SCIDS (Severe Combined Immunodeficient Syndrome)

The World Health Organization recognizes approximately 70 primary immune deficiencies including X-Linked Agammaglobulinemia, Common Variable Immune Deficiency (Hypogammaglobulinemia), Selective IgA Deficiency and Severe Combined Immune deficiency. SCID leads to severe Tand B-cell dysfunction. It is generally considered to be the most serious of the primary immunodeficiency diseases. Without intervention, death in children occurs by age 2 years.

• SCIDS X-Linked form:

  • -SCIDX

  Autosomal Recessive SCID (Swiss type Agammaglobulinemia):

  • -Janus Associated Kinase 3 Deficiency (JAK 3 Deficiency)

    Adenosine Deaminase Deficiency (ADA Deficiency)

    Purine Nucleoside Phosphorylase Deficiency (PNP Deficiency)

  Bare Lymphocyte Syndrome

  IL-2 Deficiency

  ZAP-70 Protein Tyrosine Kinase Deficiency (ZAP-70 PTK Deficiency)

  Reticular Dysgenesia

  Omenn Syndrome

1:100,000 live births. Higher incidence recently reported (1:50,000 to 1:75,000 live births), probably because of better identification of affected subjects.

Of all SCID cases, 50% are X-linked (gene mapped to Xq13) and 50% are various forms of autosomal recessive. Approximately 25% of the patients with an autosomal recessive SCID are Janus-associated kinase 3 (JAK3) deficient and 40% are adenosine deaminase (ADA) deficient. Gene mapped to 8q11, 5p13.

The pathophysiology and molecular biology vary according to the type of immunodeficiency. However, the lack of Tand B-cell function is the common endpoint in all forms of SCIDS.

X-Linked form: Mutation of the common gamma chain of the interleukin (IL-2R, IL-4R, IL-7R, IL-9R, IL-15R) resulting in loss of cytokine function. Loss of IL-2R function leads to the loss of a lymphocyte proliferation signal. Loss of IL-4R function leads to the inability of B cells to class switch. Loss of IL-7R function leads to the loss of an antiapoptotic signal, resulting in a loss of T-cell selection in the thymus. Loss of IL-7R function is also associated with the loss of a T-cell receptor (TCR) rearrangement. Loss of IL-15R function leads to the ablation of NK cell development. Lymphopenia occurs primarily from the absence of CD3+ and NK cells. Variable levels of B cells occur, which do not make functional antibodies.

Autosomal recessive SCID includes different types.

• Janus-Associated Kinase 3 (JAK3) Deficiency: JAK3 is a protein tyrosine kinase (PTK) that associates with the common gamma chain of the IL receptors. Lymphopenia occurs primarily from the absence of T cells (CD3+) and NK cells. Normal or high levels of B cells occur, which do not make functional antibodies.
• Adenosine Deaminase (ADA) Deficiency: Lymphopenia occurs from the death of T and B cells secondary to the accumulation of toxic metabolites in the purine salvage pathway. Functional antibodies are decreased or absent.
• Purine Nucleoside Phosphorylase (PNP) Deficiency: Same as ADA deficiency with circulating B cells normal in number. B-cell function is poor, as evidenced by the lack of antibody formation.
• Bare Lymphocyte Syndrome: This is a deficiency of major histocompatibility complex (MHC). The lymphocyte count is normal or mildly reduced, the CD4+ are decreased, and the CD8+ are normal or mildly increased. The B-cell numbers are normal or mildly decreased, but the ability to make antibodies is decreased.
• IL-2 Deficiency: The exact molecular defect is unknown, but it is often associated with other cytokine production defects. Normal numbers of T cells exist (both CD4+ and CD8+). The production of functional antibody is decreased.
• ZAP-70 Protein Tyrosine Kinase (PTK) Deficiency: A mutation occurs in the gene coding for this tyrosine kinase, which is important in T-cell signaling. Lymphopenia occurs because of the absence of CD8+. Functional antibodies are decreased or absent.
• Reticular Dysgenesis: Lymphopenia occurs from the absence of myeloid cells in the bone marrow. RBCs and platelets are present and functioning.
• Omenn Syndrome: A mutation that impairs the function of Ig and TCR recombinase genes. Normal or elevated T-cell numbers are present, but these are of maternal not fetal origin. The B cells are usually undetectable, NK cells are present, and the total Ig level is markedly low with poor antibody production. Eosinophils and serum IgE level are elevated.

Clinically evocated in infants with severe infections secondary to the lack of T-cell function.

Features include failure to thrive, dehydration from chronic diarrhea, eczema from graft-versus-host disease (Omenn syndrome), lymphadenopathy and hepatosplenomegaly (Omenn syndrome or Bare Lymphocyte syndrome), neurological sequelae, and developmental regression (not caused by infections but genetic in PNP deficiency). Main causes of infections are Pneumocystis carinii, atypical mycobacterium, herpes viruses (generalized herpetic infections), Candida (and other systemic fungal infections), Cryptosporidium, and Pneumococcus.

An anesthesiology consultation is highly recommended before elective surgical procedures. A complete medical history and physical examination must be obtained. The state of infection (systemic or local) must be evaluated carefully (clinical, chest radiographs, documented infectious history). Other important considerations include, hydration (clinical, electrolytes, renal function), and respiratory function in cases of recurrent lung infections (clinical, chest radiographs/CT, pulmonary function test, arterial blood gas analysis).

Strict asepsis is needed. Blood products must be irradiated to avoid graft-versus-host reaction. Regional anesthesia is best avoided in this infectious context.

These patients are immunodeficient and the choice of prophylactic antibiotics should be made on the basis of both their infectious history and their immunological status.

Primary Agammaglobulinemias (X-Linked Immunodeficiency): A group of inherited immune deficiencies characterized by insufficient antibodies. Some children with Primary Agammaglobulinemias experience joint swelling and pain.

DiGeorge Syndrome: A very rare immune deficiency that results from developmental defects in the thymus and parathyroid glands. Infantile seizures is often associated with the presence of abnormal function of the parathyroid gland. These infants cannot resist infections from viruses, fungi, and other bacteria. Chronic nasal infections, diarrhea, oral candidiasis, and Pneumocystis pneumonia are frequent.

Nezelof Syndrome: A rare immune deficiency disorder characterized by the impairment of cellular immunity in response to infections. Oral candidiasis, diarrhea, skin infections, septicemia, urinary tract infections, measles, and pulmonary infections are frequent clinical presentations.

Wiskott-Aldrich Syndrome: A rare X-linked inherited disorder characterized by an immune deficiency primarily affecting B lymphocytes. The symptoms generally begin during infancy. Excessive bleeding may happen during circumcision or minor trauma because of thrombocytopenia. Otitis media, pneumonia, meningitis, and sepsis are most often life-threatening for these infants.