PMID- 32079640 OWN - NLM STAT- MEDLINE DCOM- 20210216 LR - 20210216 IS - 1399-3003 (Electronic) IS - 0903-1936 (Linking) VI - 55 IP - 5 DP - 2020 May TI - Phenotype and outcome of pulmonary arterial hypertension patients carrying a TBX4 mutation. LID - 1902340 [pii] LID - 10.1183/13993003.02340-2019 [doi] AB - INTRODUCTION: TBX4 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. METHODS: We 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. RESULTS: 20 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 (D (LCO)) 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. 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. CI - Copyright (c)ERS 2020. FAU - Thore, Pierre AU - Thore P AUID- ORCID: 0000-0001-7378-2419 AD - Assistance Publique-Hopitaux de Paris, Dept of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hopital Bicetre, Le Kremlin-Bicetre, France. AD - Centre Hospitalier Regional Universitaire de Nancy, Departement de Pneumologie, Hopital de Brabois, Vandoeuvre-les-Nancy, France. AD - Inserm UMR_S 1116, Defaillance Cardiovasculaire Aigue et Chronique, Faculte de Medecine de Nancy, Universite de Lorraine, Nancy, France. AD - These authors contributed equally. FAU - Girerd, Barbara AU - Girerd B AD - Assistance Publique-Hopitaux de Paris, Dept of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hopital Bicetre, Le Kremlin-Bicetre, France. AD - School of Medicine, Universite Paris-Saclay, Le Kremlin-Bicetre, France. AD - INSERM UMR_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hopital Marie Lannelongue, Le Plessis-Robinson, France. AD - These authors contributed equally. FAU - Jais, Xavier AU - Jais X AD - Assistance Publique-Hopitaux de Paris, Dept of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hopital Bicetre, Le Kremlin-Bicetre, France. AD - School of Medicine, Universite Paris-Saclay, Le Kremlin-Bicetre, France. AD - INSERM UMR_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hopital Marie Lannelongue, Le Plessis-Robinson, France. FAU - Savale, Laurent AU - Savale L AUID- ORCID: 0000-0002-6862-8975 AD - Assistance Publique-Hopitaux de Paris, Dept of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hopital Bicetre, Le Kremlin-Bicetre, France. AD - School of Medicine, Universite Paris-Saclay, Le Kremlin-Bicetre, France. AD - INSERM UMR_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hopital Marie Lannelongue, Le Plessis-Robinson, France. FAU - Ghigna, Maria-Rosa AU - Ghigna MR AUID- ORCID: 0000-0001-5996-665X AD - INSERM UMR_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hopital Marie Lannelongue, Le Plessis-Robinson, France. AD - Service d'Anatomopathologie, Hopital Marie Lannelongue, Le Plessis Robinson, France. FAU - Eyries, Melanie AU - Eyries M AD - Assistance Publique-Hopitaux de Paris, UF d'Oncogenetique et Angiogenetique Moleculaire, Departement de Genetique, Groupement Hospitalier Pitie Salpetriere-Charles Foix, Hopital Pitie Salpetriere, Paris, France. FAU - Levy, Marilyne AU - Levy M AD - Assistance Publique-Hopitaux de Paris, Service de Cardiologie Pediatrique, Hopital Necker Enfants Malades, Paris, France. FAU - Ovaert, Caroline AU - Ovaert C AD - Assistance Publique-Hopitaux de Marseille, Service Medico-Chirurgical de Cardiologie Pediatrique et Congenitale, Hopital de la Timone, Marseille, France. FAU - Servettaz, Amelie AU - Servettaz A AUID- ORCID: 0000-0001-5701-3863 AD - Centre Hospitalier Universitaire de Reims, Service de Medecine Interne, Maladies Infectieuses et Immunologie Clinique, Hopital Robert Debre, Reims, France. FAU - Guillaumot, Anne AU - Guillaumot A AD - Centre Hospitalier Regional Universitaire de Nancy, Departement de Pneumologie, Hopital de Brabois, Vandoeuvre-les-Nancy, France. FAU - Dauphin, Claire AU - Dauphin C AD - Centre Hospitalier Universitaire de Clermont-Ferrand, Service de Cardiologie et Maladies Vasculaires, Hopital Gabriel Montpied, Clermont-Ferrand, France. FAU - Chabanne, Celine AU - Chabanne C AD - Centre Hospitalier Universitaire de Rennes, Service de Cardiologie et Maladies Vasculaires, Centre Cardio-Pneumologique, Rennes, France. FAU - Boiffard, Emmanuel AU - Boiffard E AD - Centre Hospitalier Departemental de Vendee, Service de Cardiologie, Hopital de La Roche sur Yon, La Roche sur Yon, France. FAU - Cottin, Vincent AU - Cottin V AUID- ORCID: 0000-0002-5591-0955 AD - Centre Hospitalier Universitaire de Lyon HCL, Service de Pneumologie, Centre de Reference des Maladies Pulmonaires Rares, Groupement Hospitalier Est, Hopital Louis Pradel, Bron, France. FAU - Perros, Frederic AU - Perros F AD - Assistance Publique-Hopitaux de Paris, Dept of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hopital Bicetre, Le Kremlin-Bicetre, France. AD - School of Medicine, Universite Paris-Saclay, Le Kremlin-Bicetre, France. AD - INSERM UMR_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hopital Marie Lannelongue, Le Plessis-Robinson, France. FAU - Simonneau, Gerald AU - Simonneau G AD - Assistance Publique-Hopitaux de Paris, Dept of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hopital Bicetre, Le Kremlin-Bicetre, France. AD - School of Medicine, Universite Paris-Saclay, Le Kremlin-Bicetre, France. AD - INSERM UMR_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hopital Marie Lannelongue, Le Plessis-Robinson, France. FAU - Sitbon, Olivier AU - Sitbon O AUID- ORCID: 0000-0002-1942-1951 AD - Assistance Publique-Hopitaux de Paris, Dept of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hopital Bicetre, Le Kremlin-Bicetre, France. AD - School of Medicine, Universite Paris-Saclay, Le Kremlin-Bicetre, France. AD - INSERM UMR_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hopital Marie Lannelongue, Le Plessis-Robinson, France. FAU - Soubrier, Florent AU - Soubrier F AUID- ORCID: 0000-0003-2571-7932 AD - Service d'Anatomopathologie, Hopital Marie Lannelongue, Le Plessis Robinson, France. FAU - Bonnet, Damien AU - Bonnet D AD - Assistance Publique-Hopitaux de Paris, Service de Cardiologie Pediatrique, Hopital Necker Enfants Malades, Paris, France. FAU - Remy-Jardin, Martine AU - Remy-Jardin M AD - Centre Hospitalier Universitaire de Lille, Service d'Imagerie Thoracique, Hopital Albert Calmette, Lille, France. FAU - Chaouat, Ari AU - Chaouat A AUID- ORCID: 0000-0001-6056-202X AD - Centre Hospitalier Regional Universitaire de Nancy, Departement de Pneumologie, Hopital de Brabois, Vandoeuvre-les-Nancy, France. AD - Inserm UMR_S 1116, Defaillance Cardiovasculaire Aigue et Chronique, Faculte de Medecine de Nancy, Universite de Lorraine, Nancy, France. FAU - Humbert, Marc AU - Humbert M AUID- ORCID: 0000-0003-0703-2892 AD - Assistance Publique-Hopitaux de Paris, Dept of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hopital Bicetre, Le Kremlin-Bicetre, France. AD - School of Medicine, Universite Paris-Saclay, Le Kremlin-Bicetre, France. AD - INSERM UMR_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hopital Marie Lannelongue, Le Plessis-Robinson, France. FAU - Montani, David AU - Montani D AUID- ORCID: 0000-0002-9358-6922 AD - Assistance Publique-Hopitaux de Paris, Dept of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hopital Bicetre, Le Kremlin-Bicetre, France david.montani@aphp.fr. AD - School of Medicine, Universite Paris-Saclay, Le Kremlin-Bicetre, France. AD - INSERM UMR_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hopital Marie Lannelongue, Le Plessis-Robinson, France. LA - eng PT - Journal Article PT - Multicenter Study DEP - 20200514 PL - England TA - Eur Respir J JT - The European respiratory journal JID - 8803460 RN - 0 (T-Box Domain Proteins) RN - 0 (TBX4 protein, human) RN - Ischiopatellar dysplasia SB - IM CIN - Eur Respir J. 2020 May 14;55(5):. PMID: 32409426 MH - Adolescent MH - Adult MH - Aged MH - Bone Diseases, Developmental/complications/*genetics MH - Child MH - Child, Preschool MH - Female MH - France MH - Hip/*abnormalities MH - Humans MH - Infant MH - Infant, Newborn MH - Ischium/*abnormalities MH - Lung Transplantation MH - Male MH - Middle Aged MH - *Mutation MH - Patella/*abnormalities MH - Phenotype MH - Pulmonary Arterial Hypertension/complications/epidemiology/*genetics MH - Retrospective Studies MH - Survival Rate MH - T-Box Domain Proteins/*genetics MH - Vascular Resistance MH - Young Adult COIS- Conflict of interest: P. Thore has nothing to disclose. Conflict of interest: B. Girerd has nothing to disclose. Conflict of interest: X. Jais reports grants and personal fees from Actelion and MSD, and grants from Bayer, outside the submitted work. Conflict of interest: L. Savale reports grants, personal fees and non-financial support from Actelion, grants and personal fees from MSD, and non-financial support from GSK, outside the submitted work. Conflict of interest: M-R. Ghigna has nothing to disclose. Conflict of interest: M. Eyries has nothing to disclose. Conflict of interest: M. Levy has nothing to disclose. Conflict of interest: C. Ovaert has nothing to disclose. Conflict of interest: A. Servettaz has nothing to disclose. Conflict of interest: A. Guillaumot has nothing to disclose. Conflict of interest: C. Dauphin has nothing to disclose. Conflict of interest: C. Chabanne has nothing to disclose. Conflict of interest: E. Boiffard has nothing to disclose. Conflict of interest: V. Cottin reports personal fees for advisory board work and non-financial (travel) support from Actelion, grants and personal fees for advisory board work, lectures and steering committee work, as well as non-financial (travel) support from Boehringer Ingelheim, personal fees for advisory board work and data monitoring committee work from Bayer/MSD and Galapagos, personal fees for advisory board work from Gilead and Novartis, personal fees for advisory board work, lectures and steering committee work, as well as non-financial (travel) support from Roche SAS, personal fees for lectures and non-financial (travel) support from Sanofi, personal fees for steering committee work and data monitoring committee work from Promedior, and personal fees for data monitoring committee work from Celgene and Galecto, outside the submitted work. Conflict of interest: F.Perros has nothing to disclose. Conflict of interest: G. Simonneau reports grants, personal fees and non-financial support from Actelion, Bayer, GSK and Merck, outside the submitted work. Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from Actelion Pharmaceuticals, Bayer HealthCare and MSD, personal fees from Acceleron Pharmaceuticals, Ferrer, Gossamer Bio and United Therapeutics, and grants from GlaxoSmithKline, outside the submitted work. Conflict of interest: F. Soubrier has nothing to disclose. Conflict of interest: D. Bonnet reports personal fees for advisory board work and steering committee work from Actelion Pharmaceuticals, Eli Lilly and Novartis, outside the submitted work. Conflict of interest: M. Remy-Jardin has nothing to disclose. Conflict of interest: A. Chaouat has nothing to disclose. Conflict of interest: M. Humbert reports personal fees from Acceleron, Actelion, MSD and United Therapeutics, and grants and personal fees from Bayer and GSK, outside the submitted work. Conflict of interest: D. Montani reports grants and personal fees from Actelion and Bayer, and personal fees from GSK, Pfizer, MSD and Chiesi, outside the submitted work. EDAT- 2020/02/23 06:00 MHDA- 2021/02/17 06:00 CRDT- 2020/02/22 06:00 PHST- 2019/12/10 00:00 [received] PHST- 2020/02/05 00:00 [accepted] PHST- 2020/02/23 06:00 [pubmed] PHST- 2021/02/17 06:00 [medline] PHST- 2020/02/22 06:00 [entrez] AID - 13993003.02340-2019 [pii] AID - 10.1183/13993003.02340-2019 [doi] PST - epublish SO - Eur Respir J. 2020 May 14;55(5):1902340. doi: 10.1183/13993003.02340-2019. Print 2020 May.