Marc S. Arkovitz

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.

Redefining outcomes in right congenital diaphragmatic hernia

PURPOSE Available data comparing the management and outcome of right-sided (R-CDH) vs left-sided congenital diaphragmatic hernia (L-CDH) are inconsistent. Large-volume CDH studies are limited by small numbers of R-CDH or are confounded by compilations from multiple institutions with multiple treatment strategies. Consequently, they are underpowered to draw conclusions. To define the behavior and outcomes of R-CDH better, we report the largest single-institution series of R-CDH and ask if factors traditionally linked to poor prognosis in L-CDH were applicable to R-CDH. METHODS We reviewed a single institutions experience with 267 consecutive evaluable neonates with unilateral CDH repaired from 1990 to 2006, with specific focus on R-CDH. chi(2) tests were performed for disease-related categorical variables. Two-tailed unpaired t tests were used for continuous variables. Factors associated with morbidity and survival were determined by univariate regression. Statistical significance was set at P < .05. RESULTS Forty right-sided (15%) and 227 (85%) left-sided cases of CDH were identified. Prenatal diagnosis was made in 20 right-sided vs 170 left-sided defects (50% vs 75%, P < .01). Survival was 22 of 40 in R-CDH compared with 175 of 227 in L-CDH (55% vs 77%, P < .01). Extracorporeal membrane oxygenation was required in 16 right-sided and 33 left-sided cases (40% vs 15%, P < .001). A diaphragmatic patch was used in 22 of 29 right-sided compared with 82 of 199 left-sided repairs (76% vs 41%, P < .01); rates of abdominal wall prosthesis were also higher in right-sided hernias (38% vs 19%, P < .05). No differences were detected in right-sided vs left-sided recurrences (14% vs 8%, P = .38), mean time from birth to operation (5.3 vs 4.8 days, P = .80), or presence of cardiac anomalies (15% vs 12%, P = .63). Morbidity persisting beyond 6 months of age was present in 16 of 22 R-CDH survivors compared with 76 of 175 L-CDH survivors (73% vs 43%, P > .05). Among R-CDHs, prenatal diagnosis was the only factor to predict survival by univariate regression (P < .01). Use of a prosthesis in the diaphragm (P < .05) for R-CDH repair correlated with morbidity. CONCLUSION Although previous reports suggest that associated anomalies, need for extracorporeal membrane oxygenation, and time to repair can influence L-CDH survival, these data do not support extrapolation to R-CDH survival. Right-sided CDH carries a disproportionately high morbidity and mortality. Prenatal diagnosis was the only factor predictive of R-CDH survival. Morbidity may correlate with use of prosthetic material for R-CDH repair. Right-sided CDH is a unique disease that may require a modified antenatal consultation.

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.

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. Bayley Scales of Infant Development (BSID-III) and Vineland Adaptive Behavior Scales (VABS-II) were performed at 2 years of age. RESULTS BSID-III and VABS-II assessments were completed on 48 and 49 children, respectively. The BSID-III mean cognitive, language, and motor scores were significantly below the norm mean with average scores of 93 ± 15, 95 ± 16, and 95 ± 11. Ten percent (5/47) scored more than 2 standard deviations below the norm on one or more domains. VABS-II scores were similar to BSID-III scores with mean communication, daily living skills, social, motor, adaptive behavior scores of 97 ± 14, 94 ± 16, 93 ± 13, 97 ± 10, and 94 ± 14. For the BSID-III, supplemental oxygen at 28 days, a prenatal diagnosis, need for extracorporeal membrane oxygenation (ECMO) and exclusive tube feeds at time of discharge were associated with lower scores. At 2 years of age, history of hospital readmission and need for tube feeds were associated with lower scores. Lower socioeconomic status correlated with lower developmental scores when adjusted for significant health factors. CONCLUSION CDH patients on average have lower developmental scores at 2 years of age compared to the norm. A need for ECMO, oxygen at 28 days of life, ongoing health issues and lower socioeconomic status are factors associated with developmental delays.

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.

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.

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.

Bowel injury as a complication of microdiscectomy: Case report and literature review

Intestinal injury is a rare complication of lumbar disc surgery, resulting from inadvertent penetration of the anterior annulus fibrosus and anterior longitudinal ligament. Patients typically complain of abdominal pain and distention developing over the course of several days. Imaging with plain upright chest radiographs or abdominal computed tomography may demonstrate free air in the abdominal cavity. We report a case of intestinal perforation after microscopic lumbar discectomy and present the diagnostic postoperative imaging. In addition, we review the relevant literature and discuss techniques that may be employed to avoid this complication.

Timing and expression of the angiopoietin-1–Tie-2 pathway in murine lung development and congenital diaphragmatic hernia

SUMMARY Congenital diaphragmatic hernia (CDH) is one of the most common congenital abnormalities. Children born with CDH suffer a number of co-morbidities, the most serious of which is respiratory insufficiency from a combination of alveolar hypoplasia and pulmonary vascular hypertension. All children born with CDH display some degree of pulmonary hypertension, the severity of which has been correlated with mortality. The molecular mechanisms responsible for the development of pulmonary hypertension in CDH remain poorly understood. Angiopoitein-1 (Ang-1), a central mediator in angiogenesis, participates in the vascular development of many tissues, including the lung. Although previous studies have demonstrated that Ang-1 might play an important role in the development of familial pulmonary hypertension, the role of Ang-1 in the development of the pulmonary hypertension associated with CDH is poorly understood. The aim of this study was to examine the role of the Ang-1 pathway in a murine model of CDH. Here, we report that Ang-1 appears important in normal murine lung development, and have established its tissue-level expression and localization patterns at key time-points. Additionally, our data from a nitrofen and bisdiamine-induced murine model of CDH suggests that altered expression patterns of Ang-1, its receptor Tie-2 and one of its transcription factors (epithelium-specific Ets transcription factor 1) might be responsible for development of the pulmonary vasculopathy seen in the setting of CDH.

Perforated appendicitis presenting as appendicoumbilical fistula

Perforated appendicitis is one of the most common diagnoses treated by pediatric surgeons. Although rare, a perforated appendix can present with a cutaneous fistula. Here we present the second reported case of perforated appendicitis presenting as an appendicoumbilical fistula.