Ann Hematol DOI 10.1007/s00277-013-1933-8
ORIGINAL ARTICLE
Congenital dyserythropoietic anemia in China: a case report from two families and a review Yongxin Ru & Gang Liu & Jie Bai & Shuxu Dong & Neng Nie & Huamei Zhang & Shixuan Zhao & Yizhou Zheng & Xiaofan Zhu & Guangjun Nie & Fengkui Zhang & Brian Eyden
Received: 4 September 2013 / Accepted: 7 October 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Congenital dyserythropoietic anemias (CDAs) are a group of hereditary disorders characterized by ineffective erythropoiesis and distinct morphological abnormalities of erythroblasts in the bone marrow. Most cases of CDA, caused by a wide spectrum of mutations, have been reported from Europe and Mediterranean countries, while a few cases have been described in China. Here, we present three cases of CDA, one from one family and two from a second unrelated family, with typical morphologic features and clinical presentations. Sequence analysis of CDA-related genes revealed that the proband with CDA Ι in the first family was a compound heterozygote of CDAN1 with mutation IVS-12+2T>C and c. 3389C>T, while both probands with CDA ΙΙ in the second family were a homozygote of the SEC23B gene with mutation c.938G>A (R313H). This study suggests that more patients with CDA, sharing a phenotype and genetic background like those of European and Mediterranean origin, remain to be diagnosed and reported in China. Y. Ru : J. Bai : S. Dong : N. Nie : H. Zhang : S. Zhao : Y. Zheng : X. Zhu : F. Zhang Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Experimental Haematology, Tianjin, China G. Liu : G. Nie CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Centre for Nanoscience and Technology, Beijing, China B. Eyden Department of Histopathology, Christie Hospital NHS Trust, Manchester, UK Y. Ru (*) Pathology Department, Institute of Hematology & Blood Diseases Hospital, Peking Union College, 288 Nanjing Road, Tianjin 300020, China e-mail: [email protected]
Keywords CDAs . Morphology . Sequencing . Chinese
Introduction Congenital dyserythropoietic anemias (CDAs) are a rare group of anemic diseases that result from heterogeneous mutations associated with dyserythropoiesis. So far, four types (types I to IV) have been defined by distinct morphologic features, genetic defects, and clinical presentations [1, 2] in which CDA I and CDA II are the predominant types. Additional variants of CDA have been reported with remarkable morphological studies, but to a certain extent, they overlap with the definite types. Seven hundred twelve cases of CDA from 614 families, including 169 cases of CDA I in 143 families and 454 cases of CDA II in 356 families, were recorded by the German Registry up to December 2011 [3]. Most of them were from Europe and Israel, but a few cases were reported sporadically from India and Japan [4, 5]. Twenty cases of CDA in unrelated Chinese families were published as single case reports up to 2012 in which two cases of CDA II and one case of CDA I were reported in the English literature [6–8], but seven cases of CDA I, six cases of CDA II, and four cases of CDA IV have been reported in Chinese journals [9]. Although some of the described cases need further examination in terms of transmission electron microscopy (TEM) and sequencing analysis to provide a more accurate diagnosis, the finding indicates that CDA I and CDA II are also predominant in China. To better understand the underlying molecular basis of patients with CDA in the Chinese population, we here present one case of CDA I and two cases of CDA II that not previously reported from unrelated Chinese families with sequencing data.
