Using biomarkers to predict the presence of FAS mutations in patients with features of the autoimmune lymphoproliferative syndrome

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

“…In addition, data obtained by evaluating our large ALPS cohort demonstrated that IL-18 is elevated in patients with either germline or somatic FAS mutations compared with controls and undefined ALPS patients. 31 Elevated IL-18 was not confirmed statistically in the current study, perhaps because of the small number of patients in each group. Of note, patients with somatic FAS mutations had slightly lower rates of splenectomy compared with patients with germline FAS mutations.…”

“…Predictive selection of possible patients with somatic FAS mutations can be accomplished from biomarkers, ie, higher DNT levels and increased IL-10, B 12 , and/or sFAS-L levels. 31,34 In addition, we have noted low total and HDL cholesterol in the somatic ALPS patients, another potential marker that may emerge as a useful finding in guiding the decision as to which patients to test for a somatic FAS defect. However, further work needs to be done to confirm this correlate.…”

“…ALPS is a multistep process requiring more than a single genetic hit for clinical expression, 35 and additional factors must contribute to the increased levels of B 12 , IL-10, and sFAS-L observed in ALPS patients but not in mutation-positive healthy relatives. 31 Further efforts to elucidate mechanisms of disease promotion and/or protection in somatic ALPS, such as the reported protective effect of HLA-B44 in germline autosomal dominant ALPS Ia, 36 are needed to provide a better understanding of the factors that contribute to clinical disease. We think that the increased plasma B 12 levels are the result of the lymphoproliferation and appear to be a useful marker of disease; we hypothesize that high levels of IL-10 help drive B-cell proliferation and cause autoimmune cytopenias 5,37 and thus may be a potential therapeutic target.…”

Sequential decisions on FAS sequencing guided by biomarkers in patients with lymphoproliferation and autoimmune cytopenia

“…12 Consequently, as secondary accessory diagnostic criteria for ALPS, these markers have become part of a suggested algorithm for the diagnostic work-up of patients with suspected ALPS. This algorithm recommends FAS germline sequencing in all patients with lymphoproliferation and elevated DNT, while further analysis for somatic FAS mutations depends on the biomarker profile.…”

“…9 Despite these important advances, a number of questions remain unresolved. In the study by Caminha et al at the National Institutes of Health (NIH) 12 , the utility of biomarkers was retrospectively evaluated in a large cohort of ALPS-FAS, ALPS-sFAS, ALPS-U, ALPS-phenotype patients as well as mutation-positive and -negative healthy relatives. It remains to be shown whether prospective analysis of an independent cohort can confirm the high predictive value of the biomarkers.…”