Laboratory Studies

Molecular genetic testing for immune dysfunction, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome can be performed by DNA sequencing of the FOXP3 gene and mutation analysis.^[21]Sixty percent of patients with IPEX syndrome have an identifiable mutation in FOXP3. Patients with IPEX-like conditions with no identifiable mutation in FOXP3 may have mutations in the regulatory sequences in the FOXP3 gene or in pathways related to regulatory T-cell development or function.^{[19, 20]}

While genetic testing modalities remain the criterion standard, one paper does highlight autoantibody markers to harmonin and villin as a possible diagnostic tool for IPEX syndrome; however, more research is needed.^{[22, 23]}

Although not diagnostic, other laboratory tests may support the diagnosis of IPEX syndrome.

Thyroid-stimulating hormone (TSH), FT4, and thyroid antibodies are used to evaluate for autoimmune thyroid disease.

Serum glucose test, oral glucose tolerance test, and anti-islet cell antibodies testing are used to assess insulin-dependent diabetes. Anti–glutamic acid decarboxylase (GAD) antibodies and anti-insulin antibodies have also been reported in patients with IPEX syndrome.^[7]

CBC count with differential is used to evaluate for autoimmune hemolytic anemia, thrombocytopenia, and/or neutropenia. Marked eosinophilia has been described. If anemia is present, evaluation for autoantibody production with Coombs testing may be performed. Patients with IPEX syndrome usually have intermittent eosinophilia.^{[12, 24]}

BUN and creatinine level measurement and urinalysis with microscopy is used to assess evidence of autoimmune renal disease.

Liver function tests assess for evidence of autoimmune liver disease.

Serum immunoglobulin E (IgE) and immunoglobulin A (IgA) levels are usually elevated in patients with IPEX syndrome.^[12]

Flow cytometry of peripheral blood CD4⁺ CD25⁺ FOXP3⁺ usually reveals decreased T cells in patients with IPEX syndrome.^[25]

Imaging Studies

Imaging studies are not routinely required for the diagnosis and management of IPEX syndrome.

Consider targeting imaging studies to evaluate for sinus disease and potential bronchiectasis.

Other Tests

Quantitative immunoglobulins (immunoglobulin G [IgG], immunoglobulin M [IgM], immunoglobulin A [IgA]), antibody response to protein and polysaccharide antigens, and B-cell subsets are normal. Low immunoglobulin levels in a patient with IPEX syndrome is suggestive of a significant protein-losing enteropathy.^[12]

T-cell subsets, in vitro lymphocyte proliferative response to mitogens, and delayed-type hypersensitivity are normal. Increased TH-2 cytokine (interleukin [IL]-4, IL-5, IL-13) and decreased TH-1 cytokine (interferon [INF]-γ) expression has been reported in patients with IPEX syndrome.^[14]

Although autoimmune neutropenia is commonly found in IPEX syndrome, neutrophil function is preserved.

Patients with IPEX syndrome have normal serum complement levels.^[12]

Procedures

Endoscopy (upper and lower) with biopsy is used to evaluate for enteropathy. Skin biopsy is used to characterize dermatitis.

Histologic Findings

All 3 of the histologic findings below are associated with various degrees of villous atrophy and cellular inflammatory infiltrate.^[13]

Graft versus host disease –like pattern associated with positive antienterocyte antibodies (most common)^[13]
Celiac disease –like pattern^[13]

Enteropathy with complete depletion of goblet cells was also associated with IPEX syndrome.^[13]

Lymphocytic infiltrate with destruction of exocrine tissue and loss of islet cells is observed.^[12]

Dermatologic findings include the following:^[26]

Eczematous dermatitis
Psoriaform lesions
Lymphocytic dermal infiltrate

Thyroid findings include the following:

Lymphocytic infiltrate^[12]
Thymus
Depletion of lymphocytes and Hassall corpuscles with cellular atrophy or dysplasia^[12]

Staging

See the list below:

No current staging classification has been established for IPEX syndrome. However, emerging research may provide a basis for development of a staging system.^[27]

Treatment & Management

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.