Short Telomere Syndromes Research Articles

The “Shrimp Sign” in a Case of Infratentorial PML Due to Short Telomere Syndrome

The “Shrimp Sign” in a Case of Infratentorial PML Due to Short Telomere Syndrome

High prevalence of short telomeres in idiopathic porto-sinusoidal vascular disorder.

Telomeres prevent damage to coding DNA as end-nucleotides are lost during mitosis. Mutations in telomere maintenance genes cause excessive telomere shortening, a condition known as short telomere syndrome (STS). One hepatic manifestation documented in STS is porto-sinusoidal vascular disorder (PSVD). As the etiology of many cases of PSVD remains unknown, this study explored the extent to which short telomeres are present in patients with idiopathic PSVD. This monocentric cross-sectional study included patients with histologically defined idiopathic PSVD. Telomere length in 6 peripheral blood leukocyte subpopulations was assessed using fluorescent in situ hybridization and flow cytometry. Variants of telomere-related genes were identified using high-throughput exome sequencing. In total, 22 patients were included, of whom 16 (73%) had short (9/22) or very short (7/22) telomeres according to age-adjusted reference ranges. Fourteen patients (64%) had clinically significant portal hypertension. Shorter telomeres were more frequent in males (p = 0.005) and patients with concomitant interstitial lung disease (p < 0.001), chronic kidney disease (p < 0.001), and erythrocyte macrocytosis (p = 0.007). Portal hypertension (p = 0.021), low serum albumin level (p < 0.001), low platelet count (p = 0.007), and hyperbilirubinemia (p = 0.053) were also associated with shorter telomeres. Variants in known STS-related genes were identified in 4 patients with VSTel and 1 with STel. Short and very short telomeres were highly prevalent in patients with idiopathic PSVD, with 31% presenting with variants in telomere-related genes. Telomere biology may play an important role in vascular liver disease development. Clinicians should consider measuring telomeres in any patient presenting with PSVD.

Alemtuzumab-based conditioning regimen before hematopoietic stem cell transplantation in patients with short telomere syndromes: a retrospective study of the SFGM-TC.

While HSCT is the only curative option for patients with short telomere syndromes (STSs) and severe bone marrow failure (BMF) or myeloid malignancies (MM), their increase sensitivity to conditioning regimen strongly affect outcomes. To minimize HSCT related mortality, alemtuzumab-based conditioning regimens have been proposed, but the number of patients transplanted with those regimens reported in the literature remains very low. We retrospectively analyzed outcome of adults and adolescents with STSs transplanted after an alemtuzumab, fludarabine and cyclophosphamide based regimen registered by the SFGM-TC. Seven patients were transplanted for a BMF and 5 for a MM (median age 34 years, (IQR [22-45])). The 2-year GRFS for patients with MM was 20% (95% CI [3;100]), and 57% (95% CI [30;100]) in others. In univariate (hazard ratio, HR = 6, 95% CI [1;31]) and multivariate analysis (HR = 26, 95% CI [2;414]) stem cell source was a predictive factor for GRFS. Three of the 5 patients with pre-transplant MM relapsed and 2 of them died at last follow up. The 2-year OS was 66% (95% CI [43;99]) in the whole cohort with a median follow up of 32 months (IQR [13-56]). In conclusion, Alemtuzumab-based conditioning regimen with bone marrow is an option for patients with STSs and BMF, but others modalities have to be explored for patients with MM.

