Fecal microbiota transplantation enhances cell therapy in a rat model of hypoganglionosis by SCFA-induced MEK1/2 signaling pathway.

Hirschsprung disease (HSCR), one of several neurocristopathies in children, is characterized by nerve loss in the large intestine and is mainly treated by surgery, which causes severe complications. Enteric neural crest-derived cell (ENCC) transplantation is a potential therapeutic strategy; however, so far with poor efficacy. Here, we assessed whether and how fecal microbiota transplantation (FMT) could improve ENCC transplantation in a rat model of hypoganglionosis; a condition similar to HSCR, with less intestinal innervation. We found that the hypoganglionosis intestinal microenvironment negatively influenced the ENCC functional phenotype in vitro and in vivo. Combining 16S rDNA sequencing and targeted mass spectrometry revealed microbial dysbiosis and reduced short-chain fatty acid (SCFA) production in the hypoganglionic gut. FMT increased the abundance of Bacteroides and Clostridium, SCFA production, and improved outcomes following ENCC transplantation. SCFAs alone stimulated ENCC proliferation, migration, and supported ENCC transplantation. Transcriptome-wide mRNA sequencing identified MAPK signaling as the top differentially regulated pathway in response to SCFA exposure, and inhibition of MEK1/2 signaling abrogated the SCFA-mediated effects on ENCC. This study demonstrates that FMT improves cell therapy for hypoganglionosis via short-chain fatty acid metabolism-induced MEK1/2 signaling.

Human enteric nervous system progenitor transplantation improves functional responses in Hirschsprung disease patient-derived tissue.

OBJECTIVE: Hirschsprung disease (HSCR) is a severe congenital disorder affecting 1:5000 live births. HSCR results from the failure of enteric nervous system (ENS) progenitors to fully colonise the gastrointestinal tract during embryonic development. This leads to aganglionosis in the distal bowel, resulting in disrupted motor activity and impaired peristalsis. Currently, the only viable treatment option is surgical resection of the aganglionic bowel. However, patients frequently suffer debilitating, lifelong symptoms, with multiple surgical procedures often necessary. Hence, alternative treatment options are crucial. An attractive strategy involves the transplantation of ENS progenitors generated from human pluripotent stem cells (hPSCs). DESIGN: ENS progenitors were generated from hPSCs using an accelerated protocol and characterised, in detail, through a combination of single-cell RNA sequencing, protein expression analysis and calcium imaging. We tested ENS progenitors' capacity to integrate and affect functional responses in HSCR colon, after ex vivo transplantation to organotypically cultured patient-derived colonic tissue, using organ bath contractility. RESULTS: We found that our protocol consistently gives rise to high yields of a cell population exhibiting transcriptional and functional hallmarks of early ENS progenitors. Following transplantation, hPSC-derived ENS progenitors integrate, migrate and form neurons/glia within explanted human HSCR colon samples. Importantly, the transplanted HSCR tissue displayed significantly increased basal contractile activity and increased responses to electrical stimulation compared with control tissue. CONCLUSION: Our findings demonstrate, for the first time, the potential of hPSC-derived ENS progenitors to repopulate and increase functional responses in human HSCR patient colonic tissue.

Transitional Care in Patients With Hirschsprung Disease: Those Left Behind.

