Giri Neelam, Ravichandran Sandhiya, Wang Youjin, Gadalla Shahinaz M, Alter Blanche P, Fontana Joseph, Savage Sharon A
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
ERJ Open Res. 2019 Nov 15;5(4). doi: 10.1183/23120541.00209-2019. eCollection 2019 Oct.
Pulmonary fibrosis and pulmonary arteriovenous malformations are known manifestations of dyskeratosis congenita (DC), a telomere biology disorder (TBD) and inherited bone marrow failure syndrome caused by germline mutations in telomere maintenance genes resulting in very short telomeres. Baseline pulmonary function tests (PFTs) and long-term clinical outcomes have not been thoroughly studied in DC/TBDs. In this retrospective study, 43 patients with DC and 67 unaffected relatives underwent baseline PFTs and were followed for a median of 8 years (range 1-14). Logistic regression and competing risk models were used to compare PFT results in relation to clinical and genetic characteristics, and patient outcomes. Restrictive abnormalities on spirometry and moderate-to-severe reduction in diffusing capacity of the lung for carbon monoxide were significantly more frequent in patients with DC than relatives (42% 12%; p=0.008). The cumulative incidence of pulmonary disease by age 20 years was 55% in patients with DC with baseline PFT abnormalities compared with 17% in those with normal PFTs (p=0.02). None of the relatives developed pulmonary disease. X-linked recessive, autosomal recessive inheritance or heterozygous variants were associated with early-onset pulmonary disease that mainly developed after haematopoietic cell transplantation (HCT). Overall, seven of 14 patients developed pulmonary disease post-HCT at a median of 4.7 years (range 0.7-12). The cumulative incidence of pulmonary fibrosis in patients with heterozygous non- pathogenic variants was 70% by age 60 years. Baseline PFT abnormalities are common in patients with DC and associated with progression to significant pulmonary disease. Prospective studies are warranted to facilitate clinical trial development for patients with DC and related TBDs.
肺纤维化和肺动静脉畸形是先天性角化不良（DC）的已知表现，DC是一种端粒生物学障碍（TBD），属于遗传性骨髓衰竭综合征，由端粒维持基因的种系突变导致端粒极短引起。在DC/TBD患者中，尚未对基线肺功能测试（PFT）和长期临床结局进行全面研究。在这项回顾性研究中，43例DC患者和67名未受影响的亲属接受了基线PFT，并进行了中位8年（范围1 - 14年）的随访。使用逻辑回归和竞争风险模型比较PFT结果与临床和遗传特征以及患者结局的关系。与亲属相比，DC患者中肺活量测定显示的限制性异常以及肺一氧化碳弥散能力中重度降低更为常见（42%对12%；p = 0.008）。基线PFT异常的DC患者中，20岁时肺部疾病的累积发病率为55%，而PFT正常的患者为17%（p = 0.02）。亲属中无人患肺部疾病。X连锁隐性、常染色体隐性遗传或杂合变异与主要在造血细胞移植（HCT）后发生的早发性肺部疾病相关。总体而言，14例患者中有7例在HCT后发生肺部疾病，中位时间为4.7年（范围0.7 - 12年）。杂合非致病性变异患者中，60岁时肺纤维化的累积发病率为70%。基线PFT异常在DC患者中很常见，并与进展为严重肺部疾病相关。有必要进行前瞻性研究以促进DC及相关TBD患者的临床试验发展。
