Sabtu, 05 Oktober 2013

DIAMOND-BLACKFAN ANEMIA



                                                                           
Introduction
Diamond-Blackfan Anemia (DBA) is characterized by anemia (low red blood cell counts) with decreased erythroid progenitors in the bone marrow. This usually develops during the neonatal period. About 47% of affected individuals also have a variety of congenital abnormalities, including craniofacial malformations, thumb or upper limb abnormalities, cardiac defects, urogenital malformations, and cleft palate.1 Low birth weight and generalized growth delay are sometimes observed. DBA patients have a modest risk of developing leukemia and other malignancies.2,3,4
                            
Diamond and Blackfan described congenital hypoplastic anemia in 1938.2 In 1961, Diamond and colleagues presented longitudinal data on 30 patients and noted an association with skeletal abnormalities.5 In 1997 a region on chromosome 19 was determined to carry a gene mutated in DBA.1,6 In 1999, mutations in the ribosomal protein S19 gene (RPS19) were found to be associated with disease in 42 of 172 DBA patients.7 In 2001, it was determined that a second DBA gene lies in a region of chromosome 8 although evidence for further genetic heterogeneity was
uncovered.3

The majority of cases are sporadic, although dominant or recessive patterns of inheritance are indicated by familial occurrence in about 15% of patients.3 The primary defects are in the erythroid progenitor cells, where there is an intrinsic defect that results in increased apoptosis (programmed cell death). High levels of erythropoietin (EPO) are present in serum and urine, although a search for mutations in the EPO receptor gene has been negative. In about 25% of sporadic and inherited cases there are mutations in a gene (DBA1) for a ribosomal protein S19, mapped to chromosome 19q13.3,7 A second gene for DBA has been linked to chromosome 8p, and most likely other genetic abnormalities will be identified. A unifying etiology for this disorder and the significance of these genetic alterations is being defined.8

 Although hematopoiesis is generally adequate in fetal life, some affected infants appear pale in the first days after birth; rarely, hydrops fetalis occurs. Profound anemia usually becomes evident by 2–6 mo of age, occasionally somewhat later. Over 50% of affected children have congenital anomalies, including short stature, craniofacial deformities, or defects of the upper extremities, including triphalangeal thumbs.1,2 The abnormalities are diverse, with no specific pattern emerging in the majority of those affected.2

The RBCs are almost always macrocytic for age, but there is no hypersegmentation of neutrophils or other peripheral blood characteristics of megaloblastic anemia. Folic acid and vitamin B12 levels are normal.2,4 Chemical evaluation of RBCs reveals an enzyme pattern similar to a “fetal” RBC population, and there is also elevated fetal hemoglobin (Hb F) and increased expression of “i” antigen. Erythrocyte adenosine deaminase (ADA) activity is increased in most patients with this disorder, a finding that helps distinguish congenital RBC aplasia from acquired transient erythroblastopenia of childhood.3,7 Also, because elevated ADA activity is not a fetal RBC feature, measurement of this enzyme is helpful in diagnosing DBA in very young infants. Thrombocytosis or thrombocytopenia and occasionally neutropenia may also be present initially. Reticulocytes are characteristically very low despite severe anemia. RBC precursors in the marrow are markedly reduced in most patients, but other marrow elements are usually normal. Serum iron levels are elevated. Bone marrow chromosome studies are normal and, unlike in Fanconi anemia, there is no increase in chromosomal breaks when lymphocytes are stressed with alkylating agents.1,4

