Blackfan-Diamond anemia (DBA) is a rare inherited syndrome with isolated anemia and erythroblastopenia as the main features. Clinically it manifests itself in the first months of life with macrocytic anemia, reticulocytopenia, increased Hb F and elevated erythrocyte adenosine deaminase levels; occasional patients have thrombocythemia. The bone marrow is normocellular with characteristic absence of erythro-blasts (<5% of nucleated cells). Growth retardation and other developmental abnormalities (including skeletal, cardiac and urogenital defects) are seen in about a third of patients. There is also a small risk (~2%) of transformation to MDS/AML.
Molecular genetics and pathogenesis. Most cases of DBA are sporadic but in multiplex families both autosomal dominant and autosomal recessive patterns of inheritance have been observed. There is a considerable degree of penetrance and phenotypic variability even in the same families.
In about 25% of cases, mutations in the ribosomal protein S19 gene (RPS19) have been identified in familial as well as in sporadic cases. The patients are heterozygous for these mutations, which would be expected to reduce the level of protein by about 50%, in keeping with haploinsufficiency. It is unclear at the moment how haploinsufficiency of RPS19 is implicated in the molecular pathogenesis of DBA, and particularly why it should have a selective effect on erythropoiesis. It is noteworthy that mutations of ribosomal proteins in Drosophila mela-nogaster lead to the so-called Minute phenotype, comprising delayed larval development, small size, and reduced viability and fertility. Interestingly, haploinsufficiency of some ribo-somal proteins may be associated with additional phenotypic features; for example, mutated RPS6 leads to hypertrophy of lymphohemopoietic organs. It is possible, therefore, that haploinsufficiency of the ribosomal function of RPS19 accounts for the somatic developmental defects, whereas an as-yet unidentified extraribosomal function accounts for the defect in erythropoiesis. Recent evidence suggests that RPS19 expression decreases during normal erythroid maturation, implying a role of RPS19 in early erythropoiesis. In another study, overexpression of RPS19 in CD34+ cells from DBA patients improved the erythroid clonogenic activity but did not restore it to normal.
Blood transfusion for moderate to severe anemia is the mainstay of treatment for DBA. Over 50% of patients respond to steroids and become independent of blood transfusion. Some sustain remission after steroid withdrawal but most either become steroid-resistant or require an unacceptably high maintenance dose. Such patients may benefit from a sibling allogeneic HSCT. The median long-term survival in a small series from the North American DBA registry was 87%; by contrast, the survival of patients receiving HSCT from an alternative donor was only 14%.
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