Size matters: Large copy number losses in Hirschsprung disease patients reveal genes involved in enteric nervous system development.

Hirschsprung disease (HSCR) is a complex genetic disease characterized by absence of ganglia in the intestine. HSCR etiology can be explained by a unique combination of genetic alterations: rare coding variants, predisposing haplotypes and Copy Number Variation (CNV). Approximately 18% of patients have additional anatomical malformations or neurological symptoms (HSCR-AAM). Pinpointing the responsible culprits within a CNV is challenging as often many genes are affected. Therefore, we selected candidate genes based on gene enrichment strategies using mouse enteric nervous system transcriptomes and constraint metrics. Next, we used a zebrafish model to investigate whether loss of these genes affects enteric neuron development in vivo. This study included three groups of patients, two groups without coding variants in disease associated genes: HSCR-AAM and HSCR patients without associated anomalies (HSCR-isolated). The third group consisted of all HSCR patients in which a confirmed pathogenic rare coding variant was identified. We compared these patient groups to unaffected controls. Predisposing haplotypes were determined, confirming that every HSCR subgroup had increased contributions of predisposing haplotypes, but their contribution was highest in isolated HSCR patients without RET coding variants. CNV profiling proved that specifically HSCR-AAM patients had larger Copy Number (CN) losses. Gene enrichment strategies using mouse enteric nervous system transcriptomes and constraint metrics were used to determine plausible candidate genes located within CN losses. Validation in zebrafish using CRISPR/Cas9 targeting confirmed the contribution of UFD1L, TBX2, SLC8A1, and MAPK8 to ENS development. In addition, we revealed epistasis between reduced Ret and Gnl1 expression and between reduced Ret and Tubb5 expression in vivo. Rare large CN losses-often de novo-contribute to HSCR in HSCR-AAM patients. We proved the involvement of six genes in enteric nervous system development and Hirschsprung disease.

Rectal atresia and rectal stenosis: the ARM-Net Consortium experience.

PURPOSE: To assess the number, characteristics, and functional short-, and midterm outcomes of patients with rectal atresia (RA) and stenosis (RS) in the ARM-Net registry. METHODS: Patients with RA/RS were retrieved from the ARM-Net registry. Patient characteristics, associated anomalies, surgical approach, and functional bowel outcomes at 1 and 5-year follow-up were assessed. RESULTS: The ARM-Net registry included 2619 patients, of whom 36 (1.3%) had RA/RS. Median age at follow-up was 7.0 years (IQR 2.3-9.0). Twenty-three patients (63.9%, RA n = 13, RS n = 10) had additional anomalies. PSARP was the most performed reconstructive surgery for both RA (n = 9) and RS (n = 6) patients. At 1-year follow-up, 11/24 patients with known data (45.8%, RA n = 5, RS n = 6) were constipated, of whom 9 required stool softeners and/or laxatives. At 5-year follow-up, 8/9 patients with known data (88.9%, RA n = 4, RS n = 4) were constipated, all requiring laxatives and/or enema. CONCLUSION: RA and RS are rare types of ARM, representing 1.3% of patients in the ARM-Net registry. Additional anomalies were present in majority of patients. Different surgical approaches were performed as reconstructive treatment, with constipation occurring in 46% and 89% of the patients at 1 and 5-year follow-up. However, accurate evaluation of long-term functional outcomes remains challenging.

Functional Outcomes After Surgery for Total Colonic, Long-Segment, Versus Rectosigmoid Segment Hirschsprung Disease.

