the effect of folate on m6A methylation levels, GAS5 stability, and the content of m6A-modified GAS5 in N2a cells. The RIP assay was used to detect the content of GAS5 bound to YTH N6-methyladenosine RNA binding protein F2 (YTHDF2) under different folate concentrations. Supplementation of folate can ameliorate the decreased ENCSC proliferation ability caused by low m6A methylation level, reduce embryonic mortality of zebrafish and increase the number of HuC/D positive neurons at 96 hpf. Furthermore, folate may reduce the expression of the demethylase alkB homologue 5 (ALKBH5), weaken ALKBH5's demethylation effect on GAS5, promote the degradation of GAS5 by YTHDF2, and subsequently reduce the expression of GAS5. Additional folate supplementation during early embryonic development may serve as a strategy for preventing HSCR.
2026-07-17 | Thymic Stromal Lymphopoietin-Driven B-Cell Hyperactivation Impairs Intestinal Epithelial Homeostasis Predisposing to Enterocolitis in Hirschsprung Disease.
Hirschsprung-associated enterocolitis, a lethal complication of Hirschsprung's disease-a prevalent congenital disorder with high morbidity-has a poorly understood pathogenesis. We investigated how aberrant immune-stromal crosstalk drives mucosal injury in Hirschsprung's disease. Integrated single-cell RNA sequencing, spatial transcriptomics, bulk RNA sequencing, and proteomics were performed using human Hirschsprung's disease tissues. Validation was conducted using murine Hirschsprung-associated enterocolitis (Ednrb-/-) models, flow cytometry, multiplex immunohistochemistry, in vitro B-cell stimulation, epithelial coculture, rescue experiments with the thymic stromal lymphopoietin inhibitor baicalein, and ex vivo intestinal organoid assays. We identified significant expansion and hyperactivation of B cells that colocalized with epithelial barrier defects in Hirschsprung's disease segments. Multiomics analysis revealed an activated phenotype in these naive and memory B cells, characterized by the upregulation of B lymphocyte kinase, B cell linker, and proliferating cell nuclear antigen, which may contribute to impaired epithelial homeostasis. Crucially, we identified profibrotic thymic stromal lymphopoietin+ fibroblasts enriched in Hirschsprung's disease. Spatial mapping and in vitro assays demonstrated that thymic stromal lymphopoietin potently activated B cells, synergizing with classical stimuli to enhance proliferation. Activated B cells, in turn, secreted proinflammatory factors, such as, ICAM1 and CCL5, which induced epithelial apoptosis, suppressed proliferation, and disrupted tight junctions-effects that were amplified by thymic stromal lymphopoietin costimulation. Activated B cells and epithelial dysfunction were conserved in Hirschsprung-associated enterocolitis (Ednrb-/-) mouse models. Coculture and ex vivo organoid experiments confirmed that thymic stromal lymphopoietin-activated B cells directly destabilized epithelial homeostasis; crucially, baicalein treatment rescued epithelial proliferation, attenuated apoptosis, and reduced inflammation-associated gene expression. Our study reveals a novel pathogenic mechanism whereby thymic stromal lymphopoietin instigates pathogenic B-cell hyperactivation, thereby disrupting epithelial integrity and increasing susceptibility to Hirschsprung-associated enterocolitis. Inhibition of thymic stromal lymphopoietin signaling with baicalein ameliorates epithelial injury, highlighting this axis as a promising therapeutic target for Hirschsprung-associated enterocolitis prevention in patients with Hirschsprung's disease.
2026-07-16 | 12-HHT is associated with epithelial barrier enhancement and reduced inflammatory responses in colon organoids of normoganglionosis in Hirschsprung's disease.
Hirschsprung-associated enterocolitis remains a major postoperative complication of Hirschsprung's disease (HD), and impaired epithelial barrier integrity has been proposed as a contributing factor. In this study, we investigated whether 12-hydroxyheptadecatrienoic acid (12-HHT), an endogenous leukotriene B4 receptor 2 (BLT2) agonist, is associated with epithelial barrier enhancement and reduced inflammatory responses in patient-derived colonic organoids. Normoganglionic specimens from rectal/rectosigmoid HD at pull-through (HD-N; n = 8) and transverse colon specimens from anorectal malformation (ARM) at colostomy closure (n = 10) were used to generate colonic organoids. Epithelia were isolated using ethylenediaminetetraacetic acid and subsequently embedded in Matrigel. Baseline expression of TJP1, TJP2, F11R (encoding junctional adhesion molecule-A), JAM2, CLDN1, CLDN3, CLDN4) and LTB4R2 (encoding BLT2) was assessed by qPCR and immunoblotting. Organoids were then treated with 12-HHT (0.4, 2, or 10 μM) for 7 days, followed by qPCR. Additional experiments assessed cytokine expression (IL1B, IL6) and TJPs after 24 h with tumor necrosis factor-α (TNF-α, 100 ng/mL) plus phosphate buffered saline or 12-HHT. Barrier function was evaluated using FITC-dextran influx assays. HD-N and ARM organoids exhibited similar growth efficiencies. Baseline expression for F11R, JAM2, CLDN1, CLDN3, CLDN4, and LTB4R2 was significantly lower in HD-N than in ARM. TJPs were upregulated by 12-HHT at 2 and 10 μM in both groups, with stronger effects in ARM. In HD-N organoids, 10 μM 12-HHT suppressed TNF-α-induced IL1B and IL6 elevation mitigated tight junction proteins (TJPs) downregulation more effectively than 2 μM. 12-HHT attenuated TNF-α-induced FITC-dextran influx in HD-N organoids. 12-HHT is associated with epithelial barrier enhancement and reduced inflammatory responses in HD-N organoids.
