Congenital Diaphragmatic Hernia Cohort Research Articles

Comparison of current to past outcomes in congenital diaphragmatic hernia using mri observed-to-expected total fetal lung volume.

Fetal Centers use imaging studies to predict congenital diaphragmatic hernia (CDH) prognosis and the need for fetal therapy. Given improving CDH survival, we hypothesized that current fetal imaging severity predictions no longer reflect true outcomes and fail to justify the risks of fetal therapy. We analyzed our single-center contemporary data in a left-sided CDH cohort (n = 58) by prognostic criteria determined by MRI observed-to-expected total fetal lung volumes: severe <25%, moderate 25-35%, and mild >35%. We compared contemporary survival to prior studies and the TOTAL trials. Contemporary survival was significantly higher than past studies for all prognostic classifications (mild 100% vs 80-94%, moderate 95% vs 59-75%, severe 79% vs 13-25%; P < 0.01), and to either control or fetal therapy arms of the TOTAL trials. Current fetal imaging criteria are overly pessimistic and may lead to unwarranted fetal intervention. Fetal therapies remain experimental. Future studies will require updated prognostic criteria.

Prenatal Brain Maturation is Delayed in Neonates with Congenital Diaphragmatic Hernia

To assess brain development in fetuses with congenital diaphragmatic hernia (CDH) using a fetal Total Maturation Score (fTMS). This is a retrospective cohort study using data from a single-center, clinical registry. Neonates with an antenatal diagnosis of CDH between 2014 - 2020 and prenatal brain magnetic resonance imaging (n = 48) were included. We compared our study sample with historical healthy controls (n = 48). The relationship between fTMS and gestational age, as well as the association between fTMS and key prenatal variables and placental pathologic findings, were evaluated. Compared with healthy controls, neonates with CDH had a significant delay in fTMS (p-value <0.001). Within the CDH cohort, there was no significant difference in fTMS based on CDH severity, intrathoracic liver position, right versus left CDH, sex, presence of abnormal echocardiogram findings, treatment with extracorporeal membrane oxygenation, or in-hospital mortality. Placentas of neonates with CDH had a high proportion of fetal vascular malperfusion (56%) and chronic inflammation (67%), and relatively large placentas had a protective effect on prenatal brain maturation (p-value = 0.025). Prenatal brain maturation in neonates with CDH is delayed. Placental pathology may influence fetal brain development. The etiology and clinical impact of prenatal brain immaturity in neonates with CDH warrant further investigation.

Quantitative Measures of Right Ventricular Size and Function by Echocardiogram Correlate with Cardiac Catheterization Hemodynamics in Congenital Diaphragmatic Hernia

To evaluate associations between cardiac catheterization (cath) hemodynamics, quantitative measures of right ventricular (RV) function by echocardiogram, and survival in patients with congenital diaphragmatic hernia (CDH). This single-center retrospective cohort study enrolled patients with CDH who underwent index cath from 2003 to 2022. Tricuspid annular plane systolic excursion z score, RV fractional area change, RV free wall and global longitudinal strain, left ventricular (LV) eccentricity index, RV/LV ratio, and pulmonary artery acceleration time were measured from preprocedure echocardiograms. Associations between hemodynamic values, echocardiographic measures, and survival were evaluated by Spearman correlation and Wilcoxon rank sum test, respectively. Fifty-three patients (68% left-sided, 74% liver herniation, 57% extracorporeal membrane oxygenation, 93% survival) underwent cath (39 during index hospitalization, 14 later) including device closure of a patent ductus arteriosus in 5. Most patients (n=31, 58%) were on pulmonary hypertension treatment at cath, most commonly sildenafil (n=24, 45%) and/or intravenous treprostinil (n=16, 30%). Overall, hemodynamics were consistent with precapillary pulmonary hypertension. Pulmonary capillary wedge pressure was >15mm Hg in 2 patients (4%). Lower fractional area change and worse ventricular strain were associated with higher pulmonary artery pressure while higher LV eccentricity index and higher RV/LV ratio were associated with both higher pulmonary artery pressure and higher pulmonary vascular resistance. Hemodynamics did not differ based on survival status. Worse RV dilation and dysfunction by echocardiogram correlate with higher pulmonary artery pressure and pulmonary vascular resistance on cath in this CDH cohort. These measures may represent novel, noninvasive clinical trial targets in this population.

