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国内首例FOXN1单倍体不足报告并文献复习

李文道 谷昊 王薇 吴润晖 宋红梅

李文道, 谷昊, 王薇, 吴润晖, 宋红梅. 国内首例FOXN1单倍体不足报告并文献复习[J]. 协和医学杂志, 2023, 14(2): 366-372. doi: 10.12290/xhyxzz.2022-0040
引用本文: 李文道, 谷昊, 王薇, 吴润晖, 宋红梅. 国内首例FOXN1单倍体不足报告并文献复习[J]. 协和医学杂志, 2023, 14(2): 366-372. doi: 10.12290/xhyxzz.2022-0040
LI Wendao, GU Hao, WANG Wei, WU Runhui, SONG Hongmei. First Case Report of FOXN1 Haploinsufficiency in China and Literature Review[J]. Medical Journal of Peking Union Medical College Hospital, 2023, 14(2): 366-372. doi: 10.12290/xhyxzz.2022-0040
Citation: LI Wendao, GU Hao, WANG Wei, WU Runhui, SONG Hongmei. First Case Report of FOXN1 Haploinsufficiency in China and Literature Review[J]. Medical Journal of Peking Union Medical College Hospital, 2023, 14(2): 366-372. doi: 10.12290/xhyxzz.2022-0040

国内首例FOXN1单倍体不足报告并文献复习

doi: 10.12290/xhyxzz.2022-0040
基金项目: 

国家重点研发计划 2021YFC2702000

国家科技资源共享服务平台计划 YCZYPT(2020)01

详细信息
    通讯作者:

    吴润晖, E-mail:runhuiwu@hotmail.com

    宋红梅, E-mail: songhm1021@126.com

    李文道、谷昊对本文同等贡献

    李文道、谷昊对本文同等贡献

  • 中图分类号: R593.3;R725.9

First Case Report of FOXN1 Haploinsufficiency in China and Literature Review

Funds: 

National Key R&D Program of China 2021YFC2702000

National S&T Resource Sharing Service Platform Project of China YCZYPT(2020)01

More Information
  • 摘要:   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。
    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  1  患儿入院查体体征