2026-07-15 | Optimized chemogenetic ablation and regeneration of enteric nervous system neurons in zebrafish.
The enteric nervous system (ENS) is the intrinsic nervous system of the gut and regulates essential functions, including motility. ENS loss is associated with gastrointestinal disorders such as Hirschsprung disease. Restoring missing neurons by stimulating neuronal regeneration presents a promising therapeutic approach for ENS disorders. To study ENS regeneration, we developed a targeted chemogenetic neuron ablation model in zebrafish using the Gal4/UAS-NTR 2.0 system. Spatially and temporally controlled neuronal death was confirmed by morphological changes, neuron loss quantification, and TUNEL assay. We observed an acute immune response that normalizes at 1 day post-treatment (dpt). We found complete restoration of ENS neuron numbers to control levels by 9 dpt, with recovery of gut motility. We identify neuronal subtype-specific differences in regenerative capacity and/or timing of cell replacement. Our study establishes a robust platform for dissecting the cellular-molecular mechanisms of ENS regeneration to develop potential treatment approaches for ENS-related disorders.
cell therapies
2026-07-21 | Extracellular vesicles in perinatal conditions: A minimally invasive approach to regenerative medicine.
Extracellular vesicles (EVs) are lipid bilayer-delimited nanoparticles released by cells to act as mediators of intercellular communication during organ development, injury, and repair. EVs carry cargo (bioactive proteins, lipids, and nucleic acids) that reflects the status of the parent cell and is transferred to recipient cells to regulate biological processes, such as inflammation, immune responses, and tissue regeneration. These properties have made EVs promising tools for investigating disease pathogenesis, improving diagnostic and prognostic accuracy, and developing cell-free regenerative therapies for conditions characterized by dysregulation of multiple biological pathways. EVs are particularly relevant in diseases that affect the pediatric population where pathogenesis often remains poorly understood, access to affected tissues is limited, and treatment options are frequently inadequate. This review summarizes current evidence on EV applications in fetal and neonatal disorders, including necrotizing enterocolitis, congenital diaphragmatic hernia, and bronchopulmonary dysplasia, and highlights emerging data in biliary atresia, spina bifida, short bowel syndrome, and Hirschsprung's disease. In this age group, human milk and amniotic fluid represent particularly attractive biologically accessible sources of EVs, combining therapeutic potential with feasibility of clinical application. Building on robust preclinical evidence, the field is now advancing toward clinical translation, but several aspects still need to be addressed such as cargo heterogeneity, scalability of production, dosing, biodistribution, safety, and regulatory standardization. Herein, we discuss the translational challenges and future directions that will shape the clinical application of EVs in perinatal conditions.
2026-07-17 | Sacral Neuromodulation in Pediatric Gastrointestinal Motility Disorders: An Exploratory Prospective Cohort Analysis of Clinical Outcomes Based on Different Approaches.
To evaluate the efficacy and safety of minimally invasive sacral neuromodulation (SNM) and noninvasive enteral neuromodulation (ENM) in children with refractory gastrointestinal motility disorders (GMD). This prospective exploratory trial enrolled pediatric patients with GMD between 2019 and 2024 at a single tertiary referral center. Children with inflammatory bowel disease or mechanical causes of GMD were excluded. Participants received either SNM through an implanted device or ENM through surface electrodes. Stimulation was delivered at 14 Hz, 210 μs pulse width, with individualized intensity (median 1.0 mA for SNM; 6.0 mA for ENM). Primary outcomes were abdominal pain, fecal incontinence, defecation frequency, and stool consistency. Treatment success was defined as clinically significant improvement in at least two of these four domains. Quality of life was assessed at baseline and 12 weeks. Safety outcomes were monitored over a 12-month follow-up. Of 70 eligible patients, 48 completed the study (18 SNM; 30 ENM). Diagnoses included Hirschsprung disease, functional constipation, and congenital neuronal malformations. Severe comorbidities were more frequent in the SNM group (45%) than the ENM group (3%; p = 0.0018). Treatment success was observed in 80% (24/30) of the ENM cohort and 83% (15/18) of SNM cohort. No significant differences were found between groups for individual outcomes. No major complications occurred. Minor adverse events were comparable (ENM 27%; SNM 17%). Both SNM and ENM are effective and safe options for treating pediatric GMD and may be considered within a multimodal therapeutic approach. This trial is registered at clinicaltrials.gov (ID NCT04713085, title "Sacral Neuromodulation in Children and Adolescents"). Web link: https://clinicaltrials.gov/study/NCT04713085.
