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1.  Congenital Diaphragmatic Hernia 
Congenital Diaphragmatic Hernia (CDH) is defined by the presence of an orifice in the diaphragm, more often left and posterolateral that permits the herniation of abdominal contents into the thorax. The lungs are hypoplastic and have abnormal vessels that cause respiratory insufficiency and persistent pulmonary hypertension with high mortality. About one third of cases have cardiovascular malformations and lesser proportions have skeletal, neural, genitourinary, gastrointestinal or other defects. CDH can be a component of Pallister-Killian, Fryns, Ghersoni-Baruch, WAGR, Denys-Drash, Brachman-De Lange, Donnai-Barrow or Wolf-Hirschhorn syndromes. Some chromosomal anomalies involve CDH as well. The incidence is < 5 in 10,000 live-births. The etiology is unknown although clinical, genetic and experimental evidence points to disturbances in the retinoid-signaling pathway during organogenesis. Antenatal diagnosis is often made and this allows prenatal management (open correction of the hernia in the past and reversible fetoscopic tracheal obstruction nowadays) that may be indicated in cases with severe lung hypoplasia and grim prognosis. Treatment after birth requires all the refinements of critical care including extracorporeal membrane oxygenation prior to surgical correction. The best hospital series report 80% survival but it remains around 50% in population-based studies. Chronic respiratory tract disease, neurodevelopmental problems, neurosensorial hearing loss and gastroesophageal reflux are common problems in survivors. Much more research on several aspects of this severe condition is warranted.
PMCID: PMC3261088  PMID: 22214468
Congenital; Diaphragm; Hernia; Retinoids; Lung; Hypoplasia; Pulmonary; Hypertension; Surgery; Fetoscopy
2.  Laparoscopic repair of congenital diaphragmatic hernia complicated with sliding hiatal hernia with reflux in adult 
Congenital diaphragmatic hernia (CDH) in adults is a relatively rare condition being asymptomatic in the majority of cases. Symptomatic CDH should prompt surgical management because they may lead to intestinal obstruction or severe pulmonary disease. This is the first reported case of a symptomatic CDH complicated with sliding hiatal hernia (SHH).
A 65 years old women with reflux and dysphagia was complaining of postprandial paroxysmal dyspnea and epigastric pain radiating to her back. Upper endoscopy diagnosed sliding and para-esophageal diaphragmatic hernia with severe esophagitis. Computed tomography-scan revealed a large Bochdalek hernia at the left diaphragm.
Diagnostic laparoscopy was decided, which confirmed the SHH, but also revealed a CDH defect at the tendonous part of the left diaphragm. The left bundle of the right crus was intact, separating the two hernia components (sliding and congenital). Extensive adhesiolysis was performed, dissecting and separating the stomach away from the diaphragm. Posterior cruroplasty at the esophageal hiatus was performed for the SHH with Nissen fundoplication as antireflux procedure. Primary continuous suture repair was performed for the CDH, reinforced with prosthetic mesh on top. Operative time was 150 min with no morbidity. The patient was discharged home uneventfully the third postoperative day. On 12-months follow-up, she reported no symptoms and improvement in quality of life.
Laparoscopy is a unique method for a precise diagnosis of symptomatic congenital diaphragmatic hernia in adults being also a safe and viable technique for a successful repair at the same time. Experience of advanced laparoscopic surgery is required.
PMCID: PMC3484816  PMID: 22986157
Laparoscopic repair; Congenital diaphragmatic hernia; Sliding diaphragmatic hernia; Bochdalek hernia
3.  Congenital Diaphragmatic Hernia Associated With Duplication of 11q23-qter 
Congenital diaphragmatic hernia (CDH) is a relatively common birth defect with a high mortality. Although little is known about its etiology, there is increasing evidence for a strong genetic contribution. Both numerical and structural chromosomal abnormalities have been described in patients with CDH. Partial trisomy 11q and partial trisomy 22 associated with the common t(11;22) has been reported in several cases of CDH. It has been assumed that the diaphragmatic defect seen in these individuals was primarily due to duplication of material from chromosome 22q11. However, in this report we describe a family with a t(11;12) in which one of two brothers with partial trisomy 11q has a left sided posterolateral CDH. This is the second case of CDH in partial trisomy 11q due to an unbalanced translocation other than t(11;22). Using array-based comparative genomic hybridization and fluorescent in situ hybridization, we mapped the breakpoints in both brothers and their mother who is a balanced translocation carrier. Our results suggest that duplication of one or more genes on a ~19 Mb region of 11q23.3-qter predisposes to the development of CDH. These effects may be the primary cause of CDH in individuals t(11;22) or may be additive to effects from the duplication of chromosome 22 material. We also conclude that the partial trisomy 11q syndrome has a variable phenotype and that CDH should be added to the spectrum of anomalies that can be present in this syndrome.
PMCID: PMC1550781  PMID: 16770801
congenital diaphragmatic hernia; partial trisomy 11q syndrome; molecular cytogenetic analysis; comparative genomic hybridization
4.  Atypical right diaphragmatic hernia (hernia of Morgagni), spigelian hernia and epigastric hernia in a patient with Williams syndrome: a case report 
Williams syndrome is rare genetic disorder resulting in neurodevelopmental problems. Hernias of the foramen of Morgagni are rare diaphragmatic hernias and they mostly present on the right side, in the anterior mediastinum. They are usually asymptomatic and are difficult to diagnose, especially in patients with learning disabilities.
