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1.  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
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.  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
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.  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
6.  Congenital Diaphragmatic Hernia and Associated Cardiovascular Malformations: Type, Frequency, and Impact on Management 
The co-occurrence of congenital diaphragmatic hernia (CDH) and cardiovascular malformations (CVMs) has important clinical, genetic, and developmental implications. Previous examinations of this topic often included patients with genetic syndromes. To correct this potential bias, we undertook an extensive review of the literature and obtained new data. The frequency of CVMs associated with isolated CDH was 11–15%. A careful analysis of CVMs indicates that atrial and ventricular septal defects, conotruncal defects, and left ventricular outflow tract obstructive defects were the most common type of CVMs, but proportional to the frequency of occurrence in the general population. The combination of CVM and CDH results in a poorer prognosis than would be expected with either malformation alone. However, the impact on survival from patients with a genetic syndrome has not been consistently evaluated. We encourage researchers to re-analyze existing series and recommend that future studies distinguish isolated CDH from that which is associated with other malformations, especially as part of genetic syndromes. Therapies should be tailored to maximize cardiac output and systemic oxygen delivery rather than systemic oxygen saturation alone. Although there is speculation about the frequency with which isolated left ventricular “hypoplasia” occurs in patients with CDH, we suggest it results from compression of a pre-load deficient left ventricle by the hypertensive right ventricle, and unlike true hypoplasia, is reversible. Irrespective of the type of severity of CVMs in patients with CDH, the degree of pulmonary hypoplasia and pulmonary vascular disease predicts outcome.
PMCID: PMC2891735  PMID: 17436301
cardiovascular malformations; congenital diaphragmatic hernia; congenital heart defects; hypoplastic left heart
7.  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
8.  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
Congential diaphragmatic herniae pose serious challenges in their management in this environment.Aim & Objective: To determine the pattern, as well as the diagnostic and management challenges of congenital diaphragmatic hernia in Dakar, Senegal.
Patients and Methods
This is a retrospective review of 14 children with congenital diaphragmatic hernia (CDH) managed within eleven years in Dakar, Senegal. Results: There were nine boys and five girls with the age range of one day to 22 months and a mean of 5 months. Respiratory signs (respiratory distress, cough, current pulmonary infection) were found in 13 patients and gastrointestinal symptoms (vomiting, Difficulty sucking, anorexia) in 6 patients. The thoracic-abdominal radiography was performed in all patients and revealed a Bochdalek hernia on the left in 10(71%) cases and 4(29%) were Morgagni hernia. Treatment was by repair of the diaphragmatic defect with non-absorbable sutures. The postoperative course was uneventful in 13 children while one patient died on the first postoperative day one.
Congenital diaphragmatic hernia presents mainly with postnatal respiratory features in this setting. Thoracic-abdominal radiography allows for early diagnosis, prompt and effective treatment with good outcome.Keywords: Congenital diaphragmatic hernia, Respiratory insufficiency, Radiological features, Good surgical outcome.
PMCID: PMC4170295  PMID: 25452981
Congenital diaphragmatic hernia; Respiratory insufficiency; Radiological features ;  Good surgical outcome
10.  Outcomes of Congenital Diaphragmatic Hernia in the modern era of management 
The Journal of pediatrics  2013;163(1):114-119.e1.
Objective To identify clinical factors associated with pulmonary hypertension and mortality in patients with congenital diaphragmatic hernia (CDH).
Study design A prospective cohort of neonates with a diaphragm defect identified at one of seven collaborating medical centers was studied. Echocardiograms were performed at one month and three months of age and analyzed at a central core by two cardiologists independently. Degree of pulmonary hypertension and survival were tested for association with clinical variables using Fischers exact test, chi-square and regression analysis.
Results 220 patients met inclusion criteria. Worse pulmonary hypertension measured at one month of life was associated with higher mortality. Other factors associated with mortality were need for extracorporeal membrane oxygenation (ECMO), patients inborn at the treating center and patients with a prenatal diagnosis of CDH. Interestingly, patients with right sided CDH did not have worse outcomes.
