Telomeres consist of non-coding DNA (TTAGGG) and associated proteins thought to maintain genomic integrity during repeated cell divisions. Critical TS can lead to diverse clinical syndromes (4). Dyskeratosis congenita is a prototype of a TS condition, which is described as a triad of oral leukoplakia, reticular pigmentation of the neck/upper chest and dysplastic nails (5). It can be associated with other features which may also be found in telomere-related FPF, such as bone marrow failure, myelodysplasia, and leukemia (6). TS syndrome can also be associated with immunodeficiency, neurological or retinal conditions (5, 7).

Telomere length decreases with age even in the absence of fibrotic lung pathology. However, this appears to be more pronounced in ILD patients (8). Those carrying a pathogenic variant (also called mutation) in a telomere-related gene (TRG) generally have shorter telomeres (<25th percentile) compared to age matched controls; while only 50% of ILD patients >60 years old and TERT, TERC or RTEL1 mutations had a telomere length > 10th percentile (9). Short telomere length is associated with worse clinical outcomes in fibrotic ILD (10–12) and poor tolerance to immunosuppressive treatments (13, 14).

Telomere abnormalities, including TS, have also been identified in sporadic cases of IPF and other forms of pulmonary fibrosis (PF) (10, 15, 16).

TRGs include TERT, TERC, RTEL1, PARN, DKC1, TINF2, NOP10, NHP2, ACD, NAF1, ZCCHC8, RPA, POT1 (5). TERT (telomerase reverse transcriptase) and TERC (telomerase RNA component) are components of the telomere complex which is a group of proteins and RNA that drive the addition of telomeric repeats (TTAGGG) to the ends of chromosomes and were the first TRGs identified in FPF (4).

The mean age of ILD diagnosis in patients with TRG mutation is approximately 58 years (16). Clinical features include a usual interstitial pneumonia (UIP) radiological pattern on chest CT which can be seen in up to 54–74% of ILD cases with TRG mutations although other radiological patterns can be present. Radiological and histological patterns can vary even within the same family (16–18). Hematological abnormalities, such as anemia (17–27%), macrocytosis (24–41%) or thrombocytopenia (8–54%) may be associated to ILD (16, 17). Patients with DKC1, TINF2 and TERC mutations are more likely to have hematological involvement compared to those with TERT, PARN or RTEL1 mutations (16). Asymptomatic liver function abnormalities (i.e., increased liver transaminases) can also be found in 5–27% TRG mutation patients and early hair greying is noted in 15–40% (11, 19).

Surfactant-related genes (SRGs) include SFTPC which has an autosomal dominant mode of inheritance with frequent de novo mutations, but low frequency in FPF cases (<5%) (5). ABCA3 is mostly associated with respiratory failure in the newborn but severe adult ILD has been reported. NKX2.1 encodes the protein TTF1 which regulates surfactant protein as well as ABCA3 gene transcription. While NKX2.1 mutation mostly causes neonatal disease it can result in an atypical UIP pattern in adults (5, 20–23). In childhood, SRG mutations are the most common, whereas in adults, TRG pathogenic variants are more common (5, 24).

The single-nucleotide polymorphism rs35705950 in the promoter of the gene encoding mucin 5B (MUC5B) was shown to be associated with both FIP and sporadic IPF (25). It showed a significant signal in large genome-wide association studies and has been associated with various fibrotic ILDs (10, 26–29). However, given the high prevalence of the MUC5B rs35705950 minor allele promoter variant and low penetrance, genotyping of the variant is not currently part of FPF gene investigations in most countries (5). Fortunately in the UK, MUC5B is listed in the FPF panel, as well as SRGs and TRGs, as part of the National Genomic Test Directory for rare and inherited disease (30).

In FPF, there is overall a 50% chance of inheriting a deleterious allele in first-degree relatives (autosomal dominant) (5). Penetrance is generally incomplete, higher for SRGs (24) compared to TRGs, and expressivity is variable. The absence of TRG mutations in a family member of an index case does not exclude risk of disease due to other telomere abnormalities. The average age of ILD onset is lower in SRG compared to TRG mutation carriers. Pulmonary-only disease is more common in patients with SRG versus TRG pathogenic variants (5).

Cellular senescence is characterized by a state of cell cycle arrest (31). PF is considered a disease of senescence (aging) with fibrogenesis requiring an interplay between genetic predisposition and repeated exogenous insults (i.e., environmental). Animal models have confirmed that increasing age and having mutations in TRGs (e.g., TERT) favor the development of fibrosis following infectious or noxious challenge. Immune processes can also be affected by cellular senescence (such as T cell dysfunction and shifting to Th17 responses leading to immune dysregulation and propensity to autoimmune responses) and environmental exposures can accelerate this process (31, 32). Genomic instability due to TERT or ABCA3 mutations and fibrogenic exposures can lead to lung epithelial cell phenotypes that correspond to age-induced senescence (33).

There is evidence that acute exacerbations of IPF may correlate to air pollution, possibly mediated by senescence in inflammatory cells (34, 35). Fibroblast senescence can be triggered directly by environmental stress as well as indirectly by neighboring senescent cells altering the cellular microenvironment (36, 37). The window when environmental challenge occurs, as well as the dose and repeated exposure, play a role in senescence and fibrotic responses (33, 38).

