Atypical Presentations of IPEX: Expect the Unexpected

Filippo Consonni, Sara Ciullini Mannurita, Eleonora Gambineri, Filippo Consonni, Sara Ciullini Mannurita, Eleonora Gambineri

Abstract

Immune dysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) syndrome is a rare disorder that has become a model of monogenic autoimmunity. IPEX is caused by mutations in FOXP3 gene, a master regulator of regulatory T cells (Treg). Cases reported in the last 20 years demonstrate that IPEX clinical spectrum encompasses more than the classical triad of early-onset intractable diarrhea, type 1 diabetes (T1D) and eczema. Atypical cases of IPEX include patients with late-onset of symptoms, single-organ involvement, mild disease phenotypes or rare clinical features (e.g., atrophic gastritis, interstitial lung disease, nephropathy etc.). Several atypical presentations have recently been reported, suggesting that IPEX incidence might be underestimated. Immunosuppression (IS) treatment strategies can control the disease, however at the moment allogeneic hematopoietic stem cell transplantation (HSCT) is the only available definitive cure, therefore it is important to achieve a prompt diagnosis. This review aims to describe unusual clinical phenotypes, beyond classical IPEX. Overall, our analysis contributes to increase awareness and finally improve diagnosis and treatment intervention in IPEX in order to ensure a good quality of life.

Keywords: FOXP3; IPEX; immune dysregulation; primary immunodeficiencies; regulatory T cells.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Consonni, Ciullini Mannurita and Gambineri.

Figures

Figure 1
Figure 1
(A) Typical and unusual clinical features in IPEX. Percentages for typical features are based on the most recently published IPEX cohort (6). Classical triad features are in bold. CIDP, Chronic Inflammatory Demyelinating Polyneuropathy; GI, Gastrointestinal. (B) Relationships among atypical IPEX subgroups revealed by our analysis. Subgroup (number of patients); IS, Immunosuppression. (C)FOXP3 gene and protein structure showing mutations associated with mild/late-onset and variable/peculiar IPEX phenotypes.

