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儿童TBX4相关肺动脉高压中变异类别特异性表型与结局

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

临床研究耳科IF 2.5Q2

文献信息

PMID42836726
原文在 PubMed 查看原文 ↗
发表日期2026
作者Cara Morgan
查看其他 12 位作者

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

作者单位UK National Paediatric Pulmonary Hypertension Service, Great Ormond Street Hospital for Children, London, UK.
查看其他 10 条单位信息

Department of Radiology, Great Ormond Street Hospital for Children, London, UK.；St George's University Hospitals NHS Foundation Trust, SW Thames Centre for Genomic Medicine, London, UK.；Department of Histopathology, Great Ormond Street Hospital for Children, London, UK.；Department of Cardiology, Adult Congenital Heart Disease Unit, Queen Elizabeth Hospital Birmingham, Birmingham, UK.；Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK.；Institute of Cardiovascular Sciences, University College London, London, UK.；Department of Paediatric Cardiology, Children's Health Ireland at Crumlin, Dublin, Ireland.；Department of Paediatric Respiratory Medicine, Great Ormond Street Hospital for Children, London, UK.；National Heart and Lung Institute and Imperial Centre for Paediatrics and Child Health, Imperial College, London, UK.；Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK.

期刊Pediatric pulmonology
SCI 分区Q2
IF2.5
研究类型临床研究 · 临床
所属专科耳科

中文摘要

目的： 描述儿童TBX4相关肺动脉高压（TBX4-PH）中变异类别与表型、自然史、治疗反应及结局的关联。
方法： 对2001年至2025年间转诊至国家儿童肺动脉高压服务的18岁以下儿童进行回顾性队列分析。
结果： 共识别出21名携带TBX4拷贝数变异（CNV组=10）或单核苷酸变异（SNV组=11）的儿童。观察到变异类别之间存在明显的表型差异。CNV组儿童转诊年龄更小（p=0.03），更常从出生起长期依赖氧气（p<0.01），肺部疾病更严重（p<0.01）并出现发绀（p=0.04）、先天性心脏病（p=0.03）、神经发育障碍（p<0.01）和耳聋（p=0.01）。SNV组儿童患任何肺部疾病的可能性较低（p=0.03）。5名儿童（CNV=3，SNV=2）的组织病理学主要显示肺生长异常，伴有不同程度的肺血管重塑。21名儿童中有20名（95%）接受了长期肺血管扩张剂治疗，9名（43%）同时接受了钙通道阻滞剂。未接受过治疗的儿童（n=12）在开始治疗后功能分级稳定/改善。中位随访时间为7.1年（范围0.7-17.2）。1年和5年无移植或Potts分流生存率分别为100%和94.4%，CNV组更差（Log-rank p<0.05）。
结论： 在这个大型儿童TBX4-PH队列中，携带CNV的儿童比携带SNV的儿童有更严重的多系统受累和更差的结局，突显了潜在遗传发现对风险分层和个体化管理策略的重要性。

英文摘要

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.