SUMMARY
1. X-linked SCID is by far the most common cause of SCID, accounting for 50% of all cases. It causes a form of T-B+NK- SCID. Patients classically present in infancy with failure to thrive, severe thrush, opportunistic infections, and chronic diarrhea.
2. This condition is caused by mutations in the common gamma chain of the IL-2 receptor. This receptor subunit is shared with other cytokine receptors including IL-4, IL-7, IL-9, IL-15, and IL-21.
3. Lymphocyte subset analysis typically shows a near absence of T cells and NK cells but normal B cell numbers. The immunoglobulin levels are low to absent despite the presence of B-cells due to absence of T-cell co-stimulatory signaling.
4. Flow cytometry may reveal the lack of common gamma chain (CD132) expression on the surface of lymphocytes. However, certain missense mutations can lead to expression of non-functional protein on lymphocytes. As a result, the presence of CD132 expression does not rule out X-linked SCID.
5. Sequencing of the IL2RG gene can confirm the diagnosis.
6. In addition to treatment of acute infections, the following immediate management steps must be implemented:
- Avoid all live viral vaccines
- Only irradiated, CMV negative blood products should be used (to prevent GVHD and infections)
- Pneumocystis jiroveci prophylaxis with trimethoprim-sulfamethoxazole
- IVIG replacement therapy
- Start HLA-typing for the patient and any siblings for possible hematopoietic stem cell transplantation (HSCT)
7. Even with supportive therapies, patients with SCID will not survive without a HSCT. Patients transplanted before 3 months of age have a greater than 80% chance of survival while patients who are transplanted later and have suffered end organ damage from infections have a much lower success rate.
OVERVIEW
X-linked SCID is the most common cause of SCID (50% of all cases) and results in a T-B+NK- phenotype. Male patients present in early infancy with a typical SCID phenotype: FTT, diarrhea, severe thrush, PJP (PCP), and severe viral respiratory infections.
The absolute lymphocyte count is markedly decreased (typically below 2800 cells/mm3). Lymphocyte subset analysis by flow cytometry will show low T cells and low NK cells but normal B cell numbers. T cell proliferation to mitogens is very low. T cell numbers may be normal if maternal T cell engraftment has occurred (these cells typically have a memory T cell (CD45 RO) phenotype and proliferate poorly to mitogens. Immunoglobulin levels will be very low (once transplacentally acquired maternal IgG levels decline) despite normal B cell numbers.
This type of SCID is caused by defects in the common gamma subunit of the IL-2 receptor (IL2RG gene). This subunit is also shared with other cytokine receptors including the IL-4, IL-7, IL-9, IL-15, and IL-21 receptor. Impaired signaling through these multiple cytokine pathways leads to severe impairment in the development of T cells and NK cells. IL-2 and IL-7 signaling are particularly important for T cell development while IL-15 signaling is important for NK cell development and proliferation. Although B cell numbers are preserved, B cell activation and class switch recombination are greatly impaired due to a lack of T cell help. Impaired IL-4 and IL-21 signaling may also contribute to B cell dysfunction.
EVALUATION
X-linked SCID should be very high on the differential diagnosis for any male patient presenting with a SCID-like phenotype (FTT, diarrhea, thrush, PJP pneumonia, severe respiratory virus infections, infections from live viral vaccines) along with low absolute lymphocyte counts. It accounts for 50% of all SCID cases.
STEP 1: Immune Evaluation
-CBC with Differential
-Lymphocyte subset enumeration by flow cytometry (CD3, CD4, CD8, CD19, CD16/56)
-Naïve (CD45RA) and memory (CD45RO) T-cell enumeration by flow cytometry
-T cell proliferation to Mitogens (PHA)
-IgG, IgA, IgM levels
-Specific Antibody levels (if older than 6 months)
-Chest X-Ray
-The absolute lymphocyte count (ALC) should be calculated from the CBC (WBC multiplied by the lymphocyte percentage). SCID presents with an ALC less than 2800 cells/mm3 in 95% of cases.
-Low T cell numbers and low NK cell numbers are seen in most cases of X-linked SCID (maternal T-cell engraftment and Omenns syndrome are notable exceptions). B cell numbers are normal.
-Very low naïve (CD45RA) T-cell numbers can be a useful clue for lack of thymic output. In cases of maternal T cell engraftment and Omenns syndrome, the circulating T-cells have a predominantly memory (CD45RO) phenotype rather than a naïve (CD45 RA) phenotype and have poor proliferation in response to mitogens.