References

    1. Powell BR, Buist NRM, Stenzel P. An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy. J Pediatr. (1982) 100:731–7. 10.1016/S0022-3476(82)80573-8
    1. Chatila TA, Blaeser F, Ho N, Lederman HM, Voulgaropoulos C, Helms C, et al. . JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest. (2000) 106:75–81. 10.1172/JCI11679
    1. Bennett CL, Yoshioka R, Kiyosawa H, Barker DF, Fain PR, Shigeoka AO, et al. . The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. (2001) 27:20–1. 10.1038/83713
    1. Bacchetta R, Barzaghi F, Roncarolo MG. From IPEX syndrome to FOXP3 mutation: a lesson on immune dysregulation. Ann NY Acad Sci. (2016) 1417:1–18. 10.1111/nyas.13011
    1. Goodwin M, Lee E, Lakshmanan U, Shipp S, Froessl L, Barzaghi F, et al. . CRISPR-based gene editing enables FOXP3 gene repair in IPEX patient cells. Sci Adv. (2020) 6:eaaz0571. 10.1126/sciadv.aaz0571
    1. Barzaghi F, Amaya Hernandez LC, Neven B, Ricci S, Kucuk ZY, Bleesing JJ, et al. . Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study. J Allergy Clin Immunol. (2018) 141:1036–49.e5. 10.1016/j.jaci.2017.10.041
    1. Jamee M, Zaki-Dizaji M, Lo B, Abolhassani H, Aghamahdi F, Mosavian M, et al. . Clinical, immunological, and genetic features in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-like syndrome. J Allergy Clin Immunol Pract. (2020) 82747–60.e7. 10.1016/j.jaip.2020.04.070
    1. Barzaghi F, Passerini L, Bacchetta R. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: a paradigm of immunodeficiency with autoimmunity. Front Immunol. (2012) 3:1–25. 10.3389/fimmu.2012.00211
    1. Gambineri E, Perroni L, Passerini L, Bianchi L, Doglioni C, Meschi F, et al. . Clinical and molecular profile of a new series of patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: Inconsistent correlation between forkhead box protein 3 expression and disease severity. J Allergy Clin Immunol. (2008) 122:1105–13. 10.1016/j.jaci.2008.09.027
    1. Ge T, Wang Y, Che Y, Xiao Y, Zhang T. Atypical late-onset immune dysregulation, polyendocrinopathy, enteropathy, X-Linked syndrome with intractable diarrhea: a case report. Front Pediatr. (2017) 5:4–7. 10.3389/fped.2017.00267
    1. Luo Y, Chen J, Fang Y, Lou J, Yu J. A case of metaplastic atrophic gastritis in immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. BMC Pediatr. (2018) 18:1–5. 10.1186/s12887-018-1169-9
    1. Zama D, Cocchi I, Masetti R, Specchia F, Alvisi P, Gambineri E, et al. . Late-onset of immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome (IPEX) with intractable diarrhea. Ital J Pediatr. (2014) 40:1–7. 10.1186/s13052-014-0068-4
    1. De Benedetti F, Insalaco A, Diamanti A, Cortis E, Muratori F, Lamioni A, et al. . Mechanistic associations of a mild phenotype of immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Clin Gastroenterol Hepatol. (2006) 4:653–9. 10.1016/j.cgh.2005.12.014
    1. Ochs HD, Gambineri E, Torgerson TR. IPEX, FOXP3 and regulatory T-cells: a model for autoimmunity. Immunol Res. (2007) 38:112–21. 10.1007/s12026-007-0022-2
    1. Shanes E, Propst L, Ouyang DW, Ernst LM. Recurrent non immune fetal hydrops associated with IPEX syndrome. Pediatr Dev Pathol. (2019) 22:465–71. 10.1177/1093526619834809
    1. Carneiro-Sampaio M, Moreira-Filho CA, Bando SY, Demengeot J, Coutinho A. Intrauterine IPEX. Front Pediatr. (2020) 8:599283 10.3389/fped.2020.599283
    1. Duclaux-Loras R, Charbit-Henrion F, Neven B, Nowak J, Collardeau-Frachon S, Malcus C, et al. . Clinical heterogeneity of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: a French multicenter retrospective study. Clin Transl Gastroenterol. (2018) 9:201. 10.1038/s41424-018-0064-x
    1. Shamriz O, Patel K, Marsh RA, Bleesing J, Joshi AY, Lucas L, et al. . Hypogammaglobulinemia with decreased class-switched B-cells and dysregulated T-follicular-helper cells in IPEX syndrome. Clin Immunol. (2018) 197:219–23. 10.1016/j.clim.2018.10.005
    1. Patey-Mariaud De Serre N, Canioni D, Ganousse S, Rieux-Laucat F, Goulet O, Ruemmele F, et al. . Digestive histopathological presentation of IPEX syndrome. Mod Pathol. (2009) 22:95–102. 10.1038/modpathol.2008.161
    1. Savova R, Arshinkova M, Houghton J, Konstantinova M, Gaydarova M, Georgieva E, et al. . Clinical case of immune dysregulation, polyendocrinopaty, enteropathy, X-linked (IPEX) syndrome with severe immune deficiency and late onset of endocrinopathy and enteropathy. Case Rep Med. (2014) 2014:564926. 10.1155/2014/564926
    1. Yong PL, Russo P, Sullivan KE. Use of sirolimus in IPEX and IPEX-like children. J Clin Immunol. (2008) 28:581–7. 10.1007/s10875-008-9196-1
