Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity.

Background: The Canale-Smith syndrome is a childhood disorder characterized by lymphadenopathy and autoimmunity. The similarity between this syndrome and that in mice with the lymphoproliferation (lpr) phenotype or the generalized-lymphoproliferative-disease (gld) phenotype led us to investigate whether it too is caused by mutations of the Fas gene (lpr mice) or the Fas ligand (gld mice), which regulate apoptosis in lymphocytes.

Methods: We studied four patients with the syndrome and their families. T-lymphocyte phenotypes were analyzed, and the susceptibility of activated T cells to Fas-mediated apoptosis in vitro was determined. Mutations of Fas were sought by nucleotide-sequence analysis.

Results: Patients with the Canale-Smith syndrome had increased numbers of circulating double-negative T cells (>20 percent) and profoundly impaired apoptosis of activated T cells incubated with an anti-Fas antibody. Three novel Fas mutations were identified, all of which were heterozygous and predicted to impair signal transduction by Fas. Autoimmune manifestations of the disease, such as hemolytic anemia and thrombocytopenia, persisted into adolescence. Two patients followed into adulthood had intermittent lymphadenopathy, which diminished over time. Neoplasms developed in both, and one died of hepatocellular carcinoma at the age of 43.

Conclusions: Patients with the Canale-Smith syndrome have mutations in Fas, which implicates this gene in the accumulation of lymphocytes and the autoimmunity characteristic of the syndrome.