Progressive pulmonary fibrosis (PPF) is the dominant phenotype seen in familial cases. There is evidence to suggest that FPF is worse, faster progressing and has higher mortality than sporadic fibrotic ILD, although data is incomplete and at times contradictory (5). In a small study, a 9.9% annual rate of FVC decline was seen in familial IPF patients compared to 4.9% in those with sporadic IPF (not statistically significant, p = 0.12) (49). The average annual rate of FVC decline amongst 115 ILD patients with TRG mutations (46% of whom had IPF) was found to be 300 ml (regardless of gene involved) (16). The mean survival from diagnosis in FPF appears to be between 2.4 and 7.3 years (18, 50). In a cohort of 1,262 ILD patients, survival was found to be worse in FPF compared to sporadic PF, both for IPF cases (HR for death or transplant of 1.8 [95% CI, 1.37–2.37]) and non-IPF ILD (HR for death or transplant of 2.08 [CI: 1.46–2.96]) (51). Regardless of the ILD diagnostic label, there was no difference in median survival comparing familial IPF to familial non-IPF (16).

As genomic tests can be expensive or only reimbursed when certain criteria are met, it is recommended to pre-screen patients based on family history and clinical features of TS prior to testing (Tables 1, 2) (5, 52). In our opinion, the easiest way to organize testing is by running dedicated FIP clinics. This allows to pool together patients with rare ILDs, screen relatives, offer personalized medicine and identify associated conditions (e.g., hematological diseases). More time for explanations can be given by a trained healthcare provider leading to a better patient experience. Genetic and psychological counselling, specialist ILD nursing and research can also be integrated within the FIP clinic structure.

Appropriate counselling and a tactful approach are necessary because genomic testing can be seen as opening a “Pandora’s box.” It often leads to major changes in patients’ lives and those of their relatives. In our experience with the Manchester FIP clinic, most patients are extremely interested in genomic tests if the wider context is clearly explained, and a pathway exists to deal with possible results. Importantly, testing provides an answer to the question “Why did I get ILD?” which leads to better acceptance of the ILD diagnosis and treatment requirements. Many patients are also very interested in research projects.

In our experience, familial and sporadic cases with telomere dysfunction frequently have atypical ILD presentations, and this can delay referral to an ILD specialist center, accurate diagnosis, and timely treatment.

As FPF cases may progress faster than sporadic ones, more frequent follow-up with lung function monitoring and early lung transplant referral should be considered as part of the MDT discussion, ideally involving transplant specialists and genetic counsellors. Transplant outcomes between FPF and sporadic PF were comparable (54, 55), therefore knowledge of a familial aggregation, TS or identified mutation should not automatically be considered contraindications for lung transplantation (54). Special considerations should be given to personalizing immunosuppressive regimens and the post-transplant follow-up as patients with telomere dysfunction (TS and/or TRG mutation) may be at increased risk of complications (13, 14, 56, 57).

Antifibrotics are just as useful in FPF as in sporadic fibrotic ILDs (IPF and PPF). Immunosuppression can increase the risk of complications and efficacy may be limited in patients who require such treatments (e.g., to treat fibrotic hypersensitivity pneumonitis) (14). It would be reasonable to encourage smoking cessation and avoidance of other inhalational exposures.

Interstitial lung abnormalities (ILAs) on chest CT scanning are a common finding in relatives of FPF patients (5). They are defined as incidental findings of nondependent abnormalities which affect >5% of any lung zone (upper, middle, lower), where ILD was not previously suspected. Respiratory symptoms may be present, and this may indicate early ILD. Three subtypes of ILAs have been described: non-subpleural nonfibrotic, subpleural nonfibrotic, subpleural fibrotic (58, 59).

Previous studies have demonstrated a prevalence of ILAs on lung cancer screening of 4–20% (60–63). Recent data from Manchester found a prevalence of ILAs on low-dose chest CT scanning of 3.9%, and 40.7% of these individuals with ILAs were subsequently diagnosed with ILD within 5 years (64).

Interstitial lung abnormalities are associated with radiological progression and mortality (64). Having traction bronchiectasis or bronchiolectasis is an important radiological risk factor to predict adverse outcomes (65, 66).

There is no clear pathway or optimal age for screening relatives of FPF patients. As there is a 1–3-year delay between symptom onset and diagnosis for FPF patients, this represents an opportunity for early diagnosis (67).

It is recommended that all first-degree relatives of FPF patients should have a screening chest high-resolution CT (HRCT) scan especially if they have non-resolving respiratory symptoms (chronic cough and dyspnea) (5). The prevalence of interstitial lung changes on CT screening of first-degree relatives of FPF patients has been reported as 14–25% (5). Among first-degree relatives of FPF without overt ILD at screening, 19.4% developed extensive HRCT abnormalities or clinical ILD at 5 years. Also, 63.3% of patients with limited ILAs at enrolment experienced progression compared to only 6.1% of patients with normal HRCT at baseline (68).

Lung function is important for screening and follow-up, but simple spirometry may not identify early cases since FVC < 80% predicted in asymptomatic relatives is rare. However, relatives with ILAs have a lower diffusing capacity of the lung for carbon monoxide (DLCO) than those with normal HRCT (68, 69). Annual lung function testing may identify trends of decline. The role of home spirometry monitoring has not been explored in this population but may hold promise for the future.

Additionally, due to the high prevalence of other TS features, a full blood count (FBC) and liver function testing should also be performed in first-degree relatives (5).

Certain relatives may be more open to screening, while others would prefer to wait and clinicians should abide by their preferences, to not cause undue anxiety. Eligible relatives may also be offered genomic testing, usually via local/regional Clinical Genetics services who follow-up families of the proband.

To date, there is no consensus on the frequency and duration of clinical, functional, and radiological evaluations of first-degree relatives of FPF patients. Management could be customized through a risk assessment, considering resources available in each country/national health system.

Figure 1 outlines a potential screening strategy for relatives of FPF patients.