Medical Care

Hematopoietic stem cell transplantation (HSCT) and chronic immunosuppression represent the two main therapeutic interventions for immune dysfunction, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. HSCT is the only curative treatment for IPEX^[28]. Although conventional myeloablative conditioning has been associated with significant treatment-related mortality, emerging evidence suggests that reduced intensity conditioning holds promise as a treatment modality. Some more limited data have suggested a higher rate of graft failure, particularly when compared to other immune disorders, but more study is required. Early identification of IPEX and treatment via HSCT hold the potential to reduce the effects of chronic immunosuppressive regimens and disease-related organ damage.^{[29, 30, 31, 32]}

Supportive therapies may be required for other disorders associated with IPEX syndrome, including the following:

Insulin-dependent diabetes mellitus: Insulin replacement is indicated.
Autoimmune thyroid disease: Hypothyroidism is treated with levothyroxine. Hyperthyroidism is treated with anti-thyroid medications, radioactive iodine¹³¹ I, or thyroidectomy.
Enteropathy: Immunosuppressive agents such as oral corticosteroids, cyclosporin A, tacrolimus, sirolimus, rituximab, and infliximab have been successful to control symptoms but fail to provide long-term remission.^[6]Nutritional support is indicated.
Dermatitis: Emollients, topical steroids, and other anti-inflammatory agents are indicated.
Autoimmune cytopenias: Corticosteroids, granulocyte-colony stimulating factor (G-CSF, filgrastim) for neutropenia, and replacement blood products
Infections: Antibiotics are indicated.

A recent study by Passerini et al (2013) highlights the possibility of using adoptive cell therapy with genetically engineered regulatory T cells as a novel therapy for IPEX syndrome.^{[33, 34]}More research is needed to explore this and related gene therapy approaches.

Consultations

Evaluation of the immune system should be performed through consultation with an immunologist.

Patients with IPEX syndrome should be referred to an endocrinologist for management of diabetes and thyroid disease.

Consultation with a gastroenterologist is indicated for diagnosis and management of enteropathy.

Patients with autoimmune cytopenias may benefit from consultation with a hematologist to assist with management.

Proper diagnosis and management of the skin manifestations associated with IPEX syndrome may require consultation with a dermatologist.

Nutrition consultation may be beneficial in patients with IPEX syndrome.

Patients with evidence of renal disease should be referred to a nephrologist for diagnosis and management.

Patients with recurrent and severe infections may benefit from consultation with an infectious disease specialist.

A transplant team should be consulted if hematopoietic stem cell transplantation (HSCT) is considered.

Patients and families with IPEX syndrome should be referred to a geneticist for evaluation and counseling.

Diet

Dietary management of IPEX syndrome varies according to the degree of enteropathy and response to treatment and may include the following:^[35]

Regular diet
Low carbohydrate diet
Elemental formula
Total parenteral nutrition

Activity

Patients with thrombocytopenia should take precautions to prevent bleeding. Patients with severe anemia should avoid strenuous activity. Patients with diabetes should monitor their glucose while exercising to avoid hypoglycemia. Patients with uncontrolled hypothyroidism may have difficulty maintaining concentration and slowed reaction times. Activities with a high risk of injury should be avoided.

Prevention

Genetic testing and prenatal diagnosis may reduce the incidence of this condition. The possibility of prenatal diagnosis has been suggested by recent research.^[36]

Early hematopoietic stem cell transplantation (HSCT) may prevent end-organ damage associated with this disease.

