Molecular Mechanisms Contributing to the Etiology of Congenital Diaphragmatic Hernia: A Review and Novel Cases.

Congenital diaphragmatic hernia (CDH) is a relatively common birth defect, affecting approximately 1 in 2500-3000 live births, with a slight male predominance (1.5:1). 1 Burgos C.M. Frenckner B. Addressing the hidden mortality in CDH: a population-based study. J Pediatr Surg. 2017; 52: 522-525 Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar , 2 Hinton C.F. Siffel C. Correa A. Shapira S.K. Survival disparities associated with congenital diaphragmatic hernia. Birth Defects Res. 2017; 109: 816-823 Crossref PubMed Scopus (10) Google Scholar , 3 Langham M.R. Kays D.W. Ledbetter D.J. Frentzen B. Sanford L.L. Richards D.S. Congenital diaphragmatic hernia, epidemiology and outcome. Clin Perinatol. 1996; 23: 671-688 Abstract Full Text PDF PubMed Google Scholar , 4 Leeuwen L. Mous D.S. van Rosmalen J. Olieman J.F. Andriessen L. Gischler S.J. et al. Congenital diaphragmatic hernia and growth to 12 years. Pediatrics. 2017; 140: e20163659 Crossref PubMed Scopus (18) Google Scholar , 5 Longoni M. High F.A. Qi H. Joy M.P. Hila R. Coletti C.M. et al. Genome-wide enrichment of damaging de novo variants in patients with isolated and complex congenital diaphragmatic hernia. Hum Genet. 2017; 136: 679-691 Crossref PubMed Scopus (36) Google Scholar , 6 Longoni M. Pober B.R. High F.A. Congenital diaphragmatic hernia overview. in: Adam M.P. Ardinger H.H. Pagon R.A. Wallace S.E. Bean L.J. Stephens K. GeneReviews. University of Washington, Seattle, Seattle (WA)2019 Google Scholar , 7 McGivern M.R. Best K.E. Rankin J. Wellesley D. Greenlees R. Addor M. et al. Epidemiology of congenital diaphragmatic hernia in Europe: a register-based study. Arch Dis Childhood Fetal Neonatal Ed. 2015; 100: F137-F144 Crossref PubMed Scopus (0) Google Scholar , 8 Pober B.R. Overview of epidemiology, genetics, birth defects, and chromosome abnormalities associated with CDH. Am J Med Genet C Semin Med Genet. 2007; 145C: 158-171 Crossref PubMed Scopus (119) Google Scholar , 9 Qi H. Yu L. Zhou X. Wynn J. Zhao H. Guo Y. et al. De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders. PLoS Genet. 2018; 14: e1007822 Crossref PubMed Scopus (44) Google Scholar , 10 Shanmugam H. Brunelli L. Botto L.D. Krikov S. Feldkamp M.L. Epidemiology and prognosis of congenital diaphragmatic hernia: a population-based cohort study in Utah. Birth Defects Res. 2017; 109: 1451-1459 Crossref PubMed Scopus (38) Google Scholar , 11 Skari H. Bjornland K. Haugen G. Egeland T. Emblem R. Congenital diaphragmatic hernia: a meta-analysis of mortality factors. J Pediatr Surg. 2000; 35: 1187-1197 Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar , 12 Stege G. Fenton A. Jaffray B. Nihilism in the 1990s: the true mortality of congenital diaphragmatic hernia. Pediatrics. 2003; 112: 532-535 Crossref PubMed Scopus (390) Google Scholar , 13 Stoll C. Alembik Y. Dott B. Roth M. Associated malformations in cases with congenital diaphragmatic hernia. Genet Couns. 2008; 19: 331-339 PubMed Google Scholar , 14 Stoll C. Alembik Y. Dott B. Roth M.P. Associated nondiaphragmatic anomalies among cases with congenital diaphragmatic hernia. Genet Couns. 2015; 26: 281-298 PubMed Google Scholar , 15 Torfs C.P. Curry C.J. Bateson T.F. Honoré L.H. A population-based study of congenital diaphragmatic hernia. Teratology. 1992; 46: 555-565 Crossref PubMed Scopus (267) Google Scholar , 16 Wang Y. Hu J. Druschel C.M. Kirby R.S. Twenty-five-year survival of children with birth defects in New York State: a population-based study. Birth Defects Res Part A Clin Mol Teratol. 