摘要目的 分析伴有血液学异常的植物固醇血症患者的临床及实验室特征.方法 回顾性分析2004至2017年在苏州大学附属第一医院就诊的20例植物固醇患者的临床资料,并进行外周血细胞、血脂分析、红细胞渗透脆性实验;高效液相色谱法检测血清中豆固醇、二氢胆固醇和谷固醇含量;PCR扩增先证者和家系成员ABCG5/8基因外显子及侧翼序列并结合测序分析突变情况.结果 20例植物固醇患者均曾被误诊为免疫性血小板减少或Evans综合征.所有患者均有脾肿大切除史,其中17例患者以血小板减少就诊并伴有不同程度的黄褐瘤,部分患者存在肝功能异常(9例)、早发型动脉粥样硬化(5例)及关节炎(4例)等.外周血溶血检查发现红细胞脆性增加,血涂片分析发现所有患者血小板大小不等、总体偏大,口形红细胞增多.患者血清谷固醇和豆固醇含量分别为331.05(276.00,670.20)mg/L和244.60(193.78,399.40)mg/L,约为健康人的10倍及24倍.测序分析共发现了ABCG5/8基因中14种突变,2/3位ABCG5基因[(E22X) 、p.(R446X) 、g.ISV7+3G＞A、p.(R446X) 、p.(R419H)、g.ISV7+3G＞A、p.(G90E)、p.(R389H)及g.7+2G＞A];而1/3位ABCG8基因[p.(M614-K628del)、p.(E25X)、p.(L86P fs X185)、p.(R263Q)、p.(E500D fs X604)、p.(G674R)],其中ABCG5 p.(R446X)突变有重现性.结论 血小板减少、口形红细胞增多及脾大是植物固醇血症患者特殊的临床表现,外周血小板及红细胞形态变化是该类患者典型的特征,临床确诊需进行ABCG5/8基因分析及血清植物固醇测定.

abstractsObjective 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.