Hematologic manifestations of sitosterolemia: Phenotypic spectrum and long-term outcomes in seven genetically confirmed patients.

BACKGROUND: Sitosterolemia is a rare autosomal recessive lipid metabolism disorder caused by pathogenic variants in ABCG5 or ABCG8 genes. Although classically associated with xanthomas and premature atherosclerosis, some patients may predominantly present with hematologic manifestations, leading to significant diagnostic challenges. METHODS: We retrospectively analyzed seven genetically confirmed cases of sitosterolemia presenting primarily with hematologic abnormalities at a tertiary care hematology center. Clinical characteristics, hematologic parameters, peripheral smear findings, molecular genetic profile, treatment response, and long-term outcomes were evaluated. RESULTS: The median age at presentation was 15 years (range: 6-17 years). All patients presented with anemia and splenomegaly, while thrombocytopenia was observed in six patients. Peripheral blood smear examination demonstrated stomatocytes and/or macrothrombocytes in a majority of cases. None of the patients had tendon xanthomas or overt dyslipidemic manifestations at presentation. Genetic analysis revealed pathogenic or likely pathogenic variants involving ABCG5 and ABCG8 genes, including homozygous and compound heterozygous mutations. Ezetimibe therapy along with dietary plant sterol restriction resulted in clinical improvement with rise in hemoglobin levels and reduction in hemolytic manifestations on follow-up. CONCLUSION: Sitosterolemia is an underrecognized but treatable cause of hemolytic anemia with macrothrombocytopenia. Careful peripheral smear examination demonstrating stomatocytes and giant platelets can provide an important diagnostic clue. Early recognition and targeted therapy can significantly improve clinical outcomes.