Bowel function, urinary tract function, and health-related quality of life in males with anorectal malformations.

PURPOSE: There is a knowledge gap regarding long-term outcomes for males undergoing surgery for an anorectal malformation (ARM). The purpose of this study was to investigate bowel function, bladder function, and health-related quality of life (HRQoL) in male patients with an anorectal malformation. METHODS: This cross-sectional questionnaire-based study included males treated for ARM at our institution between 1994 and 2017. Bowel function was assessed with bowel function score (BFS) while urinary tract function was assessed with lower urinary tract symptoms (LUTS) questionnaires. Health-related quality of life (HRQoL) was investigated using age-relevant questionnaires (KIDSCREEN and PGWBI). Patient characteristics were retrospectively collected from the medical records and descriptive statistics were used for analysis. Functional outcomes were compared with gender and age-matched controls while HRQoL was compared to normative data. The study was approved by ethics review authorities. RESULTS: A total of 58 (44.6%) of 130 males responded to the questionnaires. Regarding bowel function, 24 (42.1%) of 57 patients and 81 (95.3%) of 85 controls, respectively, reported a well-preserved bowel function represented by a BFS ≥ 17 (p < 0.001). Soiling issues and 'feels urge' items improved significantly with age. In a linear regression model, BFS increased significantly with age. For most parameters, the proportion of ARM patients with lower urinary tract symptoms was larger, though not significantly, compared to the controls. However, straining and stress incontinence were reported significantly more often by ARM patients. In patients and controls, voiding outcomes in terms of prevalence of having symptoms and the number of cumulative symptoms drop with increasing age. Children and adults reported similar or, in some domains, better HRQoL outcomes when compared to normative European data. CONCLUSION: Bowel function is impaired in male patients with ARM but significantly improves with age. Urinary tract function was affected, but overall comparable to the controls. HRQoL was unaffected. No significant association between the studied outcomes could be shown. LEVEL OF EVIDENCE: III.

National Centralization of Hirschsprung's Disease in Sweden:A Comparison of Preoperative Management and Outcomes.

BACKGROUND: Surgical treatment of Hirschsprung's disease (HSCR) in Sweden was centralized to two tertiary pediatric surgery centers 1st of July 2018. Although complex surgical care in adults seems to benefit from centralization there is little evidence to support centralization of pediatric surgical care. The aim of this study was to assess centralization of HSCR in Sweden, with special consideration to preoperative management and outcomes in this group of patients. METHODS: This study retrospectively analyzed data of patients with HSCR that had undergone or were planned to undergo pull-through at our center, from 1st of July 2013 to 30th of June 2023. Patients managed from 1st of July 2013 to 30th of June 2018 were compared with patients managed from 1st of July 2018 to 30th of June 2023 regarding diagnostic procedures, preoperative treatment, complications and time to definitive surgery. RESULTS: Thirty-six patients were managed during the first five-year period compared to 57 during the second period. There was an increased number of patients referred from other Swedish regions to our center following the centralization. Time from diagnosis to pull-through increased from 33 to 55 days after centralization. There were no significant differences in pre-operative management or complications, general or related to stoma. CONCLUSIONS: Despite increasing patient volumes and longer time from diagnosis to pull through, centralization of care for HSCR does not seem to change the preoperative management and risk of complications. With access to support from the specialist center, transanal irrigations remain a safe mode of at home management until surgery, regardless of distance to index hospital. LEVEL OF EVIDENCE: Level III.

Ernica Clinical Consensus Statements on Total Colonic and Intestinal Aganglionosis.

