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. We performed exome sequencing in 39 CDH trios and compared the frequency of de novo variants with 787 unaffected controls from the Simons Simplex Collection. We found no significant difference in overall frequency of de novo variants between cases and controls. However, among genes that are highly expressed during diaphragm development, there was a significant burden of likely gene disrupting (LGD) and predicted deleterious missense variants in cases (fold enrichment = 3.2, P-value = 0.003), and these genes are more likely to be haploinsufficient (P-value = 0.01) than the ones with benign missense or synonymous de novo variants in cases. After accounting for the frequency of de novo variants in the control population, we estimate that 15% of sporadic complex CDH patients are attributable to de novo LGD or deleterious missense variants. We identified several genes with predicted deleterious de novo variants that fall into common categories of genes related to transcription factors and cell migration that we believe are related to the pathogenesis of CDH. These data provide supportive evidence for novel genes in the pathogenesis of CDH associated with other anomalies and suggest that de novo variants play a significant role in complex CDH cases.

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. Pediatric surgeons and neonatologists from DHREAMS centers completed an online survey on GV practices in infants with CDH. The survey gathered data on how individuals defined GV including ventilator settings, blood gas parameters and other factors of respiratory management. A total of 87 respondents, from 12 DHREAMS centers completed the survey for an individual response rate of 53% and a 92% center response rate. Approximately 99% of the respondents defined GV as accepting higher carbon dioxide (PCO2) and 60% of the respondents also defined GV as accepting a lower pH. There was less consensus about the use of sedation and neuromuscular blocking agents in GV, both within and across the centers. Acceptable pH and PCO2 levels are broader than the goal ranges. Despite a lack of formal standardization, the results suggest that GV practice is consistently defined as the use of permissive hypercapnia with mild respiratory acidosis and less consistently with the use of sedation and neuromuscular blocking agents. GV is the reported practice of surveyed neonatologists and pediatric surgeons in the respiratory management of infants with CDH.

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. METHODS: We used whole exome sequencing in two families with CDH and congenital heart disease, and identified mutations in GATA6 in both. RESULTS: In the first family, we identified a de novo missense mutation (c.1366C>T, p.R456C) in a sporadic CDH patient with tetralogy of Fallot. In the second, a nonsense mutation (c.712G>T, p.G238*) was identified in two siblings with CDH and a large ventricular septal defect. The G238* mutation was inherited from their mother, who was clinically affected with congenital absence of the pericardium, patent ductus arteriosus and intestinal malrotation. Deep sequencing of blood and saliva-derived DNA from the mother suggested somatic mosaicism as an explanation for her milder phenotype, with only approximately 15% mutant alleles. To determine the frequency of GATA6 mutations in CDH, we sequenced the gene in 378 patients with CDH. We identified one additional de novo mutation (c.1071delG, p.V358Cfs34*). CONCLUSIONS: Mutations in GATA6 have been previously associated with pancreatic agenesis and congenital heart disease. We conclude that, in addition to the heart and the pancreas, GATA6 is involved in development of two additional organs, the diaphragm and the pericardium. In addition, we have shown that de novo mutations can contribute to the development of CDH, a common birth defect.

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.754C>T; p.R252W) in a familial case of CDH with incomplete penetrance. Phenotypic characterization of the family included magnetic resonance imaging of the chest and abdomen demonstrating asymptomatic defects in the diaphragm in the two "unaffected" missense variant carriers. Screening 96 additional CDH patients identified a de novo heterozygous GATA4 variant (c.848G>A; p.R283H) in a non-isolated CDH patient. In summary, GATA4 is implicated in both familial and sporadic CDH, and our data suggests that WES may be a powerful tool to discover rare variants for CDH.

Outcomes of congenital diaphragmatic hernia in the modern era of management.

