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IPEX Syndrome with Normal FOXP3 Protein Expression in Treg Cells in an Infant Presenting with Intractable Diarrhea as a Single Symptom

IPEX Syndrome with Normal FOXP3 Protein Expression in Treg Cells in an Infant Presenting with... Hindawi Case Reports in Immunology Volume 2020, Article ID 9860863, 5 pages https://doi.org/10.1155/2020/9860863 Case Report IPEX Syndrome with Normal FOXP3 Protein Expression in Treg Cells in an Infant Presenting with Intractable Diarrhea as a Single Symptom 1 2 3 2 Ali Al Maawali, Beata Derfalvi, Johan Van Limbergen, Andrew Issekutz, 2 1 1 Thomas Issekutz, Hasan Ghandourah, and Mohsin Rashid Department of Paediatrics, Faculty of Medicine, Dalhousie University, IWK Health Centre, Halifax, Nova Scotia, Canada Division of Immunology, Department of Paediatrics, Faculty of Medicine, Dalhousie University, IWK Health Centre, Halifax, Nova Scotia, Canada Division of Pediatric Gastroenterology and Nutrition, Emma Children’s Hospital, Amsterdam University Medical Centers, Amsterdam, Netherlands Correspondence should be addressed to Mohsin Rashid; mohsin.rashid@iwk.nshealth.ca Received 29 December 2019; Revised 4 July 2020; Accepted 2 September 2020; Published 9 September 2020 Academic Editor: Jiri Litzman Copyright © 2020 Ali Al maawali et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. IPEX (immune dysregulation-polyendocrinopathy-enteropathy-X-linked) syndrome is a rare, potentially fatal multisystem disorder caused by mutations in the FOXP3 gene. *is can lead to quantitative or functional deficiency of regulatory T cells (Treg), thereby affecting their immune-suppressive actions which can in turn cause autoimmune and inflammatory disorders. We describe an infant with IPEX syndrome with unremarkable maternal family history whose only presentations were severe diarrhea and malnutrition. *e patient had a normal percentage of Treg cells and FOXP3 protein expression, but further testing revealed a hemizygous missense mutation in the FOXP3 gene. IPEX syndrome should be considered in young children even if severe intractable diarrhea is the only symptom with no other autoimmune manifestations. Sequencing of the FOXP3 gene should always be considered for accurate diagnosis to look for mutations even in the face of normal FOXP3 protein expression in the Treg cell. FOXP3 can cause qualitative or functional deficiency of Treg 1. Introduction cells, thus leading to immune dysregulation and IPEX IPEX (immune dysregulation-polyendocrinopathy-enter- syndrome [2–5]. IPEX syndrome can be misdiagnosed and opathy-X-linked) syndrome is a rare multisystem disorder hence may be underreported [6]. that often presents in early childhood and can be fatal. It was first described by Powell et al. in 1982 [1]. Immune dys- 2. Case Presentation regulation is the hallmark of this disorder. Human immu- nological self-tolerance on the periphery is controlled by a A 5-month-old male was admitted with severe diarrhea and subset of T lymphocyte cells called the regulatory (Treg) cells failure to thrive. *e baby was born at term after an un- [2]. *ey play a pivotal role in suppressing autoimmunity eventful pregnancy and delivery with a birth weight of and atopy by suppressing self-reactive lymphocytes and 2.97 kg. He was exclusively breast-fed. At 2-1/2 months of preventing excessive reactions to self- and foreign antigens age, he developed frequent, large volume, watery stools with [2, 3]. *e Treg cell development and function are dependent occasional blood streaks. *ere was no fever, emesis, or any on the expression of a protein called forkhead box protein 3 infectious contacts. *e family history was only significant (FOXP3). FOXP3 is a transcription factor located on for two paternal second-degree relatives with celiac disease chromosome Xp11.23 and is considered a master switch and one-second degree relative with a thyroid disorder and gene for these Treg cells. *e absence or dysfunction of type 1 diabetes mellitus. 