Severe combined immunodeficiencies (SCIDs) are genetic disorders characterized by blocked T-lymphocyte differentiation or function and often are associated with abnormal development of other lymphocyte lineages (B cells and natural killer [NK] cells). SCID is also commonly referred to as "bubble boy disease." About 92% of U.S. newborns are now screened for SCID by molecular laboratory testing (Immune Deficiency Foundation [IDF], 2017).
Diagnosis
Indications for Testing
- In infants or children (Joint Task Force on Practice Parameters, Bonilla, 2015)
- Chronic diarrhea
- Failure to thrive
- Recurrent, persistent, or severe viral, fungal, or bacterial infections
- Pneumocystis jiroveci infection
Criteria for Diagnosis
Typical SCID | Leaky SCID | Omenn Syndrome | Reticular Dysgenesis |
---|---|---|---|
Absence of or very low CD3 T-cell number (<300/µL), and no or very low T-cell function (<10% LLN), based on PHA response, OR |
Reduced CD3 T-cell number |
Skin rash, generalized |
Absence of T cells or very low T-cell number (<300/µL) |
Presence of maternal-origin T cells |
No maternal engraftment |
No maternal engraftment |
No or very low T-cell function (<10% LLN), based on PHA response |
<30% of LLN T-cell function, based on PHA response
|
CD3 cells detectable at level of ≥300/µL |
Severe neutropenia (ANC <200/µL) |
|
Absent/low T-cell proliferation (≤30% of normal) to antigens to which patient has been exposed |
Sensorineural deafness and/or no granulopoiesis found in bone marrow exam and/or deleterious AK2 mutation |
||
ANC, absolute neutrophil count; LLN, lower level of normal; PHA, phytohemagglutinin Source: Adapted from Shearer, PIDTC, 2014 |
Laboratory Testing
- Screen for underlying diseases associated with immunodeficiency
- CBC – presence of lymphopenia (total lymphocyte count of ≤3,400 cells/µL at birth, ≤3,900 cells/µL at 5-6 months, and ≤1,000 cells/µL in adults) (Immune Deficiency Foundation [IDF], 2015)
- Normal lymphocyte count does not rule out SCIDs
- HIV testing – rule out HIV infection
- CBC – presence of lymphopenia (total lymphocyte count of ≤3,400 cells/µL at birth, ≤3,900 cells/µL at 5-6 months, and ≤1,000 cells/µL in adults) (Immune Deficiency Foundation [IDF], 2015)
- Screen for other immunodeficiencies
- T-cell and B-cell immunodeficiency profile testing
- Testing at minimum should include CD3, CD4, CD8, CD19, CD45RA, CD45RO, natural killer (NK) cell, and CD4:CD8 ratio
- Quantitative immunoglobulins
- Lymphocyte proliferation induced by mitogens – will be abnormal
- Test requires at least 4-5 days for results
- Anti-CD3/anti-CD28/IL-2-induced lymphocyte proliferation test may be useful, specifically in the context of IL-2-receptor signaling defects
- Neutrophil function testing
- Complement testing
- T-cell and B-cell immunodeficiency profile testing
- 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 lists in Background
Background
Epidemiology
- Incidence – >1/58,000 births (Joint Task Force on Practice Parameters, Bonilla, 2015)
- Age – median 4-7 months
- Sex – M:F, equal, except for X-linked forms
Identified Forms of SCID
Gene | T Cells | B Cells | NK Cells | Genetics | Associated Features |
---|---|---|---|---|---|
T-negative/B-positive SCID | |||||
IL2RG |
Very low |
Normal to high |
Low |
XL |
Impaired cytokine-mediated signaling |
JAK3 |
Very low |
Normal to high |
Low |
AR |
Impaired cytokine-mediated signaling |
IL7R |
Very low |
Normal to high |
Normal |
AR |
Impaired cytokine-mediated signaling |
PTPRC |
Very low |
Normal |
n/a |
AR |
— |
CD3D |
Very low |
Normal |
Normal |
AR |
CD3-delta deficiency |
CD3E |
Very low |
Normal |
Normal |
AR |
CD3-epsilon deficiency |
CD247 |
Very low |
Normal |
Normal |
AR |
— |
CORO1A |
Very low |
Normal |
n/a |
AR |
Detectable thymus, EBV |
LAT |
Normal to low number |
Normal to low |
n/a |
AR |
Adenopathy, splenomegaly, recurrent infections, autoimmunity |
T-negative/B-negative SCID | |||||
RAG1b |
Very low |
Very low |
Normal |
AR |
Associated with Omenn syndrome |
RAG2b |
Very low |
Very low |
Normal |
AR |
Associated with Omenn syndrome |
DCLRE1Cb |
Very low |
Very low |
Normal |
AR |
Radiation sensitivity; Omenn syndrome |
PRKDC |
Very low |
Very low |
Normal |
AR |
Radiation sensitivity; microcephaly |
NHEJ1 |
Very low |
Very low |
