Alternative titles; symbols
SNOMEDCT: 68870007; ORPHA: 85, 98873; DO: 0111401;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20p11.23 | Dyserythropoietic anemia, congenital, type II | 224100 | Autosomal recessive | 3 | SEC23B | 610512 |
A number sign (#) is used with this entry because congenital dyserythropoietic anemia type II (CDAN2) is caused by homozygous or compound heterozygous mutation in the SEC23B gene (610512) on chromosome 20p11.
For a general description and a discussion of genetic heterogeneity of CDA, see CDAN1A (224120).
Verwilghen et al. (1969) reported 2 families. De Lozzio et al. (1962) studied an affected woman with 2 affected sisters. The parents could not be examined. They demonstrated endopolyploidy by chromosome studies of bone marrow. The karyotype of skin cells was normal. They pointed out that several instances are known in plants and animals where the mitotic process is influenced by mutant genes. Crookston et al. (1969) observed 5 patients, including 2 sisters, with what appeared to be the same disorder: anemia characterized by multiple nuclei in erythroblasts, ineffective erythropoiesis, and lysis of red cells by acidified serum from some persons.
Enquist et al. (1972) described 3 cases in a sibship of 10. They described the occurrence of Gaucher-like histiocytes in bone marrow, resembling those seen in chronic myelogenous leukemia and thalassemia. They made the important observation that heterozygotes may show some of the serologic abnormalities of HEMPAS without clinical disease. Increased susceptibility to lysis by anti-I antibody (110800) is a feature of HEMPAS. Lowenthal et al. (1980) reported an atypical case in a man who was the product of a first-cousin Anglo-Saxon marriage and whose twin brother was also affected. At age 43 years, the man showed 2 unusual features: severe tophaceous gout and massive splenomegaly. Hematologic peculiarities suggested that the disorder in the twins represented a distinct form of congenital dyserythropoietic anemia.
In a retrospective study of 41 patients with CDA II, Perrotta et al. (2000) found that patients with coinheritance of Gilbert syndrome (143500) had a significantly increased risk of hyperbilirubinemia and gallstone formation and a significantly earlier age at diagnosis of gallstones.
Iolascon et al. (2001) reviewed data on 98 patients from unrelated families enrolled in the International Registry of CDA II. The mean age at presentation was 5.2 +/- 6.1 years. Anemia was present in 66% and jaundice in 53.4% of cases. The mean age at correct diagnosis was 15.9 +/- 11.8 years. In 23% of patients for whom data were available, anemia developed during the neonatal period, and 10 of these individuals required transfusions. Splenectomy produced an increased hemoglobin (P less than 0.001) and a reduced bilirubin level (P = 0.007) in comparison with values before splenectomy. Preliminary data indicated that iron overload occurs irrespective of the hemochromatosis genotype.
Bianchi et al. (2009) reported 13 patients from 10 unrelated families with CDA type II. Eleven patients were Italian, 1 was Bolivian, and 1 was Romanian. The age at diagnosis ranged from 2 to 54 years. Variable but common features included splenomegaly with splenectomy, blood transfusion, cholelithiasis, cholecystectomy, anemia, increased reticulocytes, increased unconjugated bilirubin, increased erythrocyte osmotic fragility, and hypoglycosylation of red blood cells. Only 1 patient had neonatal jaundice.
CDA type II, which is also known as 'hereditary erythroblastic multinuclearity with a positive acidified serum (HEMPAS) test,' is distinguished by a positive acidified serum test and increased red cell lysis on exposure to both anti-i and anti-I antibody (110800) (Wendt and Heimpel, 1967).
Baines et al. (1982) found an electrophoretic abnormality of the preponderant integral membrane protein, band 3--specifically in the extracellular domain of the protein, which is the glycosylated part. The finding correlates with morphologic changes in the cell membrane of the late erythroblast. Fukuda et al. (1984) found that band 3 and band 4.5 of the red cell membrane are not glycosylated by lactosaminoglycans in HEMPAS erythrocytes, whereas normally these proteins have lactosaminoglycans. By analyzing the carbohydrate structure of HEMPAS band 3, Fukuda et al. (1987) demonstrated the point at which glycosylation of lactosaminoglycans stops. They showed further that the enzyme N-acetylglucosaminyltransferase II, which functions at the site of the block, is deficient in patients with HEMPAS and suggested that this is the primary defect. They concluded that, to date, HEMPAS is unique among inborn errors of metabolism in that it is a defect in biosynthesis of a glycoprotein.
