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Objective  The objective of this study was to investigate the prognostic value of a hernia sac in isolated congenital diaphragmatic hernia (CDH) with intrathoracic liver herniation ("liver-up"). Study Design  A retrospective study from the single tertiary center. Isolated "liver-up" CDH neonates referred to our institution between 2000 and 2015 were reviewed for the presence or absence of a hernia sac. Association between the presence of a hernia sac and survival was assessed. Results  Over the study period, there were 29 isolated CDH patients with "liver-up" who were treated, 7 (24%) had a sac, and 22 (76%) did not. Demographics were similar between groups. However, disease acuity, assessed from lower Apgar scores ( p  = 0.044), lower probability of survival ( p  = 0.037), and lower admission oxygenation ( p  = 0.027), was higher in neonates without a sac. Hospital survival was significantly higher for those with sac compared with those without (7/7, 100 vs. 7/22, 32%, p  = 0.002). Conclusion  The presence of a hernia sac may be associated with better survival for isolated "liver-up" CDH. As the presence of sac can be prenatally detected, it may be a useful marker to aid perinatal decision making., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Bochdalek hernia is a type of congenital diaphragmatic hernia that typically presents in childhood, while this diseases is extremely rare in adults., Case Presentation: We review a case of a 63-year-old man with a left-sided Bochdalek hernia who was experiencing occasional pain at the left side of his chest for 8 months. The diagnosis of Bochdalek hernia was made by chest computed tomography. A part of the retroperitoneal adipose tissue was herniated into the left thoracic cavity through the diaphragmatic defect. The hernia was treated via video-assisted thoracoscopic surgery and he made an uneventful recovery., Conclusions: We report a rare case of a left-sided Bochdalek hernia for which our patient was treated successfully via video-assisted thoracoscopic surgery. Even though rare, this disorder should be recognised, examined and treated appropriately to avoid complications.

Background: Morgagni hernia presents a rare type of congenital diaphragmatic hernia (CDH, about 2-5 %) (Herman, J Perinatol 21:343-344, 2001), which is characterized by an anterior mainly right-sided defect of the diaphragm. Infrequently, this is combined with a herniation of the liver into the pericardial cavity (Aké, Prenat Diagn 11:719-724, 1991; Stevens, Pediatr Radiol 26:791-793, 1996). This may cause massive pericardial effusion and subsequently lung hypoplasia (Pober et al., Congenital diaphragmatic hernia overview, University of Washington, Seattle, 2015; Ikeda, J Perinat Med 30:336-340, 2002; Hara, J Obstet Gynaecol Res 33:561-565, 2007). So far only few cases have been reported in fetal life., Case: We report a case of Morgagni hernia with pericardiodiaphragmatic aplasia, complicated by two-compartment effusions (massive pericardial effusion and mild ascites), diagnosed in the second trimester. The case was successfully managed in utero with thoraco-amniotic shunting and late tracheal occlusion, followed by corrective surgery after birth., Discussion: A review of the literature was performed, identifying 13 cases of prenatally diagnosed Morgagni hernia. The diagnosis was established by the sonographic findings of pericardial effusion und intrathoracic herniation of the liver. In only two cases a prenatal intervention was carried out. All neonates were operated postnatally with excellent final outcome.

Background and Objective: Survival for infants with congenital diaphragmatic hernia (CDH) has gradually improved, yet substantial burden of disease remains. Although larger CDH defect sizes increase mortality, the association between defect size and morbidity has not been reported. Our objective was to evaluate the association of defect size with pulmonary, neurologic, and gastrointestinal morbidity at the time of hospital discharge., Methods: An international, prospective cohort study was performed. Patient demographics, intraoperative defect size, and clinical outcomes were reviewed. The primary outcome was morbidity at the time of discharge, which entailed supplemental oxygen requirement, abnormal neurologic clinical and radiographic findings, gastroesophageal reflux, supplemental nutrition, or pulmonary-, neurologic-, or gastrointestinal-related medications., Results: A total of 3665 patients were included in the study cohort. Overall survival was 70.9%, and 84.0% of survivors were discharged from the hospital (16.0% transferred). Median age at discharge was 38 days (interquartile range [IQR] 23-69) and ranged from 22 (IQR 16-32) days for "A" (smallest) defects to 89 (IQR 64-132) days for "D" (largest) defects (P < .001). Of those discharged from the hospital, 1522 (74.2%) had pulmonary (n = 660, 30.2%), neurologic (n = 446, 20.4%), or gastrointestinal (n = 1348, 61.7%) morbidities, and multiple morbidities were diagnosed in 701 (34.7%) patients. On multivariable regression analyses incorporating key patient characteristics, defect size was consistently the greatest predictor of overall morbidity, hospital length of stay, and duration of ventilation., Conclusions: Infants with CDH are commonly discharged with ≥1 major morbidities. The size of the diaphragmatic defect appears to be the most reliable indicator of a patient's hospital course and discharge burden of disease., (Copyright © 2016 by the American Academy of Pediatrics.)

Congenital diaphragmatic hernia (CDH) is one of the most common and lethal congenital anomalies, and significant evidence is available in support of a genetic contribution to its etiology, including single-gene knockout mice associated with diaphragmatic defects, rare monogenetic disorders in humans, familial aggregation, and association of CDH with chromosomal abnormalities. Structural lung defects in the form of lung hypoplasia are almost invariably seen in patients with CDH and frequently in animal models of this condition. Better understanding of the mechanisms of pulmonary defects in CDH has the potential for creating targeted therapies, particularly in postnatal stages, when therapeutics can have maximum clinical impact on the surviving cohorts. Successful treatment of CDH is dependent on the integration of human genomic and genetic data with developmental expression profiling, mouse knockouts, and gene network and pathway modeling, which have generated a large number of candidate genes and pathways for follow-up studies. In particular, defective alveolarization appears to be a common and potentially actionable phenotype in both patients and animal models., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

