{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T12:20:40Z","timestamp":1788956440683,"version":"build-2803163510"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T00:00:00Z","timestamp":1740700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>DNA Ligase 4 is critical to nonhomologous end joining, necessary for V(D)J recombination in T and B cell development. Ligase 4 deficiency is a rare autosomal recessive disorder caused by hypomorphic mutations in the DNA Ligase 4 gene, that can lead to a wide range of phenotypes. We describe a case of Ligase 4 deficiency causing a type of T-B-NK+ atypical SCID, highlighting the clinical and immunologic manifestations. An eight-year-old female, from S\u00e3o Nicolau Island (Cape Verde), presented at our hospital with a history of recurrent pneumonia and suppurative otitis, multiple skin lesions attributed to fungal and bacterial infections since the age of two, and recurrent diarrhea and growth impairment, beginning at the age of four. The laboratory workup showed almost absent B cells, marked hypogammaglobulinemia, and an impaired response to protein antigens. Flow cytometry revealed normal NK and T cell counts, but with nearly absent na\u00efve T cells and TCR-Va7 expressing T lymphocytes, and reduced proliferative responses to mitogens and antigens. An oligoclonal V\u03b2 repertoire was identified by FACS, and PROMIDISa analysis revealed a skewed TCRa repertoire signature. A 477 PID-related genes NGS panel identified a homozygous R278H mutation in the DNA Ligase 4 gene, previously reported to cause Ligase 4 deficiency. Immunoglobulin replacement and prophylactic therapies were started while waiting for hematopoietic stem cell transplantation. She has experienced fluctuating transaminase levels. The cutaneous biopsy was suggestive of lupus pernio. She has shown recurrent inflammatory signs in her limbs, with documented tenosynovitis on ultrasound. Homozygous R278H in Ligase 4 has been linked to various ranges of manifestations in Ligase 4 deficient patients. In our report, this genotype resulted in T-B-NK+ atypical SCID, that after proper prophylaxis has a predominant autoimmune phenotype.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1545630","type":"journal-article","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T07:11:41Z","timestamp":1740726701000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Case Report: Hypomorphic Ligase 4 deficiency \u2013 a paradigm of immunodysregulation"],"prefix":"10.3389","volume":"16","author":[{"given":"Catarina","family":"Andrade","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Isabel","family":"Cordeiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta Valente","family":"Pinto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Concei\u00e7\u00e3o","family":"Neves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catarina","family":"Martins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"Villartay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o Farela","family":"Neves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rdc.2023.06.001","article-title":"Approach to diagnosing inborn errors of immunity","volume":"49","author":"Peng","year":"2023","journal-title":"Rheum Dis Clin North Am"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1093\/abbs\/gmz076","article-title":"Pathways and assays for DNA double-strand break repair by homologous recombination","volume":"51","author":"Li","year":"2019","journal-title":"Acta Biochim Biophys Sin (Shanghai)"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2022.11.003","article-title":"DNA replication-associated inborn errors of immunity","volume":"151","author":"Willemsen","year":"2023","journal-title":"J Allergy Clin Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/bmb\/ldv020","article-title":"Congenital defects in V(D)J recombination","volume":"114","author":"Villartay","year":"2015","journal-title":"Br Med Bull"},{"key":"B5","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1093\/mutage\/gez026","article-title":"Altered DNA ligase activity in human disease","volume":"35","author":"Tomkinson","year":"2020","journal-title":"Mutagenesis"},{"key":"B6","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1038\/s41580-019-0152-0","article-title":"DNA double-strand break repair-pathway choice in somatic mammalian cells","volume":"20","author":"Scully","year":"2019","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddh274","article-title":"Analysis of DNA ligase IV mutations found in LIG4 syndrome patients: the impact of two linked polymorphisms","volume":"13","author":"Girard","year":"2004","journal-title":"Hum Mol Genet"},{"key":"B8","doi-asserted-by":"crossref","DOI":"10.1007\/978-1-4419-6448-9_16","article-title":"Ligase IV syndrome","volume-title":"Diseases of DNA Repair. 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