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, Michael J. Lenardo

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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.

Original languageEnglish
Pages (from-to)1989-1999
Number of pages11
JournalBlood
Volume123
Issue number13
DOIs
Publication statusPublished - 27 Mar 2014

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Price, S., Shaw, P. A., Seitz, A., Joshi, G., Davis, J., Niemela, J. E., Perkins, K., Hornung, R. L., Folio, L., Rosenberg, P. S., Puck, J. M., Hsu, A. P., Lo, B., Pittaluga, S., Jaffe, E. S., Fleisher, T. A., Rao, V. K., & Lenardo, M. J. (2014). Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood, 123(13), 1989-1999. https://doi.org/10.1182/blood-2013-10-535393