P. jiroveci (carinii) and other opportunistic organisms, and intractable diarrhea. Patients often have skin disease similar to eczema, possibly related to graft-versus-host disease (GVHD) from engraftment of maternal lymphocytes, which usually is not fatal. Patients with SCID are extremely susceptible to fatal GVHD from lymphocytes in blood transfusions and can be infected by cytomegalovirus-positive blood products. Patients with T-cell disorders always should receive irradiated blood products.
X-linked SCID, the most common form, is caused by mutations in the gene on chromosome Xq13.1 coding for the common gamma chain of the interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21 receptors. Affected patients have no T cells or NK cells in the peripheral blood but have normal numbers of B cells. Immunoglobulin levels are low or undetectable because there are no CD4 T cells to stimulate B cells. The defect in T-cell development results from a failure of signaling via the IL-7 receptor, and IL-15 is required for NK-cell development. There are many causes of autosomal recessive SCID. Defects in Janus kinase 3 (Jak3), which binds to the common gamma chain, results in a similar phenotype as X-linked SCID. Defects in the IL-7 receptor, ZAP-70, and subunits of the CD3 molecule result in a deficiency of T cells with normal Band NK-cell numbers. In addition there is a variety of defects that affect DNA recombination in T and B cells, including two genes called recombinase activating gene (RAG) 1 and 2 as well as other genes important in DNA excision and repair such as Artemis. Defects in any of the genes that abolish DNA recombination or DNA repair result in autosomal recessive SCID with no T cells or B cells present. Mutations in RAG1, RAG2, or Artemis that preserve limited function result in Omenn syndrome, a variant form of SCID that is characterized by exfoliative erythroderma, lymphadenopathy, hepatosplenomegaly, marked eosinophilia, elevated serum IgE, and impaired T-cell function. Patients with Omenn syndrome have T cells in the periphery, but these T cells have a limited repertoire.
Deficiencies in adenosine deaminase (ADA) and purine nucleoside phosphorylase, two enzymes involved in the purine salvage pathway, also result in SCID. Accumulation of nucleoside substrates or their metabolic products in the plasma and urine is toxic to lymphocytes, including T, B, and NK cells. Most patients exhibit severe infection early in life, although the diagnosis in patients with partial enzyme function may not be established until after 5 years of age or, occasionally, in adulthood. Patients with late-onset diagnosis are generally lymphopenic; they may have B cells and normal total immunoglobulin levels but little functional antibody (Nezelof syndrome). All patients with ADA or purine nucleoside phosphorylase deficiency SCID have lymphopenia and loss of immune function over time.
Bare lymphocyte syndrome results from defects in transcription factors that regulate expression of class II molecules or genes that affect transport of antigen peptides, which leads to the absence of either MHC class I or MHC class II molecules. Lymphoid tissue and B cells may be present in normal amounts, but CD4 T cells are decreased or absent in class II deficiency, whereas CD8 cells are decreased or absent in class I deficiency. Some patients may have normal numbers of CD4 or CD8 T cells, but none of the T cells are functional because peptide antigens cannot be presented to T cells.