    1. Bindl L, Torgerson T, Perroni L, Youssef N, Ochs H, Goulet O, et al. . Successful use of the new immune-suppressor sirolimus in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome). J Pediatr. (2005) 147:256–9. 10.1016/j.jpeds.2005.04.017
    1. Nameirakpam J, Rikhi R, Rawat SS, Sharma J, Suri D. Genetics on early onset inflammatory bowel disease: an update. Genes Dis. (2020) 7:93–106. 10.1016/j.gendis.2019.10.003
    1. Gambineri E, Mannurita SC, Hagin D, Vignoli M, Anover-Sombke S, DeBoer S, et al. . Clinical, immunological, and molecular heterogeneity of patients with the phenotype of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Front Immunol. (2018) 9:2411. 10.3389/fimmu.2018.02411
    1. Hwang JL, Park SY, Ye H, Sanyoura M, Pastore AN, Carmody D, et al. . FOXP3 mutations causing early-onset insulin-requiring diabetes but without other features of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Pediatr Diabetes. (2018) 19:388–92. 10.1111/pedi.12612
    1. Fuchizawa T, Adachi Y, Ito Y, Higashiyama H, Kanegane H, Futatani T, et al. . Developmental changes of FOXP3-expressing CD4+CD25+ regulatory T cells and their impairment in patients with FOXP3 gene mutations. Clin Immunol. (2007) 125:237–46. 10.1016/j.clim.2007.08.004
    1. Bae KW, Kim BE, Choi JH, Lee JH, Park YS, Kim GH, et al. . A novel mutation and unusual clinical features in a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Eur J Pediatr. (2011) 170:1611–5. 10.1007/s00431-011-1588-1
    1. Dogruel D, Gürbüz F, Turan I, Altintaş DU, Yilmaz M, Yüksel B. Unusual and early onset IPEX syndrome: a case report. Turk J Pediatr. (2019) 61:580–4. 10.24953/turkjped.2019.04.015
    1. Sheikine Y, Woda CB, Lee PY, Chatila TA, Keles S, Charbonnier LM, et al. . Renal involvement in the immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) disorder. Pediatr Nephrol. (2015) 30:1197–202. 10.1007/s00467-015-3102-x
    1. Halabi-Tawil M, Ruemmele FM, Fraitag S, Rieux-Laucat F, Neven B, Brousse N, et al. . Cutaneous manifestations of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Br J Dermatol. (2009) 160:645–51. 10.1111/j.1365-2133.2008.08835.x
    1. Martín-Santiago A, Hervás JA, Hervás D, Rosell A, Caimari M, de Carlos JC, et al. . Diagnostic value of the skin lesions in immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Pediatr Dermatol. (2013) 30:221–2. 10.1111/pde.12126
    1. Nieves DS, Phipps RP, Pollock SJ, Ochs HD, Zhu Q, Scott GA, et al. . Dermatologic and immunologic findings in the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Arch Dermatol. (2004) 140:466–72. 10.1001/archderm.140.4.466
    1. McMurchy AN, Gillies J, Allan SE, Passerini L, Gambineri E, Roncarolo MG, et al. . Point mutants of forkhead box P3 that cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked have diverse abilities to reprogram T cells into regulatory T cells. J Allergy Clin Immunol. (2010) 126:1242–51. 10.1016/j.jaci.2010.09.001
    1. Scaillon M, Van Biervliet S, Bontems P, Dorchy H, Hanssens L, Ferster A, et al. . Severe gastritis in an insulin-dependent child with an IPEX syndrome. J Pediatr Gastroenterol Nutr. (2009) 49:368–70. 10.1097/MPG.0b013e3181a159de
    1. Moudgil A, Perriello P, Loechelt B, Przygodzki R, Fitzerald W, Kamani N. Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: an unusual cause of proteinuria in infancy. Pediatr Nephrol. (2007) 22:1799–802. 10.1007/s00467-007-0532-0
    1. Chuva T, Pfister F, Beringer O, Felgentreff K, Büttner-Herold M, Amann K. PLA2R-positive (primary) membranous nephropathy in a child with IPEX syndrome. Pediatr Nephrol. (2017) 32:1621–4. 10.1007/s00467-017-3682-8
    1. Park E, Chang HJ, Shin J Il, Lim BJ, Jeong HJ, Lee KB, et al. . Familial IPEX syndrome: different glomerulopathy in two siblings. Pediatr Int. (2015) 57:e59–61. 10.1111/ped.12570
    1. Hashimura Y, Nozu K, Kanegane H, Miyawaki T, Hayakawa A, Yoshikawa N, et al. . Minimal change nephrotic syndrome associated with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Pediatr Nephrol. (2009) 24:1181–6. 10.1007/s00467-009-1119-8
    1. Baris S, Schulze I, Ozen A, Aydiner EK, Altuncu E, Karasu GT, et al. . Clinical heterogeneity of immunodysregulation, polyendocrinopathy, enteropathy, X-linked: pulmonary involvement as a non-classical disease manifestation. J Clin Immunol. (2014) 34:601–6. 10.1007/s10875-014-0059-7
    1. Ghosh S, Seidel MG. Editorial: current challenges in immune and other acquired cytopenias of childhood. Front Pediatr. (2016) 4:4–6. 10.3389/fped.2016.00003
    1. Hadjadj J, Aladjidi N, Fernandes H, Leverger G, Magerus-Chatinet A, Mazerolles F, et al. . Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes. Blood. (2019) 134:9–21. 10.1182/blood-2018-11-887141
