Multifactorial origin of pulmonary hypertension in a child with congenital heart disease, Down syndrome, and BMPR-2 mutation

A late preterm infant had pulmonary hypertension caused by a variety of mechanisms leading to complex management. This child had complete atrioventricular septal defect associated with mild left ventricular hypoplasia and Down syndrome diagnosed prenatally. The mother had been treated by antiretroviral HIV treatment during pregnancy. Aortic coarctation was diagnosed and rapidly repaired. After surgery, he required noninvasive ventilation for persisting elevated PCO(2). Pulmonary CT scan showed normal bronchial tree, lung parenchymal abnormalities with mosaic aspect and hyperlucent zones, and indirect signs of lung hypoplasia with peripheral microbubbles. During follow-up, severe pulmonary hypertension was diagnosed on echocardiography without recoarctation, significant intracardiac shunting or diastolic dysfunction. The patient died after four months unable to be weaned from noninvasive ventilation. Post mortem lung biopsy showed abnormally muscularized arterioles with intimal fibrosis and pulmonary immaturity. Gentetic screening identified a BMPR-2 mutation. This patient illustrates the multifactorial origin of pulmonary hypertension in the neonatal period. The respective contribution of left-to-right shunt, post-capillary obstruction, and abnormally elevated pulmonary vascular resistances led to perform right heart catheterization to exclude excessive shunting and restrictive physiology of the left heart. Subjects with Down syndrome are also highly susceptible to decreased lung vascular and alveolar growth, which may increase the risk for pulmonary hypertension and lung hypoplasia. This case highlights two issues. The first one is that right heart catheterization should be discussed in neonates with unexplained pulmonary hypertension and the second is to extend indications of genetic testing for pulmonary hypertension genes in neonates who have unusual course of neonatal pulmonary hypertension, particularly in the setting of associated congenital heart disease (CHD).