Conclusions Severity of pulmonary hypertension is associated with mortality in CDH. Other factors associated with mortality were birth weight, gestational age at birth, inborn status and need for ECMO.
PMCID: PMC3692597  PMID: 23375362
Congenital Diaphragmatic Hernia; Pulmonary Hypertension; Survival; Treatment
11.  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
12.  Thoracoscopic Repair of Congenital Diaphragmatic Hernia in Infancy 
Minimally invasive surgical techniques, specifically the thoracoscopic approach, have been applied to congenital diaphragmatic hernia (CDH) with varying outcomes from selected centers. The aim of our study was to examine the rate of successful completion and compare outcomes between open and thoracoscopic approaches in CDH repair.
We performed a retrospective analysis of infants with CDH repair (From February 2004 to January 2008). Patients were divided into thoracoscopic and open groups, based on operative approach. We analyzed demographic, clinical, and hospitalization characteristics to compare the completion rate and outcomes in these two groups.
Analysis of 31 infants with CDH (14 thorascocopic and 17 open) demonstrated no differences in sex (P = 0.132), age (P = 0.807), birthweight (P = 0.256), weight at operation (P = 0.647), pulmonary hypertension (P = 0.067), preoperative intensive care unit (ICU) days (P = 0.673), ventilator days (P = 0.944), or use of a patch (P = 0.999) between the groups. Seventy-nine percent of thoracoscopic operative approaches were completed successfully. There was a significant difference between the open and thoracoscopic groups with respect to estimated gestational age (39 versus 36.5 weeks; P = 0.006) and operating room time (70 versus 145 minutes; P = 0.004). The total (P = 0.662), ICU (P = 0.889), and postoperative (P = 0.619) length of stay and days on ventilator (P = 0.705), as well as days until initial enteral feeds (P = 0.092), were not significantly different between groups. There were no deaths and no evidence of recurrence, with a mean follow-up of 346 days.
In our early experience, the thoracoscopic approach for congenital diaphragmatic hernia repair was completed in 80% of our patient population with minimal exclusion criteria. Further study, with larger sample sizes, is needed to ascertain differences in outcomes, such as length of stay and initiation of enteral feeding.
PMCID: PMC2854018  PMID: 20059390
13.  Thoracoscopic Repair of Congenital Diaphragmatic Hernia in Infancy 
Minimally invasive surgical techniques, specifically the thoracoscopic approach, have been applied to congenital diaphragmatic hernia (CDH) with varying outcomes from selected centers. The aim of our study was to examine the rate of successful completion and compare outcomes between open and thoracoscopic approaches in CDH repair.
We performed a retrospective analysis of infants with CDH repair (From February 2004 to January 2008). Patients were divided into thoracoscopic and open groups, based on operative approach. We analyzed demographic, clinical, and hospitalization characteristics to compare the completion rate and outcomes in these two groups.
Analysis of 31 infants with CDH (14 thorascocopic and 17 open) demonstrated no differences in sex (P = 0.132), age (P = 0.807), birthweight (P = 0.256), weight at operation (P = 0.647), pulmonary hypertension (P = 0.067), preoperative intensive care unit (ICU) days (P = 0.673), ventilator days (P = 0.944), or use of a patch (P = 0.999) between the groups. Seventy-nine percent of thoracoscopic operative approaches were completed successfully. There was a significant difference between the open and thoracoscopic groups with respect to estimated gestational age (39 versus 36.5 weeks; P = 0.006) and operating room time (70 versus 145 minutes; P = 0.004). The total (P = 0.662), ICU (P = 0.889), and postoperative (P = 0.619) length of stay and days on ventilator (P = 0.705), as well as days until initial enteral feeds (P = 0.092), were not significantly different between groups. There were no deaths and no evidence of recurrence, with a mean follow-up of 346 days.
