Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations.

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.

• Authors: 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
• Journal: Blood (Blood) Vol. 123 Issue 13 Pg. 1989-99 (Mar 27 2014) ISSN: 1528-0020 [Electronic] United States
• PMID: 24398331 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• FAS protein, human
• fas Receptor

Topics

• Adolescent
• Adult
• Autoimmune Lymphoproliferative Syndrome (genetics, pathology, therapy)
• Cell Proliferation
• Child
• Disease Progression
• Female
• Follow-Up Studies
• Humans
• Lymphocytes (pathology, physiology)
• Male
• Middle Aged
• Mutation
• Penetrance
• Young Adult
• fas Receptor (genetics)