Prognostic significance of pulmonary function tests in dyskeratosis congenita, a telomere biology disorder
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 pu...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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European Respiratory Society
2019-11-01
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| Series: | ERJ Open Research |
| Online Access: | http://openres.ersjournals.com/content/5/4/00209-2019.full |
| _version_ | 1818921856900530176 |
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| author | Neelam Giri Sandhiya Ravichandran Youjin Wang Shahinaz M. Gadalla Blanche P. Alter Joseph Fontana Sharon A. Savage |
| author_facet | Neelam Giri Sandhiya Ravichandran Youjin Wang Shahinaz M. Gadalla Blanche P. Alter Joseph Fontana Sharon A. Savage |
| author_sort | Neelam Giri |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T01:44:18Z |
| format | Article |
| id | doaj.art-e9b5a2eb30bd4b7db1612c4659e4efe7 |
| institution | Directory Open Access Journal |
| issn | 2312-0541 |
| language | English |
| last_indexed | 2024-12-20T01:44:18Z |
| publishDate | 2019-11-01 |
| publisher | European Respiratory Society |
| record_format | Article |
| series | ERJ Open Research |
| spelling | doaj.art-e9b5a2eb30bd4b7db1612c4659e4efe72022-12-21T19:57:49ZengEuropean Respiratory SocietyERJ Open Research2312-05412019-11-015410.1183/23120541.00209-201900209-2019Prognostic significance of pulmonary function tests in dyskeratosis congenita, a telomere biology disorderNeelam Giri0Sandhiya Ravichandran1Youjin Wang2Shahinaz M. Gadalla3Blanche P. Alter4Joseph Fontana5Sharon A. Savage6 Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 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 Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 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.http://openres.ersjournals.com/content/5/4/00209-2019.full |
| spellingShingle | Neelam Giri Sandhiya Ravichandran Youjin Wang Shahinaz M. Gadalla Blanche P. Alter Joseph Fontana Sharon A. Savage Prognostic significance of pulmonary function tests in dyskeratosis congenita, a telomere biology disorder ERJ Open Research |
| title | Prognostic significance of pulmonary function tests in dyskeratosis congenita, a telomere biology disorder |
| title_full | Prognostic significance of pulmonary function tests in dyskeratosis congenita, a telomere biology disorder |
| title_fullStr | Prognostic significance of pulmonary function tests in dyskeratosis congenita, a telomere biology disorder |
| title_full_unstemmed | Prognostic significance of pulmonary function tests in dyskeratosis congenita, a telomere biology disorder |
| title_short | Prognostic significance of pulmonary function tests in dyskeratosis congenita, a telomere biology disorder |
| title_sort | prognostic significance of pulmonary function tests in dyskeratosis congenita a telomere biology disorder |
| url | http://openres.ersjournals.com/content/5/4/00209-2019.full |
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