2011; 91: 995-1003 Crossref PubMed Scopus (0) Google Scholar , 17 Wright J.C.E. Budd J.L.S. Field D.J. Draper E.S. Epidemiology and outcome of congenital diaphragmatic hernia: a 9-year experience. Paediatr Perinat Epidemiol. 2011; 25: 144-149 Crossref PubMed Scopus (53) Google Scholar CDH is characterized by a herniation of the abdominal viscera through a defect in the diaphragm, leading to significant pulmonary hypoplasia and pulmonary hypertension and substantial morbidity and mortality. 6 Longoni M. Pober B.R. High F.A. Congenital diaphragmatic hernia overview. in: Adam M.P. Ardinger H.H. Pagon R.A. Wallace S.E. Bean L.J. Stephens K. GeneReviews. University of Washington, Seattle, Seattle (WA)2019 Google Scholar ,8 Pober B.R. Overview of epidemiology, genetics, birth defects, and chromosome abnormalities associated with CDH. Am J Med Genet C Semin Med Genet. 2007; 145C: 158-171 Crossref PubMed Scopus (119) Google Scholar ,11 Skari H. Bjornland K. Haugen G. Egeland T. Emblem R. Congenital diaphragmatic hernia: a meta-analysis of mortality factors. J Pediatr Surg. 2000; 35: 1187-1197 Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar ,18 Ackerman K.G. Pober B.R. Congenital diaphragmatic hernia and pulmonary hypoplasia: new insights from developmental biology and genetics. Am J Med Genet C Semin Med Genet. 2007; 145C: 105-108 Crossref PubMed Scopus (58) Google Scholar , 19 Adzick N.S. Harrison M.R. Glick P.L. Nakayama D.K. Manning F.A. deLorimier A.A. Diaphragmatic hernia in the fetus: prenatal diagnosis and outcome in 94 cases. J Pediatr Surg. 1985; 20: 357-361 Abstract Full Text PDF PubMed Scopus (309) Google Scholar , 20 Jesudason E.C. Connell M.G. Fernig D.G. Lloyd D.A. Losty P.D. Early lung malformations in congenital diaphragmatic hernia. J Pediatr Surg. 2000; 35 (discussion 128): 124-127 Abstract Full Text Full Text PDF PubMed Google Scholar , 21 Greer J.J. Current concepts on the pathogenesis and etiology of congenital diaphragmatic hernia. Respir Physiol Neurobiol. 2013; 189: 232-240 Crossref PubMed Scopus (72) Google Scholar , 22 Keijzer R. Liu J. Deimling J. Tibboel D. Post M. Dual-hit hypothesis explains pulmonary hypoplasia in the nitrofen model of congenital diaphragmatic hernia. Am J Pathol. 2000; 156: 1299-1306 Abstract Full Text Full Text PDF PubMed Google Scholar , 23 Keijzer R. Puri P. Congenital diaphragmatic hernia. Semin Pediatr Surg. 2010; 19: 180-185 Crossref PubMed Scopus (157) Google Scholar , 24 Donahoe P.K. Longoni M. High F.A. Polygenic causes of congenital diaphragmatic hernia produce common lung pathologies. Am J Pathol. 2016; 186: 2532-2543 Abstract Full Text Full Text PDF PubMed Google Scholar , 25 Kardon G. Ackerman K.G. McCulley D.J. Shen Y. Wynn J. Shang L. et al. Congenital diaphragmatic hernias: from genes to mechanisms to therapies. Dis Model Mech. 2017; 10: 955-970 Crossref PubMed Scopus (78) Google Scholar Prenatal diagnosis, referrals to high volume tertiary care centers, and treatment advances in the neonatal intensive care unit have significantly improved survival rates to about 70%. When combining spontaneous miscarriages, elective terminations and postnatal demise, overall survival is approximately 50%. 1 Burgos C.M. Frenckner B. Addressing the hidden mortality in CDH: a population-based study. J Pediatr Surg. 2017; 52: 522-525 Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar ,3 Langham M.R. Kays D.W. Ledbetter D.J. Frentzen B. Sanford L.L. Richards D.S. Congenital diaphragmatic hernia, epidemiology and outcome. Clin Perinatol. 