Complex Congenital Diaphragmatic Hernia Research Articles

Rescuing lung development through embryonic inhibition of histone acetylation.

A major barrier to the impact of genomic diagnosis in patients with congenital malformations is the lack of understanding regarding how sequence variants contribute to disease pathogenesis and whether this information could be used to generate patient-specific therapies. Congenital diaphragmatic hernia (CDH) is among the most common and severe of all structural malformations; however, its underlying mechanisms are unclear. We identified loss-of-function sequence variants in the epigenomic regulator gene SIN3A in two patients with complex CDH. Tissue-specific deletion of Sin3a in mice resulted in defects in diaphragm development, lung hypoplasia, and pulmonary hypertension, the cardinal features of CDH and major causes of CDH-associated mortality. Loss of SIN3A in the lung mesenchyme resulted in reduced cellular differentiation, impaired cell proliferation, and increased DNA damage. Treatment of embryonic Sin3a mutant mice with anacardic acid, an inhibitor of histone acetyltransferase, reduced DNA damage, increased cell proliferation and differentiation, improved lung and pulmonary vascular development, and reduced pulmonary hypertension. These findings demonstrate that restoring the balance of histone acetylation can improve lung development in the Sin3a mouse model of CDH.

Recent advances in the treatment of complex congenital diaphragmatic hernia-a narrative review.

Congenital diaphragmatic hernia (CDH) is an anomaly of the cardiopulmonary system maturation process that results from both a global embryopathy and concomitant mechanical compression of the cardiopulmonary system from the abdominal contents during fetal maturation. This results in pulmonary hypertension, pulmonary hypoplasia, and cardiac dysfunction, requiring intense critical care management. The patients with highest risk CDH are the most challenging, resource-intensive, and bear most of the mortality. Advances at the basic, translational, and clinical research levels are leading to novel therapies and management strategies for complex, high-risk CDH. Our objective is to review novel approaches in thinking and management for the most complex and high-risk CDH patients. These include patients with prenatal and postnatal indicators of high-risk defects, those receiving extracorporeal life support (ECLS), and those with concomitant anomalies such as complex cardiac and/or chromosomal abnormalities. PubMed was searched in late 2022 and early 2023 to identify relevant evidence. Search terms included congenital diaphragmatic hernia (CDH)", "extracorporeal life support (ECLS)", "pulmonary hypertension", "dual-hit hypothesis", "risk reduction", "cardiac/chromosomal anomalies", and "novel therapies". We included trials, multicenter studies (prospective and retrospective), single-center reports, and review articles/expert opinion. CDH is a congenital anomaly of the cardiopulmonary and diaphragmatic systems that represents a spectrum of disease. High-risk or complex patients are defined by prenatal/postnatal risk stratification, receipt of ECLS, and/or having concomitant anomalies, representing the severe end of that spectrum. Overall survival of high-risk CDH is about 50% and comprises the vast majority of mortality, mandating special emphasis. The development of risk-stratification processes, best practices or guidelines of management, and novel therapies is critical to optimize the care of these infants. CDH patients with high-risk disease remain a challenging subset of CDH patients. Increasing opportunities for survival are being realized with novel, investigational approaches.

Congenital diaphragmatic hernia subtypes: Comparing birth prevalence, occurrence by maternal age, and mortality in a national birth cohort.

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. 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. 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. 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). Mechanisms of occurrence differed between and within CDH subtypes and 1-year mortality of complex CDH was slightly higher than for isolated CDH.

Genome-wide enrichment of damaging de novo variants in patients with isolated and complex congenital diaphragmatic hernia.

Congenital Diaphragmatic Hernia (CDH) is a common and often lethal birth defect characterized by diaphragmatic structural defects and pulmonary hypoplasia. CDH is isolated in 60% of newborns, but may also be part of a complex phenotype with additional anomalies. We performed whole exome sequencing (WES) on 87 individuals with isolated or complex CDH and on their unaffected parents, to assess the contribution of de novo mutations in the etiology of diaphragmatic and pulmonary defects and to identify new candidate genes. A combined analysis with 39 additional trios with complex CDH, previously published, revealed a significant genome-wide burden of de novo variants compared to background mutation rate and 900 control trios. We identified an increased burden of likely gene-disrupting (LGD, i.e. nonsense, frameshift, and canonical splice site) and predicted deleterious missense (D-mis) variants in complex and isolated CDH patients. Overall, an excess of predicted damaging de novo LGD and D-mis variants relative to the expected frequency contributed to 21% of complex cases and 12% of isolated CDH cases. The burden of de novo variants was higher in genes expressed in the developing mouse diaphragm and heart. Some overlap with genes responsible for congenital heart defects and neurodevelopmental disorders was observed in CDH patients within our cohorts. We propose that de novo variants contribute significantly to the development of CDH.

