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Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations

  • Author(s): 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
  • et al.
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.

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