Digenic Overlap Syndrome Masquerading as Homozygous Familial Hypercholesterolemia

Background: The development of tendinous xanthomas in childhood with a low-density lipoprotein (LDL) cholesterol level >400 mg/dL is characteristic of homozygous familial hypercholesterolemia (FH). Case Summary: We present the case of a patient with a severely elevated LDL cholesterol level and childhood-onset xanthomas who fulfilled clinical criteria for homozygous FH. However, genetic and absorption testing clarified his phenotype to be a unique digenic overlap of both heterozygous FH and heterozygous sitosterolemia with marked elevations in cholesterol absorption indices. Treatment with ezetimibe 10 mg daily resulted in a dramatic reduction in LDL cholesterol. Discussion: Sitosterolemia, a rare autosomal recessive disorder of plant sterol hyperabsorption, can also result in xanthomatosis and thus can mimic FH. Although it is usually a homozygous disease, heterozygotes may exhibit intermediary phenotypes. Take-Home Messages: Patients with severe hypercholesterolemia should undergo genetic and biochemical profiling for diagnostic confirmation and for ensuring that they receive optimal, personalized therapy.