Congenital Diaphragmatic Hernia: The Side of Diaphragmatic Defect and Associated Nondiaphragmatic Malformations.

Background Congenital diaphragmatic hernia (CDH) has different clinical presentations depending on whether it is right sided (R-CDH) or left sided (L-CDH). Some have suggested that L-CDH and R-CDH may represent different syndromic phenotypes. This theory would be indirectly supported if different nondiaphragmatic anomalies were associated with laterality. We assessed whether CDH laterality is associated with specific types of nondiaphragmatic anomalies. Methods Cases of CDH were retrospectively identified from five centers, and associated congenital anomalies, prenatal diagnosis, demographics, birth characteristics, and side of the CDH were analyzed. CDH characteristics were summarized according to the absence (isolated) or presence (complex) of nondiaphragmatic malformations. Results Among 228 neonates with CDH, 140 (61%) had isolated CDH and 88 (39%) had complex CDH. Complex CDH was significantly associated with being small for gestational age (odds ratio [95% confidence interval, CI]: 8.3 [1.9-35.7]; p = 0.005) and having L-CDH (odds ratio [95% CI]: 3.6 [1.5-8.9]; p = 0.005). The overall proportion with anomalies differed by side (42% for L-CDH, 23% for R-CDH; p = 0.02), but the rates of anomalies in specific organ systems did not differ. Conclusion The rate of associated nondiaphragmatic anomalies by specific organ system did not differ between L-CDH and R-CDH, which suggests that they represent the same phenotypic entity.

Trends in treatment and in-hospital mortality for neonates with congenital diaphragmatic hernia.

We performed a retrospective cohort study in order to examine recent trends in use of post-partum treatments and in-hospital mortality for congenital diaphragmatic hernia (CDH). Included were infants with CDH, born in 2003 to 2012 and hospitalized at ⩽7 days of age at one of 33 United States tertiary referral children's hospitals with extracorporeal membrane oxygenation (ECMO) programs. In-hospital mortality as well as use of ECMO, surfactant and a variety of vasodilators were examined for trends during the study period. Inclusion criteria were met by 3123 infants with CDH. Among 2423 term or near-term infants, odds of death decreased annually for those with isolated or complex CDH. For 700 premature or low-birth weight infants with CDH, in-hospital mortality did not change. Among treatments for CDH, increasing with time in the study cohort were use of milrinone and sildenafil individually, and use of multiple vasodilators during the hospitalization. Survival improved in large subgroups of term or near-term infants with CDH in this 10-year multicenter cohort, temporally associated with increasing use of multiple vasodilators. Use of vasodilators for infants with CDH is increasing despite a lack of evidence supporting efficacy or safety. Prospective research is needed to clarify specific causal effects contributing to improving survival in these infants.

Associated anomalies in congenital diaphragmatic hernia: perinatal characteristics and impact on postnatal survival.

We aimed to investigate the clinical characteristics and postnatal outcomes of fetuses with congenital diaphragmatic hernia (CDH) and additional anomalies. We reviewed the charts of fetuses with CDH managed between 2005 and 2013. Patients were divided into complex and isolated groups based on the presence of additional anomalies. We analyzed the respective polyhydramnios, liver herniation, stomach position, lung to thorax transverse area ratio (LTR), and prognoses of the two groups. The survival rates of both groups were assessed based on the LTR as well as on stomach and liver positions. CDH was diagnosed in 65 fetuses, and additional anomalies were found in 23. The incidences of liver herniation, polyhydramnios, and death were significantly higher, and LTR was significantly lower, in the complex group. The mortality rate of fetuses with a LTR <0.08 was lower than that of fetuses with a LTR of ≥0.08 in the complex group. Further, the survival rate of fetuses with intrathoracic liver was lower than those without liver herniation. The prognosis of complex CDH is poor. This may result from both the associated anomalies and the severity of CDH itself. Even in complex CDHs, intrathoracic liver and LTR values are useful in estimating postnatal outcome.

Maternal medical and behavioral risk factors for congenital diaphragmatic hernia

PurposeMaternal factors contributing to the etiology of congenital diaphragmatic hernia (CDH) remain unclear. We hypothesized that specific maternal medical conditions (pregestational diabetes, hypertension), and behaviors (alcohol, tobacco) would be associated with CDH. MethodsWe conducted a population-based case–control study using Washington State birth certificates linked to hospital discharge records (1987–2009). We identified all infants with CDH (n=492). Controls were randomly selected among non-CDH infants. Maternal data were extracted from the birth record. Logistic regression was used to adjust for covariates. ResultsCases and controls were generally similar regarding demographics, although CDH infants were more likely to be male than controls (58.5% vs. 52.5%). Isolated and complex (multiple-anomaly) CDH had similar characteristics. Each of the exposures of interest was more common among case mothers than among control mothers. In univariate analysis, alcohol use, hypertension, and pregestational diabetes were each significantly associated with the outcome. After multivariate adjustment, only alcohol use (OR=3.65, p=0.01) and pregestational diabetes (OR=12.53, p=0.003) maintained significance. Results were similar for both isolated and complex CDH. ConclusionsMaternal pregestational diabetes and alcohol use are significantly associated with occurrence of CDH in infants. These are important modifiable risk factors to consider with regard to efforts seeking to impact the incidence of CDH.

