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Classifications

Harrison's Chapter

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Inheritance

1

Multifactorial inheritance with a polygenic component HP:0010982

Most CDH is sporadic. Genome-wide analysis supports a liability model in which common polygenic background acts together with rare, large-effect de novo variants; Mendelian inheritance applies only to the recognised syndromic and monogenic forms (autosomal dominant with incomplete penetrance, autosomal recessive, or chromosomal).

Polygenic inheritance

Show evidence (3 references)

PMID:39332409 SUPPORT Human Clinical

"The data support a polygenic model as part of the CDH genetic architecture."

A 1,469-individual integrated de novo and common-variant study concludes that a polygenic component contributes to CDH liability.

PMID:39332409 SUPPORT Human Clinical

"Strikingly, there is no significant difference in estimated polygenic risk scores between isolated and complex CDH or between individuals harboring deleterious de novo variants and individuals without these variants."

Shows the polygenic background is shared across isolated and complex CDH rather than defining separate genetic classes.

PMID:35650272 SUPPORT Human Clinical

"Although the aetiology remains unknown, CDH has a polygenic origin in approximately one-third of cases."

Supports a polygenic contribution in a substantial fraction of cases.

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Subtypes

5

Bochdalek (posterolateral) hernia

The posterolateral defect arising from failure of pleuroperitoneal fold closure, accounting for the large majority of congenital diaphragmatic hernias and predominantly left-sided.

Show evidence (2 references)

PMID:22214468 SUPPORT Human Clinical

"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."

Establishes the posterolateral (Bochdalek) left-sided defect as the predominant anatomic form.

PMID:37990078 SUPPORT Other

"This includes the most commonly occurring Bochdalek CDH that is characterized by a hole in the posterolateral diaphragm"

Names the Bochdalek posterolateral defect as the most common anatomic form of CDH.

Morgagni (anterior retrosternal) hernia

An anterior, retrosternal parasternal defect at the sternocostal trigone, much less common than Bochdalek hernia and often presenting later in infancy or childhood.

Show evidence (1 reference)

PMID:37990078 SUPPORT Other

"anterior holes through the foramen of Morgagni"

Identifies the anterior foramen-of-Morgagni defect as a distinct anatomic subtype of CDH.

Central (septum transversum) defect

A central tendon defect derived from abnormal septum transversum development, the least common anatomic form.

Show evidence (1 reference)

PMID:37990078 PARTIAL Other

"diaphragm eventrations"

The same anatomic classification enumerates central tendon defects alongside eventrations as the rarest diaphragmatic defects; the phrase quoted here is the adjacent category in that enumeration, so support for the central-defect subtype specifically is partial.

Isolated CDH

CDH occurring without additional major structural anomalies or a recognized syndromic diagnosis. Roughly half of all cases are isolated, and isolated disease has a substantially lower genetic diagnostic yield than complex CDH.

Show evidence (1 reference)

PMID:36441118 SUPPORT Human Clinical

"Among 9.5 million livebirths, we identified 1285 with isolated CDH and 1150 with complex CDH."

A national birth cohort operationalises the isolated versus complex (syndromic) split and shows the two groups are of comparable size.

Syndromic (complex) CDH

CDH occurring as one feature of a recognized malformation syndrome or chromosomal disorder, including Fryns syndrome, Donnai-Barrow syndrome, Pallister-Killian syndrome, and 15q26 deletion involving NR2F2, plus monogenic forms attributable to ZFPM2, GATA4, WT1, LONP1, or MYRF.

Show evidence (2 references)

PMID:22214468 SUPPORT Human Clinical

"CDH can be a component of Pallister-Killian, Fryns, Ghersoni-Baruch, WAGR, Denys-Drash, Brachman-De Lange, Donnai-Barrow or Wolf-Hirschhorn syndromes."

Enumerates the recognised malformation syndromes in which CDH occurs as a component feature.

PMID:36441118 SUPPORT Human Clinical

"The 1-year mortality rate for complex CDH (33.1%, 95% CI 30.5, 35.9) was slightly higher than for isolated CDH (29.7%, 95% CI 27.3, 32.3)"

Quantifies the prognostic difference between complex (syndromic) and isolated CDH in a national cohort.

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Mechanistic Hypotheses

3

Dual-hit model (primary lung maldevelopment plus mechanical compression)

dual_hit CANONICAL

Evidence balance 3 support

The dual-hit model holds that the lung phenotype in CDH is not purely mechanical. A first hit perturbs lung development directly, in parallel with the diaphragmatic lesion and through the same mesenchymal and retinoid-dependent programmes; a second hit is the physical compression of the developing lung by herniated viscera. This model explains why the contralateral lung is also hypoplastic and why anatomic repair does not immediately reverse the lung and vascular disease.

Pathograph links

Retinoid Signaling and Pleuroperitoneal Fold Mesenchymal Deficit -> Pulmonary Hypoplasia INDIRECT UNKNOWN INTERMEDIATES The "first hit" of the dual-hit model: the same early developmental perturbation that impairs pleuroperitoneal fold outgrowth also acts directly on the developing lung, before and independently of the diaphragmatic defect. This edge is asserted only under the dual-hit hypothesis group; under the competing purely mechanical model it does not exist, and all pulmonary hypoplasia is secondary to compression.

Failure of Diaphragm Closure and Visceral Herniation -> Pulmonary Hypoplasia DIRECT Space occupation by herniated viscera restricts lung growth during the pseudoglandular and canalicular stages. This is the "second hit" of the dual-hit model and the whole of the competing purely mechanical model, so the edge is shared by both hypothesis groups.

Show evidence (3 references)

PMID:39183805 SUPPORT Other

"The occurrence of CDH and pulmonary hypoplasia is theorized to result from both abnormalities in signaling pathways of smooth muscle cells in pleuroperitoneal folds and mechanical compression by abdominal organs within the chest cavity on the developing lungs."

States both components of the dual-hit model as jointly responsible for the CDH lung phenotype.

PMID:39018718 SUPPORT Other

"in CDH, this embryologic development is impaired which, in conjunction with external compression, stifle pulmonary vascular maturation"

Applies the same dual-hit logic to the pulmonary vascular arm: intrinsic developmental impairment acting together with external compression.

PMID:10751355 SUPPORT In Vitro

"Therefore, we postulate the dual-hit hypothesis, which explains pulmonary hypoplasia in CDH by two insults, one affecting both lungs before diaphragm development and one affecting the ipsilateral lung after defective diaphragm development."

The primary statement of the dual-hit hypothesis, from nitrofen-exposed rat lung explants cultured without any diaphragmatic defect.

Purely mechanical compression model

mechanical_compression_only ALTERNATIVE

Evidence balance 1 partial 1 refute

The older and still not fully excluded model holds that the lung in CDH is intrinsically normal and that pulmonary hypoplasia is entirely secondary to mechanical compression by herniated viscera during the pseudoglandular and canalicular stages. Under this model the only causal route to pulmonary hypoplasia is the compression edge, and prenatal decompression or tracheal occlusion should be able to restore normal lung growth. It is retained here as an explicit alternative because the pathogenesis of the CDH lung phenotype is described in the primary literature as controversial, and because the fetal-lamb surgical-compression experiments that founded the field are consistent with it. Evidence against it includes hypoplasia of the contralateral lung and lung maldevelopment in explants never exposed to compression.

Pathograph links

Failure of Diaphragm Closure and Visceral Herniation -> Pulmonary Hypoplasia DIRECT Space occupation by herniated viscera restricts lung growth during the pseudoglandular and canalicular stages. This is the "second hit" of the dual-hit model and the whole of the competing purely mechanical model, so the edge is shared by both hypothesis groups.

Show evidence (2 references)

PMID:10751355 PARTIAL In Vitro

"Moreover, the pathogenesis of pulmonary hypoplasia in case of CDH is controversial."

Establishes that the compression-only versus primary-maldevelopment question is a genuine live controversy rather than a settled matter, which is why the alternative is curated rather than discarded.

PMID:10751355 REFUTE In Vitro

"Our results indicate that Nitrofen negatively influences branching morphogenesis of the lung."

Impaired branching in an explant system with no diaphragm and no compression is direct evidence against a purely mechanical model.

Retinoid hypothesis of abnormal diaphragm development

retinoid CANONICAL

Evidence balance 1 support

The retinoid hypothesis, formulated by Greer, Babiuk and Thebaud in 2003 and reviewed twenty years later, holds that abnormalities of retinoic acid signalling early in gestation underlie abnormal diaphragm development in CDH. It is supported by teratogen models that inhibit retinoic acid synthesis, by vitamin-A-deficiency models, and by human genetic lesions in retinoid transport and signalling such as STRA6 and NR2F2.

Pathograph links

Retinoid Signaling and Pleuroperitoneal Fold Mesenchymal Deficit -> Failure of Diaphragm Closure and Visceral Herniation DIRECT A deficient pleuroperitoneal fold fails to close the pleuroperitoneal canal, leaving a diaphragmatic defect.

Show evidence (1 reference)

PMID:37990078 SUPPORT Other

"The Retinoid Hypothesis is one of the leading hypotheses to explain the etiology of CDH"

Establishes the standing of the retinoid hypothesis in the field.

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Discussions and Knowledge Gaps

2

Does inhaled nitric oxide improve outcome in CDH-associated pulmonary hypertension, or does its routine use mainly delay escalation to extracorporeal support?

CONTROVERSY OPEN cdh_ino_efficacy

Attached to

pathophysiology#Persistent Pulmonary Hypertension of the Newborn

Inhaled nitric oxide is widely used in CDH by extrapolation from other causes of persistent pulmonary hypertension of the newborn, but the CDH vascular bed is structurally reduced rather than merely vasoconstricted, so a selective vasodilator may have limited substrate on which to act. The published evidence base is small and the reviewed conclusion is that the role of iNO in CDH is controversial.

Proposed experiments

Randomised trial of inhaled nitric oxide in CDH-associated pulmonary hypertension

cdh_ino_rct

An adequately powered randomised trial of inhaled nitric oxide versus placebo in CDH-associated pulmonary hypertension, stratified by echocardiographic phenotype, with time to extracorporeal support as a co-primary outcome alongside survival to discharge.

Show evidence (1 reference)

PMID:32384329 SUPPORT Other

"the role of iNO as a treatment for CDH is controversial."

Documents that the efficacy question is unresolved in the literature.

How faithfully do the nitrofen rat model and retinoid-pathway mouse mutants reproduce human CDH, given that the human disease is genetically heterogeneous and usually not attributable to a single teratogen or a single retinoid-pathway lesion?

HUMAN MODEL MISMATCH OPEN cdh_nitrofen_model_fidelity

Attached to

pathophysiology#Retinoid Signaling and Pleuroperitoneal Fold Mesenchymal Deficit

Most mechanistic knowledge of diaphragm and lung maldevelopment in CDH derives from teratogen-induced and genetically modified rodents. These models reproduce components of the phenotype - amuscular diaphragm, posterolateral defects, reduced branching - but no single model captures the full human spectrum, and rodent lethality prevents study of the chronic survivor morbidity that dominates the human disease.

Proposed experiments

Cross-species single-cell comparison of pleuroperitoneal fold mesenchyme

cdh_ppf_cross_species_sc

Single-cell profiling of human fetal pleuroperitoneal fold and lung mesenchyme compared against the corresponding rodent compartments in nitrofen-exposed and retinoid-pathway mutant animals, to test whether the cell states perturbed in the models are the ones perturbed in human CDH.

Show evidence (2 references)

PMID:35633948 SUPPORT Model Organism

"the generation of genetically modified mouse models, which show both diaphragm and lung abnormalities, has resulted in the discovery of multiple genes and signaling pathways involved in the pathogenesis of CDH"

Establishes that the mechanistic evidence base is largely murine, which is what makes translational fidelity the open question.

PMID:35633948 SUPPORT Model Organism

"whilst also discussing the significance of these genetic models for studying altered lung development with regard to the human situation"

The cited review itself frames the human relevance of these models as a question requiring discussion rather than a settled matter.

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Pathophysiology

8

Retinoid Signaling and Pleuroperitoneal Fold Mesenchymal Deficit

The proximate developmental lesion in CDH is a deficit of the pleuroperitoneal fold (PPF) mesenchyme, the transient structure whose expansion closes the pleuroperitoneal canal. Retinoic acid signaling is required for PPF outgrowth, and disruption of the retinoid pathway or of PPF mesenchymal transcriptional regulators such as ZFPM2, GATA4, NR2F2 and WT1 reduces the amplifying PPF cell population.

Dual-hit model (primary lung maldevelopment plus mechanical compression) Retinoid hypothesis of abnormal diaphragm development

pleuroperitoneal fold mesenchymal cell CL:0008019

ALDH1A2 (RALDH2) hgnc:15472

retinoic acid receptor signaling pathway GO:0048384 ↓ DECREASED diaphragm development GO:0060539 ⚠ ABNORMAL

Downstream

Failure of Diaphragm Closure and Visceral Herniation A deficient pleuroperitoneal fold fails to close the pleuroperitoneal canal, leaving a diaphragmatic defect.

Pulmonary Hypoplasia The "first hit" of the dual-hit model: the same early developmental perturbation that impairs pleuroperitoneal fold outgrowth also acts directly on the developing lung, before and independently of the diaphragmatic defect. This edge is asserted only under the dual-hit hypothesis group; under the competing purely mechanical model it does not exist, and all pulmonary hypoplasia is secondary to compression.

Show evidence (5 references)

PMID:39183805 SUPPORT Other

"The occurrence of CDH and pulmonary hypoplasia is theorized to result from both abnormalities in signaling pathways of smooth muscle cells in pleuroperitoneal folds and mechanical compression by abdominal organs within the chest cavity on the developing lungs."

Places the pleuroperitoneal fold signalling defect upstream of both the diaphragmatic defect and the lung phenotype.

PMID:37990078 SUPPORT Other

"In 2003, Greer et al. proposed the Retinoid Hypothesis, stating that the underlying cause of abnormal diaphragm development in CDH was related to altered retinoid signaling."

States the retinoid hypothesis, the leading mechanistic account of the proximate developmental lesion in CDH.

PMID:28768736 SUPPORT Other

"The affected genes identified in CDH patients include transcription factors, such as GATA4, ZFPM2, NR2F2 and WT1, and signaling pathway components, including members of the retinoic acid pathway."

Links the mesenchymal transcriptional regulators and the retinoic acid pathway named in this node to human CDH genetics.

+ 2 more references

Failure of Diaphragm Closure and Visceral Herniation

Incomplete closure of the pleuroperitoneal canal leaves a diaphragmatic defect through which abdominal viscera herniate into the thorax during fetal life. The herniated viscera occupy the hemithorax and compress the developing lung, most often on the left.

Dual-hit model (primary lung maldevelopment plus mechanical compression) Purely mechanical compression model

diaphragm morphogenesis GO:0060540 ⚠ ABNORMAL

diaphragm UBERON:0001103

Downstream

Pulmonary Hypoplasia Space occupation by herniated viscera restricts lung growth during the pseudoglandular and canalicular stages. This is the "second hit" of the dual-hit model and the whole of the competing purely mechanical model, so the edge is shared by both hypothesis groups.

Pulmonary Vascular Maldevelopment and Remodeling The same developmental window that limits airway branching also limits and distorts pulmonary vascular development.

Congenital diaphragmatic hernia The anatomic defect is the defining clinical finding.

Posterolateral diaphragmatic hernia Failure of pleuroperitoneal fold closure specifically produces the posterolateral (Bochdalek) defect.

Morgagni diaphragmatic hernia Failure of closure at the sternocostal trigone produces the anterior retrosternal (Morgagni) defect.

Central diaphragmatic hernia Abnormal septum transversum development produces the central tendon defect.

Scaphoid abdomen Relocation of abdominal viscera into the thorax leaves the abdomen empty, producing the sunken newborn abdominal contour.

Gastroesophageal reflux Distortion of the oesophageal hiatus and gastro-oesophageal junction anatomy by the defect and its repair predisposes to reflux in survivors.

Left Heart Hypoplasia in Left-Sided CDH Mediastinal shift and compression by herniated viscera, most often on the left, restrict filling and growth of the left-sided cardiac structures.

Scoliosis Thoracic cage growth asymmetry after a large defect and its repair produces spinal deformity in long-term survivors.

Pectus excavatum The same asymmetric chest wall growth, and abdominal closure under tension after repair, produce anterior chest wall deformity in survivors.

Show evidence (2 references)

PMID:35650272 SUPPORT Human Clinical

"Congenital diaphragmatic hernia (CDH) is a rare birth defect characterized by incomplete closure of the diaphragm and herniation of fetal abdominal organs into the chest that results in pulmonary hypoplasia, postnatal pulmonary hypertension owing to vascular remodelling and cardiac dysfunction."

Establishes the causal ordering from incomplete diaphragm closure and visceral herniation to pulmonary hypoplasia and pulmonary hypertension.

PMID:31519366 SUPPORT Other

"Congenital diaphragmatic hernia (CDH) is a neonatal pathology in which intrathoracic herniation of abdominal viscera via diaphragmatic defect results in aberrant pulmonary and cardiovascular development."

Supports the edge from the diaphragmatic defect to both the pulmonary parenchymal and the pulmonary vascular arms of the graph.

Pulmonary Hypoplasia

Both lungs, and particularly the ipsilateral lung, show reduced airway branching generations, reduced alveolar number and surface area, thickened alveolar septa, and surfactant abnormalities. The parenchymal deficit is bilateral even when the defect is unilateral, indicating a primary developmental component in addition to mechanical compression.

pulmonary alveolar type 2 cell CL:0002063

branching morphogenesis of an epithelial tube GO:0048754 ↓ DECREASED lung alveolus development GO:0048286 ↓ DECREASED

lung UBERON:0002048

Downstream

Refractory Hypoxemia and Neonatal Respiratory Failure Reduced alveolar surface area limits gas exchange from the first postnatal breaths.

Pulmonary hypoplasia Reduced lung parenchymal mass is the defining structural phenotype.

Chronic lung disease A structurally deficient lung that must then be ventilated develops chronic oxygen dependency and long-term respiratory morbidity.

Show evidence (2 references)

PMID:39183805 SUPPORT Other

"Congenital diaphragmatic hernia (CDH) is a congenital malformation characterized by failure of diaphragm closure during embryonic development, leading to pulmonary hypoplasia and pulmonary hypertension, which contribute significantly to morbidity and mortality."

Identifies pulmonary hypoplasia as the principal determinant of morbidity and mortality downstream of the diaphragmatic defect.

PMID:35633948 SUPPORT Model Organism

"CDH is accompanied by immature and hypoplastic lungs, being the leading cause of morbidity and mortality in patients with this condition."

Genetically modified mouse models reproduce the combination of diaphragm defect and hypoplastic, immature lung.

Pulmonary Vascular Maldevelopment and Remodeling

The pulmonary vascular bed in CDH is reduced in cross-sectional area, with fewer arterial generations per unit lung, and the pre-acinar and intra-acinar arteries show adventitial thickening and abnormal medial muscularization extending peripherally into vessels that are normally non-muscular. Endothelial dysfunction with reduced nitric oxide signaling accompanies the structural remodeling.

pulmonary artery smooth muscle cell CL:0000359 pulmonary artery endothelial cell CL:0000115

blood vessel remodeling GO:0001974 ↕ DYSREGULATED lung vasculature development GO:0060426 ⚠ ABNORMAL smooth muscle cell proliferation GO:0048659 ↑ INCREASED nitric oxide biosynthetic process GO:0006809 ↓ DECREASED

Downstream

Persistent Pulmonary Hypertension of the Newborn A reduced and abnormally muscularized vascular bed raises pulmonary vascular resistance after birth.

Show evidence (2 references)

PMID:39018718 SUPPORT Other

"in CDH, this embryologic development is impaired which, in conjunction with external compression, stifle pulmonary vascular maturation, leading to reduced lung density, increased muscularization of the pulmonary vasculature, abnormal vascular responsiveness, and altered molecular signaling, all..."

Directly describes the reduced vascular bed, increased muscularisation and abnormal vasoreactivity that constitute this node, and links them to pulmonary arterial hypertension.

PMID:31519366 SUPPORT Other

"In patients with CDH, hypoplastic pulmonary vasculature and alterations in multiple molecular pathways lead to pathophysiologic pulmonary vasculopathy and, for severe CDH, sustained, elevated pulmonary arterial pressures."

Supports the causal edge from pulmonary vascular maldevelopment and remodelling to sustained pulmonary arterial hypertension.

Persistent Pulmonary Hypertension of the Newborn

The structurally reduced and hypermuscularized pulmonary vascular bed, combined with abnormal vasoreactivity, prevents the normal postnatal fall in pulmonary vascular resistance. Suprasystemic pulmonary pressures drive right-to-left shunting across the ductus arteriosus and foramen ovale.

vasoconstriction GO:0042310 ↑ INCREASED

Downstream

Right Ventricular Pressure Overload and Failure Sustained high afterload overloads the right ventricle.

Refractory Hypoxemia and Neonatal Respiratory Failure Extrapulmonary right-to-left shunting adds a component of hypoxemia that is unresponsive to increased inspired oxygen.

Pulmonary arterial hypertension Elevated pulmonary arterial pressure is directly observed clinically.

Show evidence (2 references)

PMID:35650272 SUPPORT Human Clinical

"The high mortality and morbidity rates associated with CDH are directly related to the severity of cardiopulmonary pathophysiology."

Attributes CDH outcome to the combined pulmonary hypertensive and cardiac physiology represented by this node and its downstream targets.

PMID:39018718 SUPPORT Other

"Longitudinal re-evaluation is an important consideration due to the complexity and dynamic nature of CDH cardiopulmonary physiology."

Supports the labile, dynamic character of CDH pulmonary hypertension during and after the neonatal transition.

Right Ventricular Pressure Overload and Failure

Persistent pulmonary hypertension imposes high afterload on a right ventricle that may itself be hypoplastic or intrinsically dysfunctional in CDH. Progressive right ventricular dilation and failure reduce pulmonary blood flow and left ventricular preload, producing systemic hypoperfusion.

cardiac muscle cell CL:0000746

Downstream

Right ventricular failure Right heart decompensation is the clinical manifestation.

Show evidence (1 reference)

PMID:28768736 SUPPORT Other

"Congenital diaphragmatic hernias (CDHs) and structural anomalies of the diaphragm are a common class of congenital birth defects that are associated with significant morbidity and mortality due to associated pulmonary hypoplasia, pulmonary hypertension and heart failure."

Places heart failure alongside pulmonary hypoplasia and pulmonary hypertension as a proximate cause of death in CDH.

Left Heart Hypoplasia in Left-Sided CDH

In left-sided CDH the herniated viscera displace the mediastinum to the right and compress the left heart during the period of fetal cardiac growth. Left-sided structures (mitral valve, aortic valve, left ventricle) are correspondingly smaller, in proportion to lung size and the extent of liver herniation. This is a distinct arm from the right ventricular pressure overload driven by pulmonary hypertension, and it contributes to the low-output physiology and vasodilator intolerance of severe disease.

cardiac muscle cell CL:0000746

left cardiac ventricle UBERON:0002084

Downstream

Hypoplastic left ventricle Reduced left ventricular dimensions are the observed structural phenotype.

Show evidence (3 references)

PMID:28370263 SUPPORT Human Clinical

"Fetuses with congenital diaphragmatic hernia (CDH) demonstrate varying degrees of left heart hypoplasia."

Establishes left heart hypoplasia as a recognised structural consequence of CDH, distinct from the right ventricular arm already modelled.

PMID:28370263 SUPPORT Human Clinical

"Fetal mitral valve z-score correlated with lung-to-head ratio (p = 0.04), postnatal mitral valve z-score correlated with percent liver herniation"

Ties the degree of left-sided cardiac hypoplasia quantitatively to the classic indices of herniation severity, supporting the causal edge from visceral herniation to this node.

PMID:28370263 PARTIAL Human Clinical

"Smaller aortic valve z-score was associated with iNO use; however, left heart dimensions showed no association with extracorporeal membrane oxygenation or mortality."

Qualifies the clinical weight of this arm: left heart hypoplasia tracks with vasodilator requirement but was not shown to predict extracorporeal support or death in this cohort.

Refractory Hypoxemia and Neonatal Respiratory Failure

The combination of reduced alveolar gas-exchange surface, ventilation limited by a small and stiff lung, and extrapulmonary right-to-left shunting produces severe hypoxemia that is frequently refractory to conventional ventilation and inhaled vasodilators.

Downstream

Respiratory failure Failure of gas exchange at birth.

Hypoxemia Severe and often labile arterial desaturation.

Cyanosis Visible manifestation of arterial desaturation.

Neurodevelopmental delay Prolonged hypoxemia and the intensive care it necessitates (prolonged ventilation, extracorporeal support) are the recognised route to neurodevelopmental impairment in survivors.

Sensorineural hearing impairment Hearing loss in survivors is attributed to the same prolonged critical illness and extracorporeal support exposure rather than to a primary cochlear lesion.

Failure to thrive Increased work of breathing and prolonged respiratory morbidity drive the postnatal growth failure seen in survivors.

Show evidence (2 references)

PMID:37990078 SUPPORT Other

"Congenital diaphragmatic hernia (CDH) is a severe birth defect and a major cause of neonatal respiratory distress."

Identifies neonatal respiratory failure as the terminal clinical manifestation of the CDH causal chain.

PMID:39018718 SUPPORT Other

"extracorporeal life support (ECLS) for refractory cases"

The routine need for extracorporeal support attests to the refractory character of the hypoxemia modelled at this node.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

21

Cardiovascular 2

Pulmonary arterial hypertension FREQUENT Pulmonary arterial hypertension HP:0002092

Show evidence (2 references)

PMID:22214468 SUPPORT Human Clinical

"The lungs are hypoplastic and have abnormal vessels that cause respiratory insufficiency and persistent pulmonary hypertension with high mortality."

Documents persistent pulmonary hypertension as a core CDH phenotype arising from abnormal pulmonary vasculature. FREQUENT is a clinical estimate; neither cited abstract reports a percentage.

PMID:39018718 SUPPORT Other

"Understanding CDH-associated PH (CDH-PH) is crucial for development of novel approaches and effective management due to its significant impact on morbidity and mortality."

Confirms CDH-associated pulmonary hypertension as a frequent and outcome-determining phenotype.

