Polygenic Causes of Congenital Diaphragmatic Hernia Produce Common Lung Pathologies

Abstract

Congenital diaphragmatic hernia (CDH) is one of the most common and lethal congenital anomalies, and significant evidence is available in support of a genetic contribution to its etiology, including single-gene knockout mice associated with diaphragmatic defects, rare monogenetic disorders in humans, familial aggregation, and association of CDH with chromosomal abnormalities. Structural lung defects in the form of lung hypoplasia are almost invariably seen in patients with CDH and frequently in animal models of this condition. Better understanding of the mechanisms of pulmonary defects in CDH has the potential for creating targeted therapies, particularly in postnatal stages, when therapeutics can have maximum clinical impact on the surviving cohorts. Successful treatment of CDH is dependent on the integration of human genomic and genetic data with developmental expression profiling, mouse knockouts, and gene network and pathway modeling, which have generated a large number of candidate genes and pathways for follow-up studies. In particular, defective alveolarization appears to be a common and potentially actionable phenotype in both patients and animal models.

Figure 1

Timeline of pulmonary development. Human lung development is divided into prenatal and postnatal phases, separated by the dotted line indicating birth. Developmental stages are plotted against gestational weeks (below) and are divided into the partially overlapping embryonic, pseudoglandular, canalicular, saccular, and alveolar stages. Development of the alveolus continues with increased septation for several years during childhood. A number of CDH-associated genes affect branching morphogenesis in the lungs, but alveolarization and vascular defects are also reported in patients with CDH. The most practical window for therapeutic intervention is indicated by the pink box.

Figure 2

CDH lung abnormalities. An alveolar block is hypothesized as a late phenotype in CDH, resulting in alveolar simplification. Smaller alveoli, lined by increased type 2 and reduced type 1 pneumocytes, contain stunted septa linked with defective myofibroblast proliferation and migration. Reduced Sox9-positive progenitors indicate a defect in epithelial differentiation. The thickened interstitium suggests a delay in pulmonary maturation or abnormal resorption and results in poor oxygen exchange. α-SMA, α-smooth muscle actin; PDGFR, platelet-derived growth factor receptor; PDPL, podoplanin; SPC, surfactant protein C.