This Editorial introduces the Lung Ontogeny and Injury Theme Issue, which provides critical insights into lung development, injury, and repair as well as key pulmonary diseases., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background/purpose: This study aims to retrospectively review outcomes, including neurodevelopmental outcomes, of neonatal right sided congenital diaphragmatic hernias (RCDH) compared with left sided congenital diaphragmatic hernias (L-CDH) treated surgically at our institute., Methods: A retrospective review was undertaken of all cases of congenital diaphragmatic hernia (CDH) treated at Princess Margaret Hospital for Children (PMH), Perth, born between 1st January 2002 and 1st August 2012. The outcomes of R-CDH cases were compared with L-CDH cases. We examined duration of ventilatory support, use of patch versus primary closure, the CDH recurrence rates, the number of reoperations and neurodevelopmental follow-up at one year of age., Results: Forty-nine cases of CDH were operated on at PMH during the 10-year period. Of these, ten cases were R-CDH with 39 L-CDH cases. Of 49 cases, 34 were diagnosed antenatally, 5 R-CDH versus 29 L-CDH. Only 8/39 cases of L-CDH required patch repair for larger defects, while 5/10 R-CDH required patch repair. Postoperative mortality was 6/49 (1/10 right sided versus 5/39 left sided). Recurrence was observed in 5/10 R-CDH versus 6/39 L-CDH with p=0.03. Thirty-three of 43 surviving patients received one-year follow-up with Griffiths general quotient (GQ) assessment demonstrating a median score of 98 for L-CDH (IQR 86 to 104.25) and 91 for R-CDH (IQR 76.5 to 93)., Conclusions: R-CDH required patch repair more commonly than L-CDH because of larger defect size or complete agenesis. The rate of recurrent herniation was the only morbidity significantly higher in the R-CDH group. Survivors of R-CDH did not have a significant difference in neurodevelopmental outcome compared to L-CDH cases, with both groups exhibiting normal median GQ scores at one year of age., (Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.)

Owing to recent advances in minimally invasive surgery (MIS), laparoscopic and thoracoscopic surgery have been gradually introduced for use in neonates and infants. This review focuses on two popular MIS procedures for diaphragmatic diseases in neonates and infants: congenital diaphragmatic hernia (CHD) repair and plication for diaphragmatic eventration. While several advantages of MIS are proposed for CDH repair in neonates, there are also some concerns, namely intraoperative hypercapnia and acidosis and a higher recurrence rate than open techniques. Thus, neonates with severe CDH, along with an unstable circulatory and respiratory status, may be unsuitable for MIS repair, and the use of selection criteria is, therefore, important in these patients. It is generally believed that a learning curve is associated with the higher recurrence rate. Contrary to CDH repair, no major disadvantages associated with the use of MIS for diaphragmatic eventration have been reported in the literature, other than technical difficulty. Thus, if technically feasible, all pediatric patients with diaphragmatic eventration requiring surgical treatment are potential candidates for MIS. Due to a shortage of studies on this procedure, the potential advantages of MIS compared to open techniques for diaphragmatic eventration, such as early recovery and more rapid extubation, need to be confirmed by further studies.

Vascular growth is necessary for normal lung development. Although endothelial progenitor cells (EPCs) play an important role in vascularization, little is known about EPC function in congenital diaphragmatic hernia (CDH), a severe neonatal condition that is associated with pulmonary hypoplasia. We hypothesized that the function of endothelial colony-forming cells (ECFCs), a type of EPC, is impaired in CDH. Cord blood (CB) was collected from full-term CDH patients and healthy controls. We assessed CB progenitor cell populations as well as plasma vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1α (SDF1α) levels. CB ECFC clonogenicity; growth kinetics; migration; production of VEGF, SDF1α, and nitric oxide (NO); vasculogenic capacity; and mRNA expression of VEGF-A, fms-related tyrosine kinase 1 (FLT1), kinase insert domain receptor (KDR), nitric oxide synthase (NOS) 1-3, SDF1, and chemokine (C-X-C motif) receptor 4 (CXCR4) were also assessed. Compared with controls, CB ECFCs were decreased in CDH. CDH ECFCs had reduced potential for self-renewal, clonogenicity, proliferation, and migration. Their capacity for NO production was enhanced but their response to VEGF was blunted in CDH ECFCs. In vivo potential for de novo vasculogenesis was reduced in CDH ECFCs. There was no difference in CB plasma VEGF and SDF1α concentrations, VEGF and SDF1α production by ECFCs, and ECFC mRNA expression of VEGF-A, FLT1, KDR, NOS1-3, SDF1, and CXCR4 between CDH and control subjects. In conclusion, CB ECFC function is disrupted in CDH, but these changes may be caused by mechanisms other than alteration of VEGF-NO and SDF1-CXCR4 signaling., (Copyright © 2016 the American Physiological Society.)

Background: We currently do not know how the herbicide nitrofen induces lung hypoplasia and congenital diaphragmatic hernia in rats. Our aim was to compare the differentially expressed transcriptome of nitrofen-induced hypoplastic lungs to control lungs in embryonic day 13 rat embryos before the development of embryonic diaphragmatic defects., Methods: Using next-generation sequencing technology, we identified the expression profile of microRNA (miRNA) and mRNA genes. Once the dataset was validated by both RT-qPCR and digital-PCR, we conducted gene ontology, miRNA target analysis, and orthologous miRNA sequence matching for the deregulated miRNAs in silico., Results: Our study identified 186 known mRNA and 100 miRNAs which were differentially expressed in nitrofen-induced hypoplastic lungs. Sixty-four rat miRNAs homologous to known human miRNAs were identified. A subset of these genes may promote lung hypoplasia in rat and/or human, and we discuss their associations. Potential miRNA pathways relevant to nitrofen-induced lung hypoplasia include PI3K, TGF-β, and cell cycle kinases., Conclusion: Nitrofen-induced hypoplastic lungs have an abnormal transcriptome that may lead to impaired development.

Purpose: Congenital diaphragmatic hernia (CDH) is associated with high postnatal mortality because of pulmonary hypoplasia. The prognostic utility of serial lung-to-head circumference measurements as a marker of lung growth has not been described. Our objective was to examine the relationship between the rate of interval increase of LHR and postnatal survival in left-sided CDH., Methods: We retrospectively reviewed charts of all left-sided CDH patients from January 2004 to July 2014. All ultrasound studies performed at our institution (n=473) were reviewed. Categorical and continuous data were analyzed by chi-square and Mann-Whitney t-test, respectively, and slope analysis was performed by linear regression analysis (p<0.05)., Results: A total of 226 patients were studied, with 154 long-term survivors and 72 non-survivors. Established markers of CDH severity, including intrathoracic liver position and requirement for patch repair, were significantly increased in non-survivors (p<0.0001). The rate of LHR increase as measured by linear regression and slope analysis was significantly increased in long-term survivors (p=0.0175)., Conclusions: Our findings indicate that the interval increase in LHR levels over the course of gestation correlate with survival in left-sided CDH patients. Regular ultrasonographic re-evaluation of LHR throughout gestation following diagnosis of CDH may provide prognostic insight and help guide patient management., (Copyright © 2016. Published by Elsevier Inc.)

