Severe Hereditary Pyropoikilocytosis/Hereditary Elliptocytosis-Like Phenotype Associated With a Heterozygous SPTA1 Variant in a Cambodian Girl: A Case Report.

BACKGROUND: Hereditary elliptocytosis (HE) is typically a mild or asymptomatic red blood cell membrane disorder characterized predominantly by elliptocytes, whereas hereditary pyropoikilocytosis (HPP) represents the severe end of the HE spectrum, with early-onset hemolysis, marked poikilocytosis, red cell fragmentation, and pronounced membrane instability. We report a Cambodian girl with a severe HPP/HE-like phenotype associated with a heterozygous SPTA1 variant of uncertain significance, emphasizing the importance of integrating clinical, hematologic, morphologic, and molecular findings to support accurate diagnostic classification. CASE PRESENTATION: A 7-year-old Cambodian girl born to nonconsanguineous parents was referred for evaluation of chronic transfusion-dependent hemolytic anemia that began in the neonatal period. She developed severe jaundice at 1 week of age, requiring intensive phototherapy, and required regular packed red blood cell transfusions from 2 weeks of age. Corticosteroid therapy was initiated when immune-mediated hemolysis was suspected, modestly prolonging the transfusion interval before being discontinued because of Cushingoid features. Physical examination revealed pallor, scleral icterus, and mild splenomegaly. Laboratory evaluation showed severe anemia, markedly elevated red cell distribution width, an inappropriately low reticulocyte count for the degree of anemia, a negative direct antiglobulin test, normal G6PD activity, and red cell morphological abnormalities, including poikilocytes, elliptocytes, and red cell fragments. Phenotype-guided clinical whole-exome sequencing identified a heterozygous SPTA1 c.179G > C (p.Arg60Pro) variant of uncertain significance. The clinical presentation and red cell morphology supported classification as a severe HPP/HE-like red cell membrane phenotype, with the heterozygous SPTA1 variant considered an associated molecular finding rather than evidence of causality. CONCLUSION: This case illustrates the diagnostic complexity of severe HPP/HE-spectrum disease associated with a heterozygous SPTA1 variant. In children with early-onset transfusion-dependent hemolytic anemia and compatible red cell morphology, integrated clinical, hematologic, and molecular assessment, supported by family studies, membrane testing, and broader genomic analysis, may improve diagnostic classification when available.