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

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.

Low maternal vitamin A intake increases the incidence of teratogen induced congenital diaphragmatic hernia in mice.

BACKGROUND: Congenital diaphragmatic hernia (CDH) is a severe birth defect associated with high perinatal mortality and long-term morbidity. The etiology of CDH is poorly understood although abnormal retinoid signaling has been proposed to contribute to abnormal diaphragm development. Existing epidemiological data suggest that inadequate dietary vitamin A intake is a risk factor for developing CDH. METHODS: Using a mouse model of teratogen-induced CDH, the objective of this study was to test the hypothesis that low maternal vitamin A intake contributes to abnormal diaphragm development. To test this hypothesis, we optimized a model of altered maternal dietary vitamin A intake and a teratogenic model of CDH in mice that recapitulates the hallmark features of posterolateral diaphragmatic hernia in humans. RESULTS: Our data uniquely show that low maternal dietary vitamin A intake and marginal vitamin A status increases the incidence of teratogen-induced CDH in mice. CONCLUSION: Low dietary vitamin A intake and marginal vitamin A status lead to an increased incidence of teratogen-induced CDH in mice, highlighting the importance of adequate dietary vitamin A intake and CDH risk. IMPACT: This study describes and validates a mouse model of altered maternal and fetal vitamin A status. This study links existing epidemiological data with a mouse model of teratogen-induced congenital diaphragmatic hernia, highlighting the importance of low maternal vitamin A intake as a risk factor for the development of congenital diaphragmatic hernia. This study supports the Retinoid Hypothesis, which posits that the etiology of congenital diaphragmatic hernia is linked to abnormal retinoid signaling in the developing diaphragm.