BACKGROUND: Hirschsprung disease is a congenital intestinal motility disorder characterized by an absence of enteric ganglion cells. Total colonic aganglionosis and near total or total intestinal aganglionosis, defined as absence of ganglion cells in the entire colon and with variable length of small bowel involved, are life-threatening conditions which affect less than 10 % of all patients with Hirschsprung disease. The aim of this project was to develop clinical consensus statements within ERNICA, the European Reference Network for rare congenital digestive diseases, on four major topics: Surgical treatment of total colonic aganglionosis, surgical treatment of total intestinal aganglionosis, management of poor bowel function in total colonic and/or intestinal aganglionosis and long-term management in total colonic and or intestinal aganglionosis. METHODS: A multidisciplinary panel of representatives from ERNICA centers was invited to participate. Literature was searched, using specified search terms, in Medline (ALL), Embase and Google Scholar. Abstracts were screened and full text publications were selected. The panel was divided in four groups that extracted data from the full text publications and suggested draft statements for each of the major topics. A modified Delphi process was used to refine and agree on the statements. RESULTS: The consensus statement was conducted by a multidisciplinary panel of 24 participants from 10 European countries, 45 statements reached consensus after 3 Delphi-rounds. The availability of high-quality clinical evidence was limited, and most statements were based on expert opinion. Another 25 statements did not reach consensus. CONCLUSIONS: Total colonic and total intestinal aganglionosis are rare variants of Hirschsprung disease, with very limited availability of high-quality clinical evidence. This consensus statement provides statements on the surgical treatment, management of poor bowel function and long-term management for these rare patients. The expert panel agreed that patients benefit from multidisciplinary and personalized care, preferably in an expert center. TYPE OF STUDY: Clinical consensus statement. LEVEL OF EVIDENCE: 3a.

Delivery mode and risk of gastrointestinal disease in the offspring.

INTRODUCTION: The global increase of individuals born by cesarean section with reported levels up to 20% of all deliveries, makes it important to study cesarean section and possible associations that can increase risk of subsequent diseases in children. The aim of the study was to evaluate if cesarean section is associated with increased risk of gastrointestinal disease later in life in a large population-based cohort. MATERIAL AND METHODS: In this national population-based cohort study including all full-term individuals registered in the Medical Birth Register in Sweden between 1990 and 2000, type of delivery (exposure) was collected from the Medical Birth Register. The study population was followed until 2017 with regards to the outcomes: inflammatory bowel disease (Crohn's disease or ulcerative colitis), appendicitis, cholecystitis, or diverticulitis registered in the Swedish National Patient Register. Cox proportional-hazards models compared disease-free survival time between exposed and unexposed. RESULTS: The final study population consisted of 1 102 468 individuals of whom 11.6% were delivered by cesarean section and 88.4% were vaginally delivered. In univariate analysis, cesarean section was associated with Crohn's disease (hazard ratio [HR] 1.13, 95% confidence interval [CI] 1.02-1.25), diverticulosis (HR 1.57, 95% CI 1.13-2.18), and cholecystitis (HR 1.16, 95% CI 1.05-1.28). However, the increased risk only remained for Crohn's disease after adjustment for confounders (HR 1.14, 95% CI 1.02-1.27). No associations between delivery mode and appendicitis, ulcerative colitis, cholecystitis, or diverticulosis were found in the multivariate analysis. CONCLUSIONS: Cesarean section is associated with Crohn's disease later in life, but no other association between delivery mode and gastrointestinal disorders later in life could be found.

The risk of inflammatory bowel disease after bariatric surgery.

BACKGROUND: The association between bariatric surgery and new onset of inflammatory bowel disease has so far only been sparsely studied and with conflicting results. OBJECTIVES: To investigate the association between bariatric surgery and inflammatory bowel disease in a large population-based cohort. SETTING: Nationwide in Sweden. METHODS: This population-based retrospective cohort study included Swedish individuals registered in the Scandinavian Obesity Surgery Registry who underwent primary Roux-en-Y gastric bypass or sleeve gastrectomy during 2007-2018. Ten control individuals from the general population were matched according to age, sex, and region of residence at time of exposure. The study population was followed until 2019 with regard to the development of inflammatory bowel disease. Cox proportional hazards models were used to compare disease-free survival time between subgroups and control individuals for each outcome. RESULTS: The final cohort consisted of 64,188 exposed individuals with a total follow-up of 346,860 person-years and 634,530 controls with total follow-up of 3,444,186 person-years. Individuals who underwent Roux-en-Y-gastric bypass had an increased risk of later development of Crohn's disease (hazard ratio [HR] 1.8, 95% CI 1.5-2.2) and unclassified inflammatory bowel disease (HR 2.7, 95% CI 2.0-3.7) but not ulcerative colitis (HR .9, 95% CI .8-1.1) compared with control individuals, whereas individuals who underwent sleeve gastrectomy had an increased risk of ulcerative colitis (HR 1.8, 95% CI 1.1-3.1) but not Crohn's disease (HR .8, 95% CI .3-2.1) and unclassified inflammatory bowel disease (HR 2.5, 95% CI .8-7.8). CONCLUSIONS: Roux-en-Y gastric bypass was associated with increased risk of Crohn's disease and unclassified inflammatory bowel disease, whereas sleeve gastrectomy was associated with increased risk of ulcerative colitis only.