    A.卡介苗接种部位局部反应;B.毛发稀疏;C.反甲

    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

    图  3  患儿TCR Vβ多样性测序结果

    图  4  文献报道的FOXN1基因杂合突变位点示意图

  • [1] Bosticardo M, Yamazaki Y, Cowan J, et al. Heterozygous FOXN1 Variants Cause Low TRECs and Severe T Cell Lymphopenia, Revealing a Crucial Role of FOXN1 in Supporting Early Thymopoiesis[J]. Am J Hum Genet, 2019, 105: 549-561. doi:  10.1016/j.ajhg.2019.07.014
    [2] Adriani M, Martinez-Mir A, Fusco F, et al. Ancestral founder mutation of the nude (FOXN1) gene in congenital severe combined immunodeficiency associated with alopecia in southern Italy population[J]. Ann Hum Genet, 2004, 68: 265-268. doi:  10.1046/j.1529-8817.2004.00091.x
    [3] Auricchio L, Adriani M, Frank J, et al. Nail dystrophy associated with a heterozygous mutation of the nude/SCID human FOXN1 (WHN) gene[J]. Arch Dermatol, 2005, 141: 647-648.
    [4] Du Q, Huynh LK, Coskun F, et al. FOXN1 compound heterozygous mutations cause selective thymic hypoplasia in humans[J]. J Clin Invest, 2019, 129: 4724-4738. doi:  10.1172/JCI127565
    [5] Giardino G, Sharapova SO, Ciznar P, et al. Expanding the Nude SCID/CID Phenotype Associated with FOXN1 Homozygous, Compound Heterozygous, or Heterozygous Muta-tions[J]. J Clin Immunol, 2021, 41: 756-768. doi:  10.1007/s10875-021-00967-y
    [6] Flanagan SP. 'Nude', a new hairless gene with pleiotropic effects in the mouse[J]. Genet Res, 1966, 8: 295-309. doi:  10.1017/S0016672300010168
    [7] Nehls M, Pfeifer D, Schorpp M, et al. New member of the winged-helix protein family disrupted in mouse and rat nude mutations[J]. Nature, 1994, 372: 103-107. doi:  10.1038/372103a0
    [8] Pignata C, Fiore M, Guzzetta V, et al. Congenital Alopecia and nail dystrophy associated with severe functional T-cell immunodeficiency in two sibs[J]. Am J Med Genet, 1996, 65: 167-170. doi:  10.1002/(SICI)1096-8628(19961016)65:2<167::AID-AJMG17>3.0.CO;2-O
    [9] Markert ML, Marques JG, Neven B, et al. First use of thymus transplantation therapy for FOXN1 deficiency (nude/SCID): a report of 2 cases[J]. Blood, 2011, 117: 688-696. doi:  10.1182/blood-2010-06-292490
    [10] Firtina S, Cipe F, Ng YY, et al. A Novel FOXN1 Variant Is Identified in Two Siblings with Nude Severe Combined Immunodeficiency[J]. J Clin Immunol, 2019, 39: 144-147. doi:  10.1007/s10875-019-00615-6
    [11] Chou J, Massaad MJ, Wakim RH, et al. A novel mutation in FOXN1 resulting in SCID: a case report and literature review[J]. Clin Immunol, 2014, 155: 30-32. doi:  10.1016/j.clim.2014.08.005
    [12] Albuquerque AS, Marques JG, Silva SL, et al. Human FOXN1-deficiency is associated with alphabeta double-negative and FoxP3+ T-cell expansions that are distinctly modulated upon thymic transplantation[J]. PLoS One, 2012, 7: e37042. doi:  10.1371/journal.pone.0037042
    [13] Radha RDA, Panday NN, Naushad SM. FOXN1 Italian founder mutation in Indian family: Implications in prenatal diagnosis[J]. Gene, 2017, 627: 222-225. doi:  10.1016/j.gene.2017.06.033
    [14] Albar R, Mahdi M, Alkeraithe F, et al. Epstein-Barr virus associated with high-grade B-cell lymphoma in nude severe combined immunodeficiency[J]. BMJ Case Rep, 2019, 12: e227715. doi:  10.1136/bcr-2018-227715
    [15] Tangye SG, Al-Herz W, Bousfiha A, et al. Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee[J]. J Clin Immunol, 2020, 40: 24-64. doi:  10.1007/s10875-019-00737-x
    [16] Schorpp M, Hofmann M, Dear TN, et al. Characterization of mouse and human nude genes[J]. Immunogenetics, 1997, 46: 509-515. doi:  10.1007/s002510050312
    [17] Schuddekopf K, Schorpp M, Boehm T. The whn transcrip-tion factor encoded by the nude locus contains an evolutionarily conserved and functionally indispensable activation domain[J]. Proc Natl Acad Sci U S A, 1996, 93: 9661-9664. doi:  10.1073/pnas.93.18.9661
    [18] Žuklys S, Handel A, Zhanybekova S, et al. Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells[J]. Nat Immunol, 2016, 17: 1206. doi:  10.1038/ni.3537
    [19] Vigliano I, Gorrese M, Fusco A, et al. FOXN1 mutation abrogates prenatal T-cell development in humans[J]. J Med Genet, 2011, 48: 413-416. doi:  10.1136/jmg.2011.089532
    [20] Vaidya HJ, Briones LA, Blackburn CC. FOXN1 in thymus organogenesis and development[J]. Eur J Immunol, 2016, 46: 1826-1837. doi:  10.1002/eji.201545814
    [21] Nowell CS, Bredenkamp N, Tetelin S, et al. Foxn1 regulates lineage progression in cortical and medullary thymic epithelial cells but is dispensable for medullary sublineage divergence[J]. PLoS Genet, 2011, 7: e1002348. doi:  10.1371/journal.pgen.1002348
    [22] Chen L, Xiao S, Manley NR. Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner[J]. Blood, 2009, 113: 567-574. doi:  10.1182/blood-2008-05-156265
    [23] Cheng L, Guo J, Sun L, et al. Postnatal tissue-specific disruption of transcription factor FoxN1 triggers acute thymic atrophy[J]. J Biol Chem, 2010, 285: 5836-5847. doi:  10.1074/jbc.M109.072124
    [24] Larsen BM, Cowan JE, Wang Y, et al. Identification of an Intronic Regulatory Element Necessary for Tissue-Specific Expression of Foxn1 in Thymic Epithelial Cells[J]. J Immunol, 2019, 203: 686-695. doi:  10.4049/jimmunol.1801540
    [25] Markert ML, Alexieff MJ, Li J, et al. Complete DiGeorge syndrome: development of rash, lymphadenopathy, and oligoclonal T cells in 5 cases[J]. J Allergy Clin Immunol, 2004, 113: 734-741. doi:  10.1016/j.jaci.2004.01.766
    [26] Zampieri M, Ciccarone F, Calabrese R, et al. Reconfiguration of DNA methylation in aging[J]. Mech Ageing Dev, 2015, 151: 60-70. doi:  10.1016/j.mad.2015.02.002
    [27] Pignata C, Gaetaniello L, Masci AM, et al. Human equivalent of the mouse Nude/SCID phenotype: long-term evaluation of immunologic reconstitution after bone marrow transplantation[J]. Blood, 2001, 97: 880-885. doi:  10.1182/blood.V97.4.880
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出版历程
  • 收稿日期:  2022-01-27
  • 录用日期:  2022-02-22
  • 网络出版日期:  2022-08-22
  • 刊出日期:  2023-03-30

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