Autoimmune Lymphoproliferative Syndrome (ALPS)

Pathogenesis

• Autoimmune lymphoproliferative syndrome (ALPS), also known as Canale-Smith syndrome, primarily arises from an underlying disorder of abnormal lymphocyte apoptosis.
• The genetic deficit in the vast majority of patients is a germline or somatic pathogenic variant in the FAS gene, which produces a cell surface receptor belonging to the tumor necrosis factor (TNF) receptor superfamily (TNFRSF6).
• Under normal physiologic conditions, the stimulation of the FAS receptor by its ligand produces programmed cell death (apoptosis) to safely clear activated lymphocytes.
• Due to the FAS variant, there is persistent survival of these lymphocytes, which subsequently leads to severe immune dysregulation and autoimmunity.
• Less commonly, ALPS can be caused by pathogenic variants in other genes within the Fas pathway, specifically FASLG and CASP10.
• The failure of lymphocyte apoptosis directly leads to the accumulation of characteristic polyclonal populations of T cells, specifically termed double-negative T cells (DNT cells).
• These DNT cells characteristically express CD3 and alpha/beta antigen receptors but distinctly lack both CD4 and CD8 co-receptors (CD3+ TCR $\alpha$/$\beta$+, CD4−CD8−).
• Pathologically, these double-negative T cells respond poorly to antigens or mitogens and fail to produce vital growth or survival factors, such as interleukin-2 (IL-2).

Clinical Features

• The disease usually presents in the first year of life, with the vast majority of patients becoming highly symptomatic by 5 years of age.
• A cardinal clinical feature of ALPS is chronic, persistent, or recurrent lymphadenopathy, which can be striking in presentation.
• Massive splenomegaly is consistently observed and may produce hypersplenism; hepatomegaly is additionally present in approximately 50% of patients.
• While the lymphoproliferative process (lymphadenopathy and splenomegaly) may regress over time, the associated autoimmunity typically does not regress and is characterized by frequent exacerbations and recurrences.
• Autoimmunity frequently targets hematopoietic cells, producing multilineage cytopenias such as Coombs-positive autoimmune hemolytic anemia, immune thrombocytopenia, or mild autoimmune neutropenia.
• ALPS is a recognized cause of Evans syndrome, which is the concurrent presentation of immune thrombocytopenia and autoimmune hemolytic anemia.
• Other diverse autoimmune manifestations can occur, including urticaria, uveitis, glomerulonephritis, hepatitis, vasculitis, panniculitis, arthritis, premature ovarian failure, thyroiditis, myocarditis, pancreatitis, and central nervous system involvement (e.g., seizures, headaches, encephalopathy, transverse myelitis, Guillain-Barré syndrome, and ataxia).
• Patients harbor a lifelong, significantly elevated risk for the development of malignancies, particularly Hodgkin and non-Hodgkin lymphomas, as well as solid-tissue tumors of the thyroid, skin, heart, or lung.

Diagnostic Criteria

• The diagnosis of ALPS relies on a revised set of diagnostic criteria divided into required, primary accessory, and secondary accessory criteria.
• Required Criteria (both must be present):
• 1. The presence of chronic (>6 months), nonmalignant, noninfectious lymphadenopathy, splenomegaly, or both.
• 2. Elevated CD3+ TCR$\alpha$$\beta$+ CD4- CD8- DNT cells ($\ge$1.5% of total lymphocytes or 2.5% of CD3+ lymphocytes) in the setting of normal or elevated lymphocyte counts.
• Primary Accessory Criteria:
• 1. Demonstration of defective lymphocyte apoptosis (in two separate assays).
• 2. Identification of a somatic or germline pathogenic mutation in FAS, FASLG, or CASP10.
• Secondary Accessory Criteria:
• 1. Elevated plasma sFasL levels (>200 pg/mL) OR elevated plasma interleukin-10 levels (>20 pg/mL) OR elevated serum or plasma vitamin B12 levels (>1500 ng/L) OR elevated plasma interleukin-18 levels >500 pg/mL.
• 2. Typical immunohistologic findings as reviewed by an experienced hematopathologist.
• 3. The presence of autoimmune cytopenias (hemolytic anemia, thrombocytopenia, or neutropenia) AND elevated immunoglobulin G levels (polyclonal hypergammaglobulinemia).
• 4. A family history of a nonmalignant/noninfectious lymphoproliferation with or without autoimmunity.
• Diagnostic Confirmation: A definitive diagnosis is established by the presence of both required criteria plus one primary accessory criterion. A probable diagnosis is established by the presence of both required criteria plus one secondary accessory criterion.