Severe Combined Immunodeficiencies - SCID

Diagnosis

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 CD4, CD45RA, CD45RO, CD8, CD4:8 ratio, CD3, CD19, and NK cell
    • 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

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
  • Age – median 4-7 months
  • Sex – M:F, equal, except for X-linked forms

Identified Forms of SCID

  • Genetic testing for SCID

    Genetic Testing for SCID

    Gene

    T cell

    B cell

    NK cell

    Genetics*

    Comment

    Impaired cytokine-mediated signaling

    IL2RG

    +

    XL

     Moderate severity SCID

    JAK3

    +

    AR

     

    IL7R

    +

    +

    AR

     

    Defects in V(D)J recombination

    DCLRE1C

    +

    AR

    Omenn syndrome

    Severe combined SCID, Athabaskan type

    RAG1

    +

    AR

    Associated with Omenn syndrome

    RAG2

    +

    AR

    Associated with Omenn syndrome

    PRKDC

    +

    AR

    DNA-PKcs-deficiency

    LIG4

    +

    AR

    Radiosensitivity, LIG4 syndrome

    NHEJ1

    +

    AR

    Radiosensitivity, dysmorphic facies, microcephaly, psychomotor delay

    Impaired signaling through pre-T-cell receptors

    CD247

    +

    +/-

    AR

    Defect in CD3-zeta

    CD3D

    +

    +

    AR

    Defect in CD3-delta deficiency

    CD3E

    +

    +

    AR

    CD3-epsilon deficiency

    CORO1A

    +

    +

    AR

    CORO1A deficiency

    ZAP70

    +

    +

    AR

     

    Increased lymphocyte apoptosis

    ADA

    AR

    Skeletal alterations, hepatitis, neonatal sensorineural deafness, ADA deficiency

    AK2

    +

    AR

    Reticular dysgenesis

    PNP

    +

    AR

    Purine nucleoside phosphorylase deficiency

    Defects in thymus organogenesis

    FOXN1

    +

    +

    AR

    Alopecia, embryonic neural tube defects, nail dystrophy

    Disruption of cellular function due to defective enzyme

    RMRP

    +/-

    -/+

    AR

    Anauxetic dysplasia, cartilage-hair hypoplasia, metaphyseal dysplasia without hypotrichosis

    *AR = autosomal recessive; XL = X-linked

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
Test Name and Number Recommended Use Limitations Follow Up
CD4+ T-Cell Recent Thymic Emigrants (RTEs) 2010179
Method: Quantitative Flow Cytometry

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

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

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 CD2, 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), HLA-DR, CD19 (B cells), NK cells

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

Assess B-cell subsets in immunodeficiencies, such as common variable immunodeficiency or B-cell reconstitution after bone marrow or hematopoietic stem cell transplantation

Measures B cells (CD19+), total memory B cells (CD19+ CD27+), class switched memory B cells (CD19+ CD27+ IgD-), non-switched/marginal zone memory B cells (CD19+ CD27+ IgD+), and naive B cells (CD19+ CD27- IgD+).

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

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

Quantitative nephelometry determines serum immunoglobulin concentrations of IgG, IgM, and IgA

   
Lymphocyte Antigen and Mitogen Proliferation Panel 0096056
Method: Cell Culture

Screen for immunodeficiencies

Panel includes testing for phytohemagglutinin, concanavalin A, pokeweed mitogen, Candida antigen, and tetanus antigen

Time sensitive

 
Lymphocyte Antigen and Mitogen Proliferation Panel with Cytokine Response to Mitogens, 12 Cytokines 0051584
Method: Cell Culture/Multiplex Bead Assay

Screen for inheritance of immunodeficiencies

Components include cytokine production by mononuclear cells in response to mitogen stimulation, which include: interleukin 2, interleukin 2 receptor, interleukin 12, interferon gamma, interleukin 4, interleukin 5, interleukin 10, interleukin 13, interleukin 1 beta, interleukin 6, interleukin 8, and tumor necrosis factor alpha

Time sensitive

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

Assist in diagnosis of innate immunodeficiencies when genetic defects of the innate immune system are suspected in individuals negative for other immunodeficiencies (eg, no detectable abnormality of antibody function, complement activity, neutrophil function, or cell mediated immunity)

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

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

Preferred test for individuals with clinical phenotype of SCID or abnormal newborn screen T-cell receptor excision circles (TREC) test result suggestive of SCID

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

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
Rule out HIV
Adenosine Deaminase, RBC 0083001
Method: Kinetic Spectrophotometry

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 0051393
Method: Cell Culture/Quantitative Multiplex Bead Assay

Screen for IRAK4 deficiency in individuals negative for other immunodeficiencies

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

Interleukin 2 Receptor (CD25), Soluble 0051529
Method: Quantitative Multiplex Bead Assay

Secondary variant testing