Genetics of diaphragmatic hernia

AbstractCongenital 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. Morbidity and mortality in affected newborns are very high and at present, there is no precise prenatal or early postnatal prognostication parameter to predict clinical outcome in CDH patients. Most cases occur sporadically, however, genetic causes have long been discussed to explain a proportion of cases. These range from aneuploidy to complex chromosomal aberrations and specific mutations often causing a complex phenotype exhibiting multiple malformations along with CDH. This review summarises the genetic variations which have been observed in syndromic and isolated cases of congenital diaphragmatic hernia.

Download Full-text

Tetralogy of Fallot with congenital diaphragmatic hernia and left lung hypoplasia: assessment of the adequacy of the peripheral pulmonary vascular growth after hernia repair

Cardiology in the Young ◽

10.1017/s104795111100134x ◽

2011 ◽

Vol 22 (2) ◽

pp. 235-238 ◽

Cited By ~ 3

Author(s):

Hong Ju Shin ◽

Won Kyoung Jhang ◽

Tae Jin Yun

Keyword(s):

Congenital Diaphragmatic Hernia ◽

Tetralogy Of Fallot ◽

Diaphragmatic Hernia ◽

Left Lung ◽

Lung Hypoplasia ◽

Vascular Growth ◽

Threatening Condition ◽

Central Pulmonary Artery ◽

Life Threatening ◽

Vascular Beds

AbstractCongenital diaphragmatic hernia is a life-threatening condition frequently associated with various congenital cardiac diseases. In congenital diaphragmatic hernia associated with tetralogy of Fallot, central pulmonary artery size of the affected side may not reflect the capacitance of peripheral pulmonary vascular beds. We report a case of congenital diaphragmatic hernia associated with tetralogy of Fallot, which was repaired after assessing the adequacy of the pulmonary vascular beds by intra-operative pulmonary blood flow study.

Download Full-text

Prostaglandin E1 in infants with congenital diaphragmatic hernia (CDH) and life-threatening pulmonary hypertension

Journal of Pediatric Surgery ◽

10.1016/j.jpedsurg.2020.01.008 ◽

2020 ◽

Vol 55 (9) ◽

pp. 1872-1878

Author(s):

Kévin Le Duc ◽

Sébastien Mur ◽

Dyuti Sharma ◽

Estelle Aubry ◽

Morgan Recher ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Congenital Diaphragmatic Hernia ◽

Diaphragmatic Hernia ◽

Prostaglandin E1 ◽

Life Threatening

Download Full-text

Prevention of pulmonary hypoplasia and pulmonary vascular remodeling by antenatal simvastatin treatment in nitrofen-induced congenital diaphragmatic hernia

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00345.2014 ◽

2015 ◽

Vol 308 (7) ◽

pp. L672-L682 ◽

Cited By ~ 20

Author(s):

Martine Makanga ◽

Hidekazu Maruyama ◽

Celine Dewachter ◽

Agnès Mendes Da Costa ◽

Emeline Hupkens ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Body Weight ◽

