Diagnosis and genetics of the congenital dyserythropoietic anemias (CDA)

The congenital dyserythropoietic anemias (CDA) are hereditary diseases char acterized by a lifelong, mostly moderate anemia. CDA can be diagnosed alrea dy in early childhood. However, diagnosis is complicated due to poor knowle dge of morphological criteria and the large number of differential diagnose s that have to be excluded. CDA type I is characterized by macrocytic anemia with megaloblastic changes in erythropoiesis and chromatin bridges between isolated erythroblasts. Ty pe II shows a normocytic anemia with a positive acidified serum test and in creased agglutination with anti-i. Erythroblasts can present with 2 or more nuclei. CDA type III presents with a macrocytic anemia acid erythroblasts with up to 12 nuclei, the so called gigantoblasts. Some patients lack the t ypical morphological abnormalities of type I-III (variants or type IV). Bes ides light microscopic abnormalities, CDA type-specific changes in electron microscopy are described. The clinical picture of the patients vary betwee n the different forms: signs of hemolysis and ineffective erythropoiesis su ch as icterus, splenomegaly and gall stones can be present. Most important is the tendency of a part of patients to have an increased iron absorption and iron storage. Patients with and without transfusion dependency are desc ribed. Supportive care such as iron chelation can be necessary in some pati ents. The CDA are inherited in an autosomal recessive manner: in type III an addi tional autosomal dominant variant exists. Recently, the determination of ge ne loci for type I, II and III was enabled by linkage analysis on different regions of chromosome 15 and 22. It is considered that CDA I and II are ge netically heterogeneic. Until now no gene has been identified in either typ e of CDA. In CDA type II, a glycosylation defect of erythrocyte membrane pr oteins is present. An international group plans to do further research. Therefore, identificat ion and registration of patients in a registry is necessary. Patients' data and material would enable gene characterization. The results would allow a n extended classification according to genotype and prediction of the cours e of the disease. Additionally, information on the regulation and control o f normal and abnormal erythropoiesis could be obtained.