Blood Spotlight

Congenital dyserythropoietic anemias: molecular insights and

diagnostic approach
Achille Iolascon,1,2 Hermann Heimpel,3 Anders Wahlin,4 and Hannah Tamary5,6
1
Centro di Ingegneria Genetica, Biotecnologie Avanzate, Naples, Italy; 2Department of Molecular Medicine and Medical Biotechnologies, University
“Federico II” of Naples, Naples, Italy; 3Department of Internal Medicine III, University of Ulm, Ulm, Germany; 4Hematology, Department of Radiation
Sciences, Umeå University, Umeå, Sweden; 5Hematology Unit, Schneider Children’s Medical Center of Israel, Petah Tikva, Israel; and 6Sackler Faculty of
Medicine, Tel Aviv University, Tel Aviv, Israel

The congenital dyserythropoietic anemias been completed with the recent identifica- unknown. CDA variants with mutations
(CDAs) are hereditary disorders character- tion of the CDA III gene (KIF23). KIF23 in erythroid transcription factor genes
ized by distinct morphologic abnormalities encodes mitotic kinesin-like protein 1, (KLF1 and GATA-1) have been recently
of marrow erythroblasts. The unveiling of which plays a critical role in cytokinesis, identified. Molecular diagnosis of CDA is

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the genes mutated in the major CDA sub- whereas the cellular role of the proteins now possible in most patients. (Blood.
groups (I-CDAN1 and II-SEC23B) has now encoded by CDAN1 and SEC23B is still 2013;122(13):2162-2166)

Introduction
The congenital dyserythropoietic anemias (CDAs) are a group of rare reticulum are found beneath the plasma membrane.2 The Ham test
hereditary disorders characterized by congenital anemia, ineffective with red cell lysis in acidified allogenic sera has practically been
erythropoiesis with distinct morphologic features in bone marrow abandoned as a diagnostic tool due to the need for multiple control
(BM) late erythroblasts, and the development of secondary hemo- samples. Analysis of red cell membrane proteins by sodium dodecyl
chromatosis. Patients usually present with anemia, jaundice, spleno- sulfate polyacrylamide gel electrophoresis, identifying glycosylation
megaly, and suboptimal reticulocyte response for the degree of abnormalities with fast-moving band 3 (the anion exchanger 1) and
anemia. Aniso-poikilocytosis and basophilic stippling are commonly band 4.5 (glucose transporter 1), is highly sensitive and specific.
observed in the peripheral blood smear. The working classification CDA III is the rarest among the 3 types. Although originally
initially proposed by Heimpel and Wendt is still used in clinical reported in an American family, most patients described to date
practice (CDA I, II, and III; Table 1).1,2 However, there are families belong to 1 large Swedish kindred. In both families, the inheritance is
that fulfill the general definition of the CDAs but do not conform to dominant. Few sporadic cases have also been described with possible
any of the 3 classical types (CDA variants, Table 1). autosomal recessive inheritance.2,8 Splenomegaly is usually absent.
The genes mutated in the majority of patients with CDA I and II BM morphology is characterized by erythroid hyperplasia and
have been previously described, whereas the CDA III gene was only large pathognomonic multinucleated erythroblasts (Figure 1). A
recently identified.3-5 Additional genetic defects have been described large proportion of patients in the Swedish family exhibited monoclonal
in CDA variants. Because of these advancements, the diagnosis can gammopathy, and some developed multiple myeloma.8
now be confirmed by molecular testing in an increasing number of
patients.
The aim of this review is to update the molecular basis of this
group of disorders and to outline the current diagnostic approach. Therapeutic approach
Although most CDA patients are mildly or moderately affected and
are not transfusion dependent, many do require blood transfusions
CDA I to III: clinical picture and BM findings during the first months of life, pregnancy, and/or sporadic infections.
Iron overload with inappropriately low serum hepcidin was docu-
CDA I is an autosomal recessive disease associated with macrocytic mented and correlates with age.9,10 A minority of patients are
anemia. Skeletal abnormalities of distal limbs have also been severely affected and are transfusion dependent. Patients with CDA I
described.6 BM examination reveals erythroid hyperplasia with were found to respond to interferon a with increased hemoglobin
up to 10% binuclear erythroblasts. Pathognomonic chromatin levels and decreased iron overload.11 The role of splenectomy in the
bridges between nuclei are observed in up to 8% of erythroblasts management of CDA is yet undetermined; however, patients with
(Figure 1).7 BM EM shows a spongy (“Swiss cheese”) appearance of CDA type II seem to benefit from the procedure.12 CDA patients who
heterochromatin. are older than 10 years of age should be carefully monitored for the
CDA II is the most common form of the CDAs. BM light development of iron overload, which requires iron chelation therapy
microscopy reveals more than 10% mature binuclear erythroblasts when identified. Few transfusion-dependent children with CDA
(Figure 1), and with EM, vesicles loaded with proteins of endoplasmic underwent successful stem cell transplantation.13,14

