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.

Figure 1

Constituents of the human telomere complex and associated genetic anomalies (Key: DKC-Dyskeratosis congenita, HHS-Hoyeraal-Hreidarsson syndrome, IPF-Idiopathic pulmonary fibrosis, AA: Aplastic anemia RAP1-repressor activator protein 1, TIN2-TFR-1interacting protein 2, TFR-telomeric repeat binding factor, TPP-POT1-interacting protein, RTEL1-regulator of telomere length 1, TCAB1- Telomerase Cajal body protein1, NHP2- nuclear protein family A, member 2, NOP10-nuclear protein family A, member 3, GAR1-nuclear protein family A, member 1, TERT-telomerase reverse transcriptase, TERC-telomerase RNA component, CTC1-conserved telomere maintenance component 1).

Figure 2

Figure showing flow-FISH reports for a normal and suspected STS patient. 2A shows the report for a normal patient with telomere lengths in both lymphocytes and granulocytes around 50th centile. 2B shows the report for a patient with telomere lengths less than 1^st centile, highly suggestive for a STS (Key: FISH-fluorescence in-situ hybridization, STS: short telomere syndrome).

Figure 3

Figure summarizing various disorders associated with telomere shortening and steps in management (Key: DKC-dyskeratosis congenita, FISH-fluorescence in-situ hybridization, TERT-telomerase reverse transcriptase, TERC-telomerase RNA component, NOP10- nuclear protein family A, member 3, NHP2- nuclear protein family A, member 2, TCAB1- Telomerase Cajal body protein 1, TIN2- TFR-1 interacting protein 2, TPP1-POT1-interacting protein, RTEL1-regulator of telomere length 1, CTC1- Conserved telomere maintenance component 1, PARN-Poly(A)-specific ribonuclease, NAF1-Nuclear Assembly Factor 1 Ribonucleoprotein, BMF-bone marrow failure, CAMT- Congenital amegakaryocytic thrombocytopenia, NCPF- non-cirrhotic portal fibrosis, NRH- nodular generative hyperplasia, SFTPC-surfactant protein C, SFTPA2-surfactant protein A2, ABCA3-ATP binding cassette subfamily A member 3, MUC5B-Mucin 5B, PAI-1-plasminogen activator inhibitor 1, MTHFR-methylenetetrahydrofolate reductase).