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Prognostic significance of pulmonary function tests in dyskeratosis congenita, a telomere biology disorder

Neelam Giri, Sandhiya Ravichandran, Youjin Wang, Shahinaz M. Gadalla, Blanche P. Alter, Joseph Fontana, Sharon A. Savage
ERJ Open Research 2019 5: 00209-2019; DOI: 10.1183/23120541.00209-2019
Neelam Giri
1Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Sandhiya Ravichandran
1Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Youjin Wang
1Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Shahinaz M. Gadalla
1Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Blanche P. Alter
1Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Joseph Fontana
2National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
3These authors contributed equally
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Sharon A. Savage
1Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
3These authors contributed equally
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  • ORCID record for Sharon A. Savage
  • For correspondence: savagesh@mail.nih.gov
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  • FIGURE 1
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    FIGURE 1

    Study schema indicating the comparison groups. a) Analyses of pulmonary function tests (PFTs) and groups. b) Analyses of patient outcomes in relation to PFT. DC: dyskeratosis congenita; HCT: haematopoietic cell transplantation; XLR: X-linked recessive; AR: autosomal recessive; AD: autosomal dominant.

  • FIGURE 2
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    FIGURE 2

    High-resolution computed tomography (CT) scan of the lungs (patient NCI-6-1). a) Peripheral interstitial and ground-glass opacities with early honeycombing in bases bilaterally consistent with usual interstitial pneumonia pattern of pulmonary fibrosis in a 54-year-old female with heterozygous TERC mutation and symptoms of dyspnoea on exertion, impaired flows and diffusion with diffusing capacity of the lung for carbon monoxide (DLCO) 57% of predicted. b) The patient's symptoms had progressed 3 years later with dry cough, progressive dyspnoea, basal crackles and desaturation to 85% on 6-minute walk test; restrictive ventilatory defect and DLCO at 50%. The CT scan shows an increase in peripheral subpleural fibrosis. The advanced fibrosis in the left lung is also slightly worsened.

  • FIGURE 3
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    FIGURE 3

    Cumulative incidence of pulmonary disease in patients with normal versus abnormal baseline pulmonary function tests (PFTs). The graph starts at the age at PFT and ends at the diagnosis of pulmonary disease, death or last follow-up. The three patients with incident pulmonary disease at the time of baseline PFT were excluded from the graph. The blue line indicates patients with abnormal baseline PFTs (n=15; five patients developed pulmonary disease 2–7 years after the PFTs). The yellow dashed line depicts patients with normal baseline PFT (n=25; two patients were diagnosed with symptomatic pulmonary disease at 2 and 10 years after the baseline PFTs). The cumulative incidence of pulmonary disease by age 20 years was 55% (95% CI 28–100%) in patients with abnormal baseline PFT versus 17% (95% CI 3–100%) in those with normal PFTs (overall p=0.02).

  • FIGURE 4
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    FIGURE 4

    Competing risk of adverse events including pulmonary disease, haematopoietic cell transplantation (HCT), and death. a) autosomal recessive/X-linked recessive and TINF2 dyskeratosis congenita (DC). The first event was HCT for severe bone marrow failure in 12 patients (grey line) with a cumulative incidence of 50% (95% CI 33–77%) by age 30 years; two patients died at age 19 and 37 years from other causes (yellow line) and one developed pulmonary fibrosis plus pulmonary arteriovenous malformations at age 20 years (blue line). b) autosomal dominant non-TINF2 DC. In all, one patient received HCT, whereas four patients developed pulmonary fibrosis with a cumulative incidence of 70% (95% CI 39–100%) by age 60 years among non-HCT patients.

Tables

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  • TABLE 1

    Characteristics of study participants

    Patients with DCUnaffected relativesPatients versus relatives p-value
    AllXLR, AR, TINF2#AD non-TINF2#p-valueAllCarriers of RTEL1, TERT or PARNAll others
    Participants432514671453
    Age at diagnosis years13 (1–65)11 (1–43)32 (12–65)<0.0001
    Age at study years21 (6–69)18 (6–42)35 (12–69)0.00246 (10–60)46 (10–60)36 (7–64)0.0001
    Male/female31/1221/47/70.0325/426/819/340.001
    Smoker7 (15%)340.210 (15%)3 (21%)7 (13%)0.8
    Ethnicity
     Caucasian4024126314490.7
     African211000
     Hispanic000101
     Asian101303
    Microcephaly111100.003000
    HH/RS8800.03000
    DC triad features¶
     0–1208110.008631453
     ≥223173000
    Bone marrow failure+
     None12750.2000
     Moderate1345
     Severe18144
    Telomere length Z-score−3.9−4.5 (−1.3– −6.7)−3.1 (−1.1– −5.5)0.0007−0.9 (−1.8– −4.2)−1.9 (−0.3– −1.9)−0.7 (−0.7– −4.2)<10-9
    DC gene (inheritance)
     DKC1 (XLR)770707
     RTEL1 (AR or AD)761880
     PARN (AR)330550
     WRAP53 (AR)000303
     ACD (AR)000202
     TERT (AR or AD)615110
     TINF2 (AD)880000
     TERC (AD)808000
     Unknown40015015
     Negative026026

