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Pediatrics International (2015) 57, e59–e61
doi: 10.1111/ped.12570
Patient Report
Familial IPEX syndrome: Different glomerulopathy in two siblings Eujin Park,1 Hye Jin Chang,1 Jae Il Shin,2 Beom Jin Lim,3 Hyeon Joo Jeong,3 Kyoung Bun Lee,4 Kyoung Chul Moon,4,6 Hee Gyung Kang,1,5 Il-Soo Ha1,6 and Hae Il Cheong1,5,6 1 Department of Pediatrics, Seoul National University Children’s Hospital, Departments of 2Pediatrics and 3Pathology, Severance Children’s Hospital, 4Department of Pathology, 5Research Coordination Center for Rare Diseases, Seoul National University Hospital and 6Kidney Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea Abstract
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome (OMIM 304790) is a rare hereditary disorder of the immune regulatory system caused by FOXP3 mutations. The clinical features of this syndrome include a wide spectrum of severe autoimmune diseases and renal involvement, mostly due to tubulointerstitial diseases, in some patients. Glomerulopathy of membranous nephropathy (MN) and minimal change nephrotic syndrome (MCNS), however, have also been reported. We encountered two children with IPEX syndrome from the same family. Interestingly, they had different glomerular lesions: one had MN and the other had MCNS. Herein we describe the cases of these siblings and review the possible mechanisms for the development of two different renal lesions.
Key words FOXP3, IPEX syndrome, membranous nephropathy, minimal change nephrotic syndrome, regulatory T cell.
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome (OMIM 304790) is a rare hereditary disorder of the immune regulatory system. This syndrome is caused by mutations in FOXP3,1 a transcription factor governing the development of CD4+ CD25+ regulatory T (Treg) cells, which are involved in immune homeostasis and protection against autoimmunity.2 This syndrome is clinically characterized by a wide spectrum of severe autoimmune diseases, including autoimmune enteropathy, hemolytic anemia, thrombocytopenia, hypothyroidism, type 1 diabetes mellitus, and eczema as well as severe infection. Renal disease affects approximately 30% of cases and is mainly manifested as tubulointerstitial nephritis,3 although glomerulopathy of membranous nephropathy (MN) and minimal change nephrotic syndrome (MCNS) have also been reported.4,5 This report describes the case of two siblings with IPEX syndrome, but with different types of glomerulopathy.
Case report Patient 1, a Korean male neonate was diagnosed with congenital hypothyroidism on newborn screening, and oral thyroxine treatment was started. After 6 months, persistent watery diarrhea developed. At age 4, he experienced facial edema and foamy urine. Urinalysis indicated proteinuria (3+), and 24 h collected urine protein/creatinine (mg/mg) ratio was 12.6. Serum albumin was 1.4 mg/dL. He was diagnosed with nephrotic syndrome.
Correspondence: Hae Il Cheong, MD, Department of Pediatrics, Seoul National University Children’s Hospital, 101 Daehak-Ro, Jongno-Gu, Seoul 110-744, Korea. Email: [email protected] Received 10 July 2014; revised 2 September 2014; accepted 22 October 2014.