Submitted May 6, 2013; accepted August 6, 2013. Prepublished online as © 2013 by The American Society of Hematology
Blood First Edition paper, August 12, 2013; DOI 10.1182/blood-2013-05-
468223.

2162 BLOOD, 26 SEPTEMBER 2013 x VOLUME 122, NUMBER 13

BLOOD, 26 SEPTEMBER 2013 x VOLUME 122, NUMBER 13 CDAs: NEW INSIGHTS 2163

Table 1. Characteristic features of different types of CDA

CDA type I II III Familial III Sporadic Variants

Inheritance Autosomal recessive Autosomal recessive Dominant Variable Autosomal dominant or

X linked or recessive
Cases reported .300 .450 2 families ,20 ;70
BM morphology Abnormal chromatin Binuclearity, multinuclearity Giant multinucleated Giant multinucleated CDA I–like, CDA II–like,
(light microscopy) structure, chromatin of mature erythroblasts erythroblasts erythroblasts others
bridges
BM EM findings “Spongy” heterochromatin, Peripheral cysternae Clefts in heterochromatin, Various Various
invagination of cytoplasm beneath the plasma autophagic vacuoles,
into the nucleus membrane intranuclear cisternae
Mutated gene CDAN1, C15ORF41 SEC23B KIF23 Unknown KLF1, GATA-1, unknown
Associated Skeleton Variable, rare Monoclonal gammopathy, Variable CNS, others
dysmorphology/organ myeloma, angioid streaks
involvement

CNS, central nervous system; EM, electron microscopy.

