TY - JOUR T1 - Prognostic significance of pulmonary function tests in dyskeratosis congenita, a telomere biology disorder JF - ERJ Open Research JO - erjor DO - 10.1183/23120541.00209-2019 VL - 5 IS - 4 SP - 00209-2019 AU - Neelam Giri AU - Sandhiya Ravichandran AU - Youjin Wang AU - Shahinaz M. Gadalla AU - Blanche P. Alter AU - Joseph Fontana AU - Sharon A. Savage Y1 - 2019/10/01 UR - http://openres.ersjournals.com/content/5/4/00209-2019.abstract N2 - 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% versus 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 TINF2 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-TINF2 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.About 40% of patients with dyskeratosis congenita, a telomere biology disorder, have abnormal pulmonary function tests and progress to life-threatening pulmonary disease (PD). Prospective therapeutic studies of PD in these disorders are urgently needed. http://bit.ly/2HBSNCO ER -