BACKGROUND: The long-term effects of Hirschsprung disease are clinically variable. An improved understanding of challenges patients may face as adults can help inform transitional care management. OBJECTIVE: To explore the outcomes and transitional care experiences in adult patients with Hirschsprung. DESIGN: Cohort study. SETTING: Single center. PATIENTS: All patients treated for Hirschsprung between 1977 and 2001 (aged older than 18 years at the time of survey distribution in July 2018-2019). Eligible patients were sent validated multidomain surveys and qualitative questions regarding their transitional care. MAIN OUTCOME MEASURES: Status of transitional care, bowel function, and quality-of-life assessment. Qualitative analysis of transitional care experience. RESULTS: Of 139 patients, 20 had received transition care (10 had at least 1 visit but had been discharged and 10 were receiving ongoing follow-up). These patients had inferior bowel function and quality-of-life scores at follow-up. Twenty-three patients (17%) had issues with soiling at the time of discharge, and 7 patients received transitional care. Of these 23 patients, 9 (39%) had a normal Bowel Function Score (17 or more), 5 (22%) had a poor score (less than 12), and 1 had since had a stoma formation. Eighteen patients (13%) had active moderate-severe issues related to bowel function, only 5 had been transitioned, and just 2 remained under ongoing care. Importantly, when these patients were discharged from our pediatric center, at a median age of 14 (interquartile range, 12-16) years, 10 of 17 patients had no perceptible bowel issues, suggesting a worsening of function after discharge. LIMITATIONS: The retrospective design and reliance on clinical notes to gather information on discharge status as well as patient recall of events. CONCLUSIONS: There remains a small but significant proportion of Hirschsprung patients for whom bowel function either remains or becomes a major burden. These results support a need to better stratify patients requiring transitional care and ensure a clear route to care if their status changes after discharge. See Video Abstract . ATENCIN DE TRANSICIN EN PACIENTES CON ENFERMEDAD DE HIRSCHSPRUNG, LOS QUE SE QUEDAN ATRS: ANTECEDENTES:Los efectos a largo plazo de la enfermedad de Hirschsprung son clínicamente variables. Una mejor comprensión de los desafíos que los pacientes pueden enfrentar cuando sean adultos puede ayudar a informar la gestión de la atención de transición.OBJETIVO:Explorar los resultados y las experiencias de atención de transición en pacientes adultos con Hirschsprung.DISEÑO:Estudio de cohorte.AJUSTE:Unico centro.PACIENTES:Todos los pacientes tratados por Hirschsprung 1977-2001 (edad >18 años en el momento de la encuesta, Julio de 2018-2019). A los pacientes elegibles se les enviaron encuestas multidominio validadas, así como preguntas cualitativas sobre su atención de transición.PRINCIPALES MEDIDAS DE RESULTADOS:Estado de la atención de transición, función intestinal y evaluación de la calidad de vida. Análisis cualitativo de la experiencia de cuidados transicionales.RESULTADOS:De 139 pacientes, 20 habían recibido atención de transición (10 tuvieron al menos una visita pero habían sido dados de alta y 10 estaban recibiendo seguimiento continuo). Estos pacientes tenían puntuaciones inferiores de función intestinal y calidad de vida en el seguimiento. Veintitrés (17%) pacientes tuvieron problemas para ensuciarse en el momento del alta y 7 recibieron atención de transición. De estos, 9/23 (39%) tenían una puntuación de función intestinal normal (≥17), 5/23 (22%) tenían una puntuación baja (<12) y un paciente había tenido desde entonces una formación de estoma. Dieciocho (13%) pacientes tenían problemas activos de moderados a graves relacionados con la función intestinal, solo cinco habían realizado la transición y solo 2 permanecían bajo atención continua. Es importante destacar que cuando estos pacientes fueron dados de alta de nuestro centro pediátrico, a una edad promedio de 14 [RIQ 12-16] años, 10/17 no tenían problemas intestinales perceptibles, lo que sugiere un empeoramiento de la función después del alta.LIMITACIONES:El diseño retrospectivo y la dependencia de notas clínicas para recopilar información sobre el estado del alta, así como el recuerdo de los eventos por parte del paciente.CONCLUSIÓN:Sigue existiendo una proporción pequeña pero significativa de pacientes con Hirschsprung para quienes la función intestinal permanece o se convierte en una carga importante. Estos resultados respaldan la necesidad de estratificar mejor a los pacientes que requieren atención de transición y garantizar una ruta clara hacia la atención si su estado cambia después del alta. ( Traducción-Dr. Yesenia Rojas-Khalil ).

Treatment of Persistent Soiling in Hirschsprung Disease With Antegrade Continence Enemas.