Case presentation
This 49-year-old woman with Williams syndrome, cognitive impairment and aortic stenosis presented to physicians with right-sided chest pain. She had previously undergone repair of her right spigelian and epigastric hernia. Her abdominal examination was unremarkable. Chest X-ray suggested right-sided diaphragmatic hernia and pleural effusion for which she received treatment. The computed tomography scan showed a diaphragmatic hernia with some collapse/consolidation of the adjacent lung. Furthermore, the patient had aortic stenosis and was high risk for anaesthesia (ASA grade 3). She underwent successful laparoscopic repair of her congenital diaphragmatic hernia leading to a quick and uneventful postoperative recovery.
These multiple hernias suggest that patients with Williams syndrome may have some connective tissue disorder which makes them prone to develop hernias especially associated with those parts of the body which may have intracavity pressure variations like the abdomen. Diaphragmatic hernia may be the cause of chest pain in these patients. A computed tomography scan helps in early diagnosis, and laparoscopic repair helps in prevention of further complications, and leads to quick recovery especially in patients with learning disabilities. In the presence of significant comorbidities, a less invasive operative procedure with quick recovery becomes advisable.
PMCID: PMC2630954  PMID: 19128471
5.  Exogenous pulmonary surfactant replacement therapy in a neonate with pulmonary hypoplasia accompanying congenital diaphragmatic hernia--a case report. 
Journal of Korean Medical Science  1996;11(3):265-270.
Pulmonary hypoplasia(PH) commonly occurs in association with oligohydramnios and other congenital anomalies, especially congenital diaphragmatic hernia (CDH). Pulmonary hypoplasia is an important factor, as persistent pulmonary hypertension, in the prognosis of CDH. In some reports, there is a decrement of pulmonary surfactant in PH accompanying CDH. Recently, there are some reports that exogenous pulmonary surfactant therapy is effective in experimental animal model and neonatal respiratory distress with PH. We report a case of a 5 day-old male neonate, who had shown dyspnea and diagnosed as left pulmonary hypoplasia accompanying CDH. The CDH was surgically treated and the ipsilateral PH, with intratracheal administration of exogenous pulmonary surfactant postoperatively. After exogenous pulmonary surfactant application, the left lung volume was increased on chest roentgenogram and lung perfusion scan findings, and there was an improvement in oxygenation and clinical manifestations. We suggest that postoperative exogenous pulmonary surfactant replacement therapy is effective in the case of PH and further trials are needed to clarify the optimal dose and timing of supplementation of surfactant for treatment of infants with PH accompanying CDH.
PMCID: PMC3054049  PMID: 8843010
6.  Noninvasive Assessment of the Right and Left Ventricular Function in Neonates with Congenital Diaphragmatic Hernia with Persistent Pulmonary Hypertension Before and After Surgical Repair 
The Ochsner Journal  2006;6(2):48-53.
To measure right and left ventricular function in neonates with congenital diaphragmatic hernia (CDH) and persistent pulmonary hypertension of the newborn (PPHN) before and after surgical repair.
Ten newborns with CDH and PPHN before and after surgical repair and 24 normal newborns underwent Doppler echocardiographic measurements of the systolic time intervals (STI) and the index of myocardial performance (IMP) or Tei Index to assess pulmonary hypertension and ventricular function, respectively.
In newborns with CDH and PPHN before surgical repair, STI pre-ejection time/ejection time ratio and pre-ejection time/acceleration time ratio (0.39 ± 0.19 and 1.22 ± 0.6) were significantly prolonged when compared to newborns with CDH and PPHN after surgical repair (0.21 ± 0.05 and 0.80 ± 0.2) and normal newborns (0.20 ± 0.04 and 0.59 ± 0.2), respectively (all p < 0.001). Left IMP and right IMP were also significantly prolonged in newborns with CDH and PPHN before surgery (0.38 ± 0.16 and 0.53 ± 0.25) when compared to newborns with CDH and PPHN after surgery (0.30 ± 0.07 and 0.28 ± 0.13) and normal newborns (0.26 ± 0.09 and 0.20 ± 0.10), respectively (p < 0.05, left IMP) and (p < 0.001, right IMP).
Significant pulmonary hypertension and abnormal left and right ventricular function were found in newborns with CDH and PPHN before surgical repair when compared to the newborns with CDH and PPHN after surgical repair and normal newborns. The STI and the IMP or Tei index can accurately estimate the consequences of pulmonary hypertension and left and right ventricular function in neonates with CDH and PPHN, which may affect management in these critically ill neonates.
PMCID: PMC3121566  PMID: 21765793
Congenital diaphragmatic hernia; persistent pulmonary hypertension; neonate; ventricular function; systolic time intervals; index of myocardial performance
7.  Challenging embryological theories on congenital diaphragmatic hernia: future therapeutic implications for paediatric surgery. 
