Pathogenesis of congenital diaphragmatic hernia: Additional clues regarding the involvement of the endothelin system

Abstract

Congenital diaphragmatic hernia (CDH) has an incidence of around 1/3,000 births. The pathogenesis of this developmental anomaly remains largely unknown and the description of small chromosomal imbalances in cases of CDH is of major interest for the identification of candidate genes. We report on a tandem 4q31.23 triplication encompassing the EDNRA gene identified by array-CGH in a male presenting an isolated left postero-lateral CDH. This copy number variation was inherited from the asymptomatic father, carrier of a size-identical duplication. We demonstrate that EDNRA mRNA is over-expressed in the proband in blood tissue. Consistent with the expression of EDNRA in the developing diaphragm and the observation that the endothelin system is up-regulated in human and animal models of CDH, we conclude that the EDNRA triplication may be the cause of CDH in our patient.

A Sudden Infant Death Due to Congenital Diaphragmatic Hernia

“…Reported incidence rates for CDH range from one in 2000 to as low as one in 5000 live births (2–6), comprising approximately 8% of major congenital malformations (5). Males are more frequently affected than females by a ratio of 1.5:1 (5).…”

“…Development of the diaphragm begins during the fourth week of gestation and typically concludes between the eighth and twelfth weeks (1, 4, 7). The embryological components forming the diaphragm include the septum transversum, the dorsal mesentery of the esophagus, the pleuroperitoneal folds (PPF), and dorsal and dorsolateral body wall (1, 4, 7). Two PPF—ventral and medial mesenchymal structures that facilitate migration of pre-muscle and nervous cells—form the primordial posterolateral aspect of the diaphragm (1, 4).…”

“…The embryological components forming the diaphragm include the septum transversum, the dorsal mesentery of the esophagus, the pleuroperitoneal folds (PPF), and dorsal and dorsolateral body wall (1, 4, 7). Two PPF—ventral and medial mesenchymal structures that facilitate migration of pre-muscle and nervous cells—form the primordial posterolateral aspect of the diaphragm (1, 4). The PPF merge with the esophageal mesentery and the anterior central tendon from the ventral body wall, the septum transversum, which also contributes to the partition of the coelom, the stomach, and the duodenum (1, 4, 7).…”

“…Two PPF—ventral and medial mesenchymal structures that facilitate migration of pre-muscle and nervous cells—form the primordial posterolateral aspect of the diaphragm (1, 4). The PPF merge with the esophageal mesentery and the anterior central tendon from the ventral body wall, the septum transversum, which also contributes to the partition of the coelom, the stomach, and the duodenum (1, 4, 7). Fusion of these components completes the barrier between the abdomen and thorax (7).…”

Pulmonary hypertension in chronic lung disease of infancy

“…implicated in neonatal pulmonary hypertension in association with congenital diaphragmatic hernia, as well as in prematurity [14,15]. Ratner et al have shown that pulmonary mitochondrial dysfunction leads to delayed alveolarization secondary to mechanical ventilation and hyperoxia in neonatal mice [16,17].…”