2026-07-03 | Endoscopic-Assisted Division of Septal Formation After Duhamel Procedure for Hirschsprung Disease: Two Case Reports.
The management of septal formation after the Duhamel procedure in Hirschsprung disease remains unclear. We report two cases treated with an endoscopic-assisted approach. Case 1 is a 5-year-old girl with Hirschsprung disease who underwent the Duhamel procedure. Persistent constipation led to a contrast enema, confirming septal formation. Transanal endoscopic-assisted division with an endoscopic linear stapler improved symptoms initially. However, constipation and enterocolitis with bleeding recurred 5 months later, requiring redo surgery. Case 2 is a 21-year-old female with a history of Hirschsprung disease, treated with the Duhamel procedure. She had three episodes of severe abdominal pain and enterocolitis in the past month. Colonoscopy revealed a septal formation with proximal intestinal dilatation. Endoscopic-assisted division resulted in complete resolution of symptoms. No complications occurred. Septal formation may cause an obstruction contributing to constipation and enterocolitis. Early recognition and division of the septum are recommended in patients with severe constipation or enterocolitis after the Duhamel procedure.
2026-04-17 | Electrode Placement and Continence Outcomes in Pediatric Hirschsprung's Disease: Rectal Versus Surface Stimulation After Trans-Anal Pull-Through Surgeries.
To compare the outcome of rectal and surface electrode stimulation, when performed concomitantly with routine anal sphincter (AS) exercises and bio-feedback training, in children who have received corrective surgery to address Hirschsprung disease (HD). Sixty-seven patients (pediatric) who underwent corrective surgery due to HD were randomly assigned to Group A (rectal electrode, n=34) or Group B (surface electrode, n=33). The two groups were given the same protocols of AS and bio-feedback training. The Pediatric Quality of Life Inventory (PedsQL), Bowel Function Score (BFS), Pediatric Incontinence and Constipation Scoring System Scale (PICSS) were measured at baseline, post intervention and follow-up. There were significant improvements in both groups over time across all outcomes. PedsQL increased (d=0.42-1.28, η²p up to 0.37), BFS improved notably (d=1.21, η²p=0.35), and PICSS decreased (d up to 1.15, η²p=0.33). The greatest gains occurred from baseline to follow-up, with smaller but significant changes from post-treatment to follow-up, indicating sustained effects. Electrical stimulation with rectal electrodes, combined with AS exercises and bio-feedback training, is a major way of improving bowel functioning, continence and quality of life in Hirschsprung child. Such results highlight the promise of multimodal rehabilitation and should be supported by additional multicenter studies.
2025-12-01 | Unlocking the Neurogenic Potential of Enteric Glial Cells for Hirschsprung Disease Therapy
sponsorship: This study was funded by the National Health and Medical Research Council Medical Research Future Fund and National Stem Cell Foundation Australia. Klaas Van Mechelen was funded by a PhD Fellowship Fundamental Research (11K8523N) and Travel Grant (V465223N) from the Research Foundation Flanders (FWO) and received support from the KU Leuven Global PhD fellowship. Pieter Vanden Berghe is supported by a REACH grant (Reach Hirschsprung Foundation) . Marlene M. Hao was funded by an ARC fellowship (DE190101209) and the National Health and Medical Research Council (2021360) . Lincon A. Stamp was funded by NSCFA, and National Health and Medical Research Council Medical Research Future Fund grants (2009049, 2032801) . (National Health and Medical Research Council Medical Research Future Fund|2009049, National Health and Medical Research Council Medical Research Future Fund|2032801, National Stem Cell Foundation Australia|11K8523N, National Stem Cell Foundation Australia|V465223N, Research Foundation Flanders (FWO), KU Leuven Global PhD fellowship, ARC fellowship|DE190101209, National Health and Medical Research Council|2021360, REACH grant (Reach Hirschsprung Foundation), NSCFA, National Health and Medical Research Council Medical Research Future Fund|2009049, National Health and Medical Research Council Medical Research Future Fund|2032801)
proteins
2026-07-06 | Combinatorial multiomic analysis from a pedigree of Sox10Dom Hirschsprung mice identifies multiple high confidence candidate modifiers of Enteric Nervous System development.
Hirschsprung disease (HSCR) is characterized by absence of enteric ganglia (aganglionosis) along variable lengths of the distal intestine. This disorder results from deficient colonization of fetal intestine by enteric neural crest-derived cells (ENCDCs). HSCR exhibits complex, multifactorial inheritance with penetrance and severity varying widely even within families. SOX10 is among causal genes that predispose to aganglionosis. Yet, how gene interactions influence severity of HSCR aganglionosis is not understood. Prior mapping of aganglionosis modifiers was achieved in a standard F1-intercross utilizing the Sox10Dom HSCR mouse model. Here we deploy a novel strategy of genotyping an extended pedigree pedigree of Sox10Dom mice on a mixed genetic background. GWAS in this pedigree points to novel aganglionosis modifier intervals with replication and refinement of prior modifier regions. Complementary omics analysis of the developing Enteric Nervous System (ENS) enabled identification of multiple high-priority candidate genes within these modifier intervals based on gene expression, chromatin accessibility, and presence of conserved SOX10 binding motifs. We implemented a prioritization pipeline for ranking potential modifiers that generated candidate lists including several well-known for effects on ENS development as well as multiple novel genes. Among the novel genes, Dach1 ranked as a top priority candidate gene for modifying migration of ENCDCs and thus influencing aganglionosis severity. The results identify genome intervals with intrinsic genes that are logical candidates for modifying Sox10Dom aganglionosis severity. We also note that several human orthologs to aganglionosis modifier candidate genes are within linkage disequilibrium blocks containing genetic variants associated with human gut motility disorders, which offers opportunity for gaining biological insight into human HSCR severity.
