Features of diagnosis and management of patients with autoimmune lymphoproliferative syndrome caused by somatic defects of the FAS gene

Introduction. Autoimmune lymphoproliferative syndrome (ALPS) is an inborn error of immunity with impaired FAS-mediated apoptosis. The disease responds well to therapy with the mTORC1-inhibitor sirolimus (SRL). The diagnosis of ALPS is based on the European Society for Immunodeficiencies (ESID) diagnostic criteria, which include the main clinical manifestations in combination mainly with an increased level of double-negative T-lymphocytes (DNT) with the CD3+TCRαβ+CD4–CD8–-phenotype. Most cases of ALPS are caused by germinal mutations in the FAS gene, however, somatic changes in this gene (ALPS-sFAS) can be detected in 15–20% of patients. Aim: to analyze the diagnostic features and clinical presentation before and during SRL treatment in patients with ALPS-sFAS. Materials and methods. In our cohort of patients (n = 6), we analyzed main clinical data (clinical presentation, laboratory and instrumental data), the stages of genetic search and response to SRL therapy. We observed an early onset of the disease (median of 1.7 years), with delayed clinical (median of 3.7 years) and genetic (median of 6.2 years) diagnosis. Results. At the initial examination, only 67% of the patients met the ESID criteria. In 50% of cases with DNT levels 9.9%, somatic mutations in the FAS gene were detected in whole blood DNA, in other cases, we analyzed DNA from sorted DNT cells. All of our patients had previously undescribed somatic mutations in the FAS gene. Our experience of SRL treatment in patients with ALPS-sFAS has been more than 10 years. We observed a good clinical response, as well as continued remission of the disease at a reduced dose of SRL (1.5 mg/m2). In 67% of cases, various adverse events were observed when the SRL dose was 1.5 mg/m2. Conclusion. The obtained results demonstrate the complexity of diagnosis and the need for concern regarding ALPS-cFAS, taking into account the effectiveness of pathogenetic therapy, as well as the importance of a personalized approach in molecular genetic verification of the diagnosis.