Background: With increasing survival of patients with more severe forms of congenital diaphragmatic hernia (CDH) and risk of long-term respiratory morbidity, studies on lung morphology are needed. We used hyperpolarised (3) He MRI and anatomical (1) H MRI in a cohort of young adult CDH patients to image regional lung ventilation and microstructure, focusing on morphological and micro-structural (alveolar) abnormalities., Methods: Nine patients with left-sided CDH, born 1975-1993, were studied. Regional ventilation was imaged with hyperpolarised (3) He MRI, and the (3) He apparent diffusion coefficient (ADC) was computed separately for the ipsilateral and contralateral lungs. (1) H MRI was used to image lung anatomy, total lung volume and motion during free-breathing., Results: (3) He MRI showed ventilation abnormalities in six patients, ranging from a single ipsilateral ventilation defect (3 patients) to multiple ventilation defects in both lungs (one patient treated with extra corporeal membrane oxygenation). In eight patients, (3) He ADC values for the ipsilateral lung were significantly higher than those for the contralateral lung., Conclusions: Functional and micro-structural changes persist into adulthood in most CDH patients. Ipsilateral elevated (3) He ADC values are consistent with enlargement of mean dimensions of the confining lung micro-structure at the alveolar level., (© 2015 Wiley Periodicals, Inc.)

Background: Delayed repair of congenital diaphragmatic hernia (CDH) for days or longer has become standard, allowing improved stabilization for many, but potentially complicating treatment in severely affected infants who require extracorporeal membrane oxygenation (ECMO) and arrive unrepaired. Survival in left liver-up CDH, the most severe anatomic subset, averages 45% in published studies, with deaths often occurring in patients who failed to improve on ECMO and are repaired late, or not at all. Reliable early prediction of ECMO risk in these patients could identify the best candidates for repair before ECMO. We sought to predict ECMO risk in left liver-up CDH, and to further evaluate survival stratified by surgical timing in these patients., Study Design: We reviewed 298 single-center, consecutive CDH patients, focusing on 87 inborn left liver-up patients without associated lethal anomalies. Multivariate analysis using anatomic and physiologic markers of severity was performed to define associations with need for ECMO., Results: Sixty of 87 ECMO-eligible inborn left liver-up CDH patients required ECMO (69%). Of these, 20 of 21 (95%) repaired in the first 60 hours and before ECMO survived; whereas 13 of 20 (65%) who had repair delayed and arrived to ECMO unrepaired survived (p = 0.018). Lung-to-head ratio, Apgar scores, Congenital Diaphragmatic Hernia Study Group-predicted survival, pH, PCO2, and PO2 at 1 hour of life all correlated strongly with risk for ECMO. Accurate multivariate models to predict ECMO (area under the receiver operating characteristic curve [AUC] 0.91 and 0.91) were successfully developed., Conclusions: Early repair of left liver-up CDH before ECMO results in improved survival. Multivariate models can accurately assess risk for ECMO at 1 hour of life, permitting stratification of CDH surgical timing to maximize survival potential while minimizing risk., (Copyright © 2016. Published by Elsevier Inc.)

Fetal lung hypoplasia is associated with a series of congenital anomalies, particularly the congenital diaphragmatic hernia. Evaluation of the severity of the lung hypoplasia is important for parental counseling, assessment of prognosis and planning of postnatal management. Although a large number of studies have been performed to measure fetal lung volumes in order to predict outcome, there are little data on fetuses younger than 24 weeks of gestation, the age when parental counseling is crucial if termination is considered. Few studies have evaluated prognosis of lung hypoplasia in fetuses with congenital chest anomalies other than congenital diaphragmatic hernia. We review the studies on measurements of the fetal lung volumes by MRI.

Congenital diaphragmatic hernia (CDH) is a malformation leading to pulmonary hypoplasia, which can be treated in utero by fetal tracheal occlusion (TO). However, the changes of gene expression induced by TO remain largely unknown but could be used to further improve the clinically used prenatal treatment of this devastating malformation. Therefore, we aimed to investigate the pulmonary transcriptome changes caused by surgical induction of diaphragmatic hernia (DH) and additional TO in the fetal rabbit model. Induction of DH was associated with 378 upregulated genes compared to controls when allowing a false-discovery rate (FDR) of 0.1 and a fold change (FC) of 2. Those genes were again downregulated by consecutive TO. But DH+TO was associated with an upregulation of 157 genes compared to DH and controls. When being compared to control lungs, 106 genes were downregulated in the DH group and were not changed by TO. Therefore, the overall pattern of gene expression in DH+TO is more similar to the control group than to the DH group. In this study, we further provide a database of gene expression changes induced by surgical creation of DH and consecutive TO in the rabbit model. Future treatment strategies could be developed using this dataset. We also discuss the most relevant genes that are involved in CDH., (© 2016. Published by The Company of Biologists Ltd.)

Background: We reported two rare cases of congenital diaphragmatic hernia with abdominal wall closure defect, which were not associated with septum transversum diaphragmatic defects or Fryns syndrome., Case Presentation: Case 1: a Japanese baby boy was delivered at 37 weeks' gestation by urgent cesarean section because of the diagnosis of severe fetal distress. Congenital diaphragmatic hernia with omphalocele was prenatally diagnosed with fetal ultrasound. A ruptured omphalocele was confirmed at delivery. A silo was established on the day of his birth; direct closure of his diaphragmatic defect and abdominal wall closure was performed on the fifth day after his birth. Trisomy 13 was confirmed by genetic examination. His postoperative course was uneventful and he was discharged 5 months postnatally with home oxygen therapy. He was readmitted because of heart failure and died at 6 months. Case 2: a Japanese baby boy, who was prenatally diagnosed with gastroschisis, was delivered at 35 weeks' gestation by urgent cesarean section because of the diagnosis of fetal distress. Silo construction using a wound retractor was performed on the day of his birth and direct abdominal closure was performed on the tenth day after his birth. Trisomy 21 was confirmed by genetic examination. Treatment for his respiratory distress was continued after surgery. A retrosternal hernia was revealed at 6 months and direct closure of retrosternal diaphragm with the resection of hernia sac was performed. His postoperative course was uneventful and he was discharged with home oxygen therapy., Conclusions: Attention should be paid to chromosomal abnormality in cases in which the coexistence of congenital diaphragmatic hernia and abdominal wall closure defect are observed.

Congenital diaphragmatic hernia (CDH) and congenital pulmonary airway malformation (CPAM) are diseases in which chest-occupying lesions can result in severe pulmonary hypoplasia. However, significant postnatal mortality due to pulmonary hypertension (PH) is more often seen in patients with CDH. We analyzed prenatal echocardiographic parameters of pulmonary vascular pathology in these groups to understand whether PH in patients with CDH is secondary to a mass effect or to underlying disease. We analyzed pre- and postnatal characteristics of 26 patients with severe CDH and 23 patients with severe CPAM from 2009 to 2012. Severe mediastinal compression, indicated by a low cardiothoracic ratio, was evident in both groups. However, fetuses with severe CDH had smaller pulmonary arteries bilaterally and higher pulsatility indices in the ipsilateral lung than those with severe CPAM. Prenatal modified McGoon indices were significantly lower in patients with CDH versus CPAM. Consistent with these prenatal measurements, postnatal PH was seen more frequently in patients with CDH compared to CPAM. Patients with severe CDH have prenatal evidence of pulmonary vascular remodeling compared to patients with severe CPAM. These results suggest a multifactorial origin for PH in CDH and support the idea of using prenatal medical therapies to promote vascular remodeling in these patients., (© 2015 S. Karger AG, Basel.)

