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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 gehören das präoperative Management sowie operative und anästhesiologische Aspekte (u. a. Thorakoskopie vs. Thorakotomie, präoperative Tracheobronchoskopie, intraoperative Hyperkapnie und Azidose). Ferner wird das postoperative Management insbesondere von relevanten Komplikationen wie der Anastomosenstenose beschrieben. Trotz Fortschritten in der Behandlung der ÖA ist die Langzeitmorbidität mit Motilitätsstörungen des Ösophagus, gastroösophagealer Refluxkrankheit, rezidivierenden Infektionen der oberen und unteren Atemwege, Tracheomalazie, mangelhaftem Gedeihen sowie orthopädischen Problemen nach Thorakotomie weiterhin hoch. Zum Erreichen einer guten Lebensqualität ist daher eine gute interdisziplinäre Nachsorge wichtig.

Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene

Esophageal atresia (EA) is a congenital anomaly that entails an interrupted esophagus with or without tracheoesophageal fistula (TEF). Depending on the distance of the two esophageal pouches a "short-gap" is distinguished from a "long-gap" variant. Up to 50% of newborns have additional anomalies. EA is prenatally diagnosed in 32-63% of cases. Recently, the interdisciplinary care in these children underwent substantial changes. Therefore, we summarize the current guideline of the German society of pediatric surgery for the treatment of patients with EA and distal TEF (Gross Type C). Controversies regarding the perioperative management include surgical-technical aspects, such as the thoracoscopic approach to EA, as well as general anesthesia (preoperative tracheobronchoscopy, intraoperative hypercapnia and acidosis). Moreover, postoperative complications and their management like anastomotic stricture are outlined. Despite significant improvements in the treatment of EA, there is still a relevant amount of long-term morbidity after surgical correction. This includes dysmotility of the esophagus, gastroesophageal reflux disease, recurrent respiratory infections, tracheomalacia, failure to thrive, and orthopedic complications following thoracotomy in the neonatal age. Therefore, close follow-up is mandatory to attain optimal quality of life.Die 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 gehören das präoperative Management sowie operative und anästhesiologische Aspekte (u. a. Thorakoskopie vs. Thorakotomie, präoperative Tracheobronchoskopie, intraoperative Hyperkapnie und Azidose). Ferner wird das postoperative Management insbesondere von relevanten Komplikationen wie der Anastomosenstenose beschrieben. Trotz Fortschritten in der Behandlung der ÖA ist die Langzeitmorbidität mit Motilitätsstörungen des Ösophagus, gastroösophagealer Refluxkrankheit, rezidivierenden Infektionen der oberen und unteren Atemwege, Tracheomalazie, mangelhaftem Gedeihen sowie orthopädischen Problemen nach Thorakotomie weiterhin hoch. Zum Erreichen einer guten Lebensqualität ist daher eine gute interdisziplinäre Nachsorge wichtig.

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 performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal. Results In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants. Conclusion Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF.

Congenital malformations of the lung are presenting many different types of histological and anatomical anomalies developing during the prenatal period. Classification can be made into congenital pulmonary airway malformation, bronchopulmonary sequestration, bronchial atresia, bronchogenic cyst and congenital lobar emphysema. Prenatal imaging, most usually by ultrasound in the clinical routine, is revealing and magnet-resonance-imaging might help to specify, but only surgical treatment and histological examination can determine the definitive diagnosis. In those malformations containing the risk of cardiac affection and hydrops, dyspnoea, recurrent infections and malignancy the best therapy at the right time needs to be interdisciplinary discussed in a team of surgeons, radiologists and obstetric gynecologists specialized in prenatal diagnostic. This chapter covers the different entities of congenital lung malformations, their diagnosis and differential diagnosis as well as the therapeutic options including prenatal medication, fetal intervention, ex-utero intrapartum treatment or resection after birth, by either minimally invasive video-assisted thoracoscopic surgery (VATS) or by conventional open surgery.

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.