Ann Hematol
Family 1 A 19-year-old male, 51 kg in weight and 170 cm tall and with a brachydactylia foot (Fig. 1a), was the only son in this Chinese family. He suffered from moderate anemia from the age of 9 months, but was not treated regularly until he was 12. His hemoglobin concentration fluctuated between 70 and 100 g/L; severe hemoglobin lows were complicated with jaundice and usually followed a bad cold or an infection. He received a blood transfusion on one occasion when he was 7. The results of clinical and laboratory examinations listed in Table 1 were performed in 2012 when the patient was 19. Peripheral blood analysis showed decreased hemoglobin and hematocrit, but increased numbers of erythroblasts and reticulocytes. The biochemical examination revealed high bilirubin and feta-hemoglobin (F-HB) and low haptoglobin (HP) in serum. Red cell enzyme concentrations and osmotic hemolytic tests were within normal ranges (Table 1). Light microscope observation showed hyperplasia, irregular nuclei, internuclear bridges of erythroblasts, and high sideroblast counts in bone marrow (Fig. 1b). TEM observation illustrated more than 50 % of erythroblasts with widened
Fig. 1 a Left foot with brachydactylia (arrow); b two internuclear bridges between erythroblasts with rough chromatin (arrows) on bone marrow smear; c an erythroblast with both sponge-like nucleus; d mitochondria (arrows) entering a sponge-like nucleus of erythroblast through widened nuclear pores (arrowheads)
nuclear pores and Swiss cheese-like nuclei (Fig. 1c), as well as iron-overloaded mitochondria in late erythroblasts (Fig. 1d). His direct relatives, including parents, grandparents, an aunt, and two uncles, had no history of anemia and had normal blood and liver function tests. Genomic DNA was isolated from blood samples of the proband and his families using a QIAamp DNA Mini Kit, and coding sequence and exon/intron boundaries of CDAN1 gene were sequenced. Three different mutations of CDAN1 were found in the families (Fig. 2a). The proband was a compound heterozygote with mutation IVS-12+2T>C from the mother and c. 3389C>T from the father (Figs. 2b, c).
Family 2 Two brothers, 43 and 41 years old from a consanguineous Chinese family, suffered from same symptoms of intermittent adynamia, anemia and jaundice, and had received several blood transfusions from the age of 10. They also had complications of gallstones, hepatosplenomegaly, and hemochromatosis in recent years. Their hemoglobin concentrations fluctuated between 30 and 90 g/L, and they have received ironchelating treatment in the last 3 years. The following clinical and laboratory examinations were performed in 2012. Both of them had a macrocytic anemia as demonstrated in peripheral blood. The elder brother showed elevated bilirubin, alanine aminotransferase, ferritin, feta-hemoglobin, and soluble transferrin, but decreased transferrin receptor, TIBC, and haptoglobin in serum. Additionally, he had a short AGLT50 and an osmotic hemolysis test of borderline abnormality. The younger had a positive acidified serum test. Their parents were healthy, and the results of peripheral blood cell analysis were nearly normal. Abnormal morphologic features were observed in bone marrow of both brothers, which included erythroblast hyperplasia, cellular disruption, and rupture, as well as binucleated and multinucleated erythroblasts by light microscopy. TEM examination revealed karyopyknosis, karyorrhexis, karyolysis, dissolving and binucleated erythroblasts, and in particular the doubling-like membrane of erythroblasts (Fig. 3a through d). To identify abnormalities more specifically indicating a diagnosis of CDA II, genomic DNA isolated from the patients and parents, coding sequence, and exon/ intron boundaries of SEC23B were analyzed. The results proved that the brothers were homozygous for mutation c.938G>A in SEC23B (Fig. 2d).
Discussion CDA I is a well-defined entity within the CDAs, and diagnosis is based on dyserythropoiesis characteristics of internuclear
Ann Hematol Table 1 Clinical presentation and laboratory examination data of proband
Presentations
Biochemical test Measured value
F-HB human free hemoglobin, HP haptoglobin, HE hemoglobin electrophoresis, TS transferrin saturation, TIBC total iron-binding capacity, UIBC unsaturated iron-binding capacity, sTf soluble transferring
Iron metabolism test Ref. value
Measured value
Ref. value
Adynamia
Folic acid 4.8
3~17 μmol/L
Serum iron 12.4
8.95~28.64 μmol/L
Jaundice Syndactylous foot Hepatomegalia Gallstones
VB12 284 TBIL 44.33 DBIL 13.74 IBIL 30.59 F-HB 57.8 HP T and c.1787A>G mutations were reported as expected, but IVS-
Fig. 2 a Pedigree of family 1. b Compound heterozygous mutation of CDAN1 of the proband in family 1; c compound heterozygous mutation of CDAN1 of the proband's father in family 1; d homozygous mutation c.938G>A in SEC23B of both brothers with CDAII in family 2
Ann Hematol
A wide spectrum of mutations of SEC23B associated with 28 unrelated individuals with CDA II was identified in 2009 [16]; subsequently, a total of 53 different causative mutations of SEC23B were reported in 109 unrelated cases mainly from European countries and Israel up to 2011 [17–20]. In the present study, both brothers with CDA II were homozygous for the c. 938G>A mutation of SEC23B, which had been described in the main European Registries, and we speculate that CDA II patients from China share similar phenotypic and genetic backgrounds with those from Europe and Israel. In summary, the above three patients with CDA, from two Chinese families, shared the same phenotypes and inherited modes with patients from European and Mediterranean countries. Though most cases of CDA were reported from both areas, this is not sufficient to convince us that the number of patients with CDA and its mutant frequency are different from China. The different incidences among these areas are perhaps in part related to inconsistencies in availability of advanced diagnostic methods; it indicates more patients with CDAs remain to be diagnosed, and we should pay more attention on morbidity and genetic mechanism of CDA in China.