© 2015 Japan Pediatric Society
Serum complement C3 and C4 were 49.9 mg/dL and 11.3 mg/dL, and the antinuclear antibody was positive at 1:160 dilutions. Other autoantibodies were negative including anti-RNP, anti-Sm, anti-Ro/La, anti-cardiolipin IgM, anti-trypsin and antiphospholipid IgG/IgM except for anti-ds-DNA (1:10 weakly positive) and anti-cardiolipin IgG. Renal biopsy indicated MN stage I. Light microscopy (LM) showed several globally sclerosed glomeruli, whereas others appeared normal in size, and cellularity. Immunofluorescence (IF) showed spotty granular immune deposits of IgG in the mesangium and along the paramesangial capillary loops. Small and irregularly shaped electron-dense deposits were seen focally in the subepithelial area, and the basement membranes showed inconspicuous spikes on electron microscopy (EM). Oral steroids were tapered down after the remission of nephrotic syndrome, and cyclosporine was added. At age 8, the patient was referred due to persistent watery diarrhea, and endoscopic duodenal biopsy was performed. The biopsy showed an infiltration of lymphoplasma cells and eosinophils in the lamina propria with focal villous atrophy; these findings are compatible with autoimmune enteritis. Oral tacrolimus alleviated the watery diarrhea, and the patient was closely monitored at an outpatient clinic. When he was 10 years old, petechial rash developed over his entire body and persisted for 3 weeks. Laboratory tests indicated thrombocytopenia (10 000/μL), hemolytic anemia (hemoglobin 6.7 g/dL) with a positive Coombs test, and positivity for several autoantibodies (antinuclear antibody, 1:80; anti-neutrophil cytoplasmic antibody, weakly positive; and anti-phospholipid IgG antibody, 15.8). Serum complement C3 and C4 were 105 mg/dL and 7 mg/ dL, respectively. Serum creatinine was 0.6 mg/dL, and serum albumin was 4.1 g/dL. Urinalysis indicated proteinuria (2+) and microscopic hematuria. Spot urine protein/creatinine ratio
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(mg/mg) was 2.59. Renal biopsy was repeated at this point, although the findings were consistent with the previous biopsy result. LM indicated mildly thickened glomerular capillary loops (Fig. 1a), and IF showed peripheral fine granular depositions of IgG in the glomerular capillary loops (Fig. 1b) that matched the subepithelial electron-dense deposits on EM (Fig. 1c). Under the suspicion of some type of autoimmune disorder (autoimmune enteritis, autoimmune hemolytic anemia and thrombocytopenia, or MN), tacrolimus was discontinued, and oral steroids were started. Ten months later, the enteritis had progressed, and oral methotrexate was added. Two months after the methotrexate treatment, a generalized skin rash with pruritus developed, followed by desquamation and pigmentation, and methotrexate was discontinued. During the later disease course, all of the aforementioned symptoms waxed and waned. In the meantime, the patient was treated with oral thyroxine and tacrolimus, in addition to intermittent oral or i.v. steroids. At age 17 he was finally diagnosed with IPEX syndrome, as confirmed on hemizygous c.736-2A>G mutation in intron 7 of FOXP3. At the last follow up at age 18, the patient was in relatively good condition. Hypothyroidism was under control with oral thyroxine and there were no other endocrine comorbidities including diabetes. Urinalysis indicated no proteinuria; serum creatinine was 0.9 mg/dL; and all other laboratory findings were stable, except for his scaly, discolored skin.
Patient 1 was the third child and had two elder brothers. The first brother had died in the neonatal period because of severe enteritis. The second brother (patient 2) had had multiple episodes of lung infection, lymphadenitis, and atopic dermatitis since the neonatal period. At age 2, patient 2 developed nephrotic syndrome refractory to oral steroid and cyclosporine treatment. Renal biopsy indicated MCNS with patchy severe mononuclear cell infiltration in the interstitium, along with focal tubular atrophy and interstitial fibrosis (Fig. 1d). IF showed no deposition of immunoglobulin or complement, and EM showed no electron-dense deposits (Fig. 1e). Thereafter, oral steroid was given intermittently because of recurrent episodes of severe infection. At age 4, we added cyclosporine, which was ineffective. At age 6 after 2 years of cyclosporine treatment, renal biopsy was repeated to evaluate possible cyclosporine nephrotoxicity. The glomeruli were normal in size with cellularity on LM, and IF was negative. No electron-dense deposits were seen on EM. These findings are consistent with previous biopsy results. At age 10, the second patient contracted severe Epstein–Barr viral infection. This infection led to fulminant hepatitis, hepatic encephalopathy, septic shock, and, finally, death. During the whole disease course, other endocrine comorbidities including hypothyroidism and diabetes were not detected. Genetic analysis of the renal biopsy tissue indicated the same FOXP3 mutation.
