Combined immunodeficiency due to CRAC channel dysfunction

Combined immunodeficiency due to CRAC channel dysfunction is a rare primary immunodeficiency disorder caused by defects in calcium release-activated calcium (CRAC) channels, which are essential for T-cell activation and immune function. This condition is also known as immunodeficiency due to ORAI1 deficiency or STIM1 deficiency, reflecting the two main genes involved. CRAC channels mediate store-operated calcium entry (SOCE) in immune cells, and their dysfunction leads to severely impaired T-cell activation, resulting in combined immunodeficiency affecting both cellular and humoral immunity. Patients typically present in infancy or early childhood with severe, recurrent, and often life-threatening infections, including viral, bacterial, fungal, and opportunistic infections. A distinctive feature of this condition is that it affects multiple organ systems beyond the immune system. Patients frequently develop autoimmune manifestations, muscular hypotonia and myopathy, ectodermal dysplasia with anhidrotic features (impaired sweating) and dental enamel defects, and nonprogressive muscular hypotonia. Some patients also exhibit thrombocytopenia and hemolytic anemia as autoimmune complications. The condition is inherited in an autosomal recessive manner and is caused by biallelic pathogenic variants in either the ORAI1 gene (encoding the pore-forming subunit of the CRAC channel) or the STIM1 gene (encoding the endoplasmic reticulum calcium sensor that activates ORAI1). Treatment is primarily supportive, including aggressive management of infections, immunoglobulin replacement therapy, and prophylactic antimicrobials. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for the immunodeficiency component, though it does not correct the non-immunological features such as myopathy and ectodermal dysplasia. Without transplantation, the prognosis is poor, with significant morbidity and mortality from infections in early life.

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