Congenital dyserythropoietic anemia type II and ineffective erythropoiesis: challenges in diagnosis and management

Congenital dyserythropoietic anemia (CDA) is characterized by anemia—mild to severe, hemolysis, ineffective erythropoiesis, and in some cases, iron overload. There are three major types of CDA (I, II, and III), and the other types are rarer. The rarity of this disease, as well as signs and symptoms that overlap with other hematological diseases, can make the diagnosis difficult and delayed over several years. Evaluation includes basic laboratory testing, magnetic resonance imaging of organs for assessment of iron overload, bone marrow assessment, and genetic testing. Laboratory tests to evaluate for ineffective erythropoiesis include indirect bilirubin level, which can be normal or increased, reticulocyte production index < 2 signifying hyperproliferation of erythrocytes, and complete iron panel (serum iron, ferritin, and iron saturation), which may suggest iron overload. Genetic testing is crucial for CDA diagnosis and includes next-generation sequencing. A multidisciplinary team of providers including a hematologist, hepatologist, hematopathologist, and genetic counselor are important and sometimes necessary for the evaluation, diagnosis, and management of these patients. Management depends on the clinical phenotype, and some severe cases may require blood transfusion, iron chelation therapy, splenectomy, and in extreme cases, hematopoietic stem cell transplant may be necessary. This mini-review illustrates the challenges involved in the diagnosis and management of the most common CDA, which is type II. It will highlight clinical signs and symptoms in patients that should prompt providers to test for CDA. It will also increase awareness of this disease, discuss possible barriers to testing, and provide guidance on how to manage the disease.

1 Introduction

Erythropoiesis produces 150 billion erythrocytes daily, and defects in this process due to maturation arrest resulting in decreased red cell production, are known as dyserythropoiesis, a type of inherited bone marrow failure syndrome (1). Congenital dyserythropoietic anemia (CDA) is a rare hereditary hemolytic disease characterized by varied severity of anemia requiring blood transfusions in some patients, hemolysis, ineffective erythropoiesis, and iron overload (2). There are three classic CDA subtypes (I, II, and III) that were initially identified using bone marrow morphology criteria and later confirmed using genetic analysis; additional subtypes include transcription-factor-related CDAs and other rare CDA variants (1, 3). See recent reviews of CDA (3, 4). This article focuses on CDA type II and discusses the disease in the literature.

2 CDA type II

CDA II is an autosomal recessive disease that is the result of biallelic pathogenic variant mutations in the SEC23B gene (20p11.23), which encodes the cytoplasmic coat protein II (COPII) complex, a protein involved in intracellular vesicle trafficking in eukaryotic cells as well as autophagy (2, 3). Loss-of-function genetic variants lead to defects in the transport of newly synthesized proteins from the endoplasmic reticulum to the Golgi (1–3). Diagnosis has been reported to occur from in utero to 78 years (mean 18.2 years) (5). CDA II is most common in the Mediterranean region (Morocco, Israel, and Italy) (6). Differential diagnoses of CDA II include hemoglobinopathies, Diamond–Blackfan anemia, hereditary spherocytosis, pyruvate kinase deficiency, and Fanconi anemia (7). The morphologic findings in CDA include erythroid hyperplasia and binucleate cells (8). CDA II has the highest percent of binucleate cells at > 10% (9). Some patients previously diagnosed with CDA based on bone marrow morphology were later found to be misdiagnosed based on the identification of pathogenic variants in genes associated with other genetic conditions, such as pyruvate kinase deficiency and hereditary spherocytosis (2). Since the disease is rare and overlaps clinically with other more common hematologic disorders such as thalassemia and red cell membrane disorders, misdiagnosis earlier in life is common, which can lead to mismanagement as well as delayed diagnosis (10). Some patients may not receive the correct diagnosis of CDA II until middle age or even late adulthood (11, 12).

