Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2020 Nov 6.
Published in final edited form as: Mayo Clin Proc. 2018 Jul;93(7):834–839. doi: 10.1016/j.mayocp.2018.05.015

Clinical correlates and treatment outcomes for patients with short telomere syndromes

Abhishek A Mangaonkar 1,*, Alejandro Ferrer 2,*, Filippo Pinto e Vairo 2, Margot A Cousin 2, Ryan J Kuisle 2, Eric W Klee 2, Cassie C Kennedy 3, Steve G Peters 3, JP Scott 3, James P Utz 3, Misbah Baqir 3, Hiroshi Sekiguchi 3, Shakila P Khan 4, Vilmarie Rodriguez 4, Douglas A Simonetto 5, Patrick S Kamath 5, Thomas E Witzig 1, Roshini S Abraham 6, Mark E Wylam 3,**, Mrinal M Patnaik 1,**
PMCID: PMC7646091  NIHMSID: NIHMS1638925  PMID: 29976374

Abstract

Short telomere syndromes (STS) are accelerated aging syndromes with multisystemic manifestations that present complex management challenges. In this paper, we discuss a single institution experience in diagnosing and managing patients with inherited STS. In total, we identified 17 patients with short telomeres, defined by flow FISH (Fluorescence in-situ hybridization) telomere lengths ≤1st centile in granulocytes/lymphocytes OR the presence of a characteristic germline pathogenic variant in the context of a highly suggestive clinical phenotype. Genetic variations in the telomere complex were identified in 6 (35%) patients, with 4 being known pathogenic variants involving TERT (n=2), TERC (n=1) and DKC1 (n=1) genes, while 2 were variants of uncertain significance in TERT and RTEL1 genes. Idiopathic interstitial pneumonia (IIP) (n=12, 71%), unexplained cytopenias (n=5, 29%) and cirrhosis (n=2, 12%) were most frequent clinical phenotypes at diagnosis. At median follow up of 48 (range: 0-316) months, Kaplan-Meier estimate of overall survival, median (95% CI) was 182 (113, not reached) months. Treatment modalities included lung transplantation for IIP (n=5, 29%) with 3 patients developing signs of acute cellular rejection (2-grade A2, 1-grade A1), danazol therapy for cytopenias (n=4, 24%) with only 1 out of 4 patients showing a partial hematologic response, and allogeneic hematopoietic stem cell transplant for progressive bone marrow failure (n=2) with 1 patient dying from transplant related complications. In summary, patients with STS present with diverse clinical manifestations and require a multidisciplinary approach to management, with organ-specific transplantation capable of providing clinical benefit.

Introduction:

Telomeres are hexanucleotide (TTAGGG) DNA-protein structures at chromosome ends that prevent attrition of genetic material with each asymmetric DNA replication. A complex array of genes is responsible for telomere synthesis, assembly, trafficking and maintenance.1 Defects in one or more of these genes can cause accelerated telomere shortening and consequently affect multiple organ systems with high cell turnovers, thereby resulting in manifestations such as premature greying of hair, idiopathic interstitial pneumonia (IIP), bone marrow failure (BMF), cryptogenic cirrhosis of the liver, nodular regenerative hyperplasia (NRH) with portal hypertension and immune dysfunction.2 Although there is no consensus on a commonly accepted nomenclature, we prefer to identify disorders associated with short telomeres as ‘short telomere syndromes’ (STS). A pathognomic subtype of STS is dyskeratosis congenita (DKC), a genetically inherited disorder commonly seen in pediatric patients, secondary to mutations involving DKC1 (and additional genes), presenting with a classic triad of nail dystrophy, abnormal skin pigmentation, oral leukoplakia and progressive bone marrow failure.3, 4 Mutations in human telomere-associated genes have been identified in telomeric core components (TERT, TERC),5 telomere biogenesis (NHP2, GAR1, NOP10, PARN, NAF1, DKC1),5–9 DNA synthesis (RTEL1),10, 11 shelterin complex (RAP1 TINF2, TPP1, TRF1, TRF2),12, 13 telomere trafficking (TCAB1),14 and CST (CTC1, STN1, TEN1) complex.15, 16 However, only ~40% of patients with shortened telomeres have an identifiable pathogenic variant, suggesting that there are undiscovered genetic/epigenetic abnormalities affecting telomere lengths (TLs).