INTRODUCTION: Patients with Hirschsprung disease (HD) can experience soiling after their pull-through. We evaluated the use of antegrade continence enema (ACE) for this patient population and investigated the timing and factors associated with getting the patient clean. METHODS: We performed a single-institution retrospective review (from January 2020 to January 2023) of patients with HD and prior pull-through who had persistent soiling, failed laxative treatment or rectal enemas, and were treated with antegrade enemas. The primary outcome was time to become "clean of stool" which was defined as at least one bowel movement per day, no more than one stool accident per week, and no significant stool burden radiographically. Kaplan-Meier survival analysis was performed, and univariate cox proportional hazard regression was used to assess factors associated with time to continence. RESULTS: Thirty patients who met the criteria underwent ACE creation at a median age of 6.5 y (interquartile range 5.3-9.8) with a median follow-up time of 11.5 mo (interquartile range 5.6-16.5). Most patients became clean by 4 mo (13 of 20, 65%) with similar results at 1-y follow-up (16 of 21, 76%). The median time to becoming clean was 4.3 mo (95% confidence interval: 1.7-15.0. Patients with hypermotility were more likely to continue to soil at 1 y (80% versus 13%, P = 0.01). There were no additional factors significantly associated with time to cleanliness. CONCLUSIONS: ACE is a useful modality for HD patients with soiling. Most became clean of stool in 4 mo. The presence of hypermotility was associated with a higher incidence of persistent soiling at 1 y.

Standardization of radiograph readings during bowel management week.

INTRODUCTION: During "bowel management week," abdominal radiographs are used to monitor the amount and location of stool. A radiologist familiar with the treatment plan can provide an improved interpretation. The goal of this paper is to standardize the radiological reports during a bowel management week. METHODS: We saw 744 patients during bowel management week from May 2016 until March 2023. Diagnosis included: anorectal malformation (397), idiopathic constipation (180), Hirschsprung disease (89), and spina bifida (78). Laxatives were the treatment for 51% of patients, and 49% received enemas. Characteristic radiographs were selected for each treatment group for a proposed reading standardization. RESULTS: When the stool is visualized, it is crucial to report its location. Having a contrast enema helps with the correct interpretation of the colonic anatomy. It is also essential to always compare the amount of stool with the radiograph from the previous day to determine if there is an increase or decrease in stool. Examples of radiographs are shown to guide the use of the preferred proposed terminology. CONCLUSION: Providing information regarding which treatment modality the patient is receiving and stating that a patient is on a bowel management week treatment is crucial for the radiologist to provide adequate interpretation. The radiologist must be familiar with the treatment goals and purpose of the daily radiograph.

Stem cell-based therapy for hirschsprung disease, do we have the guts to treat?

Hirschsprung disease (HSCR) is a congenital anomaly of the colon that results from failure of enteric nervous system formation, leading to a constricted dysfunctional segment of the colon with variable lengths, and necessitating surgical intervention. The underlying pathophysiology includes a defect in neural crest cells migration, proliferation and differentiation, which are partially explained by identified genetic and epigenetic alterations. Despite the high success rate of the curative surgeries, they are associated with significant adverse outcomes such as enterocolitis, fecal soiling, and chronic constipation. In addition, some patients suffer from extensive lethal variants of the disease, all of which justify the need for an alternative cure. During the last 5 years, there has been considerable progress in HSCR stem cell-based therapy research. However, many major issues remain unsolved. This review will provide concise background information on HSCR, outline the future approaches of stem cell-based HSCR therapy, review recent key publications, discuss technical and ethical challenges the field faces prior to clinical translation, and tackle such challenges by proposing solutions and evaluating existing approaches to progress further.

Enteric mesenchymal cells support the growth of postnatal enteric neural stem cells.