Congenital heart defect FREQUENT Abnormal heart morphology HP:0001627

Show evidence (1 reference)

PMID:22214468 SUPPORT Human Clinical

"About one third of cases have cardiovascular malformations and lesser proportions have skeletal, neural, genitourinary, gastrointestinal or other defects."

Quantifies co-occurring cardiovascular malformations in approximately a third of CDH cases; one third (about 33%) falls in the FREQUENT band (30-79%).

Digestive 1

Gastroesophageal reflux FREQUENT Gastroesophageal reflux HP:0002020

Temporal: CHRONIC

Show evidence (1 reference)

PMID:22214468 SUPPORT Human Clinical

"Chronic respiratory tract disease, neurodevelopmental problems, neurosensorial hearing loss and gastroesophageal reflux are common problems in survivors."

Documents gastro-oesophageal reflux as a common long-term morbidity. The qualitative term "common" maps to the FREQUENT band (30-79%); note the denominator in the source is CDH survivors, not all CDH cases.

Ear 1

Sensorineural hearing impairment Sensorineural hearing impairment HP:0000407

Show evidence (1 reference)

PMID:22214468 SUPPORT Human Clinical

"Chronic respiratory tract disease, neurodevelopmental problems, neurosensorial hearing loss and gastroesophageal reflux are common problems in survivors."

Documents neurosensorial (sensorineural) hearing loss as a common survivor morbidity in CDH.

Integument 1

Cyanosis Cyanosis HP:0000961

Show evidence (1 reference)

PMID:31519366 PARTIAL Other

"intrathoracic herniation of abdominal viscera via diaphragmatic defect results in aberrant pulmonary and cardiovascular development"

Supports the aberrant cardiopulmonary physiology whose bedside expression is central cyanosis; the specific sign is not separately quantified in the cited abstract.

Musculoskeletal 2

Scoliosis OCCASIONAL Scoliosis HP:0002650

Course: PROGRESSIVE

Show evidence (3 references)

PMID:31482324 SUPPORT Human Clinical

"28 patients (28.6%) had at least one type of musculoskeletal deformities, 2 of which were pectus carinatum, 16 were pectus excavatum, and 18 were scoliosis."

In a 98-patient left-CDH survivor cohort, scoliosis occurred in 18/98 (18.4%), which falls in the OCCASIONAL band (5-29%).

PMID:31482324 SUPPORT Human Clinical

"There is a correlation between musculoskeletal deformities and the severity of the CDH."

Supports the causal edge from the size and severity of the diaphragmatic defect to the musculoskeletal phenotype.

PMID:35650272 SUPPORT Human Clinical

"Survivors often have long-term, multisystem morbidities, including pulmonary dysfunction, gastroesophageal reflux, musculoskeletal deformities and neurodevelopmental impairment."

Names musculoskeletal deformities among the established long-term morbidities of CDH survivors.

Pectus excavatum OCCASIONAL Pectus excavatum HP:0000767

Show evidence (2 references)

PMID:31482324 SUPPORT Human Clinical

"28 patients (28.6%) had at least one type of musculoskeletal deformities, 2 of which were pectus carinatum, 16 were pectus excavatum, and 18 were scoliosis."

In the same 98-patient left-CDH survivor cohort, pectus excavatum occurred in 16/98 (16.3%), which falls in the OCCASIONAL band (5-29%).

PMID:31482324 SUPPORT Human Clinical

"who had primary abdominal closure after ventral hernia significantly have more pectus excavatum"

Identifies tension abdominal closure after repair as the surgical correlate of the anterior chest wall deformity.

Nervous System 1

Neurodevelopmental delay Neurodevelopmental delay HP:0012758

Show evidence (1 reference)

PMID:35650272 SUPPORT Human Clinical

"Survivors often have long-term, multisystem morbidities, including pulmonary dysfunction, gastroesophageal reflux, musculoskeletal deformities and neurodevelopmental impairment."

Names neurodevelopmental impairment among the established long-term morbidities of CDH survivors.

Prenatal and Birth 1

Polyhydramnios Polyhydramnios HP:0001561

Show evidence (1 reference)

PMID:20301632 PARTIAL Human Clinical

"pulmonary hypoplasia; and associated anomalies (polyhydramnios, cloudy corneas and/or microphthalmia, orofacial clefting, renal dysplasia / renal cortical cysts"

Polyhydramnios is documented as an associated prenatal finding in Fryns syndrome, the prototypical syndromic CDH; the source does not quantify it across CDH generally, so support is partial.

Respiratory 3

Pulmonary hypoplasia VERY_FREQUENT Pulmonary hypoplasia HP:0002089

Show evidence (1 reference)

PMID:22214468 SUPPORT Human Clinical

"The lungs are hypoplastic and have abnormal vessels that cause respiratory insufficiency and persistent pulmonary hypertension with high mortality."

Describes hypoplastic lungs as a feature of clinically apparent CDH and links them to the downstream respiratory phenotype. VERY_FREQUENT is a clinical estimate (near-universal in clinically apparent CDH), not a figure extracted from the cited abstract.

Respiratory failure VERY_FREQUENT Respiratory failure HP:0002878

Temporal: ACUTE

Show evidence (1 reference)

PMID:37990078 SUPPORT Other

"Congenital diaphragmatic hernia (CDH) is a severe birth defect and a major cause of neonatal respiratory distress."

Snippet supports the disease-phenotype association between CDH and neonatal respiratory distress. VERY_FREQUENT is a clinical estimate (near-universal in prenatally diagnosed CDH), not a figure extracted from the cited abstract.

Hypoxemia Hypoxemia HP:0012418

Show evidence (1 reference)

PMID:22214468 SUPPORT Human Clinical

"The lungs are hypoplastic and have abnormal vessels that cause respiratory insufficiency"

Respiratory insufficiency from hypoplastic lungs and abnormal vessels manifests clinically as hypoxemia.

Growth 1

Failure to thrive Failure to thrive HP:0001508

Show evidence (1 reference)

PMID:35650272 PARTIAL Human Clinical

"Survivors often have long-term, multisystem morbidities, including pulmonary dysfunction, gastroesophageal reflux, musculoskeletal deformities and neurodevelopmental impairment."

Supports chronic multisystem survivor morbidity; growth failure is not itemised in the abstract, so the evidence is partial.

Other 8

Congenital diaphragmatic hernia OBLIGATE Congenital diaphragmatic hernia HP:0000776

Show evidence (1 reference)

PMID:22214468 SUPPORT Human Clinical

"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 diaphragmatic orifice with visceral herniation is definitional, hence obligate.

Posterolateral diaphragmatic hernia Posterolateral diaphragmatic hernia HP:0025193

Show evidence (1 reference)

PMID:37990078 SUPPORT Other

"This includes the most commonly occurring Bochdalek CDH that is characterized by a hole in the posterolateral diaphragm"

Defines the posterolateral (Bochdalek) defect and identifies it as the most common anatomic form.

Morgagni diaphragmatic hernia Morgagni diaphragmatic hernia HP:0025194

Show evidence (1 reference)

PMID:37990078 SUPPORT Other

"anterior holes through the foramen of Morgagni"

Identifies the anterior foramen-of-Morgagni defect as a distinct anatomic form of CDH.

Central diaphragmatic hernia Central diaphragmatic hernia HP:0025195

Show evidence (1 reference)

PMID:37990078 PARTIAL Other

"diaphragm eventrations"

The same anatomic classification enumerates central tendon defects alongside eventrations as the rarest diaphragmatic defects; the phrase quoted here is the adjacent category in that enumeration.

Right ventricular failure Right ventricular failure HP:0001708

Show evidence (1 reference)

PMID:28768736 PARTIAL Other

"associated with significant morbidity and mortality due to associated pulmonary hypoplasia, pulmonary hypertension and heart failure"

Documents heart failure as a CDH complication; the abstract does not specify right-sided failure, so the evidence is partial.

Scaphoid abdomen Scaphoid abdomen HP:0025063

Show evidence (1 reference)

PMID:22214468 PARTIAL Human Clinical

"permits the herniation of abdominal contents into the thorax"

The scaphoid abdominal contour is the direct anatomic consequence of abdominal contents relocating into the thorax; the sign itself is not named in the abstract.

Chronic lung disease FREQUENT Chronic lung disease HP:0006528

Temporal: CHRONIC

Show evidence (4 references)

PMID:21042035 SUPPORT Human Clinical

"In infants who survived until day 30, the prevalence of BPD was 41%."

A 2,078-neonate CDH Study Group cohort quantifies chronic lung disease (bronchopulmonary dysplasia, defined as oxygen dependency at day 30) at 41% of day-30 survivors, which falls in the FREQUENT band (30-79%).

PMID:21042035 SUPPORT Human Clinical

"CDH survivors have a substantial risk of developing long-term pulmonary sequelae, such as bronchopulmonary dysplasia (BPD)."

States chronic pulmonary sequelae as an expected outcome of CDH survival.

PMID:35650272 SUPPORT Human Clinical

"Survivors often have long-term, multisystem morbidities, including pulmonary dysfunction, gastroesophageal reflux, musculoskeletal deformities and neurodevelopmental impairment."

Names pulmonary dysfunction first among the established long-term morbidities of CDH survivors.

+ 1 more reference

Hypoplastic left ventricle Hypoplastic left ventricle HP:0004383

Show evidence (2 references)

PMID:28370263 SUPPORT Human Clinical

"Fetuses with congenital diaphragmatic hernia (CDH) demonstrate varying degrees of left heart hypoplasia."

Documents left heart hypoplasia as a graded structural phenotype of CDH. No frequency band is assigned because the cited cohort reports z-score distributions rather than a proportion of affected fetuses.

PMID:28370263 SUPPORT Human Clinical

"postnatal left ventricular end-diastolic dimension z-score correlated with liver herniation"

Links postnatal left ventricular size directly to the degree of visceral herniation.

🧬

Genetic Associations

11

ZFPM2

Gene: ZFPM2 hgnc:16700 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:28768736 SUPPORT Other

"The affected genes identified in CDH patients include transcription factors, such as GATA4, ZFPM2, NR2F2 and WT1"

Names ZFPM2 among the established CDH transcription-factor genes.

GATA4

Gene: GATA4 hgnc:4173 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:28768736 SUPPORT Other

"The affected genes identified in CDH patients include transcription factors, such as GATA4, ZFPM2, NR2F2 and WT1"

Names GATA4 among the established CDH transcription-factor genes.

NR2F2

Gene: NR2F2 hgnc:7976 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:28768736 SUPPORT Other

"The affected genes identified in CDH patients include transcription factors, such as GATA4, ZFPM2, NR2F2 and WT1"

Names NR2F2 among the established CDH transcription-factor genes.

WT1

Gene: WT1 hgnc:12796 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:28768736 SUPPORT Other

"The affected genes identified in CDH patients include transcription factors, such as GATA4, ZFPM2, NR2F2 and WT1"

Names WT1 among the established CDH transcription-factor genes.

PMID:22214468 SUPPORT Human Clinical

"CDH can be a component of Pallister-Killian, Fryns, Ghersoni-Baruch, WAGR, Denys-Drash, Brachman-De Lange, Donnai-Barrow or Wolf-Hirschhorn syndromes."

Lists the WT1-related WAGR and Denys-Drash syndromes among the syndromic contexts of CDH.

LONP1

Gene: LONP1 hgnc:9479 relationship_type: RISK_FACTOR

Show evidence (2 references)

PMID:34547244 SUPPORT Human Clinical

"identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals."

Establishes LONP1 as a candidate CDH risk gene in an 827-proband cohort, with a predominantly heterozygous mechanism.

PMID:34547244 SUPPORT Model Organism

"Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans."

Mouse conditional knockout reproduces the severe lung-growth reduction that drives mortality in human CDH.

MYRF

Gene: MYRF hgnc:1181 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:36375006 SUPPORT Human Clinical

"MYRF-related cardiac urogenital syndrome (MYRF-CUGS) is primarily characterized by anomalies of the internal and external genitalia, congenital heart defects, and eye anomalies."

GeneReviews defines the MYRF-related cardiac-urogenital syndrome in which congenital diaphragmatic hernia occurs as a recurrent feature.

LRP2

Gene: LRP2 hgnc:6694 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:20301732 SUPPORT Human Clinical

"Additional common features include agenesis of the corpus callosum, sensorineural hearing loss, intellectual disability, and congenital diaphragmatic hernia and/or omphalocele."

GeneReviews documents congenital diaphragmatic hernia as a common feature of Donnai-Barrow syndrome.

PMID:20301732 SUPPORT Human Clinical

"biallelic pathogenic variants in LRP2 identified by molecular genetic testing"

Establishes biallelic LRP2 variants as the molecular basis of the syndrome.

STRA6

Gene: STRA6 hgnc:30650 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:19309693 SUPPORT Human Clinical

"Matthew-Wood, Spear, PDAC or MCOPS9 syndrome are alternative names used to refer to combinations of microphthalmia/anophthalmia, malformative cardiac defects, pulmonary dysgenesis, and diaphragmatic hernia."

Defines the STRA6-related syndrome in which diaphragmatic hernia is a cardinal feature.

PMID:19309693 SUPPORT Human Clinical

"mutations in STRA6, encoding a membrane receptor for vitamin A-bearing plasma retinol binding protein, have been identified in such patients"

Links the causal gene to vitamin A/retinol uptake, directly supporting the retinoid hypothesis arm of the pathograph.

GATA6

Gene: GATA6 hgnc:4174 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (2 references)

PMID:24385578 SUPPORT Human Clinical

"We used whole exome sequencing in two families with CDH and congenital heart disease, and identified mutations in GATA6 in both."

Establishes GATA6 variants as a cause of CDH with congenital heart disease in two independent families.

PMID:24385578 SUPPORT Human Clinical

"To determine the frequency of GATA6 mutations in CDH, we sequenced the gene in 378 patients with CDH. We identified one additional de novo mutation"

A 378-patient cohort screen adds a third de novo GATA6 variant, showing the mechanism is recurrent but individually rare.

PBX1

Gene: PBX1 hgnc:8632 relationship_type: CAUSATIVE variant_origin: DE_NOVO

Show evidence (2 references)

PMID:29036646 SUPPORT Human Clinical

"Clinical findings similar to those in Pbx mutant mice were observed in all patients with varying expressivity and severity, including external ear anomalies, abnormal branchial arch derivatives, heart malformations, diaphragmatic hernia, renal hypoplasia and ambiguous genitalia."

Names diaphragmatic hernia among the recurrent malformations in eight patients with de novo PBX1 variants.

PMID:22315423 SUPPORT Model Organism

"We examined the diaphragms of knockout mice for one of the candidate genes, pre-B-cell leukemia transcription factor 1 (Pbx1), and identified a range of previously undetected diaphragmatic defects."

Mouse knockout confirms the diaphragmatic requirement for Pbx1 that the human phenotype implies.

SLIT3

Gene: SLIT3 hgnc:11087 relationship_type: RISK_FACTOR

Show evidence (2 references)

PMID:33933663 PARTIAL Human Clinical

"This is the first report of homozygous SLIT3 variant associated with CDH in humans."

A single-family report is the whole of the direct human evidence, which is why the gene is typed as a candidate risk gene.

PMID:33933663 SUPPORT Model Organism

"Previous studies showed that Slit3 null mice had congenital diaphragmatic hernias on or near the ventral midline portion of the central tendon."

Mouse null data give the mechanistic prior, and specifically predict the central (septum transversum) rather than posterolateral defect subtype.

💊

Medical Actions

7

Fetal Endoscopic Tracheal Occlusion (FETO)

Action: fetoscopic tracheal occlusion Ontology label: Surgical Procedure NCIT:C15329

Percutaneous fetoscopic placement of a detachable balloon in the fetal trachea, which retains lung fluid, raises intrapulmonary pressure and promotes lung growth, followed by balloon removal before delivery. Offered in severe isolated CDH with low observed-to-expected lung-to-head ratio.

Mechanism Target:

RESTORES Pulmonary Hypoplasia — Tracheal occlusion promotes fetal lung growth, partially reversing the parenchymal deficit.

Show evidence (6 references)

PMID:34106556 SUPPORT Human Clinical

"In fetuses with isolated severe congenital diaphragmatic hernia on the left side, FETO performed at 27 to 29 weeks of gestation resulted in a significant benefit over expectant care with respect to survival to discharge, and this benefit was sustained to 6 months of age."

Randomised trial (TOTAL) establishing a survival benefit for FETO in severe left-sided isolated CDH.

PMID:34106556 SUPPORT Human Clinical

"The incidence of preterm, prelabor rupture of membranes was higher among women in the FETO group than among those in the expectant care group"

Documents the principal harm of FETO, preterm prelabor rupture of membranes, which constrains patient selection.

PMID:34106555 PARTIAL Human Clinical

"Fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased postnatal survival among infants with severe pulmonary hypoplasia due to isolated congenital diaphragmatic hernia on the left side, but data are lacking to inform its effects in infants with moderate disease."

The companion moderate-disease trial frames FETO benefit as established for severe but not moderate hypoplasia.

+ 3 more references

Gentle Ventilation

Action: pressure-limited mechanical ventilation Ontology label: Mechanical Ventilation NCIT:C70909

A permissive-hypercapnia, pressure-limited ventilation strategy that avoids high peak inflating pressures in order to prevent barotrauma to the hypoplastic lung; the standardised approach that underpinned improved survival in contemporary CDH care.

Mechanism Target:

MODULATES Refractory Hypoxemia and Neonatal Respiratory Failure — Supports gas exchange while minimising ventilator-induced injury to the hypoplastic lung.

Show evidence (3 references)

PMID:26692079 SUPPORT Human Clinical

"The maldeveloped lungs have a high susceptibility for oxygen and ventilation damage resulting in a high incidence of bronchopulmonary dysplasia (BPD) and chronic respiratory morbidity."

States the rationale for a lung-protective ventilation strategy in CDH.

PMID:26692079 SUPPORT Human Clinical

"Other outcomes, including shorter ventilation time and lesser need of extracorporeal membrane oxygenation, favored conventional ventilation."

The VICI randomised trial favours conventional pressure-limited ventilation over high-frequency oscillation as the initial strategy.

PMID:27077664 SUPPORT Other

"target PaCO2 to be between 50 and 70 mm Hg; (5) conventional mechanical ventilation to be the optimal initial ventilation strategy"

CDH EURO Consortium consensus specifying permissive hypercapnia and conventional ventilation as the standard gentle-ventilation approach.

Inhaled Nitric Oxide

Action: Pharmacotherapy NCIT:C15986

Agent: nitric oxide CHEBI:16480

Selective inhaled pulmonary vasodilator used for pulmonary hypertension with right-to-left shunting; response in CDH is frequently poor compared with other causes of persistent pulmonary hypertension of the newborn.

Mechanism Target:

INHIBITS Persistent Pulmonary Hypertension of the Newborn — Selective pulmonary vasodilation lowers pulmonary vascular resistance.

Show evidence (2 references)

PMID:32384329 PARTIAL Other

"the role of iNO as a treatment for CDH is controversial."

A systematic review concludes that the benefit of inhaled nitric oxide in CDH-associated pulmonary hypertension is not established, which is why this treatment is curated with PARTIAL support.

PMID:39018718 SUPPORT Other

"Management strategies include lung protective ventilation, fluid optimization, pharmacotherapies including pulmonary vasodilators and hemodynamic support, and extracorporeal life support (ECLS) for refractory cases."

Places pulmonary vasodilator therapy within the standard CDH-PH management bundle.

Sildenafil

Action: Pharmacotherapy NCIT:C15986

Agent: sildenafil CHEBI:9139

Phosphodiesterase-5 inhibitor used to treat pulmonary hypertension in CDH, including as prenatal and postnatal therapy under investigation.

Mechanism Target:

INHIBITS Persistent Pulmonary Hypertension of the Newborn — Potentiates cyclic GMP mediated pulmonary vasodilation downstream of nitric oxide.

Show evidence (1 reference)

PMID:27077664 SUPPORT Other

"intravenous sildenafil to be considered in CDH patients with severe pulmonary hypertension"

CDH EURO Consortium consensus recommendation for sildenafil in severe CDH-associated pulmonary hypertension.

Milrinone

Action: Pharmacotherapy NCIT:C15986

Agent: milrinone CHEBI:50693

Phosphodiesterase-3 inhibitor with inotropic and pulmonary vasodilator effects used for right ventricular dysfunction with pulmonary hypertension in CDH.

Mechanism Target:

MODULATES Right Ventricular Pressure Overload and Failure — Inodilation supports right ventricular performance and lowers afterload.

Show evidence (1 reference)

PMID:39018718 PARTIAL Other

"pharmacotherapies including pulmonary vasodilators and hemodynamic support"

Milrinone is used as combined pulmonary vasodilator and haemodynamic support; the cited review describes the class rather than the individual agent, so support is partial.

Extracorporeal Membrane Oxygenation

Action: extracorporeal membrane oxygenation Ontology label: Extracorporeal Membrane Oxygenation NCIT:C171507

Venoarterial or venovenous extracorporeal life support used as rescue therapy for refractory hypoxemia or cardiovascular failure in CDH, permitting lung rest until pulmonary vascular resistance falls.

Mechanism Target:

BYPASSES Refractory Hypoxemia and Neonatal Respiratory Failure — Extracorporeal gas exchange bypasses the hypoplastic lung during the period of highest pulmonary vascular resistance.

Show evidence (2 references)

PMID:35650272 SUPPORT Human Clinical

"Postnatal management focuses on cardiopulmonary stabilization and, in severe cases, can involve extracorporeal life support."

Establishes extracorporeal life support as the accepted rescue therapy in severe CDH.

PMID:22214468 SUPPORT Human Clinical

"Treatment after birth requires all the refinements of critical care including extracorporeal membrane oxygenation prior to surgical correction."

Situates ECMO before, rather than after, surgical repair in the treatment sequence.

Delayed Surgical Repair of the Diaphragmatic Defect

Action: diaphragmatic hernia repair Ontology label: Herniorrhaphy NCIT:C168249

Operative closure of the diaphragmatic defect by primary repair or prosthetic patch, deferred until after physiological stabilisation rather than performed as a neonatal emergency.

Mechanism Target:

RESTORES Failure of Diaphragm Closure and Visceral Herniation — Repair restores diaphragmatic continuity and reduces the herniated viscera.

Show evidence (2 references)

PMID:22214468 SUPPORT Human Clinical

"Treatment after birth requires all the refinements of critical care including extracorporeal membrane oxygenation prior to surgical correction."

Supports delayed surgical correction after physiological stabilisation rather than emergency neonatal repair.

PMID:20301632 PARTIAL Human Clinical

"For congenital diaphragmatic hernia, the neonate is immediately intubated to prevent inflation of herniated bowel"

GeneReviews management guidance shows that airway stabilisation precedes operative repair; it speaks to the stabilise-first sequence rather than to the timing of repair itself.

🌍

Environmental Factors

2

Reduced retinoid (vitamin A) signaling during diaphragm morphogenesis

Perturbation of the vitamin A / retinoic acid axis during early gestation is the best-developed environmental hypothesis for CDH. Retinoic acid is generated from dietary vitamin A by retinaldehyde dehydrogenases; dietary vitamin A deficiency, teratogens that inhibit retinoic acid synthesis, and genetic lesions in retinoid transport and signalling all produce diaphragmatic defects, and the pathway is a locus of gene-environment interaction.

Show evidence (2 references)

PMID:37990078 SUPPORT Other

"This review provides a comprehensive update on the Retinoid Hypothesis, which links abnormal retinoic acid signaling to the etiology of congenital diaphragmatic hernia."

States the retinoid hypothesis as an aetiological account linking an environmentally modifiable pathway to CDH.

PMID:39183805 SUPPORT Other

"The retinoic acid pathway is thought to play an essential role in the interactions of genes and environment in CDH."

Identifies the retinoid pathway specifically as the gene-environment interaction locus in CDH.

Other maternal exposures

Maternal age, alcohol use and smoking have been reported as epidemiological associations with CDH. Evidence outside retinoid biology remains limited and these associations should not be read as established individual causation.

Show evidence (2 references)

PMID:37990078 PARTIAL Other

"Environmental risk factors for CDH are varied, including associations with maternal age, alcohol use, and smoking."

Lists the reported maternal exposure associations; the review presents these as associations rather than proven causes.

PMID:39183805 PARTIAL Other

"However, apart from the gradually maturing retinol hypothesis, there is limited evidence implicating other environmental factors in CDH occurrence."

Explicitly qualifies the strength of non-retinoid environmental evidence.

🔬

Biochemical Markers

1

Circulating small RNA (microRNA) severity biomarkers

Show evidence (3 references)

PMID:35650272 SUPPORT Human Clinical

"Emerging research focuses on small RNA species as biomarkers of severity and regenerative medicine approaches to improve fetal lung development."

The disease primer identifies small RNA severity biomarkers as the active biomarker frontier in CDH.

PMID:39505208 PARTIAL Human Clinical

"Random forest analysis identified miRNAs in maternal blood (miR-7850-5p_L-1R+2, miR-942-3p, and miR-197-3p) that distinguished CDH survivors from nonsurvivors, with an receiver operating characteristic area under the curve of 1.0."

Names the specific candidate maternal-blood miRNAs and their reported discrimination; support is partial because a perfect AUC in a small unreplicated cohort is not a validated biomarker claim.

PMID:39505208 SUPPORT Human Clinical

"Prenatal imaging techniques like ultrasound and MRI provide anatomical predictors of outcomes, but their limitations necessitate novel biomarkers for better prognostic accuracy."

States the unmet need this biomarker class addresses, and confirms that imaging remains the current standard for severity assessment.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Congenital Diaphragmatic Hernia:

Congenital pulmonary airway malformation MONDO:0016580

Overlapping Features A cystic lung lesion that can mimic bowel loops in the hemithorax on prenatal ultrasound or neonatal chest radiography.

Distinguishing Features

Intact diaphragm on imaging, with no defect through which viscera pass
Normal abdominal gas pattern rather than a paucity of abdominal gas
Cystic lesion follows lung architecture rather than bowel loops

Show evidence (1 reference)

PMID:22214468 SUPPORT Human Clinical

"Congenital Diaphragmatic Hernia (CDH) is defined by the presence of an orifice in the diaphragm"

The defining diaphragmatic orifice is what a cystic lung malformation lacks, which is the basis of the distinction.