Evaluation of Bowel Function, Urinary Tract Function, and Quality of Life after Transanal Endorectal Pull-Through Surgery for Hirschsprung's Disease.

INTRODUCTION: The objective of this study is to determine short-term complications and evaluate long-term bowel function, lower urinary tract symptoms, and quality of life (QoL) in patients treated for Hirschsprung's disease (HSCR) with transanal endorectal pull-though (TERPT) compared with healthy controls. MATERIALS AND METHODS: This cross-sectional case-control study included 30 HSCR patients treated with TERPT in 2006 to 2014 at Karolinska University Hospital, and 30 healthy controls matched for age and gender. Data on short-term complications were compiled from medical records and classified according to Clavien-Dindo. Bowel function and QoL were evaluated with the validated questionnaires bowel function score and KIDSCREEN-52. Lower urinary tract symptoms were evaluated through an 8-item lower urinary tract symptoms (LUTS) questionnaire. RESULTS: Six (20%) patients had a short-term postoperative complication according to Clavien-Dindo, with insufficient pain management being the most common complication. The median age at follow-up was 7 years (range = 4-11). Median bowel function score was significantly lower in HSCR patients than in controls, 14 versus 19 (p < 0.001). Twenty-one of the HSCR patients reported impaired bowel function compared with two of the controls (p < 0.001). The overall prevalence of LUTS was 11 (38%) in the HSCR patients compared with seven (23%) in the controls (p = 0.751). HSCR patients reported a slightly lower QoL in the KIDSCREEN domain "financial resources" compared with controls (p = 0.008). CONCLUSION: According to Clavien-Dindo, short-term postoperative complications occurred in 20% of the patients. Impaired bowel function persists throughout childhood for most HSCR patients. The prevalence of LUTS and QoL is not affected in HSCR patients compared with controls.

Clinical characteristics and validation of diagnosis in individuals with Hirschsprung disease and inflammatory bowel disease.

BACKGROUND/PURPOSE: Hirschsprung disease has previously been reported to be associated with inflammatory bowel disease (IBD). The aim was to clinically confirm the diagnosis and to describe characteristics among individuals with both conditions in a national populationbased cohort. METHODS: Nationwide, population-based cohort study, including all individuals with a Hirschsprung disease diagnosis and an IBD diagnosis registered between 1964 and 2016, in which clinical data were collected from the medical records of 18 validated cases with both Hirschsprung disease and IBD. The medical record of each individual in the study cohort was reviewed for age at IBD diagnosis, type of aganglionosis, type of surgical treatment, subtype of IBD, and treatment for IBD. RESULTS: Median age at follow up was 34 years (range 19-66), and 3 of 18 indivduals (17%) were females. Median age at first diagnosis of IBD was 21 years (range 10-46). Six patients had ulcerative colitis, ten had Crohn's disease and two had unclassified IBD. Most of the patients had pharmacological treatment for IBD and 5 (28%) individuals had surgical treatment. CONCLUSION: Hirschsprung disease and IBD was clinically confirmed in 18 cases. Age at IBD onset and subtype of IBD is similar to IBD patients without Hirschsprung disease. Five individuals had undergone surgical treatment for IBD.

The overall risk of malignancies is not increased in patients with Hirschsprung disease.

PURPOSE: Hirschsprung disease (HSCR) has previously been associated with increased risk of medullary thyroid cancer. The aim of this study was to assess the overall risk of malignancies in patients with Hirschsprung disease in a population-based cohort. METHODS: This was a nationwide, population-based cohort study. The study exposure was HSCR and the study outcome was malignancy. The cohort included all individuals with HSCR registered in the Swedish National Patient Register between 1964 and 2013 and ten age- and sex-matched controls per patient, randomly selected from the Population Register. Data were linked with the Swedish National Cancer Register to identify individuals with malignancy diagnosis. RESULTS: The cohort comprised 739 individuals with HSCR (565 male) and 7390 controls (5650 male). Median age of the cohort was 19 years (range 2-49). In total nine (1.2%) individuals in the exposed cohort were diagnosed with malignancies compared to 57 (0.8%) in the non-exposed cohort (p = 0.195). Median age at malignancy diagnosis was 3 years (range 0-46) in the exposed group, compared to 23 (range 0-42), p = 0.132. No cases with medullary carcinoma of the thyroid were found in this cohort. CONCLUSIONS: There was no significant difference in risk of malignancies in the exposed group compared to the unexposed group.