Long-term exercise and pulmonary function outcomes in a contemporary cohort of children with congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) survivors are at risk for long-term exercise impairment and pulmonary morbidity, but the generalizability of prior reported cohorts are limited by reduced disease severity and older surgical eras. We assessed the mid-childhood exercise and pulmonary function outcomes in a contemporary cohort of CDH survivors. In this retrospective cohort study, we identified 36 consecutive pediatric CDH survivors who underwent cardiopulmonary exercise testing (CPET) and spirometry from 2014 to 2021. Inferential statistics compared survivors with age-, sex-, and size-matched healthy controls; univariate analyses identified factors associated with abnormal testing. Maximal effort CPET and resting spirometry were completed by 27/36 (75%) and 31/36 (86%) subjects, respectively (median age: 8.1 years [interquartile range: 7.5, 10]; 16 females [44%]). Abnormal CPET (percent predicted [pp] peak VO2 < 80%) was more common in the CDH cohort (12 vs. 1, p < 0.001) and associated with longer neonatal intensive care unit (NICU) stay (p = 0.02) and oxygen therapy at discharge (p = 0.03). Exercise impairment was mild (pp peak VO2 70%-80%), moderate (60%-70%), and severe (<60%) in 6, 4, and 2 survivors, respectively. Abnormal spirometry was more common in the CDH cohort (21 vs. 3, p < 0.001; obstructive [n = 15], restrictive [n = 6]) and associated with decreased gestational age (p = 0.046), longer mechanical ventilation in the NICU (p = 0.02), and orthopedic abnormalities (p = 0.03). Exercise capacity was normal or mildly impaired in most CDH survivors, however, approximately two-thirds demonstrated abnormal spirometry. Impaired exercise capacity and lung function were associated with severity of lung disease postnatally. These data support cardiopulmonary follow-up throughout childhood.

Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene

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.

Prevalence of Acute Kidney Injury in Neonates with Congenital Diaphragmatic Hernia

Background: Congenital diaphragmatic hernia (CDH) often presents with severe cardio-respiratory impairment in the neonatal period. Affected infants may be exposed to multiple nephrotoxic insults, predisposing them to acute kidney injury (AKI). The prevalence of AKI in a CDH cohort has not previously been described. Objectives: The primary aim of this study was to quantify the prevalence of AKI in patients with CDH treated in a single national centre. Secondarily, we investigated the association between AKI, select neonatal outcomes, and recognised AKI risk factors. Methods: This was a retrospective analysis of all patients with CDH treated at our regional neonatal surgical centre between September 2011 and December 2017. Data was collected on demographics, CDH Study Group stage (size), laboratory and physiological parameters, medications, mortality, and duration of hospitalisation. AKI severity was stratified using the modified paediatric RIFLE criteria, determined by comparing the percentage increase in serum creatinine from baseline. Statistical analysis was performed using Fisher’s exact and Pearson’s χ² tests for parametric analysis and Mann-Whitney U testing for non-parametric analysis. Results: Fifty-four CDH patients met the inclusion criteria, 37% of whom developed AKI. The development of AKI was significantly associated with larger CDH defect (type C/D; p = 0.014), extracorporeal membranous oxygenation support (p = 0.003), patch repair (p = 0.004), and exposure to vancomycin, corticosteroids and diuretics (p = 0.004, p = 0.007, and p ≤ 0.001, respectively). There was no statistical association between AKI and gentamicin administration, umbilical arterial catheter insertion, or significant infection. Prolonged hospitalisation and patient mortality were significantly associated with AKI (p = 0.01 and p = 0.001, respectively). Conclusions: AKI is common in CDH cases treated in our centre and is associated with adverse outcomes. Potentially modifiable risk factors include nephrotoxic medication exposure. Prevention and early recognition of contributory factors for AKI may improve outcomes in CDH.

Trends in Mortality and Risk Characteristics of Congenital Diaphragmatic Hernia Treated With Extracorporeal Membrane Oxygenation.

