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Phenotype and outcome of pulmonary arterial hypertension patients carrying a TBX4 mutation

Authors :
Caroline Ovaert
Damien Bonnet
Gérald Simonneau
Céline Chabanne
Pierre Thoré
Olivier Sitbon
Marc Humbert
Marilyne Lévy
Claire Dauphin
Florent Soubrier
Laurent Savale
E. Boiffard
Xavier Jaïs
Martine Remy-Jardin
Amélie Servettaz
Barbara Girerd
Anne Guillaumot
Ari Chaouat
Frédéric Perros
Maria-Rosa Ghigna
David Montani
Vincent Cottin
Mélanie Eyries
AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)
Défaillance Cardiovasculaire Aiguë et Chronique (DCAC)
Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)
Service de Pneumologie [CHRU Nancy]
Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)
Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT)
Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay
Université Paris-Saclay
Centre Chirurgical Marie Lannelongue (CCML)
Centre chirurgical Marie Lannelongue
Service d'Oncogénétique et Angiogénétique Moléculaire [CHU Pitié-Salpêtrière]
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP]
Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université
Service de génétique [CHU Pitié-Salpêtrière]
Service de cardiologie pédiatrique [CHU Necker]
CHU Necker - Enfants Malades [AP-HP]
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Hôpital de la Timone [CHU - APHM] (TIMONE)
Centre Hospitalier Universitaire de Reims (CHU Reims)
CHU Clermont-Ferrand
CHU Pontchaillou [Rennes]
Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon
Service de pneumologie [Centre Hospitalier Lyon Sud - HCL]
Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS)
Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)
Centre de Référence des Maladies Pulmonaires Rares [Hôpital Louis Pradel - HCL]
Hôpital Louis Pradel [CHU - HCL]
Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
Immuno-Régulation dans les Maladies Auto-Immunes Inflammatoires et le Cancer - EA 7509 (IRMAIC)
Université de Reims Champagne-Ardenne (URCA)
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP]
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Source :
European Respiratory Journal, European Respiratory Journal, European Respiratory Society, 2020, 55 (5), pp.1902340. ⟨10.1183/13993003.02340-2019⟩
Publication Year :
2020
Publisher :
HAL CCSD, 2020.

Abstract

IntroductionTBX4 mutation causes small patella syndrome (SPS) and/or pulmonary arterial hypertension (PAH). The characteristics and outcomes of PAH associated with TBX4 mutations are largely unknown.MethodsWe report the clinical, functional, radiologic, histologic and haemodynamic characteristics and outcomes of heritable PAH patients carrying a TBX4 mutation from the French pulmonary hypertension (PH) network.Results20 patients were identified in 17 families. They were characterised by a median age at diagnosis of 29 years (0–76 years) and a female to male ratio of three. Most of the patients (70%) were in New York Heart Association (NYHA) functional class III or IV with a severe haemodynamic impairment (median pulmonary vascular resistance (PVR) 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 of the lung for carbon monoxide (DLCO) was decreased in all patients. High-resolution computed tomography (HRCT) 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 had died and two had undergone lung transplantation. One-year, three-year 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 pulmonary arterial hypertension (IPAH) and accumulation of cholesterol crystals within the lung parenchyma.ConclusionPAH 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.

Details

Language :
English
ISSN :
09031936 and 13993003
Database :
OpenAIRE
Journal :
European Respiratory Journal, European Respiratory Journal, European Respiratory Society, 2020, 55 (5), pp.1902340. ⟨10.1183/13993003.02340-2019⟩
Accession number :
edsair.doi.dedup.....f84fb335c15f375a930f25e824b0ad13