TY - JOUR T1 - Phenotype characterisation of <em>TBX4</em> mutation and deletion carriers with neonatal and pediatric pulmonary hypertension JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.01965-2018 SP - 1801965 AU - Csaba Galambos AU - Mary P. Mullen AU - Joseph T. Shieh AU - Nicolaus Schwerk AU - Matthew J. Kielt AU - Nicola Ullmann AU - Renata Boldrini AU - Irena Stucin-Gantar AU - Cristina Haass AU - Manish Bansal AU - Pankaj B. Agrawal AU - Joyce Johnson AU - Donatella Peca AU - Cecilia Surace AU - Renato Cutrera AU - Michael W. Pauciulo AU - William C. Nichols AU - Matthias Griese AU - Dunbar Ivy AU - Steven H. Abman AU - Eric D. Austin AU - Olivier Danhaive Y1 - 2019/01/01 UR - http://erj.ersjournals.com/content/early/2019/04/25/13993003.01965-2018.abstract N2 - 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. ER -