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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.

INTRODUCTION

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).

PRESENTATION OF CASE

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.

DISCUSSION

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.

CONCLUSION

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.

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.

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.

Introduction

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.

Conclusion

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.

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.

Images

Objective:

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.

Methods:

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.

Results:

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).

Conclusions:

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.

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.

Background

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.

Methods

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.

Results

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.

Conclusion

In PH and CDH defects of ANG-1/TIE-2/BMPR-related signalling are not essential for the lethal vasculopathy.

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.

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.

Background

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.

Conclusions

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

Background.

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 http://dx.doi.org/10.1371/journal.pmed.0040237.

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)

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.

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.

Methods:

A retrospective chart review was performed on a single patient for data collection purposes.

Results:

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.

Conclusion:

Laparoscopic repair of symptomatic adult Bochdalek hernias can be performed successfully and may result in significant clinical improvement.

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.

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.

Background

Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect. Most of the genetic factors that contribute to the development of CDH remain unidentified.

Objective

Identify genomic alterations that contribute to the development of diaphragmatic defects.

Methods

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.

Results

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.

Conclusions

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.

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.

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.

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.

Purpose

Operative approach, including minimally invasive surgery (MIS) in the repair of congenital diaphragmatic hernia (CDH), is variable among institutions. The short-term recurrent hernia rate is not well described. We evaluated the in-hospital recurrence rate of MIS repairs of infants with CDH from the Congenital Diaphragmatic Hernia Registry (CDHR).

Methods

Prospectively collected data from CDH infants were analyzed from the CDHR from January 1995 to January 2010. Recurrent hernia was defined as reoperations during initial hospitalization. Operative approaches included abdominal, thoracic, laparoscopic, and thoracoscopic techniques.

Results

5,480 infants with CDH were identified of which 4,516 (82.4%) were repaired. Operative data was available in 4,390 infants. One hundred fifty-one infants (3.4%) underwent MIS repairs with twelve reported recurrences (7.9%) compared to one hundred fourteen for open techniques (2.7%, p < 0.05). MIS demonstrated a significant increased odds for recurrence (OR 3.59, 95% CI:1.92 – 6.71) after adjusting for gestational age, birth weight, patch repair, and ECMO.

Conclusion

Minimally invasive techniques appear to have a significant higher recurrent hernia rate with thoracoscopy being the highest. Although adjusted for patch repair, other factors with regards to disease severity may contribute to differences in outcomes among centers. This study is limited to short-term recurrence during initial hospitalization.

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.

A newborn female infant born to a woman on immunosuppressive medications including mycophenolate mofetil (MMF) for a renal graft secondary to lupus nephritis presented with congenital diaphragmatic hernia (CDH) and additional findings of microtia, esophageal atresia with tracheoesophageal fistula, cleft palate, congenital heart defect, digital anomalies, and dysmorphic facial features. Pulmonary hypoplasia resulted in death at day two of life. She was presumed to have Fryns syndrome based on diagnostic criteria established for this recessive disorder with prominent features including CDH, facial anomalies, and nail hypoplasia. In retrospect, this infant's findings are more likely the result of teratogenic exposure to MMF, as more recent data have emerged linking aural atresia, digital anomalies, and dysmorphic features to this drug. To date, this is the only human report of CDH in an infant with prenatal exposure to MMF, although the manufacturer's package insert alludes to animal studies with a broad spectrum of malformations, including CDH. Thus, a teratogenic exposure can mimic a known Mendelian genetic syndrome, and caution is urged in presuming a genetic etiology for infants with potential teratogenic exposure to relatively new drugs with limited published animal data.

Rationale: Endothelin-1 (ET1) is dysregulated in pulmonary hypertension (PH). It may be important in the pathobiology of congenital diaphragmatic hernia (CDH).

Objectives: We hypothesized that ET1 levels in the first month would be higher in infants with CDH who subsequently expired or were discharged on oxygen (poor outcome). We further hypothesized that ET1 levels would be associated with concurrent severity of PH.

Methods: We sampled plasma at 24 to 48 hours, and 1, 2, and 4 weeks of age in 40 prospectively enrolled newborns with CDH. We performed echocardiograms to estimate pulmonary artery pressure at less than 48 hours of age and weekly to 4 weeks. PH was classified in relationship to systemic blood pressure (SBP): less than 2/3 SBP, 2/3 SBP-systemic is related to pressure, or systemic-to-suprasystemic pressure.

Measurements and Main Results: ET1 levels at 1 and 2 weeks were higher in infants with poor outcome compared with infants discharged on room air (median and interquartile range: 27.2 [22.6, 33.7] vs. 19.1 [16.1, 29.5] pg/ml, P = 0.03; and 24.9 [17.6, 39.5] vs. 17.4 [13.7, 21.8] pg/ml, P = 0.01 at 1 and 2 weeks, respectively). Severity of PH was significantly associated with increasing ET1 levels at 2 weeks (16.1 [13.7, 21.8], 21.0 [17.4, 31.1], and 23.6 [21.9, 39.5] pg/ml for increasing PH class, P = 0.03). Increasing severity of PH was also associated with poor outcome at that time (P = 0.001).

Conclusions: Infants with CDH and poor outcome have higher plasma ET1 levels and severity of PH than infants discharged on room air. Severity of PH is associated with ET1 levels.

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.