N. Engl. J. Med.

BACKGROUNDImpaired Fas-induced apoptosis of lymphocytes in vitro is a principal feature of the autoimmune lymphoproliferative syndrome (ALPS). We studied six children with ALPS whose lymphocytes had normal sensitivity to Fas-induced apoptosis in vitro.METHODSSusceptibility to Fas-mediated apoptosis and the Fas gene were analyzed in purified subgroups of T cells and other mononuclear cells from six patients with ALPS type III.RESULTSHeterozygous dominant Fas mutations were detected in the polyclonal double-negative T cells from all six patients. In two patients, these mutations were found in a fraction of CD4+ and CD8+ T cells, monocytes, and CD34+ hematopoietic precursors, but not in hair or mucosal epithelial cells.CONCLUSIONSSomatic heterozygous mutations of Fas can cause a sporadic form of ALPS by allowing lymphoid precursors to resist the normal process of cell death.Copyright 2004 Massachusetts Medical Society