Lymphoproliferative syndrome with autoimmunity: A possible genetic basis for dominant expression of the clinical manifestations

Fas (CD95/Apo-1) mutations were previously reported as the genetic defect r esponsible for human lymphoproliferative syndrome associated with autoimmun e manifestations (also known as autoimmune lymphoproliferative syndrome or Canale-Smith syndrome). We have identified 14 new heterozygous Fas mutation s. Analysis of patients and families allow us to further dissect this syndr ome with regards to the relationship between Fas mutations, inheritance pat tern, and phenotype as observed on long-term follow-up. In vitro studies sh ow that lymphocytes from all Fas mutant carriers exhibit a Fas-antibody-ind uced apoptosis defect. However, among the 8 inherited mutations, 4 of 4 Fas missense mutations were associated with high clinical penetrance, whereas 3 of 4 mutations leading to a truncated pas product were associated with va riable clinical penetrance. This suggests that a second defect, in another yet undefined factor involved in apoptosis and/or lymphoproliferation contr ol, is necessary to induce full clinical expression of the disease. These r esults also indicate that the currently available antibody-mediated in vitr o apoptosis assay does not necessarily reflect the in vivo ability of abnor mal Fas molecules to trigger lymphocyte death. In addition, we found that l ymphoproliferative manifestations resolved with age, whereas immunological disorders [ie, hypergammaglobulinemia and detection of TcR alpha beta(+) CD 4(-) CD8(-) lymphocytes] persisted. This observation suggests that Fas-medi ated apoptosis plays a more important role in lymphocyte homeostasis in ear ly childhood than later on in life. (C) 1999 by The American Society of Hem atology.