2 Case Reports in Immunology Table 1: Results of initial laboratory investigations. On initial examination, the child appeared ill, pale, malnourished, and dehydrated. *e weight was 5.19 kg Result Normal values (<3rd percentile), length was 59.7 cm (<3rd percentile), and Hemoglobin 67 96–124 g/L head circumference was 40.5 cm (between 3rd and 10th White blood cells 20.51 6.5–13.3 × 10 /L percentile). Other than some diaper rashes, the physical 9 Platelet 508 244–529 × 10 /L examination was unremarkable with no atopic dermatitis or pH 7.31 7.35–7.45 icthyosis. pCO 41.7 35–48 mmHg *e results of initial investigations are shown in Table 1. Base excess −4.7 −4.0–2.0 mmol/L *e absolute eosinophil count was only slightly elevated. HCO 12.8 16–24 mmol/L Total protein 43.9 62–78 g/L Immunoglobulins including IgE were normal. *e serum Albumin 21.7 36–49 g/L albumin was low, consistent with the protein losing en- Glucose 5.4 3.3–5.6 mmol/L teropathy. Stool examination did not reveal any pathogens. IgG 3.45 0.80–5.12 g/L Stool electrolytes showed secretory diarrhea. *e antinuclear IgA 0.45 0.03–0.42 g/L antibody and direct antiglobulin were negative. IgM 0.20 0.23–0.96 g/L Endoscopy and biopsies revealed acute and chronic IgE 95 1–110 IU/mL inflammation, marked autoimmune enteropathy with total Stool calprotectin 99 <50 mcg/g + + villous atrophy, and abundant CD3 T- and CD20 B-cell aggregates in the small intestine and colon. having eczema of typical distribution and morphology seen Further immunological workup showed intact IL-10 in toddlers and responding to high-potency topical corti- receptor function since endotoxin-induced tumor necrosis costeroids. He is immunocompetent and has sustained factor (TNF) production in mononuclear cells was sup- protective antibody titres to several vaccine antigens. pressed by IL-10. Initial T- and B-cell phenotype analysis was normal. *e percentage of circulating Treg cells and FOXP3 protein expression in these cells measured by flow 3. Discussion cytometry were also normal (Figures 1(a) and 1(b)). Analysis of all coding regions and exon/intron bound- IPEX syndrome is a rare but potentially fatal disorder re- aries of the FOXP3 gene was carried out. *is revealed a quiring a high index of suspicion for a timely diagnosis. *e hemizygous missense mutation (c.1190G> A, p.Arg397Gln) commonest mode of presentation is with intractable diar- which would result in a nonfunctional FOXP3 protein and rhea, growth problems, dermatitis, and autoimmune Treg cells, similarly in the patient’s mother, who is a healthy endocrinopathy [6, 7]. Histological finding in the IPEX career. *e anti-islet cell antibody was negative, insulin-like syndrome, as with most other autoimmune enteropathies, is growth factor-1 level was normal, and the patient never variable with the commonest finding being a graft-versus- developed type 1 diabetes mellitus. *yroid function was host disease-like pattern associated with positive anti- also normal. enterocyte antibodies [8]. Screening the enteropathy-related *e patient required intensive resuscitation with intra- autoantibodies (antivillin, antiharmonin, and antienterocyte venous fluids. He was then managed with parenteral nu- antibodies) which are 8–92% positive in sera of IPEX pa- trition and high-dose intravenous corticosteroids. He was tients could have helped the diagnosis in our patient as well maintained on oral prednisone and tacrolimus. *e clinical [9, 10]. Additional clinical features of autoimmunity such as condition gradually improved, and he was able to initiate Coombs-positive hemolytic anemia, thrombocytopenia or oral intake with an elemental formula in a few weeks. neutropenia, hypothyroidism, and interstitial nephritis [6] *e patient had a matched unrelated hematopoietic stem were tested; however, our patient is unique since his only cell transplant (HSCT) with reduced intensity conditioning presentation was severe diarrhea. *ere is a wide spectrum of including alemtuzumab, fludarabine, and melphalan at 8 disorders that can present with severe life-threatening di- months of age. Early transplant period was complicated with arrhea in infants, and these should be considered in the donor Epstein–Barr virus (EBV) reactivation treated with differential diagnosis [11]. rituximab. He developed autoimmune hemolytic anemia. *e initial laboratory findings may show eosinophilia, Initially, enteropathy significantly improved; however, co- neutropenia, anemia, or thrombocytopenia as a result of litis recurred 3 months after the transplant when, unfor- autoimmune phenomena [12], and other autoimmune ab- tunately, there was decreasing mixed chimerism and normalities should be sought, including anti-islet antibodies secondary bone marrow rejection. Donor lymphocyte in- and antithyroid antibodies. Our patient had no autoimmune fusions were unsuccessful, and the patient required a second phenomenon apart from enteritis [7, 8] and had normal transplant at 14 months of age from the same donor with serum IgG level despite severe protein loss through the gut. busulfan, fludarabine, and alemtuzumab conditioning this Serum IgE and IgA may be elevated in IPEX syndrome, but time. our