A rare TERT p.Ala880Thr variant associated with familial pulmonary fibrosis and multisystem involvement: Intrafamilial heterogeneity in a Vietnamese kindred – A case series

Abstract

Short telomere syndromes (STS) are rare telomere biology disorders caused by germline variants affecting telomere maintenance and may present with organ-limited disease (e.g., pulmonary fibrosis) or multisystem involvement. We report a Vietnamese family carrying a heterozygous TERT p. Ala880Thr variant. The proband was a 42-year-old man with cryptogenic cirrhosis who was incidentally found to have a probable usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography (HRCT) and later developed progressive interstitial lung disease (ILD). He also had marked premature graying, platypnea, digital clubbing, and hepatopulmonary syndrome. Cascade evaluation identified two monozygotic twin sisters (41 years) who also had ILD with discrepant severity: one symptomatic with probable UIP and FVC 47% predicted, while the other was asymptomatic with mild probable UIP changes and FVC 84% predicted. Further pedigree assessment identified maternal cryptogenic cirrhosis and two siblings who died in early childhood with transfusion-dependent anemia, suggesting additional hepatic and hematologic manifestations within the family. Panel-based targeted NGS identified the heterozygous TERT p. Ala880Thr variant in the proband and one affected twin sister, and targeted Sanger sequencing confirmed the familial variant in additional relatives. This case series provides detailed clinical and segregation data from a Vietnamese kindred carrying the previously reported TERT p. Ala880Thr variant. It also highlights the need to suspect telomere-related disease when ILD presents at a young age or is accompanied by extrapulmonary features such as cryptogenic liver disease, premature graying, or a suggestive family history. Early genetic testing and cascade counseling may improve recognition and longitudinal surveillance of at-risk relatives.

Introduction

Short telomere syndromes (STS) are a rare, heterogeneous group of disorders caused by germline defects in telomere maintenance that impair cellular replicative capacity and tissue repair, leading to premature senescence and multisystem organ dysfunction. The phenotype is highly variable. Some patients present with classic dyskeratosis congenita, including mucocutaneous abnormalities, whereas others develop later-onset disease involving the lungs, liver, or hematopoietic system. Because these features may be subtle or confined to one organ system, STS can be difficult to recognize in clinical practice.^1,2

Among these manifestations, pulmonary fibrosis is one of the major presentations in adults and may occur either in isolation or as part of a broader telomere-related syndrome. Rare germline variants in telomere-related genes are increasingly recognized in familial pulmonary fibrosis (FPF) and in a subset of apparently sporadic idiopathic pulmonary fibrosis, supporting the role of telomere dysfunction in fibrotic interstitial lung disease.^3,4 However, clinical expression may vary substantially even among individuals carrying the same pathogenic variant, and genotype-phenotype correlations remain incompletely understood.^1,5,6

Here, we report a family with STS carrying the TERT p. Ala880Thr variant. The kindred shows multi-organ involvement affecting the lungs, liver, and hematopoietic system, with marked variability in clinical expression and disease severity. Notably, monozygotic twins showed discordant ILD phenotypes. This observation illustrates the well recognized variable expressivity of telomere-related disease and suggests that non-genetic factors may contribute to disease manifestation.^1,4 The case also illustrates why telomere biology disorders should be considered in adults with fibrotic ILD, especially when there is familial clustering or evidence of extrapulmonary disease.

The reporting of this case series conforms to the CARE checklist. ⁷ The completed checklist was submitted as a supplemental file (see Supplemental Material 1) and used to ensure inclusion of the essential reporting components, including patient information, clinical findings, diagnostic assessment, therapeutic interventions, follow-up and outcomes, discussion, informed consent, and ethics statements.