2026-07-03 | Endogenous peptide derived from c-Cbl-associated protein counteracts its inhibitory effect on enteric neural crest cell colonization in Hirschsprung disease.
Hirschsprung disease (HSCR) is a congenital malformation characterized by the absence of the enteric nervous system (ENS) in the distal colon, resulting from defective colonization of enteric neural crest cells (ENCCs). The underlying pathogenesis of HSCR remains incompletely understood. Here, we report that c-Cbl-associated protein (CAP), also known as sorbin and SH3 domain-containing protein 1 (SORBS1), is upregulated in the aganglionic colon tissues of children with HSCR. Functional studies revealed that CAP overexpression suppresses ENCC colonization by binding the lipid raft protein flotillin-1 through its sorbin homology (SoHo) domain, followed by recruitment of the focal adhesion protein vinculin via its SH3 domain. Using mass spectrometry, we identified an endogenous CAP-derived peptide, termed PDCAP, in aganglionic colon tissues. ELISA further revealed reduced PDCAP levels in the diseased colon tissues of HSCR children. Mechanistically, PDCAP exerts a protective role by competing with its precursor protein, CAP, for binding to flotillin-1, thereby reversing CAP-mediated inhibition of ENCC colonization. This protective function was further validated in Caplsl/lsl;Nestin-Cre as well as Ednrb-/- mouse models of either sex, where PDCAP promoted ENCC colonization and ENS development. Collectively, our findings establish PDCAP as a functional antagonist of its precursor CAP, providing a rationale for exploring peptide-mediated interventions in HSCR.Significance Statement This study identifies a novel pathogenic mechanism in Hirschsprung disease (HSCR), showing that upregulated c-Cbl-associated protein (CAP) suppresses enteric neural crest cell (ENCC) colonization through interactions with flotillin-1 and vinculin. We further characterize an endogenous peptide derived from c-Cbl-associated protein (PDCAP) that competitively binds flotillin-1 and thereby counteracts CAP-mediated inhibition of ENCC colonization. By demonstrating the protective role of PDCAP in promoting ENCC colonization and enteric nervous system (ENS) development, our findings suggest a potential biological strategy to support ENS formation and provide a new direction for future therapeutic exploration.
2026-04-30 | Updated European Reference Network for rare Inherited and Congenital Digestive and Gastrointestinal Anomalies guidelines for the management of rectosigmoid Hirschsprung's disease 2025.
To revise the 2018 European Reference Network for rare Inherited and Congenital Digestive and Gastrointestinal Anomalies (ERNICA) clinical guideline for the management of rectosigmoid Hirschsprung's disease (HSCR) based on new evidence and evolving clinical priorities, ensuring continued relevance, trustworthiness, and consistency in care. The update followed a structured five-step process: identifying new evidence (2018-2024), prioritizing recommendations using the Update Priority Tool, and revising selected topics using the Grading of Recommendations Assessment, Development and Evaluation-Evidence to Decision (GRADE EtD) framework. A multidisciplinary panel of pediatric surgeons, patient representatives, and methodologists from 12 countries oversaw the process. Revised recommendations were developed through evidence review and consensus meetings. Ten prioritized clinical topics were revised. Key updates include refined recommendations on histopathological staining in diagnosis, preoperative screening for renal anomalies and malnutrition, postoperative anastomotic calibration, individualized dietary guidance, sexual and fertility health during follow-up, transition to adult care, and the role of botulinum toxin in managing Hirschsprung's-associated enterocolitis (HAEC). Routine preventive anal dilatations were no longer recommended. The guideline highlights the importance of structured, multidisciplinary, and patient-centered care throughout the lifespan and identifies several research gaps, including nutrition, transition of care, fertility, and HAEC definitions. This updated guideline reflects current evidence and expert consensus, supporting equitable, patient-centered HSCR care. Implementation will be supported via the European Pediatric Surgical Audit (EPSA), and future updates will be informed by registry data and ongoing research.
2026-03-12 | Dual roles of GDNF in enteric glial cell plasticity: direct transdifferentiation via the CaMKII/NeuroD1 pathway and cooperative regulation in a neural stem cell-inducing medium.