Congenital pulmonary sequestration Not Yet Curated MONDO:0017843

Overlapping Features A mass of non-functioning lung parenchyma with an anomalous systemic arterial supply and no connection to the bronchial tree. The extralobar form is frequently infradiaphragmatic or juxtadiaphragmatic and can be mistaken for herniated viscera on prenatal imaging; it also co-occurs with CDH.

Distinguishing Features

Systemic arterial feeding vessel, typically from the descending aorta, on Doppler or MRI
Solid echogenic mass following lung architecture rather than peristalsing bowel
Intact diaphragm with normal intra-abdominal gas pattern
Extralobar sequestration may itself sit below the diaphragm

Show evidence (2 references)

PMID:33252753 SUPPORT Human Clinical

"Fetal lung lesions include common lesions such as congenital pulmonary airway malformation (CPAM), bronchopulmonary sequestration (BPS) and combined CPAM-BPS hybrid lesions"

Establishes bronchopulmonary sequestration as a distinct fetal intrathoracic lesion that must be separated from CDH on prenatal imaging.

PMID:22214468 PARTIAL Human Clinical

"In some rare instances, X-rays may suggest a cystic malformation of the lung"

The CDH review's own differential-diagnosis section identifies cystic and other congenital lung malformations as the entities that radiography can confuse with CDH; it does not name sequestration specifically, so support is partial.

Congenital lobar emphysema Not Yet Curated MONDO:0007536

Overlapping Features Progressive hyperinflation of a single pulmonary lobe producing a hyperlucent hemithorax with mediastinal shift, which reproduces the radiographic mass effect of a left-sided CDH in a neonate with respiratory distress.

Distinguishing Features

Hyperlucent hyperinflated lobe rather than gas-filled bowel loops
Nasogastric tube remains below the diaphragm rather than curling into the chest
Intact diaphragmatic contour with a normal abdominal gas pattern
Lobar distribution respecting fissures

Show evidence (2 references)

PMID:33252753 SUPPORT Human Clinical

"as well as less common entities including congenital lobar emphysema/obstruction, bronchial atresia, bronchogenic cysts"

Names congenital lobar emphysema/obstruction as a distinct congenital thoracic lesion in the same prenatal differential as CPAM and sequestration.

PMID:22214468 PARTIAL Human Clinical

"passing a naso-gastric catheter into the stomach before a plain X-ray of the thorax and abdomen may help to locate it"

The manoeuvre that separates CDH from an intrinsic hyperlucent lung lesion is demonstrating an intrathoracic stomach; the cited review prescribes exactly this test, though it does not name lobar emphysema.

Diaphragmatic eventration Not Yet Curated MONDO:0006726

Overlapping Features An abnormally elevated but anatomically continuous hemidiaphragm, with or without phrenic nerve palsy.

Distinguishing Features

Diaphragm is thinned and elevated but anatomically continuous
No true defect, so abdominal viscera remain below a diaphragmatic membrane
May be associated with phrenic nerve palsy rather than a developmental defect

Show evidence (1 reference)

PMID:20301632 SUPPORT Human Clinical

"diaphragmatic defects (diaphragmatic hernia and diaphragm eventration, hypoplasia, or agenesis)"

GeneReviews treats eventration as a distinct diaphragmatic defect category from true hernia, which is the basis of the differential.

🔬

Clinical Trials

3

NCT01240057 NOT_APPLICABLE COMPLETED

TOTAL trial for severe hypoplasia: randomised trial of fetoscopic endoluminal tracheal occlusion versus expectant management in isolated left-sided CDH with severe pulmonary hypoplasia. Stopped early for efficacy; reported as PMID:34106556.

Target Phenotypes: Pulmonary hypoplasia HP:0002089

Show evidence (1 reference)

clinicaltrials:NCT01240057 SUPPORT Human Clinical

"This trial investigates whether prenatal intervention improves survival rate of fetuses with isolated congenital diaphragmatic hernia and severe pulmonary hypoplasia, as compared to expectant management during pregnancy, both followed by standardized postnatal care."

The registered protocol for the severe-hypoplasia arm of the TOTAL programme, which demonstrated a survival benefit for FETO.

NCT00763737 NOT_APPLICABLE COMPLETED

TOTAL trial for moderate hypoplasia: randomised trial of fetoscopic endoluminal tracheal occlusion versus expectant management in isolated left-sided CDH with moderate pulmonary hypoplasia (O/E LHR 25-34.9%, or 35-44.9% with liver herniation). Did NOT show a significant survival benefit; reported as PMID:34106555.

Target Phenotypes: Pulmonary hypoplasia HP:0002089

Show evidence (2 references)

clinicaltrials:NCT00763737 SUPPORT Human Clinical

"This trial will test whether temporary fetoscopic tracheal occlusion rather than expectant management during pregnancy, both followed by standardized postnatal management increases survival or decrease oxygen dependency at 6 months of age."

The registered protocol for the moderate-hypoplasia arm, whose published result was null for both co-primary outcomes.

clinicaltrials:NCT00763737 SUPPORT Human Clinical

"The risk for these can be predicted prenatally by the ultrasonographic measurement of the observed/expected lung area to head circumference ratio (O/E LHR) which is a measure of pulmonary hypoplasia. Also position of the liver is predictive of outcome."

Documents O/E LHR and liver position as the prospectively specified severity criteria used to enrol and stratify CDH fetuses.

NCT06179472 PHASE_III ACTIVE_NOT_RECRUITING

Single-centre study of fetoscopic endoluminal tracheal occlusion with the BALT Goldbal2 balloon in severe left OR right CDH, reporting infant survival and long-term outcome. It extends the FETO question to right-sided disease, which neither TOTAL arm randomised.

Target Phenotypes: Pulmonary hypoplasia HP:0002089 Pulmonary arterial hypertension HP:0002092

Show evidence (1 reference)

clinicaltrials:NCT06179472 SUPPORT Human Clinical

"We hypothesize that FETO balloon placement may increase survival and decrease morbidity when compared to standard prenatal care for the treatment of severe left or right congenital diaphragmatic hernia (CDH)."

Documents an active FETO study that includes severe right-sided CDH, the population left unaddressed by the randomised TOTAL trials.

