Telomere-related lung fibrosis is diagnostically heterogeneous but uniformly progressive

Abstract

Heterozygous mutations in four telomere-related genes have been linked to pulmonary fibrosis, but little is known about similarities or differences of affected individuals.115 patients with mutations in telomerase reverse transcriptase (TERT) (n=75), telomerase RNA component (TERC) (n=7), regulator of telomere elongation helicase 1 (RTEL1) (n=14) and poly(A)-specific ribonuclease (PARN) (n=19) were identified and clinical data were analysed.Approximately one-half (46%) had a multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF); others had unclassifiable lung fibrosis (20%), chronic hypersensitivity pneumonitis (12%), pleuroparenchymal fibroelastosis (10%), interstitial pneumonia with autoimmune features (7%), an idiopathic interstitial pneumonia (4%) and connective tissue disease-related interstitial fibrosis (3%). Discordant interstitial lung disease diagnoses were found in affected individuals from 80% of families. Patients with TERC mutations were diagnosed at an earlier age than those with PARN mutations (51±11 years versus 64±8 years; p=0.03) and had a higher incidence of haematological comorbidities. The mean rate of forced vital capacity decline was 300 mL·year^-1 and the median time to death or transplant was 2.87 years. There was no significant difference in time to death or transplant for patients across gene mutation groups or for patients with a diagnosis of IPF versus a non-IPF diagnosis.Genetic mutations in telomere related genes lead to a variety of interstitial lung disease (ILD) diagnoses that are universally progressive.

FIGURE 1

Spectrum of interstitial lung disease diagnoses in subjects with heterozygous TERT, TERC, RTEL1 or PARN mutations. Representative coronal (a, c, e, g) and axial (b, d, f, h) images of chest computed tomography scans from patients with diagnoses of a and b) idiopathic pulmonary fibrosis (IPF), c and d) chronic hypersensitivity pneumonitis, e and f) pleuroparenchymal fibroelastosis (PPFE) and g and h) nonspecific interstitial pneumonia (NSIP). Representative haematoxylin and eosin stained lung sections from related ILD subjects with i and j) the same TERT c.2594G>A (R865H) mutation and k and l) the same TERC r.182g>c mutation. i) Usual interstitial pneumonia (UIP) pattern with temporal and spatial heterogeneity and fibroblastic foci at the interface between normal and fibrotic lung in a 53-year-old man who underwent lung transplantation. j) Desquamative interstitial pneumonia (DIP) with organising pneumonia, thickened interstitial septi and presence of intra-alveolar pigmented macrophages (inset) in a 68-year-old never-smoker (scale bar=500 μm; inset scale bar=200 μm). k) Pleuroparenchymal fibroelastosis (PPFE) with diffuse elastic fibre deposition (inset) near the pleural edge in a lung explant from a 60-year-old female at the time of lung transplantation (scale bar=500 μm; inset scale bar=500 μm). l) Features of chronic hypersensitivity pneumonitis with bronchiolocentric fibrosis, patchy lymphoid aggregates, bridging fibrosis and loosely formed granulomas (inset) in a lung explant from her 57-year-old sister (scale bar=500 μm; inset scale bar=500 μm).

FIGURE 2

Clinical characteristics of interstitial lung disease (ILD) subjects with heterozygous TERT, TERC, RTEL1 and PARN mutations. a) Evidence of genetic anticipation with an earlier age of ILD diagnosis for patients in subsequent generations of nine kindreds, including four with TERT mutations, two with RTEL1 mutations and three with PARN mutations. The number of individuals included in the analysis is listed on the x-axis. b) Transplant-free survival of ILD patients with TERT, TERC, RTEL1 and PARN mutations as depicted in a Kaplan–Meier survival plot. There is no significant difference between survival characteristics across different gene groups. c) Transplant-free survival of patients with TERT, TERC, RTEL1 and PARN mutations and a diagnosis of idiopathic pulmonary fibrosis (IPF) or a non-IPF diagnosis as depicted in a Kaplan–Meier survival plot. There was no significant difference between survival characteristics across the two diagnosis groups.