Although the mortality of infants with congenital diaphragmatic hernia (CDH) has been improving since the late 1990s, this observation has not been paralleled among the CDH cohort receiving extracorporeal membrane oxygenation (ECMO). We sought to elucidate why the mortality rate in the CDH-ECMO population has remained at approximately 50% despite consistent progress in the field by examining the baseline risk profile/characteristics of neonates with CDH before ECMO (pre-ECMO). Neonates with a diagnosis of CDH were identified in the Extracorporeal Life Support Organization (ELSO) Registry from 1992 to 2015. Individual pre-ECMO risk score (RS) for mortality was categorized to pre-ECMO risk-stratified cohorts. Temporal trends based on individual-level mortality by risk cohorts were assessed by logistic regression. We identified 6,696 neonates with CDH. The mortality rates during this time period were approximately 50%. The average baseline pre-ECMO RS increased during this period: mean increase of 0.35 (95% confidence interval [CI]: 0.324–0.380). In the low-risk cohort, the likelihood of mortality increased over time: each 5 year change was associated with a 7.3% increased likelihood of mortality (odds ratio [OR]: 1.0726; 95% CI: 1.0060–1.1437). For the moderate-risk cohort, the likelihood of mortality decreased by 7.05% (OR: 0.9295; 95% CI: 0.8822–0.9793). There was no change in the odds of mortality for the high-risk cohort (OR: 0.9650; 95% CI: 0.8915–1.0446). Although the overall mortality rate remained approximately constant over time, the individual likelihood of death has declined over time in the moderate-risk cohort, increased in the low-risk cohort, and remained unchanged in the high-risk cohort.

Congenital heart disease associated with congenital diaphragmatic hernia: A systematic review on incidence, prenatal diagnosis, management, and outcome

PurposeThe purpose of this study was to evaluate the impact of congenital heart disease (CHD) on infants with congenital diaphragmatic hernia (CDH). MethodsUsing a defined search strategy (PubMed, Cochrane, Embase, Web of Science MeSH headings), we searched studies reporting the incidence, management, and outcome of CDH infants born with associated CHD. ResultsOf 6410 abstracts, 117 met criteria. Overall, out of 28,974 babies with CDH, 4427 (15%) had CHD, of which 42% were critical. CDH repair was performed in a lower proportion of infants with CHD (72%) than in those without (85%; p < 0.0001). Compared to CDH babies without CHD, those born with a cardiac lesion were more likely to have a patch repair (45% vs. 30%; p < 0.01) and less likely to undergo minimally invasive surgery (5% vs. 17%; p < 0.0001). CDH babies with CHD had a lower survival rate than those without CHD (52 vs. 73%; p < 0.001). Survival was even lower (32%) in babies with critical CHD. ConclusionCHD has a strong impact on the management and outcome of infants with CDH. The combination of CDH and CHD results in lower survival than those without CHD or an isolated cardiac defect. Further studies are needed to address some specific aspects of the management of this fragile CDH cohort. Type of studySystematic review and meta-analysis. Level of evidenceLevel III.

The role of FREM2 and FRAS1 in the development of congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) has been reported twice in individuals with a clinical diagnosis of Fraser syndrome, a genetic disorder that can be caused by recessive mutations affecting FREM2 and FRAS1. In the extracellular matrix, FREM2 and FRAS1 form a self-stabilizing complex with FREM1, a protein whose deficiency causes sac CDH in humans and mice. By sequencing FREM2 and FRAS1 in a CDH cohort, and searching online databases, we identified five individuals who carried recessive or double heterozygous, putatively deleterious variants in these genes which may represent susceptibility alleles. Three of these alleles were significantly enriched in our CDH cohort compared with ethnically matched controls. We subsequently demonstrated that 8% of Frem2ne/ne and 1% of Fras1Q1263*/Q1263* mice develop the same type of anterior sac CDH seen in FREM1-deficient mice. We went on to show that development of sac hernias in FREM1-deficient mice is preceded by failure of anterior mesothelial fold progression resulting in the persistence of an amuscular, poorly vascularized anterior diaphragm that is abnormally adherent to the underlying liver. Herniation occurs in the perinatal period when the expanding liver protrudes through this amuscular region of the anterior diaphragm that is juxtaposed to areas of muscular diaphragm. Based on these data, we conclude that deficiency of FREM2, and possibly FRAS1, are associated with an increased risk of developing CDH and that loss of the FREM1/FREM2/FRAS1 complex, or its function, leads to anterior sac CDH development through its effects on mesothelial fold progression.

