Very Short Telomeres Are Characteristic of Dyskeratosis Congenita and Not Other Inherited Bone Marrow Failure Syndromes

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1044-1044
Author(s):  
Blanche P. Alter ◽  
Gabriela Baerlocher ◽  
Neelam Giri ◽  
Peter M. Lansdorp ◽  
Sharon A Savage
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
B Cells ◽  
Telomere Length ◽  
Bone Marrow Failure ◽  
Dyskeratosis Congenita ◽  
Z Score ◽  
Bone Marrow Failure Syndromes ◽  
Z Scores ◽  
The Mean

Abstract Telomeres protect the ends of chromosomes, shorten with age, and are very short in dyskeratosis congenita (DC), an inherited bone marrow failure syndrome (IBMFS) associated with mutations in telomere biology genes. “Short telomeres” were reported in Fanconi Anemia (FA), Diamond-Blackfan Anemia (DBA) and Shwachman-Diamond Syndrome (SDS) using telomere restriction fragment length or Q-FISH assays of total leukocyte or mononuclear cell DNA. These reports focused on group averages, not results from individual patients. Our objective was to determine which categories of IBMFS patients have very short telomeres, and in which leukocyte subsets, using a more sensitive and specific assay. Telomere length was measured in granulocytes, lymphocytes, naïve T-cells, memory T-cells, B-cells, and NK cells using automated multicolor flow fluorescence in situ hybridization (FISH). We previously showed that very short telomeres (<1st percentile for age) in lymphocytes, naïve T-cells, and B-cells were sensitive and specific for the diagnosis of DC (Alter et al, Blood110:1439, 2007). Granulocytes were not specific, since in that study neutropenic patients without DC often had very short granulocyte telomeres. The current study included 53 DC patients and 87 relatives, 19 non-transplanted FA patients and 12 relatives, 21 DBA patients and 11 relatives, and 7 SDS patients and 7 relatives. There were 400 normal controls, ages 0 to 100; very short telomeres were defined as <1st percentile of normal for age. Z-scores were calculated to adjust for age; 0 is normal and -2 or below is significantly short (i.e. <2 standard deviations below the mean). Lymphocyte telomeres were <1st percentile (very short) in 96% of DC patients, 7% of DC relatives, 16% of FA patients, 5% of DBA patients, 14% of SDS patients, and none of the non-DC relatives. Granulocyte telomeres were very short in 94% of DC patients, 16% of DC relatives, 44% of FA patients, 19% of DBA patients, 14% of SDS patients, 8% of FA relatives, and none of the non-DC relatives. All three hallmark leukocyte subsets (lymphocytes, naïve T-cells, and B-cells) were very short in 81% of DC patients, 5% of DC relatives, 5% of DBA patients, and none of the FA or SDS patients or their relatives. Although 4 out of 47 (9%) IBMFS other than DC had very short telomeres in lymphocytes, only one, a patient with DBA (without mutations in known DC genes) had very short telomeres in all 3 of the hallmark lineages. Four of 87 DC relatives also had very short telomeres in all 3 lineages; they may be silent carriers in families in which DC genes have not yet been identified. The mean Z-score for lymphocyte telomeres in DC was -4.7; it was above -2 in all other categories (-0.3 in FA, -0.9 in DBA, -1 in SDS). The mean Z-score for granulocytes was -4.2 in DC, -1.9 in FA, -1.2 in DBA, and -1.5 in SDS. Thus, based on the Z-scores, the average telomere length was very short in DC lymphocytes and granulocytes; normal in FA lymphocytes and borderline in FA granulocytes; and normal in DBA and SDS lymphocytes and granulocytes. Flow-FISH provides analysis of multiple cell types in individual patients, and identification of specific individuals with very short telomeres, as well as the age-adjusted mean telomere length in a diagnostic subset. No FA or SDS patients, and only one with DBA, met the DC diagnostic criteria of very short telomeres in three or more lymphocyte subsets. The telomere length deficit in DC appears to be more severe and more frequent than in the other inherited bone marrow failure syndromes.

scholarly journals Telomere Length in Inherited Bone Marrow Failure Syndromes

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1609-1609
Author(s):  
Blanche P. Alter ◽  
Neelam Giri ◽  
Sharon A Savage ◽  
Philip S. Rosenberg
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Failure ◽  
Canonical Variate ◽  
Dna Repeats ◽  
Z Score ◽  
Essentially Normal ◽  
Bone Marrow Failure Syndromes ◽  
Z Scores ◽  
The Mean