Fryns syndrome is a multiple congenital anomaly syndrome with an autosomal recessive inheritance. Here we describe the autopsy case findings of a 19-week male fetus, born out of a consanguineous marriage. The dissection revealed left-sided diaphragmatic hernia, resulting in pulmonary hypoplasia and shift of heart to the right side. In addition, anencephaly and spina bifida throughout the vertebral column were observed. All six criteria for Fryns syndrome were met. Such a presentation of Fryns syndrome associated with Craniorachischisis Totalis has not been reported so far. We have also tabulated the overlapping features of some multiple congenital anomaly syndromes that need to be distinguished at autopsy for an accurate diagnosis.

In congenital diaphragmatic hernia (CDH), lung hypoplasia and secondary pulmonary hypertension are the major causes of death and severe disability. Based on new therapeutic strategies survival rates could be improved to up to 80%. However, after surgical repair of CDH, long-term follow-up of these pediatric patients is necessary. In this, dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) provides insights into the pulmonary microcirculation and might become a tool within the routine follow-up program of CDH patients. However, whole lung segmentation from DCE-MRI scans is tedious and automated procedures are warranted. Therefore, in this study, an approach to semi-automated lung segmentation is presented. Segmentation of the lung is obtained by calculating the cross correlation and the area under curve between all voxels in the data set and a reference region-of-interest (ROI), here the arterial input function (AIF). By applying an upper and lower threshold to the obtained maps and intersecting these, a final segmentation is reached. This approach was tested on twelve DCE-MRI data sets of 2-year old children after CDH repair. Segmentation accuracy was evaluated by comparing obtained automatic segmentations to manual delineations using the Dice overlap measure. Optimal thresholds for the cross correlation were 0.5/0.95 and 0.1/0.5 for the area under curve, respectively. The ipsilateral (left) lung showed reduced segmentation accuracy compared to the contralateral (right) lung. Average processing time was about 1.4s per data set. Average Dice score was 0.7±0.1 for the whole lung. In conclusion, initial results are promising. By our approach, whole lung segmentation is possible and a rapid evaluation of whole lung perfusion becomes possible. This might allow for a more detailed analysis of lung hypoplasia of children after CDH., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Lung hypoplasia in congenital diaphragmatic hernia (CDH) is a life-threatening birth defect. Severe cases can be offered tracheal occlusion to boost prenatal lung development, although defining those to benefit remains challenging. Metabonomics of (1)H NMR spectra collected from amniotic fluid (AF) can identify general changes in diseased versus healthy fetuses. AF embodies lung secretions and hence might contain pulmonary next to general markers of disease in CDH fetuses. AF from 81 healthy and 22 CDH fetuses was collected. NMR spectroscopy was performed at 400 MHz to compare AF from fetuses with CDH against controls. Several advanced feature extraction methods based on statistical tests that explore spectral variability, similarity, and dissimilarity were applied and compared. This resulted in the identification of 30 spectral regions, which accounted for 80% variability between CDH and controls. Combination with automated classification discriminates AF from CDH versus healthy fetuses with up to 92% accuracy. Within the identified spectral regions, isoleucine, leucine, valine, pyruvate, GABA, glutamate, glutamine, citrate, creatine, creatinine, taurine, and glucose were the most concentrated metabolites. As the metabolite pattern of AF changes with fetal development, we have excluded metabolites with a high age-related variability and repeated the analysis with 12 spectral regions, which has resulted in similar classification accuracy. From this analysis, it was possible to distinguish between AF from CDH fetuses versus healthy controls independent of gestational age.

Objective: to study changes in the expression of growth factors in the lungs from fetuses and newborn infants at 20-40 weeks' gestation with false left-sided congenital diaphragmatic hernia (CDH)., Material and Methods: Lung fragments obtained at autopsies were examined using immunohistochemically stained paraffin sections. The expression indices of insulin-like growth factor-1 (IGF-1), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and transforming grow factor-β (TGF-β) in the fetal lung sections were compared with the results of survey and elective staining techniques, the morphometric data of digitized lung sections, and the indicators obtained in the comparison group., Results: Morphofunctional changes in the connective tissue, pulmonary vessels, and bronchial and alveolar epithelium at 20-24, 25-27, and 28-40 weeks' gestation were characterized, partly explaining the development of bilateral pulmonary hypoplasia in CDH. There was evidence for the involvement of PDGF, IGF-1, and EGF in primary pulmonary hypoplasia. PDGF deficiency plays a certain role in secondary pulmonary hypoplasia., Conclusion: The findings can be used in researches and in the practical work of pathologists and forensic medical experts.

We present a fatal case of a gastrothorax due to an acute gastric volvulus resulting from a Bochdalek hernia. A 5-year-old boy without previous medical history was brought to our institution in a state of cardiopulmonary arrest and was subsequently pronounced dead. Postmortem computed tomography (PMCT) of the torso showed abdominal organs involving the lower section of the esophagus up to the entire stomach, the left side of the transverse colon, the entire spleen, and the tail of the pancreas herniated into the left thoracic cavity. The stomach was markedly expanded and a mesentero-axial (rotation along the short axis) volvulus was observed, displacing mediastinal structures to the right side and depressing the diaphragmatic contour. A PMCT of the thorax at the lung window setting revealed displacement of bilateral lungs. The bilateral lungs were severely atelectatic and congested. The PMCT findings mentioned above were consistent with the autopsy findings. PMCT can provide useful information for the diagnosis in cases we initially cannot predict any significant changes, for example, organ displacement., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Chromosomal abnormalities are an important factor in the pathogenesis of congenital diaphragmatic hernia (CDH), a relatively common congenital defect associated with high morbidity and mortality. The adoption of array-based platforms for chromosome analysis has resulted in the identification of numerous copy number variants (CNVs) in infants with CDH, highlighting the potential pathogenic role of many novel genes. We identified a retrospective cohort of 28 infants treated for CDH at a single institution who had microarray testing to determine the proportion of microarray abnormalities and whether these were contributory to CDH pathogenesis. Eight patients (29%) had microarray abnormality. Seven (25%) were considered likely contributory to CDH pathogenesis, including two mosaic trisomy 9s, a 9q22.31q22.32 microduplication, two atypical 22q11.21 microdeletions, a 2q35q36.1 microdeletion, and a 15q11.2 microdeletion, offering insights into the genetic mechanisms underlying CDH development., (© 2015 Wiley Periodicals, Inc.)

