Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy-number variations contribute to CDH in the population. However, most individuals with CDH remain genetically undiagnosed.

Likely damaging de novo variants in congenital diaphragmatic hernia patients are associated with worse clinical outcomes.

Purpose: Congenital diaphragmatic hernia (CDH) is associated with significant mortality and long-term morbidity in some but not all individuals. We hypothesize monogenic factors that cause CDH are likely to have pleiotropic effects and be associated with worse clinical outcomes.

Methods: We enrolled and prospectively followed 647 newborns with CDH and performed genomic sequencing on 462 trios to identify de novo variants.

Intra-Amniotic Sildenafil Treatment Promotes Lung Growth and Attenuates Vascular Remodeling in an Experimental Model of Congenital Diaphragmatic Hernia.

Background: Defective lung development resulting in lung hypoplasia and an attenuated and hypermuscularized pulmonary vasculature contributes to significant postnatal mortality in congenital diaphragmatic hernia (CDH). We hypothesize that deficient embryonic pulmonary blood flow contributes to defective lung development in CDH, which may therefore be ameliorated via enhancement of embryonic pulmonary blood flow.

Methods: The mouse nitrofen model of CDH was utilized to measure embryonic pulmonary blood flow by in utero intracardiac injection of FITC-labeled tomato lectin and color-flow Doppler ultrasound.

Comparative outcomes of right versus left congenital diaphragmatic hernia: A multicenter analysis.

Background: Congenital diaphragmatic hernia (CDH) occurs in 1 out of 2500-3000 live births. Right-sided CDHs (R-CDHs) comprise 25% of all CDH cases, and data are conflicting on outcomes of these patients. The aim of our study was to compare outcomes in patients with right versus left CDH (L-CDH).

De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders.

Congenital diaphragmatic hernia (CDH) is a severe birth defect that is often accompanied by other congenital anomalies. Previous exome sequencing studies for CDH have supported a role of de novo damaging variants but did not identify any recurrently mutated genes. To investigate further the genetics of CDH, we analyzed de novo coding variants in 362 proband-parent trios including 271 new trios reported in this study.

Intra-amniotic Sildenafil Treatment Modulates Vascular Smooth Muscle Cell Phenotype in the Nitrofen Model of Congenital Diaphragmatic Hernia.

The etiology of pulmonary vascular abnormalities in CDH is incompletely understood. Studies have demonstrated improvement in pulmonary vasculature with prenatal therapy in animal models. We hypothesize that prenatal sildenafil may attenuate defective pulmonary vascular development via modulation of vSMC phenotype from undifferentiated, proliferative phenotype to differentiated, contractile phenotype.

A definition of gentle ventilation in congenital diaphragmatic hernia: a survey of neonatologists and pediatric surgeons.

Ventilation practices have changed significantly since the initial reports in the mid 1980 of successful use of permissive hypercapnia and spontaneous ventilation [often called gentle ventilation (GV)] in infants with congenital diaphragmatic hernia (CDH). However, there has been little standardization of these practices or of the physiologic limits that define GV. We sought to ascertain among Diaphragmatic Hernia Research and Exploration; Advancing Molecular Science (DHREAMS) centers' GV practices in the neonatal management of CDH.

Increased burden of de novo predicted deleterious variants in complex congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is a serious birth defect that accounts for 8% of all major birth anomalies. Approximately 40% of cases occur in association with other anomalies. As sporadic complex CDH likely has a significant impact on reproductive fitness, we hypothesized that de novo variants would account for the etiology in a significant fraction of cases.

Defective parasympathetic innervation is associated with airway branching abnormalities in experimental CDH.

Developmental mechanisms leading to lung hypoplasia in congenital diaphragmatic hernia (CDH) remain poorly defined. Pulmonary innervation is defective in the human disease and in the rodent models of CDH. We hypothesize that defective parasympathetic innervation may contribute to airway branching abnormalities and, therefore, lung hypoplasia, during lung development in CDH.

The association between congenital diaphragmatic hernia and undescended testes.

Background: Undescended testes (UDT) is a common abnormality treated by pediatric surgeons. Embryological development of the genitourinary ridge is in close proximity with the pleuroperitoneal fold. The purpose of this paper is to describe the association between congenital diaphragmatic hernia (CDH) and UDT.

Renal blood flow and oxygenation drive nephron progenitor differentiation.

During kidney development, the vasculature develops via both angiogenesis (branching from major vessels) and vasculogenesis (de novo vessel formation). The formation and perfusion of renal blood vessels are vastly understudied. In the present study, we investigated the regulatory role of renal blood flow and O2 concentration on nephron progenitor differentiation during ontogeny.

Whole exome sequencing identifies de novo mutations in GATA6 associated with congenital diaphragmatic hernia.