patient had normal levels [6, 8, 13]. Lymphocyte subsets Two years after the second HSCT, the patient has mixed are typically not diagnostic as B- and T-cell subsets are chimerism and 65% of donor haematopoiesis but 91% of normal in most patients with IPEX syndrome. *e Treg cell donor Treg cells (Table 2). *e gut function gradually re- immunophenotyping quantitative analysis via flow cytom- covered, and graft-versus-host disease was ruled out on etry, when compared with an age-matching control, may repeated gut biopsies. Currently, he is doing well, except show absence of Treg cells; however, the presence of the Treg Case Reports in Immunology 3 CD4+ CD4+ 5 5 10 10 Non-Treg cells CD25+ FOXP3 CD127+25– Non-Treg 80.43% of Treg cells 0.64% 4 4 10 10 3 3 10 10 2 2 10 10 CD25brCD127low 2 6.3% 2 –10 –10 2 0 2 3 4 5 2 0 2 3 4 5 –10 10 10 10 10 10 –10 10 10 10 10 10 CD25 APC-A CD25 APC-A (a) CD4+ CD4+ 5 5 10 10 CD25+ Non-Treg cells Non-Treg FOXP3 CD127+25- cells 1.87% 80.67% of Treg 4 4 10 10 3 3 10 10 1 1 10 10 CD25brCD127low 2 2 –10 8.3% –10 2 1 2 3 4 5 2 1 2 3 4 5 –10 10 10 10 10 10 –10 10 10 10 10 10 CD25 APC-A CD25 APC-A (b) Figure 1: FOXP3 expression in Treg cells measured by flow cytometry: (a) control; (b) patient. Table 2: Lymphocyte subsets before and after the hematopoietic stem cell transplant (HSCT). + + + + low+ + + + − + + CD19 B CD3 CD4 25 127 CD3 4 45RA CD3 16 56 + + CD4 T cells CD8 T cells cells T cells Treg cells na¨ ıve T cells NK cells 12%, 82%, 17%, 63%, 8% of CD4 T cells, 5%, 600 cells/ At onset of disease (6 1,430 cells/ 9,700 cells/ 2,000 cells/ 7,500 cells/ 344 cells/mcL 66% mcL (50–75 months of age) mcL mcL mcL mcL (>95pc) (10–90pc) pc) (50–75pc) (>95pc) (90–95pc) 3 mo after the first 27%, HSCT 61%, 19%, 530 cells/ 29%, 560 cells/ (13 months of age), 15% 0% 1,150 cells/ 360 cells/ ND 2% mcL mcL (75pc) donor cells on total mcL (<5pc) mcL (<5pc) (10–25pc) chimerism 22%, 24 mo after the second 47%, 4% of CD4 T cells, 11%, 81%, 490 cells/ HSCT (3.5 years of age), 1,000 cells/ 40 cells/mcL 3%, 70 cells/ 250 cells/ 1,830 cells/ mcL 48% 65% of donor cells on mcL, (25pc), (10–90pc), 91% mcL (<5pc) mcL (<5pc) mcL (25pc) (5–10pc), total chimerism 78% donor donor 97% donor cell and FOXP3 expression may not exclude IPEX syndrome, As of 2018, there have been around 70 mutations as demonstrated in our patient [4, 14]. Immature Treg cells identified, including that of our patient [15–17]. Table 3 can still be generated in the presence of a mutation and shows the clinical presentation of other males reported so far alteration in the FOXP3 gene, and intact FOXP3 is essential with the same mutation as found in our patient [17–19]. for the development and, more importantly, the function of *ere is no correlation between the site of the mutation and Treg cells [13]. Gene sequencing to identify a mutation in the disease course or outcome, and the same genotype can FOXP3 is a more definite way to confirm the diagnosis, and present with variable phenotypes [10], and our case offers the presence of a normal Treg phenotype should not delay further support for this finding [20]. Overall, the lack of the diagnosis of IPEX syndrome [14, 15]. genotype-phenotype correlation may reflect the complex CD127 PE-A CD127 PE-A FOXP3 FITC-A FOXP3 FITC-A 4 Case Reports in Immunology Table 3: Male patients reported with IPEX syndrome with a mutation in FOXP3 gene c.1190G> A (p. R397Q). Organ involvement Age at onset Reference Case Others of disease # Enteropathy Endocrinopathy Dermatitis 1 4 years + Type 1 diabetes + − 18 2 1 month + − + − 19 Failure to thrive, recurrent infections (Clostridium 3 6 years + − − difficile, Candida albicans, and Mycoplasma 20 pneumoniae) Our 2 months + − − Failure to thrive patient [2] T. A. Chatila, “Role of regulatory T cells in human diseases,” intracellular interactions of FOXP3 and strongly suggests the Journal of Allergy and Clinical Immunology, vol. 116, no. 5, role of epigenetic regulation in determining the clinical pp. 949–959, 2005. picture and outcome [10, 21, 22]. [3] S. Hori, T. Nomura, and S. Sakaguchi, “Control of regulatory If untreated, IPEX syndrome can be fatal within the first T cell development by the transcription factor Foxp3,” Science, two years of life [1, 6, 14]. Hematopoietic stem cell transplant vol. 299, no. 5609, pp. 1057–1061, 2003. (HSCT) is an effective therapy for IPEX syndrome, despite its [4] L. Zhang and Y. Zhao, “*e regulation of FOXP3 expression commonly associated complications [6, 14]. Different intensity + + in regulatory CD4 CD25 T cells: multiple pathways on the conditioning regimens