Materiały źródłowe

• #1 Genetics of diaphragmatic hernia | European Journal of Human Genetics

  https://www.nature.com/articles/s41431-021-00972-0

  Congenital diaphragmatic hernia (CDH) is a life-threatening malformation characterised by failure of diaphragmatic development with lung hypoplasia and persistent pulmonary hypertension of the newborn (PPHN). The incidence is 1:2000 corresponding to 8% of all major congenital malformations. […] CDH is caused by a discontinuity in the diaphragm allowing abdominal organs to penetrate into the thoracic cavity, to interfere with heart and lung development thus causing a series of severe pathophysiologic events: pulmonary hypoplasia, pulmonary hypertension (PH) following increased pulmonary vascular resistance (PVR) and cardiac impairment are hallmarks of CDH. […] However, genetic causes ranging from aneuploidy to complex chromosomal aberrations and specific mutations have long been discussed to explain a proportion of cases of CDH often along with additional malformations.

• #2 Congenital diaphragmatic hernia: Prenatal issues – UpToDate

  https://www.uptodate.com/contents/congenital-diaphragmatic-hernia-prenatal-issues

  Congenital diaphragmatic hernia (CDH) is a developmental discontinuity of the diaphragm that allows the abdominal viscera to herniate into the chest. Although the diaphragmatic defect is surgically correctable, in utero herniation of viscera can result in pulmonary hypoplasia and pulmonary hypertension. A substantial percentage of CDH cases are associated with additional abnormalities, including major structural anomalies in other organ systems, chromosomal abnormalities, and/or single gene disorders. Affected neonates usually present in the first few hours of life with respiratory distress that may be mild or so severe as to be incompatible with life. Survival has improved with advances in antenatal diagnosis, in utero intervention, and neonatal care, but affected infants remain at significant risk of morbidity and mortality.

• #3 Congenital Diaphragmatic Hernia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK556076/

  Congenital diaphragmatic hernia is a condition resulting from the herniation of abdominal contents into the thoracic cavity resulting in lung hypoplasia and altered pulmonary vascular development. […] Congenital diaphragmatic hernia (CDH) is a condition resulting from a developmental defect in the diaphragm leading to protrusion of abdominal contents into the thoracic cavity. […] The etiology of congenital diaphragmatic hernia remains unclear. It is thought to be multifactorial with genetic, environmental, and/or nutritional factors playing a role. CDH can be an isolated anomaly or associated with anomalies in other organ systems. […] Any disturbance in the formation of the pleuroperitoneal membranes can result in diaphragmatic discontinuity and congenital diaphragmatic hernia. The associated herniation of the abdominal viscera into the thoracic cavity can interfere with normal lung development and forms the basis for the two main pathological findings noted in CDH- lung hypoplasia and abnormal pulmonary vascular development. […] Irrespective of the cause, pulmonary hypoplasia, abnormal pulmonary vasoreactivity, and PH are the major contributors to the morbidity and mortality associated with CDH.

• #4 Congenital Diaphragmatic hernia – a review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5356475/

  Congenital Diaphragmatic hernia (CDH) is a condition characterized by a defect in the diaphragm leading to protrusion of abdominal contents into the thoracic cavity interfering with normal development of the lungs. The pathophysiology of CDH is a combination of lung hypoplasia and immaturity associated with persistent pulmonary hypertension of newborn (PPHN) and cardiac dysfunction. […] The etiology of CDH largely remains unclear and currently is thought to be multifactorial. The majority of the cases have an isolated diaphragmatic defect presenting with pulmonary hypoplasia and persistent pulmonary hypertension of newborn (PPHN). […] The embryologic basis of CDH remains controversial. It was thought initially that the defect happened secondary to failure of different parts of the diaphragm to fuse resulting in a patent pleuroperitoneal canal.

• #5 Congenital Diaphragmatic Hernia: Pathophysiology and Antenatal Assessment (Chapter 47) – Fetal Therapy

  https://www.cambridge.org/core/books/fetal-therapy/congenital-diaphragmatic-hernia-pathophysiology-and-antenatal-assessment/3407E1E3A9A8E3450AB7DB26C3FC9154

  Congenital diaphragmatic hernia (CDH) is a developmental anomaly with a prevalence ranging between 1 and 4/10 000 births, hence qualifying as a rare disease. During embryogenesis the diaphragm fails to form, most often on the left side (85%), rarely on the right (13%), and sporadically bilaterally (2%). Exceptionally there is true agenesis of the hemidiaphragm, but most often the defect is confined to the posterolateral area (Bochdalek hernia). In case of a true defect, abdominal viscera can herniate into the thorax, acting as a space-occupying lesion that competes with the developing lungs. In left CDH (LCDH), this typically includes bowel, spleen, stomach, and less often the left lobe of the liver and rarely kidney. In case of a right-sided CDH (RCDH), the liver is virtually always into the thorax. These structures compromise lung development, leading to variable degrees of pulmonary hypoplasia. The lung ipsilateral to the defect is most affected, however both lungs are in essence hypoplastic. They have a lower number of airways, fewer and smaller alveoli, thickened alveolar walls, and an increased amount of interstitial tissue. This leaves less alveolar airspace, and hence reduces the gas exchange surface area. Parallel to airway changes, there is a similar reduction in arteries, essentially leaving a hypoplastic vascular bed. Morphologically, the vascular wall is thickened by an increase in the arterial media and adventitia, neo-muscularization of small pulmonary arteries and hypermuscularization of midsize and large vessels. These vessels may have an abnormal response to mechanical and chemical stimuli in the postnatal period.

• #6 Congenital Diaphragmatic Hernia (CDH) | Children’s Hospital of Philadelphia

  https://www.chop.edu/conditions-diseases/congenital-diaphragmatic-hernia-cdh

  With CDH, a hole in the diaphragm allows abdominal organs to move into the chest during fetal development. This allows abdominal organs (stomach, intestines, and/or liver) to move into the chest. When the abdominal organs are in the chest, they can crowd the heart and lungs and keep the lungs from growing normally. […] The cause of CDH is unknown. Typically CDH is an isolated finding although it can occur along with heart disease or a genetic abnormality which can lead to additional complications. […] Genetic researchers are using innovative techniques to try to find the potential underlying genetic etiology of CDH. Identifying the genetic cause(s) of CDH will allow our clinicians to better manage and counsel families with an affected child. […] The strongest prediction of the severity of CDH is the location of the liver. When the liver is up in the chest there is more pulmonary hypoplasia (small lungs). The degree of pulmonary hypoplasia can be predicted by measurements obtained during the fetal ultrasound and MRI.

• #7 Congenital diaphragmatic hernia (CDH) – CON-20472981-Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/congenital-diaphragmatic-hernia/symptoms-causes/syc-20544249

  Congenital diaphragmatic hernia (CDH) is a rare condition that happens in a baby before birth. It occurs early in pregnancy when a baby’s diaphragm the muscle that separates the chest from the abdomen fails to close as it should. This leaves a hole in the diaphragm. The hole is called a hernia. […] This hernia in the muscle of the diaphragm creates an opening between the abdomen and the chest. The intestines, stomach, liver and other abdominal organs may move through the hole into the baby’s chest. If the intestines are in the chest, they don’t develop the typical connections that hold them in place in the abdomen (malrotation). They may twist on themselves, cutting off their blood supply (volvulus). […] In addition, the lung is small on the side of the diaphragm with the hernia, but the development of both lungs is affected. The air sacs (alveoli) inside the lungs don’t develop as they should. This results in problems with blood flow and increased pressure inside the lung’s blood vessels. The blood pressure in the lungs is higher than it should be, which can make it hard for the baby to breathe after birth. Some infants may also have problems with heart development.

• #8 Congenital Diaphragmatic Hernia and Eventration – Clinical Tree

  https://clinicalpub.com/congenital-diaphragmatic-hernia-and-eventration/

  The development of the human diaphragm is a complex, multicellular, multitissue interaction that remains incompletely understood. Precursors to the diaphragm begin to form during the fourth week of gestation. Historically, the diaphragm was thought to develop from the fusion of four embryonic components: anteriorly by the septum transversum, dorsolaterally by the pleuroperitoneal folds (PPFs), dorsally by the crura from the esophageal mesentery, and posteriorly by the body wall mesoderm. According to this theory, as the embryo begins to form, the septum transversum migrates dorsally and separates the pleuropericardial cavity from the peritoneal cavity. At this point, the pleural and peritoneal cavities still communicate. The septum transversum interacts with the PPF and mesodermal tissue surrounding the developing esophagus and other foregut structures, resulting in the formation of primitive diaphragmatic structures. Bound by pericardial, pleural, and peritoneal folds, the paired PPFs now separate the pleuropericardial and peritoneal cavities. Eventually, the septum transversum develops into the central tendon. As the PPF develops during the sixth week of gestation, concurrently, the pleuroperitoneal membranes close and separate the pleural and abdominal cavities by the eighth week of gestation. Typically, the right side closes before the left. Ultimately, the phrenic axons and myogenic cells destined for neuromuscularization migrate to the PPF and form the mature diaphragm. The muscularization of the primitive diaphragm is a separate but inter-related process.

• #9 Congenital Diaphragmatic Hernia and Eventration – Clinical Tree

  https://clinicalpub.com/congenital-diaphragmatic-hernia-and-eventration/

  The development of the human diaphragm is a complex, multicellular, multitissue interaction that remains incompletely understood. Precursors to the diaphragm begin to form during the fourth week of gestation. Historically, the diaphragm was thought to develop from the fusion of four embryonic components: anteriorly by the septum transversum, dorsolaterally by the pleuroperitoneal folds (PPFs), dorsally by the crura from the esophageal mesentery, and posteriorly by the body wall mesoderm. According to this theory, as the embryo begins to form, the septum transversum migrates dorsally and separates the pleuropericardial cavity from the peritoneal cavity. At this point, the pleural and peritoneal cavities still communicate. The septum transversum interacts with the PPF and mesodermal tissue surrounding the developing esophagus and other foregut structures, resulting in the formation of primitive diaphragmatic structures. Bound by pericardial, pleural, and peritoneal folds, the paired PPFs now separate the pleuropericardial and peritoneal cavities. Eventually, the septum transversum develops into the central tendon. As the PPF develops during the sixth week of gestation, concurrently, the pleuroperitoneal membranes close and separate the pleural and abdominal cavities by the eighth week of gestation. Typically, the right side closes before the left. Ultimately, the phrenic axons and myogenic cells destined for neuromuscularization migrate to the PPF and form the mature diaphragm. The muscularization of the primitive diaphragm is a separate but inter-related process.

• #10 Congenital diaphragmatic hernia: Prenatal issues – UpToDate

  https://www.uptodate.com/contents/congenital-diaphragmatic-hernia-prenatal-issues

  The period from just after the third week postfertilization (postconception) through the 16th week of gestation is a critical period of lung development. Failure of normal closure of the pleuroperitoneal folds during the fourth to tenth weeks postfertilization allows herniation of viscera into the thoracic cavity, which interferes with normal lung development and has several potential adverse consequences, including: Reduction in bronchiolar branching. Truncation and over-muscularization of the pulmonary arterial tree, leading to smaller cross-sectional area of pulmonary vessels, structural vascular remodeling, and vasoconstriction with altered vasoreactivity.

