A heterogenous group of genetic disorders
characterized by a congenital deficit in humoral or cellular immunity.
Prototypes include: X-linked Agammaglobulinemia
(Bruton Syndrome; XLA); Hyper-IgM Syndrome (Job Syndrome);
Common; Variable Immunodeficiency (CVI); Severe Combined Immunodeficiency
(SCI); defects in the expression of the major histocompatibility complex
(MHC) (Bare Lymphocyte Syndrome); Wiskott-Aldrich Syndrome.
XLA: recessive inheritance, based
on mutations in the btk gene (Bruton, or B-cell, tyrosine kinase) on chromosome
Xq21.1-22. Hyper-IgM: X-linked recessive (Xq26) in 70% of patients, unclear in
30%. CVI: autosomal dominant, autosomal recessive, and X-linked. Most common
primary immunodeficiency among persons of European descent. SCI: 50 to 60% of
patients have an X-linked inheritance mapped to Xq13, thus the overall male
predominance in SCI. Inheritance in the remainder is autosomal recessive.
Isolated MCH class I defects are very rare. MCH class II deficiency is inherited autosomal
recessively, and is seen mostly in North African kindreds. Wiskott-Aldrich syndrome inheritance is
X-linked recessive, mapped to Xp11.23.
In XLA, the defect is in cytoplasmic
signal-transducing molecule. Hyper-IgM reflects the defective immune globulin class
switching from IgM to IgG production in the course of a humoral immune
response as a result of a defective CD40 ligand on TH cells. CVI
pathogenesis is unclear, evidence hints at a defective T-cell and B-cell
interaction. Interleukin receptor defects play a role in X-linked SCI, with a
defective purine metabolism in the autosomal recessive forms. In MHC class II deficiency, the
transcription of these molecules is defective.
Clinical picture and in XLA: agammaglobulinemia with absent
antibody formation to vaccines; Hyper-IgM: elevated IgM and IgD, and further
immunologic workup; CVI: exclusion of other causes of hypogammaglobulinemia;
CVI and MHC deficiencies: complex immunologic workup; Wiskott-Aldrich syndrome: triad of
thrombocytopenia, eczema, and susceptibility to infections, as well as immunologic workup.
The clinical picture is generally dependent on
the underlying defect.
X-linked agammaglobulinemia: Once passive immunity from maternal antibodies subsides, affected boys
suffer from recurrent pyogenic infections, mainly from Staphylococcus aureus,
Haemophilus influenzae, and Streptococcus pyogenes. Regular intravenous
immune globulin (IVIG) therapy is effective in preventing infections and formation of
bronchiectasis. Female carriers are asymptomatic because of nonrandom inactivation of
the mutant X chromosome.
Hyper-IgM syndrome: In addition to the susceptibility to pyogenic infections, male patients are
prone to Pneumocystis carinii infections and autoimmune diseases, mainly directed against blood
cells (hemolytic anemia, thrombocytopenia, and neutropenia). Neutropenia
responds to IVIG and granulocyte colony-stimulating factor (G-CSF).
Proliferation of IgM-producing plasma cells may lead to infiltration of GI
organs, and there is an increased risk for abdominal cancers.
Common variable immunodeficiency: Heterogeneous group of antibody deficiency syndromes, usually presenting in
adolescence and young adulthood. These patients are prone to pyogenic
(sinopulmonary) infections (with formation of bronchiectasis), gastrointestinal infections
(e.g., Giardia lamblia), malignancy (e.g., high risk ...