have been used with reduced intensity road,” Journal of Cellular Physiology, vol. 211, no. 3, conditioning regimens being most successful with less mor- pp. 590–597, 2007. bidity and mortality [23, 24]. However, it increases the risk for [5] C. L. Bennett, R. Yoshioka, H. Kiyosawa et al., “X-Linked graft rejection as in our patient. Mixed chimerism was detected syndrome of polyendocrinopathy, immune dysfunction, and in one-third of the patients resulting in disease remission only diarrhea maps to Xp11.23-Xq13.3,” ,e American Journal of in the half of them, especially with full-donor Treg cell origin, Human Genetics, vol. 66, no. 2, pp. 461–468, 2000. [6] R. S. Wildin, S. Smyk-Pearson, and A. H. Filipovich, “Clinical such as in our patient. Early HSCT carries more favorable and molecular features of the immunodysregulation, poly- outcome, as some of the endocrine organs can be damaged endocrinopathy, enteropathy, X linked (IPEX) syndrome,” permanently if not treated early in course of the disease [14, 25]. Journal of Medical Genetics, vol. 39, no. 8, pp. 537–545, 2002. Early HSCT in our patient prevented every autoimmune [7] A. Blanco Quiros, ´ E. Arranz Sanz, D. Bernardo Ordiz, and complication; autoimmune hemolytic anemia was secondary to J. A. Garrote Adrados, “From autoimmune enteropathy to the EBV reactivation-induced immune dysregulation or graft- IPEX (immune dysfunction, polyendocrinopathy, enteropa- versus-host disease rather than a manifestation of IPEX syn- thy, X-linked) syndrome,” Allergologia et Immunopathologia, drome. *ere are new evolving treatments such as gene therapy vol. 37, no. 4, pp. 208–215, 2009. which may offer a more definite cure in the future [10]. [8] N. Patey-Mariaud de Serre, D. Canioni, S. Ganousse et al., In conclusion, IPEX syndrome should be considered in “Digestive histopathological presentation of IPEX syndrome,” young male children with severe intractable diarrhea even in Modern Pathology, vol. 22, no. 1, pp. 95–102, 2009. the absence of eczema and other autoimmune endo- [9] V. Lampasona, L. Passerini, F. Barzaghi et al., “Autoantibodies crinopathies, regardless of the family history. Sequencing of to harmonin and villin are diagnostic markers in children with IPEX syndrome,” PLoS One, vol. 8, no. 11, Article ID e78664, the FOXP3 gene should always be carried out to look for mutations even in the face of normal FOXP3 protein ex- [10] F. Barzaghi, L. C. Amaya Hernandez, B. Neven et al., “Long- pression in the Treg cell. A timely diagnosis is essential to term follow-up of IPEX syndrome patients after different offer HSCT in this potentially fatal disorder. therapeutic strategies: an international multicenter retro- spective study,” Journal of Allergy and Clinical Immunology, Conflicts of Interest vol. 141, no. 3, pp. 1036–1049, 2018. [11] J. R. Kelsen, P. Russo, and K. E. Sullivan, “Early-onset in- *e authors declare that they have no conflicts of interest. flammatory bowel disease,” Immunology and Allergy Clinics of North America, vol. 39, no. 1, pp. 63–79, 2019. Acknowledgments [12] D. Moraes-Vasconcelos, B. T. Costa-Carvalho, T. R. Torgerson, and H. D. Ochs, “Primary immune deficiency *e authors would like to acknowledge the support of Dr. disorders presenting as autoimmune diseases: IPEX and Pierre Teira, Division of Hematology-Oncology, Depart- APECED,” Journal of Clinical Immunology, vol. 28, no. S1, ment of Pediatrics, CHU Sainte-Justine, Montreal, Canada, pp. 11–19, 2008. in the management of this case. [13] E. Ozcan, L. D. Notarangelo, and R. S. Geha, “Primary im- mune deficiencies with aberrant IgE production,” Journal of Allergy and Clinical Immunology, vol. 122, no. 6, pp. 1054– References 1062, 2008. [14] E. d’Hennezel, K. Bin Dhuban, T. Torgerson, and C. Piccirillo, [1] B. R. Powell, N. R. M. Buist, and P. Stenzel, “An X-linked syndrome of diarrhea, polyendocrinopathy, and fatal infec- “*e immunogenetics of immune dysregulation, poly- endocrinopathy, enteropathy, X linked (IPEX) syndrome,” tion in infancy,” ,e Journal of Pediatrics, vol. 100, no. 5, pp. 731–737, 1982. Journal of Medical Genetics, vol. 49, no. 5, pp. 291–302, 2012. Case Reports in Immunology 5 [15] E. Gambineri, L. Perroni, L. Passerini 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,” Journal of Allergy and Clinical Immunology, vol. 122, no. 6, pp. 1105–1112, 2008. [16] K. Otsubo, H. Kanegane, Y. Kamachi et al., “Identification of + + low FOXP3-negative regulatory T-like (CD4 CD25 CD127 ) cells in patients with immune dysregulation, poly- endocrinopathy, enteropathy, X-linked syndrome,” Clinical Immunology, vol. 