Hematologic abnormalities in Fanconi anemia.
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Fanconi Anemia↗
Biomedical subjects
B P Alter
Publications and source records attributed to B P Alter.
Effects of low oxygen tension and antioxidants on human erythropoiesis in vitro.
Cultured cells grow better in low oxygen than in room air, and the addition of a sulfhydryl-reducing agent is usually routine. It has been thought that such reagents protect cells from free-radical toxicity in atmospheric oxygen, which is higher than in physiological oxygen tension. Previous data demonstrating the efficacy of the usual antioxidant, 2-mercaptoethanol (2ME), were obtained in murine studies. We have compared the effect of 2ME and other antioxidants on human erythropoiesis using neonatal (cord) and adult blood. Without antioxidants, erythroid colony numbers were higher in 5% oxygen than in air, while colony formation could be improved even in 5% oxygen by the addition of antioxidants. In dose-response curves of each drug, the maximum increase in colony number was achieved with 0.1 microM 2ME, 10 microM reduced glutathione (GSH), 1 U/mL catalase (CAT), and 1 U/mL superoxide dismutase (SOD). Erythroid colony growth in air and in 5% oxygen was identical with 10 microM GSH and higher than in any other conditions, including with combinations of GSH and any other antioxidant. For human erythroid progenitor cell cultures, 10 microM GSH appears to be more appropriate than the usual 100 microM 2ME. Antioxidants are necessary, however, even in low oxygen tension. The mechanism of the GSH action is incompletely understood.
Adult↗
Dyskeratosis congenita.
Dyskeratosis congenita is a rare genodermatosis. Malignant deterioration and hematologic complications are well-described features of this syndrome. Correct recognition is essential for proper management. A review of diagnostic considerations and treatment guidelines is presented.
Adolescent↗
Biology of erythropoiesis.
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Antigens, Surface↗
Delta beta-thalassemia in an African-American: identification of the deletion endpoints and PCR-based diagnosis.
We describe an African-American child with beta-thalassemia intermedia. Molecular studies revealed that the proband is a compound heterozygote for the -29 (A-->G) beta (+)-thalassemia mutation and an extensive deletion involving the delta- and beta-globin genes. The proband's mother is a simple carrier of the deletion and exhibits the phenotype of delta beta-thalassemia rather than hereditary persistence of fetal hemoglobin. The deletion spans 11,767 bp, with the 5' deletion endpoint located 2,455 bp upstream of the delta-globin gene mRNA Cap site and the 3' endpoint located 441 bp downstream of the termination codon of the beta-globin gene. Based on this information, we have developed a polymerase chain reaction strategy for the rapid detection of this delta beta-thalassemia deletion.
Adult↗
Stem cell factor amplifies newborn and sickle erythropoiesis in liquid cultures.
A two-phase liquid-culture system was used to substantially amplify and differentiate erythroblasts, starting with mononuclear cells from the blood of normal adults, newborn infants, and patients with sickle cell anemia. After the first 7 days (phase 1), in medium plus fetal bovine serum (FBS) alone, or in combination with stem cell factor (SCF) or conditioned medium (CM), the cell number was unchanged, and the cells all looked like lymphocytes. These cells were then diluted into medium with erythropoietin (Ep) alone, with Ep and either SCF or CM, or in methylcellulose with the same factors (phase 2). After 14 days in liquid phase 2 with SCF and Ep, the cell numbers increased an average of 30-fold in the sickle, 24-fold in the newborn, and 4-fold in the normal adult cultures; almost all the cells were erythroblasts and erythrocytes. SCF in phase 1 increased the number of late progenitors (CFU-E) assayed in methylcellulose, with the largest number in sickle, followed by newborn cultures and then adult cultures. We conclude that erythroid progenitor cells survive for at least 7 days without Ep (but with FBS). Progenitor cells are amplified, particularly with SCF. Later in culture, SCF with Ep increases the final number of differentiated erythroid cells. Both the early and the late effects of SCF are most effective in sickle, followed by newborn cultures and then adult cultures.
Adult↗
Successful treatment of Diamond-Blackfan anemia with interleukin 3.
