A new pathogenic variant red cell membrane defect resulting in chronic hemolytic anemia

Abstract Hereditary Pyropoikilocytosis (HPP) is a red blood cell membrane defect characterized by severe and symptomatic hemolytic anemia. The peripheral blood smear typically shows abnormal RBC morphology characterized by anisopoikilocytosis, with elliptocytes and red blood cell fragments. The genetic defect is felt to be due to a decrease in membrane bound spectrin resulting in red cell membrane instability. Genetically, HPP is defined by the co-inheritance of two SPTA1 mutations and Alpha-LeLy polymorphism ( αLeLy rs28525570; SPTA1[c.5572C>G;c.6531-12C>T]) in one or both alleles We are reporting a new genotypic variant which results in a mild chronic compensated normocytic hemolytic anemia that can present in adulthood. A previously healthy 38-year-old man from Ecuador with a past medial history of acute cholecystitis at age 19 who presented with a febrile illness and a normocytic anemia. Hemoglobin(Hgb) 3.7, LDH 459, haptoglobin <10, bili 3.1 and reticulocyte count 0.5%. The direct bilirubin fraction was normal and DAT was negative. Subsequent microbiologic studies revealed IgM and IgG Parvovirus B19 antibodies consistent with acute Parvovirus infection. The clinical picture was consistent with acute Parvovirus aplastic crisis. Review of the peripheral blood smear showed a normocytic anemia with moderately reduced RBC and moderate to severe anisopoikilocytosis, many ovalocytes, elliptocytes, microcytes, schistocytes, tear drop cells, and mild polychromasia. He was treated with red blood cell transfusion and supportive care. Two months after recovery from acute illness his cbc showed a normocytic anemia hgb 12 and a persistent reticulocytosis of 6.8%. The peripheral blood smear red cell morphology showed mixed poikilocytosis and elliptocytes. Osmotic fragility was moderately increased. Hemoglobin electrophoresis and RBC enzymes were normal. EMA banding showed could not be done due to in vitro hemolysis. A Hereditary Hemolytic Anemia Gene Panel (Mayo Clinic Lab) showed variants of uncertain significance in ABCB6, SPTA1, and SPTB genes: ABCB6 (NM_005689.4), chr2(GRCh37):g.220079136A>G, c.1361T>C, p.Val454Ala (p.V454A), heterozygous SPTA1 (NM_003126.4), chr1(GRCh37):g.158648287T>G, c.716A>C, p.Gln239Pro (p.Q239P), homozygous SPTB (NM_001355436.2), chr14(GRCh37):g.65253258C>T, c.3425G>A, p.Arg1142Gln (p.R1142Q), heterozygous The following RISK FACTOR/MODIFIERS were detected: SPTA1 (NM_003126.4), chr1(GRCh37):g.158587858G>A, c.6531-12C>T, homozygous SLC4A1 (NM_000342.4), chr17(GRCh37):g.42328621G We speculate that this combination of gene polymorphisms should no longer be characterized as variants of uncertain significant and are pathogenic resulting instability of the spectrin protein and therefore red cell membrane instability resulting in a mild chronic compensated normocytic hemolytic anemia.