The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later

Abstract

Congenital diaphragmatic hernia (CDH) is a severe birth defect and a major cause of neonatal respiratory distress. Impacting ~2-3 in 10,000 births, CDH is associated with a high mortality rate, and long-term morbidity in survivors. Despite the significant impact of CDH, its etiology remains incompletely understood. In 2003, Greer et al. proposed the Retinoid Hypothesis, stating that the underlying cause of abnormal diaphragm development in CDH was related to altered retinoid signaling. In this review, we provide a comprehensive update to the Retinoid Hypothesis, discussing work published in support of this hypothesis from the past 20 years. This includes reviewing teratogenic and genetic models of CDH, lessons from the human genetics of CDH and epidemiological studies, as well as current gaps in the literature and important areas for future research. The Retinoid Hypothesis is one of the leading hypotheses to explain the etiology of CDH, as we continue to better understand the role of retinoid signaling in diaphragm development, we hope that this information can be used to improve CDH outcomes. IMPACT: This review provides a comprehensive update on the Retinoid Hypothesis, which links abnormal retinoic acid signaling to the etiology of congenital diaphragmatic hernia. The Retinoid Hypothesis was formulated in 2003. Twenty years later, we extensively review the literature in support of this hypothesis from both animal models and humans.

Fig. 1. Congenital diaphragmatic hernia and retinoic acid signaling.

The diaphragm forms an anatomical barrier between the abdominal and thoracic cavity (a). CDH is characterized by incomplete diaphragm development and herniation of abdominal organs into the thoracic cavity (b). Rodent models are widely used to models to study CDH. Here, a superior view of a whole diaphragm dissected from a teratogen-treated mouse fetus shows a large left-sided posterolateral (Bochdalek) diaphragm defect (asterisk; c). Retinoic acid signaling is thought to be essential for normal diaphragm development. A schematic representing our current knowledge regarding retinoic acid metabolism and signaling in the pleuroperitoneal fold (PPF), a key structure in the developing diaphragm is presented (d). This figure reflects known expression of specific genes and proteins in the PPF, as well as instances where mouse or human gene mutations have been associated with CDH. c scales bar = 500 µm. a, b, and d created with BioRender.com.