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Chapter 7: Congenital Dyserythropoietic Anemias

INTRODUCTION

  • Congenital dyserythropoietic anemias (CDAs) are a heterogeneous group of disorders characterized by anemia, ineffective erythropoiesis with specific morphologic alterations of erythroid precursors in the marrow, and iron overload.

  • Although rare, uncovering the molecular basis of CDA has helped unravel novel aspects of the cell biology of erythropoiesis.

  • Three classical types of CDA have been distinguished. However, some patients with the phenotype of CDA do not fit into any of these categories.

CDA TYPE I

Clinical and Laboratory Features

  • The condition presents in infancy or adolescence.

  • Autosomal recessive inheritance is caused by mutations in the CDAN1 gene, encoding codanin-1, a cell cycle–regulated protein involved in histone assembly; homozygosity is often associated with consanguinity. In a number of patients, only one or no CDAN1-mutated allele is identified. Another causative gene is CDIN1 (CDAN1-interacting nuclease 1), originally named C15ORF41; other causative genes are also suspected.

  • Moderately severe macrocytic anemia (approximately 9.0 g/dL) occurs.

  • Hepatomegaly and cholelithiasis are common.

  • Splenomegaly increases with age.

  • Specific morphologic findings of CDA type I are summarized in Table 7–1 and exemplified in Figure 7–1.

  • Dysmorphic skeletal features may be present, typically affecting hands and feet. Less common are small stature, almond-shaped blue eyes, hypertelorism, and micrognathia.

TABLE 7–1CLASSIFICATION OF CONGENITAL DYSERYTHROPOIETIC ANEMIA (CDA) CLASSICAL FORMS
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TABLE 7–1 CLASSIFICATION OF CONGENITAL DYSERYTHROPOIETIC ANEMIA (CDA) CLASSICAL FORMS
Disease Abbreviation Gene and Inheritance Main Clinical Features Bone Marrow Morphologic Features
CDA I

CDAN1–CDIN1

Autosomal recessive

 Severe or moderate anemia, generally macrocytic, with relative reticulocytopenia; congenital anomalies: skeletal abnormalities, chest deformity, and short stature Erythroid hyperplasia with binucleate late erythroblasts (2%–10%); internuclear chromatin bridges between the nuclei pairs of intermediate erythroblasts (1%–8%); “Swiss cheese” appearance of the heterochromatin of the erythroblasts at electron microscopy
CDA II

SEC23B

Autosomal recessive

 Normocytic anemia of variable degrees, with normal or slightly increased reticulocyte counts; jaundice and splenomegaly Erythroid hyperplasia with binucleate cells (>10%) with two nuclei at the same erythroid maturation stage. Under electron microscopy, the mature erythroblasts show a discontinuous double membrane
CDA III

KIF23

Autosomal dominant

 Absent or moderate normocytic anemia, slight relative reticulocytopenia, jaundice, hemolysis; visual disturbances, with macular degeneration, angioid streaks, and monoclonal gammopathy Erythroid hyperplasia with characteristic giant multinucleate erythroblasts. Under electron microscopy, clefts within heterochromatin, autophagic vacuoles, iron-laden mitochondria, and myelin figures in the cytoplasm of the erythroblasts
FIGURE 7–1

Light microscopy of marrow. A. Congenital dyserythropoietic anemia type I. The internuclear unusually long chromatin bridge is marked by an arrow. B. Congenital dyserythropoietic anemia type II. The two arrows point to binucleate erythroblasts, characteristic of this type. (Reproduced with permission from Dr. Odile Fenneteau.)

Two photomicrographs of stained marrow sections show characteristic findings of congenital dyserythropoietic anemias.
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Differential Diagnosis

  • The condition may be confused with the thalassemias (see Chap. 15...

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