Children with Hirschsprung's disease have high morbidity in the first 5 years of life.

BACKGROUND: Hirschsprung's disease is a rare congenital anomaly of the colon with absence of the ganglionic nerve cells. The treatment of the anomaly is surgical. METHODS: This population-based data-linkage cohort study was part of the EUROlinkCAT project and investigated mortality and morbidity for the first 5 years of life for European children diagnosed with Hirschsprung's disease. Nine population-based registries in five countries from the European surveillance of congenital anomalies network (EUROCAT) participated. Data on children born 1995-2014 and diagnosed with Hirschsprung's disease were linked to hospital databases. All analyses were adjusted for region and length of follow-up, which differed by registry. RESULTS: The study included 680 children with Hirschsprung's disease. One-year survival was 97.7% (95% CI: 96.4-98.7). Overall, 85% (82-87) had a code for a specified intestinal surgery within the first year increasing to 92% (90-94) before age 5 years. The median age at the first intestinal surgery up to 5 years was 28 days (11-46) and the median number of intestinal surgical procedures was 3.5 (3.1-3.9). Thirty days mortality after neonatal surgery (within 28 days after birth) was 0.9% (0.2-2.5) for children with a code for intestinal surgery within the first 28 days after birth and there were no deaths for children with a code for stoma surgery in the neonatal period. CONCLUSION: Children with Hirschsprung's disease have a high morbidity in the first 5 years of life requiring more surgical procedures in addition to the initial surgery. Mortality after neonatal surgery is low.

Duhamel and transanal endorectal pull-throughs for Hirschsprung disease: a Bayesian network meta-analysis.

BACKGROUND: To comprehensively compare the effects of open Duhamel (OD), laparoscopic-assisted Duhamel (LD), transanal endorectal pull-through (TEPT), and laparoscopic-assisted endorectal pull-through (LEPT) in Hirschsprung disease. METHODS: PubMed, Embase, Cochrane Library, Web of Science, CNKI, WanFang, and VIP were comprehensively searched up to August 4, 2022. The outcomes were operation-related indicators and complication-related indicators. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to evaluate the quality of evidence. Network plots, forest plots, league tables and rank probabilities were drawn for all outcomes. For measurement data, weighted mean differences (WMDs) and 95% credibility intervals (CrIs) were reported; for enumeration data, relative risks (RRs) and 95%CrIs were calculated. RESULTS: Sixty-two studies of 4781 patients were included, with 2039 TEPT patients, 1669 LEPT patients, 951 OD patients and 122 LD patients. Intraoperative blood loss in the OD group was more than that in the LEPT group (pooled WMD = 44.00, 95%CrI: 27.33, 60.94). Patients lost more blood during TEPT versus LEPT (pooled WMD = 13.08, 95%CrI: 1.80, 24.30). In terms of intraoperative blood loss, LEPT was most likely to be the optimal procedure (79.76%). Patients undergoing OD had significantly longer gastrointestinal function recovery time, as compared with those undergoing LEPT (pooled WMD = 30.39, 95%CrI: 16.08, 44.94). The TEPT group had significantly longer gastrointestinal function recovery time than the LEPT group (pooled WMD = 11.49, 95%CrI: 0.96, 22.05). LEPT was most likely to be the best operation regarding gastrointestinal function recovery time (98.28%). Longer hospital stay was observed in patients with OD versus LEPT (pooled WMD = 5.24, 95%CrI: 2.98, 7.47). Hospital stay in the TEPT group was significantly longer than that in the LEPT group (pooled WMD = 1.99, 95%CrI: 0.37, 3.58). LEPT had the highest possibility to be the most effective operation with respect to hospital stay. The significantly reduced incidence of complications was found in the LEPT group versus the LD group (pooled RR = 0.24, 95%CrI: 0.12, 0.48). Compared with LEPT, OD was associated with a significantly increased incidence of complications (pooled RR = 5.10, 95%CrI: 3.48, 7.45). Patients undergoing TEPT had a significantly greater incidence of complications than those undergoing LEPT (pooled RR = 1.98, 95%CrI: 1.63, 2.42). For complications, LEPT is most likely to have the best effect (99.99%). Compared with the LEPT group, the OD group had a significantly increased incidence of anastomotic leakage (pooled RR = 5.35, 95%CrI: 1.45, 27.68). LEPT had the highest likelihood to be the best operation regarding anastomotic leakage (63.57%). The incidence of infection in the OD group was significantly higher than that in the LEPT group (pooled RR = 4.52, 95%CrI: 2.45, 8.84). The TEPT group had a significantly increased incidence of infection than the LEPT group (pooled RR = 1.87, 95%CrI: 1.13, 3.18). LEPT is most likely to be the best operation concerning infection (66.32%). Compared with LEPT, OD was associated with a significantly higher incidence of soiling (pooled RR = 1.91, 95%CrI: 1.16, 3.17). Patients with LEPT had the greatest likelihood not to develop soiling (86.16%). In contrast to LD, LEPT was significantly more effective in reducing the incidence of constipation (pooled RR = 0.39, 95%CrI: 0.15, 0.97). LEPT was most likely not to result in constipation (97.81%). LEPT was associated with a significantly lower incidence of Hirschprung-associated enterocolitis (HAEC) than LD (pooled RR = 0.34, 95%CrI: 0.13, 0.85). The OD group had a significantly higher incidence of HAEC than the LEPT group (pooled RR = 2.29, 95%CrI: 1.31, 4.0). The incidence of HAEC was significantly greater in the TEPT group versus the LEPT group (pooled RR = 1.74, 95%CrI: 1.24, 2.45). LEPT was most likely to be the optimal operation in terms of HAEC (98.76%). CONCLUSION: LEPT may be a superior operation to OD, LD and TEPT in improving operation condition and complications, which might serve as a reference for Hirschsprung disease treatment.

