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The Journal of Pediatrics Jul 2020To examined outcomes for infants born with congenital diaphragmatic hernias (CDH), according to specific treatment center volume indicators.
OBJECTIVE
To examined outcomes for infants born with congenital diaphragmatic hernias (CDH), according to specific treatment center volume indicators.
STUDY DESIGN
A population-based retrospective cohort study was conducted involving neonatal intensive care units in California. Multivariable analysis was used to examine the outcomes of infants with CDH including mortality, total days on ventilation, and respiratory support at discharge. Significant covariables of interest included treatment center surgical and overall neonatal intensive care unit volumes.
RESULTS
There were 728 infants in the overall CDH cohort, and 541 infants (74%) in the lower risk subcohort according to a severity-weighted congenital malformation score and never requiring extracorporeal membrane oxygenation. The overall cohort mortality was 28.3% (n = 206), and 19.8% (n = 107) for the subcohort. For the lower risk subcohort, the adjusted odds of mortality were significantly lower at treatment centers with higher CDH repair volume (OR, 0.41; 95% CI, 0.23-0.75; P = .003), ventilator days were significantly lower at centers with higher thoracic surgery volume (OR, 0.56; 9 5% CI, 0.33-0.95; P = .03), and respiratory support at discharge trended lower at centers with higher neonatal intensive care unit admission volumes (OR, 0.51; 9 5% CI, 0.26-1.02; P = .06).
CONCLUSIONS
Overall and surgery-specific institutional experience significantly contribute to optimized outcomes for infants with CDH. These data and follow-on studies may help inform the ongoing debate over the optimal care setting and relevant quality indicators for newborn infants with major surgical anomalies.
Topics: California; Extracorporeal Membrane Oxygenation; Female; Hernias, Diaphragmatic, Congenital; Humans; Incidence; Infant, Newborn; Intensive Care Units, Neonatal; Male; Retrospective Studies; Treatment Outcome
PubMed: 32418817
DOI: 10.1016/j.jpeds.2020.03.028 -
Genes Sep 2021The genetic etiology of congenital diaphragmatic hernia (CDH), a common and severe birth defect, is still incompletely understood. Chromosomal aneuploidies, copy number... (Review)
Review
The genetic etiology of congenital diaphragmatic hernia (CDH), a common and severe birth defect, is still incompletely understood. Chromosomal aneuploidies, copy number variations (CNVs), and variants in a large panel of CDH-associated genes, both and inherited, have been described. Due to impaired reproductive fitness, especially of syndromic CDH patients, and still significant mortality rates, the contribution of variants to the genetic background of CDH is assumed to be high. This assumption is supported by the relatively low recurrence rate among siblings. Advantages in high-throughput genome-wide genotyping and sequencing methods have recently facilitated the detection of variants in CDH. This review gives an overview of the known disease-causing variants in CDH patients.
Topics: Aneuploidy; Chromosome Aberrations; DNA Copy Number Variations; Hernias, Diaphragmatic, Congenital; Humans; Mutation
PubMed: 34573387
DOI: 10.3390/genes12091405 -
Seminars in Fetal & Neonatal Medicine Aug 2022Pulmonary hypertension is an emergency in neonatal intensive care units with high morbidity and mortality. Its timely assessment and management is crucial for intact... (Review)
Review
Pulmonary hypertension is an emergency in neonatal intensive care units with high morbidity and mortality. Its timely assessment and management is crucial for intact survival. Over the last couple of decades, there have been significant advances in management and techniques, which have resulted in improved survival. The use of neonatologist-performed echocardiography (NPE) is now increasingly utilized on neonatal intensive care units to understand the pathophysiology of the disease and to direct the treatment to the underlying cause. Its use is now established not only in cases of congenital diaphragmatic hernia and in the newborn with refractory hypoxemia, but also in other conditions such as bronchopulmonary dysplasia and the premature infant with difficulty in oxygenation. The use of NPE, however, requires the availability of trained personnel, equipment, and a close working relationship with pediatric cardiology.