Management of STS is fraught with significant challenges such as delayed diagnoses, lack of routinely available diagnostic modalities and standardized treatment guidelines. With a view to address some of these shortcomings in literature, we report a single institution experience detailing a multidisciplinary approach to STS.

Methods:

In a retrospective cohort study design, we identified consecutive cases of STS, defined as TL <1st centile of the normal population in either *granulocytes or lymphocytes (*TL in lymphocytes only in case of an underlying myeloid malignancy or bone marrow failure syndrome) as detected by the flow-FISH (fluorescence in-situ hybridization) methodology or the presence of a known STS pathogenic genetic variant in the context of a clinical phenotype. Due to clinical heterogeneity and diagnostic uncertainty, we excluded patients with TL between 1-10th centile, in the absence of a known STS-associated mutation. Seventeen patients, meeting our inclusion criteria, were identified after surveying clinicians working in the pediatric and adult divisions of pulmonary and critical care medicine, gastroenterology and hematology. Flow-FISH testing was performed at an external reference laboratory, while a standard 8 gene next-generation sequencing (NGS) panel consisting of the following genes: DKC1, RTEL1, TINF2, NHP2 (NOLA2), TERC, TERT, NOP10 (NOLA3), WRAP53 (TCAB1, WDR79) was sent either to an external laboratory or performed at our institution. In patients with short telomeres and a negative NGS panel, research-based whole exome sequencing (WES) was conducted under Mayo Clinic’s pre-myeloid and bone marrow failure precision genomics protocol (NCT02958462),16

Results:

Demographic and clinical features of the 17 patients included in our study are shown in Table 1; 14 (82%) were male. Telomere testing results were available in 14 (82%) patients, of whom 11 (65%) had TL <1st centile in both granulocytes and lymphocytes, while 3 (18%) patients had TL <1st centile in granulocytes, but in the 1-10th centile range in lymphocytes (latter cases did not have any objective evidence of an underlying myeloid malignancy). Three (18%) patients (2-DKC1, 1-TERC) were diagnosed solely through NGS testing as they had a clear STS clinical phenotype. Median age at objective evidence of disease onset (defined by either imaging/laboratory evidence of unexplained pulmonary fibrosis, cirrhosis or bone marrow failure) was 57 (Range: 2-74) years; while age at actual diagnosis was 60 (Range: 9-66) years, and median time from symptom onset to diagnosis was 24 (0-81) months. At diagnosis, the most frequent disease manifestation was IIP* (n=12, 71%, *although it is debatable if telomere-related pulmonary fibrosis should be called ‘IIP’; we decided to keep the terminology as the classification of chronic lung disease has not yet changed), followed by unexplained cytopenias (n=5, 29%) and NRH (n=1, 6%); while at last median follow-up of 48 months (range, 0-316), there were 4 deaths, and the Kaplan-Meier (KM) estimate of overall survival (OS), median (95% CI) was 182 (113, not reached) months. Three patients had cirrhosis and/or NRH, IIP and bone marrow failure (BMF); 3 IIP and BMF; 1 had IIP and cirrhosis; 1 had BMF and cirrhosis; 6 patients had IIP only; and 3 had BMF only. At median (range) follow-up of 48 months (0-316), of the patients with fibrotic lung disease either at diagnosis or at subsequent follow-up, patterns of fibrosis could be ascertained in 11 patients (5-biopsy and imaging, 6-imaging only); 3 with usual interstitial pneumonia (UIP), 2 with non-specific interstitial pneumonia (NSIP), 1 with pleuroparenchymal fibroelastosis, 1 with combined features of IIP and emphysema, while 4 patients were in the ‘unclassifiable’ category. Only 3 (18%) patients had a significant history of premature greying of hair (hair greying ≤ 30 years of age). Significant family history with at least one family member with either premature greying of hair or unexplained cytopenias/cirrhosis/IIP was available in 8 (47%) patients. Among IIP patients (n=12), 6 (50%) were habitual smokers with 1 developing concurrent emphysematous changes.