OBJECTIVES: Knowledge on long-term outcomes in patients with Hirschsprung disease is progressing. Nevertheless, differences in outcomes according to aganglionic lengths are unclear. We compared long-term bowel function and generic quality of life in Hirschsprung patients with total colonic or long-segment versus rectosigmoid aganglionosis. METHODS: In this nationwide, cross-sectional study participants with proven Hirschsprung disease received the Defecation and Fecal Continence questionnaire, and the Child Health Questionnaire Child Form-87, or the WHO Quality of Life-100. We excluded deceased patients, patients who were younger than 8 years, lived abroad, had a permanent enterostomy, or were intellectually impaired. RESULTS: The study population (n = 334) was operated for rectosigmoid (83.9%), long-segment (8.7%), or total colonic aganglionosis (7.5%). Fecal incontinence in general was not significantly different between the three groups, but liquid fecal incontinence was significantly associated with total colonic aganglionosis (odds ratio [OR] = 6.00, 95% confidence interval [CI] 2.07-17.38, P = 0.001). Regarding constipation, patients with total colonic or long-segment aganglionosis were less likely to suffer from constipation than the rectosigmoid group (OR = 0.21, 95% CI, 0.05-0.91, P = 0.038 and OR = 0.11, 95% CI, 0.01-0.83, P = 0.032). Quality of life was comparable between the three groups, except for a lower physical score in children with total colonic aganglionosis (P = 0.016). CONCLUSIONS: Over time Hirschsprung patients with total colonic or long-segment aganglionosis do not suffer from worse fecal incontinence in general. A difference in stool consistency may underlie the association between liquid fecal incontinence and total colonic aganglionosis and constipation in patients with rectosigmoid aganglionosis. Despite these differences, generic quality of life is comparable on reaching adulthood.

Did Age at Surgery Influence Outcome in Patients With Hirschsprung Disease? A Nationwide Cohort Study in the Netherlands.

OBJECTIVES: Hirschsprung disease (HD) requires surgical resection of affected bowel, but the current evidence is inconclusive regarding the optimal age for resection. The aim of this study was to assess whether age at resection of the aganglionic segment is a determinant for surgical outcomes. METHODS: A cross-sectional cohort study was done including all consecutive patients with HD between 1957 and 2015, aged 8 years or older (n = 830), who were treated in 1 of the 6 pediatric surgical centers in the Netherlands. Outcome measures were mortality, postoperative complications, stoma rate and redo surgery rate, retrieved from the medical records. Additionally, constipation and fecal incontinence rate in long term were assessed with the Defecation and Continence Questionnaire (DeFeC and P-DeFeC). RESULTS: The medical records of 830 patients were reviewed, and 346 of the 619 eligible patients responded to the follow-up questionnaires (56%). There was a small increase in the risk of a permanent stoma [odds ratio (OR) 1.01 (95% confidence interval {CI}: 1.00-1.02); P = 0.019] and a temporary stoma [OR 1.01 (95% CI: 1.00-1.01); P = 0.022] with increasing age at surgery, regardless of the length of the aganglionic segment and operation technique. Both adjusted and unadjusted for operation technique, length of disease, and temporary stoma, age at surgery was not associated with the probability and the severity of constipation and fecal incontinence in long term. CONCLUSIONS: In this study, we found no evidence that the age at surgery influences surgical outcomes, thus no optimal timing for surgery for HD could be determined.

The Somatic Mutation Paradigm in Congenital Malformations: Hirschsprung Disease as a Model.

Patients with Hirschsprung disease (HSCR) do not always receive a genetic diagnosis after routine screening in clinical practice. One of the reasons for this could be that the causal mutation is not present in the cell types that are usually tested-whole blood, dermal fibroblasts or saliva-but is only in the affected tissue. Such mutations are called somatic, and can occur in a given cell at any stage of development after conception. They will then be present in all subsequent daughter cells. Here, we investigated the presence of somatic mutations in HSCR patients. For this, whole-exome sequencing and copy number analysis were performed in DNA isolated from purified enteric neural crest cells (ENCCs) and blood or fibroblasts of the same patient. Variants identified were subsequently validated by Sanger sequencing. Several somatic variants were identified in all patients, but causative mutations for HSCR were not specifically identified in the ENCCs of these patients. Larger copy number variants were also not found to be specific to ENCCs. Therefore, we believe that somatic mutations are unlikely to be identified, if causative for HSCR. Here, we postulate various modes of development following the occurrence of a somatic mutation, to describe the challenges in detecting such mutations, and hypothesize how somatic mutations may contribute to 'missing heritability' in developmental defects.

