Autoimmune Lymphoproliferative Syndrome (Alps) Disease and Alps Phenotype: Are They Two Distinct Entities?

Abstract Introduction Autoimmune Lymphoprolypherative Syndrome (ALPS) is an inherited disorder of lymphocyte homeostasis classically due to mutation of FAS, FASL, and CASP10 genes (ALPSFAS/CASP10). In spite of recent progress, about one third of ALPS patients does not carry classical mutations and still remains gene orphan (ALPS-U, undetermined genetic defects). Objective The aims of the present study were to compare the clinical and immunological features of ALPSFAS/CASP10 vs those of ALPS-U affected subjects and to deepen the genetic characteristics of this latter group. Methods Demographical, anamnestic, biochemical data were retrieved from medical record of 42 ALPS subjects. An enlarged panel of genes (Next Generation Sequencing) was applied to the ALPS-U group. Results ALPS-U subjects showed a more complex phenotype if compared to ALPSFAS/CASP10 group, characterized by multi-organ involvement (p=0.001) and positivity of autoimmune markers (p= 0.02). Multilineage cytopenia was present in both groups without differences with the exception of lymphocytopenia and autoimmune neutropenia that were more frequent in ALPS-U than in ALPS-FAS/CASP10 group (p=0.01 and p=0.04). First and second line treatments were able to control the symptoms in 100% of the ALPSFAS/CASP10 patients, while 63% of ALPS-U needed more than two lines of treatment and remission in some cases was obtained only after target therapy. In the ALPS-U group, we found in 14/28 (50%) patients 19 variants; of these 4/19 (21%) were known as pathogenic, 8/19 (42%) as likely pathogenic. A characteristic flow cytometry panel including CD3CD4-CD8-+TCRαβ+, CD3+CD25+/CD3HLADR+, TCR αβ + B220+ and CD19+CD27+ identified the ALPS FAS/CASP10 group.