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 SCID
    • HIV molecular PCR testing in infants ≤15 months – rule out HIV infection
  • Screen for more common immunodeficiencies
    • T-cell and B-cell immunodeficiency profile testing
      • T-cell 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 with cytokine response – will be abnormal
      • Test requires at least 7 days for results
  • Molecular diagnosis – available for prenatal testing for SCID
  • Second-line testing – pursue if above studies suggest SCID
    • Analyte/enzyme testing – adenosine deaminase, purine nucleoside phosphorylase
    • Genetic testing – ADA, PNP, IL2RG

Clinical Background

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

Epidemiology

  • Incidence – 1/75,000-100,000
  • Age – median 4-7 months
  • Sex – M:F, equal, except for X-linked forms

Identified Forms of SCID

  • X-linked SCID – 50-60% of SCID     
  • Adenosine deaminase (ADA) deficiency – 30% of SCID
  • T- and B-Cell Variants of SCID

    T- and B-Cell Variants of SCID

    Gene

    T-cell

    B-cell

    NK-cell

    Genetics*

    Comment

    Impaired cytokine-mediated signalling

    IL2RG

    +

    XL 

    JAK3

    +

    AR 

    IL7RA

    +

    +

    AR

    T-cell growth IL7

    Defects in V(D)J recombination

    DCCRE1C (Artemis)

    +

    AR

    Recombinant of T- and B-cell receptors

    RAG1

    +

    AR

    Recombinant of T- and B-cell receptors

    Associated with Omenn syndrome

    RAG2

    +

    AR

    Associated with Omenn syndrome

    PRKDC (DNA-PKcs)

    +

    AR

    Radiosensitivity

    LIG4 (DNA ligase IV)

    +

    AR

    Radiosensitivity, dysmorphic facies, microcephaly, psychomotor delay

    NHEJ1 (Cernunnos)

    +

    AR

    Radiosensitivity, dysmorphic facies, microcephaly, psychomotor delay

    Impaired signalling through pre-T-cell receptors

    PTPRC (CD3Z)

    +

    +/–

    AR

    T-cell receptors only

    CD3D, CD3F, CD3G

    +

    +

    AR

    T-cell receptors only

    CK

    +

    +

    AR

     

    ZAP70

    CD4 (+) CD8 (–) Lymphocytes

    +

    +

    AR

     

    Increased lymphocyte apoptosis

    ADA

    AR

    Skeletal alterations, hepatitis, neonatal sensorineural deafness

    AK2

    +

    AR

     

    NP (PNP)

    +

    AR

    Neurological problems

    Defects in thymus embryogenesis

    Winged Helix Nude (WHN)

    +

    +

    AR

    Alopecia, embryonic neural tube defects

    *AR = autosomal recessive; XL = X-linked

Inheritance

  • All but the X-linked forms are autosomal recessive

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 null 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
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 (suppressor 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 (suppressor T cells), CD4: CD8 ratio, CD3 (total T cells), HLA-DR, CD19 (B cells), NK cells

   
B-Cell Immunodeficiency Profile 0095940
Method: Quantitative Flow Cytometry

Useful in supporting diagnosis of primary B-cell immunodeficiency disorders, including bare lymphocyte syndrome and agammaglobulinemia

Measures circulating B-cells (CD19), their surface immunoglobulins (Total Ig, IgG, IgD, IgM, and IgA) and a common HLA class II antigen

   
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

 
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

Determine presence of lymphopenia

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