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chaperone involved in nucleosome assembly and disassembly.19
Molecular insights More recently, Ask et al showed that codanin-1 is part of a cytosolic
Asf1–H3-H4–importin-4 complex20 and acts as a negative regulator
CDA I of Asf1. Only after codanin-1 dissociated from the Asf1–H3.1-H4
complex in the nucleus was Asf1 able to bind other histone chaperons
The gene mutated in CDA I (CDAN1) was the first of the CDA genes (chromatin assembly factor-1 and histone cell cycle regulator) and
to be described.3 It is localized to chromosome 15, spans 28 exons, deliver histones for chromatin assembly.
and encodes a 134-kDa ubiquitous protein (codanin-1). The study of Recently, whole genome sequencing of a CDA I patient belonging
patients of different ethnic backgrounds identified more than 30 to a Pakistani family identified a new CDA I gene, C15ORF41.21 The
unique disease-causing mutations.3,6,15 Genotype-phenotype corre- cellular role of the restriction endonuclease encoded by this gene is yet
lations could not be established. No patient was homozygous for unknown. Interestingly, it has been previously shown that C15ORF41
null-type mutations, suggesting that a complete absence of codanin-1 interacts with Asf1b, possibly supporting the hypothesis that the pri-
is lethal. Indeed, CDA I knockout mice embryos die in utero at 6.5 mary defect in CDA I is in DNA replication and chromatin assembly.
days before erythropoiesis onset, probably due to the critical role of In erythroid lineage, terminal differentiation is coupled to
codanin-1 in developmental processes other than erythropoiesis.16 proliferation with few cell cycle divisions through which cell size
In ;20% of families with the CDA I phenotype, no CDAN1 mu- is also reduced.22,23 Cell cycle defects in mice result in S phase
tations in 1 or both alleles were found.17 arrest, ineffective erythropoiesis, and macrocytosis.24 Based on the
EM of control and CDA I BM stained with gold-labeled possible involvement of CDA I genes in DNA replication and
anti–codanin-1 antibody demonstrated that codanin-1 mainly local- chromatin assembly, it can be speculated that CDA I pathogenesis
izes to heterochromatin.18 A comparison of controls and CDA I may involve disruption of the intrinsic connection between cell
erythroblasts revealed that CDA I intermediate erythroblasts had cycle dynamics and terminal erythroid differentiation.
abnormal accumulation of heterochromatin protein (HP-1a) in their
Golgi apparatus. Furthermore, partial colocalization of codanin-1 and CDA II
SEC23B, the protein mutated in CDA II, was observed in CDA I
intermediate erythroblasts, suggesting intracellular transport pathway SEC23B, the gene mutated in CDA II, was originally mapped to
defects in both CDA I and II.16 Noy-Lotan et al found in nonerythroid chromosome 20 and identified by means of functional and homozy-
cells that E2F1 (a main regulator of G1/S transition) binds to the gosity mapping.4,25 This gene encodes the cytoplasmic COPII (coat
CDAN1 promoter and initiates codanin-1 transcription, resulting in protein) component SEC23B, which is involved in the secretory
a rise in its levels during S phase.18 It was further demonstrated that pathway of eukaryotic cells. This multisubunit complex mediates
codanin-1 binds the anti-silencing factor-1 (Asf1), an H3-H4 histone accumulation of secretory cargo, deformation of the membrane,

Figure 1. Pathognomonic marrow erythroblasts. The BM erythroblasts morphology (light microscopy) of different types of CDA is shown. See Table 1 for the description.
2164 IOLASCON et al BLOOD, 26 SEPTEMBER 2013 x VOLUME 122, NUMBER 13

and anterograde transport of correctly folded cargo for budding (IV-VII), each one including relatively few patients.2 Nevertheless,
from the endoplasmic reticulum toward the Golgi apparatus.26 there were still descriptions of patients not belonging to any of the
To date, 157 cases from 137 different CDA II families with groups,2,36,37 suggesting further that CDA subtypes are extremely
SEC23B mutations were molecularly characterized.27 The majority heterogeneous and probably represent multiple unrelated genetic
(52%) of CDAII cases are caused by missense mutations, whereas disorders. Indeed, in recent years additional genetic defects asso-
20% are due to nonsense, 13% to intronic, and 13% to small indel ciated with CDA phenotypes have been identified. They include
mutations. The disease inheritance is typically autosomal recessive; mutations in erythroid transcription factor genes (GATA-1 and
yet, in 13% of cases, only 1 SEC23B mutation was found. This KLF1) and mutations in other genes where CDA is part of a broader
suggests the presence of a second still unidentified mutational event, clinical syndrome.
likely in a noncoding regulatory region of the gene that has not yet Mutations in erythroid transcription factors GATA-1 and
been examined27 (A. Iolascon, Federico II University, oral commu- KLF1. GATA-1 plays an integral role in the development of
nication, December 8, 2012). These results demonstrate that erythroid and megakaryocytic lineages.38 With the help of its
mutations occur along the whole gene. In contrast, in Southern cofactor FOG-1 (friend of GATA-1), it coordinates hematopoietic
Italy, 2 mutations (R14W and E109K) account for ;50% of all cell differentiation by activating linage-specific mature forms and
cases.28 In rare cases, classified as CDA II on the basis of BM and repressing genes associated with undifferentiated states. There are
biochemical analyses, no SEC23B mutation was found. This sug- currently a few documented familial inherited forms of X-linked