Interplay between embryonic enteric neural stem cells (ENSCs) and enteric mesenchymal cells (EMCs) in the embryonic gut is essential for normal development of the enteric nervous system. Disruption of these interactions underlies the pathogenesis of intestinal aganglionosis in Hirschsprung disease (HSCR). ENSC therapy has been proposed as a possible treatment for HSCR, but whether the survival and development of postnatal-derived ENSCs similarly rely on signals from the mesenchymal environment is unknown and has important implications for developing protocols to expand ENSCs for cell transplantation therapy. Enteric neural crest-derived cells (ENCDCs) and EMCs were cultured from the small intestine of Wnt1-Rosa26-tdTomato mice. EMCs promoted the expansion of ENCDCs 9.5-fold by inducing ENSC properties, including expression of Nes, Sox10, Sox2, and Ngfr. EMCs enhanced the neurosphere-forming ability of ENCDCs, and this persisted after withdrawal of the EMCs. These effects were mediated by paracrine factors and several ligands known to support neural stem cells were identified in EMCs. Using the optimized expansion procedures, neurospheres were generated from small intestine of the Ednrb-/- mouse model of HSCR. These ENSCs had similar proliferative and migratory capacity to Ednrb+/+ ENSCs, albeit neurospheres contained fewer neurons. ENSCs derived from Ednrb-/- mice generated functional neurons with similar calcium responses to Ednrb+/+ ENSCs and survived after transplantation into the aganglionic colon of Ednrb-/- recipients. EMCs act as supporting cells to ENSCs postnatally via an array of synergistically acting paracrine signaling factors. These properties can be leveraged to expand autologous ENSCs from patients with HSCR mutations for therapeutic application.

Inpatient Care Utilization and Epidemiology of Hirschsprung Disease: Analysis of the National Inpatient Sample.

BACKGROUND/OBJECTIVES: Hirschsprung disease (HD) is associated with significant morbidities including long-term bowel dysfunction. The aim of this study was to update national and regional trends in the inpatient care utilization and epidemiology of HD in the United States between 2009 and 2014 using the National Inpatient Sample (NIS) database. METHODS: We identified all pediatric admissions with a diagnosis of HD within the NIS from 2009 through 2014. We analyzed HD discharges with respect to various demographic and clinical factors, specifically trends and group differences in inflation-adjusted cost of hospitalization, procedures, co-morbidities, hospital mortality, and length of stay (LOS). A modified Cochrane-Armitage trend test was used to analyze trends for dichotomous outcome variables, and regression analyses were conducted for continuous and binary variables. RESULTS: National estimates of HD-discharges showed no significant trend between 2009 and 2014 ( P = 0.27), with estimated relative incidence ranging from 46 to 70 per 100,000 pediatric discharges. Inflation-adjusted cost of hospitalization increased by $1137 (SE $326) per year ( P = 0.0005). Pull-through procedures in neonatal age group increased from 33.0% in 2009 to 36.5% in 2014 ( P = 0.003). Hospital mortality has remained stable between 0.4% and 1.0% ( P = 0.598). LOS decreased by 0.23 days per year ( P = 0.036). CONCLUSION: Increasing cost of HD-related hospitalization despite decreasing LOS was observed in this cohort. Stable rate of hospitalizations with increasing proportions of pull-through procedures among neonates was noted. Future studies and development of protocols to standardize patient care could improve outcomes and healthcare spending.

Identifying Needs, Challenges, and Benefits Among Adults and Parents of Children With Hirschsprung Disease.

ABSTRACT: Adults with Hirschsprung disease (HD), unaffected parents of children with HD, and affected adults with an affected child completed a cross-sectional survey with open-ended questions about greatest needs at diagnosis and at current time, greatest challenges encountered, and any benefits of having HD or having a child with HD. In the 297 respondents, information and good medical care were common needs at diagnosis and at the time of survey, but the information needed evolved with time. Managing ongoing symptoms was a frequently cited need and challenge, along with managing medical care and the social and emotional impact of HD. Perceived benefits included empathy for others and new perspectives on life. The needs and challenges identified in this study can guide healthcare providers in discussions with families. Provision of information, recommendations, and referrals based on each individual family's needs can support families with HD throughout the lifecycle and facilitate adaptation.

Deriving human ENS lineages for cell therapy and drug discovery in Hirschsprung disease.