Lung hypoplasia is central to the poor prognosis of babies with congenital diaphragmatic hernia (CDH). Prolapse of abdominal organs through a diaphragmatic defect has traditionally been thought to impair lung growth by compression. The precise developmental biology of CDH remains unresolved. Refractory to fetal correction, lung hypoplasia in CDH may instead originate during embryogenesis and before visceral herniation. Resolving these conflicting hypotheses may lead to reappraisal of current clinical strategies. Genetic studies in murine models and the fruitfly, Drosophila melanogaster are elucidating the control of normal respiratory organogenesis. Branchless and breathless are Drosophila mutants lacking fibroblast growth factor (FGF) and its cognate receptor (FGFR), respectively. Sugarless and sulphateless mutants lack enzymes essential for heparan sulphate (HS) biosynthesis. Phenotypically, all these mutants share abrogated airway branching. Mammalian organ culture and transgenic models confirm the essential interaction of FGFs and HS during airway ramification. Embryonic airway development (branching morphogenesis) occurs in a defined spatiotemporal sequence. Unlike the surgically-created lamb model, the nitrofen rat model permits investigation of embryonic lung growth in CDH. Microdissecting embryonic lung primordia from the nitrofen CDH model and normal controls, we demonstrated that disruption of stereotyped airway branching correlates with and precedes subsequent CDH formation. To examine disturbed branching morphogenesis longitudinally, we characterised a system that preserves lung hypoplasia in organ culture. We tested FGFs and heparin (an HS analogue) as potential therapies on normal and hypoplastic lungs. Observing striking differences in morphological response to FGFs between normal and hypoplastic lung primordia, we postulated abnormalities of FGF/HS signalling in the embryonic CDH lung. Evaluating this hypothesis further, we examined effects of an HS-independent growth factor (epidermal growth factor, EGF) on hypoplastic lung development. Visible differences in morphological response indicate an intrinsic abnormality of hypoplastic lung primordia that may involve shared targets of FGFs and EGE. These studies indicate that lung hypoplasia precedes diaphragmatic hernia and may involve disturbances of mitogenic signalling pathways fundamental to embryonic lung development. What does this imply for human CDH? Fetal surgery may be 'too little, too late' to correct an established lung embryopathy. In utero growth factor therapy may permit antenatal lung rescue. Prevention of the birth defect by preconceptual prophylaxis may represent the ultimate solution.
PMCID: PMC2504220  PMID: 12215028
8.  ANG-1 TIE-2 and BMPR Signalling Defects Are Not Seen in the Nitrofen Model of Pulmonary Hypertension and Congenital Diaphragmatic Hernia 
PLoS ONE  2012;7(4):e35364.
Pulmonary hypertension (PH) is a lethal disease that is associated with characteristic histological abnormalities of the lung vasculature and defects of angiopoetin-1 (ANG-1), TIE-2 and bone morphogenetic protein receptor (BMPR)-related signalling. We hypothesized that if these signalling defects cause PH generically, they will be readily identifiable perinatally in congenital diaphragmatic hernia (CDH), where the typical pulmonary vascular changes are present before birth and are accompanied by PH after birth.
CDH (predominantly left-sided, LCDH) was created in Sprague-Dawley rat pups by e9.5 maternal nitrofen administration. Left lungs from normal and LCDH pups were compared at fetal and postnatal time points for ANG-1, TIE-2, phosphorylated-TIE-2, phosphorylated-SMAD1/5/8 and phosphorylated-ERK1/2 by immunoprecipitation and Western blotting of lung protein extracts and by immunohistochemistry on lung sections.
In normal lung, pulmonary ANG-1 protein levels fall between fetal and postnatal life, while TIE-2 levels increase. Over the corresponding time period, LCDH lung retained normal expression of ANG-1, TIE-2, phosphorylated-TIE-2 and, downstream of BMPR, phosphorylated-SMAD1/5/8 and phosphorylated-p44/42.
In PH and CDH defects of ANG-1/TIE-2/BMPR-related signalling are not essential for the lethal vasculopathy.
PMCID: PMC3335125  PMID: 22539968
9.  Findings From aCGH in Patients With Congenital Diaphragmatic Hernia (CDH): A Possible Locus for Fryns Syndrome 
Congenital diaphragmatic hernia (CDH) is a common and often devastating birth defect that can occur in isolation or as part of a malformation complex. Considerable progress is being made in the identification of genetic causes of CDH. We applied array-based comparative genomic hybridization (aCGH) of ∼1Mb resolution to 29 CDH patients with prior normal karyotypes who had been recruited into our multi-site study. One patient, clinically diagnosed with Fryns syndrome, demonstrated a de novo 5Mb deletion at chromosome region 1q41–q42.12 that was confirmed by FISH. Given prior reports of CDH in association with cytogenetic abnormalities in this region, we propose that this represents a locus for Fryns syndrome, a Fryns syndrome phenocopy, or CDH.
PMCID: PMC2891730  PMID: 16333846
congenital diaphragmatic hernia; Fryns syndrome; chromosome 1q41–q42.12 deletion; array-based comparative genomic hybridization (aCGH); FISH
10.  Congenital Diaphragmatic Hernia: Review of Current Concept in Surgical Management 
ISRN Surgery  2011;2011:974041.
Congenital diaphragmatic hernias (CDHs) occur mainly in two locations: the foramen of Morgagni and the more common type involving the foramen of Bochdalek. Hiatal hernia and paraesophageal hernia have also been described as other forms of CDH. Pulmonary hypertension and pulmonary hypoplasia have been recognized as the two most important factors in the pathophysiology of congenital diaphragmatic hernia. Advances in surgical management include delayed surgical approach that enables preoperative stabilization, introduction of fetal intervention due to improved prenatal diagnosis, the introduction of minimal invasive surgery, in addition to the standard open repair, and the use of improved prosthetic devices for closure.
