Erythrocyte Disorders Mimicking Congenital Dyserythropoietic Anemia Based on Bone Marrow Pathology Exposed By Genetic Evaluation

Congenital dyserythropoietic anemias (CDAs) are a rare group of heterogeneous genetic diseases characterized by hemolysis, ineffective erythropoiesis predisposing to iron overload, and the pathologic finding of bi- and multinucleated erythroblasts in the bone marrow (BM). With the identification of causative genetic mutations over the last two decades, the current classification includes the following types with the causative gene in parenthesis: Ia ( CDAN1), Ib ( CDIN1); II ( SEC23B); IIIa ( KIF23), IIIb ( RACGAP1); IV ( KLF1) ; and XLTD ( GATA1). Clinical presentation can vary widely even within the same type, ranging from mild cases of anemia to severe cases in which patients are subject to lifelong transfusion dependency. The CDA registry (CDAR) in North America (NCT02964494) was established to allow natural history studies on patients with CDA. Participants without a genetic diagnosis are offered whole genome sequencing (WGS) for patients and parents and may elect to provide samples to the CDAR biorepository to support collaborative mechanistic studies. Currently 169 subjects from 73 different families are enrolled in CDAR (85 patients, 84 unaffected family members). After genetic evaluation, 13 patients were found to be affected not by CDA, but rather by other causes of hereditary hemolytic anemia with secondary dyserythropoiesis. Three patients were diagnosed with pyruvate kinase deficiency (PKD). Patient (pt) 1 had a history of chronic anemia requiring sporadic transfusions since birth and was diagnosed with CDA-II based on BM studies. WGS revealed that the patient was heterozygous for a known PKLR pathogenic variant c.1022G>C p.(Gly341Ala)and for a novel variant of uncertain significance (c.695-3C>G).PK activity assay confirmed the diagnosis of PKD and the patient is now treated with the PK activator mitapivat. Pt 2 had severe transfusion dependent anemia since birth and iron overload. The patient underwent splenectomy at the age of 4 with mild improvement of symptoms. He was diagnosed with CDA II based on BM pathology. Genetic testing was performed and he was found to be compound heterozygous for 2 pathogenic variants in PKLR: c.644dup p.(Arg216fs) and c.994_1003dup p.(Val335fs). Pt 3 had a history of anemia and jaundice since birth; she has not had frequent transfusions but was splenectomized at age 17. The patient was found to be homozygous for c.1436G>A p.(Arg510Gln), a known pathogenic variant in PKLR. Four patients were diagnosed with HBB pa