The enteric nervous system (ENS) is the largest component of the autonomic nervous system, with neuron numbers surpassing those present in the spinal cord. The ENS has been called the 'second brain' given its autonomy, remarkable neurotransmitter diversity and complex cytoarchitecture. Defects in ENS development are responsible for many human disorders including Hirschsprung disease (HSCR). HSCR is caused by the developmental failure of ENS progenitors to migrate into the gastrointestinal tract, particularly the distal colon. Human ENS development remains poorly understood owing to the lack of an easily accessible model system. Here we demonstrate the efficient derivation and isolation of ENS progenitors from human pluripotent stem (PS) cells, and their further differentiation into functional enteric neurons. ENS precursors derived in vitro are capable of targeted migration in the developing chick embryo and extensive colonization of the adult mouse colon. The in vivo engraftment and migration of human PS-cell-derived ENS precursors rescue disease-related mortality in HSCR mice (Ednrb(s-l/s-l)), although the mechanism of action remains unclear. Finally, EDNRB-null mutant ENS precursors enable modelling of HSCR-related migration defects, and the identification of pepstatin A as a candidate therapeutic target. Our study establishes the first, to our knowledge, human PS-cell-based platform for the study of human ENS development, and presents cell- and drug-based strategies for the treatment of HSCR.

Increased enteric neural crest cell differentiation after transplantation into aganglionic mouse gut.

PURPOSE: In recent years, many studies have made considerable progress in the development of stem cell-based therapies for Hirschsprung's disease (HD). However, the question of whether enteric neural crest-derived cells (ENCCs) that are transplanted into the aganglionic gut can migrate, proliferate, and differentiate in a normal manner remains unanswered. Thus, we designed this study to compare the behavior of ENCCs transplanted into the aganglionic gut of endothelin receptor B knockout (Ednrb-KO) mice versus wild-type (WT) mice. METHODS: ENCCs were isolated from the fetal guts of Sox10 transgenic mice, in which ENCCs were labeled with an enhanced green fluorescent protein, Venus, on an embryonic day 18.5 (E18.5). Neurospheres were generated and transplanted into the aganglionic region of either Ednrb-KO mice gut, or WT mice gut that had not yet been colonized, on E12.5. Time-lapse imaging of the transplanted ENCCs was performed after 24, 48, and 72 h of culture. Neuronal differentiation was evaluated using whole-mount immunohistochemistry. RESULTS: Sox10-positive ENCCs were seen to successfully migrate into the myenteric region of the aganglionic gut following transplantation in both the Ednrb-KO and WT mice. The ratio of Tuj1-positive/Sox10-positive cells was significantly increased after 72 h of culture compared to 24 h in the Ednrb-KO mice, which suggests that the transplanted ENCCs differentiated over time. In addition, at the 72 h timepoint, neuronal differentiation of transplanted ENCC in the aganglionic gut of Ednrb-KO mice was significantly increased compared to that of WT mice. CONCLUSIONS: The results of our study demonstrated that transplanted ENCCs migrated into the myenteric region of the aganglionic recipient gut in mice. The increased neuronal differentiation of transplanted ENCC in Endrb-KO mice gut suggests that the microenvironment of this region affects ENCC behavior following transplantation. Further research to explore the characteristics of this microenvironment will improve the potential of developing cell therapy to treat HD patients.

Roles of Enteric Neural Stem Cell Niche and Enteric Nervous System Development in Hirschsprung Disease.

The development of the enteric nervous system (ENS) is highly modulated by the synchronized interaction between the enteric neural crest cells (ENCCs) and the neural stem cell niche comprising the gut microenvironment. Genetic defects dysregulating the cellular behaviour(s) of the ENCCs result in incomplete innervation and hence ENS dysfunction. Hirschsprung disease (HSCR) is a rare complex neurocristopathy in which the enteric neural crest-derived cells fail to colonize the distal colon. In addition to ENS defects, increasing evidence suggests that HSCR patients may have intrinsic defects in the niche impairing the extracellular matrix (ECM)-cell interaction and/or dysregulating the cellular niche factors necessary for controlling stem cell behaviour. The niche defects in patients may compromise the regenerative capacity of the stem cell-based therapy and advocate for drug- and niche-based therapies as complementary therapeutic strategies to alleviate/enhance niche-cell interaction. Here, we provide a summary of the current understandings of the role of the enteric neural stem cell niche in modulating the development of the ENS and in the pathogenesis of HSCR. Deciphering the contribution of the niche to HSCR may provide important implications to the development of regenerative medicine for HSCR.