Ileocolic Intussusception as the Presenting Symptom of Primary Enteric Varicella-Zoster Virus Infection in a 7-Month-Old Infant.

Ileocolic intussusception is the invagination of ileum into the colon. In a subset of patients, the disease is caused by mesenteric lymphadenopathy in response to (viral) infection. We present a case of an ileocolic intussusception necessitating surgery in a 7-month-old immunocompetent infant with concurrent primary wild-type varicella-zoster virus (VZV) infection, in whom chickenpox rash developed 2 days after surgery. Detailed in situ analyses of resected intestine for specific cell type markers and VZV RNA demonstrated VZV-infected lymphocytes and neurons in the gut wall and in ganglion cells of the myenteric plexus.

Does the Incidence of Postoperative Complications After Inguinal Hernia Repair Justify Hospital Admission in Prematurely and Term Born Infants?

BACKGROUND: Postoperatively, young infants are admitted overnight in view of the risk for respiratory complications such as desaturation and apnea. This risk seems much lower than previously reported. Until what age this risk persists, and which infants might actually qualify for day-care treatment, is unknown. METHODS: We retrospectively reviewed medical charts from preterm infants <45 weeks postconceptional age (PCA), 45-60 weeks PCA, and term infants <3 months admitted overnight after inguinal hernia repair, from January 2011 to December 2015 in a large tertiary children's hospital. Postoperative complications (divided into respiratory, circulatory, neurologic, and other), recurrence, and reoperation were documented and compared between groups. RESULTS: Medical charts of 485 patients were reviewed. Postoperative respiratory complications (mainly desaturations or apnea) had been documented for 27 of 76 (35.5%) preterm infants <45 weeks PCA, for 13 of 221 (5.9%) preterm infants 45-60 weeks PCA, and for 3 of 188 (1.6%) term infants (P < .001). An analysis of the 221 preterm infants 45-60 weeks PCA showed statistically significantly more respiratory complications in 76 infants with a respiratory history (eg, bronchopulmonary dysplasia) compared with the others (respectively 13.2% vs 0.7%; P < .001). In these infants, lower gestational age at the time of surgery was statistically significantly predictive for the development of respiratory complications (odds ratio [OR], 0.68 [95% confidence interval {CI}, 0.52-0.89]; P = .005), but respiratory history (OR, 3.50 [0.34-36.28]; P = .294) and American Society of Anesthesiologists (ASA) physical status (OR, 1.54 [95% CI, 0.31-7.65]; P = .598 for ASA physical status II and OR, 6.11 [95% CI, 0.76-49.05]; P = .089 for ASA physical status III) were not predictive. CONCLUSIONS: Incidence of postoperative respiratory complications is high in preterm infants <45 weeks PCA requiring postoperative overnight saturation and heart rate monitoring. Incidence of postoperative complications in preterm born infants 45-60 weeks PCA varies. Gestational age and possibly presence of respiratory history can be used to estimate the need for overnight admission in these infants. Postoperative respiratory complications after inguinal hernia repair in ASA physical status I and II term born infants >1 month of age are uncommon, which justifies day-care admission for this type of surgical procedure.

Differences in Origin and Outcome of Intra-Abdominal Cysts in Male and Female Fetuses.

