Differential impact of a dyskeratosis congenita mutation in TPP1 on mouse hematopoiesis and germline

Telomerase extends chromosome ends in somatic and germline stem cells to ensure continued proliferation. Mutations in genes critical for telomerase function result in telomeropathies such as dyskeratosis congenita (DC), frequently resulting in spontaneous bone marrow failure. While knockout of telomerase in mice has been instrumental in highlighting the importance of telomere length maintenance at an organismal level, it may not be representative of human telomeropathy mutations in vivo. A DC mutation in the shelterin protein TPP1 (K170∆) that compromises telomerase recruitment to telomeres but leaves other functions of TPP1 and the integrity of the telomerase holoenzyme intact is a physiologically relevant tool to evaluate telomerase-dependent telomere length maintenance in mice. We used CRISPR-Cas9 to generate a mutant mouse knocked in for the equivalent of the TPP1 K170∆ mutation (TPP1 K82∆) and investigated both its bone marrow and germline compartments in unprecedented detail. TPP1 K82∆ caused progressive telomere erosion with increasing generation number but did not induce steady-state hematopoietic defects. Strikingly, K82∆ caused mouse infertility, consistent with gross morphological defects in the testis and sperm, the appearance of either empty or severely disorganized seminiferous tubules, and a decrease in both spermatogonia and spermatocytes. It is intriguing that both TPP1 K82∆ mice and previously characterized telomerase knockout mice show no spontaneous bone marrow failure but rather succumb to a robust infertility phenotype at steady state. We speculate that telomere length maintenance contributes differently to the evolutionary fitness of humans and mice. Telomere length maintenance in the human bone marrow can ensure progression to reproductive age, while that in the mouse germline can help meet the elevated demand for sperm to produce multiple offspring.

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

Blood ◽

10.1182/blood.v104.11.4157.4157 ◽

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.

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Significance of Telomere Length Measurement in the Diagnosis of Dyskeratosis Congenita.

Blood ◽

10.1182/blood.v110.11.836.836 ◽

2007 ◽

Vol 110 (11) ◽

pp. 836-836

Author(s):

Hong-Yan Du ◽

Elena Pumbo ◽

Akiko Shimamura ◽

Adrianna Vlachos ◽

Jeffrey M. Lipton ◽

...

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Telomere Length ◽

Bone Marrow Failure ◽

Skin Pigmentation ◽

Screening Method ◽

Dyskeratosis Congenita ◽

Telomere Maintenance ◽

Healthy Controls ◽

Mutation Carriers

Abstract Dyskeratosis congenita (DC) is a rare inherited bone marrow failure (BMF) syndrome. The classical features of DC include nail dystrophy, abnormal skin pigmentation, and mucosal leukoplakia. The diagnosis of DC can be difficult. Originally, the diagnosis was based on the presence of the classical mucocutaneous features. However, the identification of four genes responsible for DC (DKC1, TERC, TERT, and NOP10) showed that these mucocutaneous features are only present in a proportion of patients with DC. Additionally, screening for mutations in the affected genes is expensive and is negative in about 50% of patients with classical features of DC. The products of the genes mutated in DC are the components of the telomerase ribonucleoprotein complex, which is essential for telomere maintenance. Therefore it has been postulated that DC is a disease arising from excessive telomere shortening. Here we examined whether the measurement of telomeres could be used as a screening test to identify individuals with DC. For this purpose we examined telomere length in peripheral blood mononuclear cells from 169 patients who presented with bone marrow failure including 17 patients with DC, diagnosed by the presence of classical cutaneous features or the identification of mutations in DKC1, TERC or TERT, 28 patients with paroxysmal nocturnal hemoglobinuria, 25 patients with Diamond Blackfan anemia, 5 patients with Shwachman-Diamond syndrome, 8 patients with myelodysplastic syndrome, and 74 patients with aplastic anemia of unknown cause classified as idiopathic aplastic anemia. In addition we measured telomere length in 12 patients with idiopathic pulmonary fibrosis and in 45 individuals with a de novo deletion of chromosome 5p including the TERT gene. Their telomere lengths were compared with those of 202 age-matched healthy controls. Moreover, mutations were screened in the genes associated with DC. In cases where a mutation was identified, telomere length and mutations were also examined in all the family members. Our results show that all patients with DC and bone marrow failure have very short telomeres far below the first percentile of healthy controls. Not all mutation carriers, including some carriers of apparently dominant mutations, have very short telomeres. What is more, very short telomeres could be found in healthy individuals in these families, some of whom were not mutation carriers. These findings indicate that in patients with BMF the measurement of telomere length is a sensitive screening method for DC, whether very short telomeres in this setting are also specific for DC remains to be determined. However, in contrast to a previous study, we find that telomere length does not always identify mutation carriers in the families of DC.

