7例儿童原发性肾上腺皮质功能减退症临床特征及NR0B1、类固醇生成因子-1基因突变分析

目的 观察儿童原发性肾上腺皮质功能减退症(PAI)的临床特征及NR0B1、类固醇生成因子-1(SF1)基因的突变情况,并分析两者关系.方法 7例PAI患者,分别来自5个家系,记录其临床症状、体征以及血促肾上腺皮质激素(ACTH)、血皮质醇、电解质等实验室检查结果,采集患者及其家系成员的外周血进行NR0B1和SF1基因外显子测序,对测序结果阴性者进行多重连接探针扩增技术(MLPA)检测.结果 7例患者均为男性,均由儿童期起病,其中3例有家族史.全部患者均有不同程度的皮肤色素沉着、血ACTH升高及血皮质醇降低.仅1例患者存在NR0B1插入突变(5800-5801 ins G),但无肾上腺危象、低促性腺激素性性腺功能减退和生殖发育异常等表现;其母亲同时存在NR0B1同义突变(5129C>T,C38C)和插入突变(5800-5801 ins G),但无肾上腺皮质功能减退表现.所有患者及其家系成员均未检测到SF1基因突变,MLPA检测亦未发现NR0B1和SF1存在大片段缺失或重复改变.结论 儿童期PAI以遗传因素为主要病因,可能由先天性肾上腺皮质发育不良(AHC)所致,且NR0B1突变的区域、类型可能与临床表型的严重程度密切相关.除AHC外,可能存在X连锁致病基因导致PAI.

Analysis on clinical features and mutations of NR0B1 and steroidogenic factor-1 genes in 7 cases with childhood primary adrenal insufficiency

Objective To investigate the clinical features and mutations of NR0B1 and steroidogenic factor-1(SF1) genes in children with primary adrenal insufficiency,and to analyze their relationship.Methods Seven patients with primary adrenal insufficiency from 5 families were enrolled.The clinical symptoms and signs,and laboratory examination results including blood adrenocorticotropic hormone(ACTH),cortisol, and electrolytes were recorded.Blood samples of the patients and their family members were collected,then exon sequencing for NR0B1 and SF1 genes was conducted.Multiplex ligation-dependent probe amplification ( MLPA) was performed in the patients with negative results of exon sequencing.Results Seven patients were male and had childhood-onset.Three cases had family history.Skin hyperpigmentation with various degrees,elevated ACTH level,and low cortisol level were observed in all patients .Insertion mutation(5800-5801 ins G) of NR0B1 only occurred in one patient without manifestations of adrenal crisis ,hypogonadotropic hypogonadism and abnormal reproductive development synonymous mutation(5129C>T,C38C) and insertion mutation(5800-5801 ins G) of NR0B1 occurred in his mother without manifestations of adrenal insufficiency .Mutation of SF1 gene was not detected in any patients and their family members .No large fragment deletion or gene repeat of NR0B1 and SF1 was founded by MLPA .Conclusion Genetic factor is the main cause of childhood primary adrenal insufficiency ,and it is probably caused by adrenal hypoplasia congenita (AHC).The mutation region and type of NR0B1 are probably associated with severity of clinical phenotype .Other X-linked pathogenic genes except AHC may exist ,and cause primary adrenal insufficiency .