Topics: Bronchopulmonary Dysplasia; Child; Echocardiography; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Infant; Infant, Newborn; Intensive Care Units, Neonatal; Neonatologists
PubMed: 35718687
DOI: 10.1016/j.siny.2022.101366 -
European Journal of Pediatrics Sep 2022In recent years, magnetic resonance imaging (MRI) has largely increased our knowledge and predictive accuracy of congenital diaphragmatic hernia (CDH) in the fetus.... (Review)
Review
UNLABELLED
In recent years, magnetic resonance imaging (MRI) has largely increased our knowledge and predictive accuracy of congenital diaphragmatic hernia (CDH) in the fetus. Thanks to its technical advantages, better anatomical definition, and superiority in fetal lung volume estimation, fetal MRI has been demonstrated to be superior to 2D and 3D ultrasound alone in CDH diagnosis and outcome prediction. This is of crucial importance for prenatal counseling, risk stratification, and decision-making approach. Furthermore, several quantitative and qualitative parameters can be evaluated simultaneously, which have been associated with survival, postnatal course severity, and long-term morbidity.
CONCLUSION
Fetal MRI will further strengthen its role in the near future, but it is necessary to reach a consensus on indications, methodology, and data interpretation. In addition, it is required data integration from different imaging modalities and clinical courses, especially for predicting postnatal pulmonary hypertension. This would lead to a comprehensive prognostic assessment.
WHAT IS KNOWN
• MRI plays a key role in evaluating the fetal lung in patients with CDH. • Prognostic assessment of CDH is challenging, and advanced imaging is crucial for a complete prenatal assessment and counseling.
WHAT IS NEW
• Fetal MRI has strengthened its role over ultrasound due to its technical advantages, better anatomical definition, superior fetal lung volume estimation, and outcome prediction. • Imaging and clinical data integration is the most desirable strategy and may provide new MRI applications and future research opportunities.
Topics: Female; Fetus; Hernias, Diaphragmatic, Congenital; Humans; Lung; Lung Volume Measurements; Magnetic Resonance Imaging; Pregnancy; Prognosis; Retrospective Studies; Ultrasonography, Prenatal
PubMed: 35794403
DOI: 10.1007/s00431-022-04540-6 -
American Journal of Medical Genetics.... Oct 2022Congenital diaphragmatic hernia (CDH) can occur in isolation or in conjunction with other birth defects (CDH+). A molecular etiology can only be identified in a subset...
Congenital diaphragmatic hernia (CDH) can occur in isolation or in conjunction with other birth defects (CDH+). A molecular etiology can only be identified in a subset of CDH cases. This is due, in part, to an incomplete understanding of the genes that contribute to diaphragm development. Here, we used clinical and molecular data from 36 individuals with CDH+ who are cataloged in the DECIPHER database to identify genes that may play a role in diaphragm development and to discover new phenotypic expansions. Among this group, we identified individuals who carried putatively deleterious sequence or copy number variants affecting CREBBP, SMARCA4, UBA2, and USP9X. The role of these genes in diaphragm development was supported by their expression in the developing mouse diaphragm, their similarity to known CDH genes using data from a previously published and validated machine learning algorithm, and/or the presence of CDH in other individuals with their associated genetic disorders. Our results demonstrate how data from DECIPHER, and other public databases, can be used to identify new phenotypic expansions and suggest that CREBBP, SMARCA4, UBA2, and USP9X play a role in diaphragm development.
Topics: Animals; DNA Copy Number Variations; Diaphragm; Hernias, Diaphragmatic, Congenital; Mice
PubMed: 35904974
DOI: 10.1002/ajmg.a.62919 -
African Journal of Paediatric Surgery :... 2023Despite all the advances, the mortality rate of congenital diaphragmatic hernia (CDH) ranges from 30% to 60% for isolated CDH and as high as 89% when they are associated...
