HX due to heterozygousPIEZO1 mutation. A European American girl, born at term, developed neonatal hyperbilirubinemia that prevented discharge from the nursery for 4 days while receiving treatment with phototherapy. Scleral icterus was again noted at 10 months of age, and a CBC indicated reticulocytosis but a normal Hgb. She continued to have chronic hemolysis and jaundice and had an extensive workup including negative DAT, normal Hgb electrophoresis, RBC enzyme activity testing showing normal or increased activity, osmotic fragility testing that was (probably mistakenly) reported as normal rather than as decreased, alpha and beta globin genetic testing that revealed no mutation or copy number variation, a negative PNH screen by flow cytometry, and bone marrow studies showing erythroid hyperplasia, no dyserythropoiesis, and markedly increased iron stores. (A) At 10 years of age, she had osmotic gradient ektacytometry performed that demonstrated a typical HX curve, with left shift due to decreased Omin and Ohyp (Figure 2A). The CBC at the time indicated an Hgb of 14.2 g/dL, an MCV of 96 fl, an MCH of 36.5 pg, an MCHC of 37.9 g/dL, a reticulocyte count 16.9%, and an ARC of 643 × 10³/µL. (B) A blood smear was significant for polychromasia, macrocytosis, and occasional stomatocytes, target cells, and dense fragmented cells. Of note, sometimes the blood smear may be deceptively normal, with only a few target cells and no stomatocytes. A determination of the RBC intracellular cation confirmed a reduced K⁺ content without a corresponding increase in Na⁺ content. NGS for an RBC membrane disorder panel revealed 1 of the most common PIEZO1 variants (c.7367G>A, p.R2456H) causing HX. PNH, paroxysmal nocturnal hemoglobinuria.