3 Presentation of CDA type II

3.1 Hemolytic anemia

CDA should be suspected in patients with signs and symptoms of high red cell turnover (hemolysis), such as jaundice, low or undetectable haptoglobin, and indirect hyperbilirubinemia (1). Neonatal jaundice can be seen in almost 62% of CDA II patients (7). Patients with CDA II often present with a normocytic anemia (6), jaundice, and splenomegaly as a result of hemolysis (3). Peripheral blood smear examination of the red cells shows anisopoikilocytosis with basophilic stippling and rare binucleated mature erythroblasts (1). Severe anemia and extramedullary erythropoiesis result in splenomegaly and hypersplenism (1). Hemoglobin, reticulocyte count, indirect bilirubin, and haptoglobin levels in CDA II often reveal hemolytic anemia with inadequate reticulocytosis (1).

3.1.1 Mechanism of hemolytic anemia in CDA II—ineffective erythropoiesis, peripheral hemolysis, and erythroid hypo proliferation

Ineffective erythropoiesis occurs when there is inadequate reticulocytosis in the presence of immature erythroid precursors contributing to anemia (13). It is characterized by erythropoietin-driven expansion of erythroid precursors and apoptosis of late-stage erythroid precursors (14). In addition, ineffective erythropoiesis causes overexpression of erythroferrone in patients with CDA II (15), which suppresses hepcidin leading to increased iron absorption and progressive iron overload (3). This phenomenon is seen in other hematologic diseases such as non-transfusion-dependent thalassemia and sideroblastic anemia (13). Hypoxia develops because of anemia and drives an increase in erythropoietin, which further expands erythroid cells and perpetuates ineffective erythropoiesis. Hemolysis also contributes to anemia in CDA II (14).

3.2 Iron overload

The most common complications of CDA II are iron overload, splenomegaly, and cholelithiasis (1). Iron overload is often due to ineffective erythropoiesis as well as frequent blood transfusions and hemolysis (7). When excess iron accumulates in hepatocytes and other parenchymal cells, iron toxicity leads to cell death, fibrosis, and organ failure (13). About 30% of CDA II patients who are not transfusion-dependent still show increased ferritin levels of > 300 ng/mL and 17% show hemosiderosis with ferritin levels > 600 ng/mL (3). Other complications of iron overload include liver disease, hepatocellular cancer, diabetes, and heart failure and arrhythmias.

4 Diagnosis

Diagnosis includes a thorough evaluation of personal and family history, clinical signs and symptoms, bone marrow morphology, laboratory studies, and the results of genetic testing (3). Although bone marrow morphology was primarily used to identify patients with CDA, molecular testing can expedite the definitive diagnosis of CDA in some patients (2). Hypoglycosylation of band 3 is a consistent finding in CDA II and reflects the effects of the molecular defect; 95% of CDA II patients have hypoglycosylated band 3 in the membrane of their red cells (6), which is associated with hemolysis as increased clustering of the protein on the red blood cell (RBC) surface leads to IgG binding and RBC phagocytosis (7). Two cases that were reported without hypoglycosylation were due to severe hemolysis in the setting of hydrops fetalis (16).

4.1 Bone marrow morphology

The morphological features that define CDA II include erythroid hyperplasia and multinucleation, with the most specific finding being the presence of >10% binucleate cells in which both nuclei are at the same maturational stage (1, 3). Genetic testing should be included early in the evaluation for possible CDA (3) as it can prevent unnecessary bone marrow biopsies (10, 17).

4.2 Evaluation of iron status

It is important to assess iron status including serum iron, serum ferritin, and transferrin saturation, which can show signs of iron overload (14). Magnetic resonance imaging (MRI) is preferred for measuring liver iron concentration (LIC) and is an excellent surrogate of body iron status (18). It is considered more accurate for quantifying body iron compared to liver biopsy (19). MRI is also used to assess iron levels in other organs including the heart and endocrine organs; these results can be useful for deciding when an iron chelator may be indicated (20).

