629 unexplained including some patients clas- sified as having the Canale-Smith syn- drome. 4,9,10 The failure of lymphocytes to die is thought to underlie their clinical ac- cumulation in patients with ALPS, and the persistence of autoreactive lymphocytes is hypothesized to predispose these individu- als to autoimmune complications. Clinical and laboratory data suggest a possibly complex mode of inheritance, which we hypothesize could involve dominant inher- itance with incomplete penetrance for most, 1,4,6 but not all, 2,5 ALPS cases. Fas gene mutations in unrelated kindreds dif- fer, consistent with a spectrum of manifes- tations caused by variable degrees of im- pairment of Fas expression or function. For more than 25 years 1 of us has moni- tored members of a kindred containing 11 individuals of 4 generations in whom a unique Fas mutation has now been docu- mented. This large ALPS pedigree makes possible definitive correlation of a particu- lar Fas mutation with a range of pheno- types and provides long-term prognostic information. METHODS Case Definition For this study ALPS was defined as a disorder of lymphocyte apoptosis that includes chronic, nonmalignant lym- phadenopathy and splenomegaly, along with an increased proportion of T lym- phocytes that express α/β T-cell recep- tors (α/β + ) but neither CD4 nor CD8 Autoimmune lymphoproliferative syn- drome is characterized by lymphadenopa- thy, splenomegaly, and autoimmunity present from early childhood. 1-6 ALPS has been found to be caused, most often, by inherited mutations in the gene encod- ing the cell surface receptor Fas (also known as APO-1 and CD95). 7 Activated lymphocytes express Fas. Their elimina- T The clinical spectrum in a large kindred with autoimmune lymphoproliferative syndrome caused by a Fas mutation that impairs lymphocyte apoptosis Anthony J. Infante, MD, PhD, Howard A. Britton, MD, Thomas DeNapoli, MD, Lindsay A. Middelton, RN, Michael J. Lenardo, MD, Christine E. Jackson, PhD, Jin Wang, PhD, Thomas Fleisher, MD, Stephen E. Straus, MD, and Jennifer M. Puck, MD tion by apoptosis (programmed cell death) on engagement between Fas and its spe- cific ligand (Fas ligand or FasL) is a major physiologic regulatory mechanism for avoiding lymphocyte overexpansion and preserving lymphocyte homeostasis. 8 Deleterious Fas gene mutations have been found in patients in whom lymphoprolif- eration and autoimmunity were previously From the Department of Pediatrics, University of Texas Health Science Center at San Antonio and the Department of Pathology, Santa Rosa Children’s Hospital, San Antonio, Texas; the Genetics and Molecular Biology Branch, National Human Genome Research Institute; the Laboratory of Immunology and Laboratory of Clinical Investigation, National In- stitute of Allergy and Infectious Diseases; and Warren Grant Magnussen Clinical Center, National Institutes of Health, Bethesda, Maryland. Submitted for publication Dec 31, 1997; revisions received Apr 2, 1998, June 1, 1998, and Aug 6, 1998; ac- cepted Aug 13, 1998. Reprint requests: Anthony J Infante, MD, PhD, Department of Pediatrics, University of Texas Health Sci- ence Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78284-7810. Copyright © 1998 by Mosby, Inc. 0022-3476/98/$5.00 + 0 9/21/93770 ALPS Autoimmune lymphoproliferative syndrome Autoimmune lymphoproliferative syndrome (ALPS) is characterized by chron- ic, histologically benign splenomegaly and generalized lymphadenopathy, hy- pergammaglobulinemia, and autoantibody formation. ALPS has been attributed to defective programmed cell death of lymphocytes, most often arising as a re- sult of mutations in the gene encoding the lymphocyte apoptosis receptor Fas/APO-l/CD95. We identified a novel mutation in the intracellular apoptosis signaling domain of Fas in 11 members of a family, individual members of which have been monitored for up to 25 years, with 1 or more features of ALPS. This study of a large number of family members carrying the same Fas defect demonstrates that ALPS is inherited in an autosomal dominant fashion but with a high degree of variability in clinical expression. Although 1 affected individual died of postsplenectomy sepsis and 1 has been treated for lymphoma, the Fas mutation in this family has been compatible with a healthy adulthood, as clinical features of ALPS have receded with increasing age. (J Pediatr 1998;133:629-33)