Background: Studies comparing outcomes of right- and left-sided congenital diaphragmatic hernia (R-CDH and L-CDH) have yielded conflicting results. We hypothesized that R-CDH is associated with higher short-term pulmonary morbidity than L-CDH., Methods: We reviewed all CDH patients at a tertiary children's hospital over 10 y. In prenatally diagnosed CDH, the observed-to-expected total fetal lung volume and percentage liver herniation (%LH) were calculated using fetal magnetic resonance imaging-based measurements. Outcomes were compared in patients with isolated CDH. Patients were subsequently matched by %LH to compare outcomes., Results: Of 189 CDH patients, 37 (20.1 %) were R-CDH and 147 (79.9%) were L-CDH. Those with R-CDH were prenatally diagnosed at a significantly lower rate (40.5% versus 73.5%; P < 0.001) and later gestational age (26.5 ± 7.7 versus 22.6 ± 5.65 wk; P = 0.062). There was no difference in observed-to-expected total fetal lung volume between those with R-CDH and L-CDH (30.2 ± 11.1% versus 33.1 ± 14.2%; P = 0.471). Fetuses with R-CDH had a higher %LH than those with L-CDH (37.5 ± 14.1% versus 18.6 ± 12.2%; P < 0.001). Patients with isolated R-CDH had a higher need for extracorporeal membrane oxygenation than L-CDH (48% versus 27%; P = 0.055). There was no difference in duration of tracheal intubation, hospital stay, need for supplemental oxygen at 30-d of life or 6-mo mortality between groups. There was no difference in mortality and pulmonary morbidity when patients were matched by %LH., Conclusions: Compared to those with L-CDH, fetuses with R-CDH are less likely to be diagnosed prenatally and have a higher need for extracorporeal membrane oxygenation. The sidedness of the hernia defect was not associated with differences in short-term pulmonary morbidity in this large, contemporary single-institution experience of neonates with CDH., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: To describe a method of quantifying the amount of liver herniation in fetuses with isolated congenital diaphragmatic hernia (CDH) using two-dimensional ultrasonography and to correlate this finding with neonatal outcome., Methods: Ultrasound images obtained from 77 consecutive fetuses that presented with isolated CDH between January 2004 and July 2012 were reviewed. Liver herniation and thoracic area were measured in a cross-sectional plane of the fetal chest at the level of the four-chamber view of the heart (the same section as is used to measure the lung area-to-head circumference ratio) and the ultrasound-derived liver-to-thoracic area ratio (US-LiTR) was calculated by dividing the liver herniation area by the thoracic area. Receiver-operating characteristics (ROC) curve analysis was used to evaluate the performance of US-LiTR in predicting neonatal outcome (survival to 6 months after delivery and need for extracorporeal membrane oxygenation (ECMO)). In addition, the US-LiTR was compared with the magnetic resonance imaging (MRI)-derived volume ratio (MRI-LiTR) and percentage of liver herniation (MRI-%LH)., Results: The overall neonatal mortality in the 77 cases with isolated CDH was 20.8% (16/77). ECMO was needed in 35.5% (27/76) of the newborns, with a survival rate of 52%. The US-LiTR was associated statistically with mortality (P < 0.01) and with the need for ECMO (P < 0.01). Good correlations were observed between US-LiTR and MRI-LiTR (r = 0.87; P < 0.001) and between US-LiTR and MRI-%LH (r = 0.90; P < 0.001). Based on ROC curve analysis, all three parameters had similar accuracy in predicting mortality (US-LiTR: area under the ROC curve (AUC), 0.78 (95% CI, 0.65-0.92), P < 0.01; MRI-LiTR: AUC, 0.77 (95% CI, 0.63-0.90), P < 0.01; MRI-%LH: AUC, 0.79 (95% CI, 0.65-0.92), P < 0.01, respectively) as well as the need for ECMO (US-LiTR: AUC, 0.72 (95% CI, 0.60-0.84), P < 0.01; MRI-LiTR: AUC, 0.73 (95% CI, 0.60-0.88), P < 0.01; MRI-%LH: AUC, 0.77 (95% CI, 0.64-0.89), P < 0.01, respectively)., Conclusions: Two-dimensional ultrasound measurement of the amount of liver herniation in fetuses with isolated CDH is feasible and demonstrates a predictive accuracy for neonatal outcome similar to that of MRI., (Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.)

Objectives: To assess using fetal magnetic resonance imaging (MRI) the relationship between the position of the stomach as well as the volume of herniation of organs into the thorax, and the observed-to-expected total fetal lung volume (o/e-TFLV), as a measure of pulmonary hypoplasia, in fetuses with isolated left-sided congenital diaphragmatic hernia (LCDH)., Methods: This was a single-center retrospective study using archived MR images from fetuses > 20 weeks' gestation evaluated for isolated LCDH over an 11-year period between July 2002 and September 2013. We retrieved data on the gestational age at MRI, o/e-TFLV and liver position. Images were also reviewed by a single operator to determine retrospectively the position of the stomach as well as the proportion of the total thorax volume occupied by the herniated fetal liver, stomach and other viscera. Following confirmation of reproducibility, we assessed the correlation of intrathoracic organ volumes and stomach position with o/e-TFLV., Results: The study included 205 fetuses which underwent a total of 259 MR examinations. The reproducibility of organ volume measurements was excellent (intraclass correlation coefficient range, 0.928-0.997). The average time spent to obtain intrathoracic organ volumes ranged from 2.28 to 5.13 min. Of all herniated organ-to-thoracic volume ratios, the liver-to-thoracic volume ratio had the strongest correlation with o/e-TFLV (ρ = -0.429, P<0.0001). Stomach volume did not correlate, although, when categorized by the position and extent of stomach herniation, there was an inverse relationship to o/e-TFLV. No intrathoracic organ-to-thoracic volume ratio was related to gestational age., Conclusions: We observed in fetuses with isolated LCDH an inverse relationship between lung volume and the amount of liver herniated as well as the position of the stomach in the chest., (Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.)

Developmental mechanisms leading to lung hypoplasia in congenital diaphragmatic hernia (CDH) remain poorly defined. Pulmonary innervation is defective in the human disease and in the rodent models of CDH. We hypothesize that defective parasympathetic innervation may contribute to airway branching abnormalities and, therefore, lung hypoplasia, during lung development in CDH. The murine nitrofen model of CDH was utilized to study the effect of the cholinergic agonist carbachol on embryonic day 11.5 (E11.5) lung explant cultures. Airway branching and contractions were quantified. In a subset of experiments, verapamil was added to inhibit airway contractions. Sox9 immunostaining and 5-bromo-2-deoxyuridine incorporation were used to identify and quantify the number and proliferation of distal airway epithelial progenitor cells. Intra-amniotic injections were used to determine the in vivo effect of carbachol. Airway branching and airway contractions were significantly decreased in nitrofen-treated lungs compared with controls. Carbachol resulted in increased airway contractions and branching in nitrofen-treated lungs. Nitrofen-treated lungs exhibited an increased number of proliferating Sox9-positive distal epithelial progenitor cells, which were decreased and normalized by treatment with carbachol. Verapamil inhibited the carbachol-induced airway contractions in nitrofen-treated lungs but had no effect on the carbachol-induced increase in airway branching, suggesting a direct carbachol effect independent of airway contractions. In vivo treatment of nitrofen-treated embryos via amniotic injection of carbachol at E10.5 resulted in modest increases in lung size and branching at E17.5. These results suggest that defective parasympathetic innervation may contribute to airway branching abnormalities in CDH., (Copyright © 2015 the American Physiological Society.)