4.3 Genetic testing

Bone marrow morphology is not definitive for CDA (3). For example, a patient who was initially suspected of having CDA based on bone marrow morphology was ultimately diagnosed with a hemoglobinopathy when genetic testing did not reveal any pathogenic genetic variants in the genes associated with CDA but showed a heterozygous variant in HBB (c.442T>C, p.stop148Gln) for Hb Zunyi (21). Another patient was ultimately diagnosed with non-deletional hemoglobin H disease using Sanger sequencing following an incorrect diagnosis of CDA II based on bone marrow morphology (22). As these CDAII patients are often misdiagnosed especially with pyruvate kinase deficiency, multigene panel testing was shown to identify patients with congenital hemolytic anemia misdiagnosed with CDA based on clinical diagnosis and helped to render an accurate diagnosis of chronic anemia due to enzymatic defects in 10 out of 22 (45%) patients; the same team also identified syndromic cases of CDA variants (23). The diagnostic complexity is further demonstrated by patients with co-inheritance of CDA and hemoglobinopathy (24, 25).

5 Complications of CDA II

5.1 Iron overload

Iron overload is a known complication of CDA II and can even be seen in transfusion-independent patients (13). The degree of overload is due to erythropoietic expansion (14) and the levels appear to increase with age (5). Some patients may report fatigue and others may develop liver cirrhosis and portal hypertension because of secondary iron overload (5, 7). Hypogonadism may also occur due to iron overload in the hypothalamus (7).

5.2 Hydrops fetalis

CDA II can present as hydrops fetalis and intrauterine death (16). Intrauterine red cell transfusions may be helpful in such cases of CDA II (26) as in a pregnant patient who presented with fetal hydrops and cardiomegaly at 20 weeks gestation. The fetus had a hemoglobin level of 1.5 mg/dL and required intrauterine blood transfusions. Following delivery, the baby ultimately underwent a postnatal hematopoietic stem cell transplant (HSCT) and achieved transfusion independence (27). While hydrops fetalis may occur in CDA II, in utero anemia, and consequently, hydrops fetalis is more commonly seen in CDA I (7).

5.3 Cholelithiasis

Gallstones are often diagnosed in the first 40 years of life (5). Higher levels of indirect bilirubin that increases the rate of gallstone occurrence can be seen in some CDA II patients who co-inherit UGT1A1 (TA)7/(TA)7 genotype, which causes Gilbert syndrome as well as SEC23B biallelic pathogenic variants (7, 28). Symptomatic patients with cholelithiasis should undergo cholecystectomy with the same guidance as patients without CDA II (29).

5.4 Other complications

Other complications that can be seen in patients with CDA II include heart failure, diabetes, hypothyroidism and hypogonadism, and splenomegaly (splenectomy is discussed further under the clinical management of CDA). Reactive thrombocytosis can also be seen following splenectomy (5).

6 Challenges in diagnosis and diagnosis workflow

A highly experienced hemopathologist is required for accurate diagnosis of CDA by bone marrow morphology (8). Although the bone marrow morphology findings are helpful, patients with stomatocytosis and sideroblastic anemia have been misdiagnosed with CDA II based on nonspecific dyserythropoietic findings (8). Incorporating NGS early in the diagnostic approach can lead to early diagnosis, avoiding splenectomy and preventing potentially fatal thromboembolic complications (8). However, technical limitations and barriers in the current understanding of the genome contribute to missed genetic diagnoses. In addition, the use of NGS may not always be feasible due to limited resources and costs, especially in some low- and middle-income countries (30, 31). In such instances, the implementation of a thoughtful, stepwise diagnostic approach has been shown to be useful (32).

7 Clinical management

Management of CDA II is largely supportive care. The primary goal is to manage the effects of anemia as well as iron overload, and in some cases, it may be helpful to involve psychologists, nutritionists, and endocrinologists in the management (24). Stem cell transplant is curative (6). Also, see Table 1.

Table 1

Table 1 Management of CDA (not specific to CDA II).

7.1 Monitoring of laboratory markers

Management includes checking a complete blood count and iron studies (iron level, ferritin, and transferrin saturation) every 6 months (or sooner based on laboratory or clinical severity) (3). Iron studies are certainly important to check as the average ferritin was found to be 464.8 ± 55.9 ng/mL in a study of CDA II patients, with ferritin value 282.2 ± 36.7 ng/mL (15–2,097, n = 88) in non-transfusion-dependent patients while transfusion-dependent patients (25/126, 19.8%) showed a serum ferritin level of 918 ± 171 ng/mL (108–2,750, n = 21) (6).

