Chapter 7: Congenital Dyserythropoietic Anemias

• Congenital dyserythropoietic anemias (CDAs) are a heterogeneous group of disorders characterized by anemia, ineffective erythropoiesis with specific morphological 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 phenotype of CDA do not fit into any of these categories.

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 the histone assembly; homozygosity is often associated with consanguinity. In a number of patients, only one or no CDAN1 mutated allele is identified; other causative genes, such as C15ORF41, are 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.

Differential Diagnosis

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

• Megaloblastoid marrow morphology may suggest folic acid or vitamin B₁₂ deficiency (see Chap. 8).

Treatment

• Severe forms may present with hydrops fetalis. In severe cases, intrauterine red cell transfusions have been used (see Chap. 25).

• Red cell transfusions should be used judiciously because of the risk of iron overload.

• In patients with moderate anemia, small volume, regular phlebotomies, or chelating agents may be beneficial for iron overload (see Chap. 9).

• Some patients with CDA I have responded to α-interferon with improved anemia and decreased iron overload.

• Type II CDA is also known by its acronym HEMPAS for Hereditary Erythroblastic Multinuclearity associated with a Positive Acidified Serum test.

Clinical and Laboratory Features

• Autosomal recessive inheritance is due to mutations in SEC23B gene, which encodes a component of the coat protein complex II (COPII), responsible for the biogenesis of endoplasmic reticulum-derived vesicles—a component of the cis-Golgi.

• Anemia varies from mild to severe.

• Moderate-to-marked anisocytosis, poikilocytosis, anisochromia, and contracted spherocytes are present in peripheral blood. Gaucher-like cells and ring sideroblasts may be found in the marrow (Table 7–1). The more than 10% of mature bi- and multinucleated red cell precursors is a morphologic hallmark (Figure 7–1).

• Iron stores are increased and symptomatic iron overload may occur even in those not transfused.

Treatment

• Red cell transfusions may be necessary. Iron chelation should be instituted when the ferritin level exceeds 500 to 1000 μg/L.

• Partial benefit may be at times seen with splenectomy.

• Marrow transplantation has been used in few patients and should be considered early before iron overload develops (see Chap. 39).

Clinical and Laboratory Features

• Autosomal dominant inheritance is due to mutations in KIF23 gene, encoding mitotic kinesin-like protein 1, which is critical for cytokinesis.

• Most patients are asymptomatic with mild to moderate anemia, mild jaundice, and, commonly, cholelithiasis.

• Some macrocytes may be extremely large (“gigantocytes”), and poikilocytes are present. The marrow has marked erythroid hyperplasia, with large multinucleate erythroblasts with big lobulated nuclei, and giant multinucleate erythroblasts (Table 7–1).

Treatment

• Generally, none is needed. One symptomatic patient benefited from splenectomy.

Several rare types of congenital dyserythropoietic anemia do not conform to types I to III and are described in Table 7–2.