Blood Journal
Leading the way in experimental and clinical research in hematology

Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations

  1. Susan Price1,
  2. Pamela A. Shaw2,
  3. Amy Seitz3,
  4. Gyan Joshi4,
  5. Joie Davis1,
  6. Julie E. Niemela5,
  7. Katie Perkins6,
  8. Ronald L. Hornung6,
  9. Les Folio7,
  10. Philip S. Rosenberg8,
  11. Jennifer M. Puck9,
  12. Amy P. Hsu3,
  13. Bernice Lo1,
  14. Stefania Pittaluga10,
  15. Elaine S. Jaffe10,
  16. Thomas A. Fleisher5,
  17. V. Koneti Rao1, and
  18. Michael J. Lenardo1
  1. 1Molecular Development Section, Laboratory of Immunology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
  2. 2Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
  3. 3Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD;
  4. 4Biostatistics Research Branch, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD;
  5. 5Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD;
  6. 6Clinical Services Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD;
  7. 7Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD;
  8. 8Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD;
  9. 9Department of Pediatrics and Institute for Human Genetics, University of California at San Francisco, San Francisco, CA; and
  10. 10Hematopathology Section, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD

Key Points

  • Less than 60% of individuals who inherit a FAS mutation have a 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.

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.

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