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
UK National Paediatric Pulmonary Hypertension Service. Great Ormond Street Hospital for Children. St George’s University Hospitals NHS Foundation Trust. Queen Elizabeth Hospital Birmingham and University of Birmingham. University College London. Children’s Health Ireland at Crumlin. Imperial College. Royal Brompton Hospital.
United Kingdom and Ireland
Pediatric Pulmonology
Pediatr Pulmonol 2026; 61:
DOI: 10.1002/ppul.71857
Abstract
Aim: To describe the variant class associations with phenotype, natural history, treatment response, and outcomes in children with TBX4-associated pulmonary hypertension (TBX4-PH).
Methods: Retrospective cohort analysis of children < 18 years referred to the National Paediatric Pulmonary Hypertension Service between 2001 and 2025.
Results: 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).
Conclusions: 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.
Category
Genetic Factors Associated with Pulmonary Vascular Disease
Symptoms and Findings Associated with Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
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