Chronic thrombocytopenia as a marker for early detection of sitosterolemia

Sitosterolemia is a rare autosomal recessive disorder caused by mutations in the ABCG5/G8 genes, leading to impaired excretion, and therefore, increased retention, of plant sterols and cholesterol. While sitosterolemia is often linked to premature atherosclerotic cardiovascular disease (ASCVD), diagnosis can be delayed by the absence of family history or normal lipid profiles; notably, hematologic abnormalities like anemia and thrombocytopenia can also be present. We present 3 healthy siblings with chronic thrombocytopenia and no family history of ASCVD. The index case, a 42-year-old female, had an unexplained high low-density lipoprotein cholesterol (121 mg/dL) and exhibited similar thrombocytopenia since her youth; her younger brothers (35 and 39-years-old) similarly had unexplained thrombocytopenia, all initially misdiagnosed as chronic immune thrombocytopenic purpura (ITP). Comprehensive genetic evaluation revealed homozygous mutations in the ABCG5 gene in all 3 siblings, confirming the diagnosis of sitosterolemia. Despite the diagnosis, none of the siblings had clinical ASCVD. Sterol profiles showed markedly elevated sitosterol and campesterol levels. All 3 siblings were initiated on ezetimibe 10 mg daily and advised on dietary modifications to limit plant sterol intake. After 3 to 6 months, sitosterol levels declined by 40% to 51% and campesterol by 40% to 66%. Concomitantly, platelet counts increased by 22% to 39%, demonstrating a significant improvement. This case highlights that familial thrombocytopenia can be the presenting manifestation of sitosterolemia, preceding even cardiovascular complications. Genetic testing is crucial for early and accurate diagnosis, especially in cases of unexplained chronic thrombocytopenia. Ezetimibe therapy, combined with dietary changes, effectively reduces plant sterol levels and can improve associated hematologic abnormalities.