OBJECTIVE: To identify clinical factors associated with pulmonary hypertension (PH) and mortality in patients with congenital diaphragmatic hernia (CDH). STUDY DESIGN: A prospective cohort of neonates with a diaphragm defect identified at 1 of 7 collaborating medical centers was studied. Echocardiograms were performed at 1 month and 3 months of age and analyzed at a central core by 2 cardiologists independently. Degree of PH and survival were tested for association with clinical variables using Fischer exact test, χ(2), and regression analysis. RESULTS: Two hundred twenty patients met inclusion criteria. Worse PH measured at 1 month of life was associated with higher mortality. Other factors associated with mortality were need for extracorporeal membrane oxygenation, patients inborn at the treating center, and patients with a prenatal diagnosis of CDH. Interestingly, patients with right sided CDH did not have worse outcomes. CONCLUSIONS: Severity of PH is associated with mortality in CDH. Other factors associated with mortality were birth weight, gestational age at birth, inborn status, and need for extracorporeal membrane oxygenation.

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. METHODS: In this study, the authors investigated the frequency of chromosomal anomalies and copy number variants (CNVs) in 256 parent-child trios of CDH using clinical conventional cytogenetic and microarray analysis. The authors also selected a set of CDH related training genes to prioritise the genes in those segmental aneuploidies and identified the genes and gene sets that may contribute to the aetiology of CDH. RESULTS: The authors identified chromosomal anomalies in 16 patients (6.3%) of the series including three aneuploidies, two unbalanced translocation, and 11 patients with de novo CNVs ranging in size from 95 kb to 104.6 Mb. The authors prioritised the genes in the CNV segments and identified KCNA2, LMNA, CACNA1S, MYOG, HLX, LBR, AGT, GATA4, SOX7, HYLS1, FOXC1, FOXF2, PDGFA, FGF6, COL4A1, COL4A2, HOMER2, BNC1, BID, and TBX1 as genes that may be involved in diaphragm development. Gene enrichment analysis identified the most relevant gene ontology categories as those involved in tissue development (p=4.4×10(-11)) or regulation of multicellular organismal processes (p=2.8×10(-10)) and 'receptor binding' (p=8.7×10(-14)) and 'DNA binding transcription factor activity' (p=4.4×10(-10)). CONCLUSIONS: The present findings support the role of chromosomal anomalies in CDH and provide a set of candidate genes including FOXC1, FOXF2, PDGFA, FGF6, COL4A1, COL4A2, SOX7, BNC1, BID, and TBX1 for further analysis in CDH.

The Current Pediatric Surgery Job Market: A Perspective of Recent Fellowship Graduates.

PURPOSE: This study describes the job market from the perspective of recent pediatric surgery graduates. METHODS: An anonymous survey was circulated to the 137 pediatric surgeons who graduated from fellowships 2019-2021. RESULTS: The survey response rate was 49%. The majority of respondents were women (52%), Caucasian (72%), and had a median student debt burden of $225,000. Considering job opportunities, respondents strongly emphasized camaraderie (93%), mentorship (93%), case mix (85%), geography (67%), faculty reputation (62%), spousal employment (57%), compensation (51%), and call frequency (45%). 30% were satisfied with the employment opportunities available, and 21% felt strongly prepared to negotiate for their first job. All respondents were able to secure a job. Most jobs were university-based (70%) or hospital employed (18%) positions where surgeons covered median of two hospitals. 49% wanted protected research time, and 12% of respondents were able to secure substantial, protected research time. The median compensation for university-based jobs was $12,583 below the median AAMC benchmark for assistant professors for the corresponding year of graduation. CONCLUSION: These data highlight the ongoing need for assessment of the pediatric surgery workforce and for professional societies and training programs to further assist graduating fellows in preparing to negotiate their first job. TYPE OF STUDY: Survey LEVEL OF EVIDENCE: Level V.

Fulminant pH1N1-09 influenza-associated myocarditis in pediatric patients.

