0000000000016845
AUTHOR
Nadine Zwink
Human exome and mouse embryonic expression data implicate ZFHX3, TRPS1, and CHD7 in human esophageal atresia
Introduction Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development. Methods To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we perfor…
SLC20A1 Is Involved in Urinary Tract and Urorectal Development
Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exs…
Sexual function in adult patients with classic bladder exstrophy: A multicenter study
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 stu…
Treatment strategies and outcome of the exstrophy–epispadias complex in germany: data from the german CURE-Net
Introduction: To evaluate the impact of reconstructive strategies and post-operative management on short- and long-term surgical outcome and complications of classical bladder exstrophy (CBE) patients' comprehensive data of the multicenter German-wide Network for Congenital Uro-Rectal malformations (CURE-Net) were analyzed. Methods: Descriptive analyses were performed between 34 prospectively collected CBE patients born since 2009, median 3 months old [interquartile range (IQR), 2–4 months], and 113 cross-sectional patients, median 12 years old (IQR, 6–21 years). Results: The majority of included individuals were males (67%). Sixty-eight percent of the prospectively observed and 53% of the …
Comparison of environmental risk factors for esophageal atresia, anorectal malformations, and the combined phenotype in 263 German families
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 invo…
Association Between Exstrophy-epispadias Complex And Congenital Anomalies: A German Multicenter Study
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 …
Evaluation of sexual function in females with exstrophy-epispadias-complex: a survey of the multicenter German CURE-Net
Standardized knowledge about genital function in adult female individuals with exstrophy-epispadias complex (EEC) is scarce. The aim of this study was to investigate sexual function using the standardized Female Sexual Function Index (FSFI), and to assess the influence of bladder and vaginal reconstruction and the presence of incontinence on FSFI results.Sixty-one females (aged ≥18 years) recruited by the German multicenter network for congenital uro-rectal malformations (CURE-Net) were asked to complete the FSFI and a self-designed semi-structured questionnaire assessing comprehensive medical data, gynecological, and psychosocial items. Twenty-one eligible females (34%) returned both quest…
Assisted reproductive techniques and risk of exstrophy-epispadias complex: a German case-control study.
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/Epispad…
No major role for periconceptional folic acid use and its interaction with theMTHFR C677Tpolymorphism in the etiology of congenital anorectal malformations
Background: Both genetic and nongenetic factors are suggested to be involved in the etiology of congenital anorectal malformations (ARM). Maternal periconceptional use of folic acid supplements were inconsistently suggested to play a role in the prevention of ARM. Therefore, we investigated independent associations and interactions of maternal periconceptional folic acid supplement use and the infant and maternal MTHFR (methylenetetrahydrofolate reductase) C677T polymorphisms with the risk of ARM and subgroups of ARM. Methods: A case-control study was conducted among 371 nonsyndromic ARM cases and 714 population-based controls born between 1990 and 2012 using maternal questionnaires and DNA…
Genome-wide Association Study and Meta-Analysis Identify ISL1 as Genome-wide Significant Susceptibility Gene for Bladder Exstrophy
The bladder exstrophy-epispadias complex (BEEC) represents the severe end of the uro-rectal malformation spectrum, and is thought to result from aberrant embryonic morphogenesis of the cloacal membrane and the urorectal septum. The most common form of BEEC is isolated classic bladder exstrophy (CBE). To identify susceptibility loci for CBE, we performed a genome-wide association study (GWAS) of 110 CBE patients and 1,177 controls of European origin. Here, an association was found with a region of approximately 220kb on chromosome 5q11.1. This region harbors the ISL1 (ISL LIM homeobox 1) gene. Multiple markers in this region showed evidence for association with CBE, including 84 markers with…
Needs Assessment in Care of Adults With Anorectal Malformations and Exstrophy-Epispadias Complex in Germany
Introduction: Medical needs of adults with anorectal malformations (ARM) and the exstrophy-epispadias complex (EEC) are not fully understood. Therefore, the aim of the study was to evaluate how affected individuals get along with the current national medical care and what their medical or social long-term requirements are. Patients and Methods: Between 11/2014-07/2016 all adult members (≥18 years, ARM n = 113, EEC n = 126) of the German self-help organizations SoMA e.V. and Blasenekstrophie/Epispadie e.V. were contacted via email or post and asked to fill out an anonymous online questionnaire regarding medical requirements, treatment satisfaction, daily life impairment and expectations rega…
ISL1 is a major susceptibility gene for classic bladder exstrophy and a regulator of urinary tract development