Table 1:

Table summarizing demographics, clinical features, associated genomic variants & outcomes for our cohort of patients with short telomere syndromes.

Case no. Age at symptom onset/Gender Diagnosis Organ system manifestations Flow-FISH results [centile telomere lengths in granulocytes/ly mphocytes] Genomic aberration identified Zygosity Minor Allelic requency SIFT/Polyphen2 predictions Sequencing approach HSCT SOT; type Others treatments Best response to treatment Progression to AML Comments At OS (95% CI) 182 months (113, not reached), death status/age at death in years Cause of death
1 2/F DKC Bone marrow failure, liver cirrhosis, IIP N/A N/A N/A N/A N/A - Yes No Danazol None No Diagnosed elsewhere Dead/17 End-stage cirrhosis
2 64/F STS Bone marrow failure, ILD (NSIP) <1st centile/ <1st centile TERT, exon 12, missense, H983T amino acid substitution N/A N/A N/A - No No No - No - Dead/66 Acute exacerbation of IIP
3 57/M STS Bone marrow failure, cirrhosis, IIP <1st centile/ <1st centile Not tested N/A N/A N/A - No No No - No - Alive/57 -
4 54/M STS IIP (Unclassifiable) <1st centile/ <1st centile TERT VUS c.2030G>A,p.G677D Heterozygous 0% Deleterious/Prob. Damaging NGS No Yes/Lung Danazol Mild improvement in WBC count No - Alive/60 -
5 63/M STS IIP (UIP) <1st centile/1-10th centile Ongoing N/A N/A N/A NGS No Yes/Lung No - No Pirfenidone used for IIP; grade A1 allograft rejection, managed with prednisone Alive/66 -
6 47/M STS IIP (UIP) <1st centile/ <1st centile Ongoing N/A N/A N/A WES ongoing No Yes/Lung No - No Grade A2 allograft rejection, managed with prednisone Alive/49 -
7 62/F STS IIP (Pleuroparenchymal fibroelastosis) <1st centile/ 1-10th centile RTEL VUS c.101A>G, p.Q34R Heterozygous N/A Tolerated/Benign NGS No Yes/Lung No - No Grade A2 rejection managed with prednisone; developed SCC of skin & tongue around 17 years before diagnosis Alive/64 -
8 56/M STS IIP (UIP) <1st centile/ 1-10th centile Not identified N/A N/A N/A NGS No Yes/Lung No - No - Alive/63 -
9 74/M STS IIP, bone marrow failure <1st centile/ <1st centile N/A N/A N/A N/A - - - - - - Developed SCC of skin - -
10 56/M STS IIP (NSIP), macrocytosis without anemia <1st centile/ <1st centile N/A N/A N/A N/A - - - - - - Lost to follow-up Alive/57 -
11 53/M STS NRH, IIP (UIP), macrocytosis without anemia N/A; documented short telomeres N/A N/A N/A N/A N/A No No No - - N-acetylcysteine used. Dead/63 Acute exacerbation of IIP
12 4/M DKC Bone marrow failure with transfusion dependence Not done DKC1 (Variant details N/A) N/A N/A N/A NGS Yes, details not available No Danazol None - Classic DKC phenotype of oral leukoplakia, narrow tear ducts & lacy skin pigmentation Alive/30 -
13 58/M STS Bone marrow failure, IIP Not done TERC (n.214G>C, noncoding variant) Heterozygous 0% N/A NGS Yes No No - - Progressed to MDS-EB-2; developed SCC of skin Dead/59 Complications from allogeneic HSCT
14 17/M DKC Bone marrow failure <1st centile/ <1st centile TERTc.2768C >T; p.P923L; CSF3R VUS c.2422G>A; p. G808K TERT: Heterozygous CSF3R: Heterozygous TERT: 0.00041% CSF3R:0.62% TERT: Deleterious/Prob. Damaging CSF3R: Deleterious/Prob. Damaging NGS No No Immunosuppressive treatment with ATG & cyclosporine Mild improvement in platelet count No Being considered for allogeneic PBSCT; cytogenetic abnormalities show del(7)(q22). Alive/81 -
15 63/M STS Bone marrow failure, IIP (unclassifiable) <1st centile/ <1st centile - - - - WES No No Danazol None No Developing complications from IIP Alive/67 -
16 66/M STS Cryptogenic cirrhosis, IIP (unclassifiable), Bone marrow Failure <1st centile/ <1st centile Ongoing N/A N/A N/A WES Ongoing No No No - No End-stage cryptogenic cirrhosis Alive/68 -
17 60/M STS Crytpogenic cirrhosis, IIP (with combined emphysemato us changes) <1st centile/ <1st centile Ongoing N/A N/A N/A WES ongoing No No No - No Alive/61 -
Open in a new tab

