SUMMARY
1. Trisomy 21 (Down syndrome) is the most common chromosomal abnormality among newborn infants. Patients have multi-system abnormalities including dysmorphic facial features, developmental delay, heart disease, growth delay, and endocrine disorders (diabetes and thyroid disease).
2. Immunodeficiency has been reported in patients with Trisomy 21 and include the following abnormalities:
-Decreased B cell numbers
-Decreased specific antibody response
-Decreased T cell numbers
-Decreased T cell proliferation to mitogens
-Normal phagocyte number but impaired chemotaxis and oxidative burst
3. Patients typically suffer from recurrent sinopulmonary infections at high frequency. Opportunistic infections are rare despite the decreased T cell numbers and function in some patients.
4. One potential mechanism for the immunodeficiency in Trisomy 21 involves decreased NFAT activation (NFAT is a key transcription factor involved in T cell activation).
5. Patients with specific antibody deficiency may benefit from a trial of prophylactic antibiotics. For patients with refractory infections, immunoglobulin replacement therapy may be beneficial.
OVERVIEW
Trisomy 21 (Down syndrome) is the most common chromosomal abnormality among newborn infants. Patients have multi-system abnormalities including dysmorphic facial features, developmental delay, heart disease, growth delay, and endocrine disorders (diabetes and thyroid disease).
Immunodeficiency has been reported in patients with Trisomy 21. The following abnormalities have been described:
- Decreased B cell numbers
- Decreased specific antibody response
- Decreased T cell numbers
- Decreased T cell proliferation to mitogens
- Normal phagocyte number but impaired chemotaxis and oxidative burst
Patients typically suffer from recurrent sinopulmonary infections at high frequency. Opportunistic infections are rare despite the decreased T cell numbers and function in some patients.
PATHOGENESIS
Patients with Trisomy 21 have decreased NFAT activation (NFAT is a key transcription factor involved in T cell activation). Specifically, 2 proteins are over-expressed: DSCR1 (a calcineurin inhibitor) and DYRK1 (a nuclear phosphatase that promotes the export of NFAT from the nucleus to the cytosol). As a result, there is decreased NFAT translocation into the nucleus.
EVALUATION
Step 1: Immune Evaluation
- IgG, IgM, IgA
- Specific antibody responses to vaccine antigens
- Lymphocyte subset enumeration by flow cytometry (CD3, CD4, CD8, CD19, CD16/56)
- T cell proliferation to Mitogens (PHA, ConA, PWM)
- DHR Assay
- Patients may have decreased immunoglobulin levels.
- Responses to both protein antigens (tetanus and diphtheria) as well as polysaccharide antigens (pneumovax) should be evaluated. Impaired specific vaccine responses have been reported in patients.
- Decreased T cell numbers and B cell numbers may be present.
- Decreased in vitro T cell proliferation to mitogens may be present.
- Phagocyte oxidative burst function may be impaired.
MANAGEMENT
Patients with specific antibody deficiency may benefit from a trial of prophylactic antibiotics. For patients with refractory infections, immunoglobulin replacement therapy may be beneficial. IVIG is typically dosed at 400-600 mg/kg every 3 to 4 weeks. Alternatively, subcutaneous immunoglobulin therapy can be given weekly at a dose of 100-150 mg/kg once weekly.
RESOURCES
Literature Resources
1. Arron 2006
NFAT Dysregulation by increased dosage of DSCR1 and DYRK1A
2. Ram 2010
Infections and immunodeficiency in Down syndrome
3. Verstegen 2010
Down syndrome B cell subpopulations - Intrinsic defect or decreased T cell help
4. Lima 2011
Decreased AIRE expression and thymic hypofunction in Down Syndrome