Experiences of youth growing up with anorectal malformation or Hirschsprung's disease: a multicenter qualitative in-depth interview study.

PURPOSE: Patients with anorectal malformation (ARM) and Hirschsprung's disease (HD) live with long-term impact of these diseases even into adulthood. We aimed to explore the physical, social and emotional impact of these diseases in adolescents and young adults to develop best practices for transition care. METHODS: We conducted one-on-one in-depth interviews with ARM and HD patients aged ≥ 11 years who had undergone surgery at four tertiary referral centers. All interviews were audio-recorded and transcribed verbatim. We analyzed transcripts for recurring themes, and data were collected until data saturation was reached. Three researchers independently coded the transcripts for major themes using thematic analysis approach. RESULTS: We interviewed 16 participants (11 males) between October 2022 and April 2023. Ages ranged from 11 to 26 years. Five major themes emerged: (1) personal impact (subthemes: physical, emotional and mental health, social, school), (2) impact on family, (3) perceptions of their future (subthemes: relationships, career, state of health), (4) sources of support (subthemes: family, peers, partner), and (5) transition care (subthemes: concerns, expectations). Only females expressed concerns regarding future fertility. CONCLUSION: This study highlights the evolving problems faced by adolescents and young adults with ARM and HD, especially gender-specific concerns. Our findings can inform efforts to provide individualized care.

Altered oral microbiome, but normal human papilloma virus prevalence in cartilage-hair hypoplasia patients.

BACKGROUND: Cartilage-hair hypoplasia (CHH) is a rare syndromic immunodeficiency with metaphyseal chondrodysplasia and increased risk of malignancy. In this cross-sectional observational study, we examined HPV status and oral microbiome in individuals with CHH. Oral brush samples were collected from 20 individuals with CHH (aged 5-59 years) and 41 controls (1-69 years). Alpha HPVs (43 types) were tested by nested PCR followed by bead-based probe hybridization. Separately, beta-, gamma-, mu- and nu- HPV types were investigated, and a genome-based bacterial microbiome sequencing was performed. RESULTS: We found a similar alpha HPV prevalence in individuals with CHH (45%) and controls (36%). The HPV types of individuals with CHH were HPV-16 (25%), 27, 28, and 78, and of controls HPV-3, 16 (21%), 27, and 61. Beta HPV positivity and combined beta/gamma/mu/nu prevalence was detected in 11% and 11% of individuals with CHH and in 5% and 3% of the controls, respectively. Individuals with CHH differed from the controls in bacterial microbiota diversity, richness, and in microbial composition. Individuals with CHH had lower abundance of species Mitsuokella sp000469545, Parascardovia denticolens, Propionibacterium acidifaciens, UMGS1907 sp004151455, Salinicola halophilus, Haemophilus_A paraphrohaemolyticus, Fusobacterium massiliense, and Veillonella parvula, and higher abundance of Slackia exigua. CONCLUSIONS: Individuals with CHH exhibit similar prevalence of HPV DNA but different bacterial microbiota on their oral mucosa compared to healthy controls. This may partly explain the previously observed high prevalence of oral diseases in CHH, and regular oral examination is warranted.