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Longitudinal Changes In Telomere Length In Patients with Dyskeratosis Congenita

Blood ◽

10.1182/blood.v116.21.2230.2230 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2230-2230

Author(s):

Blanche P Alter ◽

Neelam Giri ◽

Peter M. Lansdorp ◽

Gabriela M. Baerlocher ◽

Philip S Rosenberg ◽

...

Keyword(s):

Bone Marrow ◽

Telomere Length ◽

Bone Marrow Failure ◽

Dyskeratosis Congenita ◽

Premature Aging ◽

Bone Marrow Failure Syndrome ◽

Cross Sectional ◽

Telomere Shortening ◽

Early Presentation ◽

Telomere Attrition

Abstract Abstract 2230 Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome with a complex clinical phenotype, including dysplastic nails, lacy reticular pigmentation, and oral leukoplakia (the diagnostic triad). Numerous other physical abnormalities may be present, in addition to cytopenias due to bone marrow failure, and a high risk of leukemia or solid tumors. However, many patients have no physical findings at diagnosis. Patients with DC have very short telomeres, and approximately one-half have a mutation in one of six genes important in telomere biology. Telomere length in leukocyte subsets, measured by automated flow fluorescence in situ hybridization (flow-FISH), is both sensitive and specific for identifying individuals with DC. Telomeres consist of nucleotide repeats and a protein complex at chromosome ends that are critical in chromosomal stability which shorten during normal cell division. Cross-sectional studies of normal individuals suggest that telomere length decreases with age in a sigmoid pattern from birth to old age. In a cross-sectional analysis of 26 patients with DC, we previously observed that telomere length appeared to be stable or even to slightly increase with age (BP Alter et al, Blood 110:149, 2007). Similar results were shown in 23 different DC patients by others (M Bessler et al, FEBS Lett 2010 in press). We speculated that these data were influenced by early presentation (or recognition) of clinically more severe patients, while patients with similar telomere length who were clinically milder were identified at older ages. In this pilot study, we examined, for the first time, the longitudinal age-association of telomere attrition in nine patients with DC who were followed for five to seven years (currently 8 – 50 years of age). These include three patients with mutations in TERC, and two each with TINF2, TERT, and DKC1 mutations. When first studied, four had normal hematopoiesis, three moderate cytopenias, one was receiving androgens, and one was on transfusions. Subsequently, one with normal hematopoiesis developed mild thrombocytopenia, one who was on transfusions responded to androgens, and one with moderate aplastic anemia became severe. In all cases, telomere length decreased with age. In a linear regression model, the average annual decrease in telomere length in lymphocytes was 167 base pairs/year (bp/yr) + 104, similar to the rate in granulocytes, 159 + 92 bp/yr. According to the literature, the rate of telomere attrition in longitudinal studies in normal blood is ∼45-50 bp/yr, albeit by methods other than flow-FISH; the rate of telomere shortening appears to decrease with increasing age. The average patient Z-scores at the beginning of the study were -3.9 standard deviations below the median for age in healthy normal controls, and were -4.3 at the end, consistent with the impression that DC patient telomeres shorten somewhat more than expected from normal aging. These data support the hypothesis that the earlier cross-sectional results for patients with DC indeed were influenced by the cross-sectional rather than longitudinal nature of the data. The current longitudinal data suggest that telomere shortening could possibly be accelerated in patients with DC, but larger studies are required. Our results indicate that patients with DC have telomeres that are much shorter than normal for their age, and that over time they continue to shorten, consistent with DC being classified as a disorder of premature aging. Disclosures: Lansdorp: Repeat Diagnostics: Equity Ownership.