Abstract Background: Telomeres are short DNA repeats and a protein complex at chromosome ends that are essential for genome integrity. Telomeres are very short in patients with dyskeratosis congenita (DC) due to germline mutations in telomere biology genes. Telomere lengths (TL) were reported to be “short” in a few small studies of patients with other inherited bone marrow failure syndromes (IBMFS), specifically Fanconi anemia (FA), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS), although their relation to the very short TL seen in DC was not clear, and various analytic methods were used. Objectives: 1) To compare TL in a cohort of patients with FA, DBA, and SDS, with TL in DC. 2) To determine whether any individuals with non-DC IBMFS had TL as short as in DC. Methods: Blood was obtained from 100 patients with DC, 30 FA, 34 DBA, and 14 SDS enrolled in the NCI IBMFS Cohort Study. TL was measured by flow cytometry with fluorescence in situ hybridization (flow-FISH) in 6 leukocyte subsets: granulocytes, total lymphocytes, CD45RA-positive/CD20-negative naïve T cells, CD45RA-negative memory T cells, CD20-positive B cells, and CD57-positive NK/NKT cells. “Very short” TL was below the 1st percentile for age (defined by 400 normal controls). The diagnosis of DC required very short TL in 3 of 4 lymphocyte lineages including total lymphocytes. Z-scores were used to adjust for age; a Z-score of -2.3 equals the 1st percentile. Canonical Variate Analysis (CVA) including all 6 Z-score measurements was used for group comparisons and outlier identification. Results: Two patients with FA and 1 each with DBA and SDS had TL slightly below the 1st percentile in 3 or more lymphocyte lineages. In univariate analysis, the mean of the DC TL Z-scores was approximately -4, versus approximately -0.5 in FA, DBA, and SDS. Most individual DC Z-score measurements were well below -2.3, and all were below zero (the mean for the control data). Seventy percent of the FA, DBA and SDS lymphocyte TL Z-scores clustered in the bottom half of the normal range (i.e. -2.3 to 0, p <0.001), compared with the expected 50% if the non-DC patients had essentially normal TLs. In addition, short lymphocyte TL correlated with severity of marrow failure in DC; there was a non-significant trend in FA and no trend in DBA or SDS. Further refinement of interpretation utilized the CVA analysis. The first canonical variate captured 89.7% of the total variance, and separated DC widely from the other three IBMFS. The second canonical variate captured 10% of the variance, and separated DBA, FA, and SDS. In the CVA analysis, only 2 patients with FA and 1 each with DBA and SDS had results closer to the mean for DC patients than to the mean for their own disorder. Conclusions: Only 5% of individuals with FA, DBA, or SDS had TL in the DC range, and thus non-DC IBMFS in general do not have “very short” TL. However, 70% of non-DC IBMFS patients did have average TLs below the average for normal individuals. Thus disorders of DNA repair or ribosome biogenesis may result in TL changes, but the deficit in TL is not nearly as extreme as in DC itself. Disclosures No relevant conflicts of interest to declare.

scholarly journals Very short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita

Blood ◽  
2007 ◽  
Vol 110 (5) ◽  
pp. 1439-1447 ◽  
Author(s):  
Blanche P. Alter ◽  
Gabriela M. Baerlocher ◽  
Sharon A. Savage ◽  
Stephen J. Chanock ◽  
Babette B. Weksler ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
In Situ Hybridization ◽  
Fluorescence In Situ Hybridization ◽  
Telomere Length ◽  
Bone Marrow Failure ◽  
Correct Diagnosis ◽  
Dyskeratosis Congenita ◽  
Telomere Maintenance

Abstract Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome in which the known susceptibility genes (DKC1, TERC, and TERT) belong to the telomere maintenance pathway; patients with DC have very short telomeres. We used multicolor flow fluorescence in situ hybridization analysis of median telomere length in total blood leukocytes, granulocytes, lymphocytes, and several lymphocyte subsets to confirm the diagnosis of DC, distinguish patients with DC from unaffected family members, identify clinically silent DC carriers, and discriminate between patients with DC and those with other bone marrow failure disorders. We defined “very short” telomeres as below the first percentile measured among 400 healthy control subjects over the entire age range. Diagnostic sensitivity and specificity of very short telomeres for DC were more than 90% for total lymphocytes, CD45RA+/CD20− naive T cells, and CD20+ B cells. Granulocyte and total leukocyte assays were not specific; CD45RA− memory T cells and CD57+ NK/NKT were not sensitive. We observed very short telomeres in a clinically normal family member who subsequently developed DC. We propose adding leukocyte subset flow fluorescence in situ hybridization telomere length measurement to the evaluation of patients and families suspected to have DC, because the correct diagnosis will substantially affect patient management.