• #11 Congenital diaphragmatic hernia: Prenatal issues – UpToDate

  https://www.uptodate.com/contents/congenital-diaphragmatic-hernia-prenatal-issues/print

  Congenital diaphragmatic hernia (CDH) is a developmental discontinuity of the diaphragm that allows the abdominal viscera to herniate into the chest. […] Failure of normal closure of the pleuroperitoneal folds during the fourth to tenth weeks postfertilization allows herniation of viscera into the thoracic cavity, which interferes with normal lung development and has several potential adverse consequences, including: […] Reduction in bronchiolar branching. […] Truncation and over-muscularization of the pulmonary arterial tree, leading to smaller cross-sectional area of pulmonary vessels, structural vascular remodeling, and vasoconstriction with altered vasoreactivity.

• #12 Congenital Diaphragmatic hernia – a review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5356475/

  Congenital Diaphragmatic hernia (CDH) is a condition characterized by a defect in the diaphragm leading to protrusion of abdominal contents into the thoracic cavity interfering with normal development of the lungs. The pathophysiology of CDH is a combination of lung hypoplasia and immaturity associated with persistent pulmonary hypertension of newborn (PPHN) and cardiac dysfunction. […] The etiology of CDH largely remains unclear and currently is thought to be multifactorial. The majority of the cases have an isolated diaphragmatic defect presenting with pulmonary hypoplasia and persistent pulmonary hypertension of newborn (PPHN). […] The embryologic basis of CDH remains controversial. It was thought initially that the defect happened secondary to failure of different parts of the diaphragm to fuse resulting in a patent pleuroperitoneal canal.

• #13 Congenital Diaphragmatic Hernia and Eventration – Clinical Tree

  https://clinicalpub.com/congenital-diaphragmatic-hernia-and-eventration/

  More recently, the role of the PPF and, specifically, a subset of PPF-derived muscle connective tissue fibroblasts, in the development of CDH has been further elucidated. Through the use of mouse genetics, the PPFs were identified as the source of the central tendon, muscle connective tissue, and muscle connective tissue fibroblasts. The migration of these PPF cells has been found to control diaphragm morphogenesis. In this model, mice with mutated Gata4, strongly expressed in the PPFs, universally developed diaphragmatic hernias. Muscle connective tissue produced by mutated PPF fibroblasts was found to be phenotypically abnormal, allowing herniation of peritoneal contents into the thorax. The herniated tissue was shown to physically impede lung development (though mutations in Gata4 also have a primary effect on lung development). Therefore, this investigation identified a critical role of the PPF and muscle connective tissue fibroblasts in normal and abnormal diaphragmatic development.

• #14 Congenital Diaphragmatic Hernia and Eventration – Clinical Tree

  https://clinicalpub.com/congenital-diaphragmatic-hernia-and-eventration/

  More recently, the role of the PPF and, specifically, a subset of PPF-derived muscle connective tissue fibroblasts, in the development of CDH has been further elucidated. Through the use of mouse genetics, the PPFs were identified as the source of the central tendon, muscle connective tissue, and muscle connective tissue fibroblasts. The migration of these PPF cells has been found to control diaphragm morphogenesis. In this model, mice with mutated Gata4, strongly expressed in the PPFs, universally developed diaphragmatic hernias. Muscle connective tissue produced by mutated PPF fibroblasts was found to be phenotypically abnormal, allowing herniation of peritoneal contents into the thorax. The herniated tissue was shown to physically impede lung development (though mutations in Gata4 also have a primary effect on lung development). Therefore, this investigation identified a critical role of the PPF and muscle connective tissue fibroblasts in normal and abnormal diaphragmatic development.

• #15 New Insights Into Little Known But Common Birth Defect: Congenital Diaphragmatic Hernia | University of Utah Health

  https://healthcare.utah.edu/press-releases/2015/03/new-insights-little-known-common-birth-defect-congenital-diaphragmatic

  This suggested that genetic defects within connective tissue might be a cause of CDH. […] They tested their hypothesis by silencing the Gata4 gene in the connective tissue cells and observing how this affected development. In every case in which the Gata4 gene was „knocked out,” the mouse developed a hernia in its diaphragm. […] Without Gata4 in the connective tissue, muscle develops incompletely creating a localized region made entirely of connective tissue. […] Their genetic studies, aided by computer models made in collaboration with bioengineers, show that CDH only develops when a weaker region of connective tissue is surrounded by stronger muscular tissue; counterintuitively, diaphragms made entirely of connective tissue did not develop hernias. […] Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias. […] Research from the University of Utah provides new information on how CDH arises, opening avenues for researching therapeutic interventions.

• #16 Hemodynamic management of congenital diaphragmatic hernia: the role of targeted neonatal echocardiography | World Journal of Pediatric Surgery

  https://wjps.bmj.com/content/7/2/e000790

  Using the well-known nitrofen model, Keijzer et al. proposed the Dual-hit Hypothesis, suggesting an initial insult affecting both lungs before diaphragm development, followed by the second insult affecting the ipsilateral lung after defective diaphragm development and resulting extrinsic compression. […] The severity of CDH is notably linked with a variable degree of pulmonary hypoplasia, PHT, and cardiac dysfunction, constituting the triad of pathophysiological hallmark features of this complex disorder. […] The altered pulmonary vasoreactivity and pathological vascular remodeling, secondary to the reduced lung size and changes in pulmonary microarchitecture, are central to the pathophysiology of CDH-associated PHT. […] The confluence of low ventricular output and PHT leads to hypoxemia, respiratory and metabolic acidosis, systemic hypotension, and shock.

• #17 Congenital Diaphragmatic Hernia: A Major Challenge for Neonatologists | IntechOpen

  https://www.intechopen.com/chapters/74635

  Congenital diaphragmatic hernia (CDH) is a major congenital anomaly of the neonates, characterized by the herniation of abdominal contents into the thoracic cavity during fetal life. This results in significant pulmonary hypertension and hypoxemia after birth, which responds poorly to therapeutic interventions. The exact pathogenesis is not well understood, and genetic factors have been proposed. […] The dual-hit hypothesis, proposed by Keijzer et al, has suggested that the early insult in lungs development is bilateral, occurring before and independent of the diaphragmatic defect; and a later second hit to the ipsilateral lung via compression from the herniated abdominal content leads to the characteristic pulmonary hypertension and hypoxemia in the neonate. […] Environmental factors contributing to CDH are not well investigated. Maternal vitamin A deficiency, nitrofen treatment and retinoid receptor knock-out in animal model are reported to result in CDH in their offsprings, suggesting a role of retinoid signaling pathway in the pathogenesis.

• #18 Congenital Diaphragmatic Hernia: A Major Challenge for Neonatologists | IntechOpen

  https://www.intechopen.com/chapters/74635

  Congenital diaphragmatic hernia (CDH) is a major congenital anomaly of the neonates, characterized by the herniation of abdominal contents into the thoracic cavity during fetal life. This results in significant pulmonary hypertension and hypoxemia after birth, which responds poorly to therapeutic interventions. The exact pathogenesis is not well understood, and genetic factors have been proposed. […] The dual-hit hypothesis, proposed by Keijzer et al, has suggested that the early insult in lungs development is bilateral, occurring before and independent of the diaphragmatic defect; and a later second hit to the ipsilateral lung via compression from the herniated abdominal content leads to the characteristic pulmonary hypertension and hypoxemia in the neonate. […] Environmental factors contributing to CDH are not well investigated. Maternal vitamin A deficiency, nitrofen treatment and retinoid receptor knock-out in animal model are reported to result in CDH in their offsprings, suggesting a role of retinoid signaling pathway in the pathogenesis.

• #19 The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later | Pediatric Research

  https://www.nature.com/articles/s41390-023-02905-7

  Congenital diaphragmatic hernia (CDH) is a severe birth defect and a major cause of neonatal respiratory distress. […] Despite the significant impact of CDH, its etiology remains incompletely understood. […] 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. […] The Retinoid Hypothesis is one of the leading hypotheses to explain the etiology of CDH, as we continue to better understand the role of retinoid signaling in diaphragm development. […] It is generally considered that the two main factors that contribute to CDH are genetic and/or environmental. […] Approximately 30-40% of CDH cases have an identifiable genetic cause. […] Of this number, chromosomal defects account for about ~10% of CDH cases, and de novo mutations account for 10-22% of cases.

• #20 The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later | Pediatric Research

  https://www.nature.com/articles/s41390-023-02905-7

  The Retinoid Hypothesis was based on research dating back to the 1940s, drawing together several threads of evidence to justify the notion that altered retinoid signaling may cause CDH. […] The foundation for the Retinoid Hypothesis included evidence from animal models of CDH, as well as emerging clinical data. […] The Retinoid Hypothesis was founded on reports that nitrofen can inhibit RALDH2 and suppress activation of RAR signaling. […] This work provided further evidence that nitrofen inhibits RALDH2 using a RARE-LacZ reporter system in P19 cells, which could be overcome by adding excess enzyme substrate in the form of retinal. […] Indeed, nitrofen and three other CDH-inducing teratogens that inhibit RALDH2 all decrease embryonic retinoid acid signaling throughout the critical period of diaphragm development.

• #21 Congenital Diaphragmatic Hernia and Eventration – Clinical Tree

  https://clinicalpub.com/congenital-diaphragmatic-hernia-and-eventration/

  Other teratogens structurally similar to nitrofen have been shown to induce CDH in animal models as well. Although the exact etiology of CDH is unknown, these teratogens commonly affect the retinoic acid synthesis pathway by inhibiting retinol dehydrogenase-2 and causing similar diaphragmatic defects. Several clinical observations and molecular studies have supported the importance of the retinoic acid pathways in CDH development. Vitamin A-deficient rodents will produce offspring with CDH of variable severity. Retinoic acid receptor knockout mice produce fetuses with CDH. Failure to convert retinoic acid to retinaldehyde following administration of nitrofen produces posterolateral diaphragmatic defects in rats. Lower plasma levels of retinoic acid and retinol binding protein in infants with CDH have been found compared with controls.

• #22 Congenital Diaphragmatic Hernia: A Major Challenge for Neonatologists | IntechOpen

  https://www.intechopen.com/chapters/74635

  Congenital diaphragmatic hernia (CDH) is a major congenital anomaly of the neonates, characterized by the herniation of abdominal contents into the thoracic cavity during fetal life. This results in significant pulmonary hypertension and hypoxemia after birth, which responds poorly to therapeutic interventions. The exact pathogenesis is not well understood, and genetic factors have been proposed. […] The dual-hit hypothesis, proposed by Keijzer et al, has suggested that the early insult in lungs development is bilateral, occurring before and independent of the diaphragmatic defect; and a later second hit to the ipsilateral lung via compression from the herniated abdominal content leads to the characteristic pulmonary hypertension and hypoxemia in the neonate. […] Environmental factors contributing to CDH are not well investigated. Maternal vitamin A deficiency, nitrofen treatment and retinoid receptor knock-out in animal model are reported to result in CDH in their offsprings, suggesting a role of retinoid signaling pathway in the pathogenesis.

• #23 The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later | Pediatric Research

  https://www.nature.com/articles/s41390-023-02905-7

  The Retinoid Hypothesis was based on research dating back to the 1940s, drawing together several threads of evidence to justify the notion that altered retinoid signaling may cause CDH. […] The foundation for the Retinoid Hypothesis included evidence from animal models of CDH, as well as emerging clinical data. […] The Retinoid Hypothesis was founded on reports that nitrofen can inhibit RALDH2 and suppress activation of RAR signaling. […] This work provided further evidence that nitrofen inhibits RALDH2 using a RARE-LacZ reporter system in P19 cells, which could be overcome by adding excess enzyme substrate in the form of retinal. […] Indeed, nitrofen and three other CDH-inducing teratogens that inhibit RALDH2 all decrease embryonic retinoid acid signaling throughout the critical period of diaphragm development.