PMCID: PMC3251163  PMID: 22229104
11.  Infants With Bochdalek Diaphragmatic Hernia 
Congenital diaphragmatic hernia (CDH) is a common and often devastating birth defect. In order to learn more about possible genetic causes, we reviewed and classified 203 cases of the Bochdalek hernia type identified through the Brigham and Women’s Hospital (BWH) Active Malformation Surveillance Program over a 28-year period. Phenotypically, 55% of the cases had isolated CDH, and 45% had complex CDH defined as CDH in association with additional major malformations or as part of a syndrome. When classified according to likely etiology, 17% had a Recognized Genetic etiology for their CDH, while the remaining 83% had No Apparent Genetic etiology. Detailed analysis using this largest cohort of consecutively collected cases of CDH showed low precurrence among siblings. Additionally, there was no concordance for CDH among five monozygotic twin pairs. These findings, in conjunction with previous reports of de novo dominant mutations in patients with CDH, suggest that new mutations may be an important mechanism responsible for CDH. The twin data also raise the possibility that epigenetic abnormalities contribute to the development of CDH.
PMCID: PMC2891716  PMID: 16094667
congenital diaphragmatic hernia; discordant monozygotic twins; precurrence risk; review
12.  Surfactant Maturation Is Not Delayed in Human Fetuses with Diaphragmatic Hernia 
PLoS Medicine  2007;4(7):e237.
Pulmonary hypoplasia and persistent pulmonary hypertension account for significant mortality and morbidity in neonates with congenital diaphragmatic hernia (CDH). Global lung immaturity and studies in animal models suggest the presence of surfactant deficiency that may further complicate the pathophysiology of CDH. However, data about surfactant status in human fetuses with CDH at birth are contradictory. The lack of a chronological study of surfactant content in late pregnancy has been a significant limitation. The appropriateness of administering surfactant supplements to neonates with CDH is therefore a debated question.
Methods and Findings
We investigated surfactant content in human fetuses with CDH compared to age-matched fetuses with nonpulmonary diseases used as controls. Concentrations of disaturated phosphatidylcholine and surfactant proteins were found to be similar at a given stage of pregnancy, with both components showing a similar pattern of increase with progressing pregnancy in fetuses with CDH and in control fetuses. Thyroid transcription factor 1, a critical regulator of surfactant protein transcription, similarly displayed no difference in abundance. Finally, we examined the expression of three glucocorticoid-regulated diffusible mediators involved in lung epithelial maturation, namely: keratinocyte growth factor (KGF), leptin, and neuregulin 1 beta 1 (NRG1-β1). KGF expression decreased slightly with time in control fetuses, but remained unchanged in fetuses with CDH. Leptin and NRG1-β1 similarly increased in late pregnancy in control and CDH lungs. These maturation factors were also determined in the sheep fetus with surgical diaphragmatic hernia, in which surfactant deficiency has been reported previously. In contrast to the findings in humans, surgical diaphragmatic hernia in the sheep fetus was associated with decreased KGF and neuregulin expression. Fetoscopic endoluminal tracheal occlusion performed in the sheep model to correct lung hypoplasia increased leptin expression, partially restored KGF expression, and fully restored neuregulin expression.
Our results indicate that CDH does not impair surfactant storage in human fetuses. CDH lungs exhibited no trend toward a decrease in contents, or a delay in developmental changes for any of the studied surfactant components and surfactant maturation factors. Surfactant amounts are likely to be appropriate to lung size. These findings therefore do not support the use of surfactant therapy for infants with CDH. Moreover, they raise the question of the relevance of CDH animal models to explore lung biochemical maturity.
In an autopsy study of human fetuses, Jacques Bourbon and colleagues report that pulmonary surfactant content is not decreased in congenital diaphragmatic hernia.
Editors' Summary
Congenital diaphragmatic hernia (CDH), a fetal malformation in which the abdominal organs are displaced into the chest cavity, occurs in approximately one out of 3,000 live births and accounts for approximately 8% of major birth defects. The displaced lungs tend to be underdeveloped at birth, and decreased lung function is a major cause of sickness and death in affected babies.
Pulmonary surfactant, a substance naturally produced by cells in the lungs in the weeks before birth, is necessary for normal breathing. Surfactant acts to keep the walls of the lung's airspaces from collapsing onto each other, much as detergent can keep the walls of a moist plastic bag from sticking together.
Why Was This Study Done?
The specific aspects of lung immaturity that cause decreased function in babies with CDH are not fully understood. In particular, it has been unclear whether abnormally low levels of pulmonary surfactant contribute to the lung problems caused by CDH. Some studies in sheep or rat models of CDH have found that surfactant levels are abnormally low, while others have found normal or even increased levels of surfactant. Studies in human CDH have also shown controversial results, and few have investigated surfactant production in lung tissue itself.
Doctors can artificially increase babies' pulmonary surfactant levels if necessary through the instillation of exogenous surfactant material, but doing so involves some risk. This is a routine treatment with demonstrated benefit in premature neonates with normal, although not fully developed, lungs. Pulmonary surfactant is sometimes given also to babies with CDH, but in this particular instance, the benefit of this practice is unclear. The authors of this study wanted to determine whether or not babies with CDH really have low levels of pulmonary surfactant.