Bone Marrow Cellular Composition and Inflammatory Cytokine Expression in Patients with Inherited Bone Marrow Failure Syndromes

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4401-4401
Author(s):  
Neelam Giri ◽  
Ken Matsui ◽  
Blanche P Alter ◽  
Sharon A Savage ◽  
Yuanji Pan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
B Cells ◽  
Mononuclear Cells ◽  
Bone Marrow Failure ◽  
Somatic Mosaicism ◽  
Bone Marrow Failure Syndromes ◽  
Cd34 Cells ◽  
Tnf Α ◽  
Ifn Γ

Abstract Abstract 4401 Proinflammatory cytokines, TNF-α and IFN-γ, are potent inhibitors of hematopoiesis, and may be relevant in the pathogenesis of bone marrow failure in inherited bone marrow failure syndromes (IBMFS). Increased levels of these cytokines in sera and in bone marrow CD3+ cells have been reported in Fanconi anemia (FA) patients. However, our study did not find increased TNF-α or IFN-γ in sera, or supernatants from phytohemagglutinin-stimulated peripheral blood mononuclear cells from IBMFS patients. To assess whether production of these cytokines is dysregulated in BM of these patients, we examined intracellular expression of TNF-α and IFN-γ in BM mononuclear cells from 16 FA, 20 dyskeratosis congenita (DC), 21 Diamond-Blackfan anemia (DBA) and 7 Shwachman-Diamond syndrome (SDS) patients by flow cytometry; 14 healthy adults were studied as controls. To detect intracellular TNF-α and IFN-γ, BM lymphocytes and monocytes were stimulated with phorbol 12-myristate 13-acetate plus ionomycin (P+I), or lipopolysaccharide (LPS), respectively. Separately, unstimulated cells were stained with antibodies to CD45, CD3, CD19, CD14, and CD34 to determine the proportion of cellular subsets. Percentages of T cells in patients with IBMFS were comparable to the controls, while DC patients had lower proportion of B cells (p=0.02). The percentages of monocytes were lower in FA (p=0.04), DC (p=0.009), and DBA (p<0.001) patients. The proportions of CD34+ cells were also lower in IBMFS patients (≤0.02 for all) except for those with DBA, who had similar proportions as the controls. When we compared the effect of cytopenia (counts below normal for age), only the proportion of CD34+ cells in DC patients was significantly affected. DC patients with cytopenia (n=15) had lower numbers of CD34+ cells (p=0.007) compared with those without (n=5). We also analyzed the effect of somatic mosaicism in FA because it may correct the hematopoietic defect in these patients. FA patients without mosaicism (n=11) had lower proportions of CD19+, CD14+, and CD34+ cells than those with mosaicism (n=5), while the CD3+ cell numbers were unaffected. We detected both intracellular TNF-α and IFN-γ in T cells, but only TNF-α in B cells in response to P+I, while LPS stimulation led to TNF-α production only in monocytes. Percentages of cytokine-producing T and B cells were significantly lower for patients with DBA when compared with healthy adult controls (p<0.006 for T cells and p=0.001 for B cells). There were no significant differences in the other syndromes. Comparison of intracellular cytokines between cytopenic and non-cytopenic patients showed that TNF-α-producing T cells were affected in FA (p=0.03), where the cytopenic patients had a higher proportion of TNF-α-positive T cells. For the LPS-stimulated monocytes, FA (p=0.01) and DBA (p=0.05) patients had significantly lower proportions of TNF-α-producing cells than the controls, and this was independent of cytopenia. There was no effect of mosaicism on cytokine production. Contrary to previous reports, we did not find an increase in intracellular TNF-α or IFN-γ in T cells from FA patients. However, the number of TNF-α-producing monocytes in FA was lower than that in healthy adult controls. This is consistent with reported dysregulation of monocytes in FA patients. We also identified reduced cytokine expression in lymphocytes and monocytes from DBA patients, but not from DC or SDS. As expected, we found reduced proportions of CD34+ cells in FA, DC and SDS, syndromes associated with multilineage cytopenia, and not in DBA which is associated with pure red cell aplasia. And, we ascertained that FA patients with somatic mosaicism had significantly higher percentages of cells including CD34+, suggesting that the corrected stem cell pool in FA mosaics is able to maintain hematopoiesis in contrast to non-mosaic FA patients who develop progressive cytopenia over time. Overall, the effect of cytopenia on cytokine production was mild; however, this may be related to the small sample size. In conclusion, our results suggest that mechanisms other than an excess of inflammatory cytokines may be responsible for bone marrow failure in IBMFS, and this area of research deserves a further attention in larger studies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Monitoring and treatment of MDS in genetically susceptible persons

Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 105-109 ◽  
Author(s):  
Stella M. Davies
Keyword(s):  
Bone Marrow ◽  
Dna Damage ◽  
Bone Marrow Failure ◽  
Treatment Strategies ◽  
Informed Choice ◽  
Dyskeratosis Congenita ◽  
Careful Consideration ◽  
Host Susceptibility ◽  
Bone Marrow Failure Syndromes ◽  
Severe Infections

Abstract Genetic susceptibility to myelodysplastic syndrome (MDS) occurs in children with inherited bone marrow failure syndromes, including Fanconi anemia, Shwachman Diamond syndrome, and dyskeratosis congenita. Available evidence (although not perfect) supports annual surveillance of the blood count and bone marrow in affected persons. Optimal treatment of MDS in these persons is most commonly transplantation. Careful consideration must be given to host susceptibility to DNA damage when selecting a transplant strategy, because significant dose reductions and avoidance of radiation are necessary. Transplantation before evolution to acute myeloid leukemia (AML) is optimal, because outcomes of AML are extremely poor. Children and adults can present with germline mutations in GATA2 and RUNX1, both of which are associated with a 30% to 40% chance of evolution to MDS. GATA2 deficiency may be associated with a clinically important degree of immune suppression, which can cause severe infections that can complicate transplant strategies. GATA2 and RUNX1 deficiency is not associated with host susceptibility to DNA damage, and therefore, conventional treatment strategies for MDS and AML can be used. RUNX1 deficiency has a highly variable phenotype, and MDS can occur in childhood and later in adulthood within the same families, making annual surveillance with marrow examination burdensome; however, such strategies should be discussed with affected persons, allowing an informed choice.

Marrow Failure

Hematology ◽  
2004 ◽  
Vol 2004 (1) ◽  
pp. 318-336 ◽  
Author(s):  
Grover C. Bagby ◽  
Jeffrey M. Lipton ◽  
Elaine M. Sloand ◽  
Charles A. Schiffer
Keyword(s):  
Bone Marrow ◽  
Immunosuppressive Therapy ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Allogeneic Bone Marrow Transplantation ◽  
Dyskeratosis Congenita ◽  
Allogeneic Bone ◽  
Diagnosis And Management ◽  
Bone Marrow Failure Syndromes ◽  
Made In

