Anemia, Congenital Dyserythropoietic, Type Ia

A number sign (#) is used with this entry because congenital dyserythropoietic anemia type Ia (CDAN1A) is caused by homozygous or compound heterozygous mutation in the gene encoding codanin-1 (CDAN1; 607465) on chromosome 15q15.

Description

CDA type I is a rare inherited red blood cell disorder characterized by macrocytic anemia, ineffective erythropoiesis, and secondary hemochromatosis. It is occasionally associated with bone abnormalities, especially of the hands and feet (acrodysostosis), nail hypoplasia, and scoliosis (Tamary et al., 2005). Striking morphologic abnormalities of erythroblasts, reviewed by Wickramasinghe and Wood (2005), include the 'Swiss-cheese' abnormality of erythroblasts on electron microscopy.

Four types of CDA, all of which show show ineffective erythropoiesis and multinuclear erythroblasts, have been characterized by clinical and hematopoietic findings. The classification of the first 3 types is based on that described by Wendt and Heimpel (1967). Type I is characterized by megaloblastic changes. The more common type II (224100) is characterized by normocytic binuclear or multinuclear red cells, which on electron microscopy contain double cytoplasmic membranes. Type III (105600), which shows autosomal dominant inheritance, has prominent erythroblastic multinuclearity forming 'gigantoblasts' with up to 12 nuclei. Type IV (613673) is the designation given to a form of CDA with characteristics different from those of types I, II, and III (Wickramasinghe et al., 1991; Arnaud et al., 2010).

Genetic Heterogeneity of Congenital Dyserythropoietic Anemia

CDAN1B (615631) is caused by mutation in the C15ORF41 gene (615626) on chromosome 15q14; CDAN2 (224100) is caused by mutation in the SEC23B gene (610512) on chromosome 20p11; CDAN3 (105600) maps to chromosome 15q21; and CDAN4 (613673) is caused by mutation in the KLF1 gene (600599) on chromosome 19p13.

For a possible additional form of CDA type I, see 603529.

Clinical Features

Wendt and Heimpel (1967) described dizygotic twins with a macrocytic form of dyserythropoietic anemia in which the bone marrow contained megaloblastoid erythroblasts with characteristic chromatin bridges between the nuclei.

Benjamin et al. (1975) described a single patient with a form of dyserythropoietic anemia that did not satisfy any of the known criteria. Her red cells had normoblastic multinuclearity and normocytosis but lacked the ultrastructural and serologic features of type II.

Heimpel (1976) counted 21 reported cases of CDA I, the rarest type. These included 3 pairs of sibs.

Lay et al. (1978) reported 2 brothers with neonatal jaundice, requiring transfusion at 8 weeks of age but subsequently remaining well, with only mild anemia.

Kuribayashi et al. (1979) reported affected brother and sister with first-cousin parents.

Mori et al. (1986) reported the sixth family with more than 1 affected sib.

Facon et al. (1990) reported affected identical twins; both children had mild hemochromatosis. Moderate growth retardation appeared to be related to pituitary failure.

Carter et al. (1989) and Williams et al. (1990) reported cases of congenital erythropoietic anemia presenting as hydrops fetalis. The patient reported by Carter et al. (1989) was the product of first-cousin parents.

Al-Fawaz and Al-Mashhadani (1995) described the cases of a brother and sister with CDA I. The girl presented in the neonatal period with anemia, jaundice, and hepatosplenomegaly and required 4 blood transfusions in the first 7 months of life, while her brother was discovered to be anemic and jaundiced only at the age of 2 years and did not receive any blood transfusions. The children were reported from Saudi Arabia; the parents were first cousins. The authors referred to a previous report of 3 cases from Kuwait (Zaki et al., 1989).

Tamary et al. (1996) described CDA I among Israeli Bedouins. In affected persons, the erythroid precursors demonstrated S phase arrest and ultrastructural morphologic features consistent with apoptosis.

