The telomeropathies are a newly described group of human diseases based on the genetics and molecular biology of the telomeres, the ends of chromosomes. Telomeres are repeated hexanucleotides and their associated
proteins; the protect chromosomes from recognition as damaged
DNA, and their inevitable gradual loss with DNA replication is harmless as they are noncoding. However, when telomeres become critically short in a cell, senescence, apoptosis, or, rarely malignant transformation results. In individuals with mutations in genes involved in telomere repair, especially the enzymatic
telomerase complex, telomere attrition is accelerated. Severe deficiencies result in
dyskeratosis congenita, a congenital
aplastic anemia with associated mucocutaneous abnormalities. Mutations in TERT, the catalytic component, and
TERC, the
RNA template, can behave as risk factors for the development of
bone marrow failure,
pulmonary fibrosis, and
hepatic cirrhosis. Both penetrance and organ specificity are variable and not well understood.
Chromosome instability is a result of critical shortening of telomeres and
cancer. For example, short telomeres are the major prognostic risk factor for clonal evolution to myelodysplasia and acute
leukemia. Practically, hematologists need to recognize the multisystem presentation of telomere disease, implications for outcomes, and options for
therapy.