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Anorectal malformations (ARM) represent a spectrum of rare malformations originating from a perturbated development of the embryonic hindgut. Approximately 60% occur as a part of a defined genetic syndrome or within the spectrum of additional congenital anomalies. Rare copy number variations (CNVs) have been associated with both syndromic and non-syndromic forms. The present study represents the largest study to date to explore the contribution of CNVs to the expression of ARMs. SNP-array-based molecular karyotyping was applied in 450 individuals with ARM and 4392 healthy controls. CNVs were identified from raw intensity data using PennCNV. Overlapping CNVs between cases and controls were discarded. Remaining CNVs were filtered using a stringent filter algorithm of nine filter steps. Prioritized CNVs were confirmed using qPCR. Filtering prioritized and qPCR confirmed four microscopic chromosomal anomalies and nine submicroscopic CNVs comprising seven microdeletions (del2p13.2, del4p16.2, del7q31.33, del9p24.1, del16q12.1, del18q32, del22q11.21) and two microduplications (dup2p13.2, dup17q12) in 14 individuals (12 singletons and one affected sib-pair). Within these CNVs, based on their embryonic expression data and function, we suggest FOXK2, LPP, and SALL3 as putative candidate genes. Overall, our CNV analysis identified putative microscopic and submicroscopic chromosomal rearrangements in 3% of cases. Functional characterization and re-sequencing of suggested candidate genes is warranted.

The acronym VATER/VACTERL association describes the combination of at least three component features (CFs): vertebral defects (V), anorectal malformations (ARM) (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). Individuals presenting two CFs have been termed VATER/VACTERL-like. Recently, FOXF1, HSPA6, HAAO, KYNU, TRAP1, and ZIC3 have been proposed as candidate genes for VATER/VACTERL, VATER/VACTERL-like, and ARM. Re-sequencing studies identified disease-causing variants in TRAP1 and ZIC3, the contribution of other genes was not independently investigated. One affected variant carrier in FOXF1 was previously identified. Here we re-sequenced FOXF1, HSPA6, HAAO, and KYNU in 522 affected individuals.Using molecular inversion probe (MIP) technology, re-sequencing was performed in 63 individuals with VATER/VACTERL association, 313 with VATER/VACTERL-like association, and 146 with ARM. All individuals were of European ethnicity. Variant filtering considered variants with a minor allele frequency (MAF) ≤0.01 for putative recessive disease-genes HSPA6, HAAO, and KYNU. For the putative dominant disease-gene FOXF1 we considered variants with a MAF ≤0.0001. In silico prediction tools were used for further prioritization.Only two variants in FOXF1 in two independently affected individuals [c.443GT, p.(Cys148Phe); c.850TC, p.(Tyr284His)] passed our filter criteria. One individual presented with ARM, the second presented with TE and C comprising atrial and ventricular septal defects. Sanger sequencing confirmed both variants but also their inheritance from the healthy mother.Our analysis suggests that FOXF1, HSPA6, HAAO and KYNU do not play a major role in the formation of VACTER/VACTERL phenotypes or ARM.

In the past, an anteriorly located anus was often misdiagnosed and treated as an anorectal malformation (ARM) with a perineal fistula (PF). The paper aims to define the criteria for a normal anus, an anterior anus (AA) as an anatomic variant, and milder types of ARM such as congenital anal stenosis (CAS) and PF. An extensive literature search was performed by a working group of the ARM-Net Consortium concerning the subject “Normal Anus, AA, and mild ARM”. A consensus on definitions, clinical characteristics, diagnostic management, and treatment modalities was established, and a diagnostic algorithm was proposed. The algorithm enables pediatricians, midwives, gynecologists, and surgeons to make a timely correct diagnosis of any abnormally looking anus and initiate further management if needed. Thus, the routine physical inspection of a newborn should include the inspection of the anus and define its position, relation to the external sphincter, and caliber. A correct diagnosis and use of the presented terminology will avoid misclassifications and allow the initiation of correct management. This will provide a reliable comparison of different therapeutic management and outcomes of these patient cohorts in the future.

To further investigate associated anomalies in exstrophy-epispadias complex (EEC) patients congenital uro-rectal malformations network (CURE-Net) database was systematically screened. In literature the EEC comprises a spectrum of anomalies, mainly occurring "isolated" without additional congenital defects. Nevertheless, previous epidemiological studies indicated a higher association with renal, anorectal, and lower neurotubular anomalies, which may originate from the same developmental morphogenetic fields.Seventy-three prospectively (born since 2009) and 162 cross-sectional recruited EEC patients (born 1948-2008) were analyzed. Associated anomalies were derived from patient's medical data as well as from a physical examination during a physician's interview, classified according to the international statistical classification of diseases and related health problems and grouped with the London Dysmorphology Database. Descriptive statistical analyses were performed.Majority of participants were male (68%) and expressed the classical bladder exstrophy phenotype (71%). Exstrophy variants occurred significantly more often in newborns (21%, P.0001). Anomalies such as inguinal hernias, skeleton, and joint anomalies were equally present in both groups (P = .65 and P = .67). Heart defects were seen more often in newborns (6%) than in the cross-sectional group (1%; P = .033) and the general German population (1%). In total, 59% of the prospective and 48% of the cross-sectional patients had associated anomalies outside the spectrum (P = .16).Phenomenological multicenter data confirmed the dimension of associated anomalies inside and outside the EEC spectrum. The detected anomalies are either important in preparing for the primary reconstruction or later in long-term follow-up. Associated anomalies of EEC should be spotlighted during routine check-up in all EEC patients.

Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) and anorectal malformations (ARM) represent the severe ends of the fore- and hindgut malformation spectra. Previous research suggests that environmental factors are implicated in their etiology. These risk factors might indicate the influence of specific etiological mechanisms on distinct developmental processes (e.g. fore- vs. hindgut malformation). The present study compared environmental factors in patients with isolated EA/TEF, isolated ARM, and the combined phenotype during the periconceptional period and the first trimester of pregnancy in order to investigate the hypothesis that fore- and hindgut malformations involve differing environmental factors. Patients with isolated EA/TEF (n = 98), isolated ARM (n = 123), and the combined phenotype (n = 42) were included. Families were recruited within the context of two German multicenter studies of the genetic and environmental causes of EA/TEF (great consortium) and ARM (CURE-Net). Exposures of interest were ascertained using an epidemiological questionnaire. Chi-square, Fisher's exact, and Mann-Whitney U-tests were used to assess differences between the three phenotypes. Newborns with isolated EA/TEF and the combined phenotype had significantly lower birth weights than newborns with isolated ARM (P = 0.001 and P < 0.0001, respectively). Mothers of isolated EA/TEF consumed more alcohol periconceptional (80%) than mothers of isolated ARM or the combined phenotype (each 67%). Parental smoking (P = 0.003) and artificial reproductive techniques (P = 0.03) were associated with isolated ARM. Unexpectedly, maternal periconceptional multivitamin supplementation was most frequent among patients with the most severe form of disorder, i.e. the combined phenotype (19%). Significant differences in birth weight were apparent between the three phenotype groups. This might be attributable to the limited ability of EA/TEF fetuses to swallow amniotic fluid, thus depriving them of its nutritive properties. Furthermore, the present data suggest that fore- and hindgut malformations involve differing environmental factors. Maternal periconceptional multivitamin supplementation was highest among patients with the combined phenotype. This latter finding is contrary to expectation, and warrants further analysis in large prospective epidemiological studies.

Item does not contain fulltext Anorectal malformations (ARM) have a low prevalence, patients need specialized surgical care, and in many cases, patients born with ARM even need life-long aftercare. Due to its low prevalence most patients are still treated in low-volume pediatric surgical centers without any adequate monitoring of the outcome. Data on prevalence, comparison of different surgical techniques, and prospective outcome measurements are still scarce and difficult to interpret. In 2010, a consortium was founded (ARM-Net consortium) including several European pediatric surgical centers to collaborate more in research and share knowledge on ARM. One of the structures started by the consortium was an ARM-Net registry for the inclusion of all future patients treated in these centers. With this review, we report the structure of the ARM-Net registry, some of the results, and discuss the challenges we faced and still face after its introduction in 2010.

Background: Anorectal malformations (ARM) have a prevalence of around 1 in 2500 live births. In around 50% of patients, the malformation is isolated, while in the remainder it arises within the context of complex genetic abnormalities or a defined genetic syndrome. Recent studies have implicated rare copy number variations (CNVs) in both isolated and nonisolated ARM, and identified plausible candidate genes. Methods: In the present study, array-based molecular karyotyping was performed to identify causative CNVs in 32 sporadic ARM patients with comorbid abnormalities of the central nervous system (CNS). This phenotype was selected to enrich for rare CNVs, since previous research has implicated rare CNVs in both CNS abnormalities and ARM. Results: In five patients, a probable disease-causing CNV was identified (del6q14.3q16.3, del14q32.2, del17q12q21.2, and two patients with del22q11.21). In three of these patients, the CNVs were de novo. For the remaining two patients, no parental DNA was available. Deletions at 22q11.21 and 6q14.3 have been associated with both CNS abnormalities and ARM. In contrast, deletions at 14q32.2 have only been described in patients with CNS abnormalities, and the del17q12q21.2 is a novel CNV. Expression studies in mice suggest that NEUROD2 and RARA, which reside within the newly identified del17q12q21.2 region, are candidate genes for the formation of microcephaly and ARM. Conclusion: The present data suggest that CNVs are a frequent cause of the ARM with CNS abnormalities phenotype, and that array-analysis is indicated in such patients. Birth Defects Research (Part A) 103:235–242, 2015. © 2014 Wiley Periodicals, Inc.

