Chapter 7: Congenital Dyserythropoietic Anemias

• 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.

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.

Differential Diagnosis

• May be confused with the thalassemia syndromes because of similar blood findings and evidence of ineffective erythropoiesis.

• Megaloblastoid marrow findings may suggest folic acid or vitamin B₁₂ deficiency.

Treatment

• Severe forms may present with hydrops fetalis. In some cases, intrauterine red cell transfusions are warranted by the severity of the anemia.

• Red cell transfusions for long-term therapy should be avoided whenever possible because of the risk of iron overload.

• In compensated moderate anemia, small volume, regular phlebotomies, if tolerable, or chelating agents may be beneficial for 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, due to mutations in SEC23B, the gene encoding a protein component of the coat protein complex II (COPII). COPII is responsible for the biogenesis of endoplasmic reticulum-derived vesicles destined for the cis-Golgi compartment. These protein complexes are thought to be the primary determinants underlying deformation of membranes into vesicles.

• Anemia varies from mild to severe.

• Moderate-to-marked anisocytosis and poikilocytosis, anisochromia, and contracted spherocytes are present in the blood film. Gaucher-like cells and ring sideroblasts may be present in the marrow (Table 7–1). Multinuclearity of red cell precursors is a morphologic hallmark (Fig. 7–1).

• Body iron stores are increased and frank hemochromatosis may occur even in the absence of transfusions.

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 obtained with splenectomy.

• Marrow transplantation has been used in few patients.

Clinical and Laboratory Features

• Autosomal dominant inheritance due to an as yet unidentified mutation that maps to chromosome 15q22-25.

• 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.