Pulmonary hypertension in patients with Noonan syndrome

Background Noonan syndrome (NS) is a RASopathy inherited in an autosomal dominant manner, mainly caused by gain-of-function variants activating the RAS/MAPK signalling pathway. Pulmonary hypertension (PH) may occur in NS, but its mechanisms, clinical characteristics, and outcomes remain poorly defined. Methods We analysed data from the French PH Network to characterize the phenotype of NS patients who develop PH, and conducted a systematic analysis of the literature. Results Seven patients were identified from the French PH Network (male/female ratio: 1.1), with a median age at PH diagnosis of 9 years (range 5–21). Genetic analysis revealed five pathogenic variants in PTPN11 and one in SOS1 . Associated features included facial dysmorphism, growth retardation, atrial septal defect and pulmonary valve stenosis. Hemodynamics showed severe precapillary PH without acute vasodilator response: mean pulmonary artery pressure 55 mmHg (40–78), cardiac output 3.95 L.min −1 (3.12–4.95) and pulmonary vascular resistance 13 WU (10–15.3). Computed tomography of the chest identified perivascular ground-glass opacities, mediastinal infiltration, dilated bronchial arteries, distal pulmonary vascular tortuosity and possible arteriovenous shunts. Five patients were treated with drugs approved for PAH. Three patients died and one underwent lung transplantation. Explanted lungs revealed plexiform lesions associated with diffuse lymphangiectasia. Twelve additional cases from the literature included seven with precapillary PH, four with postcapillary PH due to cardiomyopathy, and one without RHC. Conclusion Precapillary and postcapillary PH may complicate the course of NS, potentially in association with congenital heart defects and multisystem manifestations. Further studies are needed to better delineate the phenotype of PH in patients with NS.