Phenotype characterisation of TBX4 mutation and deletion carriers with neonatal and pediatric pulmonary hypertension

Csaba Galambos, Mary P Mullen, Joseph T Shieh, Nicolaus Schwerk, Matthew J Kielt, Nicola Ullmann, Renata Boldrini, Irena Stucin-Gantar, Cristina Haass, Manish Bansal, Pankaj B Agrawal, Joyce Johnson, Donatella Peca, Cecilia Surace, Renato Cutrera, Michael W Pauciulo, William C Nichols, Matthias Griese, Dunbar Ivy, Steven H AbmanEric D Austin, Olivier Danhaive

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
JournalEuropean Respiratory Journal
Publication statusE-pub ahead of print - May 31 2019


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