Kenneth S. Azarow

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.

Blast injury in children: an analysis from Afghanistan and Iraq, 2002-2010.

BACKGROUND Throughout history, children have been victims of armed conflict, including the blast injury complex, however, the pattern of injury, physiologic impact, and treatment needs of children with this injury are not well documented. METHODS The Joint Theatre Trauma Registry provides data on all civilians admitted to US military treatment facilities from 2002 to 2010 with injuries from an explosive device. The data were stratified by age and analyzed for differences in anatomic injury patterns, Injury Severity Score (ISS), Revised Trauma Score (RTS), mortality, intensive care unit days, and length of hospitalization. Multivariate logistic regression was done to determine independent predictors of mortality. All operative procedures with a specified site were tabulated and categorized by body region and age. RESULTS A total of 4,983 civilian patients were admitted, 25% of whom were younger than 15 years. Pediatric patients aged 8 to 14 years had a higher ISS and hospital stay than other age groups, and children younger than 15 years had a longer intensive care unit stay. Injuries in children were more likely to occur in the head and neck and less likely in the bony pelvis and extremities. Children had a lower RTS than the other age groups. Mortality correlated highly with burns, head injury, transfusion, and RTS. Adolescent patients had a lower mortality rate than the other age groups. Improvised explosive devices were the most common cause of injury in all age groups. CONCLUSION Children experiencing blast injury complex have an anatomic pattern that is unique and an RTS that reflects more severe physiologic derangement. Injuries requiring transfusion or involving the head and neck and burns were predictive of mortality, and this persisted across all age groups. The mortality rate of children with blast injury is significant (7%), and treatment is resource intensive, requiring many surgical subspecialties. LEVEL OF EVIDENCE Epidemiologic study, level III.

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.

National trends in minimally invasive and open operative experience of graduating general surgery residents: implications for surgical skills curricula development?

BACKGROUND The aim of this study was to analyze national trends in minimally invasive and open cases of all graduating residents in general surgery. METHODS A retrospective analysis was performed on data obtained from Accreditation Council for Graduate Medical Education logs (1999-2008) of graduating residents from all US general surgery residency programs. Data were analyzed using Mantel-Haenszel χ(2) tests and the Bonferroni adjustment to detect trends in the number of minimally invasive and open cases. RESULTS Minimally invasive procedures accounted for an increasing proportion of cases performed (3.7% to 11.1%, P < .0001), with a proportional decrease in open cases. An increase in minimally invasive procedures with a proportional decrease in open procedures was noted in subcategories such as alimentary tract, abdominal, vascular, thoracic, and pediatric surgery (P < .0001). CONCLUSIONS The results of this study demonstrate that general surgery residents in the United States are performing a greater number of minimally invasive and fewer open procedures for common surgical conditions.

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.

Pathologic changes in biliary dyskinesia

PURPOSE For children with upper abdominal pain and evaluation for acalculous biliary disease, laparoscopic cholecystectomy is an accepted treatment with inconsistent outcomes. The purpose of this study was to identify predictors of outcomes. METHODS One hundred sixty-seven children underwent laparoscopic cholecystectomy at a single childrens hospital. Radiographic findings, histopathology, family history, and demographics (sex, age, height, weight, body mass index-for-age percentile) were evaluated as predictors of postoperative symptomatic resolution using a binomial probability model. The data for radiologic studies and pathologic specimens were obtained via re-review in a blinded fashion. RESULTS Of 167 children, 43 (25.7%) had a preoperative diagnosis of biliary dyskinesia and 41 (95.3%) had documented follow-up. Mean follow-up was 8.4 months. Twenty-eight patients (68.3%) had symptom resolution. Ejection fraction less than or equal to 15%, pain upon cholecystokinin injection, and a family history of biliary disease were not predictors of symptomatic resolution. Nonoverweight patients (body mass index-for-age <85th percentile) were more likely to have symptom resolution than their overweight counterparts (odds ratio, 2.13). Most patients (68.3%) had a pathologic gallbladder on blinded review. However, this did not correlate with outcome. CONCLUSIONS Most gallbladders removed for biliary dyskinesia are pathologic. Being overweight can be considered a relative contraindication to cholecystectomy for biliary dyskinesia.