This report describes the response of 18 Diamond-Blackfan anemia (DBA) patients to recombinant human interleukin 3 (rhIL-3). rhIL-3 was administered s.c. once daily on an escalating dose schedule (0.5-10 micrograms/kg/day). The rhIL-3 dose was escalated every 21 days until erythroid response was attained, grade III or IV nonhematologic toxicity was observed, or the maximal rhIL-3 dose was reached. Four patients experienced clinically significant erythroid responses. Two of the responders were steroid-dependent and transfusion-independent, while two were steroid-independent and transfusion-dependent. Baseline clinical or laboratory parameters, in particular in vitro bone marrow erythroid progenitor assays, were not useful in predicting rhIL-3 response. Two of the responding patients remain on maintenance rhIL-3 without diminution of effect at 490 and 855+ days. rhIL-3 was discontinued in the other two responders because of the development of deep venous thrombi.
Animals↗
Lack of effect of corticosteroids in W/Wv and S1/S1d mice: these strains are not a model for steroid-responsive Diamond-Blackfan anemia.
W/Wv and S1/S1d mice with macrocytic anemias are a potential model for human inherited pure red cell anemia, called Diamond-Blackfan anemia (DBA). The W mutation involves the gene for c-kit, and the S1 mutation the gene for the kit ligand, called mast cell growth factor, steel factor, or stem cell factor. Since many children with DBA respond to treatment with corticosteroids, we administered steroids to these genetically anemic mice, to determine whether they might provide a model for the human disease. There was no improvement in the murine anemia, consistent with other evidence suggesting that mutations in kit or steel may not be involved in Diamond-Blackfan anemia.
Adrenal Cortex Hormones↗
Effects of treatment with 5-azacytidine on the in vivo and in vitro hematopoiesis in patients with myelodysplastic syndromes.
The myelodysplastic syndrome (MDS) comprises a group of clonal hematopoietic disorders derived from an abnormality affecting a multipotent hematopoietic stem cell. Despite trials testing numerous agents in patients with MDS, no single drug has yet emerged as the accepted standard of treatment. Observation and supportive care with blood products and antibiotics, when necessary, continue to be the mainstays of therapy. We administered 5-azacytidine, a cell-cycle specific ring analog of the pyrimidine nucleoside cytosine, as a continuous intravenous infusion, 75 mg/m2 per day for 7 days every 4 weeks. Patients had refractory anemia with excess blasts (RAEB) or refractory anemia with excess blasts in transformation (RAEB-T). Responses were seen in 21 (49%) of 43 evaluable patients: five (12%) in complete remission (CR, complete normalization of bone marrow and peripheral blood counts); 11 (25%) in partial remission (PR, > or = 50% restoration of the deficit from normal of all three peripheral blood cell lines, elimination of transfusion requirements, and a decrease in percentage bone marrow blasts by > or = 50% from prestudy values); five (12%) improved (> or = 50% restoration in the deficit from normal of one or more peripheral blood cell lines and/or a > or = 50% decrease in transfusion requirements). A trilineage improvement (CR and PR) occurred in 37% of the patients. The median survival for all patients was 13.3 months and the median duration of remission for those with CR and PR was 14.7 months. Mild to moderate nausea and/or vomiting was the most common side effect (63%). Myelosuppression, either bone marrow hypoplasia or drug related cytopenias requiring a reduction in the dose of azacitidine, occurred in only 33% of the patients. Prior to treatment, bone marrow erythroid progenitor cells were assayed in vitro. Colonies derived from erythroid burst-forming units (BFU-e) were undetectable in one patient and reduced in two. The number of colonies derived from erythroid colony-forming units (CFU-e)) were also reduced in two of the three patients. In the two patients with detectable colony growth prior to treatment, colony number decreased by day 8 of the first cycle, followed by a subsequent increase. Continued treatment with azacitidine led to normalization of the number of CFU-e derived colonies as well as an increase in the number of BFU-e derived colonies. This improvement in erythroid colony number correlated with the spontaneous rise in hemoglobin levels and red cell transfusion independence.(ABSTRACT TRUNCATED AT 400 WORDS)
Aged↗
Effect of stem cell factor on in vitro erythropoiesis in patients with 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.
Adolescent↗
The SCF and c-kit genes in Diamond-Blackfan anemia.
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Blotting, Southern↗
Leukemia and preleukemia in Fanconi's anemia.
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Adolescent↗
Arm anomalies and bone marrow failure may go hand in hand.