Medical alert card: a valuable tool in the management of Hirschsprung's-associated enterocolitis from parental perspective.

PURPOSE: Awareness of Hirschsprung's-associated enterocolitis (HAEC) among patient's families and medical staff can lead to prompt recognition of symptoms and earlier implementation of management. We designed an HAEC medical alert card to raise awareness of HAEC among medical staff and carers of children with Hirschsprung's disease (HD). Our aim was to investigate parental opinion on the utility of this tool. METHODS: All patients diagnosed with HD in two institutions over a period of 14 years received an HAEC alert card and were invited to answer a 1-year follow-up structured questionnaire. RESULTS: A total of 123 patients received an HAEC card. The response rate for the follow-up questionnaire was 62% (n = 76). The majority 96% (n = 73) of the responders considered the card useful. A total of 89% (n = 68) of patients or parents stated that they carry the card with them, while 39% (n = 30) of them have used it on 57 occasions. The majority (83%; n = 25) of these declared that, when presented, the card increased awareness among medical staff and on 53% (n = 16) occasions prompted contact with the tertiary centre. CONCLUSION: The HAEC medical card was found useful by most parents of HD patients. This tool increased awareness of HAEC and improved communication between peripheral hospitals and tertiary paediatric institutions. Therefore, we feel the HAEC alert card may be used in institutions with high HD addressability.

Intestinal organoids in infants and children.

Recent advances in culturing of intestinal stem cells and pluripotent stem cells have led to the development of intestinal organoids. These are self-organizing 3D structures, which recapitulate the characteristics and physiological features of in vivo intestinal epithelium. Intestinal organoids have allowed the development of novel in vitro models to study various gastrointestinal diseases expanding our understanding of the pathophysiology of diseases and leading to the development of innovative therapies. This article aims to summarize the current usage of intestinal organoids as a model of gastrointestinal diseases and the potential applications of intestinal organoids in infants and children. Intestinal organoids allow the study of intestinal epithelium responses to stress factors. Mimicking intestinal injury such as necrotizing enterocolitis, intestinal organoids increases the expression of pro-inflammatory cytokine genes and shows disruption of tight junctions after they are injured by lipopolysaccharide and hypoxia. In cystic fibrosis, intestinal organoids derived from rectal biopsies have provided benefits in genetic studies and development of novel therapeutic gene modulation. Transplantation of intestinal organoids via enema has been shown to rescue damaged colonic epithelium in mice. In addition, tissue-engineered small intestine derived from intestinal organoids have been successfully established providing a potential novel treatment and a new hope for children with short bowel syndrome.

Hirschsprung's Disease-Recent Understanding of Embryonic Aspects, Etiopathogenesis and Future Treatment Avenues.

Hirschsprung's disease is a neurocristopathy, caused by defective migration, proliferation, differentiation and survival of neural crest cells, leading to gut aganglionosis. It usually manifests rapidly after birth, affecting 1 in 5000 live births around the globe. In recent decades, there has been a significant improvement in the understanding of its genetics and the association with other congenital anomalies, which share the pathomechanism of improper development of the neural crest. Apart from that, several cell populations which do not originate from the neural crest, but contribute to the development of Hirschsprung's disease, have also been described, namely mast cells and interstitial cells of Cajal. From the diagnostic perspective, researchers also focused on "Variants of Hirschsprung's disease", which can mimic the clinical signs of the disease, but are in fact different entities, with distinct prognosis and treatment approaches. The treatment of Hirschsprung's disease is usually surgical resection of the aganglionic part of the intestine, however, as many as 30-50% of patients experience persisting symptoms. Considering this fact, this review article also outlines future hopes and perspectives in Hirschsprung's disease management, which has the potential to benefit from the advancements in the fields of cell-based therapy and tissue engineering.

Feasibility and efficacy of home rectal irrigation in neonates and early infancy with Hirschsprung disease.

