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Abstract：
The Forkhead box protein P3 (FOXP3) is a transcription factor 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, an X-linked syndrome (IPEX) characterized by the triad of early-onset intractable diarrhea, type 1 diabetes, and eczema. An atypical presentation of IPEX has been reported.
We report rare cases with equivocal clinical associations that included inflammatory, kidney, and hematologic involvements screened with massively parallel sequencing techniques.
Two patients with hemizygous mutations of FOXP3 [c.779T>A (p.L260Q)] and [c.1087A>G (p.I363V)] presented clinical manifestations not included in typical cases of IPEX: one was a 16-year-old male patient with an initial clinical diagnosis of autoimmune lymphoproliferative syndrome (ALPS) and who developed proteinuria and decreased kidney function due to membranous nephropathy, an autoimmune renal condition characterized by glomerular sub-epithelial antibodies. The second patient was a 2-year-old child with bone marrow failure who developed the same glomerular lesions of membranous nephropathy and received a bone marrow transplantation. High levels of IgG4 in serum, bone marrow, and kidney led to the definition of IgG4-related kidney disease (IgG4 RKD) in this young boy. The circulating Treg levels were normal in the former case and very low in the second.
Two atypical associations of functional mutations of FOXP3 that include ALPS and IgG4 RKD are described. Membranous nephropathy leading to renal failure completed in both cases the clinical phenotypes that should be included in the clinical panorama of FOXP3 failure.
We report rare cases with equivocal clinical associations that included inflammatory, kidney, and hematologic involvements screened with massively parallel sequencing techniques.
Two patients with hemizygous mutations of FOXP3 [c.779T>A (p.L260Q)] and [c.1087A>G (p.I363V)] presented clinical manifestations not included in typical cases of IPEX: one was a 16-year-old male patient with an initial clinical diagnosis of autoimmune lymphoproliferative syndrome (ALPS) and who developed proteinuria and decreased kidney function due to membranous nephropathy, an autoimmune renal condition characterized by glomerular sub-epithelial antibodies. The second patient was a 2-year-old child with bone marrow failure who developed the same glomerular lesions of membranous nephropathy and received a bone marrow transplantation. High levels of IgG4 in serum, bone marrow, and kidney led to the definition of IgG4-related kidney disease (IgG4 RKD) in this young boy. The circulating Treg levels were normal in the former case and very low in the second.
Two atypical associations of functional mutations of FOXP3 that include ALPS and IgG4 RKD are described. Membranous nephropathy leading to renal failure completed in both cases the clinical phenotypes that should be included in the clinical panorama of FOXP3 failure.
摘要：
叉头盒蛋白P3(FOXP3)是调节性T细胞(Treg)功能的核心转录因子。FOXP3基因的突变导致了一种称为免疫失调的全身性疾病，多内分泌病,和肠病，一种X连锁综合征（IPEX），其特征是早发性顽固性腹泻的三联征，1型糖尿病,还有湿疹.已经报道了IPEX的非典型表现。
我们报告了罕见的病例，这些病例的临床关联不明确，包括炎症，肾,和用大规模平行测序技术筛查的血液学参与。
两名FOXP3半合子突变患者[c.779T>A（p。L260Q）]和[c.1087A>G（p。I363V）]呈现IPEX典型病例中未包括的临床表现：一名16岁男性患者，最初临床诊断为自身免疫性淋巴组织增生综合征（ALPS），因膜性肾病而出现蛋白尿和肾功能下降，以肾小球上皮下抗体为特征的自身免疫性肾脏疾病。第二名患者是一名2岁的骨髓衰竭儿童，他发展了与膜性肾病相同的肾小球病变，并接受了骨髓移植。血清中高水平的IgG4，骨髓,和肾脏导致了这个小男孩IgG4相关肾脏疾病（IgG4RKD）的定义。循环Treg水平在前一种情况下是正常的，在第二种情况下是非常低的。
描述了包括ALPS和IgG4RKD的FOXP3的功能性突变的两种非典型关联。导致肾功能衰竭的膜性肾病在两种情况下都完成了临床表型，应包括在FOXP3失败的临床全景中。
我们报告了罕见的病例，这些病例的临床关联不明确，包括炎症，肾,和用大规模平行测序技术筛查的血液学参与。
两名FOXP3半合子突变患者[c.779T>A（p。L260Q）]和[c.1087A>G（p。I363V）]呈现IPEX典型病例中未包括的临床表现：一名16岁男性患者，最初临床诊断为自身免疫性淋巴组织增生综合征（ALPS），因膜性肾病而出现蛋白尿和肾功能下降，以肾小球上皮下抗体为特征的自身免疫性肾脏疾病。第二名患者是一名2岁的骨髓衰竭儿童，他发展了与膜性肾病相同的肾小球病变，并接受了骨髓移植。血清中高水平的IgG4，骨髓,和肾脏导致了这个小男孩IgG4相关肾脏疾病（IgG4RKD）的定义。循环Treg水平在前一种情况下是正常的，在第二种情况下是非常低的。
描述了包括ALPS和IgG4RKD的FOXP3的功能性突变的两种非典型关联。导致肾功能衰竭的膜性肾病在两种情况下都完成了临床表型，应包括在FOXP3失败的临床全景中。