    Data are presented as median (range) unless otherwise stated. DC: dyskeratosis congenita; XLR: X-linked recessive; AR: autosomal recessive; AD: autosomal dominant; HH: Hoyeraal–Hreidarsson syndrome; RS: Revesz syndrome. #: the number of patients with XLR/AR/TINF2 and AD non-TINF2 do not add up to the total of 43 because the causative gene was not identified in four patients; ¶: oral leukoplakia, dysplastic nails and abnormal skin pigmentation; +: “moderate” was defined as single or multilineage cytopenia not on treatment, and “severe” was cytopenia needing treatment. Significant p-values (<0.05) are in bold.

    • TABLE 2

      Pulmonary function tests (PFTs) in study participants

      PFT abnormalitiesPatients with DCUnaffected relativesPatients versus relatives
      AllXLR, AR, TINF2AD non-TINF2p-valueAllRTEL1, TERT, PARNAll othersp-valueOR (95% CI)p-value
      Number with spirometry#432514671453
      Spirometry abnormal12841.0111100.41.97 (0.77–4.9)0.159
       Obstructive2111.07161.00.4 (0.08–2)0.47
       Restrictive10730.74040.64.7 (1.3–16.3)0.016
       Mixed000000
      Number with DLCO data4224141.0661452
       Mild DLCO change231280.7335280.41.2 (0.5–2.6)0.695
       Moderate DLCO abnormality11831.05230.35.4 (1.7–16.7)0.003
       Severe DLCO abnormality211000
      Abnormal spirometry and/or moderate/severe DLCO reduction181261.0122101.03.3 (1.3–7.8)0.008

      DC: dyskeratosis congenita; XLR: X-linked recessive; AR: autosomal recessive; AD: autosomal dominant; DLCO: diffusing capacity of the lung for carbon monoxide. #: the number of patients with XLR/AR/TINF2 and AD non-TINF2 do not add up to the total of 43 because the causative gene was not identified in four patients. Significant odds ratios and p-values are in bold.

      • TABLE 3

        Factors associated with pulmonary function test abnormalities

        Factors evaluatedOR (95% CI)p-value
        DC inheritance: AD non-TINF2 versus AR/XLR/TINF20.04 (<0.001–1.57)0.08
        DC triad features: 2 or 3 versus 0–10.90 (0.12–6.55)0.92
        Smoker versus nonsmoker70.85 (1.84– >999.999)0.02
        Sex: male versus female0.25 (0.02–2.70)0.25
        Age in years at PFT1.11 (0.99–1.24)0.07
        Lymphocyte telomere Z-score0.63 (0.20–1.94)0.42
        BMF: severe versus none or moderate17.36 (1.82–165.30)0.01

        The multivariable regression model used includes dyskeratosis congenita (DC) inheritance (autosomal recessive (AR)/X-linked recessive (XLR)/TINF2 versus autosomal dominant (AD) non-TINF2), DC triad (0–1 versus 2–3), smoking, sex, age at pulmonary function testing (PFT) (integer), lymphocyte telomere Z-score, and bone marrow failure (BMF) (severe versus none/moderate). Overall, 38 patients were included in the multivariable regression model; five patients were excluded (four with unknown gene status and one without telomere length Z-score data). Significant p-values are in bold.