Hirschsprung disease (HSCR) is a congenital condition featuring aganglionosis in the distal colon, causing functional obstruction. While EGF and bFGF are well-characterized neurogenic factors, the precise mechanistic role of GDNF in modulating enteric glial cell plasticity remains incompletely understood. EGCs were identified via proteomic profiling and immunofluorescence in Ednrb⁻/⁻ mice modeling HSCR. EGC/PK060399egfr and primary EGCs were induced with neural stem cell-inducing medium (NSC-Med). Morphological changes, EdU assay, immunofluorescence, RT‒qPCR, and Western blotting were employed to assess the expression of stemness- and neuron-associated markers. Metabolomic and transcriptomic analyses were performed to evaluate metabolic remodeling and signaling pathways. Following treatment with NSC-Med, immunofluorescence analysis revealed that neurospheres expressed high proportions of Nestin-positive (97.09%), Sox2-positive (50.11%), and p75NTR-positive (77.87%) cells. Metabolomic profiling revealed a significant enhancement of the Warburg effect in the NSC-Med group. Western blot analysis further revealed elevated expression of PKM2, along with significant increases in both extracellular and intracellular lactate levels following NSC-Med treatment. NSC-Med treatment significantly enhanced proliferation, as demonstrated by a 2.3-fold increase in EdU incorporation (P < 0.05). Transcriptomic analysis revealed the activation of the calcium signaling pathway in the GDNF group. Western blotting revealed a significant increase in CaMKII phosphorylation, and treatment with the calcium chelator BAPTA-AM attenuated GDNF-induced NeuroD1 upregulation. NSC-Med promotes stem cell-associated features and gene expression in enteric glial cells. GDNF-a key component of NSC-Med-activates a neurogenic cascade via the calcium signaling pathway (CaMKII-NeuroD1 axis), which offers a potential targeted molecular strategy for HSCR therapy.
2026-02-27 | Surgical Complications in Hirschsprung Disease and the Impact of Botulinum Toxin Injection on Hirschsprung-Associated Enterocolitis.
Background: Hirschsprung disease (HD) is associated with substantial postoperative morbidity, particularly due to Hirschsprung-associated enterocolitis (HAEC), despite definitive surgical treatment. Postoperative outcomes may vary according to the length of the aganglionic segment and the surgical technique used, and optimal management of recurrent HAEC remains a significant clinical challenge. Methods: The medical records of patients who underwent corrective surgery for HD between 2011 and 2023 were retrospectively reviewed. Demographic characteristics, disease segment length, surgical technique, postoperative complications, and HAEC episodes were recorded. HAEC diagnosis and follow-up assessments were conducted in accordance with the Delphi criteria. Patients with recurrent HAEC and obstructive symptoms refractory to standard conservative management were evaluated for botulinum toxin injection (BTI). Results: A total of 72 patients were included in the study. The majority of the patients were male (83.3%), with a mean age at diagnosis of 11 months. The Duhamel procedure was the most frequently performed surgical technique. Although the rate of anastomotic leakage was greater in patients who underwent the Swenson procedure compared with the Duhamel group, this difference did not reach statistical significance when the appropriate statistical methods were used because the small sample size. No significant difference in the incidence of HAEC was observed among the different surgical techniques. BTI was administered to 13 patients, and regression of enterocolitis episodes according to the Delphi criteria was observed in 11 patients (84.6%). Most postoperative complications are observed in patients with long-segment Hirschsprung disease. Conclusions: Postoperative complications and HAEC remain major clinical challenges in the management of Hirschsprung disease, particularly in patients with long-segment involvement. Although the surgical technique may influence certain complication rates, HAEC appears to be a multifactorial condition. Botulinum toxin injection may serve as a supportive treatment option in selected patients with refractory HAEC; however, prospective controlled studies are needed to further clarify its role.
gene therapies
2026-07-06 | BxbI-mediated insertion of a 77kb human RET sensitive haplotype into the mouse genome to generate a humanized model of Hirschsprung disease
Abstract Hirschsprung disease (HSCR) is a complex developmental disorder of the enteric nervous system, primarily driven by regulatory variants within enhancer elements of the RET gene. To investigate how these variants lead to aganglionosis, we developed a humanized mouse model by inserting an intact 77kb human RET genomic locus into the Rosa26 safe-harbor locus. Utilizing “big DNA” synthetic biology and Bxb1-mediated recombination, we integrated the complete human locus including all exons, introns, and upstream regulatory elements which we validated via nanopore and short-read sequencing. Functional analysis confirmed in vivo human RET expression; however, our initial HSCR-associated “sensitive” haplotype expressed at only 21% of wild-type levels. This significant reduction proved insufficient to rescue the viability when endogenous mouse Ret was deleted. We identified that this deficiency is partially driven by five risk SNPs within established enhancers. Specifically, using CRISPR/Cas9 to restore a conserved So×10 binding site (converting a sensitive SNP to a protective one) increased RET expression by 1.9-fold and restored transcription factor binding. This study provides a robust framework for modeling human-specific regulatory disorders and demonstrates the critical impact of non-coding variation on disease pathogenesis.
2026-05-11 | FDA-approved RET protein-tyrosine kinase inhibitors in the management of RET-driven thyroid and lung cancer.
