Severe Combined Immunodeficiencies - SCID

Severe combined immunodeficiencies (SCIDs) are genetic disorders characterized by blocked T-lymphocyte differentiation or function and often are associated with abnormal development of other lymphocyte lineages (B cells and natural killer [NK] cells). SCID is also commonly referred to as "bubble boy disease." About 92% of U.S. newborns are now screened for SCID by molecular laboratory testing (Immune Deficiency Foundation [IDF], 2017).

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

Indications for Testing

  • In infants or children (Joint Task Force on Practice Parameters, Bonilla, 2015)
    • Chronic diarrhea
    • Failure to thrive
    • Recurrent, persistent, or severe viral, fungal, or bacterial infections
    • Pneumocystis jiroveci infection

Criteria for Diagnosis

Laboratory Testing

  • Screen for underlying diseases associated with immunodeficiency
    • CBC – presence of lymphopenia (total lymphocyte count of ≤3,400 cells/µL at birth, ≤3,900 cells/µL at 5-6 months, and ≤1,000 cells/µL in adults (Immune Deficiency Foundation [IDF], 2015)
      • Normal lymphocyte count does not rule out SCIDs
    • 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, natural killer (NK) cell, and CD4:CD8 ratio
    • Quantitative immunoglobulins
    • Lymphocyte antigen and mitogen proliferation – will be abnormal
      • Test requires at least 7 days for results
    • Neutrophil function testing
    • Complement testing
  • 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 lists in Background section


  • Incidence – >1/58,000 births (Joint Task Force on Practice Parameters, Bonilla, 2015)
  • Age – median 4-7 months
  • Sex – M:F, equal, except for X-linked forms

Identified Forms of Severe Combined Immunodeficiencies (SCID)


Blockage 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 gastrointestinal 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 other donor
  • Omenn syndrome – atypical SCIDs associated with hypomorphic mutations
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

Natural Killer Cell and Natural Killer T-Cell Panel 2013805
Method: Semi-Quantitative Flow Cytometry

Natural Killer Cells Enumeration 0092404
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


Time sensitive

Lymphocyte Antigen and Mitogen Proliferation Panel with Cytokine Response 2013117
Method: Cell Culture/Multiplex Bead Assay

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


Results should be interpreted in conjunction with the individual’s clinical status

Defects in the TLR3 gene 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 polyinosinic-polycytidylic acid (Poly I:C) in fibroblasts but not peripheral blood mononuclear cell (PBMCs)

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


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

Refer to Additional Testing Information document for further content


Bonilla FA, Khan DA, Ballas ZK, Chinen J, Frank MM, Hsu JT, Keller M, Kobrynski LJ, Komarow HD, Mazer B, Nelson RP, Orange JS, Routes JM, Shearer WT, Sorensen RU, Verbsky JW, Bernstein DI, Blessing-Moore J, Lang D, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph CR, Schuller D, Spector SL, Tilles S, Wallace D, Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology; the American College of Allergy, Asthma & Immunology; and the Joint Council of Allergy, Asthma & Immunology. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015; 136(5): 1186-205.e1-78. PubMed

Diagnostic & Clinical Care Guidelines for Primary Immunodeficiencies. Immune Deficiency Foundation. Towson, MD [Accessed: Dec 2017]

IDF SCID Newborn Screening Campaign. Immune Deficiency Foundation. Towson, MD [Accessed: Dec 2017]

Picard C, Gaspar B, Al-Herz W, Bousfiha A, Casanova J, Chatila T, Crow YJ, Cunningham-Rundles C, Etzioni A, Franco JL, Holland SM, Klein C, Morio T, Ochs HD, Oksenhendler E, Puck J, Tang ML, Tangye SG, Torgerson TR, Sullivan KE. International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity. J Clin Immunol. 2018; 38(1): 96-128. PubMed

Shearer WT, Dunn E, Notarangelo LD, Dvorak CC, Puck JM, Logan BR, Griffith LM, Kohn DB, O'Reilly RJ, Fleisher TA, Pai S, Martinez CA, Buckley RH, Cowan MJ. Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience. J Allergy Clin Immunol. 2014; 133(4): 1092-8. 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 BA, Dasu T, Verbsky JW. 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 AR. 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 NH, Pasi BM, Hill HR. 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 SD, Hill HR. Recent advances in the genetics of primary immunodeficiency syndromes. J Pediatr. 1996; 129(1): 8-24. PubMed

Medical Reviewers

Content Reviewed: 
January 2018

Last Update: February 2018