Fukuda et al. (1990) studied a new case (G.C.) of HEMPAS which changed their thinking about the nature of the basic defect in the disorder. Enzyme defect in most HEMPAS patients had previously been proposed as a lowered activity of N-acetylglucosaminyltransferase II, resulting in a lack of polylactosamine on proteins and leading to the accumulation of polylactosaminyl lipids. Fukuda et al. (1990) found that G.C. cells showed significantly decreased glycosylation of polylactosaminyl glycan proteins and incompletely processed asparagine-linked oligosaccharides in erythrocyte membranes. In contrast to the earlier studied cases, G.C. cells were normal in N-acetylglucosaminyltransferase II activity but were low in alpha-mannosidase II (alpha-ManII) activity. Northern (RNA) analysis of poly(A)+ mRNA from normal, G.C., and other unrelated HEMPAS cells all showed double bands at the 7.6-kb position, detected by an alpha-ManII cDNA probe, but expression of these bands in G.C. cells was reduced to less than 10% of normal. In Southern analysis of G.C. and normal genomic DNA, the restriction fragment patterns detected by the alpha-ManII cDNA probe were indistinguishable. The results were interpreted as suggesting that G.C. cells contained a mutation in the alpha-ManII-encoding gene that results in inefficient expression of alpha-ManII mRNA, either through reduced transcription or message instability. Thus, the authors concluded that HEMPAS is caused by a defective gene encoding an enzyme necessary for the synthesis of asparagine-linked oligosaccharides.
Misago et al. (1995) demonstrated that the gene encoding Golgi alpha-mannosidase II (MAN2A1; 154582) maps to chromosome 5q21-q22. However, Gasparini et al. (1997) excluded linkage to this and 2 other candidate genes in CDAN type II. They performed a genomewide linkage search in 12 southern Italian families, including 1 consanguineous pedigree. Positive lod scores were obtained with 7 markers on chromosome 20q. A lod score of 4.73 at theta = 0.0 was obtained with D20S863. The HOMOG program demonstrated genetic homogeneity. Linkage disequilibrium studies showed a strong association between 1 allele of D20S863 and the disorder, suggesting that a major mutation arose from a common ancestor. In the full report, Gasparini et al. (1997) stated the cytogenetic location of the CDA II gene to be 20q11.2. A maximum 2-point lod score of 5.4 at a recombination fraction of 0.00 was obtained with marker D20S863. Strong evidence of allelic association with the disease was detected with the same marker.
Schwarz et al. (2009) studied 5 consanguineous families with CDAN type II using genomewide SNP analysis to screen for homozygous chromosomal regions. They identified a single homozygous region on chromosome 20p12.1-p11.23. They noted that the CDAN2 locus had originally been mapped to 20q11.2; however, more current contig builds have relocated the markers with the highest CDAN2 lod scores to the minimal homozygosity region on chromosome 20p11.
Exclusion Studies
Fukuda et al. (1992) presented biochemical data suggesting that CDA type II is due to a deficiency of either N-acetylglucoaminyltransferase II or alpha-mannosidase II. However, linkage analysis by Iolascon et al. (1997), which placed the CDAN2 gene on 20q11.2, excluded the genes encoding these proteins.
The retsina (ret) phenotype in zebrafish results from mutation in the gene encoding the erythroid anion exchange protein-1 (AE1; 109270). The high number of binucleated erythroblasts, the presence of 'double membranes,' and the reduction in posttranslational glycosylation of AE1 observed in the ret fish are reminiscent of human CDA II. Perrotta et al. (2003) excluded the AE1 gene as the cause of CDA II in humans. This was not an unlikely finding, since AE1 maps to chromosome 17 and most CDA II families show linkage to 20q. Furthermore, complete inactivation of AE1 in mice and cattle causes severe hemolytic anemia, but not the CDA II phenotype. In humans, absence of erythroid AE1 causes severe hereditary spherocytosis (109270), but not CDA II.
Genetic heterogeneity in type II congenital dyserythropoietic anemia was demonstrated by Iolascon et al. (1998) who found 2 unrelated families in which CDA II was not linked to the CDAN2 locus on chromosome 20q11. The first family came from a little town on the Ionian Sea in southern Italy. Three of the grandparents of the affected individuals had the same family name. The propositus was born in 1982; at 3 days of age, severe icterus required exchange transfusion. Severe thrombocytopenia was observed. In later years, anemia seldom required transfusions and the platelet count was always low. Bone marrow studies and electron microscopy showed the characteristic features of CDA II associated with severe reduction of megakaryocytes, which did not show double membranes. The second family came from Lecce, a province of southern Italy, and had 2 affected sibs.
The transmission pattern of CDAN2 in the families reported by Schwarz et al. (2009) was consistent with autosomal recessive inheritance.
In affected individuals from 23 families with congenital dyserythropoietic anemia type II, Schwarz et al. (2009) identified 18 different mutations and 1 deletion in the SEC23B gene (see, e.g., 610512.0001-610512.0005). All mutations were in the homozygous or compound heterozygous state, consistent with autosomal recessive inheritance.
