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Phenotype and outcome of PAH patients carrying a TBX4 mutation

Pierre Thore 1, 2, 3 Barbara Girerd 2, 4, 5 Xavier Jaïs 2, 4, 5 Laurent Savale 2, 4, 5 Maria-Rosa Ghigna 4, 6 Mélanie Eyries 7 Marilyne Levy 8 Caroline Ovaert 9 Amélie Servettaz 10 Anne Guillaumot 1 Claire Dauphin 11 Céline Chabanne 12 Emmanuel Boiffard 13 Vincent Cottin 14 Frédéric Perros 15 Gérald Simonneau 16, 15 Olivier Sitbon 16, 15 Florent Soubrier 17 Damien Bonnet 18 Martine Rémy-Jardin 19 Ari Chaouat 20, 3 Marc Humbert 15 David Montani 16, 15
Abstract : 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.
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Submitted on : Thursday, May 7, 2020 - 9:37:57 AM
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Pierre Thore, Barbara Girerd, Xavier Jaïs, Laurent Savale, Maria-Rosa Ghigna, et al.. Phenotype and outcome of PAH patients carrying a TBX4 mutation. European Respiratory Journal, European Respiratory Society, 2020, pp.1902340. ⟨10.1183/13993003.02340-2019⟩. ⟨inserm-02566471⟩



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