Noonan综合征患者的肺动脉高压特征

原文

BACKGROUND: Noonan syndrome is a RASopathy inherited in an autosomal dominant manner, mainly caused by gain-of-function variants activating the RAS/mitogen-activated protein kinase signalling pathway. Pulmonary hypertension (PH) may occur in Noonan syndrome, but its mechanisms, clinical characteristics and outcomes remain poorly defined. METHODS: We analysed data from the French PH Network to characterise the phenotype of Noonan syndrome 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 1.3:1), with a median (range) age at PH diagnosis of 9 (5-21) years. Genetic analysis revealed five pathogenic variants in PTPN11 and one in SHOC2. Associated features included facial dysmorphism, growth retardation, atrial septal defect and pulmonary valve stenosis. Haemodynamics showed severe pre-capillary PH without acute vasodilator response: mean pulmonary arterial pressure 55 (40-78) mmHg, cardiac output 3.95 (3.12-4.95) L·min-1 and pulmonary vascular resistance 13 (10-15.3) WU. 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 pulmonary arterial hypertension. Three patients died and one underwent lung transplantation. Explanted lungs revealed plexiform lesions associated with diffuse lymphangiectasia. 12 additional cases from the literature included seven with pre-capillary PH, four with post-capillary PH due to cardiomyopathy and one without right heart catheterisation. CONCLUSION: Pre-capillary and post-capillary PH may complicate the course of Noonan syndrome, potentially in association with congenital heart defects and multisystem manifestations. Further studies are needed to better delineate the phenotype of PH in patients with Noonan syndrome.