ヒルシュスプルング病（全結腸型又は小腸型）

PURPOSE: Hirschsprung disease (HD) is a rare condition. It requires well-oriented care regardless of birthplace. We aimed to understand global HD management and identify areas of consensus and variability in perioperative care. METHODS: The Hendren Project distributed a survey to all members of its global network of pediatric surgeons and invited those who had performed five or more HD operations at their institution to participate. Surgeons were asked to retrospectively review their five most recent operations and answer a series of questions regarding diagnostic workup, surgical intervention, and complications. RESULTS: 105 surgeons completed the survey, representing 81 hospitals in 58 cities and 42 countries, reporting on 403 distinct patients. HD diagnosis was most often made by open transanal biopsy (52.4%). Preoperative rectal irrigations, used as medical treatment for obstruction, were administered to 84.8% of patients. Primary pull-through was performed in 58.8% of patients, and staged repair with a previously created colostomy was performed in 41.2%. Postoperative complications occurred in 23.6% of patients, most commonly stricture and reoperation. CONCLUSION: A global survey of pediatric surgeons identified variation in perioperative management of patients with HD, with 25% of patients experiencing surgical complications. Opportunities for quality improvement and educational efforts to improve outcomes and surgical disparities were detected.

PURPOSE: Patients with congenital surgical conditions require lifelong follow-up. However, the transition from pediatric to adult care remains poorly established. This study aimed to evaluate the long-term follow-up outcomes and transition rates of seven pediatric congenital surgical conditions. METHODS: This single-institution retrospective study included 337 patients born before 2008 who underwent surgery for esophageal atresia/tracheoesophageal fistula (TEF-EA, n = 30), choledochal cyst (CC, n = 53), biliary atresia (BA, n = 62), Hirschsprung's disease (HD, n = 60), high/intermediate anorectal malformation (ARM, n = 56), low ARM (n = 69), and cloacal malformation (Cloaca, n = 7). Follow-up outcomes and transition status were assessed. RESULTS: Overall, 146 patients (43%) were lost to the follow-up, and only 10 (3%) achieved formal transition. The lost to follow-up rates were highest in High/Int ARM (61%), HD (55%), and Low ARM (54%), with median last visit ages of 15.0, 5.5, and 7.6 years. Conversely, BA (21%) and cloacal (0%) anomalies demonstrated low attrition despite early surgical ages, suggesting that disease severity drives follow-up retention. One patient with Cloaca who disengaged from follow-up died from a urinary tract infection at 35 years old. CONCLUSION: Follow-up attrition was paradoxically the highest among patients with favorable postoperative outcomes. Targeted transition programs focusing on ARM and HD populations are urgently needed.

Hirschsprung disease (HSCR) is a congenital enteric neuropathy caused by disrupted development of enteric neural crest-derived cells (ENCDCs). Although pathogenic coding variants in RET account for many cases, the largest genetic contribution to HSCR risk arises from a common noncoding variant (rs2435357) within a SOX10-bound RET enhancer (MCS+9.7) that reduces RET gene expression in vivo and triggers expression changes in other ENS genes in the human fetal gut. However, the ENS cell types affected by this enhancer and the mechanisms by which these transcriptional changes lead to HSCR remain unknown. Here, we investigated the role of this enhancer by generating mice carrying a deletion of the orthologous Ret mcs+9.7 enhancer (Δmcs+9.7). Single-cell RNA sequencing of E14.5 embryonic gut demonstrated that enhancer deletion reduced Ret expression by 8% without altering ENS cell composition. However, reduced Ret expression was restricted to differentiating neurons and inhibitory motor neuron lineages, revealing cell type-specific enhancer activity. To determine the functional consequences of further reducing Ret dosage, we generated compound heterozygous mice carrying both the enhancer deletion and a Ret coding null allele (+/Δmcs+9.7;+/CFP). These mice exhibited additive reductions in Ret expression, altered Sox10 expression, dysregulation of cell-cycle and neuronal differentiation programs, and selective depletion of developing inhibitory motor neuron lineages. These findings establish a cell type-specific role for the mcs+9.7 enhancer in modulating Ret dosage and reveal how subtle enhancer perturbations alter neural subtype specification without overt hypoganglionosis, suggesting that HSCR arises from a cascade of cellular defects triggered by >50% loss of Ret function.