PURPOSE: A single-stage pull-through (SSPT) is the most commonly performed procedure for Hirschsprung disease (HSCR) and has been shown to be better than multi-stage procedures. However, performing a SSPT in the neonatal period or early in infancy is a risk factor for an inaccurate diagnosis, post-operative enterocolitis, and a protracted post-operative recovery. The present study was primarily designed to evaluate the feasibility and efficacy of home rectal irrigation in the neonatal period and early in infancy, followed by a delayed and planned SSPT in a prospective cohort with HSCR. METHODS: Between January 2014 and December 2016, a total of 147 neonates diagnosed with HSCR were enrolled in the study. Six patients were excluded as a result of ganglion cells found in second rectal biopsies after the neonatal period. One hundred twenty-two patients successfully underwent 2-4 months of home rectal irrigation during the neonatal period, followed by a SSPT procedure after the neonatal period (group A, n = 122). Nineteen patients were not candidates for home rectal irrigation, and thus, colostomies were performed during the neonatal period followed by multi-stage procedures after the neonatal period (group B, n = 19). One hundred twenty-two healthy children, age- and gender-matched to group A were enrolled as the healthy control group for assessment of nutrition status (group C, n = 122). The birth weight, gender ratio, aganglionic segment, age, and Hirschsprung-associated enterocolitis (HAEC) score at the time of HSCR diagnosis were measured to evaluate the feasibility of home rectal irrigation in neonates and early in infancy. The nutritional indices, including weight, body length, serum albumin, serum prealbumin, serum retinol-binding protein, and incidence of HAEC after 2-4 successful home rectal irrigation, were used to assess the efficacy of home rectal irrigation. Anastomotic strictures or leakage, perianal excoriation, frequency of defecation, and morbidity of post-operative HAEC were recorded to evaluate the beneficial effects to pull through (PT), which were facilitated by home rectal irrigation. RESULTS: Higher HAEC scores and older age at the time of diagnosis of HSCR were associated with group B, compared to group A (4.34 ± 1.25 vs. 11.0 ± 2.56 [t = 18.20, p < 0.05] and 2.8 ± 1.46 days vs. 12.1 ± 5.3 days [t = 16.10, p < 0.05], respectively). The ratio of rectosigmoid HSCR to non-rectosigmoid HSCR was higher in group A than group B (104/18 vs. 4/15 [χ2 = 34.29, p < 0.05]). There were no differences in birth weight, weight at the time of diagnosis of HSCR, and gender ratio between groups A and B. There were no differences in birth weight, birth length, post-home rectal irrigation age, post-home rectal irrigation weight, post-home rectal irrigation length, and post-home rectal irrigation serum albumin between groups A and C (3.47 ± 0.42 kg vs. 3.48 ± 0.40 kg [t = 0.10, p > 0.05], 50.02 ± 0.49 cm vs. 50.05 ± 0.46 cm [t = 0.61, p > 0.05], 98.59 ± 13.34 days vs. 97.83 ± 13.58 days [t = 0.44, p > 0.05], 6.77 ± 0.66 kg vs. 6.97 ± 0.87 kg [t = 1.95, p > 0.05], 61.55 ± 2.14 cm vs. 61.70 ± 2.07 cm [t = 0.59, p > 0.05], and 41.78 ± 2.42 g/L vs. 41.85 ± 2.37 g/L [t = 0.22, p > 0.05], respectively). The rate of HAEC in the period of home rectal irrigation in group A was low; however, the post-home rectal irrigation serum prealbumin level and retinol-binding protein were significantly lower in group A than group C (0.15 ± 0.04 g/L vs. 0.17 ± 0.05 g/L [t = 3.50, p < 0.05] and 22.51 ± 7.53 g/L vs. 30.57 ± 9.26 g/L [t = 7.46, p < 0.05], respectively). There were no anastomotic strictures or leakage after definitive PT performed in group A. The frequency of defecation ranged from 2-6 times per day, 10 patients had perianal excoriation 3 months after PT, and 11 patients had post-operative HAEC during 6 months of follow-up after PT. CONCLUSION: Home rectal irrigation in neonates and early in infancy, followed by a delayed and planned SSPT is feasible and effective in patients with HSCR, and could be beneficial to definitive PT. However, for patients with an extended aganglionic segment, older age, or high HAEC score at the time of diagnosis of HSCR, rectal irrigation maybe not suitable. TRIAL REGISTRATION: This was a prospective comparative study designed to evaluate the effects of home rectal irrigation for facilitating and enhancing recovery after PT, and was registered at Clinical Trials.gov as NCT02776176.