The association of 46,XY disorder of sex development (DSD) with congenital diaphragmatic hernia (CDH) is rare, but has been previously described with and without other congenital anomalies. Literature review identified five cases of 46,XY DSD associated with CDH and other congenital anomalies. These five cases share characteristics including CDH, 46,XY karyotype with external female appearing or ambiguous genitalia, cardiac anomalies, and decreased life span. The present case had novel features including truncus arteriosus, bifid thymus, gut malrotation, and limb anomalies consisting of rhizomelia and adactyly. With this case report, we present a review of the literature of cases of 46,XY DSD and CDH in association with multiple congenital abnormalities. This case may represent a unique syndrome of 46,XY DSD and diaphragmatic hernia or a more severe presentation of a syndrome represented in the previously reported cases., (© 2015 Wiley Periodicals, Inc.)

Objective: To evaluate lung growth in healthy fetuses and those with congenital diaphragmatic hernia (CDH) using two-dimensional (2D) ultrasound., Methods: Fetal right lung measurements obtained by 2D ultrasound between 19 and 37 weeks' gestation were evaluated longitudinally in 66 healthy fetuses and 52 fetuses with isolated left-sided CDH. Right lung areas were determined by the 'tracing' and 'longest-diameters' methods and, subsequently, lung area-to-head circumference ratios (LHRs) were calculated. Functions fitted to these size parameters with respect to gestational age were evaluated for three sets of group-wise comparisons: (1) healthy vs CDH fetuses; (2) different degrees of severity of CDH; and (3) CDH fetuses that survived vs those that died by 6 months postpartum., Results: There was a significantly slower increase in right lung areas and LHRs with advancing gestational age in CDH fetuses than in healthy individuals (P < 0.05). Compared to those with milder forms of CDH, lung areas and LHRs of fetuses with more severe forms displayed a smaller increase (P < 0.05) and LHRs of fetuses with severe CDH did not increase during pregnancy (P > 0.05). Individuals who died postpartum did not show any increase in LHR (P > 0.05) throughout gestation., Conclusions: The right lung area and LHR, calculated using either the longest-diameters or tracing method, display reduced growth rates during gestation in cases of isolated left-sided CDH as compared with healthy fetuses. The growth curve characteristics of fetal lung areas and LHRs may be useful for predicting neonatal mortality., (Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.)

The diaphragm is an essential mammalian skeletal muscle, and defects in diaphragm development are the cause of congenital diaphragmatic hernias (CDHs), a common and often lethal birth defect. The diaphragm is derived from multiple embryonic sources, but how these give rise to the diaphragm is unknown, and, despite the identification of many CDH-associated genes, the etiology of CDH is incompletely understood. Using mouse genetics, we show that the pleuroperitoneal folds (PPFs), which are transient embryonic structures, are the source of the diaphragm's muscle connective tissue and regulate muscle development, and we show that the striking migration of PPF cells controls diaphragm morphogenesis. Furthermore, Gata4 mosaic mutations in PPF-derived muscle connective tissue fibroblasts result in the development of localized amuscular regions that are biomechanically weaker and more compliant, leading to CDH. Thus, the PPFs and muscle connective tissue are critical for diaphragm development, and mutations in PPF-derived fibroblasts are a source of CDH.

Objective: To evaluate the role of prenatal prognostic markers obtained routinely by ultrasound examination and magnetic resonance imaging (MRI) in the prediction of development of postnatal pulmonary arterial hypertension (PAH) in isolated congenital diaphragmatic hernia (CDH)., Methods: One hundred and ten cases of isolated CDH were referred to our fetal medicine unit between January 2004 and April 2013. Mortality and morbidity rates were reviewed for those presenting with postnatal PAH. The following prenatal markers were evaluated as potential predictive factors of PAH: liver position, side of the CDH defect, lung area to head circumference ratio (LHR) and observed/expected LHR (o/e-LHR), which were measured by ultrasound, and observed/expected total fetal lung volume (o/e-TFLV), which was measured by MRI. Univariable logistic regression was used to assess associations., Results: PAH was significantly associated with perinatal mortality and morbidity (P < 0.001). The occurrence of PAH decreased significantly with an increasing LHR, o/e-LHR and o/e-TFLV and was significantly increased for cases with an intrathoracic liver, but not for those with right-sided defects. Univariable regression revealed that o/e-TFLV (odds ratio (OR), 0.9 (95% CI, 0.86-0.95); P < 0.05 for percentage unit change in o/e), LHR (OR, 0.19 (95% CI, 0.09-0.40); P < 0.05 for unit change), o/e-LHR (OR, 0.95 (95% CI, 0.93-0.98); P < 0.05 for percentage unit change in o/e) and liver position (OR, 2.82 (95% CI, 1.13-7.00); P < 0.05 for intrathoracic liver) were significant predictors of subsequent PAH. No differences were found after adjusting for gestational age at delivery. The areas under the receiver-operating characteristics curve were 0.80 and 0.75 for o/e-TFLV and o/e-LHR, respectively., Conclusion: In cases of CDH, PAH is associated with high rates of mortality and morbidity. Routinely obtained prenatal markers, usually used for the assessment of pulmonary hypoplasia, are also relevant for the postnatal prediction of PAH., (Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.)

Background: Pulmonary hypertension (PH) secondary to vascular remodeling contributes to poor outcomes in congenital diaphragmatic hernia (CDH), however mechanisms responsible are unknown. We hypothesized that pulmonary artery endothelial cell (PAEC) dysfunction contributes to smooth muscle cell (SMC) hyperplasia in experimental CDH., Methods: PAEC and SMC were isolated from fetal sheep with experimental CDH and controls. SMC growth was assessed alone and with SOD plus catalase and during coculture with control or CDH PAEC with and without ET-1 siRNA transfection. ET-1 protein was measured in PAEC and SMC lysates and supernatant. ROS production was measured in normal and CDH PAECs with and without ET-1 siRNA. PAEC growth and tube formation were measured with SOD plus catalase., Results: CDH SMC growth was decreased and increased with coculture with CDH PAEC more than control PAEC. Treatment of CDH PAEC with SOD plus catalase or ET-1 siRNA prevented the increase in SMC growth seen with coculture. ET-1 protein was increased in CDH PAEC and SMC. ROS production was increased in CDH PAEC and decreased with ET-1 SiRNA. SOD plus catalase restored CDH PAEC growth and tube formation., Conclusion: PAEC dysfunction in experimental CDH increases SMC proliferation via ET-1 induced ROS production by PAEC.

