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…

Duodenal Atresia Repair Using a Miniature Stapler Compared to Laparoscopic Hand-Sewn and Open Technique

Abstract Background: Laparoscopic duodenal atresia (DA) repair is a demanding procedure that requires performing a watertight anastomosis in a small working space. Drawbacks of the approach have be...

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 …

Behandlung der Ösophagusatresie mit unterer tracheoösophagealer Fistel – Zusammenfassung der aktuellen S2K-Leitlinie der DGKCH

ZusammenfassungDie Ösophagusatresie (ÖA) ist eine angeborene Kontinuitätsunterbrechung der Speiseröhre mit oder ohne Fistel zur Trachea (Tracheoösophageale Fistel, TÖF). Je nach Abstand zwischen den beiden Ösophagusenden unterscheidet man eine „kurzstreckige“ von einer „langstreckigen“ Form. Bis zu 50% der Neugeborenen weisen weitere Anomalien auf. Eine pränatale Diagnose der ÖA gelingt in 32–63% der Fälle. Die interdisziplinäre Betreuung dieser Kinder hat sich in den letzten Jahren gewandelt. In der folgenden Arbeit wird die aktuelle S2K-Leitlinie der Deutschen Gesellschaft für Kinderchirurgie zur Behandlung der ÖA mit unterer TÖF, die etwa 90% aller Fälle ausmacht, zusammengefasst. Hierzu…

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…

Tracheostomy in Infants

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 …

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…

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 …

Inter- and Intraobserver Variation in the Assessment of Preoperative Colostograms in Male Anorectal Malformations: An ARM-Net Consortium Survey

Aim:Male patients with anorectal malformations (ARM) are classified according to presence and level of the recto-urinary fistula. This is traditionally established by a preoperative high-pressure distal colostogram that may be variably interpreted by different surgeons. The aim of this study was to evaluate the inter- and intraobserver variation in the assessment by pediatric surgeons of preoperative colostograms with respect to the level of the recto-urinary fistula. Materials and Methods:Sixteen pediatric surgeons from 14 European centers belonging to the ARM-Net Consortium twice scored 130 images of distal colostograms taken in sagittal projection at a median age of 66 days of life (rang…