Diminished Cardiac Performance and Left Ventricular Dimensions in Neonates with Congenital Diaphragmatic Hernia.

Newborns with congenital diaphragmatic hernia (CDH) have varying degrees of pulmonary hypoplasia and pulmonary hypertension (PH), and there is limited evidence that cardiac dysfunction is present. We sought to study early neonatal biventricular function and performance in these patients by reviewing early post-natal echocardiography (ECHO) measurements and comparing them to normal term newborns. Retrospective case-control study reviewing clinical and ECHO data on term newborns with CDH and normal controls born between 2009 and 2016. Patients were excluded if major anomalies, genetic syndromes, or no ECHO available. PH was assessed by ductal shunting and tricuspid regurgitant jet velocity. Speckle-tracking echocardiography was used to assess myocardial deformation using velocity vector imaging. Forty-four patients with CDH and 18 age-matched controls were analyzed. Pulmonary pressures were significantly higher in the CDH cohort (systolic pulmonary arterial pressure to systolic blood pressure of 103 ± 13 vs. 78 ± 29%, p = 0.0001). CDH patients had decreased RV fractional area change (FAC - 28.6 ± 11.1 vs. 36.2 ± 9.6%, p = 0.02), tricuspid annular plane of systolic excursion (TAPSE-5.6 ± 1.6 vs. 8.6 ± 1.6mm, p = 0.0001), and RV outflow tract stroke distance (8.6 ± 2.7 vs. 14.0 ± 4.5cm, p = 0.0001) compared with controls. The left ventricular (LV) ejection fraction was similar in both groups, but CDH patients had a decreased LV end-diastolic volume by Simpson's rule (2.7 ± 1.0 vs. 5.0 ± 1.8mL, p = 0.0001) and LVOT stroke distance (9.7 ± 3.4 vs. 12.6 ± 3.6cm, p = 0.004). Biventricular global longitudinal strain (GLS) was markedly decreased in the CDH population compared to controls (RV-GLS: - 9.0 ± 5.3 vs. - 19.5 ± 1.4%, p = 0.0001; LV GLS: - 13.2 ± 5.8 vs. - 20.8 ± 3.5%, p = 0.0001). CDH newborns have evidence of biventricular dysfunction and decreased cardiac output. Abnormal function may be a factor in the non-response to pulmonary arterial vasodilators in CDH patients. A two-pronged management strategy aimed at improving cardiac function, as well as reducing pulmonary artery pressure in CDH newborns, may be warranted.

Clinical Outcome for Congenital Diaphragmatic Hernia at the Age of 1 Year in the Era of Fetal Intervention

Background: Congenital diaphragmatic hernia (CDH) is an abnormal development of the diaphragm leading to high neonatal mortality and morbidity. Beyond the neonatal period, prospective data on overall long-term outcome in CDH survivors is scarce. In particular, for those treated with fetoscopic endoluminal tracheal occlusion (FETO), a promising new technique to increase survival chances for severe cases, the outcomes are even less documented. Aim: To prospectively document the clinical outcome of CDH at 1 year including FETO-treated infants in relation to ante- and postnatal variables. Methods: A single-centre prospective clinical follow-up at 1 year of age included a standardised respiratory questionnaire. Results: Thirty-four CDH survivors were included, 10 of which were FETO-treated infants. At 1 year, the median weight z score was -1.50 (interquartile range [IQR]: -2.45 to -0.88) and 10/34 were “failure to thrive” (FTT) cases. Gastro-intestinal (GI) problems at 1 year were mainly related to gastro-oesophageal reflux (16/34) with a high need for tube feeding in the first year (9/34). Tachypnoea was present in 10/29 (34%) and 8/34 (24%) were on chronic inhaled medication. The median total respiratory symptom score was 20 (IQR: 13-32) and correlated with the number of neonatal ventilation days (p = 0.048). Hospital re-admission occurred in 19/34 infants (56%), and was for respiratory problems in almost half of them (8/19). Conclusion: In this CDH cohort, morbidity at 1 year was determined more by GI problems and FTT than respiratory morbidity. The respiratory questionnaire may, however, have underestimated the respiratory morbidity since respondents had a 1-in-4 chance to have persistent tachypnoea and be on chronic inhalation therapy.