Background The acronym VATER/VACTERL association describes the combination of at least three of the following cardinal features: vertebral defects, anorectal malformations, cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal malformations, and limb defects. Although fibroblast growth factor-8 (FGF8) mutations have mainly found in patients with Kallmann syndrome, mice with a hypomorphic Fgf8 allele or complete gene invalidation display, aside from gonadotropin-releasing hormone deficiency, parts or even the entire spectrum of human VATER/VACTERL association. Methods We performed FGF8 gene analysis in 49 patients with VATER/VACTERL association and 27 patients presenting with a VATER/VACTERL-like phenotype (two cardinal features). Results We identified two heterozygous FGF8 mutations in patients displaying either VATER/VACTERL association (p.Gly29_Arg34dup) or a VATER/VACTERL-like phenotype (p.Pro26Leu) without limb anomalies. Whereas the duplication mutation has not been reported before, p.Pro26Leu was once observed in a Kallmann syndrome patient. Both our patients had additional bilateral cryptorchidism, a key phenotypic feature in males with FGF8 associated Kallmann syndrome. Each mutation was paternally inherited. Besides delayed puberty in both and additional unilateral cryptorchidism in one of the fathers, they were otherwise healthy. Serum hormone levels downstream the gonadotropin-releasing hormone in both patients and their fathers were within normal range. Conclusion Our results suggest FGF8 mutations to contribute to the formation of the VATER/VACTERL association. Further studies are needed to support this observation.

Item does not contain fulltext Anorectal malformations (ARMs) comprise a broad spectrum of conditions ranging from mild anal anomalies to complex cloacal malformations. In 40-50% of cases, ARM occurs within the context of defined genetic syndromes or complex multiple congenital anomalies, such as VATER/VACTERL (vertebral defects [V], ARMs [A], cardiac defects [C], tracheoesophageal fistula with or without esophageal atresia [TE], renal malformations [R], and limb defects [L]) association. Here, we report the identification of deletions at chromosome 13q using single nucleotide polymorphism-based array analysis in two patients with mild ARM as part of VATER/VACTERL and VATER/VACTERL-like associations. Both deletions overlap the previously defined critical region for ARM. Heterozygous Efnb2 murine knockout models presenting with mild ARM suggest EFNB2 as an excellent candidate gene in this region. Our patients showed a mild ARM phenotype, closely resembling that of the mouse. We performed a comprehensive mutation analysis of the EFNB2 gene in 331 patients with isolated ARM, or ARM as part of VATER/VACTERL or VATER/VACTERL-like associations. However, we did not identify any disease-causing mutations. Given the convincing argument for EFNB2 as a candidate gene for ARM, analyses of larger samples and screening of functionally relevant non-coding regions of EFNB2 are warranted. In conclusion, our report underlines the association of chromosome 13q deletions with ARM, suggesting that routine molecular diagnostic workup should include the search for these deletions. Despite the negative results of our mutation screening, we still consider EFNB2 an excellent candidate gene for contributing to the development of ARM in humans. (c) 2013 Wiley Periodicals, Inc.

Item does not contain fulltext The acronym VATER/VACTERL association describes the combination of at least three of the following congenital anomalies: vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). We aimed to identify highly penetrant de novo copy number variations (CNVs) that contribute to VATER/VACTERL association. Array-based molecular karyotyping was performed in a cohort of 41 patients with VATER/VACTERL association and 6 patients with VATER/VACTERL-like phenotype including all of the patients' parents. Three de novo CNVs were identified involving chromosomal regions 1q41, 2q37.3, and 8q24.3 comprising one (SPATA17), two (CAPN10, GPR35), and three (EPPK1, PLEC, PARP10) genes, respectively. Pre-existing data from the literature prompted us to choose GPR35 and EPPK1 for mouse expression studies. Based on these studies, we prioritized GPR35 for sequencing analysis in an extended cohort of 192 patients with VATER/VACTERL association and VATER/VACTERL-like phenotype. Although no disease-causing mutation was identified, our mouse expression studies suggest GPR35 to be involved in the development of the VATER/VACTERL phenotype. Follow-up of GPR35 and the other genes comprising the identified duplications is warranted.

In order to prevent stricture of the neoanus after surgical correction, regular dilatation is recommended. There is a lack of knowledge about the performance of anal dilatation and the occurrence of pain. The aim of our investigation was to describe the practice of dilatation and to identify possible risk factors for painful procedures. Congenital Uro-Rectal Malformations Network is a German interdisciplinary multicenter research network. With standard questionnaires, physicians interviewed 243 patients and/or their parents at home, additional 103 patients born since 2009 were assessed through their treating physicians. In total, 88 % of the patients received dilatations. Treatment lasted for 7 months in median (range 1–156 months), until the age of 13 months (range 1–171 months). In 69 % painful dilatation was reported; without a significant differences in age or gender. In 32 % bleeding was reported. In 30 % at least one dilatation was performed under general anesthesia. In 11 % some kind of analgesia was used. Type of fistula, dilatations lasting longer than 10 months and Hegar size above 15 were relevant factors for experience of pain. There were about 16 % postoperative strictures of the neoanus, without reported differences in dilatation procedures; but there was a relation to type of malformation. Considering the high number of painful treatments, predictors for painful dilatations should be further clarified through standardized documentation and prospective evaluation in order to improve follow-up.

