Chest

Chest

Volume 139, Issue 5, May 2011, Pages 1203-1209
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Selected Report
Natural History of Pulmonary Fibrosis in Two Subjects With the Same Telomerase Mutation

https://doi.org/10.1378/chest.10-2048Get rights and content

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.

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Subjects

Two subjects, who were previously part of a familial pulmonary fibrosis research study,6 provided written consent to participate in protocols approved by the Institutional Review Board of the National Human Genome Research Institute (04-HG-0211) and/or the National Heart, Lung, and Blood Institute (04-H-0012). The two subjects were initially evaluated in 1982, and they were subsequently studied in 2009. Bronchoscopy and BAL were performed as previously described.9 Cytospins from BAL fluid cells

Progressive Natural History of Familial Pulmonary Fibrosis

Two white sisters were initially evaluated at the National Institutes of Health in 1982 to 1983 as part of a familial pulmonary fibrosis study.6 Their father, paternal aunt, and cousin died of biopsy-proven IPF, but they were asymptomatic for lung disease (Fig 1A). (Subjects 1 and 2 were previously reported as B4 and B5 [family B in Reference 6], respectively.)6 Their clinical examination, chest radiographs, and pulmonary function tests were normal (Table 2), but they had alveolar inflammation

Discussion

This work defines the natural history of preclinical pulmonary fibrosis and demonstrates for the first time that alveolar inflammation in familial pulmonary fibrosis progresses to clinical disease over two to three decades. It also provides evidence that immune-cell dysregulation in the lung is a characteristic of early fibrotic lung disease. Furthermore, siblings at risk for familial pulmonary fibrosis, despite having an identical genetic mutation, can manifest variable long-term clinical

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: We thank Irina Maric, MD, Department of Laboratory Medicine, Clinical Center, for reviewing the bone marrow biopsy and the patients who participated in this study for their contributions.

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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).

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Copyright © 2011 The American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.