Severe Combined Immunodeficiencies - SCID

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Content

Indications for Testing

Laboratory Testing

  • Screen for underlying diseases associated with immunodeficiency
    • CBC – presence of lymphopenia; absolute lymphocyte count often <500 cells/µL
      • Normal lymphocyte count does not rule out severe combined immunodeficiencies (SCID)
    • HIV testing – rule out HIV infection
  • Screen for other immunodeficiencies
    • T-cell and B-cell immunodeficiency profile testing
      • Testing at minimum should include CD3, CD4, CD8, CD19, CD45RA, CD45RO, NK cell, and CD4:CD8 ratio
    • Neutrophil function testing
    • Quantitative immunoglobulins
    • Complement testing
    • Lymphocyte antigen and mitogen proliferation – will be abnormal
      • Test requires at least 7 days for results
  • Analyte/enzyme testing may be considered prior to genetic testing
    • Adenosine deaminase, purine nucleoside phosphorylase
  • Molecular diagnosis
    • Available for prenatal/postnatal testing for SCID
    • Genetic testing – see list in Clinical Background

Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm

Clinical Background

Severe combined immunodeficiencies (SCID) are genetic disorders characterized by blocking T-lymphocyte differentiation or function and often are associated with abnormal development of other lymphocyte lineages (B cells and NK cells).

Epidemiology

  • Incidence – >1/50,000 births
  • Age – median 4-7 months
  • Sex – M:F, equal, except for X-linked forms

Identified Forms of SCID (based on the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency, 2013)

Pathophysiology

  • Block in T-lymphocyte differentiation or growth and variable abnormal development of other lymphocyte lineages

Clinical Presentation

  • Most newborns appear normal
  • Early onset of severe infections (earliest are Pneumocystis jirovecii, viral, also fungal, followed in many cases at 4-6 months by bacterial infection)
  • Growth failure
  • Persistent diarrhea
  • Desquamative skin rash, elevated liver enzymes, and GI bleeding
  • Occurrence of graft-versus-host disease upon exposure to maternal lymphocytes, during delivery, or by nonirradiated blood transfusion
    • Most prominent in skin and liver
    • May be associated with autoimmune thrombocytopenia or pancytopenia
    • Rejection of hematopoietic stem cell transplant from father or donors
  • Omenn syndrome – atypical SCID associated with hypomorphic mutations

Treatment

  • Prophylaxis for P. jirovecii, fungal infections, and, in some cases, bacterial infections
  • Hematopoietic stem cell transplant
  • For ADA deficiency – exogenous enzyme replacement
  • Gene therapy for X-linked SCID and ADA deficiency

Indications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations.
Click on number for test-specific information in the ARUP Laboratory Test Directory

CD4+ T-Cell Recent Thymic Emigrants (RTEs) 2010179
Method: Quantitative Flow Cytometry

Lymphocyte Subset Panel 6 - Total Lymphocyte Enumeration with CD45RA and CD45RO 0095862
Method: Quantitative Flow Cytometry

Lymphocyte Subset Panel 7 - Congenital Immunodeficiencies 0095899
Method: Quantitative Flow Cytometry

B-Cell Memory and Naive Panel 2008901
Method: Flow Cytometry

Immunoglobulins (IgA, IgG, IgM), Quantitative 0050630
Method: Quantitative Nephelometry

Lymphocyte Antigen and Mitogen Proliferation Panel 0096056
Method: Cell Culture

Limitations

Time sensitive

Lymphocyte Antigen and Mitogen Proliferation Panel with Cytokine Response to Mitogens, 12 Cytokines (INACTIVE as of 04/04/16: Refer to February 2016 Hot Line for Replacement Test: 2013117, ACTIVE 04/04/16) 0051584
Method: Cell Culture/Multiplex Bead Assay

Limitations

Time sensitive

Toll-Like Receptor Function 0051589
Method: Cell Culture/Quantitative Multiplex Bead Assay

Limitations

Results should be interpreted in light of the individual’s clinical status

Defects in TLR3 associated with herpes simplex encephalitis may not be detected in this assay based on the reported instance of a patient with compound heterozygous mutations in TLR3 leading to decreased cytokine production in response to Poly I:C in fibroblasts but not PBMCs1

Severe Combined Immunodeficiency (SCID) Panel, Sequencing and Deletion/Duplication, 19 Genes 2010219
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Limitations