The aim of the German Network for Congenital Uro-REctal Malformations is to collect data of affected patients with anorectal malformation (ARM) or extrophy–epispadias complex, and to investigate molecular causes, clinical implications, and psychosocial outcome. The current issue was to assess the postoperative sequelae related to lower urinary tract dysfunction in patients with ARM. Two hundred and sixty-seven patients with ARM (112 females, 155 males, median age 6 years, range 0–56 years) were investigated via standardized case report forms comprising interview, analysis of medical data, and personal questionnaires. Thirty-two patients (12%, 23 males, 9 females) suffered from neurogenic bladder dysfunction, mainly associated with recto-urethral fistula (11 cases, 34%), and recto-vesical fistula (6 cases, 19%). Sixty-eight patients (26%, 35 males, 57 females) have experienced lifetime urinary tract infection, primarily associated with recto-urethral fistula (21 cases, 31%), and vestibular fistula (13 cases, 19%). According to type of operation, the highest number of postoperative urologic problems was reported after abdominosacroperineal pull-through. Besides reconstructing the ARM, another main goal is the preservation of lower urinary tract function. In our data, there seems to be a close correlation between operative strategies and postoperative complications.

Following a recent classification of the VATER Association provided by the CURE-Net consortium (submitted), we investigate medical predictors of psychological stress and anxieties in this particular condition.We developed a new set of questionnaires measuring psychological adjustment and quality of life outcome in conditions associated with anorectal and/or urogenital malformation (one self- report form to be completed by patients 7-17 years of age, two parent report forms with one relating to patients with an age range of 0-6 years, resp. 7-17 years of age). The questionnaire "Malformation-related Stress and Anxieties" comprises 26 items belonging to five subscales (I. Functional and cosmetic impairment, II. Intimacy and relationship, III. Social inclusion, IV. Psychological functioning, V. Family functioning). Every item can be responded to with respect to both actual, present problems already experienced as well as to future anxieties anticipating future development and adjustment (a perspective which especially applies in younger patients). Internal consistencies of the scales are good, resp. very good (Cronbach's α = .85 concerning present sources of anxiety scale, resp., .94 concerning future anxieties scale). The items are supplied with a Likert-type 5-point scale. We administered the questionnaire in N = 17 children and adolescents suffering from VATER via parental (proxy) report.As most medical risk factors affected nearly the entire sample, statistical analysis excluded investigation of differential impact on psychological stress experience and anxieties in subjects exposed versus not exposed. Special attention, therefore, was paid to those medical parameters with the best statistical power to differentiate between individuals of high versus low psychological outcome. Medical predictors differentiating between individuals with high versus low adjustment comprise post-operative infections of the urinary tract (t[15] = -3.78, p = .09), wound infections (t[15] = -3.04, p .01), stoma complications (t[15] = -2.11, p = .08) (e.g., prolapsed (t[13] = -2.37, p = .05), other treatment complications (t[15] = -2.59, p .05) and presence of a megacolon (t[13] = -2.44, p = .06).From the perspective of stress psychology, the findings may indicate that particular medical characteristics of a malformation may operate via two different pathways: (a) pathway of severity of a particular medical risk factor: the presence of a megacolon, for example, may restrict quality of life and successful adjustment via multiple and long term functional impairments associated and (b) pathway of subjective predictability and controllability of treatment course. In accordance with theoretical models from stress psychology, the psychological impact of complicating factors such as wound-healing infections is not operating via severity of impairment, but via implicit messages they convey, indicating a low predictability and controllability of course of disease and treatment. As a result, they may increase intensity of worry and anxieties upon further difficulties still to come during future development. As a conclusion, psychological counseling may not only address concrete functional impairments and stressors, but also basic feelings of insecurity, controllability and self-efficacy.

De Novo Duplication of 18p11.21–18q12.1 in a Female With Anorectal Malformation Charlotte Schramm, Markus Draaken, Enrika Bartels, Thomas M. Boemers, Eberhard Schmiedeke, Sabine Grasshoff-Derr, Stefanie M€arzheuser, Stuart Hosie, Stefan Holland-Cunz, Friederike Baudisch, Lutz Priebe, Per Hoffmann, Alexander M. Zink, Hartmut Engels, Felix F. Brockschmidt, Stefan Aretz, Markus M. N€othen, Michael Ludwig, and Heiko Reutter* Institute of Human Genetics, University of Bonn, Bonn, Germany Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany Department of Pediatric Surgery and Pediatric Urology, Children’s Hospital, Cologne, Germany Department of Pediatric Surgery and Urology, Center for Child and Adolescent Health, Hospital Bremen-Mitte, Bremen, Germany Department of Pediatric Surgery, University Hospital W€urzburg, W€urzburg, Germany Department of Pediatric Surgery, Campus Virchow Clinic, Charit e University Hospital Berlin, Berlin, Germany Department of Pediatric Surgery, Klinikum Schwabing, Technische Universit€at M€unchen, M€unchen, Germany Department of Pediatric Surgery, University of Heidelberg, Heidelberg, Germany Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany Department of Neonatology, Children’s Hospital, University of Bonn, Bonn, Germany

