Pitfalls and diagnostic challenges in TRECS-based newborn screening for Artemis, FOXN1 and Moesin deficiencies
11 affiliations
- 1Department of Immunology, Hospital Universitario 12 de Octubre , ,
- 2Department of Hematology and Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca , ,
- 3Department of Peadriatics, Hospital Universitario San Pedro , ,
- 4Department of Genetics, Hospital Universitario 12 de Octubre , ,
- 5Genetics Section, Department of Clinical Analysis, Hospital Universitario San Pedro , ,
- 6Newborn Screening Unit, Department of Clinical Chemistry, Hospital Universitario Miguel Servet , ,
- 7Hematopoietic Stem Cell Transplantation Unit, Hospital Universitario Niño Jesus , ,
- 8Department of Clinical Analysis, Hospital Universitario San Pedro , ,
- 9Department of Hemato-Oncology Peadriatics, Hospital Universitario Miguel Servet , ,
- 10Instituto de Investigación Sanitaria Hospital 12 Octubre (imas12) , ,
- 11Department of Peadriatics, Hospital Universitario 12 de Octubre , ,
Abstract
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.
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BibTeX
@article{ruigomezmartin2026pitfalls,
title = {{Pitfalls and diagnostic challenges in TRECS-based newborn screening for Artemis, FOXN1 and Moesin deficiencies}},
author = {Carlota C. Ruigómez-Martín and Celia Nieto-López and Lucía Dueñas-Prieto and Juan D. Acevedo-Ávila and Francisco J. Gil-Etayo and Inés Esteban-Díez and Cristina García-Muro and Juan F. Quesada-Espinosa and María J. Díaz-Madroñero and Leyre Echeverría-Sádaba and Samuel Martín-Rodríguez and Elena García-González and Marta González-Vicent and Iván Bernardo and Carmen Rodríguez-Vigil Iturrate and José T. Ramos-Amador and Marta Fernández-Gaitán and Nerea Salmón-Rodríguez and Luis I. González-Granado and Luis M. Allende},
journal = {Frontiers in immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1947649},
url = {https://europepmc.org/article/PMC/PMC13668555},
note = {CC BY},
}
RIS
TY - JOUR
TI - Pitfalls and diagnostic challenges in TRECS-based newborn screening for Artemis, FOXN1 and Moesin deficiencies
AU - Carlota C. Ruigómez-Martín
AU - Celia Nieto-López
AU - Lucía Dueñas-Prieto
AU - Juan D. Acevedo-Ávila
AU - Francisco J. Gil-Etayo
AU - Inés Esteban-Díez
AU - Cristina García-Muro
AU - Juan F. Quesada-Espinosa
AU - María J. Díaz-Madroñero
AU - Leyre Echeverría-Sádaba
AU - Samuel Martín-Rodríguez
AU - Elena García-González
AU - Marta González-Vicent
AU - Iván Bernardo
AU - Carmen Rodríguez-Vigil Iturrate
AU - José T. Ramos-Amador
AU - Marta Fernández-Gaitán
AU - Nerea Salmón-Rodríguez
AU - Luis I. González-Granado
AU - Luis M. Allende
PY - 2026
DA - 2026/10/01
JO - Frontiers in immunology
DO - 10.3389/fimmu.2026.1947649
UR - https://europepmc.org/article/PMC/PMC13668555
AB - 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.
SN - 1664-3224
ER -