• #24 The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later | Pediatric Research

  https://www.nature.com/articles/s41390-023-02905-7

  The potent effect of direct supplementation with RA to prevent CDH was further emphasized in teratogen-treated mice. […] The observation that Rar knock-out mice developed CDH was integral to the original formulation of the Retinoid Hypothesis. […] The only direct genetic evidence supporting the Retinoid Hypothesis obtained from mice with targeted mutations in RA signaling come from studies of Rar compound mutant mice. […] The presence of diaphragm defects in Wt1, Coup-tf2, Gata4, and Fog2 mutant mice indicates their individual importance in normal diaphragm development. […] As we learn increasingly more about the genetics of CDH, a common pathway that has emerged is RA signaling, providing support for the Retinoid Hypothesis in human CDH.

• #25 The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later | Pediatric Research

  https://www.nature.com/articles/s41390-023-02905-7

  The potent effect of direct supplementation with RA to prevent CDH was further emphasized in teratogen-treated mice. […] The observation that Rar knock-out mice developed CDH was integral to the original formulation of the Retinoid Hypothesis. […] The only direct genetic evidence supporting the Retinoid Hypothesis obtained from mice with targeted mutations in RA signaling come from studies of Rar compound mutant mice. […] The presence of diaphragm defects in Wt1, Coup-tf2, Gata4, and Fog2 mutant mice indicates their individual importance in normal diaphragm development. […] As we learn increasingly more about the genetics of CDH, a common pathway that has emerged is RA signaling, providing support for the Retinoid Hypothesis in human CDH.

• #26 Congenital Diaphragmatic Hernia and Eventration – Clinical Tree

  https://clinicalpub.com/congenital-diaphragmatic-hernia-and-eventration/

  Other teratogens structurally similar to nitrofen have been shown to induce CDH in animal models as well. Although the exact etiology of CDH is unknown, these teratogens commonly affect the retinoic acid synthesis pathway by inhibiting retinol dehydrogenase-2 and causing similar diaphragmatic defects. Several clinical observations and molecular studies have supported the importance of the retinoic acid pathways in CDH development. Vitamin A-deficient rodents will produce offspring with CDH of variable severity. Retinoic acid receptor knockout mice produce fetuses with CDH. Failure to convert retinoic acid to retinaldehyde following administration of nitrofen produces posterolateral diaphragmatic defects in rats. Lower plasma levels of retinoic acid and retinol binding protein in infants with CDH have been found compared with controls.

• #27 The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later | Pediatric Research

  https://www.nature.com/articles/s41390-023-02905-7

  The potent effect of direct supplementation with RA to prevent CDH was further emphasized in teratogen-treated mice. […] The observation that Rar knock-out mice developed CDH was integral to the original formulation of the Retinoid Hypothesis. […] The only direct genetic evidence supporting the Retinoid Hypothesis obtained from mice with targeted mutations in RA signaling come from studies of Rar compound mutant mice. […] The presence of diaphragm defects in Wt1, Coup-tf2, Gata4, and Fog2 mutant mice indicates their individual importance in normal diaphragm development. […] As we learn increasingly more about the genetics of CDH, a common pathway that has emerged is RA signaling, providing support for the Retinoid Hypothesis in human CDH.

• #28 The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later | Pediatric Research

  https://www.nature.com/articles/s41390-023-02905-7

  Congenital diaphragmatic hernia (CDH) is a severe birth defect and a major cause of neonatal respiratory distress. […] Despite the significant impact of CDH, its etiology remains incompletely understood. […] 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. […] The Retinoid Hypothesis is one of the leading hypotheses to explain the etiology of CDH, as we continue to better understand the role of retinoid signaling in diaphragm development. […] It is generally considered that the two main factors that contribute to CDH are genetic and/or environmental. […] Approximately 30-40% of CDH cases have an identifiable genetic cause. […] Of this number, chromosomal defects account for about ~10% of CDH cases, and de novo mutations account for 10-22% of cases.

• #29 The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later | Pediatric Research

  https://www.nature.com/articles/s41390-023-02905-7

  Congenital diaphragmatic hernia (CDH) is a severe birth defect and a major cause of neonatal respiratory distress. […] Despite the significant impact of CDH, its etiology remains incompletely understood. […] 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. […] The Retinoid Hypothesis is one of the leading hypotheses to explain the etiology of CDH, as we continue to better understand the role of retinoid signaling in diaphragm development. […] It is generally considered that the two main factors that contribute to CDH are genetic and/or environmental. […] Approximately 30-40% of CDH cases have an identifiable genetic cause. […] Of this number, chromosomal defects account for about ~10% of CDH cases, and de novo mutations account for 10-22% of cases.

• #30 Congenital Diaphragmatic Hernia: A Major Challenge for Neonatologists | IntechOpen

  https://www.intechopen.com/chapters/74635

  CDH is genetically heterogeneous although can be monogenic. A genetic cause is found in 30% of the cases, even though most cases are sporadic and about 1-2% familial. […] The defect in CDH is due to an abnormal development of diaphragm during the embryonic phase. Human post mortem reports and animal studies have demonstrated that in CDH, both lungs are hypoplastic, the ipsilateral one being more that the contralateral lung. Characteristically the lungs have decreased DNA and protein contents; diminished airway generations, terminal bronchioles and alveolar volume; thickened alveolar septum, and decreased complexity of the respiratory acinus. There is thickening of the pulmonary arterial medial wall and muscularisation of the smaller pre-acinar arteries.

• #31 Management of Congenital Diaphragmatic Hernia (CDH): Role of Molecular Genetics

  https://www.mdpi.com/1422-0067/22/12/6353

  Defects in diaphragm development lead to CDH. […] Some CDH-associated genetic mutations and related defects in different molecular pathways can directly affect diaphragm development and of other organs, such as the lungs and the heart. […] Advances in genomics, coupled with functional studies in animal models, are increasingly identifying the causes of CDH in both familial and sporadic cases. […] Through these approaches, we are beginning to elucidate the mechanisms and molecular pathways that are responsible for diaphragm and lung development abnormalities in CDH patients. […] A better insight into the mechanisms regulating diaphragm development and genetic causes leading to CDH appeared essential to the development of new therapeutic strategies and evidence-based genetic counselling to parents. […] Integrated sequencing, development, and bioinformatics strategies could direct future functional studies on CDH; could be applied to cohorts and consortia for CDH and other birth defects; and could pave the way for potential therapies by providing molecular targets for drug discovery.

• #32 Management of Congenital Diaphragmatic Hernia (CDH): Role of Molecular Genetics

  https://www.mdpi.com/1422-0067/22/12/6353

  Defects in diaphragm development lead to CDH. […] Some CDH-associated genetic mutations and related defects in different molecular pathways can directly affect diaphragm development and of other organs, such as the lungs and the heart. […] Advances in genomics, coupled with functional studies in animal models, are increasingly identifying the causes of CDH in both familial and sporadic cases. […] Through these approaches, we are beginning to elucidate the mechanisms and molecular pathways that are responsible for diaphragm and lung development abnormalities in CDH patients. […] A better insight into the mechanisms regulating diaphragm development and genetic causes leading to CDH appeared essential to the development of new therapeutic strategies and evidence-based genetic counselling to parents. […] Integrated sequencing, development, and bioinformatics strategies could direct future functional studies on CDH; could be applied to cohorts and consortia for CDH and other birth defects; and could pave the way for potential therapies by providing molecular targets for drug discovery.

• #33 Congenital Diaphragmatic Hernia (CDH) | Children’s Hospital Colorado

  https://www.childrenscolorado.org/conditions-and-advice/conditions-and-symptoms/conditions/congenital-diaphragmatic-hernia-cdh/

  A congenital diaphragmatic hernia (CDH) occurs when a baby’s diaphragm doesn’t form completely during fetal development. This leaves an opening between the chest and abdominal cavities, allowing abdominal organs to herniate (protrude or enter) into the chest cavity and prevent lung development. […] A diaphragmatic hernia usually develops about 9 to 10 weeks into pregnancy but might occur as early as 5 to 6 weeks. There is no known way to prevent CDH, and there is nothing the mother did or does that could cause their unborn baby to develop CDH. […] CDH may occur by itself (known as isolated CDH) or with other conditions. In about 10% to 20% of cases, CDH is caused by or associated with a genetic disorder, such as Down syndrome (trisomy 21), Edward’s syndrome (trisomy 18) or Patau syndrome (trisomy 13). About 60% of the time, CDH occurs with another congenital condition that affects organ structure and 40% of the time those are congenital heart defects.

• #34 Genetics of diaphragmatic hernia | European Journal of Human Genetics

  https://www.nature.com/articles/s41431-021-00972-0

  Recent scientific evidence sheds light on this relatively new genetic approach, revealing a subset of as much as 10% of CDH cases as attributable to CNVs. […] Notably, most CNVs that have so far been identified to play a role in the development of CDH are deletions, which in the context of haploinsufficiency are considered deleterious in the process of diaphragm development. […] Disruption of essential signalling pathways can lead to CDH. […] Furthermore, there is evidence for functional Wnt/-catenin-signalling in the developing diaphragm upstream of which acts WT1 to promote -catenin expression and cell proliferation especially in the posterior diaphragm. […] A mutational hotspot for structural chromosomal aberrations (e.g., translocations, inversions) and microaberrations (e.g., point mutations, base deletions, indels) is the short arm of chromosome 8.

• #35 Congenital diaphragmatic hernia – Wikipedia

  https://en.wikipedia.org/wiki/Congenital_diaphragmatic_hernia

  Congenital diaphragmatic hernia (CDH) is a birth defect of the diaphragm. Malformation of the diaphragm allows the abdominal organs to push into the chest cavity, hindering proper lung formation. […] There are genetic causes of CDH including aneuploidies, chromosome copy number variants, and single gene mutations. Research implicates a few gene mutations including LONP1 and MYRF. It involves three major defects: A failure of the diaphragm to completely close during development, Herniation of the abdominal contents into the chest, Pulmonary hypoplasia.

• #36 The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later | Pediatric Research

  https://www.nature.com/articles/s41390-023-02905-7

  The potent effect of direct supplementation with RA to prevent CDH was further emphasized in teratogen-treated mice. […] The observation that Rar knock-out mice developed CDH was integral to the original formulation of the Retinoid Hypothesis. […] The only direct genetic evidence supporting the Retinoid Hypothesis obtained from mice with targeted mutations in RA signaling come from studies of Rar compound mutant mice. […] The presence of diaphragm defects in Wt1, Coup-tf2, Gata4, and Fog2 mutant mice indicates their individual importance in normal diaphragm development. […] As we learn increasingly more about the genetics of CDH, a common pathway that has emerged is RA signaling, providing support for the Retinoid Hypothesis in human CDH.

• #37 Genetics of diaphragmatic hernia | European Journal of Human Genetics

  https://www.nature.com/articles/s41431-021-00972-0

  Recent scientific evidence sheds light on this relatively new genetic approach, revealing a subset of as much as 10% of CDH cases as attributable to CNVs. […] Notably, most CNVs that have so far been identified to play a role in the development of CDH are deletions, which in the context of haploinsufficiency are considered deleterious in the process of diaphragm development. […] Disruption of essential signalling pathways can lead to CDH. […] Furthermore, there is evidence for functional Wnt/-catenin-signalling in the developing diaphragm upstream of which acts WT1 to promote -catenin expression and cell proliferation especially in the posterior diaphragm. […] A mutational hotspot for structural chromosomal aberrations (e.g., translocations, inversions) and microaberrations (e.g., point mutations, base deletions, indels) is the short arm of chromosome 8.