Outcome Analysis of Congenital Diaphragmatic Hernia Cohort before and after Implementation of Standardized Protocol in a Tertiary Neonatal Unit.

Despite evolving evidence and increased understanding, there is a strong argument that best outcomes in managing congenital diaphragmatic hernia (CDH) patients are achieved in centers which have a high admission rate of such patients and follow standardized operating protocols of management. Pneumothorax and air leak syndromes are one of the main causes of pre- and postoperative morbidity in these patients and experts believe that delivery room sedation and gentle ventilation strategies can minimize this. We observed a significant drop in incidence of pneumothorax and reduction of mortality following implementation of standardized guidelines at the neonatal unit at Southampton which is a tertiary-level neonatal care in the southern United Kingdom and a regional referral center for CDH patients.

Adult Outcomes After Newborn Respiratory Failure Treated With Extracorporeal Membrane Oxygenation.

To describe the outcome of young adults treated for hypoxemic respiratory failure with extracorporeal membrane oxygenation as neonates. The study was designed as a multisite, cross sectional survey. The survey was completed electronically or on paper by subjects and stored in a secure data base. Subjects were surviving neonatal extracorporeal membrane oxygenation patients from eight institutions who were18 years old or older. None. A questionnaire modified from the 2011 Behavioral Risk Factor Surveillance System and the 2011 National Health Interview Survey with additional unique questions was completed by subjects. Results were compared to age-matched national Behavioral Risk Factor Surveillance System and National Health Interview Survey data. One hundred and forty-six subjects participated (8.9% of eligible candidates). The age at questionnaire submission was 23.7 ± 2.89 years. Subjects differed statistically from national cohorts by being more satisfied with life (93% vs 84.2%); more educated (some college or degree; 80.1% vs 57.7%); more insured for healthcare (89.7% vs 72.3%); less frequent users of healthcare in the last 12 months (47.3% vs 58.2%); more limited because of physical, mental, and developmental problems (19.9% vs 10.9%); and having more medical complications. Furthermore, learning problems occurred in 29.5% of the study cohort. The congenital diaphragmatic hernia group was generally less healthy and less well educated, but equally satisfied with life. Perinatal variables contributed little to outcome prediction. Most young adult survivors in this study cohort treated with extracorporeal membrane oxygenation as neonates are satisfied with their lives, working and/or in college, in good health and having families. These successes are occurring despite obstacles involving health issues such as asthma, attention deficit disorder, learning difficulties, and vision and hearing problems; this is especially evident in the congenital diaphragmatic hernia cohort. Selection bias inherent in such a long-term study may limit generalizability, and it is imperative to note that our sample may not be representative of the whole.

Addressing the causes of late mortality in infants with congenital diaphragmatic hernia

IntroductionDespite improvements of neonatal intensive care, mortality among patients born with congenital diaphragmatic hernia (CDH), remains high, and there is a significant late mortality in this cohort. ObjectiveThe aim of this study was to evaluate the causes of death among 251 consecutive CDH patients treated at our institution during the last 26years period. MethodsRetrospective review of all causes of death between 1990 and 2015 of the CDH cohort prospectively collected in a database. ResultsOf the 251 CDH patients treated in our department since 1990, 49 were not alive by the end of 2015. Thirty-six patients (14%) died before discharge, and 13 (5%) after the first care event. The mean age at death was 262days (±653days, median 34days). Eighty six % (42 cases) of the fatalities occurred during the first year of life, more than half of the patients died before 1month of age and only 13% after the age of 1year (7 patients) (late mortality). The causes of early mortality (before 1year of age) were mainly cardio-respiratory, whereas GI complications occurred in the late mortality group. ConclusionThe most common cause of death among CDH patients is respiratory insufficiency and associated pulmonary hypertension, and most of the fatalities occur before 1year of age. Among older patients, gastrointestinal morbidity as cause of death is highly represented.Level of evidence: II.

