以肺栓塞起病的遗传性蛋白S缺乏症家系并文献复习

A family of hereditary protein S deficiency with the onset of pulmonary embolism and literature review

目的探讨以儿童肺栓塞起病的PROS1基因相关遗传性蛋白S缺乏症(PSD)的临床特征和基因变异特点。方法回顾性分析北京大学第一医院儿科于2020年诊断的以肺栓塞起病的PSD 1个家系2例患儿的临床表现、实验室检查、影像学、遗传学等资料,并对其家系成员进行蛋白S活性和PROS1基因的筛查。以“PROS1”“蛋白S缺乏症”“纯合”“复合杂合”“protein S deficiency”“homozygous”and“complex heterozygous”为关键词分别查阅PubMed数据库、中国知网数据库、万方数据库自建库至2021年10月相关文献报道,并结合本组患儿,进行PROS1基因纯合或复合杂合变异引起的PSD患者的临床特征、蛋白S活性和遗传学分析总结。结果先证者,女,14岁,因“咳嗽9 d,胸痛4 d”于2020年11月收住入院,检查发现D-二聚体8.38 mg/L(参考值<0.24 mg/L),行CT肺动脉造影证实双肺动脉栓塞及右下肺梗死,彩超发现左下肢深静脉血栓,蛋白S活性<10%。先证者二妹12岁于2020年12月收住入院,筛查蛋白S活性为8%,彩超发现右下肢深静脉血栓。先证者父母的蛋白S活性分别为36%和26%。家系全外显子组测序发现先证者及其二妹PROS1基因复合杂合变异c.-168C>T和c.200A>C(p.E67A),分别遗传自其父母。先证者三妹蛋白S活性28%,与先证者外祖父均携带PROS1基因c.200A>C(p.E67A)变异。对合并血栓的先证者及其二妹,应用利伐沙班抗凝治疗,随访3个月后血栓均溶解。共检索到中文文献1篇,英文文献18篇,最终纳入14例PROS1基因纯合或复合杂合变异引起的PSD患者,其中男8例、女6例,起病年龄为4日龄至35岁,3例表现为新生儿早期起病的暴发性紫癜或严重颅内出血,11例表现为儿童期至青年期起病的静脉血栓栓塞症。11例患者检测了蛋白S活性,结果均<10%。结论对于儿童期起病的缺乏血栓危险因素的肺栓塞患儿,应考虑到PSD的可能,并在口服抗凝药物前检测蛋白S,如活性<10%,需考虑PROS1基因纯合或复合杂合变异引起的PSD。

Objective To explore the clinical characteristics and genotype of PROS1 gene related hereditary protein S deficiency(PSD)with the onset of pulmonary embolism in children.Methods A family with pulmonary embolism was diagnosed as hereditary PSD in the Department of Pediatrics of Peking University First Hospital in November 2020,and the clinical data,including clinical manifestations,laboratory tests,imaging and genetic results,were collected for a retrospective research.The family members were also screened for protein S activity and PROS1 gene mutations.A literature search with"PROS1""protein S deficiency""homozygous"and"complex heterozygous"as key words was conducted at PubMed,China National Knowledge Infrastructure,and Wanfang Data Knowledge Service Platform(up to October 2021).Case reports of patients with PROS1 gene homozygous or complex heterozygous variants and related clinical features,protein S activity,and genotype were reviewed and analyzed.Results The proband,a 14-year-old girl,was admitted to the hospital for a 9-day history of coughing and a 4-day history of chest pain in November 2020.After admission,laboratory tests showed that D-dimer was 8.38 mg/L(reference:<0.24 mg/L).An urgent CT pulmonary angiography confirmed bilateral pulmonary embolism and right lower pulmonary infarction,while an ultrasonography showed deep vein thrombosis in her left leg.Further examination revealed that protein S activity was less than 10%.The proband′s second sister,a 12-year-old girl,was admitted to the hospital in December 2020.Her protein S activity was 8%and an ultrasonography showed deep vein thrombosis in her right leg.The protein S activity of the proband′s father and mother were 36%and 26%,respectively.Trio-whole-exome sequencing detected compound heterozygous PROS1 gene variants(c.-168C>T and c.200A>C(p.E67A))for the proband and her second sister,that were inherited from her father and mother,respectively.The proband′s third sister′s protein S activity was 28%;she and the proband′s grandfather both carried c.200A>C(p.E67A)variants.The proband and her younger sister were treated with rivaroxaban and responded well during the 3-month follow-up.A total of 1 Chinese report in literature and 18 English literature were retrieved and 14 patients with protein S deficiency caused by homozygous or complex heterozygous variants of PROS1 gene were enrolled,including 8 male and 6 female patients.The ages ranged from 4 days to 35 years.Three patients experienced fulminant purpura or severe intracranial hemorrhage in early neonatal-period,while the remaining 11 patients developed venous thromboembolism in adolescence.Protein S activity was examined in 11 patients,and all showed less than 10%of activity.Missense variants was the most common type of gene variants.Conclusions For children with pulmonary embolism,if there are no clear risk factors for thrombosis,hereditary protein S deficiency should be considered,and protein S activity should be examined before oral anticoagulant drugs.If protein S activity is less than 10%,protein S deficiency caused by homozygous or complex heterozygous variants should be considered.