Normal |
AR |
Radiation sensitivity; microcephaly |
LIG4 |
Very low |
Very low |
Normal |
AR |
Radiation sensitivity; microcephaly |
AK2 |
Very low |
Normal to low |
n/a |
AR |
Granulocytopenia and deafness; reticular dysgenesis |
ADAb |
Very low |
Low, decreasing |
Low |
AR |
Bone defects; may have pulmonary alveolar proteinosis; cognitive defects |
aSources in addition to the International Union of Immunological Societies Primary Immunodeficiency Diseases Committee report (Picard, 2018) include Cossu (2010) and van der Burg (2011) bGene included on Primary Antibody Deficiency Panel, Sequencing and Deletion/Duplication – ARUP test code 2011156 ADA, adenosine deaminase; AR, autosomal recessive; EBV, Epstein-Barr virus; n/a, not applicable; NK, natural killer; XL, X-linked |
Gene | T Cells | B Cells | Genetics | Comment |
---|---|---|---|---|
DOCK2 |
Low |
Normal |
AR |
Impaired interferon response in hematopoietic and nonhematopoietic cells; normal NK numbers but defective function |
CD40LGb |
Normal to low |
sIgM+ and sIgD+ B cells present, other surface isotype positive B cells absent |
XL |
Neutropenia; thrombocytopenia; hemolytic anemia; liver/biliary tract disease; opportunistic infections |
CD40b |
Normal |
IgM+ and IgD+ cells present, other isotypes absent |
AR |
Neutropenia; GI and liver/biliary tract disease; opportunistic infections |
ICOSb |
Normal |
Normal |
AR |
Recurrent infections; autoimmunity; gastroenteritis; granulomas in some cases |
PNP |
Progressive decrease |
Normal |
AR |
Autoimmune hemolytic anemia; neurological impairment |
CD3G |
Normal number; low TCR expression |
Normal |
AR |
— |
CD8A |
Absent CD8, normal CD4 cells |
Normal |
AR |
Recurrent infections; may be asymptomatic |
ZAP70 |
Low CD8, normal CD4 cells |
Normal |
AR |
In some cases, immune dysregulation, autoimmunity |
TAP1, TAP2, or TAPBP |
Low CD8, normal CD4 cells |
Normal |
AR |
Vasculitis; pyoderma gangrenosum |
B2M |
— |
Normal |
AR |
— |
CIITA, RFXANK, RFX5, RFXAP |
Low CD4 cells |
Normal |
AR |
Respiratory and GI infections; liver/biliary tract disease |
ITK |
Progressive decrease |
Normal |
AR |
EBV-associated B-cell lymphoproliferation, lymphoma; normal or low IgG |
MAGT1 |
Low CD4 cells |
Normal |
XL |
EBV infection; lymphoma; viral infections; respiratory and GI infections |
DOCK8 |
Low |
Low; low CD27+ memory B cells |
AR |
Eosinophilia; recurrent infections; severe atopy; cutaneous viral, staphylococcal, and fungal infections; cancer susceptibility; low/impaired function NK cells |
RHOH |
Normal number |
Normal |
AR |
HPV infection; lymphoma; lung granulomas; molluscum contagiosum |
SH2D1Ab |
Normal or increased activated T cells |
Reduced memory B cells |
XL |
Clinical and immunologic features induced by EBV infection; HLH; lymphoproliferation; aplastic anemia; lymphoma; hypogammaglobulinemia |
RMRP |
Varies from severely low to normal; impaired lymphocyte proliferation |
Normal |
AR |
Short-limbed dwarfism with metaphyseal dysostosis; sparse hair; bone marrow failure; autoimmunity; cancer/lymphoma susceptibility; impaired spermatogenesis; neuronal dysplasia of the intestine |
STK4 |
Low |
Low |
AR |
Recurrent bacterial, viral/HPV, and candidal infections; intermittent neutropenia; EBV lymphoproliferation; lymphoma; congenital heart disease; autoimmune cytopenias |
TRAC |
Absent TCR alpha beta cells |
Normal |
AR |
Recurrent viral, bacterial, and fungal infections; immune dysregulation autoimmunity; diarrhea |
LCK |
Low CD4+ and T regulatory cells |
Normal |
AR |
Recurrent infections; immune dysregulation; autoimmunity |
MALT1 |
Normal number |
Normal |
AR |
Bacterial, fungal, and viral infections |
CARD11b |
Normal number |
Normal predominance of transitional B cells |
AD, AR |
Pneumocystis jirovecii pneumonia, bacterial and viral infections |
BCL10 |
Normal number |
Normal number |
AR |
Recurrent bacterial and viral infections; candidiasis; gastroenteritis |
BCL11B |
Low |
Normal |
AD |
Congenital abnormalities, neonatal teeth, facies abnormalities, absent corpus callosum, neurocognitive defects |
IL21 |
Normal number |
Low |
AR |
Severe onset early colitis; sinopulmonary infections |
IL21Rb |
Normal number |
Normal number |
AD |
Recurrent infections; susceptibility to cryptosporidium and pneumocystis infections and liver disease |