7.2 Blood transfusion

Approximately 7%–20% of cases require transfusion (1, 3) while about 10% of these patients are asymptomatic (3). Blood transfusion should be considered for hemoglobin levels < 7 g/dL. If diagnosed in utero, then in utero transfusions must be carried out, and evaluation for hydrops during prenatal ultrasonography should be employed in cases of a positive family history (29).

7.3 Iron chelation therapy

Unlike patients with hereditary hemochromatosis, patients with CDA II are often anemic and so, therapeutic phlebotomy is not an option for managing iron load. Therefore, iron chelators are the sole option, and the management is extrapolated from iron chelation therapy in patients with beta thalassemia. Treatment is recommended once the serum ferritin is 800–1,000 ng/mL or LIC > 3–5 mg/g, and treatment is withheld when ferritin is < 300 ng/mL or LIC < 3 mg/g (20, 33, 34). A normal LIC is 0.8 to 1.5 mg/g dry weight (18). Currently, there are three FDA-approved iron chelators, namely, one parenteral (deferoxamine) and two oral (deferiprone and deferasirox) medications (20). In reality, practice patterns are quite variable with iron chelators being initiated based on ferritin levels 500–2,000 ng/mL and LIC 3–10 mg/g (35). Combination iron chelation therapy can also be used to decrease LIC rapidly (20).

7.4 Splenectomy

Splenomegaly was seen in a cohort of CDA Type II patients in the first 3 decades of life (5). A retrospective study of 205 patients with CDA II found that 83.6% (102/122) of the patients presented with splenomegaly (6). Since damaged and abnormal erythrocytes traversing the spleen red pulp are removed by the splenic macrophage system, splenectomy is often suggested as a therapeutic approach (36). There are well known complications of splenectomy including post splenectomy infections with encapsulated bacteria, post-splenectomy thromboembolism (acute splenic and portal vein thrombosis), late cardiovascular events (arterial and venous thromboembolism, as well as pulmonary arterial hypertension), and perioperative complications such as laceration (36). Therefore, it is prudent to avoid splenectomy whenever possible. However, splenectomy is recommended for the management of CDA II in transfusion-dependent patients or those with symptomatic splenomegaly (36). A study of 17 patients with CDA II showed about a 1-g increase in hemoglobin on average to 10.6 ± 1.6 g/dL following splenectomy from 9.3 ± 1.2 g/dL in all but three patients (6). Therefore, splenectomy does not normalize hemoglobin levels in CDA II. Also notable is that splenectomy does not alleviate additional iron loading in these patients (5) Splenic artery embolization is less invasive with fewer complications, including a lower risk for early in-hospital infections and may be an attractive alternative to splenectomy (37).

7.5 Hematopoietic stem cell transplant

HSCT is currently the only curative option and has been successful in some cases of CDA II leading to transfusion independence (6, 25, 38). Several HSCTs have been reported in pediatric cases of CDA II, some with partial resolution (39). One patient required up to three HSCTs in order to achieve transfusion independence; of note, this case of CDA II was diagnosed by bone marrow morphology without a positive CDA II genetic marker (40), raising the possibility of an incorrect diagnosis. A retrospective study, which described a large cohort of 39 CDA patients including 13 with CDA II, showed that matched sibling donor HSCT patients had a superior overall survival compared to unrelated donor transplant (41). The study also showed better outcomes for patients without iron overload and so patients should be assessed and treated with chelation prior to transplant (41).

7.6 Potential future therapy

Interferon improves anemia and iron loading in some cases of CDA I and some patients become transfusion-independent shortly after starting interferon (2). However, interferon is not associated with clinical improvement in CDA II, and there are no approved medications for achieving transfusion independence in CDA II. In beta thalassemia, ineffective erythropoiesis is exacerbated by decreased erythroid cell differentiation (14) and so the approval of luspatercept for transfusion-dependent thalassemia has been revolutionary.