Shalev et al. (2000) reported 3 sibs from a Bedouin family with CDA I who presented with persistent pulmonary hypertension of the newborn. They suggested that the diagnosis of CDA I should be considered in any neonate with persistent pulmonary hypertension and anemia.

Parez et al. (2000) described a patient with severe pre- and postnatal manifestations of CDA I. Exchange transfusions were required for fetal anemia at 28 and 30 weeks' gestation. Transfusions were administered at birth by cesarean section at week 35 and at regular intervals thereafter. Successful treatment with alpha-interferon was initiated at 14 months.

Tamary et al. (2005) reported 6 French patients, 1 European American patient, and 1 Israeli Arab patient. Four of the 8 patients had neonatal manifestations, 3 had complex bone disease, and 2 had both. Three patients had only mild anemia and hyperferritinemia. The bony abnormalities were described as acrodysostosis with vertebral anomalies.

Heimpel et al. (2006) followed 21 patients from 19 families with CDA I for up to 37 years. All patients exhibited chronic macrocytic anemia of variable severity, requiring regular red cell transfusions in only 2 individuals. Additional congenital malformations were seen in 7 patients, involving a sixth toe and syndactyly in 3 patients and a ventricular septal defect, short stature, double kidneys, and hip dysplasia in 1 each. Gallstones developed in 4 patients before the age of 30 years, and iron overloading was found in 20 of 21 patients. Splenectomy, which was performed in 7 patients, did not result in improvement of hemoglobin parameters. Five patients were treated with interferon alpha-2a (see 147562), and all responded with a rise in hemoglobin concentration of 2.5 to 3.5 g/dL.

Pathogenesis

Many patients with CDA I develop iron overload, even if transfusion-independent. Among 17 CDA I patients, Tamary et al. (2008) found significantly increased levels of the cytokine GDF15 (605312) compared to controls. GDF15 suppresses hepcidin (606464), a regulator of iron homeostasis. Increased GDF15 was associated with ineffective hematopoiesis and iron-loading complications.

Mapping

Tamary et al. (1996) concluded that the gene for CDA I is located on 15q15.1-q15.3. The locus for CDA III had been mapped to approximately the same region, 15q21, and the locus for CDA II to 20q11.2. Tamary et al. (1996) employed homozygosity linkage mapping to localize the genetic defect responsible for CDA type I in 4 large consanguineous Israeli Bedouin families with 24 affected patients. They reported linkage to markers on 15q15.1-q15.3; 3 markers yielded maximum lod scores ranging from 5.025 to 6.585 with values of theta ranging from 0.02 to 0.06. Informative crossover events identified by haplotype analysis narrowed the area containing the CDA I gene to approximately 5 cM within the region stated. They suggested that the site where the CDA III gene had been mapped was approximately 20 cM telomeric to the locus for CDA I. In the full report, Tamary et al. (1998) reported studies in 25 Bedouins from the 4 large consanguineous families. A founder haplotype was identified. Identification of historical crossover events further narrowed the gene location to between D15S779 and D15S778. The data suggested localization of the CDA I gene within a 0.5-cM interval. The founder mutation probably occurred at least 400 years earlier. The only known erythroid-specific gene mapped to this region was that for erythrocyte surface protein band 4.2 (EPB42; 177070). Sequence analysis of the coding region of the EPB42 gene revealed no mutations in the CDA I patients.

Molecular Genetics

Dgany et al. (2002) identified CDAN1, the gene responsible for CDA I, through the identification of 12 different mutations in 9 families with the disorder (e.g., 607465.0001).

In 15 of 16 CDA I patients analyzed, Heimpel et al. (2006) identified 17 different mutations in at least 1 allele of the CDAN1 gene. All but 1 of the mutations were located in exons 12 to 28; 1 mutation was found in exon 6.

Population Genetics

The R1042W mutation in the CDAN1 gene (607465.0001) is a founder mutation in the Bedouin population (Tamary et al., 2008).