TNFRSF4 |
Normal number |
Normal number |
AR |
Kaposi sarcoma; impaired immunity to HHV8 |
IKBKB |
Normal number |
Normal number |
AR |
Recurrent bacterial, viral, and fungal infections; opportunistic infections |
PIK3CDb |
— |
Low or absent pro-B cells |
AD |
Severe bacterial infections; EBV |
LRBAb |
Normal/decreased CD4 number |
Low or normal number |
AR |
Recurrent infections; IBD; autoimmunity; EBV infection |
CD27b |
Normal |
No memory B cells |
AR |
Clinical and immunologic features triggered by EBV infection; HLH; aplastic anemia; lymphoma; hypogammaglobulinemia; low iNKT cells |
RELB |
Normal number |
— |
AR |
Recurrent infections |
MSN |
Normal number |
Low number |
XL |
Recurrent infections with bacteria, varicella, neutropenia |
TFRC |
Normal number |
Normal number, low memory B cells |
AR |
Recurrent infections, neutropenia, thrombocytopenia |
MAP3K14 |
Normal number |
Low |
AR |
Recurrent bacterial, viral, and Cryptosporidium infections; low NK cell number |
CTPS1 |
Normal or decreased |
Normal or decreased |
AR |
Recurrent/chronic viral infections (particularly EBV, VZV), lymphoproliferation; B-cell NHL |
aBased on the International Union of Immunological Societies Primary Immunodeficiency Diseases Committee report (Picard, 2018); see original source for additional detail about T-cell and B-cell status and function bGene included on Primary Antibody Deficiency Panel, Sequencing and Deletion/Duplication– ARUP test code 2011156 AD, autosomal dominant; AR, autosomal recessive; CMV, cytomegalovirus; EBV, Epstein-Barr virus; GI, gastrointestinal; HHV8, human herpesvirus 8; HLH, hemophagocytic lymphohistiocytoses; HPV, human papillomavirus; IBD, irritable bowel disease; iNK, invariant natural killer; NHL, non-Hodgkin lymphoma; NK, natural killer; TEMRA, terminal differentiated effector memory cells; Treg, regulatory T cells; VZV, varicella-zoster virus; XL, X-linked |
Pathophysiology
Blockage 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 gastrointestinal 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 other donor
- Omenn syndrome – atypical SCIDs associated with hypomorphic mutations
ARUP Laboratory Tests
Assess thymic function in suspected severe combined immunodeficiencies (SCIDs), DiGeorge syndrome (22q11.2 deletion 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
Quantitative Flow Cytometry
Useful for assessing primary T-cell immunodeficiency disorders
Quantitative Flow Cytometry
Evaluate NK- and NKT-cell subsets
Semi-Quantitative Flow Cytometry
Panel includes:
- Pct CD3-CD16-/+CD56br/dim (total NK cells)
- Abs CD3-CD16-/+CD56br/dim (total NK cells)
- Pct CD3-CD16+CD56dim (cytotoxic NK cells)
- Abs CD3-CD16+CD56dim (cytotoxic NK cells)
- Pct CD3-CD16-CD56br (cyto secreting NK cells)
- Abs CD3-CD16-CD56br (cyto secreting NK cells)
- Pct CD3-CD57+ (CD57 NK cells)
- Abs CD3-CD57+ (CD57 NK cells)
- Pct CD3+CD56+ (CD56 NKT cells)
- Abs CD3+CD56+ (CD56 NKT cells)
- Pct CD3+CD57+ (CD57 NKT cells)
- Abs CD3+CD57+ (CD57 NKT cells)
- Pct CD45+CD3+ (T cells)
- Abs CD45+CD3+ (T cells)
- Pct CD45+CD3- (Non T cells)
- Abs CD45+CD3- (Non T cells)
- NKT-cell panel interpretation
Evaluate NK cells in patients with suspected immune deficiency
Quantitative Flow Cytometry
Acceptable lymphocyte subset panel for the investigation of primary immunodeficiency disorders
Quantitative Flow Cytometry
Assess B-cell subsets in immunodeficiencies (eg, common variable immunodeficiency [CVID], B-cell reconstitution after bone marrow, or hematopoietic stem cell transplantation)
Supports the diagnosis of CVID and may help predict the clinical phenotype
Assess 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-/IgM-), nonswitched/marginal zone memory B cells (CD19+/CD27+/IgD+/IgM+), IgM only memory B cells, and naive B cells (CD19+/CD27-/IgD+)
Not recommended for rituximab monitoring; refer to B-cell CD20 expression
Refer to Additional Technical Information document for further content
Flow Cytometry
Initial test in the workup of immunoglobulin disorders
In adults and children >15 years with suspected hypogammaglobulinemia, order in conjunction with serum protein electrophoresis and immunofixation to rule out plasma cell dyscrasia
Quantitative Immunoturbidimetry