• #38 Genetics of diaphragmatic hernia | European Journal of Human Genetics

  https://www.nature.com/articles/s41431-021-00972-0

  The observation, that vitamin A deficiency during rat dams pregnancy did not only impede lung development but did also cause diaphragm defects in the pups led to the hypothesis that vitamin A signalling would be involved in its morphogenesis. […] By demonstrating RA-inducible NR2F2 activity, at least one possible mechanism of RA-regulated CDH development has been revealed.

• #39 Congenital Diaphragmatic Hernia: A Major Challenge for Neonatologists | IntechOpen

  https://www.intechopen.com/chapters/74635

  Congenital diaphragmatic hernia (CDH) is a major congenital anomaly of the neonates, characterized by the herniation of abdominal contents into the thoracic cavity during fetal life. This results in significant pulmonary hypertension and hypoxemia after birth, which responds poorly to therapeutic interventions. The exact pathogenesis is not well understood, and genetic factors have been proposed. […] The dual-hit hypothesis, proposed by Keijzer et al, has suggested that the early insult in lungs development is bilateral, occurring before and independent of the diaphragmatic defect; and a later second hit to the ipsilateral lung via compression from the herniated abdominal content leads to the characteristic pulmonary hypertension and hypoxemia in the neonate. […] Environmental factors contributing to CDH are not well investigated. Maternal vitamin A deficiency, nitrofen treatment and retinoid receptor knock-out in animal model are reported to result in CDH in their offsprings, suggesting a role of retinoid signaling pathway in the pathogenesis.

• #40 Congenital Diaphragmatic Hernia and Eventration – Clinical Tree

  https://clinicalpub.com/congenital-diaphragmatic-hernia-and-eventration/

  The nitrofen rodent model has led to improved understanding of abnormal pulmonary development in CDH. Nitrofen (2,4-dichloro-phenyl-p-nitrophenyl ether) is an environmental teratogen. If a specific dose is administered at a specific time during gestation, it can cause pulmonary, cardiac, skeletal, and diaphragmatic abnormalities, analogous to the human condition. Diaphragmatic defects resulting from the administration of nitrofen in mice are very similar to the diaphragmatic defects seen in babies with severe CDH in regard to size, location, and herniation of abdominal viscera. The side of the CDH depends on the time of nitrofen exposure during gestation. In nitrofen-exposed fetal mice, a defect is clearly seen in the posterolateral portions of the PPF. In addition, nitrofen exposure appears to affect muscularization of the PPF. Finally, the offspring will exhibit features of pulmonary vasculopathy including increased muscularization and pulmonary vessel hyporesponsiveness, as well as pulmonary hypoplasia, including reduced airway branching, decreased alveolarization, and surfactant deficiency, all leading to respiratory failure at birth.

• #41 Congenital Diaphragmatic Hernia and Eventration – Clinical Tree

  https://clinicalpub.com/congenital-diaphragmatic-hernia-and-eventration/

  Other teratogens structurally similar to nitrofen have been shown to induce CDH in animal models as well. Although the exact etiology of CDH is unknown, these teratogens commonly affect the retinoic acid synthesis pathway by inhibiting retinol dehydrogenase-2 and causing similar diaphragmatic defects. Several clinical observations and molecular studies have supported the importance of the retinoic acid pathways in CDH development. Vitamin A-deficient rodents will produce offspring with CDH of variable severity. Retinoic acid receptor knockout mice produce fetuses with CDH. Failure to convert retinoic acid to retinaldehyde following administration of nitrofen produces posterolateral diaphragmatic defects in rats. Lower plasma levels of retinoic acid and retinol binding protein in infants with CDH have been found compared with controls.

• #42 Congenital diaphragmatic hernia: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/congenital-diaphragmatic-hernia/

  About 25 percent of individuals with congenital diaphragmatic hernia that is not associated with a known syndrome also have abnormalities of one or more major body systems. Affected body systems can include the heart, brain, skeleton, intestines, genitals, kidneys, or eyes. In these individuals, the multiple abnormalities likely result from a common underlying disruption in development that affects more than one area of the body, but the specific mechanism responsible for this disruption is not clear. […] More than 80 percent of individuals with congenital diaphragmatic hernia have no known genetic syndrome or chromosomal abnormality. In these cases, the cause of the condition is unknown. Researchers are studying changes in several genes involved in the development of the diaphragm as possible causes of congenital diaphragmatic hernia. Some of these genes are transcription factors, which provide instructions for making proteins that help control the activity of particular genes (gene expression). Others provide instructions for making proteins involved in cell structure or the movement (migration) of cells in the embryo. Environmental factors that influence development before birth may also increase the risk of congenital diaphragmatic hernia, but these environmental factors have not been identified.

• #43 Management of Congenital Diaphragmatic Hernia (CDH): Role of Molecular Genetics

  https://www.mdpi.com/1422-0067/22/12/6353

  Congenital diaphragmatic hernia (CDH) is a relatively common major life-threatening birth defect that results in significant mortality and morbidity depending primarily on lung hypoplasia, persistent pulmonary hypertension, and cardiac dysfunction. […] Despite its high impact on neonatal health, pathogenesis and etiology of CDH remain poorly understood. CDH is thought to be multi-factorial, with genetic, environmental, and nutritional factors playing a role. […] The involvement of multiple genetic factors is suggested by recent advances in our understanding of the genetic pathways regulating normal diaphragm development and genetic mutations leading to CDH. […] Recently, progress has been made in understanding the genetic pathways regulating diaphragm development and the genetic mutations leading to CDH.

• #44 Congenital Diaphragmatic Hernia (CDH): What Parents Need To Know

  https://my.clevelandclinic.org/health/diseases/24308-diaphragmatic-hernia

  A congenital diaphragmatic hernia (CDH) is a birth defect (congenital disorder) that occurs during fetal development. It means that a fetus’s diaphragm isn’t fully formed or strong enough to be a muscle barrier between its belly (abdomen) and chest. That means organs can pass between them. When an organ passes through a muscle barrier, it’s called a hernia. […] When a diaphragmatic hernia occurs during fetal development, it affects the way the fetus’s body forms. Its abdominal organs the stomach, intestines, liver, gallbladder, pancreas and spleen can shift upward into the chest cavity while everything is still developing. […] Physicians don’t know the exact cause of CDH. Research suggests the following factors may play a role in its development: Genetics, Harmful environmental exposure during pregnancy, Fetal malnutrition.

• #45 Congenital Diaphragmatic Hernia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK556076/

  Congenital diaphragmatic hernia is a condition resulting from the herniation of abdominal contents into the thoracic cavity resulting in lung hypoplasia and altered pulmonary vascular development. […] Congenital diaphragmatic hernia (CDH) is a condition resulting from a developmental defect in the diaphragm leading to protrusion of abdominal contents into the thoracic cavity. […] The etiology of congenital diaphragmatic hernia remains unclear. It is thought to be multifactorial with genetic, environmental, and/or nutritional factors playing a role. CDH can be an isolated anomaly or associated with anomalies in other organ systems. […] Any disturbance in the formation of the pleuroperitoneal membranes can result in diaphragmatic discontinuity and congenital diaphragmatic hernia. The associated herniation of the abdominal viscera into the thoracic cavity can interfere with normal lung development and forms the basis for the two main pathological findings noted in CDH- lung hypoplasia and abnormal pulmonary vascular development. […] Irrespective of the cause, pulmonary hypoplasia, abnormal pulmonary vasoreactivity, and PH are the major contributors to the morbidity and mortality associated with CDH.

• #46 Congenital Diaphragmatic hernia – a review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5356475/

  Thus the major underlying pathophysiology of CDH appears to be a combination of lung immaturity and hypoplasia that leads to PPHN. This may be further aggravated by left ventricular underdevelopment and right ventricular hypertrophy resulting in ventricular dysfunction. […] Lung hypoplasia occurs on the ipsilateral side of herniation, with the contralateral side being affected to a variable extent. […] The total pulmonary vascular bed is reduced with decreased number of vessels per unit of lung. In addition, pulmonary vascular remodeling with medial hyperplasia and peripheral extension of the muscle layer into small arterioles is evident. […] In CDH, the total pulmonary vascular bed is reduced with decreased number of vessels per unit of lung. […] The absence of a difference does not rule out pulmonary hypertension. In some patients with CDH the immediate postnatal phase, there is a short period of better oxygenation referred to as honeymoon period. However, progressive deterioration in oxygenation is commonly observed with deteriorating PPHN. […] Inhaled Nitric Oxide (iNO) is the first agent of choice for treatment of pulmonary hypertension in infants 34 weeks gestation. It is a selective pulmonary vasodilator and relaxes pulmonary vascular smooth muscle cells.

• #47 Congenital diaphragmatic hernia: Prenatal issues – UpToDate

  https://www.uptodate.com/contents/congenital-diaphragmatic-hernia-prenatal-issues/print

  Congenital diaphragmatic hernia (CDH) is a developmental discontinuity of the diaphragm that allows the abdominal viscera to herniate into the chest. […] Failure of normal closure of the pleuroperitoneal folds during the fourth to tenth weeks postfertilization allows herniation of viscera into the thoracic cavity, which interferes with normal lung development and has several potential adverse consequences, including: […] Reduction in bronchiolar branching. […] Truncation and over-muscularization of the pulmonary arterial tree, leading to smaller cross-sectional area of pulmonary vessels, structural vascular remodeling, and vasoconstriction with altered vasoreactivity.

• #48 Congenital Diaphragmatic Hernia: Pathophysiology and Antenatal Assessment (Chapter 47) – Fetal Therapy

  https://www.cambridge.org/core/books/fetal-therapy/congenital-diaphragmatic-hernia-pathophysiology-and-antenatal-assessment/3407E1E3A9A8E3450AB7DB26C3FC9154

  Congenital diaphragmatic hernia (CDH) is a developmental anomaly with a prevalence ranging between 1 and 4/10 000 births, hence qualifying as a rare disease. During embryogenesis the diaphragm fails to form, most often on the left side (85%), rarely on the right (13%), and sporadically bilaterally (2%). Exceptionally there is true agenesis of the hemidiaphragm, but most often the defect is confined to the posterolateral area (Bochdalek hernia). In case of a true defect, abdominal viscera can herniate into the thorax, acting as a space-occupying lesion that competes with the developing lungs. In left CDH (LCDH), this typically includes bowel, spleen, stomach, and less often the left lobe of the liver and rarely kidney. In case of a right-sided CDH (RCDH), the liver is virtually always into the thorax. These structures compromise lung development, leading to variable degrees of pulmonary hypoplasia. The lung ipsilateral to the defect is most affected, however both lungs are in essence hypoplastic. They have a lower number of airways, fewer and smaller alveoli, thickened alveolar walls, and an increased amount of interstitial tissue. This leaves less alveolar airspace, and hence reduces the gas exchange surface area. Parallel to airway changes, there is a similar reduction in arteries, essentially leaving a hypoplastic vascular bed. Morphologically, the vascular wall is thickened by an increase in the arterial media and adventitia, neo-muscularization of small pulmonary arteries and hypermuscularization of midsize and large vessels. These vessels may have an abnormal response to mechanical and chemical stimuli in the postnatal period.

