Congenital dyserythropoietic anemia (ORPHA:85)
Congenital dyserythropoietic anemia (CDA) is a heterogenous group of hematological disorders of late erythropoiesis and red cell abnormalities that lead to anemia. Five types of CDA are defined: CDA I, CDA II, CDA III, CDA IV and thrombocytopenia with CDA (see these terms).
Epidemiology
A global CDA prevalence figure is not precisely known. Over a 42 year period (1967-2009), 122 CDA I and 367 CDA II cases were reported in Europe. About 60 cases of CDA III have been reported worldwide as well as 4 cases of CDA IV to date. Three families have been reported to have thrombocytopenia with CDA.
Clinical description
Onset of CDA generally occurs in childhood or early adulthood, even if clinical signs can occasionally be observed in the neonatal period. Patients share chronic anemia of variable severity and jaundice, frequently associated with splenomegaly and/or hepatomegaly. Symptoms of anemia include fatigue, failure to thrive in infants, headache, dizziness, leg cramps, tachycardia and insomnia. Erythropoiesis is always dysfunctional, as revealed by cellular anomalies and erythroid hyperplasia. CDA I patients have a moderate macrocytic anemia with frequent splenomegaly and occasional hepatomegaly. Jaundice is intermittent and approximately 1/3 of patients have congenital malformations, mostly involving the limbs, but also the heart, kidneys or hip. The main complication is iron overload which can lead to organ damage. In CDA II, the most frequent type, anemia and/or jaundice is usually detected in children or young adults with splenomegaly. Liver iron overload and gallstones are frequent. CDA III is a very rare subtype characterized by mild hemolytic anemia and a predisposition to retinal angioid streaks, gammopathies and myeloma. CDA IV is characterized by the presence of a very large number of nucleated erythrocytes in the peripheral blood. Thrombocytopenia with CDA is characterized by dysmorphic erythrocytes and paucity of the platelets.
Etiology
Etiology of CDA is not fully defined. CDA I is due to mutations in the CDAN1 gene (15q15.2), coding for a histone chaperone interacting protein, or in the C15ORF41 gene (15q14), coding for a predicted endonuclease putatively involved in DNA replication and/or chromatin assembly. Since some cases of CDA I have no known mutations in any of these two genes, a third locus may exist. Most cases of CDA II are caused by mutations in the SEC23B gene (20p11.23), coding for a coating protein involved in reticulum-Golgi trafficking. CDA III is due to mutations in the KIF23 gene (15q23), encoding a conserved mitotic kinesin (MKLP1) crucial for cytokinesis. The last 2 CDA types are caused by mutations in the erythroid transcription factor genes KLF1 (19p13.2) and GATA1 (Xp11.23).
Genetic counseling
CDA I and CDA II are inherited autosomal recessively while CDA III and CDA IV are inherited autosomal dominantly. Thrombocytopenia with CDA has an X-linked inheritance pattern. Genetic counseling is possible for all types of CDA with a known mutation.

                            Last update: 
                            September 2013


                            - Expert reviewer(s): 
                            Dr Mayka SÁNCHEZ FERNÁNDEZ