CDA I is a rare inherited red blood cell disorder characterized by macrocytic anemia, ineffective erythropoiesis, and secondary hemochromatosis. It is occasionally associated with bone abnormalities, especially of the hands and feet (acrodysostosis), nail hypoplasia, and scoliosis (Tamary ... CDA I is a rare inherited red blood cell disorder characterized by macrocytic anemia, ineffective erythropoiesis, and secondary hemochromatosis. It is occasionally associated with bone abnormalities, especially of the hands and feet (acrodysostosis), nail hypoplasia, and scoliosis (Tamary et al., 2005). Striking morphologic abnormalities of erythroblasts, reviewed by Wickramasinghe and Wood (2005), include the 'Swiss-cheese' abnormality of erythroblasts on electron microscopy. - Classification and Genetic Heterogeneity of Congenital Dyserythropoietic Anemia There are 4 types of congenital dyserythropoietic anemia: CDAN2 (224100), caused by mutation in the SEC23B gene (610512); CDAN3 (105600), which maps to chromosome 15q21; and CDAN4 (613673), caused by mutation in the KLF1 gene (600599). All forms of CDAN are characterized by ineffective erythropoiesis and multinuclear erythroblasts. The classification of the first 3 types is based on that described by Wendt and Heimpel (1967). Type I is characterized by megaloblastic changes. The more common type II (224100) is characterized by normocytic binuclear or multinuclear red cells, which on electron microscopy contain double cytoplasmic membranes. Type III (105600), which is autosomal dominant, shows prominent erythroblastic multinuclearity forming 'gigantoblasts' with up to 12 nuclei. Type IV (613673) is the designation given to a form of CDA with characteristics different from those of types I, II, and III (Wickramasinghe et al., 1991; Arnaud et al., 2010).
Wendt and Heimpel (1967) described dizygotic twins affected with a macrocytic form of dyserythropoietic anemia in which the bone marrow contained megaloblastoid erythroblasts with characteristic chromatin bridges between the nuclei.
Benjamin et al. (1975) described a ... Wendt and Heimpel (1967) described dizygotic twins affected with a macrocytic form of dyserythropoietic anemia in which the bone marrow contained megaloblastoid erythroblasts with characteristic chromatin bridges between the nuclei. Benjamin et al. (1975) described a single patient with a form of dyserythropoietic anemia that did not satisfy any of the known criteria. Her red cells had normoblastic multinuclearity and normocytosis but lacked the ultrastructural and serologic features of type II. Heimpel (1976) counted 21 reported cases of CDA I, the rarest type. These included 3 pairs of sibs. Lay et al. (1978) reported 2 brothers with neonatal jaundice, requiring transfusion at 8 weeks of age but remaining well with only mild anemia subsequently. Kuribayashi et al. (1979) reported affected brother and sister with first-cousin parents. Mori et al. (1986) reported the sixth family with more than 1 affected sib. Facon et al. (1990) reported affected identical twins; both children had mild hemochromatosis. Moderate growth retardation appeared to be related to pituitary failure. Carter et al. (1989) and Williams et al. (1990) reported cases of congenital erythropoietic anemia presenting as hydrops fetalis. The patient reported by Carter et al. (1989) was the product of first-cousin parents. Al-Fawaz and Al-Mashhadani (1995) described the cases of a brother and sister with CDA I. The girl presented in the neonatal period with anemia, jaundice, and hepatosplenomegaly and required 4 blood transfusions in the first 7 months of life, while her brother was discovered to be anemic and jaundiced only at the age of 2 years and did not receive any blood transfusions. The children were reported from Saudi Arabia; the parents were first cousins. The authors referred to a previous report of 3 cases from Kuwait (Zaki et al., 1989). Tamary et al. (1996) described CDA I among Israeli Bedouins. In affected persons, the erythroid precursors demonstrated S phase arrest and ultrastructural morphologic features consistent with apoptosis. Shalev et al. (2000) reported 3 sibs from a Bedouin family with CDA I who presented with persistent pulmonary hypertension of the newborn. They suggested that the diagnosis of CDA I should be considered in any neonate with persistant pulmonary hypertension and anemia. Parez et al. (2000) described a patient with severe pre- and postnatal manifestations of CDA I. Exchange transfusions were required for fetal anemia at 28 and 30 weeks' gestation. Transfusions were administered at birth by cesarean section at week 35 and at regular intervals thereafter. Successful treatment with alpha-interferon was initiated at 14 months. Tamary et al. (2005) reported 6 French patients, 1 European American patient, and 1 Israeli Arab patient. Four of the 8 patients had neonatal manifestations, 3 had complex bone disease, and 2 had both. Three patients had only mild anemia and hyperferritinemia. The bony abnormalities were described as acrodysostosis with vertebral anomalies. Heimpel et al. (2006) followed 21 patients from 19 families with CDA I for up to 37 years. All patients exhibited chronic macrocytic anemia of variable severity, requiring regular red cell transfusions in only 2 individuals. Additional congenital malformations were seen in 7 patients, involving a sixth toe and syndactyly in 3 patients and a ventricular septal defect, short stature, double kidneys, and hip dysplasia in 1 each. Gallstones developed in 4 patients before the age of 30 years, and iron overloading was found in 20 of 21 patients. Splenectomy, which was performed in 7 patients, did not result in improvement of hemoglobin parameters. Five patients were treated with interferon alpha-2a (see 147562), and all responded with a rise in hemoglobin concentration of 2.5 to 3.5 g/dL.
