Phenotype characterisation of TBX4 mutation and deletion carriers with neonatal and paediatric pulmonary hypertension
Phenotype characterisation of TBX4 mutation and deletion carriers with neonatal and paediatric pulmonary hypertension
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DOI：
10.1183/13993003.01965-2018
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发表时间：
2019-08-01
影响因子：
24.3
通讯作者：
Danhaive, Olivier
中科院分区：
文献类型：
--
作者：
Galambos, Csaba;Mullen, Mary P.;Danhaive, Olivier
T-box转录因子4基因（TBX 4）的罕见变异最近被认为是儿科肺动脉高压（PH）的一个新的原因。其病理生理学和新生儿持续性肺动脉高压（PPHN）的贡献是未知的。我们试图确定新生儿和PH儿童中与TBX 4变异相关的临床表现和组织病理学谱。我们评估了19名PH儿童（包括PPHN）的临床数据和肺组织，这些儿童携带由下一代测序和拷贝数变异阵列鉴定的TBX 4罕见变异。变异包括6个17 q23缺失，包括整个TBX 4基因座和邻近基因，和12种可能的破坏性突变10名婴儿出现新生儿缺氧性呼吸衰竭和PPHN，随后出院回家。PH在婴儿期或儿童期被诊断出来。三名儿童死亡，两名需要肺移植。相关畸形包括动脉导管未闭、间隔缺损、足部畸形和发育障碍，后者在缺失携带者中的患病率较高。7例患儿的组织学检查显示远端肺发育异常和肺动脉高压重塑。TBX 4突变和17 q23缺失是一种新的发育性肺病的基础，在出生时和/或婴儿期和儿童期表现为严重的双相PH，通常与骨骼异常、心脏缺陷、神经发育障碍和其他异常相关。
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.