Fig. 1 Renal biopsy findings of (a–c) patient 1 and (d,e) patient 2, his sibling. (a) The glomerulus showed segmental mesangial hypercellularity with mild thickening of the glomerular capillary loops (periodic acid–Schiff). (b) Diffuse granular peripheral staining of IgG (2+) on immunofluorescence. (c) Scattered subepithelial and intramembranous deposits with small mesangial deposits (arrows) on electron microscopy (bar, 2 μm). (d) Normal-looking glomeruli with patchy areas of mononuclear cell infiltration with focal tubular atrophy on light microscopy (periodic acid–Schiff). (e) Diffuse effacement of the podocyte foot processes without electron-dense deposits on electron microscopy (bar, 2 μm). © 2015 Japan Pediatric Society
Familial IPEX syndrome Discussion IPEX syndrome involves multiple organs, including the kidney. Although most of the renal involvement in IPEX syndrome is seen as tubulointerstitial damage, there have been several reports of glomerulopathy manifesting as nephrotic syndrome3 with the pathologic features of MN4 or MCNS.5 In the present familial case, two siblings with the same genetic mutation were observed to have distinct glomerular lesions. Although early lesion of MN with sparse immune deposits may be confused with MCNS, MCNS was confirmed on the second renal biopsy in the second brother (patient 2), which was performed 4 years after the onset of nephrotic syndrome. Membranous nephropathy is an immune-mediated disease characterized by the deposition of immune complexes in the subepithelial space, which causes a membrane-like thickening of the glomerular basement membranes. Antigen–antibody complexes may develop at this location due to the production of immune complexes in situ or by the deposition of circulating immune complexes. Idiopathic MN is usually considered as an autoimmune disease, whereas exogenous antigens, such as viral and tumoral antigens, are thought to be involved in secondary forms of MN.6 In both idiopathic and secondary MN, the complement system is activated, and the membrane attack complex is admixed with immune complexes. The formation of subepithelial immune deposits and complement activation together are responsible for functional impairment of the glomerular capillary wall, causing proteinuria. The association with MN in IPEX syndrome can be explained as an autoimmune-mediated lesion, even if the target antigen is unknown, or as a secondary lesion associated with chronic infections. Unlike MN, there are no immune complexes or complement components in the glomeruli of MCNS. MCNS has long been known as a T-cell disorder mediated by a circulating factor, based on the following observations: rapid response to steroids and cyclophosphamide; association with Hodgkin’s disease; remission after measles infection; and viral respiratory tract infection as a trigger.7 Normally, the expression and release of cytokines by T cells is transient due to the activation of the Treg cells, which in turn act on T effector (Teff) cells to suppress their production of cytokines. In MCNS, the Treg cell suppressor mechanism is deficient, thereby enhancing the cytokine release by Teff cells and altering podocyte function with the result of massive proteinuria.8 Foxp3 protein is a transcription factor that is crucial for the generation and maturation of Treg cells.9 Therefore, the development of MCNS in IPEX syndrome can be explained by the altered Treg cell function. Most patients with this disease die within the first 2 years of life because of infection.3 Unlike in the case of patient 1, who had a favorable clinical course, his brother, patient 2, with early fatal outcome had recurrent episodes of severe infection, which eventually caused fatality. We cannot explain the different clinical features between these siblings with the same genetic background. T-cell-directed immunosuppressive medications have been used to treat IPEX syndrome, including corticosteroids,
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tacrolimus and cyclosporine. In addition, recent studies have reported the effect of rituximab, a monoclonal antibody against CD20-positive B cells, in some patients. Chronic immunosuppression, however, has been proven to be only partially effective; bone marrow transplantation is currently the only cure for IPEX syndrome.10 In the present case, we did not consider bone marrow transplantation because the patient is doing relatively well on tacrolimus and intermittent low-dose oral steroids without any toxicity. If, however, his clinical course deteriorates at a later date, bone marrow transplantation should be considered. Conclusion
Glomerulopathies in IPEX syndrome can be caused by either altered Treg cell function (MCNS) or accelerated autoimmunity (MN). As shown in the present sibling cases, however, genetic mutations might not be a crucial determinant of the pathophysiology of glomerulopathies.