OBJECTIVE: To investigate the origin and outcome in a cohort of male and female fetuses with intra-abdominal cysts, in order to provide recommendations on management and to improve prenatal counselling. METHODS: From 2002 to 2016, intra-abdominal cysts were detected by ultrasound in 158 fetuses. Cases with an umbilical vein varix were excluded. Fetal, neonatal, and maternal characteristics were retrieved from electronic patient files. RESULTS: In female fetuses (n = 114), intra-abdominal cysts were diagnosed at a later gestational age compared with male fetuses (n = 44) (median 32.0 vs. 21.5 weeks, p < 0.001). The maximum prenatal cyst diameter was larger in female fetuses (median 35 vs. 17 mm, p < 0.001). Associated anomalies were less frequent in females (n = 15, 13.2%) compared with males (n = 15, 34.1%). In females (n = 114), most cysts were of ovarian origin (n = 81, 71.1%). Surgery was performed in 30 (26.3%) female and 15 (34.1%) male neonates (p = 0.33). Anorectal malformations were present in 6 cases and often not recognized prenatally. CONCLUSIONS: The differences in the origin of intra-abdominal cysts between male and female fetuses, resulting in differences in prenatal presentation and postnatal outcome should be taken into account in prenatal counseling within a multidisciplinary team. Evaluation of the fetal perianal muscular complex is indicated.

Previous miscarriages and GLI2 are associated with anorectal malformations in offspring.

STUDY QUESTION: Are anorectal malformations (ARMs) associated with previous miscarriages or single nucleotide polymorphisms (SNPs) in the Bone Morphogenetic Protein 4 (BMP4) and GLI family zinc finger 2 (GLI2) genes? SUMMARY ANSWER: The SNP rs3738880 in GLI2 and miscarriages were associated with ARM, especially in patients with multiple congenital anomalies (MCA). WHAT IS KNOWN ALREADY: ARM are one of the most common birth defects of the gastrointestinal tract. The etiology is likely to be multifactorial, involving both environmental and genetic factors. SNPs in BMP4 and GLI2 genes were associated with ARM in non-Caucasian populations. During a patient information day, several mothers of ARM patients reported their concerns about previous miscarriages. STUDY DESIGN, SIZE, DURATION: A case-control study was performed among 427 ARM patients and 663 population-based controls. PARTICIPANTS/MATERIALS, SETTING, METHODS: We examined the associations of ARM with SNPs in GLI2 and BMP4 using DNA samples of the children and associations with previous miscarriages using parental questionnaires. In addition, gene-gene and gene-environment interaction analyses were performed. MAIN RESULTS AND THE ROLE OF CHANCE: The SNP rs3738880 in GLI2 was associated with ARM, especially in patients with MCA (homozygous GG-genotype: odds ratio (OR): 2.1; 95% CI: 1.2, 3.7). We identified previous miscarriages as a new risk factor for ARM, especially when occurring in the pregnancy directly preceding the index pregnancy and in patients with MCA (OR: 2.1; 95% CI: 1.3, 3.5). No association with rs17563 in BMP4, nor gene-gene or gene-environment interactions were found. LIMITATIONS, REASONS FOR CAUTION: The possibility of recall errors for previous miscarriage, but we expect these errors to be limited, as a miscarriage is a major life event. In addition, potential misclassification regarding miscarriages and stillbirth, but sensitivity analyses showed that this did not influence our results. WIDER IMPLICATIONS OF THE FINDINGS: This study showed associations of ARM with rs3738880 in GLI2 and with previous miscarriages. Both associations were stronger in patients with MCA, showing the importance of stratifying the analyses by patients with isolated ARM or MCA. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Radboudumc. The authors have no conflict of interest to disclose.

Laparoscopic antireflux surgery increases health-related quality of life in children with GERD.