Fig. 3 a Two binucleated erythroblasts with karyopyknosis (arrows); b doubling-like membrane around an erythroblast (arrowheads); c a binucleated erythroblast with doubling-like membrane in dissolving state; d from c doubling-like membrane on higher power
12 +2T >C was a de novo mutation whose properties and significance remain to be clarified. The proband was a compound heterozygote with mutation IVS -12 +2T >C and c. 3389C>T. Interestingly, the proband's father and grandfather did not develop anemia, though they were also compound heterozygous for mutation c.1787A>G and c. 3389C>T. The findings indicate that the c.1787A>G mutation in CDNA1 is not enough to disturb normal biological function, and the IVS12 +2T >C mutation is capable of interfering with the encoding or transcription of condanin1 as one of pathogenic factors. This constitution was similar to another reported Chinese case [7] despite the fact that the mutated loci are different in the CDAN1 gene. CDA II is also known as hereditary erythroblast multinuclearity with positive acidified serum [13]. The majority of patients affected by CDA II has mild anemia (HGB, 9~ 10 g/dL), jaundice, splenomegaly, gallstones, and dermatopathy resulting from iron overload; some patients may have severe anemia and a poor prognosis due to a heavy iron overload. Abnormalities of morphology include anisopoikilocytosis, increased binucleated and multinucleated erythroblasts in CDA II. Doubling-like membrane, a long cisterna beneath the inner surface of the plasmalemma is distinctive on TEM [14, 15].
Conflict of interest The authors have no potential conflicts of interest, including specific financial interests, relationships, or affiliations relevant to the subject of this manuscript. Ethical standards All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent has been obtained from all patients for being included in the study.
References 1. Iolascon A, Esposito MR, Russo R (2012) Clinical aspects and pathogenesis of congenital dyserythropoietic anemias: from morphology to molecular approach. Haematologica 97:1786–1794 2. Liljeholm M, Irvine AF, Vikberg AL et al (2013) Congenital dyserythropoietic anemia type III (CDA III) is caused by a mutation in kinesin family member, KIF23. Blood 6(121):4791–4799 3. Heimpel H, Matuschek A, Ahmed M et al (2010) Frequency of congenital dyserythropoietic anemias in Europe. Eur J Haematol 85:20–25 4. Singh KI, Shartsho JT, Singh WR et al (2007) Congenital dyserythropoietic anemia type II—a case report of two siblings in a family. Indian J Hematol Blood Transfus 23:116–118 5. Kawabata H, Doisaki S, Okamoto A et al (2012) A case of congenital dyserythropoietic anemia type 1 in a Japanese adult with a CDAN1 gene mutation and an inappropriately low serum hepcidin-25 level. Intern Med 51:917–920 6. Szeto SC, Ng CS (1986) A case of congenital dyserythropoietic anemia in a male Chinese. Pathology 18:165–168 7. Ru YX, Zhu XF, Yan WW et al (2008) Congenital dyserythropoietic anemia in a Chinese family with a mutation of the CDAN1-gene. Ann Hematol 87:751–754
Ann Hematol 8. Liu G, Niu S, Dong A et al (2012) A Chinese family carrying novel mutations in SEC23B and HFE2, the genes responsible for congenital dyserythropoietic anaemia II (CDA II) and primary iron overload, respectively. Br J Haematol 158:143–145 9. Yongxin Ru (2013). Current situation of congenital dyserythropoietic anemia diagnosis in a China. J Clin Hematol (in press) 10. Heimpel H, Forteza-Vila J, Queisser W et al (1971) Electron and light microscopic study of the erythropoiesis of patients with congenital dyserythropoietic anemia. Blood 37:299–310 11. Dgany O, Avidan N, Delaunay J et al (2002) Congenital dyserythropoietic anemia type I is caused by mutations in codanin1. Am J Hum Genet 71:1467–1474 12. Iolascon A, Russo R, Delaunay J (2011) Congenital dyserythropoietic anemias. Curr Opin Hematol 18:146–151 13. Crookston JH, Crookston MC, Burnie KL et al (1969) Hereditary erythroblastic multinuclearity associated with a positive acidifiedserum test: a type of congenital dyserythropoietic anaemia. Br J Haematol 17:11–26 14. Iolascon I, D'Agostaro G, Perrotta S et al (1996) Congenital dyserythropoietic anemia type II: molecular basis and clinical aspect. Haematologica 81:543–559