FISH=Fluorescence in-situ hybridization; HSCT=Allogeneic Hematopoietic Stem Cell Transplantation; SOT=Solid organ transplant; IIP=Idiopathic interstitial pneumonia; NSIP=Non-specific interstitial pneumonia; UIP=Usual interstitial pneumonia; N/A=Not available; NGS=Next generation sequencing; WES=Whole exome sequencing panel; SCC=squamous cell cancer.

Genetic alterations were identified in 6 (35%) patients (all through commercial NGS testing), with 4 being known pathogenic heterozygous variants; namely 2 TERT, 1 TERC, 1 DKC1, while 2 patients had variants of uncertain significance (VUS) in TERT and RTEL1 genes (details in table 1). TL were available in 3 of the 6 aforementioned patients, with 2 demonstrating TL <1st centile in lymphocytes and granulocytes, while 1 had TL < 1st centile in granulocytes but in the 1-10th centile range in lymphocytes.

At a median follow-up of 48 (range: 0-316) months, there were 4 deaths, the KM estimate of OS, median (95% CI) was 182 (113, not reached) months, with the most common cause of death being, acute exacerbations of IIP (n=2), while 1 patient each died from complications of cirrhosis and allogeneic hematopoietic stem cell transplant (HSCT) respectively.. One patient with a TERC (n.214G>C, noncoding) pathogenic variant at diagnosis, presented with an aggressive myeloid neoplasm (myelodysplastic syndrome with excess blasts-2 or MDS-EB-2); while another patient with the TERT (c.2768C>T; p.Pro923Leu) pathogenic variant developed clonal cytopenias [abnormal cytogenetics [46, XY, del(7)(q22)[1]/46,XY[39])] without bone marrow dysplasia. Four (24%) patients were treated with danazol for cytopenias with only 1 showing a partial improvement in white blood cell count. Three (18%) patients developed squamous cell carcinoma of skin, 2 of whom were chronically immunosuppressed.

Five (29%) patients underwent lung transplant (all for IIP, 3-bilateral, 2-single lung), while 2 (12%) underwent allogeneic HSCT, 1 for progressive BMF and 1 for progression to high-risk MDS (MDS-EB-2). The patient with progression to MDS had concurrent IIP and died from post-transplant multi organ failure. Of the patients who underwent lung transplant, 3 developed signs of acute cellular rejection (2-grade A2, 1-grade A1) which were managed with low-dose prednisone therapy with no deaths.