INTRODUCTION: Improving health-related quality of life (HRQoL) is increasingly recognized as an essential part of patient care outcome. Little is known about the effect of laparoscopic antireflux surgery (LARS) on the HRQoL in the pediatric patients. The aims of this study were to evaluate the effect of LARS on HRQoL in children with gastroesophageal reflux disease (GERD) and to identify predictors that influence HRQoL outcome after LARS. METHODS: Between 2011 and 2013, 25 patients with therapy-resistant GERD [median age 6 (2-18) years] were included prospectively. Caregivers and children with normal neurodevelopment (>4 years) were asked to fill out the validated PedsQL 4.0 Generic Core Scales before and 3-4 months after LARS. RESULTS: The PedsQL was completed by all caregivers (n = 25) and 12 children. HRQoL total score improved significantly after LARS, both from a parental (p = 0.009) and child's perspective (p = 0.018). The psychosocial health summary and physical health summary scores also improved significantly after LARS. HRQoL before and after LARS was significantly lower in children with impaired neurodevelopment (p < 0.001). However, neurodevelopment did not influence the effect of LARS on HRQoL. The only significant predictor for improvement in HRQoL after LARS was age at the time of operation (p = 0.001). CONCLUSIONS: HRQoL significantly improves after LARS. Although children with impaired neurodevelopment had lower overall HRQoL, neurodevelopment by itself does not predict inferior improvement in HRQoL after LARS. Older children have a more favorable HRQoL outcome after LARS compared to younger children. This may suggest caution when considering LARS in younger GERD patients.

Esophageal mucosal integrity improves after laparoscopic antireflux surgery in children with gastroesophageal reflux disease.

BACKGROUND: Esophageal intraluminal baseline impedance reflects the conductivity of the esophageal mucosa and may be an instrument for in vivo evaluation of mucosal integrity in children with gastroesophageal reflux disease (GERD). Laparoscopic antireflux surgery (LARS) is a well-established treatment option for children with proton pump inhibitory (PPI) therapy resistant GERD. The effect of LARS in children on baseline impedance has not been studied in detail. The aim of this study was to evaluate the effect of LARS on baseline impedance in children with GERD. METHODS: This is a prospective, multicenter, nationwide cohort study (Dutch national trial registry: NTR2934) including 25 patients [12 males, median age 6 (range 2-18) years] with PPI-resistant GERD scheduled to undergo LARS. Twenty-four hour multichannel intraluminal impedance pH monitoring (MII-pH monitoring) was performed before and 3 months after LARS. Baseline impedance was evaluated during consecutive 2-h intervals in the 24-h tracings. RESULTS: LARS reduced acid exposure time from 8.5 % (6.0-16.2 %) to 0.8 % (0.2-2.8 %), p < 0.001. Distal baseline impedance increased after LARS from 2445 Ω (1147-3277 Ω) to 3792 Ω (3087-4700 Ω), p < 0.001. Preoperative baseline impedance strongly correlated with acid exposure time (r -0.76, p < 0.001); however, no association between symptomatic outcome and baseline impedance was identified. CONCLUSIONS: LARS significantly increased baseline impedance likely reflecting recovery of mucosal integrity. As the change in baseline impedance was not associated with the clinical outcome of LARS, other factors besides mucosal integrity may contribute to symptom perception in children with GERD.

Choledochal Malformation in Children: Lessons Learned from a Dutch National Study.

INTRODUCTION: A choledochal malformation (CM) is a rare entity, especially in the Western world. We aimed to determine the incidence of CM in the Netherlands and the outcome of surgery for CM in childhood. METHODS: All pediatric patients who underwent a surgical procedure for type I-IV CM between 1989 and 2014 were entered into the Netherlands Study group on choledochal cyst/malformation. Patients with type V CM were excluded from the present analysis. Symptoms, surgical details, short-term (<30 days) and long-term (>30 days) complications were studied retrospectively. RESULTS: Between January 1989 and December 2014, 91 pediatric patients underwent surgery for CM at a median age of 2.1 years (0.0-17.7 years). All patients underwent resection of the extrahepatic biliary tree with restoration of the continuity via Roux-en-Y hepaticojejunostomy. Twelve patients (12%) were operated laparoscopically. Short-term complications, mainly biliary leakage and cholangitis, occurred in 20 patients (22%), without significant correlations with weight or age at surgery or surgical approach. Long-term postoperative complications were mainly cholangitis (13%) and anastomotic stricture (4%). Eight patients (9%) required radiological intervention or additional surgery. Surgery before 1 year of age (OR 9.3) and laparoscopic surgery (OR 4.4) were associated with more postoperative long-term complications. We did not observe biliary malignancies during treatment or follow-up. CONCLUSION: Surgery for CM carries a significant short- and long-term morbidity. Given the low incidence, we would suggest that (laparoscopic) hepatobiliary surgery for CM should be performed in specialized pediatric surgical centers with a wide experience in laparoscopy and hepatobiliary surgery.

