IPEX syndrome

Definition: IPEX is a X-inked fatal disorder characterized by immune dysregulation, polyendocrinopathy, enteropathy and X-linked inheritance (MIM.304930).

Patients typically present in infancy with severe diarrhea and failure to thrive. Most children die by 1 year of age without therapy. The diagnosis is established by genetic analysis, which often takes several weeks to complete and can sometimes delay crucial immunosuppressive treatment.

Synopsis

 dysimmune enteropathy (autoimmune enteropathy)

• total or subtotal intestinal villous atrophy
• ileus and secretory diarrhea (intractable diarhhea)
• mucosal chronic inflammation
• failure to thrive
• severe gastritis (19633572)
• autoimmune enteropathy
• exsudative enteropathy
• enterocolitis
• perirectal abcesses, perineal abcesses
• rectoperineal fistulas, perineal fistulas

 atopy

• eczema

 severe recurrent infections

• abcesses
• fungal infections

 variable autoimmune disorders

• autoimmune enteropathy
• autoimmune polyendocrinopathy
  • autoimmunediabetes with absent islet cells (insulin-dependent diabetes mellitus or type I diabetes)
  • hypothyroidism (autoimmune thyroiditis)

• autoimmune hemolytic anemia Coombs+
• autoimmune myocarditis

 lipodystrophy
 lymphadenopathy
 death usually occurs in infancy or childhood
 minimal change nephrotic syndrome (19189134)
 allergic bronchopulmonary aspergillosis (19205054)
 perineal abcesses
 multiple perineal fistulas

Biology

 autoimmune hemolytic anemia
 autoimmune thrombocytopenia (idiopathic thrombopenic purpura)
 immune dysregulation
 possible T-cell activation
 autoantibodies

Histological synospsis

 autoimmune enteropathy

• graft-vs-host disease-like changes (9/12 patients) (18820676)
• coeliac disease-like pattern (2/12) (18820676)
• enteropathy with a complete depletion of goblet cells (1/12) (18820676)

Circulating antibodies

 anti-brush border pattern (11/12)
 anti-goblet cell antibodies (1/12)

The histological presentation of autoimmune enteropathy is rather variable. However, a graft-vs-host disease-like pattern associated with positive anti-enterocyte antibodies is the most frequent intestinal presentation of IPEX syndrome, and constitutes a very valuable tool for pathologists to suspect this diagnosis. (18820676)

Etiology

 mutation in the FOXP3 of the gene (11137992) at Xp11.23-q13.3

Immunochemistry

 Patients with classic IPEX syndrome due to protein-truncating mutations in FOXP3 had markedly decreased staining of FOXP3+ T cells in the lamina propria and lymphoid aggregates. (17378693)

 Patients with a missense mutation in FOXP3 had intact staining of FOXP3+ cells. (17378693)

Mouse model

 scurfy mice (Foxp3 mutation)

• Scurfy mice have a deletion in the Foxp3 gene, resulting in a failure to generate Foxp3(+) regulatory T cells, and they subsequently develop severe CD4(+) T-cell-mediated autoimmune inflammation.
• Multiple organs are involved, but the skin is one of the main organs affected.
• During the course of disease, Scurfy mice develop autoantibodies; however, the targeted antigens are unknown.
• Autoantibodies in Scurfy mice and patients with IPEX target keratins.