Discussion:

Pathogenic variants associated with short telomeres have been well-described in invertebrates such as yeast, however only a small number of genes have been identified in human beings signifying the need for a precision genomics based approach to identify novel genetic and epigenetic mechanisms of telomere length regulation.17 The clinical implications of this process are profound, as a significant percentage of these patients are treated with either solid organ or HSCT;18 procedures mandating search of donors within the same family (bone marrow and liver) and more importantly, screening of family members, including children. For example, siblings may have the same pathogenic variants as patients, thereby making them unsuitable donors.

In a study authored by Armanios MY et al., frequency of heterozygous pathogenic germline alterations in TERT or TERC genes in patients with IIP has been reported to be around 8% and TL in mutation carriers were found be <10th centile of normal age-matched controls.19 In our cohort, a majority (59%) of patients had IIP at diagnosis with diverse patterns of fibrosis. The clinical/radiological heterogeneity (fibrotic NSIP, UIP, pleuroparenchymal fibroelastosis, unclassifiable and combined emphysematous changes) along with the characteristic uniform disease progression seen in this series, is consistent with prior reports on patients with telomere-related lung fibrosis.20 Gastrointestinal manifestations, often overlooked in STS, are seen in approximately 16% of patients with short telomeres.21, 22 In our cohort, 26% patients developed either cryptogenic cirrhosis or NRH, one of whom died from related complications. Interestingly, patients with IIP or cirrhosis had a trend towards worse overall survival, suggesting a negative prognostic impact related to the involvement of these organs.

A significant proportion of patients with IIP underwent lung transplant (29%), all of them developed persistent cytopenias (>3 months) thereafter, which is consistent with a previous report by Silhan et al.23 Further, these patients were intolerant of standard antimetabolite medications and their leukopenias were managed with colony stimulating factors. Published data suggests lung transplant recipients with shorter TL have decreased likelihood of developing acute cellular rejection, however 3 out of 5 patients who underwent a lung transplant in our series developed rejection.24

Conclusion:

Short telomere syndromes are multisystemic disorders with protean clinical manifestations and outcomes. Early recognition of these premature aging syndromes should be encouraged with consideration for organ specific transplantation based on clinical phenotype. With the help of this patient series, we demonstrate the potential of using a targeted genomics approach through a unique clinic to identify novel genetic abnormalities associated with short telomeres, and follow such patients prospectively. Our standard approach, in the context of a relevant phenotype, includes a thorough history and physical examination, followed by TL measurement and NGS. If the aforementioned testing is negative, we proceed to perform a research-based WES after discussion in a multidisciplinary tumor board comprising of clinicians, bioinformaticians and molecular biologists.

Acknowledgement:

We acknowledge ‘The Gerstner Family Career Development Award’, Mayo Clinic Center for Individualized Medicine and CTSA Grant number KL2 TR000136 from the National Center for Advancing Translational Science for providing grant support. Its contents do not necessarily represent the official views of the U. S National Institutes of Health and authors are solely responsible for its contents.

Abbreviations:

IIP

Idiopathic interstitial pneumonia

BMF

Bone marrow failure

NRH

Nodular regenerative hyperplasia

STS

Short telomere syndromes

DKC

Dyskeratosis congenita

TL

Telomere length

FISH

Fluorescence in-situ hybridization

CST complex

CTC1, STN1 and TEN1 complex

NGS

Next-generation sequencing

WES

Whole exome sequencing

KM

Kaplan-Meier

OS

Overall Survival

UIP

Usual Interstitial Pneumonia

NSIP

Non-specific interstitial pneumonia

HSCT

hematopoietic stem cell transplant

MDS-EB

Myelodysplastic syndrome with excess blasts

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Conflicts of interest: Significant findings from this study have been presented at the European Molecular Biology Organization workshop on ‘Telomere Biology in Health and Human Disease’ in Troia, Portugal from 1st to 6th May 2018.