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gests the existence of another causative gene as demonstrated by thrombocytopenia characterized by macrothrombocytopenia, bleed-
linkage exclusion.29 Compound heterozygosity for missense and ing tendency with varying degrees of dyserythropoiesis ranging from
nonsense mutations tends to produce more severe clinical presenta- hydrops fetalis and transfusion dependency to dyserythropoiesis
tions.30 Homozygosity or compound heterozygosity for null muta- without anemia.39 All identified mutations affect the GATA-1:FOG-1
tions was never found and is presumably lethal. Recently, the presence interaction. One additional mutation affecting DNA binding is
of 2 hypomorphic alleles accounting for mild CDA II clinical forms associated with X-linked thrombocytopenia and thalassemia
was described. It has been suggested that compensatory expression with unbalanced a/b hemoglobin chain production resembling
of SEC23A, a related gene, could ameliorate the effect of reduced b-thalassemia.39
SEC23B expression.31 KLF1 is an erythroid transcription factor involved in promoting
Sec23b-deficient mice (Sec23b gt/gt) have no apparent anemia erythropoiesis and attenuating megakaryocytic differentiation.40
phenotype, but they die shortly after birth with degeneration of Additionally, it takes part in the developmental switch between
secretory tissues, including pancreas and salivary glands.32 The fetal and adult hemoglobin. KLF1 is also required for cell cycle
disparate mouse and human phenotypes may result from either divisions preceding terminal erythroid differentiation and cell
residual SEC23B function associated with the hypomorphic mutations cycle exit during erythroid maturation. One KLF1 mutation
found in humans or a species-specific shift in function between the (c.937G.A), resulting in substitution of the evolutionary con-
closely related paralogues SEC23A and SEC23B. served glutamate 325 by lysine (E325K), has been identified in more
than 5 CDA patients.41-45 In some of these patients other red blood
CDA III
cell abnormalities have been documented including persistent
The gene causing CDA III in a Swedish family has been previously expression of embryonic § and e globin chains, high fetal hemoglobin
mapped to a region on chromosome 15q23.33 This region was (40%), novel intra erythroblastic and intra erythrocytic inclusions,
targeted by array-based sequence capture, and a novel mutation, deficiency of erythroid CD44 and aquaporin 1.41,42 Interestingly,
c.2747C.G(p.P916R) in the KIF23 gene, was shown to be asso- one of those patients41,42 was first identified by Wickramasinghe
ciated with the autosomal dominant form of CDA III.5 The same in 1991 and was classified as having a distinct form of CDA (non-
mutation was also found in CDA III patients from an American IV–VII group).46 She was born with hydrops fetalis, required red
family without any known relation to the Swedish kindred.5 KIF23 cell transfusions over the first year of life, and thereafter developed
encodes a kinesin-superfamily molecule, mitotic kinesin-like protein a non-transfusion dependent anemia.
1 (MKLP1), a mitotic protein essential for cytokinesis.34,35 MKLP1 CDA as part of a broader syndrome. Three different syndromes
interacts with Arf6 (adenosine 59-diphosphate–ribosylation factor 6), including CDA have been molecularly studied so far:
ultimately forming an extended b sheet, which interacts with the 1. Majeed syndrome is a rare autosomal recessive disorder char-
membrane surface at the cleavage furrow. The Arf6-MKLP1 complex acterized by early onset of chronic recurrent multifocal osteomyelitis,
has a crucial role in cytokinesis by connecting the microtubule bundle
inflammatory dermatosis, and microcytic dyserythropoietic anemia
and membranes at the cleavage plane.34 Knockdown of Arf6 results in
with increased marrow erythropoiesis and up to 25% binucleated and
binucleated and multinucleated cells, which is a clinical hallmark of
trinucleated erythroblasts.47 The disease is caused by LPIN2 mutations.
CDA III erythroblasts.33 In knockdown and rescue experiments with
Lipin2 is involved in lipid metabolism by affecting phosphatide
HeLa cells, cytokinesis failure and binucleated cells were seen more
phosphatase activity.48,49 The link between lipin2 and the hematologic
frequently with the P916R mutant than the wild-type GFP-MKLP1,
features or the autoinflammatory bone disease is unclear.
indicating that the P916R mutation impairs the function of MKLP1 in
2. CDA with exocrine pancreatic insufficiency and calvarial
cytokinesis.5 Two isoforms of MKLP1 were also identified, with
hyperostosis caused by a mutation in COX4I2 was also described.50
varying expression in different tissues, possibly explaining the
Blood smear revealed aniso-pokilocyosis, basophilic stippling, and
mutation’s heterogenic effects in between tissues.5
few normoblasts. In BM erythroid hyperplasia, megaloblastic changes
CDA variants
and bi- and multinucleated erythroblasts were present. The COX4I2
isoform of the COX4 protein is an essential structural subunit of
Several forms of CDAs do not fulfill classical BM morphologic or cytochrome c oxidase complex.
biochemical criteria.2,7 Based on light microscopy and EM of BM, 3. Mevalonate kinase deficiency is a rare inborn error of metab-
Wickramasinghe classified them into 4 additional CDA groups olism caused by mutations in the mevalonate kinase gene. A recent
BLOOD, 26 SEPTEMBER 2013 x VOLUME 122, NUMBER 13 CDAs: NEW INSIGHTS 2165