Zinc finger protein, FOG2 family member 2 (ZFPM2) (previously named FOG2) gene defects result in the highly morbid congenital diaphragmatic hernia (CDH) in humans and animal models. In a cohort of 275 CDH patient exomes, we estimated the prevalence of damaging ZFPM2 mutations to be almost 5%. Genetic analysis of a multigenerational family identified a heritable intragenic ZFPM2 deletion with an estimated penetrance of 37.5%, which has important implications for genetic counseling. Similarly, a low penetrance ZFPM2 frameshift mutation was observed in a second multiplex family. Isolated CDH was the predominant phenotype observed in our ZFPM2 mutation patients. Findings from the patients described herein indicate that ZFPM2 point mutations or deletions are a recurring cause of CDH., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Congenital diaphragmatic hernia is a congenital malformation of the diaphragm, resulting in the herniation of the abdominal organs into the thoracic cavity. The most common types of congenital diaphragmatic hernia are Bochdalek hernia (postero-lateral hernia), Morgagni hernia (anterior defect), and diaphragm eventration (abnormal displacement of part or all of an otherwise intact diaphragm into the chest cavity). Congenital diaphragmatic hernia is a life-threatening pathology in infants, and a major cause of death due to pulmonary hypoplasia and pulmonary hypertension. We present a fatal case of congenital diaphragmatic hernia in a newborn. At the autopsy, a central defect of the diaphragm was found, 8 × 5 cm in size, that led to a herniation of the small intestine, the right lobe of the liver, and the right adrenal gland into the thorax. An esophageal atresia was associated with the congenital diaphragmatic hernia. The lungs showed severe hypoplasia and atelectasia. Physicians should pay attention to a prenatal diagnosis of congenital diaphragmatic hernia in order to prevent newborn fatalities., (© The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

This study aimed to demonstrate that congenital diaphragmatic hernia (CDH) results in vascular abnormalities that are directly associated with the severity of pulmonary hypoplasia and hypertension. These events increase right ventricle (RV) afterload and may adversely affect disease management and patient survival. Our objective was to investigate cardiac function, specifically right ventricular changes, immediately after birth and relate them to myocardial histological findings in a CDH model. Pregnant New Zealand rabbits underwent the surgical procedure at 25 days of gestation (n=14). CDH was created in one fetus per horn (n=16), and the other fetuses were used as controls (n=20). At term (30 days), fetuses were removed, immediately dried and weighed before undergoing four-parameter echocardiography. The lungs and the heart were removed, weighed, and histologically analyzed. CDH animals had smaller total lung weight (P<0.005), left lung weight (P<0.005), and lung-to-body ratio (P<0.005). Echocardiography revealed a smaller left-to-right ventricle ratio (LV/RV, P<0.005) and larger diastolic right ventricle size (DRVS, P<0.007). Histologic analysis revealed a larger number of myocytes undergoing mitotic division (186 vs 132, P<0.05) in CDH hearts. Immediate RV dilation of CDH hearts is related to myocyte mitosis increase. This information may aid the design of future strategies to address pulmonary hypertension in CDH.

Objective: The aim of this study was to determine whether fetal lung volume and visceral herniation are associated with changes in intrathoracic space in congenital diaphragmatic hernia(CDH)., Methods: We retrospectively examined the relationship between magnetic resonance imaging-derived measurements of intrathoracic space [predicted lung volume (PLV)] and residual lung volume or visceral herniation among isolated left-sided CDH fetuses., Results: Data from fetal magnetic resonance imaging studies of 60 isolated left-sided CDH cases were analyzed. The median PLV of the CDH fetuses was found to be much greater than the expected total lung volume (eTLV) of a normal fetus at the same gestational age. Surprisingly, liver herniation and observed TLV(oTLV) were positively correlated with the PLV. Although the PPLV was consistently less than the o/eTLV, both indices were greater in survivors than in non-survivors, whereas no significant difference was seen in the PLV/eTLV ratio in regard to survivorship., Conclusion: The intrathoracic domain available for lungs and viscera is expanded in CDH fetuses and positively affected by the lung volume and the presence of liver herniation, leading to the difference in the PPLV and o/eTLV. Future study of intrathoracic space as it relates to the growth of the lung and herniated viscera is needed to better characterize the relationship between these parameters., (© 2014 John Wiley & Sons, Ltd.)

Congenital diaphragmatic hernia (CDH) is a common life-threatening congenital anomaly resulting in high rates of perinatal death and neonatal respiratory distress. Some of the nonisolated forms are related to single-gene mutations or genomic rearrangements, but the genetics of the isolated forms (60% of cases) still remains a challenging issue. Retinoid signaling (RA) is critical for both diaphragm and lung development, and it has been hypothesized that subtle disruptions of this pathway could contribute to isolated CDH etiology. Here we used time series of normal and CDH lungs in humans, in nitrofen-exposed rats, and in surgically induced hernia in rabbits to perform a systematic transcriptional analysis of the RA pathway key components. The results point to CRPBP2, CY26B1, and ALDH1A2 as deregulated RA signaling genes in human CDH. Furthermore, the expression profile comparisons suggest that ALDH1A2 overexpression is not a primary event, but rather a consequence of the CDH-induced lung injury. Taken together, these data show that RA signaling disruption is part of CDH pathogenesis, and also that dysregulation of this pathway should be considered organ specifically.

Objective: To describe a new grading method for stomach position (SP) in fetuses with left-sided congenital diaphragmatic hernia (L-CDH) using ultrasound and to correlate SP to liver position and to liver-to-thoracic cavity volume ratio (LiTR) using magnetic resonance imaging., Methods: SP were graded at the level of the 4-chamber view as following: grade 1-to-4 for stomach not visualised, visualised anteriorly at the apex of the heart, stomach showing abdominal structures anteriorly and stomach with its larger part posterior to the level of the atrial-ventricular heart valves, respectively. The LiTR was calculated and correlated to SP using the Mann-Whitney U test., Results: Seventy-four fetuses were included. Median LiTR for grade 1 SP was 0% and was not different from median LiTR for grade 2 SP (0%, p=NS). Median LiTR for grade 3 SP was 14.9% and was significantly higher than for grade 2 SP (p<0.001). Similarly, median LiTR for grade 4 SP was 20.7% and was significantly higher than for grade 3 SP (p<0.05). When SP was grade 1 or 2, liver was intra-abdominal in 21 (84%) out of 25 fetuses while it was always intrathoracic for SP 3 or 4., Conclusion: In L-CDH, SP as described represents a simple indirect measurement of intrathoracic position and quantification of liver.