{ }

Source YAML

click to show

name: Congenital Diaphragmatic Hernia
creation_date: "2026-07-31T00:00:00Z"
category: Congenital
disease_term:
  preferred_term: congenital diaphragmatic hernia
  term:
    id: MONDO:0005711
    label: congenital diaphragmatic hernia
parents:
- Congenital malformation
- Diaphragm disorder
description: >-
  Congenital diaphragmatic hernia (CDH) is a developmental defect of diaphragm
  formation in which incomplete closure of the developing diaphragm (most often
  the pleuroperitoneal canal, less commonly the sternocostal trigone or the
  central tendon) permits herniation of abdominal viscera into the fetal
  thorax. The primary morbidity
  is not the anatomic defect itself but the associated lung disease: pulmonary
  hypoplasia with reduced airway branching and alveolarization, together with
  pulmonary vascular maldevelopment and remodeling that produce persistent
  pulmonary hypertension of the newborn, right ventricular dysfunction, and
  refractory hypoxemia.
synonyms:
- CDH
- Congenital diaphragmatic defect
- Diaphragmatic hernia
has_subtypes:
- name: Bochdalek
  display_name: Bochdalek (posterolateral) hernia
  description: >-
    The posterolateral defect arising from failure of pleuroperitoneal fold
    closure, accounting for the large majority of congenital diaphragmatic
    hernias and predominantly left-sided.
  evidence:
  - reference: PMID:22214468
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      Establishes the posterolateral (Bochdalek) left-sided defect as the
      predominant anatomic form.
  - reference: PMID:37990078
    reference_title: "The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This includes the most commonly occurring Bochdalek CDH that is
      characterized by a hole in the posterolateral diaphragm
    explanation: >-
      Names the Bochdalek posterolateral defect as the most common anatomic
      form of CDH.
- name: Morgagni
  display_name: Morgagni (anterior retrosternal) hernia
  description: >-
    An anterior, retrosternal parasternal defect at the sternocostal trigone,
    much less common than Bochdalek hernia and often presenting later in
    infancy or childhood.
  evidence:
  - reference: PMID:37990078
    reference_title: "The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      anterior holes through the foramen of Morgagni
    explanation: >-
      Identifies the anterior foramen-of-Morgagni defect as a distinct
      anatomic subtype of CDH.
- name: Central
  display_name: Central (septum transversum) defect
  description: >-
    A central tendon defect derived from abnormal septum transversum
    development, the least common anatomic form.
  evidence:
  - reference: PMID:37990078
    reference_title: "The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      diaphragm eventrations
    explanation: >-
      The same anatomic classification enumerates central tendon defects
      alongside eventrations as the rarest diaphragmatic defects; the phrase
      quoted here is the adjacent category in that enumeration, so support for
      the central-defect subtype specifically is partial.
- name: Isolated CDH
  description: >-
    CDH occurring without additional major structural anomalies or a
    recognized syndromic diagnosis. Roughly half of all cases are isolated,
    and isolated disease has a substantially lower genetic diagnostic yield
    than complex CDH.
  evidence:
  - reference: PMID:36441118
    reference_title: "Congenital diaphragmatic hernia subtypes: Comparing birth prevalence, occurrence by maternal age, and mortality in a national birth cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among 9.5 million livebirths, we identified 1285 with isolated CDH and
      1150 with complex CDH.
    explanation: >-
      A national birth cohort operationalises the isolated versus complex
      (syndromic) split and shows the two groups are of comparable size.
- name: Syndromic CDH
  display_name: Syndromic (complex) CDH
  description: >-
    CDH occurring as one feature of a recognized malformation syndrome or
    chromosomal disorder, including Fryns syndrome, Donnai-Barrow syndrome,
    Pallister-Killian syndrome, and 15q26 deletion involving NR2F2, plus
    monogenic forms attributable to ZFPM2, GATA4, WT1, LONP1, or MYRF.
  evidence:
  - reference: PMID:22214468
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CDH can be a component of Pallister-Killian, Fryns, Ghersoni-Baruch,
      WAGR, Denys-Drash, Brachman-De Lange, Donnai-Barrow or Wolf-Hirschhorn
      syndromes.
    explanation: >-
      Enumerates the recognised malformation syndromes in which CDH occurs as
      a component feature.
  - reference: PMID:36441118
    reference_title: "Congenital diaphragmatic hernia subtypes: Comparing birth prevalence, occurrence by maternal age, and mortality in a national birth cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 1-year mortality rate for complex CDH (33.1%, 95% CI 30.5, 35.9) was
      slightly higher than for isolated CDH (29.7%, 95% CI 27.3, 32.3)
    explanation: >-
      Quantifies the prognostic difference between complex (syndromic) and
      isolated CDH in a national cohort.
pathophysiology:
- name: Retinoid Signaling and Pleuroperitoneal Fold Mesenchymal Deficit
  role: trigger
  biological_scale: CELLULAR
  description: >-
    The proximate developmental lesion in CDH is a deficit of the
    pleuroperitoneal fold (PPF) mesenchyme, the transient structure whose
    expansion closes the pleuroperitoneal canal. Retinoic acid signaling is
    required for PPF outgrowth, and disruption of the retinoid pathway or of
    PPF mesenchymal transcriptional regulators such as ZFPM2, GATA4, NR2F2 and
    WT1 reduces the amplifying PPF cell population.
  cell_types:
  - preferred_term: pleuroperitoneal fold mesenchymal cell
    term:
      id: CL:0008019
      label: mesenchymal cell
  genes:
  - preferred_term: ALDH1A2 (RALDH2)
    term:
      id: hgnc:15472
      label: ALDH1A2
  biological_processes:
  - preferred_term: retinoic acid receptor signaling pathway
    term:
      id: GO:0048384
      label: retinoic acid receptor signaling pathway
    modifier: DECREASED
  - preferred_term: diaphragm development
    term:
      id: GO:0060539
      label: diaphragm development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:39183805
    reference_title: "Role of genetics and the environment in the etiology of congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The occurrence of CDH and pulmonary hypoplasia is theorized to result from
      both abnormalities in signaling pathways of smooth muscle cells in
      pleuroperitoneal folds and mechanical compression by abdominal organs
      within the chest cavity on the developing lungs.
    explanation: >-
      Places the pleuroperitoneal fold signalling defect upstream of both the
      diaphragmatic defect and the lung phenotype.
  - reference: PMID:37990078
    reference_title: "The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In 2003, Greer et al. proposed the Retinoid Hypothesis, stating that the
      underlying cause of abnormal diaphragm development in CDH was related to
      altered retinoid signaling.
    explanation: >-
      States the retinoid hypothesis, the leading mechanistic account of the
      proximate developmental lesion in CDH.
  - reference: PMID:28768736
    reference_title: "Congenital diaphragmatic hernias: from genes to mechanisms to therapies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The affected genes identified in CDH patients include transcription
      factors, such as GATA4, ZFPM2, NR2F2 and WT1, and signaling pathway
      components, including members of the retinoic acid pathway.
    explanation: >-
      Links the mesenchymal transcriptional regulators and the retinoic acid
      pathway named in this node to human CDH genetics.
  - reference: PMID:25416379
    reference_title: "Metabolic disturbances of the vitamin A pathway in human diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      pharmacological ALDH1A2 inhibition results in posterolateral diaphragm
      defect
    explanation: >-
      ALDH1A2 (RALDH2) is the principal retinaldehyde dehydrogenase of
      development and the enzyme the nitrofen teratogen model perturbs; its
      pharmacological inhibition reproduces the posterolateral defect, which is
      why the gene is carried on this node as a pathway component.
  - reference: PMID:25416379
    reference_title: "Metabolic disturbances of the vitamin A pathway in human diaphragmatic hernia."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Taken together, these data show that RA signaling disruption is part of
      CDH pathogenesis
    explanation: >-
      Transcriptional profiling of human CDH lung places retinoid signalling
      disruption in the pathogenic chain; the same study concludes the observed
      ALDH1A2 overexpression is secondary to lung injury rather than a primary
      lesion, so ALDH1A2 is modelled as a pathway component of this node rather
      than as a Mendelian CDH gene.
  downstream:
  - target: Failure of Diaphragm Closure and Visceral Herniation
    description: >-
      A deficient pleuroperitoneal fold fails to close the pleuroperitoneal
      canal, leaving a diaphragmatic defect.
    hypothesis_groups:
    - retinoid
    causal_link_type: DIRECT
  - target: Pulmonary Hypoplasia
    description: >-
      The "first hit" of the dual-hit model: the same early developmental
      perturbation that impairs pleuroperitoneal fold outgrowth also acts
      directly on the developing lung, before and independently of the
      diaphragmatic defect. This edge is asserted only under the dual-hit
      hypothesis group; under the competing purely mechanical model it does
      not exist, and all pulmonary hypoplasia is secondary to compression.
    hypothesis_groups:
    - dual_hit
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:10751355
      reference_title: "Dual-hit hypothesis explains pulmonary hypoplasia in the nitrofen model of congenital diaphragmatic hernia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        These data indicate that Nitrofen interferes with early lung development
        before and separate from (aberrant) diaphragm development.
      explanation: >-
        Organotypic rat lung explants exposed to nitrofen without any
        diaphragmatic defect show impaired branching morphogenesis, which is
        the experimental basis for a compression-independent first hit. This is
        explant (ex vivo) rodent evidence and is not the sole support for the
        human claim; the human-facing support sits on the hypothesis block.
- name: Failure of Diaphragm Closure and Visceral Herniation
  role: central_effector
  biological_scale: TISSUE
  description: >-
    Incomplete closure of the pleuroperitoneal canal leaves a diaphragmatic
    defect through which abdominal viscera herniate into the thorax during
    fetal life. The herniated viscera occupy the hemithorax and compress the
    developing lung, most often on the left.
  locations:
  - preferred_term: diaphragm
    term:
      id: UBERON:0001103
      label: diaphragm
  biological_processes:
  - preferred_term: diaphragm morphogenesis
    term:
      id: GO:0060540
      label: diaphragm morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:35650272
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital diaphragmatic hernia (CDH) is a rare birth defect
      characterized by incomplete closure of the diaphragm and herniation of
      fetal abdominal organs into the chest that results in pulmonary
      hypoplasia, postnatal pulmonary hypertension owing to vascular
      remodelling and cardiac dysfunction.
    explanation: >-
      Establishes the causal ordering from incomplete diaphragm closure and
      visceral herniation to pulmonary hypoplasia and pulmonary hypertension.
  - reference: PMID:31519366
    reference_title: "Congenital diaphragmatic hernia-associated pulmonary hypertension."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Congenital diaphragmatic hernia (CDH) is a neonatal pathology in which
      intrathoracic herniation of abdominal viscera via diaphragmatic defect
      results in aberrant pulmonary and cardiovascular development.
    explanation: >-
      Supports the edge from the diaphragmatic defect to both the pulmonary
      parenchymal and the pulmonary vascular arms of the graph.
  downstream:
  - target: Pulmonary Hypoplasia
    description: >-
      Space occupation by herniated viscera restricts lung growth during the
      pseudoglandular and canalicular stages. This is the "second hit" of the
      dual-hit model and the whole of the competing purely mechanical model,
      so the edge is shared by both hypothesis groups.
    hypothesis_groups:
    - dual_hit
    - mechanical_compression_only
    causal_link_type: DIRECT
  - target: Pulmonary Vascular Maldevelopment and Remodeling
    description: >-
      The same developmental window that limits airway branching also limits
      and distorts pulmonary vascular development.
    causal_link_type: DIRECT
  - target: Congenital diaphragmatic hernia
    description: The anatomic defect is the defining clinical finding.
    causal_link_type: DIRECT
  - target: Posterolateral diaphragmatic hernia
    description: >-
      Failure of pleuroperitoneal fold closure specifically produces the
      posterolateral (Bochdalek) defect.
    causal_link_type: DIRECT
  - target: Morgagni diaphragmatic hernia
    description: >-
      Failure of closure at the sternocostal trigone produces the anterior
      retrosternal (Morgagni) defect.
    causal_link_type: DIRECT
  - target: Central diaphragmatic hernia
    description: >-
      Abnormal septum transversum development produces the central tendon
      defect.
    causal_link_type: DIRECT
  - target: Scaphoid abdomen
    description: >-
      Relocation of abdominal viscera into the thorax leaves the abdomen
      empty, producing the sunken newborn abdominal contour.
    causal_link_type: DIRECT
  - target: Gastroesophageal reflux
    description: >-
      Distortion of the oesophageal hiatus and gastro-oesophageal junction
      anatomy by the defect and its repair predisposes to reflux in survivors.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Left Heart Hypoplasia in Left-Sided CDH
    description: >-
      Mediastinal shift and compression by herniated viscera, most often on the
      left, restrict filling and growth of the left-sided cardiac structures.
    causal_link_type: DIRECT
  - target: Scoliosis
    description: >-
      Thoracic cage growth asymmetry after a large defect and its repair
      produces spinal deformity in long-term survivors.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Pectus excavatum
    description: >-
      The same asymmetric chest wall growth, and abdominal closure under
      tension after repair, produce anterior chest wall deformity in survivors.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Pulmonary Hypoplasia
  role: effector
  biological_scale: TISSUE
  description: >-
    Both lungs, and particularly the ipsilateral lung, show reduced airway
    branching generations, reduced alveolar number and surface area, thickened
    alveolar septa, and surfactant abnormalities. The parenchymal deficit is
    bilateral even when the defect is unilateral, indicating a primary
    developmental component in addition to mechanical compression.
  cell_types:
  - preferred_term: pulmonary alveolar type 2 cell
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: branching morphogenesis of an epithelial tube
    term:
      id: GO:0048754
      label: branching morphogenesis of an epithelial tube
    modifier: DECREASED
  - preferred_term: lung alveolus development
    term:
      id: GO:0048286
      label: lung alveolus development
    modifier: DECREASED
  evidence:
  - reference: PMID:39183805
    reference_title: "Role of genetics and the environment in the etiology of congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Congenital diaphragmatic hernia (CDH) is a congenital malformation
      characterized by failure of diaphragm closure during embryonic
      development, leading to pulmonary hypoplasia and pulmonary hypertension,
      which contribute significantly to morbidity and mortality.
    explanation: >-
      Identifies pulmonary hypoplasia as the principal determinant of morbidity
      and mortality downstream of the diaphragmatic defect.
  - reference: PMID:35633948
    reference_title: "Genetically Modified Mouse Models of Congenital Diaphragmatic Hernia: Opportunities and Limitations for Studying Altered Lung Development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      CDH is accompanied by immature and hypoplastic lungs, being the leading
      cause of morbidity and mortality in patients with this condition.
    explanation: >-
      Genetically modified mouse models reproduce the combination of diaphragm
      defect and hypoplastic, immature lung.
  downstream:
  - target: Refractory Hypoxemia and Neonatal Respiratory Failure
    description: >-
      Reduced alveolar surface area limits gas exchange from the first
      postnatal breaths.
    causal_link_type: DIRECT
  - target: Pulmonary hypoplasia
    description: Reduced lung parenchymal mass is the defining structural phenotype.
    causal_link_type: DIRECT
  - target: Chronic lung disease
    description: >-
      A structurally deficient lung that must then be ventilated develops
      chronic oxygen dependency and long-term respiratory morbidity.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Pulmonary Vascular Maldevelopment and Remodeling
  role: effector
  biological_scale: TISSUE
  conforms_to: "pulmonary_vascular_remodeling#Obstructive Pulmonary Vascular Remodeling"
  description: >-
    The pulmonary vascular bed in CDH is reduced in cross-sectional area, with
    fewer arterial generations per unit lung, and the pre-acinar and
    intra-acinar arteries show adventitial thickening and abnormal medial
    muscularization extending peripherally into vessels that are normally
    non-muscular. Endothelial dysfunction with reduced nitric oxide signaling
    accompanies the structural remodeling.
  cell_types:
  - preferred_term: pulmonary artery smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  - preferred_term: pulmonary artery endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: blood vessel remodeling
    term:
      id: GO:0001974
      label: blood vessel remodeling
    modifier: DYSREGULATED
  - preferred_term: lung vasculature development
    term:
      id: GO:0060426
      label: lung vasculature development
    modifier: ABNORMAL
  - preferred_term: smooth muscle cell proliferation
    term:
      id: GO:0048659
      label: smooth muscle cell proliferation
    modifier: INCREASED
  - preferred_term: nitric oxide biosynthetic process
    term:
      id: GO:0006809
      label: nitric oxide biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:39018718
    reference_title: "Congenital diaphragmatic hernia-associated pulmonary hypertension."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      in CDH, this embryologic development is impaired which, in conjunction
      with external compression, stifle pulmonary vascular maturation, leading
      to reduced lung density, increased muscularization of the pulmonary
      vasculature, abnormal vascular responsiveness, and altered molecular
      signaling, all contributing to pulmonary arterial hypertension.
    explanation: >-
      Directly describes the reduced vascular bed, increased muscularisation
      and abnormal vasoreactivity that constitute this node, and links them to
      pulmonary arterial hypertension.
  - reference: PMID:31519366
    reference_title: "Congenital diaphragmatic hernia-associated pulmonary hypertension."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In patients with CDH, hypoplastic pulmonary vasculature and alterations
      in multiple molecular pathways lead to pathophysiologic pulmonary
      vasculopathy and, for severe CDH, sustained, elevated pulmonary arterial
      pressures.
    explanation: >-
      Supports the causal edge from pulmonary vascular maldevelopment and
      remodelling to sustained pulmonary arterial hypertension.
  downstream:
  - target: Persistent Pulmonary Hypertension of the Newborn
    description: >-
      A reduced and abnormally muscularized vascular bed raises pulmonary
      vascular resistance after birth.
    causal_link_type: DIRECT
- name: Persistent Pulmonary Hypertension of the Newborn
  role: consequence
  biological_scale: ORGANISM
  conforms_to: "pulmonary_vascular_remodeling#Pulmonary Arterial Hypertension"
  description: >-
    The structurally reduced and hypermuscularized pulmonary vascular bed,
    combined with abnormal vasoreactivity, prevents the normal postnatal fall
    in pulmonary vascular resistance. Suprasystemic pulmonary pressures drive
    right-to-left shunting across the ductus arteriosus and foramen ovale.
  biological_processes:
  - preferred_term: vasoconstriction
    term:
      id: GO:0042310
      label: vasoconstriction
    modifier: INCREASED
  evidence:
  - reference: PMID:35650272
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The high mortality and morbidity rates associated with CDH are directly
      related to the severity of cardiopulmonary pathophysiology.
    explanation: >-
      Attributes CDH outcome to the combined pulmonary hypertensive and cardiac
      physiology represented by this node and its downstream targets.
  - reference: PMID:39018718
    reference_title: "Congenital diaphragmatic hernia-associated pulmonary hypertension."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Longitudinal re-evaluation is an important consideration due to the
      complexity and dynamic nature of CDH cardiopulmonary physiology.
    explanation: >-
      Supports the labile, dynamic character of CDH pulmonary hypertension
      during and after the neonatal transition.
  downstream:
  - target: Right Ventricular Pressure Overload and Failure
    description: Sustained high afterload overloads the right ventricle.
    causal_link_type: DIRECT
  - target: Refractory Hypoxemia and Neonatal Respiratory Failure
    description: >-
      Extrapulmonary right-to-left shunting adds a component of hypoxemia that
      is unresponsive to increased inspired oxygen.
    causal_link_type: DIRECT
  - target: Pulmonary arterial hypertension
    description: Elevated pulmonary arterial pressure is directly observed clinically.
    causal_link_type: DIRECT
- name: Right Ventricular Pressure Overload and Failure
  role: consequence
  biological_scale: ORGANISM
  description: >-
    Persistent pulmonary hypertension imposes high afterload on a right
    ventricle that may itself be hypoplastic or intrinsically dysfunctional in
    CDH. Progressive right ventricular dilation and failure reduce pulmonary
    blood flow and left ventricular preload, producing systemic hypoperfusion.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:28768736
    reference_title: "Congenital diaphragmatic hernias: from genes to mechanisms to therapies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Congenital diaphragmatic hernias (CDHs) and structural anomalies of the
      diaphragm are a common class of congenital birth defects that are
      associated with significant morbidity and mortality due to associated
      pulmonary hypoplasia, pulmonary hypertension and heart failure.
    explanation: >-
      Places heart failure alongside pulmonary hypoplasia and pulmonary
      hypertension as a proximate cause of death in CDH.
  downstream:
  - target: Right ventricular failure
    description: Right heart decompensation is the clinical manifestation.
    causal_link_type: DIRECT
- name: Left Heart Hypoplasia in Left-Sided CDH
  role: effector
  biological_scale: TISSUE
  description: >-
    In left-sided CDH the herniated viscera displace the mediastinum to the
    right and compress the left heart during the period of fetal cardiac
    growth. Left-sided structures (mitral valve, aortic valve, left ventricle)
    are correspondingly smaller, in proportion to lung size and the extent of
    liver herniation. This is a distinct arm from the right ventricular
    pressure overload driven by pulmonary hypertension, and it contributes to
    the low-output physiology and vasodilator intolerance of severe disease.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: left cardiac ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:28370263
    reference_title: "Fetal left-sided cardiac structural dimensions in left-sided congenital diaphragmatic hernia - association with severity and impact on postnatal outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fetuses with congenital diaphragmatic hernia (CDH) demonstrate varying
      degrees of left heart hypoplasia.
    explanation: >-
      Establishes left heart hypoplasia as a recognised structural consequence
      of CDH, distinct from the right ventricular arm already modelled.
  - reference: PMID:28370263
    reference_title: "Fetal left-sided cardiac structural dimensions in left-sided congenital diaphragmatic hernia - association with severity and impact on postnatal outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fetal mitral valve z-score correlated with lung-to-head ratio (p = 0.04),
      postnatal mitral valve z-score correlated with percent liver herniation
    explanation: >-
      Ties the degree of left-sided cardiac hypoplasia quantitatively to the
      classic indices of herniation severity, supporting the causal edge from
      visceral herniation to this node.
  - reference: PMID:28370263
    reference_title: "Fetal left-sided cardiac structural dimensions in left-sided congenital diaphragmatic hernia - association with severity and impact on postnatal outcomes."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Smaller aortic valve z-score was associated with iNO use; however, left
      heart dimensions showed no association with extracorporeal membrane
      oxygenation or mortality.
    explanation: >-
      Qualifies the clinical weight of this arm: left heart hypoplasia tracks
      with vasodilator requirement but was not shown to predict extracorporeal
      support or death in this cohort.
  downstream:
  - target: Hypoplastic left ventricle
    description: Reduced left ventricular dimensions are the observed structural phenotype.
    causal_link_type: DIRECT
- name: Refractory Hypoxemia and Neonatal Respiratory Failure
  role: consequence
  biological_scale: ORGANISM
  description: >-
    The combination of reduced alveolar gas-exchange surface, ventilation
    limited by a small and stiff lung, and extrapulmonary right-to-left
    shunting produces severe hypoxemia that is frequently refractory to
    conventional ventilation and inhaled vasodilators.
  evidence:
  - reference: PMID:37990078
    reference_title: "The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Congenital diaphragmatic hernia (CDH) is a severe birth defect and a
      major cause of neonatal respiratory distress.
    explanation: >-
      Identifies neonatal respiratory failure as the terminal clinical
      manifestation of the CDH causal chain.
  - reference: PMID:39018718
    reference_title: "Congenital diaphragmatic hernia-associated pulmonary hypertension."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      extracorporeal life support (ECLS) for refractory cases
    explanation: >-
      The routine need for extracorporeal support attests to the refractory
      character of the hypoxemia modelled at this node.
  downstream:
  - target: Respiratory failure
    description: Failure of gas exchange at birth.
    causal_link_type: DIRECT
  - target: Hypoxemia
    description: Severe and often labile arterial desaturation.
    causal_link_type: DIRECT
  - target: Cyanosis
    description: Visible manifestation of arterial desaturation.
    causal_link_type: DIRECT
  - target: Neurodevelopmental delay
    description: >-
      Prolonged hypoxemia and the intensive care it necessitates (prolonged
      ventilation, extracorporeal support) are the recognised route to
      neurodevelopmental impairment in survivors.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Sensorineural hearing impairment
    description: >-
      Hearing loss in survivors is attributed to the same prolonged critical
      illness and extracorporeal support exposure rather than to a primary
      cochlear lesion.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Failure to thrive
    description: >-
      Increased work of breathing and prolonged respiratory morbidity drive
      the postnatal growth failure seen in survivors.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
phenotypes:
- name: Congenital diaphragmatic hernia
  category: Structural
  description: >-
    A defect in the diaphragm permitting herniation of abdominal viscera into
    the thorax, typically detected on prenatal ultrasound or in the immediate
    newborn period.
  phenotype_term:
    preferred_term: Congenital diaphragmatic hernia
    term:
      id: HP:0000776
      label: Congenital diaphragmatic hernia
  frequency: OBLIGATE
  evidence:
  - reference: PMID:22214468
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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.
    explanation: >-
      The diaphragmatic orifice with visceral herniation is definitional, hence
      obligate.
- name: Posterolateral diaphragmatic hernia
  category: Structural
  subtype: Bochdalek
  description: >-
    The posterolateral (Bochdalek) defect, the most common anatomic form of
    CDH and predominantly left-sided.
  phenotype_term:
    preferred_term: Posterolateral diaphragmatic hernia
    term:
      id: HP:0025193
      label: Posterolateral diaphragmatic hernia
  evidence:
  - reference: PMID:37990078
    reference_title: "The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This includes the most commonly occurring Bochdalek CDH that is
      characterized by a hole in the posterolateral diaphragm
    explanation: >-
      Defines the posterolateral (Bochdalek) defect and identifies it as the
      most common anatomic form.
- name: Morgagni diaphragmatic hernia
  category: Structural
  subtype: Morgagni
  description: >-
    An anterior retrosternal diaphragmatic defect, less common and frequently
    diagnosed beyond the neonatal period.
  phenotype_term:
    preferred_term: Morgagni diaphragmatic hernia
    term:
      id: HP:0025194
      label: Morgagni diaphragmatic hernia
  evidence:
  - reference: PMID:37990078
    reference_title: "The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      anterior holes through the foramen of Morgagni
    explanation: >-
      Identifies the anterior foramen-of-Morgagni defect as a distinct
      anatomic form of CDH.
- name: Central diaphragmatic hernia
  category: Structural
  subtype: Central
  description: A central tendon defect of the diaphragm.
  phenotype_term:
    preferred_term: Central diaphragmatic hernia
    term:
      id: HP:0025195
      label: Central diaphragmatic hernia
  evidence:
  - reference: PMID:37990078
    reference_title: "The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      diaphragm eventrations
    explanation: >-
      The same anatomic classification enumerates central tendon defects
      alongside eventrations as the rarest diaphragmatic defects; the phrase
      quoted here is the adjacent category in that enumeration.
- name: Pulmonary hypoplasia
  category: Structural
  description: >-
    Reduced lung volume with fewer airway branching generations and reduced
    alveolar number, affecting both lungs but more severely the lung
    ipsilateral to the defect.
  phenotype_term:
    preferred_term: Pulmonary hypoplasia
    term:
      id: HP:0002089
      label: Pulmonary hypoplasia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:22214468
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The lungs are hypoplastic and have abnormal vessels that cause
      respiratory insufficiency and persistent pulmonary hypertension with high
      mortality.
    explanation: >-
      Describes hypoplastic lungs as a feature of clinically apparent CDH and
      links them to the downstream respiratory phenotype. VERY_FREQUENT is a
      clinical estimate (near-universal in clinically apparent CDH), not a
      figure extracted from the cited abstract.
- name: Pulmonary arterial hypertension
  category: Cardiovascular
  description: >-
    Persistent pulmonary hypertension of the newborn with failure of the
    normal postnatal fall in pulmonary vascular resistance.
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  frequency: FREQUENT
  evidence:
  - reference: PMID:22214468
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The lungs are hypoplastic and have abnormal vessels that cause
      respiratory insufficiency and persistent pulmonary hypertension with high
      mortality.
    explanation: >-
      Documents persistent pulmonary hypertension as a core CDH phenotype
      arising from abnormal pulmonary vasculature. FREQUENT is a clinical
      estimate; neither cited abstract reports a percentage.
  - reference: PMID:39018718
    reference_title: "Congenital diaphragmatic hernia-associated pulmonary hypertension."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Understanding CDH-associated PH (CDH-PH) is crucial for development of
      novel approaches and effective management due to its significant impact
      on morbidity and mortality.
    explanation: >-
      Confirms CDH-associated pulmonary hypertension as a frequent and
      outcome-determining phenotype.
- name: Respiratory failure
  category: Respiratory
  description: >-
    Neonatal respiratory failure presenting within minutes to hours of birth
    in severe cases.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
    temporality: ACUTE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:37990078
    reference_title: "The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Congenital diaphragmatic hernia (CDH) is a severe birth defect and a
      major cause of neonatal respiratory distress.
    explanation: >-
      Snippet supports the disease-phenotype association between CDH and
      neonatal respiratory distress. VERY_FREQUENT is a clinical estimate
      (near-universal in prenatally diagnosed CDH), not a figure extracted from
      the cited abstract.
- name: Hypoxemia
  category: Respiratory
  description: Severe, often labile arterial hypoxemia refractory to supplemental oxygen.
  phenotype_term:
    preferred_term: Hypoxemia
    term:
      id: HP:0012418
      label: Hypoxemia
  evidence:
  - reference: PMID:22214468
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The lungs are hypoplastic and have abnormal vessels that cause
      respiratory insufficiency
    explanation: >-
      Respiratory insufficiency from hypoplastic lungs and abnormal vessels
      manifests clinically as hypoxemia.
- name: Cyanosis
  category: Respiratory
  description: Central cyanosis reflecting right-to-left shunting and impaired gas exchange.
  phenotype_term:
    preferred_term: Cyanosis
    term:
      id: HP:0000961
      label: Cyanosis
  evidence:
  - reference: PMID:31519366
    reference_title: "Congenital diaphragmatic hernia-associated pulmonary hypertension."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      intrathoracic herniation of abdominal viscera via diaphragmatic defect
      results in aberrant pulmonary and cardiovascular development
    explanation: >-
      Supports the aberrant cardiopulmonary physiology whose bedside expression
      is central cyanosis; the specific sign is not separately quantified in
      the cited abstract.
- name: Right ventricular failure
  category: Cardiovascular
  description: >-
    Right ventricular dysfunction and failure secondary to pulmonary
    hypertensive afterload.
  phenotype_term:
    preferred_term: Right ventricular failure
    term:
      id: HP:0001708
      label: Right ventricular failure
  evidence:
  - reference: PMID:28768736
    reference_title: "Congenital diaphragmatic hernias: from genes to mechanisms to therapies."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      associated with significant morbidity and mortality due to associated
      pulmonary hypoplasia, pulmonary hypertension and heart failure
    explanation: >-
      Documents heart failure as a CDH complication; the abstract does not
      specify right-sided failure, so the evidence is partial.
- name: Scaphoid abdomen
  category: Structural
  description: >-
    A sunken abdominal contour in the newborn resulting from displacement of
    abdominal viscera into the thorax.
  phenotype_term:
    preferred_term: Scaphoid abdomen
    term:
      id: HP:0025063
      label: Scaphoid abdomen
  evidence:
  - reference: PMID:22214468
    reference_title: "Congenital diaphragmatic hernia."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      permits the herniation of abdominal contents into the thorax
    explanation: >-
      The scaphoid abdominal contour is the direct anatomic consequence of
      abdominal contents relocating into the thorax; the sign itself is not
      named in the abstract.
- name: Polyhydramnios
  category: Prenatal
  description: >-
    Excess amniotic fluid, attributed to impaired fetal swallowing when the
    herniated stomach or oesophagus is displaced. The cited evidence documents
    it in the syndromic (Fryns) context rather than in CDH generally.
  phenotype_term:
    preferred_term: Polyhydramnios
    term:
      id: HP:0001561
      label: Polyhydramnios
  evidence:
  - reference: PMID:20301632
    reference_title: "Fryns Syndrome."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      pulmonary hypoplasia; and associated anomalies (polyhydramnios, cloudy
      corneas and/or microphthalmia, orofacial clefting, renal dysplasia /
      renal cortical cysts
    explanation: >-
      Polyhydramnios is documented as an associated prenatal finding in Fryns
      syndrome, the prototypical syndromic CDH; the source does not quantify it
      across CDH generally, so support is partial.
- name: Congenital heart defect
  category: Cardiovascular
  description: >-
    Structural cardiac malformations co-occur in a substantial minority of CDH
    cases and worsen prognosis.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:22214468
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      About one third of cases have cardiovascular malformations and lesser
      proportions have skeletal, neural, genitourinary, gastrointestinal or
      other defects.
    explanation: >-
      Quantifies co-occurring cardiovascular malformations in approximately a
      third of CDH cases; one third (about 33%) falls in the FREQUENT band
      (30-79%).
  frequency: FREQUENT
- name: Gastroesophageal reflux
  category: Gastrointestinal
  description: >-
    A common long-term morbidity in CDH survivors, related to distortion of
    the oesophageal hiatus and altered gastro-oesophageal anatomy.
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
    temporality: CHRONIC
  evidence:
  - reference: PMID:22214468
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chronic respiratory tract disease, neurodevelopmental problems,
      neurosensorial hearing loss and gastroesophageal reflux are common
      problems in survivors.
    explanation: >-
      Documents gastro-oesophageal reflux as a common long-term morbidity. The