7.6.1 Transforming growth factor beta inhibitor

Luspatercept binds select TGF-β superfamily ligands and promotes late-stage erythroid maturation (42). Luspatercept was approved by the U.S. Food and Drug Administration in 2019 and the European Medicines Agency for the treatment of transfusion-dependent beta thalassemia based on the BELIEVE phase III trial, which showed a 33% reduction from baseline during weeks 13–24 compared to placebo and 11% of patients achieved transfusion independence at any 8-week interval (43). Luspatercept also led to a decrease in serum ferritin from baseline by week 48 while the ferritin levels in the placebo group increased; however, there was no change in the liver iron concentration or myocardial iron deposition (43). It also increases the use and redistribution of iron in the body (42).

Sotatercept, another TGF inhibitor, inhibits GDF11, which is a negative regulator of erythropoiesis and murine ortholog of sotatercept, known as RAP-011 improved anemia and decreased iron overload in a murine model of beta thalassemia (44). Sotacercept has also been found to reduce transfusion burden in beta thalassemia patient in phase II clinical trials (45).

As CDA II and thalassemia share a major similarity of ineffective erythropoiesis, the clinical improvements seen with the use of luspatercept and sotatercept suggest a possible role for TGF beta inhibitors in the treatment of CDA II.

7.6.2 Gene therapy

While there are currently no human CDA II gene therapy approaches available, CRISPR/cas9 gene editing system used to knock-out SEC23B gene in K562 cells as well as in hematopoietic stem and progenitor cells has led to a decrease in SEC23B protein in both cell models. Consequently, in vitro and in vivo erythroid differentiation of the edited cells showed an increased number of binucleated and multinucleated cells (46). RAP-011 rescues the disease phenotype in SEC23B-silenced K562 cells by restoring the gene expression of erythroid markers through inhibition of the phosphorylated SMAD2 pathway; it also reduces the expression of erythroferrone in vitro (44). Finally, the increased expression of SEC23A (the SEC23B paralog in mice) using CRISPR rescues the SEC23B-deficient erythroid defect in mice (47). All these suggest that gene therapy may be a new therapeutic target as well as a potential treatment option for CDA II in the future.

Author contributions

IA: Writing – original draft, Writing – review & editing. KB: Writing – review & editing. RL: Writing – review & editing. JW: Investigation, Writing – review & editing. RF: Writing – review & editing.

Funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

1. Iolascon A, Esposito MR, Russo R. Clinical aspects and pathogenesis of congenital dyserythropoietic anemias: from morphology to molecular approach. Haematologica. (2012) 97:1786–94. doi: 10.3324/haematol.2012.072207

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Niss O, Lorsbach RB, Berger M, Chonat S, McLemore M, Buchbinder D, et al. Congenital dyserythropoietic anemia type I: First report from the Congenital Dyserythropoietic Anemia Registry of North America (CDAR). Blood Cells Mol Dis. (2021) 87:102534. doi: 10.1016/j.bcmd.2020.102534

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Iolascon A, Andolfo I, Russo R. Congenital dyserythropoietic anemias. Blood. (2020) 136:1274–83. doi: 10.1182/blood.2019000948

PubMed Abstract | CrossRef Full Text | Google Scholar

4. King R, Gallagher PJ, Khoriaty R. The congenital dyserythropoieitic anemias: genetics and pathophysiology. Curr Opin Hematol. (2022) 29:126–36. doi: 10.1097/MOH.0000000000000697

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Heimpel H, Anselstetter V, Chrobak L, Denecke J, Einsiedler B, Gallmeier K, et al. Congenital dyserythropoietic anemia type II: epidemiology, clinical appearance, and prognosis based on long-term observation. Blood. (2003) 102:4576–81. doi: 10.1182/blood-2003-02-0613

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Russo R, Gambale A, Langella C, Andolfo I, Unal S, Iolascon A. Retrospective cohort study of 205 cases with congenital dyserythropoietic anemia type II: definition of clinical and molecular spectrum and identification of new diagnostic scores. Am J Hematol. (2014) 89:E169–75. doi: 10.1002/ajh.23800

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Gambale A, Iolascon A, Andolfo I, Russo R. Diagnosis and management of congenital dyserythropoietic anemias. Expert Rev Hematol. (2016) 9:283–96. doi: 10.1586/17474086.2016.1131608