Medication

Bennett CL, Ochs HD. IPEX is a unique X-linked syndrome characterized by immune dysfunction, polyendocrinopathy, enteropathy, and a variety of autoimmune phenomena. Curr Opin Pediatr. 2001 Dec. 13(6):533-8. [QxMD MEDLINE Link].
Torgerson TR, Ochs HD. Regulatory T cells in primary immunodeficiency diseases. Curr Opin Allergy Clin Immunol. 2007 Dec. 7(6):515-21. [QxMD MEDLINE Link].
Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet. 2002 Aug. 39(8):537-45. [QxMD MEDLINE Link].
Sharma R, Ju ST. Genetic control of the inflammatory T-cell response in regulatory T-cell deficient scurfy mice. Clin Immunol. 2010 Aug. 136(2):162-9. [QxMD MEDLINE Link].
Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: forkhead box protein 3 mutations and lack of regulatory T cells. J Allergy Clin Immunol. 2007 Oct. 120(4):744-50; quiz 751-2. [QxMD MEDLINE Link].
van der Vliet HJ, Nieuwenhuis EE. IPEX as a result of mutations in FOXP3. Clin Dev Immunol. 2007. 2007:89017. [QxMD MEDLINE Link]. [Full Text].
Su MA, Anderson MS. Monogenic autoimmune diseases: insights into self-tolerance. Pediatr Res. 2009 May. 65(5 Pt 2):20R-25R. [QxMD MEDLINE Link]. [Full Text].
Otsubo, K, H Kanegane, Y Kamachi, I Kobayashi, I Tsuge, et al. Identification of FOXP3-negative regulatory T-like (CD4+CD25+CD127low) cells in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Clinical Immunology. 2011. 141:111-120.
Passerini L, Di Nunzio S, Gregori S, et al. Functional type 1 regulatory T cells develop regardless of FOXP3 mutations in patients with IPEX syndrome. Eur J Immunol. 2011 Apr. 41(4):1120-31. [QxMD MEDLINE Link]. [Full Text].
d'Hennezel E, Bin Dhuban K, Torgerson T, Piccirillo CA, Piccirillo C. The immunogenetics of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet. 2012 May. 49(5):291-302. [QxMD MEDLINE Link].
Kinnunen T, Chamberlain N, Morbach H, Choi J, Kim S, Craft J. Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells. Blood. 2013 Feb 28. 121(9):1595-603. [QxMD MEDLINE Link].
Moraes-Vasconcelos D, Costa-Carvalho BT, Torgerson TR, Ochs HD. Primary immune deficiency disorders presenting as autoimmune diseases: IPEX and APECED. J Clin Immunol. 2008 May. 28 Suppl 1:S11-9. [QxMD MEDLINE Link].
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 Jan. 22(1):95-102. [QxMD MEDLINE Link].
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 Apr. 140(4):466-72. [QxMD MEDLINE Link].
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Genetics Home Reference. Available at https://ghr.nlm.nih.gov/condition/immune-dysregulation-polyendocrinopathy-enteropathy-x-linked-syndrome. 2019 Jul 16; Accessed: May, 2017.
Immunodysregulation, polyendocrinopathy and enteropathy X-linked. Genetic and Rare Diseases Information Center. Available at https://rarediseases.info.nih.gov/diseases/1850/immunodysregulation-polyendocrinopathy-and-enteropathy-x-linked. 2019 Aug 01; Accessed: February 2, 2016.
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 Dec. 122(6):1105-1112.e1. [QxMD MEDLINE Link].
Barzaghi F, Passerini L, Gambineri E, Ciullini Mannurita S, Cornu T, Kang ES, et al. Demethylation analysis of the FOXP3 locus shows quantitative defects of regulatory T cells in IPEX-like syndrome. J Autoimmun. 2012 Feb. 38(1):49-58. [QxMD MEDLINE Link]. [Full Text].
Ochs HD, Gambineri E, Torgerson TR. IPEX, FOXP3 and regulatory T-cells: a model for autoimmunity. Immunol Res. 2007. 38(1-3):112-21. [QxMD MEDLINE Link].
Verbsky JW, Chatila TA. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders: an evolving web of heritable autoimmune diseases. Curr Opin Pediatr. 2013 Dec. 25(6):708-14. [QxMD MEDLINE Link].
Myers AK, Perroni L, Costigan C, Reardon W. Clinical and molecular findings in IPEX syndrome. Arch Dis Child. 2006 Jan. 91(1):63-4. [QxMD MEDLINE Link]. [Full Text].
Lampasona V, Passerini L, Barzaghi F, Lombardoni C, Bazzigaluppi E, Brigatti C, et al. Autoantibodies to harmonin and villin are diagnostic markers in children with IPEX syndrome. PLoS One. 2013. 8(11):e78664. [QxMD MEDLINE Link]. [Full Text].
Rosenberg JM, Maccari ME, Barzaghi F, Allenspach EJ, Pignata C, Weber G, et al. Neutralizing Anti-Cytokine Autoantibodies Against Interferon-α in Immunodysregulation Polyendocrinopathy Enteropathy X-Linked. Front Immunol. 2018. 9:544. [QxMD MEDLINE Link]. [Full Text].
Navabi B, Upton JE. Primary immunodeficiencies associated with eosinophilia. Allergy Asthma Clin Immunol. 2016. 12:27. [QxMD MEDLINE Link]. [Full Text].
Le Bras S, Geha RS. IPEX and the role of Foxp3 in the development and function of human Tregs. J Clin Invest. 2006 Jun. 116(6):1473-5. [QxMD MEDLINE Link]. [Full Text].
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 Mar. 160(3):645-51. [QxMD MEDLINE Link].
Zennaro D, Scala E, Pomponi D, Caprini E, Arcelli D, Gambineri E, et al. Proteomics plus genomics approaches in primary immunodeficiency: the case of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Clin Exp Immunol. 2012 Jan. 167(1):120-8. [QxMD MEDLINE Link]. [Full Text].
Barzaghi F, Amaya Hernandez LC, Neven B, et al. Primary Immune Deficiency Treatment Consortium (PIDTC) and the Inborn Errors Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT). Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study. J Allergy Clin Immunol. 2018 Mar. 141 (3):1036-1049.e5. [QxMD MEDLINE Link]. [Full Text].
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 Dec. 170(12):1611-5. [QxMD MEDLINE Link].
Kasow KA, Morales-Tirado VM, Wichlan D, Shurtleff SA, Abraham A, Persons DA, et al. Therapeutic in vivo selection of thymic-derived natural T regulatory cells following non-myeloablative hematopoietic stem cell transplant for IPEX. Clin Immunol. 2011 Nov. 141(2):169-76. [QxMD MEDLINE Link]. [Full Text].
Rao A, Kamani N, Filipovich A, Lee SM, Davies SM, Dalal J, et al. Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Blood. 2007 Jan 1. 109(1):383-5. [QxMD MEDLINE Link].
Kucuk ZY, Bleesing JJ, Marsh R, Zhang K, Davies S, Filipovich AH. A challenging undertaking: Stem cell transplantation for immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. J Allergy Clin Immunol. 2016 Mar. 137 (3):953-5.e4. [QxMD MEDLINE Link].
Passerini L, Mel ER, Sartirana C, Fousteri G, Bondanza A, Naldini L, et al. CD4+ T cells from IPEX patients convert into functional and stable regulatory T cells by FOXP3 gene transfer. Sci Transl Med. 2013 Dec 11. 5(215):215ra174. [QxMD MEDLINE Link].
Passerini L, Santoni de Sio FR, Porteus MH, Bacchetta R. Gene/cell therapy approaches for Immune Dysregulation Polyendocrinopathy Enteropathy X-linked syndrome. Curr Gene Ther. 2014. 14 (6):422-8. [QxMD MEDLINE Link].
Gambarara M, Bracci F, Diamanti A, Ambrosini MI, Pietrobattista A, Knafelz D, et al. Long-term parenteral nutrition in pediatric autoimmune enteropathies. Transplant Proc. 2005 Jun. 37(5):2270-1. [QxMD MEDLINE Link].
Harbuz R, Lespinasse J, Boulet S, Francannet C, Creveaux I, Benkhelifa M, et al. Identification of new FOXP3 mutations and prenatal diagnosis of IPEX syndrome. Prenat Diagn. 2010 Nov. 30(11):1072-8. [QxMD MEDLINE Link].