Fecal incontinence and constipation are major problems after correction of anorectal malformation (ARM), caused not only by the somatic defects but also by a psychosomatic dysfunction of defecation. To better release patients from this dysfunction we offered a multidisciplinary, psycho-and physiotherapeutic therapy according to an approach developed in Nijmegen (Netherlands). We herein summarize the preliminary results to evaluate whether the approach can be adopted with similar success. Since January 2002 multidisciplinary behavioural treatment (MBT) has been offered to children above 3 years of age and suffering from fecal incontinence and constipation after surgical correction of ARM in our department or elsewhere. Prerequisites included no anal stenosis, regulation of stool consistency, and a suitable defecation diary over 2 weeks. MBT contained regular consultations by a pediatric psychologist and a physiotherapist, teaching the child to establish a regular defecation pattern and how to push while relaxing the pelvic floor. The entry-and post-treatment situation was prospectively monitored by means of defecation and constipation scoring systems. Complete data were available in 10 patients (9 males, 1 female) with high (8 patients) and low (2) forms of anal atresia initially, who finished MBT 2–36 months ago (mean: 13 months). The average amount of stool reaching the toilet was 27% before and 90% after therapy. Clean days were absent before, reaching 3.7 days on average after therapy. Constipation was present in 6 patients before (3 of them on enemas) and in 2 after therapy (no enemas needed). The duration of MBT was 7 months on average, range 3–23 months, with 8–9 sessions per patient, each lasting 60–90 minutes. An observation period of 7 months after treatment confirmed stable results. MBT turned out to improve body-consciousness and self-confidence. MBT is effective in reducing incontinence and constipation in patients after ARM. It helps the children and their families to relieve psychosocial stress. The approach can be successfully adopted, if a team of committed specialists is available and sufficient compliance of patients and families is given. compliance of patients and families is given.

Item does not contain fulltext BACKGROUND: Pediatric surgeons and patient organisations agree that fewer centers for anorectal malformations with larger patient numbers are essential to reach better treatment. The European Union transacts a political process which aims to realize such centers of expertise for a multitude of rare diseases. All the centers on a specific rare disease should constitute an ERN on that disease. ARM-Net members in different countries report on first experiences with the implementation of national directives, identifying opportunities and risks of this process. METHODS: Relevant details from the official European legislation were analyzed. A survey among the pediatric surgeons of the multidisciplinary ARM-Net consortium about national implementation was conducted. RESULTS: European legislation calls for multidisciplinary centers treating children with rare diseases, and proposes a multitude of quality criteria. The member states are called to allocate sufficient funding and to execute robust governance and oversight, applying clear methods for evaluation. Participation of the patient organisations is mandatory. The national implementations all over Europe differ a lot in respect of extent and timeframe. CONCLUSIONS: Establishing Centers of Expertise and a ERN for anorectal malformations offers great opportunities for patient care and research. Pediatric surgeons should be actively engaged in this process.

Anorectal malformations (ARM) have a prevalence of around 1 in 2500 live births. In around 50% of patients, the malformation is isolated, while in the remainder it arises within the context of complex genetic abnormalities or a defined genetic syndrome. Recent studies have implicated rare copy number variations (CNVs) in both isolated and nonisolated ARM, and identified plausible candidate genes.In the present study, array-based molecular karyotyping was performed to identify causative CNVs in 32 sporadic ARM patients with comorbid abnormalities of the central nervous system (CNS). This phenotype was selected to enrich for rare CNVs, since previous research has implicated rare CNVs in both CNS abnormalities and ARM.In five patients, a probable disease-causing CNV was identified (del6q14.3q16.3, del14q32.2, del17q12q21.2, and two patients with del22q11.21). In three of these patients, the CNVs were de novo. For the remaining two patients, no parental DNA was available. Deletions at 22q11.21 and 6q14.3 have been associated with both CNS abnormalities and ARM. In contrast, deletions at 14q32.2 have only been described in patients with CNS abnormalities, and the del17q12q21.2 is a novel CNV. Expression studies in mice suggest that NEUROD2 and RARA, which reside within the newly identified del17q12q21.2 region, are candidate genes for the formation of microcephaly and ARM.The present data suggest that CNVs are a frequent cause of the ARM with CNS abnormalities phenotype, and that array-analysis is indicated in such patients.