Clinical Impact of Telomere Length Testing for Interstitial Lung Disease

BackgroundShortened telomere length (TL) is a genomic risk factor for fibrotic interstitial lung disease (ILD), but its role in clinical management is unknown. Research QuestionWhat is the clinical impact of TL testing on the management of ILD? Study Design and MethodsPatients were evaluated in the Columbia University ILD clinic and underwent CLIA-certified TL testing by flow cytometry and fluorescence in-situ hybridization (FlowFISH) as part of clinical management. Short TL was defined as below the 10th age-adjusted percentile for either granulocytes or lymphocytes by FlowFISH. Patients were offered genetic counseling and testing if they had short TL or a family history of ILD. FlowFISH TL was compared against research qPCR TL measurement. ResultsA total of 108 patients underwent TL testing, including those with clinical features of short telomere syndrome such as familial pulmonary fibrosis (50%) or extrapulmonary manifestations in the patient (25%) or a relative (41%). The overall prevalence of short TL was 46% and was similar across clinical ILD diagnoses. The number of short telomere clinical features was independently associated with detecting short TL (OR 2.00, 95% CI [1.27, 3.32]). TL testing led to clinical management changes for 35 (32%) patients, most commonly resulting in reduction or avoidance of immunosuppression. Of the patients who underwent genetic testing (n=34), a positive or candidate diagnostic finding in telomere-related genes was identified in 10 (29%) patients. Inclusion of TL testing below the 1st percentile helped reclassify 8 of 9 variants of uncertain significance (VUS) into actionable findings. The qPCR test correlated with FlowFISH, but age-adjusted percentile cutoffs may not be equivalent between the two assays. InterpretationIncorporating TL testing in ILD impacted clinical management and led to the discovery of new actionable genetic variants.

(1045) - Title: Clinical Outcomes of Lung Transplant Recipients with Myelodysplastic Syndrome and Short Telomere Syndrome

(1045) - Title: Clinical Outcomes of Lung Transplant Recipients with Myelodysplastic Syndrome and Short Telomere Syndrome

Shorter telomere length increases the risk of lymphocyte immunodeficiency: A Mendelian randomization study.

For a long time, the prevailing viewpoint suggests that shorter telomere contribute to chromosomal instability, which is a shared characteristic of both aging and cancer. The newest research presented that T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to some cancers. However, the relationship between genetically determined telomere length (TL) and immune cells remains unclear. The two-sample Mendelian randomization analysis was conducted to elucidate the potential causal relationship. The genetic data of TL and immune cells were obtained from the Genome-Wide Association Study. The inverse variance weighted (IVW) method was used to estimate the effects primarily and another four methods were as a supplement. Sensitivity analysis was used to test the results. The IVW method showed a significant correlation between TL and the percentage of T cells in lymphocytes (odds ratio [OR]: 1.222, 95% confidence interval [CI]: 1.014-1.472, p = .035), indicating that shorter TL significantly increases the risk of low T cell percentage. Further analysis of T cell subsets indicated that shorter TL may primarily lead to a lower percentage of Natural Killer T cells (OR: 1.574, 95% CI: 1.281-1.935, p < .001). Analysis of B cell subsets revealed that shorter TL may be associated with a higher percentage of Naive-mature B cells, and a lower percentage of Memory B cells. And the sensitivity analysis indicated the validity and robustness of our findings. In summary, our findings suggest that shorter TL may be associated with a decline in the percentage of T cell, as well as impediments in the differentiation of B cell, consequently leading to the onset of immunosenescence and immunodeficiency. The relevant mechanisms and potential therapeutic avenues still need further investigation.

Immune aging: biological mechanisms, clinical symptoms, and management in lung transplant recipients.

While chronologic age can be precisely defined, clinical manifestations of advanced age occur in different ways and at different rates across individuals. The observed phenotype of advanced age likely reflects a superposition of several biological aging mechanisms which have gained increasing attention as the world contends with an aging population. Even within the immune system, there are multiple age-associated biological mechanisms at play, including telomere dysfunction, epigenetic dysregulation, immune senescence programs, and mitochondrial dysfunction. These biological mechanisms have associated clinical syndromes, such as telomere dysfunction leading to short telomere syndrome (STS), and optimal patient management may require recognition of biologically based aging syndromes. Within the clinical context of lung transplantation, select immune aging mechanisms are particularly pronounced. Indeed, STS is increasingly recognized as an indication for lung transplantation. At the same time, common aging phenotypes may be evoked by the stress of transplantation because lung allografts face a potent immune response, necessitating higher levels of immune suppression and associated toxicities, relative to other solid organs. Age-associated conditions exacerbated by lung transplant include bone marrow suppression, herpes viral infections, liver cirrhosis, hypogammaglobulinemia, frailty, and cancer risk. This review aims to dissect the molecular mechanisms of immune aging and describe their clinical manifestations in the context of lung transplantation. While these mechanisms are more likely to manifest in the context of lung transplantation, this mechanism-based approach to clinical syndromes of immune aging has broad relevance to geriatric medicine.