The sterno-costal hernia of Morgagni is a congenital vice in which is represented unfinished fusion of the transverse septum and the muscular diaphragmal wall. The malrotation syndrome is an embryonic vice as well, with various degree of incomplete and even reverse rotation of the gut, because of disturbed or unfinished development of the midgut. The described case presents a 37 years old female without anamnesis of any previous complains, who was pointed to the clinic after a X-ray photograph because of breathless and asteno-adynamic syndrome. After a precise CT investigation performance was found the presence of the above described anomalities, as well as ectopy of the right kidney and the right liver part. An operative treatment was performed with correction of the hernia and the bowel malrotation. The patient was followed up to the 12th month post-operatively. After a review of the literature in the discussion we inspect the diagnostics and the definition of the right surgical tactics and operative approach in this case with combined malformative pathology.

We present a case of severe isolated congenital diaphragmatic hernia (CDH) diagnosed at 19 weeks of gestation and treated at 28 weeks with Fetal Endoscopic Tracheal Occlusion (FETO). The CDH was left-sided with part of the liver in the thorax and lung area to head circumference ratio (LHR) of 0.9. The FETO was successfully performed under spinal anesthesia. The pregnancy is progressing uneventfully and ultrasound examination 10 days after the FETO demonstrated an increased LHR to 1.1. Treatment with FETO for severe CDH has been performed for the first time in Bulgaria and this procedure addressed several questions for optimal management by an experienced interdisciplinary team.

Over the past 20 years, prenatal detection of congenital diaphragmatic hernia (CDH) has improved worldwide, reaching up to 60% in Europe. Pulmonary hypoplasia and persistent pulmonary hypertension are the two main determinants of neonatal mortality and morbidity, so new tools have been focused on their evaluation. Fetal surgery for severe cases requires proper evaluation of the prognosis of fetuses with CDH. Observed-to-expected lung-to-head ratio, liver position, and total lung volume measured by magnetic resonance are the prognostic factors most often used, and have been shown to correlate not only with neonatal mortality but also with morbidity. In daily practice, pulmonary hypertension by itself, although most often associated with lung hypoplasia, is more difficult to predict., (Copyright © 2014. Published by Elsevier Ltd.)

There is a paucity of level 1 and level 2 evidence for best practice in surgical management of CDH. Antenatal imaging and prognostication is developing. Observed to expected lung-to-head ratio on ultrasound allows better predictive value over simple lung-to-head ratio. Based on 2 randomised studies, the verdict is still out in terms the best group and indication for antenatal intervention and their outcome. Tracheal occlusion is best suited for prospective randomised studies of benefit and outcome. Only one pilot randomised controlled study of thoracoscopic repair exists, suggesting increased acidosis; blood gases and CO2 levels should be closely monitored. Only poorly controlled retrospective studies suggest higher recurrence rates. Randomised studies on the outcome of thoracoscopic repair are needed. Careful selection, anaesthetic vigilance, monitoring and follow-up of these cases are required. There is no evidence to suggest the best patch material to decrease recurrences. Evidence suggests no benefit from routine fundoplication based on the one randomised study. Multi-disciplinary follow-up is required. This can be visits to different specialities, but may be best served by a multi-disciplinary one-stop clinic., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A co-existing right congenital diaphragmatic hernia and omphalocele is rare. We present images of a fetus diagnosed with this rare combination of anomalies. Early neonatal death occurred immediately after full-term birth due to severe respiratory insufficiency. In this case, disturbance of chest wall development due to the omphalocele rather than the diaphragmatic hernia was considered as the main cause of lung hypoplasia. Our experience suggests that caution should be exercised for severe respiratory insufficiency in a neonate with an omphalocele and diaphragmatic hernia, even in the absence of an intra-thoracic liver, one of the indicators of poor outcome for congenital diaphragmatic hernia., (© 2014 Japanese Teratology Society.)

In man, mutations of the megalin-encoding gene causes the rare Donnai-Barrow/Facio-Oculo-Acoustico-Renal Syndrome, which is partially characterized by high-grade myopia. Previous studies of renal megalin function have established that megalin is crucial for conservation of renal filtered nutrients including vitamin A; however, the role of megalin in ocular physiology and development is presently unknown. Therefore, we investigate ocular megalin expression and the ocular phenotype of megalin-deficient mice. Topographical and subcellular localization of megalin as well as the ocular phenotype of megalin-deficient mice were examined with immunological techniques using light, confocal and electron microscopy. We identified megalin in the retinal pigment epithelium (RPE) and non-pigmented ciliary body epithelium (NPCBE) in normal mouse eyes. Immunocytochemical investigations furthermore showed that megalin localizes to vesicular structures in the RPE and NPCBE cells. Histological investigations of ocular mouse tissue also identified a severe myopia phenotype as well as enlarged RPE melanosomes and abnormal ciliary body development in the megalin-deficient mice. In conclusion, the complex ocular phenotype observed in the megalin-deficient mice suggests that megalin-mediated developmental abnormalities may contribute to the high myopia phenotype observed in the Donnai-Barrow Syndrome patients and, thus, that megalin harbors important roles in ocular development and physiology. Finally, our data show that megalin-deficient mice may provide a valuable model for future studies of megalin in ocular physiology and pathology.

Two siblings, from a consanguineous Iraqi family, were investigated to identify the underlying genetic cause of their high myopia, esotropia, vitreous changes and cataract. Subsequent investigation identified low molecular weight proteinuria as part of their syndrome. Exome sequencing of one of the probands revealed a new non-synonymous variant in the LRP2 gene. Sanger sequencing confirmed the mutation and segregation in the family. No mutation was identified in COL9A1/2, COL11A1/2, or COL2A1 genes. The variant (c.11483A>G; p.Asp3828Gly) is predicted to be damaging and is conserved among vertebrate species. Mutations in LRP2 have been shown to cause the Donnai-Barrow syndrome (DBS) or facio-oculo-acoustico-renal (FOAR) syndrome, a syndrome associated with facial dysmorphism, ocular anomalies, sensorineural hearing loss, low molecular weight proteinuria, and diaphragmatic hernia and absent corpus callosum, although there is variability in the expression of some features. This family shows a milder phenotype with a predominant eye phenotype similar to the Stickler syndrome and only a few features of the DBS, including microglobulinuria. The presence of microglobulinuria was only detected after molecular results were known. In conclusion, with the identification of a new mutation in LRP2 associated with a predominant eye phenotype similar to the Stickler syndrome, we have broadened the phenotypic spectrum of LRP2 mutations., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)