We assessed the risk of exstrophy-epispadias complex in children conceived by in vitro fertilization or intracytoplasmic sperm injection.Data from the German Network for Congenital Uro-REctal malformations were compared to nationwide data from the German In Vitro Fertilization Register and the German Federal Statistical Office. Odds ratios (95% CI) were determined to quantify associations using logistic regression.A total of 123 patients with exstrophy-epispadias complex born in Germany between 1997 and 2011 were recruited through participating departments of pediatric urology and pediatric surgery throughout the country as well as the German self-help organizations Blasenekstrophie/Epispadie e.V. and Kloakenekstrophie. All German live births (10,069,986) between 1997 and 2010 comprised the controls. Overall, 12 subjects (10%) and 129,982 controls (1%) were conceived by in vitro fertilization or intracytoplasmic sperm injection. Conception by assisted reproductive technique was associated with a more than eightfold increased risk of exstrophy-epispadias complex compared to spontaneous conception (OR 8.3, 95% CI 4.6-15.0, p0.001). Separate analyses showed a significantly increased risk of exstrophy-epispadias complex in children conceived by in vitro fertilization (OR 14.0, 95% CI 6.5-30.0, p0.0001) or intracytoplasmic sperm injection (OR 5.3, 95% CI 2.2-12.9, p0.0001).This study provides evidence that assisted reproductive techniques such as in vitro fertilization and intracytoplasmic sperm injection are associated with a markedly increased risk of having a child born with exstrophy-epispadias complex. However, it remains unclear whether this finding may be due to assisted reproduction per se and/or underlying infertility/subfertility etiology or parent characteristics.

Item does not contain fulltext The VATER/VACTERL association is typically defined by the presence of at least three of the following congenital malformations: vertebral anomalies, anal atresia, cardiac malformations, tracheo-esophageal fistula, renal anomalies, and limb abnormalities. The identification of 14 twin pairs with an initial diagnosis of VATER/VACTERL association at our clinical centers led to the performance of a classical twin study. This involved a thorough evaluation of these 14 twin pairs and a further 55 twin pairs identified from a systematic review of the literature. The zygosity, concordance, and malformation status of all 69 twin pairs were evaluated. Twenty-four twin pairs fulfilled the criteria for inclusion in a comparison of the concordance rates between monozygous (MZ) and dizygous (DZ) twin pairs. The pairwise concordance rates were 15% [95% confidence interval (CI) 4-42%] for MZ and 18% (95% CI 5-48%) for DZ twin pairs (P=0.53). The probandwise concordance rates were 27% (95% CI 11-52%) for MZ and 31% (95% CI 13-58%) for DZ twin pairs (P=0.40). Although based on a limited number of twin pairs, the findings of the present study are consistent with the low number of familial cases reported to date, and suggest that the role of inherited genetic factors in the majority of VATER/VACTERL cases is limited. 01 oktober 2012

To determine the anorectal function in patients with anorectal malformations (ARM) in order to facilitate patient counseling and follow-up.Data were collected by the German network for urorectal malformations (CURE-Net) according to the International Krickenbeck consensus. Questionnaires on bowel function and a defecation protocol were completed by the families/patients. The clinical findings were assessed from the patients' clinical records.Two hundred and ninety-seven patients with ARM were assessed, 175 patients gave complete data on continence, 52 of them were excluded due to mental retardation, age, and earlier type of pullthrough. Complete continence was found in 27 %, perineal fistula in 40 %, rectourethral/vesical in 10 %, vestibular in 24 %, cloaca in 0 %. Krickenbeck grade 1 soiling: 42 %, grade 2 and 3: 31 %. Forty-nine percent of the incontinent patients practiced bowel management, reaching continence in 19 %. The statement of constipation (67 %) was validated with the last clinical findings, showing coprostasis in 46 %, "Not suffering constipation" was confirmed in 61 % and falsified in 29 %.ARM patients in Germany, as assessed by independent researchers, show a high rate of fecal incontinence and insufficiently treated constipation. Parents should be counseled accordingly and motivated to engage in consequent follow-up. Intensified efforts in the conservative treatment of constipation and fecal incontinence are crucial to improvement.

Anorectal malformations (ARMs) comprise a broad spectrum of anomalies, including anal atresia, congenital anal fistula and persistence of the cloaca. Research suggests that genetic factors play an important role in ARM development. However, few genetic variants have been identified. Embryogenesis is orchestrated by crosstalk of the wingless-type MMTV integration site family (WNT) and fibroblast growth factor (FGF) signaling pathways in a process that involves several intracellular cascades. Studies in mice have implicated several genes from these pathways in the etiology of ARMs. We performed sequencing analysis of seven of these previously reported genes in 78 patients with ARMs occurring within the context of at least one additional congenital anomaly. No associations were identified with variants in WNT3A, WNT5A, WNT11, DACT1, FGF10 or the T gene. In the FGFR2 gene, three novel heterozygous nucleotide substitutions were identified. Further investigations, including the study of family members, revealed that these variants were not causally related to the phenotype in the present ARM cohort. Mutations in the seven investigated genes may nonetheless be a cause of ARMs in rare cases. However, further studies should consider genes encoding other proteins in the WNT/FGF signaling pathways as possible candidates.

