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 CD3, CD4, CD8, CD19, CD45RA, CD45RO, NK cell, and CD4:CD8 ratio
    • 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 (based on the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency, 2013)

  • Combined immunodeficiencies

    Combined Immunodeficiencies

    Gene

    T cell

    B cell

    NK cell

    Genetics*

    Comment

    T-B+ SCID

    IL2RG

    Markedly decreased

    Normal or increased

    Markedly decreased

    XL

    Impaired cytokine-mediated signaling; moderate severity SCID

    JAK3

    Markedly decreased

    Normal or increased

    Markedly decreased

    AR

    Impaired cytokine-mediated signaling

    IL7RA

    Markedly decreased

    Normal or increased

    Normal

    AR

    Impaired cytokine-mediated signaling

    PTPRC

    Markedly decreased

    Normal

    n/a

    AR

    CD3D

    Markedly decreased

    Normal

    Normal

    AR

    CD3-delta deficiency

    CD3E

    Markedly decreased

    Normal

    Normal

    AR

    CD3-epsilon deficiency

    CD3Z

    Markedly decreased

    Normal

    Normal

    AR

    CORO1A

    Markedly decreased

    Normal

    n/a

    AR

    Detectable thymus

    EBV-associated B-cell lymphoproliferation

    T-B-SCID

    RAG1

    Markedly decreased

    Markedly decreased

    n/a

    AR

    Associated with Omenn syndrome

    RAG2

    Markedly decreased

    Markedly decreased

    n/a

    AR

    Associated with Omenn syndrome

    ARTEMIS

    Markedly decreased

    Markedly decreased

    n/a

    AR

    Radiation sensitivity; Omenn syndrome; severe combined SCID, Athabaskan type

    PRKDC

    Markedly decreased

    Markedly decreased

    n/a

    AR

    Radiation sensitivity; microcephaly; developmental defects, DNA-PKcs-deficiency

    AK2

    Markedly decreased

    Decreased or normal

    n/a

    AR

    Granulocytopenia and deafness; reticular dysgenesis

    ADA

    Absent from birth (null mutations) or progressive decrease

    Absent from birth or progressive decrease

    Decreased

    AR

    Costochondral junction flaring; neurological features; hearing impairment; lung and liver manifestations; partial ADA deficiency may lead to delayed or milder presentation

    *AR = autosomal recessive; XL = X-linked

    Combined immunodeficiencies generally less profound than SCID

    Combined Immunodeficiencies Generally Less Profound Than SCID

    Gene

    T cell

    B cell

    Genetics*

    Comment

    CD40LG

    Normal; may progressively decrease

    sIgM+ and sIgD+ B-cells present, other surface isotype positive B cells absent

    XL

    Neutropenia; thrombocytopenia; hemolytic anemia; biliary tract and liver disease; opportunistic infections

    CD40 

    Normal

    IgM+ and IgD+ B cells present, other isotypes absent

    AR

    Neutropenia; gastrointestinal and liver/biliary tract disease; opportunistic infections

    PNP

    Progressive decrease

    Normal

    AR

    Autoimmune hemolytic anemia; neurological impairment; purine nucleoside phosphorylase deficiency

    CD3G

    Normal, but reduced TCR expression

    Normal

    AR

    n/a

    CD8

    Absent CD8, normal CD4 cells

    Normal

    AR

    n/a

    ZAP70

    Decreased CD8, normal CD4 cells

    Normal

    AR

    Autoimmunity in some cases

    TAP1, TAP2, or TAPBP

    Decreased CD8, normal CD4

    Normal

    AR

    Vasculitis; pyoderma gangrenosum

    CIITA, RFX5, RFXAP, RFXANK

    Normal number, decreased CD4 cells

    Normal

    AR

    Failure to thrive; diarrhea; respiratory tract infections; liver/biliary tract disease

    ITK

    Progressive decline

    Normal

    AR

    EBV-associated B cell lymphoproliferation; lymphoma; normal or decreased IgG

    SH2D1A

    Normal or increased activated T cells

    Reduced memory B cells

    XL

    Clinical and immunologic features triggered by EBV infection; hemophagocytic lymphohistiocytoses (HLH);  lymphoproliferation; aplastic anemia; lymphoma; hypogammaglobulinemia