-Extremely low T cell proliferation to mitogens is seen in SCID (<10% of control). The large blood volume required to perform mitogen proliferation is often an issue with small infants. Performing the proliferation assay with one stimulus (PHA) is acceptable and requires less blood.
-Immunoglobulin levels before 6 months of age may reflect transplacentally aquired maternal IgG). However, immunoglobulin levels can be low prior to 6 months in SCID due to accelerated consumption from recurrent infections.
-A chest X-ray may reveal absent thymic tissue.
STEP 2: Additional Immune Evaluation
The following tests may provide additional support for a diagnosis of SCID and can be helpful in certain clinical situations.
-TREC Analysis
-TCR Gene Rearrangement PCR (TCR Spectratyping)
-Maternal Engraftment Study
-TRECs (T-cell receptor excision circles) are loops of DNA excised during TCR rearrangement in the thymus. Because TRECs are not replicated with cell division, they are gradually diluted as T-cells become activated and expand. Thus, naïve T-cells that are recent thymic emigrants have high TREC numbers. SCID patients typically have very low TREC numbers. TRECs are useful for monitoring engraftment following HSCT.
-TCR gene rearrangement is useful for identifying oligoclonally expanded T-cells. This can be seen in maternal engraftment as well as Omenns syndrome.
-Maternal engraftment (T cell expansion) can occur in patients with SCID. Maternal T cells typically are CD45RO+ and proliferate poorly to mitogen stimulation. Assessing for the presence of maternal cells in circulation is useful because it can affect the selection of a stem cell donor and it may necessitate immunosuppression prior to transplantation as opposed to no conditioning.
STEP 3: If lymphocyte subset analysis reveals a T-B+NK- phenotype, further evaluation for X-linked SCID should be pursued. Autosomal recessive SCID from JAK3 deficiency (which also causes a T-B+NK- phenotype) should also be high on the differential diagnosis.
-Lymphocyte flow cytometry for the common gamma chain (CD132)
-Genetic testing for Common Gamma Chain (c) Deficiency (IL2RG)
-Flow cytometry for CD132 may reveal the complete absence of the surface protein, which would strongly suggest the diagnosis of X-linked SCID. However, the presence of protein does NOT rule out the diagnosis because certain missense mutations will allow for non-functional gamma chain protein to be expressed on the cell surface. One advantage of this test is that it is much faster to perform (less than 1 week) than gene sequencing.
-Genetic testing for IL2RG is commercially available through correlagen diagnostics. Concurrent testing for JAK3 deficiency should also be considered because it can present with an identical phenotype. Gene sequencing typically takes 4-6 weeks.
MANAGEMENT
Pending the completion of an immunologic evaluation for suspected X-linked SCID, it is critical to initiate certain measures to prevent life-threatening complications for patients. The following precautions should be implemented immediately:
1. Avoid all live viral vaccines (rotavirus, varicella, MMR, BCG)
- Severe vaccine strain disease can occur if SCID patients receive these vaccines.
2. Only irradiated, CMV negative blood products should be used
- Leukocytes from non-irradiated blood can cause graft versus host disease and CMV can cause severe infections.
3. Pneumocystis jiroveci pneumonia prophylaxis with trimethoprim-sulfamethoxazole
- 4-6mg/kg/day of Trimethoprim component divided twice daily 3 days per week
4. IVIG replacement therapy
5. High resolution HLA-typing for the patient and any siblings
- For possible Hematopoietic Stem Cell Transplantation (HSCT)
RESOURCES
Diagnostic Resources
SPECIFIC RESOURCES FOR X-LINKED SCID:
1. CD132 by Flow Cytometry
-Childrens Hospital of Philadelphia DiGeorge Panel (includes CD132)
-Cincinnati Childrens
2. Correlagen - SCID Genetic Testing
The following tests resources are accessible on the SCID overview page:
1. Lymphocyte Subsets by Flow Cytometry for T-cell (CD3, CD4, CD8), B-cell
(CD19), and NK cell (CD16/56).
2. Naïve (CD45 RA) and Memory (CD45 RO) T cells by Flow Cytometry
3. T-cell proliferation to Mitogens and Specific Antigens (candida, tetanus)
4. TREC (T-cell receptor excision circle) Analysis
5. T-cell Receptor Gene Rearrangement (TCR Spectratyping)
Literature Resources
1. Noguchi 1993
IL2RG mutations cause X-linked SCID
2. Kovanen 2004
Cytokine signaling and X-linked SCID
3. Kohn 2010
Update on gene therapy for SCID