The aim of the German Network for Congenital Uro-REctal Malformations (CURE-Net) is to collect data of affected patients with anorectal malformation (ARM) to investigate molecular causes, clinical implications and psychosocial outcome. The current issue was to examine sexual function and to explore psychosocial adaptation in adults with ARM.This qualitative study using narrative inquiry is part of a larger multi-center study of clinical queries and quality of life in patients with ARM. The guided interview focused on analysis of sexual function.55 adult patients with ARM (23 females, 32 males, median age 23 years, range from 18 to 56 years) were investigated via standardized case-report forms comprising interview, analysis of medical data and personal questionnaires. In the female patients, 8 (35 %) of them lived alone and 15 (65 %) had sexual intercourse. In the male patients, the majority of 20 (69 %) patients lived alone and 13 (45 %) had sexual intercourse. 6 of the females got pregnant, 5 got 2 or more children. 3 of the men induced 2 or more pregnancies and fathered children.Besides reconstructing the ARM, another main goal is the preservation of sexual function. According to our data, there seems to be a close relationship between psychosocial development and sexual activity.

The aim of the German Network for Congenital Uro-REctal malformations (CURE-Net) is to collect data of affected patients with anorectal malformation (ARM) to investigate molecular causes, clinical implications and psychosocial outcome. The current issue was to examine the transition to adulthood in adults with ARM and to explore condition-related needs and skills required.This qualitative study is part of a larger multi-center study of clinical queries and quality of life in patients with ARM. The guided interview focused on the analysis of medical data and personal questionnaires.Interviews were completed with 55 (23 females, 32 males) participants, age ranging from 18 to 56 years. Twenty-one patients suffered from mucosal prolapse, 18 patients had had megasigmoid/megacolon. Relevant stenosis of the neo-anus occurred in 13 (42 %) males and 4 (18 %) females, permanent neurogenic bladder dysfunction in 10 (32 %) males and 4 (18 %) females, recurrent urinary tract infections in 10 (32 %) males and 13 (59 %) females, latex allergy in 10 (32 %) males and 7 (32 %) females. Thirty-seven (70 %) patients had to be reoperated. Forty-one (75 %) patients needed means of aftercare to achieve social continence.The study wants to contribute to a better understanding of the challenges of transition for adults with ARM.

VATER/VACTERL association refers to the non-random co-occurrence of the following component features: vertebral defects, anal atresia, cardiac malformations, tracheoesophageal atresia, renal abnormalities, and limb defects. Recently, Solomon et al. (Hum Genet 127:731–733, 2010) observed an increased prevalence of component features among first-degree relatives of VATER/VACTERL patients suggesting that in some patients, the disorder may be inherited. To replicate these findings, we investigated 87 VATER/VACTERL patients with the presence of a minimum of three component features and their first-degree relatives (n = 271). No increase in the overall prevalence of component features was observed in first-degree relatives compared to the general population (χ² = 2.68, p = 0.10). Separate analysis for the prevalence of single component features showed a higher prevalence of tracheoesophageal fistula/atresia among first-degree relatives compared to the general population (OR 17.65, 95 % CI 2.47–126.05). However, this was based on occurrence in one family only. Our findings suggest that although familial occurrence renders a genetic contribution likely, the overall risk of recurrence among the first-degree relatives of patients with VATER/VACTERL association is probably very low. Since the patients in the present study were young and no offspring could be studied, estimation of the role of de novo mutations in the development of VATER/VACTERL was not possible.

BACKGROUND Isolated esophageal atresia (EA) is a rare congenital malformation whose etiology remains largely unknown. Nine twin pairs with EA were identified from our clinical service, prompting the performance of a systematic review of the literature and the first reported twin study of isolated EA. METHODS A total of 330 twin pairs with EA were identified from the literature. The zygosity, concordance, and malformation (isolated vs. nonisolated) status of all 339 twin pairs were evaluated. A total of 72 twin pairs (4 of 9 / 68 of 330) fulfilled the criteria for inclusion in a classic twin study of isolated EA. RESULTS The pairwise concordance rates were 50% (95% confidence interval [CI], 34–66%) for monozygous (MZ) twin pairs and 26% (95% CI, 15–42%) for dizygous (DZ) twin pairs (p = 0.033). The probandwise concordance rates were 67% (95% CI, 53–78%) for MZ twin pairs and 42% (95% CI, 29–56%) for DZ twin pairs (p = 0.011). The MZ/DZ ratios were 1.9 for pairwise analysis and 1.6 for probandwise analysis. The familial risk ratios for MZ and DZ twin pairs were 1700 and 900, respectively. CONCLUSION The observation of higher concordance rates for MZ compared to DZ twin pairs indicates that genetic factors contribute to isolated EA. Birth Defects Research (Part A) 2012. © 2012 Wiley Periodicals, Inc.