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Shefer Averbuch N, Steinberg-Shemer O, Dgany O, Krasnov T, Noy-Lotan S, Yacobovich J, et al. Targeted next generation sequencing for the diagnosis of patients with rare congenital anemias. Eur J Haematol. (2018) 101:297–304. doi: 10.1111/ejh.13097

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Heimpel H, Kellermann K, Neuschwander N, Hogel J, Schwarz K. The morphological diagnosis of congenital dyserythropoietic anemia: results of a quantitative analysis of peripheral blood and bone marrow cells. Haematologica. (2010) 95:1034–6. doi: 10.3324/haematol.2009.014563

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Heimpel H, Schwarz K, Ebnother M, Goede JS, Heydrich D, Kamp T, et al. Congenital dyserythropoietic anemia type I (CDA I): molecular genetics, clinical appearance, and prognosis based on long-term observation. Blood. (2006) 107:334–40. doi: 10.1182/blood-2005-01-0421

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Tandon B, Peterson LC, Norwood S, Zakarija A, Chen Y. Congenital dyserythropoietic anemia type II (CDA II) diagnosed in an adult patient. J Hematopathol. (2010) 3:149–53. doi: 10.1007/s12308-010-0073-5

CrossRef Full Text | Google Scholar

12. Greiner TC, Burns CP, Dick FR, Henry KM, Mahmood I. Congenital dyserythropoietic anemia type II diagnosed in a 69-year-old patient with iron overload. Am J Clin Pathol. (1992) 98:522–5. doi: 10.1093/ajcp/98.5.522

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Camaschella C, Nai A. Ineffective erythropoiesis and regulation of iron status in iron loading anaemias. Br J Haematol. (2016) 172:512–23. doi: 10.1111/bjh.13820

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Cazzola M. Ineffective erythropoiesis and its treatment. Blood. (2022) 139:2460–70. doi: 10.1182/blood.2021011045

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Russo R, Andolfo I, Manna F, De Rosa G, De Falco L, Gambale A, et al. Increased levels of ERFE-encoding FAM132B in patients with congenital dyserythropoietic anemia type II. Blood. (2016) 128:1899–902. doi: 10.1182/blood-2016-06-724328

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Fermo E, Bianchi P, Notarangelo LD, Binda S, Vercellati C, Marcello AP, et al. CDAII presenting as hydrops foetalis: molecular characterization of two cases. Blood Cells Mol Dis. (2010) 45:20–2. doi: 10.1016/j.bcmd.2010.03.005

PubMed Abstract | CrossRef Full Text | Google Scholar

17. Roy NBA, Babbs C. The pathogenesis, diagnosis and management of congenital dyserythropoietic anaemia type I. Br J Haematol. (2019) 185:436–49. doi: 10.1111/bjh.15817

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Coates TD, Wood JC. How we manage iron overload in sickle cell patients. Br J Haematol. (2017) 177:703–16. doi: 10.1111/bjh.14575

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Wood JC, Zhang P, Rienhoff H, Abi-Saab W, Neufeld EJ. Liver MRI is more precise than liver biopsy for assessing total body iron balance: a comparison of MRI relaxometry with simulated liver biopsy results. Magn Reson Imaging. (2015) 33:761–7. doi: 10.1016/j.mri.2015.02.016

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Aydinok Y. Iron chelation therapy as a modality of management. Hematol Oncol Clin North Am. (2018) 32:261–75. doi: 10.1016/j.hoc.2017.12.002

PubMed Abstract | CrossRef Full Text | Google Scholar

21. Nagahama J, Nishikawa T, Nakamura T, Nakagawa S, Kodama Y, Terazono H, et al. Severe beta-thalassemia (Hb Zunyi) mimicking congenital dyserythropoietic anemia. Pediatr Blood Cancer. (2023) 70:e30706. doi: 10.1002/pbc.30706

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Jamwal M, Sreedharanunni S, Taak R, Singh N, Chhabra S, Kaur J, et al. Non-deletional haemoglobin H (Hb H) disease morphologically masquerading as congenital dyserythropoietic anaemia type II: a diagnostic pitfall. J Clin Pathol. (2024) 77:257–8. doi: 10.1136/jcp-2023-209179

