Clinical characteristics.

Congenital dyserythropoietic anemia type I (CDA I) is characterized by moderate-to-severe macrocytic anemia presenting occasionally in utero as severe anemia associated with hydrops fetalis but more commonly in neonates as hepatomegaly, early jaundice, and intrauterine growth restriction. Some individuals present in childhood or adulthood. After the neonatal period, most affected individuals have lifelong moderate anemia, usually accompanied by jaundice and splenomegaly. Secondary hemochromatosis develops with age as a result of increased iron absorption even in those who are not transfused. Distal limb anomalies occur in 4%-14% of affected individuals.

Diagnosis/testing.

The diagnosis of CDA I is suspected based on hematologic findings and established with identification of biallelic pathogenic variants in CDAN1 or CDIN1.

Management.

Treatment of manifestations: Intramuscular or subcutaneous injections of interferon IFN-α2a or IFN-α2b are given two or three times a week or peginterferon-α2b once a week to increase hemoglobin and decrease iron overload. Allogeneic bone marrow transplantation should be considered only in transfusion-dependent persons who are resistant to IFN therapy. Treatment of iron overload using iron chelation as necessary; laparoscopic cholecystectomy for biliary stones; treatment of scoliosis per orthopedist; calcium and vitamin D supplementation for osteoporosis; treatment of extramedullary hematopoiesis including regular blood transfusions, surgical debulking, or low-dose radiation; treatment of vision issues per ophthalmologist.

Surveillance: Measurement of hemoglobin every three to six months and more frequently at the time of infections, measurement of bilirubin, iron, transferrin, and serum ferritin concentration every six to 12 months starting at age ten years to monitor anemia and iron overload; annual myocardial and liver T₂-weighted MRI starting at age ten years (if available). Annual abdominal ultrasound beginning at age five years; examination for scoliosis with orthopedist as needed; bone densitometry for osteoporosis as recommended by bone specialist; annual assessment of visual acuity and fundoscopic examination by ophthalmologist beginning at age 40 years or earlier if symptomatic.

Agents/circumstances to avoid: Any preparation containing iron.

Genetic counseling.

CDA I is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CDA I-causing pathogenic variant, each sib of an affected individual has at conception 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 the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Congenital dyserythropoietic anemia type I (CDA I) should be suspected in individuals with the following laboratory and clinical findings.

Laboratory features

• Moderate-to-severe macrocytic anemia with mean corpuscular volume (MCV) >90 fL in the presence of normal folic acid and serum vitamin B₁₂ levels
• Inappropriately low number of reticulocytes for the degree of anemia compared to other hemolytic anemias (secondary to ineffective erythropoiesis)
• On peripheral blood smear: macrocytosis, elliptocytes, basophilic stippling, and occasional mature nucleated erythrocytes
• In bone marrow aspirate:
  • On light microscopy, erythroid hyperplasia, few double-nucleated erythroblasts, and interchromatin bridges between erythroblasts (in 0.6%-2.8% of erythroblasts)
  • On electron microscopy, erythroid precursors with spongy appearance of heterochromatin (in ≤60% of erythroblasts) and invaginations of the nuclear membrane

Clinical features

• Jaundice
• Splenomegaly resulting from marrow expansion secondary to ineffective erythropoiesis
• Distal limb anomalies including hypoplastic nails and syndactyly

Establishing the Diagnosis

The diagnosis of CDA I is established in a proband with suggestive findings and biallelic pathogenic variants in CDAN1 or CDIN1 identified on molecular genetic testing.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with anemia are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Prenatal findings. Rarely, congenital dyserythropoietic anemia type I (CDA I) presents as severe in utero anemia that may be associated with hydrops fetalis, requiring intrauterine red blood cell (RBC) transfusion. 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.

Neonatal presentation. 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.