report described a patient with an intermediate form of the disease and of multinucleated erythroblasts. Codanin-1 and possibly C15ORF41
6% to 8% of marrow erythroblasts demonstrating dyserythropoietic may facilitate histone assembly into chromatin during cell cycle. The
features.51 fact that the proteins encoded by the CDA I, II, and III genes are
ubiquitously expressed while the disease manifestations are mainly
erythroid restricted remains a quandary. Further studies on CDA-
related proteins and identification of new genes causing CDA
variants will continue to offer insight into different pathways
Current diagnostic approach underlying erythropoiesis.
The identification of the mutated genes involved in the majority of
CDA patients improved the diagnostic possibilities. When the clinical
picture is suggestive and the findings in peripheral blood and BM light
microscopy are compatible with one of the classical I to III types Acknowledgments
(Table 1; Figure 1), the next diagnostic step should be to sequence
the appropriate gene. For these patients, additional specialized tests The authors thank Lucio Luzzatto, Roberta Russo, and Mitchell
including BM EM and/or sodium dodecyl sulfate polyacrylamide gel J. Weiss from the Children’s Hospital of Philadelphia for helpful

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electrophoresis of red cell membranes are not required. Whenever discussions. The authors also thank Dr Joanne Yacobovich from
clinical and hematologic findings are generally compatible with CDA the Schneider Children’s Medical Center of Israel for her help in
despite the absence of specific microscopic features of CDA I to III, a preparation of this manuscript.
variant CDA should be considered. In these selected cases, mutations This work was supported by the Italian Ministero dell’Università
in KLF1 and GATA-1 should be explored by DNA sequencing. Future e della Ricerca; by Telethon, Italy (GGP09044) (A.I.); by contract
analysis will probably include high-throughput genomic analyzing grant MUR-PS 35-126/Ind; and by Regione Campania (grant DGRC
technology, which will eventually lead to identification of new 1901/200) (A.I.).
causative genetic factors.

Conclusions Authorship
The hallmark of the CDAs is failure of terminal erythropoiesis. The Contribution: A.I., H.H., A.W., and H.T. wrote the manuscript.
identification of several CDA genes has improved the diagnostic Conflict-of-interest disclosure: The authors declare no compet-
aspect of this disease; however, no comprehensive explanation for ing financial interests.
the mechanism of erythropoietic disruption has been disclosed. Correspondence: Achille Iolascon, CEINGE, Biotecnologie
CDA type III gene (KIF23) encodes a protein playing a critical role Avanzate, Via Gaetano Salvatore, 486, 80145 Naples, Italy; e-mail:
in cytokinesis, suggesting a possible mechanism for the development achille.iolascon@unina.it.

