Immunodysregulation Polyendocrinopathy Enteropathy X-Linked Syndrome (IPEX) Clinical Presentation
- Author: Satyen M Gada, MD; Chief Editor: Harumi Jyonouchi, MD more...
Immune dysfunction, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome should be considered in young male patients with intractable diarrhea with accompanying villous atrophy or failure to thrive. Further support for the diagnosis is gained by the presence of the other 2 elements of the predominant triad: eczematous or psoriasiform dermatitis and early onset, insulin-dependent diabetes.[5, 12]
Failure to thrive, growth retardation, and/or cachexia in the setting of watery, secretory diarrhea are common historical elements. The diarrhea is occasionally present prior to feeding but generally appears or worsens after feeds. Enteric rest and gluten-free diet do little to alter the course of the enteropathy.
Glucose intolerance can present at birth, but generally the patients manifest symptoms after 3-4 months of life. Anti-islet cell antibodies have been found in some patients.
Thyroid disease, both hyperthyroidism and hypothyroidism, has been noted in as many as 30% of patients; hypothyroidism is more common.
The forms of dermatitis vary, with many patients presenting with an eczematous rash; however, a diffuse erythematous rash, psoriasiform rashes, pemphigoid nodularis, and, rarely, alopecia universalis have been noted.[5, 14]
One third of patients develop renal disease, with proteinuria and hematuria representing the most common presenting symptoms.
A history of thrombocytopenia or Coombs test–positive anemia may also be present.
Patients’ general appearance, growth, and development are important to note. Cachexia, small size, and poor weight gain related to failure to thrive are often present.
Skin examination can detect the several possible forms of dermatitis, including eczematous, psoriasiform, and a more generalized erythematous rash and, rarely, alopecia universalis.[5, 14]
A joint examination may reveal signs of arthritis, such as edema, erythema, and limitation of range of motion, but joint involvement is not common.
Lymphadenopathy and splenomegaly are variably present.
The FOXP3 gene at Xp11.23-Xq13.3 is the causative gene for IPEX syndrome. This gene is critical for the development of CD4+ CD25+ regulatory T cells (Treg). The absence of these cells has been linked to autoimmune disease and other forms of immune dysregulation.
Of patients with IPEX syndrome, 60% have identifiable mutations in the FOXP3 gene. Some patients with IPEX-like conditions may have mutations involving the regulatory sequences in the FOXP3 gene.[17, 18] A growing understanding of related, IPEX-like conditions now includes mutations in CD25, STAT5b, and ITCH syndrome. These conditions also impact Treg cells or signaling pathways in which FOXP3 also participates.
It is an X-linked recessive disease process, and a male child of a female carrier has a 50% chance of being affected. A female child has a 50% probability of being an asymptomatic carrier.
The phenotypic manifestations of this disease vary, and their relationship to the monogenic origin is unclear.
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. [Medline].
Torgerson TR, Ochs HD. Regulatory T cells in primary immunodeficiency diseases. Curr Opin Allergy Clin Immunol. 2007 Dec. 7(6):515-21. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].
van der Vliet HJ, Nieuwenhuis EE. IPEX as a result of mutations in FOXP3. Clin Dev Immunol. 2007. 2007:89017. [Medline]. [Full Text].
Su MA, Anderson MS. Monogenic autoimmune diseases: insights into self-tolerance. Pediatr Res. 2009 May. 65(5 Pt 2):20R-25R. [Medline]. [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. [Medline]. [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. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].
Myers AK, Perroni L, Costigan C, Reardon W. Clinical and molecular findings in IPEX syndrome. Arch Dis Child. 2006 Jan. 91(1):63-4. [Medline]. [Full Text].
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. [Medline].
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. [Medline]. [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. [Medline].
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. [Medline].
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. [Medline]. [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. [Medline]. [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. [Medline].
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. [Medline]. [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. [Medline].
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. [Medline]. [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. [Medline].
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. [Medline].
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. [Medline].
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. [Medline].