Media Gallery

of 0

Author

Taylor Banks, MD Chief, Allergy/Immunology Clinic, Walter Reed National Military Medical Center; Assistant Professor of Pediatrics, Assistant Professor of Medicine, Uniformed Services University of the Health Sciences; Associate Program Director, NCC Allergy-Immunology Fellowship Program

Taylor Banks, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology

Disclosure: Nothing to disclose.

Coauthor(s)

Satyen M Gada, MD Assistant Professor, Department of Pediatrics and Medicine, Uniformed Services University of the Health Sciences; Staff, Department of Allergy and Immunology, Walter Reed Army Medical Center, Bethesda, MD

Satyen M Gada, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology

Disclosure: Nothing to disclose.

Cecilia P Mikita, MD, MPH Associate Professor of Pediatrics and Medicine, Uniformed Services University of the Health Sciences; Staff Allergist/Immunologist, Walter Reed National Military Medical Center

Cecilia P Mikita, MD, MPH is a member of the following medical societies: American Academy of Allergy Asthma and Immunology

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD Faculty, Division of Allergy/Immunology and Infectious Diseases, Department of Pediatrics, Saint Peter's University Hospital

Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Pediatric Research, Society for Mucosal Immunology

Disclosure: Nothing to disclose.

Additional Contributors

C Lucy Park, MD Chief, Division of Allergy, Immunology, and Pulmonology, Associate Professor, Department of Pediatrics, University of Illinois at Chicago College of Medicine

C Lucy Park, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, Chicago Medical Society, American Medical Association, Clinical Immunology Society, Illinois State Medical Society

Disclosure: Nothing to disclose.