Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations

Susan Price, Pamela A. Shaw, Amy Seitz, Gyan Joshi, Joie Davis, Julie E. Niemela, Katie Perkins, Ronald L. Hornung, Les Folio, Philip S. Rosenberg, Jennifer M. Puck, Amy P. Hsu, Bernice Lo, Stefania Pittaluga, Elaine S. Jaffe, Thomas A. Fleisher, V. Koneti Rao and Michael J. Lenardo

Key points

  • Less than 60% of individuals who inherit a FAS mutation have clinical manifestation of ALPS implying a high carrier rate.

  • Major causes of morbidity and mortality in ALPS patients are sepsis following splenectomy and development of lymphoma.


The 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" TCRαβ+ T (DNT) 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, 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 two decades. Our principal findings are that FAS mutations have a clinical penetrance of less than 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 post-splenectomy sepsis (OPSI) 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 has been registered at (identifier: NCT00001350).

  • Submitted October 31, 2013.
  • Accepted December 31, 2013.