Progression of Neuroimaging Features Associated with Dyskeratosis Congenita and Short Telomere Syndrome: A Case Report

Background: Dyskeratosis congenita is a rare genetic disorder resulting from mutations that lead to shortened telomeres and premature cellular aging. Although it classically presents with a triad of mucocutaneous abnormalities, it has diverse clinical manifestations, affecting multiple organ systems. Neurological involvement, often seen in severe variants, constitutes a significant element of the disease’s pathophysiology, highlighting the vast array of observed complications. Case Presentation: A 5-year-old girl with a known diagnosis of dyskeratosis congenita due to a WRAP53 mutation presents with bloody stools and epilepsy. Her clinical course was marked by gastrointestinal disturbances, hematologic sequelae, and severe hepatic manifestations, including recurrent bleeding episodes. Discussion: This case highlights the complex interplay between telomere dysfunction and the systemic and neurological manifestations in dyskeratosis congenita. The serial brain MRI findings reveal progressive white matter disease, brain volume loss, and choroid plexus calcifications, indicating a rapid neurodegenerative progression and premature aging. Enhanced surveillance and tailored management strategies are crucial to mitigate disease-associated morbidity. Conclusion: Dyskeratosis congenita due to a WRAP53 mutation enriches our understanding of its neurodegenerative dimensions and emphasizes the pivotal role of telomeres in systemic and neurological health. Integrating advanced imaging with comprehensive multidisciplinary management improves disease monitoring and optimizes patient care.

A new variant in the ZCCHC8 gene: diverse clinical phenotypes and expression in the lung.

Pulmonary fibrosis is a severe disease which can be familial. A genetic cause can only be found in ∼40% of families. Searching for shared novel genetic variants may aid the discovery of new genetic causes of disease. Whole-exome sequencing was performed in 152 unrelated patients with a suspected genetic cause of pulmonary fibrosis from the St Antonius interstitial lung disease biobank. Variants of interest were selected by filtering for novel, potentially deleterious variants that were present in at least three unrelated pulmonary fibrosis patients. The novel c.586G>A p.(E196K) variant in the ZCCHC8 gene was observed in three unrelated patients: two familial patients and one sporadic patient, who was later genealogically linked to one of the families. The variant was identified in nine additional relatives with pulmonary fibrosis and other telomere-related phenotypes, such as pulmonary arterial venous malformations, emphysema, myelodysplastic syndrome, acute myeloid leukaemia and dyskeratosis congenita. One family showed incomplete segregation, with absence of the variant in one pulmonary fibrosis patient who carried a PARN variant. The majority of ZCCHC8 variant carriers showed short telomeres in blood. ZCCHC8 protein was located in different lung cell types, including alveolar type 2 (AT2) pneumocytes, the culprit cells in pulmonary fibrosis. AT2 cells showed telomere shortening and increased DNA damage, which was comparable to patients with sporadic pulmonary fibrosis and those with pulmonary fibrosis carrying a telomere-related gene variant, respectively. The ZCCHC8 c.586G>A variant confirms the involvement of ZCCHC8 in pulmonary fibrosis and short-telomere syndromes and underlines the importance of including the ZCCHC8 gene in diagnostic gene panels for these diseases.

Germline landscape of RPA1, RPA2 and RPA3 variants in pediatric malignancies: identification of RPA1 as a novel cancer predisposition candidate gene.

Replication Protein A (RPA) is single-strand DNA binding protein that plays a key role in the replication and repair of DNA. RPA is a heterotrimer made of 3 subunits - RPA1, RPA2, and RPA3. Germline pathogenic variants affecting RPA1 were recently described in patients with Telomere Biology Disorders (TBD), also known as dyskeratosis congenita or short telomere syndrome. Premature telomere shortening is a hallmark of TBD and results in bone marrow failure and predisposition to hematologic malignancies. Building on the finding that somatic mutations in RPA subunit genes occur in ~1% of cancers, we hypothesized that germline RPA alterations might be enriched in human cancers. Because germline RPA1 mutations are linked to early onset TBD with predisposition to myelodysplastic syndromes, we interrogated pediatric cancer cohorts to define the prevalence and spectrum of rare/novel and putative damaging germline RPA1, RPA2, and RPA3 variants. In this study of 5,993 children with cancer, 75 (1.25%) harbored heterozygous rare (non-cancer population allele frequency (AF) < 0.1%) variants in the RPA heterotrimer genes, of which 51 cases (0.85%) had ultra-rare (AF < 0.005%) or novel variants. Compared with Genome Aggregation Database (gnomAD) non-cancer controls, there was significant enrichment of ultra-rare and novel RPA1, but not RPA2 or RPA3, germline variants in our cohort (adjusted p-value < 0.05). Taken together, these findings suggest that germline putative damaging variants affecting RPA1 are found in excess in children with cancer, warranting further investigation into the functional role of these variants in oncogenesis.