References
1. Heimpel H, Wendt F. Congenital dyserythropoietic 8. Sandström H, Wahlin A. Congenital 15. Heimpel H, Schwarz K, Ebnöther M, et al.
anemia with karyorrhexis and multinuclearity of dyserythropoietic anemia type III. Haematologica. Congenital dyserythropoietic anemia type I
erythroblasts. Helv Med Acta. 1968;34(2): 2000;85(7):753-757. (CDA I): molecular genetics, clinical appearance,
103-115. 9. Tamary H, Shalev H, Perez-Avraham G, et al. and prognosis based on long-term observation.
Elevated growth differentiation factor 15 Blood. 2006;107(1):334-340.
2. Wickramasinghe SN, Wood WG. Advances in the
understanding of the congenital dyserythropoietic expression in patients with congenital 16. Renella R, Roberts NA, Brown JM, et al. Codanin-
anaemias. Br J Haematol. 2005;131(4):431-446. dyserythropoietic anemia type I. Blood. 2008; 1 mutations in congenital dyserythropoietic
112(13):5241-5244. anemia type 1 affect HP1alpha localization in
3. Dgany O, Avidan N, Delaunay J, et al. Congenital 10. Casanovas G, Swinkels DW, Altamura S, et al. erythroblasts. Blood. 2011;117(25):6928-6938.
dyserythropoietic anemia type I is caused by Growth differentiation factor 15 in patients with 17. Ahmed MR, Chehal A, Zahed L, et al. Linkage
mutations in codanin-1. Am J Hum Genet. 2002; congenital dyserythropoietic anaemia (CDA) type and mutational analysis of the CDAN1 gene
71(6):1467-1474. II. J Mol Med (Berl). 2011;89(8):811-816. reveals genetic heterogeneity in congenital
4. Schwarz K, Iolascon A, Verissimo F, et al. 11. Lavabre-Bertrand T, Ramos J, Delfour C, et al. dyserythropoietic anemia type I. Blood. 2006;
Mutations affecting the secretory COPII coat Long-term alpha interferon treatment is effective 107(12):4968-4969.
component SEC23B cause congenital on anaemia and significantly reduces iron 18. Noy-Lotan S, Dgany O, Lahmi R, et al. Codanin-1,
dyserythropoietic anemia type II. Nat Genet. overload in congenital dyserythropoiesis type I. the protein encoded by the gene mutated in
2009;41(8):936-940. Eur J Haematol. 2004;73(5):380-383. congenital dyserythropoietic anemia type I
12. Heimpel H, Anselstetter V, Chrobak L, et al. (CDAN1), is cell cycle-regulated. Haematologica.
5. Liljeholm M, Irvine AF, Vikberg AL, et al. 2009;94(5):629-637.
Congenital dyserythropoietic anemia type III Congenital dyserythropoietic anemia type II:
(CDA III) is caused by a mutation in kinesin family epidemiology, clinical appearance, and prognosis 19. Tamary H, Marcoux N, Noy-Lotan S, Yaniv I,
member, KIF23. Blood. 2013;121(23):4791-4799. based on long-term observation. Blood. 2003; Dgany O. Codanin-1, the product of the gene
102(13):4576-4581. mutated in congenital dyserythropoietic anemia
6. Tamary H, Dgany O, Proust A, et al. Clinical 13. Buchbinder D, Nugent D, Vu D, et al. Unrelated type I (CDA I), binds to histone chaperone Asf1a
and molecular variability in congenital hematopoietic stem cell transplantation in a and inhibits its nucleosome assembly activity
dyserythropoietic anaemia type I. Br J Haematol. patient with congenital dyserythropoietic anemia [abstract]. Blood. 2010;116(21). Abstract 1004.
2005;130(4):628-634. and iron overload. Pediatr Transplant. 2012;16(3): 20. Ask K, Jasencakova Z, Menard P, Feng Y,
7. Heimpel H, Kellermann K, Neuschwander N, E69-E73. Almouzni G, Groth A. Codanin-1, mutated in the
Högel J, Schwarz K. The morphological diagnosis 14. Ayas M, al-Jefri A, Baothman A, et al. anaemic disease CDAI, regulates Asf1 function in
of congenital dyserythropoietic anemia: results of Transfusion-dependent congenital S-phase histone supply. EMBO J. 2012;31(8):
a quantitative analysis of peripheral blood and dyserythropoietic anemia type I successfully 2013-2023.
bone marrow cells. Haematologica. 2010;95(6): treated with allogeneic stem cell transplantation. 21. Babbs C, Roberts NA, Sanchez-Pulido L,
1034-1036. Bone Marrow Transplant. 2002;29(8):681-682. et al. Homozygous mutations in a predicted
2166 IOLASCON et al BLOOD, 26 SEPTEMBER 2013 x VOLUME 122, NUMBER 13