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 fundoplication. Regular bougienages of anastomotic strictures were necessary in 68% with 36% requiring repeated dilatations in the first postoperative year. Enteral nutrition via a nasogastric tube was performed in 66% after surgery. In 40%, the tube was needed until their sixth week of life. In 25%, nutritional support was necessary more than 1 year out of surgery. Quality of life in general was felt to be impaired according to the patients' parents in 50%. Regarding medical advice about long-term morbidities, more than 50% of the parents felt insufficiently advised. There were no statistical differences between the EA/TEF subtypes regarding GER symptoms, frequency of esophageal dilatations, eating behaviors, or support of the parents in feeding management. Conclusion Our observations indicate that a high percentage of EA/TEF patients and families require more intensive aftercare and support during the first year following primary reconstruction than previously thought. We observed a higher need for adequate parental information on long-term complications of their children compared with current practice.

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 patients of a large German multicenter study born between 1980 and 2012. After evaluation of all available clinical records, 235 patients were included in our analysis. We compared our results with existing data. Results The highest risk for co-occurring anomalies was seen in patients with most common Vogt 3b (p = 0.024), especially for additional gastrointestinal anomalies (p = 0.04). Co-occurring anomalies of the skin were significantly more common in patients with subtype Vogt 2 (p = 0.024). A significant correlation was observed for an impaired neurodevelopmental outcome and EA/TEF Vogt 3a (p = 0.041). Patients with EA/TEF showed a higher risk to present with any additional congenital anomaly compared with the general population (p Conclusion Our results warrant thorough clinical workup for gastrointestinal anomalies especially in patients with Vogt 3b. Moreover, it might be necessary to focus on a thorough aftercare for neurocognitive development in patients with Vogt 3a. The here presented observations need to be confirmed by future studies.

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 of the first-degree relatives displayed any form of EA/TEF. In two families, a first-degree relative presented with malformations from the VATER/VACTERL association spectrum. However, no increase in the risk for malformations of the VATER/VACTERL association spectrum was found compared with the control cohort (p = 0.87). In three families, one more distantly related relative presented with EA/TEF. CONCLUSION In contrast to previous studies, our results suggest a very low recurrence risk for isolated EA/TEF and/or for malformations of the VATER/VACTERL association spectrum among first-degree relatives. Birth Defects Research (Part A), 97:786–791, 2013. © 2013 Wiley Periodicals, Inc.

The autosomal recessive proximal spinal muscular atrophy (SMA) gene was mapped to the region 5q11.2-q13.3 in 1990. Here, we present a large genetic linkage study of 100 SMA families and 11 CEPH families using 14 polymorphic simple sequence repeats (SSRs) and one RFLP in the region 5q11.2-q13.3. The genetic interval between the closest SMA flanking loci D5S435 and D5S557 comprises 1 cM at zmax = 27.94. Two recombinants were identified between the SMA gene and the closest telomeric marker D5S557 (theta = 0.02 at zmax = 8.63). The first places the SMA gene centromeric to this marker; the second suggests a double recombinant at D5S557, which is very unlikely. More likely explanations are discussed in the paper. No recombinant was found between D5S435 and the SMA gene (theta = 0.00 at zmax = 25.36). We localized a recently described polymorphic marker, D5S351 (Hudson et al., 1992), close to the SMA (theta = 0.00 at zmax = 19.01) and the 3'MAP1B gene (theta = 0.01 at zmax = 38.76). Due to its high PIC value of 0.70, it represents a very useful marker for prenatal diagnosis. In addition, we developed a new reverse primer for the nearest centromeric locus D5S435 (Soares et al., 1993), a useful marker for prenatal diagnosis, which has been very difficult to amplify in the past. Three of the markers presented here are newly developed polymorphic SSRs (one tetranucleotide repeat, D5S507/W15CATT, and two dinucleotide repeats, D5S544/C88.2GT and D5S682/C88.3GT). These markers are too far from the SMA gene to be relevant for cloning; nevertheless, as part of the human genome project, they are contributing to the fine genetic mapping of the region 5q11.2-q13.3. The most likely order of the loci based on two-point and multipoint linkage analyses as well as on specific recombination events and physical mapping studies is D5S76-D5S507- D5S6-D5S125-D5S680-D5S435-SMA-D5S557- D5S351-5'MAP1B-3'MAP1B-JK53CA1/2-(D5S127- D5S39)-(D5S544-D5S682). In general, the genetic distances obtained from the SMA and CEPH families are comparable.