MO1033: Kidney and Bone Marrow Involvement in Ipex Syndrome with Atypical Presentation: the ‘Fil Rouge’ of Treg Between Ipex Features and Other Clinical Entities

Abstract BACKGROUND AND AIMS The transcription factor Forkhead box protein P3 (FOXP3) is central to the function of regulatory T cells (Treg). Mutations in the FOXP3 gene lead to a systemic disease called immune dysregulation, polyendocrinopathy and enteropathy, X-linked syndrome (IPEX). Some FOXP3 mutations were associated with atypical presentation including rare diseases such as IgG4 related disease (IgG4 RD) and autoimmune lymphoproliferative syndrome (ALPS). IgG4 RD is characterized by fibro-inflammatory tissue damage and often by elevated serum IgG4, whereas ALPS is presented by early-onset, chronic, nonmalignant lymphoproliferation, splenomegaly and autoimmune manifestations due to defective lymphocyte apoptosis, due mainly to mutation of genes involved in the apoptosis pathway. Kidney involvement in ALPS is uncommon, whereas in IPEX and IgG4 RD is more frequent, with different renal manifestations. METHOD We reported two atypical cases of IPEX characterized by the kidney and haematologic involvement. These cases are anecdotal for the wide spectrum of possible phenotypes associated with FOXP3 mutations. RESULTS Case 1. A 16-year male with clinical diagnosis of ALPS was treated with an mTOR inhibitor. Due to the onset of proteinuria until 650 mg/day and estimated glomerular filtration rate (eGFR) 66 mL/min, a kidney biopsy was performed and light microscopy showed a membranous pattern. The M-type phospholipase A2 receptor (PLA2R) on serum was negative as well as immunofluorescence (IF) on tissue. IgG-IgG4 immunohistochemical (IHC) staining was negative. We decided to re-evaluate the genetics of the patient, implementing the HPO (Human Phenotype Ontology) code. We found a mutation of the FOXP3 gene (NM_014009.3): c.779T > A (p.L260Q), never reported before on the GnomAD database and predicted to be ‘Likely Pathogenic’ by the suite of variant annotation. The patient does not present the classical triad of IPEX and Treg resulted normal. He was treated with steroids and continues mTOR inhibitor with good control of proteinuria and stable kidney function. Case 2. A 2-year boy was diagnosed with a trilinear bone marrow failure, genetic investigations were negative. He presented elevated serum levels of IgG4 subclass and kidney failure with tubular acidosis. A renal biopsy showed MGP associated with TIN. IF and IHC for PLA2R resulted positive. IHC staining for IgG4 showed overlapping positivity for IgG and IgG4. After the diagnosis of IgG4 RD, steroid thera