    RMRP

    Varies from severely decreased to normal; impaired lymphocyte proliferation

    Normal

    AR

    Can be present just as combined immunodeficiency without other features of short-limbed dwarfism

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

    MAGT1

    Decreased CD4 cells reduced numbers of RTE, impaired T cell proliferation in response to CD3

    Normal

    XL

    EBV infection; lymphoma; viral infections; respiratory and GI infections

    DOCK8

    Decreased impaired T lymphocyte proliferation

    Decreased, low CD27+ memory B cells

    AR

    Hypereosinophilia; recurrent infections;  severe atopy; extensive cutaneous viral and bacterial infections; susceptibility to cancer; low/impaired function NK cells

    RHOH

    Normal

    Normal

    AR

    HPV infection; lymphoma; lung granulomas; molluscum contagiosum

    STK4

    Decreased

    Decreased

    AR

    Recurrent bacterial, viral, and candidal infections; intermittent neutropenia; EBV-driven lymphoproliferation; lymphoma; congenital heart disease; autoimmune cytopenias; HPV infection

    TRAC

    Normal

    Normal

    AR

    Recurrent viral, bacterial, and fungal infection; immune dysregulation autoimmunity; diarrhea

    LCK

    Normal

    Normal

    AR

    Diarrhea; recurrent infections; immune dysregulation autoimmunity

    MALT1

    Normal

    Normal

    AR

    Bacterial; fungal and viral infections

    IL-21R

    Abnormal

    Normal

    AR

    Susceptibility to cryptosporidium and pneumocystis and cholangitis

    UNC119

    Low

    Mostly low

    AD

    Recurrent bacterial, fungal, and viral infections

    CARD11

    Normal

    Normal

    AR

    P. jirovecii pneumonia, bacterial infections

    OX40

    Normal

    Normal

    AR

    Kaposi sarcoma; impaired immunity to HHV8

    IKBKB

    Normal

    Normal

    AR

    Recurrent bacterial, viral, and fungal infections; clinical phenotype of SCID

    PIK3CD

    Decreased

    Decreased

    AD

    Respiratory infections; bronchiectasis, autoimmunity, chronic EBV, and CMV

    LRBA

    Normal/decreased

    Low/normal

    AR

    Recurrent infections; IBD; autoimmunity; EBV

    CD27

    Normal

    Absent

    AR

    Clinical and immunologic features triggered by EBV infection; HLH aplastic anemia; lymphoma; hypogammaglobulinemia

    Hypomorphic mutations in RAG1, RAG2, ARTEMIS, IL7RA, RMRP, ADA, DNA LIGASE IV, IL-2RG, AK2, or associated with DiGeorge syndrome (some have no defined gene mutation)

    Present

    Normal or decreased

    n/a

    Erythroderma; eosinophilia; adenopathies; hepatosplenomegaly

    *AR = autosomal recessive; XL = X-linked; AD = autosomal dominant

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

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

Preferred test for individuals with clinical phenotype of antibody deficiency (eg, agammaglobulinemia, common variable immunodeficiency)

Preferred genetic test for individual with clinical phenotype of primary antibody deficiency (eg, common variable immunodeficiency)

For hyper-IgM syndrome genetic testing, refer to hyper-IgM syndrome sequencing and deletion/duplication panel; for agammaglobulinemia genetic testing, refer to agammaglobulinemia sequencing and deletion/duplication panel

Genes sequenced –  ADA, AICDA, ATM, BLNK, BTK, CD19, CD40, CD40LG, CD79A, CD79B, CD81, CR2, ICOS, IGHM, IGLL1, IKBKG, LRBA, LRRC8A, MRE11A, MS4A1, NBN/NBS1, NFKB2, NFKBIA, PIK3CD, PIK3R1, PLCG2, PRKCD, PTPRC, RAG2, SH2D1A, TNFRSF13B, TNFRSF13C, UNG, VAV1, XIAP/BIRC4

Genes analyzed for deletions/duplications – ADA, AICDA, ATM, BLNK, BTK, CD19, CD40, CD40LG, CD79A, CD79B, CD81, CR2, ICOS, IGHM, IGLL1, MRE11A, MS4A1, NBN/NBS1, NFKB2, NFKBIA, PTPRC, RAG2, TNFRSF13B, TNFRSF13C, UNG, VAV1

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

 
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