title: Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations.
abstract: Autoimmune lymphoproliferative syndrome (ALPS) presents in childhood with nonmalignant lymphadenopathy and splenomegaly associated with a characteristic expansion of mature CD4 and CD8 negative or double negative T-cell receptor αβ(+) T lymphocytes. Patients often present with chronic multilineage cytopenias due to autoimmune peripheral destruction and/or splenic sequestration of blood cells and have an increased risk of B-cell lymphoma. Deleterious heterozygous mutations in the FAS gene are the most common cause of this condition, which is termed ALPS-FAS. We report the natural history and pathophysiology of 150 ALPS-FAS patients and 63 healthy mutation-positive relatives evaluated in our institution over the last 2 decades. Our principal findings are that FAS mutations have a clinical penetrance of <60%, elevated serum vitamin B12 is a reliable and accurate biomarker of ALPS-FAS, and the major causes of morbidity and mortality in these patients are the overwhelming postsplenectomy sepsis and development of lymphoma. With longer follow-up, we observed a significantly greater relative risk of lymphoma than previously reported. Avoiding splenectomy while controlling hypersplenism by using corticosteroid-sparing treatments improves the outcome in ALPS-FAS patients. This trial was registered at www.clinicaltrials.gov as #NCT00001350.
authors.affiliation: Molecular Development Section, Laboratory of Immunology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
authors.forename: Susan
authors.initials: S
authors.lastname: Price
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Shaw
authors.forename: Amy
authors.initials: A
authors.lastname: Seitz
authors.forename: Gyan
authors.initials: G
authors.lastname: Joshi
authors.forename: Joie
authors.initials: J
authors.lastname: Davis
authors.forename: Julie E
authors.initials: JE
authors.lastname: Niemela
authors.forename: Katie
authors.initials: K
authors.lastname: Perkins
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hornung
authors.forename: Les
authors.initials: L
authors.lastname: Folio
authors.forename: Philip S
authors.initials: PS
authors.lastname: Rosenberg
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Puck
authors.forename: Amy P
authors.initials: AP
authors.lastname: Hsu
authors.forename: Bernice
authors.initials: B
authors.lastname: Lo
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fleisher
authors.forename: V Koneti
authors.initials: VK
authors.lastname: Rao
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lenardo
mesh_terms: D000293:Adolescent; D000328:Adult; D056735:Autoimmune Lymphoproliferative Syndrome / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D049109:Cell Proliferation; D002648:Child; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008214:Lymphocytes / Q000473:pathology / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019683:Penetrance; D055815:Young Adult; D019014:fas Receptor / Q000235:genetics*
chemical_list: C491901:FAS protein, human; D019014:fas Receptor