Volume 14 Issue 2
Mar.  2023
Turn off MathJax
Article Contents
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

First Case Report of FOXN1 Haploinsufficiency in China and Literature Review

doi: 10.12290/xhyxzz.2022-0040
Funds:

National Key R&D Program of China 2021YFC2702000

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

More Information
  • Corresponding author: WU Runhui, E-mail: runhuiwu@hotmail.com; SONG Hongmei, E-mail: songhm1021@126.com
  • Received Date: 2022-01-27
  • Accepted Date: 2022-02-22
  • Available Online: 2022-08-22
  • Publish Date: 2023-03-30
  •   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.
  • loading
  • [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
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(4)

    Article Metrics

    Article views (2305) PDF downloads(38) Cited by()
    Proportional views
    Related

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return