Phenotypic and Genotypic Landscape of Sitosterolemia in China: Including a Rare Case With Nephronophthisis

Sitosterolemia (STSL) is a rare autosomal recessive disorder caused by mutations in ABCG5 or ABCG8, characterized by hemolytic anemia, xanthomas, and atherosclerosis. Nephronophthisis (NPHP), another autosomal recessive disorder, is characterized by its devastating progression toward renal failure.

We analyzed the clinical, laboratory, and genetic data of a Chinese boy with concurrent STSL and NPHP. Separately, we conducted a comprehensive review of the phenotypic and genotypic profiles of all previously reported STSL cases in China.

The proband presented with recurrent fever, thrombocytopenia, splenomegaly, and renal dysfunction and was initially misdiagnosed with hemophagocytic lymphohistiocytosis. Genetic testing confirmed biallelic ABCG8 mutations (c.490C>T and c.323-1G>C) and a homozygous NPHP1 deletion. A comprehensive review of 131 Chinese STSL cases (130 from the literature) found that xanthomas, hypercholesterolemia, and elevated low-density lipoprotein cholesterol (LDL-C) were the most common manifestations (each with a prevalence of 82.4%), followed by splenomegaly (32.1%), thrombocytopenia (32.1%), and anemia (30.5%). Hypercholesterolemia and high LDL-C were more common in children, whereas hematologic abnormalities and organ damage were more prevalent in adults. Mutations in ABCG5 accounted for 77.1% of patients.

Genetic testing is crucial when clinical findings conflict with the initial diagnosis. This study summarizes the largest cohort of Chinese STSL patients to date, which may aid in the early recognition and management of this condition.