BACKGROUND: Current surgical treatment of Hirschsprung disease (HSCR), a rare congenital intestinal disorder, is frequently complicated by defecation dysfunction. The role of glycogen synthase kinase 3 beta (GSK3β), aberrantly highly expressed in HSCR tissues, in the HSCR pathogenesis remains unclear. METHODS: Publicly available scRNA-seq data of HSCR were analyzed. Histopathological characteristics of clinical samples were observed from HSCR children using Hematoxylin-Eosin staining. Regulation of the CXCL9:SPP1 (CS) polarization of glial cells by the GSK3β-NOTCH axis was assessed in both clinical samples and Schwann cells through immunofluorescence (IF), qRT-PCR, and Western blot. Regulation of neuronal development by the CS polarization was assessed in a co-culture system of Schwann cells and mouse dorsal root ganglion neurons using TUNEL staining, ELISA, IF, and patch-clamp techniques. In an Ednrb knockout mouse model, we verified in vivo that GSK3β regulated CS polarization of enteric glial cells via the NOTCH signaling pathway, which exacerbated developmental abnormalities of the enteric nervous system (ENS) and accelerated the progression of HSCR in vivo. RESULTS: Enteric glial cells were significantly increased in HSCR mouse samples, mainly as an SPP1+ subpopulation where GSK3β was highly expressed and the NOTCH signaling pathway was significantly enriched. GSK3β knockdown significantly attenuated CS polarization and blocked the NOTCH pathway. Mechanistically, GSK3β promoted enteric glial cell CS polarization by activating the NOTCH signaling pathway and aggravated the developmental abnormalities of the ENS, ultimately exacerbating postnatal ENS dysfunction and thereby potentially worsening HSCR-associated complications. CONCLUSION: GSK3β upregulation promotes NOTCH signaling pathway activation, which in turn regulates CS polarization and potentially exacerbates postnatal ENS dysfunction and aggravates HSCR-associated complications.

PURPOSE: This study evaluates the role of intraoperative frozen-section circumferential biopsies ("donuts") in preventing transition zone (TZ) pull-through (PT) in patients with Hirschsprung disease (HSCR). METHODS: We performed a single-institution retrospective review of intraoperative and final pathology reports for all PTs between 2020-2026 in which a frozen-section donut was obtained from planned anastomotic site based on previously confirmed normal full-thickness biopsy. If the initial donut was abnormal, additional proximal donuts were obtained. Donuts were considered normal when ganglion cells were present circumferentially, and fewer than two hypertrophic submucosal nerves were observed per high-power field. RESULTS: Frozen-section donuts were sent for intraoperative consultation in 134 PTs. Fourteen cases required two donuts, and two cases required three; among these 16 cases, 14 were due to abnormal pathology, and two for technical reasons. Final pathology was concordant with frozen-section findings in 130 patients (97.0%). Additional donuts prevented TZ PT in 13 patients (9.6%). Two patients (1.5%) had circumferential ganglion cells with hypertrophic nerves on final pathology despite normal frozen-section results. Non-circumferential ganglion cells were identified in two patients: one was accepted after two abnormal donuts and discussion with family; the other resulted from inaccurate donut processing. CONCLUSION: In this series, frozen-section circumferential biopsies reduced the incidence of TZ in PT, with only 3.0% of patients demonstrating TZ on final pathology and an additional 9.6% prevented intraoperatively. Routine use of this technique, alongside ongoing improvements in pathologic processing, enhances intraoperative decision-making and may contribute to safer, more effective PT procedures for HSCR. LEVEL OF EVIDENCE: IV.