Chapter 39: The Congenital Dyserythropoietic Anemias

SUMMARY

The congenital dyserythropoietic anemias (CDAs) are a heterogeneous group of rare disorders characterized by anemia, the presence of erythroid hyperplasia with multinuclear erythroid precursors in the marrow, ineffective erythropoiesis and secondary iron overload.^* Only the erythroid series shows significant abnormalities, with rare exceptions. Patients have been classified as types I, II, and III, but several patients appearing with these general characteristics do not fit into any of the three groups. CDA types I and II are inherited as autosomal recessive disorders, and type III disease is inherited as an autosomal dominant disorder. Type I disease is caused by mutations of the CDAN1 gene. Codanin-1, the gene product, is a cell-cycle-regulated protein of currently unknown function. In codanin-negative cases, C15ORF41 mutations can cause type I CDA. Type II CDA is also known as hereditary erythroblastic multinuclearity with a positive acidified serum test, or by its acronym HEMPAS. The vast majority of CDA type II cases are caused by mutations of the SEC23B gene. This gene encodes the cytoplasmic COPII (coat protein) component SEC23B, which is involved in the secretory pathway of eukaryotic cells. CDA type III disease is rarer than the other two forms and its erythroid production failure is accompanied by a tendency for the development of retinal angioid streaks and of myeloma in the long term. It is caused by KIF23 mutations, a gene encoding mitotic kinesin-like protein 1, which plays a critical role in cytokinesis. There is no specific treatment for these disorders. Management includes red cell transfusion, removal of excess body iron by chelation therapy or judicious phlebotomy, splenectomy, and allogeneic hematopoietic stem cell transplantation. Only in severe forms of type I CDA does interferon-α decrease transfusion needs.

Acronyms and Abbreviations:

AE1, band 3 anion transport protein; Arf6, adenosine diphosphate (ADP)-ribosylation factor 6; Asf1a, a protein that is a member of the H3/H4 family of histone chaperones; C15ORF41, gene encoding a protein with two predicted helix-turn-helix domains of unknown function; CDA, congenital dyserythropoietic anemia; CDAN1 gene, 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, hematopoietic transcription factor; GDF15, growth differentiation factor 15; HEMPAS, hereditary erythroblastic multinuclearity associated with a positive acidified serum test; HJV, hemojuvelin gene; HLA, human leukocyte antigens; HS, hereditary spherocytosis; KIF23, mitotic kinesin-like protein 1; LPIN2 (18p11.31), encoding lipin 2; KLF1, a hematopoietic transcription factor; MCV, mean cell volume; MKD, mevalonate kinase deficiency; MKLP1, gene encoding mitotic kinesin-like protein 1; SAR1B, a gene encoding a small guanosine triphosphatase (GTPase) protein; SDS-PAGE, sodium dodecylsulfate polyacrylamide gel electrophoresis; UGT1A1, bilirubin uridine diphosphate (UDP)-glucuronosyltransferase 1A1 gene.