Classification of short-term complications after transanal endorectal pullthrough for Hirschsprung's disease using the Clavien-Dindo-grading system.

PURPOSE: Hirschsprung's disease (HSCR) is a developmental defect of the enteric nervous system. Transanal endorectal pullthrough (TERPT) is one of the surgical procedures for HSCR. Clavien-Dindo is an objective classification system, used worldwide, to describe postoperative complications. The aim of this study was to use Clavien-Dindo grading for short-term complication after TERPT. METHODS: This was a cohort study including all 69 individuals, with biopsy-verified HSCR, managed with TERPT at our institution between 2006 and 2018. Data on the surgical procedure, as well as short-term complications, were retrieved from the medical records. The main outcome was postoperative complications graded according to Clavien-Dindo. RESULTS: Fifteen (22%) of the 69 patients (51 males) had a short-term postoperative complication graded according to Clavien-Dindo. The complications were Grade I in ten patients, Grade II in four patients, and Grade IIIb in one patient. Individuals with a Clavien-Dindo complication had a significantly longer post-operative hospital stay [median 6 days (4-30) compared to 4 days (1-22), p = 0.035]. CONCLUSIONS: It is important to describe postoperative complications in a structured way to make it possible to compare studies. Post-operative complications, according to Clavien-Dindo, occurred in 22% of the patients after TERPT.

Selective serotonin reuptake inhibitors during pregnancy Do not increase the risk of Hirschsprung disease.

PURPOSE: Hirschsprung disease (HSCR) is a multifactorial disease. Maternal intake of selective serotonin reuptake inhibitors (SSRI) during early pregnancy has previously been associated with increased risk for HSCR. The aim of this study was to assess the risk for HSCR in newborns after maternal intake of SSRI in a population-based Swedish cohort. METHODS: This was a Swedish nationwide, population-based, case-control cohort study containing all children born in Sweden between 1/12006 and 31/122012. The cases were identified in the Swedish National Patient Register and the controls (five age- and sex-matched controls per case) were randomly selected among children without HSCR in the cohort. Data on maternal SSRI use during pregnancy were collected from the Swedish Prescribed Drug Register. RESULTS: Out of 775,024 born children during the study period, 150 cases of HSCR (112 males) and 750 controls (560 males) were included. Five (3.3%) mothers of newborns with HSCR had used SSRI during pregnancy compared to 16 (2.1%) mothers of the controls (p = 0.372). The mean age was similar in mothers who had used SSRI compared to those who had not (30.9 (SD +/- 5.1) versus 30.6 (SD +/- 5.0), p = 0.81). CONCLUSIONS: There was no increased risk of HSCR owing to maternal intake of SSRI in this cohort. LEVEL OF EVIDENCE: Level I.

Swedish national population-based study shows an increased risk of depression among patients with Hirschsprung disease.

AIM: Hirschsprung disease is usually treated during infancy. The long-term impact on mental health has not been well studied. The aim of this study was to assess the risk for depressive disorders in individuals with Hirschsprung disease. METHODS: This was a nationwide, population-based cohort study. The study exposure was Hirschsprung disease and the study outcome was depression. The exposed cohort included all individuals with Hirschsprung disease, registered in the Swedish National Patient Register between 1964 and 2013 and the unexposed cohort included ten age- and sex-matched controls per patient. The diagnosis of depression was confirmed by diagnosis in the Swedish National Patient Register. RESULTS: The cohort included 739 (76.5% males) individuals with Hirschsprung disease and 7390 (76.5% males) controls. Among the patients with Hirschsprung disease, 35 (4.7%) of the patients had had a depressive disorder and 187 (2.5%) of controls, hazard ratio 1.98, 95% confidence interval 1.38-2.84. The mean age at diagnosis of first depression was 21.9 years (SD ± 7) in Hirschsprung disease patients and 23.4 years (SD ± 7), p = 0.236 in the unexposed group. There were no significant gender differences. CONCLUSION: We found an increased risk of having depressive disorders among individuals with Hirschsprung disease compared to controls.