Acknowledgments This study was supported by a grant (HI12C0014) from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea. Conflicts of interest: none.
References 1 Ochs HD, Zieglet SF, Torgerson TR. FOXP3 acts as a rheostat of the immune response. Immunol. Rev. 2005; 203: 156–64. 2 van der Vliet HJ, Nieuwenhuis EE. IPEX as a result of mutations in FOXP3. Clin. Dev. Immunol. 2007; 2007: 89017. 3 Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J. Med. Genet. 2002; 39: 537–45. 4 Moudgil A, Perriello P, Loechelt B, Przygodzki R, Fitzgerald W, Kamani N. Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: An unusual cause of proteinuria in infancy. Pediatr. Nephrol. 2007; 22: 1799–802. 5 Hashimura Y, Nozu K, Kanegane H et al. Minimal change nephrotic syndrome associated with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Pediatr. Nephrol. 2009; 24: 1181–6. 6 Ronco P, Debiec H. Pathogenesis of membranous nephropathy: Recent advances and future challenges. Nat. Rev. Nephrol. 2012; 8: 203–13. 7 Shalhoub RJ. Pathogenesis of lipoid nephrosis: A disorder of T-cell function. Lancet 1974; 2: 556–60. 8 Araya C, Diaz L, Wasserfall C et al. T regulatory cell function in idiopathic minimal lesion nephrotic syndrome. Pediatr. Nephrol. 2009; 24: 1691–8. 9 Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299: 1057–61. 10 Baud O, Goulet O, Canioni D et al. Treatment of the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) by allogeneic bone marrow transplantation. N. Engl. J. Med. 2001; 344: 1758–62.
© 2015 Japan Pediatric Society
Copyright of Pediatrics International is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Pediatrics International (2015) 57, e59–e61
doi: 10.1111/ped.12570
Patient Report
Familial IPEX syndrome: Different glomerulopathy in two siblings Eujin Park,1 Hye Jin Chang,1 Jae Il Shin,2 Beom Jin Lim,3 Hyeon Joo Jeong,3 Kyoung Bun Lee,4 Kyoung Chul Moon,4,6 Hee Gyung Kang,1,5 Il-Soo Ha1,6 and Hae Il Cheong1,5,6 1 Department of Pediatrics, Seoul National University Children’s Hospital, Departments of 2Pediatrics and 3Pathology, Severance Children’s Hospital, 4Department of Pathology, 5Research Coordination Center for Rare Diseases, Seoul National University Hospital and 6Kidney Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea Abstract
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome (OMIM 304790) is a rare hereditary disorder of the immune regulatory system caused by FOXP3 mutations. The clinical features of this syndrome include a wide spectrum of severe autoimmune diseases and renal involvement, mostly due to tubulointerstitial diseases, in some patients. Glomerulopathy of membranous nephropathy (MN) and minimal change nephrotic syndrome (MCNS), however, have also been reported. We encountered two children with IPEX syndrome from the same family. Interestingly, they had different glomerular lesions: one had MN and the other had MCNS. Herein we describe the cases of these siblings and review the possible mechanisms for the development of two different renal lesions.
Key words FOXP3, IPEX syndrome, membranous nephropathy, minimal change nephrotic syndrome, regulatory T cell.
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome (OMIM 304790) is a rare hereditary disorder of the immune regulatory system. This syndrome is caused by mutations in FOXP3,1 a transcription factor governing the development of CD4+ CD25+ regulatory T (Treg) cells, which are involved in immune homeostasis and protection against autoimmunity.2 This syndrome is clinically characterized by a wide spectrum of severe autoimmune diseases, including autoimmune enteropathy, hemolytic anemia, thrombocytopenia, hypothyroidism, type 1 diabetes mellitus, and eczema as well as severe infection. Renal disease affects approximately 30% of cases and is mainly manifested as tubulointerstitial nephritis,3 although glomerulopathy of membranous nephropathy (MN) and minimal change nephrotic syndrome (MCNS) have also been reported.4,5 This report describes the case of two siblings with IPEX syndrome, but with different types of glomerulopathy.
