1. IL-7 Receptor Alpha Chain Deficiency causes an autosomal recessive form of T-B+NK+ SCID. It accounts for approximately 10% of all SCID cases.
2. IL-7 signaling plays a key role in early T cell development. However, B cell and NK cell development does not require this cytokine.
3. Lymphocyte subset analysis typically shows a near absence of T cells but normal B cells and NK cells. The immunoglobulin levels are low to absent despite the presence of B cells due to absence of T cell co-stimulatory signaling.
4. Patients typically present with a classic SCID phenotype during infancy (FTT, candidiasis, chronic diarrhea, Pneumocystis jiroveci pneumonia, severe viral infections). However, patients can also present with an Omennssyndrome phenotype.
5. Sequencing of the IL-7R 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. Stem cell transplantation is the definitive treatment for this condition. Patients transplanted before 3 months of age have a greater than 80% chance of survival while patients who are transplanted later and who have suffered end organ damage from infections have a much lower success rate.
IL-7 Receptor Alpha Deficiency is an autosomal recessive form of SCID and results in a T-B+NK+ phenotype. It causes approximately 10% of all SCID cases. Male or female patients present in early infancy with a classic SCID phenotype: FTT, diarrhea, severe thrush, Pneumocystis jiroveci pneumonia, and severe viral respiratory infections. However, cases of patients presenting with an Omenn syndrome phenotype (erythroderma, highi IgE, hepatosplenomegaly, oligoclonal T cell expansion) have also been described.
The absolute lymphocyte count will be low (typically below 2800 cells/mm3). Lymphocyte subset analysis by flow cytometry will show low T cell numbers but normal B cell and NK cell numbers. 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 IL-7 Receptor alpha chain. IL-7 signaling is critical for early T cell development. IL-7 signaling, however, is not required for B cell or NK cell differentiation.
IL-7 R deficiency should be considered in male or female patients presenting with a SCID-like phenotype (FTT, diarrhea, thrush, Pneumocystis jiroveci pneumonia, severe respiratory virus infections) along with low absolute lymphocyte counts.
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)
-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 are seen in most cases of IL-7R deficiency SCID. B cell and NK cell numbers are normal. T cell numbers may be normal for patients presenting with an Omenn syndrome phenotype.
-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 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 but not necessarily required.
-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.
-TCR gene rearrangement is useful for identifying oligoclonally expanded T-cells. This can be seen in maternal engraftment as well as Omenns syndrome.
-Maternal T cells can occasionally undergo clonal expansion in patients with SCID. Maternal T cells typically are CD45RO+ and proliferate poorly to mitogen stimulation. An evaluation for the presence of maternal cells in circulation (maternal engraftment) is useful because it can affect the selection of a stem cell donor and it may necessitate immunosuppression prior to transplantation.
STEP 3: If lymphocyte subset analysis reveals a T-B+NK+ phenotype, further evaluation for IL-7R deficiency should be pursued. Other causes of T-B+NK+ SCID include CD3 deficiencies, CD45 deficiency, and Coronin 1A deficiency.
-Genetic testing for IL-7 Receptor Alpha Chain
-Genetic testing for IL-7R is commercially available through correlagen diagnostics. Concurrent testing for CD3 deficiency should also be considered because it can present with an identical immunologic phenotype. Gene sequencing typically takes 4-6 weeks.
Pending the completion of an immunologic evaluation for suspected IL-7 R Deficiency 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 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)
Stem cell transplantation is the definitive treatment for this condition. Patients transplanted before 3 months of age have a greater than 80% chance of survival while patients who are transplanted later and who have suffered end organ damage from infections have a much lower success rate.
Diagnostic Resources (LAB ORDER FORMS)
SPECIFIC RESOURCES FOR IL-7R DEFICIENCY SCID:
The following tests resources are accessible on the SCID overview diagnostic resources 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)
1. Gilliani 2005
IL-7R Alpha Deficiency (Review)
2. Puel 2000
IL-7R deficiency causes T-B+NK+ SCID
3. Roifman 2000
IL-7R alpha deficiency causes SCID