Severe combined immunodeficiency is characterized by 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 mo 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 bone marrow stem cell transplantation.
Severe combined immunodeficiency (SCID) 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]). Most types 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. In all 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 is X-linked. It affects the IL-2 receptor common γ 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 γ 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 α-chain deficiency; phenotype is T- B+ NK+.
Symptoms and Signs
By age 6 mo, most infants with SCID develop candidiasis, persistent viral infections, Pneumocystis jirovecii 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 mo. Exfoliative dermatitis may develop as part of Omenn syndrome, one form of SCID. 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.
Screening all neonates using the T-cell receptor excision circle (TREC) test is often recommended and is done routinely in many US states.
SCID is suspected in infants with a history of persistent infections or other characteristic manifestations. CBC, including absolute WBC count and differential, is done; Ig 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:
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, RBCs, 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.
Patients must be kept in reverse isolation. Treatment with IVIG, antibiotics (including P. jirovecii prophylaxis), and antifungals can help prevent infections but is not curative. In 90 to 100% of infants with SCID or its variants, bone marrow stem cell transplantation from an HLA-identical, mixed leukocyte culture–matched sibling restores immunity. When an HLA-identical sibling is not available, haploidentical bone marrow from a parent that is rigorously depleted of T cells can be used. If SCID is diagnosed by age 3 mo, the survival rate after transplantation with either type of bone marrow 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/wk.
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.
Last full review/revision November 2013 by James Fernandez, MD, PhD
Content last modified November 2013