15. Wong KY, Hug G, Lampkin BC (1972) Congenital dyserythropoietic anemia type II: ultrastructural and radioautographic studies of blood and bone marrow. Blood 39:23–30 16. Schwarz K, Iolascon A, Verissimo F et al (2009) Mutations in the human secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II (CDA II). Nat Gen 41:936–940 17. Bianchi P, Fermo E, Vercellati C et al (2009) Congenital dyserythropoietic anemia type II (CDAII) is caused by mutations in the SEC23B gene. Hum Mutat 30:1292–1298 18. Iolascon A, Russo R, Esposito MR et al (2010) Molecular analysis of forty two CDA II patients: New mutations in the SEC23B gene and a search for a genotype-phenotype relationship. Haematologica 95: 708–715 19. Fermo E, Bianchi P, Notarangelo LD et al (2010) CDA II presenting as hydrops foetalis: molecular characterization of two cases. Blood Cells Mol Dis 45:20–22 20. Russo R, Esposito MR, Asci R et al (2010) Mutational spectrum in congenital dyserythropoietic anemia type II: identification of 19 novel mutations in SEC23B gene. Am J Hematol 85:915–920
ORIGINAL ARTICLE
Congenital dyserythropoietic anemia in China: a case report from two families and a review Yongxin Ru & Gang Liu & Jie Bai & Shuxu Dong & Neng Nie & Huamei Zhang & Shixuan Zhao & Yizhou Zheng & Xiaofan Zhu & Guangjun Nie & Fengkui Zhang & Brian Eyden
Received: 4 September 2013 / Accepted: 7 October 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Congenital dyserythropoietic anemias (CDAs) are a group of hereditary disorders characterized by ineffective erythropoiesis and distinct morphological abnormalities of erythroblasts in the bone marrow. Most cases of CDA, caused by a wide spectrum of mutations, have been reported from Europe and Mediterranean countries, while a few cases have been described in China. Here, we present three cases of CDA, one from one family and two from a second unrelated family, with typical morphologic features and clinical presentations. Sequence analysis of CDA-related genes revealed that the proband with CDA Ι in the first family was a compound heterozygote of CDAN1 with mutation IVS-12+2T>C and c. 3389C>T, while both probands with CDA ΙΙ in the second family were a homozygote of the SEC23B gene with mutation c.938G>A (R313H). This study suggests that more patients with CDA, sharing a phenotype and genetic background like those of European and Mediterranean origin, remain to be diagnosed and reported in China. Y. Ru : J. Bai : S. Dong : N. Nie : H. Zhang : S. Zhao : Y. Zheng : X. Zhu : F. Zhang Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Experimental Haematology, Tianjin, China G. Liu : G. Nie CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Centre for Nanoscience and Technology, Beijing, China B. Eyden Department of Histopathology, Christie Hospital NHS Trust, Manchester, UK Y. Ru (*) Pathology Department, Institute of Hematology & Blood Diseases Hospital, Peking Union College, 288 Nanjing Road, Tianjin 300020, China e-mail: [email protected]
Keywords CDAs . Morphology . Sequencing . Chinese
Introduction Congenital dyserythropoietic anemias (CDAs) are a rare group of anemic diseases that result from heterogeneous mutations associated with dyserythropoiesis. So far, four types (types I to IV) have been defined by distinct morphologic features, genetic defects, and clinical presentations [1, 2] in which CDA I and CDA II are the predominant types. Additional variants of CDA have been reported with remarkable morphological studies, but to a certain extent, they overlap with the definite types. Seven hundred twelve cases of CDA from 614 families, including 169 cases of CDA I in 143 families and 454 cases of CDA II in 356 families, were recorded by the German Registry up to December 2011 [3]. Most of them were from Europe and Israel, but a few cases were reported sporadically from India and Japan [4, 5]. Twenty cases of CDA in unrelated Chinese families were published as single case reports up to 2012 in which two cases of CDA II and one case of CDA I were reported in the English literature [6–8], but seven cases of CDA I, six cases of CDA II, and four cases of CDA IV have been reported in Chinese journals [9]. Although some of the described cases need further examination in terms of transmission electron microscopy (TEM) and sequencing analysis to provide a more accurate diagnosis, the finding indicates that CDA I and CDA II are also predominant in China. To better understand the underlying molecular basis of patients with CDA in the Chinese population, we here present one case of CDA I and two cases of CDA II that not previously reported from unrelated Chinese families with sequencing data.