Congenital Diaphragmatic Hernia: Not Quite There Yet

Congenital Diaphragmatic Hernia: Not Quite There Yet

Comparable Low-Level Mosaicism in Affected and Non Affected Tissue of a Complex CDH Patient

In this paper we present the detailed clinical and cytogenetic analysis of a prenatally detected complex Congenital Diaphragmatic Hernia (CDH) patient with a mosaic unbalanced translocation (5;12). High-resolution whole genome SNP array confirmed a low-level mosaicism (20%) in uncultured cells, underlining the value of array technology for identification studies. Subsequently, targeted Fluorescence In-Situ Hybridization in postmortem collected tissues demonstrated a similar low-level mosaicism, independently of the affected status of the tissue. Thus, a higher incidence of the genetic aberration in affected organs as lung and diaphragm cannot explain the severe phenotype of this complex CDH patient. Comparison with other described chromosome 5p and 12p anomalies indicated that half of the features presented in our patient (including the diaphragm defect) could be attributed to both chromosomal areas. In contrast, a few features such as the palpebral downslant, the broad nasal bridge, the micrognathia, microcephaly, abnormal dermatoglyphics and IUGR better fitted the 5p associated syndromes only. This study underlines the fact that low-level mosaicism can be associated with severe birth defects including CDH. The contribution of mosaicism to human diseases and specifically to congenital anomalies and spontaneous abortions becomes more and more accepted, although its phenotypic consequences are poorly described phenomena leading to counseling issues. Therefore, thorough follow–up of mosaic aberrations such as presented here is indicated in order to provide genetic counselors a more evidence based prediction of fetal prognosis in the future.

Characterization of the chromosome 1q41q42.12 region, and the candidate gene DISP1, in patients with CDH.

Cytogenetic and molecular cytogenetic studies demonstrate association between congenital diaphragmatic hernia (CDH) and chromosome 1q41q42 deletions. In this study, we screened a large CDH cohort (N=179) for microdeletions in this interval by the multiplex ligation-dependent probe amplification (MLPA) technique, and also sequenced two candidate genes located therein, dispatched 1 (DISP1) and homo sapiens H2.0-like homeobox (HLX). MLPA analysis verified deletions of this region in two cases, an unreported patient with a 46,XY,del(1)(q41q42.13) karyotype and a previously reported patient with a Fryns syndrome phenotype [Kantarci et al., 2006]. HLX sequencing showed a novel but maternally inherited single nucleotide variant (c.27C>G) in a patient with isolated CDH, while DISP1 sequencing revealed a mosaic de novo heterozygous substitution (c.4412C>G; p.Ala1471Gly) in a male with a left-sided Bochdalek hernia plus multiple other anomalies. Pyrosequencing demonstrated the mutant allele was present in 43%, 12%, and 4.5% of the patient's lymphoblastoid, peripheral blood lymphocytes, and saliva cells, respectively. We examined Disp1 expression at day E11.5 of mouse diaphragm formation and confirmed its presence in the pleuroperitoneal fold, as well as the nearby lung which also expresses Sonic hedgehog (Shh). Our report describes the first de novo DISP1 point mutation in a patient with complex CDH. Combining this finding with Disp1 embryonic mouse diaphragm and lung tissue expression, as well as previously reported human chromosome 1q41q42 aberrations in patients with CDH, suggests that DISP1 may warrant further consideration as a CDH candidate gene.

Concomitant malformations and chromosomal abnormalities in prenatally diagnosed congenital diaphragmatic hernia

