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INTRODUCTION

SUMMARY

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 C15ORF41 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, 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).

DEFINITION AND HISTORY

The congenital dyserythropoietic anemias (CDAs) are a group of hereditary disorders characterized by anemia of variable severity resulting from a defect in the later stages of erythroid differentiation (Fig. 40–1A) and distinct morphologic features of the marrow erythroblasts. The abbreviation CDA was used first by Crookston et al1 and by Heimpel and Wendt.2 The CDAs are classically divided into three major types (CDA I to CDA III), although additional variants have also been described (Fig. 40–1B).3 Several marrow features are shared by all of the CDAs, including erythroid hyperplasia and increased percentage of bi-/multinucleated erythroid precursors. However, each CDA type has additional unique characteristics (Fig. 40–2). Except for the GATA1-mutated CDA, the nonerythroid hematopoietic lineages are generally unaffected.

Figure 40–1.

Differential diagnosis of CDAs versus other marrow failure syndromes. A. Erythroid maturation arrest occurs at different stages in various marrow failure syndromes. The CDA marrow is characterized by erythroid hyperplasia because the maturation arrest occurs in the later stages of erythroid development. B. Flow diagram for ...

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