Case presentation

Case 1: Proband (patient C in the pedigree)

A 42-year-old man had Child–Pugh class C cryptogenic cirrhosis, diagnosed 3 years earlier after an esophageal variceal rupture. At that time, high-resolution computed tomography (HRCT) incidentally showed a probable usual interstitial pneumonia (UIP) pattern (Figure 1(a)) despite the absence of respiratory symptoms. Over the course of two years, he developed dry cough and exertional dyspnea, and a repeat HRCT demonstrated progression of ILD (Figure 1(b)).

Figure 1.

Chest imaging and extrapulmonary features in the proband. (a) HRCT (2022) demonstrates subpleural, basal predominant fibrotic changes, consistent with probable UIP pattern. (b) HRCT (2025) demonstrates progression of ILD. (c) and (d) Premature graying of the hair and beard. (e) CT pulmonary angiography demonstrates enlarged pulmonary arteries, suggestive of pulmonary vascular dilatation. (f) Contrast echocardiography demonstrates a positive bubble study, with dense microbubbles in the right ventricle (arrowhead) and appearance of microbubbles in the left ventricle (arrow) approximately six cardiac cycles later.

This time, he was admitted with a 3-day history of fever, abdominal pain and ascites, accompanied by platypnea. Physical examination showed stigmata of cirrhosis (jaundice, palmar erythema, spider angiomata), digital clubbing, bibasilar fine crackles, marked premature graying (Figure 1(c) and (d)), and orthodeoxia, with oxygen saturation decreasing from 90% in the supine position to 85% when sitting upright. Laboratory testing showed leukopenia (WBC 2.69 × 10⁹/L), macrocytic anemia (Hb 112 g/L; MCV 108 fL; MCH 37.6 pg), severe thrombocytopenia (platelets 31 × 10⁹/L), hypoalbuminemia (albumin 21.6 g/L), and elevated aminotransferases (AST 95 U/L, ALT 32 U/L). Ascitic fluid analysis showed neutrophils 3,034/mm³, consistent with spontaneous bacterial peritonitis. He was treated with supplemental oxygen, ceftriaxone, diuretics, and intravenous albumin, and by day 5 he was afebrile with resolution of abdominal pain and improvement in ascites.

Further etiologic evaluation of cirrhosis was unrevealing. Alcohol intake was modest (approximately 5 units/week for 10 years), and viral hepatitis serology and autoimmune hepatitis markers (SMA by indirect immunofluorescence, anti-LKM1, anti-Sm), screening tests for Wilson disease or alpha 1 antitrypsin deficiency were negative. Although anti-gp210 was detected, there were no supporting clinical or laboratory features sufficient to establish autoimmune liver disease as the primary explanation for cirrhosis.

ILD evaluation showed limited smoking exposure (5 pack years) and a history of cannabis misuse. Infectious studies were negative (sputum bacterial culture, acid-fast bacilli smear, and Xpert MTB/RIF), and bronchoscopy was not performed because the patient declined the procedure. Autoimmune serology showed non-specific positivity (anti–Jo-1, and cANCA), without corresponding clinical features of connective tissue disease, inflammatory myopathy or vasculitis. Pulmonary function tests demonstrated a markedly reduced DLCO (Z-score −4.59, 46% predicted), with a post-bronchodilator FVC of 77% predicted. In the context of cirrhosis, the presence of platypnea–orthodeoxia prompted further evaluation for hepatopulmonary syndrome, which was confirmed by pulmonary vascular dilatation on CT (Figure 1(e)) and contrast echocardiography, with delayed appearance of microbubbles in left heart at the sixth cardiac cycle (Figure 1(f)).

Given the combination of early-onset pulmonary fibrosis, cirrhosis, hepatopulmonary syndrome, premature graying, and concern for an inherited disorder, STS was suspected. Further review of the family history revealed that his mother had cirrhosis of unclear etiology and that two younger sisters had died at around 4 years of age from suspected hematologic disease requiring weekly transfusions. A multigenerational pedigree suggested familial clustering of unexplained disease (Figure 2).

Figure 2.

