{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:48:00Z","timestamp":1785905280924,"version":"3.56.0"},"reference-count":12,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82394420"],"award-info":[{"award-number":["82394420"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82394423"],"award-info":[{"award-number":["82394423"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82394420"],"award-info":[{"award-number":["82394420"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82394423"],"award-info":[{"award-number":["82394423"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Key Research and Development Program of China","award":["2022YFC2703900"],"award-info":[{"award-number":["2022YFC2703900"]}]},{"name":"CAMS Innovation Fund for Medical Sciences","award":["2025-I2M-KJ-011"],"award-info":[{"award-number":["2025-I2M-KJ-011"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: DNA Ligase 4 (LIG4) catalyzes the final ligation step during V(D)J recombination. Biallelic pathogenic variants in LIG4 cause severe combined immunodeficiency (SCID), a life-threatening immunodeficiency characterized by the lack of mature T and B cells. Case Presentation: An 18-year-old male exhibited widespread verrucous and keratotic cutaneous lesions across the face, neck, and extremities. The proband manifested early-onset short stature, chronic malnutrition, recurrent pulmonary infections with bronchiectasis, chronic diarrhea, and bilateral tenosynovitis. Immunophenotyping revealed persistent panhypogammaglobulinemia, absent B cells, reduced T and natural killer (NK) cells, and nearly undetectable na\u00efve T cells. Both \u03b1-HPV and \u03b2-HPV were detected in the cutaneous lesions. Compound heterozygous LIG4 variants (hg19, NM206937.2, c.833G &gt; T; p.Arg278Leu inherited from the mother; c.833G &gt; A; p.Arg278 His inherited from the father) were identified. Conclusions: This study reports a proband with LIG4 syndrome presenting with rare phenotypes of multiple viral warts and combined lymphopenia of T, B, and NK cells. This proband harbors compound heterozygous variants at the same codon (c.833G), which not only confirm the clinical diagnosis but also enrich the known phenotypic spectrum of LIG4 syndrome.<\/jats:p>","DOI":"10.3390\/genes17080917","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T17:26:52Z","timestamp":1785778012000},"page":"917","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["LIG4 Syndrome Presenting with Extensive Cutaneous Viral Warts Caused by Multi-Type HPV Infection"],"prefix":"10.3390","volume":"17","author":[{"given":"Kaichen","family":"Tang","sequence":"first","affiliation":[{"name":"McKusick-Zhang Center for Genetic Medicine, State Key Laboratory for Complex Severe and Rare Diseases, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9812-0451","authenticated-orcid":false,"given":"Shiqi","family":"Fan","sequence":"additional","affiliation":[{"name":"McKusick-Zhang Center for Genetic Medicine, State Key Laboratory for Complex Severe and Rare Diseases, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Zhang","sequence":"additional","affiliation":[{"name":"McKusick-Zhang Center for Genetic Medicine, State Key Laboratory for Complex Severe and Rare Diseases, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miao","family":"Sun","sequence":"additional","affiliation":[{"name":"McKusick-Zhang Center for Genetic Medicine, State Key Laboratory for Complex Severe and Rare Diseases, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Lai","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Skin and Immune Diseases, Beijing 100730, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Zhang","sequence":"additional","affiliation":[{"name":"McKusick-Zhang Center for Genetic Medicine, State Key Laboratory for Complex Severe and Rare Diseases, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1007\/s10875-022-01289-3","article-title":"Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee","volume":"42","author":"Tangye","year":"2022","journal-title":"J. Clin. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Schim van der Loeff, I., Ahuja, M., Chen, R., Patane, E., and Hambleton, S. (2026). An update on inborn errors of V(D)J recombination. Physiology.","DOI":"10.1152\/physiol.00004.2026"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1146\/annurev-biochem-080320-110356","article-title":"Repair of DNA Double-Strand Breaks by the Nonhomologous End Joining Pathway","volume":"90","author":"Stinson","year":"2021","journal-title":"Annu. Rev. Biochem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/41358","article-title":"Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells","volume":"388","author":"Grawunder","year":"1997","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1186\/s13023-016-0520-1","article-title":"DNA ligase IV syndrome; a review","volume":"11","author":"Altmann","year":"2016","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1016\/S1097-2765(01)00408-7","article-title":"DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency","volume":"8","author":"Cerosaletti","year":"2001","journal-title":"Mol. Cell"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Luo, X., Liu, Q., Jiang, J., Tang, W., Ding, Y., Zhou, L., Yu, J., Tang, X., An, Y., and Zhao, X. (2021). Characterization of a Cohort of Patients With LIG4 Deficiency Reveals the Founder Effect of p.R278L, Unique to the Chinese Population. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.695993"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3024","DOI":"10.1073\/pnas.0914865107","article-title":"Homozygous DNA ligase IV R278H mutation in mice leads to leaky SCID and represents a model for human LIG4 syndrome","volume":"107","author":"Rucci","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1111\/ijd.14196","article-title":"A novel approach to the classification of epidermodysplasia verruciformis","volume":"57","author":"Huang","year":"2018","journal-title":"Int. J. Dermatol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"de Jong, S.J., Imahorn, E., Itin, P., Uitto, J., Orth, G., Jouanguy, E., Casanova, J.L., and Burger, B. (2018). Epidermodysplasia Verruciformis: Inborn Errors of Immunity to Human Beta-Papillomaviruses. Front. Microbiol., 9.","DOI":"10.3389\/fmicb.2018.01222"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.clim.2015.07.004","article-title":"Novel compound heterozygous DNA ligase IV mutations in an adolescent with a slowly-progressing radiosensitive-severe combined immunodeficiency","volume":"160","author":"Tamura","year":"2015","journal-title":"Clin. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1056\/NEJMoa2102715","article-title":"Treatment of Relapsing HPV Diseases by Restored Function of Natural Killer Cells","volume":"385","author":"Lisco","year":"2021","journal-title":"N. Engl. J. Med."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/8\/917\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:15:40Z","timestamp":1785903340000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/8\/917"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,3]]},"references-count":12,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["genes17080917"],"URL":"https:\/\/doi.org\/10.3390\/genes17080917","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,3]]}}}