Severe Combined Immunodeficiencies - SCID

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).

Quick Answers for Clinicians

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

Primary Immune Deficiency Treatment Consortium Diagnostic Criteria for

SCID, Leaky SCID, Omenn Syndrome, and Reticular Dysgenesis

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
  • 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
  • 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

Combined Immunodeficiencies (Based on the Classification Update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Committee, Picard, 2018a)
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

DCLRE1C

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

Combined Immunodeficiencies Typically Less Profound Than SCIDa
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

MALT1b

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

IL21b

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

MAP3K14b

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

Useful for assessing primary T-cell immunodeficiency disorders

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

Evaluate NK- and NKT-cell subsets

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

Acceptable lymphocyte subset panel for the investigation of primary immunodeficiency disorders

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

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

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

Defects in the TLR3 gene associated with herpes simplex encephalitis may not be detected in this assay based on the reported instance of a patient with compound heterozygous mutations in TLR3 leading to decreased cytokine production in response to polyinosinic-polycytidylic acid (Poly I:C) in fibroblasts but not peripheral blood mononuclear cell (PBMCs)

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

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

Evaluate patients with suspected immunodeficiency diseases, including SCID

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

Time sensitive

Primarily for evaluating T-cell 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

Not a first-level test; order after lymphocyte proliferation, mitogen induced, by flow cytometry has been performed

Related Tests

Initial screening for immunodeficiency

Rule out HIV

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

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

Monitor engraftment of maternal T cells in patients with SCID prior to allogenic stem cell transplantation

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

Monitor engraftment of maternal T cells in patients with SCID prior to allogenic stem cell transplantation

Medical Experts

Contributor

Delgado

Julio Delgado, MD, MS
Executive Vice President, ARUP Laboratories
Division Chief of Clinical Pathology, University of Utah and ARUP Laboratories
Professor of Clinical Pathology, University of Utah
Medical Director, Protein Immunology and Immunologic Flow Laboratories, ARUP Laboratories
Contributor

Hill

Harry R. Hill, MD
Professor of Clinical Pathology, Pediatrics, and Medicine, University of Utah
Medical Director, Cellular and Innate Immunology, ARUP Laboratories
Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®