Clinical features of 20 patients with phytosterolemia causing hematologic abnormalities

Objective To investigate the clinical and laboratory features of Phytosterolemia with hematological abnormalities. Methods A retrospective study was performed on 20 patients with phytosterolemia admitted to the hematology department of the First Affiliated Hospital of Suzhou University during 2004—2017. History of patients was collected and the platelet counts, lipidomic analysis of plasma and osmotic fragility of erythrocytes were carried out. The erythrocyte and platelet morphology was examined by light microscope. Phytosterol levels in serum were measured by high performance liquid chromatography method. All of ABCG5/8 exons and intron-exon boundaries were amplified by PCR and directly sequenced to identify mutations. Results All patients had been misdiagnosed as immune thrombocytopenia (ITP), or Evans syndrome with a mean delay of 21 years between symptom onset and accuracy diagnosis. The clinical manifestations of the patients were variable, but most of them presented with thrombocytopenia, anemia, splenomegaly from early ages, and xanthomas. Other major features were also observed, such as impaired liver functions (9 cases), premature atherosclerosis (5 cases) and/or arthritis (4 cases). Interestingly, all patients displayed an increased osmotic fragility of red cells and unique blood film features: large unequal platelets surrounded by a circle of vacuoles and various abnormal erythrocyte shapes, especially stomatocyte. Serum levels of the sitosterol and stigmasterol in the patients were remarkably elevated up to 331.05(276.00, 670.20)mg/L and 244.60(193.78,399.40)mg/L, about 10 and 24 times higher than those of normal subjects. There were 14 mutations in ABCG5/8 genes found in the patients. Among them, 2/3 of the mutations were in ABCG5 gene, including p.(E22X), p.(R446X),g.ISV7+3G>A, p.(R446X), p.(R419H), g.ISV7+3G>A, p.(G90E), p.(R389H) and g.7+2G>A), and 1/3 in ABCG8 gene involving p.(M614-K628del), p.(E25X), p.(L86P fs X185), p.(R263Q), p.(E500D fs X604) and p.(G674R) mutation. The ABCG5 p.(R446X) mutation was found in 3 separate families. Conclusions The phenomena of thrombocytopenia/ stomatocyte/splenomegaly represents a special clinical manifestations of phytosterolemia, and distinct changes of blood cell morphology are the typical characters. Plasma plant sterols and ABCG5/ABCG8 genes should be analyzed when such hematologic abnormalities are unexplained. Key words: Phytosterols; Thrombocytopenia; Abnormal erythrocytes; Splenomegaly; Gene; Mutation