Ann Hematol
Family 1 A 19-year-old male, 51 kg in weight and 170 cm tall and with a brachydactylia foot (Fig. 1a), was the only son in this Chinese family. He suffered from moderate anemia from the age of 9 months, but was not treated regularly until he was 12. His hemoglobin concentration fluctuated between 70 and 100 g/L; severe hemoglobin lows were complicated with jaundice and usually followed a bad cold or an infection. He received a blood transfusion on one occasion when he was 7. The results of clinical and laboratory examinations listed in Table 1 were performed in 2012 when the patient was 19. Peripheral blood analysis showed decreased hemoglobin and hematocrit, but increased numbers of erythroblasts and reticulocytes. The biochemical examination revealed high bilirubin and feta-hemoglobin (F-HB) and low haptoglobin (HP) in serum. Red cell enzyme concentrations and osmotic hemolytic tests were within normal ranges (Table 1). Light microscope observation showed hyperplasia, irregular nuclei, internuclear bridges of erythroblasts, and high sideroblast counts in bone marrow (Fig. 1b). TEM observation illustrated more than 50 % of erythroblasts with widened
Fig. 1 a Left foot with brachydactylia (arrow); b two internuclear bridges between erythroblasts with rough chromatin (arrows) on bone marrow smear; c an erythroblast with both sponge-like nucleus; d mitochondria (arrows) entering a sponge-like nucleus of erythroblast through widened nuclear pores (arrowheads)
nuclear pores and Swiss cheese-like nuclei (Fig. 1c), as well as iron-overloaded mitochondria in late erythroblasts (Fig. 1d). His direct relatives, including parents, grandparents, an aunt, and two uncles, had no history of anemia and had normal blood and liver function tests. Genomic DNA was isolated from blood samples of the proband and his families using a QIAamp DNA Mini Kit, and coding sequence and exon/intron boundaries of CDAN1 gene were sequenced. Three different mutations of CDAN1 were found in the families (Fig. 2a). The proband was a compound heterozygote with mutation IVS-12+2T>C from the mother and c. 3389C>T from the father (Figs. 2b, c).
Family 2 Two brothers, 43 and 41 years old from a consanguineous Chinese family, suffered from same symptoms of intermittent adynamia, anemia and jaundice, and had received several blood transfusions from the age of 10. They also had complications of gallstones, hepatosplenomegaly, and hemochromatosis in recent years. Their hemoglobin concentrations fluctuated between 30 and 90 g/L, and they have received ironchelating treatment in the last 3 years. The following clinical and laboratory examinations were performed in 2012. Both of them had a macrocytic anemia as demonstrated in peripheral blood. The elder brother showed elevated bilirubin, alanine aminotransferase, ferritin, feta-hemoglobin, and soluble transferrin, but decreased transferrin receptor, TIBC, and haptoglobin in serum. Additionally, he had a short AGLT50 and an osmotic hemolysis test of borderline abnormality. The younger had a positive acidified serum test. Their parents were healthy, and the results of peripheral blood cell analysis were nearly normal. Abnormal morphologic features were observed in bone marrow of both brothers, which included erythroblast hyperplasia, cellular disruption, and rupture, as well as binucleated and multinucleated erythroblasts by light microscopy. TEM examination revealed karyopyknosis, karyorrhexis, karyolysis, dissolving and binucleated erythroblasts, and in particular the doubling-like membrane of erythroblasts (Fig. 3a through d). To identify abnormalities more specifically indicating a diagnosis of CDA II, genomic DNA isolated from the patients and parents, coding sequence, and exon/ intron boundaries of SEC23B were analyzed. The results proved that the brothers were homozygous for mutation c.938G>A in SEC23B (Fig. 2d).
