Autoimmune lymphoproliferative syndrome-recurrent viral infections due to CASP8 deficiency

Autoimmune lymphoproliferative syndrome due to CASP8 deficiency (also known as ALPS-related CASP8 deficiency, or caspase-8 deficiency state) is an extremely rare inherited immune disorder caused by biallelic (homozygous or compound heterozygous) mutations in the CASP8 gene, which encodes caspase-8, a critical enzyme involved in both apoptosis (programmed cell death) and lymphocyte activation. This condition is classified within the broader spectrum of autoimmune lymphoproliferative syndrome (ALPS) but has distinctive features that set it apart from classical ALPS. The disease primarily affects the immune system, leading to a unique combination of lymphoproliferative features and immunodeficiency. Patients typically present with splenomegaly (enlarged spleen) and lymphadenopathy (enlarged lymph nodes) due to accumulation of lymphocytes that fail to undergo normal apoptosis. A hallmark finding is an expansion of double-negative T cells (CD3+TCRαβ+CD4−CD8−). Unlike classical ALPS, patients with CASP8 deficiency also exhibit significant immunodeficiency characterized by recurrent and sometimes severe viral infections, particularly herpesvirus infections, as well as recurrent sinopulmonary bacterial infections. Autoimmune manifestations, including autoimmune cytopenias, may also occur. The defective caspase-8 impairs both the death receptor-mediated apoptosis pathway and the activation of T cells, B cells, and natural killer cells, explaining the dual phenotype of lymphoproliferation and immunodeficiency. Management is largely supportive and individualized. Treatment may include immunoglobulin replacement therapy for antibody deficiency, prophylactic antimicrobials to prevent recurrent infections, and immunosuppressive agents such as sirolimus (rapamycin) for lymphoproliferative and autoimmune manifestations. Hematopoietic stem cell transplantation may be considered in severe cases. Given the extreme rarity of this condition, management is typically guided by expert centers with experience in primary immunodeficiencies and ALPS-related disorders.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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