Clinical Information

Autoimmune lymphoproliferative syndrome (ALPS) is a complex clinical disorder of dysregulated lymphocyte homeostasis characterized by chronic nonmalignant lymphoproliferative disease, splenomegaly, lymphadenopathy, and autoimmunity (mainly autoimmune cytopenias), with an increased susceptibility to lymphomas. Typically, ALPS is diagnosed by childhood or young adulthood. Lymphoproliferation and autoimmunity are usually the first presentations. Lymphomas (Hodgkin and non-Hodgkin) can occur at any age but are usually late complications. ALPS is reported worldwide in various racial and ethnic backgrounds but affects more men than women (approximately 2.2 affected men per 1.6 affected women).

Laboratory investigations showed that ALPS patients have an increase in a normally rare population of T cells (typically <1%) that are alpha beta T-cell receptor-positive, as well as negative for both CD4 and CD8 coreceptors (double-negative T cells). In addition, there are elevated peripheral blood interleukin (IL)-10, IL-18, vitamin B12, and soluble FAS ligand (FASL) levels. Defective FAS-mediated apoptosis on in vitro assays is another main characteristic of ALPS.

Genetic defects in the apoptosis (programmed cell death) pathway have been determined for most cases of ALPS. Apoptosis plays a role in normal immune homeostasis by limiting lymphocyte accumulation and autoimmune reactivity. The interaction of the surface receptor CD95 (FAS) and its ligand (FASL or CD95L) triggers the apoptotic pathway in lymphocytes. Germline variants in CD95 (FAS) are the most common cause (60%-75%) of ALPS (ALPS-FAS), followed by somatic mutations in CD95 (ALPS-sFAS). Variants in CD95L (ALPS-FASL), CASP10 (ALPS-CAS10), and others are rare causes. Currently, up to 20% of patients do not have an identifiable genetic variant (ALPS-U).

All these forms present with the main clinical features of ALPS, but there are differences in the results of laboratory tests used to evaluate ALPS patients. Genotype-phenotype correlations are noted in ALPS-FAS, which is the only form common enough for these studies. Both mono- and bi-allelic variants in FAS can cause disease. Dominant negative, haploinsufficient mechanisms are invoked to explain the disease mechanism. It appears that biallelic disease-causing FAS variants cause a more severe clinical phenotype than the monoallelic forms. Lymphomas are mostly associated with disease-causing variants in the intracellular domain of FAS. Penetrance of the clinical phenotype is reduced and varies based on the location and type of causative variant (30%-90%).

The latest diagnostic criteria for ALPS were published in 2010.(1) A definitive diagnosis is based on the presence of both required criteria and one primary accessory criterion. A probable diagnosis is based on the presence of both required criteria plus one secondary accessory criterion.

Several other diseases can present with an ALPS-like phenotype, including other inborn errors of immunity, like CTLA4 deficiency (also known as CTLA4 haploinsufficiency or CTLA4 haploinsufficiency with autoimmune infiltration [CHAI]) and LRBA (lipopolysaccharide-responsive and beige-like anchor protein) deficiency, gain-of-function variants in STAT3 and CARD11 genes, as well as conditions like Evans syndrome (a combination of autoimmune hemolytic anemia and autoimmune thrombocytopenic purpura) and malignant conditions like Hodgkin disease and large granular lymphocyte leukemias. Genes associated with several ALPS-like disorders are also included on this panel.