Alternative titles; symbols
SNOMEDCT: 26409005; ORPHA: 85, 98870; DO: 0111399;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q23 | Anemia, congenital dyserythropoietic, type IIIA | 105600 | Autosomal dominant | 3 | KIF23 | 605064 |
A number sign (#) is used with this entry because of evidence that congenital dyserythropoietic anemia type IIIa (CDAN3A) is caused by heterozygous mutation in the KIF23 gene (605064) on chromosome 15q23.
Congenital dyserythropoietic anemia type IIIa (CDAN3A) is a rare autosomal dominant hematologic disorder characterized by nonprogressive mild to moderate hemolytic anemia, macrocytosis in the peripheral blood, intravascular hemolysis, and giant multinucleated erythroblasts in the bone marrow. The disorder results from ineffective erythropoiesis. Laboratory studies show evidence of intravascular hemolysis, including increased thymidine kinase, lactate dehydrogenase, and/or undetectable haptoglobin (summary by Lind et al., 1995; Liljeholm et al., 2013).
For a discussion of genetic heterogeneity of congenital dyserythropoietic anemia, see 224120.
In an American mother and all 3 of her children, Wolff and von Hofe (1951) described mild anemia, macrocytosis in the peripheral blood, and giant multinuclear erythroblasts in the bone marrow. They termed the disorder 'familial erythroid multinuclearity.'
Bergstrom and Jacobsson (1962) reported 15 cases in a family from the Vasterbotten area of northern Sweden. They called the disorder 'hereditary benign erythroreticulosis.' An autosomal dominant pattern of inheritance was observed.
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. Liljeholm et al. (2013) stated that the patient reported by Goudsmit et al. (1972) may have a had a different condition because the pattern of inheritance was most consistent with an autosomal recessive disorder.
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.
Mendez et al. (2021) reported a 19-year-old Cuban man (patient 6a) who was diagnosed with Gilbert syndrome due to hyperbilirubinemia at age 14 years. At age 17, he was hospitalized with a hemolytic crisis associated with a febrile illness. Features included mild macrocytic anemia, splenomegaly, and severe erythroid hyperplasia, anisocytosis, and poikilocytosis in a blood smear. Bone marrow aspirate showed large multinucleated erythroblasts; karyorrhexis and basophilic stippling were also observed. Electron microscopy showed irregular distribution of euchromatin and heterochromatin in red cells. He did not require blood transfusion. His mother (patient 6B) was clinically asymptomatic, but had splenomegaly and had undergone cholecystectomy. Her peripheral blood smear showed some abnormalities.
The transmission pattern of CDAN3A in the large Swedish family reported by Bergstrom and Jacobsson (1962) was consistent with autosomal dominant inheritance.
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 chromosome 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.
In 39 affected members of a Swedish family (Bergstrom and Jacobsson, 1962) and in 4 affected members of an American family (Wolff and von Hofe, 1951) with CDAN3A, Liljeholm et al. (2013) identified a heterozygous missense mutation in the KIF23 gene (P916R; 605064.0001).The mutation, which was found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in both families. It was not present in 356 Swedish controls or in the dbSNP database. In vitro functional expression assays showed that the P916R mutant was unable to rescue failed cytokinesis in KIF23-null HeLa cells. Erythrocytes appeared to be most affected by this variant, which explained the presence of multinucleated erythroblasts in the bone marrow.
In a 19-year-old Cuban man (patient 6a) with CDAN3A, Mendez et al. (2021) identified a heterozygous frameshift mutation in the KIF23 gene, predicted to result in abnormal elongation of the protein (605064.0002). The mutation, which was found by targeted sequencing of a gene panel and confirmed, was inherited from the mildly affected mother (patient 6b) who was clinically asymptomatic. The mutation was not present in the dbSNP or gnomAD database. The authors noted that the mutation would eliminate the second nuclear localization signal and thereby interfere with nuclear distribution of the KIF23 protein essential for cytokinesis. Immunofluorescence studies of cells transfected with the mutation showed diffuse cytoplasmic KIF23 staining or intense KIF23 staining around the nucleus, whereas cells transfected with wildtype showed KIF23 staining as intense dots within the nucleus.
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.
Bergstrom, I., Jacobsson, L. Hereditary benign erythroreticulosis. Blood 19: 296-303, 1962. [PubMed: 13867810]
Bjorksten, B., Holmgren, G., Roos, G., Stenling, R. Congenital dyserythropoietic anaemia type III: an electron microscopic study. Brit. J. Haemat. 38: 37-42, 1978. [PubMed: 638061] [Full Text: https://doi.org/10.1111/j.1365-2141.1978.tb07106.x]
Clauvel, J. P., Cosson, A., Breton-Gorius, J., Flandrin, G., Faille, A., Bonnet-Gajdos, M., Turpin, F., Bernard, J. Dyserythropoiese congenitale: etude de 6 observations. Nouv. Rev. Franc. Hemat. 12: 635-672, 1972.
