Chapter 7: Congenital Dyserythropoietic Anemias

INTRODUCTION

Congenital dyserythropoietic anemias (CDA) are a heterogeneous group of disorders characterized by anemia, the presence of multinuclear erythroid precursors in the marrow, ineffective erythropoiesis, and iron overload.
Although rare, uncovering the molecular basis of CDA has helped unravel novel aspects of the cell biology of erythropoiesis.
Three types of CDA have been distinguished. In addition, a number of patients with forms of congenital dyserythropoietic anemia that do not fit these categories have been described.

CDA TYPE I

Clinical and Laboratory Features

Presents in infancy or adolescence.
Autosomal recessive inheritance, caused by mutations of the CDAN1 gene (codanin-1), encoding a cell-cycle-regulated protein of yet unknown function; homozygosity is often associated with consanguinity. In a number of patients, only one CDAN1 allele is identified with a mutation; other causative genes suspected because in rare CDA I families, no mutations of the CDAN1 gene found.
Moderately severe macrocytic anemia (approximately 9.0 g/dL).
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 Fig. 7–1.
Dysmorphologic features may be present, the most common involve the bones of the hand and the foot. Other, less common features are small stature, almond-shaped blue eyes, hypertelorism (increased distance between two body parts or organs), and micrognathism.

TABLE 7–1MAIN FEATURES OF TYPES I, II, AND III CONGENITAL DYSERYTHROPOIETIC ANEMIAS

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TABLE 7–1 MAIN FEATURES OF TYPES I, II, AND III CONGENITAL DYSERYTHROPOIETIC ANEMIAS

CDA Type

Light Microscopy

Electron Microscopy

Serology

Inheritance

Most erythroid cells abnormal: double nuclei, internuclear chromatin bridges (Fig. 7–1)

Widened nuclear pores, spongy appearance of the heterochromatin, invasion by the cytoplasm containing various organelles

No serologic abnormalities

Autosomal recessive

Mature stage erythroblasts with two or more nuclei, lobulated nuclei, karyorrhexis, pseudo-Gaucher cells (Fig. 7–1)

Endoplasmic reticulum cisternae lining the inner surface of the red cell plasma membrane

Cells containing the HEMPAS antigen are lysed by 30% of acidified normal sera; strong reactivity with anti-"i" autoantibodies

Autosomal recessive

III

Giant erythroblasts, up to 50 μm in diameter, with up to 12 nuclei, basophilic stippling

Clefts and blebs within nuclear areas, some iron-filled mitochondria, autophagic vacuoles and myelin figures in the cytoplasm

No clearly defined abnormalities

Autosomal dominant (not all cases)

Source: Williams Hematology, 8th ed, Chap. 39, Table 39–1, p. 514.

FIGURE 7–1

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

(Source: Williams Hematology, 8th ed, Chap. 39, Fig. 39–2, p. 515.)