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Title: Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations.
Authors: Price S,  Shaw PA,  Seitz A,  Joshi G,  Davis J,  Niemela JE,  Perkins K,  Hornung RL,  Folio L,  Rosenberg PS,  Puck JM,  Hsu AP,  Lo B,  Pittaluga S,  Jaffe ES,  Fleisher TA,  Rao VK,  Lenardo MJ
Journal: Blood
Date: 2014 Mar 27
Branches: BB
PubMed ID: 24398331
PMC ID: PMC3968385
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.