Congenital diaphragmatic hernias: from genes to mechanisms to therapies

Gabrielle Kardon, Kate G Ackerman, David J McCulley, Yufeng Shen, Julia Wynn, Linshan Shang, Eric Bogenschutz, Xin Sun, Wendy K Chung, Gabrielle Kardon, Kate G Ackerman, David J McCulley, Yufeng Shen, Julia Wynn, Linshan Shang, Eric Bogenschutz, Xin Sun, Wendy K Chung

Abstract

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, such as GATA4, 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.

Keywords: Congenital diaphragmatic hernia (CDH); Congenital heart disease (CHD); Diaphragm; Genetics; Pulmonary hypertension; Pulmonary hypoplasia; Structural birth defects.

Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

© 2017. Published by The Company of Biologists Ltd.

Figures

Fig. 1.
Fig. 1.
Anatomy of the human diaphragm at birth and types of diaphragmatic defects. Anatomy and localization of diaphragm defects depicted from a cranial view, with anterior (this is called the ventral region in the embryo) at top and posterior (dorsal region in the embryo) at bottom. (A) A normal diaphragm (top). Different types of diaphragm defects (below). The first row of defects shows different types of Bochdalek hernias. The second row shows other types of hernias, including anterior lateral and anterior parasternal defects that are considered to be Morgagni hernias. (B) Different diaphragm defects from a posterior view. Drawings by K. Ackerman.
Fig. 2.
Fig. 2.
Development of the diaphragm and diaphragm defects. (A) Normal development of the mouse diaphragm. Pleuroperitoneal folds (PPFs; green) give rise to muscle connective tissue and to the central tendon. Somites (red) give rise to muscle. Septum transversum (gray) is proposed to give rise to cells of the central tendon, but this has not been formally tested. The stage of embryonic development is indicated above each representative image, for mouse and humans. (B) Development of CDH with a hole (featuring loss of muscle and connective tissue), which allows abdominal contents to herniate into the thoracic cavity. This is generally thought to result from defects in the PPF cells. (C) Development of CDH with a muscle-less connective tissue ‘sac’ covering herniated tissue. In one case, this has been demonstrated to result from genetic defects in the PPFs, which in turn lead to the development of muscle-less patches that allow herniation (Merrell et al., 2015). Note that the size and location of defects can vary. (D) Development of diaphragm that lacks muscle on the left side. Muscle-less hemi-diaphragm can also develop on the right side. Note that for all diaphragm defects, the size and location of the defect can vary. Drawings by G. Kardon.

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