Short Telomere Syndromes in Clinical Practice: Bridging Bench and Bedside

Abstract

Short telomere syndromes (STSs) are accelerated aging syndromes often caused by inheritable gene mutations resulting in decreased telomere lengths. Consequently, organ systems with increased cell turnover, such as the skin, bone marrow, lungs, and gastrointestinal tract, are commonly affected. Owing to diverse clinical presentations, STSs pose a diagnostic challenge, with bone marrow failure and idiopathic pulmonary fibrosis being frequent manifestations, occurring in association with gene mutations involving DKC1 (for expansion of gene symbols, use search tool at www.genenames.org), TERT, TERC, and others. Inherited STSs demonstrate genetic anticipation, occurring at an earlier age with more severe manifestations in the affected progeny. Telomere lengths can be assessed in peripheral blood granulocytes and lymphocytes using a sensitive technique called flow cytometry-fluorescence in situ hybridization, and mutational analysis can be performed using next-generation sequencing assays. In approximately 40% of patients with shortened telomere lengths, gene mutations cannot be identified due to the fact that all STS-associated genes have not yet been defined or due to alternative mechanisms of telomere shortening. Danazol, an anabolic steroid, has been associated with hematologic responses in patients with STSs and associated bone marrow failure; however, its reported ability to increase telomerase activity and reduce telomere attrition needs further elucidation. Organ transplant is reserved for patients with end-organ failure and is associated with substantial morbidity and mortality. Herein, we summarize the clinical and laboratory characteristics of STSs and offer a stepwise approach to diagnose and manage complications in affected patients.

Acute Myeloid Leukemia: Aging and Epigenetics

“…Employing an inducible telomerase reverse transcriptase-estrogen receptor (TERT ER ) mouse model, it was demonstrated that persistent physiological DNA damage (from eroded telomeres) drives MDS in mice by inducing aberrant RNA splicing [110]. In human, short telomeres syndromes are also associated with accelerated aging syndromes characterized by diverse clinical manifestations and with bone marrow failure and idiopathic pulmonary fibrosis being frequent manifestations [111,112]. Similarly, skewing in X-chromosome inactivation has been more frequently detected in blood from elderly women [113] and deregulation of X-chromosome inactivation in the hematopoietic compartment is known to cause typical aging-like myelodysplastic syndromes (MDS) with 100% penetrance in mice [114].…”

Functional validation of TERT and TERC variants of uncertain significance in patients with short telomere syndromes

“…In our experience, a pathogenic variant in the coding sequence of a telomere-associated gene can be identified in only 40% of STS cases using current sequencing approaches, with the remaining cases either having no identifiable variant or possessing a variant(s) of uncertain significance (VUS) 1,3 . In addition, in some of these cases, the TL values were not conclusively shortened (i.e., not < first percentile in lymphocytes and/or granulocytes documented by a CLIA-certified FlowFISH assay) complicating the diagnosis.…”

“…Accelerated shortening of telomeres can induce premature cell senescence that can clinically manifest as bone marrow failure (BMF), idiopathic pulmonary fibrosis (IPF), cryptogenic cirrhosis, nodular regenerative hyperplasia, vascular malformations, immunodeficiency, and structural brain abnormalities, all of which are included under the umbrella term of short telomere syndromes (STSs) 1 . Two main criteria used to diagnose STS include the documentation of shortened telomere lengths (TLs) by a Clinical Laboratory Improvement Amendments (CLIA)-certified flowFISH (fluorescence in situ hybridization) assay 2 and the presence of pathogenic variants in genes related to telomere maintenance identified through next-generation sequencing (NGS).…”

“…These genes include, but are not limited to, hTERT (human telomerase reverse transcriptase) and hTERC (human telomerase RNA component), the two main components of the telomerase holoenzyme complex that is responsible for creating new telomeric DNA ( Supplementary Fig. 1) 1 .…”

Early Senescence and Leukocyte Telomere Shortening in SCHIZOPHRENIA: A Role for Cytomegalovirus Infection?

“…In addition, the production of reactive oxygen species associated with chronic inflammation, that can also be produced in response to chronic infection, several drugs and toxic products, or radiation exposure, also cause DNA damage and telomere loss [ 49 ]. Finally, inheritable gene mutations affecting the telomerase or the telomere protein complex, resulting in decreased telomere lengths (short telomere syndromes, STSs) [ 50 , 51 ]. These syndromes are characterized by severe alterations in hematopoiesis (bone marrow failure) and in organs with high cell turnover, such as skin (dyskeratosis), gastrointestinal tract (esophageal stenosis, enterocolitis, celiac-like enteropathy) and lungs (idiopathic pulmonary fibrosis) [ 50 , 51 ].…”