• #49 Congenital Diaphragmatic Hernia: Pathophysiology and Antenatal Assessment (Chapter 47) – Fetal Therapy

  https://www.cambridge.org/core/books/fetal-therapy/congenital-diaphragmatic-hernia-pathophysiology-and-antenatal-assessment/3407E1E3A9A8E3450AB7DB26C3FC9154

  Congenital diaphragmatic hernia (CDH) is a developmental anomaly with a prevalence ranging between 1 and 4/10 000 births, hence qualifying as a rare disease. During embryogenesis the diaphragm fails to form, most often on the left side (85%), rarely on the right (13%), and sporadically bilaterally (2%). Exceptionally there is true agenesis of the hemidiaphragm, but most often the defect is confined to the posterolateral area (Bochdalek hernia). In case of a true defect, abdominal viscera can herniate into the thorax, acting as a space-occupying lesion that competes with the developing lungs. In left CDH (LCDH), this typically includes bowel, spleen, stomach, and less often the left lobe of the liver and rarely kidney. In case of a right-sided CDH (RCDH), the liver is virtually always into the thorax. These structures compromise lung development, leading to variable degrees of pulmonary hypoplasia. The lung ipsilateral to the defect is most affected, however both lungs are in essence hypoplastic. They have a lower number of airways, fewer and smaller alveoli, thickened alveolar walls, and an increased amount of interstitial tissue. This leaves less alveolar airspace, and hence reduces the gas exchange surface area. Parallel to airway changes, there is a similar reduction in arteries, essentially leaving a hypoplastic vascular bed. Morphologically, the vascular wall is thickened by an increase in the arterial media and adventitia, neo-muscularization of small pulmonary arteries and hypermuscularization of midsize and large vessels. These vessels may have an abnormal response to mechanical and chemical stimuli in the postnatal period.

• #50 The Pathogenesis of Pulmonary Hypoplasia in Congenital Diaphragmatic Hernia: A continuing quest

  https://repub.eur.nl/pub/32523

  Congenital diaphragmatic hernia or CDH is a developmental defect of the diaphragm that allows abdominal organs, such as intestines and liver, to herniate into the thoracic cavity during lung development. […] Children with a CDH suffer from a substantial amount of morbidity and mortality due to the associated abnormal pulmonary development resulting in two clinical problems, pulmonary hypoplasia and persistent pulmonary hypertension of the neonate (PPHN). […] Characteristics of pulmonary hypoplasia in CDH are thickened alveolar walls, an increase in interstitial tissue, reduced alveolar air spaces and reduced gas-exchange surface area. […] A sound understanding of the etiology and pathogenesis of CDH is necessary in order to prevent the severe morbidity or the anomalies altogether. […] Consequently, the aim of this dissertation was to improve our understanding of the pathogenesis of pulmonary hypoplasia in CDH, to eventually aid in finding ways to modulate the natural course in a prenatally diagnosed child.

• #51 Congenital Diaphragmatic Hernia: Pathophysiology and Antenatal Assessment (Chapter 47) – Fetal Therapy

  https://www.cambridge.org/core/books/fetal-therapy/congenital-diaphragmatic-hernia-pathophysiology-and-antenatal-assessment/3407E1E3A9A8E3450AB7DB26C3FC9154

  Congenital diaphragmatic hernia (CDH) is a developmental anomaly with a prevalence ranging between 1 and 4/10 000 births, hence qualifying as a rare disease. During embryogenesis the diaphragm fails to form, most often on the left side (85%), rarely on the right (13%), and sporadically bilaterally (2%). Exceptionally there is true agenesis of the hemidiaphragm, but most often the defect is confined to the posterolateral area (Bochdalek hernia). In case of a true defect, abdominal viscera can herniate into the thorax, acting as a space-occupying lesion that competes with the developing lungs. In left CDH (LCDH), this typically includes bowel, spleen, stomach, and less often the left lobe of the liver and rarely kidney. In case of a right-sided CDH (RCDH), the liver is virtually always into the thorax. These structures compromise lung development, leading to variable degrees of pulmonary hypoplasia. The lung ipsilateral to the defect is most affected, however both lungs are in essence hypoplastic. They have a lower number of airways, fewer and smaller alveoli, thickened alveolar walls, and an increased amount of interstitial tissue. This leaves less alveolar airspace, and hence reduces the gas exchange surface area. Parallel to airway changes, there is a similar reduction in arteries, essentially leaving a hypoplastic vascular bed. Morphologically, the vascular wall is thickened by an increase in the arterial media and adventitia, neo-muscularization of small pulmonary arteries and hypermuscularization of midsize and large vessels. These vessels may have an abnormal response to mechanical and chemical stimuli in the postnatal period.

• #52 The Pathogenesis of Pulmonary Hypoplasia in Congenital Diaphragmatic Hernia: A continuing quest

  https://repub.eur.nl/pub/32523

  Congenital diaphragmatic hernia or CDH is a developmental defect of the diaphragm that allows abdominal organs, such as intestines and liver, to herniate into the thoracic cavity during lung development. […] Children with a CDH suffer from a substantial amount of morbidity and mortality due to the associated abnormal pulmonary development resulting in two clinical problems, pulmonary hypoplasia and persistent pulmonary hypertension of the neonate (PPHN). […] Characteristics of pulmonary hypoplasia in CDH are thickened alveolar walls, an increase in interstitial tissue, reduced alveolar air spaces and reduced gas-exchange surface area. […] A sound understanding of the etiology and pathogenesis of CDH is necessary in order to prevent the severe morbidity or the anomalies altogether. […] Consequently, the aim of this dissertation was to improve our understanding of the pathogenesis of pulmonary hypoplasia in CDH, to eventually aid in finding ways to modulate the natural course in a prenatally diagnosed child.

• #53 Congenital Diaphragmatic Hernia: Pathophysiology and Antenatal Assessment (Chapter 47) – Fetal Therapy

  https://www.cambridge.org/core/books/fetal-therapy/congenital-diaphragmatic-hernia-pathophysiology-and-antenatal-assessment/3407E1E3A9A8E3450AB7DB26C3FC9154

  Congenital diaphragmatic hernia (CDH) is a developmental anomaly with a prevalence ranging between 1 and 4/10 000 births, hence qualifying as a rare disease. During embryogenesis the diaphragm fails to form, most often on the left side (85%), rarely on the right (13%), and sporadically bilaterally (2%). Exceptionally there is true agenesis of the hemidiaphragm, but most often the defect is confined to the posterolateral area (Bochdalek hernia). In case of a true defect, abdominal viscera can herniate into the thorax, acting as a space-occupying lesion that competes with the developing lungs. In left CDH (LCDH), this typically includes bowel, spleen, stomach, and less often the left lobe of the liver and rarely kidney. In case of a right-sided CDH (RCDH), the liver is virtually always into the thorax. These structures compromise lung development, leading to variable degrees of pulmonary hypoplasia. The lung ipsilateral to the defect is most affected, however both lungs are in essence hypoplastic. They have a lower number of airways, fewer and smaller alveoli, thickened alveolar walls, and an increased amount of interstitial tissue. This leaves less alveolar airspace, and hence reduces the gas exchange surface area. Parallel to airway changes, there is a similar reduction in arteries, essentially leaving a hypoplastic vascular bed. Morphologically, the vascular wall is thickened by an increase in the arterial media and adventitia, neo-muscularization of small pulmonary arteries and hypermuscularization of midsize and large vessels. These vessels may have an abnormal response to mechanical and chemical stimuli in the postnatal period.

• #54 The Pathogenesis of Pulmonary Hypoplasia in Congenital Diaphragmatic Hernia: A continuing quest

  https://repub.eur.nl/pub/32523

  Congenital diaphragmatic hernia or CDH is a developmental defect of the diaphragm that allows abdominal organs, such as intestines and liver, to herniate into the thoracic cavity during lung development. […] Children with a CDH suffer from a substantial amount of morbidity and mortality due to the associated abnormal pulmonary development resulting in two clinical problems, pulmonary hypoplasia and persistent pulmonary hypertension of the neonate (PPHN). […] Characteristics of pulmonary hypoplasia in CDH are thickened alveolar walls, an increase in interstitial tissue, reduced alveolar air spaces and reduced gas-exchange surface area. […] A sound understanding of the etiology and pathogenesis of CDH is necessary in order to prevent the severe morbidity or the anomalies altogether. […] Consequently, the aim of this dissertation was to improve our understanding of the pathogenesis of pulmonary hypoplasia in CDH, to eventually aid in finding ways to modulate the natural course in a prenatally diagnosed child.

• #55 Congenital Diaphragmatic Hernia: Pathophysiology and Antenatal Assessment (Chapter 47) – Fetal Therapy

  https://www.cambridge.org/core/books/fetal-therapy/congenital-diaphragmatic-hernia-pathophysiology-and-antenatal-assessment/3407E1E3A9A8E3450AB7DB26C3FC9154

  Congenital diaphragmatic hernia (CDH) is a developmental anomaly with a prevalence ranging between 1 and 4/10 000 births, hence qualifying as a rare disease. During embryogenesis the diaphragm fails to form, most often on the left side (85%), rarely on the right (13%), and sporadically bilaterally (2%). Exceptionally there is true agenesis of the hemidiaphragm, but most often the defect is confined to the posterolateral area (Bochdalek hernia). In case of a true defect, abdominal viscera can herniate into the thorax, acting as a space-occupying lesion that competes with the developing lungs. In left CDH (LCDH), this typically includes bowel, spleen, stomach, and less often the left lobe of the liver and rarely kidney. In case of a right-sided CDH (RCDH), the liver is virtually always into the thorax. These structures compromise lung development, leading to variable degrees of pulmonary hypoplasia. The lung ipsilateral to the defect is most affected, however both lungs are in essence hypoplastic. They have a lower number of airways, fewer and smaller alveoli, thickened alveolar walls, and an increased amount of interstitial tissue. This leaves less alveolar airspace, and hence reduces the gas exchange surface area. Parallel to airway changes, there is a similar reduction in arteries, essentially leaving a hypoplastic vascular bed. Morphologically, the vascular wall is thickened by an increase in the arterial media and adventitia, neo-muscularization of small pulmonary arteries and hypermuscularization of midsize and large vessels. These vessels may have an abnormal response to mechanical and chemical stimuli in the postnatal period.

• #56 The Pathogenesis of Pulmonary Hypoplasia in Congenital Diaphragmatic Hernia: A continuing quest

  https://repub.eur.nl/pub/32523

  Congenital diaphragmatic hernia or CDH is a developmental defect of the diaphragm that allows abdominal organs, such as intestines and liver, to herniate into the thoracic cavity during lung development. […] Children with a CDH suffer from a substantial amount of morbidity and mortality due to the associated abnormal pulmonary development resulting in two clinical problems, pulmonary hypoplasia and persistent pulmonary hypertension of the neonate (PPHN). […] Characteristics of pulmonary hypoplasia in CDH are thickened alveolar walls, an increase in interstitial tissue, reduced alveolar air spaces and reduced gas-exchange surface area. […] A sound understanding of the etiology and pathogenesis of CDH is necessary in order to prevent the severe morbidity or the anomalies altogether. […] Consequently, the aim of this dissertation was to improve our understanding of the pathogenesis of pulmonary hypoplasia in CDH, to eventually aid in finding ways to modulate the natural course in a prenatally diagnosed child.

• #57 Congenital diaphragmatic hernia: Prenatal issues – UpToDate

  https://www.uptodate.com/contents/congenital-diaphragmatic-hernia-prenatal-issues

  The period from just after the third week postfertilization (postconception) through the 16th week of gestation is a critical period of lung development. Failure of normal closure of the pleuroperitoneal folds during the fourth to tenth weeks postfertilization allows herniation of viscera into the thoracic cavity, which interferes with normal lung development and has several potential adverse consequences, including: Reduction in bronchiolar branching. Truncation and over-muscularization of the pulmonary arterial tree, leading to smaller cross-sectional area of pulmonary vessels, structural vascular remodeling, and vasoconstriction with altered vasoreactivity.

