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Eur Respir J. 2019 Aug 22;54(2). pii: 1801965. doi: 10.1183/13993003.01965-2018. Print 2019 Aug.

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

Author information

1
Dept of Pathology and Laboratory Services, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO, USA.
2
Contributed equally to this work as joint first authors.
3
Dept of Cardiology, Boston Children's Hospital and Pediatrics Harvard Medical School, Boston, MA, USA.
4
Institute for Human Genetics, Medical Genetics, University of California San Francisco, UCSF Benioff Children's Hospital, San Francisco, CA, USA.
5
Clinic for Pediatric Pulmonology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.
6
Division of Pediatric Pulmonology, Vanderbilt University Medical Center, Nashville, TN, USA.
7
Division of Pediatric Pulmonology, Bambino Gesù Children's Hospital, Rome, Italy.
8
Dept of Laboratory Medicine, Bambino Gesù Children's Hospital, Rome, Italy.
9
Division of Perinatology, University Medical Centre, Ljubljana, Slovenia.
10
Division of Neonatology, San Pietro-Fatebenefratelli Hospital, Rome, Italy.
11
Division of Pediatric Cardiology, University of Iowa Children's Hospital, Iowa City, IA, USA.
12
Division of Newborn Medicine and Genetics and Genomics, Harvard School of Medicine, Boston Children's Hospital, Boston, MA, USA.
13
Dept of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.
14
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Dept of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
15
Division of Pediatric Pulmonology, Ludwig-Maximilians-University, Munich, Germany.
16
Division of Pediatric Cardiology, Dept of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO, USA.
17
Division of Pulmonary Medicine, Dept of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO, USA.
18
Division of Neonatology, University of California San Francisco Benioff Children's Hospital, San Francisco, CA, USA olivier.danhaive@ucsf.edu.
19
Division of Neonatology, Catholic University of Louvain, Brussels, Belgium.

Abstract

Rare variants in the T-box transcription factor 4 gene (TBX4) have recently been recognised as an emerging cause of paediatric 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 six 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 two 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 PH at birth and/or later in infancy and childhood, often associated with skeletal anomalies, cardiac defects, neurodevelopmental disability and other anomalies.

Conflict of interest statement

Conflict of interest: C. Galambos has nothing to disclose. Conflict of interest: M.P. Mullen has acted as a site principal investigator on trials sponsored by United Therapeutics, Actelion, Ikaria and GSK, and received travel support from Actelion, outside the submitted work. Conflict of interest: J.T. Shieh has nothing to disclose. Conflict of interest: N. Schwerk has nothing to disclose. Conflict of interest: M.J. Kielt has nothing to disclose. Conflict of interest: N. Ullmann has nothing to disclose. Conflict of interest: R. Boldrini has nothing to disclose. Conflict of interest: I. Stucin-Gantar has nothing to disclose. Conflict of interest: C. Haass has nothing to disclose. Conflict of interest: M. Bansal has nothing to disclose. Conflict of interest: P.B. Agrawal has nothing to disclose. Conflict of interest: J. Johnson has nothing to disclose. Conflict of interest: D. Peca has nothing to disclose. Conflict of interest: C. Surace has nothing to disclose. Conflict of interest: R. Cutrera has nothing to disclose. Conflict of interest: M.W. Pauciulo has nothing to disclose. Conflict of interest: W.C. Nichols has nothing to disclose. Conflict of interest: M. Griese has nothing to disclose. Conflict of interest: D. Ivy has contracts (through the University of Colorado School of Medicine) with Actelion, Bayer, Lilly and United Therapeutics for consultancy and research studies. Conflict of interest: S.H. Abman has nothing to disclose. Conflict of interest: E.D. Austin has nothing to disclose. Conflict of interest: O. Danhaive has nothing to disclose.

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