Patients with anorectal malformation and upper limb anomalies: genetic evaluation is warranted.

UNLABELLED: The objective of this study was to compare the prevalence of genetic disorders in anorectal malformation (ARM) patients with upper limb anomalies to that in ARM patients with other associated anomalies. A retrospective case study was performed in two pediatric surgery centers. All patients born between 1990 and 2012 were included. VACTERL (vertebral defects (V), anal atresia (A), cardiac malformations (C), tracheoesophageal fistula with esophageal atresia (TE), renal dysplasia (R), and limb anomalies (L)) was defined as at least three components present. We included 700 ARM patients: 219 patients (31 %) had isolated ARM, 43 patients (6 %) had a major upper limb anomaly, and 438 patients (63 %) had other associated anomalies. The most prevalent upper limb anomalies were radial dysplasia (n = 12) and hypoplastic thumb (n = 11). Ten of the 43 patients (23 %) with an upper limb anomaly were diagnosed with a genetic disorder-nine also met the VACTERL criteria-vs. 9 % of ARM patients with other anomalies (p = 0.004, chi-squared test). CONCLUSION: Genetic disorders are twice as frequently diagnosed in ARM patients with upper limb anomalies than in those with other anomalies. As they also frequently meet the VACTERL criteria, it is important to consider VACTERL as a diagnosis per exclusionem. Genetic counseling is certainly warranted in these patients. WHAT IS KNOWN: • Anorectal malformations (ARMs) often co-occur with other congenital anomalies, including upper limb anomalies, mainly of pre-axial origin. • Co-occurrence of ARMs and upper limb anomalies is seen in disorders such as Townes-Brocks syndrome, Fanconi anemia, and VACTERL association. What is New: • ARM patients with a major upper limb anomaly-with or without other congenital anomalies-have a twofold greater chance of a genetic disorder than have non-isolated ARM patients without upper limb anomalies. • Not all upper limb anomalies in ARM patients are part of the VACTERL association; a workup for genetic evaluation is proposed.

Children with congenital colorectal malformations often require special education or remedial teaching, despite normal intelligence.

AIM: This study prospectively evaluated neuropsychological functioning in 8-year-old patients with anorectal malformation (ARM) and Hirschsprung's disease (HD). METHODS: School functioning and behaviour were assessed in a standardised interview. Intelligence, attention, self-esteem and quality of life were evaluated with validated tests and questionnaires. The following predictors were assessed: socio-economic status, number of episodes of general anaesthesia, laxative treatment and premature birth. Severely intellectually disabled patients were excluded. RESULTS: In total, twelve of the 23 (52%) patients with ARM and 11 (55%) of the 20 patients with HD received special education or remedial teaching. The intelligence quotient was normal: mean (standard deviation or SD) was 98 (17) and 96 (17), respectively. However, sustained attention was below the norm: mean (SD) Z-score was -1.90 (1.94) and -1.43 (1.98) for ARM and HD patients; both p < 0.01. Self-esteem was normal: mean (SD) Z-score was 0.10 (1.29) and -0.20 (1.11) for ARM and HD patients. Quality of life was normal in ARM patients and slightly impaired in HD patients. No predictors for neuropsychological outcome were identified. CONCLUSION: Despite normal intelligence, more than half of these patients received special education or remedial teaching. In addition, problems with sustained attention were found. These findings are important for long-term care.