AbstractPreviously genome-wide association methods in patients with classic bladder exstrophy (CBE) found association with ISL1, a master control gene expressed in pericloacal mesenchyme. This study sought to further explore the genetics in a larger set of patients following-up on the most promising genomic regions previously reported. Genotypes of 12 markers obtained from 268 CBE patients of Australian, British, German Italian, Spanish and Swedish origin and 1,354 ethnically matched controls and from 92 CBE case-parent trios from North America were analysed. Only marker rs6874700 at the ISL1 locus showed association (p = 2.22 × 10−08). A meta-analysis of rs6874700 of our previous and prese…
Genome-wide mapping of copy number variations in patients with both anorectal malformations and central nervous system abnormalities
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 implica…
Array-based molecular karyotyping in 115 VATER/VACTERL and VATER/VACTERL-like patients identifies disease-causing copy number variations
Background The acronym VATER/VACTERL refers to the rare nonrandom association of the following component features (CF): vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia, renal malformations (R), and limb defects (L). Patients presenting with at least three CFs are diagnosed as having VATER/VACTERL association while patients presenting with only two CFs are diagnosed as having VATER/VACTERL-like phenotypes. Recently, rare causative copy number variations (CNVs) have been identified in patients with VATER/VACTERL association and VATER/VACTERL-like phenotypes. Methods To detect further causative CNVs we perfor…
Phenotype severity in the bladder exstrophy-epispadias complex: analysis of genetic and nongenetic contributing factors in 441 families from North America and Europe.
Objective To identify genetic and nongenetic risk factors that contribute to the severity of the bladder exstrophy-epispadias complex (BEEC). Study design Patients with BEEC from North America (n = 167) and Europe (n = 274) were included. The following data were collected: associated anomalies, parental age at conception, mode of conception, periconceptional folic acid supplementation, maternal risk factors during pregnancy, and environmental risk factors. The patients were divided into 3 subgroups according to phenotype severity: (i) mild, epispadias (n = 43); (ii) intermediate, classic bladder exstrophy (n = 366); and (iii) severe, cloacal exstrophy (n = 31). These subgroups then were com…
De novo 13q deletions in two patients with mild anorectal malformations as part of VATER/VACTERL and VATER/VACTERL-like association and analysis of EFNB2 in patients with anorectal malformations
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 ass…
Second study on the recurrence risk of isolated esophageal atresia with or without trachea-esophageal fistula among first-degree relatives: no evidence for increased risk of recurrence of EA/TEF or for malformations of the VATER/VACTERL association spectrum.
BACKGROUND Esophageal atresia with/without trachea-esophageal fistula (EA/TEF) denotes a spectrum of severe congenital malformations. The aim of this systematic study was to determine both the recurrence risk for EA/TEF, and the risk for malformations of the VATER/VACTERL association spectrum, in first-degree relatives of patients with isolated EA/TEF. METHODS A total of 108 unrelated patients with isolated EA/TEF were included. These individuals had 410 first-degree relatives including 194 siblings. The presence of EA/TEF and malformations of the VATER/VACTERL association spectrum in relatives was systematically assessed. Data from the EUROCAT network were used for comparison. RESULTS None…
Genome-wide association study and mouse expression data identify a highly conserved 32 kb intergenic region between WNT3 and WNT9b as possible susceptibility locus for isolated classic exstrophy of the bladder
Item does not contain fulltext Bladder exstrophy-epispadias complex (BEEC), the severe end of the urorectal malformation spectrum, has a profound impact on continence as well as sexual and renal functions. It is widely accepted that for the majority of cases the genetic basis appears to be multifactorial. Here, we report the first study which utilizes genome-wide association methods to analyze a cohort comprising patients presenting the most common BEEC form, classic bladder exstrophy (CBE), to identify common variation associated with risk for isolated CBE. We employed discovery and follow-up samples comprising 218 cases/865 controls and 78 trios in total, all of European descent. Our disc…
HeterozygousFGF8mutations in patients presenting cryptorchidism and multiple VATER/VACTERL features without limb anomalies
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 …
Parental risk factors of anorectal malformations: Analysis with a regional population-based control group
BACKGROUND Adequate evidence on environmental risk factors for anorectal malformations (ARMs) is very limited. We assessed maternal body weight and several prenatal exposures of the parents to tobacco, pregestational diabetes, chronic cardiovascular and respiratory diseases, periconceptional folic acid and multivitamin intake. METHODS Data from the German Network for Congenital Uro-REctal malformations (CURE-Net) were compared with data from the Malformation Monitoring Centre Saxony-Anhalt of the Otto-von-Guericke University in Magdeburg, Germany. Controls were matched to cases by gender and birth year of the child. Crude and adjusted odds ratios (95% confidence intervals) were calculated f…
Quality of Life after Surgical Treatment for Esophageal Atresia: Long-Term Outcome of 154 Patients.