Goudsmit, R., Beckers, D., De Bruijne, J. I., Engelfriet, C. P., James, J., Morselt, A. F. W., Reynierse, T. Congenital dyserythropoietic anaemia, type III. Brit. J. Haemat. 23: 97-105, 1972. [PubMed: 5045964] [Full Text: https://doi.org/10.1111/j.1365-2141.1972.tb03463.x]
Holmgren, G. Personal Communication. Umea, Sweden 1/15/1985.
Koskinen, P. J., Kurkipaa, M., Airaksinen, K. Massive heterotopia of bone marrow simulating mediastinal tumour. Ann. Med. Int. Fenn. 51: 145-149, 1962. [PubMed: 14458656]
Liljeholm, M., Irvine, A. F., Vikberg, A.-L., Norberg, A., Month, S., Sandstrom, H., Wahlin, A., Mishima, M., Golovleva, I. Congenital dyserythropoietic anemia type III (CDA III) is caused by a mutation in kinesin family member, KIF23. Blood 121: 4791-4799, 2013. [PubMed: 23570799] [Full Text: https://doi.org/10.1182/blood-2012-10-461392]
Lind, L., Sandstrom, H., Wahlin, A., Eriksson, M., Nilsson-Sojka, B., Sikstrom, C., Holmgren, G. Localization of the gene for congenital dyserythropoietic anemia type III, CDAN3, to chromosome 15q21-q25. Hum. Molec. Genet. 4: 109-112, 1995. [PubMed: 7711721] [Full Text: https://doi.org/10.1093/hmg/4.1.109]
Lind, L., Sikstrom, C., Sandstrom, H., Wahlin, A., Eriksson, M., Nilsson, B., Holmgren, G. The locus for congenital dyserythropoietic anemia type III (CDA III), associated with monoclonal gammopathy and myeloma, is localized on chromosome 15q21. (Abstract) Am. J. Hum. Genet. 53 (suppl.): A1035 only, 1993.
Mendez, M., Moreno-Carralero, M. I., Peri, V. L., Camacho-Galan, R., Bosch-Benitez, J. M., Huerta-Aragones, J., Sanchez-Calero-Guilate, J., Moreno-Risco, M. B., Alonso-Dominguez, J. M., Moran-Jimenez, M. J. Congenital dyserythropoietic anemia types Ib, II, and III: novel variants in the CDIN1 gene and functional study of a novel variant in the KIF23 gene. Ann. Hemat. 100: 353-364, 2021. [PubMed: 33159567] [Full Text: https://doi.org/10.1007/s00277-020-04319-5]
Ohisalo, J. J., Viitala, J., Lintula, R., Ruutu, T. A new congenital dyserythropoietic anaemia. Brit. J. Haemat. 68: 111-114, 1988. [PubMed: 3345287] [Full Text: https://doi.org/10.1111/j.1365-2141.1988.tb04187.x]
Sandstrom, H., Wahlin, A., Eriksson, M., Bergstrom, I., Wickramasinghe, S. N. Intravascular haemolysis and increased prevalence of myeloma and monoclonal gammopathy in congenital dyserythropoietic anaemia, type III. Europ. J. Haemat. 52: 42-46, 1994. [PubMed: 8299769] [Full Text: https://doi.org/10.1111/j.1600-0609.1994.tb01283.x]
Weatherly, T. L., Flannery, E. P., Doyle, W. F., Shohet, S. B., Garratty, G. Congenital dyserythropoietic anemia (CDA) with increased red cell lipids. Am. J. Med. 57: 912-919, 1974. [PubMed: 4432872] [Full Text: https://doi.org/10.1016/0002-9343(74)90169-7]
Wickramasinghe, S. N., Parry, T. E., Williams, C., Bond, A. N., Hughes, M., Crook, S. A new case of congenital dyserythropoietic anaemia, type III: studies of the cell cycle distribution and ultrastructure of erythroblasts and of nucleic acid synthesis in marrow cells. J. Clin. Path. 35: 1103-1109, 1982. [PubMed: 6182166] [Full Text: https://doi.org/10.1136/jcp.35.10.1103]
Wickramasinghe, S. N., Wahlin, A., Anstee, D., Parsons, S. F., Stopps, G., Bergstrom, I., Eriksson, M., Sandstrom, H., Shiels, S. Observations on two members of the Swedish family with congenital dyserythropoietic anaemia, type III. Europ. J. Haemat. 50: 213-221, 1993. [PubMed: 8500603] [Full Text: https://doi.org/10.1111/j.1600-0609.1993.tb01923.x]
Wolff, J. A., von Hofe, F. M. Familial erythroid multinuclearity. Blood 6: 1274-1283, 1951. [PubMed: 14886400]