RET is a transmembrane receptor protein-tyrosine kinase that is required for the (i) survival and maturation of the enteric nervous system, the autonomic nervous system, and sensory neurons, (ii) renal development, and (iii) spermatogenesis. RET activation by its glial-cell derived neurotrophic factor (GDNF) ligands differs from that of all other receptor protein-tyrosine kinases because of the requirement for additional GDNF family receptor-α co-receptors (GFRα1/2/3/4, GFRAL). Activating RET-point mutations occur in multiple endocrine neoplasia syndromes (MEN2A, MEN2B) and in isolated medullary thyroid cancer. RET-fusion proteins, commonly KIF5B-RET, occur in NSCLC. More than three dozen fusion partners of RET have been described in papillary thyroid cancer. Several multikinase blockers targeting RET have been approved by the FDA for the treatment of cancer: (i) vandetanib for medullary thyroid carcinoma and (ii) cabozantinib, lenvatinib, and sorafenib for differentiated thyroid cancer. Pralsetinib is a specific RET blocker that is FDA-approved for the treatment of medullary thyroid cancer, RET-fusion positive thyroid cancer and NSCLC. Selpercatinib is FDA-approved for the management of RET-mutant medullary thyroid cancer, RET-fusion-positive thyroid cancer, and other RET-fusion-positive solid tumors. The RET signaling pathway participates in the pathogenesis of cancer, particularly in thyroid and lung cancer. Currently, the number of new cases of thyroid cancer bearing RET mutations or RET-fusion proteins is about 13,000 per year and the number of cases of RET-driven NSCLC range from about 2000-4000 per year in the United States. Inactivating RET mutations result in Hirschsprung disease, a congenital disorder leading to aganglionosis of the gastrointestinal tract.
2026-04-27 | Hirschsprung Disease: Pathophysiology, Clinical Manifestations, Diagnostic Evaluation, and Nursing Management
Hirschsprung disease (HD), also known as congenital aganglionic megacolon, is a developmental disorder of the enteric nervous system characterized by the congenital absence of parasympathetic ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexuses of the distal colon and rectum. This absence results in functional intestinal obstruction and extreme proximal colonic dilatation. The recto-sigmoid colon is the most frequently affected segment. HD has a well-established predilection for the male sex. Clinical presentation varies significantly by age of onset: neonates typically exhibit delayed meconium passage, abdominal distention, and bilious vomiting, while older children present with chronic constipation, failure to thrive, and progressive abdominal distention. Diagnosis is confirmed through a combination of contrast enema studies, anorectal manometry, and definitive rectal biopsy demonstrating the absence of ganglion cells. Surgical management includes initial colostomy for intestinal decompression, followed by definitive resection of the aganglionic segment with primary anastomosis. Nursing assessment, perioperative care, and family education are central pillars of comprehensive management.
2026-04-12 | Ostomy Complications: A Narrative Review for Emergency Clinicians.
An ostomy is a surgical opening between a hollow organ and the body surface. These are necessary for several conditions, but complications may arise following ostomy creation. This narrative review provides emergency clinicians with a focused overview of ostomy complications. An ostomy is a diverting measure for management of several conditions, including gastrointestinal malignancy, inflammatory bowel disease, bowel obstruction, perforation, and trauma, and in pediatric patients, other indications include bowel malformations, Hirschsprung's disease, and necrotizing enterocolitis. Ileostomies connect the small bowel to the skin surface and are typically on the right side of the abdomen with a smaller stoma, while colostomies connect the large bowel to the skin and are typically on the left side with a larger stoma. A number of complications may occur, most commonly within the first 5 years after ostomy creation. Early complications include high-output, stoma necrosis, stoma retraction, and skin irritation/dermatitis, while later complications include parastomal hernia, stomal prolapse, stomal stenosis, and bleeding. Surgical consultation is recommended for many of these complications. Emergent surgical intervention may be necessary in those with stoma necrosis and parastomal hernia with strangulated bowel, as well as those with obstruction. An understanding of ostomy complications can assist emergency clinicians.
2026-03-27 | Radiological phenotyping in patients with SOX10 pathogenic variants: insights into neck, brain and temporal bones abnormalities.
The SOX10 gene is essential for developing neural crest-derived tissues, including the temporal bone, peripheral and central nervous systems, and melanocytes. Pathogenic SOX10 variants are linked to a broad clinical spectrum, including Waardenburg syndrome (WS) in isolation, Kallmann syndrome (KS), as well as an entity characterised by the combination of peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease (PCWH). This study aims to characterise the full spectrum of abnormalities in the brain, temporal bone and neck regions, and their syndromic associations. 15 pediatric patients with genetically confirmed SOX10 germline pathogenic variants were included. All underwent MRI, and 9 also had CT of the temporal bone. Imaging and clinical data were systematically analysed by two pediatric neuroradiologists. Phenotypic analysis revealed bilateral temporal bone abnormalities in all patients, mainly characterised by a specific combination of semicircular canal (SCC) dysplasia/hypoplasia (with high prevalence of severely hypoplastic or absent posterior SCC) and a very reproducible form of cochlear hypoplasia called "flattened cochlea". Olfactory bulb agenesis or hypoplasia was identified in all patients but two. Other abnormalities include white matter changes suggestive of a hypomyelination pattern or deficient myelination in four and neck findings typically characterised by parotid gland aplasia/hypoplasia (15/15, 100%) or lacrimal gland aplasia/hypoplasia (13/15, 86%). Clinical phenotypes ranged from SNHL to WS type II or IV and PCWH. These results confirm the strong correlation between pathogenic SOX10 variants and characteristic temporal bone malformations, which, in association with other radiological abnormalities, represent highly specific diagnostic markers. The constellation of findings reflects the shared neural crest origin of the affected tissues and should always be investigated to support appropriate genetic testing. Early identification of these features via MRI can aid diagnosis, especially in children without classic syndromic signs, and support the patients' management.
