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.