141, no. 1, pp. 111–120, 2011. [17] A. Mart´ ın-Santiago, J. A. Hervas, ´ D. Hervas ´ et al., “Diagnostic value of the skin lesions in immune dysregulation, poly- endocrinopathy, enteropathy, X-linked syndrome,” Pediatric Dermatology, vol. 30, no. 6, pp. e221–e222, 2013. [18] M. Tsuda, T. R. Torgerson, C. Selmi et al., “*e spectrum of autoantibodies in IPEX syndrome is broad and includes anti- mitochondrial autoantibodies,” Journal of Autoimmunity, vol. 35, no. 3, pp. 265–268, 2010. [19] T. Ge, Y. Wang, Y. Che, Y. Xiao, and T. Zhang, “Atypical late- onset immune dysregulation, polyendocrinopathy, enterop- athy, X-linked syndrome with intractable diarrhea: a case report,” Frontiers in Pediatrics, vol. 5, p. 267, 2017. [20] E. Gambineri, S. Ciullini Mannurita, D. Hagin et al., “Clinical, immunological, and molecular heterogeneity of 173 patients with the phenotype of immune dysregulation, poly- endocrinopathy, enteropathy, X-linked (IPEX) syndrome,” Frontiers in Immunology, vol. 9, p. 2411, 2018. [21] S. Horino, Y. Sasahara, M. Sato et al., “Selective expansion of donor-derived regulatory T cells after allogeneic bone marrow transplantation in a patient with IPEX syndrome,” Pediatric Transplantation, vol. 18, no. 1, pp. E25–E30, 2014. [22] R. Bacchetta, F. Barzaghi, and M.-G. Roncarolo, “From IPEX syndrome to FOXP3 mutation: a lesson on immune dysre- gulation,” Annals of the New York Academy of Sciences, vol. 1417, no. 1, pp. 5–22, 2018. [23] M. M. Xavier-da-Silva, C. A. Moreira-Filho, E. Suzuki, F. Patricio, A. Coutinho, and M. Carneiro-Sampaio, “Fetal- onset IPEX: report of two families and review of literature,” Clinical Immunology, vol. 156, no. 2, pp. 131–140, 2015. [24] O. Baud, O. Goulet, D. Canioni et al., “Treatment of the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) by allogeneic bone marrow transplantation,” New England Journal of Medicine, vol. 344, no. 23, pp. 1758–1762, 2001. [25] L. Passerini, F. Sio, M. Porteus, and R. Bacchetta, “Gene/Cell therapy approaches for immune dysregulation poly- endocrinopathy enteropathy X-linked syndrome,” Current Gene ,erapy, vol. 14, no. 6, pp. 422–428, 2014. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Case Reports in Immunology Hindawi Publishing Corporation

IPEX Syndrome with Normal FOXP3 Protein Expression in Treg Cells in an Infant Presenting with Intractable Diarrhea as a Single Symptom

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Copyright © 2020 Ali Al maawali et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract

Hindawi Case Reports in Immunology Volume 2020, Article ID 9860863, 5 pages https://doi.org/10.1155/2020/9860863 Case Report IPEX Syndrome with Normal FOXP3 Protein Expression in Treg Cells in an Infant Presenting with Intractable Diarrhea as a Single Symptom 1 2 3 2 Ali Al Maawali, Beata Derfalvi, Johan Van Limbergen, Andrew Issekutz, 2 1 1 Thomas Issekutz, Hasan Ghandourah, and Mohsin Rashid Department of Paediatrics, Faculty of Medicine, Dalhousie University, IWK Health Centre, Halifax, Nova Scotia, Canada Division of Immunology, Department of Paediatrics, Faculty of Medicine, Dalhousie University, IWK Health Centre, Halifax, Nova Scotia, Canada Division of Pediatric Gastroenterology and Nutrition, Emma Children’s Hospital, Amsterdam University Medical Centers, Amsterdam, Netherlands Correspondence should be addressed to Mohsin Rashid; mohsin.rashid@iwk.nshealth.ca Received 29 December 2019; Revised 4 July 2020; Accepted 2 September 2020; Published 9 September 2020 Academic Editor: Jiri Litzman Copyright © 2020 Ali Al maawali et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. IPEX (immune dysregulation-polyendocrinopathy-enteropathy-X-linked) syndrome is a rare, potentially fatal multisystem disorder caused by mutations in the FOXP3 gene. *is can lead to quantitative or functional deficiency of regulatory T cells (Treg), thereby affecting their immune-suppressive actions which can in turn cause autoimmune and inflammatory disorders. We describe an infant with IPEX syndrome with unremarkable maternal family history whose only presentations were severe diarrhea and malnutrition. *e patient had a normal percentage of Treg cells and FOXP3 protein expression, but further testing revealed a hemizygous missense mutation in the FOXP3 gene. IPEX syndrome should be considered in young children even if severe intractable diarrhea is the only symptom with no other autoimmune manifestations. Sequencing of the FOXP3 gene should always be considered for accurate diagnosis to look for mutations even in the face of normal FOXP3 protein expression in