Non-syndromic Hirschsprung's disease as a result of a RET gene variant. / Enfermedad de Hirschsprung no sindrómica por variante en el gen RET.

INTRODUCTION: Hirschsprung's disease (HD) is characterized by the absence of ganglion cells in the submucosal and myenteric plexuses of the colon as a result of disorders in the migration and differentiation of enteric neural crest cells during embryogenesis. It is a cross-factor condition, with more than 11 genes identified in its pathogenesis, including the RET proto-onco gene. CASE REPORTS: We present the case of two siblings with total colon HD where a potentially pathogenic variant of the RET gene was found. Their father also had this condition. DISCUSSION: Prenatal diagnosis through genetic testing allows for informed decisions and care planning for the newborn, thus reducing delayed diagnosis and treatment, and minimizing long-term complications. Mutations such as the RET gene variant highlight the importance of the genetic approach in understanding and managing HD.

INTRODUCCION: La enfermedad de Hirschsprung (EH) se caracteriza por la ausencia de células ganglionares en los plexos submucoso y mientérico del intestino grueso, resultante de deficiencias en la migración y diferenciación de las células de la cresta neural entérica durante la embriogénesis. Es una condición multifactorial, con más de 11 genes identificados en su patogénesis, incluyendo el protooncogén RET. CASO CLINICO: Se presenta el caso de dos hermanos con EH de colon total, cuyo padre también padeció la enfermedad, y en quien se encontró una variante potencialmente patogénica en el gen RET. COMENTARIOS: El diagnóstico prenatal mediante pruebas genéticas permite decisiones informadas y la planificación de cuidados para el neonato afectado, reduciendo demoras en el diagnóstico y tratamiento, y minimizando las complicaciones a largo plazo. La identificación de mutaciones como la variante en el gen RET destaca la importancia del enfoque genético en la comprensión y manejo de la EH.

Clinical characteristics and influence of postoperative Hirschsprung-associated enterocolitis: retrospective study at a tertiary children's hospital.

PURPOSE: To explore the influence of postoperative Hirschsprung-associated enterocolitis (post-HAEC) on long-term outcomes and to identify risk factors of post-HAEC. METHODS: The medical records of 304 eligible patients diagnosed with Hirschsprung's disease (HSCR) were reviewed. We analyzed the clinical characteristics of post-HAEC and its influence on long-term outcomes. Furthermore, risk factors for early and recurrent HAEC were identified separately. RESULTS: The overall incidence of post-HAEC was 29.9% (91/304). We categorized early HAEC as occurring within postoperative 3 months (n = 39) and recurrent HAEC as occurring ≥ 3 episodes within postoperative 6 months (n = 25). Patients with early HAEC were more likely to experience worse nutritional status, defecation function, and quality of life compared to those with late or no episodes (P < 0.05). Similarly, the adverse influences of recurrent HAEC on these outcomes were also significant (P < 0.05). The risk factors for early HAEC included preoperative undernutrition, long-segment HSCR, and postoperative Grade 3-4 complications within 30 days. For recurrent HAEC, risk factors were preoperative malnutrition, non-parental caregivers, long-segment HSCR, and postoperative Grade 3-4 complications within 30 days. CONCLUSION: Classification of post-HAEC based on the first episode time and frequency was necessary. The earlier or more frequent episodes of post-HAEC have detrimental influences on long-term outcomes. Furthermore, risk factors for early and recurrent HAEC were different.

Impact of Colorectal Nurse Specialist supervised parental administration of rectal washouts on Hirschsprung's disease outcomes: a retrospective review.

