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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