the Treg cell. FOXP3 can cause qualitative or functional deficiency of Treg 1. Introduction cells, thus leading to immune dysregulation and IPEX IPEX (immune dysregulation-polyendocrinopathy-enter- syndrome [2–5]. IPEX syndrome can be misdiagnosed and opathy-X-linked) syndrome is a rare multisystem disorder hence may be underreported [6]. that often presents in early childhood and can be fatal. It was first described by Powell et al. in 1982 [1]. Immune dys- 2. Case Presentation regulation is the hallmark of this disorder. Human immu- nological self-tolerance on the periphery is controlled by a A 5-month-old male was admitted with severe diarrhea and subset of T lymphocyte cells called the regulatory (Treg) cells failure to thrive. *e baby was born at term after an un- [2]. *ey play a pivotal role in suppressing autoimmunity eventful pregnancy and delivery with a birth weight of and atopy by suppressing self-reactive lymphocytes and 2.97 kg. He was exclusively breast-fed. At 2-1/2 months of preventing excessive reactions to self- and foreign antigens age, he developed frequent, large volume, watery stools with [2, 3]. *e Treg cell development and function are dependent occasional blood streaks. *ere was no fever, emesis, or any on the expression of a protein called forkhead box protein 3 infectious contacts. *e family history was only significant (FOXP3). FOXP3 is a transcription factor located on for two paternal second-degree relatives with celiac disease chromosome Xp11.23 and is considered a master switch and one-second degree relative with a thyroid disorder and gene for these Treg cells. *e absence or dysfunction of type 1 diabetes mellitus. 2 Case Reports in Immunology Table 1: Results of initial laboratory investigations. On initial examination, the child appeared ill, pale, malnourished, and dehydrated. *e weight was 5.19 kg Result Normal values (<3rd percentile), length was 59.7 cm (<3rd percentile), and Hemoglobin 67 96–124 g/L head circumference was 40.5 cm (between 3rd and 10th White blood cells 20.51 6.5–13.3 × 10 /L percentile). Other than some diaper rashes, the physical 9 Platelet 508 244–529 × 10 /L examination was unremarkable with no atopic dermatitis or pH 7.31 7.35–7.45 icthyosis. pCO 41.7 35–48 mmHg *e results of initial investigations are shown in Table 1. Base excess −4.7 −4.0–2.0 mmol/L *e absolute eosinophil count was only slightly elevated. HCO 12.8 16–24 mmol/L Total protein 43.9 62–78 g/L Immunoglobulins including IgE were normal. *e serum Albumin 21.7 36–49 g/L albumin was low, consistent with the protein losing en- Glucose 5.4 3.3–5.6 mmol/L teropathy. Stool examination did not reveal any pathogens. IgG 3.45 0.80–5.12 g/L Stool electrolytes showed secretory diarrhea. *e antinuclear IgA 0.45 0.03–0.42 g/L antibody and direct antiglobulin were negative. IgM 0.20 0.23–0.96 g/L Endoscopy and biopsies revealed acute and chronic IgE 95 1–110 IU/mL inflammation, marked autoimmune enteropathy with total Stool calprotectin 99 <50 mcg/g + + villous atrophy, and abundant CD3 T- and CD20 B-cell aggregates in the small intestine and colon. having eczema of typical distribution and morphology seen Further immunological workup showed intact IL-10 in toddlers and responding to high-potency topical corti- receptor function since endotoxin-induced tumor necrosis costeroids. He is immunocompetent and has sustained factor (TNF) production in mononuclear cells was sup- protective antibody titres to several vaccine antigens. pressed by IL-10. Initial T- and B-cell phenotype analysis was normal. *e percentage of circulating Treg cells and FOXP3 protein expression in these cells measured by flow 3. Discussion cytometry were also normal (Figures 1(a) and 1(b)). Analysis of all coding regions and exon/intron bound- IPEX syndrome is a rare but potentially fatal disorder re- aries of the FOXP3 gene was carried out. *is revealed a quiring a high index of suspicion for a timely diagnosis. *e hemizygous missense mutation (c.1190G> A, p.Arg397Gln) commonest mode of presentation is with intractable diar- which would result in a nonfunctional FOXP3 protein and rhea, growth problems, dermatitis, and autoimmune Treg cells, similarly in the patient’s mother, who is a healthy endocrinopathy [6, 7]. Histological finding in the IPEX career. *e anti-islet cell antibody was negative, insulin-like syndrome, as with most other autoimmune enteropathies, is growth factor-1 level was normal, and the patient never variable with the commonest finding being a graft-versus- developed type 1 diabetes mellitus. *yroid function was host disease-like pattern