Congenital dyserythropoietic anemia type III (ORPHA:98870)
A rare form of congenital dyserythropoietic anemia (CDA) characterized by dyserythropoiesis, with big multinucleated erythroblasts in the bone marrow, and manifesting with mild to moderate anemia.
Epidemiology
The prevalence is unknown. Three families have been reported with autosomal dominant CDA III in Sweden, America and Argentina. Four families have been described for the autosomal recessive CDA IIIb form with Spanish or latinoamerican origin. Other sporadic CDA III-like cases have been described. In total, more than 60 cases have been reported worldwide.
Clinical description
The clinical presentation is variable. CDA III can manifest with mild anaemia 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. The autosomal dominant (AD) CDA IIIa form was associated with monoclonal gammopathies, multiple myeloma and retinal angioid streaks, which can lead to visual impairment. The autosomal recessive CDA IIIb form was associated with macrocytic anaemia with marked dyserythropoiesis, erythroid hyperplasia, giant multinucleated erythroblasts, hepatospenomegaly and skull defects secondary to increased extramedullary hematopoiesis. Other sporadic cases of CDA III have been associated with severe erythroid hyperplasia, skeletal disorders, intellectual deficit, and hepatosplenomegaly.
Etiology
Mutations in KIF23 gene (15q23) has been identified as the causal mutation for AD CDA IIIa. Recently, mutations in the RACGAP1 gene (12q13) were reported as the cause for the autosomal recessive form of CDAIII (named CDAIIIb). KIF23 encodes mitotic kinesin-like protein (MKLP1), which dimerizes and combines with a homodimer of the RACGAP1 protein (Rac GTPase-activating protein 1), to form the centralspindlin complex, crucial for cytokinesis.
Diagnostic methods
Diagnosis is based on laboratory findings. The disorder is characterized by mild anaemia, 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 or the RACGAP1 gene can also determine a diagnosis of CDA III, type a or b, respectively.
Differential diagnosis
The diagnosis of CDA IIIa/CDAIIIb should be considered following exclusion of other causes of macrocytosis (B12 deficiency, folic acid deficiency or other megaloblastic anemias such as pernicious anemia or thiamine-responsive megaloblastic anemia syndrome), acquired dyserythropoiesis (myelodysplastic syndrome, acute erythroid leukemia), hemolytic anemias (hereditary spherocytosis) or microcytic anemias (thalassemias and iron deficiency anemias). Gilbert syndrome and infections should be also excluded.
Antenatal diagnosis
Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutations in the family.
Genetic counseling
Genetic counseling is possible in CDA IIIa and CDA IIIb. CDA IIIa is inherited in an autosomal dominant mode (50% risk of having an affected child at each pregnancy), while CDA IIIb is inherited in an autosomal recessive mode (25% risk of having an affected child at each pregnancy).
Management and treatment
In most cases anaemia is mild and treatment is not necessary. Only during times of extreme anaemia (often due to pregnancy or surgery), may a transfusion be needed. Ophthalmological follow-up is recommended in those with eye manifestations in CDA IIIa cases. In some cases, splenectomy could be necessary to manage with splenomegaly. Iron overload was reported in one CDAIIIb patient that was regularly treated with blood transfusions. Chelation treatment is recommended for managing iron overload.
Prognosis
In most cases the prognosis is good and there is no decrease in life expectancy. Quality of life may be affected in those with visual impairment or with iron overload complications.

                            Last update: 
                            July 2023


                            - Expert reviewer(s): 
                            Dr Mayka SÁNCHEZ FERNÁNDEZ