autoimmune lymphoproliferative syndrome

Autoimmune lymphoproliferative syndrome (ALPS) is an immune dysregulation disorder in which certain white blood cells grow or survive longer than they should, leading to enlarged lymph nodes, an enlarged spleen, and a tendency toward autoimmune blood problems. Variants in several genes that regulate programmed cell death and immune checkpoints—including CTLA4, PRKCD, FAS, FASLG, CASP8, CASP10, KRAS, and NRAS—have been linked to the condition, but the exact inheritance pattern can differ from family to family. Because these immune cells remain active, individuals also carry a lifelong increased risk of developing Hodgkin and non-Hodgkin lymphoma. Precise population frequency figures are not available, and cases are considered uncommon worldwide. ALPS can be diagnosed at any age and affects people of all sexes.

ALPS primarily involves the lymphatic and hematologic systems. The most consistent features are persistent, non-infectious swelling of lymph nodes and enlargement of the spleen, which are reported in most individuals. Autoimmune destruction of blood cells is also common and can present as anemia, low platelet counts causing easy bruising or bleeding, and episodes of low neutrophil counts that increase infection risk. Over time, many patients exhibit high numbers of so-called double-negative T cells, elevated immunoglobulin levels, and other laboratory signs of immune overactivity. Less frequently, people may experience skin rashes such as urticaria, vasculitis, or high eosinophil counts. Severity and symptoms vary widely between individuals, and not all affected people experience every feature.

Research has identified pathogenic variants in several genes involved in the Fas-mediated apoptosis pathway (FAS, FASLG, CASP8, CASP10) as well as immune checkpoint or signaling genes (CTLA4, PRKCD, KRAS, NRAS) as underlying causes of ALPS. These genes help control how immune cells grow, die, or become activated. When the pathway is disrupted, immune cells that should normally self-destruct can accumulate and attack the body’s own tissues. Because multiple genes are implicated, inheritance patterns can differ between families and may be autosomal dominant, autosomal recessive, or arise as new (de novo) variants. Determining the exact pattern for a given family requires molecular testing of the specific gene involved. Genetic counseling is recommended for families to understand individual recurrence risks and testing options.

Currently, management focuses on supportive care and controlling immune-related complications. Acute episodes of autoimmune hemolytic anemia or thrombocytopenia are typically treated with immune-modulating therapies directed by a hematology or immunology specialist. Long-term management includes regular surveillance for cytopenias, organ enlargement, and early signs of lymphoma. A multidisciplinary care team—often including immunology, hematology-oncology, and primary care providers—helps coordinate monitoring schedules and individualized treatment plans. Patients should discuss all therapy options, including potential participation in clinical trials, with their healthcare team.

Outcomes for ALPS are diverse and depend on the frequency of autoimmune episodes, response to immune-modulating therapies, and the development of lymphoma. Many individuals lead active lives with appropriate monitoring and timely treatment of complications. Lifelong follow-up is essential because lymphoma can arise at any age, although not everyone with ALPS will develop cancer. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialists familiar with ALPS and to seek genetic counseling for personalized guidance and family planning.

ALPS is an active research area, with numerous ongoing clinical trials investigating targeted immune therapies and novel treatment strategies. Individuals who are interested in research participation can search ClinicalTrials.gov or consult their care team about eligibility and potential benefits.