associated with positive anti- also normal. enterocyte antibodies [8]. Screening the enteropathy-related *e patient required intensive resuscitation with intra- autoantibodies (antivillin, antiharmonin, and antienterocyte venous fluids. He was then managed with parenteral nu- antibodies) which are 8–92% positive in sera of IPEX pa- trition and high-dose intravenous corticosteroids. He was tients could have helped the diagnosis in our patient as well maintained on oral prednisone and tacrolimus. *e clinical [9, 10]. Additional clinical features of autoimmunity such as condition gradually improved, and he was able to initiate Coombs-positive hemolytic anemia, thrombocytopenia or oral intake with an elemental formula in a few weeks. neutropenia, hypothyroidism, and interstitial nephritis [6] *e patient had a matched unrelated hematopoietic stem were tested; however, our patient is unique since his only cell transplant (HSCT) with reduced intensity conditioning presentation was severe diarrhea. *ere is a wide spectrum of including alemtuzumab, fludarabine, and melphalan at 8 disorders that can present with severe life-threatening di- months of age. Early transplant period was complicated with arrhea in infants, and these should be considered in the donor Epstein–Barr virus (EBV) reactivation treated with differential diagnosis [11]. rituximab. He developed autoimmune hemolytic anemia. *e initial laboratory findings may show eosinophilia, Initially, enteropathy significantly improved; however, co- neutropenia, anemia, or thrombocytopenia as a result of litis recurred 3 months after the transplant when, unfor- autoimmune phenomena [12], and other autoimmune ab- tunately, there was decreasing mixed chimerism and normalities should be sought, including anti-islet antibodies secondary bone marrow rejection. Donor lymphocyte in- and antithyroid antibodies. Our patient had no autoimmune fusions were unsuccessful, and the patient required a second phenomenon apart from enteritis [7, 8] and had normal transplant at 14 months of age from the same donor with serum IgG level despite severe protein loss through the gut. busulfan, fludarabine, and alemtuzumab conditioning this Serum IgE and IgA may be elevated in IPEX syndrome, but time. our patient had normal levels [6, 8, 13]. Lymphocyte subsets Two years after the second HSCT, the patient has mixed are typically not diagnostic as B- and T-cell subsets are chimerism and 65% of donor haematopoiesis but 91% of normal in most patients with IPEX syndrome. *e Treg cell donor Treg cells (Table 2). *e gut function gradually re- immunophenotyping quantitative analysis via flow cytom- covered, and graft-versus-host disease was ruled out on etry, when compared with an age-matching control, may repeated gut biopsies. Currently, he is doing well, except show absence of Treg cells; however, the presence of the Treg Case Reports in Immunology 3 CD4+ CD4+ 5 5 10 10 Non-Treg cells CD25+ FOXP3 CD127+25– Non-Treg 80.43% of Treg cells 0.64% 4 4 10 10 3 3 10 10 2 2 10 10 CD25brCD127low 2 6.3% 2 –10 –10 2 0 2 3 4 5 2 0 2 3 4 5 –10 10 10 10 10 10 –10 10 10 10 10 10 CD25 APC-A CD25 APC-A (a) CD4+ CD4+ 5 5 10 10 CD25+ Non-Treg cells Non-Treg FOXP3 CD127+25- cells 1.87% 80.67% of Treg 4 4 10 10 3 3 10 10 1 1 10 10 CD25brCD127low 2 2 –10 8.3% –10 2 1 2 3 4 5 2 1 2 3 4 5 –10 10 10 10 10 10 –10 10 10 10 10 10 CD25 APC-A CD25 APC-A (b) Figure 1: FOXP3 expression in Treg cells measured by flow cytometry: (a) control; (b) patient. Table 2: Lymphocyte subsets before and after the hematopoietic stem cell transplant (HSCT). + + + + low+ + + + − + + CD19 B CD3 CD4 25 127 CD3 4 45RA CD3 16 56 + + CD4 T cells CD8 T cells cells T cells Treg cells na¨ ıve T cells NK cells 12%, 82%, 17%, 63%, 8% of CD4 T cells, 5%, 600 cells/ At onset of disease (6 1,430 cells/ 9,700 cells/ 2,000 cells/ 7,500 cells/ 344 cells/mcL 66% mcL (50–75 months of age) mcL mcL mcL mcL (>95pc) (10–90pc) pc) (50–75pc) (>95pc) (90–95pc) 3 mo after the first 27%, HSCT 61%, 19%, 530 cells/ 29%, 560 cells/ (13 months of age), 15% 0% 1,150 cells/ 360 cells/ ND 2% mcL mcL (75pc) donor cells on total mcL (<5pc) mcL (<5pc) (10–25pc) chimerism 22%, 24 mo after the second 47%, 4% of CD4 T cells, 11%, 81%, 490 cells/ HSCT (3.5 years of age), 1,000 cells/ 40 cells/mcL 3%, 70 cells/ 250 cells/ 1,830 cells/ mcL 48% 65% of donor cells on mcL, (25pc), (10–90pc), 91% mcL (<5pc) mcL (<5pc) mcL (25pc) (5–10pc), total chimerism 78% donor donor 97% donor cell and FOXP3 expression may not exclude IPEX syndrome, As of 2018, there have been around 70 mutations as demonstrated in our patient [4, 