Dgany et al. (2002) identified CDAN1, the gene responsible for CDA I, through the identification of 12 different mutations in 9 families with the disorder (e.g., 607465.0001).
In 15 of 16 CDA I patients analyzed, Heimpel ... Dgany et al. (2002) identified CDAN1, the gene responsible for CDA I, through the identification of 12 different mutations in 9 families with the disorder (e.g., 607465.0001). In 15 of 16 CDA I patients analyzed, Heimpel et al. (2006) identified 17 different mutations in at least 1 allele of the CDAN1 gene. All but 1 of the mutations were located in exons 12 to 28; 1 mutation was found in exon 6.
The diagnosis of congenital dyserythropoietic anemia type I (CDA I) is based on the findings of: ...
DiagnosisClinical Diagnosis The diagnosis of congenital dyserythropoietic anemia type I (CDA I) is based on the findings of: Macrocytic anemia. Moderate to severe with MCV >90 flBone marrow aspirate Light microscopy. Erythroid hyperplasia, few double-nucleated erythroblasts, and interchromatin bridges between erythroblasts (in 0.6-2.8% of erythroblasts)Electron microscopy. Erythroid precursors with spongy appearance of heterochromatin (in ≤60% of erythroblasts) and invaginations of the nuclear membranePeripheral blood smear. Macrocytosis, elliptocytes, basophilic stippling, and occasional mature nucleated erythrocytesReticulocytes. Inappropriately low for the degree of anemia compared to other hemolytic anemias (secondary to ineffective erythropoiesis) Other Jaundice Splenomegaly resulting from marrow expansion secondary to ineffective erythropoiesisMolecular Genetic Testing Gene. CDAN1 is the only gene in which mutation is currently known to cause CDA I [Dgany et al 2002].Evidence for locus heterogeneity. In a consanguineous Kuwaiti family that includes three sibs with CDA I, no homozygosity for CDAN1 was found, suggesting that in this family mutation in a different gene may be causative of CDA I [Ahmed et al 2006]. Clinical testingTargeted mutation analysis. One founder mutation, c.3124C>T, is observed in the Bedouin population.Sequencing of the entire coding sequence of CDAN1 detects mutations in 75% of affected individuals. Among 53 affected individuals [Authors’ and others’ unpublished data]:Both mutations were identified in 32 (60%)A single mutation was identified in 15 (28%). Note: Testing to detect splice-site mutations was not performed.No mutation was identified in six (11%). Note: Testing to detect splice-site mutations and large deletions was not performed.Table 1. Summary of Molecular Genetic Testing Used in Congenital Dyserythropoietic Anemia Type I View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityCDAN1Sequence analysisSequence variants 2~75% 3ClinicalTargeted mutation analysisc.3124C>T100% 41. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. In 60% of affected individuals two mutations were identified, in 28% only one mutation was identified, and in 11% no mutation was identified [combined data of Authors and other labs, unpublished].4. In persons of Bedouin ancestryTesting Strategy To confirm/establish the diagnosis in a probandComplete blood count revealing macrocytic anemia Exclusion of common entities with macrocytic anemia (e. g., megaloblastic disease, liver disease, myeloid dysplastic syndromes) Bone marrow aspirate demonstrating erythroid hyperplasia, few double-nucleated erythroblasts, and internuclear chromatin bridges between erythroblasts by light microscopyBone marrow aspirate demonstrating erythroid precursors with spongy appearance of heterochromatin by EMIf bone marrow EM is unavailable and erythroid internuclear chromatin bridges are observed, molecular genetic testing Molecular genetic testing Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family. Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with mutations in CDAN1.
Rarely, CDA I presents as severe in utero anemia that may be associated with hydrops fetalis, requiring intrauterine red blood cell (RBC) transfusion....
