一个格里塞利综合征2型家系分析

Family analysis of Griscelli syndrome type 2:a case report

目的探讨由RAB27A基因缺陷导致的格里塞利综合征2型(Griscelli syndrome type 2,GS2)的临床及免疫学特征。方法收集1家系2例GS2患儿组成的临床资料、生化检查及病理活检结果,采集头发显微镜检查,抽取外周静脉血进行免疫系统基因外显子阵列测序,桑格测序验证患儿及父母RAB27A基因突变位点,采用蛋白印迹法检测外周血单个核细胞RAB27A蛋白表达水平,采用流式细胞术进行CTL细胞及NK细胞毒性功能检测,健康对照为正常同龄儿童。结果2例患者为亲兄妹,生后均表现毛发色素减退合,均以反复发热、反复呼吸道感染合并噬血细胞性淋巴组织细胞增生症(HLH)为主要临床表现,妹妹伴全身弥漫靶形损害样皮疹。2例患者头发内均有不规则黑色素团块堆积,妹妹皮损组织病理示表皮基底层黑色素细胞不规则分布,RAB27A基因5号外显子发生c.377 delC纯合移码突变,其父母为近亲结婚,均为携带者,2例患儿RAB27A蛋白表达均明显降低,NK细胞及CTL的细胞毒功能均受损。2例患儿均未接受化疗及造血干细胞移植(HSCT),先后因HLH死亡。结论GS2的确诊依赖临床表现及基因检测,免疫功能检测亦有助于诊断,同种异体造血干细胞移植是目前根治GS2的唯一方法。

Objective To investigate the clinical and immunological features of Griscelli syndrome type 2(GS2)caused by RAB27A gene defect.Methods The clinical data,biochemical examination and pathological biopsy results of 2 children with GS2 in 1 family were collected.Hair was collected for microscopic examination.Peripheral venous blood was extracted for immune-related gene sequencing,and the RAB27A mutation site in the children and their parents was verified by Sanger sequencing.The expression level of RAB27A protein in peripheral blood mononuclear cells was detected by western blot.Flow cytometry was performed to detect CD107a expression in NK and CTL cells,and an age-matched healthy child was used as control.Results The two patients were siblings,and both presented with postnatal hypopigmentation of hair.The main clinical manifestations of both patients were recurrent fever,recurrent respiratory infection combined with hemophagocytic lymphohistiocytosis(HLH),and the younger sister was accompanied by generalized diffuse target-shaped lesions.Accumulation of irregular melanin clusters in the hair were observed in both patients,and the histopathology of the younger sister's lesions showed an irregular distribution of melanocytes in the basal layer of the epidermis.Gene sequencing identified a homozygous frameshift mutation of c.377delC in exon 5 of RAB27A gene,and the parents were consanguineous and both were carriers.Reduced expression of RAB27A protein and defects in the cytotoxicity of NK cells and CTL were observed in peripheral blood mononuclear cells of both patients.Neither patient received chemotherapy or hematopoietic stem cell transplantation(HSCT)and died of HLH successively.Conclusions The definitive diagnosis of GS2 relies on clinical manifestations and genetic testing,immune function testing also contributes to the diagnosis.Currently,allogeneic HSCT is the only method to cure GS2.