RT Journal Article SR Electronic T1 Phenotype and outcome of PAH patients carrying a TBX4 mutation JF European Respiratory Journal JO Eur Respir J FD European Respiratory Society SP 1902340 DO 10.1183/13993003.02340-2019 A1 Pierre Thoré A1 Barbara Girerd A1 Xavier Jaïs A1 Laurent Savale A1 Maria-Rosa Ghigna A1 Mélanie Eyries A1 Marilyne Levy A1 Caroline Ovaert A1 Amélie Servettaz A1 Anne Guillaumot A1 Claire Dauphin A1 Céline Chabanne A1 Emmanuel Boiffard A1 Vincent Cottin A1 Frédéric Perros A1 Gérald Simonneau A1 Olivier Sitbon A1 Florent Soubrier A1 Damien Bonnet A1 Martine Remy-Jardin A1 Ari Chaouat A1 Marc Humbert A1 David Montani YR 2020 UL http://erj.ersjournals.com/content/early/2020/02/06/13993003.02340-2019.abstract AB Introduction TBX4 mutation cause small patella syndrome (SPS) and/or pulmonary arterial hypertension (PAH). The characteristics and outcomes of PAH associated with TBX4 mutations are largely unknown.Methods We report the clinical, functional, radiologic, histologic and haemodynamic characteristics and outcomes of heritable PAH patients carrying a TBX4 mutation from the French PH Network.Results Twenty patients were identified in 17 families. They were characterised by a median age at diagnosis of 29 (0–76) year-old and a female to male ratio of 3. Most of the patients were in NYHA functional class III or IV (70%) with a severe hemodynamic impairment (median pulmonary vascular resistance of 13.6 [6.2–41.8] Wood Units). Skeletal signs of SPS were present in 80% of cases. Half of the patients had mild restrictive or obstructive limitation and diffusing capacity for carbon monoxide was decreased in all patients. High-resolution computed tomography showed bronchial abnormalities, peri-bronchial cysts, mosaic distribution and mediastinal lymphadenopathies. PAH therapy was associated with significant clinical improvement. At follow-up (median 76 months), two patients died and two underwent lung transplantation. One-, three- and five-year event-free survival rates were 100%, 94% and 83%, respectively. Histologic examination of explanted lungs revealed alveolar growth abnormalities, major pulmonary vascular remodelling similar to that observed in idiopathic PAH, and accumulation of cholesterol crystals within the lung parenchyma.Conclusion PAH due to TBX4 mutations may occur with or without skeletal abnormalities across a broad age range from birth to late adulthood. PAH is usually severe and associated with bronchial and parenchymal abnormalities.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr Thoré has nothing to disclose.Conflict of interest: Dr Girerd has nothing to disclose.Conflict of interest: Dr Jaïs reports grants and personal fees from Actelion, grants and personal fees from MSD, grants from Bayer, outside the submitted work.Conflict of interest: Dr SAVALE reports grants, personal fees and non-financial support from Actelion, grants and personal fees from MSD, non-financial support from GSK, outside the submitted work.Conflict of interest: Dr Ghigna has nothing to disclose.Conflict of interest: Dr EYRIES has nothing to disclose.Conflict of interest: Dr Levy has nothing to disclose.Conflict of interest: Dr Ovaert has nothing to disclose.Conflict of interest: Dr Servettaz has nothing to disclose.Conflict of interest: Dr GUILLAUMOT has nothing to disclose.Conflict of interest: Dr Dauphin has nothing to disclose.Conflict of interest: Dr Chabanne has nothing to disclose.Conflict of interest: Dr Boiffard has nothing to disclose.Conflict of interest: Dr Cottin reports personal fees and non-financial support from Actelion, grants, personal fees and non-financial support from Boehringer Ingelheim, personal fees from Bayer / MSD, personal fees from Gilead, personal fees from Novartis, personal fees and non-financial support from Roche SAS, personal fees from Sanofi, personal fees from Promedior, personal fees from Celgene, personal fees from Galapagos, personal fees from Galecto, outside the submitted work.Conflict of interest: Dr Perros has nothing to disclose.Conflict of interest: Dr Simonneau reports grants, personal fees and non-financial support from Actelion, grants, personal fees and non-financial support from Bayer, grants, personal fees and non-financial support from GSK, grants, personal fees and non-financial support from Merck, outside the submitted work.Conflict of interest: Dr Sitbon reports grants, personal fees and non-financial support from Actelion Pharmaceuticals, personal fees from Acceleron Pharmaceuticals, grant, personal fees and non-financial support from Bayer HealthCare, personal fees from Ferrer, grants from GlaxoSmithKline, personal fees from Gossamer Bio, grants, personal fees and non-financial support from MSD, personal fees from United Therapeutics, outside the submitted work.Conflict of interest: Dr Soubrier has nothing to disclose.Conflict of interest: Dr BONNET reports personal fees from Actelion Pharmaceuticals, personal fees from Eli Lilly, personal fees from Novartis, outside the submitted work.Conflict of interest: Dr Remy Jardin has nothing to disclose.Conflict of interest: Dr Chaouat has nothing to disclose.Conflict of interest: Dr Humbert reports personal fees from Acceleron, personal fees from Actelion, grants and personal fees from Bayer, grants and personal fees from GSK, personal fees from MSD, personal fees from United Therapeutics, outside the submitted work.Conflict of interest: Dr MONTANI reports grants and personal fees from Actelion, grants and personal fees from Bayer, personal fees from GSK, personal fees from Pfizer, personal fees from MSD, personal fees from Chiesi, outside the submitted work.