endonuclease cause congenital dyserythropoietic 32. Tao J, Zhu M, Wang H, et al. SEC23B is required dyserythropoeitic anemia (CDA)-further definition
anemia type I [published online ahead of print May for the maintenance of murine professional of emerging new syndrome and possible
28, 2013]. Haematologica. secretory tissues. Proc Natl Acad Sci USA. 2012; association with gonadal dysgenesis.
109(29):E2001-E2009. ASH Annual Meeting Abstracts. 2011;118(21):
22. Walkley CR, Sankaran VG, Orkin SH. Rb and
33. Lind L, Sandström H, Wahlin A, et al. Localization 2101.
hematopoiesis: stem cells to anemia. Cell Div.
2008;3:13. of the gene for congenital dyserythropoietic 44. Mitchell WB, Gnanapragasam MN, Jaffray JA,
anemia type III, CDAN3, to chromosome 15q21- Bieker JJ, Manwani D. Case report of erythroid
23. Sankaran VG, Ludwig LS, Sicinska E, et al. Cyclin q25. Hum Mol Genet. 1995;4(1):109-112.
D3 coordinates the cell cycle during differentiation transcription factor EKLF mutation causing a rare
to regulate erythrocyte size and number. Genes 34. Makyio H, Ohgi M, Takei T, et al. Structural form of congenital dyserythropoetic anemia in
Dev. 2012;26(18):2075-2087. basis for Arf6-MKLP1 complex formation on the a patient of Taiwanese origin. ASH Annual
Flemming body responsible for cytokinesis. Meeting Abstracts. 2011;118(21):2154.
24. Li FX, Zhu JW, Hogan CJ, DeGregori J. Defective EMBO J. 2012;31(11):2590-2603.
gene expression, S phase progression, and 45. Jaffray JA, Mitchell WB, Gnanapragasam MN,
35. Matuliene J, Kuriyama R. Kinesin-like protein et al. Erythroid transcription factor EKLF/KLF1
maturation during hematopoiesis in E2F1/E2F2
CHO1 is required for the formation of midbody mutation causing congenital dyserythropoietic
mutant mice. Mol Cell Biol. 2003;23(10):
matrix and the completion of cytokinesis in anemia type IV in a patient of Taiwanese origin:
3607-3622.
mammalian cells. Mol Biol Cell. 2002;13(6): review of all reported cases and development of
25. Bianchi P, Fermo E, Vercellati C, et al. Congenital 1832-1845. a clinical diagnostic paradigm. Blood Cells Mol
dyserythropoietic anemia type II (CDAII) is Dis. 2013;51(2):71-75.
36. Heimpel H, Kohne E, Schrod L, Schwarz K,
caused by mutations in the SEC23B gene. Hum
Wickramasinghe S. A new type of transfusion-
Mutat. 2009;30(9):1292-1298. 46. Wickramasinghe SN, Illum N, Wimberley PD.
dependent congenital dyserythropoietic anemia.
Congenital dyserythropoietic anaemia with novel

Downloaded from http://ashpublications.org/blood/article-pdf/122/13/2162/1367635/2162.pdf by guest on 11 May 2024

