Pediatric Immune Dysregulation,Polyendocrinopathy,Enteropathy,X-Linked Syndrome-associated Membranous Nephropathy: 2 Cases Report And Literature Review

Objective: To report patients with immune dysregulation,polyendocrinopathy,enteropathy,X-linked syndrome(IPEX)-associated membranous nephropathy and explore the pathogenesis of membranous nephropathy in IPEX.Methods: The retrospective study analyzed 2 cases of membranous nephropathy caused by IPEX.The clinical manifestations,renal pathologies,and genotypes were summarized in the study.The literature review was searched with " immune dysregulation,polyendocrinopathy,enteropathy,X-linked syndrome,IPEX,IPEX syndrome" as keywords in Pubmedand Chinese databases up to August 2020.Results: Patient 1 was an IPEX patient with T1 DM at age of 4y1 m,without digestive disease and dermatitis.Nephrotic range proteinuria occurred at 5y3 m.Renal biopsy indicated membranous nephropathy(MN)stage II with immunofluorescence negative in PLA2 R and THSD7 A.Immunohistology staining showed positive Ig G4 and C4 d.WES of this case showed a novel missense mutation c.766A>G.Flow cytometry indicated that the number of CD4+CD25+FOXP3+Treg cells was slightly reduced.Patient 2 was an IPEX patient with T1 DM at age of7y5 m.Nephrotic range proteinuria and renal insufficiency occurred at 10y11 m.Renal biopsy showed MN stage II too.WES of this case showed a frameshift mutation c.277 del T.Literature review shows that the most common mutation region of FOXP3 gene mutation is the leucine zipper region(55%,11/20),the most common mutation exon is exon(70%,8/20),and the most common mutation site is c.751-753 del GAG in the LZ domain(30%,6/20).The most frequent clinical manifestation of renal involvement in IPEX is proteinuria(100%,11/11),with at least one of the three classic clinical manifestations.MN is the most common type of renal pathology(59.1%,13/22).The main choice of treatment strategy is oral immunosuppressive agents(61.1%,11/18).The prognosis of renal damage is not bad in patients with early and timely treatment.Among 4 patients who died in the literature review,infection was the main factor,instead of renal failure.Conclusion: This study is the first report of 2 cases of membranous nephropathy caused by IPEX in China.one of them is a novel mutation,and the other is a new phenotype.Based on the summary of renal injury in IPEX patients with pathological biopsy,the most common pathological damage is membranous nephropathy,and the most common clinical manifestation is proteinuria.The complement system is activated in membranous nephropathy caused by IPEX and the mannose-binding lectin pathway may be involved in the pathogenesis of membranous nephropathy caused by IPEX.The clinical manifestations of IPEX are diverse.We recommend that clinicians be aware of IPEX as the primary disease that causes membranous nephropathy when diagnosing membranous nephropathy with other autoimmune diseases.