• #58 Diaphragmatic Hernias: Practice Essentials, Anatomy, Pathophysiology

  https://emedicine.medscape.com/article/934824-overview

  CDH occurs early in fetal development as a consequence of incomplete fusion of diaphragmatic structures leading to herniation of intra-abdominal organs into the thoracic cavity. […] Most authors have postulated that CDH develops from failure of diaphragm muscularization prior to closure of the pleuroperitoneal canals, resulting in diaphragmatic weakness prone to herniation. Others have suggested that abnormal lung development results in a weakened mesenchymal plate with impaired diaphragm fusion. Disruptions or mutations in myofibroblasts derived from pleuroperitoneal folds may also play a role, ultimately causing abnormal diaphragm development. […] The herniation of intra-abdominal organs during critical stages of lung development results in significantly reduced bronchial branching, alveolar surface area, and pulmonary vascularizationhallmark pathologic findings in pulmonary hypoplasia. […] Abnormal vascular smooth-muscle development is another hallmark feature associated with CDH. Specifically, pulmonary arterial smooth-muscle hypertrophy results in increased pulmonary artery resistance and consequently in pulmonary hypertension.

• #59 Congenital Diaphragmatic hernia – a review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5356475/

  Thus the major underlying pathophysiology of CDH appears to be a combination of lung immaturity and hypoplasia that leads to PPHN. This may be further aggravated by left ventricular underdevelopment and right ventricular hypertrophy resulting in ventricular dysfunction. […] Lung hypoplasia occurs on the ipsilateral side of herniation, with the contralateral side being affected to a variable extent. […] The total pulmonary vascular bed is reduced with decreased number of vessels per unit of lung. In addition, pulmonary vascular remodeling with medial hyperplasia and peripheral extension of the muscle layer into small arterioles is evident. […] In CDH, the total pulmonary vascular bed is reduced with decreased number of vessels per unit of lung. […] The absence of a difference does not rule out pulmonary hypertension. In some patients with CDH the immediate postnatal phase, there is a short period of better oxygenation referred to as honeymoon period. However, progressive deterioration in oxygenation is commonly observed with deteriorating PPHN. […] Inhaled Nitric Oxide (iNO) is the first agent of choice for treatment of pulmonary hypertension in infants 34 weeks gestation. It is a selective pulmonary vasodilator and relaxes pulmonary vascular smooth muscle cells.

• #60 Congenital Diaphragmatic hernia – a review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5356475/

  Thus the major underlying pathophysiology of CDH appears to be a combination of lung immaturity and hypoplasia that leads to PPHN. This may be further aggravated by left ventricular underdevelopment and right ventricular hypertrophy resulting in ventricular dysfunction. […] Lung hypoplasia occurs on the ipsilateral side of herniation, with the contralateral side being affected to a variable extent. […] The total pulmonary vascular bed is reduced with decreased number of vessels per unit of lung. In addition, pulmonary vascular remodeling with medial hyperplasia and peripheral extension of the muscle layer into small arterioles is evident. […] In CDH, the total pulmonary vascular bed is reduced with decreased number of vessels per unit of lung. […] The absence of a difference does not rule out pulmonary hypertension. In some patients with CDH the immediate postnatal phase, there is a short period of better oxygenation referred to as honeymoon period. However, progressive deterioration in oxygenation is commonly observed with deteriorating PPHN. […] Inhaled Nitric Oxide (iNO) is the first agent of choice for treatment of pulmonary hypertension in infants 34 weeks gestation. It is a selective pulmonary vasodilator and relaxes pulmonary vascular smooth muscle cells.

• #61 Congenital Diaphragmatic Hernia: Pathophysiology and Antenatal Assessment (Chapter 47) – Fetal Therapy

  https://www.cambridge.org/core/books/fetal-therapy/congenital-diaphragmatic-hernia-pathophysiology-and-antenatal-assessment/3407E1E3A9A8E3450AB7DB26C3FC9154

  Congenital diaphragmatic hernia (CDH) is a developmental anomaly with a prevalence ranging between 1 and 4/10 000 births, hence qualifying as a rare disease. During embryogenesis the diaphragm fails to form, most often on the left side (85%), rarely on the right (13%), and sporadically bilaterally (2%). Exceptionally there is true agenesis of the hemidiaphragm, but most often the defect is confined to the posterolateral area (Bochdalek hernia). In case of a true defect, abdominal viscera can herniate into the thorax, acting as a space-occupying lesion that competes with the developing lungs. In left CDH (LCDH), this typically includes bowel, spleen, stomach, and less often the left lobe of the liver and rarely kidney. In case of a right-sided CDH (RCDH), the liver is virtually always into the thorax. These structures compromise lung development, leading to variable degrees of pulmonary hypoplasia. The lung ipsilateral to the defect is most affected, however both lungs are in essence hypoplastic. They have a lower number of airways, fewer and smaller alveoli, thickened alveolar walls, and an increased amount of interstitial tissue. This leaves less alveolar airspace, and hence reduces the gas exchange surface area. Parallel to airway changes, there is a similar reduction in arteries, essentially leaving a hypoplastic vascular bed. Morphologically, the vascular wall is thickened by an increase in the arterial media and adventitia, neo-muscularization of small pulmonary arteries and hypermuscularization of midsize and large vessels. These vessels may have an abnormal response to mechanical and chemical stimuli in the postnatal period.

• #62 Congenital diaphragmatic hernia: Prenatal issues – UpToDate

  https://www.uptodate.com/contents/congenital-diaphragmatic-hernia-prenatal-issues/print

  Congenital diaphragmatic hernia (CDH) is a developmental discontinuity of the diaphragm that allows the abdominal viscera to herniate into the chest. […] Failure of normal closure of the pleuroperitoneal folds during the fourth to tenth weeks postfertilization allows herniation of viscera into the thoracic cavity, which interferes with normal lung development and has several potential adverse consequences, including: […] Reduction in bronchiolar branching. […] Truncation and over-muscularization of the pulmonary arterial tree, leading to smaller cross-sectional area of pulmonary vessels, structural vascular remodeling, and vasoconstriction with altered vasoreactivity.

• #63 Hemodynamic management of congenital diaphragmatic hernia: the role of targeted neonatal echocardiography | World Journal of Pediatric Surgery

  https://wjps.bmj.com/content/7/2/e000790

  Using the well-known nitrofen model, Keijzer et al. proposed the Dual-hit Hypothesis, suggesting an initial insult affecting both lungs before diaphragm development, followed by the second insult affecting the ipsilateral lung after defective diaphragm development and resulting extrinsic compression. […] The severity of CDH is notably linked with a variable degree of pulmonary hypoplasia, PHT, and cardiac dysfunction, constituting the triad of pathophysiological hallmark features of this complex disorder. […] The altered pulmonary vasoreactivity and pathological vascular remodeling, secondary to the reduced lung size and changes in pulmonary microarchitecture, are central to the pathophysiology of CDH-associated PHT. […] The confluence of low ventricular output and PHT leads to hypoxemia, respiratory and metabolic acidosis, systemic hypotension, and shock.

• #64 Congenital diaphragmatic hernia: Prenatal issues – UpToDate

  https://www.uptodate.com/contents/congenital-diaphragmatic-hernia-prenatal-issues/print

  Congenital diaphragmatic hernia (CDH) is a developmental discontinuity of the diaphragm that allows the abdominal viscera to herniate into the chest. […] Failure of normal closure of the pleuroperitoneal folds during the fourth to tenth weeks postfertilization allows herniation of viscera into the thoracic cavity, which interferes with normal lung development and has several potential adverse consequences, including: […] Reduction in bronchiolar branching. […] Truncation and over-muscularization of the pulmonary arterial tree, leading to smaller cross-sectional area of pulmonary vessels, structural vascular remodeling, and vasoconstriction with altered vasoreactivity.

• #65 Congenital Diaphragmatic hernia – a review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5356475/

  Congenital Diaphragmatic hernia (CDH) is a condition characterized by a defect in the diaphragm leading to protrusion of abdominal contents into the thoracic cavity interfering with normal development of the lungs. The pathophysiology of CDH is a combination of lung hypoplasia and immaturity associated with persistent pulmonary hypertension of newborn (PPHN) and cardiac dysfunction. […] The etiology of CDH largely remains unclear and currently is thought to be multifactorial. The majority of the cases have an isolated diaphragmatic defect presenting with pulmonary hypoplasia and persistent pulmonary hypertension of newborn (PPHN). […] The embryologic basis of CDH remains controversial. It was thought initially that the defect happened secondary to failure of different parts of the diaphragm to fuse resulting in a patent pleuroperitoneal canal.

• #66 The Pathogenesis of Pulmonary Hypoplasia in Congenital Diaphragmatic Hernia: A continuing quest

  https://repub.eur.nl/pub/32523

  Congenital diaphragmatic hernia or CDH is a developmental defect of the diaphragm that allows abdominal organs, such as intestines and liver, to herniate into the thoracic cavity during lung development. […] Children with a CDH suffer from a substantial amount of morbidity and mortality due to the associated abnormal pulmonary development resulting in two clinical problems, pulmonary hypoplasia and persistent pulmonary hypertension of the neonate (PPHN). […] Characteristics of pulmonary hypoplasia in CDH are thickened alveolar walls, an increase in interstitial tissue, reduced alveolar air spaces and reduced gas-exchange surface area. […] A sound understanding of the etiology and pathogenesis of CDH is necessary in order to prevent the severe morbidity or the anomalies altogether. […] Consequently, the aim of this dissertation was to improve our understanding of the pathogenesis of pulmonary hypoplasia in CDH, to eventually aid in finding ways to modulate the natural course in a prenatally diagnosed child.

• #67 Congenital Diaphragmatic hernia – a review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5356475/

  Thus the major underlying pathophysiology of CDH appears to be a combination of lung immaturity and hypoplasia that leads to PPHN. This may be further aggravated by left ventricular underdevelopment and right ventricular hypertrophy resulting in ventricular dysfunction. […] Lung hypoplasia occurs on the ipsilateral side of herniation, with the contralateral side being affected to a variable extent. […] The total pulmonary vascular bed is reduced with decreased number of vessels per unit of lung. In addition, pulmonary vascular remodeling with medial hyperplasia and peripheral extension of the muscle layer into small arterioles is evident. […] In CDH, the total pulmonary vascular bed is reduced with decreased number of vessels per unit of lung. […] The absence of a difference does not rule out pulmonary hypertension. In some patients with CDH the immediate postnatal phase, there is a short period of better oxygenation referred to as honeymoon period. However, progressive deterioration in oxygenation is commonly observed with deteriorating PPHN. […] Inhaled Nitric Oxide (iNO) is the first agent of choice for treatment of pulmonary hypertension in infants 34 weeks gestation. It is a selective pulmonary vasodilator and relaxes pulmonary vascular smooth muscle cells.

• #68 Hemodynamic management of congenital diaphragmatic hernia: the role of targeted neonatal echocardiography | World Journal of Pediatric Surgery

  https://wjps.bmj.com/content/7/2/e000790

  Congenital diaphragmatic hernia (CDH) is a major congenital anomaly, resulting from the herniation of abdominal contents into the thoracic cavity, thereby impeding the proper development of the lungs and pulmonary vasculature. CDH severity correlates with a spectrum of pulmonary hypoplasia, pulmonary hypertension (PHT), and cardiac dysfunction, constituting the pathophysiological triad of this complex condition. […] The pathophysiological complexities associated with CDH principally arise from pulmonary hypoplasia and pulmonary hypertension (PHT), characterized by diminished alveolarization and an increased muscularization of the pulmonary arterioles. The severity of PHT and the accompanying ventricular dysfunction serve as a pivotal determinant of clinical outcomes. […] CDH is a congenital anomaly with pathogenesis and etiology that remain incompletely understood. Rivas et al. proposed the Retinoid Hypothesis, stating that the underlying cause of abnormal diaphragm development in CDH was related to altered retinoid signaling.

