CDAII is an autosomal recessive disorder characterized by ineffective erythropoiesis, anemia, hemolysis, hepatosplenomegaly and morphologic abnormalities. While rare, more than 300 cases of CDAII have been described worldwide, making it the most common form of congenital dyserythropoietic anemia. In patients with CDAII, bone marrow specimens often demonstrate hypercellularity, erythroid hyperplasia and the presence of 10–45% bi- and multinucleated erythroid precursors. Generally, all patients will have a positive serum acid hemolysin test. The clinical picture includes a mild to moderate anemia and hemolysis with typical hemoglobin levels that range from 8 to 11 g/dL. In less than 10 percent of reported cases, severe anemia is seen requiring frequent red blood cell transfusions. Mutations in SEC23B are the underlying defect in the majority of patients with CDAII. SEC23B encodes an essential component of coat protein complex II coated vesicles, resulting in ineffective trafficking of secretory proteins from the endoplasmic reticulum to the Golgi apparatus. Here we report a patient with a severe presentation of CDA II associated with a novel nonsense mutation in the SEC23Bgene.
Our patient was born at 36 weeks estimated gestational age with IUGR and hypospadias. The family history included a brother born with severe anemia, severe hypospadias and hydrops fetalis who died at 4 days of life. Parents were of nonconsanguinious Samoan decent. The initial hemoglobin was 7 g/d; red blood cell transfusions were required on days of life 1, 10 and 15. Total bilirubin peaked at 3.3 and phototherapy was unnecessary. Now 20 months of age, he continues to be transfusion-dependent. Reticulocytopenia is pronounced with absolute reticulocyte counts consistently <20000/mL. Treatment with glucocorticoids produced a minimal increase in reticulocytes without a decrease in frequency of transfusions. Additional laboratory evaluation demonstrated mild indirect hyperbilirubinemia (1–3.4 mg/dL) that presented around one year of age, normal LDH and decreased haptoglobin. Bone marrow evaluation revealed dyserythropoiesis and reticulin fibrosis. Bi- and multinucleated cells were present and comprised 6% of the erythrocyte precursors.
Exome sequencing was performed using Illumina hybrid capture, HiSeq sequencing and a full analysis pipeline. Sequencing revealed compound heterozygosity for two mutations in the SEC23B gene: c.53G>A (p.Arg18His) and c.1507C>T (p.Arg503X). The p.Arg18His has been previously reported in patients with CDAII. The p.Arg503X is a novel nonsense mutation that is expected to be pathogenic, likely resulting in nonsense-mediated decay of the mRNA. These mutations were confirmed clinically by Sanger sequencing and each parent was found to carry one mutation. Compound heterozygosity including a nonsense mutation in SEC23B has been reported to result in a more severe phenotype with reticulocytopenia, a finding consistent with the presentation of our patient. This case demonstrates that exome sequencing, with confirmatory dideoxy sequencing of the affected individual and the parents, can be a powerful new diagnostic approach in inherited hematologic disorders that feature genetic heterogeneity.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.