DC is a multisystem
bone marrow failure syndrome exhibiting marked clinical and genetic heterogeneity. X-linked, autosomal dominant and autosomal recessive subtypes are recognized. The gene mutated in X-linked DC (DKC1) encodes a highly conserved
nucleolar protein called dyskerin. Dyskerin associates with the H/ACA motif class of small nucleolar RNAs in
small nucleolar ribonucleoprotein particles that are important in guiding the conversion of
uracil to pseudouracil during the maturation of
ribosomal RNA. Dyskerin also associates with the
TERC, which is important in the maintenance of telomeres. Mutations in
TERC have been identified in patients with autosomal dominant DC and in a subset of patients with
aplastic anemia and myelodysplasia. Recently, heterozygous mutations in TERT have been found in some patients with autosomal dominant DC and
aplastic anemia. Additionally, patients with the severe multisystem disorder,
Hoyeraal-Hreidarsson syndrome, have been found to have DKC1 mutations. Collectively, these observations have demonstrated that classical DC,
Hoyeraal-Hreidarsson syndrome and a subset of
aplastic anemia are due to a primary defect in
telomerase. The critical role of telomeres and
telomerase in humans is seen in the multisystem abnormalities found in these patients, including the increased incidence of
malignancy. As
bone marrow failure is the principal cause of death, conventional allografts have been attempted with limited success due to the high rate of pulmonary and endothelial complications. However, outcomes have improved with the use of non-myeloablative protocols, although the follow up is too short to evaluate long term toxicity and the natural course of the disease and it may be that correction of the
telomerase defect is essential for the treatment of these patients.