Discussion CDA I is a well-defined entity within the CDAs, and diagnosis is based on dyserythropoiesis characteristics of internuclear
Ann Hematol Table 1 Clinical presentation and laboratory examination data of proband
Presentations
Biochemical test Measured value
F-HB human free hemoglobin, HP haptoglobin, HE hemoglobin electrophoresis, TS transferrin saturation, TIBC total iron-binding capacity, UIBC unsaturated iron-binding capacity, sTf soluble transferring
Iron metabolism test Ref. value
Measured value
Ref. value
Adynamia
Folic acid 4.8
3~17 μmol/L
Serum iron 12.4
8.95~28.64 μmol/L
Jaundice Syndactylous foot Hepatomegalia Gallstones
VB12 284 TBIL 44.33 DBIL 13.74 IBIL 30.59 F-HB 57.8 HP T and c.1787A>G mutations were reported as expected, but IVS-
Fig. 2 a Pedigree of family 1. b Compound heterozygous mutation of CDAN1 of the proband in family 1; c compound heterozygous mutation of CDAN1 of the proband's father in family 1; d homozygous mutation c.938G>A in SEC23B of both brothers with CDAII in family 2
Ann Hematol
A wide spectrum of mutations of SEC23B associated with 28 unrelated individuals with CDA II was identified in 2009 [16]; subsequently, a total of 53 different causative mutations of SEC23B were reported in 109 unrelated cases mainly from European countries and Israel up to 2011 [17–20]. In the present study, both brothers with CDA II were homozygous for the c. 938G>A mutation of SEC23B, which had been described in the main European Registries, and we speculate that CDA II patients from China share similar phenotypic and genetic backgrounds with those from Europe and Israel. In summary, the above three patients with CDA, from two Chinese families, shared the same phenotypes and inherited modes with patients from European and Mediterranean countries. Though most cases of CDA were reported from both areas, this is not sufficient to convince us that the number of patients with CDA and its mutant frequency are different from China. The different incidences among these areas are perhaps in part related to inconsistencies in availability of advanced diagnostic methods; it indicates more patients with CDAs remain to be diagnosed, and we should pay more attention on morbidity and genetic mechanism of CDA in China.
Fig. 3 a Two binucleated erythroblasts with karyopyknosis (arrows); b doubling-like membrane around an erythroblast (arrowheads); c a binucleated erythroblast with doubling-like membrane in dissolving state; d from c doubling-like membrane on higher power
12 +2T >C was a de novo mutation whose properties and significance remain to be clarified. The proband was a compound heterozygote with mutation IVS -12 +2T >C and c. 3389C>T. Interestingly, the proband's father and grandfather did not develop anemia, though they were also compound heterozygous for mutation c.1787A>G and c. 3389C>T. The findings indicate that the c.1787A>G mutation in CDNA1 is not enough to disturb normal biological function, and the IVS12 +2T >C mutation is capable of interfering with the encoding or transcription of condanin1 as one of pathogenic factors. This constitution was similar to another reported Chinese case [7] despite the fact that the mutated loci are different in the CDAN1 gene. CDA II is also known as hereditary erythroblast multinuclearity with positive acidified serum [13]. The majority of patients affected by CDA II has mild anemia (HGB, 9~ 10 g/dL), jaundice, splenomegaly, gallstones, and dermatopathy resulting from iron overload; some patients may have severe anemia and a poor prognosis due to a heavy iron overload. Abnormalities of morphology include anisopoikilocytosis, increased binucleated and multinucleated erythroblasts in CDA II. Doubling-like membrane, a long cisterna beneath the inner surface of the plasmalemma is distinctive on TEM [14, 15].