In our early experience, the thoracoscopic approach for congenital diaphragmatic hernia repair was completed in 80% of our patient population with minimal exclusion criteria. Further study, with larger sample sizes, is needed to ascertain differences in outcomes, such as length of stay and initiation of enteral feeding.
PMCID: PMC2854018  PMID: 20059390
14.  Radiological Diagnosis of Congenital Diaphragmatic Hernia in 17th Century Korean Mummy 
PLoS ONE  2014;9(7):e99779.
Congenital diaphragmatic hernia (CDH) is a birth defect of the diaphragm resulting in pulmonary sequelae that threaten the lives of infants. In computed tomography (CT) images of a 17th century middle-aged male mummy (the Andong mummy), we observed that the abdominal contents had protruded into the right thoracic cavity through the diaphragmatic defect, accompanied by a mediastinal shift to the left. On autopsy, the defect in the right posterolateral aspect of the diaphragm was reconfirmed, as was the herniation of the abdominal organs. The herniated contents included the right lobe of the liver, the pyloric part of the stomach, a part of the greater omentum, and the right colic flexure connecting the superior part of the ascending colon and the right part of the transverse colon. Taking our CT and autopsy results together, this case was diagnosed as the Bochdalek-type CDH. Herein we make the first ever report of a CT-assisted diagnosis of a pre-modern historical case of CDH. Our results show the promising utility of this modality in investigations of mummified human remains archaeologically obtained.
PMCID: PMC4079512  PMID: 24988465
15.  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
16.  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
17.  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
18.  Late presentation of congenital diaphragmatic Hernia after a diagnostic laparoscopic surgery (a case report) 
The authors report a rare case of 17-year-old lady with late presentation of congenital diaphragmatic hernia. She presented with vague abdominal pain and was thought to have urinary tract infection, ruptured ovarian cyst, and appendicitis by different medical teams in the first few days. She eventually underwent a diagnostic laparoscopy with no significant findings. In the early postoperative recovery period, she suffered from severe cardiorespiratory distress and a large intestinal left diaphragmatic hernia was diagnosed subsequently. At further operation a strangulated loop of large bowel herniating through a left antero-lateral congenital diaphragmatic hernia was discovered, which was reduced and repaired with a prolene mesh through thoracotomy. She made an excellent recovery and was discharged a few days after the operation. The authors postulate a mechanism of positive pressure from laparoscopic surgery causing herniation of large bowel through a pre-existing diaphragmatic defect. This case highlights the diagnostic challenge of this disease due to its diverse clinical presentation, the importance of prompt diagnosis and intervention.
PMCID: PMC3557185  PMID: 23317447
Congenital diaphragmatic hernia; Delayed presentation; Diagnosis; Laparoscopic surgery; Prolene mesh; Hernia repair
19.  Pleural and pericardial effusion: a potential ultrasonographic marker for the prenatal differential diagnosis between congenital diaphragmatic eventration and congenital diaphragmatic hernia 
To determine whether or not the presence of pleural and/or pericardial effusion can be used prenatally as an ultrasonographic marker for the differential diagnosis between diaphragmatic eventration and diaphragmatic hernia.
We present two case reports of non-isolated diaphragmatic eventration associated with pleural and/or pericardial effusion. Additionally, we reviewed the literature for all cases of congenital diaphragmatic hernia (CDH) and diaphragmatic eventration that met the following criteria: (1) prenatal diagnosis of a diaphragmatic defect and (2) definitive diagnosis by autopsy or surgery. The frequencies of pleural effusion, pericardial effusion, and hydrops were compared between the two conditions using the Fisher’s exact test. A subanalysis was conducted of cases with isolated diaphragmatic defects (i.e. diaphragmatic defects not associated with hydrops and other major structural or chromosomal anomalies).