1996; 23: 671-688 Abstract Full Text PDF PubMed Google Scholar ,6 Longoni M. Pober B.R. High F.A. Congenital diaphragmatic hernia overview. in: Adam M.P. Ardinger H.H. Pagon R.A. Wallace S.E. Bean L.J. Stephens K. GeneReviews. University of Washington, Seattle, Seattle (WA)2019 Google Scholar ,8 Pober B.R. Overview of epidemiology, genetics, birth defects, and chromosome abnormalities associated with CDH. Am J Med Genet C Semin Med Genet. 2007; 145C: 158-171 Crossref PubMed Scopus (119) Google Scholar ,11 Skari H. Bjornland K. Haugen G. Egeland T. Emblem R. Congenital diaphragmatic hernia: a meta-analysis of mortality factors. J Pediatr Surg. 2000; 35: 1187-1197 Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar ,12 Stege G. Fenton A. Jaffray B. Nihilism in the 1990s: the true mortality of congenital diaphragmatic hernia. Pediatrics. 2003; 112: 532-535 Crossref PubMed Scopus (390) Google Scholar ,21 Greer J.J. Current concepts on the pathogenesis and etiology of congenital diaphragmatic hernia. Respir Physiol Neurobiol. 2013; 189: 232-240 Crossref PubMed Scopus (72) Google Scholar ,24 Donahoe P.K. Longoni M. High F.A. Polygenic causes of congenital diaphragmatic hernia produce common lung pathologies. Am J Pathol. 2016; 186: 2532-2543 Abstract Full Text Full Text PDF PubMed Google Scholar , 25 Kardon G. Ackerman K.G. McCulley D.J. Shen Y. Wynn J. Shang L. et al. Congenital diaphragmatic hernias: from genes to mechanisms to therapies. Dis Model Mech. 2017; 10: 955-970 Crossref PubMed Scopus (78) Google Scholar , 26 Colvin J. Bower C. Dickinson J.E. Sokol J. Outcomes of congenital diaphragmatic hernia: a population-based study in western Australia. Pediatrics. 2005; 116: 356 Crossref PubMed Scopus (328) Google Scholar , 27 Downard C.D. Jaksic T. Garza J.J. Dzakovic A. Nemes L. Jennings R.W. et al. Analysis of an improved survival rate for congenital diaphragmatic hernia. J Pediatr Surg. 2003; 38: 729-732 Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar , 28 Harrison M.R. Bjordal R.I. Langmark F. Knutrud O. Congenital diaphragmatic hernia: the hidden mortality. J Pediatr Surg. 1978; 13: 227-230 Abstract Full Text PDF PubMed Scopus (264) Google Scholar , 29 Javid P.J. Jaksic T. Skarsgard E.D. Lee S. Survival rate in congenital diaphragmatic hernia: the experience of the Canadian neonatal network. J Pediatr Surg. 2004; 39: 657-660 Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar , 30 Longoni M. High F.A. Russell M.K. Kashani A. Tracy A.A. Coletti C.M. et al. Molecular pathogenesis of congenital diaphragmatic hernia revealed by exome sequencing, developmental data, and bioinformatics. Proc Natl Acad Sci U S A. 2014; 111: 12450-12455 Crossref PubMed Scopus (0) Google Scholar , 31 Mohseni-Bod H. Bohn D. Pulmonary hypertension in congenital diaphragmatic hernia. Semin Pediatr Surg. 2007; 16: 126-133 Crossref PubMed Scopus (104) Google Scholar , 32 Pober B.R. Genetic aspects of human congenital diaphragmatic hernia. Clin Genet. 2008; 74: 1-15 Crossref PubMed Scopus (77) Google Scholar , 33 Tsao K. Lally K.P. Innovations in the surgical management of congenital diaphragmatic hernia. Clin Perinatol. 2012; 39: 363-374 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar , 34 Zaiss I. Kehl S. Link K. Neff W. Schaible T. Sütterlin M. et al. Associated malformations in congenital diaphragmatic hernia. Am J Perinatol. 2011; 28: 211-218 Crossref PubMed Scopus (0) Google Scholar