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目的 报道国内首例FOXN1单倍体不足患儿的临床及免疫学特点，并总结国外既往报道病例特征。 方法 回顾性分析1例FOXN1单倍体不足患儿的临床表现、全外显子组测序结果，并对T淋巴细胞抗原受体剪切环(T cell receptor rearrangement excision circles，TRECs)和κ-删除重组切除环(κ-deleting recombination excision circles，κRECs)水平、TB淋巴细胞亚群及T淋巴细胞受体(T cell receptor，TCR)Vβ多样性进行检测。以“FOXN1 deficiency”“FOXN1 haploinsufficiency”“FOXN1缺陷”“FOXN1单倍体不足”为检索词，检索PubMed、万方数据知识服务平台和中国知网，并进行文献复习。 结果 患儿为女婴，1岁5个月，以反复自身免疫性溶血性贫血为主要表现，伴毛发稀疏、甲营养不良。基因检测提示FOXN1基因c.1392_1401delTCCTGGACCC(p.P465Rfs*82)新生杂合突变，诊断为FOXN1单倍体不足。TRECs检测提示T淋巴细胞生成缺陷，κRECs正常，TCR Vβ显示TCR多样性受限。TB淋巴细胞亚群检测提示CD4+ T淋巴细胞减少，初始CD4+ T淋巴细胞减少，以记忆CD4+ T淋巴细胞为主。检索到5篇相关英文文献，目前全球共报道41例FOXN1单倍体不足患者，突变类型以移码突变为主。 结论 FOXN1单倍体不足是联合免疫缺陷病的一种，以婴幼儿期T淋巴细胞减少、反复感染为主要表现，可伴毛发发育异常、甲营养不良以及自身免疫现象，骨髓移植不能治愈此类疾病。 Abstract:Objective To analyze the clinical and immunological characteristics of the first case of FOXN1 haploinsufficiency in China and summarize the clinical characteristics of previous reported cases in other countries. Methods The whole-exome sequencing(WES) and Sanger sequencing were conducted to verify the mutation of FOXN1.The T cell receptor rearrangement excision circles(TRECs)and κ-deleting recombination excision circles(κRECs)copies, peripheral blood lymphocyte subsets and T cell receptor (TCR) Vβ repertoire were further detected。A literature search was conducted using PubMed, Wangfang Med Online and CNKI with search terms "FOXN1 deficiency" and "FOXN1 haploinsufficiency". Results A 1-year-old girl manifested with recurrent autoimmune hemolytic anemia, hair loss and nail dystrophy. Genetic mutation of FOXN1 (c.1392_1401delTCCTGGACCC, p.P465Rfs*82) was confirmed by WES and Sanger sequencing. The TRECs were 0.35 copies/μL, κRECs were normal. The TCR Vβ repertoire in this patient was markedly oligoclonal. Lymphocytes subsets revealed a predominate decrease of CD4+ T cell and Naïve CD4+ T, and an increase of effector memory helper T cells. A total of 5 publications were included (5 English and 0 Chinese). Thus far, 41 cases have been reported worldwide who mostly manifested with the decrease of T cells in early childhood. Conclusions FOXN1 haploinsufficiency deficiency is a kind of combined immunodeficiency disease, which is mainly manifested by the decrease of T cells and repeated infection in infants and young children, and may also be accompanied by hair loss, nail dystrophy and autoimmune disease, which cannot be cured by hematopoietic stem cell transplantation. -
Key words:
- FOXN1 mutation /
- combined immunodeficiency /
- syndromic features
作者贡献：李文道负责临床资料分析、完成实验及论文撰写；谷昊负责临床资料分析及患者随访；王薇负责测序数据分析与解读；吴润晖、宋红梅负责制订患者诊疗决策，指导论文撰写及修订。利益冲突：所有作者均声明不存在利益冲突注：本研究已通过北京协和医院伦理审查委员会批准(审批号：JS-2560) -
图 2 患儿及其父母FOXN1基因Sanger测序图(箭头为突变位点)
A. 患儿FOXN1基因存在移码突变c.1392_ 1401del TCCTGGACCC；B. 患儿父亲无该突变；C. 患儿母亲无该突变
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