高IgM综合征临床、分子及免疫特征分析并文献复习

Clinical,immunological and genetic characteristics of patients with hyper-immunoglobulin M syndrome

目的探讨高IgM综合征(HIGM)患者的临床、分子及免疫特点,提高临床诊治的认识。方法回顾分析首都医科大学附属北京儿童医院免疫科2021年4月至2021年8月收治的3例HIGM患者的病例资料,文献复习97例HIGM患者的临床、分子及免疫特点。结果纳入的3例患者感染的病原菌有大肠埃希菌、草绿色链球菌、结核杆菌及乙肝病毒;感染部位有呼吸道、消化道、神经系统、口腔和耳,其中1例为首次报道的HIGM合并肠结核病例;1例有IgM升高,均有中性粒细胞及记忆B细胞减少;2例基因型为错义突变,1例为拷贝数变异,其中基因型CD40L exon5 deletion,为国内外首次报道的拷贝数变异的新突变。97例HIGM患者男女比例为5∶1,起病中位年龄1岁,感染最常累及的5个部位为:下呼吸道(73.2%)、上呼吸道(36.08%)、消化道(29.9%)、血液系统(23.71%)、口腔(16.49%)。最常感染的病原菌有:耶氏肺孢子菌(12.4%)、白色念珠菌及其他真菌(11.3%)、巨细胞病毒(10.3%)、铜绿假单胞菌(9.3%)、链球菌(6.2%)和隐孢子虫(6.2%)。免疫学特点:血IgM升高者占51.5%,血IgA降低者占83.5%,血IgG降低者占82.5%。基因型中,CD40L基因突变占82.5%,AICDA基因突变为14.4%,CD40基因突变占2.1%,1%为UNG基因突变。结论对于反复感染,IgM高或不高,IgA、IgG低于正常水平,记忆性B细胞减少伴或不伴中性粒细胞减少者需警惕HIGM可能。

Objective Our aim was to analyze the clinical,genetic and immune characteristics of patients with hyperimmunoglobulin M(hyper-IgM)syndrome(HIGM).Methods The clinical data of three HIGM patients admitted to the Department of Immunology of Beijing Children’s Hospital from April 2021 to August 2021 were retrospectively analyzed.The clinical,molecular and immunological characteristics of a total of 97 HIGM patients were analyzed through literature review.Results These three patients were infected with Escherichia coli,Streptococcus griseus,Mycobacterium tuberculosis,and hepatitis B virus.The common sites of infection were respiratory,gastrointestinal,neurological,oral and ear,and one of which was the first reported case of HIGM combined with intestinal tuberculosis.One of the patients had elevated IgM,and all had decreased neutrophils and memory B cells.Two patients had a missense mutation in the genotype,and one had a copy-number variant,and genotype CD40L exon5 deletion,a novel mutation with copy number variant.Among 97 HIGM patients by literature review,the male-to-female ratio was 5∶1,and the median age of onset was 1 year-old.The five most frequently affected sites of infection were lower respiratory tract(73.2%),upper airways(36.08%),gastrointestinal tract(29.9%),hematologic system(23.71%),and oral cavity(16.49%).The frequently infected pathogens included Pneumocystis jirovecii(12.4%),Candida albicans and other fungi(11.3%),cytomegalovirus(10.3%),Pseudomonas aeruginosa(9.3%),Streptococcus(6.2%),and Cryptosporidium(6.2%).Serum IgM level was elevated in 51.5%patients,IgA decreased in 83.5%,and IgG decreased in 82.5%.CD40L gene variants were found in 82.5%patients,AICDA variants in 14.4%,CD40 variants in 2.1%,and UNG variants in 1%.Conclusions Serum IgM level was not always elevated in HIGM.HIGM should be considered in children with recurrent infection,concomitant decreased levels of IgA and IgG,and memory B-cell reduction with or without neutropenia.