Natural History Rarely, CDA I presents as severe in utero anemia that may be associated with hydrops fetalis, requiring intrauterine red blood cell (RBC) transfusion.Of 70 Bedouin neonates with CDA I, 45 (64%) were symptomatic [Shalev et al 2004]. Of those with symptoms, 65% had hepatomegaly, 53% had early jaundice, and 27% were small for gestational age. A few had persistent pulmonary hypertension, direct hyperbilirubinemia, and transient thrombocytopenia. The majority of affected infants required at least one blood transfusion during the neonatal period. Splenomegaly may be absent in infants or young children, but develop later with age. Most affected individuals have lifelong moderate anemia (mean hemoglobin levels 85±6 g/L). Anemia is usually accompanied by jaundice and splenomegaly, which was present in 17 of 21 (80%) individuals [Heimpel et al 2006]. Few are transfusion-dependent: Heimpel et al [2006] found that only two of 21 individuals followed for up to 37 years were dependent on transfusion. Even in those with CDA I who are not transfused, secondary hemochromatosis develops with age as a result of increased iron absorption. Free iron precipitating in parenchymal organs and especially in the heart can cause congestive heart failure and arrhythmias. Low hepcidin levels have been documented in individuals with CDA I. Gall stones were detected in four of 21 individuals before age 30 years. Distal limb anomalies including syndactyly, hypoplastic nails, and duplication of fourth metatarsal bone were described in 4%-14% of affected individuals. Lumbar scoliosis resulting from a partly duplicated L3 vertebra was also described. Retinal angioid streaks with deterioration of vision have been reported in two adults [Tamary et al 2008]. Fertility is not affected; however, the anemia places pregnancies of affected women at high risk for delivery-related and outcome complications. Sixty-four percent of 28 pregnancies in Bedouin women with CDA I were complicated [Shalev et al 2008]. One pregnancy aborted spontaneously in the first trimester and one resulted in stillbirth at 26 weeks’ gestation. Cesarean section was performed in ten deliveries (36%). Eleven of 26 (42%) newborns had a low birth weight: six were premature and five were small for gestational age. Careful maternal and fetal follow-up during pregnancy was associated with significantly better fetal outcome.
No phenotype-genotype correlations are known. Marked clinical variability is observed even among individuals with the same mutations. ...
Genotype-Phenotype Correlations No phenotype-genotype correlations are known. Marked clinical variability is observed even among individuals with the same mutations.
The following congenital anemias are included in the differential diagnosis of CDA I:...
Differential DiagnosisThe following congenital anemias are included in the differential diagnosis of CDA I:Congenital dyserythropoietic anemia type II (CDA II) is the most common CDA. It is also known as HEMPAS (hereditary erythroblastic multinuclearity with positive acidified serum lysis test) because patients' RBCs are lysed by acidified sera of 40%-60% of healthy adults because of the presence of natural cold-reacting IgM antibody. CDA II is characterized by mild to severe anemia, jaundice, and splenomegaly, which is observed in 50%-60% of affected individuals. Up to 15% of affected individuals are transfusion-dependent [Heimpel et al 2003, Wickramasinghe & Wood 2005]. Beyond age 20 years most affected individuals develop iron overload. The diagnosis of CDA II requires evidence of congenital anemia, ineffective erythropoiesis, and typical bone marrow findings with binuclearity in 10%-50% of erythroblasts. SEC23B, the gene in which mutation causes CDA II, has recently been cloned [Schwarz et al 2009].Congenital dyserythropoietic anemia type III (CDA III) is the rarest CDA. It was first described in 1951 in an American family by Wolfe and von Hofe, and in 1962 in a large family from Northern Sweden [Wickramasinghe & Wood 2005]. The clinical presentation is similar to that of CDA I and CDA II; however, in the Swedish family, the anemia is not severe and transfusions are not required. The most marked anomaly in the bone marrow is the presence of giant multinucleated erythroblasts with up to 12 nuclei per cell. Additional findings include retinal angioid streaks, macular degeneration, and monoclonal gammopathy with or without multiple myeloma. The gene in which mutation was causative was mapped close to CDAN1 in a 4.5-cM interval between 15q21 and 15q25. CDA III has been described in fewer than 20 well-documented simplex cases (i.e., single occurrence in a family).Other. The diagnosis of CDA should be considered following exclusion of other causes of macrocytosis (mainly B12 deficiency and folic acid deficiency) and dyserythropoiesis, including thalassemia syndromes and hereditary sideroblastic anemia. However, the latter two are associated with microcytic anemia.