{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:00:46Z","timestamp":1790830846817,"version":"4.1.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"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>Newborn screening (NBS) based on T-cell receptor excision circles (TRECs) has revolutionized the early diagnosis of severe combined immunodeficiency (SCID), facilitating the identification of affected newborns before the onset of life-threatening infections. However, reduced TRECs levels are a surrogate marker of impaired thymic output rather than a disease-specific finding. Accordingly, low values can result from highly heterogeneous and distinct biological mechanisms of T-cell ontogeny that extend beyond classical SCID phenotypes. This study describes three patients with inborn errors of immunity (IEI) identified through abnormal TRECs screening who were subsequently diagnosed with Artemis, FOXN1, and Moesin deficiencies. These clinical cases demonstrate that primary T-cell immunodeficiencies can arise from defects at distinct biological levels of T-cell development, specifically in impaired antigen receptor V(D)J recombination (characteristic of NHEJ deficiencies and other SCID conditions), disrupted thymic stromal microenvironment function and compromised peripheral lymphocyte homeostasis, respectively. Consequently, optimizing clinical outcomes after a positive newborn screening requires the systematic integration of clinical, immunological and molecular findings. This diagnostic approach should involve specialized immunodeficiency centers with access to advanced flow cytometry techniques and molecular confirmation to ensure an accurate and definitive diagnosis. Ultimately, therapeutic decisions from supportive care to definitive hematopoietic stem cell transplantation or gene\/enzymatic therapy for SCID patients must be guided by the precise underlying pathogenic mechanism and the specific molecular defect.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1947649","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:49:11Z","timestamp":1790830151000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Pitfalls and diagnostic challenges in TRECS-based newborn screening for Artemis, FOXN1 and Moesin deficiencies"],"prefix":"10.3389","volume":"17","author":[{"given":"Carlota C.","family":"Ruig\u00f3mez-Mart\u00edn","sequence":"first","affiliation":[{"name":"Department of Immunology, Hospital Universitario 12 de Octubre","place":["Madrid, Spain"]},{"name":"Instituto de Investigaci\u00f3n Sanitaria Hospital 12 Octubre (imas12)","place":["Madrid, 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