Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations

Abstract

• Less than 60% of individuals who inherit a FAS mutation have a clinical manifestation of ALPS, implying a high carrier rate.• Major causes of morbidity and mortality in ALPS patients are sepsis following splenectomy and development of lymphoma.Autoimmune lymphoproliferative syndrome (ALPS) presents in childhood with nonmalignant lymphadenopathy and splenomegaly associated with a characteristic expansion of mature CD4 and CD8 negative or double negative T-cell receptor ab 1 T lymphocytes.Patients often present with chronic multilineage cytopenias due to autoimmune peripheral destruction and/or splenic sequestration of blood cells and have an increased risk of B-cell lymphoma. Deleterious heterozygous mutations in the FAS gene are the most common cause of this condition, which is termed ALPS-FAS. We report the natural history and pathophysiology of 150 ALPS-FAS patients and 63 healthy mutation-positive relatives evaluated in our institution over the last 2 decades. Our principal findings are that FAS mutations have a clinical penetrance of <60%, elevated serum vitamin B 12 is a reliable and accurate biomarker of ALPS-FAS, and the major causes of morbidity and mortality in these patients are the overwhelming postsplenectomy sepsis and development of lymphoma.With longer follow-up, we observed a significantly greater relative risk of lymphoma than previously reported. Avoiding splenectomy while controlling hypersplenism by using corticosteroid-sparing treatments improves the outcome in ALPS-FAS patients. This trial was registered at www.clinicaltrials.gov as

Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment

“…In the future, other novel substances for use in antibody-mediated cytopenias may include the proteasome inhibitor bortezomib, the anti-B-cell-activating factor antibody belimumab, the anti-IL-6-directed antibody tocilizumab, the anti-CD22 antibody epratuzumab, and an anti-APRIL antibody, which are currently used only within phase 1 to 3 clinical trials against refractory autoimmunity in certain indications such as in subgroups of patients with SLE, multiple sclerosis, other severe autoimmune diseases, in antibody-mediated graft rejection, or as a treatment adjunct in certain B-cell malignancies. [90][91][92] The recommendation to avoid splenectomy, which is still one of the widely accepted (and likely least expensive) options for treating hypersplenismassociated thrombocytopenia associated with the risk of overwhelming post-splenectomy infection, is increasingly confirmed and corroborated by long-term follow-up data (eg, from ALPS patients in Price et al 15 ). In conclusion, this review provides a conceptual description of known and novel observations of cytopenias in PID and their management.…”

“…15,16 In addition to these two entities, overlapping syndromes have been reported between CVID and ALPS (with ALPS-linked increased T-cell receptor a/b-positive CD4 17 One of the novel PIDs in this subgroup of autoantibody-mediated cytopenia is lipopolysaccharide-responsive beige-like anchor deficiency, a rare B-cell defect involving autophagy and apoptosis that, along with immune cytopenia, is often linked to inflammatory bowel disease, multiorgan autoimmune phenomena, severe infections, and hypogammaglobulinemia [18][19][20] [Markus G. Seidel, Tatjana Hirschmugl, Wolfgang Schwinger, Laura Gamez-Diaz, Nina Serwas, Andrea Deutschmann, Gregor Gorkiewicz, Werner Zenz, Christian Windpassinger, Bodo Grimbacher, Christian Urban, and Kaan Boztug; manuscript submitted July 2014]. Although the pathomechanism of this novel disease is incompletely understood, in vitro and in vivo immunologic analyses and human clinical data point toward a B-cell intrinsic defect in lipopolysaccharide-responsive beige-like anchor deficiency.…”

Sirolimus is effective in relapsed/refractory autoimmune cytopenias: results of a prospective multi-institutional trial

“…8, 10 The risk has been noted to be even higher in patients with ALPS because they For personal use only. on May 13, 2018.…”

“…Rarely, ALPS patients have mutations in FASL (,1%) and CASP10 (2% to 3%). 9,10 Approximately one-third of patients with ALPS have yet undetermined genetic defects (ALPS-U). 11 Treatment of patients with ALPS varies significantly, with no consensus on the management.…”

The Evolving Landscape of Primary Immunodeficiencies

“…Heterozygous mutations in FAS are a cause of autoimmune lymphoproliferative syndrome, but penetrance is incomplete, with affected and non-affected family members in the same kindred [2]. Heterozygous mutations in TACI are associated with IgA deficiency and with common variable immunodeficiency.…”