Somatic FAS mutations are common in patients with genetically undefined autoimmune lymphoproliferative syndrome

Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by childhood onset of lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias, elevated numbers of double-negative T (DNT) cells, and increased risk of lymphoma. Most cases of ALPS are associated with germline mutations of the FAS gene (type Ia), whereas some cases have been noted to have a somatic mutation of FAS primarily in their DNT cells. We sought to determine the proportion of patients with somatic FAS mutations among a group of our ALPS patients with no detectable germline mutation and to further characterize them. We found more than one-third (12 of 31) of the patients tested had somatic FAS mutations, primarily involving the intracellular domain of FAS resulting in loss of normal FAS signaling. Similar to ALPS type Ia patients, the somatic ALPS patients had increased DNT cell numbers and elevated levels of serum vitamin B(12), interleukin-10, and sFAS-L. These data support testing for somatic FAS mutations in DNT cells from ALPS patients with no detectable germline mutation and a similar clinical and laboratory phenotype to that of ALPS type Ia. These findings also highlight the potential role for somatic mutations in the pathogenesis of nonmalignant and/or autoimmune hematologic conditions in adults and children.

Figure 1

Elevated IL-10, vitamin B₁₂, and sFAS-L associated with FAS mutations. (A) IL-10 levels were determined from plasma samples by ELISA. Dashed line indicates upper normal limit at 20 pg/mL. (B) Vitamin B₁₂ plasma levels were determined by the National Institutes of Health Clinical Center laboratory. Dashed line indicates upper normal limit at 1000 pg/L. Upper limit of assay was 4000 pg/L. Results greater than 4000 pg/L were made to equal 4000 pg/L for analysis. (C) Soluble FAS-L levels were determined from plasma samples by ELISA. Dashed line indicates upper normal limit at 200 pg/mL. Long horizontal bars represent means; short horizontal bars, SE. *P < .05, **P < .01, compared with somatic or type Ia patients.