Genetic studies by NGS Panels
Panel for Congenital dyserythropoietic Anemia (Code 10040)
Congenital dyserythropoietic anemia (CDA) is a group of heterogeneous hereditary disorders of hematopoiesis with defective production of red blood cells, characterized by refractory anemia of variable severity. Several forms of CDA s have been characterized: type I, II, III and IV. The shared symptoms include variable intensity anemia, intermittent jaundice, hepato-splenomegaly, and progressive iron overload, most manifest in types I and II. Type I and II CDAs are transmitted with an autosomal recessive hereditary pattern and according to the most recent estimations, their incidence does not exceed 1 / 100,000 births per year (Iolascon A, et al. Blood. 2013; Iolascon A, et al. Haematologica. 2012; Russo R, et al. Am J Hematol. 2014).
Type I CDA may be due to mutations in the CDAN1 gene (Dgany O et al., Am J Hum Genet, 2002 Dec; 71 (6): 1467-74) (OMIM # 224120). This gene codes for a protein implicated in maintaining the integrity of the nuclear envelope. Type I CDA is characterized by moderate to severe anemia that is generally diagnosed in childhood or adolescence, although in some cases, it can be detected before birth. Iron overload can lead to an abnormal heart rhythm (arrhythmia), congestive heart failure, diabetes, and chronic liver disease (cirrhosis). Mutations in gene C15ORF41 has been also described as causative for CDA type I (Babbs C, et al. Haematologica. 2013).
Mutations in the SEC23B gene are causative of type II CDA (Schwarz K et al., NatGenet, 2009) (OMIM # 224100). CDAII is characterized by the presence of binucleated erythroblasts (diplo erythroblasts) with a double membrane derived from endoplasmic reticulum residues that are visualized by electron microscopy. Patients with type II CDA present a serum acidification test, Ham test, positive.
Type III dyserythropoietic anemia (CDA III) is a rare form of dyserythropoietic anemia characterized by moderate to mild and non-progressive hemolytic anemia, dyserythropoiesis, large multinucleated erythroblasts in bone marrow, and macrocytosis in the peripheral blood. The prevalence of this disease is Unknown. Three families have been reported for the autosomal dominant CDA III in Sweden, the United States and Argentina. Four families have been described with the autosomal recessive CDA IIIb form with Spanish or Latinoamerican origin. In addition, other sporadic cases with CDA III have been described. In total, about 60 cases have been described worldwide. The clinical presentation is variable. CDA III can be manifested with mild anemia and jaundice in newborns, but may not be discovered until infancy or in adulthood. The intensity of symptoms increases during infections, after trauma, and during pregnancy. The autosomal dominant (AD) CDA IIIa may be associated with monoclonal gammopathies, multiple myeloma and angioid streaks in the retina. The autosomal recessive CDA IIIb form was associated with macrocytic anaemia with marked dyserythropoiesis, erythroid hyperplasia, giant multinucleated erythroblasts, hepatospenomegaly and skull defects secondary to increased extramedullary hematopoiesis. The KIF23 gene has been identified as the gene that causes the autosomal dominant CDA IIIa form. Recently, mutations in the RACGAP1 gene (12q13) were reported as the cause for the autosomal recessive form of CDA III (named CDA IIIb) (Hernández G, et al. Haematologica 2023). KIF23 codes for the protein MKLP1 (mitotickinesin-likeprotein 1), which dimerizes and combines with a homodimer of the RACGAP1 protein (Rac GTPase-activating protein 1) to form the centralspindlin complex, crucial for cytokinesis (Liljeholm M, et al. Blood 2013). The diagnosis is based on laboratory findings. The disorder is characterized by mild anemia, peripheral macrocytosis, and multinucleated giant erythroblasts (containing up to 12 nuclei) in the bone marrow. Increased serum levels of thymidine kinase, lactate dehydrogenase and bilirubin and very low or undetectable haptoglobin are also characteristic of this disease. Mutations in the KIF23 gene or the RACGAP1 gene may also determine a diagnosis of CDA III.
CDA IV (ORPHA293825, OMIM #613673) is characterized by ineffective erythropoiesis and hemolysis that leads to severe anemia at birth with the requirement of multiple repeated transfusions. Hepatomegaly, splenomegaly, jaundice, hypertrophic cardiomyopathy, and occasional dysmorphic features (large anterior fontanel, hypertelorism, micropenis, and hypospadias) have also been reported. These cases showed increased levels of fetal hemoglobin, a very large number of nucleated red blood cells in peripheral blood and bone marrow erythroblast morphologic abnormalities. CDA IV is due to mutations in the KLF1 gene, encoding an erythroid transcription factor that plays a fundamental role in the development of the erythroid lineage, including the expression of globin genes and additional erythropoiesis genes (Arnaud L, et al. Am J Hum Genet. 2010).