other
2026-07-06 | Child health and education outcomes in children with Hirschsprung disease: a population-based data linkage study in England
Hirschsprung disease (HSCR) is a rare congenital intestinal condition that, despite lifesaving surgery, can result in a lower quality of life throughout childhood and into adulthood. There is a lack of population-level research on the reasons why children with HSCR are frequently hospitalised throughout childhood, or on school experiences. We used linked administrative data from health and education services (ECHILD) to create a cohort of births from 2002-2020. We evaluated admission and mortality rates, number of surgical procedures, and reasons for admissions for children with and without HSCR at ages 0-14. We assessed how many children had recorded Special Educational Needs by Year 1 of primary school (age 6). Of the 11,261,227 children in our cohort, 3227 (0.03%) had HSCR. 95.0% of children with HSCR were readmitted by age 4 compared with 40.2% of those without. Across ages and sexes, children with HSCR were frequently admitted for constipation, gastroenteritis, intestinal infections, abdominal pain, and nausea and vomiting. 44.0% of children with HSCR had recorded Special Educational Needs by age 6 compared with 17.9% of those without HSCR. Improvements to treatment success, including novel or complementary approaches, are required in order to improve quality of life for children with HSCR. Further research is needed to understand the impact of HSCR and its treatment at the transition from paediatric to adult services, and on child development, progress in school, and other psychosocial factors including mental health.
2026-06-27 | Maternal nonylphenol exposure induces offspring intestinal injury and enteric neuronal defects involving proinflammatory macrophage polarization.
Nonylphenol (NP), an environmental endocrine disruptor with estrogenic activity, has been reported to exert marked neurotoxic effects. Hirschsprung's disease (HSCR) is a congenital intestinal disease characterized by the absence of enteric neurons in the gut. However, it remains unclear whether maternal exposure to NP would induce HSCR-related intestinal lesions in the offspring. Sprague Dawley rat model of maternal NP exposure during pregnancy was established to explore the effects of prenatal NP exposure on the development of enteric nervous system in offspring. In vivo and in vitro experiments and clinical samples were conducted to explore the underlying mechanisms. Results showed that prenatal NP exposure inhibited proliferation, promoted apoptosis and decreased the number of enteric neurons in offsprings. Prenatal NP exposure promoted the pro-inflammatory polarization of macrophages. NP promoted the pro-inflammatory polarization of macrophages, whereas LINC00294 overexpression attenuated the expression of pro-inflammatory cytokines in NP-treated macrophages. Conditioned medium from NP-treated macrophages inhibited the proliferation and migration of SH-SY5Y cells and promoted apoptosis. LINC00294 overexpression and NF-κB inhibitor in macrophages significantly alleviated SH-SY5Y cells damage induced by NP. In conclusion, maternal NP exposure would induce HSCR-related intestinal injury and enteric neuronal defects in offspring, potentially through NP-mediated pro-inflammatory macrophage polarization via the LINC00294-mediated modulation of NF-κB signaling pathway. These findings deepen our understanding of NP toxicity and provide a theoretical basis for developing rational strategies to reduce its adverse effects on human health.
2026-06-15 | Redefining PHOX2B-Related Neurodevelopmental Disorders as Circuitopathies: A New Paradigm in Autonomic Network Medicine.
The paired-like homeobox transcription factor 2B (PHOX2B) is a master regulator whose mutations cause a spectrum of severe neurological and neurodevelopmental disorders, including Congenital central hypoventilation syndrome (CCHS), Hirschsprung disease, and neuroblastoma. For decades, a central paradox has challenged the field: how can PHOX2B's seemingly restricted expression in the brainstem account for the broad, multi-system clinical phenotypes observed in patients? Here, we elucidate how this paradox has been resolved by recent methodological advances. We synthesize evidence from multiple complementary methodologies, including single-cell transcriptomics, spatial transcriptomics, and viral circuit tracing, which have revealed a vastly expanded PHOX2B anatomical landscape. These advances uncover previously unrecognized expression in caudal midbrain and higher brainstem regions, supportive glial populations, and peripheral components, extending far beyond classical autonomic nuclei. Furthermore, while mapping evidence predominantly derives from murine models, insights from human disease models, such as pluripotent stem cell-derived brainstem organoids, suggest that PHOX2B orchestrates integrated neuro-glial networks rather than isolated functions. Consequently, we propose reconceptualizing CCHS and related conditions as a class of multi-system network disorders termed PHOX2B circuitopathies. This circuitopathy framework critically differentiates primary circuit disruptions from secondary systemic cascades (such as hypoxia-induced cognitive deficits), providing a cohesive mechanistic basis for the constellation of cardiovascular, metabolic, and neurobehavioral symptoms. Crucially, it advances the field beyond the reactive, symptomatic management predominantly outlined in current clinical guidelines. By shifting the focus toward proactive, precision drug discovery and circuit-targeted strategies, this paradigm establishes a roadmap for developing network-based biomarkers and exploring novel disease-modifying interventions beyond conventional ventilatory support.