Familial Clonal Hematopoiesis in a Long Telomere Syndrome

BackgroundTelomere shortening is a well-characterized cellular aging mechanism, and short telomere syndromes cause age-related disease. However, whether long telomere length is advantageous is poorly understood.MethodsWe examined the clinical and molecular features of aging and cancer in persons carrying heterozygous loss-of-function mutations in the telomere-related gene POT1 and noncarrier relatives.ResultsA total of 17 POT1 mutation carriers and 21 noncarrier relatives were initially included in the study, and a validation cohort of 6 additional mutation carriers was subsequently recruited. A majority of the POT1 mutation carriers with telomere length evaluated (9 of 13) had long telomeres (>99th percentile). POT1 mutation carriers had a range of benign and malignant neoplasms involving epithelial, mesenchymal, and neuronal tissues in addition to B- and T-cell lymphoma and myeloid cancers. Five of 18 POT1 mutation carriers (28%) had T-cell clonality, and 8 of 12 (67%) had clonal hematopoiesis of indeterminate potential. A predisposition to clonal hematopoiesis had an autosomal dominant pattern of inheritance, as well as penetrance that increased with age; somatic DNMT3A and JAK2 hotspot mutations were common. These and other somatic driver mutations probably arose in the first decades of life, and their lineages secondarily accumulated a higher mutation burden characterized by a clocklike signature. Successive generations showed genetic anticipation (i.e., an increasingly early onset of disease). In contrast to noncarrier relatives, who had the typical telomere shortening with age, POT1 mutation carriers maintained telomere length over the course of 2 years.ConclusionsPOT1 mutations associated with long telomere length conferred a predisposition to a familial clonal hematopoiesis syndrome that was associated with a range of benign and malignant solid neoplasms. The risk of these phenotypes was mediated by extended cellular longevity and by the capacity to maintain telomeres over time. (Funded by the National Institutes of Health and others.)

Telomere Shortening Induces T-cell Dysfunction and Squamous Cell Cancers.

Patients with short telomere syndromes are predisposed to squamous cell carcinomas due to T-cell dysfunction.

Short Telomere Syndrome presenting with pulmonary fibrosis, liver cirrhosis and hepatopulmonary syndrome: a case report

BackgroundIdiopathic pulmonary fibrosis is thought to result from aberrant post-injury activation of epithelial cells leading to fibroblast proliferation and activation. A number of genetic aetiologies have been implicated in this disease process, including, among others, the short telomere syndromes. Short telomere syndromes follow an autosomal dominant pattern of inheritance resulting in shortened telomere length, which consequently leads to accelerated cell death. Organs with rapid cell turnover are most affected.Case presentationWe describe a case of a 53-year-old man with a chief complaint of cough and dyspnea on exertion. His presentation was otherwise significant for features of accelerated aging, including a history of osteoporosis and early greying, and a family history of pulmonary fibrosis in his father. Pulmonary function testing revealed a restrictive pattern with severely reduced diffusion capacity and high resolution CT of the chest showed diffuse lung disease with mild fibrosis, in pattern suggesting an alternative diagnosis to IPF. Biopsy of the lung was in keeping with chronic fibrosing interstitial pneumonia. Imaging of the abdomen showed splenomegaly, hepatic cirrhosis and portal hypertension. Transthoracic contrast echocardiogram showed intrapulmonary shunting consistent with hepatopulmonary syndrome. Given the constellation of early aging, idiopathic pulmonary fibrosis, cryptogenic cirrhosis and a family history of pulmonary fibrosis in this patient, the Short Telomere Syndrome was suspected. Peripheral blood was sent for Flow-cytometry FISH, which demonstrated granulocyte telomere length below the 10th percentile for the patient’s age, consistent with a diagnosis of Short Telomere Syndrome in this clinical context. Targeted genetic testing of mutations known to be associated with short telomere was negative though it was acknowledged that the full spectrum of disease-causing mutations remains unknown. Given the extensive fibrosis on biopsy and his progressive hypoxemia he was treated with mycophenolate and prednisone. Ultimately, he developed progressive respiratory failure and underwent double lung and concurrent liver transplant 18 months after the initial diagnosis was made.ConclusionsShort Telomere Syndrome is a rare cause of end stage organ disease and testing lacks sensitivity making diagnosis challenging. Organ transplant is still the mainstay of treatment. Nevertheless, disease identification is important because of implications for family member screening and the possibility of future treatment options.

