*Sitosterolemia due to a new combination of ABCG8 variants presenting as hemolytic anemia and thrombocytopenia: A case report

Background/Synopsis

Sitosterolemia is a rare autosomal recessive disorder caused by mutations in ATP binding cassette subfamily G member 5 or 8 (ABCG5/8), leading to excessive plant sterol absorption and accumulation. Patients can present with xanthelasma, tendon xanthomas, premature atherosclerosis, and hematologic abnormalities.

Objective/Purpose

Here, we report a case of sitosterolemia in an adult male presenting with hemolytic anemia, macrothrombocytopenia, and hypercholesterolemia. His diagnosis was ultimately confirmed through genetic testing, which identified a new combination of ABCG8 variants

Methods

Case Presentation: A 61-year-old man with a history of hypothyroidism, hypercholesterolemia, obesity, and metabolic dysfunction-associated steatotic liver disease (MASLD) was referred to the Hematology Clinic at UT Southwestern for the evaluation of hemolytic anemia and moderate thrombocytopenia. He was diagnosed with hypercholesterolemia in early adulthood and was taking Rosuvastatin 5 mg daily for several years.

On examination, he had splenomegaly and bilateral xanthelasma (Figure 1). Laboratory evaluation revealed LDL-C of 126 mg/dL, low hemoglobin and platelet count, elevated lactate dehydrogenase, and undetectable haptoglobin (Table 1). A peripheral blood smear revealed marked stomatocytosis and macrothrombocytopenia (Figure 2).

Given the combination of hemolytic anemia, macro-thrombocytopenia, and stomatocytosis, sitosterolemia was suspected. Serum plant sterol levels were markedly elevated (Table1). Genetic testing identified multiple heterozygous variants in ABCG8. A likely pathogenic c.250_280dup variant on one allele, and two variants (c.1721G>A [p.Gly574Glu] and c.1723G>C [p. Gly575Arg]) on the other which together cause a novel deletion and insertion of two amino acids. Cascade screening revealed his healthy sister carried c.250_280dup variant.

He was subsequently seen at the UT Southwestern Lipid Metabolism Clinic and was started on ezetimibe 10 mg daily in addition to the Rosuvastatin 5 mg daily. He consulted a nutritionist to transition his diet from a heart-healthy diet to a low plant sterol diet. At three months follow-up, his lipid profile and hemoglobin had improved, but platelet counts and markers of sterol absorption remain unchanged (Table 1).

Results

This case underscores key clinical features of sitosterolemia, including xanthelasma and hematologic abnormalities. His genetic findings expand the known spectrum of ABCG8 mutations: the c.250_280dup variant has not been previously reported in sitosterolemia, and while the c.1721G>A (p.Gly574Glu) and c.1723G>C (p.Gly575Arg) missense variants have been individually documented, their co-occurrence on the same allele, leading to a novel mutation, is unreported.

Improvement in plant sterol levels and platelet counts can take up to eight months, making long-term follow-up essential to assess the effects of ezetimibe and dietary modifications.

Conclusions

This case highlights the importance of considering sitosterolemia in patients with stomatocytosis, macrothrombocytopenia, and dyslipidemia. Identification of a new combination of ABCG8 mutations broadens the genetic understanding of this rare disorder.