Children with congenital anomalies involving the hand, the forearm, or both are often seen by hand surgeons. An unknown proportion have inherited bone marrow-failure syndromes, such as Fanconi's anemia, Diamond-Blackfan anemia, thrombocytopenia-absent radii, and others. In many cases the hematologic cytopenias are not yet apparent at the time of surgery. This review discusses these syndromes, summarizing the types of malformation, the types of hematologic complication, and the ages at which they occur. There are often clues in otherwise normal hematologic data, such as macrocytic red cells or slow decreases in blood counts that are still at a level at which surgery can be performed. Early and often presymptomatic diagnosis is of value for the planning of staged surgery before cytopenias preclude intervention, the performance of surgery after hematologic improvements, and genetic counseling for young families in which syndromes with a known inheritance pattern might be detected in utero. Hand surgeons may be the first to make these important diagnoses.
Adolescent↗
Erythropoiesis is distinct at each stage of ontogeny.
In vitro erythropoiesis from fetuses, newborn infants, and adults was compared in methyl cellulose cultures. Fetal and newborn blood erythroid colony formation tended to be more sensitive to erythropoietin than adult. The day of maximal colony formation was earlier in fetal than in newborn or adult cultures. The number of colonies/100,000 mononuclear cells on d 13 of culture and on the day of peak growth was highest in fetal, intermediate in newborn, and lowest in adult cultures. Burst forming units-erythroid/mL of blood on culture d 13 and the day of peak growth were similar in fetuses and newborns, and both were significantly greater than in adults. The proportional synthesis of gamma-globin in fetal colonies was 2-fold greater than in newborn colonies, and 6-fold greater than in adult colonies. Thus, fetal, newborn, and adult erythroid progenitor cultures are each unique with regard to erythropoietin sensitivity, growth time course, number of erythroid colonies, and the proportion of gamma-globin synthesis.
Adult↗
Sickle and thalassemic erythroid progenitor cells are different from normal.
Blood erythroid progenitors (BFU-E) from patients with sickle and thalassemic syndromes were compared with those from normal individuals. The day of maximal colony formation in methyl cellulose was slightly later in the cultures from the patients with hemoglobinopathies than in the normal cultures. The number of colonies/100,000 mononuclear cells was similar in all cultures on day 13, but was higher in the hemoglobinopathy cultures on the day of maximal growth. The number of BFU-E/mL of blood was significantly higher than normal at all times in both sickle cell anemia and thalassemia. The proportional synthesis of gamma globin was twice normal in all sickle cultures, and 4 times normal in those from beta+-thalassemia. Hemin and interleukin-3 increased the numbers of erythroid colonies in all cultures, but did not consistently alter the globin synthesis patterns. Each progenitor population has a unique pattern in terms of time course, number of BFU-E, and level of gamma globin synthesis. These features indicate distinct types of BFU-E, or differences in accessory cells, or both, which distinguish blood-borne erythropoiesis in normals and those with hemoglobinopathies.
Adolescent↗
Dyskeratosis congenita: clinical and genetic heterogeneity. Report of a new case and review of the literature.
Dyskeratosis congenita (DC) is a rare form of ectodermal dysplasia consisting of dystrophic nails, hyperpigmentation, and leukoplakia often associated with aplastic anemia. DC is considered to be an X-linked recessive trait, but affected females suggest genetic heterogeneity. We report an additional female with DC and review the world literature, indicating transmission in X-linked recessive, autosomal recessive, and autosomal dominant manners. The clinical and genetic aspects of DC are heterogeneous, and different patterns of inheritance are associated with distinct clinical manifestations. DC should be considered in the diagnosis of a patient with any features of the syndrome regardless of gender. Conversely, DC should be considered in patients with aplastic anemia at any age.
Adolescent↗
Fanconi's anemia. Current concepts.
Fanconi's anemia is an autosomal recessive disorder with a high incidence (greater than 90%) of aplastic anemia and a premalignant component with a greater than 10% risk of leukemia or solid tumors. The diagnosis of Fanconi's anemia depends on increased chromosomal breakage in lymphocytes following treatment with a DNA cross-linking agent; patients have been identified who are clinically well and whose physical appearance is normal. Although bone marrow or cord blood transplants can be curative, treatment for the aplastic anemia usually depends on androgens. Close to 20 patients with Fanconi's anemia have delivered normal babies, and the mothers' hematologic status was not significantly adversely affected by the pregnancy. A few patients have clonal cytogenetic abnormalities in their bone marrow that do not necessarily indicate leukemic transformation, but further follow-up is important. Studies of in vitro erythropoiesis indicate a correlation between the clinical hematologic status and the presence of erythroid progenitors in the blood or bone marrow. Certain hematopoietic growth factors do increase growth in vitro, suggesting that new types of therapy may become available. Not every patient has a poor prognosis. There are now many adults with Fanconi's anemia, some with families of their own.
Adolescent↗