Not determined or evaluated – mutations in genes not included on the panel, deep intronic and regulatory region mutations, breakpoints for large deletions/duplications

Deletions/duplications will not be detected in exon 1 in ADA gene, exon 11 in CORO1A gene, exons 4, 6, and 8 in DCLRE1C gene, exons 3, 6, and 9 in JAK3 gene

Small deletions or insertions may not be detected

Diagnostic errors can occur due to rare sequence variations

Lack of a detectable gene mutation does not exclude a diagnosis of SCID

Primary Antibody Deficiency Panel, Sequencing (35 Genes) and Deletion/Duplication (26 Genes)  2011156
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Limitations

Not determined or evaluated – mutations in genes not included on the panel, deep intronic and regulatory region mutations, breakpoints for large deletions/duplications, translocations

Deletions/duplications will not be detected in IKBKG, LRBA, LRRC8A, PIK3CD, PIK3R1, PLCG2, PRKCD, SH2D1A, or XIAP/BIRC4 gene

Small deletions or insertions may not be detected

Diagnostic errors can occur due to rare sequence variations

Lack of a detectable gene mutation does not exclude a diagnosis of primary antibody deficiency

Additional Tests Available

CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Comments

Initial screening for immunodeficiency

Human Immunodeficiency Virus Type 1 (HIV-1) Antibody by CIA with Reflex to HIV-1 Antibody Confirmation by Western Blot 2005375
Method: Qualitative Chemiluminescent Immunoassay/Qualitative Western Blot

Comments

Rule out HIV

Reflex pattern – if Human Immunodeficiency Virus Type 1 (HIV-1) Antibody by CIA screen is repeatedly reactive, then Human Immunodeficiency Virus Type 1 (HIV-1) Antibody Confirmation by Western Blot will be added

Adenosine Deaminase, RBC 0083001
Method: Kinetic Spectrophotometry

Comments

May be used as a marker of SCID; lack of ADA allows deoxyadenosine to accumulate and kill lymphocytes

Interleukin-1-Receptor-Associated Kinase-4 (IRAK-4) Deficiency Screen (INACTIVE as of 04/04/16: Refer to February 2016 Hot Line Test 0051589) 0051393
Method: Cell Culture/Quantitative Multiplex Bead Assay

Comments

Screen for IRAK4 or MYD88 deficiency in children with recurrent life-threatening bacterial infections with weak signs of inflammation or negative evaluation for other more common immunodeficiencies

Results should be interpreted in light of the individual’s clinical status

Guidelines

Al-Herz W, Bousfiha A, Casanova J, Chatila T, Conley M, Cunningham-Rundles C, Etzioni A, Franco J, Gaspar B, Holland S, Klein C, Nonoyama S, Ochs H, Oksenhendler E, Picard C, Puck J, Sullivan K, Tang M. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2014; 5: 162. PubMed

General References

Aloj G, Giardino G, Valentino L, Maio F, Gallo V, Esposito T, Naddei R, Cirillo E, Pignata C. Severe combined immunodeficiences: new and old scenarios. Int Rev Immunol. 2012; 31(1): 43-65. PubMed

Cossu F. Genetics of SCID. Ital J Pediatr. 2010; 36: 76. PubMed

Locke B, Dasu T, Verbsky J. Laboratory diagnosis of primary immunodeficiencies. Clin Rev Allergy Immunol. 2014; 46(2): 154-68. PubMed

Niehues T, Perez-Becker R, Schuetz C. More than just SCID--the phenotypic range of combined immunodeficiencies associated with mutations in the recombinase activating genes (RAG) 1 and 2. Clin Immunol. 2010; 135(2): 183-92. PubMed

van der Burg M, Gennery A. Educational paper. The expanding clinical and immunological spectrum of severe combined immunodeficiency. Eur J Pediatr. 2011; 170(5): 561-71. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Augustine N, Pasi B, Hill H. Comparison of ATP production in whole blood and lymphocyte proliferation in response to phytohemagglutinin. J Clin Lab Anal. 2007; 21(5): 265-70. PubMed

Shyur S, Hill H. Recent advances in the genetics of primary immunodeficiency syndromes. J Pediatr. 1996; 129(1): 8-24. PubMed

Medical Reviewers

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Last Update: February 2016