Telomere biology disorder associated lung disease- case report of a TERT gene variant as the cause of pleuroparenchymal fibroelastosis

Abstract

Case presentation

Description of a patient with a progressive destructive lung disease resembling pleuroparenchymal fibroelastosis, liver cirrhosis and bone marrow changes. Genetic workup identified a rare heterozygous coding variant in the TERT (telomerase reverse transcriptase) gene c.472 C>T; p.(Leu158Phe) and telomere length testing revealed significant telomere shortening, supporting the diagnosis of telomere biology disorder (TBD).

Discussion

TBD is an underrecognized cause of interstitial lung disease (ILD). It is a heterogeneous disease that can affect different organs, including lungs, liver and bone marrow. Genetic testing in ILD is crucial for early diagnosis, risk assessment, and family screening. Identifying this variant enables targeted genetic testing for relatives, allowing preventive measures and lifestyle modifications.

Introduction

Telomere biology disorders (TBD) are a heterogeneous group of diseases, including syndromes of short and long telomeres and are an underdiagnosed cause of interstitial lung diseases (ILD). ¹ This report describes a short telomere syndrome caused of a variant in the telomerase reverse transcriptase (TERT) gene, c.472 C>T; p.(Leu158Phe), which has never been described in ILD. Written informed consent was obtained from the patient for publication of this case report.

Case presentation

Report of a Caucasian male who has had elevated liver enzyme levels since the age of four. At an age of 36 thrombocytopenia and lymphopenia were detected, without any identifiable trigger. Subsequent examinations, including bone marrow analysis, revealed no specific findings. Because of worsening cough at that time, a CT-scan of the lung was performed which showed extensive infiltration and large consolidations in the right lower lobe and fine reticulations in both upper lobes. 10 years later, another CT-scan showed worsened findings with consolidation and tractional bronchial dilatation in the right upper lobe. A lung biopsy confirmed fibroelastic scarred lung parenchyma, leading to a diagnosis of pleuroparenchymal fibroelastosis.

At an age of 49 persistent dry cough and exertional dyspnea (WHO-Fc III) were described.There was no evidence of exposure to inhaled toxins in either his personal or professional environments and he had never smoked. Allergies were not reported. Extensive anamnesis and broad immunodiagnostic testing did not suggest an autoimmune disease. The family history was unremarkable.

Clinical examination revealed scleral icterus, watch-glass nails, the absence of body hair and mild basal crackles in both lungs upon auscultation. Further assessments including lung function testing indicated restrictive ventilation disorder, diffusion disorder and respiratory hypoxaemic insufficiency in the blood gas analysis. A follow-up CT scan of the lung demonstrated increased apical, right accentuated lung consolidation and reticular opacities with traction bronchiectasis basal on both sides (Figure 1). Bronchoscopy with broncho-alveolar lavage revealed mild lymphocytic alveolitis. Because of persistently elevated liver enzymes another magnetic resonance imaging (MRI) (Figure 2) and a biopsy of the liver were performed showing extensive parenchymal damage with signs of portal hypertension and splenomegaly, culminating in the diagnosis of liver cirrhosis (Child-Pugh B). The bone marrow examination showed hypocellular and reactive changes.

Figure 1.

CT scan of the lung with coronal (1a), axial (2b) and sagital (3c) views of the lung showing pronounced apical, predominantly right-sided consolidations, and reticular opacities (↙), along with bilateral basal tractional bronchial dilatation (○).

Figure 2.

MRI of the liver in axial plane, fat-saturated T1-weighted after administration of contrast medium in the arterial phase (a) and in the portal venous phase (b) showing advanced signs of cirrhotic liver parenchymal remodelling with coarse nodular changes of the liver parenchyma and fibrotic strands (↙).

As there was no definitive diagnosis evident, taking all clinical findings of lung, liver, bone marrow and the lack of body hair into account, we suspected a TBD as the underlying cause.