    1. Consonni F, Dotta L, Todaro F, Vairo D, Badolato R. Signal transducer and activator of transcription gain-of-function primary immunodeficiency/immunodysregulation disorders. Curr Opin Pediatr. (2017) 29:1. 10.1097/MOP.0000000000000551
    1. Schwab C, Gabrysch A, Olbrich P, Patino V, Warnatz K, Wolff D, et al. . Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. J Allergy Clin Immunol. (2018) 142:1932–46. 10.1016/j.jaci.2018.02.055
    1. Tsuda M, Torgerson TR, Selmi C, Gambineri E, Carneiro-Sampaio M, Mannurita SC, et al. . The spectrum of autoantibodies in IPEX syndrome is broad and includes anti-mitochondrial autoantibodies. J Autoimmun. (2010) 35:265–8. 10.1016/j.jaut.2010.06.017
    1. 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. 10.1136/jmg.39.8.537
    1. Torgerson TR, Linane A, Moes N, Anover S, Mateo V, Rieux-Laucat F, et al. . Severe food allergy as a variant of IPEX syndrome caused by a deletion in a noncoding region of the FOXP3 gene. Gastroenterology. (2007) 132:1705–17. 10.1053/j.gastro.2007.02.044
    1. Otsubo K, Kanegane H, Kamachi Y, Kobayashi I, Tsuge I, Imaizumi M, et al. . Identification of FOXP3-negative regulatory T-like (CD4 +CD25 +CD127 low) cells in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Clin Immunol. (2011) 141:111–20. 10.1016/j.clim.2011.06.006
    1. Bacchetta R, Passerini L, Gambineri E, Dai M, Allan SE, Perroni L, et al. . Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J Clin Invest. (2006) 116:1713–22. 10.1172/JCI25112
    1. Seidel MG, Boztug K, Haas OA. Immune dysregulation syndromes (IPEX, CD27 deficiency, and others): always doomed from the start? J Clin Immunol. (2016) 36:6–7. 10.1007/s10875-015-0218-5
    1. Rubio-Cabezas O, Minton JAL, Caswell R, Shield JP, Deiss D, Sumnik Z, et al. . Clinical heterogeneity in patients with FOXP3 mutations presenting with permanent neonatal diabetes. Diabetes Care. (2009) 32:111–6. 10.2337/dc08-1188
    1. Okou DT, Mondal K, Faubion WA, Kobrynski LJ, Denson LA, Mulle JG, et al. . Exome sequencing identifies a novel FOXP3 mutation in a 2-generation family with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. (2014) 58:561–8. 10.1097/MPG.0000000000000302
    1. Chen CA, Chung WC, Chiou YY, Yang YJ, Lin YC, Ochs HD, et al. . Quantitative analysis of tissue inflammation and responses to treatment in immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, and review of literature. J Microbiol Immunol Infect. (2016) 49:775–82. 10.1016/j.jmii.2015.10.015
    1. Dorsey MJ, Petrovic A, Morrow MR, Dishaw LJ, Sleasman JW. FOXP3 expression following bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Immunol Res. (2009) 44:179–84. 10.1007/s12026-009-8112-y
    1. Moes N, Rieuxlaucat F, Begue B, Verdier J, Neven B, Patey N, et al. . Reduced expression of FOXP3 and regulatory T-cell function in severe forms of early-onset autoimmune enteropathy. Gastroenterology. (2010) 139:770–8. 10.1053/j.gastro.2010.06.006
    1. Burroughs LM, Torgerson TR, Storb R, Carpenter PA, Rawlings DJ, Sanders J, et al. . Stable hematopoietic cell engraftment after low-intensity nonmyeloablative conditioning in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. J Allergy Clin Immunol. (2010) 126:1000–5. 10.1016/j.jaci.2010.05.021
    1. An YF, Xu F, Wang M, Zhang ZY, Zhao XD. Clinical and molecular characteristics of immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome in China. Scand J Immunol. (2011) 74:304–9. 10.1111/j.1365-3083.2011.02574.x
    1. Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature. (2010) 463:808–12. 10.1038/nature08750
    1. Kobayashi I, Shiari R, Yamada M, Kawamura N, Okano M, Yara A. Novel mutations of FOXP3 in two Japanese patients with immune dysregulation, polyendocrinopathy, enteropathy, X linked syndrome (IPEX). J Med Genet. (2001) 38:874–6. 10.1136/jmg.38.12.874
    1. Alkorta-Aranburu G, Carmody D, Cheng YW, Nelakuditi V, Ma L, Dickens JT, et al. . Phenotypic heterogeneity in monogenic diabetes: the clinical and diagnostic utility of a gene panel-based next-generation sequencing approach. Mol Genet Metab. (2014) 113:315–20. 10.1016/j.ymgme.2014.09.007
    1. Mailer RKW. Alternative splicing of FOXP3-virtue and vice. Front Immunol. (2018) 9:530. 10.3389/fimmu.2018.00530
    1. Bin Dhuban K, D'Hennezel E, Nagai Y, Xiao Y, Shao S, Istomine R, et al. . Suppression by human FOXP3(+) regulatory T cells requires FOXP3-TIP60 interactions. Sci Immunol. (2017) 2:eaai9297. 10.1126/sciimmunol.aai9297
    1. Roncarolo MG, Gregori S, Bacchetta R, Battaglia M, Gagliani N. The biology of T regulatory type 1 cells and their therapeutic application in immune-mediated diseases. Immunity. (2018) 49:1004–19. 10.1016/j.immuni.2018.12.001

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