Case report Patient 1, a Korean male neonate was diagnosed with congenital hypothyroidism on newborn screening, and oral thyroxine treatment was started. After 6 months, persistent watery diarrhea developed. At age 4, he experienced facial edema and foamy urine. Urinalysis indicated proteinuria (3+), and 24 h collected urine protein/creatinine (mg/mg) ratio was 12.6. Serum albumin was 1.4 mg/dL. He was diagnosed with nephrotic syndrome.
Correspondence: Hae Il Cheong, MD, Department of Pediatrics, Seoul National University Children’s Hospital, 101 Daehak-Ro, Jongno-Gu, Seoul 110-744, Korea. Email: [email protected] Received 10 July 2014; revised 2 September 2014; accepted 22 October 2014.
© 2015 Japan Pediatric Society
Serum complement C3 and C4 were 49.9 mg/dL and 11.3 mg/dL, and the antinuclear antibody was positive at 1:160 dilutions. Other autoantibodies were negative including anti-RNP, anti-Sm, anti-Ro/La, anti-cardiolipin IgM, anti-trypsin and antiphospholipid IgG/IgM except for anti-ds-DNA (1:10 weakly positive) and anti-cardiolipin IgG. Renal biopsy indicated MN stage I. Light microscopy (LM) showed several globally sclerosed glomeruli, whereas others appeared normal in size, and cellularity. Immunofluorescence (IF) showed spotty granular immune deposits of IgG in the mesangium and along the paramesangial capillary loops. Small and irregularly shaped electron-dense deposits were seen focally in the subepithelial area, and the basement membranes showed inconspicuous spikes on electron microscopy (EM). Oral steroids were tapered down after the remission of nephrotic syndrome, and cyclosporine was added. At age 8, the patient was referred due to persistent watery diarrhea, and endoscopic duodenal biopsy was performed. The biopsy showed an infiltration of lymphoplasma cells and eosinophils in the lamina propria with focal villous atrophy; these findings are compatible with autoimmune enteritis. Oral tacrolimus alleviated the watery diarrhea, and the patient was closely monitored at an outpatient clinic. When he was 10 years old, petechial rash developed over his entire body and persisted for 3 weeks. Laboratory tests indicated thrombocytopenia (10 000/μL), hemolytic anemia (hemoglobin 6.7 g/dL) with a positive Coombs test, and positivity for several autoantibodies (antinuclear antibody, 1:80; anti-neutrophil cytoplasmic antibody, weakly positive; and anti-phospholipid IgG antibody, 15.8). Serum complement C3 and C4 were 105 mg/dL and 7 mg/ dL, respectively. Serum creatinine was 0.6 mg/dL, and serum albumin was 4.1 g/dL. Urinalysis indicated proteinuria (2+) and microscopic hematuria. Spot urine protein/creatinine ratio
e60
E Park et al.
(mg/mg) was 2.59. Renal biopsy was repeated at this point, although the findings were consistent with the previous biopsy result. LM indicated mildly thickened glomerular capillary loops (Fig. 1a), and IF showed peripheral fine granular depositions of IgG in the glomerular capillary loops (Fig. 1b) that matched the subepithelial electron-dense deposits on EM (Fig. 1c). Under the suspicion of some type of autoimmune disorder (autoimmune enteritis, autoimmune hemolytic anemia and thrombocytopenia, or MN), tacrolimus was discontinued, and oral steroids were started. Ten months later, the enteritis had progressed, and oral methotrexate was added. Two months after the methotrexate treatment, a generalized skin rash with pruritus developed, followed by desquamation and pigmentation, and methotrexate was discontinued. During the later disease course, all of the aforementioned symptoms waxed and waned. In the meantime, the patient was treated with oral thyroxine and tacrolimus, in addition to intermittent oral or i.v. steroids. At age 17 he was finally diagnosed with IPEX syndrome, as confirmed on hemizygous c.736-2A>G mutation in intron 7 of FOXP3. At the last follow up at age 18, the patient was in relatively good condition. Hypothyroidism was under control with oral thyroxine and there were no other endocrine comorbidities including diabetes. Urinalysis indicated no proteinuria; serum creatinine was 0.9 mg/dL; and all other laboratory findings were stable, except for his scaly, discolored skin.