Epigenetic Mechanisms in Hirschsprung Disease.

Hirschsprung disease (HSCR, OMIM 142623) is due to a failure of enteric precursor cells derived from neural crest (EPCs) to proliferate, migrate, survive or differentiate during Enteric Nervous System (ENS) formation. This is a complex process which requires a strict regulation that results in an ENS specific gene expression pattern. Alterations at this level lead to the onset of neurocristopathies such as HSCR. Gene expression is regulated by different mechanisms, such as DNA modifications (at the epigenetic level), transcriptional mechanisms (transcription factors, silencers, enhancers and repressors), postranscriptional mechanisms (3'UTR and ncRNA) and regulation of translation. All these mechanisms are finally implicated in cell signaling to determine the migration, proliferation, differentiation and survival processes for correct ENS development. In this review, we have performed an overview on the role of epigenetic mechanisms at transcriptional and posttranscriptional levels on these cellular events in neural crest cells (NCCs), ENS development, as well as in HSCR.

Cartilage hair hypoplasia with cutaneous lymphomatoid granulomatosis.

Cartilage-hair hypoplasia (CHH) is an autosomal recessive chondrodysplasia characterized by short-stature, sparse hair and impaired cellular immunity. We describe a young girl who was diagnosed with CHH based on the findings of recurrent infections, short stature with metaphyseal chondrodysplasia, and a confirmed bi-allelic RMRP gene mutation. At 13 years, the patient developed an Epstein-Barr virus (EBV)-driven lymphoproliferative disorder involving the lung, which responded partially to chemotherapy. Simultaneously, she developed multiple indurated plaques involving her face, which had histological findings of granulomatous inflammation and EBV-associated low-grade lymphomatoid granulomatosis. The patient received a matched unrelated peripheral blood stem cell transplant at 15 years of age, and her immunological parameters and skin lesions improved. Lymphomatoid forms of granulomatosis and cutaneous EBV-associated malignancies have not been described previously in CHH. This case highlights the possibility of EBV-associated cutaneous malignancy in CHH.

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

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

Identifying Information Needs for Hirschsprung Disease Through Caregiver Involvement via Social Media: A Prioritization Study and Literature Review.

BACKGROUND: Patient and public involvement in health research is important to produce relevant and impactful results. OBJECTIVE: This paper aimed to prioritize and summarize Hirschsprung disease (HD)-related information needs among caregivers of children with HD and pediatric surgeons through partnership with a parent-initiated social media campaign. METHODS: We conducted a Web-based survey with the 2 stakeholder groups to identify information needs. The caregiver survey was conducted through a global Web-based community, and the surgeon survey was distributed to members of the Canadian Association of Paediatric Surgeons (CAPS). We conducted a literature review to identify evidence on the prioritized topics. RESULTS: Our findings showed that 54.9% (89/162) of the individuals completed the caregiver survey and 23.8% (52/218 listed members) of the pediatric surgeons completed the survey distributed through CAPS. Only 20% (18/89) of the caregivers reported being very satisfied or satisfied with the current HD-related resources. A final prioritized list of information needs included bowel management, nutrition and growth, infection, perianal irritation, gastrointestinal pain, surgical diagnostics, and surgical complications. In total, 87 studies were included in the literature review, which included the following: 8 reviews, 2 randomized controlled trials, 74 cohort studies, and 3 practice guidelines. Two priority issues identified by caregivers had only a single study that met the inclusion criteria, whereas 1 topic had none. CONCLUSIONS: With caregiver and surgeon input, we identified 7 information priority areas related to HD. A review of the literature on the priorities found little evidence to support the development of high-quality guidelines. More research is necessary to meet the information needs related to HD as identified by stakeholders.