INTRODUCTION
Despite all the advances, the mortality rate of congenital diaphragmatic hernia (CDH) ranges from 30% to 60% for isolated CDH and as high as 89% when they are associated with additional structural or chromosomal anomalies. Hence, a study was conducted to evaluate the factors contributing to the mortality of neonates treated for CDH or the eventration of diaphragm.
MATERIALS AND METHODS
A retrospective study was conducted in the department of paediatric surgery at a tertiary centre. The neonates admitted with a diagnosis of CDH or eventration requiring surgery, between March 2013 and March 2021, were included in the study.
RESULTS
A total of 123 neonates were included in the study. The variables, earlier median age at presentation (1 [1-23] vs. 3 [1-28]; P < 0.001; Mann-Whitney U-test), preterm birth (10/79 vs. 0/44; P = 0.01; Fischer's exact test), inborn (68/79 vs. 27/44; P = 0.002; Chi-square test), weight ≤2 kg (18/79 vs. 1/44; P = 0.003; Chi-square test), central cyanosis at presentation (21/79 vs. 1/44; P < 0.001; Chi-square test), antenatal detection (47/79 vs. 14/44; P = 0.003; Chi-square test) and earlier mean age at surgery (3.66 ± 1.47 vs. 7.66 ± 6.88; P < 0.001; Independent sample t-test) were associated with increased mortality. On multinominal logistic regression analysis, the factors preterm (odd's Ratio [OR] =4.735; P = 0.03), weight ≤2 kg (OR = 5.081; P = 0.02), central cyanosis at presentation (OR = 6.969; P = 0.008) and antenatal detection (OR = 7.471; P = 0.006) were found to be independently associated with increased mortality in CDH/eventration.
CONCLUSION
The factors: prematurity, weight <2 kg, cyanosis at presentation and antenatal diagnosis were independently associated with increased mortality in neonates with CDH/eventration requiring surgery.
Topics: Child; Infant, Newborn; Humans; Female; Pregnancy; Hernias, Diaphragmatic, Congenital; Retrospective Studies; Premature Birth; Cyanosis
PubMed: 36960499
DOI: 10.4103/ajps.ajps_165_21 -
The Journal of Surgical Research Feb 2023Congenital diaphragmatic hernia is associated with pulmonary hypoplasia, pulmonary hypertension, and significant neonatal morbidity. Although intrathoracic liver...
INTRODUCTION
Congenital diaphragmatic hernia is associated with pulmonary hypoplasia, pulmonary hypertension, and significant neonatal morbidity. Although intrathoracic liver herniation (LH) >20% is associated with adverse outcomes, the relationship between LH <20% and outcomes is poorly characterized.
METHODS
A single-center retrospective cohort study was performed from 2011 to 2020 of 80 fetuses with left-sided congenital diaphragmatic hernia that were delivered and repaired at our institution. Perinatal, perioperative, and postoperative data were collected. We evaluated the association of %LH with outcomes as a stratified ordinal variable (0%-10% LH, 10%-19% LH, and >20% LH) and as a continuous variable. Data were analyzed by analysis of variance with Bonferroni post hoc analysis, chi-square analyses, and univariate logistic regression.
RESULTS
Extracorporeal membrane oxygenation (ECMO) (P < 0.001), repair on ECMO (P = 0.002), repair with patch (P < 0.001), length of stay (P = 0.002), inhaled nitric oxide use (P < 0.001), and sildenafil use at discharge (P < 0.001), showed significant differences among LH groups. There were no differences among the groups concerning survival (at discharge, 6 mo, and 1 y) and tracheostomy. On further analysis there was no difference between 10% and 19% LH and ≥20% LH patients concerning ECMO (P = 0.55), repair on ECMO (P = 0.54), repair with patch (P = 1.00), length of stay (P = 1.00), and inhaled nitric oxide use (P = 0.33). Logistic regression analysis displayed a significant association with LH and ECMO, repair on ECMO, repair with patch, inhaled nitric oxide use, and sildenafil use.