        • TABLE 4

          Features of patients with dyskeratosis congenita and pulmonary disease

          NCI UPNGeneAge at diagnosis yearsAge at PFT yearsDLCOSpirometryAge at HCT yearsHCT regimenAge at PD yearsPulmonary symptomsHRCT scan lungsAVMOutcome
          160-1TINF23.66.665%Restrictive9.5Cy/Flu/TBI12Dyspnoea, ↓SO2Bibasilar fibrosis progressed over 2 years with features of UIPNoDied from pulmonary fibrosis, age 14 years
          216-1AR-RTEL168.951%Obstructive9.1Cy/Flu/Bu14Dyspnoea, ↓SO2, worse with exerciseInterstitial changes with ground-glass opacities mainly in apices c/w NSIP; 2 AVMsYes, largePulmonary AVM coiled at age 17 years; alive age 18 years
          145-1TINF239.562%Normal10.9Cy/Flu/Bu15Dyspnoea, ↓SO2NormalYes, liverDied from HPS, age 16 years
          87-1DKC1310.649%Restrictive16.2Cy/Flu/TBI17Cough, air hungerPatchy ground-glass opacities with honeycombing c/w UIPNoDied from pulmonary fibrosis, age 18 years
          297-2AR-RTEL11418.361%Restrictive19.3Flu/C/TBI22Dyspnoea, ↓SO2Numerous small micronodular opacities c/w hypersensitive pneumonitis; linear opacities c/w mild interstitial fibrosisYes, portalAlive with pulmonary symptoms, age 23 years
          204-1#TINF2312.7<40%Restrictive4.2Cy/ATG11Cough, air hungerMultifocal areas of reticular and ground-glass opacities with honeycombing c/w UIPNoLung transplant age 13 years; died from oral cancer, age 19 years
          231-1#UK39.853%Restrictive3.9Cy/Flu/TBI14Cough, dyspnoea, air hungerPatchy diffuse ground-glass opacities c/w NSIP patternNoDied from pulmonary fibrosis, age 17 years
          291-1¶PARN1319.225%Restrictive21Clubbing, ↓SO2Increased reticular markings with architectural distortion in upper lung zones suggestive of NSIPYes, portalUnderwent HCT at age 22 years; alive with pulmonary symptoms, age 25 years
          6-1TERC2844.688%Restrictive54Cough, dyspnoea, ↓SO2Peripheral interstitial and ground-glass opacities with honeycombing in bases bilaterally c/w UIPNoAlive on supplemental O2, age 58 years
          114-1TERC3456.757%Restrictive56.7Dyspnoea on exertionProgressive polygonal and reticular opacities both lung bases and upper lobes c/w UIPAlive, has dyspnoea and ↓SO2 on exertion, age 59 years
          350-1¶TERC4459.561%Obstructive59.54Cough, dyspnoea, ↓SO2Decreased lung volume; both lower lobes with increased interstitial markings in the periphery with areas of honeycombing (UIP and NSIP pattern)NoUnderwent HCT at age 63 years; died from HCT complications
          329-1TERT656934%Restrictive65Dyspnoea, ↓SO2Extensive areas of honeycombing and peripheral fibrosis more marked in lung bases c/w UIPNoDied from pulmonary fibrosis, age 69 years

          NCI UPN: National Cancer Institute unique patient number; PFT: pulmonary function test; DLCO: diffusing capacity of the lung for carbon monoxide; HCT: haematopoietic cell transplantation; PD: pulmonary disease; HRCT: high-resolution computed tomography; AVM: arteriovenous malformation; AR: autosomal recessive; UK: unknown; Cy: cyclophosphamide; Flu: fludarabine; TBI: total body irradiation; Bu: busulfan; ATG: antithymocyte globulin; SO2: oxygen saturation; UIP: usual interstitial pneumonia; c/w: consistent with; NSIP: nonspecific interstitial pneumonia; HPS: hepatopulmonary syndrome. #: underwent HCT prior to PFT evaluation; ¶: underwent HCT after the diagnosis of AVM and interstitial fibrosis.

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          Prognostic significance of pulmonary function tests in dyskeratosis congenita, a telomere biology disorder
          Neelam Giri, Sandhiya Ravichandran, Youjin Wang, Shahinaz M. Gadalla, Blanche P. Alter, Joseph Fontana, Sharon A. Savage
          ERJ Open Research Oct 2019, 5 (4) 00209-2019; DOI: 10.1183/23120541.00209-2019

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          Prognostic significance of pulmonary function tests in dyskeratosis congenita, a telomere biology disorder
          Neelam Giri, Sandhiya Ravichandran, Youjin Wang, Shahinaz M. Gadalla, Blanche P. Alter, Joseph Fontana, Sharon A. Savage
          ERJ Open Research Oct 2019, 5 (4) 00209-2019; DOI: 10.1183/23120541.00209-2019
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