PURPOSE: To highlight the utility of Colorectal Nurse Specialist (CNS) supervised parental administration of rectal washouts in the management of Hirschsprung's disease (HD). METHODS: Retrospective case note review of HD patients treated at a tertiary children's hospital in United Kingdom from January 2011 to December 2022. Data collected included demographics, complications, enterocolitis, obstructive symptoms and stomas. Primary pull-through (PT) is done 8-12 weeks after birth. Parental expertise in performing rectal washouts at home is ensured by our CNS team before and after PT. RESULTS: PT was completed in 69 of 74 HD patients. Rectal washouts were attempted on 63 patients before PT. Failure of rectal washout efficacy necessitated a stoma in four patients (6.4%). Of the 65 patients who had PT and stoma closed, three (4.5%) required a further stoma over a mean follow-up period of 57 months (Range 7-144 months). Two of these had intractable diarrhoea due to Total Colonic Aganglionosis (TCA). One patient (1.5%) had unmanageable obstructive symptoms requiring re-diversion. Hirschsprung-associated enterocolitis (HAEC) requiring hospital admission occurred in 14 patients (21%). CONCLUSION: Our stoma rates are lower compared to recent UK data. This could potentially be due to emphasis on parental ability to perform effective rectal washouts at home under CNS supervision.

Autologous cell transplantation for treatment of colorectal aganglionosis in mice.

Neurointestinal diseases cause significant morbidity and effective treatments are lacking. This study aimes to test the feasibility of transplanting autologous enteric neural stem cells (ENSCs) to rescue the enteric nervous system (ENS) in a model of colonic aganglionosis. ENSCs are isolated from a segment of small intestine from Wnt1::Cre;R26iDTR mice in which focal colonic aganglionosis is simultaneously created by diphtheria toxin injection. Autologous ENSCs are isolated, expanded, labeled with lentiviral-GFP, and transplanted into the aganglionic segment in vivo. ENSCs differentiate into neurons and glia, cluster to form neo-ganglia, and restore colonic contractile activity as shown by electrical field stimulation and optogenetics. Using a non-lethal model of colonic aganglionosis, our results demonstrate the potential of autologous ENSC therapy to improve functional outcomes in neurointestinal disease, laying the groundwork for clinical application of this regenerative cell-based approach.

Children with Hirschsprung disease exhibited alterations in host-microbial co-metabolism after pull-through operation.

PURPOSE: This study aims to compare the fecal metabolome in post pull-through HD with and without HAEC patients and healthy young children using nuclear magnetic resonance (NMR) spectroscopy. METHODS: Fresh fecal samples were collected from children under 5 years of age in both post-pull-through HD patients and healthy Thai children. A total of 20 fecal samples were then analyzed using NMR spectroscopy. RESULTS: Thirty-four metabolites identified among HD and healthy children younger than 5 years were compared. HD samples demonstrated a significant decrease in acetoin, phenylacetylglutamine, and N-acetylornithine (corrected p value = 0.01, 0.04, and 0.004, respectively). Succinate and xylose significantly decreased in HD with HAEC group compared to HD without HAEC group (corrected p value = 0.04 and 0.02, respectively). Moreover, glutamine and glutamate metabolism, and alanine, aspartate, and glutamate metabolism were the significant pathways involved, with pathway impact 0.42 and 0.50, respectively (corrected p value = 0.02 and 0.04, respectively). CONCLUSION: Differences in class, quantity, and metabolism of protein and other metabolites in young children with HD after pull-through operation were identified. Most of the associated metabolic pathways were correlated with the amino acids metabolism, which is required to maintain intestinal integrity and function.

CLINICAL FEATURES OF THE COURSE OF HIRSCHSPRING'S DISEASE INCHILDREN OF THE FIRST YEAR.

