MO1033: Kidney and Bone Marrow Involvement in Ipex Syndrome with Atypical Presentation: the ‘Fil Rouge’ of Treg Between Ipex Features and Other Clinical Entities
Authors: La Porta Edoardo , Gentile Micaela , Marco Ghiggeri Gian , Angeletti Andrea , Caridi Gianluca , Fiaccadori Enrico , Eugenio Verrina Enrico 
Published: May 2022

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 &gt; 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 therapy was started, without clinical response. Thereafter the patient underwent a bone marrow transplant from his brother (HLA-identical). In consideration of the rarity of IgG4 RD in children, we decided to perform a new genetic exam. A whole-exome sequencing on the proband and relatives was done. A hemizygous mutation of the FOXP3 gene (NM_014009.3), c.1087A &gt; G (p.I363V), was found. This variant, inherited by the mother and found also in the proband's brother, was already described in the literature, thus a diagnosis of IPEX was done. Therefore, Treg resulted normal for brother and mother but not in our patient (0.3%). The patient underwent kidney transplantation, and after 1 year he presents normal kidney function.

CONCLUSION
MGP and IgG4 RD are rare in paediatrics, and they encouraged us to perform further investigations and reconsider the previous diagnosis. MGP pathogenesis in IPEX is consistent with recent evidence of unbalance of Th17/Treg in idiopathic MGP, with a significant reduction of Treg cell and FOXP3 expression. Th17/Treg may be implicated also in the pathogenesis of IgG4 RD as sources of cytokines production responsible for fibrosis and IgG4-producing B cells. FOXP3 + Treg and FAS-ligand are crucial for autoimmunity and self-tolerance. In ALPS patients a reduced expression of FOXP3 + Treg subsets but with the normal suppressive function was found. IPEX poses a diagnostic challenge considering the spectrum of different phenotypes, but to recognize kidney involvement, together with the growing use of wide genomic analysis, could play a central role.