T cell immune deficiency rather than chromosome instability predisposes patients with short telomere syndromes to squamous cancers

Patients with short telomere syndromes (STS) are predisposed to developing cancer, believed to stem from chromosome instability in neoplastic cells. We tested this hypothesis in a large cohort assembled over the last 20 years. We found that the only solid cancers to which patients with STS are predisposed are squamous cell carcinomas of the head and neck, anus, or skin, a spectrum reminiscent of cancers seen in patients with immunodeficiency. Whole-genome sequencing showed no increase in chromosome instability, such as translocations or chromothripsis. Moreover, STS-associated cancers acquired telomere maintenance mechanisms, including telomerase reverse transcriptase (TERT) promoter mutations. A detailed study of the immune status of patients with STS revealed a striking T cell immunodeficiency at the time of cancer diagnosis. A similar immunodeficiency that impaired tumor surveillance was documented in mice with short telomeres. We conclude that STS patients’ predisposition to solid cancers is due to T cell exhaustion rather than autonomous defects in the neoplastic cells themselves.

(350) Evaluation of Immunosuppressant Drug Tolerability and Infections in Lung Transplant Recipients with Short Telomere Syndrome

(350) Evaluation of Immunosuppressant Drug Tolerability and Infections in Lung Transplant Recipients with Short Telomere Syndrome

Short Telomere Syndromes and Inherited Predisposition to Bone Marrow Diseases: The MDACC Experience

Introduction: Telomeres are noncoding nucleotide repeats at chromosomal ends, which provide genomic stability and are maintained and regulated by specific protein complexes. Their length physiologically decreases with age, although it is known that germline mutations in telomeric regulators can accelerate this process, which is related to a wide variety of clinical situations. Herein we report on the experience of patients diagnosed with Short Telomere Syndromes (STS) evaluated in the Hereditary Hematologic Malignancy Clinic (HHMC) of the MD Anderson Cancer Center. Methods: We retrospectively analyzed clinical characteristics and outcomes of patients with a diagnosis of STS referred or diagnosed in the HHMC. Germline mutation origin was confirmed by genetic analysis of cultured skin fibroblasts or blood/saliva in patients without hematologic disease. Telomere length was assessed by Flow-FISH techniques in a clinically validated external laboratory (John Hopkins Medical Laboratories, Baltimore, MD). Individuals with confirmed STS were recommended to follow a specialized cancer surveillance program to achieve early-diagnosis or prevention of potential complications related to STS. A baseline bone marrow evaluation was recommended to evaluate underlying morphology and assess for somatic comutations. Results: A total of 24 patients with STS were identified (13 males, 54%), with a median age of presentation to the clinic of 53 years old (5-78). Although the reasons of referral for STS testing for each individual patient were diverse, they can be summarized in these categories: unexplained cytopenia (n=9), myeloid malignancy with relevant PMH or FH (n=8), affected sibling (n=5), skin lesions (n=1) and multiple cancer diagnosis (n=1). Pathogenic or likely pathogenic germline variants were confirmed in the TERT gene (n=13, 54%), TERC gene (n=7, 29%), RTEL1 (n=2, 8%), while 2 patients had no telomere-related detectable mutations (Figure 1). Telomere flow-FISH confirmed age-predicted telomere length <1st percentile for age in 67(%). All patients underwent a bone marrow biopsy, being described as hypocellullar in 17 patients (71%). With the bone marrow evaluation, eleven patients were diagnosed with myelodysplastic syndrome (MDS, 46%), two patients with acute leukemia (myeloid and mixed phenotype, 8%), two patients with clonal cytopenia of unknown significance (CCUS, 8%), one aplastic anemia (4%) and eight patients (33%) did not have hematologic malignancy. During the follow-up, three patients underwent an allogeneic stem cell transplantation due to their hematologic disease. Solid neoplasms are frequent in patients with STS, and 11 patients (46%) had a PMH of at least one solid tumor with a median age of 54 (33-78 yrs). Squamous cell carcinoma was the most frequent histology (6/11 patients). Sixteen patients (67%) had a positive FH of cancer in one or more first or second-degree sibling. Pulmonary fibrosis (PF) was diagnosed in 4 patients (17%), two with TERT mutations and two with TERC mutations. Moreover, 7 patients (4 diagnosed with PF,30%) had a positive FH of PF in first degree siblings. Liver diseases were also frequent: 3 patients had non-alcoholic hepatic cirrhosis, one patient had chronic hepatitis with periportal fibrosis and one with idiopathic portal hypertension. One patient had received a liver transplantation and one required a lung transplantation prior to presentation to the HHMC. Finally, twelve patients (50%) were reported to have premature grey hair and eight patients were reported to have nail dysplasia and/or skin abnormalities related to STS (such as unexplained reticular rash). A summary of the described patients is depicted in Figure 2. Conclusion: STS are genetic diseases that can go unnoticed until adulthood. Patients with myeloid malignancies (especially MDS) with hypocellular bone marrow and suspicious findings (i.e. FH or PMH of PF, premature grey hair, long standing cytopenias) should be considered for underlying STS. An early diagnosis is essential to start cancer surveillance programs and provide timely genetic counseling to the patient and relatives. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immune Dysregulation in Human Telomere Diseases