2025-09-02 | Microenvironmental TFPI2 in Hirschsprung Disease: Mechanisms in ENCC Development.
Hirschsprung disease (HSCR) is a relatively common disorder in pediatric surgery, characterized by the absence of enteric ganglion cells due to defective colonization of enteric neural crest cells (ENCCs) in the intestine. This study aims to investigate alterations in the intestinal microenvironment, focusing on the tissue factor pathway inhibitor 2 (TFPI2) as a potential pathogenic factor. Transcriptomic datasets from HSCR patients and fetal mouse intestines were analyzed to identify candidate genes. TFPI2 expression was validated by qRT-PCR, immunohistochemistry, and Western blotting. Recombinant TFPI2 protein was applied to ENCC cultures to evaluate its effects on proliferation, apoptosis, and migration, using CCK-8, EdU, flow cytometry, Western blotting, and real-time cell observation. KEGG and GSEA analyses of transcriptomic data were conducted to explore potential mechanisms, and functional rescue was assessed using the PI3K-AKT pathway agonist IGF-1. TFPI2 was identified as a novel microenvironmental factor associated with HSCR. Its expression was significantly elevated in the aganglionic segments of HSCR patients and in the intestines of E14.5 fetal mice. TFPI2 inhibited ENCC proliferation and migration while promoting apoptosis, likely via downregulation of the PI3K-AKT signaling pathway. IGF-1 partially rescued TFPI2-induced effects on proliferation, migration, and apoptosis. This study identifies TFPI2 as a novel microenvironmental factor contributing to ENCC dysfunction in HSCR by inhibiting the PI3K-AKT signaling pathway. These findings provide new insights into the pathogenesis of HSCR and suggest that TFPI2 could be a potential therapeutic target.
2025-08-02 | circANKRD12/circTIMMDC1 synergistically regulates enteric neural crest cell migration via miR-181b-5p-PROX1-NOTCH1 axis in Hirschsprung's disease.
Circular RNAs (circRNAs) are implicated in Hirschsprung's disease (HSCR), a genetic disorder caused by defective migration and proliferation of enteric neural crest cells (ENCCs). Expression patterns of circANKRD12 and circTIMMDC1, and related molecules in the miR-181b-5p-PROX1-NOTCH1 axis were analyzed in human and mouse fetal intestines and HSCR patient tissues. Functional assays, including in vitro neural cell experiments, ex vivo ENCC explant, and in vivo zebrafish models, were conducted to assess the effects on neural cell behavior. circANKRD12 and circTIMMDC1 were significantly downregulated in HSCR patient tissues. Single-cell analysis confirmed PROX1, NOTCH1, and HES1 expression in ENCCs from human and mouse fetal intestines. Both circRNAs synergistically regulated PROX1 by sponging miR-181b-5p, activating the NOTCH1-HES1 signaling pathway, and enhancing neural cell migration. Knockdown of these circRNAs impaired ENCC proliferation and migration. Zebrafish lacking prox1a showed reduced enteric neurons. circANKRD12 and circTIMMDC1 synergistically modulate ENCC function via the miR-181b-5p-PROX1-NOTCH1 axis, providing insights into HSCR pathogenesis and potential therapies. The study identifies circANKRD12 and circTIMMDC1 as pathogenic circRNAs in HSCR, revealing their synergistic effects on regulating ENCC migration. The study reveals that prox1a (human PROX1 homolog) deficiency in zebrafish induces HSCR-like phenotypes. The study elucidates the detailed mechanistic insights into the circANKRD12/circTIMMDC1-miR-181b-5p-PROX1-NOTCH1 axis in ENCC migration. The study contributes to the development of diagnostic tools and therapies targeting the ceRNA network in HSCR, alongside improved prenatal screening methods for early detection.
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Drug Discovery Landscape
3 orphan drug designations for Hirschsprung disease.
3 orphan drug designations for Hirschsprung disease.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Glial cell line-derived neurotrophic factor, sodium butyrate | small molecules | EMA | 2025-10-22 | — | CATS Consultants GmbH |
glial cell derived neurotrophic factor and sodium butyrate | other | FDA | 2025-03-03 | — | Neurenati Therapeutics |
autologous neurospheres containing enteric neural stem cells, enteric neurons, and glia | cell therapies | FDA | 2024-09-26 | — | Mass General Brigham |
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