XLTDA, X-linked thrombocytopenia and dyserythropoietic anemia, (ORPHA67044, OMIM #300367) is a rare hematological disorder characterized by dysmorphic erythrocytes, moderate to severe thrombocytopenia with hemorrhages with or without the presence of mild to severe anemia. The disease affects mainly males as females are usually asymptomatic or have only mild symptoms (X-linked inheritance pattern). It presents in infancy or in neonates (in severe cases) with patients bruising easily along with further manifestations of thrombocytopenia including epistaxis, petechiae, ecchymoses, or splenomegaly. Excessive hemorrhage and/or bruising can occur in some patients after trauma or spontaneously in others. Cryptorchidism has also been reported in several cases. Diagnosis is based on family history of the disease and laboratory findings. Blood count reveals thrombocytopenia, in some cases anemia, and very rarely neutropenia. Peripheral blood smear shows abnormal erythrocyte size and shape as well as paucity of platelets. Platelets often have functional abnormalities, shown by a defect in the aggregation response to agonists. Bone marrow biopsy can reveal dyserythropoiesis, dysmorphic erythroblasts, and dysplastic platelets and megakaryocytes. Mutations in the erythroid transcription factor GATA1 gene lead to the CDA variant XLTDA. GATA1 tanscriptional factors play an integral role in the development of erythroid lineage and also in megakaryocytic maturation. Different mutations found in this gene account for a variable phenotypic spectrum of different disorders, not only XLTDA but also X-linked beta-thalassemia with thrombocytopenia (OMIM #314050), and X-linked anemia with/without neutropenia and/or platelet abnormalities (OMIM #300835) (Nichols KE, et al., Nat Genet. 2000).
References
- Arnaud L, Saison C, Helias V, Lucien N, Steschenko D, Giarratana MC, Prehu C, Foliguet B, Montout L, de Brevern AG, Francina A, Ripoche P, Fenneteau O, Da Costa L, Peyrard T, Coghlan G, Illum N, Birgens H, Tamary H, Iolascon A, Delaunay J, Tchernia G, Cartron JP. A dominant mutation in the gene encoding the erythroid transcription factor KLF1 causes a congenital dyserythropoietic anemia. Am J Hum Genet. 2010 Nov 12;87(5):721-7. [PubMed PMID: 21055716]
- Babbs C, Roberts NA, Sanchez-Pulido L, et al. Homozygous mutations in a predicted endonuclease cause Congenital Dyserythropoietic Anemia Type I. Haematologica. 2013.
- Dgany O, Avidan N, Delaunay J, et al. Congenital dyserythropoietic anemia type I is caused by mutations in codanin-1. Am J Hum Genet. 2002;71(6):1467-1474.
- Hernández G, Romero-Cortadellas L, Ferrer-Cortès X, Venturi V, Dessy-Rodriguez M, Olivella M, Husami A, De Soto CP, Morales-Camacho RM, Villegas A, González-Fernández FA, Morado M, Kalfa TA, Quintana-Bustamante O, Pérez-Montero S, Tornador C, Segovia JC, Sánchez M. Mutations in the RACGAP1 gene cause autosomal recessive congenital dyserythropoietic anemia type III. Haematologica. 2023; 108(2):581-587.[PubMed PMID: 36200420].
- Iolascon A, Esposito MR, Russo R. Clinical aspects and pathogenesis of congenital dyserythropoietic anemias: from morphology to molecular approach. Haematologica. 2012;97(12):1786-1794.
- Iolascon A, Heimpel H, Wahlin A, Tamary H. Congenital dyserythropoietic anemias: molecular insights and diagnostic approach. Blood. 2013;122(13):2162-2166.
- Liljeholm M, Irvine AF, Vikberg AL, et al. Congenital dyserythropoietic anemia type III (CDA III) is caused by a mutation in kinesin family member, KIF23. Blood. 2013;121(23):4791-4799.
- Nichols KE, Crispino JD, Poncz M, White JG, Orkin SH, Maris JM, Weiss MJ. Familial dyserythropoietic anaemia and thrombocytopenia due to an inherited mutation in GATA1. Nat Genet. 2000 Mar;24(3):266-70. [PubMed PMID: 10700180].
- 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(10):E169-175.
- Schwarz K, Iolascon A, Verissimo F, et al. Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II. Nat Genet. 2009;41(8):936-940.