Abstract

Introduction:

Congenital dyserythropoietic anemia (CDA) is a rare autosomal recessive condition that results in dyserythropoiesis and iron overload. Bone marrow evaluation in these patients demonstrates distinctive abnormalities in red cell precursors including multinucleated erythroblasts and chromatin bridges. Dysmorphisms such as distal limb abnormalities, skin pigmentation defects, vertebral malformations, and short stature may also be present. Mutations in the CDAN1/codanin-1 gene underlie the majority of CDA type I cases. We describe a previously unreported pathogenic variant.

Case report:

The female fetus of a gravida 2 para 1 woman was noted to have hepatomegaly, cardiomegaly, and elevated middle cerebral artery velocity concerning for severe intrauterine anemia at approximately 20 weeks gestation. The parents had one previous pregnancy that resulted in a stillborn male infant with hydrops fetalis and club foot. Given concern for anemia with this pregnancy, percutaneous umbilical cord blood sampling was performed demonstrating a fetal hematocrit of 9%. This severe fetal anemia was initially thought to be secondary to ABO incompatibility as mother was O- with a positive antibody screen and infant was A+. The fetus required four intrauterine transfusions and was delivered at 34 weeks 6 days via cesarean section due to history of previous cesarean. Exam revealed a phenotypically normal female with APGARs of 9/9 and a birth weight of 2130 grams.

Following delivery the infant had serial blood counts performed over a 6-week period, which noted a steady decrease in her hematocrit to 16%. A transfusion was given, and a bone marrow evaluation revealed a cellular marrow with red cell hyperplasia and dyserythropoiesis. Next generation sequencing through PreventionGenetics was performed revealing a novel CDAN1 alteration.

Results:

The patient was found to be heterozygous for two mutations in trans in the CDAN1 gene: c.2072dupT and c.2093A>T.

Discussion:

We present a patient with severe fetal and infant transfusion dependent anemia who has two novel CDAN1 gene variants not previously described. The sequence variant c.2072dupT is predicted to result in a frameshift and premature protein termination and is expected to be pathogenic. The second variant c.2093A>T is predicted to result in an amino acid substitution (p.Glu698Val). Another amino acid substitution (p.Glu698Lys) was previously reported as pathogenic in an individual with congenital dyserythropoietic anemia. Based upon the clinical picture, morphologic characteristics, and genetic findings, we have concluded that this presentation is consistent with a diagnosis of CDA type I. Through the utilization of improved diagnostic techniques we continue to gain knowledge regarding the molecular underpinnings of CDA type I.

Disclosures

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.