Parental subfertility, fertility treatment, and the risk of congenital anorectal malformations.

BACKGROUND: Fertility treatment seems to play a role in the etiology of congenital anorectal malformations, but it is unclear whether the underlying parental subfertility, ovulation induction, or the treatment itself is involved. Therefore, we investigated the odds of anorectal malformations among children of subfertile parents who conceived with or without treatment compared with fertile parents. METHODS: We performed a case-control study among 380 cases with anorectal malformations treated at 3 departments of pediatric surgery in The Netherlands and 1973 population-based controls born between August 1988 and August 2012. Parental questionnaires were used to obtain information on fertility-related issues and potential confounders. RESULTS: In singletons, increased risks of anorectal malformations were observed for parents who underwent intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF) treatment compared with fertile parents (odds ratio = 2.4 [95% confidence interval = 1.0-5.9] and 4.2 [1.9-8.9], respectively). For subfertile parents who conceived after IVF treatment, an elevated risk was also found when they were compared with subfertile parents who conceived without treatment (3.2 [1.4-7.2]). Among children of the latter category of parents, only the risk of anorectal malformations with other major congenital malformations was increased compared with fertile parents (2.0 [1.3-3.3]). No associations were found with intrauterine insemination or use of hormones for ovulation induction. CONCLUSIONS: We found evidence of a role of ICSI and IVF treatments in the etiology of anorectal malformations. However, subfertility without treatment increased only the risk of anorectal malformations with additional congenital malformations.

Psychosexual Well-Being after Childhood Surgery for Anorectal Malformation or Hirschsprung's Disease.

INTRODUCTION: Anorectal malformations (ARMs) and Hirschsprung's disease (HD) are congenital malformations requiring pelvic floor surgery in early childhood, with possible sequelae for psychosexual development. AIMS: To assess psychosexual well-being in adult ARM and HD patients related to health-related quality of life. METHODS: Eligible for this cross-sectional two-center study were all patients aged ≥18 years who had been operated for ARM or HD. Exclusion criteria were intellectual disability, comorbidity affecting sexual functioning, and cloacal malformation. MAIN OUTCOME MEASURES: Participants completed the International Index of Erectile Functioning, Female Sexual Functioning Index, Female Sexual Distress Scale, Hirschsprung and Anorectal Malformation Quality of Life Questionnaire, and sexual education questionnaire. RESULTS: Response rates were 32% and 37% for ARM and HD patients, respectively. We studied 70 participating ARM and 36 HD patients (median age 26 years). We excluded 10 patients with sexual inactivity in the past 4 weeks. Six of 37 men with ARM (16%) reported moderate to severe erectile dysfunction, vs. two of 18 men with HD (11%). Thirteen and 10 of 26 women with ARM (50% and 38%) reported sexual dysfunction or sexual distress, respectively, vs. eight and three of 15 women with HD (53% and 20%). Quality of life and type of malformation or operation were not associated with self-reported psychosexual problems. Addressing sexuality with special interest to the congenital anomaly during medical care was reported to be insufficient by 42 ARM (60%) and 22 HD patients (61%). CONCLUSION: Approximately 13% of male ARM and HD patients reported erectile dysfunction, while 50% female ARM and HD patients reported sexual dysfunction not related to quality of life or type of malformation. Both ARM and HD patients felt a need for better addressing sexual concerns during medical care. Further research is needed to optimize form and timing of this education.

High resolution MRI for preoperative work-up of neonates with an anorectal malformation: a direct comparison with distal pressure colostography/fistulography.

