X连锁高IgM综合征的临床特征及基因诊断

Clinical features and gene diagnosis of X-linked hyper-immunoglobulin M syndromes

目的探讨X连锁高IgM综合征(X-linkedhyper-immunoglobulin M syndromes,XHICM)的临床特征及基因型的特点。方法 2017年7月16日,山东省立医院儿科收治1例反复粒细胞减少的患儿,分析其临床特点、实验室检查和治疗经过。利用二代测序对患儿行基因检测,并用Sanger测序对患儿及父母的基因突变进行验证。结果患儿男,2岁8个月。曾于2岁2个月时因重症肺炎住院,出院后反复出现粒细胞减低,骨髓穿刺检查提示粒细胞缺乏症。本次入院检查结果显示,IgG、IgA和IgE明显降低,IgM处于正常高值。基因检测结果显示,患儿CD40LG基因第5外显子有1个半合子突变:c.76IC>G(编码区第761号核苷酸由胞嘧啶变异为鸟嘌呤),导致氨基酸改变p.T254R (第254号氨基酸由苏氨酸变异为精氨酸),为错义突变。该变异不属于多态性位点,在人群中发生频率极低,在HGMD专业版数据库中未见报道。进一步家系验证分析显示,患儿母亲该位点杂合变异,该位点为疑似致病性变异,为X连锁隐性遗传,变异来源于母亲。基因诊断明确后,每间隔1～2个月输注人免疫球蛋白,每次7.5 g。出院后随访8个月,共输注4次,期间偶有感冒,未再患肺炎。结论反复中性粒细胞减少的婴幼儿应早期行免疫功能筛查,加强对原发性免疫缺陷病的识别。基因检测是诊断XHIGM的金标准。

Objective To explore the clinical features and genotypic characteristics of the X-linkedhyper-immunoglobulin M syndrome. MethodsOn July 16th 2017, the clinical features, laboratorytests, and treatment process of one infant diagnosed as recurrent granulocytopenia in the departmentof Pediatrics in Shandong Provincial Hospital were analyzed. The next generation sequence （NGS）was used to detect the gene of the infant; the gene mutation of the infant and his patient was confirmedby Sanger sequencing method. Results The infant was a male of 2 years and 8 months old, whowas hospitalized because of severe pneumonia at age of 2 years and 2 months and suffered withgranulocytopenia recurrently after discharging. Bone marrow puncture showed agranulocytosis. Thetest results of this hospitalization indicated significant decrease levels of IgG、IgA and IgE and normallevel of IgM. Genetic test result showed that there was a hemizygous mutation c.761C〉G （number761 nucleotide in the coding region was varied from cytosine to guanine） in gene CD40LG exon 5 of the infant, causing the amino acid to change p.T254R （number 254 amino acid was altered fromthreonine to arginine）, which was a missense mutation. The mutation did not belong to polymorphismloci and the frequency of occurrence was extremely low in the population, which was not discoveredin the HGMD professional database. Further pedigree analysis was performed that the infant＇s motherproved to be a heterozygous variation of the specific locus of suspecting as pathogenic variation, whichwas X-linked recessive inheritance and inherited from his mother. The patient was infused with 7.5 ghuman immunoglobulin every 1-2 month after the genetic diagnosis. Being followed up for 8 monthsafter discharge, the patient was infused 4 times with occasional common cold and without pneumonia.Conclusion The infants with recurrent granulocytopenia should be given immune function screening assoon as possible. The identifying of primary immunodeficiency diseases should be strengthen. Genetictest is the gold standard for X-linked HIGM diagnosis.