OBJECTIVE: To report an atypical presentation of pH1N1-09 influenza infection in children as fulminant myocarditis and tamponade and the successful treatment with extracorporeal membrane oxygenation. DESIGN: Case report. SETTING: Pediatric cardiac intensive care unit in a quarternary care children's hospital. PATIENTS: Two girls, 5 and 7 yrs of age, infected with pH1N1-09 influenza virus who presented in cardiogenic shock with a pericardial effusion and echocardiographic evidence of tamponade from fulminant myocarditis. INTERVENTIONS: Both patients received a pericardiocentesis. One was managed with multiple, high-dose inotropic agents, whereas the other required institution of extracorporeal membrane oxygenation. MEASUREMENTS AND MAIN RESULTS: Acute respiratory distress syndrome is the major reported clinical manifestation of pH1N1-09 influenza virus infection in hospitalized pediatric patients. In this report we describe two children with confirmed pH1N1-09 influenza infection that required intensive care for fulminant myocarditis. Neither patient had the typical symptoms of influenza-like illness, respiratory compromise, or evidence of pulmonary involvement. One child required extracorporeal membrane oxygenation. Both children survived to hospital discharge. CONCLUSIONS: pH1N1-09 influenza infection can cause fulminant myocarditis in the healthy pediatric population. The clinical presentation may be nonspecific, and the lack of pulmonary symptoms may make diagnosis difficult. Extracorporeal membrane oxygenation support may offer an effective bridge to the recovery of heart function.

The role of fiberoptic endoscopy in the evaluation and management of long gap isolated esophageal atresia.

Accurate measurement of gap length is useful for operative planning in cases of esophageal atresia (EA) without distal fistula. This paper demonstrates how fiberoptic endoscopy of the distal esophagus enables measurement of the gap in the case of isolated EA, and compares other commonly practiced techniques.

Surgical correction of pectus excavatum.

Pectus deformities arise from overgrowth of the cartilagenous portion of the ribs. Traditional resective/open procedures have been almost entirely replaced by video assisted retrosternal bar placement with excellent outcomes. This review considers the comprehensive evaluation and care of a pectus patinet as well as technical details regarding conduct of the surgery.

Outcomes of infants with congenital diaphragmatic hernia treated with venovenous versus venoarterial extracorporeal membrane oxygenation: A propensity score approach.

PURPOSE: Previous studies comparing extracorporeal membrane oxygenation (ECMO) modality for congenital diaphragmatic hernia (CDH) have not accounted for confounding by indication. We therefore hypothesized that using a propensity score (PS) approach to account for selection bias may identify outcome differences based on ECMO modality for infants with CDH. METHODS: We utilized ELSO Registry data (2000-2016). Patients with CDH were divided to either venoarterial (VA) or venovenous (VV) ECMO. Patients were matched by PS to control for nonrandom treatment assignment. Subgroup analyses were conducted based on timing of CDH repair relative to ECMO. Primary analysis was the "intent-to-treat" cohort based on the initial ECMO mode. Mortality was the primary outcome, and severe neurologic injury (SNI) was a secondary outcome. RESULTS: PS matching (3:1) identified 3304 infants (VA = 2470, VV = 834). In the main group, mortality was not different between VA and VV ECMO (OR = 1.01, 95% CI: 0.86-1.18) and there was no difference in SNI between VA and VV (OR = 0.80; 95% CI: 0.63-1.01). For the pre-ECMO CDH repair subgroup, 175 VA cases were matched to 70 VV. In these neonates, mortality was higher for VV compared to VA (OR = 2.10, 95% CI: 1.19-3.69), without any difference in SNI (OR = 1.48; 95% CI: 0.59-3.71). For the subgroup that did not have pre-ECMO CDH repair, 2030 VA cases were matched to 683 VV cases. In this subgroup, VV was associated with 27% lower risk of SNI relative to VA (OR = 0.73, 95% CI: 0.56-0.95) without any difference in mortality (OR = 0.94, 95% CI: 0.79-1.11). CONCLUSION: This study revalidates that ECMO mode does not significantly affect mortality or SNI in infants with CDH. In the subset of infants who require pre-ECMO CDH repair, VA favors survival, whereas, in the subgroup of infants that did not have pre-ECMO CDH repair, VV favors lower rates of SNI. We conclude that neither mode appears consistently superior across all situations, and clinical judgment should remain a multifactorial decision. LEVEL OF EVIDENCE: Level III.