A genetic testing was initiated and whole exome sequencing was performed. A rare heterozygous variant in the TERT gene c.472 C>T; p.(Leu158Phe), was identified. The single nucleotide variant is located in coding exon 2 of the TERT gene at nucleotide position 472, leading to a replacement of leucine at codon 158 by phenylalanine. This variant has not been described before in patients with TERT-related lung diseases. In public databases it is classified as a variant of unknown significance. In silico predictions suspected this variant to have a damaging effect. For a functional assessment of the clinical significance of the detected variant, telomere length was determined using quantitative polymerase chain reaction (PCR) as described previously. In comparison to the control group the telomere length showed significant shortening, with a Telomere-to-Single Copy Gene ratio of 0.37. A ratio <1 indicates that the sample has an average telomere length shorter than standard deoxyribonucleic acid (DNA), confirming in this case the diagnosis of TBD. ²

In summary, taking the in vitro assay into account, we finally classified the variant c.472 C>T as a probably pathogenic variant and diagnosed a TERT-related TBD in our patient. The clinical findings of ILD, a pleuroparenchymal fibroelastosis, liver cirrhosis and changes in the bone marrow with leukopenia are consistent with this diagnosis.

Discussion

TBD is probably an underdiagnosed cause of a hereditary ILD. This report describes a multisystem disease potentially attributed to a gene variant in the TERT gene, c.472 C>T; p.(Leu158Phe).

Telomeres are non-coding structures at the end of chromosomes, preventing genomic instability and genomic degradation. ³ The telomere length is influenced by many factors for example telomerase activity, oxidative stress, physical activity, age, inflammation, alcohol and smoking. The telomerase adds TTAGGG repeats, protecting the telomere against critically shortening by elongating the chromosome ends. The protein is encoded by the TERT gene, coding for the protein component with a reverse transcriptase activity and the telomerase RNA component (TERC) gene, a ribonucleic acid (RNA) component, serving as a template for the repeats.^1,4

Short telomere syndromes are a heterogenous group of diseases that can lead to clinical features in all organ systems with a higher risk of organ damage especially bone marrow failure, malignancy and mucocutaneous abnormalities. ¹ Possible organ manifestations and symptoms can vary, even among family members with the same genetic variant. ⁵ There is evidence that age of manifestations, and severity of the symptoms is dependent of the degree of telomere shortening. ¹

The first report of pulmonary fibrosis linked to TERT gene mutation dates back to 2007. ⁶ Pulmonary complications affect 20% of patients with telomere biology disorders. In a study with familial cases of pulmonary fibrosis, approximately 20-25%, are associated with telomeropathies. ⁵ Further in 262 sporadic cases of pulmonary fibrosis in 11.3%, compared to 0.3% in the control group, variants of telomere-related genes with a significant difference were detected. ⁷ These findings highlight the importance of genetic testing in ILD, as genetic changes are an underdiagnosed cause for those diseases. Knowing the underlying genetic change can help understanding the patients disease and identify other organ involvement risk.

In 2023 a study showed high risk of disease and high mortality among relatives with idiopathic pulmonary fibrosis (IPF). Because of that, screening examination is useful also in asymptomatic relatives. ⁸ The statement of the European Respiratory Society from 2023 proposes to offer genetic testing to any patient with suspected short telomere syndrome, a fibrosing before the age of 50, with a relative carrying a likely pathogenic variant known to cause ILD and patients with fibrosing ILD and one or more first- or second-degree relative with fibrosing ILD. With the identification of a genetic mutation, targeted genetic testing can be offered to all relatives. ⁹

In a study analysing families of IPF patients, carriers of TERT gene mutations displayed shorter telomeres and an increased probability to develop an IPF. ⁶ Another study observed 134 patients with TERT mutations, showing a higher prevalence of lung fibrosis in older individuals, particularly in those exposed to cigarette smoking. ¹⁰ This underlines the significant impact of environmental factors as trigger on organ involvement and disease progression. It is another argument for testing asymptomatic relatives to ensure lifestyle modification even before manifest disease. ⁹

Conclusion

Telomeropathies manifest in a broad clinical spectrum of symptoms and are likely underdiagnosed in ILD. This report delineates a case of a multisystem disease with identification of a variant in the TERT gene c.472 C>T; p.(Leu158Phe), and telomere-shortening. The identified TERT variant is most likely the underlying cause for the TBD in our patient, has never been described in ILD, and allows targeted genetic testing in relatives. This case illustrates the importance of genetic testing in ILD and subsequent family screening.