What Did the Researchers Do and Find?
The researchers performed autopsies to study lung tissue from human fetuses in pregnancies that ended in fetal death, were terminated for medical reasons, or resulted in death immediately after birth. They compared surfactant production in 16 fetuses with CDH to that in 33 fetuses with conditions not involving the lungs. They found that, taking fetal age into account, surfactant was present at similar levels in lung tissue from both groups, and that production of surfactant components and other factors involved in lung maturation was not delayed in CDH.
The researchers also studied sheep fetuses with surgically induced CDH, a model that has been used in the past to study lung development in CDH. In contrast with the findings in humans, they found that factors stimulating surfactant production were decreased in sheep with surgically induced CDH.
What Do These Findings Mean?
These findings suggest that surfactant deficiency is not a major contributor to lung problems in babies with CDH, and that further clinical research may be appropriate to determine whether administering surfactant to these babies is beneficial. The findings also suggest that commonly used animal models of CDH may be of limited relevance to human CDH.
Additional Information.
Please access these Web sites via the online version of this summary at
Read the related Perspective on this article by Marcus Davey
Information from the MedlinePlus Encyclopedia (US National Library of Medicine) on diaphragmatic hernia
Article from eMedicine on congenital diaphragmatic hernia
Wikipedia entry on pulmonary surfactant (note: Wikipedia is an online encyclopedia that anyone can edit)
PMCID: PMC1950205  PMID: 17676984
13.  Deficiency of FRAS1-related extracellular matrix 1 (FREM1) causes congenital diaphragmatic hernia in humans and mice 
Human Molecular Genetics  2012;22(5):1026-1038.
Congenital diaphragmatic hernia (CDH) is a common life-threatening birth defect. Recessive mutations in the FRAS1-related extracellular matrix 1 (FREM1) gene have been shown to cause bifid nose with or without anorectal and renal anomalies (BNAR) syndrome and Manitoba oculotrichoanal (MOTA) syndrome, but have not been previously implicated in the development of CDH. We have identified a female child with an isolated left-sided posterolateral CDH covered by a membranous sac who had no features suggestive of BNAR or MOTA syndromes. This child carries a maternally-inherited ∼86 kb FREM1 deletion that affects the expression of FREM1's full-length transcripts and a paternally-inherited splice site mutation that causes activation of a cryptic splice site, leading to a shift in the reading frame and premature termination of all forms of the FREM1 protein. This suggests that recessive FREM1 mutations can cause isolated CDH in humans. Further evidence for the role of FREM1 in the development of CDH comes from an N-ethyl-N-nitrosourea -derived mouse strain, eyes2, which has a homozygous truncating mutation in Frem1. Frem1eyes2 mice have eye defects, renal agenesis and develop retrosternal diaphragmatic hernias which are covered by a membranous sac. We confirmed that Frem1 is expressed in the anterior portion of the developing diaphragm and found that Frem1eyes2 embryos had decreased levels of cell proliferation in their developing diaphragms when compared to wild-type embryos. We conclude that FREM1 plays a critical role in the development of the diaphragm and that FREM1 deficiency can cause CDH in both humans and mice.
PMCID: PMC3561915  PMID: 23221805
14.  Symptomatic Bochdalek Hernia in an Adult 
Rare congenital diaphragmatic defects resulting from failure of posterolateral diaphragmatic foramina to fuse may be approached laparoscopically and repaired successfully.
Background and Objectives:
Bochdalek hernias are congenital diaphragmatic defects resulting from the failure of posterolateral diaphragmatic foramina to fuse in utero. Symptomatic Bochdalek hernias in adults are infrequent and may lead to gastrointestinal dysfunction or severe pulmonary disease. We describe our experience with this rare entity.
A retrospective chart review was performed on a single patient for data collection purposes.
The patient is a morbidly obese 53-year-old female who presented with epigastric pain and diffuse abdominal tenderness. Computed tomography scans of the chest and abdomen revealed a small posterior diaphragmatic defect containing gastric fundal diverticulum. Laboratory work and imaging revealed no other findings. Laparoscopic repair of the Bochdalek hernia was done via an abdominal approach and utilized primary closure with an AlloDerm patch apposed to the defect. The patient has had significant clinical improvement and continues to do well at 9 months postoperatively.
Laparoscopic repair of symptomatic adult Bochdalek hernias can be performed successfully and may result in significant clinical improvement.
PMCID: PMC3043584  PMID: 20932385
Bochdalek; Diaphragm; Hernia
15.  Prostanoids in bronchoalveolar lavage fluid do not predict outcome in congenital diaphragmatic hernia patients 
Mediators of Inflammation  1997;6(3):217-224.
Vasoactive prostanoids may be involved in persistent pulmonary hypertension (PPH) in infants with a congenital diaphragmatic hernia (CDH). We hypothesized that increased levels of prostanoids in bronchoalveolar lavage (BAL) fluid would predict clinical outcome. We measured the concentrations of 6-keto-prostaglandin F1α (6-keto-PGF1α), thromboxane B2 (TxB2), protein, albumin, total cell count, and elastase-α1-proteinase-inhibitor complex in BAL fluid of 18 CDH patients and of 13 control subjects without PPH. We found different concentrations of prostanoids in BAL fluid of CDH patients with PPH: infants with a poor prognosis had either high levels of both 6-keto-PGF1α and TxB2 compared to controls, or high levels of 6-keto-PGF1α only. TxB2 levels showed a large variability in all CDH patients irrespective of outcome. We conclude that prostanoid levels in BAL fluid do not predict clinical outcome in CDH patients.