Congenital Diaphragmatic Hernia ◽

Diaphragmatic Hernia ◽

Weight Ratio ◽

The Body ◽

Lung Hypoplasia ◽

External Diameter ◽

Pathological Features ◽

Pulmonary Vessel

Congenital diaphragmatic hernia (CDH) has a high mortality rate mainly due to lung hypoplasia and persistent pulmonary hypertension of the newborn (PPHN). Simvastatin has been shown to prevent the development of pulmonary hypertension (PH) in experimental models of PH. We, therefore, hypothesized that antenatal simvastatin would attenuate PPHN in nitrofen-induced CDH in rats. The efficacy of antenatal simvastatin was compared with antenatal sildenafil, which has already been shown to improve pathological features of PPHN in nitrofen-induced CDH. On embryonic day (E) 9.5, nitrofen or vehicle was administered to pregnant Sprague-Dawley rats. On E11, nitrofen-treated rats were randomly assigned to antenatal simvastatin (20 mg·kg−1·day−1 orally), antenatal sildenafil (100 mg·kg−1·day−1 orally), or placebo administration from E11 to E21. On E21, fetuses were delivered by cesarean section, killed, and checked for left-sided CDH. Lung tissue was then harvested for further pathobiological evaluation. In nitrofen-induced CDH, simvastatin failed to reduce the incidence of nitrofen-induced CDH in the offspring and to increase the body weight, but improved the lung-to-body weight ratio and lung parenchyma structure. Antenatal simvastatin restored the pulmonary vessel density and external diameter, and reduced the pulmonary arteriolar remodeling compared with nitrofen-induced CDH. This was associated with decreased lung expression of endothelin precursor, endothelin type A and B receptors, endothelial and inducible nitric oxide synthase, together with restored lung activation of apoptotic processes mainly in the epithelium. Antenatal simvastatin presented similar effects as antenatal therapy with sildenafil on nitrofen-induced CDH. Antenatal simvastatin improves pathological features of lung hypoplasia and PPHN in experimental nitrofen-induced CDH.

Download Full-text

Lung Transplantation for Late-Onset Pulmonary Hypertension in a Patient with Congenital Diaphragmatic Hernia

European Journal of Pediatric Surgery Reports ◽

10.1055/s-0038-1675377 ◽

2018 ◽

Vol 06 (01) ◽

pp. e100-e103

Author(s):

Chiara Iacusso ◽

Francesco Morini ◽

Irma Capolupo ◽

Andrea Dotta ◽

Stefania Sgrò ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Respiratory Failure ◽

Lung Transplantation ◽

Congenital Diaphragmatic Hernia ◽

Diaphragmatic Hernia ◽

Late Onset ◽

Severe Malnutrition ◽

Lung Hypoplasia ◽

Tract Infections ◽

End Stage

AbstractLung hypoplasia and pulmonary hypertension (PH) in association with congenital diaphragmatic hernia (CDH) may cause fatal respiratory failure. Lung transplantation (Ltx) may represent an option for CDH-related end-stage pulmonary failure. The aim of this study is to report a patient with CDH who underwent Ltx or combined heart-lung transplantation (H-Ltx). Our patient was born at 33 weeks of gestation, with a prenatally diagnosed isolated left CDH. Twenty-four hours after birth, she underwent surgical repair of a type D defect (according to the CDH Study Group staging system). Postoperative course was unexpectedly uneventful, and she was discharged home at 58 days of life. Echocardiography before discharge was unremarkable. Periodic follow-up revealed gastroesophageal reflux (GER) and initial scoliosis. At the age of 10, she was readmitted for severe PH. Lung function progressively deteriorated, and at the age of 14, she underwent H-Ltx due to end-stage respiratory failure. After discharge, she developed recurrent respiratory tract infections, severe malnutrition, and drug-induced diabetes. Scoliosis and GER progressed, requiring posterior vertebral arthrodesis and antireflux surgery, respectively. Bronchiolitis obliterans further impaired her respiratory function, and though she had a second Ltx, she died at the age of 18, 4 and 1.5 years after the first and the second Ltx, respectively. Late-onset PH is an ominous complication of CDH. From our patient and the six further cases collected from the literature, Ltx may be considered as a last-resource treatment in CDH patients with irreversible and fatal respiratory failure, although its prognosis seems unfair.

Download Full-text

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

International Journal of Molecular Sciences ◽

10.3390/ijms22126353 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6353

Author(s):

Giulia Cannata ◽

Chiara Caporilli ◽

Federica Grassi ◽

Serafina Perrone ◽

Susanna Esposito

Keyword(s):

Congenital Diaphragmatic Hernia ◽

Diaphragmatic Hernia ◽

De Novo ◽

Current Knowledge ◽

Lung Hypoplasia ◽

Cellular Mechanisms ◽

Major Life ◽

Mortality And Morbidity ◽

Functional Studies ◽

Life Threatening

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 clinical relevance, CDH multifactorial etiology is still not completely understood. We reviewed current knowledge on normal diaphragm development and summarized genetic mutations and related pathways as well as cellular mechanisms involved in CDH. Our literature analysis showed that the discovery of harmful de novo variants in the fetus could constitute an important tool for the medical team during pregnancy, counselling, and childbirth. 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.

Download Full-text