Introduction:
Autoimmune lymphoproliferative syndrome (ALPS) is caused by a disruption of the apoptotic pathways that down-regulate lymphocyte activity.1-2 Patients present with lymphadenopathy, splenomegaly, autoimmunity, and characteristic laboratory markers including CD3 positive, but CD4 and CD8 negative T-cells, known as double-negative T-cells (DNTs).3 Additional biomarkers include elevated levels of B12, IgG, IL-10, IL-18, and soluble FAS ligand.4 The severity of disease is widely variable, with symptoms often presenting in childhood and following a relapsing/remitting pattern.5 While the lymphocyte proliferation is typically polyclonal and benign, patients with ALPS are also at increased risk of developing lymphoma, with incidence of Hodgkin lymphoma over 100 times greater than in the general population.6
Many genetic mutations have been identified in patients with ALPS, most commonly affecting the FAS receptor, its ligand, or caspases 8 and 10, which are downstream in the apoptosis pathway.7-8 Of note, many healthy family members of patients with ALPS have been found to have similar mutations, suggesting variable penetrance or the need for a “two-hit” process to induce clinical symptoms.6 We present a patient with clinical features of ALPS and evidence of FAS dysfunction who was found to have a genetic variant of unknown significance in the FAS gene. Given our patient’s phenotype and laboratory findings, we posit that this mutation is likely pathogenic and causative of ALPS.