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Defining SCID: circling in on a more precise diagnosis

Published: November 28, 2022

Severe combined immunodeficiency (SCID) is a group of rare genetic disorders that share a common phenotype of very low numbers of autologous T lymphocytes with deficient numbers or function of B and/or natural killer (NK) cells, causing affected individuals to be at risk for life-threatening infections. Subtypes of SCID are recognized, including: 1) Typical SCID with very few or undetectable autologous T cells; 2) Leaky/Atypical SCID with decreased numbers of T cells; and 3) Omenn syndrome with autoreactive/hyperinflammatory T cells. Historically, there was no universal definition of SCID or its subtypes, which limited multi-institutional studies. In 2014, Dr. William Shearer and members of the Primary Immune Deficiency Treatment Consortium (PIDTC) published inclusion criteria to facilitate rigorous observational and prospective studies of SCID outcomes following hematopoietic cell transplantation (HCT), gene therapy (GT), or enzyme-replacement therapy (ERT). In 2022, revised PIDTC definitions have been developed to reflect changes in clinical practice, particularly population-based newborn screening (NBS) for SCID and increased utilization of genetic sequencing, which has become rapid, inexpensive, and widely available.

In this edition of The Journal of Allergy and Clinical Immunology (JACI), Dvorak et al. describe the performance of the PIDTC 2022 definitions, applied to 379 patients proposed for enrollment in a prospective study of SCID. The revised PIDTC definitions highlight the diagnostic value of pathogenic variant(s) in recognized SCID genes, while decreasing reliance on the in vitro T-cell proliferative response to mitogens. Major changes in the 2022 definitions include: 1) modification of the term “Leaky” to “Leaky/Atypical,” to reflect cases with hypomorphic variants in known SCID genes or without established genotype, respectively; 2) reducing the T cell cutoff for Typical SCID to <0.05 x 10^9/L (unless maternal T cells are present); 3) recognizing a low percentage (<20%) of naïve T cells or presence of oligoclonal T cells as defining features of Leaky/Atypical SCID; 4) simplifying criteria for Omenn syndrome by scoring the number of supporting features, which include eosinophilia, elevated IgE, low TRECs, lymphadenopathy, hepato-splenomegaly, and oligoclonal T cells; 5) eliminating reticular dysgenesis as a separate SCID subtype, assigning these patients to one of the above categories based on phenotype; and 6) excluding all known thymic disorders and cases of idiopathic T-cell lymphopenia.

Typical SCID represents 69% of cases, with Leaky/Atypical SCID seen in 26% of cases and Omenn syndrome in 5%. Five percent of patients considered to have SCID by 2014 criteria were determined not to have SCID by the 2022 definitions – this included patients with thymic disorders, idiopathic T-cell lymphopenia, and combined immunodeficiency due to pathologic variants in ZAP70. Conversely, a small number of patients previously considered to not have SCID (primarily on the basis of normal or only moderately decreased proliferative responses to mitogens) were classified as SCID by the 2022 definitions – this included patients with pathogenic variants in RMRP, RAG1, and RAC2. Pathogenic variant(s) in SCID-associated genes were identified in 93% of patients, with 7 genes (IL2RG, RAG1, ADA, IL7R, DCLRE1C, JAK3, and RAG2) accounting for 89% of typical SCID. Three predominant genotypes (RAG1, ADA, and RMRP) accounted for 57% of cases of Leaky/Atypical SCID, with the remainder caused by 13 rarer genotypes. Most of cases of Omenn syndrome (88%) were due to pathogenic variants in RAG1 or RAG2, and 21% of all patients with RAG1 or RAG2 SCID developed Omenn syndrome. Though repeat testing proved important, an initial CD3 T cell count of <0.05x10^9/L differentiated cases of Typical SCID lacking maternal cells from leaky/atypical SCID: 97% vs. 7%. Presence of maternal T cells was sufficient to diagnose Typical SCID.

Based on recent diagnostic advances, the revised PIDTC 2022 definitions provide more stringent and universally applicable definitions of SCID than did the original PIDTC 2014 criteria, which had been designed to determine eligibility for enrollment in PIDTC protocols. The new definitions will facilitate rigorous analyses of patient outcomes following various approaches to allogeneic hematopoietic cell transplant or gene therapy. This in turn may provide clinicians with increased insights into risks of progression to Omenn syndrome, resistance to engraftment, and other factors. These definitions may continue to evolve with improving diagnostic techniques and refinements, further honing our understanding of SCID.

The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.

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