What laboratory findings are consistent with Severe Combined Immunodeficiency (SCID)?

Laboratory Findings Consistent with Severe Combined Immunodeficiency (SCID)

The primary laboratory findings consistent with SCID include profound T-cell lymphopenia (CD3+ T cells <300/μL), absent or very low T-cell receptor excision circles (TRECs), and severely impaired T-cell function with poor proliferation to mitogens. 1, 2

Core Immunologic Abnormalities

• T-cell abnormalities: Severe T-cell lymphopenia with CD3+ T-cell counts typically <300/μL, which is the hallmark laboratory finding in SCID 2
• Lymphopenia: Absolute lymphocyte counts <2,500/μL are present in approximately 63% of SCID patients 3
• T-cell function: Profoundly reduced proliferation in response to mitogens such as phytohemagglutinin (PHA) 1, 4
• TRECs: Very low or absent T-cell receptor excision circles, which are used in newborn screening programs to identify SCID 5, 1
• Naïve T cells: Less than 20% of CD4+ T cells expressing naïve markers (CD45RA+) 2

Immunophenotypic Patterns

SCID can be classified based on the presence or absence of T, B, and NK cells, which helps determine the underlying genetic defect:

• T-B-NK-: Seen in adenosine deaminase (ADA) deficiency, affecting all lymphocyte lineages 1
• T-B+NK-: Common in X-linked SCID (IL2RG mutations) and JAK3 deficiency 1, 6
• T-B-NK+: Characteristic of RAG1/2 deficiencies and other defects in V(D)J recombination 1
• T-B+NK+: Observed in IL-7 receptor deficiency and CD3 complex defects 1

Immunoglobulin Abnormalities

• Hypogammaglobulinemia: Low or absent IgA and IgM levels 1
• Variable IgG levels: May be normal early in life due to maternal transfer across the placenta 1
• Poor specific antibody production: Impaired responses to vaccines or natural infections 5

Additional Laboratory Findings

• Maternal T-cell engraftment: Presence of maternal T cells in the infant's circulation, which can be detected by HLA typing or short tandem repeat analysis 2
• Oligoclonal T cells: Limited T-cell receptor diversity in patients with leaky/atypical SCID 2
• Eosinophilia and elevated IgE: Particularly in Omenn syndrome, a variant of SCID 2

Diagnostic Approach

• Complete blood count: Initial screening should include absolute lymphocyte count to identify lymphopenia 1, 3
• Flow cytometry: Essential to enumerate T, B, and NK cell numbers and determine the immunophenotypic pattern 1
• T-cell function tests: Lymphocyte proliferation assays in response to mitogens (PHA) 4
• Genetic testing: Molecular diagnosis to identify the specific gene defect 3

Clinical Implications

• A suspicion of SCID should be considered an urgent clinical condition requiring immediate intervention 5
• Early diagnosis through laboratory testing is critical as outcomes are significantly better when treatment (HSCT) is initiated before 3.5 months of age 5
• Patients with typical SCID have <500 CD3+ T cells/μL, while those with leaky/atypical SCID have reduced but detectable T cells with impaired function 4, 2

Common Pitfalls

• Some forms of combined immunodeficiency may have normal TREC levels and would not be detected by newborn screening programs (e.g., FOXP3, CD40L, and IL10RA mutations) 4
• Maternal T-cell engraftment can mask the diagnosis by providing apparently normal T-cell counts 2
• Premature infants may have transiently low TREC counts that increase over time, potentially leading to false-positive screening results 5