Background The short- and long-term surgical results in patients with esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) have been described in depth from a physician's perspective. Contrarily, the perception and coping strategies of affected patients and their parents have rarely been reported. The aim of this study was to generate data on this matter. Patients and Methods A total of 154 patients who had operative reconstruction for EA between 1971 and 2012 were evaluated for demographic data, surgical technique, affection of daily life, and coping strategies. Results Gastroesophageal reflux (GER) symptoms were reported in 59% of cases with 33% requiring fundoplicatio…
A Prevalence Estimation of Exstrophy and Epispadias in Germany From Public Health Insurance Data
Introduction: The prevalence of rare diseases is very important for health care research. According to the European Surveillance of Congenital Anomalies (EUROCAT) registers, the live prevalence for exstrophy and/or epispadias (grades 1–3) is reported with 1:23,255 (95% CI: 1:26,316; 1:20,000). A Europe-wide prevalence evaluation based on reports from excellence centers estimates a prevalence for exstrophies of 1:32,200 and for isolated epispadias of 1:96,800 in 2010. However, the frequency of exstrophy [International Statistical Classification of Diseases and Related Health Problems revision 10 (ICD-10): Q64.1] and epispadias (ICD-10: Q64.0) treated in different age groups in Germany remain…
Esophageal Atresia with or without Tracheoesophageal Fistula (EA/TEF): Association of Different EA/TEF Subtypes with Specific Co-occurring Congenital Anomalies and Implications for Diagnostic Workup.
Background Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) represents the most common developmental malformation of the upper digestive tract. It is classified into six subtypes according to the classification of Vogt, depending on anatomical variation of this malformation. Around 50% of the patients with EA/TEF present additional anomalies, which often influence, next to the EA/TEF subtype, the overall prognosis of EA/TEF newborns. Here, we investigated the association of the different EA/TEF subtypes with co-occurring congenital anomalies in EA/TEF patients and demonstrate their implications for postnatal diagnostic workup. Materials and Methods We investigated 333 …
Sexual Function and Quality of Life in Adult Male Individuals with Exstrophy-Epispadias Complex—a Survey of the German CURE-Network
Objective To investigate sexual function and quality of life (QoL) in adult male individuals with exstrophy-epispadias complex (EEC). Data from the German Network for Congenital Urorectal Malformations (CURE-Net) were used. Patients and Methods Fifty-one male participants (≥18 years) recruited by CURE-Net between 2009 and 2012 were re-contacted per mail and asked to fill out 4 questionnaires including International Index of Erectile Function (IIEF-5), Cologne Assessment of Erectile Dysfunction (KEED), the Short-Form 36 (SF-36), and one self-designed questionnaire about their medical history, current health status, and sexual experience. The SF-36 results were compared with general German po…
Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations
IntroductionAnorectal malformations (ARM) are rare congenital malformations, resulting from disturbed hindgut development. A genetic etiology has been suggested, but evidence for the involvement of specific genes is scarce. We evaluated the contribution of rare and low-frequency coding variants in ARM etiology, assuming a multifactorial model.MethodsWe analyzed 568 Caucasian ARM patients and 1,860 population-based controls using the Illumina Human Exome Beadchip array, which contains >240,000 rare and low-frequency coding variants. GenomeStudio clustering and calling was followed by re-calling of 'no-calls' using zCall for patients and controls simultaneously. Single variant and gene-bas…