PMCID: PMC2365827  PMID: 18472823
16.  Impaired mesenchymal cell function in Gata4 mutant mice leads to diaphragmatic hernias and primary lung defects 
Developmental biology  2006;301(2):602-614.
Congenital diaphragmatic hernia (CDH) is an often fatal birth defect that is commonly associated with pulmonary hypoplasia and cardiac malformations. Some investigators hypothesize that this constellation of defects results from genetic or environmental triggers that disrupt mesenchymal cell function in not only the primordial diaphragm but also the thoracic organs. The alternative hypothesis is that the displacement of the abdominal viscera in the chest secondarily perturbs the development of the heart and lungs. Recently, loss-of-function mutations in the gene encoding FOG-2, a transcriptional co-regulator, have been linked to CDH and pulmonary hypoplasia in humans and mice. Here we show that mutagenesis of the gene for GATA-4, a transcription factor known to functionally interact with FOG-2, predisposes inbred mice to a similar set of birth defects. Analysis of wild-type mouse embryos demonstrated co-expression of Gata4 and Fog2 in mesenchymal cells of the developing diaphragm, lungs, and heart. A significant fraction of C57Bl/6 mice heterozygous for a Gata4 deletion mutation died within one day of birth. Developmental defects in the heterozygotes included midline diaphragmatic hernias, dilated distal airways, and cardiac malformations. Heterozygotes had any combination of these defects or none. In chimeric mice, Gata4−/− cells retained the capacity to contribute to cells in the diaphragmatic central tendon and lung mesenchyme, indicating that GATA-4 is not required for differentiation of these lineages. We conclude that GATA-4, like its co-regulator FOG-2, is required for proper mesenchymal cell function in the developing diaphragm, lungs, and heart.
PMCID: PMC1808541  PMID: 17069789
birth defect; diaphragm; pulmonary hypoplasia; transcription factor
17.  Late-Presenting Congenital Diaphragmatic Hernia in Children: The Experience of Single Institution in Korea 
Yonsei Medical Journal  2013;54(5):1143-1148.
Late-presenting congenital diaphragmatic hernia (CDH) beyond the neonatal period is rare and often misdiagnosed, with delayed treatment.
Materials and Methods
We retrospectively reviewed our experience with late-presenting CDH over 30 years at a single institution to determine the characteristics of late-presenting CDH for early diagnosis.
Seven patients had operations due to late-presenting CHD in our institution over 30 years. The patients' ages ranged from 2.5 months to 16 years. There were six boys and one girl. Five hernias were left-sided, one was right-sided and one was a retrosternal hernia. All patients had normal intestinal rotation. Non-specific gastrointestinal or respiratory symptoms and signs were usually presented. Intestinal malrotations were absent; therefore, only organs adjacent to the defect or relatively movable organs such as the small bowel and transverse colon were herniated. Two cases were accompanied by stomach herniation with the volvulus and liver, respectively. The duration from presentation to diagnosis varied from 5 days to 1 year. Diagnoses were made by chest X-ray, upper gastrointestinal series and chest computed tomography. All patients underwent primary repair with interrupted non-absorbable sutures by a transabdominal approach. None had postoperative complications. The follow-up period in six patients ranged from 4 months to 20 years (median 3.8 years). There was no recurrence in any of the patients on follow-up.
A high index of suspicion is important for the diagnosis of late-presenting CDH because it can be a life-threatening condition such as CDH with a gastric volvulus. Early diagnosis and appropriate treatment can lead to a good prognosis.
PMCID: PMC3743178  PMID: 23918563
Congenital diaphragmatic hernia; late-presentation
18.  Diaphragmatic hernia in the south-west of England. 
Journal of Medical Genetics  1976;13(4):253-262.
A retrospective anatomical, family, and epidemiological study was made of 143 patients (81 female and 62 male) with diaphragmatic hernia who were born in the south-west of England between 1943 and 1974. Thirty-nine cases were stillborn. Seventy-five per cent of patients had a left-sided diaphragmatic defect, 22% had a right-sided defect, and 3% had a bilateral defect. Fifty per cent of the patients had other congenital malformations, most frequently of the nervous system. No maternal age or birth order effect was noted. Cases of diaphragmatic hernia without other malformations had in general a normal fetal growth rate. Eight per cent of the cases were illegitimate. There were two pairs of twins discordant for diaphragmatic hernia, one pair being dizygotic and the other monozygotic. In no case of diaphragmatic hernia was there a relative affected with a diaphragmatic hernia. The most common type of diaphragmatic defect was a posterolateral hernia (92%), followed in frequency by an eventration of the diaphragm (5%), the least common defect being a retrocostosternal hernia (2%). Diaphragmatic hernia appears to be aetiologically as well as anatomically heterogeneous. In this series there were two cases of trisomy 18, one case of trisomy 21, one case trisomic for a small part of chromosome 20, and two cases with the Pierre Robin syndrome. It seems likely that diaphragmatic hernia is a non-specific consequence of several teratological processes.
PMCID: PMC1013411  PMID: 957374
19.  Genomic Alterations that Contribute to the Development of Isolated and Non-Isolated Congenital Diaphragmatic Hernia 
Journal of medical genetics  2011;48(5):299-307.
Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect. Most of the genetic factors that contribute to the development of CDH remain unidentified.
Identify genomic alterations that contribute to the development of diaphragmatic defects.
A cohort of 45 unrelated patients with CDH or diaphragmatic eventrations were screened for genomic alterations by array comparative genomic hybridization (aCGH) or SNP-based copy number analysis.
Genomic alterations that were likely to have contributed to the development of CDH were identified in eight patients. Inherited deletions of ZFPM2 were identified in two patients with isolated diaphragmatic defects and a large de novo 8q deletion overlapping the same gene was found in a patient with non-isolated CDH. A de novo microdeletion of chromosome 1q41q42 and two de novo microdeletions on chromosome 16p11.2 were identified in patients with non-isolated CDH. Duplications of distal 11q and proximal 13q were found in a patient with non-isolated CDH and a de novo single gene deletion of FZD2 was also identified in a patient with a partial pentalogy of Cantrell phenotype.
Haploinsufficiency of ZFPM2 can cause dominantly inherited isolated diaphragmatic defects with incomplete penetrance. Our data define a new minimal deleted region for CDH on 1q41q42, provide evidence for the existence of CDH-related genes on chromosomes 16p11.2, 11q23-24 and 13q12 and suggest a possible role for FZD2 and Wnt signaling in pentalogy of Cantrell phenotypes. These results demonstrate the clinical utility of screening for genomic alterations in individuals with both isolated and non-isolated diaphragmatic defects.
PMCID: PMC3227222  PMID: 21525063
Diaphragmatic hernia; ZFPM2; microdeletion 1q41q42; microdeletion 16p11.2; FZD2
20.  Prenatal Diagnosis of Congenital Diaphragmatic Hernia in a Fetus with 46,XY/46,X,-Y,+der(Y)t(Y;1)(q12;q12) Mosaicism : A Case Report 
Journal of Korean Medical Science  2005;20(5):895-898.
Congenital diaphragmatic hernia (CDH) is often associated with major anomalies and chromosomal abnormalities. Chromosomal abnormalities are usually detected in 9.5% to 34% of fetuses with CDH prenatally diagnosed and the defect has also been reported in association with multiple syndromes such as Pallister-Killian syndrome, Fryns syndrome, Di George syndrome and Apert syndrome. Among the chromosomal abnormalities associated with CDH, trisomy 21, 18, and 13 are most common. Association with complex chromosomal aberrations such as mosaicism has also been reported. However, CDH presented in a fetus with Y-autosome translocation is extremely rare. Herein, we reported a case of fetus with 46,XY/46,X,-Y,+der(Y)t(Y;1)(q12;q12) mosaicism who presented with CDH diagnosed by ultrasonography at 19 weeks' gestation.
PMCID: PMC2779294  PMID: 16224171
Hernia, Diaphragmatic; Translocation, Genetics; Mosaicism; Prenatal Diagnosis
21.  A Family-Based Paradigm to Identify Candidate Chromosomal Regions for Isolated Congenital Diaphragmatic Hernia 
Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that causes high newborn mortality. Isolated or non-syndromic CDH is considered a multifactorial disease, with strong evidence implicating genetic factors. As low heritability has been reported in isolated CDH, family-based genetic methods have yet to identify the genetic factors associated with the defect. Using the Utah Population Database, we identified distantly related patients from several extended families with a high incidence of isolated CDH. Using high-density genotyping, seven patients were analyzed by homozygosity exclusion rare allele mapping (HERAM) and phased haplotype sharing (HapShare), two methods we developed to map shared chromosome regions. Our patient cohort shared three regions not previously associated with CDH, i.e. 2q11.2-q12.1, 4p13 and 7q11.2, and two regions previously involved in CDH, i.e. 8p23.1 and 15q26.2. The latter regions contain GATA4 and NR2F2, two genes implicated in diaphragm formation in mice. Interestingly, three patients shared the 8p23.1 locus and one of them also harbored the 15q26.2 segment. No coding variants were identified in GATA4 or NR2F2, but a rare shared variant was found in intron 1 of GATA4. This work shows the role of heritability in isolated CDH. Our family-based strategy uncovers new chromosomal regions possibly associated with disease, and suggests that non-coding variants of GATA4 and NR2F2 may contribute to the development of isolated CDH. This approach could speed up the discovery of the genes and regulatory elements causing multifactorial diseases, such as isolated CDH.
PMCID: PMC3507422  PMID: 23165927
congenital diaphragmatic hernia; Utah population database; shared segment analysis; GATA4; NR2F2
22.  Lung eicosanoids in perinatal rats with congenital diaphragmatic hernia 
Mediators of Inflammation  1997;6(1):39-45.
Abnormal levels of pulmonary eicosanoids have been reported in infants with persistent pulmonary hypertension (PPH) and congenital diaphragmatic hernia (CDH). We hypothesized that a dysbalance of vasoconstrictive and vasodilatory eicosanoids is involved in PPH in CDH patients. The levels of several eicosanoids in lung homogenates and in bronchoalveolar lavage fluid of controls and rats with CDH were measured after caesarean section or spontaneous birth. In controls the concentration of the stable metabolite of prostacyclin (6-keto-PGF1α), thromboxane A2 (TxB2), prostaglandin E2 (PGE2), and leukotriene B4 (LTB4) decreased after spontaneous birth. CDH pups showed respiratory insufficiency directly after birth. Their lungs had higher levels of 6- keto-PGF1α, reflecting the pulmonary vasodilator prostacyclin (PGI2), than those of controls. We conclude that in CDH abnormal lung eicosanoid levels are present perinatally. The elevated levels of 6-keto-PGF1α in CDH may reflect a compensation mechanism for increased vascular resistance.