The purpose of the work - to investigate the peculiarities of the clinical course of Hirschsprung's disease in children of the first year of life and to determine the significance of symptoms in the verification of the disease. From 1980 to 2021, at the pediatric surgery clinic of the National Medical University named after O.O. Bogomolets on the basis of the National Children's Specialized Hospital "OKHMATDYT" and in the pediatric surgery clinic of the Ivano-Frankivsk National Medical University on the basis of the Ivano-Frankivsk Regional Children's Clinical Hospital, 483 children of the first year of life suffering from Hirschsprung's disease were examined and treated. The clinical manifestation and course of aganglionosis varied in length at the time of hospitalization and depended on the time after birth. During the first month of life, 97 (20.08%) patients were hospitalized, of which 39 (8.07%) hadatypical clinical picture due to: colonic atresia in 15 (3.10%), colonic atresia + gastroschisis in 3 (0.62%), ileal atresia in 9 (1.86%), esophageal atresia in 3 (0 .62%), clefts of the hard and soft palate in 9 (1.86%). Depending on the age, there were 280 (57.97%) patients under 6 months, and 203 (42.03%) patients between 6 months and 1 year. The classic typical clinical picture was in 444 (91.93%) patients, which was characterized by the absence of meconium excretion, abdominal distension in 444 (91.93%), delayed physiological weight gain against the background of nutritional insufficiency with the development of hypotrophy in 327 (67.70%) , vomiting of stagnant gastric and intestinal contents in 417 (86.34%). On the other hand, enterocolitis in 315 (65.22%), toxic megacolon in 16 (3.31%), and anemia of various degrees occurred in 241 (49.89%) patients among the complications that arose during the examination of patients with Hirschsprung's disease. According to the results of a comprehensive examination, the following extent of aganglionosis was established: rectal in 100 (20.70%), rectosigmoid in 192 (39.75%), subtotal in 150 (31.06%) and total in 41 (8.49%) patients. Concomitant malformations were found in 98 (20.29%) patients: renal malformations were diagnosed in 7 (1.45%) patients, concomitant heart malformations in 18 (3.73%) patients. Associated intraoperative findings were Meckel's diverticulum in 5 (1.03%) and congenital cyst of the right ovary in 1 (0.21%) patient. The clinical course was affected by concomitant malformations: incomplete bowel rotation in 10 (2.07%) and internal abdominal hernia in 2 (0.42%). The clinical manifestations and course of Hirschsprung's disease primarily depend on the presence of accompanying developmental defects, which may prevail during the examination due to vital disorders. In the clinical course of Hirschsprung's disease, it is necessary to distinguish between typical and atypical forms. Typical clinical symptoms were in 444 (91.93%), and atypical in 39 (8.07%).

Delayed diagnosis in Hirschsprung disease.

INTRODUCTION: Diagnostic delay in Hirschsprung disease is uncommon. Different definitions have been proposed but that of a diagnosis achieved after 12 months of age seems to be the most reliable and resorted to. Some authors reported a worse outcome in case of delay. Our study aims at providing the most relevant features of a series of patients who received a delayed diagnosis of Hirschsprung disease. MATERIALS AND METHODS: All consecutive patients admitted to our Center with a delayed diagnosis of Hirschsprung diseases between January 2017 and July 2023 have been retrospectively enrolled. Demographic data, phenotype, genotype, surgical complications, and outcome were assessed and compared to those of literature. A number of variables were also compared to those of a series of patients admitted during the same study period without a delayed diagnosis. RESULTS: A total of 45 patients were included (16.4% out of a series of 346 patients with data regarding age at diagnosis). Male to female ratio was 3.1:1. Median age at diagnosis was 41 months with a wide variation (range between 17 months and 58 years). All patients but 2 suffered from classic rectosigmoid aganglionosis. Normal meconium passage (58%) was reported in a significantly higher number of patients compared to what observed in a series without diagnostic delay (p = 0.0140). All other variables (associated anomalies, preoperative enterocolitis, complications, and functional outcome) proved not to have statistically significant differences compared to a series of patients without a diagnostic delay. CONCLUSIONS: The results of our study underline that a significant percentage of patients are basically missed in the neonatal period mostly due to mild symptoms. Overall outcome does not differ from that of patients without diagnostic delay. Nonetheless, we underline the importance of a throughout investigation of all patients with meconium delay/failure and that of adopting a low threshold for performing rectal suction biopsies in constipated children to avoid misdiagnosis to serve the best for our patients.

Aberrant SOX10 and RET expressions in patients with Hirschsprung disease.

