Severe combined immunodeficiency (SCID) is a rare primary immunodeficiency that combines the absence of T and B lymphocyte functions. SCID can be caused by various genetic mutations, leading to extreme susceptibility to severe infections. This condition is generally considered the most severe of all primary immunodeficiencies. Fortunately, effective treatments exist, such as bone marrow transplantation, and in the future, gene therapy may become an option.
SCID is a rare syndrome caused by various genetic factors and a combined absence of T and B lymphocyte functions (and, in many cases, also the absence of natural killer (NK) cell function). These genetic defects result in extreme vulnerability to severe infections. Currently, twelve genetic causes of SCID are known. Despite their differences in specific defects leading to immunodeficiency, certain laboratory findings, and inheritance patterns, all SCID cases are characterized by severe impairments in T and B lymphocyte function.
Common Forms of SCID
Deficiency of the Common Gamma Chain in Six Cytokine Receptors
The most frequent form of SCID, accounting for approximately 45% of all cases, is caused by a mutation in an X-linked gene encoding a component (or chain) present in the receptor for T-cell growth factors as well as other growth factor receptors. This component is known as γc or the common gamma chain. Mutations in this gene lead to very low numbers of T and NK cells while B cells remain abundant (T-, B+, NK- phenotype). However, despite their abundance, B cells are non-functional because they require T-cell assistance for proper function. This disorder is inherited as an X-linked recessive trait, affecting only males, while female carriers have a 50% chance of passing it to their sons.
Adenosine Deaminase (ADA) Deficiency
Another form of SCID results from mutations in the gene encoding the enzyme adenosine deaminase (ADA), which is essential for cellular metabolism, particularly in T cells. The absence of this enzyme leads to the accumulation of toxic metabolic byproducts in lymphocytes, causing cell death. ADA deficiency accounts for approximately 15% of SCID cases. Infants with this form have extremely low levels of all lymphocytes (T, B, and NK cells). ADA deficiency is inherited as an autosomal recessive trait, affecting both boys and girls.
Interleukin-7 Receptor Alpha Chain (IL-7Rα) Deficiency
This form of SCID is caused by mutations in a gene on chromosome 5 that encodes a different component of the T-cell growth factor receptor—the alpha chain of the interleukin-7 receptor (IL-7Rα). Infants with this type of SCID have B and NK cells but lack T cells. However, B cells remain non-functional due to the absence of T cells. IL-7Rα deficiency accounts for about 11% of SCID cases and is inherited as an autosomal recessive trait, affecting both boys and girls.
Janus Kinase 3 (JAK3) Deficiency
Another form of SCID is caused by mutations in a gene on chromosome 19 encoding Janus kinase 3 (JAK3), an enzyme necessary for the function of the common gamma chain (γc) mentioned above. The T-, B+, NK- phenotype in JAK3-deficient patients resembles X-linked SCID. However, since JAK3 deficiency follows an autosomal recessive inheritance pattern, it affects both males and females. This form of SCID accounts for at least 10% of cases.
Other Genetic Defects Causing SCID
Several additional genetic defects result in SCID, including mutations in:
- CD3 chains, crucial components of the T-cell receptor complex
- CD45, a protein essential for T-cell signaling
- Recombination-activating genes (RAG1 and RAG2), required for developing T- and B-cell receptors (sometimes associated with Omenn syndrome)
- Artemis, an enzyme involved in DNA repair during immune cell development
- Ligase-4, another protein involved in DNA repair
Less Severe Combined Immunodeficiencies
Some genetic conditions cause immunodeficiencies that resemble SCID but are less severe. These include:
- Bare lymphocyte syndrome (MHC class II deficiency)
- Purine nucleoside phosphorylase (PNP) deficiency
- ZAP70 deficiency
- CD25 deficiency
- Cartilage-hair hypoplasia
- MHC class I deficiency
Clinical Manifestations
The most common sign of SCID in infancy is frequent infections. These infections are often much more severe than typical childhood illnesses and can be life-threatening. They may include pneumonia, meningitis, and bloodstream infections. SCID patients are also highly susceptible to normally harmless microbes and live vaccines.
Particularly dangerous pathogens for SCID patients include:
- Pneumocystis jirovecii, causing severe pneumonia
- Varicella-zoster virus (chickenpox), which can spread to the lungs, liver, and brain
- Cytomegalovirus (CMV), potentially leading to fatal pneumonia
- Herpes simplex virus, Epstein-Barr virus (EBV), adenovirus, and rotavirus
Live vaccines (e.g., for measles, chickenpox, and rotavirus) can cause severe infections in SCID patients, making it essential to screen newborns with a family history of SCID before vaccination.
Other symptoms include:
- Persistent fungal (Candida) infections, including oral thrush
- Chronic diarrhea leading to malnutrition and weight loss
- Severe skin infections and rashes, sometimes mistaken for eczema
Diagnosis
SCID is suspected based on clinical symptoms or family history. The first step in diagnosis is a lymphocyte count from a blood sample. Normal infants have over 4,000 lymphocytes per mm³ of blood, whereas SCID patients typically have fewer than 1,500.
Further diagnostic tests include:
- Flow cytometry to count T, B, and NK cells
- T-cell function tests to measure their response to stimulation
- Immunoglobulin levels, which are typically very low in SCID patients
Treatment
Bone marrow transplantation (BMT) is the standard curative treatment for SCID. If performed early, especially from a matched sibling donor, it can lead to long-term survival. Gene therapy is also emerging as a potential cure for certain genetic forms of SCID.
Other supportive treatments include:
- Immunoglobulin replacement therapy to provide passive immunity
- Prophylactic antibiotics to prevent infections
- Enzyme replacement therapy (e.g., for ADA deficiency)
With early diagnosis and appropriate treatment, SCID patients can survive and lead relatively normal lives.