女性CYBB突变嵌合体遗传致X连锁慢性肉芽肿病

Female CYBB Mutation Mosaicism Leading to Inheritance of X⁃linked Chronic Granulomatous Disease

慢性肉芽肿病(CGD)是一种罕见的原发性免疫缺陷病,临床主要表现为反复严重的细菌、真菌感染以及肉芽肿形成。诊断主要依据中性粒细胞功能检测和基因检测。CYBB基因突变导致的X连锁CGD(XL⁃CGD)是最常见的类型。本文报道了1例罕见的女性CYBB基因突变嵌合体遗传导致XL⁃CGD。先证者为一例7岁男性患儿,存在反复下呼吸道感染,生后接种卡介苗出现发热,局部皮肤出现疱疹。既往有左跟骨骨髓炎、肛周脓肿史。中性粒细胞呼吸爆发功能检测结果患儿%DHR+0.051%,母亲%DHR+76%,父亲%DHR+97%。外周血全外显子测序及Sanger测序验证发现患者CYBB基因8号外显子半合子突变,c.866G>A,p.W289X,家系验证结果显示该突变位点来源于母亲。外祖母无CYBB基因突变。母亲外周血和口腔黏膜细胞Sanger测序结果显示母亲变异峰值低,外周血CYBB基因高深度二代测序结果显示突变比率为19.5%,提示母亲为CYBB嵌合突变。本文在国内首次报道CYBB嵌合突变遗传导致XL⁃CGD,以丰富临床医生对该病的认识,并对该病的遗传咨询提供新思路。

Chronic granulomatous disease(CGD)is a heterogeneous primary immunodeficiency characterized by severe bacterial and fungal infections and tissue granuloma formation early in life.Diagnosis of CGD involves the granulocyte function assays and gene mutation analysis.X⁃linked CGD(XL⁃CGD)caused by gene defects of CYBB is the most prevalent type of CGD.The clinical data and gene characteristics of a rare female X⁃chromosome mosaicism leading to inheritance of XL⁃CGD were reported here.The patient is a 7⁃year⁃old boy manifested as recurrent lower respiratory tract infection and failed to thrive.The patient had a history of osteomyelitis and perianal abscess,with Bacille Calmette⁃Guérin(BCG)vaccine complications.Respiratory burst of neutrophils was measured with DHR oxidation assay and the histogram showing no significant change in neutrophil fluorescence after stimulation of the patient and the mother's histogram had a pattern of 2 peaks after stimulation.A heterozygous mutation in the CYBB gene(c.866G>A,p.W289X)was identified through inheritance from the patient's mother.Genetic analysis from blood and cheek mucosal cells indicated the female was a mosaicism in CYBB with mutation was present in about 19.5%of her leukocytes.We reported the clinical data and gene characteristics of a rare female X⁃chromosome mosaicism leading to inheritance of XL⁃CGD for the first time in China to enrich the understanding of XL⁃CGD and provide new sights for the hereditary counseling.