MYH9相关疾病六个家系临床特征和基因变异分析

Gene analysis and clinical features of MYH9-related disease

目的分析非肌性肌球蛋白重链9相关疾病(MYH9-RD)家系患者的临床特征、基因变异和实验室检查特点。方法回顾性分析2017年7月至2020年9月在深圳市儿童医院诊断的MYH9-RD 6个家系的一般情况、临床表现、基因变异和实验室检查结果,通过t检验比较血小板计数仪器法与手工法的结果。结果6例先证者中男4例、女2例,年龄4.0(0.5~7.6)岁,主要临床表现为血小板减低6例,鼻衄3例,皮肤淤点淤斑2例,外伤血肿1例,天冬氨酸转氨酶、丙氨酸转氨酶、γ谷氨酰转移酶升高1例。其中1例先证者无家族史,余5例均为家系患病。6个家系共12例患者,2个家系2例患者长期存在镜下肾源性血尿,1个家系2例患者有早发性白内障病史,3个家系5例患者天冬氨酸转氨酶、丙氨酸转氨酶、γ谷氨酰转移酶水平呈慢性轻度升高。12例患者共发现4种MYH9基因变异,分别为第17号外显子c.2104C>T(p.R702C)变异,第31号外显子c.4270G>A(p.D1424N)变异,第39号外显子c.5521G>A(p.E1841K)变异,第41号外显子c.5797C>T(p.R1933X)变异。经家系验证分析,第一个变异是自发变异,其余变异均来自父亲或母亲。血常规示12例患者血小板数量均下降,仪器法计数结果明显低于手工计数法[(33±17)×10^(9)比(60±21)×10^(9)/L,t=-5.83,P<0.05],血涂片可见巨大血小板、血小板减少、粒细胞异常包涵体“三联征”。MYH9基因变异的位置在编码非肌性肌球蛋白重链ⅡA的N端具有ATP酶活性的动力区域“头部”(R702C)患者血小板数量严重减低(<20×10^(9)/L),包涵体不明显;而C端“体尾部”位置变异患者包涵体明显可见,血小板数量相对较高(40×10^(9)~80×10^(9)/L)。结论MYH9-RD临床表型异质性明显,MYH9基因变异位置与血小板数量和包涵体特征有一定关系。对于病史较长、病因不明和常规治疗效果欠佳的原发性免疫性血小板减少症患者,不管有无家族史,均应警惕MYH9-RD可能。血常规分析和血涂片形态学是筛查和诊断该病的首要步骤,实验室应重视形态学复检规则和规范报告。

Objective To identify gene variants and investigate clinical features of nonmuscle myosin heavy chain 9-related disease(MYH9-RD).Methods In this retrospective study,the data of patients with MYH9-RD admitted to Shenzhen Children′s Hospital from July 2017 to September 2020 were extracted.The gene variants,clinical features and laboratory tests results were summarized.Results Among the 6 children,4 were males and 2 were females,aged 4.0(0.5-7.6)years.Main clinical manifestations included thrombocytopenia(6 cases),epistaxis(3 cases),petechias(2 cases),traumatic hematoma(1 case),and abnormal liver enzymes(1 case).One patient had no family history,and the other 5 cases were pedigrees.Two pedigrees(2 cases)had long-term microscopic hematuria,one pedigree(2 cases)had history of early cataract,and three pedigrees(5 cases)had chronic mild elevation of liver enzymes.Four MYH9 gene variants were found in 12 patients,including c.2104C>T(p.R702C)in exon 17,c.4270G>A(p.D1424N)in exon 31,c.5521G>A(p.E1841K)in exon 39,and c.5797C>T(p.R1933X)in exon 41.According to the family pedigrees analysis,except for the case of variant in exon 17 which was spontaneous mutation with no family history,the other variants were from their father or mother.The complete blood count results showed a decreased platelet number in these patients,and the counting results of the automated hematology analyzer were significantly lower than that of manual counting method((33.4±17.2)×10^(9)vs.(60.4±21.0)×10^(9)/L,t=-5.83,P<0.05).The examination of the peripheral blood smear revealed the presence of thrombocytopenia with giant platelets and granulocyte inclusion bodies.The MYH9 gene variant(R702C)located at the N-terminus head domain of non-muscle myosin heavy chainⅡA(NMMHC-ⅡA),which has ATPase activity,led to severe reduction of platelet number(<20×/L)and obscure granulocyte inclusion bodies.However,higher platelet numbers(40×10^(9)-80×10^(9)/L)and obvious granulocyte inclusion bodies were observed in patients with tail-position mutations at C-terminus.Conclusions The clinical phenotypes of MYH9-RD were variable.The mutations in certain regions of MYH9 gene were related to platelet count and granulocyte inclusion bodies.MYH9-RD should be considered in individuals with unknown etiology and persistent thrombocytopenia which is non-responsive to conventional treatment,regardless of family history.Complete blood count and blood smear morphology examinations are the first steps to screen and diagnose the disease.The laboratory should pay attention to the morphological review rules and standardized reports.