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.