BACKGROUND: HSCR is a complex genetic disorder characterized by the absence of ganglion cells in the intestine, leading to a functional obstruction. It is due to a disruption of complex signaling pathways within the gene regulatory network (GRN) during the development of the enteric nervous system (ENS), including SRY-Box Transcription Factor 10 (SOX10) and REarranged during Transfection (RET). This study evaluated the expressions of SOX10 and RET in HSCR patients in Indonesia. METHODS: Total RNA of 19 HSCR ganglionic and aganglionic colons and 16 control colons were analyzed using quantitative real-time polymerase chain reaction for SOX10 and RET with GAPDH as the reference gene. Livak's method (2-ΔΔCT) was used to determine the expression levels of SOX10 and RET. RESULTS: Most patients were males (68.4%), in the short aganglionosis segment (78.9%), and had undergone transanal endorectal pull-through (36.6%). There were significant upregulated SOX10 expressions in both ganglionic (2.84-fold) and aganglionic (3.72-fold) colon of HSCR patients compared to controls' colon (ΔCT 5.21 ± 2.04 vs. 6.71 ± 1.90; p = 0.032; and ΔCT 4.82 ± 1.59 vs. 6.71 ± 1.90; p = 0.003; respectively). Interestingly, the RET expressions were significantly downregulated in both ganglionic (11.71-fold) and aganglionic (29.96-fold) colon of HSCR patients compared to controls' colon (ΔCT 12.54 ± 2.21 vs. 8.99 ± 3.13; p = 0.0004; and ΔCT 13.90 ± 2.64 vs. 8.99 ± 3.13; p = 0.0001; respectively). CONCLUSIONS: Our study shows aberrant SOX10 and RET expressions in HSCR patients, implying the critical role of SOX10 and RET in the pathogenesis of HSCR, particularly in the Indonesian population. Our study further confirms the involvement of SOX10-RET within the GNR during the ENS development.

Skipped Aganglionic Lengthening Transposition (SALT) is highly effective to achieve enteral autonomy in selected patients with intestinal failure secondary to total intestinal aganglionosis.

BACKGROUND: Intestinal Failure, parenteral nutrition (PN) dependence, and subsequent liver disease are the most challenging and life-threatening complications of short bowel syndrome experienced by patients with total intestinal aganglionosis. Skipped Aganglionic Lengthening Transposition (SALT) showed to be a promising procedure to overcome such problems. We herein report the results of two patients who underwent SALT at the Umberto Bosio Center for Digestive Diseases. PATIENTS AND METHODS: Between November 2019 and July 2022, 2 patients with total intestinal aganglionosis underwent SALT as autologous intestinal lengthening procedure. Perioperative data and long-term outcomes are reported. Patient #1-A 18 month-old male (PN dependant) with 30 cm of ganglionated bowel at birth experienced a 35% increase of intestinal length after SALT (from 43 to 58 cm) thanks to three 5 cm interposed aganglionic loops. Postoperative course was uneventful and he was totally weaned by PN after 28 months postoperatively. He is without PN only receiving enteric feeding 53 months after the procedure. Patient #2-A 11 year-old female (PN dependant) with 100 cm of ganglionated jejunum underwent SALT at 11 years and experienced a 19% increase of bowel length thanks to four 5 to 7 cm interposed aganglionic loops. Postoperatively she required excision of two out of the four loops due to severe strictures and inadequate perfusion with a subsequent overall 10% increase of length after SALT. Of note, she improved significantly with a progressive reduction of PN that has been stopped after 18 months. CONCLUSION: Skipped aganglionic lengthening transposition (SALT) seems to be very effective in improving nutrients absorption in patients with total intestinal aganglionosis by increasing absorptive bowel surface and decelerating intestinal flow for a longer and more effective contact of enteric material with ileal mucosa. Provided these impressive results are confirmed in the very long-term, SALT could become a valid alternative for the treatment of patients with total intestinal aganglionosis carrying at birth at least 20 to 30 cm of ganglionated jejunum.

RMRP-related short stature: A report of six additional Japanese individuals with cartilage hair hypoplasia and literature review.

