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

Pierre Thoré, Barbara Girerd, Xavier Jaïs, Laurent Savale, Maria-Rosa Ghigna, Mélanie Eyries, Marilyne Levy, Caroline Ovaert, Amélie Servettaz, Anne Guillaumot, Claire Dauphin, Céline Chabanne, Emmanuel Boiffard, Vincent Cottin, Frédéric Perros, Gérald Simonneau, Olivier Sitbon, Florent Soubrier, Damien Bonnet, Martine Remy-Jardin, Ari Chaouat, Marc Humbert, David Montani
European Respiratory Journal 2020 55: 1902340; DOI: 10.1183/13993003.02340-2019
Pierre Thoré
1Assistance Publique-Hôpitaux de Paris, Dept of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
2Centre Hospitalier Régional Universitaire de Nancy, Département de Pneumologie, Hôpital de Brabois, Vandoeuvre-lès-Nancy, France
3Inserm UMR_S 1116, Défaillance Cardiovasculaire Aigüe et Chronique, Faculté de Médecine de Nancy, Université de Lorraine, Nancy, France
16These authors contributed equally
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Barbara Girerd
1Assistance Publique-Hôpitaux de Paris, Dept of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
4School of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France
5INSERM UMR_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hôpital Marie Lannelongue, Le Plessis-Robinson, France
16These authors contributed equally
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Xavier Jaïs
1Assistance Publique-Hôpitaux de Paris, Dept of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
4School of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France
5INSERM UMR_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hôpital Marie Lannelongue, Le Plessis-Robinson, France
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Laurent Savale
1Assistance Publique-Hôpitaux de Paris, Dept of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
4School of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France
5INSERM UMR_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hôpital Marie Lannelongue, Le Plessis-Robinson, France
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Maria-Rosa Ghigna
5INSERM UMR_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hôpital Marie Lannelongue, Le Plessis-Robinson, France
6Service d'Anatomopathologie, Hôpital Marie Lannelongue, Le Plessis Robinson, France
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Mélanie Eyries
7Assistance Publique-Hôpitaux de Paris, UF d'Oncogénétique et Angiogénétique Moléculaire, Département de Génétique, Groupement Hospitalier Pitié Salpêtrière-Charles Foix, Hôpital Pitié Salpêtrière, Paris, France
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Marilyne Levy
8Assistance Publique-Hôpitaux de Paris, Service de Cardiologie Pédiatrique, Hôpital Necker Enfants Malades, Paris, France
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Caroline Ovaert
9Assistance Publique-Hôpitaux de Marseille, Service Médico-Chirurgical de Cardiologie Pédiatrique et Congénitale, Hôpital de la Timone, Marseille, France
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Amélie Servettaz
10Centre Hospitalier Universitaire de Reims, Service de Médecine Interne, Maladies Infectieuses et Immunologie Clinique, Hôpital Robert Debré, Reims, France
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Anne Guillaumot
2Centre Hospitalier Régional Universitaire de Nancy, Département de Pneumologie, Hôpital de Brabois, Vandoeuvre-lès-Nancy, France
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Claire Dauphin
11Centre Hospitalier Universitaire de Clermont-Ferrand, Service de Cardiologie et Maladies Vasculaires, Hôpital Gabriel Montpied, Clermont-Ferrand, France
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Céline Chabanne
12Centre Hospitalier Universitaire de Rennes, Service de Cardiologie et Maladies Vasculaires, Centre Cardio-Pneumologique, Rennes, France
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Emmanuel Boiffard
13Centre Hospitalier Départemental de Vendée, Service de Cardiologie, Hôpital de La Roche sur Yon, La Roche sur Yon, France
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Vincent Cottin
14Centre Hospitalier Universitaire de Lyon HCL, Service de Pneumologie, Centre de Référence des Maladies Pulmonaires Rares, Groupement Hospitalier Est, Hôpital Louis Pradel, Bron, France
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Frédéric Perros
1Assistance Publique-Hôpitaux de Paris, Dept of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
4School of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France
5INSERM UMR_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hôpital Marie Lannelongue, Le Plessis-Robinson, France
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Gérald Simonneau
1Assistance Publique-Hôpitaux de Paris, Dept of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
4School of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France
5INSERM UMR_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hôpital Marie Lannelongue, Le Plessis-Robinson, France
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Olivier Sitbon
1Assistance Publique-Hôpitaux de Paris, Dept of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
4School of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France
5INSERM UMR_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hôpital Marie Lannelongue, Le Plessis-Robinson, France
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Florent Soubrier
6Service d'Anatomopathologie, Hôpital Marie Lannelongue, Le Plessis Robinson, France
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Damien Bonnet
8Assistance Publique-Hôpitaux de Paris, Service de Cardiologie Pédiatrique, Hôpital Necker Enfants Malades, Paris, France
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Martine Remy-Jardin
15Centre Hospitalier Universitaire de Lille, Service d'Imagerie Thoracique, Hôpital Albert Calmette, Lille, France
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Ari Chaouat
2Centre Hospitalier Régional Universitaire de Nancy, Département de Pneumologie, Hôpital de Brabois, Vandoeuvre-lès-Nancy, France
3Inserm UMR_S 1116, Défaillance Cardiovasculaire Aigüe et Chronique, Faculté de Médecine de Nancy, Université de Lorraine, Nancy, France
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Marc Humbert
1Assistance Publique-Hôpitaux de Paris, Dept of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
4School of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France
5INSERM UMR_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hôpital Marie Lannelongue, Le Plessis-Robinson, France
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David Montani
1Assistance Publique-Hôpitaux de Paris, Dept of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
4School of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France
5INSERM UMR_S 999, Pulmonary Hypertension: Pathophysiology and Novel Therapies, Hôpital Marie Lannelongue, Le Plessis-Robinson, France
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  • For correspondence: david.montani@aphp.fr
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Abstract

