PB1945: CLINICAL AND MOLECULAR CHARACTERISTICS OF CHILDREN WITH DIAMOND-BLACKFAN ANEMIA (DBA): A SINGLE CENTER EXPERIENCE IN ARGENTINA

Abstract

Background: DBA is an inherited bone marrow failure characterized by erythroblastopenia due to an intrinsic defect in erythropoietic progenitors. Half the patients (pts) present with physical malformations. To date 20 ribosomal proteins (RP) genes associated with DBA and 4 non-RP genes related to non-classical DBA (GATA1, TSR2, EPO, ADA2) have been described. Aims: To describe clinical and molecular characteristics and outcomes of a pediatric cohort with DBA admitted at a single tertiary pediatric center in Argentina Methods: Patients diagnosed with DBA between 2004 and 2020 were retrospectively analyzed. DBA diagnosis was based on constitutional normocytic/macrocytic anemia, reticulocytopenia, paucity of bone marrow erythroid precursors and congenital anomalies. Demographic, clinical, and laboratory data, genetic evaluation and outcomes were recorded. Pts were screened for DNA changes by using a custom designed NGS panel with 19 genes related to DBA (RPS19, RPL11, RPL15, RPL18, RPL27, RPL31, RPL35, RPL35A, RPL5, RPS10, RPS15A, RPS24, RPS26, RPS27, RPS28, RPS29, RPS7, TSR2 and GATA1). All identified variants were classified according to the American College of Medical Genetics guidelines. Results: Fifteen unrelated pts with DBA were analyzed, 10 (66%) males, median age at diagnosis 3,7months (25days-6yrs). Twelve pts (80%) had physical malformations. All pts showed paucity of bone marrow erythroid precursors, and only two presented with compromise of other linages. Thirteen pts (87%) received treatment with prednisone, 8 (62%) achieved transfusion independence and half of them achieved complete treatment independency, while five pts (33%) did not respond to steroids and are under transfusion regimen. These 5pts developed liver iron overload and are under chelation therapy. No therapy was required in two pts with variants in GATA1 and RPL5. Median follow-up was 7.1years (1.7-16.7 years), no pts received HSCT and no pts died. Molecular variants were detected in 10/15 pts (66%), 8/10 were novel. Eight variants were classified as ¨pathogenic¨ or ¨likely pathogenic” and two as “of uncertain significance”. Three pts (30%) presented variants in RPS19, two (20%) in RPS26, four (40%) in other RP genes and one pt with non-classical DBA, presented a variant in GATA1. Phenotype and molecular results of the pts are summarized in Table1. Image:Summary/Conclusion: In this cohort of pts with DBA, molecular diagnosis was achieved in the majority. RPS19 variants were the most common. Interestingly, all pts with RPS19 variants presented with malformations, one of them had also pancytopenia at onset. As the penetrance of DBA is incomplete, the molecular diagnosis is important for detecting silent phenotype carriers in the family that will allow for an accurate selection of stem cell donors, genetic counseling and tailored treatment.