Objective To analyze the concomitant malforrnations,chromosomal abnormalities and outcomes in prenatally diagnosed congenital diaphragmatic hernia (CDH) cases. Methods Cases of fetal CDH,prenatally identified in the First Affiliated Hospital of Sun Yat-sen University from January 2002 to November 2008,were recruited.The concomitant realformations,chromosomal abnormalities and outcomes of fetal CDlH were analyzed.Fisher's exact test was applied. Results During the study period,71 CDH cases were identified including 62(87.3%) left-sided CDH and 9 (12.7%) right-sided ones.Among the 71 CDH fetuses,38(53.5%)were isolated CDH.33 (46.5%)were complicated with other realformations(complex CDH),including 18(54.5 0A) cardiovascular defects,10 (30.3%)central nervous system abnormalities,9(27.2 0A)genitourinary abnormalities and others.Fetal karyotying was performed in 19 out of the 71 CDH fetuses.among which 12 were isolated CDH cases with normal karyotype,and 4 of the rest 7(4/7)complex CDH cases with chromosomal abnormalities showing a significant differenee compared to the isolated CDH (P.0.009).Sixty-five pregnancies were terminated including all complex CDH(n=33)and 32 isolated CDH.The rest 6 isolated CDH fetuses were term delivered and 5 of them survived after repair of diaphragmatic hernia and one died after birth. Conclusions Left-sided CDH are more common than right-sided ones. Approximately half of the CDH cases are complicated with other malformations,especially cardiovascular abnormalities.The risk of chromosomal abnormalities increases in complex CDH and is relatively low in isolated CDH.The influence of surgical procedure on the prognosis of CDH has not yet determined. Key words: Hernia,diaphragmatic; Ultrasonography,prenatal; Chromosome aberrations

Congenital diaphragmatic hernia and pulmonary hypoplasia: New insights from developmental biology and genetics

Congenital diaphragmatic hernia and pulmonary hypoplasia: New insights from developmental biology and genetics

Infants with Bochdalek diaphragmatic hernia: Sibling precurrence and monozygotic twin discordance in a hospital‐based malformation surveillance program

Congenital diaphragmatic hernia (CDH) is a common and often devastating birth defect. In order to learn more about possible genetic causes, we reviewed and classified 203 cases of the Bochdalek hernia type identified through the Brigham and Women's Hospital (BWH) Active Malformation Surveillance Program over a 28-year period. Phenotypically, 55% of the cases had isolated CDH, and 45% had complex CDH defined as CDH in association with additional major malformations or as part of a syndrome. When classified according to likely etiology, 17% had a Recognized Genetic etiology for their CDH, while the remaining 83% had No Apparent Genetic etiology. Detailed analysis using this largest cohort of consecutively collected cases of CDH showed low precurrence among siblings. Additionally, there was no concordance for CDH among five monozygotic twin pairs. These findings, in conjunction with previous reports of de novo dominant mutations in patients with CDH, suggest that new mutations may be an important mechanism responsible for CDH. The twin data also raise the possibility that epigenetic abnormalities contribute to the development of CDH.

Complications of neonatal extracorporeal membrane oxygenation: Collective experience from the Extracorporeal Life Support Organization

Since 1973, 7667 neonates have been treated with extracorporeal membrane oxygenation for severe respiratory failure and their cases reported to the Extracorporeal Life Support Organization Registry. The overall survival was 81% in these neonates, who were thought to have a survival of 20% without extracorporeal membrane oxygenation. A total of 4322 mechanical complications (0.56 ± 0.84 per case) and 13,827 patient complications (1.80 ± 2.12 per case) were reported overall. The most common mechanical complications included clots in the circuit (19%), cannula placement (9%), oxygenator failure (4%), and others (9%). Common patient complications included cardiopulmonary (43%), neurologic (35%), bleeding (35%), metabolic (32%), renal (25%), and infectious (9%). From the initial experience to 1988 the average number of mechanical complications per case was 0.27 per case and this significantly increased during 1990 to 1992 to 0.75 per case ( p < 0.05). Likewise, from 1973-1985 to 1988 the average patient complications per case were 1.44 per case and this significantly increased during 1990 to 1992 to 2.10 per case. During the same periods, patient survival significantly decreased from 84% (1973-1985 to 1988, n = 2463) to 80% (1990 to 1992, n = 4005). Venovenous double-lumen single cannula extracorporeal membrane oxygenation had a higher survival than venoarterial extracorporeal membrane oxygenation (91% versus 81%) and a lower rate of major neurologic complications. The incidence and survival with seizures (6% and 89% venovenous versus 13% and 61% venoarterial) or cerebral infarction (9% and 69% venovenous versus 14% and 46% venoarterial) was significantly lower with the venovenous method and appeared to have a substantial impact on overall survival. The correlation of patient complication rate and total complication rate with survival was highly significant, however, causality cannot be established. Explanations for the increase in complications, relative to a decrease in survival, despite a growing nationwide experience include (1) increased complexity of cases as many programs expand entry criteria (more premature infants, infants with grade 1 or 2 intracranial hemorrhage, and complex congenital diaphragmatic hernia), (2) a growing number of programs with fewer cases per program, yet greater accessibility, (3) less reluctance to report complications encountered during extracorporeal membrane oxygenation as group experience grows, and (4) changes in the Extracorporeal Life Support Organization data form to be more inclusive of more minor complications. (J THORAC CARDIOVASC SURG 1994;107:838-49)