      qualitative term "common" maps to the FREQUENT band (30-79%); note the
      denominator in the source is CDH survivors, not all CDH cases.
  frequency: FREQUENT
- name: Failure to thrive
  category: Growth
  description: >-
    Poor postnatal growth in survivors, driven by increased work of breathing,
    feeding difficulty, and reflux.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:35650272
    reference_title: "Congenital diaphragmatic hernia."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Survivors often have long-term, multisystem morbidities, including
      pulmonary dysfunction, gastroesophageal reflux, musculoskeletal
      deformities and neurodevelopmental impairment.
    explanation: >-
      Supports chronic multisystem survivor morbidity; growth failure is not
      itemised in the abstract, so the evidence is partial.
- name: Neurodevelopmental delay
  category: Neurological
  description: >-
    Neurodevelopmental impairment in survivors, reported in association with
    prolonged hypoxemia, extracorporeal support, and prolonged intensive care.
  phenotype_term:
    preferred_term: Neurodevelopmental delay
    term:
      id: HP:0012758
      label: Neurodevelopmental delay
  evidence:
  - reference: PMID:35650272
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Survivors often have long-term, multisystem morbidities, including
      pulmonary dysfunction, gastroesophageal reflux, musculoskeletal
      deformities and neurodevelopmental impairment.
    explanation: >-
      Names neurodevelopmental impairment among the established long-term
      morbidities of CDH survivors.
- name: Sensorineural hearing impairment
  category: Neurological
  description: >-
    Hearing loss reported in CDH survivors, described in association with
    extracorporeal support and prolonged intensive care exposure.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:22214468
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chronic respiratory tract disease, neurodevelopmental problems,
      neurosensorial hearing loss and gastroesophageal reflux are common
      problems in survivors.
    explanation: >-
      Documents neurosensorial (sensorineural) hearing loss as a common
      survivor morbidity in CDH.
- name: Chronic lung disease
  category: Respiratory
  description: >-
    Chronic oxygen dependency and long-term pulmonary morbidity in survivors,
    the CDH counterpart of bronchopulmonary dysplasia. It reflects the
    hypoplastic, immature lung compounded by exposure to mechanical ventilation
    and oxygen.
  phenotype_term:
    preferred_term: Chronic lung disease
    term:
      id: HP:0006528
      label: Chronic lung disease
    temporality: CHRONIC
  frequency: FREQUENT
  evidence:
  - reference: PMID:21042035
    reference_title: "Risk factors for chronic lung disease and mortality in newborns with congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In infants who survived until day 30, the prevalence of BPD was 41%.
    explanation: >-
      A 2,078-neonate CDH Study Group cohort quantifies chronic lung disease
      (bronchopulmonary dysplasia, defined as oxygen dependency at day 30) at
      41% of day-30 survivors, which falls in the FREQUENT band (30-79%).
  - reference: PMID:21042035
    reference_title: "Risk factors for chronic lung disease and mortality in newborns with congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CDH survivors have a substantial risk of developing long-term pulmonary
      sequelae, such as bronchopulmonary dysplasia (BPD).
    explanation: >-
      States chronic pulmonary sequelae as an expected outcome of CDH survival.
  - reference: PMID:35650272
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Survivors often have long-term, multisystem morbidities, including
      pulmonary dysfunction, gastroesophageal reflux, musculoskeletal
      deformities and neurodevelopmental impairment.
    explanation: >-
      Names pulmonary dysfunction first among the established long-term
      morbidities of CDH survivors.
  - reference: PMID:26692079
    reference_title: "Conventional Mechanical Ventilation Versus High-frequency Oscillatory Ventilation for Congenital Diaphragmatic Hernia: A Randomized Clinical Trial (The VICI-trial)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The maldeveloped lungs have a high susceptibility for oxygen and
      ventilation damage resulting in a high incidence of bronchopulmonary
      dysplasia (BPD) and chronic respiratory morbidity.
    explanation: >-
      Supports the mechanism of the phenotype: the hypoplastic lung plus
      ventilator and oxygen exposure produce chronic lung disease.
- name: Scoliosis
  category: Skeletal
  description: >-
    Spinal deformity in long-term survivors, one component of the
    musculoskeletal morbidity that follows a large diaphragmatic defect and its
    repair. It correlates with defect severity rather than being an intrinsic
    developmental feature of the diaphragmatic lesion.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
    clinical_course: PROGRESSIVE
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31482324
    reference_title: "Left congenital diaphragmatic hernia-associated musculoskeletal deformities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      28 patients (28.6%) had at least one type of musculoskeletal deformities,
      2 of which were pectus carinatum, 16 were pectus excavatum, and 18 were
      scoliosis.
    explanation: >-
      In a 98-patient left-CDH survivor cohort, scoliosis occurred in 18/98
      (18.4%), which falls in the OCCASIONAL band (5-29%).
  - reference: PMID:31482324
    reference_title: "Left congenital diaphragmatic hernia-associated musculoskeletal deformities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is a correlation between musculoskeletal deformities and the
      severity of the CDH.
    explanation: >-
      Supports the causal edge from the size and severity of the diaphragmatic
      defect to the musculoskeletal phenotype.
  - reference: PMID:35650272
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Survivors often have long-term, multisystem morbidities, including
      pulmonary dysfunction, gastroesophageal reflux, musculoskeletal
      deformities and neurodevelopmental impairment.
    explanation: >-
      Names musculoskeletal deformities among the established long-term
      morbidities of CDH survivors.
- name: Pectus excavatum
  category: Skeletal
  description: >-
    Anterior chest wall depression in survivors, the second component of the
    musculoskeletal morbidity of CDH. Primary abdominal closure under tension
    after repair is associated with a higher rate.
  phenotype_term:
    preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31482324
    reference_title: "Left congenital diaphragmatic hernia-associated musculoskeletal deformities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      28 patients (28.6%) had at least one type of musculoskeletal deformities,
      2 of which were pectus carinatum, 16 were pectus excavatum, and 18 were
      scoliosis.
    explanation: >-
      In the same 98-patient left-CDH survivor cohort, pectus excavatum
      occurred in 16/98 (16.3%), which falls in the OCCASIONAL band (5-29%).
  - reference: PMID:31482324
    reference_title: "Left congenital diaphragmatic hernia-associated musculoskeletal deformities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      who had primary abdominal closure after ventral hernia significantly have
      more pectus excavatum
    explanation: >-
      Identifies tension abdominal closure after repair as the surgical
      correlate of the anterior chest wall deformity.
- name: Hypoplastic left ventricle
  category: Cardiovascular
  description: >-
    Reduced left ventricular and left-sided valvar dimensions in left-sided
    CDH, proportional to lung size and liver herniation. This is a hypoplasia
    of degree rather than hypoplastic left heart syndrome.
  phenotype_term:
    preferred_term: Left ventricular hypoplasia
    term:
      id: HP:0004383
      label: Hypoplastic left ventricle
  evidence:
  - reference: PMID:28370263
    reference_title: "Fetal left-sided cardiac structural dimensions in left-sided congenital diaphragmatic hernia - association with severity and impact on postnatal outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fetuses with congenital diaphragmatic hernia (CDH) demonstrate varying
      degrees of left heart hypoplasia.
    explanation: >-
      Documents left heart hypoplasia as a graded structural phenotype of CDH.
      No frequency band is assigned because the cited cohort reports z-score
      distributions rather than a proportion of affected fetuses.
  - reference: PMID:28370263
    reference_title: "Fetal left-sided cardiac structural dimensions in left-sided congenital diaphragmatic hernia - association with severity and impact on postnatal outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      postnatal left ventricular end-diastolic dimension z-score correlated
      with liver herniation
    explanation: >-
      Links postnatal left ventricular size directly to the degree of visceral
      herniation.
biochemical:
- name: Circulating small RNA (microRNA) severity biomarkers
  notes: >-
    No CDH-specific circulating diagnostic biomarker is in clinical use;
    severity is still assessed by imaging. Circulating small RNA species are
    the leading investigational candidate. In a prospective study of maternal
    blood, amniotic fluid, cord blood and neonatal blood, miRNA profiles
    separated CDH pregnancies from controls, and a maternal-blood miRNA set
    separated survivors from non-survivors. These are research-stage measures
    from a single small cohort, not validated clinical prognosticators.
  specificity: >-
    Not established. Reported discrimination comes from a single small
    prospective cohort without external validation.
  evidence:
  - reference: PMID:35650272
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Emerging research focuses on small RNA species as biomarkers of severity
      and regenerative medicine approaches to improve fetal lung development.
    explanation: >-
      The disease primer identifies small RNA severity biomarkers as the active
      biomarker frontier in CDH.
  - reference: PMID:39505208
    reference_title: "microRNAs in congenital diaphragmatic hernia: insights into prenatal and perinatal biomarkers and altered molecular pathways."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Random forest analysis identified miRNAs in maternal blood
      (miR-7850-5p_L-1R+2, miR-942-3p, and miR-197-3p) that distinguished CDH
      survivors from nonsurvivors, with an receiver operating characteristic
      area under the curve of 1.0.
    explanation: >-
      Names the specific candidate maternal-blood miRNAs and their reported
      discrimination; support is partial because a perfect AUC in a small
      unreplicated cohort is not a validated biomarker claim.
  - reference: PMID:39505208
    reference_title: "microRNAs in congenital diaphragmatic hernia: insights into prenatal and perinatal biomarkers and altered molecular pathways."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prenatal imaging techniques like ultrasound and MRI provide anatomical
      predictors of outcomes, but their limitations necessitate novel
      biomarkers for better prognostic accuracy.
    explanation: >-
      States the unmet need this biomarker class addresses, and confirms that
      imaging remains the current standard for severity assessment.
genetic:
- name: ZFPM2
  gene_term:
    preferred_term: ZFPM2
    term:
      id: hgnc:16700
      label: ZFPM2
  relationship_type: CAUSATIVE
  notes: >-
    ZFPM2 (FOG2) encodes a GATA cofactor expressed in the developing
    diaphragm; loss-of-function variants cause both isolated and syndromic
    diaphragmatic defects.
  evidence:
  - reference: PMID:28768736
    reference_title: "Congenital diaphragmatic hernias: from genes to mechanisms to therapies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The affected genes identified in CDH patients include transcription
      factors, such as GATA4, ZFPM2, NR2F2 and WT1
    explanation: Names ZFPM2 among the established CDH transcription-factor genes.
- name: GATA4
  gene_term:
    preferred_term: GATA4
    term:
      id: hgnc:4173
      label: GATA4
  relationship_type: CAUSATIVE
  notes: >-
    GATA4 is expressed in the pleuroperitoneal fold mesenchyme; haploinsufficiency
    from 8p23.1 deletion or point mutation causes CDH, often with congenital
    heart disease.
  evidence:
  - reference: PMID:28768736
    reference_title: "Congenital diaphragmatic hernias: from genes to mechanisms to therapies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The affected genes identified in CDH patients include transcription
      factors, such as GATA4, ZFPM2, NR2F2 and WT1
    explanation: Names GATA4 among the established CDH transcription-factor genes.
- name: NR2F2
  gene_term:
    preferred_term: NR2F2
    term:
      id: hgnc:7976
      label: NR2F2
  relationship_type: CAUSATIVE
  notes: >-
    NR2F2 (COUP-TFII) lies within the 15q26 region whose deletion is a
    recurrent cause of CDH; it is a retinoic-acid-responsive nuclear receptor
    expressed in diaphragmatic mesenchyme.
  evidence:
  - reference: PMID:28768736
    reference_title: "Congenital diaphragmatic hernias: from genes to mechanisms to therapies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The affected genes identified in CDH patients include transcription
      factors, such as GATA4, ZFPM2, NR2F2 and WT1
    explanation: Names NR2F2 among the established CDH transcription-factor genes.
- name: WT1
  gene_term:
    preferred_term: WT1
    term:
      id: hgnc:12796
      label: WT1
  relationship_type: CAUSATIVE
  notes: >-
    WT1 variants cause syndromic CDH with disorders of sex development and
    nephropathy (Meacham and Denys-Drash phenotypes).
  evidence:
  - reference: PMID:28768736
    reference_title: "Congenital diaphragmatic hernias: from genes to mechanisms to therapies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The affected genes identified in CDH patients include transcription
      factors, such as GATA4, ZFPM2, NR2F2 and WT1
    explanation: Names WT1 among the established CDH transcription-factor genes.
  - reference: PMID:22214468
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CDH can be a component of Pallister-Killian, Fryns, Ghersoni-Baruch,
      WAGR, Denys-Drash, Brachman-De Lange, Donnai-Barrow or Wolf-Hirschhorn
      syndromes.
    explanation: >-
      Lists the WT1-related WAGR and Denys-Drash syndromes among the syndromic
      contexts of CDH.
- name: LONP1
  gene_term:
    preferred_term: LONP1
    term:
      id: hgnc:9479
      label: LONP1
  relationship_type: RISK_FACTOR
  notes: >-
    LONP1 encodes the mitochondrial Lon protease. In an 827-proband CDH cohort,
    de novo and ultra-rare inherited, largely heterozygous LONP1 variants
    clustered in the functional domains and segregated with CDH, implicating
    LONP1 as a CDH risk gene rather than a classical Mendelian cause. This is
    mechanistically distinct from the biallelic LONP1 phenotype (CODAS
    syndrome), which does not feature congenital diaphragmatic hernia.
  evidence:
  - reference: PMID:34547244
    reference_title: "Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identified LONP1 as a risk gene contributing to CDH through both de novo
      and ultra-rare inherited largely heterozygous variants clustered in the
      core of the domains and segregating with CDH in affected familial
      individuals.
    explanation: >-
      Establishes LONP1 as a candidate CDH risk gene in an 827-proband cohort,
      with a predominantly heterozygous mechanism.
  - reference: PMID:34547244
    reference_title: "Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mice with lung epithelium-specific deletion of Lonp1 die immediately
      after birth, most likely because of the observed severe reduction of lung
      growth, a known contributor to the high mortality in humans.
    explanation: >-
      Mouse conditional knockout reproduces the severe lung-growth reduction
      that drives mortality in human CDH.
- name: MYRF
  gene_term:
    preferred_term: MYRF
    term:
      id: hgnc:1181
      label: MYRF
  relationship_type: CAUSATIVE
  notes: >-
    De novo MYRF variants cause a cardiac-urogenital syndrome that includes
    congenital diaphragmatic hernia.
  evidence:
  - reference: PMID:36375006
    reference_title: "MYRF-Related Cardiac Urogenital Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MYRF-related cardiac urogenital syndrome (MYRF-CUGS) is primarily
      characterized by anomalies of the internal and external genitalia,
      congenital heart defects, and eye anomalies.
    explanation: >-
      GeneReviews defines the MYRF-related cardiac-urogenital syndrome in which
      congenital diaphragmatic hernia occurs as a recurrent feature.
- name: LRP2
  gene_term:
    preferred_term: LRP2
    term:
      id: hgnc:6694
      label: LRP2
  relationship_type: CAUSATIVE
  notes: >-
    Biallelic LRP2 variants cause Donnai-Barrow syndrome, in which
    diaphragmatic hernia occurs with agenesis of the corpus callosum, high
    myopia, sensorineural hearing loss, and proteinuria.
  evidence:
  - reference: PMID:20301732
    reference_title: "Donnai-Barrow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional common features include agenesis of the corpus callosum,
      sensorineural hearing loss, intellectual disability, and congenital
      diaphragmatic hernia and/or omphalocele.
    explanation: >-
      GeneReviews documents congenital diaphragmatic hernia as a common feature
      of Donnai-Barrow syndrome.
  - reference: PMID:20301732
    reference_title: "Donnai-Barrow Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      biallelic pathogenic variants in LRP2 identified by molecular genetic
      testing
    explanation: Establishes biallelic LRP2 variants as the molecular basis of the syndrome.
- name: STRA6
  gene_term:
    preferred_term: STRA6
    term:
      id: hgnc:30650
      label: STRA6
  relationship_type: CAUSATIVE
  notes: >-
    STRA6 encodes the cellular retinol-binding-protein receptor; biallelic
    variants cause Matthew-Wood/PDAC syndrome with diaphragmatic hernia,
    supporting the retinoid hypothesis of CDH.
  evidence:
  - reference: PMID:19309693
    reference_title: "Phenotypic spectrum of STRA6 mutations: from Matthew-Wood syndrome to non-lethal anophthalmia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Matthew-Wood, Spear, PDAC or MCOPS9 syndrome are alternative names used
      to refer to combinations of microphthalmia/anophthalmia, malformative
      cardiac defects, pulmonary dysgenesis, and diaphragmatic hernia.
    explanation: >-
      Defines the STRA6-related syndrome in which diaphragmatic hernia is a
      cardinal feature.
  - reference: PMID:19309693
    reference_title: "Phenotypic spectrum of STRA6 mutations: from Matthew-Wood syndrome to non-lethal anophthalmia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mutations in STRA6, encoding a membrane receptor for vitamin A-bearing
      plasma retinol binding protein, have been identified in such patients
    explanation: >-
      Links the causal gene to vitamin A/retinol uptake, directly supporting
      the retinoid hypothesis arm of the pathograph.
- name: GATA6
  gene_term:
    preferred_term: GATA6
    term:
      id: hgnc:4174
      label: GATA6
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  notes: >-
    GATA6 is a GATA-family transcription factor paralogous to GATA4. De novo
    and mosaic-inherited loss-of-function variants cause CDH with congenital
    heart disease, extending the GATA4/ZFPM2 axis already modelled at the
    pleuroperitoneal fold node.
  evidence:
  - reference: PMID:24385578
    reference_title: "Whole exome sequencing identifies de novo mutations in GATA6 associated with congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We used whole exome sequencing in two families with CDH and congenital
      heart disease, and identified mutations in GATA6 in both.
    explanation: >-
      Establishes GATA6 variants as a cause of CDH with congenital heart
      disease in two independent families.
  - reference: PMID:24385578
    reference_title: "Whole exome sequencing identifies de novo mutations in GATA6 associated with congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To determine the frequency of GATA6 mutations in CDH, we sequenced the
      gene in 378 patients with CDH. We identified one additional de novo
      mutation
    explanation: >-
      A 378-patient cohort screen adds a third de novo GATA6 variant, showing
      the mechanism is recurrent but individually rare.
- name: PBX1
  gene_term:
    preferred_term: PBX1
    term:
      id: hgnc:8632
      label: PBX1
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  notes: >-
    PBX1 encodes a TALE-homeodomain transcription factor that partners with HOX
    proteins. De novo deleterious variants cause a pleiotropic developmental
    syndrome in which diaphragmatic hernia occurs alongside branchial arch, ear,
    cardiac, renal and genital anomalies, mirroring the Pbx1-null mouse.
  evidence:
  - reference: PMID:29036646
    reference_title: "De novo, deleterious sequence variants that alter the transcriptional activity of the homeoprotein PBX1 are associated with intellectual disability and pleiotropic developmental defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical findings similar to those in Pbx mutant mice were observed in
      all patients with varying expressivity and severity, including external
      ear anomalies, abnormal branchial arch derivatives, heart malformations,
      diaphragmatic hernia, renal hypoplasia and ambiguous genitalia.
    explanation: >-
      Names diaphragmatic hernia among the recurrent malformations in eight
      patients with de novo PBX1 variants.
  - reference: PMID:22315423
    reference_title: "Congenital diaphragmatic hernia candidate genes derived from embryonic transcriptomes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We examined the diaphragms of knockout mice for one of the candidate
      genes, pre-B-cell leukemia transcription factor 1 (Pbx1), and identified
      a range of previously undetected diaphragmatic defects.
    explanation: >-
      Mouse knockout confirms the diaphragmatic requirement for Pbx1 that the
      human phenotype implies.
- name: SLIT3
  gene_term:
    preferred_term: SLIT3
    term:
      id: hgnc:11087
      label: SLIT3
  relationship_type: RISK_FACTOR
  notes: >-
    SLIT3 encodes a secreted axon-guidance ligand acting through ROBO
    receptors. Slit3-null mice develop central tendon diaphragmatic hernias,
    and a homozygous SLIT3 variant has been reported in dizygotic twins with
    isolated CDH. Human evidence is currently limited to that single family, so
    SLIT3 is typed as a candidate risk gene rather than CAUSATIVE, following
    the same convention applied to LONP1 in this entry.
  evidence:
  - reference: PMID:33933663
    reference_title: "Isolated congenital diaphragm hernia associated with homozygous SLIT3 gene variant in dizygous twins."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is the first report of homozygous SLIT3 variant associated with CDH
      in humans.
    explanation: >-
      A single-family report is the whole of the direct human evidence, which
      is why the gene is typed as a candidate risk gene.
  - reference: PMID:33933663
    reference_title: "Isolated congenital diaphragm hernia associated with homozygous SLIT3 gene variant in dizygous twins."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Previous studies showed that Slit3 null mice had congenital diaphragmatic
      hernias on or near the ventral midline portion of the central tendon.
    explanation: >-
      Mouse null data give the mechanistic prior, and specifically predict the
      central (septum transversum) rather than posterolateral defect subtype.
treatments:
- name: Fetal Endoscopic Tracheal Occlusion (FETO)
  description: >-
    Percutaneous fetoscopic placement of a detachable balloon in the fetal
    trachea, which retains lung fluid, raises intrapulmonary pressure and
    promotes lung growth, followed by balloon removal before delivery. Offered
    in severe isolated CDH with low observed-to-expected lung-to-head ratio.
  treatment_term:
    preferred_term: fetoscopic tracheal occlusion
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Pulmonary Hypoplasia
    treatment_effect: RESTORES
    description: >-
      Tracheal occlusion promotes fetal lung growth, partially reversing the
      parenchymal deficit.
  evidence:
  - reference: PMID:34106556
    reference_title: "Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In fetuses with isolated severe congenital diaphragmatic hernia on the
      left side, FETO performed at 27 to 29 weeks of gestation resulted in a
      significant benefit over expectant care with respect to survival to
      discharge, and this benefit was sustained to 6 months of age.
    explanation: >-
      Randomised trial (TOTAL) establishing a survival benefit for FETO in
      severe left-sided isolated CDH.
  - reference: PMID:34106556
    reference_title: "Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The incidence of preterm, prelabor rupture of membranes was higher among
      women in the FETO group than among those in the expectant care group
    explanation: >-
      Documents the principal harm of FETO, preterm prelabor rupture of
      membranes, which constrains patient selection.
  - reference: PMID:34106555
    reference_title: "Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fetoscopic endoluminal tracheal occlusion (FETO) has been associated with
      increased postnatal survival among infants with severe pulmonary
      hypoplasia due to isolated congenital diaphragmatic hernia on the left
      side, but data are lacking to inform its effects in infants with moderate
      disease.
    explanation: >-
      The companion moderate-disease trial frames FETO benefit as established
      for severe but not moderate hypoplasia.
  - reference: PMID:34106555
    reference_title: "Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This trial involving fetuses with moderate congenital diaphragmatic
      hernia on the left side did not show a significant benefit of FETO
      performed at 30 to 32 weeks of gestation over expectant care with respect
      to survival to discharge or the need for oxygen supplementation at 6
      months.
    explanation: >-
      The companion randomised trial found NO significant benefit of FETO in
      moderate left-sided CDH. Curated as REFUTE so the entry does not
      generalise the severe-disease benefit; the indication is confined to
      severe hypoplasia.
  - reference: PMID:34106555
    reference_title: "Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FETO increased the risks of preterm, prelabor rupture of membranes and
      preterm birth.
    explanation: >-
      Confirms in the moderate-disease trial that the prematurity harm is
      incurred regardless of whether a survival benefit is obtained, which is
      the core of the risk-benefit argument against offering FETO in moderate
      disease.
  - reference: PMID:35650272
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At specialized centres, prenatal management includes fetal endoscopic
      tracheal occlusion, which is a surgical intervention aimed at promoting
      lung growth in utero.
    explanation: Confirms the mechanism of action as promotion of in utero lung growth.
- name: Gentle Ventilation
  description: >-
    A permissive-hypercapnia, pressure-limited ventilation strategy that
    avoids high peak inflating pressures in order to prevent barotrauma to the
    hypoplastic lung; the standardised approach that underpinned improved
    survival in contemporary CDH care.
  treatment_term:
    preferred_term: pressure-limited mechanical ventilation
    term:
      id: NCIT:C70909
      label: Mechanical Ventilation
  target_mechanisms:
  - target: Refractory Hypoxemia and Neonatal Respiratory Failure
    treatment_effect: MODULATES
    description: >-
      Supports gas exchange while minimising ventilator-induced injury to the
      hypoplastic lung.
  evidence:
  - reference: PMID:26692079
    reference_title: "Conventional Mechanical Ventilation Versus High-frequency Oscillatory Ventilation for Congenital Diaphragmatic Hernia: A Randomized Clinical Trial (The VICI-trial)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The maldeveloped lungs have a high susceptibility for oxygen and
      ventilation damage resulting in a high incidence of bronchopulmonary
      dysplasia (BPD) and chronic respiratory morbidity.
    explanation: >-
      States the rationale for a lung-protective ventilation strategy in CDH.
  - reference: PMID:26692079
    reference_title: "Conventional Mechanical Ventilation Versus High-frequency Oscillatory Ventilation for Congenital Diaphragmatic Hernia: A Randomized Clinical Trial (The VICI-trial)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other outcomes, including shorter ventilation time and lesser need of
      extracorporeal membrane oxygenation, favored conventional ventilation.
    explanation: >-
      The VICI randomised trial favours conventional pressure-limited
      ventilation over high-frequency oscillation as the initial strategy.
  - reference: PMID:27077664
    reference_title: "Standardized Postnatal Management of Infants with Congenital Diaphragmatic Hernia in Europe: The CDH EURO Consortium Consensus - 2015 Update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      target PaCO2 to be between 50 and 70 mm Hg; (5) conventional mechanical
      ventilation to be the optimal initial ventilation strategy
    explanation: >-
      CDH EURO Consortium consensus specifying permissive hypercapnia and
      conventional ventilation as the standard gentle-ventilation approach.
- name: Inhaled Nitric Oxide
  description: >-
    Selective inhaled pulmonary vasodilator used for pulmonary hypertension
    with right-to-left shunting; response in CDH is frequently poor compared
    with other causes of persistent pulmonary hypertension of the newborn.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: nitric oxide
      term:
        id: CHEBI:16480
        label: nitric oxide
  target_mechanisms:
  - target: Persistent Pulmonary Hypertension of the Newborn
    treatment_effect: INHIBITS
    description: Selective pulmonary vasodilation lowers pulmonary vascular resistance.
  evidence:
  - reference: PMID:32384329
    reference_title: "The Use of Inhaled Nitric Oxide in Congenital Diaphragmatic Hernia."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      the role of iNO as a treatment for CDH is controversial.
    explanation: >-
      A systematic review concludes that the benefit of inhaled nitric oxide in
      CDH-associated pulmonary hypertension is not established, which is why
      this treatment is curated with PARTIAL support.
  - reference: PMID:39018718
    reference_title: "Congenital diaphragmatic hernia-associated pulmonary hypertension."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Management strategies include lung protective ventilation, fluid
      optimization, pharmacotherapies including pulmonary vasodilators and
      hemodynamic support, and extracorporeal life support (ECLS) for
      refractory cases.
    explanation: >-
      Places pulmonary vasodilator therapy within the standard CDH-PH
      management bundle.
- name: Sildenafil
  description: >-
    Phosphodiesterase-5 inhibitor used to treat pulmonary hypertension in CDH,
    including as prenatal and postnatal therapy under investigation.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sildenafil
      term:
        id: CHEBI:9139
        label: sildenafil
  target_mechanisms:
  - target: Persistent Pulmonary Hypertension of the Newborn
    treatment_effect: INHIBITS
    description: >-
      Potentiates cyclic GMP mediated pulmonary vasodilation downstream of
      nitric oxide.
  evidence:
  - reference: PMID:27077664
    reference_title: "Standardized Postnatal Management of Infants with Congenital Diaphragmatic Hernia in Europe: The CDH EURO Consortium Consensus - 2015 Update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      intravenous sildenafil to be considered in CDH patients with severe
      pulmonary hypertension
    explanation: >-
      CDH EURO Consortium consensus recommendation for sildenafil in severe
      CDH-associated pulmonary hypertension.
- name: Milrinone
  description: >-
    Phosphodiesterase-3 inhibitor with inotropic and pulmonary vasodilator
    effects used for right ventricular dysfunction with pulmonary hypertension
    in CDH.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: milrinone
      term:
        id: CHEBI:50693
        label: milrinone
  target_mechanisms:
  - target: Right Ventricular Pressure Overload and Failure
    treatment_effect: MODULATES
    description: Inodilation supports right ventricular performance and lowers afterload.
  evidence:
  - reference: PMID:39018718
    reference_title: "Congenital diaphragmatic hernia-associated pulmonary hypertension."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      pharmacotherapies including pulmonary vasodilators and hemodynamic
      support
    explanation: >-
      Milrinone is used as combined pulmonary vasodilator and haemodynamic
      support; the cited review describes the class rather than the individual
      agent, so support is partial.
- name: Extracorporeal Membrane Oxygenation
  description: >-
    Venoarterial or venovenous extracorporeal life support used as rescue
    therapy for refractory hypoxemia or cardiovascular failure in CDH,
    permitting lung rest until pulmonary vascular resistance falls.
  treatment_term:
    preferred_term: extracorporeal membrane oxygenation
    term:
      id: NCIT:C171507
      label: Extracorporeal Membrane Oxygenation
  target_mechanisms:
  - target: Refractory Hypoxemia and Neonatal Respiratory Failure
    treatment_effect: BYPASSES
    description: >-
      Extracorporeal gas exchange bypasses the hypoplastic lung during the
      period of highest pulmonary vascular resistance.
  evidence:
  - reference: PMID:35650272
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Postnatal management focuses on cardiopulmonary stabilization and, in
      severe cases, can involve extracorporeal life support.
    explanation: >-
      Establishes extracorporeal life support as the accepted rescue therapy in
      severe CDH.
  - reference: PMID:22214468
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment after birth requires all the refinements of critical care
      including extracorporeal membrane oxygenation prior to surgical
      correction.
    explanation: >-
      Situates ECMO before, rather than after, surgical repair in the treatment
      sequence.
- name: Delayed Surgical Repair of the Diaphragmatic Defect
  description: >-
    Operative closure of the diaphragmatic defect by primary repair or
    prosthetic patch, deferred until after physiological stabilisation rather
    than performed as a neonatal emergency.
  treatment_term:
    preferred_term: diaphragmatic hernia repair
    term:
      id: NCIT:C168249
      label: Herniorrhaphy
  target_mechanisms:
  - target: Failure of Diaphragm Closure and Visceral Herniation
    treatment_effect: RESTORES
    description: Repair restores diaphragmatic continuity and reduces the herniated viscera.
  evidence:
  - reference: PMID:22214468
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment after birth requires all the refinements of critical care
      including extracorporeal membrane oxygenation prior to surgical
      correction.
    explanation: >-
      Supports delayed surgical correction after physiological stabilisation
      rather than emergency neonatal repair.
  - reference: PMID:20301632
    reference_title: "Fryns Syndrome."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For congenital diaphragmatic hernia, the neonate is immediately intubated
      to prevent inflation of herniated bowel
    explanation: >-
      GeneReviews management guidance shows that airway stabilisation precedes
      operative repair; it speaks to the stabilise-first sequence rather than to
      the timing of repair itself.
environmental:
- name: Reduced retinoid (vitamin A) signaling during diaphragm morphogenesis
  description: >-
    Perturbation of the vitamin A / retinoic acid axis during early gestation
    is the best-developed environmental hypothesis for CDH. Retinoic acid is
    generated from dietary vitamin A by retinaldehyde dehydrogenases; dietary
    vitamin A deficiency, teratogens that inhibit retinoic acid synthesis, and
    genetic lesions in retinoid transport and signalling all produce
    diaphragmatic defects, and the pathway is a locus of gene-environment
    interaction.
  effect: Risk factor
  chemicals:
  - retinoic acid
  - retinol
  evidence:
  - reference: PMID:37990078
    reference_title: "The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This review provides a comprehensive update on the Retinoid Hypothesis,
      which links abnormal retinoic acid signaling to the etiology of
      congenital diaphragmatic hernia.
    explanation: >-
      States the retinoid hypothesis as an aetiological account linking an
      environmentally modifiable pathway to CDH.
  - reference: PMID:39183805
    reference_title: "Role of genetics and the environment in the etiology of congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The retinoic acid pathway is thought to play an essential role in the
      interactions of genes and environment in CDH.
    explanation: >-
      Identifies the retinoid pathway specifically as the gene-environment
      interaction locus in CDH.
- name: Other maternal exposures
  description: >-
    Maternal age, alcohol use and smoking have been reported as epidemiological
    associations with CDH. Evidence outside retinoid biology remains limited
    and these associations should not be read as established individual
    causation.
  effect: Reported epidemiological association
  evidence:
  - reference: PMID:37990078
    reference_title: "The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      Environmental risk factors for CDH are varied, including associations
      with maternal age, alcohol use, and smoking.
    explanation: >-
      Lists the reported maternal exposure associations; the review presents
      these as associations rather than proven causes.
  - reference: PMID:39183805
    reference_title: "Role of genetics and the environment in the etiology of congenital diaphragmatic hernia."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      However, apart from the gradually maturing retinol hypothesis, there is
      limited evidence implicating other environmental factors in CDH
      occurrence.
    explanation: >-
      Explicitly qualifies the strength of non-retinoid environmental evidence.
inheritance:
- name: Multifactorial inheritance with a polygenic component
  description: >-
    Most CDH is sporadic. Genome-wide analysis supports a liability model in
    which common polygenic background acts together with rare, large-effect de
    novo variants; Mendelian inheritance applies only to the recognised
