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When Screening for Severe Combined Immunodeficiency (SCID) with T Cell Receptor Excision Circles Is Not SCID: a Case-Based Review

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Abstract

Newborn screening efforts focusing on the quantification of T cell receptor excision circles (TRECs), as a biomarker for abnormal thymic production of T cells, have allowed for the identification and definitive treatment of severe combined immunodeficiency (SCID) in asymptomatic neonates. With the adoption of TREC quantification in Guthrie cards across the USA and abroad, typical, and atypical SCID constitutes only ~ 10% of cases identified with abnormal TRECs associated with T cell lymphopenia. Several other non-SCID-related conditions may be identified by newborn screening in a term infant. Thus, it is important for physicians to recognize that other factors, such as prematurity, are often associated with low TRECs initially, but often improve with age. This paper focuses on a challenge that immunologists face: the diagnostic evaluation and management of cases in which abnormal TRECs are associated with variants of T cell lymphopenia in the absence of a genetically defined form of typical or atypical SCID. Various syndromes associated with T cell impairment, secondary forms of T cell lymphopenia, and idiopathic T cell lymphopenia are identified using this screening approach. Yet there is no consensus or guidelines to assist in the evaluation and management of these newborns, despite representing 90% of the patients identified, resulting in significant work for the clinical teams until a diagnosis is made. Using a case-based approach, we review pearls relevant to the evaluation of these newborns, as well as the management dilemmas for the families and team related to the resolution of genetic ambiguities.

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Authors and Affiliations

  1. Department of Hematology, Children’s Hospital of Orange County, Orange, CA, USA

    David Buchbinder & Diane J. Nugent

  2. Department of Pediatrics, University of California at Irvine, Orange, CA, USA

    David Buchbinder & Diane J. Nugent

  3. Division of Pediatric, University of South Florida at Johns Hopkins All Children’s Hospital, Allergy/ Immunology, St. Petersburg, FL, USA

    Jolan E. Walter & Maria Chitty Lopez

  4. Division of Pediatric Allergy and Immunology, Massachusetts General Hospital for Children, Boston, MA, USA

    Jolan E. Walter

  5. Division of Immunology, Allergy, and Rheumatology, Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA

    Manish J. Butte

  6. Department of Allergy & Immunology, Children’s Hospital of Orange County, Orange, CA, USA

    Wan-Yin Chan

  7. Division of Allergy, Immunology & Rheumatology, Department of Pediatrics, Sacramento, CA, USA

    Victoria R. Dimitriades

  8. Department of Allergy & Immunology, University of California, San Francisco, CA, USA

    Morna J. Dorsey & Jennifer M. Puck

  9. Department of Infectious Disease, Children’s Hospital of Orange County, Orange, CA, USA

    Jasjit Singh

  10. Department of Pediatrics, Division of Allergy Immunology, University of California at San Diego, La Jolla, CA, USA

    Cathleen A. Collins

  11. Department of Pediatrics, Division of Allergy Immunology, Rady Children’s Hospital, San Diego, CA, USA

    Cathleen A. Collins

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  1. David Buchbinder
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Contributions

All authors helped draft and approved the submitted manuscript. CAC and DB coordinated the creation of the original draft manuscript. DB, MJB, WYC, VRD, MJD, DJN, JMP, JS, and CAC participated in regular teleconferences surrounding the diagnostic evaluation and treatment of the immune disorders depicted in each case. All authors helped review the literature and cases. JEW and MCL helped illustrate the manuscript with the accompanying tables.

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Correspondence to David Buchbinder.

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Buchbinder, D., Walter, J.E., Butte, M.J. et al. When Screening for Severe Combined Immunodeficiency (SCID) with T Cell Receptor Excision Circles Is Not SCID: a Case-Based Review. J Clin Immunol 41, 294–302 (2021). https://doi.org/10.1007/s10875-020-00931-2

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