Germline variants in a diversity of genes involved in telomere maintenance result in premature telomere shortening and cause clinical conditions that are collectively called telomeropathies, which range from mucocutaneous findings (skin hypopigmentation, nail dystrophy and oral leukoplakia) to bone marrow failure, myeloid neoplasms, pulmonary fibrosis and cirrhosis. Even though pulmonary fibrosis and liver cirrhosis develop in up to a quarter of patients with telomeropathies, the exact mechanisms promoting the fibrotic pathology remain unclear. Considering that the hematopoietic compartment is particularly sensitive to telomere erosion, we aimed to investigate whether the immune response may play a role on the development of fibrotic lesions in a murine model, and to evaluate immunological biomarkers in patients diagnosed with telomere diseases. To assess the effects of telomere attrition on the development of liver fibrosis and immune response, G3 Terc-/- and Tert-/- mice (background C57BL/6J) and wild-type (WT) mice were infected with S. mansoni cercariae and euthanized after 12 weeks. Telomere length (TL) was determined by qPCR in leukocytes and liver sections and confirmed to be shorter in both knockout (KO) models in comparison to WT animals (p≤0.01). Collagen deposition in liver tissue was quantified with Picro Sirius Red staining and showed larger fibrotic areas in WT mice (14 ± 5,2%) when compared to Terc-/- (7,2 ± 4,3%; p≤0.05) and Tert-/- (6,3 ± 2,4%; p≤0.05). Macrophage infiltration was evaluated by immunostaining using antibodies against F4/80, CD206 and iNOS, and revealed less positive cells within the liver of Terc-/- and Tert-/- mice in comparison to WT (p≤0.001). We studied the ability of bone marrow-derived macrophages (BMDMs) to be polarized towards M1 and M2-like phenotypes ex vivo, upon stimulation with either LPS or IL-4, respectively. Expression of TNF-alpha, IL-6 and MMP9 demonstrated that the classical activation of Terc-/- and Tert-/- BMDMs was impaired in a similar fashion, and these cells did not exhibit the M1-like phenotype as observed in the WT BMDMs. Conversely, CD206 and ARG1 were significantly upregulated in KOs stimulated with IL-4, suggesting that telomerase-null BMDMs are skewed towards an M2 polarization. We also evaluated 18 patients with telomere diseases (median age, 33.9 years; range, 12.8-62.5 years; male/female, 9/9; marrow failure, 15; pulmonary manifestations, 5; hepatic manifestations, 5) and 10 healthy individuals (median age, 32.1; range, 13.9-56.3 years; male/female, 5/5) for their immune profile. Eight patients had very short TL (<1st percentile) and ten had short TL (<10th percentile). All healthy individuals had TL >10th percentile. We measured serum levels of cytokines, chemokines and growth factors using a customized Luminex panel to assess 32 analytes in a single assay. Spearman's correlation coefficient was used to analyze associations between TL z-scores and the variables of interest. Analysis showed significant correlations (p≤0.05) with angiopoietin-1, IL-1α, IL-1β, IL-1RA, IL-3, IL-4, IL-7, IL-23, IL-27, MCP-1, M-CSF, MIP-3α and PDGF-BB and, in all cases, Spearman's rho was positive, indicating that shorter telomeres were correlated with decreased protein serum levels. In order to study the maturation of T- and B-cells, T-cell receptor excision circles (TRECs) and kappa-deleting excision circles (KRECs) were quantified by qPCR in dried blood spot samples from ten patients with short telomeres and ten age-matched healthy individuals. Both biomarkers were significantly reduced in patients (p≤0.05), showing that production and/or maturation of T- and B-lymphocytes is impaired. TRECs were negatively correlated to age in the control group, (rs = -0.66; p = 0.043), but not in patients (p>0.05), suggesting that TRECs do not follow the same pattern of age-dependent decrease in short telomere syndromes. Altogether, the results demonstrate that telomere erosion contributes to impaired immune responses and T- and B-cell maturation, which may contribute to the pathophysiology of several clinical manifestations in telomeropathies. Further studies are necessary to deeply characterize innate and adaptative immune response in telomere syndromes and better understand how it correlates to fibrosis development. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Genetics of human telomere biology disorders.

Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes that prevent the activation of DNA damage response and repair pathways. Numerous factors localize at telomeres to regulate their length, structure and function, to avert replicative senescence or genome instability and cell death. In humans, Mendelian defects in several of these factors can result in abnormally short or dysfunctional telomeres, causing a group of rare heterogeneous premature-ageing diseases, termed telomeropathies, short-telomere syndromes or telomere biology disorders (TBDs). Here, we review the TBD-causing genes identified so far and describe their main functions associated with telomere biology. We present molecular aspects of TBDs, including genetic anticipation, phenocopy, incomplete penetrance and somatic genetic rescue, which underlie the complexity of these diseases. We also discuss the implications of phenotypic and genetic features of TBDs on fundamental aspects related to human telomere biology, ageing and cancer, as well as on diagnostic, therapeutic and clinical approaches.

The Role of Telomeres in Human Disease.

Telomere biology was first studied in maize, ciliates, yeast, and mice, and in recent decades, it has informed understanding of common disease mechanisms with broad implications for patient care. Short telomere syndromes are the most prevalent premature aging disorders, with prominent phenotypes affecting the lung and hematopoietic system. Less understood are a newly recognized group of cancer-prone syndromes that are associated with mutations that lengthen telomeres. A large body of new data from Mendelian genetics and epidemiology now provides an opportunity to reconsider paradigms related to the role of telomeres in human aging and cancer, and in some cases, the findings diverge from what was interpreted from model systems. For example, short telomeres have been considered potent drivers of genome instability, but age-associated solid tumors are rare in individuals with short telomere syndromes, and T cell immunodeficiency explains their spectrum. More commonly, short telomeres promote clonal hematopoiesis, including somatic reversion, providing a new leukemogenesis paradigm that is independent of genome instability. Long telomeres, on the other hand, which extend the cellular life span in vitro, are now appreciated to be the most common shared germline risk factor for cancer in population studies. Through this contemporary lens, I revisit here the role of telomeres in human aging, focusing on how short and long telomeres drive cancer evolution but through distinct mechanisms.

Experience using a flexible reinforced fiber suture for sternal closure in bilateral lung transplantation recipients undergoing bilateral transverse thoracosternotomy.

Experience using a flexible reinforced fiber suture for sternal closure in bilateral lung transplantation recipients undergoing bilateral transverse thoracosternotomy.