    syndromic and monogenic forms (autosomal dominant with incomplete
    penetrance, autosomal recessive, or chromosomal).
  inheritance_term:
    preferred_term: Polygenic inheritance
    term:
      id: HP:0010982
      label: Polygenic inheritance
  evidence:
  - reference: PMID:39332409
    reference_title: "Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The data support a polygenic model as part of the CDH genetic
      architecture.
    explanation: >-
      A 1,469-individual integrated de novo and common-variant study concludes
      that a polygenic component contributes to CDH liability.
  - reference: PMID:39332409
    reference_title: "Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Strikingly, there is no significant difference in estimated polygenic
      risk scores between isolated and complex CDH or between individuals
      harboring deleterious de novo variants and individuals without these
      variants.
    explanation: >-
      Shows the polygenic background is shared across isolated and complex CDH
      rather than defining separate genetic classes.
  - reference: PMID:35650272
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although the aetiology remains unknown, CDH has a polygenic origin in
      approximately one-third of cases.
    explanation: Supports a polygenic contribution in a substantial fraction of cases.
prevalence:
- population: Worldwide
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 25.0
  rate_low: 20.0
  rate_high: 30.0
  notes: Approximately 2 to 3 per 10,000 live births.
  evidence:
  - reference: PMID:37990078
    reference_title: "The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Impacting ~2-3 in 10,000 births, CDH is associated with a high mortality
      rate, and long-term morbidity in survivors.
    explanation: Gives the worldwide birth prevalence of CDH.
- population: England, singleton livebirths 2002-2018
  subtype: Isolated CDH
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 14.0
  notes: 1.4 per 10,000 livebirths for isolated CDH in a national birth cohort.
  evidence:
  - reference: PMID:36441118
    reference_title: "Congenital diaphragmatic hernia subtypes: Comparing birth prevalence, occurrence by maternal age, and mortality in a national birth cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among 9.5 million livebirths, we identified 1285 with isolated CDH and
      1150 with complex CDH.
    explanation: National cohort birth prevalence, isolated CDH arm.
- population: England, singleton livebirths 2002-2018
  subtype: Syndromic CDH
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 12.0
  notes: 1.2 per 10,000 livebirths for complex (syndromic) CDH in a national birth cohort.
  evidence:
  - reference: PMID:36441118
    reference_title: "Congenital diaphragmatic hernia subtypes: Comparing birth prevalence, occurrence by maternal age, and mortality in a national birth cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      and 1.2 (95% CI 1.1, 1.3) per 10,000 livebirths, respectively
    explanation: National cohort birth prevalence, complex (syndromic) CDH arm.
progression:
- phase: Fetal
  age_range: Second and third trimester
  notes: >-
    Most cases are now recognised before birth. Antenatal ultrasound screening
    detects the majority of fetuses, which allows in utero referral to a
    tertiary centre, severity stratification, and delivery planning; the
    prenatally measurable indices of lung size and liver position already
    separate outcome groups at this stage.
  evidence:
  - reference: PMID:29924391
    reference_title: "Proposal for standardized prenatal ultrasound assessment of the fetus with congenital diaphragmatic hernia by the European reference network on rare inherited and congenital anomalies (ERNICA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Antenatal ultrasound screening identifies more than 70% of cases,
      providing the opportunity for in utero referral to a tertiary care center
      for expert assessment and perinatal management.
    explanation: >-
      Establishes prenatal recognition as the normal entry point of the disease
      course in contemporary practice.
  - reference: PMID:29924391
    reference_title: "Proposal for standardized prenatal ultrasound assessment of the fetus with congenital diaphragmatic hernia by the European reference network on rare inherited and congenital anomalies (ERNICA)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The combination of lung size and liver herniation is a widely accepted
      method to stratify fetuses into groups with an increasing degree of
      pulmonary hypoplasia and corresponding mortality rates.
    explanation: >-
      Shows that outcome stratification is already possible in the fetal phase.
- phase: Neonatal
  age_range: Birth to 30 days
  notes: >-
    The first month carries most of the mortality. In a 2,078-neonate
    multicentre cohort, 56% of infants had either died or met criteria for
    chronic lung disease by day 30 and overall mortality was 31%; among those
    surviving to day 30, 41% had bronchopulmonary dysplasia. Population-based
    survival is substantially worse than survival reported by specialist
    hospital series, the so-called hidden mortality of CDH.
  evidence:
  - reference: PMID:21042035
    reference_title: "Risk factors for chronic lung disease and mortality in newborns with congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At day 30, 56% of the patients had either died or met the criteria for
      BPD. In infants who survived until day 30, the prevalence of BPD was 41%.
      The overall mortality rate was 31%.
    explanation: >-
      Quantifies neonatal mortality and chronic lung disease in a large
      multicentre CDH cohort.
  - reference: PMID:22214468
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The best hospital series report 80% survival but it remains around 50% in
      population-based studies.
    explanation: >-
      Contrasts referral-centre survival with population-based survival.
- phase: Long-term survivorship
  age_range: Infancy through childhood
  notes: >-
    Survival is not recovery. Survivors carry chronic respiratory, nutritional,
    gastrointestinal, musculoskeletal and neurodevelopmental morbidity, and
    those repaired for a large defect are at risk of recurrent herniation:
    recurrence reached 46.7% after patch repair versus 6.3% after muscle flap
    repair over a median 5-year follow-up. Recurrence surveillance and
    multidisciplinary follow-up are therefore part of care rather than optional.
  evidence:
  - reference: PMID:40834916
    reference_title: "Long-term outcomes after muscle flap repair in congenital diaphragmatic hernia: A retrospective study at a single institution."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the MFR group, 5/80 (6.3 %) had a recurrence compared to 7/15 (46.7 %)
      in the patch group (p=<0.001).
    explanation: >-
      Quantifies post-repair recurrence and its dependence on the repair
      technique used for a large defect.
  - reference: PMID:31482324
    reference_title: "Left congenital diaphragmatic hernia-associated musculoskeletal deformities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This fact leads to an increase in the morbidity and extrapulmonary
      complications in the long term such as failure to thrive, hernia
      recurrence, neurodevelopmental delay, gastrointestinal problems, and
      musculoskeletal anomalies.
    explanation: >-
      Enumerates the long-term extrapulmonary complication burden that defines
      this phase.
  - reference: PMID:35650272
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Survivors often have long-term, multisystem morbidities, including
      pulmonary dysfunction, gastroesophageal reflux, musculoskeletal
      deformities and neurodevelopmental impairment.
    explanation: >-
      Names the four morbidity domains that dominate the survivorship phase.
mechanistic_hypotheses:
- hypothesis_group_id: dual_hit
  hypothesis_label: Dual-hit model (primary lung maldevelopment plus mechanical compression)
  status: CANONICAL
  description: >-
    The dual-hit model holds that the lung phenotype in CDH is not purely
    mechanical. A first hit perturbs lung development directly, in parallel
    with the diaphragmatic lesion and through the same mesenchymal and
    retinoid-dependent programmes; a second hit is the physical compression of
    the developing lung by herniated viscera. This model explains why the
    contralateral lung is also hypoplastic and why anatomic repair does not
    immediately reverse the lung and vascular disease.
  evidence:
  - reference: PMID:39183805
    reference_title: "Role of genetics and the environment in the etiology of congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The occurrence of CDH and pulmonary hypoplasia is theorized to result
      from both abnormalities in signaling pathways of smooth muscle cells in
      pleuroperitoneal folds and mechanical compression by abdominal organs
      within the chest cavity on the developing lungs.
    explanation: >-
      States both components of the dual-hit model as jointly responsible for
      the CDH lung phenotype.
  - reference: PMID:39018718
    reference_title: "Congenital diaphragmatic hernia-associated pulmonary hypertension."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      in CDH, this embryologic development is impaired which, in conjunction
      with external compression, stifle pulmonary vascular maturation
    explanation: >-
      Applies the same dual-hit logic to the pulmonary vascular arm: intrinsic
      developmental impairment acting together with external compression.
  - reference: PMID:10751355
    reference_title: "Dual-hit hypothesis explains pulmonary hypoplasia in the nitrofen model of congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Therefore, we postulate the dual-hit hypothesis, which explains pulmonary
      hypoplasia in CDH by two insults, one affecting both lungs before
      diaphragm development and one affecting the ipsilateral lung after
      defective diaphragm development.
    explanation: >-
      The primary statement of the dual-hit hypothesis, from nitrofen-exposed
      rat lung explants cultured without any diaphragmatic defect.
- hypothesis_group_id: mechanical_compression_only
  hypothesis_label: Purely mechanical compression model
  status: ALTERNATIVE
  description: >-
    The older and still not fully excluded model holds that the lung in CDH is
    intrinsically normal and that pulmonary hypoplasia is entirely secondary to
    mechanical compression by herniated viscera during the pseudoglandular and
    canalicular stages. Under this model the only causal route to pulmonary
    hypoplasia is the compression edge, and prenatal decompression or tracheal
    occlusion should be able to restore normal lung growth. It is retained here
    as an explicit alternative because the pathogenesis of the CDH lung
    phenotype is described in the primary literature as controversial, and
    because the fetal-lamb surgical-compression experiments that founded the
    field are consistent with it. Evidence against it includes hypoplasia of
    the contralateral lung and lung maldevelopment in explants never exposed to
    compression.
  evidence:
  - reference: PMID:10751355
    reference_title: "Dual-hit hypothesis explains pulmonary hypoplasia in the nitrofen model of congenital diaphragmatic hernia."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: >-
      Moreover, the pathogenesis of pulmonary hypoplasia in case of CDH is
      controversial.
    explanation: >-
      Establishes that the compression-only versus primary-maldevelopment
      question is a genuine live controversy rather than a settled matter,
      which is why the alternative is curated rather than discarded.
  - reference: PMID:10751355
    reference_title: "Dual-hit hypothesis explains pulmonary hypoplasia in the nitrofen model of congenital diaphragmatic hernia."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      Our results indicate that Nitrofen negatively influences branching
      morphogenesis of the lung.
    explanation: >-
      Impaired branching in an explant system with no diaphragm and no
      compression is direct evidence against a purely mechanical model.
- hypothesis_group_id: retinoid
  hypothesis_label: Retinoid hypothesis of abnormal diaphragm development
  status: CANONICAL
  description: >-
    The retinoid hypothesis, formulated by Greer, Babiuk and Thebaud in 2003
    and reviewed twenty years later, holds that abnormalities of retinoic acid
    signalling early in gestation underlie abnormal diaphragm development in
    CDH. It is supported by teratogen models that inhibit retinoic acid
    synthesis, by vitamin-A-deficiency models, and by human genetic lesions in
    retinoid transport and signalling such as STRA6 and NR2F2.
  evidence:
  - reference: PMID:37990078
    reference_title: "The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The Retinoid Hypothesis is one of the leading hypotheses to explain the
      etiology of CDH
    explanation: Establishes the standing of the retinoid hypothesis in the field.
discussions:
- discussion_id: cdh_ino_efficacy
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Does inhaled nitric oxide improve outcome in CDH-associated pulmonary
    hypertension, or does its routine use mainly delay escalation to
    extracorporeal support?
  attaches_to:
  - "pathophysiology#Persistent Pulmonary Hypertension of the Newborn"
  rationale: >-
    Inhaled nitric oxide is widely used in CDH by extrapolation from other
    causes of persistent pulmonary hypertension of the newborn, but the CDH
    vascular bed is structurally reduced rather than merely vasoconstricted, so
    a selective vasodilator may have limited substrate on which to act. The
    published evidence base is small and the reviewed conclusion is that the
    role of iNO in CDH is controversial.
  proposed_experiments:
  - experiment_id: cdh_ino_rct
    name: Randomised trial of inhaled nitric oxide in CDH-associated pulmonary hypertension
    description: >-
      An adequately powered randomised trial of inhaled nitric oxide versus
      placebo in CDH-associated pulmonary hypertension, stratified by
      echocardiographic phenotype, with time to extracorporeal support as a
      co-primary outcome alongside survival to discharge.
  evidence:
  - reference: PMID:32384329
    reference_title: "The Use of Inhaled Nitric Oxide in Congenital Diaphragmatic Hernia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the role of iNO as a treatment for CDH is controversial.
    explanation: Documents that the efficacy question is unresolved in the literature.
- discussion_id: cdh_nitrofen_model_fidelity
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    How faithfully do the nitrofen rat model and retinoid-pathway mouse mutants
    reproduce human CDH, given that the human disease is genetically
    heterogeneous and usually not attributable to a single teratogen or a
    single retinoid-pathway lesion?
  attaches_to:
  - "pathophysiology#Retinoid Signaling and Pleuroperitoneal Fold Mesenchymal Deficit"
  rationale: >-
    Most mechanistic knowledge of diaphragm and lung maldevelopment in CDH
    derives from teratogen-induced and genetically modified rodents. These
    models reproduce components of the phenotype - amuscular diaphragm,
    posterolateral defects, reduced branching - but no single model captures
    the full human spectrum, and rodent lethality prevents study of the chronic
    survivor morbidity that dominates the human disease.
  proposed_experiments:
  - experiment_id: cdh_ppf_cross_species_sc
    name: Cross-species single-cell comparison of pleuroperitoneal fold mesenchyme
    description: >-
      Single-cell profiling of human fetal pleuroperitoneal fold and lung
      mesenchyme compared against the corresponding rodent compartments in
      nitrofen-exposed and retinoid-pathway mutant animals, to test whether the
      cell states perturbed in the models are the ones perturbed in human CDH.
  evidence:
  - reference: PMID:35633948
    reference_title: "Genetically Modified Mouse Models of Congenital Diaphragmatic Hernia: Opportunities and Limitations for Studying Altered Lung Development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the generation of genetically modified mouse models, which show both
      diaphragm and lung abnormalities, has resulted in the discovery of
      multiple genes and signaling pathways involved in the pathogenesis of CDH
    explanation: >-
      Establishes that the mechanistic evidence base is largely murine, which
      is what makes translational fidelity the open question.
  - reference: PMID:35633948
    reference_title: "Genetically Modified Mouse Models of Congenital Diaphragmatic Hernia: Opportunities and Limitations for Studying Altered Lung Development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      whilst also discussing the significance of these genetic models for
      studying altered lung development with regard to the human situation
    explanation: >-
      The cited review itself frames the human relevance of these models as a
      question requiring discussion rather than a settled matter.
diagnosis:
- name: Prenatal ultrasound with observed-to-expected lung-area-to-head-circumference ratio (O/E LHR)
  description: >-
    Mid-trimester ultrasound establishes the diagnosis by demonstrating
    intrathoracic stomach or bowel, mediastinal shift, and a small ipsilateral
    lung. The observed-to-expected lung-area-to-head-circumference ratio is the
    primary sonographic severity metric: unlike the raw LHR it is independent
    of gestational age, and it predicts postnatal survival. It is the
    measurement on which FETO eligibility thresholds are set.
  diagnosis_term:
    preferred_term: ultrasound imaging
    term:
      id: NCIT:C17230
      label: Ultrasound Imaging
  evidence:
  - reference: PMID:17587219
    reference_title: "Observed to expected lung area to head circumference ratio in the prediction of survival in fetuses with isolated diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In fetuses with both left- and right-sided CDH, measurement of the
      observed to expected LHR provides a useful prediction of subsequent
      survival.
    explanation: >-
      The multicentre study of 354 fetuses that established O/E LHR as the
      standard prenatal severity metric in isolated CDH.
  - reference: PMID:17587219
    reference_title: "Observed to expected lung area to head circumference ratio in the prediction of survival in fetuses with isolated diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In CDH, the LHR increases while observed to expected LHR is independent
      of gestational age.
    explanation: >-
      States why the observed-to-expected ratio, and not the raw LHR, is the
      metric that can be compared across gestational ages.
- name: Fetal MRI total fetal lung volume (O/E TFLV)
  description: >-
    Fetal magnetic resonance imaging measures observed-to-expected total fetal
    lung volume, complements ultrasound severity assessment, and better
    delineates the extent of liver herniation. Its discriminative performance
    against O/E LHR is comparable in some centres and superior in others, so
    the two are used together rather than as substitutes.
  diagnosis_term:
    preferred_term: magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:39133867
    reference_title: "Observed-to-expected lung-area-to-head-circumference ratio on ultrasound examination vs total fetal lung volume on magnetic resonance imaging in prediction of survival in fetuses with left-sided diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the survival rates at discharge were lower in left-sided CDH (odds ratio
      (OR), 0.349 (95% CI, 0.133-0.918), P = 0.033) and those with
      intrathoracic liver (OR, 0.297 (95% CI, 0.141-0.628), P = 0.001), and
      higher with increasing O/E-TFLV
    explanation: >-
      Quantifies O/E TFLV, laterality and intrathoracic liver as independent
      predictors of survival to discharge.
  - reference: PMID:39133867
    reference_title: "Observed-to-expected lung-area-to-head-circumference ratio on ultrasound examination vs total fetal lung volume on magnetic resonance imaging in prediction of survival in fetuses with left-sided diaphragmatic hernia."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the predictive value for postnatal survival of O/E-TFLV on MRI
      examination and O/E-LHR on ultrasound examination was similar in one
      center (Mannheim)
    explanation: >-
      Records honestly that MRI volumetry did not uniformly outperform
      ultrasound; the comparison was centre-dependent.
- name: Prenatal risk stratification (liver position, defect side and size)
  description: >-
    Beyond lung size, prognosis is stratified by side of the defect, the
    presence and extent of intrathoracic liver herniation, defect size,
    gestational age at diagnosis and delivery, and the presence of additional
    structural or genetic anomalies. Stratification drives counselling, fetal
    intervention eligibility, and planned delivery at a centre with
    extracorporeal support.
  diagnosis_term:
    preferred_term: ultrasound imaging
    term:
      id: NCIT:C17230
      label: Ultrasound Imaging
  evidence:
  - reference: PMID:39431204
    reference_title: "Prenatal diagnosis and risk stratification of congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Factors that may affect the immediate and long-term prognosis for CDH
      include prenatal diagnosis, gestational age at detection and delivery,
      side of the defect, presence of additional structural or genetic
      abnormalities, defect size, estimation of fetal lung volume, the extent
      of visceral herniation, and the delivery center's experience in caring
      for neonates with CDH.
    explanation: >-
      Enumerates the prenatal variables that constitute contemporary CDH risk
      stratification.
  - reference: PMID:39431204
    reference_title: "Prenatal diagnosis and risk stratification of congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Advanced antenatal imaging, including ultrasound and magnetic resonance
      imaging, has made it possible to prognosticate severity of CDH and to
      stratify risk when counseling expectant parents.
    explanation: >-
      Establishes combined ultrasound and MRI assessment as the basis of
      prenatal severity prognostication.
- name: Postnatal chest radiography with nasogastric tube
  description: >-
    Plain radiography of the chest and abdomen shows bowel loops or solid
    viscera in the hemithorax, mediastinal shift, and a paucity of abdominal
    gas. Passing a nasogastric tube before the film localises the stomach and
    is the manoeuvre that separates CDH from an intrinsic cystic or hyperlucent
    lung lesion.
  diagnosis_term:
    preferred_term: radiographic imaging
    term:
      id: NCIT:C38101
      label: X-Ray Imaging
  evidence:
  - reference: PMID:22214468
    reference_title: "Congenital diaphragmatic hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      passing a naso-gastric catheter into the stomach before a plain X-ray of
      the thorax and abdomen may help to locate it
    explanation: >-
      Describes the standard postnatal radiographic manoeuvre for confirming
      CDH and excluding its imaging mimics.
- name: Neonatal echocardiography
  description: >-
    Echocardiography excludes associated structural heart disease, estimates
    pulmonary arterial pressure and the direction of shunting, and assesses
    right and left ventricular function. Because CDH cardiopulmonary physiology
    is labile, serial rather than single assessment is required.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:39018718
    reference_title: "Congenital diaphragmatic hernia-associated pulmonary hypertension."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Longitudinal re-evaluation is an important consideration due to the
      complexity and dynamic nature of CDH cardiopulmonary physiology.
    explanation: >-
      Supports serial rather than one-off cardiopulmonary assessment in CDH.
- name: Chromosomal microarray
  description: >-
    First-tier genetic test once CDH is identified, aimed at the pathogenic
    copy number variants (including the recurrent 15q26 deletion involving
    NR2F2 and the 8p23.1 deletion involving GATA4) that account for a
    substantial share of complex disease.
  diagnosis_term:
    preferred_term: chromosomal microarray analysis
    term:
      id: NCIT:C18477
      label: Microarray Analysis
  results: >-
    Reported diagnostic yield of karyotype or chromosomal microarray after a
    prenatal CDH diagnosis is approximately 10%.
  evidence:
  - reference: PMID:34911129
    reference_title: "Genetic Diagnostic Strategies and Counseling for Families Affected by Congenital Diaphragmatic Hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Until recently, the common practice was (molecular) karyotyping or
      chromosome microarray if the CDH diagnosis is made prenatally with a 10%
      diagnostic yield.
    explanation: >-
      Establishes chromosomal microarray as the first-tier genetic test and
      quantifies its yield.
- name: Trio exome or genome sequencing
  description: >-
    Second-tier genetic test for microarray-negative patients, detecting the
    sequence variants in genes such as ZFPM2, GATA4, GATA6, WT1, MYRF, LONP1
    and PBX1. A family-based trio design is recommended because a large share
    of causal variants are de novo, and testing is offered irrespective of
    whether the CDH is isolated or complex.
  diagnosis_term:
    preferred_term: trio exome or genome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  results: >-
    Additional diagnostic yield of 10 to 20% over chromosomal microarray.
  evidence:
  - reference: PMID:34911129
    reference_title: "Genetic Diagnostic Strategies and Counseling for Families Affected by Congenital Diaphragmatic Hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Undiagnosed patients can be reflexed to trio exome/genome sequencing with
      an additional diagnostic yield of 10 to 20%.
    explanation: >-
      Establishes the reflex-to-sequencing step of the workup and quantifies
      the incremental yield.
  - reference: PMID:34911129
    reference_title: "Genetic Diagnostic Strategies and Counseling for Families Affected by Congenital Diaphragmatic Hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All families with a child with CDH with or without additional
      malformations should be offered genetic counseling and testing in a
      family-based trio approach.
    explanation: >-
      Supports offering trio testing and counselling to all CDH families, not
      only those with syndromic features.
  - reference: PMID:34911129
    reference_title: "Genetic Diagnostic Strategies and Counseling for Families Affected by Congenital Diaphragmatic Hernia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Even with a genetic diagnosis, there can be a range of clinical outcomes.
    explanation: >-
      Counselling caveat: a molecular diagnosis does not by itself predict
      severity.
clinical_trials:
- name: NCT01240057
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    TOTAL trial for severe hypoplasia: randomised trial of fetoscopic
    endoluminal tracheal occlusion versus expectant management in isolated
    left-sided CDH with severe pulmonary hypoplasia. Stopped early for efficacy;
    reported as PMID:34106556.
  target_phenotypes:
  - preferred_term: Pulmonary hypoplasia
    term:
      id: HP:0002089
      label: Pulmonary hypoplasia
  evidence:
  - reference: clinicaltrials:NCT01240057
    reference_title: "Randomized Trial of Fetoscopic Endoluminal Tracheal Occlusion (FETO) Versus Expectant Management During Pregnancy in Fetuses With Left Sided and Isolated Congenital Diaphragma Hernia and Severe Pulmonary Hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This trial investigates whether prenatal intervention improves survival
      rate of fetuses with isolated congenital diaphragmatic hernia and severe
      pulmonary hypoplasia, as compared to expectant management during
      pregnancy, both followed by standardized postnatal care.
    explanation: >-
      The registered protocol for the severe-hypoplasia arm of the TOTAL
      programme, which demonstrated a survival benefit for FETO.
- name: NCT00763737
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    TOTAL trial for moderate hypoplasia: randomised trial of fetoscopic
    endoluminal tracheal occlusion versus expectant management in isolated
    left-sided CDH with moderate pulmonary hypoplasia (O/E LHR 25-34.9%, or
    35-44.9% with liver herniation). Did NOT show a significant survival
    benefit; reported as PMID:34106555.
  target_phenotypes:
  - preferred_term: Pulmonary hypoplasia
    term:
      id: HP:0002089
      label: Pulmonary hypoplasia
  evidence:
  - reference: clinicaltrials:NCT00763737
    reference_title: "Randomized Trial of Fetoscopic Endoluminal Tracheal Occlusion (FETO) Versus Expectant Management During Pregnancy in Fetuses With Left Sided and Isolated Congenital Diaphragmatic Hernia and Moderate Pulmonary Hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This trial will test whether temporary fetoscopic tracheal occlusion
      rather than expectant management during pregnancy, both followed by
      standardized postnatal management increases survival or decrease oxygen
      dependency at 6 months of age.
    explanation: >-
      The registered protocol for the moderate-hypoplasia arm, whose published
      result was null for both co-primary outcomes.
  - reference: clinicaltrials:NCT00763737
    reference_title: "Randomized Trial of Fetoscopic Endoluminal Tracheal Occlusion (FETO) Versus Expectant Management During Pregnancy in Fetuses With Left Sided and Isolated Congenital Diaphragmatic Hernia and Moderate Pulmonary Hypoplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The risk for these can be predicted prenatally by the ultrasonographic
      measurement of the observed/expected lung area to head circumference
      ratio (O/E LHR) which is a measure of pulmonary hypoplasia. Also position
      of the liver is predictive of outcome.
    explanation: >-
      Documents O/E LHR and liver position as the prospectively specified
      severity criteria used to enrol and stratify CDH fetuses.
- name: NCT06179472
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Single-centre study of fetoscopic endoluminal tracheal occlusion with the
    BALT Goldbal2 balloon in severe left OR right CDH, reporting infant
    survival and long-term outcome. It extends the FETO question to right-sided
    disease, which neither TOTAL arm randomised.
  notes: >-
    The registered study title states Phase III; the ClinicalTrials.gov design
    field is recorded as not applicable. Curated as PHASE_III per the title.
  target_phenotypes:
  - preferred_term: Pulmonary hypoplasia
    term:
      id: HP:0002089
      label: Pulmonary hypoplasia
  - preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  evidence:
  - reference: clinicaltrials:NCT06179472
    reference_title: "Infant Survival and Long-term Outcome Following Fetoscopic Endoluminal Tracheal Occlusion in Severe Left and Right Congenital Diaphragmatic Hernia, A Phase III Trial"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We hypothesize that FETO balloon placement may increase survival and
      decrease morbidity when compared to standard prenatal care for the
      treatment of severe left or right congenital diaphragmatic hernia (CDH).
    explanation: >-
      Documents an active FETO study that includes severe right-sided CDH, the
      population left unaddressed by the randomised TOTAL trials.
classifications:
  harrisons_chapter:
  - classification_value: RESPIRATORY
    evidence:
    - reference: PMID:35650272
      reference_title: "Congenital diaphragmatic hernia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Congenital diaphragmatic hernia (CDH) is a rare birth defect
        characterized by incomplete closure of the diaphragm and herniation of
        fetal abdominal organs into the chest that results in pulmonary
        hypoplasia, postnatal pulmonary hypertension owing to vascular
        remodelling and cardiac dysfunction.
      explanation: >-
        The clinically decisive disease in CDH is respiratory - pulmonary
        hypoplasia and pulmonary hypertension - which places the entry in the
        respiratory chapter rather than the gastrointestinal one.
differential_diagnoses:
- name: Congenital pulmonary airway malformation
  description: >-
    A cystic lung lesion that can mimic bowel loops in the hemithorax on
    prenatal ultrasound or neonatal chest radiography.
  disease_term:
    preferred_term: congenital pulmonary airway malformation
    term:
      id: MONDO:0016580
      label: congenital pulmonary airway malformation
  evidence:
  - reference: PMID:22214468
    reference_title: Congenital diaphragmatic hernia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital Diaphragmatic Hernia (CDH) is defined by the presence of an
      orifice in the diaphragm
    explanation: >-
      The defining diaphragmatic orifice is what a cystic lung malformation
      lacks, which is the basis of the distinction.
  distinguishing_features:
  - Intact diaphragm on imaging, with no defect through which viscera pass
  - Normal abdominal gas pattern rather than a paucity of abdominal gas
  - Cystic lesion follows lung architecture rather than bowel loops
- name: Congenital pulmonary sequestration
  description: >-
    A mass of non-functioning lung parenchyma with an anomalous systemic
    arterial supply and no connection to the bronchial tree. The extralobar
    form is frequently infradiaphragmatic or juxtadiaphragmatic and can be
    mistaken for herniated viscera on prenatal imaging; it also co-occurs with
    CDH.
  disease_term:
    preferred_term: congenital pulmonary sequestration
    term:
      id: MONDO:0017843
      label: congenital pulmonary sequestration
  evidence:
  - reference: PMID:33252753
    reference_title: "Fetal ultrasound and magnetic resonance imaging: a primer on how to interpret prenatal lung lesions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fetal lung lesions include common lesions such as congenital pulmonary
      airway malformation (CPAM), bronchopulmonary sequestration (BPS) and
      combined CPAM-BPS hybrid lesions
    explanation: >-
      Establishes bronchopulmonary sequestration as a distinct fetal
      intrathoracic lesion that must be separated from CDH on prenatal imaging.
  - reference: PMID:22214468
    reference_title: "Congenital diaphragmatic hernia."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In some rare instances, X-rays may suggest a cystic malformation of the
      lung
    explanation: >-
      The CDH review's own differential-diagnosis section identifies cystic
      and other congenital lung malformations as the entities that radiography
      can confuse with CDH; it does not name sequestration specifically, so
      support is partial.
  distinguishing_features:
  - Systemic arterial feeding vessel, typically from the descending aorta, on Doppler or MRI
  - Solid echogenic mass following lung architecture rather than peristalsing bowel
  - Intact diaphragm with normal intra-abdominal gas pattern
  - Extralobar sequestration may itself sit below the diaphragm
- name: Congenital lobar emphysema
  description: >-
    Progressive hyperinflation of a single pulmonary lobe producing a
    hyperlucent hemithorax with mediastinal shift, which reproduces the
    radiographic mass effect of a left-sided CDH in a neonate with respiratory
    distress.
  disease_term:
    preferred_term: congenital lobar emphysema
    term:
      id: MONDO:0007536
      label: congenital lobar emphysema
  evidence:
  - reference: PMID:33252753
    reference_title: "Fetal ultrasound and magnetic resonance imaging: a primer on how to interpret prenatal lung lesions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      as well as less common entities including congenital lobar
      emphysema/obstruction, bronchial atresia, bronchogenic cysts
    explanation: >-
      Names congenital lobar emphysema/obstruction as a distinct congenital
      thoracic lesion in the same prenatal differential as CPAM and
      sequestration.
  - reference: PMID:22214468
    reference_title: "Congenital diaphragmatic hernia."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      passing a naso-gastric catheter into the stomach before a plain X-ray of
      the thorax and abdomen may help to locate it
    explanation: >-
      The manoeuvre that separates CDH from an intrinsic hyperlucent lung
      lesion is demonstrating an intrathoracic stomach; the cited review
      prescribes exactly this test, though it does not name lobar emphysema.
  distinguishing_features:
  - Hyperlucent hyperinflated lobe rather than gas-filled bowel loops
  - Nasogastric tube remains below the diaphragm rather than curling into the chest
  - Intact diaphragmatic contour with a normal abdominal gas pattern
  - Lobar distribution respecting fissures
- name: Diaphragmatic eventration
  description: >-
    An abnormally elevated but anatomically continuous hemidiaphragm, with or
    without phrenic nerve palsy.
  disease_term:
    preferred_term: diaphragmatic eventration
    term:
      id: MONDO:0006726
      label: diaphragmatic eventration
  evidence:
  - reference: PMID:20301632
    reference_title: Fryns Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      diaphragmatic defects (diaphragmatic hernia and diaphragm eventration,
      hypoplasia, or agenesis)
    explanation: >-
      GeneReviews treats eventration as a distinct diaphragmatic defect
      category from true hernia, which is the basis of the differential.
  distinguishing_features:
  - Diaphragm is thinned and elevated but anatomically continuous
  - No true defect, so abdominal viscera remain below a diaphragmatic membrane
  - May be associated with phrenic nerve palsy rather than a developmental defect
references:
- reference: PMID:35650272
  title: Congenital diaphragmatic hernia.
- reference: PMID:34911129
  title: Genetic Diagnostic Strategies and Counseling for Families Affected by Congenital Diaphragmatic Hernia.
- reference: PMID:29924391
  title: Proposal for standardized prenatal ultrasound assessment of the fetus with congenital diaphragmatic hernia by the European reference network on rare inherited and congenital anomalies (ERNICA).
- reference: PMID:20301632
  title: Fryns Syndrome.
  tags:
  - GeneReviews
- reference: PMID:20301732
  title: Donnai-Barrow Syndrome.
  tags:
  - GeneReviews
- reference: PMID:36375006
  title: MYRF-Related Cardiac Urogenital Syndrome.
  tags:
  - GeneReviews
notes: >-
  Deep research for this entry was performed with the Edison Scientific
  (falcon) provider; the raw report is at
  research/Congenital_Diaphragmatic_Hernia-deep-research-falcon.md. Every PMID
  and snippet was independently re-fetched and verified against the cached
  abstract. The GeneReviews "Congenital Diaphragmatic Hernia Overview" chapter
  (PMID:20301533) is retired and was therefore not used as a phenotype
  baseline; the syndrome-specific GeneReviews chapters listed above were used
  instead.