Abstract New discoveries in cell biology, molecular biology and genetics have unveiled some of the pathophysiological mysteries of some of the bone marrow failure syndromes. Many of these discoveries have revealed why these syndromes show so much clinical overlap and some hold the potential for influencing the development of new therapies. In children and adults with pancytopenia and hypoplastic bone marrows proper differential diagnosis requires that some attention be directed toward defining molecular and cellular pathogenetic mechanisms because, once identified, some of these mechanisms will clearly suggest rational therapeutic approaches, treatment options that should be avoided, or both. In Section I, Drs. Jeffrey Lipton and Grover Bagby review the approach to diagnosis and management of patients with the inherited bone marrow failure syndromes, Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and the Shwachman-Diamond syndrome. Extraordinary progress has been made in identifying the genes bearing pathogenetically relevant mutations in these disorders, but slower progress has been made in defining the precise functions of the proteins these genes encode in normal cells, in part because it is increasingly obvious that the proteins are multifunctional. In practice, it is clear that in patients with dyskeratosis congenita and Fanconi anemia, the diagnosis must be considered not only in children but in adults as well. In Section II, Dr. Elaine Sloand outlines a very practical and evidence-based approach to diagnosis and management of acquired hypoplastic states emphasizing overlap between non-clonal and clonal hematopoiesis is such conditions. The pathogenesis of T lymphocyte–mediated marrow failure is presented as a clear-cut rationale for use of immunosuppressive therapy and stem cell transplantation. Practical management of patients with refractory disease with and without evidence of clonal evolution (either paroxysmal nocturnal hemoglobinuria [PNH] or myelodysplasia [MDS]) is presented. In Section III, the challenge of hypoplastic MDS is reviewed by Dr. Charles Schiffer. After reviewing the most up-to-date classification scheme, therapeutic options are reviewed, focusing largely on agents that have most recently shown some promising activity, including DNA demethylating agents, thalidomide and CC5013, arsenic trioxide, and immunosuppressive therapy. Here are also outlined the rationale and the indications for choosing allogeneic bone marrow transplantation, the only therapy with known curative potential.

A Novel hTERC Deletion Manifesting with Features of Dyskeratosis Congenita and Genetic Anticipation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4157-4157
Author(s):  
Stan Benke ◽  
D. S. Houston ◽  
Inderjeet Dokal ◽  
Tom Vulliamy
Keyword(s):  
Bone Marrow ◽  
Telomere Length ◽  
Peripheral Blood ◽  
Autosomal Dominant ◽  
Bone Marrow Failure ◽  
Macrocytic Anemia ◽  
Phenotypic Expression ◽  
Dyskeratosis Congenita ◽  
Sequencing Analysis ◽  
Genetic Anticipation

Abstract The gene encoding the RNA component of human telomerase (hTERC) is mutated in families with the autosomal dominant form of dyskeratosis congenita (DC). The phenomenon of genetic anticipation has recently been reported to accompany this form of DC, with disease severity increasing in offspring of affected individuals. It has been postulated that anticipation in these families relates to the adverse impact of hTERC mutations on inherited telomere length, with progressive telomere shortening seen in succeeding generations (Nat Gen2004; 36:447). We describe here a novel hTERC mutation, with affected individuals presenting in adulthood with mild mucocutaneous abnormalities, bone marrow failure and a pattern of penetrance supporting the presence of disease anticipation. The proband in the family studied presented at age 49 with squamous cell carcinoma of the tongue and a history of oral leukoplakia which he had developed at age 30. Peripheral blood on presentation was remarkable only for a mild macrocytic anemia. During treatment of his malignancy, severe and irreversible bone marrow hypoplasia was precipitated by a single cycle of cisplatinum chemotherapy. The patient’s brother at age 25 had been previously diagnosed with severe aplastic anemia; this was refractory to standard immunosuppression with cyclosporine and antithymocyte globulin. No somatic abnormailites were identified in this patient. Testing for Fanconi anemia in both siblings was negative. Direct sequencing analysis of hTERC in these patients revealed both to be heterozygous for a novel hTERC mutation (79 deletion C). Further studies among family members documented heterozygosity for the mutation in the mother of these two siblings. At age 77, she displayed none of the mucocutaneous signs associated with DC, while the only abnormality seen in her peripheral blood was an elevated mean corpuscular volume. The hTERC mutation seen in this family most likely exerts its effects through disruption of the pseudoknot domain. The findings of an individual with normal longevity, minimal phenotypic expression and affected offspring are further evidence of genetic anticipation being an important feature of autosomal dominant DC. Correlation with determination of telomere length has been initiated.

Utility of Telomere in Diagnosis of Bone Marrow Failure Syndromes

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4793-4793
Author(s):  
Hasan Ahmed Abdel-ghaffar ◽  
Hosam Zaghloul ◽  
Ahmed El-Waseef ◽  
Mohamed El-Naggar ◽  
Mohamed Mabed ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Telomere Length ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Quantitative Polymerase Chain Reaction ◽  
Control Group ◽  
Hematopoietic Stem ◽  
Relative Telomere Length ◽  
Bone Marrow Failure Syndromes ◽  
Significant Difference

