The hereditary dyserythropoietic anemias also known as congenital dyserythropoietic anemias (CDAs) are a group of hereditary disorders characterized by (1) anemia caused by ineffective erythropoiesis, (2) erythroid hyperplasia with increased percentage of bi/multinucleated erythroid precursors in the marrow, and often (3) hemochromatosis resulting from increased absorption of iron. The CDAs are classically divided into three types (CDA I, II, and III). CDA I is an autosomal recessive disease resulting from mutations in either CDAN1 or CDIN1 and is characterized by a “Swiss cheese” appearance of heterochromatin and internuclear chromatin bridges. CDA II, also an autosomal recessive disease, is the most common CDA type and results from mutations in SEC23B. CDA II is characterized by a double-membrane appearance of the red blood cell (RBC) plasma membrane, faster mobility of the RBC membrane protein band 3 by sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE), and lysis of erythrocytes in a subset of acidified human sera, hence its prior designation as hereditary erythroblastic multinuclearity with a positive acidified serum test (commonly known as HEMPAS). CDA III is an autosomal dominant disease resulting from mutations in KIF23. CDA III is characterized by giant multinucleated erythroblasts and increased risk of development of angioid streaks and myeloma. Additional CDA variants resulting from mutations in KLF1, GATA1, ALAS2, LPIN2, CAD, COX4I2, and MVK have been reported. The CDA disease severity is highly variable, ranging from hydrops fetalis to minimal or no anemia. Treatment is largely individualized and depends on the severity of the disease and the specific clinical manifestation. Although allogeneic stem cell transplantation is the only curative modality, it can be justified in only a small subset of patients because of risks associated with the procedure. Other treatment modalities include RBC transfusion support, iron chelation, splenectomy, and interferon-α (for CDA I patients only).
Acronyms and Abbreviations:
AE1, band 3 anion transport protein; ALAS2, gene encoding 5′-aminolevulinate synthase 2; Arf6 and Asf1b, protein paralogs that are members adenosine diphosphate (ADP)-ribosylation factor 6; Asf1a, a protein that is a member of the H3/H4 family of histone chaperones; ASCT, allogeneic stem cell transplantation; C15ORF41, gene encoding a protein with two predicted helix-turn-helix domains of unknown function; CAD, gene encoding a trifunctional enzyme (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase); CDA, congenital dyserythropoietic anemia; CDAN1, gene encoding codanin-1; COP, cytoplasmic coat protein; COX4I2, gene encoding cytochrome c oxidase subunit IV isoform; E2F1, transcription factor 1; ER, endoplasmic reticulum; G6PD, glucose-6-phosphate dehydrogenase; GATA1, transcription factor 1 binding to the DNA sequence GATA; GDF15, growth differentiation factor 15; FLAG-tag, a polypeptide protein tag that can be added to a protein to which specific, high affinity monoclonal antibodies have been developed; HEMPAS, hereditary erythroblastic multinuclearity associated with a positive acidified serum test; HJV, hemojuvelin gene; HLA, human leukocyte antigen; HP1α, heterochromatin protein 1; HS, hereditary spherocytosis; IgM, immunoglobulin M; KIF23, mitotic kinesin-like protein 1; KLF1, a hematopoietic transcription factor; ...