A higher proportion of fetuses with diaphragmatic eventration had associated pleural and pericardial effusions compared with fetuses with diaphragmatic hernia (58% (7/12) vs. 3.7% (14/382), respectively, P < 0.001). This observation remained true when only cases of diaphragmatic defects not associated with hydrops and other major structural or chromosomal anomalies were compared (29% (2/7) with eventration vs. 2.2% (4/178) with CDH, P < 0.02).
The presence of pleural and/or pericardial effusion in patients with diaphragmatic defects should raise the possibility of a congenital diaphragmatic eventration. This information is clinically important for management and counseling because the prognosis and treatment for CDH and congenital diaphragmatic eventration are different.
PMCID: PMC2391071  PMID: 17366518
congenital diaphragmatic hernia; diaphragmatic eventration; pericardial effusion; pleural effusion
20.  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
21.  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
22.  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
23.  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
24.  Repair of diaphragmatic hernia following spinal surgery by laparoscopic mesh application: a case report and review of the literature 
We describe the laparoscopic management of diaphragmatic hernia (DH) caused by vertebral pedicle screw displacement.
A 58-year-old woman underwent surgery for scoliosis and underwent posterior pedicle screw fixation. In the first postoperative (PO)day, she developed mild dyspnea. An anteroposterior chest radiograph revealed bilateral pleural effusion, which was more pronounced on the left side.
A thoracoabdominal computed tomography (CT) scan, performed in the second PO day, revealed a solid mass in the pleural cavity that was associated with screw displacement, which had also entered into the peritoneal cavity without apparent other lesion of hollow and solid viscous. In the third PO day, after the screw was removed, explorative laparoscopy was carried out. We observed herniation of the omentum through a small diaphragmatic tear. Once the absence of visceral injury was confirmed, we reduced the omentum into the abdomen. Then, we repaired the hernia by applying a dual layer polypropylene mesh over the defect with a 3-cm overlap. The remainder of the postoperative period was uneventful.
Iatrogenic DH due to a pedicle screw displacement has never been described before. In cases of pleural effusion following spinal surgery, rapid assessment and treatment are crucial. We conclude that a laparoscopic approach to iatrogenic DH could be feasible and effective in a hemodynamically stable patient with negative CT findings because it enables the completion of the diagnostic cascade and the repair of the tear, providing excellent visualization of the abdominal viscera and diaphragmatic tears.
PMCID: PMC4012096  PMID: 24808922
Diaphragmatic hernia; Surgical complication; Mesh repair; Laparoscopic repair
25.  Intrathoracic intestinal diverticulum in a late presenting congenital bilateral diaphragmatic hernia: a case report 
Hernias comprise 3% of all defects of the diaphragm. Bilateral hernias are extremely rare and usually occur in children. Here we present a case report of a bilateral Morgagni-Larrey diaphragmatic hernia with an intrathoracic intestinal diverticulum and late presentation. To the best of our knowledge this is the first report of this type.
Case presentation
A 37-year-old Hispanic man was admitted to our emergency department with a 4-day history of obstipation, abdominal pain, distension, nausea, and vomiting. During the initial evaluation, chest and abdominal X-rays were performed, which revealed intestinal displacement into his right and left hemithorax. During laparotomy, a Morgagni-Larrey hernia with a sac was found. His small bowel with a large diverticulum, transverse colon, descending colon, and epiploic fat were herniated into his thorax. Tissues were returned to his abdominal cavity and the hernia defects were corrected with running non-absorbable sutures. He had no postoperative complications.
Bilateral congenital diaphragmatic hernias remain extremely rare. However, they should be considered in adult patients with intestinal obstruction even when respiratory symptoms are absent. This is the first description of a patient with a prolapsed intestinal diverticulum and bilateral diaphragmatic hernias.
PMCID: PMC3892098  PMID: 24377864
Bilateral congenital diaphragmatic hernia; Congenital diaphragmatic hernia; Late presenting diaphragmatic hernia; Morgagni-Larrey hernia

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