Childhood and later

• Anemia. 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.
• Iron overload. 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.
• Splenomegaly may be absent in infants or young children but develop later with age.
• Gallstones were detected in four of 21 individuals before age 30 years.
• Skeletal findings. Distal limb anomalies including syndactyly, hypoplastic nails, and duplication of the fourth metatarsal bone were described in 4%-14% of affected individuals. Lumbar scoliosis resulting from a partly duplicated L3 vertebra was also described.
  Osteoporosis was found in the majority of individuals [Shalev et al 2017]. Progression should be monitored with bone densitometry. Treatment includes calcium and vitamin D supplementation.
• Extramedullary hematopoiesis (EMH) is a known complication of CDA I although the prevalence is unclear. Treatment is as in non-transfusion-dependent thalassemia, including regular blood transfusions to suppress EMH, surgical debulking, or low-dose radiation [Taher et al 2017].
• Pregnancy complications. A high rate of pregnancy complications was described among 28 women with CDA I, including one stillbirth, one first-trimester spontaneous abortion, and low birth weight in 42% of infants [Shalev et al 2008]. The incidence of cæsarean section was high compared to the control group. Follow up in a high-risk pregnancy unit is therefore recommended.
• Ophthalmic concerns. Retinal angioid streaks with deterioration of vision have been reported as a rare complication in four adults aged 45-57 years [Roberts et al 2006, Tamary et al 2008, Frimmel & Kniestedt 2016].

Life span. Five (23%) of 21 adults described by Heimpel et al [2006] died, mainly as a result of iron overload. According to the authors' published follow-up data, 9% (3/32) of adults died at age 46-59 years. Causes of death included sepsis and severe arterial pulmonary hypertension [Shalev et al 2017]. It should be noted that all deceased individuals previously underwent splenectomy.

Phenotype Correlations by Gene

The phenotype does not differ based on associated gene.

Genotype-Phenotype Correlations

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

Nomenclature

CDAN1-related CDA I is also referred to as CDA type Ia. CDIN1-related CDA I is also referred to as CDA type Ib.

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. Six CDIN1 variants have been described so far in 15 individuals [Babbs et al 2013, Palmblad et al 2018, Rathe et al 2018, Russo et al 2018, Wang et al 2018, Russo et al 2019.]

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CDA I, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

Avoid any preparation containing iron.

Evaluation 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 pathogenic variants 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 [Shalev et al 2008]. Management by a high-risk obstetrics team is recommended.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

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., presumed to be carriers of one CDA I-causing pathogenic variant based on family history).
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CDAN1 or CDIN1 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a CDA I-causing pathogenic variant, each sib of an affected individual has at conception 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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

• Unless an individual with CDA I has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a CDA I-causing pathogenic variant.
• In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that the reproductive partner of the proband is affected or is a carrier. Thus, the risk to offspring is most accurately determined after molecular genetic testing of the proband's reproductive partner (see Prevalence).

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a CDA I-causing pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the CDA I-causing pathogenic variants in the family.

Related Genetic Counseling Issues

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

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative genetic alteration/s are unknown).

Prenatal Testing and Preimplantation Genetic Testing

If the CDA I-causing pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The mechanism by which pathogenic variants in CDAN1 and CDIN1 cause CDA type I is not completely understood. It has been shown that codanin-1 binds ASF1 histone chaperone and acts as a negative regulator of ASF1 function in chromatin assembly [Ask et al 2012]. CDIN1 binds to codanin-1 and stabilizes its structure [Swickley et al 2020]. It has recently also been shown that codanin-1 is essential for embryonal erythropoiesis [Noy-Lotan et al 2021]; however, whether CDA I is directly due to abnormal chromatin assembly remains to be discovered.

Mechanism of disease causation. Predicted loss of function

Revision History

• 29 July 2021 (sw) Comprehensive update posted live
• 25 August 2016 (ha) Comprehensive update posted live
• 20 February 2014 (me) Comprehensive update posted live
• 1 September 2011 (me) Comprehensive update posted live
• 21 April 2009 (et) Review posted live
• 12 November 2008 (ht) Original submission

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