An array of genes is responsible for telomere synthesis, assembly, trafficking, and maintenance.
Defects in one or more of these complex array of genes can cause accelerated telomere shortening and consequently affect multiple organ systems with high cell turnover, resulting in premature graying of hair, interstitial pneumonia, bone marrow failure, cryptogenic cirrhosis, portal hypertension, and immune dysfunction.
Shorten telomere syndromes can involve multiple organ systems defined by premature loss of progenitor stem cells, affecting regenerative capacity of involved cells, tissues and organs.
Commonly associated with bone marrow failure syndromes including aplastic anemia.
A characteristics of telomere disease is that the phenomenon of genetic anticipation is such that disease manifestations tend to occur in an earlier age in subsequent generations, with severe manifestations: this is due to the fact that offspring inherit not only the telomere related mutation but also shortened germline telomere lengths.
Dyskeratosis congenita is a pathognomic subtype of short telomere syndrome a genetically inherited disorder commonly seen in pediatric patients, secondary to mutations involving DKC1 presenting with the classic triad of nail dystrophy, abnormal skin pigmentation, oral leukoplakia and progressive bone marrow failure.
Dyskeratosis congenita associated features include: pulmonary fibrosis, emphysema, cryptogenic cirrhosis, lacrimal duct, esophageal, and urethral stenosis, premature graying of the hair, avascular necrosis of hips and shoulders, periodontal disease, increased predisposition to epithelial and hematologic malignancyies.
Types of Cancers a ssociated with dyskeratosis congenita include head and neck cancers, anogenital squamous cell carcinomas, myelodysplastic syndromes, and acute myeloid leukemia.
Mutations in telomere-associated genes have been identified in telomeric core components (TERT, TERC), telomere biogenesis (NHP2, GAR1, DNA synthesis, sheltering complex, telomere trafficking, and CST complex.
Only approximately 40% of patients with shorten telomeres have a identifiable pathologic variant.
Shortened telomere links play a critical role in the pathogenesis a variety of multi system disorders, resulting in bone marrow failure, primary immuno deficiency, enterocolitis, idiopathic pulmonary fibrosis, premature onset emphysema, cryptogenic cirrhosis, nodular regenerative hyperplasia of the liver, premature graying of hair, fibrous Cartilage dysplasia, osteoporosis, and predisposition to cancer syndromes.