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

Blood ◽

10.1182/blood-2007-02-075598 ◽

2007 ◽

Vol 110 (5) ◽

pp. 1439-1447 ◽

Cited By ~ 217

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.

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Telomere Dysfunction in Bone Marrow Failure.

Blood ◽

10.1182/blood.v114.22.sci-12.sci-12 ◽

2009 ◽

Vol 114 (22) ◽

pp. SCI-12-SCI-12

Author(s):

Peter M. Lansdorp

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Stem Cell ◽

Aplastic Anemia ◽

Telomere Length ◽

Bone Marrow Failure ◽

Tumor Development ◽

Dyskeratosis Congenita ◽

Cell Numbers ◽

Tert Gene

Abstract Abstract SCI-12 In order to distinguish a normal telomere from a double strand break, a minimum number of telomere repeats must “cap” each chromosome end. The length of each repeat array will reflect a unique history of addition and losses. Telomere losses are known to occur sporadic as well as with every replication cycle. Losses of telomeric DNA are countered by the telomerase enzyme containing telomerase RNA (encoded by the TERC gene) and a reverse transcriptase protein (encoded by TERT gene) as minimal components. Telomerase levels are high in cells of the germline and immortal cellines and the telomere length is typically maintained in such cells. In contrast, telomerase activity is limiting in most human somatic (stem) cells and as a result the average length of telomere repeats in most somatic cells shows a highly significant decline with age. The hypothesis that loss of telomere repeats acts as a “mitotic clock” and a tumor suppressor mechanism in stem cells is strongly supported by recent studies of patients with mild telomerase deficiency resulting from haplo-insufficiency for either the TERC or TERT gene. Such genetic defects can give rise to various disorders including autosomal dominant Dyskeratosis Congenita (DKC), aplastic anemia, liver fibrosis and pulmonary fibrosis. Other recent studies have revealed that amplification of the hTERT gene is one of the most common genetic abnormalities in various cancers. Paradoxically, it is becoming clear that SNPs within the TERT locus are among the most reproducible risk factors for the development of different types of cancer including lung cancer, acute myeloid leukemia and chronic lymphocytic leukemia. The links between hypo- and hyperproliferative consequences of inborn telomerase deficiencies and SNP's in the TERT gene are poorly understood. It seems plausible that the increased risk of leukemia development in aplastic anemia, myelodysplastic syndrome and Dyskeratosis Congenita, results from stem cell failure. Could reduced stem cell numbers by itself provide a risk factor for tumor development? More direct measures of stem cell numbers in vivo are needed to examine this possibility and the relationship between stem cell numbers and tumor development in patients with defective telomere maintenance as well as in normal individuals as a function of age. Measurements of the average telomere length as well as the length of telomere repeats at individual chromosome ends in specific cells and tissues will further calrify the involvement of telomeres in bone marrow failure, normal aging and tumor biology. Disclosures Lansdorp: Repeat Diagnostics Inc.: Equity Ownership.

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Telomere Length Measurement by Flow-FISH Distinguishes Dyskeratosis Congenita from Other Bone Marrow Failure Syndromes.

Blood ◽

10.1182/blood.v108.11.183.183 ◽

2006 ◽

Vol 108 (11) ◽

pp. 183-183

Author(s):

Blanche P. Alter ◽

Gabriela Baerlocher ◽

Sharon A. Savage ◽

Stephen Jacob Chanock ◽

Babette B. Weksler ◽

...

