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儿童原发性肾上腺皮质功能减退的临床特征和基因突变研究

泰然健康网
2024-12-31 14:53

摘要：

目的分析儿童原发性肾上腺皮质功能减退患者的临床特征及其DAX1、SF1基因突变的发生率，探讨导致该病可能的分子机制。方法选择原发性肾上腺皮质功能减退的男性患儿25例，观察患儿的临床特征并行辅助检查。抽提外周血基因组DNA，对DAX1基因2个外显子（外显子1和2）的PCR扩增产物进行测序分析；无突变者行SF1基因(外显子2~7)突变筛查。结果患儿均有不同程度的皮肤色素沉着、乏力、恶心、呕吐及脱水等表现；18例曾出现肾上腺危象；8例有明确家族史。15例达到青春发育年龄的患儿中，8例（53.3%）伴性发育不良。DAX1基因检测共发现8种突变，包括1种错义、6种移码和1种无义突变；其中6种（c.291delC、c.332-333delCT、p.E137X、c.605delG、c.731delG和c.838delG）为新发现突变，余为已报道过的突变：2例为p.L262P（表兄弟），1例为c.652-653delCA；未发现SF1基因突变存在。DAX1基因突变率为40%（10/25），伴性发育不良患儿突变率为62.5%（5/8），有明确家族史患儿DAX1基因突变率为100%（8/8）；DAX1基因突变患儿的发病年龄不同，临床表现呈多样性。结论 DAX1基因突变是导致儿童原发性肾上腺皮质功能减退的常见分子病因，而SF1突变较罕见；DAX1基因突变临床表现不一，尚未发现基因突变类型与临床表型之间存在明确关系。

关键词: 原发性肾上腺皮质功能减退, DAX1基因, SF1基因, 突变, 儿童

Abstract:

Objective To observe the clinical manifestations in children with primary adrenal insufficiency, investigate the prevalences of DAX1 and SF1 gene mutations, and explore the possible mechanism of the disease. Methods Twentyfive boys with primary adrenal insufficiency were enrolled, the clinical characteristics were observed, and assistant examinations were performed. Genome DNA was extracted from peripheral blood, exon 1 and exon 2 of DAX1 gene were amplified by PCR for sequencing, and mutation screening of SF1 gene (exon 2-7) was conducted. Results There were symptoms of hyperpigmentation in skin, fatigue and weakness, nausea, vomiting and dehydration in all patients. Adrenal crisis occurred in 18 patients, and 8 patients had definite family history. Eight (53.3%) of the 15 adolescents had impaired sex development. Analysis of DAX1 gene identified 8 mutations (6 frameshift mutations,1 missense mutation and 1 nonsense mutation), six of which were novel (c.291delC, c.332-333delCT, p.E137X, c.605delG, c.731delG and c.838delG), and the other two (p.L262P in two male cousins and c.652-653delCA in 1 patient) had been reported. No SF1 gene mutation was identified. DAX1 gene mutations were found in 40% (10/25) of patients, in 62.5% (5/8) of those with impaired sex development, and in 100%(8/8) of those with family history. There were various clinical presentations and ages in patients with DAX1 gene mutations. Conclusion DAX1 gene mutations may be a frequent cause of primary adrenal insufficiency in children, while mutation in SF1 seldomly occurs. There are various clinical manifestations for gene mutations, and there may be no definite relationship between gene mutations and clinical manifestations.

Key words: primary adrenal insufficiency, DAX1 gene, SF1 gene, mutation, children