Variant Class-Specific Phenotypes and Outcomes in Pediatric TBX4-Associated Pulmonary Hypertension.

Authors

Cara Morgan, Alistair Calder, Matina Prapa, Thivya Sekar, Andrew Constantine, Tomas Woodgate, Annabelle Barnes, Eimear McGovern, Paul Aurora, Rossa Brugha, Sadia Quyam, Andrew Bush, Shahin Moledina

Published in

Pediatric pulmonology. Volume 61. Issue 10. Pages e71857.

Abstract

To describe the variant class associations with phenotype, natural history, treatment response, and outcomes in children with TBX4-associated pulmonary hypertension (TBX4-PH).
Retrospective cohort analysis of children < 18 years referred to the National Paediatric Pulmonary Hypertension Service between 2001 and 2025.
Twenty-one children were identified carrying either a copy number variant (CNV group = 10) encompassing TBX4 or a single nucleotide variant (SNV group = 11). Distinct phenotypic differences were observed between variant classes. Children in the CNV group were referred at a younger age (p = 0.03), more frequently had prolonged oxygen dependence from birth (p < 0.01), more severe lung disease (p < 0.01) and cyanosis (p = 0.04), congenital heart disease (p = 0.03), neurodevelopmental disorders (p < 0.01), and deafness (p = 0.01). Children in the SNV group were less likely to have any lung disease (p = 0.03). Histopathology from five children (CNV = 3, SNV = 2) demonstrated predominantly lung growth abnormalities with variable pulmonary vascular remodeling. Twenty of 21 (95%) children received long-term pulmonary vasodilator therapy, and 9 (43%) received concurrent calcium-channel blockers. Treatment-naïve children (n = 12) demonstrated stable/improved functional class with therapy initiation. Median follow-up was 7.1 years (range 0.7-17.2). Transplant- or Potts shunt-free survival at 1 and 5 years was 100% and 94.4% respectively and was worse in the CNV group (Log-rank p < 0.05).
In this large pediatric TBX4-PH cohort, children carrying CNVs had greater multisystem involvement and poorer outcomes than those carrying SNVs, highlighting the importance of the underlying genetic finding for risk stratification and tailored management strategies.

PMID:
42836726
Bibliographic data and abstract were imported from PubMed on 06 Oct 2026.

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