Diagnostic and Treatment Challenges in a Pediatric Patient with Progressive Refractory ALPS-like Disease

Abstract

Introduction: Diagnostic criteria for Autoimmune Lymphoproliferative Syndrome (ALPS) is based on clinical, laboratory and genetic findings. The underlying pathomechanisms are largely related to defects in the lymphocyte apoptosis pathways (FAS, FAS ligand, or CASP10) but other combined immunodeficiencies may also present with ALPS-like features (e.g. CASP8, NFKB1, CTLA4, ALP1). Clinically, patients often present with progressive autoimmune cytopenias and treatment relies on T cell immune modulation. Hereby, we present diagnostic and treatment challenges in a pediatric patient with ALPS-like phenotype with rapid decline during an episode of severe autoimmune hemolytic anemia. MethodsRetrospective chart review for clinical and laboratory data. Deep immune phenotyping was obtained for T, B and NK cells subsets at several timepoints during the acute illness. Genetic evaluation for both germline and somatic mutations were pursued.Case presentation: Patient is an 11-year-old Syrian male of consanguineous parents who presented at age 6 with immune thrombocytopenic purpura (ITP) and met criteria for ALPS with required criteria (chronic lymphadenopathy and increased T Cell Receptor αβ CD4-CD8- double negative T cells (TCRαβDNT) (4.2%, normal <2%), primary accessory criteria (defective lymphocyte apoptosis twice) and secondary accessory criteria (elevated B12, IgG and FAS-L). Panel sequencing (207 genes of inborn errors of immunity) and later Whole Exome Sequencing were both unrevealing. At 11 years of age, he was admitted with a Coombs positive severe autoimmune hemolytic anemia (hemoglobin of 3.5) that was complicated by EBV and parvovirus viremia, and aplastic anemia. Treatment course was complex including steroid, high dose IvIg, rituximab, sirolimus, mycophenolate mofetil, eculizumab, and epoetin alpha. Biomarkers of immune dysregulation, such as TCRαβDNT, follicular helper T cells and CD19hiCD21lo B cells were monitored closely and improved on therapy. Total T cell, CD4, CD8, and Treg populations were all initially low but returned to baseline following combined treatment. Screening for somatic mutations and whole genome sequencing is ongoing. Discussion/ConclusionOur case highlights the diagnostic and treatment challenges in a pediatric patient with ALPS-like Disease. Cellular biomarkers may guide therapy if autoimmune cytopenia recurs. Somatic and germline testing is needed to understand the underpinning of this disorder and may further guide treatment strategies.