  Genetic architecture: the `genetic` block lists genes with Mendelian or
  near-Mendelian support (mostly through recognised syndromic forms), while the
  `inheritance` block records the polygenic liability component demonstrated by
  genome-wide analysis (PMID:39332409). These are complementary rather than
  contradictory - rare large-effect variants and common polygenic background
  contribute additively, and polygenic risk does not differ between isolated
  and complex CDH. LONP1 is typed RISK_FACTOR rather than CAUSATIVE for this
  reason. Individual susceptibility loci (the WNT5A- and SHH-adjacent regions)
  are regulatory rather than coding and are not curated as `genetic` entries.


  Dual-hit debate: the pathograph encodes the question of compression versus
  primary maldevelopment as two competing hypothesis groups rather than
  asserting a settled answer. `dual_hit` (CANONICAL) owns an extra edge from
  the retinoid/pleuroperitoneal-fold trigger straight to Pulmonary Hypoplasia -
  the compression-independent "first hit" - while `mechanical_compression_only`
  (ALTERNATIVE) owns only the compression edge. The compression edge itself is
  tagged with both groups, because it is common to the two models. Readers who
  reject the dual-hit model can therefore delete the `dual_hit` edges and
  recover the purely mechanical graph. The founding nitrofen explant evidence
  (PMID:10751355) is tagged IN_VITRO and is never the sole support for a human
  claim.


  Unconnected phenotypes: `Congenital heart defect` and `Polyhydramnios` are
  deliberately left with no incoming causal edge. Co-occurring cardiovascular
  malformation is a parallel developmental-field anomaly rather than a
  consequence of the CDH cascade, and polyhydramnios is a prenatal association
  curated here from the syndromic (Fryns) context. Asserting a `downstream`
  edge for either would overstate the evidence.


  Module conformance: the pulmonary vascular node conforms to
  `pulmonary_vascular_remodeling` for the muscularization and vasoconstriction
  arm, which is genuinely shared. The developmental hypoplasia of the CDH
  vascular bed (fewer arterial generations, an arrested rather than obliterated
  bed) is disease-specific and is not represented in that module, and plexiform
  lesions are not a feature of neonatal CDH.


  ALDH1A2 placement: ALDH1A2 (RALDH2) is carried on the retinoid
  pathophysiology node as a pathway component rather than in `genetic`, because
  there is no human variant evidence implicating it in CDH. The supporting
  study (PMID:25416379) finds ALDH1A2 deregulated in human CDH lung but
  concludes the overexpression is a consequence of CDH-induced lung injury
  rather than a primary event; the causal link is pharmacological (ALDH1A2
  inhibition produces a posterolateral defect), which is a mechanism claim, not
  a gene-disease validity claim. SLIT3 is typed RISK_FACTOR, not CAUSATIVE, for
  the parallel reason: the human evidence is a single consanguineous family.


  Recurrent post-repair herniation is curated in `progression` (long-term
  survivorship) rather than as a phenotype, because HPO has no term for
  recurrence of a repaired diaphragmatic hernia and reusing HP:0000776
  (Congenital diaphragmatic hernia) for a post-surgical complication would be a
  term misuse.


  Left heart hypoplasia is modelled as its own node and phenotype (HP:0004383)
  rather than folded into the right ventricular arm. It is a hypoplasia of
  degree driven by mediastinal compression in left-sided disease, not
  hypoplastic left heart syndrome, and the cited cohort reports z-score
  distributions rather than a proportion affected, so no frequency band is
  asserted.

📚

References & Deep Research

References

6

PMID:35650272

Congenital diaphragmatic hernia.

No top-level findings curated for this source.

PMID:34911129

Genetic Diagnostic Strategies and Counseling for Families Affected by Congenital Diaphragmatic Hernia.

No top-level findings curated for this source.

PMID:29924391

Proposal for standardized prenatal ultrasound assessment of the fetus with congenital diaphragmatic hernia by the European reference network on rare inherited and congenital anomalies (ERNICA).

No top-level findings curated for this source.

PMID:20301632

Fryns Syndrome.

No top-level findings curated for this source.

PMID:20301732

Donnai-Barrow Syndrome.

No top-level findings curated for this source.

PMID:36375006

MYRF-Related Cardiac Urogenital Syndrome.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Congenital Diaphragmatic Hernia: Disease-Characteristics Research Report

Edison Scientific Literature 47 citations 2026-07-31T17:14:59.989179

Congenital Diaphragmatic Hernia: Disease-Characteristics Research Report

Scope and evidence note. This report prioritizes human clinical and genomic evidence from 2023–2024, supplemented by the authoritative 2022 Nature Reviews Disease Primers review and model-organism literature. The retrieval corpus supplied DOI URLs but not PubMed identifiers for most papers; therefore, DOI-linked citations are provided rather than inventing PMIDs. Ontology identifiers marked “suggested” should be validated against the current ontology release before database ingestion.

domain	key quantitative finding	evidence type	source/year/DOI
Epidemiology	Prevalence ~2.3 per 10,000 live births	Human clinical review	Rivas & Clugston 2024, Pediatr Res, doi:10.1038/s41390-023-02905-7 (rivas2024theetiologyof pages 1-2)
Genetics	Identifiable genetic cause in ~30–40% of cases; chromosomal defects ~10%; de novo variants 10–22%	Human genomic review	Rivas & Clugston 2024, doi:10.1038/s41390-023-02905-7; Liu & Yu 2024, doi:10.1136/wjps-2024-000884 (rivas2024theetiologyof pages 1-2)
Genetics	Common variants explain 19% heritability of susceptibility	Human GWAS/genome sequencing	Qiao et al. 2024, Am J Hum Genet, doi:10.1016/j.ajhg.2024.08.024 (qiao2024commonvariantsincrease pages 1-3, qiao2024commonvariantsincrease pages 15-16)
Genetics	De novo damaging variants account for ~25% population attributable risk	Human trio genomics	Qiao et al. 2024, doi:10.1016/j.ajhg.2024.08.024 (qiao2024commonvariantsincrease pages 15-16, qiao2024commonvariantsincrease pages 16-17)
Phenotype / outcome	Associated malformations in ~40% of patients, especially cardiovascular/urogenital	Human clinical review	Liu & Yu 2024, doi:10.1136/wjps-2024-000884 (liu2024roleofgenetics pages 1-2)
Phenotype / outcome	Mortality 20–30% in high-resource settings; >50% of survivors have long-term morbidity	Human clinical reviews	Rivas & Clugston 2024, doi:10.1038/s41390-023-02905-7; Zani et al. 2022, doi:10.1038/s41572-022-00362-w (rivas2024theetiologyof pages 1-2, zani2022congenitaldiaphragmatichernia pages 1-2)
Prenatal prognostic markers	Liver herniation: survival ~45% vs 74% without liver-up; ECMO need 80% vs 25%	Human prognostic review	Perveen et al. 2022, Front Pediatr, doi:10.3389/fped.2022.932463 (perveen2022cellularmolecularand pages 1-2)
Prenatal prognostic markers	O/E-TFLV >35%: survival 94% vs 56% when <35%	Human prognostic review	Perveen et al. 2022, doi:10.3389/fped.2022.932463 (perveen2022cellularmolecularand pages 1-2)
Fetal therapy	TOTAL severe left CDH: FETO survival 40% vs 15% expectant management	Human interventional trial summary/review	Zani et al. 2022, Nat Rev Dis Primers, doi:10.1038/s41572-022-00362-w (zani2022congenitaldiaphragmatichernia pages 8-9)
Model organisms	Nitrofen rat model induces CDH with pulmonary hypoplasia in ~70%	Animal teratogen model	Liu & Yu 2024, doi:10.1136/wjps-2024-000884 (liu2024roleofgenetics pages 3-4)
Model organisms	Conditional Wt1 deletion: CDH incidence ~80% and PPF deletion penetrance 80–90%	Genetic mouse model	Rivas & Clugston 2024, doi:10.1038/s41390-023-02905-7 (rivas2024theetiologyof pages 4-5)

Table: This table summarizes high-yield quantitative findings for congenital diaphragmatic hernia across epidemiology, genetics, prognosis, fetal therapy, and model systems. It is useful as a compact evidence backbone for a disease knowledge base entry.

1. Disease information

Definition and classification

Congenital diaphragmatic hernia (CDH) is a developmental defect in which incomplete formation or closure of the diaphragm permits abdominal viscera to enter the thorax. The resulting disease is not merely a mechanical hernia: disrupted fetal lung growth causes pulmonary hypoplasia, abnormal pulmonary vascular development and persistent pulmonary hypertension of the newborn (PPHN), often accompanied by cardiac dysfunction. A concise 2024 definition states that CDH is “characterized by failure of diaphragm closure during embryonic development, leading to pulmonary hypoplasia and pulmonary hypertension.” [Review; published August 2024; DOI: https://doi.org/10.1136/wjps-2024-000884] (liu2024roleofgenetics pages 1-2)

Anatomic forms. Bochdalek/posterolateral defects predominate. Recent reviews give somewhat different distributions because of classification and ascertainment differences: approximately 70–95% are Bochdalek defects and about 85% of these are left-sided; Morgagni/anterior defects account for approximately 3% in one modern morphologic classification, while eventration accounts for 2–3% and central tendon defects for 1–2%. Right-sided and bilateral defects are less common but often severe. (liu2024roleofgenetics pages 1-2, rivas2024theetiologyof pages 1-2)

Key identifiers and synonyms

Suggested database mappings are:

MONDO: congenital diaphragmatic hernia; commonly mapped as MONDO:0005711, but release-level verification is advised.
ICD-10-CM: Q79.0, congenital diaphragmatic hernia.
ICD-11: congenital diaphragmatic hernia under developmental anomalies of the respiratory system/diaphragm; verify the current extension code in the target ICD-11 release.
MeSH: Hernias, Diaphragmatic, Congenital.
OMIM: genetically heterogeneous; DIH1/diaphragmatic hernia 1, OMIM 142340 is often used as an entry point, but CDH should not be represented as a single Mendelian disorder.
Orphanet: congenital diaphragmatic hernia; verify the current ORPHA identifier against Orphanet before production ingestion.
Synonyms: congenital diaphragmatic defect, congenital diaphragmatic hernia/defect, Bochdalek hernia, posterolateral diaphragmatic hernia, Morgagni hernia, anterior diaphragmatic hernia and congenital diaphragmatic eventration. Bochdalek and Morgagni designate anatomic subtypes, not exact synonyms for all CDH.

The evidence summarized here is aggregated disease-level information from cohorts, registries, reviews and trials, not individual EHR-derived patient data.

2. Etiology and risk/protective factors

CDH is etiologically heterogeneous and usually sporadic. Approximately 30–40% of patients have an identifiable chromosomal or single-gene contribution; chromosomal defects account for about 10%, while de novo coding variants account for roughly 10–22%. More than 70 syndromes and approximately 150 implicated gene variants have been reported. Complex CDH has a much higher genetic diagnostic yield than isolated disease. (rivas2024theetiologyof pages 1-2, liu2024roleofgenetics pages 1-2, liu2024roleofgenetics pages 2-3)

Genetic risk

Established or strongly supported genes include GATA4, GATA6, ZFPM2/FOG2, NR2F2/COUP-TFII, WT1, MYRF, LONP1, ALDH1A2, STRA6, CRABP1, FREM1, PIGN, KIF7, PBX1, EFNB1, FZD2, GPC3 and SLIT3. Relevant recurrent regions include 8p23.1 (including GATA4), 15q26 (including NR2F2), 11p13 (WT1/PAX6), and 17q regions involving FZD2. Disease-associated variants include de novo loss-of-function and missense SNVs, small indels, inherited dominant variants with incomplete penetrance, recessive/biallelic variants, and large deletions or other CNVs. Most clinically causal variants are germline; somatic mutation is not an established general mechanism. (schreiner2021geneticsofdiaphragmatic pages 2-3, liu2024roleofgenetics pages 12-12, perveen2022cellularmolecularand pages 7-7)

The major 2024 genomic development was a study of 1,469 affected individuals, including 1,064 parent-child trios and 6,133 ancestry-matched controls. It found 15 de novo candidate genes, including eight novel candidates, and two replicated common-variant loci: rs55705711 at 3p14.3, near WNT5A (OR 1.65; P=5.1×10⁻¹⁷), and rs7777647 at 7q36.3, near regulatory elements of SHH (OR 1.27; P=1.9×10⁻⁹). Common variants explained an estimated 19% of susceptibility heritability, whereas damaging de novo variants accounted for approximately 25% of population-attributable risk. This supports a liability model in which polygenic background and rare, large-effect variants act additively. [Human genome sequencing/GWAS; published November 2024; DOI: https://doi.org/10.1016/j.ajhg.2024.08.024] (qiao2024commonvariantsincrease pages 1-3, qiao2024commonvariantsincrease pages 15-16, qiao2024commonvariantsincrease pages 9-11)

Penetrance and expressivity are variable. Identical GATA4 variants in monozygotic twins have been associated with CDH in only one twin, illustrating incomplete penetrance and likely modifier or environmental effects. No genetic anticipation or repeat-expansion mechanism is established. Germline mosaicism is theoretically relevant to recurrence after an apparently de novo variant, but robust CDH-specific frequency estimates are unavailable. Founder effects and carrier frequencies are not established for CDH overall because it is genetically heterogeneous. (schreiner2021geneticsofdiaphragmatic pages 2-3)

Environmental and lifestyle associations

Reported maternal associations include age, smoking, alcohol exposure, pregestational diabetes and agricultural pesticide exposure. These are epidemiologic associations rather than proof of individual causation, and evidence outside retinoid biology remains limited. There is no infectious cause and CDH is not transmissible. (liu2024roleofgenetics pages 1-2)

The best-developed gene–environment hypothesis concerns vitamin A/retinoic acid signaling. Retinoic acid is synthesized from dietary vitamin A through retinaldehyde dehydrogenases, including ALDH1A2/RALDH2. Vitamin-A deficiency causes diaphragmatic defects in rodents; nitrofen inhibits RALDH2 and lowers fetal retinoic acid during a critical developmental window; supplementation reduces defect incidence or size in several models. Ethanol can perturb retinol metabolism, providing a plausible interaction between exposure and genetically reduced pathway reserve. Human dietary studies are supportive but do not justify high-dose vitamin-A prophylaxis, which itself can be teratogenic. (liu2024roleofgenetics pages 12-12, rivas2024theetiologyof pages 1-2, rivas2024theetiologyof pages 4-5)

No reproducible genetic “protective variant” is established. Adequate—not excessive—maternal nutrition and avoidance of known teratogens are prudent general measures, but no intervention has been proven to prevent sporadic CDH.

3. Phenotypes

Phenotype	Type, onset and course	Frequency/severity and impact	Suggested HPO term
Diaphragmatic defect/visceral herniation	Congenital structural sign; stable anatomically until repaired	Defining feature; size ranges from small defect to near-total hemidiaphragm agenesis	Diaphragmatic hernia, HP:0000776
Pulmonary hypoplasia	Congenital developmental manifestation; severe and non-reversible at birth, with compensatory growth thereafter	Nearly universal in clinically important neonatal CDH; major mortality determinant	Pulmonary hypoplasia, HP:0002089
Neonatal respiratory distress/failure	Symptom/sign beginning immediately after birth in severe disease	Variable from mild oxygen need to refractory failure requiring ECLS	Neonatal respiratory distress; respiratory failure
PPHN	Cardiopulmonary sign, neonatal onset; fluctuating with transitional circulation	Major cause of death; in a 2024 genomic cohort, 45% had PH at one month	Pulmonary hypertension, HP:0002092
Cardiac dysfunction/hypoplasia	Prenatal or neonatal sign	Particularly left-ventricular hypoplasia/dysfunction in left CDH; worsens systemic perfusion	Abnormal cardiac morphology/function
Feeding difficulty, growth failure and GERD	Usually infancy/childhood; may be chronic	More than 10% require tube access; substantial nutritional and caregiver burden	Feeding difficulties, HP:0011968; gastroesophageal reflux, HP:0002020; failure to thrive
Chronic lung disease/recurrent infection	Childhood, chronic or episodic	Chronic lung disease in up to 50%; respiratory infections in 10–70% during year one	Chronic lung disease; recurrent respiratory infections
Neurodevelopmental, executive and behavioral impairment	Childhood; variable, often persistent	Risk rises after prolonged ventilation, ECLS or patch repair; autism/ADHD risks are elevated	Global developmental delay, HP:0001263; behavioral abnormality
Hearing impairment	Infancy/childhood, sometimes progressive	Associated with critical illness, ototoxic exposure and ECMO; exact pooled frequency varies	Sensorineural hearing impairment
Chest-wall deformity/scoliosis	Childhood/adolescence, progressive	Chest asymmetry >50%, scoliosis ~30%, pectus excavatum ~20%	Scoliosis, HP:0002650; pectus excavatum, HP:0000767
Recurrent hernia	Post-repair complication	May reach 50% by age three after large patch-repaired defects	Recurrent diaphragmatic hernia

Associated malformations occur in approximately 40%, especially cardiovascular and urogenital anomalies; complex cases can also have gastrointestinal, CNS, craniofacial or skeletal abnormalities. In a 2024 genomic cohort, 37% had complex CDH; among these, cardiovascular anomalies occurred in 54%, neurodevelopmental sequelae in 25%, and gastrointestinal anomalies in 17%. (liu2024roleofgenetics pages 1-2, qiao2024commonvariantsincrease pages 6-7)

Quality-of-life impact extends beyond organ morbidity. More than half of survivors have complex long-term morbidity; 77% of surveyed families described the experience as very or extremely stressful, and parental post-traumatic stress symptoms are common. Exercise capacity, school performance, feeding, sleep, repeated admissions and chronic specialist care can all be affected. (zani2022congenitaldiaphragmatichernia pages 14-15, zani2022congenitaldiaphragmatichernia pages 1-2)

4. Genetic and molecular information

Variant interpretation and testing implications

No single CDH gene accounts for more than approximately 1–3% of cases. Variant classification should therefore follow ACMG/AMP criteria using phenotype fit, inheritance, population frequency, predicted loss-of-function intolerance, segregation and functional data. Pathogenic variants are generally extremely rare or absent from population reference databases; a numerical allele-frequency threshold cannot be assigned uniformly across all genes. A VUS must not be treated as causal without additional evidence. (qiao2024commonvariantsincrease pages 3-4)

Representative functional mechanisms include:

Haploinsufficiency/loss of function: GATA4, ZFPM2, NR2F2, WT1, MYRF, GATA6 and several chromatin regulators.
Recessive hypomorphic or loss-of-function disease: ALDH1A2 and PIGN in appropriate syndromic contexts.
Regulatory/common susceptibility: WNT5A- and SHH-adjacent loci identified in 2024.
Chromatin/transcriptional regulation: SIN3A, STAG2, POGZ and other constrained genes identified by de novo burden analyses. Conditional Sin3a loss in mice causes membranous diaphragm and lung hypoplasia. (qiao2024commonvariantsincrease pages 13-15, qiao2024commonvariantsincrease pages 9-11)

Epigenetic dysregulation is biologically plausible because multiple implicated genes regulate chromatin and transcription, and ALYREF may affect epigenetic modifications. Nevertheless, no validated CDH-specific methylation signature is ready for routine diagnosis. Modifier genes are likely but few have been clinically validated.

5. Environmental information

CDH is not an infectious, occupationally acquired or lifestyle disease of the affected infant. The relevant exposure period is early embryogenesis. Maternal tobacco, alcohol, diabetes, nutritional inadequacy and pesticide exposure are candidate risks, but effect estimates are heterogeneous and residual confounding is important. Nitrofen is a research teratogen, not a common documented human exposure. Radiation and pollution have no established disease-specific causal role. (liu2024roleofgenetics pages 1-2, rivas2024theetiologyof pages 1-2)

CHEBI suggestions: retinoic acid (CHEBI:15367), retinol/vitamin A, retinaldehyde, nitric oxide (CHEBI:16480) and sildenafil. Ontology identifiers should be release-checked.

6. Mechanism and pathophysiology

Causal chain

Upstream developmental disturbance: genetic, chromosomal and/or retinoid-pathway perturbation affects lateral plate/septum-transversum mesenchyme and pleuroperitoneal folds (PPFs) during approximately gestational weeks 4–12.
Defective PPF expansion/fusion and myogenesis: abnormal mesenchymal signaling and impaired migration of somite-derived muscle progenitors produce amuscular regions or failure of posterolateral closure.
Primary lung-development defect: altered mesenchymal–epithelial signaling, including deficient airway smooth-muscle progenitor function and FGF10 signaling, reduces branching morphogenesis before or independently of visceral compression.
Secondary mechanical hit: herniated stomach, bowel, spleen and/or liver compress the ipsilateral and contralateral fetal lungs, further reducing airway and vascular growth.
Pulmonary vascular disease: reduced vascular bed, excessive smooth-muscle proliferation, endothelial dysfunction, increased endothelin-1 signaling and impaired vasodilator responsiveness produce high pulmonary vascular resistance and right-to-left shunting.
Clinical phenotype: hypoxemia, hypercapnia, PPHN, ventricular dysfunction and systemic hypoperfusion cause neonatal respiratory/circulatory failure; ventilator injury and oxygen toxicity can add downstream chronic lung damage. (perveen2022cellularmolecularand pages 2-4, liu2024roleofgenetics pages 2-3, liu2024roleofgenetics pages 3-4, perveen2022cellularmolecularand pages 1-2)

The “dual-hit” model—primary abnormal lung development followed by compression—is better supported than a compression-only explanation. Molecular pathways include retinoic-acid/RAR signaling, GATA4–ZFPM2 transcriptional regulation, WT1 and NR2F2/COUP-TFII programs, WNT5A patterning, SHH signaling and FGF10-dependent branching. Relevant processes include mesenchymal differentiation, muscle-progenitor migration, epithelial–mesenchymal signaling, extracellular-matrix organization, airway branching, angiogenesis and pulmonary vascular remodeling. (friedmacher2022geneticallymodifiedmouse pages 2-3, liu2024roleofgenetics pages 3-4, perveen2022cellularmolecularand pages 4-5)

GO suggestions: diaphragm development; lung morphogenesis (GO:0060425); branching involved in lung morphogenesis; respiratory-system development; skeletal-muscle cell differentiation; mesenchymal-cell migration; angiogenesis (GO:0001525); smooth-muscle-cell proliferation; response to retinoic acid; extracellular-matrix organization (GO:0030198).

Cell Ontology suggestions: mesenchymal cell (CL:0000134), skeletal-muscle progenitor, smooth-muscle cell (CL:0000192), pulmonary-artery endothelial cell, lung epithelial cell, fibroblast (CL:0000057) and mesothelial cell (CL:0000077).

Molecular profiling

Reported metabolic features include elevated lactate, ATP depletion and changes in antioxidant, glycolytic and nucleotide metabolites. Hypoxia increases reactive oxygen species, promoting endothelial dysfunction and smooth-muscle hyperplasia. Transcriptomic studies identify altered mesenchymal, vascular and developmental programs, but no transcriptomic, proteomic, lipidomic or metabolomic signature is clinically validated. Patient-derived fibroblasts and iPSCs, animal lung transcriptomics and emerging single-cell/spatial methods are research tools, not diagnostic standards. (perveen2022cellularmolecularand pages 5-6, perveen2022cellularmolecularand pages 4-5)

7. Anatomical structures affected

The primary site is the diaphragm—usually the left posterolateral hemidiaphragm. Herniated organs can include stomach, small and large bowel, spleen, liver and occasionally kidney. The lungs and pulmonary vasculature are the principal secondary targets; the heart, especially the left ventricle in left-sided disease, is compressed and developmentally affected. Gastrointestinal, musculoskeletal and nervous systems become important in long-term morbidity. (zani2022congenitaldiaphragmatichernia pages 1-2, zani2022congenitaldiaphragmatichernia pages 2-3)

Suggested UBERON mappings: diaphragm (UBERON:0001103), pleuroperitoneal fold, lung (UBERON:0002048), pulmonary artery, thoracic cavity, abdominal cavity, liver (UBERON:0002107) and left/right hemidiaphragm where available. At the subcellular level there is no single target organelle; nuclear transcription/chromatin regulation and mitochondrial/metabolic dysfunction are gene- or context-specific rather than universal.

8. Temporal development and natural history

The lesion originates during embryonic diaphragm formation, with PPF development around week 5 and pleuroperitoneal canal closure by approximately week 8. Clinical onset is therefore congenital, although detection may be prenatal, at birth or—especially for smaller defects—later in childhood or adulthood. (liu2024roleofgenetics pages 2-3)

Severe neonatal disease evolves rapidly over minutes to days as fetal circulation transitions and pulmonary vascular resistance fails to fall. Surgery corrects anatomy but does not immediately reverse hypoplastic lung or vascular disease. Survivors have a chronic, lifelong risk of pulmonary limitation, GERD, feeding/growth problems, recurrence, scoliosis and neurodevelopmental or hearing impairment. There is no “remission” in a conventional sense; stabilization, repair and developmental lung growth can produce major functional improvement.

