摘要目的 自身免疫性多内分泌腺病综合征Ⅰ型(APS-Ⅰ)是由自身免疫调节因子(AIRE)基因突变导致的罕见遗传病.本研究对2例APS-Ⅰ患者进行临床特征及AIRE基因分析,以提高对此病的认识.方法 采集2例APS-Ⅰ患者及家属外周血并提取DNA,应用PCR扩增AIRE基因,通过生物信息学进行功能预测,并选取100名健康对照,对新突变位点进行检测.结果 病例1为31岁女性,10岁出现手足指甲念珠菌样改变,后诊断为原发性甲状旁腺功能减退症、Addison病、桥本甲状腺炎及卵巢功能早衰.AIRE基因检测发现该患者为c.483484insC纯合突变,其父母、弟弟均为c.483484insC杂合突变,符合常染色体隐性遗传.病例2为34岁男性,幼时出现手足指甲念珠菌病样改变,后诊断为Addison病、原发性甲状旁腺功能减退症及桥本甲状腺炎.AIRE基因检测发现该患者有c.179A>G及c.463+2T>C复合杂合突变,其父有c.179A>G杂合突变,其母有c.463+2T>C杂合突变,符合常染色体隐性遗传.AIRE基因c.483484insC突变可造成AIRE蛋白截短,c.463+2T>C突变位于内含子3的5'端高度保守剪切位点,这2个突变均曾报道为致病突变,而c.179A>G突变经SIFT及PolyPhen-2生物信息学预测为致病性突变,在100名健康人群中未检出,人类基因突变数据库(HGMD)未见报道,认为是新发突变.结论 本研究发现了1个新的AIRE基因突变c.179A>G,拓宽了对APS-Ⅰ发病机制的认识.APS-Ⅰ临床表现多样,易误诊及漏诊,早期识别APS-I相关症状,加强基因筛查及随访有助于本病的早期诊断及治疗.

abstractsObjective Autoimmune polyendocrine syndrome typeⅠ( APS-Ⅰ) is caused by mutations in the autoimmune regulator gene ( AIRE) gene. In this study, phenotype and AIRE gene analysis were performed in two patients with APS-Ⅰ. Methods Peripheral blood samples were collected from two patients with APS-Ⅰand their families. All exons of the AIRE gene and adjacent exon-intron sequences were amplified by PCR and subsequently sequenced. The silico analysis was performed to predict the possible impact of the mutations on the function of the AIRE protein. At the same time, 100 healthy controls were selected to confirm the mutation. Results Case 1 was a 31-year-old female who exhibited chronic mucocutaneous candidiasis, hypoparathyroidism, Addison' s disease, Hashimoto's thyroiditis, and premature ovarian failure. A homozygous c.483484insC mutation in exon 4 of AIRE gene was identified in this patient. Her parents, siblings and son were heterozygous for this mutation, which is consistent with the autosomal recessive inheritance pattern. Case 2 was a 34-year-old male who had mucocutaneous candidiasis, Addison' s disease, primary hypoparathyroidism, and Hashimoto' s thyroiditis. A compound heterozygous AIRE mutation (c.179A>G/C.463+2T>C) were identified in this patient. His father was heterozygous for c.179A>G mutation, and his mother was heterozygous for C.463+2T>C, which is consistent with autosomal recessive inheritance mode. The c.483484insC and c. 463+2T>C have been reported to be pathogenic. The c. 179A>G mutation was predicted pathogenic by SIFT and PolyPhen2 software, which was not detected in 100 healthy controls. It has not been reported in the HGDM database and is a novel mutation. Conclusion We identified a novel AIRE gene mutation ( c.179A>G) , which contributed to further understanding of the pathogenesis of APS-Ⅰ. The clinical variation and rarity of APS-Ⅰmakes the syndrome hard to recognize. Early recognition of symptoms and screening for AIRE mutation in patients with APS-Ⅰhas important clinical implications for the diagnosis and treatment.