Congenital diaphragmatic hernia (CDH) mortality without surgical repair? A plea to clarify surgical ineligibility

PurposeLittle is known about liveborn CDH patients who die without surgery. We audited a national CDH cohort to determine whether these patients were different from patients who received CDH repair. MethodsA national CDH database was analyzed (2005–2009). After excluding infants with severe physiologic instability and genetic/congenital malformations, a potential surgical candidate (PSC) subgroup was identified. PSCs were compared to the operative group (OG) and the operative non-survivor (ONS) subgroup. Standard statistical analyses were performed. ResultsOf 275 liveborns, 35 (13%) died without surgery. The PSC subgroup (n=11) had a median survival of 10days (range: 3–18). Ten of 11 PSC infants were treated in ECMO centers, with 4 receiving ECMO. No differences in BW, GA, and rates of minor malformation were observed between PSC and OG patients. While neonatal illness severity (SNAP-II) predicted overall mortality, SNAP-II scores were similar between PSC and ONS groups (34 vs. 29; p=0.431). Furthermore, greater than 80% of infants with SNAP-II scores between 30 and 39 survived in the OG cohort. ConclusionOur analysis demonstrated that PSCs were similar to infants offered surgery based on illness severity and the presence of congenital malformations. We suggest that criteria for surgical ineligibility be developed to standardize the selection of surgical candidates.

Mouse model reveals the role of SOX7 in the development of congenital diaphragmatic hernia associated with recurrent deletions of 8p23.1

Recurrent microdeletions of 8p23.1 that include GATA4 and SOX7 confer a high risk of both congenital diaphragmatic hernia (CDH) and cardiac defects. Although GATA4-deficient mice have both CDH and cardiac defects, no humans with cardiac defects attributed to GATA4 mutations have been reported to have CDH. We were also unable to identify deleterious GATA4 sequence changes in a CDH cohort. This suggested that haploinsufficiency of another 8p23.1 gene may contribute, along with GATA4, to the development of CDH. To determine if haploinsufficiency of SOX7-another transcription factor encoding gene-contributes to the development of CDH, we generated mice with a deletion of the second exon of Sox7. A portion of these Sox7(Δex2/+) mice developed retrosternal diaphragmatic hernias located in the anterior muscular portion of the diaphragm. Anterior CDH is also seen in Gata4(+/-) mice and has been described in association with 8p23.1 deletions in humans. Immunohistochemistry revealed that SOX7 is expressed in the vascular endothelial cells of the developing diaphragm and may be weakly expressed in some diaphragmatic muscle cells. Sox7(Δex2/Δex2) embryos die prior to diaphragm development with dilated pericardial sacs and failure of yolk sac remodeling suggestive of cardiovascular failure. Similar to our experience screening GATA4, no clearly deleterious SOX7 sequence changes were identified in our CDH cohort. We conclude that haploinsufficiency of Sox7 or Gata4 is sufficient to produce anterior CDH in mice and that haploinsufficiency of SOX7 and GATA4 may each contribute to the development of CDH in individuals with 8p23.1 deletions.

Chylothorax after congenital diaphragmatic hernia repair: a population-based study

PurposeChylothorax is a recognized complication of congenital diaphragmatic hernia (CDH) repair. Our aims were to describe the frequency and outcomes of chylothorax and to seek predictors of chylothorax occurrence within a population-based CDH cohort. MethodsRecords for patients with CDH born between 2006 and 2010 were abstracted from a national database and were compared according to presence/absence of postrepair chylothorax. Univariate, and where appropriate, multivariate analyses were performed for group comparisons and chylothorax outcome prediction. ResultsOf 243 newborns with CDH surviving to repair, 11 (4.5%) developed a chylothorax. All were managed nonoperatively. Factors predictive of chylothorax outcome on multivariate analysis included need for preoperative transfusion (odds ratio, 13.2; 95% confidence interval, 2.1-83.7; P = .006) and preoperative high-frequency oscillatory ventilation (odds ratio, 7.1; 95% confidence interval, 1.6-31.2; P = .01). Preoperative vasopressor use was significant on univariate analysis only. The groups were comparable for survival, length of stay, and duration of ventilation, but chylothorax patients had prolonged total parenteral nutrition (53 vs 21 days, P = .006) and more central line days (46 vs 24 days, P = .03). ConclusionsOur data suggest that severity of preoperative cardiopulmonary derangement and not anatomical or technical factors predicts chylothorax occurrence after CDH repair.

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.