Patient 1 was the third child and had two elder brothers. The first brother had died in the neonatal period because of severe enteritis. The second brother (patient 2) had had multiple episodes of lung infection, lymphadenitis, and atopic dermatitis since the neonatal period. At age 2, patient 2 developed nephrotic syndrome refractory to oral steroid and cyclosporine treatment. Renal biopsy indicated MCNS with patchy severe mononuclear cell infiltration in the interstitium, along with focal tubular atrophy and interstitial fibrosis (Fig. 1d). IF showed no deposition of immunoglobulin or complement, and EM showed no electron-dense deposits (Fig. 1e). Thereafter, oral steroid was given intermittently because of recurrent episodes of severe infection. At age 4, we added cyclosporine, which was ineffective. At age 6 after 2 years of cyclosporine treatment, renal biopsy was repeated to evaluate possible cyclosporine nephrotoxicity. The glomeruli were normal in size with cellularity on LM, and IF was negative. No electron-dense deposits were seen on EM. These findings are consistent with previous biopsy results. At age 10, the second patient contracted severe Epstein–Barr viral infection. This infection led to fulminant hepatitis, hepatic encephalopathy, septic shock, and, finally, death. During the whole disease course, other endocrine comorbidities including hypothyroidism and diabetes were not detected. Genetic analysis of the renal biopsy tissue indicated the same FOXP3 mutation.
Fig. 1 Renal biopsy findings of (a–c) patient 1 and (d,e) patient 2, his sibling. (a) The glomerulus showed segmental mesangial hypercellularity with mild thickening of the glomerular capillary loops (periodic acid–Schiff). (b) Diffuse granular peripheral staining of IgG (2+) on immunofluorescence. (c) Scattered subepithelial and intramembranous deposits with small mesangial deposits (arrows) on electron microscopy (bar, 2 μm). (d) Normal-looking glomeruli with patchy areas of mononuclear cell infiltration with focal tubular atrophy on light microscopy (periodic acid–Schiff). (e) Diffuse effacement of the podocyte foot processes without electron-dense deposits on electron microscopy (bar, 2 μm). © 2015 Japan Pediatric Society
Familial IPEX syndrome Discussion IPEX syndrome involves multiple organs, including the kidney. Although most of the renal involvement in IPEX syndrome is seen as tubulointerstitial damage, there have been several reports of glomerulopathy manifesting as nephrotic syndrome3 with the pathologic features of MN4 or MCNS.5 In the present familial case, two siblings with the same genetic mutation were observed to have distinct glomerular lesions. Although early lesion of MN with sparse immune deposits may be confused with MCNS, MCNS was confirmed on the second renal biopsy in the second brother (patient 2), which was performed 4 years after the onset of nephrotic syndrome. Membranous nephropathy is an immune-mediated disease characterized by the deposition of immune complexes in the subepithelial space, which causes a membrane-like thickening of the glomerular basement membranes. Antigen–antibody complexes may develop at this location due to the production of immune complexes in situ or by the deposition of circulating immune complexes. Idiopathic MN is usually considered as an autoimmune disease, whereas exogenous antigens, such as viral and tumoral antigens, are thought to be involved in secondary forms of MN.6 In both idiopathic and secondary MN, the complement system is activated, and the membrane attack complex is admixed with immune complexes. The formation of subepithelial immune deposits and complement activation together are responsible for functional impairment of the glomerular capillary wall, causing proteinuria. The association with MN in IPEX syndrome can be explained as an autoimmune-mediated lesion, even if the target antigen is unknown, or as a secondary lesion associated with chronic infections. Unlike MN, there are no immune complexes