References:

  • 1.Townsley DM, Dumitriu B, Young NS. Bone marrow failure and the telomeropathies. Blood. 2014;124(18):2775–2783. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Calado RT, Young NS. Telomere diseases. N Engl J Med. 2009;361(24):2353–2365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Heiss NS, Knight SW, Vulliamy TJ, et al. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nature genetics. 1998;19(1):32–38. [DOI] [PubMed] [Google Scholar]
  • 4.Shimamura A, Alter BP. Pathophysiology and management of inherited bone marrow failure syndromes. Blood reviews. 2010;24(3):101–122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Armanios M, Blackburn EH. The telomere syndromes. Nat Rev Genet. 2012;13(10):693–704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Stanley SE, Gable DL, Wagner CL, et al. Loss-of-function mutations in the RNA biogenesis factor NAF1 predispose to pulmonary fibrosis–emphysema. Science Translational Medicine. 2016;8:351ra107–351ra107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Stuart BD, Choi J, Zaidi S, et al. Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening. Nature genetics. 2015;47(5):512–517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Moon DH, Segal M, Boyraz B, et al. Poly(A)-specific ribonuclease (PARN) mediates 3′-end maturation of the telomerase RNA component. Nature genetics. 2015;47(12):1482–1488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Knight SW, Heiss NS, Vulliamy TJ, et al. Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal-Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1. Br J Haematol. 1999;107(2):335–339. [DOI] [PubMed] [Google Scholar]
  • 10.Codd V, Nelson CP, Albrecht E, et al. Identification of seven loci affecting mean telomere length and their association with disease. Nature genetics. 2013;45(4):422–427, 427e421–422. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Marsh JCW, Gutierrez-Rodrigues F, Cooper J, et al. Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms. Blood advances. 2018;2(1):36–48. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.de Lange T Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 2005;19(18):2100–2110. [DOI] [PubMed] [Google Scholar]
  • 13.Savage SA, Giri N, Baerlocher GM, Orr N, Lansdorp PM, Alter BP. TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am J Hum Genet. 2008;82(2):501–509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Zhong F, Savage SA, Shkreli M, et al. Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. Genes Dev. 2011;25(1):11–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Anderson BH, Kasher PR, Mayer J, et al. Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus. Nature genetics. 2012;44(3):338–342. [DOI] [PubMed] [Google Scholar]
  • 16.Mangaonkar AA, Patnaik MM. Short Telomere Syndromes In Clinical Practice – Bridging Bench and Bedside. Mayo Clinic Proceedings. 2018. (In Press) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Holohan B, Wright WE, Shay JW. Cell biology of disease: Telomeropathies: an emerging spectrum disorder. J Cell Biol. 2014;205(3):289–299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Alder JK, Hanumanthu VS, Strong MA, et al. Diagnostic utility of telomere length measurement in a hospital setting. Proc Natl Acad Sci U.S.A 2018;115(10):E2358–E2365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Armanios MY, Chen JJ, Cogan JD, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007;356(13):1317–1326. [DOI] [PubMed] [Google Scholar]
  • 20.Newton CA, Batra K, Torrealba J, et al. Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive. The European respiratory journal. 2016;48(6):1710–1720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Jonassaint NL, Guo N, Califano JA, Montgomery EA, Armanios M. The gastrointestinal manifestations of telomere-mediated disease. Aging Cell. 2013;12(2):319–323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Calado RT, Regal JA, Kleiner DE, et al. A spectrum of severe familial liver disorders associate with telomerase mutations. PLoS One. 2009;4(11):e7926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Silhan LL, Shah PD, Chambers DC, et al. Lung transplantation in telomerase mutation carriers with pulmonary fibrosis. The European respiratory journal. 2014;44(1):178–187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Courtwright AM, Fried S, Villalba JA, et al. Association of Donor and Recipient Telomere Length with Clinical Outcomes following Lung Transplantation. PLoS One. 2016;11(3):e0162409. [DOI] [PMC free article] [PubMed] [Google Scholar]

RESOURCES