Bianchi et al. (2009) identified 12 different mutations in the SEC23B gene (see, e.g., R217X, 610512.0006) in 13 patients from 10 unrelated families with CDAN2. The most common mutations were E109K (610512.0001) and R14W (610512.0002). Most of the patients were Italian.
Crookston and Crookston (1972) suggested the designation HEMPAS, an acronym for 'hereditary erythroblastic multinuclearity with positive acidified-serum test' (also called Ham test). This appears to be the commonest form of inherited dyserythropoietic anemia. It is called type II hereditary dyserythropoietic anemia in the classification of Wendt and Heimpel (1967). (See 105600 and 224120 for 2 distinct forms of CDA that do not have a positive acidified-serum test.)
Schwarz et al. (2009) found that knockdown of the Sec23b gene in zebrafish embryos led to a pronounced reduction of the lower jaw on day 3 postfertilization. Erythrocytes derived from the Sec23b-silenced zebrafish showed an increase in immature, binucleated erythrocytes compared to wildtype. However, the complete human phenotype was not replicated, probably due to early lethality in the zebrafish. There was no evidence of N-linked hypoglycosylation or duplication of rough endoplasmic reticulum.
Baines, A. J., Banga, J. P. S., Gratzer, W. B., Linch, D. C., Huehns, E. R. Red cell membrane protein anomalies in congenital dyserythropoietic anaemia, type II (HEMPAS). Brit. J. Haemat. 50: 563-574, 1982. [PubMed: 7066206] [Full Text: https://doi.org/10.1111/j.1365-2141.1982.tb01956.x]
Bianchi, P., Fermo, E., Vercellati, C., Boschetti, C., Barcellini, W., Iurlo, A., Marcello, A. P., Righetti, P. G., Zanella, A. Congenital dyserythropoietic anemia type II (CDAII) is caused by mutations in the SEC23B gene. Hum. Mutat. 30: 1292-1298, 2009. [PubMed: 19621418] [Full Text: https://doi.org/10.1002/humu.21077]
Crookston, J. H., Crookston, M. C., Burnie, K. L., Francombe, W. H., Dacie, J. V., Davis, J. A., Lewis, S. M. Hereditary erythroblastic multinuclearity associated with a positive acidified-serum test: a type of congenital dyserythropoietic anaemia. Brit. J. Haemat. 17: 11-26, 1969. [PubMed: 5807784] [Full Text: https://doi.org/10.1111/j.1365-2141.1969.tb05660.x]
Crookston, J. H., Crookston, M. C. Hereditary anemia with multinuclear erythroblasts ('HEMPAS'). Birth Defects Orig. Art. Ser. VIII(3): 15-19, 1972.
de Lozzio, C. B., Valencia, J. I., Acame, E. Chromosomal study in erythroblastic endopolyploidy. Lancet 279: 1004-1005, 1962. Note: Originally Volume I. [PubMed: 13884336] [Full Text: https://doi.org/10.1016/s0140-6736(62)92038-x]
Dewar, C. L., Lowenthal, R. M. Ultrastructural studies of an unusual variant of congenital dyserythropoietic anaemia type II. Acta Haemat. 64: 53-57, 1980. [PubMed: 6774576] [Full Text: https://doi.org/10.1159/000207210]
Enquist, R. W., Gockerman, J. P., Jenis, E. H., Warkel, R. L., Dillon, D. E. Type II congenital dyserythropoietic anemia. Ann. Intern. Med. 77: 371-376, 1972. [PubMed: 4340898] [Full Text: https://doi.org/10.7326/0003-4819-77-3-371]
Fukuda, M. N., Dell, A., Scartezzini, P. Primary defect of congenital dyserythropoietic anaemia type II: failure in glycosylation of erythrocyte lactosaminoglycan proteins caused by lowered N-acetylglucosaminyltransferase II. J. Biol. Chem. 262: 7195-7206, 1987. [PubMed: 2953718]
Fukuda, M. N., Gaetani, G. F., Izzo, P., Scartezzini, P., Dell, A. Incompletely processed N-glycans of serum glycoproteins in congenital dyserythropoietic anaemia type II (HEMPAS). Brit. J. Haemat. 82: 745-752, 1992. [PubMed: 1482662] [Full Text: https://doi.org/10.1111/j.1365-2141.1992.tb06953.x]
Fukuda, M. N., Masri, K.A., Dell, A., Luzzatto, L., Moremen, K. W. Incomplete synthesis of N-glycans in congenital dyserythropoietic anemia type II caused by a defect in the gene encoding alpha-mannosidase II. Proc. Nat. Acad. Sci. 87: 7443-7447, 1990. [PubMed: 2217175] [Full Text: https://doi.org/10.1073/pnas.87.19.7443]
Fukuda, M. N., Papayannopoulou, T., Gordon-Smith, E. C., Rochant, H., Testa, U. Defect in glycosylation of erythrocyte membrane proteins in congenital dyserythropoietic anaemia type II (HEMPAS). Brit. J. Haemat. 56: 55-68, 1984. [PubMed: 6538436] [Full Text: https://doi.org/10.1111/j.1365-2141.1984.tb01271.x]
Gasparini, P., Miraglia del Giudice, E., Delaunay, J., Totaro, A., Granatiero, M., Melchionda, S., Zelante, L., Iolascon, A. Localization of the congenital dyserythropoietic anemia II locus to chromosome 20q11.2 by genomewide search. Am. J. Hum. Genet. 61: 1112-1116, 1997. [PubMed: 9345103] [Full Text: https://doi.org/10.1086/301609]
Gasparini, P., Miraglia del Giudice, E., Delaunay, J., Totaro, A., Granatiero, M., Melchionda, S., Zelante, L., Iolascon, A. Mapping of congenital dyserythropoietic anemia II (CDAII) locus on the long arm of chromosome 20 by genome wide search. (Abstract) Am. J. Hum. Genet. 61 (suppl.): A276 only, 1997.