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 (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.

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.

Abstract

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 parenchymal abnormalities, alveolar and pulmonary vascular remodelling, and low DLCO. http://bit.ly/38jM37U

Footnotes

  • This article has an editorial commentary: https://doi.org/10.1183/13993003.00585-2020

  • This article has supplementary material available from erj.ersjournals.com

  • Conflict of interest: P. Thoré has nothing to disclose.

  • Conflict of interest: B. Girerd has nothing to disclose.

  • Conflict of interest: X. Jaïs 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.

  • Received December 10, 2019.
  • Accepted February 5, 2020.
  • Copyright ©ERS 2020
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Phenotype and outcome of pulmonary arterial hypertension patients carrying a TBX4 mutation
Pierre Thoré, Barbara Girerd, Xavier Jaïs, Laurent Savale, Maria-Rosa Ghigna, Mélanie Eyries, Marilyne Levy, Caroline Ovaert, Amélie Servettaz, Anne Guillaumot, Claire Dauphin, Céline Chabanne, Emmanuel Boiffard, Vincent Cottin, Frédéric Perros, Gérald Simonneau, Olivier Sitbon, Florent Soubrier, Damien Bonnet, Martine Remy-Jardin, Ari Chaouat, Marc Humbert, David Montani
European Respiratory Journal May 2020, 55 (5) 1902340; DOI: 10.1183/13993003.02340-2019

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Phenotype and outcome of pulmonary arterial hypertension patients carrying a TBX4 mutation
Pierre Thoré, Barbara Girerd, Xavier Jaïs, Laurent Savale, Maria-Rosa Ghigna, Mélanie Eyries, Marilyne Levy, Caroline Ovaert, Amélie Servettaz, Anne Guillaumot, Claire Dauphin, Céline Chabanne, Emmanuel Boiffard, Vincent Cottin, Frédéric Perros, Gérald Simonneau, Olivier Sitbon, Florent Soubrier, Damien Bonnet, Martine Remy-Jardin, Ari Chaouat, Marc Humbert, David Montani
European Respiratory Journal May 2020, 55 (5) 1902340; DOI: 10.1183/13993003.02340-2019
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