T-Cell Deficiency Disorders, Inherited

Cell-mediated immunity is accomplished by T lymphocytes (T cells) and their effector response and interactions with other immune cells. T-cell immunodeficiency diseases include severe combined immunodeficiencies (SCIDs), Wiskott-Aldrich syndrome, ataxia telangiectasia, DiGeorge syndrome (22q11.2 deletion syndrome), immuno-osseous dysplasias, dyskeratosis congenita, and chronic mucocutaneous candidiasis.

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

Indications for Testing

Recurrent infections, particularly with opportunistic organisms

Criteria for Diagnosis

Laboratory Testing

  • Initial testing
    • HIV testing
      • Infants ≤15 months – qualitative or quantitative polymerase chain reaction (PCR)
      • Adults – screen for antibodies; confirm positive results with Western blot
    • CBC with differential – profound thrombocytopenia with small, nonfunctioning platelets suggests Wiskott-Aldrich syndrome
    • Immunoglobulin (quantitative) – if low, proceed with B-cell immunodeficiency testing
    • Sweat chloride – if positive, proceed with cystic fibrosis genetic testing
    • T-cell immunodeficiency profile testing
      • T-cell testing at minimum should include CD4, CD45RA, CD45RO, CD8, CD4:8 ratio, CD3, CD19, and natural killer (NK) cells
      • If abnormal, proceed with lymphocyte antigen and mitogen test
  • Cell-mediated immune screen
    • Lymphocyte antigen and mitogen proliferation test
      • Measures tritiated thymidine (3H-TdR) uptake by lymphocytes in response to stimulus (requires 5-7 days)
      • Low with low T cells confirms T-cell disorder
    • Lymphocyte antigen and mitogen stimulation with cytokines
  • Further specific genetic testing based on results of above testing

Differential Diagnosis

Epidemiology

  • Incidence – rare
  • Age – most commonly discovered during neonatal period and infancy
    •  Adult onset rare
  • Sex – M:F, equal, except for X-linked diseases
    • M>F for X-linked severe combined immunodeficiencies (SCIDs) and Wiskott-Aldrich syndrome

Inheritance

For inheritance, refer to Identified Forms of SCID tables below

Pathophysiology

  • Defective lymphocyte responses to stimulants may occur
    • Nonspecific mitogens (phytohemagglutinin, concanavalin A, and pokeweed mitogen)
    • Specific antigens, such as Candida or tetanus
  • Characterized by increased susceptibility to infections from opportunistic organisms

Clinical Presentation

  • Clinical presentation is highly variable but can be divided into 2 main types
    • Immunodeficiencies with associated or syndromic features (including both immune and nonimmune manifestations, as in Wiskott-Aldrich syndrome and DiGeorge syndrome [22q11.2 deletion syndrome])
      • Ataxia telangiectasia (European Society for Immunodeficiencies [ESID])
        • Progressive cerebellar ataxia
        • Ocular or facial telangiectasia
        • Recurrent respiratory infections
        • Difficulty walking; wheelchair bound by teenage years
        •  Increased risk of malignancy – leukemia/lymphoma in 10-15% of patients
      • DiGeorge syndrome (22q11.2 deletion syndrome) (ESID)
        • Cardiac defect – may be conotruncal
        • Persistent infections (fungal or viral)
        • Hypocalcemia, hypocalcemic tetany (due to hypoparathyroidism)
        • Abnormal facies
        • Palatal abnormalities
        • Autoimmune disorders
      • Wiskott-Aldrich syndrome – in males (ESID)
        • Congenital thrombocytopenia with small platelets
        • Bloody diarrhea
        • Otitis, sinusitis
        • Recurrent infections (bacterial or viral)
        • Eczema
        • Commonly, associated autoimmune disease
        • Increased risk for malignancy
    • Immunodeficiencies without associated or syndromic features
      • Omenn syndrome (Genetic and Rare Diseases Information Center)
        • Erythroderma and desquamation; alopecia
        • Chronic diarrhea
        • Failure to thrive
        • Lymphadenopathy
        • Eosinophilia
        • Hepatosplenomegaly
        • High susceptibility to infection (viral, fungal, bacterial)
      • SCID – often in first 2-7 months of life (ESID)
        • Failure to thrive
        • Persistent diarrhea
        • Respiratory symptoms and/or thrush
        • Pneumocystis pneumonia
        • Disseminated bacillus Calmette-Guérin infection
        • Refer to Identified Forms of SCID table (below)
      • Leaky SCID (National Organization for Rare Diseases)
        • Severe itchy rashes
        • Enlarged lymph nodes, spleen, and liver
        • Chronic diarrhea

Identified Forms of SCID

 

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.

Human Immunodeficiency Virus 1 (HIV-1) by Qualitative PCR 0093061
Method: Qualitative Polymerase Chain Reaction

Human Immunodeficiency Virus 1 by Quantitative PCR 0055598
Method: Quantitative Polymerase Chain Reaction

Human Immunodeficiency Virus Types 1 and 2 (HIV-1, HIV-2) Antibodies by CIA with Reflex to HIV-1 Antibody Confirmation by Western Blot 2005377
Method: Qualitative Chemiluminescent Immunoassay/Qualitative Western Blot

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

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

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

Lymphocyte Antigen and Mitogen Proliferation Panel 0096056
Method: Cell Culture

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

Natural Killer Cells Enumeration 0092404
Method: Quantitative Flow Cytometry

Guidelines

Clinical: Diagnostic criteria for PID. European Society for Immunodeficiencies (ESID). Geneva, Switzerland [Accessed: Jan 2018]

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

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

Filipovich A, Johnson J, Zhang K. WAS-Related Disorders. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews. University of Washington, 1993-2015. Seattle, WA [Last updated: Mar 2014; Accessed: Jan 2018]

Gatti R, Perlman S. Ataxia-Telangiectasia. In:Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last updated: Oct 2016; Accessed: Jan 2018]

Hershfield M. Adenosine Deaminase Deficiency. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated: Jun 2014; Accessed: Jan 2018]

Immune Deficiency Foundation. Towson, MD [Accessed: Feb 2017]

Kirkpatrick CH. Chronic mucocutaneous candidiasis. Pediatr Infect Dis J. 2001; 20(2): 197-206. PubMed

Omenn Syndrome. National Center for Advancing Translational Sciences, Genetic and Rare Diseases Information Center. Bethesda MD [Last updated: Dec 2017; Accessed: Jan 2018]

Severe Combined Immunodeficiency. National Organization for Rare Disorders (NORD). Danbury CT [Accessed: Jan 2018]

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

Efimova OV, Kelley TW. Induction of granzyme B expression in T-cell receptor/CD28-stimulated human regulatory T cells is suppressed by inhibitors of the PI3K-mTOR pathway. BMC Immunol. 2009; 10: 59. PubMed

Shyur SD, Hill HR. Immunodeficiency in the 1990s. Pediatr Infect Dis J. 1991; 10(8): 595-611. PubMed

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

Wang S, Delgado JC, Ravkov E, Eckels DD, Georgelas A, Pavlov IY, Cusick M, Sebastian K, Gleich GJ, Wagner LA. Penaeus monodon tropomyosin induces CD4 T-cell proliferation in shrimp-allergic patients. Hum Immunol. 2012; 73(4): 426-31. PubMed

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Content Reviewed: 
January 2018

Last Update: February 2018