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. 1 Molecular Development Section, Laboratory of Immunology, DIR, NIAID, NIH, Bethesda, MD, United States;
  2. 2 Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States;
  3. 3 Laboratory of Clinical Infectious Diseases, NIAID, NIH, Bethesda, MD, United States;
  4. 4 Biostatistics Research Branch, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, United States;
  5. 5 Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, MD, United States;
  6. 6 Clinical Services Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, United States;
  7. 7 Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, MD, United States;
  8. 8 Division of Cancer Epidemiology and Genetics, NCI, Bethesda, MD, United States;
  9. 9 Department of Pediatrics and Institute for Human Genetics, University of California San Francisco, San Francisco, CA, United States;
  10. 10 Hematopathology Section, Laboratory of Pathology, NCI, NIH, Bethesda, MD, United States
  1. * Corresponding author; email: koneti{at}nih.gov

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.

Abstract

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 www.clinicaltrials.gov (identifier: NCT00001350).

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