Congenital hypoplastic anemia must be differentiated from other anemias with low reticulocyte counts. The anemia of hemolytic disease of the newborn can have a protracted course and, on occasion, be associated with markedly reduced erythropoiesis. This usually terminates spontaneously at 5–8 wk of age. Aplastic anemic crises characterized by reticulocytopenia and by decreased numbers of RBC precursors, frequently caused by parvovirus B19 infections, may complicate various types of chronic hemolytic disease, but usually after the first several months of life.5 Infection with parvovirus B19 in utero may also cause pure RBC aplasia in infancy, even with hydrops fetalis at birth. The absence of parvovirus B19 detected by polymerase chain reaction (PCR) is now considered an essential feature in establishing the diagnosis of Diamond-Blackfan anemia in young infants. The syndrome of transient erythroblastopenia of childhood may be differentiated from Diamond-Blackfan syndrome by its relatively late onset (although it may occasionally develop in infants younger than 6 mo).6 In very young infants whose RBCs have many fetal features, a determination of elevated erythrocyte ADA activity is particularly useful because this increased enzyme activity is not a characteristic of fetal RBCs.1

Corticosteroid therapy is beneficial in three fourths of patients who respond initially.2,4 The mechanism of its effect is unknown. Prednisone in three divided doses totaling 2 mg/kg/24 hr is used as an initial trial. An increase in RBC precursors appears in bone marrow 1–3 wk after therapy is begun, and this is followed by peripheral reticulocytosis. The hemoglobin may reach normal levels in 4–6 wk, although there is much variability in the rate of response. Once the hemoglobin concentration is clearly increasing, the dose of corticosteroid may be reduced gradually by tapering divided doses and then by eliminating all except a single, lowest effective daily dose. This dose should then be doubled, used on alternate days, and tapered still further while maintaining the hemoglobin level at 9 g/dL or above. In some patients, very small amounts of prednisone, as low as 2.5 mg twice a week, may be sufficient to sustain adequate erythropoiesis. Overall, 60% of children with Diamond-Blackfan anemia initially started on steroids stop taking the drug. This occurs because of unacceptable steroid side effects or evolution of steroid refractoriness at acceptable steroid doses, or, occasionally, there is spontaneous remission of anemia.2,6

In patients who do not respond to corticosteroid therapy, transfusions at intervals of 4–8 wk are necessary to sustain normal growth and activities. Chelation therapy for iron overload with deferoxamine administered subcutaneously through a portable pump should be started when excess iron accumulation is reflected by serum ferritin levels exceeding 1,500 mg/dL, but preferably after 5 yr of age, because the medication may interfere with normal growth. An oral iron chelator, deferiprone (L1), is in clinical trials and may be almost as effective as deferoxamine; however, there is some controversy related to possible hepatic toxicity. The drug is licensed for use in Canada, the United Kingdom, and India but not in the United States. Other therapies, including androgens, cyclosporine, cyclophosphamide, antithymocyte globulin (ATG), high-dose intravenous immunoglobulin, high-dose methylprednisolone, EPO, and interleukin-3 have not had a consistent beneficial effect and may have a high incidence of side effects. Splenectomy may decrease the need for transfusion if hypersplenism or isoimmunization develops. Stem cell transplantation from a related histocompatible donor has a role in children who do not respond to corticosteroids and who have demonstrated a several-year need for RBC transfusions. The survival results for matched-related donors have been very encouraging, but the responses have been much inferior with the use of partially mismatched siblings or matched unrelated donors.2

Median survival is probably more than 40 yr of age, although definitive data are lacking. The outlook is best in those who respond to corticosteroid therapy.2 About half of patients are long-term responders. In the others, survival depends on transfusions. Some children in each group may eventually have spontaneous remissions (about 20%), and most of these remissions occur in the first decade. In children who are regularly transfused, total body iron increases and hemosiderosis ensues.5 The liver and spleen may enlarge, and secondary hypersplenism with leukopenia and thrombocytopenia can occur.2,5 The complications of chronic transfusions in DBA are similar to those in β-thalassemia major, and prevention and treatment of iron overload should be equally aggressive in both groups of transfused patients . DBA may be a premalignant syndrome, with acute leukemia (usually myeloid) and myelodysplasia occurring in a small fraction (less than 5%) of patients.2,4 Solid tumor malignancies also have been reported, in particular osteosarcoma. Other significant causes of death include complications associated with stem cell transplantation, steroid therapy (opportunistic infections), and iron overload.2,5

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