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Severe Combined Immunodeficiency (SCID)


James Fernandez

, MD, PhD, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University

Medically Reviewed Apr 2021 | Modified Sep 2022
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Severe combined immunodeficiency is characterized by low to absent T cells and a low, high, or normal number of B cells and natural killer cells. Most infants develop opportunistic infections within the first 3 months of life. Diagnosis is by detecting lymphopenia, absence or a very low number of T cells, and impaired lymphocyte proliferative responses to mitogens. Patients must be kept in a protected environment; definitive treatment is hematopoietic stem cell transplantation.

Severe combined immunodeficiency (SCID) is a primary immunodeficiency disorder Primary Immunodeficiencies Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies... read more that involves combined humoral and cellular immunity deficiencies Combined humoral and cellular immunity deficiencies Immunodeficiency disorders are associated with or predispose patients to various complications, including infections, autoimmune disorders, and lymphomas and other cancers. Primary immunodeficiencies... read more . It is caused by mutations in any one of many different genes (eg, for autosomal recessive forms, Janus kinase 3 [JAK3], protein tyrosine phosphatase, receptor type, C [PTPRC, or CD45], recombination activating genes 1 [RAG1] and 2 [RAG2]). There are various forms of SCID that are autosomal recessive defects, so for the infant to be affected with SCID, the same gene must be mutated on both chromosomes.

There are 4 different abnormal lymphocyte phenotypes:

  • B cell positive, NK cell negative

  • B cell negative, NK cell positive

  • B cell negative, NK cell negative

  • B cell positive, NK cell positive

In most forms of SCID, T cells are absent (T-); the number of B cells and/or natural killer (NK) cells may be low or none (B-; NK-) or high or normal (B+; NK+), depending on the form of SCID. However, B cells, even when normal in number, cannot function because T cells are absent. Natural killer cell function is usually impaired.

The most common form of SCID is X-linked. It affects the interleukin (IL)-2 receptor common gamma chain (a component of at least 6 cytokine receptors) and thus causes severe disease; phenotype is T- B+ NK-. It results from a mutation in the IL-2 receptor gamma gene (IL-2RG).

The 2nd most common form results from adenosine deaminase (ADA) deficiency, which leads to apoptosis of precursors for B, T, and NK cells; phenotype is T- B- NK-.

The next most common form results from IL-7 receptor alpha-chain deficiency; phenotype is T- B+ NK+.

Mutations in recombination activating gene 1-2 (RAG1 or RAG2) represent a T-B-NK+ SCID phenotype.

Omenn syndrome is another T-B-NK+ SCID phenotype. It typically is the result of one defective RAG allele and therefore is commonly referred to as atypical SCID, or leaky SCID. It is an autosomal recessive form of SCID. Frequently the levels of IgA, IgG, and IgM are low while there is elevated IgE and eosinophilia. These patients usually have a varying degree of lymphopenia with low numbers of T and B cells and present with inflammation and lymphadenopathy.

Symptoms and Signs of SCID

By age 6 months, most infants with SCID develop candidiasis Candidiasis (Mucocutaneous) Candidiasis is skin and mucous membrane infection with Candida species, most commonly Candida albicans. Infections can occur anywhere and are most common in skinfolds, digital... read more Candidiasis (Mucocutaneous) , persistent viral infections, Pneumocystis jirovecii pneumonia Pneumocystis jirovecii Pneumonia Pneumocystis jirovecii is a common cause of pneumonia in immunosuppressed patients, especially in those infected with human immunodeficiency virus (HIV) and in those receiving systemic... read more <i >Pneumocystis jirovecii</i> Pneumonia , and diarrhea, leading to failure to thrive. Some have graft-vs-host disease due to maternal lymphocytes or blood transfusions. Other infants present at age 6 to 12 months. Patients with Omenn syndrome may develop exfoliative dermatitis, erythroderma, desquamation, alopecia, chronic diarrhea, failure to thrive, lymphadenopathy, eosinophilia, hepatosplenomegaly, and elevated serum IgE levels. ADA deficiency may cause bone abnormalities. In all forms, the thymus is extremely small, and lymphoid tissue may be decreased or absent.

All forms of SCID are fatal during infancy unless they are diagnosed and treated early.

Diagnosis of SCID

Screening all neonates using the TREC test is often recommended and is done routinely in many US states.

Severe combined immunodeficiency is suspected in infants with a history of persistent infections or other characteristic manifestations. Complete blood count, including absolute WBC count and differential, is done; immunoglobulin levels are measured. Responses to mitogens and to standard vaccine antigens are determined to evaluate WBC and antibody function.

The disorder is diagnosed in patients with the following:

  • Lymphopenia

  • A low number of or no T cells

  • Absent lymphocyte proliferative responses to mitogens

Other tests are done to determine the type of SCID; they include flow cytometry to determine T, B, and natural killer cell counts. ADA and purine nucleoside phosphorylase levels in WBCs, red blood cells, and fibroblasts are measured. X-inactivation tests may be done to determine whether SCID is X-linked. To help determine severity and prognosis, clinicians often test patients for common mutations that are characteristic of SCID (eg, IL-2RG, RAG1 and RAG2, JAK3, Artemis [DCLRE1C]).

Genetic testing of relatives is not recommended, except for siblings born after the diagnosis is made.

Treatment of SCID

  • Reverse isolation

  • Supportive care using immune globulin replacement therapy, antibiotics, and antifungals

  • Hematopoietic stem cell transplantation

  • Enzyme replacement for ADA deficiency

  • Gene therapy for ADA-deficient SCID

Patients with severe combined immunodeficiency must be kept in reverse isolation.

In 90 to 100% of infants with SCID or its variants, hematopoietic stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more from an HLA-identical, mixed leukocyte culture–matched sibling restores immunity. When an HLA-identical sibling is not available, haploidentical hematopoietic stem cells from a parent that is rigorously depleted of T cells can be used. If SCID is diagnosed by age 3 months, the survival rate after transplantation with either type of hematopoietic stem cells is 96%. Pretransplantation chemotherapy is unnecessary because patients do not have T cells and therefore cannot reject a graft.

Patients with ADA deficiency who do not receive a bone marrow graft may be treated with injections of polyethylene glycol–modified bovine ADA once or twice a week.

Gene therapy has been successful in ADA-deficient SCID, and no posttreatment leukemias or lymphomas have been reported. Gene therapy has also been successful in X-linked SCID but has caused T-cell leukemias, precluding its use. Gene therapy for other forms of SCID is under study.

Key Points

  • Suspect severe combined immunodeficiency (SCID) if infants have recurrent infections, graft-vs-host disease, or exfoliative dermatitis.

  • The diagnosis is confirmed if patients have lymphopenia, deficient numbers of T cells, and no lymphocyte proliferative responses to mitogens.

  • Determine T, B, and natural killer cell counts to identify the type of SCID.

  • Give prophylactic immune globulin and antimicrobials.

  • Do hematopoietic stem cell transplantation early whenever possible.

  • If patients with ADA-deficient SCID do not receive a bone marrow graft, use ADA replacement and sometimes gene therapy.

Drugs Mentioned In This Article

Drug Name Select Trade
GaviLax, GIALAX , GlycoLax, Healthylax, MiraLax, Visine Dry Eye Relief, Vita Health
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