Iolascon, A., De Mattia, D., Perrotta, S., Carella, M., Gasparini, P., Deliliers, G. L. Genetic heterogeneity of congenital dyserythropoietic anemia type II. (Letter) Blood 92: 2593-2594, 1998. [PubMed: 9746803]
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Iolascon, A., Miraglia del Giudice, E., Perrotta, S., Granatiero, M., Zelante, L., Gasparini, P. Exclusion of three candidate genes as determinants of congenital dyserythropoietic anemia type II (CDA-II). Blood 90: 4197-4200, 1997. [PubMed: 9354691]
Lowenthal, R. M., Marsden, K. A., Dewar, C. L., Thompson, G. R. Congenital dyserythropoietic anaemia (CDA) with severe gout, rare Kell phenotype and erythrocyte, granulocyte and platelet membrane reduplication: a new variant of CDA type II. Brit. J. Haemat. 44: 211-220, 1980. [PubMed: 7378299] [Full Text: https://doi.org/10.1111/j.1365-2141.1980.tb01203.x]
Misago, M., Liao, Y.-F., Kudo, S., Eto, S., Mattei, M.-G., Moremen, K. W., Fukuda, M. N. Molecular cloning and expression of cDNAs encoding human alpha-mannosidase II and a previously unrecognized alpha-mannosidase II(X) isozyme. Proc. Nat. Acad. Sci. 92: 11766-11770, 1995. [PubMed: 8524845] [Full Text: https://doi.org/10.1073/pnas.92.25.11766]
Perrotta, S., del Giudice, E. M., Carbone, R., Servedio, V., Schettini, F., Jr., Nobili, B., Iolascon, A. Gilbert's syndrome accounts for the phenotypic variability of congenital dyserythropoietic anemia type II (CDA-II). J. Pediat. 136: 556-559, 2000. [PubMed: 10753261] [Full Text: https://doi.org/10.1016/s0022-3476(00)90026-x]
Perrotta, S., Luzzatto, L., Carella, M., Iolascon, A. Congenital dyserythropoietic anemia type II in human patients is not due to mutations in the erythroid anion exchanger 1. (Letter) Blood 102: 2704-2705, 2003. [PubMed: 14504075] [Full Text: https://doi.org/10.1182/blood-2003-07-2389]
Roberts, P. D., Wallis, P. G., Jackson, A. D. M. Haemolytic anaemia with multinucleated normoblasts in the marrow. (Letter) Lancet 279: 1186, 1962. Note: Originally Volume I.
Schwarz, K., Iolascon, A., Verissimo, F., Trede, N. S., Horsley, W., Chen, W., Paw, B. H., Hopfner, K.-P., Holzmann, K., Russo, R., Esposito, M. R., Spano, D., and 10 others. Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II. Nature Genet. 41: 936-940, 2009. [PubMed: 19561605] [Full Text: https://doi.org/10.1038/ng.405]
Seip, M., Skrede, S., Bjerve, K. S., Hovig, T., Gaarder, P. I. Congenital dyserythropoietic anaemia with features of both type I and type II. Scand. J. Haemat. 15: 272-286, 1975. [PubMed: 1198066] [Full Text: https://doi.org/10.1111/j.1600-0609.1975.tb01083.x]
Verwilghen, R. L., Lewis, S. M., Dacie, J. V., Crookston, J. H., Crookston, M. C. HEMPAS: congenital dyserythropoietic anaemia (type II). Quart. J. Med. 42: 257-278, 1973. [PubMed: 4785435]
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Wendt, F., Heimpel, H. Kongenitale dyserythropoietische Anamie bei einem zweieiigen Zwillingspaar. Med. Klin. 62: 172-177, 1967. [PubMed: 5590186]