Biallelic pathogenic variants in RMRP, the gene encoding the RNA component of RNase mitochondrial RNA processing enzyme complex, have been reported in individuals with cartilage hair hypoplasia (CHH). CHH is prevalent in Finnish and Amish populations due to a founder pathogenic variant, n.71A > G. Based on the manifestations in the Finnish and Amish individuals, the hallmarks of CHH are prenatal-onset growth failure, metaphyseal dysplasia, hair hypoplasia, immunodeficiency, and other extraskeletal manifestations. Herein, we report six Japanese individuals with CHH from four families. All probands presented with moderate short stature with mild metaphyseal dysplasia or brachydactyly. One of them had hair hypoplasia and the other immunodeficiency. By contrast, the affected siblings of two families showed only mild short stature. We also reviewed all previously reported 13 Japanese individuals. No n.71A > G allele was detected. The proportions of Japanese versus Finnish individuals were 0% versus 70% for birth length < -2.0 SD, 84% versus 100% for metaphyseal dysplasia and 26% versus 88% for hair hypoplasia. Milder manifestations in the Japanese individuals may be related to the difference of genotypes. The mildest form of CHH phenotypes is mild short stature without overt skeletal alteration or extraskeletal manifestation and can be termed "RMRP-related short stature".

Prevalence of Mental Health Disorders in Individuals With Gastrointestinal Congenital Surgical Anomalies: A Systematic Review and Meta-analysis.

PURPOSE: Studies examining functional outcomes and health-related quality of life for patients with congenital surgical anomalies (CSA) are increasingly common. However, the prevalence of mental health disorders in this population has not been determined. The purpose of this review is to summarize the reported prevalence of mental health disorders in children born with gastrointestinal CSA. METHODS: A systematic review of the literature was conducted on Medline (OVID), EMBASE (OVID), CINAHL (EbscoHost), and Scopus to identify studies reporting mental health diagnoses in children with a gastrointestinal CSA. A meta-analysis of the prevalence of anxiety disorders and depressive disorders was completed. RESULTS: Of 2546 manuscripts, seven met the inclusion criteria. All included manuscripts looked at patients with anorectal malformation (ARM) and/or Hirschsprung disease (HD). No studies assessed other gastrointestinal CSAs. A total of 183 psychiatric diagnoses were reported in 1167 patients. A pooled analysis of ARM patients revealed a 14.0% prevalence of anxiety disorders (N = 208; CI95 = 4.4-23.4%) and an 18.75% prevalence of depressive disorders (N = 48; CI95 = 7.7-29.8%). A pooled analysis of HD patients revealed a 15.8% prevalence of anxiety disorders (N = 19; CI95 = 0.6-32.2%) and a 4.75% prevalence of depressive disorders (N = 758; CI95 = 3.23-6.26%). CONCLUSIONS: There is a paucity of evidence on mental health outcomes of individuals born with gastrointestinal CSA. However, the available evidence suggested a high prevalence of mental health diagnoses in individuals born with ARM or HD with 1 in 7 having an anxiety disorder. Additionally, 1 in 5 ARM patients and 1 in 20 HD patients were diagnosed with a depressive disorder. TYPE OF STUDY: Systematic review and meta-analysis. LEVEL OF EVIDENCE: IV.

Agrin Inhibition in Enteric Neural Stem Cells Enhances Their Migration Following Colonic Transplantation.

Regenerative cell therapy to replenish the missing neurons and glia in the aganglionic segment of Hirschsprung disease represents a promising treatment option. However, the success of cell therapies for this condition are hindered by poor migration of the transplanted cells. This limitation is in part due to a markedly less permissive extracellular environment in the postnatal gut than that of the embryo. Coordinated interactions between enteric neural crest-derived cells (ENCDCs) and their local environment drive migration along the embryonic gut during development of the enteric nervous system. Modifying transplanted cells, or the postnatal extracellular environment, to better recapitulate embryonic ENCDC migration could be leveraged to improve the engraftment and coverage of stem cell transplants. We compared the transcriptomes of ENCDCs from the embryonic intestine to that of postnatal-derived neurospheres and identified 89 extracellular matrix (ECM)-associated genes that are differentially expressed. Agrin, a heparin sulfate proteoglycan with a known inhibitory effect on ENCDC migration, was highly over-expressed by postnatal-derived neurospheres. Using a function-blocking antibody and a shRNA-expressing lentivirus, we show that inhibiting agrin promotes ENCDC migration in vitro and following cell transplantation ex vivo and in vivo. This enhanced migration is associated with an increased proportion of GFAP + cells, whose migration is especially enhanced.