Two decades of experience with thoracoscopic lobectomy in infants and children: standardizing techniques for advanced thoracoscopic surgery.

OBJECTIVES: This study evaluates the safety and efficacy of thoracoscopic lobectomy in infants and children. MATERIALS AND METHODS: From January 1994 to November 2013, 347 patients underwent video-assisted thoracoscopic lobe resection at two institutions. All procedures were performed by or under the direct guidance of a single surgeon. Patients' ages ranged from 1 day to 18 years, and weights ranged from 2.8 to 78 kg. Preoperative diagnosis included sequestration/congenital pulmonary airway malformation (n=306), severe bronchiectasis (n=24), congenital lobar emphysema (n=13), and malignancy (n=4). RESULTS: Of the 347 procedures, 342 were completed thoracoscopically. Operative times ranged from 35 minutes to 240 minutes (average, 115 minutes). Average operative time when a trainee was the primary surgeon was 160 minutes. There were 81 upper, 25 middle, and 241 lower lobe resections. There were four intraoperative complications (1.1%) requiring conversion to an open thoracotomy. The postoperative complication rate was 3.3%, and 3 patients required re-exploration for a prolonged air leak. Hospital length of stay (LOS) ranged from 1 to 16 days (average). In patients <5 kg and <3 months of age, the average operative time was 90 minutes, and the LOS was 2.1 days. CONCLUSIONS: Thoracoscopic lung resection is a safe and efficacious technique. With proper mentoring it is an exportable technique, which can be performed by pediatric surgical trainees. The procedures are safe and effective even when performed in the first 3 months of life. Early resection avoids the risk of later infection and malignancy.

Lung growth and function in children and adolescents with idiopathic pectus excavatum.

Patterns of lung growth and function were studied retrospectively in 103 patients (73 male and 30 female) with idiopathic pectus excavatum in order to determine: 1) the prevalence of restrictive lung defect and/or other lung function abnormalities; 2) the possible association between type of lung function abnormalities and age of the patient; and 3) whether the type of lung function is associated with other clinical conditions. Forty-three patients (42%) were between 5-9 years of age; 36 (35%) were between 10-14 years; and 24 (23%) were between 15-19 years. Restrictive lung disease was detected only in 5 patients (5%), whereas 42 patients (41%) had evidence of obstructive pattern, and the remaining 56 patients (54%) had a normal pattern. The mean values for lung volume (total lung capacity (TLC) and/or forced vital capacity (FVC)) were lowest in the 10-14-year group, whereas the mean values of the indices of lower airway function (forced expiratory volume at 1 sec (FEV(1)), FEV(1)/FVC, forced expiratory flow at 25-75% of forced vital capacity (FEF(25-75)), and FEF(25-75)/FVC) were higher in the younger group. Residual volume (RV) and RV/TLC were elevated in all age groups, but they declined toward normalization with increasing age. There were no significant differences between groups (stratified either by pattern of lung function or by age) with regard to their demographics or clinical characteristics (scoliosis, direction of sternal rotation, history of asthma/reactive airways disease, or exercise intolerance). We conclude that idiopathic pectus excavatum may be associated with a variety of lung function abnormalities (in particular, lower airway obstruction) even in the absence of overt clinical symptoms. There was no evidence of significant worsening of lung function with increasing age.

Recurrent diaphragmatic hernia.

Recurrent congenital diaphragmatic hernia (CDH) is a well-known complication, but one that has not been examined systematically. Review of the literature shows a varied incidence as well as a myriad of treatment strategies. Evaluation of the available data is made more difficult by lack of standardized repair techniques and comparable patient groups. As an increasing number of diaphragmatic hernia patients survive the newborn period, a study of the true incidence of recurrent diaphragmatic hernia, its etiologic factors, and the methods of repair is essential to prevent and treat this problem.

First employment characteristics for the 2011 pediatric surgery fellowship graduates.