Anorectal malformations (ARM) encompass a broad clinical spectrum which ranges from mild anal stenosis to severe anorectal anomalies such as complex cloacal malformations. The overall incidence of ARM is around 1 in every 2,500 live births. Although causative genes for a few syndromic forms have been identified, the molecular genetic background of most ARM remains unknown. The present report describes a patient with a de novo 13.2-Mb deletion of chromosome 18q22.3–qter and a 2.2-Mb de novo duplication of chromosomal region 18pter–p11.32 located at the telomeric end of chromosome 18q. The patient presented with ARM and the typical features of 18q– syndrome (De-Grouchy syndrome). The combination of a partial duplication of the short arm and a partial deletion of the long arm of chromosome 18 has been described in 16 previous cases. However, this is the first report of an association between this complex chromosomal rearrangement and ARM.

Anorectal malformations (ARM) range from mild anal to severe anorectal anomalies. Approximately 50% are estimated to be non-syndromic with multiple familial cases reported that suggest underlying genetic factors. These, however, still await identification. We report a familial case of non-syndromic ARM with a mother and her two children being affected. Mother and daughter had mild ARM that had only been diagnosed after the index patient was born with a more severe form and ultrashort Hirschsprung’s disease. To reveal the genetic cause in our family genome-wide array analysis was carried out to ascertain microaberrations characterized by loss or gain of genomic material. In addition, sequence analysis of four major Hirschsprung’s disease genes (RET, EDNRB, EDN3, and GDNF) and the HLXB9 gene was performed to identify a mutation common to all three family members; however, these analyses did not reveal any causal genetic alteration. To demonstrate the frequency of familial non-syndromic cases, we performed a literature search revealing 59 families with at least two affected members. Sufficient description of ARM phenotype and affection status of relatives to surely classify them as familial non-syndromic forms was given for 22 families. The present family suggests that mild ARM may be overlooked in patients with non-specific clinical symptoms and that the incidence of ARM may thus be higher than previously estimated. With the new possibilities of whole exome sequencing, even small families hold the possibility to identify causal defects.

Summary Background The bladder exstrophy–epispadias complex (BEEC) comprises a spectrum of congenital anomalies that represents the severe end of urorectal malformations, and has a profound impact on continence as well as sexual and renal functions. Objective The relation between severity of BEEC and its associated functional impairments, on one hand, and the resulting restrictions in quality of life and potential psychopathology determine the patients' outcome. It is important for improving further outcome to identify BEEC-related sources of distress in the long term. Genital function and sexuality becomes an important issue for adolescent and adult BEEC individuals. Hence, the present study focused on sexual function and psychological adaption in patients with BEEC. Study design In a multicenter study 52 patients (13 females, 39 males) with classic bladder exstrophy (BE) with their bladders in use were assessed by a self-developed questionnaire about sexual function, and psychosexual and psychosocial outcome. The patients were born between 1948 and 1994 (median age 31 years). Results Twelve of 13 (92%) females and 25 of 39 (64%) males with classic BE had answered the questions on sexual function. Of these, 50% females and 92% males answered that they masturbated. Females had sexual intercourse more frequently. Six (50%) females affirmed dyspareunia whereas only two (8%) males reported pain during erection. Eight (67%) females specified having orgasms. Eighteen (72%) males were able to ejaculate. Two males and none of the females lived in a committed partnership (Figure). Two (15%) females and 13 (33%) males answered all psychosocial questions. The majority of these patients had concerns about satisfactory sexuality and lasting, happy partnerships. A minority of patients of both sexes were willing to answer psychosocial questions. Sexual activity and relationships of many adult BE patients seems to be impaired. Not surprisingly, sexual activity and awareness were different in males and females even in a multi-organ anomaly. Download : Download high-res image (267KB) Download : Download full-size image Figure . Sexuality of adult female and male bladder exstrophy patients. Discussion To date, one of the main goals of the medical treatment of BEEC/BE patients is to enable normal sexual life and fertility. However, only a few outcome studies have focused on these issues with contradicting results, most of them not using standardized outcome measures. In accordance with other studies, our female BE patients have dyspareunia and most of our male BE patients were able to ejaculate. But the question of normal force of ejaculation, ejaculated volume, or semen analysis remains unanswered. Despite partial confirmation of previous findings, there is inconsistency referring to the outcome measured by the available studies. This might in part be explained by the fact that, other than this study, most previous studies are the result of single-institution experience. Thus, selection bias in the patient sampling due to different a clinical collective in different hospitals may be the consequence. Furthermore, patients' honesty and self-reflection in answering difficult questions regarding their sexual and cosmetic impairments is questionable. In addition, studies include a wide range of age groups and are connected with this life period. Fears and condition-specific anxieties might change over time. Hence, the strengths of this study are the nationwide and treating physician-independent data acquisition as well as the large sample size of adult patients with a very rare congenital malformation. Unfortunately, more detailed analyses on sexual function and current psychosocial situation, for example correlation of data with clinical symptoms such as continence status, was not possible as data were mainly not answered by patients. Conclusion To improve the quality of life of patients with BEEC/BE, treatment and follow-up should emphasize physical but also psychological care in these patients. Physicians should further re-evaluate their preconceptions and should take care of the patients throughout their lives.