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Natural History of Pulmonary Fibrosis in Two Subjects With the Same Telomerase Mutation

Souheil El-Chemaly, MD, MPH; Shira G. Ziegler, BS; Rodrigo T. Calado, MD, PhD; Kirkland A. Wilson; Hai Ping Wu, BS; Mary Haughey, RN; Nathan R. Peterson, BS; Neal S. Young, MD; William A. Gahl, MD, PhD; Joel Moss, MD, PhD, FCCP; Bernadette R. Gochuico, MD
Author and Funding Information

From the Cardiovascular and Pulmonary Branch (Drs El-Chemaly and Moss and Mss Wu and Haughey), and the Hematology Branch (Drs Calado and Young and Mr Peterson), National Heart, Lung, and Blood Institute; and the Medical Genetics Branch (Ms Ziegler, Mr Wilson, and Drs Gahl and Gochuico), National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.

Correspondence to: Bernadette R. Gochuico, MD, 10 Center Dr, MSC 1851, Bethesda, MD 20892-1851; e-mail: gochuicb@mail.nih.gov


Funding/Support: This research was sponsored in part by the Intramural Research Program of the National Heart, Lung, and Blood Institute and the National Human Genome Research Institute, National Institutes of Health.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2011 American College of Chest Physicians


Chest. 2011;139(5):1203-1209. doi:10.1378/chest.10-2048
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Previous studies have identified subclinical lung disease in family members of probands with familial pulmonary fibrosis, but the natural history of preclinical pulmonary fibrosis is uncertain. The purpose of this study was to determine whether individuals with preclinical lung disease will develop pulmonary fibrosis. After a 27-year interval, two subjects with manifestations of preclinical familial pulmonary fibrosis, including asymptomatic alveolar inflammation and alveolar macrophage activation, were reevaluated for lung disease. CT scans of the chest, pulmonary function tests, and BAL were performed, and genomic DNA was analyzed for mutations in candidate genes associated with familial pulmonary fibrosis. One subject developed symptomatic familial pulmonary fibrosis and was treated with oxygen; her sister remained asymptomatic but had findings of pulmonary fibrosis on high-resolution CT scan of the chest. High concentrations of lymphocytes were found in BAL fluid from both subjects. Genetic sequencing and analyses identified a novel heterozygous mutation in telomerase reverse transcriptase (TERT, R1084P), resulting in telomerase dysfunction and short telomeres in both subjects. In familial pulmonary fibrosis, asymptomatic preclinical alveolar inflammation associated with mutation in TERT and telomerase insufficiency can progress to fibrotic lung disease over 2 to 3 decades.

Trial registry:  ClinicalTrials.gov; No.: NCT00071045; URL: www.clinicaltrials.gov

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