Phenotype characterisation of TBX4 mutation and deletion carriers with neonatal and pediatric pulmonary hypertension
- Csaba Galambos1,*,
- Mary P. Mullen2,*,
- Joseph T. Shieh3,
- Nicolaus Schwerk4,
- Matthew J. Kielt5,
- Nicola Ullmann6,
- Renata Boldrini7,
- Irena Stucin-Gantar8,
- Cristina Haass9,
- Manish Bansal10,
- Pankaj B. Agrawal11,
- Joyce Johnson12,
- Donatella Peca7,
- Cecilia Surace7,
- Renato Cutrera6,
- Michael W. Pauciulo13,
- William C. Nichols13,
- Matthias Griese14,
- Dunbar Ivy15,
- Steven H. Abman16,
- Eric D. Austin5 and
- Olivier Danhaive17,18⇑
- 1Departments of Pathology and Laboratory Medicine, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado
- 2Department of Cardiology, Boston Children's Hospital and Pediatrics Harvard Medical School, Boston, Massachusetts, USA
- 3Institute for Human Genetics, Medical Genetics, University of California San Francisco, UCSF Benioff Children's Hospital, San Francisco, California, USA
- 4Clinic for Pediatric Pulmonology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
- 5Division of Pediatric Pulmonology, Vanderbilt University Medical Center
Nashville, Tennessee, US - 6Division of Pediatric Pulmonology, Bambino Gesù Children's Hospital, Rome, Italy
- 7Department of Laboratory Medicine, Bambino Gesù Children's Hospital, Rome, Italy
- 8Division of Perinatology, University Medical Centre, Ljubljana, Slovenia
- 9Division of Neonatology, San Pietro-Fatebenefratelli Hospital, Rome, Italy
- 10Division of Pediatric Cardiology, University of Iowa Children's Hospital, Iowa City, Iowa, USA
- 11Division of Newborn Medicine and Genetics & Genomics, Harvard School of Medicine, Boston Children's Hospital, Massachusetts, USA
- 12Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- 13Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- 14Division of Pediatric Pulmonology, Ludwig-Maximilians-University, Munich, Germany
- 15Division of Pediatric Cardiology, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA
- 16Division of Pulmonary Medicine, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA
- 17Division of Neonatology, University of California San Francisco Benioff Children's Hospital, San Francisco, California, USA
- 18Division of Neonatology, Catholic University of Louvain, Brussels, Belgium
- Olivier Danhaive. E-mail: olivier.danhaive{at}ucsf.edu
* Contributed equally to work as co – first-authors
Abstract
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.
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. 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 studies
Conflict 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.
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- Copyright ©ERS 2019