RT Journal Article SR Electronic T1 Phenotype characterisation of TBX4 mutation and deletion carriers with neonatal and pediatric pulmonary hypertension JF European Respiratory Journal JO Eur Respir J FD European Respiratory Society SP 1801965 DO 10.1183/13993003.01965-2018 A1 Csaba Galambos A1 Mary P. Mullen A1 Joseph T. Shieh A1 Nicolaus Schwerk A1 Matthew J. Kielt A1 Nicola Ullmann A1 Renata Boldrini A1 Irena Stucin-Gantar A1 Cristina Haass A1 Manish Bansal A1 Pankaj B. Agrawal A1 Joyce Johnson A1 Donatella Peca A1 Cecilia Surace A1 Renato Cutrera A1 Michael W. Pauciulo A1 William C. Nichols A1 Matthias Griese A1 Dunbar Ivy A1 Steven H. Abman A1 Eric D. Austin A1 Olivier Danhaive YR 2019 UL http://erj.ersjournals.com/content/early/2019/04/25/13993003.01965-2018.abstract AB Rare variants in the T-Box transcription factor 4 gene (TBX4) have been recently recognised as an emerging cause of pediatric pulmonary hypertension (PH). Their pathophysiology and contribution to persistent pulmonary hypertension in neonates (PPHN) are unknown. We sought to define the spectrum of clinical manifestations and histopathology associated with TBX4 variants in neonates and children with PH. We assessed clinical data and lung tissue in 19 children with PH, including PPHN, carrying TBX4 rare variants identified by next generation sequencing and copy number variation arrays. Variants included 6 17q23 deletions encompassing the entire TBX4 locus and neighbouring genes, and 12 likely damaging mutations. 10 infants presented with neonatal hypoxic respiratory failure and PPHN, and were subsequently discharged home. PH was diagnosed later in infancy or childhood. Three children died and 2 required lung transplantation. Associated anomalies included patent ductus arteriosus, septal defects, foot anomalies and developmental disability, the latter with a higher prevalence in deletion carriers. Histology in seven infants showed abnormal distal lung development and pulmonary hypertensive remodelling. TBX4 mutations and 17q23 deletions underlie a new form of developmental lung disease manifesting with severe, often biphasic pulmonary hypertension at birth and/or later in infancy and childhood, often associated with skeletal anomalies, cardiac defects neurodevelopmental disability and other anomalies.FootnotesThis 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. Surace has nothing to disclose.Conflict of interest: Dr. Shieh has nothing to disclose.Conflict of interest: Dr. Abman has nothing to disclose.Conflict of interest: Dr. Schwerk has nothing to disclose.Conflict of interest: Dr. Austin has nothing to disclose.Conflict of interest: Dr. Peca has nothing to disclose.Conflict of interest: Dr. Agrawal has nothing to disclose.Conflict of interest: Dr. Galambos has nothing to disclose.Conflict of interest: Dr. Griese has nothing to disclose.Conflict of interest: Dr. Nichols has nothing to disclose.Conflict of interest: Dr. Stucin Gantar has nothing to disclose.Conflict of interest: Dr. Haass has nothing to disclose.Conflict of interest: Dr. Ullmann has nothing to disclose.Conflict of interest: Dr. Danhaive has nothing to disclose.Conflict of interest: The University of Colorado School of medicine contracts with Actelion, Bayer, Lilly and United Therapeutics for Dr Ivy to be a consultant and perform research studiesConflict of interest: Dr. Johnson has nothing to disclose.Conflict of interest: Dr. Kielt has nothing to disclose.Conflict of interest: Dr. Cutrera has nothing to disclose.Conflict of interest: Dr. Boldrini has nothing to disclose.Conflict of interest: Dr. Bansal has nothing to disclose.Conflict of interest: Dr. Pauciulo has nothing to disclose.Conflict of interest: Dr. Mullen reports other from United Therapeutics, non-financial support and other from Actelion, other from Ikaria, other from GSK, outside the submitted work.