Anemia, Congenital Dyserythropoietic, Type Iv

A number sign (#) is used with this entry because congenital dyserythropoietic anemia type IV (CDAN4) is caused by heterozygous mutation in the KLF1 gene (600599), which encodes a transcriptional activator, on chromosome 19p13.

Description

Congenital dyserythropoietic anemia type IV is an autosomal dominant inherited red blood cell disorder characterized by ineffective erythropoiesis and hemolysis resulting in anemia. Circulating erythroblasts and erythroblasts in the bone marrow show various morphologic abnormalities. Affected individuals with CDAN4 also have increased levels of fetal hemoglobin (summary by Arnaud et al., 2010).

For a discussion of genetic heterogeneity of congenital dyserythropoietic anemia, see CDAN1 (224120).

Clinical Features

Wickramasinghe et al. (1991) described an 8-year-old Danish girl who was severely anemic and hydropic at birth due to a novel form of congenital dyserythropoietic anemia. She had a moderate normochromic anemia, increased levels of fetal hemoglobin (HbF) at 50%, increased reticulocyte count, and hyperbilirubinemia. Bone marrow smear showed intense normoblastic erythroid hyperplasia with morphologic evidence of dyserythropoiesis; the most common dysplastic features were basophilic stippling of polychromatic erythroblasts and erythrocytes, and marked abnormalities of nuclear shape in polychromatic erythroblasts. Electron microscopic studies showed that some polychromatic erythroblasts and several erythrocytes contained inclusions which were rounded, elongated, or irregular. There appeared to be a prolongation of, or an arrest at, the polychromatic erythroblast phase. Further studies of this patient showed that she had persistent embryonic and fetal hemoglobin (Tang et al., 1993), and absent red cell expression of CD44 (107269) (Parsons et al., 1994). The patient also had a unique blood group phenotype: In(a-b-), Co(a-b-). Agre et al. (1994) showed that the red cells from this patient contained less than 10% of the normal level of AQP1 (107776) and had remarkably low osmotic water permeability, but no mutation was identified in the AQP1 gene. The characteristics of CDA in this patient were different from those of the 3 other types of CDA. The CD44 and AQP1 deficiencies were not thought to represent primary defects.

Arnaud et al. (2010) reported an infant boy, born at 28 weeks' gestation due to acute fetal distress, with congenital dyserythropoietic anemia. Hydrops fetalis-associated anemia had been detected at 23 weeks' gestation and treated with 2 intrauterine transfusions. At birth, he had severe hyperbilirubinemia, hepatomegaly, hypertrophic cardiomyopathy, and several dysmorphic features, including micropenis, hypospadias, large anterior fontanel, and hypertelorism. He required transfusions every 2 to 3 weeks until age 4 years when splenectomy was performed. He became transfusion independent after splenectomy and showed short stature at age 13 years. Bone marrow smear showed marked hyperplasia of the erythroid lineage, leading to a diagnosis of CDA, but the dysplastic changes in the erythroblasts did not clearly fit any established classification. Peripheral blood smear showed very large numbers of nucleated red blood cells, suggesting a failure of enucleation and a defect in terminal erythroid differentiation. Electron microscopy showed various ultrastructural abnormalities, including atypical cytoplasmic inclusions and enlarged nuclear pores. Flow cytometry showed a combined deficiency of CD44 and AQP1 expression limited to erythrocytes. Isoelectric focusing showed large amounts of fetal hemoglobin, indicating a dysregulation of globin gene expression (see, e.g., HBB, 141900 and HBG1, 142200).

Molecular Genetics

In 2 unrelated patients with congenital dyserythropoietic anemia type IV, one of whom was the patient reported by Wickramasinghe et al. (1991), Arnaud et al. (2010) identified a heterozygous de novo mutation in the KLF1 gene (E325K; 600599.0006). The mutant protein showed markedly decreased transcriptional activity toward CD44 and AQP1 compared to wildtype, consistent with the clinical findings. The mutant KLF1 protein also showed a dominant-negative effect. The findings indicated that the KLF1 gene plays a critical role in the regulation of several genes during erythropoiesis, and that dysregulation of certain gene targets can result in dyserythropoiesis.