在儿童慢性/难治性血小板减少症中识别非免疫相关遗传性血小板减少症的临床研究

Identification of non-immunity-associated hereditary thrombocytopenia in children with chronic or refractory thrombocytopenia

目的总结儿童非免疫相关的遗传性血小板减少症(non-immunity-associatedhereditary thrombocytopenia, NIAHT)病例的临床特点,为早期识别及诊断儿童期血小板减少症中的NIAHT提供依据。方法对2016年4月至2019年5月首都医科大学附属北京儿童医院血液肿瘤中心初步诊断为血小板减少症,但一线免疫治疗无效的慢性/难治性血小板减少症患儿进行基因二代测序(next generation sequencing,NGS),检测出NIAHT患儿。对该组经临床证实符合遗传规律的NIAHT病例资料进行回顾分析。结果 (1)203例慢性/难治性血小板减少症患儿中共筛选出NIAHT 13例(6.4%),中位发病年龄1.16岁,最小0.5岁,最大9.75岁,46.1%发病年龄≤1岁;中位病程3.16年,最短1.66年,最长9年。(2)临床以轻度出血倾向(Buchanan评分0~2分占84.6%)为主要症状;10例经外周血涂片检测提示80%存在血小板体积增大;骨髓形态学检查提示增生活跃或明显活跃,巨核细胞增多,4例可见大血小板、1例见畸形血小板;10例(76.9%)患儿曾接受免疫治疗,临床症状未改善。(3)该组包含MYH9、ABCG5、ACTN1、ETV6、GP1BA、ITGA2B、TUBB1、MASTL共8种基因突变类型,MYH9最常见,共5例(38.4%);包括MYH9相关疾病、遗传性血小板减少症2型、遗传性血小板减少症5型、植物固醇血症、巨大血小板综合征、血小板无力症等6种临床表型。结论儿童NIAHT起病早,病程长,易合并血小板形态异常,仅依靠临床症状和骨髓形态学检查难以早期识别;对于起病早、血小板形态异常、免疫治疗效果不佳的儿童期血小板减少症应尽早行NGS检查,以明确诊断并制定针对性治疗及随访方案。

Objective To summarize the clinical characteristics of non-immunity-associated hereditary thrombocytopenia(NIAHT),and provide the basis for early diagnosis of NIAHT in children with thrombocytopenic. Methods The NIAHT children were identified from the children who were diagnosed with chronic or refractory thrombocytopenia in the Hematology Oncology Center of Beijing Children’s Hospital,Capital Medical University from April 2016 to May 2019 by next generation sequencing(NGS). The clinical data of cases which were consistent with clinical and hereditary law were summerized and analyzed retrospectively. Results 1. Thirteen cases(6.4%)were diagnosed as NIAHT from 203 children with chronic or refractory thrombocytopenia. The median age of onset was 1.16 years(from 0.5 year to 9.75 years). The ratio of age of onset less than 1 year old was 46.1%. The median course of disease was 3.16 years(from 1.66 years to 9 years). 2. The main clinical manifestation was mild hemorrhage with Buchanan score being 0-2(84.6%). The result of microscopic examination of perpheral blood smear showed that 80% of the 10 cases had increased volume of platelets. All cases showed hyperplasia or marked hyperplasia by bone marrow morphology examination. Megacaryoaytes increased the number of cases with large platelets and malformation platelet were 4 and 1 respectively. 76.9% patients didn’t improve after immunotherapy. 3. These cases included eight types of gene mutations, namely MYH9, ABCG5, ACTN1, ETV6, GP1 BA, ITGA2 B, TUBB1 and MASTL,in which MYH9 was the most common gene mutation(38.4%). there were 6 disease phenotypes,including MYH9-related diseases, phytosteroemia, giant platelet syndrome, thromboasthenia, thrombocytopenia 2 and thrombocytopenia 5. Conclusion Childhoool non-immunity-associated hereditary thrombocytopenia shows the characteristics of early onset age, long course and abnormal platelet morphology. It’s difficult to make early diagnosis only by clinical manifestations and bone marrow morphology. Next generation sequencing should be carried out as early as possible to make a definite diagnosis and make targeted treatment and following plans in thrombocytopenia children with early onset, abnormal platelet morphology and poor immunotherapeutic effect.