See also

 Immunodeficiencies

• primary immunodeficiencies
  • X-linked immune syndromes

 FOXP3

References

 Autoantibodies in Scurfy mice and IPEX patients recognize keratin 14. Huter EN, Natarajan K, Torgerson TR, Glass DD, Shevach EM. J Invest Dermatol. 2010 May;130(5):1391-9. PMID: 20147963

 Patey-Mariaud de Serre N, Canioni D, Ganousse S, Rieux-Laucat F, Goulet O, Ruemmele F, Brousse N. Digestive histopathological presentation of IPEX syndrome. Mod Pathol. 2008 Sep 26. PMID: 18820676

 Selective engraftment of donor CD4+25high FOXP3-positive T cells in IPEX syndrome after nonmyeloablative hematopoietic stem cell transplantation. Seidel MG, Fritsch G, Lion T, Jürgens B, Heitger A, Bacchetta R, Lawitschka A, Peters C, Gadner H, Matthes-Martin S. Blood. 2009 May 28;113(22):5689-91. PMID: 19478054

 FOXP3 expression following bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Dorsey MJ, Petrovic A, Morrow MR, Dishaw LJ, Sleasman JW. Immunol Res. 2009;44(1-3):179-84. PMID: 19471859

 Minimal change nephrotic syndrome associated with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Hashimura Y, Nozu K, Kanegane H, Miyawaki T, Hayakawa A, Yoshikawa N, Nakanishi K, Takemoto M, Iijima K, Matsuo M. Pediatr Nephrol. 2009 Jun;24(6):1181-6. PMID: 19189134

 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. Gambineri E, Perroni L, Passerini L, Bianchi L, Doglioni C, Meschi F, Bonfanti R, Sznajer Y, Tommasini A, Lawitschka A, Junker A, Dunstheimer D, Heidemann PH, Cazzola G, Cipolli M, Friedrich W, Janic D, Azzi N, Richmond E, Vignola S, Barabino A, Chiumello G, Azzari C, Roncarolo MG, Bacchetta R. J Allergy Clin Immunol. 2008 Dec;122(6):1105-1112.e1. PMID: 18951619

 Clinical heterogeneity in patients with FOXP3 mutations presenting with permanent neonatal diabetes. Rubio-Cabezas O, Minton JA, Caswell R, Shield JP, Deiss D, Sumnik Z, Cayssials A, Herr M, Loew A, Lewis V, Ellard S, Hattersley AT. Diabetes Care. 2009 Jan;32(1):111-6. PMID: 18931102

 Digestive histopathological presentation of IPEX syndrome. Patey-Mariaud de Serre N, Canioni D, Ganousse S, Rieux-Laucat F, Goulet O, Ruemmele F, Brousse N. Mod Pathol. 2009 Jan;22(1):95-102. PMID: 18820676

 Cutaneous manifestations of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Halabi-Tawil M, Ruemmele FM, Fraitag S, Rieux-Laucat F, Neven B, Brousse N, De Prost Y, Fischer A, Goulet O, Bodemer C. Br J Dermatol. 2009 Mar;160(3):645-51. PMID: 18795917

 Immune reconstitution and recovery of FOXP3 (forkhead box P3)-expressing T cells after transplantation for IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome. Zhan H, Sinclair J, Adams S, Cale CM, Murch S, Perroni L, Davies G, Amrolia P, Qasim W. Pediatrics. 2008 Apr;121(4):e998-1002. PMID: 18316354

 IPEX as a result of mutations in FOXP3. van der Vliet HJ, Nieuwenhuis EE. Clin Dev Immunol. 2007;2007:89017. PMID: 18317533

 Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: forkhead box protein 3 mutations and lack of regulatory T cells. Torgerson TR, Ochs HD. J Allergy Clin Immunol. 2007 Oct;120(4):744-50; quiz 751-2. PMID: 17931557

 Heltzer ML, Choi JK, Ochs HD, Sullivan KE, Torgerson TR, Ernst LM. A potential screening tool for IPEX syndrome. Pediatr Dev Pathol. 2007 Mar-Apr;10(2):98-105. PMID: 17378693

 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. PMID: 11753102

 Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001 Jan;27(1):20-1. PMID: 11137993

 Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, Levy-Lahad E, Mazzella M, Goulet O, Perroni L, Bricarelli FD, Byrne G, McEuen M, Proll S, Appleby M, Brunkow ME. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001 Jan;27(1):18-20. PMID: 11137992