Congenital diaphragmatic hernias (CDHs) and structural anomalies of the diaphragm are a common class of congenital birth defects that are associated with significant morbidity and mortality due to associated pulmonary hypoplasia, pulmonary hypertension and heart failure. In ∼30% of CDH patients, genomic analyses have identified a range of genetic defects, including chromosomal anomalies, copy number variants and sequence variants. The affected genes identified in CDH patients include transcription factors, suchasGATA4, ZFPM2, NR2F2 and WT1, and signaling pathway components, including members of the retinoic acid pathway. Mutations in these genes affect diaphragm development and can have pleiotropic effects on pulmonary and cardiac development. New therapies, including fetal endoscopic tracheal occlusion and prenatal transplacental fetal treatments, aim to normalize lung development and pulmonary vascular tone to prevent and treat lung hypoplasia and pulmonary hypertension, respectively. Studies of the association between particular genetic mutations and clinical outcomes should allow us to better understand the origin of this birth defect and to improve our ability to predict and identify patients most likely to benefit from specialized treatment strategies.
Bibliographical noteFunding Information:
K.G.A. is partially supported by the National Institutes of Health (NIH) R01 HL085459. E.B. is supported by NIH Genetics Training Grant (T32GM007464). D.J.M. is supported by NIH (KL2TR000428, UL1TR000427). G.K. is supported by NIH (R01HD087360), March of Dimes Foundation and the Wheeler Foundation. X.S. is supported by NIH (R01HL122406, R01HL119946, R01HL113870) and Wisconsin Partnership Program funding. W.K.C., J.W., Y.S., L.S. are supported by NIH (HD057036 and UL1 RR024156), CHERUBS, the National Greek Orthodox Ladies Philoptochos Society, Inc., the Wheeler Foundation, Vanech Family Foundation, Larsen Family, Fore Hanley Foundation and Wilke Family.
- Congenital diaphragmatic hernia (CDH)
- Congenital heart disease (CHD)
- Pulmonary hypertension
- Pulmonary hypoplasia
- Structural birth defects