FADD Deficiency Mimicking ALPS-FAS: An Expanding Phenotype.

Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is caused due to defects in the Fas-mediated apoptotic pathway. This disease is characterised by chronic non -malignant lymphoproliferation, autoimmune cytopenias and accumulation of double-negative T cells. FAS is the most commonly affected gene observed in patients with ALPS. There is a paucity of data in other ALPS associated genes. Mutations in the FADD gene is extremely rare, and to date, only five patients with a homozygous mutation in exon 2 and one patient with a compound heterozygous mutation are reported. The clinical spectrum of FADD includes neurological dysfunction, recurrent bacterial and viral infections and liver dysfunction. Here we report two patients with novel FADD mutation with clinical phenotype like ALPS-FAS. This article provides an expanding phenotype of FADD deficiency where patients can solely present with lymphoproliferation and autoimmunity without any features of febrile episodes or neurodevelopmental delay. We identified a novel homozygous FADD mutation by targeted Next-generation sequencing (NGS). We performed a comprehensive immune evaluation along with biomarker estimation, mTOR activity on DNTs and apoptosis assay. We describe two siblings born to third-degree consanguineous marriage with homozygous FADD mutation. The index patient P1 presented with lymphoproliferation, autoimmune manifestations in the form of Evans phenotype, lymphocytosis and elevated DNTs, whereas P2 only had mild lymphoproliferation with no autoimmune manifestations. The mutation in our patients lies in exon 2 of the FADD gene, encoding the death domain. The death domain (DD) of FADD protein interacts directly with the death domains of Fas, and mutation at this site disrupts binding to Fas and abolishes apoptosis. FADD deficiency should also be considered in patients presenting with lymphoproliferation and autoimmunity since they can mimic clinical features of ALPS-FAS.