Keyword(s):

Bone Marrow ◽

Telomere Length ◽

Sensitivity And Specificity ◽

Bone Marrow Failure ◽

Correct Diagnosis ◽

White Blood Cells ◽

Dyskeratosis Congenita ◽

Length Measurement ◽

Specific Method ◽

Telomere Biology

Abstract This study was designed to evaluate the utility of flow-FISH telomere length measurement in white blood cells (WBC) as a screening test for Dyskeratosis congenita (DC). We studied 26 patients: 17 with DC, 1 silent carrier (clinically normal; mutation in TERC), 4 with the Hoyeraal-Hreidarsson variant (HH), and 4 with Revesz Syndrome. Five had mutations in DKC1, 5 in TERC, and 2 in TERT. 23 had hematologic abnormalities, 19 had 2 or 3 of the DC diagnostic triad (lacey pigmentation, dyskeratotic nails, and leukoplakia), and 4 had soft signs of DC. We evaluated 54 first-degree relatives of DC patients, 16 Fanconi Anemia patients (FA), 14 with Diamond-Blackfan Anemia (DBA), 5 with Shwachman Diamond Syndrome (SDS), and 10 with other possibly inherited cytopenias (Other). Telomere length was measured in granulocytes and lymphocyte subsets by automated multicolor flow-FISH; results were compared with age-matched values from 400 normal controls. “Very low (VL)” telomere length was defined as a mean telomere length below the normal first percentile for age and specific WBC type. We observed VL telomeres in all subsets in the silent carrier, all HH and Revesz patients, and 15/17 with DC. Eight of 51 DC relatives had VL telomeres in granulocytes versus 2/54 with VL telomeres in lymphocytes. The sensitivities for distinguishing a DC patient from an unaffected relative were 92% in lymphocytes and 96% in granulocytes; the specificities were 96% and 98%, respectively; the sensitivity and specificity for VL telomeres in both cell types were 96% and 96%. The silent carrier with a TERC mutation developed thrombocytopenia, hypocellular marrow, and a cytogenetic clone during follow-up. The 2 DC relatives with VL telomeres in lymphocytes were from a family without a known mutant gene; they may also be silent carriers. The latter possibility disqualified an HLA-matched sibling as a donor for DC-related aplastic anemia, because of engraftment concerns; another sibling donor with normal telomere length was selected. VL granulocyte telomeres were observed in 5/16 FA, 3/14 DBA, 1/5 SDS, and 1/10 Other patients, versus 2/16 FA, 1/14 DBA, 1/5 SDS, and 0/10 Other in lymphocytes, and in both lineages in only 1 each of FA, DBA, and SDS. The sensitivity and specificity for distinguishing DC from non-DC patients using VL telomeres in both lineages were 96% and 93%, respectively. Only DC patients had consistently VL telomeres in all cell subsets. Flow-FISH telomere length measurement provides a sensitive and specific method for identifying patients with DC among families, regardless of mutation status, and distinguishes patients with DC from those with other inherited or acquired marrow failure syndromes. It may also help to detect silent carriers, and facilitate identification of mutations in other telomere biology genes. Our data suggest that the diagnostic triad, soft physical findings and/or bone marrow failure may not be required for the diagnosis of DC. Correct diagnosis of DC will enhance genetic counseling and hematologic management.

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

Blood ◽

10.1182/blood.v112.11.1044.1044 ◽

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.

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Monitoring and treatment of MDS in genetically susceptible persons

Hematology ◽

10.1182/hematology.2019000020 ◽

2019 ◽

Vol 2019 (1) ◽

pp. 105-109 ◽

Cited By ~ 1

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.

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The Inherited Bone Marrow Failure Syndromes: Fanconi Anemia, Dyskeratosis Congenita and Diamond‐Blackfan Anemia

Reviews in Clinical and Experimental Hematology ◽

10.1046/j.1468-0734.2000.00015.x ◽

2000 ◽

Vol 4 (3) ◽

pp. 183-215 ◽

Cited By ~ 2

Author(s):

Inderjeet Dokal

Keyword(s):

Bone Marrow ◽

Fanconi Anemia ◽

Bone Marrow Failure ◽

Dyskeratosis Congenita ◽

Diamond Blackfan Anemia ◽

Bone Marrow Failure Syndromes

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