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with congenital dyserythropoietic anemia type I (CDA I), the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with congenital dyserythropoietic anemia type I (CDA I), the following evaluations are recommended:Hemoglobin concentration and serum bilirubin concentrationSerum ferritin concentration and other modalities used to assess iron overload including liver and myocardial T2* MRI and hepatic R2* MRI Abdominal ultrasound examination to evaluate for biliary stonesGenetics consultationTreatment of ManifestationsIntramuscular or subcutaneous injections of interferon (IFN)-α2a or INF-α2b given two or three times a week increase hemoglobin and decrease iron overload in the majority of treated individuals [Lavabre-Bertrand et al 2004]. Peginterferon-α2b has also been given once a week. The mechanism behind this response is unknown. To date, only a limited number of individuals, including infants, have been treated.Successful allogenic bone marrow transplantation has been described in a few individuals and should be considered only in those transfusion-dependent persons who are resistant to IFN therapy.Splenectomy is of unproved value; failure of this procedure to increase hemoglobin levels has been described in the literature. Prevention of Secondary ComplicationsTreatment of iron overload with regular phlebotomies, if possible, along with iron chelators as necessary, is indicated. Iron overload therapy should follow the guidelines used for thalassemia [Angelucci et al 2008].SurveillanceMonitoring for iron overload by:At least annual measurement of serum ferritin concentration Myocardial T2* MRI and hepatic R2* MRI, if available, starting in adolescence Agents/Circumstances to AvoidAvoid any preparation containing iron. Evaluation of Relatives at RiskEvaluation of the younger sibs of a proband for early manifestations of CDA I is recommended so that monitoring of hemoglobin and ferritin levels and treatment can begin as soon as necessary in those who are affected. Evaluation of at-risk family members should include CBC to identify macrocytic anemia as well as typical findings on blood smear including macrocytosis, elliptocytes, and basophilic stippling. The diagnosis can be confirmed by molecular genetic testing if the disease-causing mutations in the family have been identified.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementAnemia places pregnancies of affected women at high risk for delivery-related and outcome complications. Prenatal management of pregnancies at risk for complications of CDA I involves monitoring of fetal hemoglobin by Doppler ultrasonography and fetal transfusions to prevent hydrops fetalis if severe fetal anemia is detected. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Congenital Dyserythropoietic Anemia Type I: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCDAN115q15.2Codanin-1CDAN1 homepage - Mendelian genesCDAN1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Congenital Dyserythropoietic Anemia Type I (View All in OMIM) View in own window 224120ANEMIA, DYSERYTHROPOIETIC CONGENITAL, TYPE I; CDAN1 607465CODANIN 1; CDAN1Normal allelic variants. The normal allele consists of 28 exons spanning 15 kb of genomic DNA. It encompasses a putative mRNA of 4738 nucleotides encoding a protein of 1226 amino acids. Pathologic allelic variants. Most mutations (23/36) are missense. Other types of mutations identified to date include: five frameshift, four stop codon, and four splice site. No affected individual was found to be homozygous for null-type mutations. Most mutations (28/36) are found on the 3' half of the gene; most are in exons 14 and 24. Fourteen mutations are recurring, including the following from Europe: c.2012C>T (9/75, 12% of affected alleles)c.3389C<T (5/75, 7% of affected alleles)c.3128A>T (4/75, 5% of affected alleles) And the following from Europe and China:c.2140C>T (4/75, 5% of affected alleles) The Bedouin mutation, c.3124C>T, was recently found in a French individual of European ancestry. In 28% of affected individuals only one mutation in CDAN1 has been identified, and in 12% of affected individuals no mutation in CDAN1 identified; however, in most individuals splice-site or large deletions have not been ruled out.Table 2. Selected CDAN1 Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference SequencesNormalc.320A>Tp.Gln107LeuNM_138477.2 NP_612486.2c.386G>Ap.Arg129Hisc.1787A>Gp.Gln596Argc.2671C>Tp.Arg891CysPathologicc.156C>Gp.Phe52Leuc.2012C>Tp.Pro671Leuc.2140C>Tp.Arg714Trpc.3124C>Tp.Arg1042Trp 1c.3128A>Tp.Asp1043Valc.3389C<Tp.Pro1130LeuSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. In persons of Bedouin ancestryNormal gene product. The function of the gene product, codanin-1 protein, is still unknown. It has 1226 amino acids [Ahmed et al 2006].Abnormal gene product. It is not known how abnormal codanin-1 causes the disorder, but it is thought to result from loss of normal protein function. Molecular genetic testing has shown that affected individuals have at least one mutant allele that is predicted to result in a translated protein product, suggesting that the codanin-1 protein may be essential for life.