14]. Immature Treg cells identified, including that of our patient [15–17]. Table 3 can still be generated in the presence of a mutation and shows the clinical presentation of other males reported so far alteration in the FOXP3 gene, and intact FOXP3 is essential with the same mutation as found in our patient [17–19]. for the development and, more importantly, the function of *ere is no correlation between the site of the mutation and Treg cells [13]. Gene sequencing to identify a mutation in the disease course or outcome, and the same genotype can FOXP3 is a more definite way to confirm the diagnosis, and present with variable phenotypes [10], and our case offers the presence of a normal Treg phenotype should not delay further support for this finding [20]. Overall, the lack of the diagnosis of IPEX syndrome [14, 15]. genotype-phenotype correlation may reflect the complex CD127 PE-A CD127 PE-A FOXP3 FITC-A FOXP3 FITC-A 4 Case Reports in Immunology Table 3: Male patients reported with IPEX syndrome with a mutation in FOXP3 gene c.1190G> A (p. R397Q). Organ involvement Age at onset Reference Case Others of disease # Enteropathy Endocrinopathy Dermatitis 1 4 years + Type 1 diabetes + − 18 2 1 month + − + − 19 Failure to thrive, recurrent infections (Clostridium 3 6 years + − − difficile, Candida albicans, and Mycoplasma 20 pneumoniae) Our 2 months + − − Failure to thrive patient [2] T. A. Chatila, “Role of regulatory T cells in human diseases,” intracellular interactions of FOXP3 and strongly suggests the Journal of Allergy and Clinical Immunology, vol. 116, no. 5, role of epigenetic regulation in determining the clinical pp. 949–959, 2005. picture and outcome [10, 21, 22]. [3] S. Hori, T. Nomura, and S. Sakaguchi, “Control of regulatory If untreated, IPEX syndrome can be fatal within the first T cell development by the transcription factor Foxp3,” Science, two years of life [1, 6, 14]. Hematopoietic stem cell transplant vol. 299, no. 5609, pp. 1057–1061, 2003. (HSCT) is an effective therapy for IPEX syndrome, despite its [4] L. Zhang and Y. Zhao, “*e regulation of FOXP3 expression commonly associated complications [6, 14]. Different intensity + + in regulatory CD4 CD25 T cells: multiple pathways on the conditioning regimens have been used with reduced intensity road,” Journal of Cellular Physiology, vol. 211, no. 3, conditioning regimens being most successful with less mor- pp. 590–597, 2007. bidity and mortality [23, 24]. However, it increases the risk for [5] C. L. Bennett, R. Yoshioka, H. Kiyosawa et al., “X-Linked graft rejection as in our patient. Mixed chimerism was detected syndrome of polyendocrinopathy, immune dysfunction, and in one-third of the patients resulting in disease remission only diarrhea maps to Xp11.23-Xq13.3,” ,e American Journal of in the half of them, especially with full-donor Treg cell origin, Human Genetics, vol. 66, no. 2, pp. 461–468, 2000. [6] R. S. Wildin, S. Smyk-Pearson, and A. H. Filipovich, “Clinical such as in our patient. Early HSCT carries more favorable and molecular features of the immunodysregulation, poly- outcome, as some of the endocrine organs can be damaged endocrinopathy, enteropathy, X linked (IPEX) syndrome,” permanently if not treated early in course of the disease [14, 25]. Journal of Medical Genetics, vol. 39, no. 8, pp. 537–545, 2002. Early HSCT in our patient prevented every autoimmune [7] A. Blanco Quiros, ´ E. Arranz Sanz, D. Bernardo Ordiz, and complication; autoimmune hemolytic anemia was secondary to J. A. 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Sequencing of to harmonin and villin are diagnostic markers in children with IPEX syndrome,” PLoS One, vol. 8, no. 11, Article ID e78664, the FOXP3 gene should always be carried out to look for mutations even in the face of normal FOXP3 protein ex- [10] F. Barzaghi, L. C. Amaya Hernandez, B. Neven et al., “Long- pression in the Treg cell. A timely diagnosis is essential to term follow-up of IPEX syndrome patients after different offer HSCT in this potentially fatal disorder. therapeutic strategies: an international multicenter retro- spective study,” Journal of Allergy and Clinical Immunology, Conflicts of Interest vol. 141, no. 3, pp. 1036–1049, 2018. [11] J. R. Kelsen, P. Russo, and K. E. Sullivan, “Early-onset in- *e authors declare that they have no conflicts of interest. flammatory bowel disease,” Immunology and Allergy Clinics of North America, vol. 39, no. 1, pp. 63–79, 2019. Acknowledgments [12] D. Moraes-Vasconcelos, B. T. Costa-Carvalho, T. R. Torgerson, and H. D. 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