Clinical 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 fl

• Bone 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 membrane

• Peripheral blood smear. Macrocytosis, elliptocytes, basophilic stippling, and occasional mature nucleated erythrocytes

• Reticulocytes. 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 erythropoiesis

Molecular 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 testing

• Targeted 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  Among 53 affected individuals [Authors’ and others’ unpublished data]: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 window

Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
CDAN1	Sequence analysis	Sequence variants 2	~75% 3	Clinical
	Targeted mutation analysis	c.3124C>T	100% 4

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. 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 ancestry

Testing Strategy

To confirm/establish the diagnosis in a proband

• Complete 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 microscopy

• Bone marrow aspirate demonstrating erythroid precursors with spongy appearance of heterochromatin by EM

• If 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.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in CDAN1.

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.

Genotype-Phenotype Correlations

No phenotype-genotype correlations are known. Marked clinical variability is observed even among individuals with the same mutations.

Prevalence

About 100 simplex cases (i.e., single occurrences in a family) mainly from Europe and about 70 consanguineous Israeli Bedouin families have been described in the literature.

Evaluations 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 concentration

• Serum 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 stones

• Genetics consultation

Treatment of Manifestations

Intramuscular or subcutaneous injections of interferon (IFN)-α_2a or INF-α_2b 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-α_2b 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 Complications

Treatment 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].

Surveillance

Monitoring 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 Avoid

Avoid any preparation containing iron.

Testing of Relatives at Risk

Evaluation 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 Management

Anemia 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 Investigation

Search 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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Congenital dyserythropoietic anemia type I (CDA I) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).

• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with CDA I are obligate heterozygotes (carriers) for a disease-causing mutation in CDAN1.

Other family members of a proband. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing of at-risk relatives is possible if the disease-causing mutations have been identified in the family.

In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that the reproductive partner of the proband may be affected or a carrier. Thus, the risk to offspring is most accurately determined after molecular genetic testing of the proband's reproductive partner.

Related Genetic Counseling Issues

See Management, Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as CDA I are very uncommon. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

1. Ahmed MR, Chehal A, Zahed L, Taher A, Haidar J, Shamseddine A, O'Hea AM, Bienz N, Dgany O, Avidan N, Beckmann JS, Tamary H, Higgs D, Vyas P, Wood WG, Wickramasinghe SN. Linkage and mutational analysis of the CDAN1 gene reveals genetic heterogeneity in congenital dyserythropoietic anemia type I. Blood. 2006;107:4968–9. [PubMed: 16754775]
2. Angelucci E, Barosi G, Camaschella C, Cappellini MD, Cazzola M, Galanello R, Marchetti M, Piga A, Tura S. Italian Society of Hematology practice guidelines for the management of iron overload in thalassemia major and related disorders. Haematologica. 2008;93:741–52. [PubMed: 18413891]
3. Dgany O, Avidan N, Delaunay J, Krasnov T, Shalmon L, Shalev H, Eidelitz-Markus T, Kapelushnik J, Cattan D, Pariente A, Tulliez M, Crétien A, Schischmanoff PO, Iolascon A, Fibach E, Koren A, Rössler J, Le Merrer M, Yaniv I, Zaizov R, Ben-Asher E, Olender T, Lancet D, Beckmann JS, Tamary H. Congenital dyserythropoietic anemia type I is caused by mutations in codanin-1. Am J Hum Genet. 2002;71:1467–74. [PMC free article: PMC378595] [PubMed: 12434312]
4. Heimpel H, Anselstetter V, Chrobak L, Denecke J, Einsiedler B, Gallmeier K, Griesshammer A, Marquardt T, Janka-Schaub G, Kron M, Kohne E. Congenital dyserythropoietic anemia type II: epidemiology, clinical appearance, and prognosis based on long-term observation. Blood. 2003;102:4576–81. [PubMed: 12933587]
5. Heimpel H, Schwarz K, Ebnöther M, Goede JS, Heydrich D, Kamp T, Plaumann L, Rath B, Roessler J, Schildknecht O, Schmid M, Wuillemin W, Einsiedler B, Leichtle R, Tamary H, Kohne E. Congenital dyserythropoietic anemia type I (CDA I): molecular genetics, clinical appearance, and prognosis based on long-term observation. Blood. 2006;107:334–40. [PubMed: 16141353]
6. Lavabre-Bertrand T, Ramos J, Delfour C, Henry L, Guiraud I, Carillo S, Wagner A, Bureau JP, Blanc P. Long-term alpha interferon treatment is effective on anaemia and significantly reduces iron overload in congenital dyserythropoiesis type I. Eur J Haematol. 2004;73:380–3. [PubMed: 15458519]
7. Schwarz K, Iolascon A, Verissimo F, Trede NS, Horsley W, Chen W, Paw BH, Hopfner KP, Holzmann K, Russo R, Esposito MR, Spano D, De Falco L, Heinrich K, Joggerst B, Rojewski MT, Perrotta S, Denecke J, Pannicke U, Delaunay J, Pepperkok R, Heimpel H. Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II. Nat Genet. 2009;41:936–40. [PubMed: 19561605]
8. Shalev H, Avraham GP, Hershkovitz R, Levy A, Sheiner E, Levi I, Tamary H. Pregnancy outcome in congenital dyserythropoietic anemia type I. Eur J Haematol. 2008;81:317–21. [PubMed: 18573172]
9. Shalev H, Kapelushnik J, Moser A, Dgany O, Krasnov T, Tamary H. A comprehensive study of the neonatal manifestations of congenital dyserythropoietic anemia type I. J Pediatr Hematol Oncol. 2004;26:746–8. [PubMed: 15543010]
10. Tamary H, Offret H, Dgany O, Foliguet B, Wickramasinghe SN, Krasnov T, Rumilly F, Goujard C, Fénéant-Thibault M, Cynober T, Delaunay J. Congenital dyserythropoietic anaemia, type I, in a Caucasian patient with retinal angioid streaks (homozygous Arg1042Trp mutation in codanin-1). Eur J Haematol. 2008;80:271–4. [PubMed: 18081704]
11. Wickramasinghe SN, Wood WG. Advances in the understanding of the congenital dyserythropoietic anaemias. Br J Haematol. 2005;131:431–46. [PubMed: 16281933]

Suggested Reading

1. Heimpel H, Iolascon A. Congenital dyserythropoietic anemia. In: Beaumont C, Beris Ph, Beuzard Y, Brugnara C, eds. Disorders of Homeostasis, Erythrocytes, Erythropoiesis. Paris, France: European School of Haematology; 2006:120-42.

Revision History

• 1 September 2011 (me) Comprehensive update posted live

• 21 April 2009 (et) Review posted live

• 12 November 2008 (ht) Original submission