T-Cell Deficiency Disorders, Inherited

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

Indications for Testing

  • Recurrent infections, particularly with opportunistic organisms

Laboratory Testing

  • Initial testing
    • HIV testing
      • Infants ≤15 months – PCR qualitative or quantitative
      • 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 NK-cell
      • If abnormal, proceed with lymphocyte antigen and mitogen test
  • Cell-mediated immune screen – lymphocyte mitogen stimulated ATP production (LMPS); rapid overnight test
    • 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 the results of the above testing

Differential Diagnosis

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 (SCID)
    • Wiskott-Aldrich syndrome (WAS)
    • Ataxia telangiectasia
    • DiGeorge syndrome
    • Immuno-osseous dysplasias
    • Dyskeratosis congenta
    • Chronic mucocutaneous candidiasis

Epidemiology

  • Incidence – rare (<1/1,000,000)
  • 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 SCID and WAS

Inheritance

  • Autosomal recessive for all diseases except X-linked SCID and WAS

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

  • Ataxia telangiectasia
    • Recurrent infections – sinopulmonary are most common
    • Progressive cerebellar dysfunction
    • Oculocutaneous telangiectasia
    • Cancer risk 35-40% in affected individuals
      • Increased risk of solid tumors in older population
      • Leukemia and lymphoma in children
      • Risk ~4 times greater than general population, especially for breast cancer
  • Chronic mucocutaneous candidiasis
    • Persistent or recurrent Candida infections of the skin, nails and mucous membranes
    • Often have an associated autoimmune disease
    • May be associated with multiple endocrinopathies
  • DiGeorge syndrome
    • Recurrent infections – fungal, viral, bacterial, Pneumocystis
    • Congenital heart disease
    • Hypocalcemic tetany (due to hypoparathyroidism)
    • Abnormal facies
    • Palatal abnormalities
    • Thymic hypoplasia
  • SCID
    • Early onset of severe infections (intracellular bacterial, viral, fungal, Pneumocystis)
    • Growth failure
    • Persistent diarrhea
    • Graft-versus-host disease upon exposure to maternal lymphocytes or blood transfusions
    • Earliest onset in X-linked SCID, adenosine deaminase (ADA) deficiency, purine nucleoside phosphorylase deficiency (PNP), ZAP70 defects, and T- and B-cell variants
    • Refer to T- and B-cell Variants of SCID table in the SCID ARUP Consult topic
  • WAS
    • Recurrent infections – viral, pneumococcal
    • Eczema
    • Associated autoimmune disease common
    • Increased risk for malignancy
    • IgA nephropathy
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

Recommended Use 

Initial testing for infants ≤15 months

Qualitative screen for presence of HIV-1 infection

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

Recommended Use 

Initial testing for infants ≤15 months

Qualitative screen for presence of HIV-1 infection

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

Recommended Use 

Initial testing for adults

Screen for antibodies against HIV-1 and HIV-2

Reflex pattern – if test is repeatedly reactive, confirmation will be made by Western Blot

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

Recommended Use 

Initial testing

Assess for thrombocytopenia

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

Recommended Use 

Initial test in the workup of immunoglobulin disorders

In adults and older children with suspected hypogammaglobulinemia, order in conjunction with serum protein electrophoresis and immunofixation

Follow-up 

If results low, proceed to B-cell immunodeficiency testing

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

Recommended Use 

Assess thymic function in suspected SCID, DiGeorge syndrome and other T-cell immune deficiency disorders

Evaluate immune reconstitution during highly active antiviral therapy (HAART) in HIV patients and post chemotherapy and hematopoietic cell transplant

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

Recommended Use 

Useful for assessing primary T-cell immunodeficiency disorders

Test enumerates the percent and absolute cell count of lymphocyte subsets in whole blood for CD4  (helper T cells), CD45RA (naive helper T cells), CD45RO (memory helper T cells), CD8 (cytotoxic T cells), CD4: CD8 ratio, CD3 (total T cells), CD19 (B cells), NK cells

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

Recommended Use 

Acceptable lymphocyte subset panel for the investigation of primary immunodeficiency disorders

