[Diagnosis and genetics of congenital dyserythropoietic anemias (CDA)]

The congenital dyserythropoietic anemias (CDA) are hereditary diseases characterized by a lifelong, mostly moderate anemia. CDA can be diagnosed already in early childhood. However, diagnosis is complicated due to poor knowledge of morphological criteria and the large number of differential diagnoses that have to be excluded. CDA type I is characterized by macrocytic anemia with megaloblastic changes in erythropoiesis and chromatin bridges between isolated erythroblasts. Type II shows a normocytic anemia with a positive acidified serum test and increased agglutination with anti-i. Erythroblasts can present with 2 or more nuclei. CDA type III presents with a macrocytic anemia and erythroblasts with up to 12 nuclei, the so called gigantoblasts. Some patients lack the typical morphological abnormalities of type I-III (variants or type IV). Besides light microscopic abnormalities, CDA type-specific changes in electron microscopy are described. The clinical picture of the patients vary between the different forms: signs of hemolysis and ineffective erythropoiesis such 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 described. Supportive care such as iron chelation can be necessary in some patients. The CDA are inherited in an autosomal recessive manner; in type III an additional autosomal dominant variant exists. Recently, the determination of gene 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 genetically heterogenic. Until now no gene has been identified in either type of CDA. In CDA type II, a glycosylation defect of erythrocyte membrane proteins is present. An international group plans to do further research. Therefore, identification and registration of patients in a registry is necessary. Patients' data and material would enable gene characterization. The results would allow an extended classification according to genotype and prediction of the course of the disease. Additionally, information on the regulation and control of normal and abnormal erythropoiesis could be obtained.