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Russo R, Andolfo I, Manna F, Gambale A, Marra R, Rosato BE, et al. Multi-gene panel testing improves diagnosis and management of patients with hereditary anemias. Am J Hematol. (2018) 93:672–82. doi: 10.1002/ajh.25058

PubMed Abstract | CrossRef Full Text | Google Scholar

24. Li EW, Walsh R, Ho PJ. Benign clinical phenotype of co-inherited congenital dyserythropoietic anaemia type I and heterozygous haemoglobin Lepore. Eur J Haematol. (2023) 111:161–4. doi: 10.1111/ejh.13974

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Iolascon A, Sabato V, de Mattia D, Locatelli F. Bone marrow transplantation in a case of severe, type II congenital dyserythropoietic anaemia (CDA II). Bone Marrow Transplant. (2001) 27:213–5. doi: 10.1038/sj.bmt.1702764

PubMed Abstract | CrossRef Full Text | Google Scholar

26. Remacha AF, Badell I, Pujol-Moix N, Parra J, Muniz-Diaz E, Ginovart G, et al. Hydrops fetalis-associated congenital dyserythropoietic anemia treated with intrauterine transfusions and bone marrow transplantation. Blood. (2002) 100:356–8. doi: 10.1182/blood-2001-12-0351

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Braun M, Wolfl M, Wiegering V, Winkler B, Ertan K, Bald R, et al. Successful treatment of an infant with CDA type II by intrauterine transfusions and postnatal stem cell transplantation. Pediatr Blood Cancer. (2014) 61:743–5. doi: 10.1002/pbc.24786

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Perrotta S, del Giudice EM, Carbone R, Servedio V, Schettini F Jr, Nobili B, et al. Gilbert’s syndrome accounts for the phenotypic variability of congenital dyserythropoietic anemia type II (CDA-II). J Pediatr. (2000) 136:556–9. doi: 10.1016/S0022-3476(00)90026-X

PubMed Abstract | CrossRef Full Text | Google Scholar

29. Manes G, Paspatis G, Aabakken L, Anderloni A, Arvanitakis M, Ah-Soune P, et al. Endoscopic management of common bile duct stones: European Society of Gastrointestinal Endoscopy (ESGE) guideline. Endoscopy. (2019) 51:472–91. doi: 10.1055/a-0862-0346

PubMed Abstract | CrossRef Full Text | Google Scholar

30. Kingsmore SF, Lantos JD, Dinwiddie DL, Miller NA, Soden SE, Farrow EG, et al. Next-generation community genetics for low- and middle-income countries. Genome Med. (2012) 4:25. doi: 10.1186/gm324

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Mudau MM, Seymour H, Nevondwe P, Kerr R, Spencer C, Feben C, et al. A feasible molecular diagnostic strategy for rare genetic disorders within resource-constrained environments. J Commun Genet. (2024) 15:39–48. doi: 10.1007/s12687-023-00674-8

CrossRef Full Text | Google Scholar

32. Aly NH, Elalfy MS, Elhabashy SA, Mowafy NM, Russo R, Andolfo I, et al. A stepwise diagnostic approach for undiagnosed Anemia in children: A model for low-middle income country. Blood Cells Mol Dis. (2023) 103:102779. doi: 10.1016/j.bcmd.2023.102779

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Taher AT, Weatherall DJ, Cappellini MD. Thalassaemia. Lancet. (2018) 391:155–67. doi: 10.1016/S0140-6736(17)31822-6

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Saliba AN, Musallam KM, Taher AT. How I treat non-transfusion-dependent beta-thalassemia. Blood. (2023) 142:949–60. doi: 10.1182/blood.2023020683

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Lal A, Wong TE, Andrews J, Balasa VV, Chung JH, Forester CM, et al. Transfusion practices and complications in thalassemia. Transfusion. (2018) 58:2826–35. doi: 10.1111/trf.14875

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Iolascon A, Andolfo I, Barcellini W, Corcione F, Garcon L, De Franceschi L, et al. Recommendations regarding splenectomy in hereditary hemolytic anemias. Haematologica. (2017) 102:1304–13. doi: 10.3324/haematol.2016.161166

