Congenital Dyserythropoietic Anemias
Congenital Dyserytropoietic anemias (CDA) are a heterogeneous group of inherited hematopoiesis disorders presenting with defective production of red blood cells, characterized by refractory anemia of varying severity.
They have been characterized in several ways CDA: type I, II, III and IV. Shared symptoms include anemia of variable intensity, intermittent jaundice, hepatosplenomegaly, and progressive iron overload, the latter is more evident in the types I and II.
The CDA type I and II are transmitted with autosomal recessive inheritance pattern according to the latest estimates, the impact will not exceed 1:100,000 births a year.
CDA type 1 is caused by mutations in the CDAN1 gene (Dgany O, et al Am J Hum Genet. Dec 2002, 71 (6) :1467-74) (OMIM # 224120) This gene encodes for a protein believed to be involved in the maintaining the integrity of the nuclear envelope. CDA Type I is characterized by moderate to severe anemia which is generally diagnosed in childhood or adolescence, although in some cases can be detected before birth. Iron overload can cause an abnormal heart rhythm (arrhythmia), congestive heart failure, diabetes, and chronic liver disease (cirrhosis).
It has recently been reported that mutations in the SEC23B gene are causing CDA type II (Schwarz K et al., Nat Genet. 2009) (OMIM # 224100). CDA II is characterized by the presence of binucleate erythroblasts (diploeritroblastos) with double membranes from the endoplasmic reticulum, which can be visualized by electron microscopy. Patients with type II CDA present a positive serum acidification test (Ham test).
Congenital dyserythropoietic anemia type 3 (CDA III) is a rare form of CDA characterized by nonprogressive mild to moderate hemolytic anemia, dyserythropoiesis, with big multinucleated erythroblasts in the bone marrow, and macrocytosis in the peripheral blood.
The prevalence is unknown. Three families have been reported with autosomal dominant CDA III in Sweden, America and Argentina. Other sporadic CDA III-like cases have been described. In total, about 60 cases have been reported worldwide.
The clinical presentation is variable. CDA III can manifest with mild anemia and jaundice in neonates but it may not be discovered until childhood or adulthood. Intensity of symptoms increases during infections, following trauma, and during pregnancy. It can also be associated with monoclonal gammopathies, multiple myeloma and retinal angioid streaks. Recently, the KIF23 gene has been identified as the causal mutation for autosomal dominant CDAIII. This gene encodes mitotic kinesin-like protein 1 (MKLP1) which is crucial for cytokinesis (Liljeholm M, et al. Blood 2013;121:4791-4799).
Diagnosis is based on laboratory findings. The disorder is characterized by mild anemia, macrocytosis in the peripheral blood, and giant multinucleated erythroblasts (containing up to 12 nuclei) in the bone marrow. Increased levels of serum thymidine kinase, lactate dehydrogenase and bilirubin and very low or undetectable haptoglobin are also characteristic of this disease. Mutations in the KIF23 gene can also determine a diagnosis of CDA III.