No increased risk of attention deficit hyperactivity disorders in patients with Hirschsprung disease.

PURPOSE: Hirschsprung disease (HSCR) has previously been associated with increased need of special education services despite normal intelligence. The aim of this study was to assess the risk of attention deficit hyperactivity disorders (ADHD) in individuals with HSCR in a population-based cohort. METHODS: This was a nationwide, population-based cohort study. The study exposure was HSCR and the study outcome was ADHD. The cohort included all individuals with HSCR registered in the Swedish National Patient Register between 1964 and 2013 and ten age- and sex-matched controls per patient, randomly selected from the Population Register. RESULTS: The cohort comprised 739 individuals with HSCR and 7390 controls. Twenty-six of the 739 individuals with HSCR and 202 of the 7390 controls were diagnosed with ADHD, Odds ratio (OR) 1.30, Confidence interval (CI) 95% 0.84-1.93, indicating no difference in risk for ADHD. The mean age at diagnosis of ADHD was not different between the groups; 18.1 years (SD 8.4) vs 16.7 years (SD 7.8), p = 0.39. Down syndrome did not affect the risk for ADHD, OR 2.26 (CI 95% 0.68-5.53). Female gender decreased the risk for ADHD, OR 0.58 (CI 95% 0.40-0.83). CONCLUSIONS: There is no increased risk of ADHD in patients with Hirschsprung disease. LEVEL OF EVIDENCE: Prognosis study, level of evidence: Level I.

Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus.

Hirschsprung disease (HSCR) is a congenital disorder with a population incidence of ~1/5000 live births, defined by an absence of enteric ganglia along variable lengths of the colon. HSCR genome-wide association studies (GWAS) have found common associated variants at RET, SEMA3, and NRG1, but they still fail to explain all of its heritability. To enhance gene discovery, we performed a GWAS of 170 cases identified from the Danish nationwide pathology registry with 4717 controls, based on 6.2 million variants imputed from the haplotype reference consortium panel. We found a novel low-frequency variant (rs144432435), which, when conditioning on the lead RET single-nucleotide polymorphism (SNP), was of genome-wide significance in the discovery analysis. This conditional association signal was replicated in a Swedish HSCR cohort with discovery plus replication meta-analysis conditional odds ratio of 6.6 (P = 7.7 × 10-10; 322 cases and 4893 controls). The conditional signal was, however, not replicated in two HSCR cohorts from USA and Finland, leading to the hypothesis that rs144432435 tags a rare haplotype present in Denmark and Sweden. Using the genome-wide complex trait analysis method, we estimated the SNP heritability of HSCR to be 88%, close to estimates based on classical family studies. Moreover, by using Lasso (least absolute shrinkage and selection operator) regression we were able to construct a genetic HSCR predictor with a area under the receiver operator characteristics curve of 76% in an independent validation set. In conclusion, we combined the largest collection of sporadic Hirschsprung cases to date (586 cases) to further elucidate HSCR's genetic architecture.

Hirschsprung disease-Bowel function beyond childhood.

Hirschsprung disease is a developmental defect of the enteric nervous system characterized by lack of enteric neurons in the distal hindgut. There are numerous reports on short-term outcomes indicating that impaired bowel function is common. Recently, several controlled studies show that bowel function outcomes are affected beyond childhood, in adolescents and adults, compared with healthy control subjects. Constipation and fecal incontinence are common. The impaired bowel function appears to have a negative impact on quality of life, although, a majority of patients have adapted to their symptoms. On the other hand, Hirschsprung disease seems to have limited impact on education and occupation in adult life. The aim of this review was to summarize current knowledge of bowel function outcome beyond childhood in patients with Hirschsprung disease.

Population-based study shows that Hirschsprung disease does not have a negative impact on education and income.