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Aiolfi A, Inaba K, Strumwasser A, Matsushima K, Grabo D, Benjamin E, et al. Splenic artery embolization versus splenectomy: Analysis for early in-hospital infectious complications and outcomes. J Trauma Acute Care Surg. (2017) 83:356–60. doi: 10.1097/TA.0000000000001550

PubMed Abstract | CrossRef Full Text | Google Scholar

38. Modi G, Shah S, Madabhavi I, Panchal H, Patel A, Uparkar U, et al. Successful allogeneic hematopoietic stem cell transplantation of a patient suffering from type II congenital dyserythropoietic anemia A rare case report from western India. Case Rep Hematol. (2015) 2015:792485. doi: 10.1155/2015/792485

PubMed Abstract | CrossRef Full Text | Google Scholar

39. Uygun V, Russo R, Karasu G, Daloglu H, Iolascon A, Yesilipek A. Hematopoietic stem cell transplantation in congenital dyserythropetic anemia type II: A case report and review of the literature. J Pediatr Hematol Oncol. (2020) 42:e507–e10. doi: 10.1097/MPH.0000000000001612

PubMed Abstract | CrossRef Full Text | Google Scholar

40. Macaraeg M, Proytcheva M, Katsanis E. Transfusion independence after repeated haploidentical hematopoietic cell transplants in a patient with congenital dyserythropoietic anemia type II and hemosiderosis. Pediatr Transplant. (2019) 23:e13587. doi: 10.1111/petr.13587

PubMed Abstract | CrossRef Full Text | Google Scholar

41. Miano M, Eikema DJ, Aljurf M, Van't Veer PJ, Ozturk G, Wolfl M, et al. Stem cell transplantation for congenital dyserythropoietic anemia: an analysis from the European Society for Blood and Marrow Transplantation. Haematologica. (2019) 104:e335–e9. doi: 10.3324/haematol.2018.206623

PubMed Abstract | CrossRef Full Text | Google Scholar

42. Garbowski MW, Ugidos M, Risueno A, Shetty JK, Schwickart M, Hermine O, et al. Luspatercept stimulates erythropoiesis, increases iron utilization, and redistributes body iron in transfusion-dependent thalassemia. Am J Hematol. (2024) 99:182–92. doi: 10.1002/ajh.27102

PubMed Abstract | CrossRef Full Text | Google Scholar

43. Cappellini MD, Viprakasit V, Taher AT, Georgiev P, Kuo KHM, Coates T, et al. A phase 3 trial of luspatercept in patients with transfusion-dependent beta-thalassemia. N Engl J Med. (2020) 382:1219–31. doi: 10.1056/NEJMoa1910182

PubMed Abstract | CrossRef Full Text | Google Scholar

44. De Rosa G, Andolfo I, Marra R, Manna F, Rosato BE, Iolascon A, et al. RAP-011 rescues the disease phenotype in a cellular model of congenital dyserythropoietic anemia type II by inhibiting the SMAD2–3 pathway. Int J Mol Sci. (2020) 21:5577. doi: 10.3390/ijms21155577

PubMed Abstract | CrossRef Full Text | Google Scholar

45. Cappellini MD, Porter J, Origa R, Forni GL, Voskaridou E, Galacteros F, et al. Sotatercept, a novel transforming growth factor beta ligand trap, improves anemia in beta-thalassemia: a phase II, open-label, dose-finding study. Haematologica. (2019) 104:477–84. doi: 10.3324/haematol.2018.198887

PubMed Abstract | CrossRef Full Text | Google Scholar

46. Dessy-Rodriguez M, Fañanas-Baquero S, Venturi V, Payan-Pernia S, Tornador C, Hernandez G, et al. Modelling congenital dyserythropoietic anemia type II through gene editing in hematopoietic stem and progenitor. Blood. (2020) 136:27. doi: 10.1182/blood-2020-139207

CrossRef Full Text | Google Scholar

47. King R, Lin Z, Balbin-Cuesta G, Myers G, Friedman A, Zhu G, et al. SEC23A rescues SEC23B-deficient congenital dyserythropoietic anemia type II. Sci Adv. (2021) 7:eabj5293. doi: 10.1126/sciadv.abj5293

PubMed Abstract | CrossRef Full Text | Google Scholar