Dyskeratosis congenita: Advances in the understanding of the telomerase defect and the role of stem cell transplantation

Abstract

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.

Reduced intensity conditioning is effective for hematopoietic SCT in dyskeratosis congenita-related BM failure

“…Previous reports (Table 3) have described progression of the clinical signs of DKC after transplantation, which was indistinguishable from the natural course of disease. [8][9][10][11][20][21][22][23] In our series, all patients except one received low intensity conditioning regimens. The conditioning protocol was different across different centers.…”

“…Commonly observed transplant-related problems include graft failure, GVHD, sepsis and, more importantly, the increased propensity to develop organ toxicity, namely pulmonary fibrosis, hepatic cirrhosis and veno-occlusive disease, among others. [8][9][10] As a result, long-term survival of persons with DKC following HSCT has been poor. Reduced intensity preparative regimens are less likely to cause organ toxicity and may improve long-term outcomes.…”

Reduced intensity conditioning regimen with fludarabine, cyclophosphamide, low dose TBI and alemtuzumab leading to successful unrelated umbilical cord stem cell engraftment and survival in two children with dyskeratosis congenita

“…1 Bone marrow failure along with pulmonary complications and malignancies are all common causes of premature death in patients with DC as well as a myriad of other abnormalities. 2,3 Hematopoietic stem cell transplantation (HSCT) with fully myeloablative regimens has historically been the only curative treatment. 2,3 Attempts at reducing morbidity and mortality post HSCT with reduced intensity conditioning regimens instead of myeloablative regimens have been reported, and over the past decade, experience treating DC associated marrow failure with reduced intensity HSCT has increased.…”

Dyskeratosis congenita

“…Patients with BMF due to DC do not respond to immunosuppressive therapy [45]. They are also at high risk of HSCT-related complications due to underlying pulmonary and liver disease [46][47][48][49][50]. In addition, recent studies have shown individuals can be "silent" carriers of a pathogenic mutation in a DC gene [12].…”

“…HSCT is clearly a life-saving measure, but has substantial risks either from toxicity from radiochemotherapy or immune-related complications. Reported problems include graft failure, GVHD, sepsis, pulmonary fibrosis, cirrhosis, and veno-occlusive disease [49;66], due, in part, to underlying pulmonary and liver disease [46][47][48][49][50]. As a result, long-term survival of patients with DC following HSCT has been very poor [49;66].…”