AIM: Hirschsprung disease is a multifactorial disease, which is mainly treated during childhood. There is a risk of impaired bowel function for a long time after surgery, and its impact on adult life has not been well studied. This study assessed whether having Hirschsprung disease affected social parameters such as educational level and income. METHODS: This nationwide, population-based cohort study included all patients with Hirschsprung disease, registered in the Swedish National Patient Register from 1964 and 2013, who were each matched by age and sex to ten individuals randomly selected from the Swedish Population Register. The study outcomes were the highest educational level and individual disposable income in 2013 registered by Statistics Sweden. RESULTS: The study comprised 389 patients and 3847 controls, both 76% male, with a median age of 25 years. There were no statistically significant differences in highest educational level between the groups (p = 0.327). The median individual disposable income was 142 200 (0-817 200) Swedish Krona in the patient group and 159 000 (0-3 418 900) in the control group (p = 0.615). CONCLUSION: The highest educational level and the individual disposable income did not differ between patients with Hirschsprung disease and controls, indicating that the disease had a low impact on these parameters.

Adult outcomes after surgery for Hirschsprung's disease: Evaluation of bowel function and quality of life.

BACKGROUND AND AIMS: Hirschsprung's disease (HSCR) is treated surgically. There is a risk for faecal incontinence and constipation postoperatively. The long-term bowel functional outcome in adults and quality of life are sparsely studied. The aim of this study was to assess bowel function and quality of life in patients who had undergone surgery for HSCR during childhood. METHODS: All patients treated between 1969 and 1994 at St. Göran's Children's Hospital in Stockholm were invited to participate in the study. After consent, the patients received questionnaires containing general questions, validated questions on bowel function, questions about urinary function, SF-36 health survey (SF-36) and the Gastrointestinal Quality of Life Index (GIQLI). Clinical data were extracted from the case records. Controls matched for sex and age were randomly selected from the National Swedish Population Register. RESULTS: 48 of 60 (80%) invited patients responded to the questionnaires. Nine patients were excluded since the HSCR diagnosis could not be confirmed. The median age of the included patients was 28 (20-43) years. Most patients had undergone Soave's operation (73.4%) and two patients had a stoma at the time of follow-up. The bowel function was impaired in the HSCR group compared to controls, especially problems with flatulence, need to strain at defecation and several defecations for emptying. Patients in the HSCR group also had significantly more problems with faecal incontinence than controls. Quality of life according to SF-36 did not differ significantly between patients and controls, but the GIQLI score showed a significantly worse outcome in the HSCR group compared to the controls. CONCLUSION: General quality of life in adults treated for HSCR during childhood is comparable to controls. However, they have impaired bowel function and gastrointestinal quality of life.

Botulinum toxin is efficient to treat obstructive symptoms in children with Hirschsprung disease.

BACKGROUND: Obstructive symptoms are common after pull-through for Hirschsprung disease. Botulinum toxin injection treatment may improve the bowel function if internal sphincter achalasia is the cause of obstructive symptoms. The aim of this study was to review the outcome in patients treated with intrasphincteric botulinum toxin injections after pull-through for Hirschsprung disease. METHODS: The operative records were used to identify children with Hirschsprung disease who were treated with botulinum toxin injections at Karolinska University Hospital, Stockholm, Sweden, from September 2007 to November 2014. Data on age, sex, associated syndromes, length of aganglionic segment, age at pull-through, type of pull-through, age at first botulinum toxin injection, indication for botulinum toxin injection, and effect of first botulinum toxin injection were retrieved from the case records. Bowel function at last follow-up visit or telephone contact was recorded. RESULTS: Nineteen patients were identified. All had biopsy-verified Hirschsprung disease. Eighteen (15 males and 3 females) children had undergone intrasphincteric botulinum toxin injection treatment for obstructive symptoms after pull-through, which was done at 127 (18-538) days of age. Four children had total colonic aganglionosis. The first botulinum toxin injection was given at 2.4 (0.53-6.9) years of age. Thirteen children (72 %) had a good response to the first injection treatment. The children underwent 3 (1-13) injection treatments. At follow-up four patients had improved and did not need treatment for obstruction, four were scheduled for further botulinum toxin injections, eight had persistent obstructive symptoms treated with laxatives or enemas, and two children had an ileostomy. CONCLUSION: Botulinum toxin injection treatment improves the obstructive symptoms in children after pull-through for Hirschsprung disease. The effect is reversible and a majority of patients need repeat injections. When injection treatment is not repeated, a large proportion of children need laxatives or enemas due to recurrent symptoms.

A novel stop mutation in the EDNRB gene in a family with Hirschsprung's disease associated with multiple sclerosis.