Critical windows are early gestation for causation, mid-gestation for severity assessment, 27–29 weeks for FETO in selected severe disease, delivery for lung-protective stabilization and infancy/childhood for surveillance and rehabilitation. (NCT06179472 chunk 2, NCT06179472 chunk 1)

9. Inheritance and population epidemiology

Global birth prevalence is approximately 2.3 per 10,000 live births, with estimates ranging from about 1:2,000 to 1:3,500 depending on inclusion of stillbirths and terminations. Approximately 50–60% are isolated. Males constituted 59% of a large 2024 genomic cohort, but sex effects are modest and population dependent. (perveen2022cellularmolecularand pages 1-2, rivas2024theetiologyof pages 1-2, zani2022congenitaldiaphragmatichernia pages 2-3, qiao2024commonvariantsincrease pages 6-7)

Most cases are sporadic and multifactorial. Depending on the causal lesion, inheritance may be autosomal dominant with incomplete penetrance, autosomal recessive, X-linked/syndromic, or chromosomal; de novo dominant variation is prominent. Expressivity is highly variable. Consanguinity mainly matters for rare recessive syndromic forms. There is no meaningful universal carrier frequency. Geographic outcome disparities are pronounced: mortality is approximately 20–30% in high-resource settings but can exceed 90% in low-resource settings, reflecting prenatal detection, neonatal intensive care, surgery and ECLS access rather than known population-genetic differences. (rivas2024theetiologyof pages 1-2, zani2022congenitaldiaphragmatichernia pages 1-2)

10. Diagnostics

Prenatal diagnosis and severity assessment

Routine fetal ultrasonography can show intrathoracic stomach/bowel or liver, mediastinal shift, abnormal cardiac axis and reduced lung area. Detection rose from approximately 15% in the 1980s to 60–80% by the 2010s. Fetal echocardiography evaluates structural heart disease and ventricular function; MRI quantifies total fetal lung volume and liver herniation. (zani2022congenitaldiaphragmatichernia pages 1-2)

Key prognostic measures are observed-to-expected lung-to-head ratio (O/E-LHR), MRI observed-to-expected total fetal lung volume (O/E-TFLV), liver position and defect side. LHR <1 historically indicates poor prognosis. O/E-TFLV >35% was associated with 94% survival versus 56% below 35%; intrathoracic liver was associated with 45% versus 74% survival and ECMO use of 80% versus 25%. No single measure predicts an individual outcome perfectly. (perveen2022cellularmolecularand pages 1-2)

Postnatal diagnosis

Chest radiography typically shows bowel loops or stomach in the hemithorax, mediastinal shift and a paucity of abdominal gas. Echocardiography assesses PPHN, shunts and ventricular function. Serial blood gases, oxygenation index, lactate, blood pressure, renal/hepatic chemistry and coagulation monitor severity; none is a CDH-specific diagnostic biomarker. CT or MRI is reserved for equivocal late presentations, recurrence or complex anatomy. Biopsy and pathology are not routinely required.

Genetic workflow

Offer genetic counseling and prenatal/postnatal testing, especially for non-isolated disease. A practical sequence is karyotype when aneuploidy is suspected, chromosomal microarray for pathogenic CNVs, then trio exome or genome sequencing for SNVs/indels and additional structural variants. Prenatal cells are commonly obtained by second-trimester amniocentesis or first-trimester chorionic-villus sampling. Rapid sequencing can return results in approximately seven days in urgent settings. (zani2022congenitaldiaphragmatichernia pages 5-6, zani2022congenitaldiaphragmatichernia pages 3-4)

Reported diagnostic yield was 57% in complex/syndromic CDH in one series—73% cytogenetic and 27% single-gene diagnoses—but only 2% in isolated CDH under older, largely cytogenetic testing strategies. Yield in isolated disease may rise with modern trio genome analysis but remains lower than in complex cases. (perveen2022cellularmolecularand pages 5-6)

Targeted single-gene tests are appropriate only when phenotype strongly indicates a syndrome. Mitochondrial DNA and repeat-expansion testing are not routine. RNA-seq, methylomics, proteomics, metabolomics and liquid biopsy remain investigational.

Differential diagnoses include congenital pulmonary airway malformation, bronchopulmonary sequestration, diaphragmatic eventration/paralysis, congenital lung hypoplasia, cystic thoracic lesions, hiatal hernia and transient radiographic confusion with pneumothorax.

11. Outcomes and prognosis

High-income-center mortality is approximately 20–30%, while population survival—including fetal deaths and terminations—is about two-thirds. In a 2024 genomic cohort, 17% died before discharge, 30% required ECMO and 45% still had pulmonary hypertension at one month. Prognosis is worse with low O/E-LHR or O/E-TFLV, liver-up position, right-sided or bilateral disease, large C/D defect, associated anomalies/genetic diagnosis, severe ventricular dysfunction, persistent PH, prolonged ventilation and ECLS requirement. (zani2022congenitaldiaphragmatichernia pages 1-2, zani2022congenitaldiaphragmatichernia pages 2-3, qiao2024commonvariantsincrease pages 6-7)

Complications include chylothorax (5–10%), recurrent hernia, bowel obstruction, GERD, feeding failure, chronic lung disease, recurrent respiratory infection, hearing loss and neurodevelopmental impairment. Thoracoscopic repair has been associated with a 3.5-fold higher recurrence risk, and recurrence after large patch repair may approach 50% by age three. Ventilation/perfusion mismatch occurs in more than 60% of survivors. (zani2022congenitaldiaphragmatichernia pages 12-13)

Survival statistics are not equivalent to complete recovery. More than half of survivors have chronic morbidity, and robust adult life-expectancy data remain limited. Multidisciplinary longitudinal follow-up is therefore part of disease treatment, not optional surveillance.

12. Treatment and current implementation

Postnatal stabilization

Delivery should occur at a tertiary center when prenatal CDH is known. Avoid routine bag-mask ventilation; promptly intubate, decompress the stomach with an oro-/nasogastric tube and use lung-protective ventilation. Management prioritizes permissive hypercapnia, avoidance of high peak pressures and adequate preductal oxygenation rather than “normalizing” all blood gases. Echocardiography-guided hemodynamic care addresses PPHN and ventricular dysfunction. (zani2022congenitaldiaphragmatichernia pages 1-2, zani2022congenitaldiaphragmatichernia pages 8-9)

Pulmonary/cardiac therapies may include inhaled nitric oxide, sildenafil, milrinone, prostacyclin-class agents and vasoactive support, individualized to physiology. iNO is used in up to 60%, but aggregate evidence shows limited benefit and possible harm if it delays ECLS; it should not be considered uniformly effective. Surfactant is not routinely beneficial in term CDH unless another indication exists. There is no established pharmacogenomic algorithm. (NCT06179472 chunk 2, zani2022congenitaldiaphragmatichernia pages 8-9)

Suggested NCIt terms: mechanical ventilation, high-frequency oscillatory ventilation, inhaled nitric oxide therapy, extracorporeal membrane oxygenation, sildenafil therapy, milrinone therapy and supportive care.

ECLS/ECMO

Approximately 30% of severe cases require extracorporeal support. ECLS is considered for refractory hypoxemia, acidosis, hemodynamic failure or severe PH despite optimized ventilation and cardiovascular care. In selected high-risk infants, ECLS improved survival; however, mortality approaches 80% after four weeks of support. Repair during versus after ECLS remains center- and physiology-dependent. (zani2022congenitaldiaphragmatichernia pages 1-2, zani2022congenitaldiaphragmatichernia pages 8-9)

Surgical repair

Repair follows physiologic stabilization rather than emergency closure at birth; about 80% undergo repair during the first week. Small defects receive primary closure. Large defects require a prosthetic patch or muscle flap, preferably configured as a dome/cone without tension. Open abdominal repair remains common; thoracoscopic repair is generally reserved for stable, lower-risk infants because recurrence is higher in some series. (zani2022congenitaldiaphragmatichernia pages 10-11)

Fetal therapy

Fetoscopic endoluminal tracheal occlusion (FETO) temporarily traps fetal lung fluid to stimulate lung growth. In the TOTAL severe-left trial, survival was 40% with FETO versus 15% with expectant care; moderate-left disease showed 63% versus 50%, a non-significant difference. Severe right-sided observational data showed 41% versus 15%. Benefits must be balanced against preterm prelabor rupture of membranes, preterm birth, balloon displacement, fetal injury and fatal airway obstruction if emergency delivery precedes balloon removal. (zani2022congenitaldiaphragmatichernia pages 8-9)

Current implementation remains concentrated in specialist fetal centers. Examples include NCT06179472, using balloon placement at 27–29 weeks and removal near 34 weeks for severe left CDH (O/E-LHR <30%) or right CDH (<45%) with liver up, and NCT06739356, an 80-participant North American registry tracking survival, PH, oxygen dependence and complications through 24 months. NCT05962346 is a 20-patient severe-left pilot using O/E-LHR <25%. Trial records are dynamic and should be checked directly at https://clinicaltrials.gov/. (NCT06179472 chunk 2, NCT06739356 chunk 1, NCT05962346 chunk 1)

NIV-NAVA is being compared with assist-control ventilation in NCT05839340 (estimated n=18), reflecting attempts to reduce ventilator asynchrony and barotrauma. No approved gene, RNA or cell therapy exists. Amniotic-fluid stem-cell extracellular vesicles and prenatal pulmonary-vascular drugs remain preclinical. (liu2024roleofgenetics pages 2-3, NCT05839340 chunk 1)

Nutrition and rehabilitation

Term infants may require more than 125 kcal/kg/day and 2.3 g/kg/day protein; over 10% require feeding-tube access. Follow-up should include pulmonology, cardiology, surgery, gastroenterology/nutrition, audiology, neurodevelopment, physiotherapy and psychosocial support. (zani2022congenitaldiaphragmatichernia pages 10-11)

13. Prevention

There is no proven primary prevention for most sporadic CDH and no vaccine or prophylactic drug. General preconception measures include diabetes optimization, smoking/alcohol avoidance, medication/teratogen review and adequate guideline-concordant nutrition. High-dose vitamin A should not be used experimentally because excess retinoids are teratogenic.

Secondary prevention means early detection and severity stratification through routine prenatal ultrasound, referral for fetal MRI/echocardiography and delivery planning at an expert center. FETO is treatment for a highly selected affected fetus, not population prevention.

Tertiary prevention includes lung-protective ventilation, timely ECLS when indicated, tension-free repair, recurrence surveillance, immunization according to standard pediatric schedules, respiratory-infection prevention, nutritional support, hearing screening, neurodevelopmental assessment and long-term cardiopulmonary follow-up. Families with a pathogenic variant or chromosomal diagnosis should receive recurrence-risk counseling and discussion of prenatal diagnosis or preimplantation genetic testing. Empiric recurrence counseling is appropriate when testing is negative, acknowledging multifactorial risk.

14. Other species and natural disease

Naturally occurring congenital diaphragmatic defects are reported sporadically in domestic mammals, including dogs, cats and livestock, but robust breed-specific prevalence, VBO mappings and validated Mendelian veterinary loci were not established in the retrieved evidence. These defects are congenital, not zoonotic, and have no cross-species transmission.

Relevant taxa for experimental work include Mus musculus (NCBI Taxonomy 10090), Rattus norvegicus (10116) and fetal sheep, Ovis aries (9940). Orthologues of WT1, GATA4, ZFPM2, NR2F2 and retinoid-pathway genes are evolutionarily conserved, enabling comparative developmental study.

15. Model organisms

The nitrofen rat model is the most widely used induced model: maternal exposure around embryonic day 9 produces CDH with pulmonary hypoplasia in approximately 70% of offspring. It reproduces diaphragm defects, reduced branching, vascular remodeling and PH and is useful for prenatal drug, ventilation and FETO studies. Limitations are teratogen-specific off-target effects, variable defect penetrance and uncertain equivalence to human environmental exposure. (liu2024roleofgenetics pages 3-4, rivas2024theetiologyof pages 7-8)

Vitamin-A-deficient rodents and RAR-mutant mice directly test the retinoid hypothesis. Vitamin A repletion reduces defects in several models, but RAR-null animals often have low CDH penetrance and extensive cranial, vertebral, limb, cardiac and foregut abnormalities unlike typical isolated human CDH. (nakamura2020transgenicanimalmodels pages 1-2, friedmacher2022geneticallymodifiedmouse pages 1-2)

Genetic mouse models include Wt1, Nr2f2/Coup-tf2, Gata4, Zfpm2/Fog2, Slit3, Kif7, Tcf21/Msc, Gli2/Gli3, Fbln4, Lrp1 and others. They reproduce different components—amuscular diaphragm, posterolateral defects, failed mesenchymal attachment, lung hypoplasia, abnormal alveoli or impaired branching. Conditional Wt1 deletion produces approximately 80–90% penetrance in relevant mesenchymal/PPF compartments, while conditional Nr2f2 deletion produces about 50% CDH. (friedmacher2022geneticallymodifiedmouse pages 3-4, nakamura2020transgenicanimalmodels pages 2-4, rivas2024theetiologyof pages 4-5)

These models are strongest for lineage tracing, developmental timing, tissue-specific gene function and testing retinoid or regenerative interventions. Their limitations include strain effects, incomplete penetrance, syndromic phenotypes, small fetal anatomy and frequent embryonic/perinatal lethality that prevents study of chronic survivor morbidity. Eighteen phenotypically relevant transgenic mouse models were catalogued by 2020, but no single model captures the full human spectrum. (nakamura2020transgenicanimalmodels pages 1-2, friedmacher2022geneticallymodifiedmouse pages 7-8)

Evidence synthesis and expert interpretation

The current expert view is that CDH is a developmental systems disorder rather than a simple hole in the diaphragm. The strongest integrated model combines (1) genetically and environmentally sensitive PPF/mesenchymal development, (2) a primary lung-development defect, (3) secondary thoracic compression and (4) downstream pulmonary vascular and cardiac maladaptation. The 2024 genome study materially advances this model by showing that common polygenic susceptibility coexists with rare de novo variation rather than defining mutually exclusive disease classes. (liu2024roleofgenetics pages 2-3, qiao2024commonvariantsincrease pages 15-16)

Major unmet needs are improved individual prognostication, diverse-population genomics, functional validation of candidate variants, standardized cardiovascular treatment, safer fetal therapy, and adult natural-history data. Current molecular findings support better diagnosis and counseling, but—with the exception of selecting recognized syndromic care—do not yet direct genotype-specific therapy.

References

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(zani2022congenitaldiaphragmatichernia pages 14-15): Augusto Zani, Wendy K. Chung, Jan Deprest, Matthew T. Harting, Tim Jancelewicz, Shaun M. Kunisaki, Neil Patel, Lina Antounians, Pramod S. Puligandla, and Richard Keijzer. Congenital diaphragmatic hernia. Jun 2022. URL: https://doi.org/10.1038/s41572-022-00362-w, doi:10.1038/s41572-022-00362-w. This article has 279 citations.
(qiao2024commonvariantsincrease pages 3-4): Lu Qiao, Carrie L. Welch, Rebecca Hernan, Julia Wynn, Usha S. Krishnan, Jill M. Zalieckas, Terry Buchmiller, Julie Khlevner, Aliva De, Christiana Farkouh-Karoleski, Amy J. Wagner, Andreas Heydweiller, Andreas C. Mueller, Annelies de Klein, Brad W. Warner, Carlo Maj, Dai Chung, David J. McCulley, David Schindel, Douglas Potoka, Elizabeth Fialkowski, Felicitas Schulz, Florian Kipfmuller, Foong-Yen Lim, Frank Magielsen, George B. Mychaliska, Gudrun Aspelund, Heiko Martin Reutter, Howard Needelman, J. Marco Schnater, Jason C. Fisher, Kenneth Azarow, Mahmoud Elfiky, Markus M. Nöthen, Melissa E. Danko, Mindy Li, Przemyslaw Kosiński, Rene M.H. Wijnen, Robert A. Cusick, Samuel Z. Soffer, Suzan C.M. Cochius-Den Otter, Thomas Schaible, Timothy Crombleholme, Vincent P. Duron, Patricia K. Donahoe, Xin Sun, Frances A. High, Charlotte Bendixen, Erwin Brosens, Yufeng Shen, and Wendy K. Chung. Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants. Nov 2024. URL: https://doi.org/10.1016/j.ajhg.2024.08.024, doi:10.1016/j.ajhg.2024.08.024. This article has 16 citations.
(qiao2024commonvariantsincrease pages 13-15): Lu Qiao, Carrie L. Welch, Rebecca Hernan, Julia Wynn, Usha S. Krishnan, Jill M. Zalieckas, Terry Buchmiller, Julie Khlevner, Aliva De, Christiana Farkouh-Karoleski, Amy J. Wagner, Andreas Heydweiller, Andreas C. Mueller, Annelies de Klein, Brad W. Warner, Carlo Maj, Dai Chung, David J. McCulley, David Schindel, Douglas Potoka, Elizabeth Fialkowski, Felicitas Schulz, Florian Kipfmuller, Foong-Yen Lim, Frank Magielsen, George B. Mychaliska, Gudrun Aspelund, Heiko Martin Reutter, Howard Needelman, J. Marco Schnater, Jason C. Fisher, Kenneth Azarow, Mahmoud Elfiky, Markus M. Nöthen, Melissa E. Danko, Mindy Li, Przemyslaw Kosiński, Rene M.H. Wijnen, Robert A. Cusick, Samuel Z. Soffer, Suzan C.M. Cochius-Den Otter, Thomas Schaible, Timothy Crombleholme, Vincent P. Duron, Patricia K. Donahoe, Xin Sun, Frances A. High, Charlotte Bendixen, Erwin Brosens, Yufeng Shen, and Wendy K. Chung. Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants. Nov 2024. URL: https://doi.org/10.1016/j.ajhg.2024.08.024, doi:10.1016/j.ajhg.2024.08.024. This article has 16 citations.
(perveen2022cellularmolecularand pages 2-4): Shahana Perveen, Marta Frigeni, Helene Benveniste, and Dalibor Kurepa. Cellular, molecular, and metabolic aspects of developing lungs in congenital diaphragmatic hernia. Frontiers in Pediatrics, Nov 2022. URL: https://doi.org/10.3389/fped.2022.932463, doi:10.3389/fped.2022.932463. This article has 10 citations.
(friedmacher2022geneticallymodifiedmouse pages 2-3): Florian Friedmacher, Udo Rolle, and Prem Puri. Genetically modified mouse models of congenital diaphragmatic hernia: opportunities and limitations for studying altered lung development. Frontiers in Pediatrics, May 2022. URL: https://doi.org/10.3389/fped.2022.867307, doi:10.3389/fped.2022.867307. This article has 6 citations.
(perveen2022cellularmolecularand pages 4-5): Shahana Perveen, Marta Frigeni, Helene Benveniste, and Dalibor Kurepa. Cellular, molecular, and metabolic aspects of developing lungs in congenital diaphragmatic hernia. Frontiers in Pediatrics, Nov 2022. URL: https://doi.org/10.3389/fped.2022.932463, doi:10.3389/fped.2022.932463. This article has 10 citations.
(perveen2022cellularmolecularand pages 5-6): Shahana Perveen, Marta Frigeni, Helene Benveniste, and Dalibor Kurepa. Cellular, molecular, and metabolic aspects of developing lungs in congenital diaphragmatic hernia. Frontiers in Pediatrics, Nov 2022. URL: https://doi.org/10.3389/fped.2022.932463, doi:10.3389/fped.2022.932463. This article has 10 citations.
(zani2022congenitaldiaphragmatichernia pages 2-3): Augusto Zani, Wendy K. Chung, Jan Deprest, Matthew T. Harting, Tim Jancelewicz, Shaun M. Kunisaki, Neil Patel, Lina Antounians, Pramod S. Puligandla, and Richard Keijzer. Congenital diaphragmatic hernia. Jun 2022. URL: https://doi.org/10.1038/s41572-022-00362-w, doi:10.1038/s41572-022-00362-w. This article has 279 citations.
(NCT06179472 chunk 2): Inna Lobeck. Infant Survival and Long-term Outcome Following Fetoscopic Endoluminal Tracheal Occlusion in Severe Left and Right Congenital Diaphragmatic Hernia, A Phase III Trial. Inna Lobeck. 2024. ClinicalTrials.gov Identifier: NCT06179472
(NCT06179472 chunk 1): Inna Lobeck. Infant Survival and Long-term Outcome Following Fetoscopic Endoluminal Tracheal Occlusion in Severe Left and Right Congenital Diaphragmatic Hernia, A Phase III Trial. Inna Lobeck. 2024. ClinicalTrials.gov Identifier: NCT06179472
(zani2022congenitaldiaphragmatichernia pages 5-6): Augusto Zani, Wendy K. Chung, Jan Deprest, Matthew T. Harting, Tim Jancelewicz, Shaun M. Kunisaki, Neil Patel, Lina Antounians, Pramod S. Puligandla, and Richard Keijzer. Congenital diaphragmatic hernia. Jun 2022. URL: https://doi.org/10.1038/s41572-022-00362-w, doi:10.1038/s41572-022-00362-w. This article has 279 citations.
(zani2022congenitaldiaphragmatichernia pages 3-4): Augusto Zani, Wendy K. Chung, Jan Deprest, Matthew T. Harting, Tim Jancelewicz, Shaun M. Kunisaki, Neil Patel, Lina Antounians, Pramod S. Puligandla, and Richard Keijzer. Congenital diaphragmatic hernia. Jun 2022. URL: https://doi.org/10.1038/s41572-022-00362-w, doi:10.1038/s41572-022-00362-w. This article has 279 citations.
(zani2022congenitaldiaphragmatichernia pages 12-13): Augusto Zani, Wendy K. Chung, Jan Deprest, Matthew T. Harting, Tim Jancelewicz, Shaun M. Kunisaki, Neil Patel, Lina Antounians, Pramod S. Puligandla, and Richard Keijzer. Congenital diaphragmatic hernia. Jun 2022. URL: https://doi.org/10.1038/s41572-022-00362-w, doi:10.1038/s41572-022-00362-w. This article has 279 citations.
(zani2022congenitaldiaphragmatichernia pages 10-11): Augusto Zani, Wendy K. Chung, Jan Deprest, Matthew T. Harting, Tim Jancelewicz, Shaun M. Kunisaki, Neil Patel, Lina Antounians, Pramod S. Puligandla, and Richard Keijzer. Congenital diaphragmatic hernia. Jun 2022. URL: https://doi.org/10.1038/s41572-022-00362-w, doi:10.1038/s41572-022-00362-w. This article has 279 citations.
(NCT06739356 chunk 1): Anthony Johnson. North American Fetal Therapy Network for Long-term Outcome Following Fetoscopic Endoluminal Tracheal Occlusion in Severe Left and Right Congenital Diaphragmatic Hernia. The University of Texas Health Science Center, Houston. 2025. ClinicalTrials.gov Identifier: NCT06739356
(NCT05962346 chunk 1): Mauro H. Schenone. Fetal Endoscopic Tracheal Occlusion for Congenital Diaphragmatic Hernia. Mauro H. Schenone. 2026. ClinicalTrials.gov Identifier: NCT05962346
(NCT05839340 chunk 1): Anne Greenough. Neurally Adjusted Ventilatory Assist for Neonates With Congenital Diaphragmatic Hernias. King's College Hospital NHS Trust. 2023. ClinicalTrials.gov Identifier: NCT05839340
(rivas2024theetiologyof pages 7-8): Juan F. Garcia Rivas and Robin D. Clugston. The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later. Pediatric Research, 95:912-921, Nov 2024. URL: https://doi.org/10.1038/s41390-023-02905-7, doi:10.1038/s41390-023-02905-7. This article has 24 citations and is from a domain leading peer-reviewed journal.
(nakamura2020transgenicanimalmodels pages 1-2): Hiroki Nakamura, Takashi Doi, Prem Puri, and Florian Friedmacher. Transgenic animal models of congenital diaphragmatic hernia: a comprehensive overview of candidate genes and signaling pathways. Pediatric Surgery International, 36:991-997, Jun 2020. URL: https://doi.org/10.1007/s00383-020-04705-0, doi:10.1007/s00383-020-04705-0. This article has 20 citations and is from a peer-reviewed journal.
(friedmacher2022geneticallymodifiedmouse pages 1-2): Florian Friedmacher, Udo Rolle, and Prem Puri. Genetically modified mouse models of congenital diaphragmatic hernia: opportunities and limitations for studying altered lung development. Frontiers in Pediatrics, May 2022. URL: https://doi.org/10.3389/fped.2022.867307, doi:10.3389/fped.2022.867307. This article has 6 citations.
(friedmacher2022geneticallymodifiedmouse pages 3-4): Florian Friedmacher, Udo Rolle, and Prem Puri. Genetically modified mouse models of congenital diaphragmatic hernia: opportunities and limitations for studying altered lung development. Frontiers in Pediatrics, May 2022. URL: https://doi.org/10.3389/fped.2022.867307, doi:10.3389/fped.2022.867307. This article has 6 citations.
(nakamura2020transgenicanimalmodels pages 2-4): Hiroki Nakamura, Takashi Doi, Prem Puri, and Florian Friedmacher. Transgenic animal models of congenital diaphragmatic hernia: a comprehensive overview of candidate genes and signaling pathways. Pediatric Surgery International, 36:991-997, Jun 2020. URL: https://doi.org/10.1007/s00383-020-04705-0, doi:10.1007/s00383-020-04705-0. This article has 20 citations and is from a peer-reviewed journal.
(friedmacher2022geneticallymodifiedmouse pages 7-8): Florian Friedmacher, Udo Rolle, and Prem Puri. Genetically modified mouse models of congenital diaphragmatic hernia: opportunities and limitations for studying altered lung development. Frontiers in Pediatrics, May 2022. URL: https://doi.org/10.3389/fped.2022.867307, doi:10.3389/fped.2022.867307. This article has 6 citations.

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Congenital Diaphragmatic Hernia: Disease-Characteristics Research Report

1. Disease information

Definition and classification

Key identifiers and synonyms

2. Etiology and risk/protective factors

Genetic risk

Environmental and lifestyle associations

3. Phenotypes

4. Genetic and molecular information

Variant interpretation and testing implications

5. Environmental information

6. Mechanism and pathophysiology

Causal chain

Molecular profiling

7. Anatomical structures affected

8. Temporal development and natural history

9. Inheritance and population epidemiology

10. Diagnostics

Prenatal diagnosis and severity assessment

Postnatal diagnosis

Genetic workflow

11. Outcomes and prognosis

12. Treatment and current implementation

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