• #69 Hemodynamic management of congenital diaphragmatic hernia: the role of targeted neonatal echocardiography | World Journal of Pediatric Surgery

  https://wjps.bmj.com/content/7/2/e000790

  Using the well-known nitrofen model, Keijzer et al. proposed the Dual-hit Hypothesis, suggesting an initial insult affecting both lungs before diaphragm development, followed by the second insult affecting the ipsilateral lung after defective diaphragm development and resulting extrinsic compression. […] The severity of CDH is notably linked with a variable degree of pulmonary hypoplasia, PHT, and cardiac dysfunction, constituting the triad of pathophysiological hallmark features of this complex disorder. […] The altered pulmonary vasoreactivity and pathological vascular remodeling, secondary to the reduced lung size and changes in pulmonary microarchitecture, are central to the pathophysiology of CDH-associated PHT. […] The confluence of low ventricular output and PHT leads to hypoxemia, respiratory and metabolic acidosis, systemic hypotension, and shock.

• #70 Congenital Diaphragmatic hernia – a review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5356475/

  Thus the major underlying pathophysiology of CDH appears to be a combination of lung immaturity and hypoplasia that leads to PPHN. This may be further aggravated by left ventricular underdevelopment and right ventricular hypertrophy resulting in ventricular dysfunction. […] Lung hypoplasia occurs on the ipsilateral side of herniation, with the contralateral side being affected to a variable extent. […] The total pulmonary vascular bed is reduced with decreased number of vessels per unit of lung. In addition, pulmonary vascular remodeling with medial hyperplasia and peripheral extension of the muscle layer into small arterioles is evident. […] In CDH, the total pulmonary vascular bed is reduced with decreased number of vessels per unit of lung. […] The absence of a difference does not rule out pulmonary hypertension. In some patients with CDH the immediate postnatal phase, there is a short period of better oxygenation referred to as honeymoon period. However, progressive deterioration in oxygenation is commonly observed with deteriorating PPHN. […] Inhaled Nitric Oxide (iNO) is the first agent of choice for treatment of pulmonary hypertension in infants 34 weeks gestation. It is a selective pulmonary vasodilator and relaxes pulmonary vascular smooth muscle cells.

• #71 Congenital Diaphragmatic hernia – a review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5356475/

  Thus the major underlying pathophysiology of CDH appears to be a combination of lung immaturity and hypoplasia that leads to PPHN. This may be further aggravated by left ventricular underdevelopment and right ventricular hypertrophy resulting in ventricular dysfunction. […] Lung hypoplasia occurs on the ipsilateral side of herniation, with the contralateral side being affected to a variable extent. […] The total pulmonary vascular bed is reduced with decreased number of vessels per unit of lung. In addition, pulmonary vascular remodeling with medial hyperplasia and peripheral extension of the muscle layer into small arterioles is evident. […] In CDH, the total pulmonary vascular bed is reduced with decreased number of vessels per unit of lung. […] The absence of a difference does not rule out pulmonary hypertension. In some patients with CDH the immediate postnatal phase, there is a short period of better oxygenation referred to as honeymoon period. However, progressive deterioration in oxygenation is commonly observed with deteriorating PPHN. […] Inhaled Nitric Oxide (iNO) is the first agent of choice for treatment of pulmonary hypertension in infants 34 weeks gestation. It is a selective pulmonary vasodilator and relaxes pulmonary vascular smooth muscle cells.

• #72 Hemodynamic management of congenital diaphragmatic hernia: the role of targeted neonatal echocardiography | World Journal of Pediatric Surgery

  https://wjps.bmj.com/content/7/2/e000790

  Using the well-known nitrofen model, Keijzer et al. proposed the Dual-hit Hypothesis, suggesting an initial insult affecting both lungs before diaphragm development, followed by the second insult affecting the ipsilateral lung after defective diaphragm development and resulting extrinsic compression. […] The severity of CDH is notably linked with a variable degree of pulmonary hypoplasia, PHT, and cardiac dysfunction, constituting the triad of pathophysiological hallmark features of this complex disorder. […] The altered pulmonary vasoreactivity and pathological vascular remodeling, secondary to the reduced lung size and changes in pulmonary microarchitecture, are central to the pathophysiology of CDH-associated PHT. […] The confluence of low ventricular output and PHT leads to hypoxemia, respiratory and metabolic acidosis, systemic hypotension, and shock.

• #73 Hemodynamic management of congenital diaphragmatic hernia: the role of targeted neonatal echocardiography | World Journal of Pediatric Surgery

  https://wjps.bmj.com/content/7/2/e000790

  The accurate diagnosis and successful management of PHT and cardiac dysfunction are crucial for enhancing the clinical outcomes in infants with CDH. Recognition of CDH-specific hemodynamic patterns or phenotypes by standardized echocardiographic assessment enables individualized targeting of therapies to encourage pulmonary and systemic vascular stabilization.

• #74 Hemodynamic management of congenital diaphragmatic hernia: the role of targeted neonatal echocardiography | World Journal of Pediatric Surgery

  https://wjps.bmj.com/content/7/2/e000790

  The accurate diagnosis and successful management of PHT and cardiac dysfunction are crucial for enhancing the clinical outcomes in infants with CDH. Recognition of CDH-specific hemodynamic patterns or phenotypes by standardized echocardiographic assessment enables individualized targeting of therapies to encourage pulmonary and systemic vascular stabilization.

• #75 Congenital diaphragmatic hernia: pathogenesis, prenatal diagnosis and management — literature review | Kosiński | Ginekologia Polska

  https://journals.viamedica.pl/ginekologia_polska/article/view/49464

  Congenital diaphragmatic hernia (CDH) is a developmental discontinuity of the diaphragm. It allows abdominal viscera to herniate into the chest and leads to lung hypoplasia. Congenital diaphragmatic hernia is one of the most severe birth defects, with extremely high neonatal mortality. […] In selected cases, a prenatal procedure to improve neonatal survival is possible. The authors of this manuscript believe their work might contribute to a better understanding of congenital diaphragmatic hernia and patient selection for the FETO (fetal endoscopic tracheal occlusion) surgery or expectant management.

• #76 Fetoscopic Endoluminal Tracheal Occlusion (FETO) to Treat CDH | Fetal Care Center

  https://www.cincinnatichildrens.org/service/f/fetal-care/conditions/congenital-diaphragmatic-hernia/feto

  Fetoscopic endoluminal tracheal occlusion, or FETO, is a surgical procedure to treat the most severe cases of congenital diaphragmatic hernia (CDH) that are diagnosed in utero. CDH occurs when a hole develops in your unborn baby’s diaphragm (the breathing muscle that separates the chest from the abdomen). The opening allows the abdominal organs to push into the baby’s chest and crowd the developing lungs. This can cause the lungs to remain small and underdeveloped. […] Research has shown that building up this tracheal pressure and fluid content can stimulate lung growth. The FETO procedure provides an artificial way to block your baby’s trachea and promote lung development. […] FETO is an experimental procedure. It is not an appropriate treatment for all cases of CDH diagnosed in utero. It is only offered in instances of severe CDH where we feel the mother and baby will have the most potential to benefit from the procedure.

• #77 Congenital Diaphragmatic Hernia (CDH) | Lurie Children’s

  https://www.luriechildrens.org/en/specialties-conditions/congenital-diaphragmatic-hernia/

  Simple observations like the position of the fetal liver and stomach taken from a routine ultrasound provides the earliest assessment of the CDH severity. As the liver and stomach progressively herniate into the fetal chest, the fetal lungs will be smaller than normal which is a condition known as lung hypoplasia. Additionally, the blood vessels within the lungs may also develop poorly leading to high blood pressure in the lungs; a condition known as pulmonary hypertension. […] Experienced fetal centers can perform a specialized CDH ultrasound and fetal MRI examination to provide a more detailed assessment of the impact of the CDH on fetal lung development. […] In the most severe forms of CDH, a surgical intervention called Fetoscopic Endoluminal Tracheal Occlusion (FETO) may be recommended to improve the babys outcome. FETO is an innovative treatment option that helps the babys lungs to develop as much as possible before birth.

• #78 Congenital Diaphragmatic Hernia (CDH): What Parents Need To Know

  https://my.clevelandclinic.org/health/diseases/24308-diaphragmatic-hernia

  Congenital diaphragmatic hernia treatment begins as soon as your healthcare provider diagnoses it. These treatments may seem scary, but your healthcare provider is doing everything they can to keep your baby safe. […] If your healthcare provider discovers CDH during your pregnancy, they’ll monitor you closely. They’ll look for congenital issues in other organ systems that can be part of a more complex disease. […] In some cases, your healthcare team may be able to treat the fetus before birth. Fetoscopic tracheal occlusion (FETO) is a fetal surgery that, in very specific cases, can help improve the size and function of the fetus’s lungs while it’s still growing. […] Through FETO, your provider places a balloon in the fetus’s trachea (windpipe). This allows the amniotic fluid it breathes to build up in its lungs behind the balloon, causing its lungs to expand. This expansion can improve the growth and function of the lungs and reverse some of the damage CDH caused.

• #79 Fetoscopic Endoluminal Tracheal Occlusion (FETO) to Treat CDH | Fetal Care Center

  https://www.cincinnatichildrens.org/service/f/fetal-care/conditions/congenital-diaphragmatic-hernia/feto

  Fetoscopic endoluminal tracheal occlusion, or FETO, is a surgical procedure to treat the most severe cases of congenital diaphragmatic hernia (CDH) that are diagnosed in utero. CDH occurs when a hole develops in your unborn baby’s diaphragm (the breathing muscle that separates the chest from the abdomen). The opening allows the abdominal organs to push into the baby’s chest and crowd the developing lungs. This can cause the lungs to remain small and underdeveloped. […] Research has shown that building up this tracheal pressure and fluid content can stimulate lung growth. The FETO procedure provides an artificial way to block your baby’s trachea and promote lung development. […] FETO is an experimental procedure. It is not an appropriate treatment for all cases of CDH diagnosed in utero. It is only offered in instances of severe CDH where we feel the mother and baby will have the most potential to benefit from the procedure.

• #80 Congenital Diaphragmatic Hernia (CDH): What Parents Need To Know

  https://my.clevelandclinic.org/health/diseases/24308-diaphragmatic-hernia

  Congenital diaphragmatic hernia treatment begins as soon as your healthcare provider diagnoses it. These treatments may seem scary, but your healthcare provider is doing everything they can to keep your baby safe. […] If your healthcare provider discovers CDH during your pregnancy, they’ll monitor you closely. They’ll look for congenital issues in other organ systems that can be part of a more complex disease. […] In some cases, your healthcare team may be able to treat the fetus before birth. Fetoscopic tracheal occlusion (FETO) is a fetal surgery that, in very specific cases, can help improve the size and function of the fetus’s lungs while it’s still growing. […] Through FETO, your provider places a balloon in the fetus’s trachea (windpipe). This allows the amniotic fluid it breathes to build up in its lungs behind the balloon, causing its lungs to expand. This expansion can improve the growth and function of the lungs and reverse some of the damage CDH caused.

• #81 Congenital Diaphragmatic Hernia (CDH) | Lurie Children’s

  https://www.luriechildrens.org/en/specialties-conditions/congenital-diaphragmatic-hernia/

  The first phase of the babys NICU care is the resuscitation and stabilization phase which begins at delivery and continues for approximately 3 5 days. […] For this reason, the surgery to repair the CDH is typically not performed until after the newborn has stabilized and can better tolerate an operation. […] In cases of a small defect, the CDH repair is done by closing the hole with stitches. […] The final phase of the NICU care for CDH babies is the feeding and growing phase. After the baby recovers from the repair of the CDH, the goal for the remainder of the NICU care is for the baby to breathe and eat independently. […] The vast majority of CDH babies survive and grow up to have normal, active and independent lives. Lung growth continues for the first decade of life allowing for normal lung development to occur even when severe lung hypoplasia was present at birth.

