Sitosterolemia presenting as unexplained cytopenias: hematologic manifestations and genetic spectrum

BACKGROUND: Sitosterolemia is a rare autosomal recessive disorder caused by pathogenic variants in the ATP-binding cassette subfamily G member 5 (ABCG5) or ATP-binding cassette subfamily G member 8 (ABCG8) gene, which increase the intestinal absorption of plant sterols and reduce their biliary excretion. It is classically linked to xanthomas and premature cardiovascular disease; however, many patients first present with haematologic abnormalities, often leading to diagnostic delay. METHODS: We retrospectively reviewed six consecutive patients with clinical features suggestive of sitosterolemia and molecular variants in the ABCG5 or ABCG8 gene who were treated at a tertiary referral center between January 2024 and June 2026. We analyzed their clinical features, hematologic findings, genetic variants, treatment, and follow-up outcomes. RESULTS: Six patients (three men and three women; median age, 40 years [range, 22-55 years]) presented with anemia, thrombocytopenia, and splenomegaly but were initially misdiagnosed with more common disorders, such as immune thrombocytopenia, iron-deficiency anemia, megaloblastic anemia, and Evans syndrome. All patients had stomatocytes and giant platelets on peripheral blood smears; three also had tendon xanthomas, and one had premature coronary artery disease. Genetic testing predominantly identified ABCG8 variants, as well as two ABCG5 variants, including a homozygous ABCG5 c.1724 T > G (p.Leu575Arg) variant that has not been previously reported and is currently classified as a variant of uncertain significance. All patients were advised to follow a phytosterol-restricted diet, and five received ezetimibe. Four patients with available follow-up data showed improvements in hemoglobin, platelet count, and spleen size during 4-12 months of follow-up. One patient was lost to follow-up, and one patient had insufficient follow-up for outcome assessment. CONCLUSION: Sitosterolemia should therefore be considered in patients with unexplained cytopenias, stomatocytosis, macrothrombocytopenia, and splenomegaly. Early recognition and genetic confirmation of this condition allows timely treatment with dietary modification and ezetimibe, thereby improving hematologic outcomes and preventing unnecessary investigations.