Phenotype and outcome of PAH patients carrying a TBX4 mutation
- Pierre Thoré1,*,
- Barbara Girerd1,2,3,*,
- Xavier Jaïs1,2,3,
- Laurent Savale1,2,3,
- Maria-Rosa Ghigna3,4,
- Mélanie Eyries5,
- Marilyne Levy6,
- Caroline Ovaert7,
- Amélie Servettaz8,
- Anne Guillaumot9,
- Claire Dauphin10,
- Céline Chabanne11,
- Emmanuel Boiffard12,
- Vincent Cottin13,
- Frédéric Perros1,2,3,
- Gérald Simonneau1,2,3,
- Olivier Sitbon1,2,3,
- Florent Soubrier4,
- Damien Bonnet6,
- Martine Remy-Jardin14,
- Ari Chaouat9,15,
- Marc Humbert1,2,3 and
- David Montani1,2,3⇑
- 1Assistance Publique - Hôpitaux de Paris (AP-HP), Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
- 2Université Paris-Saclay, School of Medicine, Le Kremlin-Bicêtre, France
- 3INSERM UMR_S 999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, Hôpital Marie Lannelongue, Le Plessis-Robinson, France
- 4Service d'anatomopathologie, Hôpital Marie Lannelongue, Le Plessis Robinson, France
- 5Assistance Publique Hôpitaux de Paris, UF d'oncogénétique et angiogénétique moléculaire, Département de génétique, Groupement Hospitalier Pitié Salpêtrière-Charles Foix, Hôpital Pitié Salpêtrière, Paris, France
- 6Assistance Publique Hôpitaux de Paris, Service de Cardiologie pédiatrique, Hôpital Necker Enfants Malades, Paris, France
- 7Assistance Publique Hôpitaux de Marseille, Service médico-chirurgical de Cardiologie pédiatrique et congénitale, Hôpital de la Timone, Marseille, France
- 8Centre Hospitalier Universitaire de Reims, Service de Médecine interne, Maladies infectieuses et Immunologie clinique, Hôpital Robert Debré, Reims, France
- 9Centre Hospitalier Régional Universitaire de Nancy, Département de Pneumologie, Hôpital de Brabois, Vandoeuvre-lès-Nancy, France
- 10Centre Hospitalier Universitaire de Clermont-Ferrand, Service de Cardiologie et maladies vasculaires, Hôpital Gabriel Montpied, Clermont-Ferrand, France
- 11Centre Hospitalier Universitaire de Rennes, Service de Cardiologie et maladies vasculaires, Centre cardio-pneumologique, Rennes, France
- 12Centre Hospitalier Départemental de Vendée, Service de Cardiologie, Hôpital de La Roche sur Yon, La Roche sur Yon, France
- 13Centre Hospitalier Universitaire de Lyon HCL, Service de Pneumologie, Centre de Référence des Maladies Pulmonaires Rares, Groupement Hospitalier Est, Hôpital Louis Pradel, Bron, France
- 14Centre Hospitalier Universitaire de Lille, Service d'Imagerie thoracique, Hôpital Albert Calmette, Lille, France
- 15Inserm UMR_S 1116, Défaillance Cardiovasculaire Aigüe et Chronique, Faculté de Médecine de Nancy, Université de Lorraine, Nancy, France
- David Montani, Service de Pneumologie, Hôpital Bicêtre, 78, Rue du général Leclerc, 94270 Le Kremlin-Bicêtre, France. E-mail: david.montani{at}aphp.fr
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.
Footnotes
This 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.
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- Received December 10, 2019.
- Accepted February 5, 2020.
- Copyright ©ERS 2020