CONCLUSIONS
Our analysis displays no significant difference in perinatal management between patients with 10%-19% and ≥20% LH. These findings suggest that the historical cutoff of ≥20% LH may not be sufficient alone to guide perinatal counseling and decision-making.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Hernias, Diaphragmatic, Congenital; Retrospective Studies; Sildenafil Citrate; Nitric Oxide; Liver; Risk Assessment
PubMed: 36306587
DOI: 10.1016/j.jss.2022.09.002 -
American Journal of Human Genetics Oct 2021Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of...
Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.
Topics: ATP-Dependent Proteases; Animals; Case-Control Studies; Cohort Studies; Craniofacial Abnormalities; DNA Copy Number Variations; Eye Abnormalities; Female; Growth Disorders; Hernias, Diaphragmatic, Congenital; Hip Dislocation, Congenital; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Proteins; Mutation, Missense; Osteochondrodysplasias; Pedigree; Tooth Abnormalities
PubMed: 34547244
DOI: 10.1016/j.ajhg.2021.08.011 -
Paediatric and Perinatal Epidemiology Feb 2023Population-based administrative data have rarely been used to compare the birth prevalence, risk factors for occurrence, and mortality of congenital diaphragmatic hernia...
BACKGROUND
Population-based administrative data have rarely been used to compare the birth prevalence, risk factors for occurrence, and mortality of congenital diaphragmatic hernia (CDH) subtypes.
OBJECTIVES
We used a national birth cohort to identify CDH subtypes and compared their birth prevalence, relationship with maternal age after accounting for sociodemographic factors, and 1-year mortality rates.
METHODS
Linked hospital admission and death records were used to identify isolated and complex CDH cases (involving additional anomalies) among singleton livebirths in England between 2002 and 2018. The prevalence of each CDH subtype per 10,000 livebirths was estimated overall and by infant, birth and maternal characteristics. The relationship between maternal age and each subtype relative to no CDH was examined using multivariable log-binomial regression to estimate risk ratios (RRs). One-year mortality rates were examined using Kaplan-Meier curves and the hazard ratio (HR) of complex versus isolated CDH was calculated using Cox regression.
RESULTS
Among 9.5 million livebirths, we identified 1285 with isolated CDH and 1150 with complex CDH. The overall prevalence of isolated and complex CDH was 1.4 (95% confidence interval [CI] 1.3, 1.4) and 1.2 (95% CI 1.1, 1.3) per 10,000 livebirths, respectively. Only complex CDH was associated with maternal age. Compared with maternal age 25-34 years, complex CDH risk was elevated for maternal age < 20 years (RR 1.31, 95% CI 1.00, 1.72). Risk was highest for maternal age ≥ 40 years (RR 1.61, 95% CI 1.21, 2.15) although accounting for chromosomal anomalies attenuated the risk (RR 1.39, 95% CI 1.00, 1.92). The 1-year mortality rate for complex CDH (33.1%, 95% CI 30.5, 35.9) was slightly higher than for isolated CDH (29.7%, 95% CI 27.3, 32.3) (HR 1.10, 95% CI 0.96, 1.27).
CONCLUSIONS
Mechanisms of occurrence differed between and within CDH subtypes and 1-year mortality of complex CDH was slightly higher than for isolated CDH.
Topics: Adult; Humans; Infant; Young Adult; Birth Cohort; Hernias, Diaphragmatic, Congenital; Maternal Age; Prevalence; Retrospective Studies; Risk Factors; Infant Mortality; Female; Infant, Newborn
PubMed: 36441118
DOI: 10.1111/ppe.12939 -
Genetics in Medicine : Official Journal... Jan 2023Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full...
Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study.
PURPOSE
Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported.
METHODS
Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp).
RESULTS
Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period.
CONCLUSION
We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered.
Topics: Pregnancy; Female; Humans; Muscle Hypotonia; Epilepsy; Abnormalities, Multiple; Hernia, Diaphragmatic; Seizures; Phenotype; Genetic Association Studies; Congenital Disorders of Glycosylation; Syndrome
PubMed: 36322149
DOI: 10.1016/j.gim.2022.09.007