SUMMARY
1. Defects in the Ca2+ release-activated channel (CRAC) result in an autosomal recessive form of severe combined immunodeficiency. Unlike most other types of SCID, patients have normal lymphocyte development but lymphocyte activation is profoundly impaired.
2. Patients present with a SCID-like phenotype with FTT, invasive bacterial, viral, fungal, mycobacterial, and opportunistic infections. The life-expectancy is very poor without a hematopoietic stem cell transplantation (HSCT).
3. Muscular hypotonia is a unique clinical feature manifesting as poor head control after birth, delayed ambulation, and positive gowers sign.
4. Anhydrotic ectodermal dysplasia is also present - patients present with an inability to sweat and defective calcification of the dental enamel matrix (loss of dental enamel results in painful exposure of underlying dentin). Other features of ectodermal dysplasia such as hair and nail abnormalities have not been reported.
5. Laboratory findings include normal or slightly reduced major lymphocyte subset values (T, B, NK cells) and normal or elevated quantitative immunoglobulin levels (particularly elevated IgM and IgA). However, patients have poor in vitro T cell proliferation to mitogens and poor specific antibody responses to vaccine antigens.
6. Two molecular etiologies for CRAC deficiency have been identified:
-ORAI 1 Deficiency - ORAI 1 is the pore-forming subunit of the CRAC channel. Patients suffer from severe combined immunodeficiency, myopathy, and ectodermal dysplasia.
-STIM 1 Deficiency - STIM 1 senses the initial release of Ca2+ from the ER stores and activates the CRAC channel. Patients suffer from severe immunodeficiency, myopathy, and ectodermal dysplasia. In addition, autoimmunity (autoimmune thrombocytopenia, hemolytic anemia) and lymphoproliferation (lymphadenopathy and hepatosplenomegaly) are common.
7. The diagnosis should be suspected in patients with combined immunodeficiency, mypoathy, and ectodermal dysplasia. All patients have abnormal extracellular Ca2+ influx following cell activation. Sequencing of the ORAI 1 and STIM 1 genes can confirm the diagnosis.
8. 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
9. Given the poor life expectancy of patients, HSCT is indicated. However, it should be noted that HSCT will not correct the non-immunologic features found in patients (myopathy and ectodermal dysplasia).
OVERVIEW
Defects in the Ca2+ release-activated channel (CRAC) result in an autosomal recessive form of severe combined immunodeficiency. Unlike most other types of SCID, patients have normal lymphocyte development but lymphocyte activation is profoundly impaired.
Patients present with a SCID-like phenotype with FTT, invasive bacterial, viral, fungal, mycobacterial, and opportunistic infections. The life-expectancy is very poor without a hematopoietic stem cell transplantation (HSCT).
Muscular hypotonia is a unique clinical feature manifesting as poor head control after birth, delayed ambulation, and positive gowers sign.
Anhydrotic ectodermal dysplasia is also present; patients present with an inability to sweat and defective calcification of the dental enamel matrix (loss of dental enamel results in painful exposure of underlying dentin). Other features of ectodermal dysplasia such as hair and nail abnormalities have not been reported.
Laboratory findings include normal or slightly reduced major lymphocyte subset values (T, B, NK cells) and normal or elevated quantitative immunoglobulin levels (particularly elevated IgM and IgA). However, patients have poor in vitro T cell proliferation to mitogens and poor specific antibody responses to vaccine antigens.
Two molecular etiologies for CRAC deficiency have been identified:
-ORAI 1 Deficiency - ORAI 1 is the pore-forming subunit of the CRAC channel. Mutations have been reported in 6 patients from three unrelated families. All patients suffered from severe combined immunodeficiency, myopathy, and ectodermal dysplasia.
-STIM 1 Deficiency - STIM 1 senses the initial release of Ca2+ from the ER stores and activates the CRAC channel. This deficiency has been reported in 3 siblings from a single consanguineous family. Patients suffered from severe immunodeficiency, myopathy, and ectodermal dysplasia. In addition, all three patients developed autoimmunity (autoimmune thrombocytopenia, hemolytic anemia) and lymphoproliferation (lymphadenopathy and hepatosplenomegaly).
PATHOGENESIS
Following antigen binding to the TCR, ZAP70 dependent phosphorylation of phospholipase C gamma occurs, which leads to cleavage of PIP and generation of diacylglycerol (DAG) and IP3. IP3 binding to IP3 receptors on the ER induces release of Ca2+ from ER stores. Following depletion of ER Ca2+ stores, STIM 1 is activated and opens the CRAC channel (encoded for by ORAI 1), allowing extracellular Ca2+ influx. Ca2+ binding to calmodulin results in activation of calcineurin, a phosphatase that dephosphorylates NFAT. Dephosphorylated NFAT is able to translocate to the nucleus and initiate gene transcription. The sustained Ca2+ influx through CRAC channels is a critical for T cell activation (release of ER Ca2+ stores alone is insufficient).
EVALUATION
The diagnosis of ORAI 1 or STIM 1 deficiency should be strongly suspected in patients presenting with a SCID phenotype, non-progressive congenital myopathy, and ectodermal dysplasia. The differential diagnosis includes other types of SCID, combined immunodeficiencies, and NEMO deficiency.
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 responses to vaccine antigens
-The absolute lymphocyte count (ALC) is typically normal in ORAI1/STIM 1 deficiency while in classic SCID it is typically less than 2800 cells/mm3.
-T cell, B cell and NK cell numbers are typically normal because mutations do not interfere with lymphocyte development. T cell numbers are markedly decreased in classic SCID.
-Very low naïve (CD45RA) T-cell numbers can be a useful clue for lack of thymic output in classic SCID. In cases of maternal T cell engraftment the circulating T cells have a predominantly memory (CD45RO) phenotype and have poor proliferation in response to mitogens.
-Very low T cell proliferation to mitogens is seen in patients with ORAI1/STIM 1 deficiency as well as classic SCID.
-Immunoglobulin levels are typically normal or elevated in ORAI1/STIM 1 deficiency.
-Specific antibody responses are markedly impaired in ORAI1/STIM 1 deficiency.
STEP 2: The definitive diagnosis for ORAI1/STIM 1 deficiency is made by demonstrating the presence of mutations in the ORAI 1 or STIM 1 gene. Gene sequencing for ORAI1/STIM1 is now commercially available (Cincinnati Children's Hospital).
MANAGEMENT
Given the severe immunodeficiency and poor life expectancy of patients, HSCT is indicated. However, it should be noted that HSCT will not correct the non-immunologic features found in patient (myopathy and ectodermal dysplasia).
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)
RESOURCES
Diagnostic Resources
The following tests resources are accessible on the SCID overview diagostic 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)
Literature Resources
1. Feske 2010
Immunodeficiency due to mutations in ORAI1 and STIM1