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.

Figure 1

Signal transduction by the FAS receptor whose gene is mutated in ALPS as detailed in the Introduction. (A) Schematic of the signaling complex formed after the engagement of FAS by FAS ligand that leads to apoptosis. Shown at the top left is an example of a mutant FAS receptor chain lacking the death domain bound to a wild-type chain through the PLAD, which prevents it from signaling causing dominant interference. (B) Diagram showing the intron-exon structure of the FAS gene with delineation of exons coding for the extracellular, transmembrane, and intracellular portions of the protein incorporating the death domain and the location and types of mutations associated with ALPS-FAS. It is notable that R250 in the α2 helical region of the death domain is the most frequently altered residue and exhibits haploinsufficiency due to reduced Fas surface expression, as well as dominant interference.^,

Figure 2

Kaplan-Meier curve for lymphoma risk in ALPS-FAS (N = 150). Dashed lines show the 95% confidence bands. Total numbers are not censored and numbers of patients still at risk are shown below x-axis.

Figure 3

Splenectomy is a common intervention that leads to sepsis but does not prevent cytopenias. (A) Kaplan-Meier curve for time to splenectomy by severity classification (N = 150). Dashed lines show the 95% confidence bands. (B) Kaplan-Meier curve for time until first occurrence of cytopenia after splenectomy. Time to first cytopenia of any kind is shown, and time until first occurrence of anemia, neutropenia, and thrombocytopenia are shown. (C) Kaplan-Meier curve for sepsis-free survival after splenectomy (N = 66). Dashed lines show the 95% confidence bands. Total numbers are not censored and still at risk are shown below x-axis.

Figure 4

Causes and consequences of splenectomy in ALPS-FAS. Outcomes for all 66 patients undergoing splenectomy are shown. Note that each blue bar represents the timeline of events in 1 patient’s lifetime, and all the bars are stacked from the oldest at the bottom to the youngest patient in the cohort at the top. All 6 deaths due to sepsis were seen in patients who underwent splenectomy at a younger age (<10 years).

Figure 5

Kaplan-Meier curve for overall survival (N = 150). Dashed lines show the 95% confidence bands. Total number alive and not censored are shown below x-axis.