Pulmonary hypertension in patients carrying FLNA loss-of-function variants.

Background: Pulmonary hypertension (PH) is an unusual complication of X-linked disease caused by loss-of-function (LOF) variants in the filamin A (FLNA) gene. Patients with FLNA LOF may also present dysmorphic facial features, aortic dilation, thrombocytopenia and periventricular nodular heterotopia (PVNH).

Methods: We reported the clinical, functional, haemodynamic and radiological characteristics of patients with FLNA LOF variants and PH from the French PH Network.

Results: Nine patients were identified with a female:male ratio of 8:1. PH was diagnosed at a median (range) age of 36 (0-69) years. Associated conditions included epilepsy (n=5), PVNH (n=7), valvular heart disease (n=8), congenital heart diseases (n=4), thrombocytopenia (n=4) and hyperlaxity (n=4). Right heart catheterisation confirmed moderate-to-severe pre-capillary PH with a median (range) mean pulmonary arterial pressure of 33 (22-49) mmHg and pulmonary vascular resistance of 4.7 (2.4-8.0) WU. The median (range) diffusing capacity of the lung for carbon monoxide corrected for haemoglobin was markedly decreased (48% (22-64%) of predicted values) and five patients had obstructive ventilatory disorder. High-resolution computed tomography showed heterogeneous parenchyma (n=8), emphysema (n=3), presence of a peripheral hyperclear band (n=3) and aortic ectasia (n=4). Pathological assessment available in one patient revealed significant remodelling of small pulmonary arteries, interstitial oedema and irregular alveoli shapes. During follow-up, three patients died, including two from right heart failure. No patient died from aortic rupture.

Conclusions: Pre-capillary PH, likely due to multiple mechanisms, may complicate the course of patients with FLNA LOF variants and may be the presenting symptom leading to diagnosis. The combination of PH with parenchymal involvement and extrapulmonary symptoms (epilepsy, congenital heart diseases, valvular and aortic involvement, and thrombocytopenia) should prompt genetic screening for FLNA.