Test enumerates the percent and absolute cell count of lymphocyte subsets in whole blood for CD4  (helper T cells), CD45RA (naive helper T cells), CD45RO (memory helper T cells), CD8 (cytotoxic T cells), CD4: CD8 ratio, CD2, CD3 (total T cells), HLA-DR, CD19 (B cells), NK cells

Follow-up 

Severe deficiencies in T cells should initiate differential workup based on deficiency

Lymphocyte Antigen and Mitogen Proliferation Panel 0096056
Method: Cell Culture

Recommended Use 

Primarily for research and to support attempts to understand the pathogenesis of immune, infectious, allergic, or inflammatory disorders 

Test for lymphocyte proliferation in response to the following

  • Phytohemagglutinin 
  • Concanavalin A
  • Pokeweed mitogen
  • Candida antigen
  • Tetanus antigens

Use to evaluate T-cell mediated immune deficiency

Limitations 

Bacterial or endotoxin contamination of sample profoundly affects test results

Follow-up 

T-cell immunodeficiency profile (short and extended)

In addition, evaluate chronic infection based on clinical history and in conjunction with other tests

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

Recommended Use 

Preferred test for individuals with clinical phenotype of SCID, Omenn syndrome, or other combined immunodeficiency disorders or abnormal newborn screen T-cell receptor excision circles (TREC) test result suggestive of SCID

Panel includes ADA, AK2, CD247, CD3D, DC3E, CORO1A, DCLRE1C, FOXN1, IL2RG, IL7R, JAK3, LIG4, NHEJ1, PNP, PRKDC, PTPRC, RAG1, RAG2, RMRP

Clinical sensitivity – ~90%

 Analytical sensitivity – ~95% for sequencing; 100% for deletion/duplication analysis

 Analytical specificity – >99% for sequencing; 99.5% for deletion/duplication analysis

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, and 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

Chromosome Analysis - Breakage, Ataxia Telangiectasia, Whole Blood 2005749
Method: Giemsa Band

Recommended Use 

May be useful in diagnosing ataxia telangiectasia; not recommended for diagnosing Fanconi anemia or similar breakage syndromes

Limitations 

Carriers are not detected by this test

Guidelines

Al-Herz W, Bousfiha A, Casanova J, Chapel H, Conley ME, Cunningham-Rundles C, Etzioni A, Fischer A, Franco JL, Geha RS, Hammarström L, Nonoyama S, Notarangelo LD, Ochs HD, Puck JM, Roifman CM, Seger R, Tang ML. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2011; 2: 54. PubMed

General References

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: Nov 2015]

Gatti R. Ataxia-Telangiectasia. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated Mar 2010; Accessed: Nov 2015]

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: Nov 2015]

Immune Deficiency Foundation. Towson, MD [Accessed: Nov 2015]

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

Medical Reviewers

Delgado, Julio, MD, MS, Head, Histocompatibility and Immunogenetics; Section Chief, Immunology Division at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Heikal, Nahla, MD, MS, Assistant Medical Director, Immunology and Hemostasis/Thrombosis at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Hillyard, David R., MD, Medical Director, Molecular Infectious Diseases at ARUP Laboratories; Professor of Clinical Pathology, Adjunct Professor of Biology, University of Utah

Kumanovics, Attila, MD, Assistant Medical Director, Co-Director, Immunology Laboratory, Immunogenetics at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Lamb, Allen N., PhD, FACMG, Medical Director, Cytogenetics and Genomic Microarray, ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Slev, Patricia R., PhD, Medical Director, Serological Hepatitis/Retrovirus, and Co-Medical Director of Immunogenetics at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Wittwer, Carl T., MD, PhD, Medical Director and Technical Vice President, General Flow Cytometry at ARUP Laboratories; Professor of Clinical Pathology, University of Utah

Agammaglobulinemia
Chronic Granulomatous Disease - CGD
Common Variable Immune Deficiency Syndromes - CVID
Complement Deficiency
Congenital Neutrophil Disorders
Human Immunodeficiency Virus - HIV
Immunodeficiency, TLR-Signaling Defects
Immunoglobulin Disorders
Leukocyte Adhesion Deficiency
Severe Combined Immunodeficiencies - SCID

Last Update: August 2016

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