Diamond-Blackfan anemia: a congenital defect in erythropoiesis

Diamond-Blackfan anemia (DBA) is a congenital pure red blood cell aplasia diagnosed in the first year of life. Familiarity is apparent in 10% of patients, with all other cases being sporadic. Physical abnormalities are present in at least one third of patients, pointing to a defect in early embryo development. The main clinical sign is profound isolated anemia, with normal numbers and functioning of the other hemopoietic cells. Reticulocyte counts are very low. Bone marrow reflects defective erythropoiesis, showing a very low number of erythropoietic precursors and a reduction of BFU-E progenitor cells. Proliferation and differentiation of the other lineages are normal. The very high erythropoietin (EPO) levels are usually not proportionate to the level of anemia and reflect relative EPO insensitivity, which is also apparent in vitro. Conversely, erythroid progenitors from DBA patients also show a defective or incomplete response to other erythropoietic growth factors, such as IL-3 or IL-6. A significant response has been observed in vitro to stem cell factor in many, but not all patients. Many patients respond clinically to corticosteroids and some develop hematologic remissions, both after corticosteroids and spontaneously. Patients who do not respond to corticosteroids and those who have to discontinue treatment because of side effects must rely on chronic transfusion and are thus exposed to all its complications. Bone marrow transplantation has been performed in some individuals, usually with a successful outcome. This suggests a normal marrow microenvironment and rules out the hypothesis of defective stromal cell function. The variable clinical and biological patterns may be the expression of multiple etiologies or represent variable expressivity of a single genetic defect. Only identification of the responsible gene(s) will solve this question. Growth factors exerting an effect on erythropoiesis (and relative receptors) or transacting proteins which regulate their expression are likely candidates in the hunt for a causal gene.