Autoimmune lymphoproliferative syndrome

Autoimmune lymphoproliferative syndrome (ALPS), also known as Canale-Smith syndrome, is a rare inherited disorder of immune regulation characterized by defective lymphocyte apoptosis (programmed cell death). Because immune cells, particularly lymphocytes, fail to undergo normal apoptosis after an immune response, they accumulate in lymphoid organs, leading to chronic, non-malignant lymphoproliferation. The hallmark features include chronic lymphadenopathy (enlarged lymph nodes), splenomegaly (enlarged spleen), and hepatomegaly (enlarged liver), often presenting in early childhood. A distinctive laboratory finding is an elevated population of double-negative T cells (CD3+TCRαβ+CD4−CD8−) in the peripheral blood. ALPS primarily affects the immune and hematologic systems. Patients frequently develop autoimmune cytopenias, including autoimmune hemolytic anemia, immune thrombocytopenic purpura, and autoimmune neutropenia. These autoimmune manifestations can range from mild to life-threatening. Patients with ALPS also carry an increased lifetime risk of developing lymphoma, particularly Hodgkin and non-Hodgkin lymphoma, necessitating long-term surveillance. The most common form, ALPS-FAS (ALPS type Ia), is caused by germline mutations in the FAS gene (TNFRSF6), which encodes a key death receptor involved in lymphocyte apoptosis. Other genetic subtypes include mutations in FASLG (ALPS type Ib), CASP10 (ALPS type IIa), and somatic FAS mutations (ALPS-sFAS). Treatment is tailored to clinical severity and may include immunosuppressive agents such as mycophenolate mofetil and sirolimus (rapamycin), which have shown efficacy in controlling lymphoproliferation and autoimmune cytopenias. Corticosteroids, rituximab, and intravenous immunoglobulin (IVIG) may be used for acute autoimmune episodes. Splenectomy was historically performed but is now generally avoided due to the high risk of overwhelming post-splenectomy sepsis in these patients. Regular monitoring for malignancy and autoimmune complications is essential for long-term management.

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

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