Conflict of interest The authors have no potential conflicts of interest, including specific financial interests, relationships, or affiliations relevant to the subject of this manuscript. Ethical standards All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent has been obtained from all patients for being included in the study.
References 1. Iolascon A, Esposito MR, Russo R (2012) Clinical aspects and pathogenesis of congenital dyserythropoietic anemias: from morphology to molecular approach. Haematologica 97:1786–1794 2. Liljeholm M, Irvine AF, Vikberg AL et al (2013) Congenital dyserythropoietic anemia type III (CDA III) is caused by a mutation in kinesin family member, KIF23. Blood 6(121):4791–4799 3. Heimpel H, Matuschek A, Ahmed M et al (2010) Frequency of congenital dyserythropoietic anemias in Europe. Eur J Haematol 85:20–25 4. Singh KI, Shartsho JT, Singh WR et al (2007) Congenital dyserythropoietic anemia type II—a case report of two siblings in a family. Indian J Hematol Blood Transfus 23:116–118 5. Kawabata H, Doisaki S, Okamoto A et al (2012) A case of congenital dyserythropoietic anemia type 1 in a Japanese adult with a CDAN1 gene mutation and an inappropriately low serum hepcidin-25 level. Intern Med 51:917–920 6. Szeto SC, Ng CS (1986) A case of congenital dyserythropoietic anemia in a male Chinese. Pathology 18:165–168 7. Ru YX, Zhu XF, Yan WW et al (2008) Congenital dyserythropoietic anemia in a Chinese family with a mutation of the CDAN1-gene. Ann Hematol 87:751–754
Ann Hematol 8. Liu G, Niu S, Dong A et al (2012) A Chinese family carrying novel mutations in SEC23B and HFE2, the genes responsible for congenital dyserythropoietic anaemia II (CDA II) and primary iron overload, respectively. Br J Haematol 158:143–145 9. Yongxin Ru (2013). Current situation of congenital dyserythropoietic anemia diagnosis in a China. J Clin Hematol (in press) 10. Heimpel H, Forteza-Vila J, Queisser W et al (1971) Electron and light microscopic study of the erythropoiesis of patients with congenital dyserythropoietic anemia. Blood 37:299–310 11. Dgany O, Avidan N, Delaunay J et al (2002) Congenital dyserythropoietic anemia type I is caused by mutations in codanin1. Am J Hum Genet 71:1467–1474 12. Iolascon A, Russo R, Delaunay J (2011) Congenital dyserythropoietic anemias. Curr Opin Hematol 18:146–151 13. Crookston JH, Crookston MC, Burnie KL et al (1969) Hereditary erythroblastic multinuclearity associated with a positive acidifiedserum test: a type of congenital dyserythropoietic anaemia. Br J Haematol 17:11–26 14. Iolascon I, D'Agostaro G, Perrotta S et al (1996) Congenital dyserythropoietic anemia type II: molecular basis and clinical aspect. Haematologica 81:543–559
15. Wong KY, Hug G, Lampkin BC (1972) Congenital dyserythropoietic anemia type II: ultrastructural and radioautographic studies of blood and bone marrow. Blood 39:23–30 16. Schwarz K, Iolascon A, Verissimo F et al (2009) Mutations in the human secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II (CDA II). Nat Gen 41:936–940 17. Bianchi P, Fermo E, Vercellati C et al (2009) Congenital dyserythropoietic anemia type II (CDAII) is caused by mutations in the SEC23B gene. Hum Mutat 30:1292–1298 18. Iolascon A, Russo R, Esposito MR et al (2010) Molecular analysis of forty two CDA II patients: New mutations in the SEC23B gene and a search for a genotype-phenotype relationship. Haematologica 95: 708–715 19. Fermo E, Bianchi P, Notarangelo LD et al (2010) CDA II presenting as hydrops foetalis: molecular characterization of two cases. Blood Cells Mol Dis 45:20–22 20. Russo R, Esposito MR, Asci R et al (2010) Mutational spectrum in congenital dyserythropoietic anemia type II: identification of 19 novel mutations in SEC23B gene. Am J Hematol 85:915–920