Background: Congenital diaphragmatic hernia (CDH) is a common birth defect affecting 1 in 3000 births. It is characterised by herniation of abdominal viscera through an incompletely formed diaphragm. Although chromosomal anomalies and mutations in several genes have been implicated, the cause for most patients is unknown.

First 24-h SNAP-II score and highest PaCO2 predict the need for ECMO in congenital diaphragmatic hernia.

Background/purpose: Early clinical predictors for the use of ECMO in patients with congenital diaphragmatic hernia (CDH) are lacking. We sought to evaluate the first 24-h SNAP-II score and highest PaCO2 as predictors of ECMO support and in-hospital mortality in neonates with CDH.

Methods: Retrospective review of 47 consecutive neonates with CDH admitted to our institution from January 2007 to December 2010 was performed.

Developmental outcomes of children with congenital diaphragmatic hernia: a multicenter prospective study.

Purpose: To determine developmental outcomes and associated factors in patients with congenital diaphragmatic hernia (CDH) at 2 years of age.

Methods: This is a multicenter prospective study of a CDH birth cohort. Clinical and socioeconomic data were collected.

Variants in GATA4 are a rare cause of familial and sporadic congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is characterized by incomplete formation of the diaphragm occurring as either an isolated defect or in association with other anomalies. Genetic factors including aneuploidies and copy number variants are important in the pathogenesis of many cases of CDH, but few single genes have been definitively implicated in human CDH. In this study, we used whole exome sequencing (WES) to identify a paternally inherited novel missense GATA4 variant (c.

De novo copy number variants are associated with congenital diaphragmatic hernia.

Background: Congenital diaphragmatic hernia (CDH) is a common birth defect with significant morbidity and mortality. Although the aetiology of CDH remains poorly understood, studies from animal models and patients with CDH suggest that genetic factors play an important role in the development of CDH. Chromosomal anomalies have been reported in CDH.

Defective pulmonary innervation and autonomic imbalance in congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is associated with significant mortality due to lung hypoplasia and pulmonary hypertension. The role of embryonic pulmonary innervation in normal lung development and lung maldevelopment in CDH has not been defined. We hypothesize that developmental defects of intrapulmonary innervation, in particular autonomic innervation, occur in CDH.

Embryonic mouse blood flow and oxygen correlate with early pancreatic differentiation.

The mammalian embryo represents a fundamental paradox in biology. Its location within the uterus, especially early during development when embryonic cardiovascular development and placental blood flow are not well-established, leads to an obligate hypoxic environment. Despite this hypoxia, the embryonic cells are able to undergo remarkable growth, morphogenesis, and differentiation.

Feasibility of laparoscopic Nissen fundoplication after pediatric lung or heart-lung transplantation: should this be the standard?

Background: Five-year graft survival in the pediatric lung transplant (LTxp) population is less than 50%, with obliterative bronchiolitis (OB) the leading cause of death at 1, 3, and 5 years post-transplant. Bronchiolitis obliterans syndrome (BOS), defined using spirometry values, is the clinical surrogate for the histological diagnosis of obliterative bronchiolitis. Surgical correction of documented gastroesophageal reflux disease (GERD) has been proposed as a means to potentially delay the onset of BOS and prolong allograft survival in adults before or after lung transplantation but only one such study exists in children.

Minimally invasive congenital diaphragmatic hernia repair: a 7-year review of one institution's experience.

Background: Minimally invasive surgery (MIS) has been described for the repair of congenital diaphragmatic hernias (CDH) in neonates, infants, and children. This report evaluates patient selection, operative technique, and clinical outcomes for MIS repair of CDHs from a single center's experience.

Methods: All cases of CDH at a tertiary care pediatric hospital with an initial attempt at MIS repair from January 2001 to December 2007 were reviewed.

Thoracoscopic aortopexy for vascular compression of the trachea: approach from the right.

Tracheomalacia resulting from vascular compression of the trachea may require aortopexy for symptomatic relief. Several operative approaches have been described for infants and children. The authors describe the technique of aortopexy by means of a right-sided thoracoscopic method as the initial approach to relieve tracheal compression in 2 children.

Laparoscopic versus open Nissen fundoplication in infants after neonatal laparotomy.

Background: Nissen fundoplication is an effective treatment of gastroesophageal reflux in infants. Laparoscopic procedures after previous laparotomy are technically more challenging. The role of laparoscopic Nissen fundoplication after neonatal laparotomy for diseases unrelated to reflux is poorly described.

Triple fistula: management of a double tracheoesophageal fistula with a third H-type proximal fistula.

Esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) is a relatively common congenital condition in which there have been several described anatomical variants. The most common type, EA with distal TEF, comprises more than 75% of cases in many reports. Less commonly, a smaller proximal pouch fistula (H-type) will be associated with this most common variant in 1.