Pedigree of the family carrying the TERT p. Ala880Thr variant, showing multisystem manifestations suggestive of short telomere syndrome. The arrow indicates the proband (Patient C, male, 42 years). Monozygotic twin sisters D and E (41 years) carried the same TERT variant and showed discordant ILD severity; offspring H, I, and J also carried the variant. Two younger sisters, F and G, died at 4 years of age with transfusion-dependent anemia suggestive of severe hematologic disease.

Because these multisystem findings were compatible with a genetically heterogeneous inherited disorder, broad clinical exome sequencing was selected. Targeted next-generation sequencing (NGS) using G4500, a broad clinical exome sequencing panel, identified a heterozygous TERT variant, NM_198253.3:c.2638G>A (p.Ala880Thr) (see Genetic analysis below), classified as pathogenic/likely pathogenic according to American College of Medical Genetics and Genomics criteria/Association for Molecular Pathology criteria, ⁸ supporting the diagnosis of STS.

He received intermittent home oxygen therapy and was treated with diuretics for ascites control, lactulose for hepatic encephalopathy prophylaxis, and carvedilol for secondary prophylaxis of esophageal variceal bleeding. Antifibrotic therapy was not initiated because of advanced liver disease. Because his hypoxemia was considered to be related to HPS, liver transplantation evaluation was prioritized. At the most recent follow-up, his liver disease remained clinically stable, although exertional dyspnea and positional dyspnea persisted. He is currently considering liver transplantation and is seeking a suitable donor.

Case 2: Monozygotic twin sister 1 (patient D in the pedigree)

Following identification of the TERT variant in the proband, cascade evaluation was performed in available family members. The proband’s younger sister, a 41-year-old woman with type 2 diabetes mellitus, presented with a 2-year history of exertional dyspnea and a dry cough. HRCT showed a probable UIP pattern (Figure 3(a)), and spirometry demonstrated a post-bronchodilator FVC of 1.72 L (47% predicted). Autoimmune serology showed anti-SRP positivity with borderline anti-MDA5 and anti-SAE1, without clinical features of idiopathic inflammatory myopathy or connective tissue disease. Targeted NGS using the same G4500 panel identified the heterozygous TERT p. Ala880Thr variant. Screening for extrapulmonary manifestations showed a normal complete blood count with borderline macrocytosis (MCV 98.8 fL, above the reference range), and mildly elevated aminotransferases (AST 35 U/L, ALT 79 U/L). Targeted Sanger sequencing showed that her 12-year-old son carried the familial TERT variant and was asymptomatic. She is currently receiving pirfenidone, which she is tolerating well, while glycemic control is being maintained. At the most recent follow-up, her respiratory symptoms remained clinically stable.

Figure 3.

Variable severity of ILD across the proband and his monozygotic twin sisters. (a) and (b) correspond to the monozygotic twin sisters, Patients D and E, respectively, demonstrating different degrees of probable UIP-pattern changes. (c) Shows the proband, with probable UIP-pattern changes and associated pulmonary vascular dilatation.

Case 3: Monozygotic twin sister 2 (patient E in the pedigree)

The other 41-year-old monozygotic twin sister of Patient D was asymptomatic and presented for family screening. HRCT showed basal, bilateral probable UIP-pattern changes (Figure 3(b)). For comparison, HRCT imaging of the proband (Patient C) is shown in Figure 3(c). Spirometry demonstrated relatively preserved lung volumes (post-test FVC 3.16 L, 84% predicted). Autoimmune serology was negative. Targeted Sanger sequencing for the familial TERT variant confirmed the heterozygous p. Ala880Thr variant. Screening for extra-pulmonary manifestations showed a normal complete blood count and normal aminotransferases. Targeted Sanger sequencing showed that her two sons (12 and 8 years) also carried the familial TERT variant and were asymptomatic. She was placed on 6-month follow-up with symptom assessment and pulmonary function testing to monitor for progression.

