Congenital dyserythropoietic anemia type I (ORPHA:98869)
Congenital dyserythropoietic anemiatype I (CDA I) is a hematologic disorder of erythropoiesis characterized by moderate to severe macrocytic anemia occasionally associated with limb or nail deformities and scoliosis.
Epidemiology
The prevalence is unknown. Over a 42 year period (from 1967-2009), 122 CDA I cases were reported in Europe.
Clinical description
CDA I usually presents in the first decade of life. Manifestations include a moderate macrocytic anemia associated with intermittent jaundice, frequent splenomegaly and occasional hepatomegaly. Approximately 1/3 of CDA I patients may also have congenital malformations of the limbs (supernummary toes, hand or feet syndactyly, absence of nails) or heart (ventricular septal defect), double kidneys, short stature or hip dysplasia. Later, cholelithiasis or gallstones may occur. The main complication is iron overload which can lead to organ damage.
Etiology
CDA I etiology is not fully understood, but most cases have been associated with mutations in the CDAN1 gene (15q15.2), coding for a histone chaperone interacting protein. Mutations in a predicted endonulease protein encoded by the C15ORF41 gene (15q14) have recently been described in three CDAN1 mutation-negative patients, making it a second causative gene of CDA I. Since some cases of CDA I have no known mutations in either of these two genes, a third locus may exist.
Diagnostic methods
Laboratory findings, characterization of erythrocytes and bone marrow (BM) observation are diagnostic. Hemoglobin and haptoglobin are low, bilirubin and ferritin are high, blood smear shows anisopoikilocytosis and basophilic stippled erythrocytes. BM aspirate or trephine biopsy reveals erythroid hyperplasia (erythropoietic to granulopoietic cells ratio of 3 to 8), megablastoid aberrations of chromatin structure, large polyploidy cells with irregular nuclear shape, some bi-, tri- or tetra-nucleated polychromatic erythroblasts and internuclear chromatin bridges in 1-8% of all erythroblasts. Electon microscopy shows spongy heterochromatin with a ''Swiss cheese'' appearance.
Differential diagnosis
The diagnosis of CDA 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; see this term), acquired dyserythropoiesis (myelodysplastic disorders) and hemolytic anemias. Gilbert syndrome (see this term) 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 I. It is inherited in an autosomal recessive manner.
Management and treatment
Treatment focuses on hemoglobin normalization with the administration of interferon (IFN) alpha for patients with CDAN1 mutations. The 3 cases reported with mutations in the C15ORF41 gene were unresponsive to IFN-alpha treatment. Serum ferritin must be thoroughly controlled to monitor iron overload and induce iron depletion when needed. Splenectomy is not recommended and individual decisions have to be made in cases with transfusion dependency and enlarged spleen. Transfusion may be necessary in some cases. In-utero transfusions are required for severe cases of fetal anemia. Cholecystectomy is often indicated. Successful allogenic bone marrow transplantation has been described in a few individuals and should be considered only in those transfusion-dependent persons who are resistant to IFN therapy.
Prognosis
Prognosis is usually good even if life expectancy is slightly reduced. Morbidity may be important due to iron overload complications that can be fatal if untreated.

                            Last update: 
                            September 2013


                            - Expert reviewer(s): 
                            Dr Mayka SÁNCHEZ FERNÁNDEZ