OBJECTIVE: To compare MRI and colostography/fistulography in neonates with anorectal malformations (ARM), using surgery as reference standard. METHODS: Thirty-three neonates (22 boys) with ARM were included. All patients underwent both preoperative high-resolution MRI (without sedation or contrast instillation) and colostography/fistulography. The Krickenbeck classification was used to classify anorectal malformations, and the level of the rectal ending in relation to the levator muscle was evaluated. RESULTS: Subjects included nine patients with a bulbar recto-urethral fistula, six with a prostatic recto-urethral fistula, five with a vestibular fistula, five with a cloacal malformation, four without fistula, one with a H-type fistula, one with anal stenosis, one with a rectoperineal fistula and one with a bladderneck fistula. MRI and colostography/fistulography predicted anatomy in 88 % (29/33) and 61 % (20/33) of cases, respectively (p = 0.012). The distal end of the rectal pouch was correctly predicted in 88 % (29/33) and 67 % (22/33) of cases, respectively (p = 0.065). The length of the common channel in cloacal malformation was predicted with MRI in all (100 %, 5/5) and in 80 % of cases (4/5) with colostography/fistulography. Two bowel perforations occurred during colostography/fistulography. CONCLUSIONS: MRI provides the most accurate evaluation of ARM and should be considered a serious alternative to colostography/fistulography during preoperative work-up. KEY POINTS: • High-resolution MRI is feasible without the use of sedation or anaesthesia. • MRI is more accurate than colostography/fistulography in visualising the type of ARM. • MRI is as reliable as colostography/fistulography in predicting the level of the rectal pouch. • Colostography/fistulography can be complicated by bowel perforation.

Sequencing of the DKK1 gene in patients with anorectal malformations and hypospadias.

UNLABELLED: Anorectal malformations (ARM) are rare congenital malformations of the gastrointestinal tract. Approximately 60% of the patients have additional congenital malformations, such as hypospadias. A recently published article showed that deletion of one single gene, dickkopf WNT signaling pathway inhibitor-1 (Dkk1), resulted in an imperforate anus with rectourinary fistula and preputial hypospadias in mice. To determine whether DKK1 also plays a role in the etiology of ARM and hypospadias in humans, we sequenced the four exons of the DKK1 gene in 17 patients affected with both ARM and hypospadias. No new potential disease-causing variant was identified. However, we detected a known non-synonymous variant in one patient, which was predicted in silico to be damaging, and the corresponding unaffected amino acid is highly conserved. CONCLUSION: In this human study, a potential interesting non-synonymous variant was found in the DKK1 gene. Whether this variant plays a contributory role in the genesis of ARM or hypospadias would require a much larger study.

Effects of reconstructive surgery on bladder function in patients with anorectal malformations.

PURPOSE: Bladder dysfunction is common in patients with anorectal malformations and can be congenital or acquired as a consequence of surgery. We investigated the effects of surgical correction of anorectal malformations on bladder function. MATERIALS AND METHODS: The charts of all 341 patients who underwent surgery at our center between 1990 and 2010 were retrospectively analyzed for preoperative and postoperative videourodynamics. A total of 52 patients were eligible for study inclusion. Each assessment was scored according to International Children's Continence Society standards. RESULTS: Urodynamic study indicated normal bladder function preoperatively in 36 patients (69%) and postoperatively in 37 (71%). Median bladder emptying efficiency and relative bladder capacity changed significantly after posterior sagittal anorectoplasty. Bladder function according to International Children's Continence Society standards did not change postoperatively in 43 patients (83%). In 1 of 4 patients with deterioration of bladder function the deterioration could be attributed solely to surgery. Clinical outcome was available in 38 patients and showed complete urinary continence with spontaneous voiding in 24 (63%). Seven of 25 patients (28%) with preoperative videourodynamics indicating normal bladder function demonstrated dysfunctional voiding at latest followup. CONCLUSIONS: Urodynamic and clinical outcomes after anorectal malformation repair are good, with 63% of patients being continent of urine. Urodynamic studies are of limited value in preoperative settings in these patients. Current techniques of reconstructive surgery for anorectal malformations seem to preserve bladder function in the majority of patients.