or complement components in the glomeruli of MCNS. MCNS has long been known as a T-cell disorder mediated by a circulating factor, based on the following observations: rapid response to steroids and cyclophosphamide; association with Hodgkin’s disease; remission after measles infection; and viral respiratory tract infection as a trigger.7 Normally, the expression and release of cytokines by T cells is transient due to the activation of the Treg cells, which in turn act on T effector (Teff) cells to suppress their production of cytokines. In MCNS, the Treg cell suppressor mechanism is deficient, thereby enhancing the cytokine release by Teff cells and altering podocyte function with the result of massive proteinuria.8 Foxp3 protein is a transcription factor that is crucial for the generation and maturation of Treg cells.9 Therefore, the development of MCNS in IPEX syndrome can be explained by the altered Treg cell function. Most patients with this disease die within the first 2 years of life because of infection.3 Unlike in the case of patient 1, who had a favorable clinical course, his brother, patient 2, with early fatal outcome had recurrent episodes of severe infection, which eventually caused fatality. We cannot explain the different clinical features between these siblings with the same genetic background. T-cell-directed immunosuppressive medications have been used to treat IPEX syndrome, including corticosteroids,
e61
tacrolimus and cyclosporine. In addition, recent studies have reported the effect of rituximab, a monoclonal antibody against CD20-positive B cells, in some patients. Chronic immunosuppression, however, has been proven to be only partially effective; bone marrow transplantation is currently the only cure for IPEX syndrome.10 In the present case, we did not consider bone marrow transplantation because the patient is doing relatively well on tacrolimus and intermittent low-dose oral steroids without any toxicity. If, however, his clinical course deteriorates at a later date, bone marrow transplantation should be considered. Conclusion
Glomerulopathies in IPEX syndrome can be caused by either altered Treg cell function (MCNS) or accelerated autoimmunity (MN). As shown in the present sibling cases, however, genetic mutations might not be a crucial determinant of the pathophysiology of glomerulopathies.
Acknowledgments This study was supported by a grant (HI12C0014) from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea. Conflicts of interest: none.
References 1 Ochs HD, Zieglet SF, Torgerson TR. FOXP3 acts as a rheostat of the immune response. Immunol. Rev. 2005; 203: 156–64. 2 van der Vliet HJ, Nieuwenhuis EE. IPEX as a result of mutations in FOXP3. Clin. Dev. Immunol. 2007; 2007: 89017. 3 Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J. Med. Genet. 2002; 39: 537–45. 4 Moudgil A, Perriello P, Loechelt B, Przygodzki R, Fitzgerald W, Kamani N. Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: An unusual cause of proteinuria in infancy. Pediatr. Nephrol. 2007; 22: 1799–802. 5 Hashimura Y, Nozu K, Kanegane H et al. Minimal change nephrotic syndrome associated with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Pediatr. Nephrol. 2009; 24: 1181–6. 6 Ronco P, Debiec H. Pathogenesis of membranous nephropathy: Recent advances and future challenges. Nat. Rev. Nephrol. 2012; 8: 203–13. 7 Shalhoub RJ. Pathogenesis of lipoid nephrosis: A disorder of T-cell function. Lancet 1974; 2: 556–60. 8 Araya C, Diaz L, Wasserfall C et al. T regulatory cell function in idiopathic minimal lesion nephrotic syndrome. Pediatr. Nephrol. 2009; 24: 1691–8. 9 Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299: 1057–61. 10 Baud O, Goulet O, Canioni D et al. Treatment of the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) by allogeneic bone marrow transplantation. N. Engl. J. Med. 2001; 344: 1758–62.
© 2015 Japan Pediatric Society
Copyright of Pediatrics International is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