Genetic analysis

The proband (Patient C) and one of his affected sisters (Patient D) underwent targeted next-generation sequencing using G4500, a broad clinical exome panel covering 4,503 disease-associated genes, including relevant telomere biology and FPF genes (Supplemental Material 2). Genomic DNA from peripheral blood was sequenced on the Illumina NextSeq platform and aligned to GRCh38, with a mean depth of approximately 100× and at least 95% of target regions covered at >10×. The assay assessed single-nucleotide variants and short insertions or deletions within coding regions and adjacent intronic sequences (−10 to +10 nucleotides from exon boundaries).

The heterozygous TERT NM_198253.3:c.2638G>A (p.Ala880Thr) variant was identified in Patients C and D and confirmed by Sanger sequencing. No additional pathogenic or likely pathogenic variants explaining the hepatic or hematologic phenotype were identified in either patient within the scope of the assay. Targeted Sanger sequencing was subsequently used for cascade testing in Patient E and the available offspring (Supplemental Material 3).

As a limitation, deep intronic and regulatory variants were not systematically assessed. In addition, in relatives who underwent targeted Sanger sequencing only, other variants in telomere-related genes or additional disease-associated genes could not be excluded.

Discussion

In this case series, we provide detailed phenotypic and familial genetic data from a Vietnamese kindred carrying the TERT p. Ala880Thr variant, which has been classified as pathogenic/likely pathogenic. ⁸ The co-occurrence of FPF, cryptogenic cirrhosis with hepatopulmonary syndrome, premature graying, and suspected hematologic manifestations, together with markedly discordant ILD severity in monozygotic twins, illustrates the recognized clinical variability associated with this rare variant within a single family. Alongside previously reported cases (Table 1),^3,4,9,10 these findings further support the recognized phenotypic variability of this variant and provide clinically relevant observations on variable and age-related expression.

Table 1.

Summary of previously reported patients with TERT p.Ala880Thr and short telomere syndrome related phenotypes.

Author	Demographics	Phenotype	Family/segregation
Vogiatzi et al. 9 ; Perdigones et al. 10	Female, 1 year	Hoyeraal–Hreidarsson syndrome	Proband carried maternal TERT p.Ala880Thr and paternal TERT P530L; mother had lung disease, whereas the father was asymptomatic
Borie et al. 4	70 years	Pulmonary fibrosis; liver disease; hematologic disease	NA
	68 years
Dressen et al. 3	NA	Pulmonary fibrosis	NA
Our report	- male, 42 years	Familial pulmonary fibrosis; cryptogenic cirrhosis; hepatopulmonary syndrome; premature graying	Mother with cryptogenic cirrhosis; 2 younger sisters died in childhood with transfusion-dependent anemia; 3 offspring carried TERT p.Ala880Thr
	- monozygotic twin sisters, 41 years

STS are inherited telomere biology disorders caused by germline variants in genes involved in telomere maintenance, including TERT and other telomerase-pathway genes. ⁵ By impairing telomere preservation, these variants accelerate telomere attrition, reduce cellular replicative capacity, and promote premature senescence, particularly in tissues with high regenerative demand.^1,11,12 This biological mechanism explains the multisystem nature of STS, which may involve the lungs, liver, bone marrow, and other organs, as well as the marked variability in clinical expression observed across affected individuals.

Despite these recognized features, STS remain diagnostically challenging because no universally accepted diagnostic criteria currently exist. The ERS statement on FPF emphasizes several clinical clues that should raise suspicion for telomere-related disease ¹³ (Table 2), including pulmonary fibrosis accompanied by premature greying, liver disease, cytopenias, or a suggestive family history. One previously proposed diagnostic framework relies on the presence of the classic mucocutaneous triad of dyskeratosis congenita, or compatible clinical manifestations such as bone marrow failure or pulmonary fibrosis, telomere testing when available, and identification of a pathogenic germline variant. ² In this context, our family fits a clinically recognizable telomere-related pattern despite the absence of telomere length measurement.

Table 2.

Suggested indicators for evaluating telomere-related disease in pulmonary fibrosis.