Undescended testes: Does age at orchiopexy affect survival of the testis?

PURPOSE The optimal age at which to perform orchiopexy for cryptorchidism has long been debated. The aim of this study was to determine if age at orchiopexy affected testicular atrophy. METHODS A retrospective review of patients undergoing orchiopexy from 2000 to 2010 was conducted. An individual testis, rather than patient, was used as the dependent variable. A total of 349 testicles from 1126 charts (ICD-9=752.51) were identified. Primary study outcome was testicular survival without atrophy. RESULTS Mean follow up for the study was 25 months. There was postoperative atrophy in 27 testes (7.7%). Intraabdominal testicle was independently associated with increased postsurgical atrophy (p<0.0001). The odds of postsurgical atrophy were 15.66 times higher for an abdominal vs. inguinal location (95% CI: 5.5-44.6). Testicular atrophy was highest for orchiopexy at ages 13-24 months (n=16 of 133, 12%) vs. those less than 13 months (n=3 of 64, 5%), and those greater than 24 months (n=8 of 152, 5%) (p=0.0024). After adjusting for location, age was not statistically significant with postsurgical atrophy (p=0.055). CONCLUSIONS From this study we conclude that there is no increase in testicular atrophy in patients less than 13 months.

Identifying strategies to decrease infectious complications of gastroschisis repair

PURPOSE We describe the infectious complications of gastroschisis in order to identify modifiable factors to decrease these complications. METHODS Data from 155 gastroschisis patients (2001-2013) were reviewed. Complicated gastroschisis (intestinal atresia, necrotic bowel, or perforation) were excluded, leaving 129 patients for review. Patient demographics, surgical details, postoperative infections and complications, and length of stay were reviewed. We used CDC definitions of infectious complications. RESULTS The average gestational age of patients was 35.97weeks. Silos were used in 46% of patients (n=59) for an average of 7.4days. Thirty-one patients (24%) acquired an infection within the first 60days of life. Patients who developed an infection were born earlier in gestation (P=0.02), weighed less (P=0.01), required silos more often (P=0.01), and received a sutured repair (P=0.04). Length of stay of patients with an infection was longer than in patients without infection (P=0.01). CONCLUSIONS Infectious complications following gastroschisis repair are common. Subsets of gastroschisis patients at increased risk of infection include patients with silos, preterm delivery, low birth weight, and sutured repair. Based on our findings, our recommendation would be to carry gastroschisis patients to term and advocate against the routine use of silos, reserving their use for those cases when primary closure is not possible.

Trends in surgical management of urachal anomalies

PURPOSE We have noted an increasing frequency of diagnosed urachal anomalies. The purpose of this study is to evaluate this increase, as well as the outcomes of management at our institution over 10 years. METHODS A retrospective analysis of urachal anomalies at our institution was performed. Inclusion criteria were Anomalies of Urachus (ICD 753.7) or Urinary Anomaly NOS (ICD 753.9) between January 2000 and December 2010. Exclusion criteria were having an asymptomatic urachal remnant incidentally excised. RESULTS Eighty-five patients (49 male, 36 female) presented between 0 and 17 years of age (mean 1.5 years). Diagnoses increased from 0 in 2000 to 21 in 2010. Zero was surgically managed in 2000 while 21 were managed in 2010 (p=0.0145). Fifteen patients (17.6%) were observed with 13 (13/15, or 15.3%) resolving without complication while 2 were operated on. Average time to resolution (clinical or radiologic) was 4.9 months (Range: 0.4-12.6). A total of seventy-two patients (84.7%) underwent excision. Thirty-nine (54%) surgical cases were outpatient while 33 (46%) were admitted. Thirteen (18%) had post-operative complications. Ten (77%) of the complications were wound infections. Patients under 6 months of age accounted for 60% (6 of 10) of all wound infections and 52% (17 of 33) of hospitalizations. CONCLUSIONS Our experience and review of the literature suggest a high complication rate with surgical management in young patients, mostly from infections and support non-operative management of all non-infected urachal remnants in children.