Anemia, Congenital Dyserythropoietic, Type Iii

Description

Congenital dyserythropoietic anemia type III is a rare disorder characterized by nonprogressive mild to moderate hemolytic anemia, macrocytosis in the peripheral blood, and giant multinucleated erythroblasts in the bone marrow (Lind et al., 1995).

For a discussion of genetic heterogeneity of congenital dyserythropoietic anemia, see 224120.

Clinical Features

In a mother and all 3 of her children, Wolff and Van Hofe (1951) described mild anemia, macrocytosis in the peripheral blood, and giant multinuclear erythroblasts in the bone marrow.

Bergstrom and Jacobsson (1962) reported 15 cases in a family from northern Sweden. They called the disorder hereditary benign erythroreticulosis.

Weatherly et al. (1974) described a form of congenital dyserythropoietic anemia in a Filipino mother and 2 of her daughters. There were no serologic abnormalities and the proband's red cells showed a lipid abnormality not previously described in CDA.

Bjorksten et al. (1978) stated that, including the reports of Clauvel et al. (1972) and Goudsmit et al. (1972), only 23 cases of CDA III in 4 families had been reported.

Wickramasinghe et al. (1982) reported an asymptomatic 19-year-old man from the British Isles with CDA III.

Some electron-microscopic differences from CDA I (224120) were reported by Bjorksten et al. (1978), who studied a mother and daughter from the kindred reported by Bergstrom and Jacobsson (1962). Holmgren (1985) stated that 17 cases had been identified in this family, all living in northern Sweden. In a study of 2 affected members of this family, Wickramasinghe et al. (1993) found unusual features: hemosiderinuria, grossly disorganized erythroblast nuclei, differences in the ultrastructural appearance of individual nuclei within the same multinucleate erythroblast, and intraerythroblastic inclusions resembling precipitated globin chains. In both cases, the giant mononucleate erythroblasts and the multinucleate erythroblasts had total DNA contents up to 28 and 48 times, respectively, the haploid DNA content. They commented that the findings were similar to those that occur in patients with presumed autosomal recessive inheritance of CDA III.

Lind et al. (1993) pointed out that affected members of the Swedish family originally reported by Bergstrom and Jacobsson (1962) displayed mild to moderate anemia, multinuclear erythroblasts, and elevated levels of serum thymidine kinase. Lind et al. (1995) further characterized the disorder in this family with known affected members in 5 generations and by inference in a sixth. They found an unusual concurrence of type III CDA with myeloma or benign monoclonal gammopathy. Among 20 CDA III patients examined (Sandstrom et al., 1994), 1 had multiple myeloma and 3 had monoclonal gammopathy of undetermined significance (MGUS), whereas the healthy relatives did not show any sign of gammopathy. A deceased member of the family had had both CDA III and myeloma, whereas no signs of gammopathy had been recorded among family members not affected by CDA III.

Ohisalo et al. (1988) reported what they suggested was a 'new' type of CDA in father and daughter. The father's case had been described by Koskinen et al. (1962). He became icteric at the age of 10 years and anemia was established at the age of 23. The bone marrow showed highly hyperplastic erythropoiesis, and reticulocyte counts ranged from 4.2 to 28.5%. Constitutional anomalies included dome-shaped head and slightly protruding eyes with high and sharply arched palate. He had hemolysis and died of hemochromatosis at the age of 37 years. Massive heterotopia of bone marrow simulated mediastinal tumor. The daughter had been icteric from the age of 8 months. Cholecystectomy was performed at the age of 13 years. Mild anemia and marked hypercellularity of the bone marrow were found. The concentration of bilirubin was lowered markedly by administration of phenobarbital.

Inheritance

The pedigree pattern in the large Swedish family with CDA reported by Bergstrom and Jacobsson (1962) established autosomal dominant inheritance.

Mapping

Lind et al. (1993) performed linkage studies in the large kindred originally reported by Bergstrom and Jacobsson (1962), which could be traced back to a couple born in northern Sweden in the 19th century. Using microsatellite markers, they found linkage of the disorder to 15q21, between D15S125 and D15S114. The lod scores were 6.0 or greater with both markers. Lind et al. (1995) demonstrated close linkage of the CDAN3 locus to microsatellite markers within an 11-cM interval within 15q21-q25.