Congenital Dyserythropoietic Anemia Type I

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Retrieved

2021-01-18

Source

Gene_reviews

Trials

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Genes

CDAN1, C15orf41, SEC23B, KLF1, GDF15, CBX5, HAMP, ERFE

Drugs

(S)-3'-(OH)-desazadesferrithiocin-polyether, magnesium salt

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Summary

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 retardation. Some cases 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.

Diagnosis of CDA I is suspected based on hematologic findings and established with identification of biallelic pathogenic variants in CDAN1 or CDIN1 (C15orf41).

Management.

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. Successful allogenic bone marrow transplantation has been described in three children and should be considered only in those transfusion-dependent persons who are resistant to IFN therapy.

Prevention of secondary complications: Treatment of iron overload using standard guidelines for regular phlebotomy and iron chelation as needed.

Surveillance: Recommended monitoring for iron overload:

Measurement of hemoglobin, bilirubin, iron, transferrin and serum ferritin concentration every three months starting at age ten years.
Annual myocardial T₂* MRI and hepatic R₂* MRI (if available) starting at age ten years.

Agents/circumstances to avoid: Any preparation containing iron.

Genetic counseling.

CDA I is inherited in an autosomal recessive manner. 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 the pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible options.

Diagnosis

Suggestive Findings

Congenital dyserythropoietic anemia type I (CDA I) should be suspected in individuals with the following findings:

Moderate-to-severe macrocytic anemia with MCV >90 fL
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
Other:
- Jaundice
- Splenomegaly resulting from marrow expansion secondary to ineffective erythropoiesis
- Anemia and distal limb dimorphism including hypoplastic nails and syndactyly

Establishing the Diagnosis

The diagnosis of CDA I is established in a proband with suggestive findings and identification of biallelic pathogenic variants in one of the genes listed in Table 1.

Molecular testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

Serial single-gene testing can be considered if (1) mutation of a particular gene accounts for a large proportion of the disease or (2) factors including clinical findings, laboratory findings, or ancestry indicate that mutation of a particular gene is most likely.

Sequence analysis of the gene of interest is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.*

Targeted analysis for the c.3124C>T pathogenic variant in CDAN1 can be performed first in individuals of Bedouin ancestry.
In all other ethnicities, full gene sequencing of CDAN1 should be performed first.
If no CDAN1 pathogenic variant is found, full sequencing of CDIN1 (C15orf41) should be performed in all populations.

*Note: The authors are not aware of deletion/duplication analysis having been performed on either CDAN1 or CDIN1.

A multigene panel that includes CDIN1 and CDAN1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes CDIN1 and CDAN1) fails to confirm a diagnosis in an individual with features of CDA 1. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Congenital Dyserythropoietic Anemia Type I (CDA I)

Gene ¹	Proportion of CDA1 Attributed to Pathogenic Variants in Gene	Proportion of Pathogenic Variants ² Detectable by Method
Gene ¹		Sequence analysis ³	Gene-targeted deletion/duplication analysis ⁴
CDIN1	~1% ⁵	3/3	Unknown ⁶
CDAN1	90% ⁷	97/97	Unknown ⁶
Unknown ⁸	9%	NA

1.: See Table A. Genes and Databases for chromosome locus and protein.
2.: See Molecular Genetics for information on allelic variants detected in this gene.
3.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
4.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
5.: Author, personal observation
6.: No data on detection rate of gene-targeted deletion/duplication analysis are available.
7.: In 60% of affected individuals two pathogenic variants were identified by sequence analysis, in 28% only one pathogenic variant was identified, and in 11% no pathogenic variant was identified (Note: Testing to detect splice site variants and large deletions was not performed) [Authors and other labs, combined data, unpublished].
8.: The existence of at least one additional locus is suggested by the absence of pathogenic variants in CDAN1 or CDIN1 in seven families with CDA I [Babbs et al 2013].

Clinical Characteristics

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.
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 fourth metatarsal bone were described in 4%-14% of affected individuals. Lumbar scoliosis resulting from a partly duplicated L3 vertebra was also described.
Ophthalmic concerns. Retinal angioid streaks with deterioration of vision have been reported is a rare complication of inherited hemolytic anemia in 4 adults aged 45-57 years [Roberts et al 2006, Tamary et al 2008, Frimmel & Kniestedt 2016].

Life span. Five (23%) of 21 adult patients described by Heimpel et al [2006] died, mainly as a result of iron overload. According to the authors’ recently published follow-up data, 9% (3/32) of adult patients 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 patients previously underwent splenectomy.

Genotype-Phenotype Correlations

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

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. CDIN1 (C15orf41) variants have been described in one family originating in Kuwait and in two South Asian (Pakistani) families [Babbs et al 2013].

Differential Diagnosis

The following congenital anemias are included in the differential diagnosis of CDA I:

Congenital dyserythropoietic anemia type II (CDA II; OMIM 224100) is the most common CDA. It is also known as HEMPAS (hereditary erythroblastic multinuclearity with positive acidified serum lysis test) because the RBCs of affected individuals are lysed by acidified sera of 40%-60% of healthy adults due to the presence of natural cold-reacting IgM antibody. CDA II is characterized by mild-to-severe anemia, jaundice, and (in 50%-60% of affected individuals) splenomegaly. 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. CDA II is caused by mutation of SEC23B and inherited in an autosomal recessive manner [Schwarz et al 2009].
Congenital dyserythropoietic anemia type III (CDA III; OMIM 105600) is the rarest CDA. It was first described in 1951 in an American family by Wolfe and von Hofe, and again 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 pathogenic variants were 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., a single occurrence in a family).
Congenital dyserythropoietic anemia type IV (CDAN IV; OMIM 613673) is caused by mutation of KLF1 and inherited in an autosomal dominant manner.

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.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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
Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Intramuscular 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.Treatment should be given by a physician who is experienced in interferon administration.

Successful allogenic bone marrow transplantation has been described in three children [Ayas et al 2002] 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 and also thromboembolic complications may follow splenectomy. Therefore, splenectomy should be cautiously considered in patients with CDA I, as is recommended for non-transfusion-dependent thalassemia [Taher et al 2013].

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 non-transfusion dependent thalassemia [Taher et al 2013].

Surveillance

Recommended monitoring for iron overload:

Measurement of hemoglobin, bilirubin, iron, transferrin and serum ferritin concentration every three months starting at age ten years
Annual myocardial T₂* MRI and hepatic R₂* MRI, if available, starting at age ten years

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].

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.