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CHAPTER 39 SEC23B, which is involved in the secretory pathway of eukaryotic cells. CDA

THE CONGENITAL 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
DYSERYTHROPOIETIC 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
ANEMIAS 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
Achille Iolascon * transfusion needs.

SUMMARY
DEFINITION AND HISTORY
The congenital dyserythropoietic anemias (CDAs) are a heterogeneous group The term congenital dyserythropoietic anemia (CDA), coined by Heimpel
of rare disorders characterized by anemia, the presence of erythroid hyper- and Wendt, applies to a group of rare hereditary refractory anemias
1
plasia with multinuclear erythroid precursors in the marrow, ineffective characterized by ineffective erythropoiesis, erythroid hyperplasia,
erythropoiesis and secondary iron overload. Only the erythroid series shows abnormal morphology of erythroid precursors, and secondary accumu-
significant abnormalities, with rare exceptions. Patients have been classi- lation of tissue iron.
fied as types I, II, and III, but several patients appearing with these general Dyserythropoiesis is a result of derangement of the multistep pro-
characteristics do not fit into any of the three groups. CDA types I and II are cess of normal erythroid maturation caused by a maturation arrest at
inherited as autosomal recessive disorders, and type III disease is inherited as early and late polychromatic erythroblasts and a consequent reduction
an autosomal dominant disorder. Type I disease is caused by mutations of the of daily red cell production (Fig. 39–1A). Depending on the degree of
CDAN1 gene. Codanin-1, the gene product, is a cell-cycle-regulated protein of the cellular defect, variable degrees of anemia can result.
Dyserythropoiesis can be considered a subtype of marrow failure
currently unknown function. In codanin-negative cases, C15ORF41 mutations syndromes characterized by monolineage involvement and abnor-
can cause type I CDA. Type II CDA is also known as hereditary erythroblastic malities in erythroid precursor cells (see Fig. 39–1B). Microscopic
multinuclearity with a positive acidified serum test, or by its acronym HEMPAS. morphologic characterization defines the heterogeneity of these syn-
The vast majority of CDA type II cases are caused by mutations of the SEC23B dromes (Fig. 39–2). Indeed, the appearance of abnormal morphology
gene. This gene encodes the cytoplasmic COPII (coat protein) component of erythroid progenitors can be from other hereditary defects (such
as thalassemias) and acquired causes (rapid regeneration of marrow,
myelodysplasia, etc.), but these are usually readily apparent from the
history, blood examination, and laboratory tests in the former and
multilineage involvement and the absence of prevalent multinuclear-
Acronyms and Abbreviations: AE1, band 3 anion transport protein; Arf6, ity in the latter. Furthermore, the term congenital could be confusing,
adenosine diphosphate (ADP)-ribosylation factor 6; Asf1a, a protein that is a as the clinical appearance of hereditary dyserythropoietic anemias can
be present during different ages. In addition, it is an archaic residual
member of the H3/H4 family of histone chaperones; C15ORF41, gene encod- of older nomenclature and should be replaced by “hereditary” as it
ing a protein with two predicted helix-turn-helix domains of unknown func- has been in diseases such as congenital spherocytosis (now hereditary
tion; CDA, congenital dyserythropoietic anemia; CDAN1 gene, codanin-1; COP, spherocytosis).
cytoplasmic coat protein; COX4I2, gene encoding cytochrome c oxidase sub- Anemia is usually first noted in infancy or childhood. The life
unit IV isoform; E2F1, transcription factor 1; ER, endoplasmic reticulum; G6PD, span of circulating erythrocytes is moderately reduced, and the dom-
glucose-6-phosphate dehydrogenase; GATA1, hematopoietic transcription inant factor in pathogenesis is a large component of ineffective ery-
factor; GDF15, growth differentiation factor 15; HEMPAS, hereditary erythrob- thropoiesis (intramedullary cell death as a result of precursor cell
lastic multinuclearity associated with a positive acidified serum test; HJV, apoptosis) resulting in anemia of variable severity, normal or slightly
hemojuvelin gene; HLA, human leukocyte antigens; HS, hereditary spherocy- elevated reticulocytes, moderate increase in indirect bilirubin, low
tosis; KIF23, mitotic kinesin-like protein 1; LPIN2 (18p11.31), encoding lipin haptoglobin, and, typically, a gradual increase in ferritin levels. Sple-
2; KLF1, a hematopoietic transcription factor; MCV, mean cell volume; MKD, nomegaly is common. Congenital dyserythropoietic anemias have
been classified into three types—types I, II, and III. In addition, a
mevalonate kinase deficiency; MKLP1, gene encoding mitotic kinesin-like pro- number of cases that do not fit clearly into any of these three catego-
tein 1; SAR1B, a gene encoding a small guanosine triphosphatase (GTPase) ries have been described. 2
protein; SDS-PAGE, sodium dodecylsulfate polyacrylamide gel electropho-
resis; UGT1A1, bilirubin uridine diphosphate (UDP)-glucuronosyltransferase
1A1 gene. EPIDEMIOLOGY
The prevalence of CDAs is likely higher than reported as a result of their
clinical heterogeneity and diagnostic difficulties, as demonstrated by the
* Dr. Jean Delaunay wrote this chapter in the 8th edition of this text- fact that the correct diagnosis is often delayed into adulthood.
book. Some of the material from the 8th edition has been retained. Dr. Merging of information from European registries suggests that
Roberta Russo collaborated in the preparation of this manuscript. the prevalence of CDA I and CDA II in Europe is approximately

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