PURPOSE: We identified a girl with Hirschsprung's disease (HSCR) whose mother and grandmother had HSCR associated with multiple sclerosis (MS). The aim of this study was to outline mutations in HSCR-related genes and MS susceptibility alleles in these three individuals. METHODS: The phenotypes were reviewed based on medical records. The three subjects had rectosigmoid HSCR verified with histopathology. The mother and grandmother fulfilled the McDonald criteria for MS. DNA was isolated from EDTA-preserved blood according to standard procedures. Exome sequencing aiming mainly at analyzing HSCR associated genes as well as Sanger sequencing for confirmation was performed. RESULTS: All affected individuals carry a novel heterozygous nonsense mutation in the EDNRB gene (c.C397T,p.R133X,refNM_000115), changing an arginine at position 133 into a premature stop codon. None of the subjects were homozygous for the HLA risk alleles for MS. CONCLUSION: We report a novel non-sense EDNRB gene mutation in a girl with HSCR and her mother and grandmother with HSCR and MS. We propose that this EDNRB gene mutation plays a role in the etiology of HSCR and also makes the subjects susceptible to MS.

Laparoscopic-assisted pull-through for Hirschsprung's disease, a prospective repeated evaluation of functional outcome.

AIM OF THE STUDY: To evaluate the functional outcome of laparoscopic-assisted endorectal pull-through (LAP) for Hirschsprung's disease (HSCR) over time. METHODS: Thirty-five children with HSCR underwent laparoscopic-assisted pull-through at our institution between 1998 and 2009. The diagnosis was histologically confirmed in all cases. Clinical data was extracted from the case records. A prospective assessment of the functional outcome was performed in 2009 and 2012. Exclusion criteria were a follow-up of less than 6 months after treatment (1 case) and total colonic aganglionosis (1 case). An independent examiner, not involved in the clinical care of the patients, performed interviews using a semi-structured questionnaire. Four patients could not be traced for the first interview. Two cases were lost for the second interview. Altogether twenty-seven patients completed the study. Data from the two interviews were compared. The regional ethical review board approved the study. MAIN RESULTS: The median patient age was 4 years old (range 2-16) at the time of the first interview and 7 years old (range 5-19) at the time of the second interview . There were 23 males and 4 females in the study group. The median age at laparoscopic-assisted pull-through was 104 days old (range 29 days-8 years). In the first interview 11 patients reported constipation, 18 patients reported soiling more frequently than once per week when they had loose stools and 16 patients when they had solid stools. Laxatives or irrigations were used by 13 of the patients. In the second interview 4 patients reported constipation, 16 patients reported soiling when they had loose stools and 15 patients reported soiling when they had solid stools. Eight patients used laxatives or irrigations. The decrease in constipation was statistically significant (p=0,023). CONCLUSIONS: Our study shows a statistically significant reduction of constipation over time. There is a high risk of incontinence after laparoscopic-assisted pull-through, with few signs of short-term improvement.

Nerve growth factor receptor immunohistochemistry has a limited additional value to diagnose Hirschsprung's disease.

PURPOSE: The diagnosis of Hirschsprung's disease (HSCR) is based on the histopathological evaluation of rectal suction biopsies (RSB), using haematoxylin and eosin (H&E) stains and acetylcholinesterase (AChE) histochemistry. The use of different immunohistochemical markers, such as nerve growth factor receptor (NGFR), has been suggested to facilitate the diagnosis of HSCR. The aim of this study was to evaluate the addition of NGFR immunohistochemistry to diagnose HSCR. METHODS: RSB from 23 HSCR patients and 16 patients investigated for, but not diagnosed with, HSCR were retrospectively reviewed. The histopathology report supported or did not support the diagnosis of HSCR. RESULTS: In patients with HSCR, the primary biopsies confirmed the diagnosis in 21 of 23 cases with H&E staining, in 16 of 23 cases with AChE histochemistry, and in 8 of 23 cases with NGFR immunohistochemistry. Due to inadequate biopsies or equivocal interpretation, the biopsies were repeated in seven of the patients with HSCR and two patients underwent biopsies a third time. In the 16 patients investigated for but not diagnosed with HSCR, the three tests were normal in all cases. CONCLUSION: We conclude that NGFR immunohistochemistry has limited additional value to diagnose HSCR.