Abstract Background and aim of the work: Bone marrow failure syndromes (BMFS) includes inherited and acquired conditions. Inherited bone marrow failure includes a number of syndromes; with Fanconi anemia (FA) being the most common one of them. Telomeres are eroded with cell division, but in hematopoietic stem cell, maintenance of their length is mediated by telomerase. Short telomeres can result in instability of cell function where diseases occur. Bone Marrow Failure might be developed due to low telomerase activity or short telomeres. Our study is aiming to evaluate the utility of Real Time Quantitative-Polymerase Chain Reaction (RT-qPCR) in measuring the relative telomere length and its significance in diagnosis and prognosis of patients with BMFS. Materials and methods: The study includes 3 groups: A group of congenital BMF (29 patients), a group of acquired BMF (10 patients) and a third control group (15 cases). The relative telomere length is evaluated for them using RT-qPCR. Results: We have found that there is a significant difference in relative telomere length between congenital group and controls (p=0.001), also a significant difference between acquired group and controls (p= 0.029). However, there is no significant difference between congenital and acquired groups (p= 0.479). There is no significant correlation between the telomere length and the overall survival or prognosis of the patients of BMFS. Conclusion: We conclude that the telomere length is significantly altered in patients with BMFS whether being congenital or acquired compared to the control group. Disclosures No relevant conflicts of interest to declare.

scholarly journals Effect of stem cell factor on in vitro erythropoiesis in patients with bone marrow failure syndromes

Blood ◽  
1992 ◽  
Vol 80 (12) ◽  
pp. 3000-3008
Author(s):  
BP Alter ◽  
ME Knobloch ◽  
L He ◽  
AP Gillio ◽  
RJ O'Reilly ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stem Cell Factor ◽  
Mononuclear Cells ◽  
Bone Marrow Failure ◽  
Dyskeratosis Congenita ◽  
Normal Numbers ◽  
Erythroid Progenitors ◽  
Bone Marrow Failure Syndromes

Stem cell factor (SCF) enhances normal hematopoiesis. We examined its effect in vitro on bone marrow and blood progenitors from patients with inherited bone marrow failure syndromes, including 17 patients each with Diamond-Blackfan anemia (DBA) and Fanconi's anemia (FA), 3 with dyskeratosis congenita (DC), and 1 each with amegakaryocytic thrombocytopenia (amega) and transient erythroblastopenia of childhood (TEC). Mononuclear cells were cultured with erythropoietin (Ep) alone or combined with SCF or other factors. SCF increased the growth of erythroid progenitors in cultures from 50% of normal controls, 90% of DBA, 70% of FA, 30% of DC, and the amega and TEC patients; normal numbers were reached in 25% of DBA studies. Improved in vitro erythropoiesis with SCF in all types of inherited marrow failure syndromes does not suggest a common defect involving kit or SCF, but implies that SCF may be helpful in the treatment of hematopoietic defects of varied etiologies.

scholarly journals Treatment of inherited bone marrow failure syndromes beyond transplantation

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 96-101 ◽  
Author(s):  
Rodrigo T. Calado ◽  
Diego V. Clé
Keyword(s):  
Bone Marrow ◽  
Liver Toxicity ◽  
Bone Marrow Failure ◽  
Dyskeratosis Congenita ◽  
Hematopoietic Stem ◽  
Diamond Blackfan Anemia ◽  
Bone Marrow Failure Syndromes ◽  
Thrombopoietin Receptor ◽  
Cell Sources ◽  
Stimulating Factor

Abstract Despite significant progress in transplantation by the addition of alternative hematopoietic stem cell sources, many patients with inherited bone marrow failure syndromes are still not eligible for a transplant. In addition, the availability of sequencing panels has significantly improved diagnosis by identifying cryptic inherited cases. Androgens are the main nontransplant therapy for bone marrow failure in dyskeratosis congenita and Fanconi anemia, reaching responses in up to 80% of cases. Danazol and oxymetholone are more commonly used, but virilization and liver toxicity are major adverse events. Diamond-Blackfan anemia is commonly treated with corticosteroids, but most patients eventually become refractory to this treatment and toxicity is limiting. Growth factors still have a role in inherited cases, especially granulocyte colony-stimulating factor in congenital neutropenias. Novel therapies are warranted and thrombopoietin receptor agonists, leucine, quercetin, and novel gene therapy approaches may benefit inherited cases in the future.

Sign in / Sign up

Export Citation Format

Share Document