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 conjunction with the individual’s clinical status
Cell Culture/Quantitative Multiplex Bead Assay
Preferred genetic test for individual with clinical phenotype of primary antibody deficiency (eg, agammaglobulinemia, hyper-IgM syndrome, or CVID)
Refer to Test Fact Sheet for complete list of genes tested
Refer to Test Fact Sheet for complete list of limitations
Massively Parallel Sequencing/Sequencing
Evaluate patients with suspected immunodeficiency diseases, including SCID
Panel includes testing for phytohemagglutinin, concanavalin A, pokeweed mitogen, Candida antigen, and tetanus antigen
Time sensitive
Cell Culture
Rule out HIV
Qualitative Chemiluminescent Immunoassay /Qualitative Western Blot
Reflex pattern: if HIV-1,2 combo antigen/antibodies screen is repeatedly reactive, then HIV-1 antibody confirmation by Western Blot will be added
Primarily for evaluating recall antigen responses in patients with suspected cellular immune dysfunction, such as primary and secondary immunodeficiencies
Other uses include monitoring lymphocyte recovery and competence after hematopoietic stem cell transplantation and monitoring lymphocyte function during immunosuppressive therapy
Do not order for patients younger than 3 months unless clinical history of candidiasis is present
Cell Culture
Primarily for evaluating lymphocyte function in patients with suspected cellular immune dysfunction, such as primary and secondary immunodeficiencies
Other uses include monitoring lymphocyte recovery and competence after hematopoietic stem cell transplantation and monitoring lymphocyte function during immunosuppressive therapy
Cell Culture
Monitor engraftment of maternal T cells in patients with SCID prior to allogenic stem cell transplantation
Polymerase Chain Reaction/Fragment Analysis
May be used as a marker of severe combined immunodeficiencies (SCIDs); lack of adenosine deaminase (ADA) allows deoxyadenosine to accumulate and kill lymphocytes
If patient has been recently transfused, ADA deficiency may be masked; interpret results with caution
Heterozygotes cannot be identified by this test; if clinical suspicion remains, consider testing to determine ADA genotype
Kinetic Spectrophotometry
Monitor engraftment of maternal T cells in patients with SCID prior to allogenic stem cell transplantation
Polymerase Chain Reaction/Fragment Analysis
Polymerase Chain Reaction/Fragment Analysis
References
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Aloj G, Giardino G, Valentino L, et al. Severe combined immunodeficiences: new and old scenarios. Int Rev Immunol. 2012;31(1):43-65.
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Bonilla FA, Khan DA, Ballas ZK, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015;136(5):1186-1205.e2078.
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Cossu F. Genetics of SCID. Ital J Pediatr. 2010;36:76.
IDF - Diagnostic & Clinical Care Guidelines for Primary Immunodeficiencies
Diagnostic and clinical care guidelines for primary immunodeficiencies. Immune Deficiency Foundation. [Accessed: Dec 2017]
IDF - SCID Newborn Screening Campaign
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Locke BA, Dasu T, Verbsky JW. Laboratory diagnosis of primary immunodeficiencies. Clin Rev Allergy Immunol. 2014;46(2):154-168.
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Niehues T, Perez-Becker R, Schuetz C. More than just SCID--the phenotypic range of combined immunodeficiencies associated with mutations in the recombinase activating genes (RAG) 1 and 2. Clin Immunol. 2010;135(2):183-192.
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Picard C, Gaspar B, Al-Herz W, et al. International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee report on inborn errors of immunity. J Clin Immunol. 2018;38(1):96-128.
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Shearer WT, Dunn E, Notarangelo LD, et al. 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):1092-1098.
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van der Burg M, Gennery AR. Educational paper. The expanding clinical and immunological spectrum of severe combined immunodeficiency. Eur J Pediatr. 2011;170(5):561-571.
Medical Experts
Delgado

Hill

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