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.
Abstract
TBX4 mutations and deletions are associated with abnormal distal lung development, persistent pulmonary hypertension of the newborn, paediatric pulmonary hypertension, multiple congenital anomalies and developmental disabilities http://bit.ly/2UXDrl3
Footnotes
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Author contributions: O. Danhaive and S.H. Abman designed the study and supervised the project; O. Danhaive, C. Galambos, E.D. Austin and M.P. Mullen co-wrote the manuscript; C. Galambos performed the pathology studies in collaboration with J. Johnson and R. Boldrini; J.T. Shieh performed the genetic analysis with the contribution of C. Surace, D. Peca, P.B. Agrawal, M.W. Pauciulo and W.C. Nichols; M.P. Mullen and D. Ivy contributed to the cardiology and haemodynamic analysis; E.D. Austin, M.J. Kielt, M. Griese and S.H. Abman contributed to the pulmonology analysis; N. Schwerk, N. Ullmann, R. Cutrera, I. Stucin-Gantar, C. Haass and M. Bansal contributed to clinical data.
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.
Support statement: This publication was supported in part by the Frederick and Margaret L. Weyerhaeuser Foundation, the Jayden de Luca Foundation (D. Ivy, C. Galambos), NIH grants R01HL114753 and U01HL121518 (S.H. Abman), NIH/NCATS Colorado CTSA grant number UL1 TR002535, NIH grant HL105333 (W.C. Nichols, M.W. Pauciulo), and an unrestricted grant from the Chiesi Foundation, Parma, Italy (O. Danhaive, R. Cutrera, D. Peca). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received October 17, 2018.
- Accepted April 19, 2019.
- Copyright ©ERS 2019
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