• #82 Congenital Diaphragmatic hernia – a review

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5356475/

  Thus the major underlying pathophysiology of CDH appears to be a combination of lung immaturity and hypoplasia that leads to PPHN. This may be further aggravated by left ventricular underdevelopment and right ventricular hypertrophy resulting in ventricular dysfunction. […] Lung hypoplasia occurs on the ipsilateral side of herniation, with the contralateral side being affected to a variable extent. […] The total pulmonary vascular bed is reduced with decreased number of vessels per unit of lung. In addition, pulmonary vascular remodeling with medial hyperplasia and peripheral extension of the muscle layer into small arterioles is evident. […] In CDH, the total pulmonary vascular bed is reduced with decreased number of vessels per unit of lung. […] The absence of a difference does not rule out pulmonary hypertension. In some patients with CDH the immediate postnatal phase, there is a short period of better oxygenation referred to as honeymoon period. However, progressive deterioration in oxygenation is commonly observed with deteriorating PPHN. […] Inhaled Nitric Oxide (iNO) is the first agent of choice for treatment of pulmonary hypertension in infants 34 weeks gestation. It is a selective pulmonary vasodilator and relaxes pulmonary vascular smooth muscle cells.

• #83 Congenital Diaphragmatic Hernia (CDH) | Lurie Children’s

  https://www.luriechildrens.org/en/specialties-conditions/congenital-diaphragmatic-hernia/

  The first phase of the babys NICU care is the resuscitation and stabilization phase which begins at delivery and continues for approximately 3 5 days. […] For this reason, the surgery to repair the CDH is typically not performed until after the newborn has stabilized and can better tolerate an operation. […] In cases of a small defect, the CDH repair is done by closing the hole with stitches. […] The final phase of the NICU care for CDH babies is the feeding and growing phase. After the baby recovers from the repair of the CDH, the goal for the remainder of the NICU care is for the baby to breathe and eat independently. […] The vast majority of CDH babies survive and grow up to have normal, active and independent lives. Lung growth continues for the first decade of life allowing for normal lung development to occur even when severe lung hypoplasia was present at birth.

• #84 Congenital Diaphragmatic Hernia (CDH) | Lurie Children’s

  https://www.luriechildrens.org/en/specialties-conditions/congenital-diaphragmatic-hernia/

  The first phase of the babys NICU care is the resuscitation and stabilization phase which begins at delivery and continues for approximately 3 5 days. […] For this reason, the surgery to repair the CDH is typically not performed until after the newborn has stabilized and can better tolerate an operation. […] In cases of a small defect, the CDH repair is done by closing the hole with stitches. […] The final phase of the NICU care for CDH babies is the feeding and growing phase. After the baby recovers from the repair of the CDH, the goal for the remainder of the NICU care is for the baby to breathe and eat independently. […] The vast majority of CDH babies survive and grow up to have normal, active and independent lives. Lung growth continues for the first decade of life allowing for normal lung development to occur even when severe lung hypoplasia was present at birth.

• #85 Congenital Diaphragmatic Hernia (CDH) | Lurie Children’s

  https://www.luriechildrens.org/en/specialties-conditions/congenital-diaphragmatic-hernia/

  The first phase of the babys NICU care is the resuscitation and stabilization phase which begins at delivery and continues for approximately 3 5 days. […] For this reason, the surgery to repair the CDH is typically not performed until after the newborn has stabilized and can better tolerate an operation. […] In cases of a small defect, the CDH repair is done by closing the hole with stitches. […] The final phase of the NICU care for CDH babies is the feeding and growing phase. After the baby recovers from the repair of the CDH, the goal for the remainder of the NICU care is for the baby to breathe and eat independently. […] The vast majority of CDH babies survive and grow up to have normal, active and independent lives. Lung growth continues for the first decade of life allowing for normal lung development to occur even when severe lung hypoplasia was present at birth.

• #86 Congenital diaphragmatic hernia: Prenatal issues – UpToDate

  https://www.uptodate.com/contents/congenital-diaphragmatic-hernia-prenatal-issues

  Congenital diaphragmatic hernia (CDH) is a developmental discontinuity of the diaphragm that allows the abdominal viscera to herniate into the chest. Although the diaphragmatic defect is surgically correctable, in utero herniation of viscera can result in pulmonary hypoplasia and pulmonary hypertension. A substantial percentage of CDH cases are associated with additional abnormalities, including major structural anomalies in other organ systems, chromosomal abnormalities, and/or single gene disorders. Affected neonates usually present in the first few hours of life with respiratory distress that may be mild or so severe as to be incompatible with life. Survival has improved with advances in antenatal diagnosis, in utero intervention, and neonatal care, but affected infants remain at significant risk of morbidity and mortality.

• #87 Congenital Diaphragmatic Hernia (CDH): What Parents Need To Know

  https://my.clevelandclinic.org/health/diseases/24308-diaphragmatic-hernia

  Babies who are born with CDH usually require immediate intensive care by a specialized team. If your baby is born with pulmonary hypoplasia (underdeveloped lungs), they’ll need oxygen support first. […] For the surgery, a pediatric anesthesiologist will put your baby to sleep with anesthesia. A pediatric surgeon will operate on your baby to move their organs back into their abdomen and repair the defect in their diaphragm. […] The reported survival rate for babies born with CDH has improved. Between 7 and 9 out of every 10 babies survive. These babies are born critically ill, but for those who make it through the tense early days of their condition, the outlook gets better. Some children may have long-term complications, but they’ll still live long and full lives. Continuing advances in medicine improve the odds of both short-term survival and long-term health.

• #88 Congenital Diaphragmatic Hernia (CDH) | Lurie Children’s

  https://www.luriechildrens.org/en/specialties-conditions/congenital-diaphragmatic-hernia/

  The first phase of the babys NICU care is the resuscitation and stabilization phase which begins at delivery and continues for approximately 3 5 days. […] For this reason, the surgery to repair the CDH is typically not performed until after the newborn has stabilized and can better tolerate an operation. […] In cases of a small defect, the CDH repair is done by closing the hole with stitches. […] The final phase of the NICU care for CDH babies is the feeding and growing phase. After the baby recovers from the repair of the CDH, the goal for the remainder of the NICU care is for the baby to breathe and eat independently. […] The vast majority of CDH babies survive and grow up to have normal, active and independent lives. Lung growth continues for the first decade of life allowing for normal lung development to occur even when severe lung hypoplasia was present at birth.

• #89

  https://openarchive.ki.se/articles/thesis/Lung_growth_and_lung_hypoplasia_in_congenital_diaphragmatic_hernia/26912014

  Pulmonary hypoplasia and persistent pulmonary hypertension are the main causes of mortality and morbidity in newborns with congenital diaphragmatic hernia (CDH). […] The aim of the present study is to increase the understanding of the biological mechanisms underlying growth and development after prenatal TL in the fetal lung and the underlying pathogenesis of CDH, in order to improve outcomes for neonates with CDH. […] The pathogenesis of lung hypoplasia and congenital diaphragmatic hernia in the nitrofen model includes alteration at a molecular level of several pathways involved in lung growth and development, fluid balance and vascular development. […] Increased understanding of the molecular mechanisms that control lung growth may be the key to develop novel therapeutic techniques in order to stimulate pre and postnatal lung growth.

• #90 Management of Congenital Diaphragmatic Hernia (CDH): Role of Molecular Genetics

  https://www.mdpi.com/1422-0067/22/12/6353

  Defects in diaphragm development lead to CDH. […] Some CDH-associated genetic mutations and related defects in different molecular pathways can directly affect diaphragm development and of other organs, such as the lungs and the heart. […] Advances in genomics, coupled with functional studies in animal models, are increasingly identifying the causes of CDH in both familial and sporadic cases. […] Through these approaches, we are beginning to elucidate the mechanisms and molecular pathways that are responsible for diaphragm and lung development abnormalities in CDH patients. […] A better insight into the mechanisms regulating diaphragm development and genetic causes leading to CDH appeared essential to the development of new therapeutic strategies and evidence-based genetic counselling to parents. […] Integrated sequencing, development, and bioinformatics strategies could direct future functional studies on CDH; could be applied to cohorts and consortia for CDH and other birth defects; and could pave the way for potential therapies by providing molecular targets for drug discovery.

• #91 [Congenital diaphragmatic hernia – mechanisms of pulmonary hypoplasia]. – Archive ouverte HAL

  https://hal.science/hal-01927193v1

  Although multifactorial inheritance may best explain most cases of CDH in humans, much has been learned about the genetic factors that play a role in the development of CDH by studies of patients with CDH caused by specific genetic syndromes and chromosome anomalies. More research is warranted to improve our understanding of normal and abnormal lung development in relation to CDH. Such investigations will help in the design of new treatment strategies to improve the natural course or even to prevent this anomaly.

• #92 New Insights Into Little Known But Common Birth Defect: Congenital Diaphragmatic Hernia | University of Utah Health

  https://healthcare.utah.edu/press-releases/2015/03/new-insights-little-known-common-birth-defect-congenital-diaphragmatic

  This suggested that genetic defects within connective tissue might be a cause of CDH. […] They tested their hypothesis by silencing the Gata4 gene in the connective tissue cells and observing how this affected development. In every case in which the Gata4 gene was „knocked out,” the mouse developed a hernia in its diaphragm. […] Without Gata4 in the connective tissue, muscle develops incompletely creating a localized region made entirely of connective tissue. […] Their genetic studies, aided by computer models made in collaboration with bioengineers, show that CDH only develops when a weaker region of connective tissue is surrounded by stronger muscular tissue; counterintuitively, diaphragms made entirely of connective tissue did not develop hernias. […] Muscle connective tissue controls development of the diaphragm and is a source of congenital diaphragmatic hernias. […] Research from the University of Utah provides new information on how CDH arises, opening avenues for researching therapeutic interventions.

• #93 Management of Congenital Diaphragmatic Hernia (CDH): Role of Molecular Genetics

  https://www.mdpi.com/1422-0067/22/12/6353

  Defects in diaphragm development lead to CDH. […] Some CDH-associated genetic mutations and related defects in different molecular pathways can directly affect diaphragm development and of other organs, such as the lungs and the heart. […] Advances in genomics, coupled with functional studies in animal models, are increasingly identifying the causes of CDH in both familial and sporadic cases. […] Through these approaches, we are beginning to elucidate the mechanisms and molecular pathways that are responsible for diaphragm and lung development abnormalities in CDH patients. […] A better insight into the mechanisms regulating diaphragm development and genetic causes leading to CDH appeared essential to the development of new therapeutic strategies and evidence-based genetic counselling to parents. […] Integrated sequencing, development, and bioinformatics strategies could direct future functional studies on CDH; could be applied to cohorts and consortia for CDH and other birth defects; and could pave the way for potential therapies by providing molecular targets for drug discovery.

• #94

  https://link.springer.com/article/10.1007/BF01349971

  The first description diaphragmatic hernia appeared in 1575. […] In recent years, an enormous effort has been made by research groups all over the world to describe the pathogenesis and pathophysiology of CDH, and apply these findings to clinical practice. […] Pulmonary hypoplasia and pulmonary hypertension were early recognised as important reasons for the high mortality rate. […] Despite these efforts, the mortality remains unacceptably high. The challenge for the future is to continue development of therapeutic approaches in order to improve survival of neonates with CDH.

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