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. 2025 Mar 6;65(3):2401132.
doi: 10.1183/13993003.01132-2024. Print 2025 Mar.

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

Laura Stourm  1   2   3 , Julien Grynblat  4   5   6   3 , Laurent Savale  5   6   7 , Thomas Lacoste-Palasset  5   6   7 , Xavier Jaïs  5   6   7 , Florence Coulet  8 , Marilyne Levy  4 , Olivier Meyrignac  9 , Maria-Rosa Ghigna  6   10 , Vincent Cottin  11 , Olivier Sitbon  5   6   7 , Damien Bonnet  4 , Francois Goupil  1 , Marc Humbert  5   6   7 , Frederic Gagnadoux  2 , David Montani  12   6   7 ; French PH Network PULMOTENSION Investigators
Affiliations

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

Laura Stourm et al. Eur Respir J. .

Abstract

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.

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Conflict of interest statement

Conflicts of interest: L. Stourm declares having received support for attending the 2024 European Respiratory Society Congress from Respifil. L. Savale reports grants from Merck Sharp & Dohme, KEROS and Gossamer, payment or honoraria for lectures, presentations, manuscript writing or educational events from MSD, and support for attending meetings from Merck Sharp & Dohme and Johnson & Johnson. T. Lacoste-Palasset declares having received support for attending the 2024 European Respiratory Society Congress. X. Jaïs declares grants or contracts to their institution from Janssen and Bayer HealthCare, and consulting fees and payments or honoraria from Merck Sharp & Dohme. V. Cottin declares consulting fees and payments or honoraria from Ferrer and United Therapeutics, and participation on a data safety monitoring board or advisory board for Galapagos, Galecto and GSK. O. Sitbon declares grants paid to their institution from Janssen, AOP Orphan, Aerovate, Ferrer, Gossamer Bio and Merck Sharp & Dohme, consulting fees from Janssen, Ferrer, AOP Health, Gossamer Bio, Merck Sharp & Dohme, Enzyvant, Liquidia, Respira Therapeutics and Roivant Sciences, speaker fees from Janssen, AOP Health, Ferrer, Merck Sharp & Dohme and Aerovate, support for attending steering committee meetings from Janssen, Gossamer Bio, Enzyvant and Ferrer, and advisory board membership for Janssen, AOP Health, Ferrer, Merck Sharp & Dohme, Enzyvant, Gossamer Bio, Respira Therapeutics, Roivant Sciences and Liquidia. D. Bonnet declares consulting fees from Janssen and Merck, and participation on an advisory board for Lupin. M. Humbert declares grants or contracts to their institution from Acceleron, AOP Orphan, Janssen, Merck and Shou Ti, consulting fees from Acceleron, Aerovate, Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck, MorphogenIX, Shou Ti and United Therapeutics, payments or honoraria from Janssen and Merck, and participation on a data safety monitoring board or advisory board for Acceleron, Altavant, Janssen, Merck and United Therapeutics. F. Gagnadoux declares support for attending meetings and/or travel from Merck Sharp & Dohme. D. Montani declares grants or contracts to their institution from Acceleron, Janssen and Merck Sharp & Dohme, consulting fees (pulmonary hypertension steering committee) from Acceleron, Merck Sharp & Dohme, Janssen and Ferrer, and payment or honoraria for speaking at conferences from Bayer, Janssen, Boehringer, Chiesi, GSK, Ferrer and Merck Sharp & Dohme. All other authors declare no competing interests.

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