PURPOSE: Information regarding initial employment of graduating pediatric surgery fellows is limited. More complete data could yield benchmarks of initial career environment. METHODS: An anonymous survey was distributed in 2011 to 41 pediatric surgery graduates from all ACGME training programs interrogating details of initial positions and demographics. RESULTS: Thirty-seven of 41 (90%) fellows responded. Male to female ratio was equal. Graduates carried a median debt of $220,000 (range: $0-$850,000). The majority of fellows were married with children. 70% were university/hospital employees, and 68% were unaware of a business plan. Median starting compensation was $354,500 (range: $140,000-$506,000). Starting salary was greatest for >90% clinical obligation appointments (median $427,500 vs. $310,000; p=0.002), independent of geographic location. Compensation had no relationship to private practice vs. hospital/university/military position, coastal vs. inland location, and practice sites number. Median clinical time was 75% and research time 10%. 49% identified a formal mentor. Graduates covered 1-5 different offices (median 1) and 1-5 surgery sites (median 2). 60% were satisfied with their compensation. CONCLUSION: Recent pediatric surgery graduates are engaged mainly in clinical care. Research is not incentivized. Compensation is driven by clinical obligations. Graduates have limited knowledge of the business plan supporting their compensation, nature of malpractice coverage, and commitments to resources including research. Graduates have important fiscal and parenting obligations.

Trends in operative experience of pediatric surgical residents in the United States and Canada.

PURPOSE: Expansion of the number of training programs in pediatric surgery occurred from 2003 through 2010. We sought to determine the effect of program expansion on case volume and distribution of operative experience. METHODS: Public domain data on pediatric surgery resident summary statistics available from the Accreditation Council for Graduate Medical Education (ACGME) from July 2003 through June 2010 were analyzed. Total case volume as primary surgeon or teaching assistant, mean case volume per resident, standard deviation, mode, minimum, and maximum number of cases per resident were evaluated. Mean total cases per resident, minimally invasive laparoscopic and thoracoscopic cases, and requisite cases as defined by the ACGME categories of: tumor, important pediatric surgical, and neonatal cases were analyzed by a Cuzick Wilcoxon-type nonparametric trend statistic using a significance level of 0.05. Skew was assessed by Pearson coefficient with levels of -0.5 to 0.5 defining a parametric distribution. RESULTS: The number of pediatric surgical training residents increased by 42% during the years reported, from 24 to 34. No statistically significant difference was found in the mean number of total cases or requisite cases per resident. The mean volume of minimally invasive procedures increased significantly. Case volume per resident was non-parametrically distributed with increasing positive skew over time. CONCLUSIONS: The increase in number of pediatric surgical resident training positions has not adversely affected overall operative experience or exposure to highly specialized requisite cases, on average. The increasing positive skew of total and index cases, however, suggests that variability between programs in case exposure is increasing over time.

Lung to head ratio in infants with congenital diaphragmatic hernia does not predict long term pulmonary hypertension.

PURPOSE: Lung-to-head ratio (LHR) has been used for antenatal evaluation of infants with congenital diaphragmatic hernia (CDH). We hypothesized that LHR was predictive of acute and chronic pulmonary hypertension in infants with CDH. METHODS: Echocardiograms on all inborn infants with CDH (December 2001-March 2011) were reviewed. Echocardiograms at 1 and 3 months post-repair and most recent follow-up were assessed for presence of pulmonary hypertension (PAH). LHR, gestational age, birth weight, extracorporeal membrane oxygenation (ECMO), and death rate were obtained. Bivariate and multivariate analyses were performed. RESULTS: 106 infants with CDH had LHR obtained at median 28 weeks gestation (median LHR=1.25 [range 0.4-5.3]). Median follow-up was 26.6 months (range 4.6-97.5). The long-term incidence of pulmonary hypertension was 16%. LHR was significantly associated with pulmonary hypertension at one month (p=0.0001) but not at 3 months (p=0.22) or long-term (p=0.54). LHR was predictive of ECMO use (p=0.01) and death (p=0.001). CONCLUSIONS: The overall incidence of PAH in infants with CDH decreases over time. Prenatal LHR predicts PAH at one month but not long-term in infants with CDH. The ability for LHR to predict PAH at one month but not long term may suggest remodeling of the pulmonary vasculature over time.