Pulmonary fibrosis and one or more of the following in the patients and/or family members:
Pulmonary fibrosis
Haematological abnormalities: macrocytosis, neutropenia, lymphopenia, thrombocytopenia, myelodysplasia, acute leukaemia and/or
Hepatic abnormalities: cryptogenic elevated liver enzymes, portal hypertension, hepato-pulmonary syndrome, liver cirrhosis and/or
Early hair greying (significant greying before age 30 years)
Recognised telomere disease such as dyskeratosis congenita

Consistent with the recognized variable expression of telomere-related disease,^1,4,5 the phenotype varied substantially among carriers of the familial TERT p. Ala880Thr variant, ranging from asymptomatic or mild probable UIP-pattern abnormalities to progressive pulmonary fibrosis with major extrapulmonary involvement. Two siblings died at approximately 4 years of age requiring weekly transfusions. Although confirmatory genetic testing and telomere length data are unavailable for these siblings, this raises the possibility of an early-onset hematologic phenotype within the same family. In contrast, the three surviving siblings developed manifestations around 40 years of age, predominantly fibrotic ILD. This pattern is consistent with prior observations that severe telomere-related phenotypes such as dyskeratosis congenita and the Hoyeraal–Hreidarsson syndrome spectrum typically have emerged in childhood,^2,10 whereas pulmonary fibrosis more often develops after 40 years of age and may show higher penetrance in males. ¹⁴ Intrafamilial phenotypic variability may be partly explained by differences in inherited telomere length reserve and baseline set points, which may shape age at onset and predominant organ involvement despite the same telomere-related genetic defect. ¹⁵

The possibility of an additional contributory genetic factor should also be considered. This is particularly relevant because TERT p. Ala880Thr has previously been reported in a patient with Hoyeraal–Hreidarsson syndrome who carried a second TERT variant in a compound heterozygous state. ⁹ In Patient C and Patient D, broad panel-based sequencing did not identify additional pathogenic or likely pathogenic variants suggesting a biallelic state or a second monogenic explanation within the genes assessed. However, the two deceased siblings with suspected severe childhood hematologic disease could not be tested, and Patient E and the available offspring underwent targeted Sanger sequencing only for the familial TERT variant. Therefore, additional missense variants or other rare variants in telomere-related, fibrotic lung disease, or bone marrow failure genes could not be assessed across the entire kindred and may have contributed to the observed differences in disease severity.

In addition, prior studies suggest that in carriers of TERT or TERC variants, smoking and chronic inflammatory states may increase ILD risk and contribute to earlier onset. This may support a gene-environment interaction model in which telomerase mutations and short telomeres confer susceptibility, while environmental factors act as a second hit that accelerates onset and increases severity.^4,14,16 In our family, this framework may partly account for the marked phenotypic discordance observed even between monozygotic twins: Patient D developed symptomatic ILD with severe physiologic impairment, whereas Patient E remained asymptomatic, with preserved lung volumes and only mild probable UIP-pattern abnormalities detected on screening HRCT. Similarly, Patient C had the most severe clinical course and had a history of cigarette smoking, cannabis use, and alcohol intake.

From a variant-specific perspective, TERT p. Ala880Thr is a pathogenic germline missense located within the reverse transcriptase domain of telomerase, a functionally critical region responsible for catalytic activity. ¹ In a previous report, this variant was associated with very short telomere length in affected family members and markedly reduced telomerase activity in vitro. ⁹ ClinVar currently classifies this variant as pathogenic/likely pathogenic. ⁸ However, telomere length measurement and functional assays were not performed in the present family; therefore, we could not directly confirm telomere shortening or altered telomerase function in these relatives. To date, our literature review identified five previously reported individuals carrying the TERT p. Ala880Thr variant, with phenotypes ranging from Hoyeraal–Hreidarsson syndrome in infancy to adult-onset pulmonary fibrosis with liver and hematologic involvement (Table 1).^3,4,9,10 Notably, missense variants in TERT often retain partial enzymatic function, which may contribute to incomplete penetrance and variable expressivity, in contrast to more deleterious loss-of-function variants. ¹⁴ Together with previously reported cases of TERT p. Ala880Thr,^3,4,9,10 our family provides additional clinical and familial data on the variable presentation of this rare variant in adult FPF.

