Objective: To investigate clinical, molecular genetic characteristics, and treatment outcomes of 3 children with sitosterolemia. Methods: Three cases of children presented with multiple xanthomas during June 2016 to June 2017 were included. The clinical manifestations, laboratory examinations and follow-up data were retrospectively analyzed. DNA was extracted from peripheral blood and analyzed with whole exome sequencing(WES). All the detected variants were confirmed by Sanger sequencing. Plasma plant sterol concentrations were measured by gas chromatography-mass spectrometry. Results: Three cases of children including 1 boy and 2 girls presented with multiple linear and intertriginous xanthomas around skin of the joint areas at the age from 15 months to 6 years and 2 months. Total cholesterol of the 3 cases was elevated to 14.45, 15.47 and 15.85 mmol/L (3.36-6.46), and low density lipoprotein cholesterol was 9.02, 13.54 and 12.47 mmol/L (< 3.36) respectively. Genetic analysis with WES revealed that 2 cases carried compound heterozygous variants in ABCG5 gene, 1 case carried compound heterozygous variants in ABCG8 gene. Two reported variants (p. N437K, p.R446X) and one novel variant (p.Q251X) of ABCG5 were identified in case 2 and 3. Two novel ABCG8 variants (p.R263Q, c.1528_1530delATC) were found in case 1. All these children had extremely high plasma plant sterol levels, thus the diagnosis of sitosterolemia was confirming. The campesterol level was 111.35, 102.86 and 58.91 μmol/L(0.01-10.00), the stigmasterol was 14.97, 29.43 and 17.79 μmol/L (0.10-8.50) and the sitosterol was 231.20, 177.66 and 114.20 μmol/L (1.00-15.00) respectively. The total serum cholesterol levels of three children decreased to nomal after the patients were placed on the low plant sterol/low cholesterol diet. The xanthomas regressed gradually, and almost disappeared after 8 months of treatment in case 1 and 3. Conclusions: Children with sitosterolemia presented with skin xanthomas around the joint areas. The level of total cholesterol, low density lipoprotein cholesterol and plant sterols increased obviously. One novel variant (p.Q251X) of ABCG5 and 2 novel variants (p.R263Q, c.1528_1530delATC) of ABCG8 were identified. Children with sitosterolemia responded well to a low plant sterols/low cholesterol diet.
目的： 研究谷固醇血症的临床、基因分析及治疗效果。 方法： 回顾性分析了2016年6月—2017年6月因皮肤黄瘤病就诊的3例患儿临床和实验室检查特点，通过全外显子测序对3例患儿致病基因进行分析，采用Sanger测序方法对所发现的ABCG5和ABCG8基因变异及父母来源进行验证，气相色谱质谱分析患儿植物固醇水平。 结果： 3例患儿男1例、女2例，于15月龄~6岁2月龄因关节附近的皮肤皱褶处多发线状或颗粒状黄瘤就诊，3例患儿血总胆固醇分别为14.45、15.47和15.85 mmol/L（正常范围3.36~6.46），低密度脂蛋白胆固醇分别为9.02、13.54和12.47 mmol/L（正常范围<3.36）。全外显子测序发现2例携带ABCG5基因复合杂合变异，1例携带ABCG8基因复合杂合变异，共发现3种ABCG5基因变异，包含2种已报道变异（p. N437K，p.R446X）和1种新变异（p.Q251X）及2种ABCG8基因新变异（p.R263Q，c.1528_1530delATC）。3例患儿的菜油固醇分别为111.35、102.86和58.91 μmol/L（正常范围0.01~10.00），豆固醇分别为14.97、29.43、17.79 μmol/L（正常范围0.10~8.50），β-谷固醇分别为231.20、177.66和114.20 μmol/L（正常范围1.00~15.00），确诊为谷固醇血症。采取限制植物固醇和动物固醇的饮食治疗后，3例患儿血脂基本恢复正常，其中2例患儿皮肤黄瘤变小甚至消失，另一例未见改变。 结论： 谷固醇血症患儿主要表现为关节附近的皮肤黄瘤，血总胆固醇、低密度脂蛋白胆固醇及植物固醇明显升高，发现1种ABCG5基因新变异（p.Q251X）及2种ABCG8基因新变异（p.R263Q，c.1528_1530delATC），对低植物固醇/动物固醇饮食治疗反应良好。.
Keywords: Genes; High-throughput nucleotide sequencing; Hypercholesterolemia; Xanthomatosis.