26. De Matteis MA, Luini A. Mendelian disorders of Haematologica. 2007;92(10):1427-1428.
intra-erythroblastic and intra-erythrocytic
membrane trafficking. N Engl J Med. 2011; 37. Gay J, Fournier M, Pierre-Eugène C, et al. inclusions. Br J Haematol. 1991;79(2):322-330.
365(10):927-938. New variant of unclassified congenital
dyserythropoietic anaemia: the concept of the 47. Majeed HA, Kalaawi M, Mohanty D, et al.
27. Iolascon A, Esposito MR, Russo R. Clinical
erythroid regulator? Br J Haematol. 2012;157(1): Congenital dyserythropoietic anemia and chronic
aspects and pathogenesis of congenital
148-151. recurrent multifocal osteomyelitis in three related
dyserythropoietic anemias: from morphology to
children and the association with Sweet syndrome
molecular approach. Haematologica. 2012; 38. Weiss MJ, Keller G, Orkin SH. Novel insights into in two siblings. J Pediatr. 1989;115(5 Pt 1):
97(12):1786-1794. erythroid development revealed through in vitro 730-734.
28. Russo R, Gambale A, Esposito MR, et al. Two differentiation of GATA-1 embryonic stem cells.
founder mutations in the SEC23B gene account Genes Dev. 1994;8(10):1184-1197. 48. Ferguson PJ, Chen S, Tayeh MK, et al.
for the relatively high frequency of CDA II in the Homozygous mutations in LPIN2 are responsible
39. Ciovacco WA, Raskind WH, Kacena MA. Human
Italian population. Am J Hematol. 2011;86(9): for the syndrome of chronic recurrent multifocal
phenotypes associated with GATA-1 mutations.
727-732. osteomyelitis and congenital dyserythropoietic
Gene. 2008;427(1-2):1-6.
anaemia (Majeed syndrome). J Med Genet. 2005;
29. Iolascon A, De Mattia D, Perrotta S, Carella M, 40. Siatecka M, Bieker JJ. The multifunctional role of 42(7):551-557.
Gasparini P, Lambertenghi Deliliers G. Genetic EKLF/KLF1 during erythropoiesis. Blood. 2011;
heterogeneity of congenital dyserythropoietic 118(8):2044-2054. 49. Morbach H, Hedrich CM, Beer M, Girschick HJ.
anemia type II. Blood. 1998;92(7):2593-2594. Autoinflammatory bone disorders. Clin Immunol.
41. Singleton BK, Fairweather VS, Lau W, et al.
2013;147(3):185-196.
30. Iolascon A, Russo R, Esposito MR, et al. A novel EKLF mutation in a patient with
Molecular analysis of 42 patients with congenital dyserythropoietic anemia: the first association of 50. Shteyer E, Saada A, Shaag A, et al. Exocrine
dyserythropoietic anemia type II: new mutations in EKLF with disease in man. ASH Annual Meeting pancreatic insufficiency, dyserythropoeitic
the SEC23B gene and a search for a genotype- Abstracts. 2009;114(22):162. anemia, and calvarial hyperostosis are caused by
phenotype relationship. Haematologica. 2010; 42. Arnaud L, Saison C, Helias V, et al. A dominant a mutation in the COX4I2 gene. Am J Hum Genet.
95(5):708-715. mutation in the gene encoding the erythroid 2009;84(3):412-417.

31. Russo R, Langella C, Esposito MR, et al. transcription factor KLF1 causes a congenital 51. Samkari A, Borzutzky A, Fermo E, Treaba DO,
Hypomorphic mutations of SEC23B gene dyserythropoietic anemia. Am J Hum Genet. Dedeoglu F, Altura RA. A novel missense
account for mild phenotypes of congenital 2010;87(5):721-727. mutation in MVK associated with MK deficiency
dyserythropoietic anemia type II. Blood Cells Mol 43. Ravindranath Y, Goyette G, Buck S, et al. A new and dyserythropoietic anemia. Pediatrics. 2010;
Dis. 2013;51(1):17-21. case of KLF1 G973A mutation and congenital 125(4):e964-e968.