There is currently no specific therapy for pulmonary fibrosis associated with STS.^13,17 Antifibrotic treatment is still recommended by the ERS consensus in line with other forms of fibrotic progressive pulmonary fibrosis that are not primarily genetic, together with exposure avoidance and careful medication selection to minimize hematologic and pulmonary toxicity. ¹³ Lung transplantation for STS-related IPF appears to have outcomes comparable to non genetic IPF; however, post transplant immunosuppression may exacerbate pre-existing hematologic complications in patients with STS.^12,13 Several limitations in our report should be acknowledged, primarily the absence of telomere length measurement. Therefore, we could not directly confirm telomere shortening in affected relatives or determine whether telomere length was related to disease severity within this family. Despite the absence of telomere-length data, the combination of a compatible multisystem phenotype and identification of a pathogenic germline TERT variant provided molecular support for a telomere biology disorder, consistent with established diagnostic frameworks. ² In addition, Patient C had pancytopenia, but a bone marrow examination was not performed to determine whether the cytopenias were secondary to cirrhosis or reflected an underlying hematologic disorder. Furthermore, although hepatic involvement was documented in the proband, genetic confirmation was not available for the deceased siblings or the affected mother. As a result, segregation of the familial TERT variant with the maternal liver disease and the suspected childhood hematologic phenotype could not be established. Functional validation specific to this family was also not performed. Finally, because this is a single-family case series, the role of environmental exposures in shaping disease severity remains hypothesis-generating rather than causal.

Conclusion

This Vietnamese kindred adds clinical and familial data on familial fibrotic ILD and extrapulmonary manifestations associated with the previously reported TERT p. Ala880Thr variant. The monozygotic twin pair, in whom ILD severity differed substantially, underscores the clinical relevance of intrafamilial variability in telomere-related disease. Early recognition of at-risk patients, such as those with ILD presenting before 50 years of age and accompanied by extrapulmonary features involving the liver or hematologic system, premature hair graying, or a family history of ILD or cirrhosis of unknown etiology, is crucial. In such patients, clinicians should consider STS, pursue telomere-related genetic testing (TERT, TERC, and others), and provide genetic counseling for the family. A timely and accurate diagnosis informs treatment planning, including the selection of agents with lower marrow, pulmonary, and hepatic toxicity, careful evaluation of transplant indications, and early screening of at-risk family members.

Appendix.

Abbreviations

STS

Short telomere syndromes

FPF

Familial pulmonary fibrosis

HRCT

High-resolution computed tomography

ILD

Interstitial lung disease

IPF

Idiopathic pulmonary fibrosis

NGS

next-generation sequencing

TERC

Telomerase RNA component

TERT

Telomerase reverse transcriptase

UIP

Usual interstitial pneumonia.

ORCID iDs

Nghi Nguyen-Dang https://orcid.org/0009-0003-8612-6746

Quoc-Khanh Tran-Le https://orcid.org/0000-0002-7788-3767

Khoa Nguyen-Dang https://orcid.org/0009-0002-3144-7561

Ngoc Duong-Minh https://orcid.org/0009-0000-8372-2794

Lam Nguyen-Ho https://orcid.org/0000-0001-7171-2257

Ethical considerations

This manuscript was written in compliance with the ethical standards of the institutional ethics committee and with the Helsinki Declaration. According to our institutional policy, approval from the ethics committee is not required for case reports.

Consent to participate

Written informed consent was obtained from the patients for publication of this case report and any accompanying images.

Consent for publication

Written informed consent for publication was obtained from the patients.

Data Availability Statement

The datasets used and/or analyzed in the current study are available from the corresponding author upon request.*