PMCID: PMC2365837  PMID: 18472832
23.  The congenital diaphragmatic hernia composite prognostic index correlates with survival in left-sided congenital diaphragmatic hernia 
Journal of pediatric surgery  2012;47(1):10.1016/j.jpedsurg.2011.10.020.
We developed the congenital diaphragmatic hernia congenital prognostic index (CDH-CPI) to incorporate all known prognostic variables into a single composite index to improve prognostic accuracy. The purpose of this study is to examine the ability of the CDH-CPI to predict survival in patients with left-sided congenital diaphragmatic hernia and to determine if the index has a stronger correlation with survival than each of the individual components.
A retrospective review of patients with left-sided congenital diaphragmatic hernia between 2004 and 2010 was conducted. Ten prenatal parameters of the CDH-CPI were collected, total score was tabulated, and patients stratified according to total score and survival.
Sixty-four patients with a prenatal diagnosis of left-sided congenital diaphragmatic hernia were identified. Patients with a CDH-CPI score of 8 or higher had a significantly higher survival than patients with a CDH-CPI score of lower than 8. The CDH-CPI has the strongest correlation with survival compared with the individual parameters measured. The CDH-CPI correlates with extracorporeal membrane oxygenation use, and 75% of patients with a score of 5 or lower were placed on extracorporeal membrane oxygenation.
The CDH-CPI accurately stratifies survival in left-sided congenital diaphragmatic hernia. The amalgamation of 10 prenatal parameters of the CDH-CPI may be a better prenatal predictor than any single prognostic variable currently used.
PMCID: PMC3870853  PMID: 22244393
Congenital diaphragmatic hernia; Survival; Prognosis; CDH-CPI
24.  Fetal lung compliance in premature and term lambs after two methods of in utero repair of diaphragmatic hernia. 
Thorax  1994;49(10):1015-1019.
BACKGROUND--In utero surgery was used to correct a surgically induced model of congenital diaphragmatic hernia (CDH) in premature and term lambs, resulting in an improvement in lung mechanics at birth. METHODS--The differences between the in utero "patch" repair method and the "silo" repair method were assessed in 55 lambs by measuring the static respiratory system compliance (CST,RS) at birth in term (approximately 145 day) and in premature (128 day) animals. RESULTS--Both methods resulted in similar improvements in CST,RS in term lambs, but in premature lambs only the silo method produced an increase in compliance. Comparisons of specific compliance related to length or birth weight did not alter these findings; however, corrections related to lung weight or a measure of lung volume showed there was no difference between any experimental groups in either term or premature lambs. CONCLUSIONS--These findings suggest that there was no difference in the intrinsic compliance of the lung tissue between normal, unrepaired and repaired animals, and that the differences in respiratory system compliance measured at birth may be due primarily to differences in lung size. The silo repair method appears to provide an earlier improvement in CST,RS than the patch repair method.
PMCID: PMC475240  PMID: 7974295
25.  De novo copy number variants are associated with congenital diaphragmatic hernia 
Journal of medical genetics  2012;49(10):650-659.
Congenital diaphragmatic hernia (CDH) is a common birth defect with significant morbidity and mortality. Although the etiology of CDH remains poorly understood, studies from animal models and patients with CDH suggest that genetic factors play an important role in the development of CDH. Chromosomal anomalies have been reported in CDH.
In this study, the authors investigate the frequency of chromosomal anomalies and copy number variants in 256 parent-child trios of CDH using clinical conventional cytogenetic and microarray analysis. The authors also selected a set of CDH related training genes to prioritize the genes in those segmental aneuploidies and identified the genes and gene sets that may contribute to the etiology of CDH.
The authors identified chromosomal anomalies in 16 patients (6.3 %) of the series including 3 aneuploidies, 2 unbalanced translocation, and 11 patients with de novo CNVs ranging in size from 95 kb to 104.6 Mb. The authors prioritized the genes in the CNV segments and identified KCNA2, LMNA, CACNA1S, MYOG, HLX, LBR, AGT, GATA4, SOX7, HYLS1, FOXC1, FOXF2, PDGFA, FGF6, COL4A1, COL4A2, HOMER2, BNC1, BID, and TBX1 as genes that may be involved in diaphragm development. Gene enrichment analysis identified the most relevant gene ontology (GO) categories as those involved in tissue development (p=4.4×10−11) or regulation of multicellular organismal processes (p=2.8×10−10) and “receptor binding” (p = 8.7×10−14) and “DNA binding transcription factor activity” (p= 4.4×10−10).
Our findings support the role of chromosomal anomalies in CDH and provide a set of candidate genes including FOXC1, FOXF2, PDGFA, FGF6, COL4A1, COL4A2, SOX7,BNC1, BID, and TBX1 for further analysis in CDH.
PMCID: PMC3696999  PMID: 23054247
Congenital diaphragmatic hernia (CDH); copy number variant (CNV); chromosomal anomalies; gene priority; gene enrichment

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