Translation and validation of the Hirschsprung and anorectal malformation quality of life (HAQL) questionnaire in a Danish Hirschsprung population.

BACKGROUND: Hirschsprung's disease (HD) may result in an impaired quality of life (QoL) due to bowel problems, postoperative complications and other health-related issues. The Hirschsprung and Anorectal Malformation Quality of Life (HAQL) questionnaire is a disease-specific instrument developed in the Netherlands to measure the QoL in patients with HD and anorectal malformations. The aim of this study was to translate, culturally adapt and validate HAQL in a Danish Hirschsprung population. MATERIAL AND METHODS: Translation and cultural adaptation were performed according to international guidelines. Invitations to participate in the validation were sent to 401 patients operated for HD during the period from 1985 to 2012. A total of 156 patients completed the translated and culturally adapted Danish versions of HAQL and 35 parents of children and adolescents completed the corresponding parent questionnaire. Reliability was evaluated in terms of internal consistency using Cronbach's α and test-retest reliability using Intraclass Correlation Coefficient for the retest step. Known groups comparison was performed with comparison of mild HD (defined as recto-sigmoidal HD) and serious HD (defined as more proximal disease). RESULTS: The internal consistency of the dimensions was overall satisfactory for adults and adolescents but more problematic for children, where Cronbach's α was less than 0.7 in 60% of the dimensions. For both children and adolescents, the α-value was unsatisfactory for social functioning, emotional functioning, and body image. The test-retest reliability was overall good. The known groups comparison was only able to demonstrate a significant difference between mild and severe HD within one dimension. CONCLUSIONS: The translated version of the HAQL questionnaires provides an overall reliable instrument for evaluating disease-specific QoL in a Danish HD population, but it is important to acknowledge the limitations of the questionnaire, especially in children and adolescents.

Neurodevelopmental evaluation of children who were operated due to congenital anomaly with the 'Ages and Stages Questionnaire (ASQ)' and 'ASQ: Social-Emotional'.

BACKGROUND: The purpose of surgeries performed for congenital anomalies in children is to increase the survival rates and provide a developmental comparison to that of their peers. AIM: The objective of this study was to investigate the development of children following surgery for congenital anomalies and the risk factors affecting their development. METHODS: Our study included 33 children who underwent surgery for gastrointestinal anomalies in our clinic between 2011 and 2016, and did not have any syndrome, chromosomal abnormality, or additional abnormality. Developmental levels were evaluated using the Ages and Stages Questionnaire (ASQ) and the ASQ: Social-Emotional (ASQ: SE) scales adapted for the use on Turkish children. Data on patient history were obtained retrospectively from patient files. RESULTS: The study included 33 patients, including 11 with esophageal atresia, 6 with intestinal atresia, 11 with anorectal malformation, and 5 with Hirschsprung's disease. Developmental delay was found in the ASQ of 72.7% of the patients and the ASQ: SE tool was 27% of the patients. The rate of patients with scores below the threshold from each parameter of ASQ was higher than that of the normal population (p < 0.05). Development delay was detected using the ASQ scale in 100% of those with microcephaly at birth, in 91% of premature infants born between 1500 and 2500 g, and in 83.3% of those with low birth weight to gestational age. CONCLUSIONS: In children who underwent surgery due to congenital anomalies, an evaluation through developmental tests, a post-surgical follow-up process, and a referral to the relevant disciplines when necessary may increase the success of surgery as well as increase the life quality of the patient.

Unilateral progressive anterior iris adhesions in Mowat-Wilson syndrome: a new ocular finding.

Ocular associations in Mowat-Wilson syndrome (MWS) are rare. Those involving the anterior segment are scarce in the literature. We describe a child with genetic confirmation of MWS that presented with acquired onset of unilateral anterior iris adhesions with no known trauma.