IPEX Syndrome (Immune Dysregulation, Polyendocrinopathy, Autoimmune Enteropathy, X-linked)

Definition

• Hereditary autoimmune enteritis with associated autoimmune disorders due to mutation in FOXP3 gene

See also for non-X linked form of disease:

• Autoimmune enteropathy

Diagnostic Criteria

• Autoimmune enteropathy associated with any of several autoimmune disorders and mutation in FOXP3 gene
  • A wide variety of organ systems may be involved with variability between patients
• Autoimmune enteropathy usually presents in first six months of life
• Principally involves small intestine
  • May also involve stomach and large intestine
• Nearly all show partial or complete villous atrophy
• Nearly all show an increase in lamina propria lymphocytes
  • Infiltrate predominantly composed of CD3+ CD4+ alpha beta T cells
• Mild to marked increase in intra-epithelial lymphocytes
  • Variable reports in the literature
  • Infiltrate predominantly composed of CD3+ CD4+ alpha beta T cells
• Inconspicuous to prominent apoptosis in crypts
• Crypts may be hyperplastic or destroyed
  • Goblet cells may be absent
• Anti-enterocyte brush border antibodies demonstrable by indirect immunofluorescence
  • Anti-goblet cell antibodies may be present but less specific
• Polyendocrinopathy - frequently multiple systems involved
• Most frequent is insulin dependent diabetes mellitus
• Due to autoimmune destruction of islets
• Thyroiditis, adrenal insufficiency
• Immune dysregulation frequently occurs in addition to the above
• Coombs positive hemolytic anemia
• Autoimmune thrombocytopenia
• Neutropenia
• Interstitial nephropathy and/or glomerulonephritis
• Eczema
• Elevated IgE
• X-linked heredity
  • Mutations in FOXP3 gene (Xp11.23) identifiable by sequencing
• Rare cases have the same constellation of findings but are not X-linked

Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting/updates : 11/20/11

Differential Diagnosis

• Tropical sprue
• Prolonged post-enteritis syndrome
• Celiac disease
• Common variable immunodeficiency
• Food allergy
• Crohn disease

Tropical Sprue

• Confined to tropics
• Responds to anti-microbial therapy

Prolonged Post-enteritis Syndrome

• History of preceding viral or bacterial gastroenteritis

Celiac Disease	Autoimmune Enteropathy
Usually occurs in childhood or older	Usually begins under 6 months of age, but can occur in adults
Responds to gluten withdrawal	Refractory to gluten withdrawal
Anti-endomysial and - tissue transglutaminase antibodies	Anti-enterocyte antibodies
CD4 negative T cells predominate	CD4+ T cells predominate
Gamma delta T cell receptors predominate	Alpha beta T cell receptors predominate

For pediatric autoimmune enteropathy with associated polyendocrinopathy see IPEX syndrome.
Some adult autoimmune enteropathy cases have been discovered in the workup of patients thought to have celiac disease but who do not respond to removal of gluten from the diet

 

Autoimmune Enteropathy	Common Variable Immunodeficiency – GI Involvement
Numerous plasma cells	Plasma cells frequently markedly decreased
Diffuse infiltrate primarily composed of T lymphocytes	Prominent nodular lymphoid hyperplasia
Prominent villous atrophy	Villous atrophy may be mild to severe
Prominent crypt destruction	Crypt destruction not prominent
Anti-enterocyte antibody	All antibodies generally depressed; humoral testing is not reliable in CVID

The two entities may be histologically indistinguishable.
For pediatric autoimmune enteropathy with associated polyendocrinopathy see IPEX syndrome.

 

Food Protein Enteropathy	Autoimmune Enteropathy
Predominantly eosinophilic infiltrate	Predominantly T cell infiltrate
Frequent associated allergy or atopy	No association with other allergies or atopy
Resolved by elimination of offending food from diet	Not related to diet

For pediatric autoimmune enteropathy with associated polyendocrinopathy see IPEX syndrome.

 

Crohn Disease	Autoimmune Enteropathy
Skip lesions predominate	Usually diffuse
Usually involves large intestine	Principal involvement is duodenum, jejunum and stomach
Transmural inflammation	Mucosal inflammation
Granulomas may be seen	Granulomas absent
Deep fissures frequent	No fissures or deep ulcers

For pediatric autoimmune enteropathy with associated polyendocrinopathy see IPEX syndrome.

Clinical

• Usually presents <6 months of age
  • Intractable diarrhea
    • Results in hypoalbuminemia
    • Non-responsive to TPN and bowel rest
  • High mortality if not treated
• Extra-intestinal associations frequently multiple
  • Insulin dependent diabetes mellitus
  • Hypothyroidism
  • Membranous glomerulonephritis
  • Sclerosing cholangitis
  • Autoimmune hepatitis
  • Coombs+ hemolytic anemia
  • Other (non-intestinal) autoantibodies
    • Anti-mitochondrial antibody
    • Anti-nuclear antibody
    • Anti-parietal cell antibody

Bibliography

• Noffsinger A, Fenoglio-Preiser CM, Maru D, Gilinisky N.  Gastrointestinal Diseases, AFIP Atlas of Nontumor Pathology, First Series, Fascicle 5, 2007.
• Freeman HJ. Adult autoimmune enteropathy. World J Gastroenterol. 2008 Feb 28;14(8):1156-8.
• Cuenod B, Brousse N, Goulet O, De Potter S, Mougenot JF, Ricour C, Guy-Grand D, Cerf-Bensussan N. Classification of intractable diarrhea in infancy using clinical and immunohistological criteria. Gastroenterology. 1990 Oct;99(4):1037-43.
• Russo PA, Brochu P, Seidman EG, Roy CC. Autoimmune enteropathy. Pediatr Dev Pathol. 1999 Jan-Feb;2(1):65-71.
• Akram S, Murray JA, Pardi DS, Alexander GL, Schaffner JA, Russo PA, Abraham SC. Adult autoimmune enteropathy: Mayo Clinic Rochester experience. Clin Gastroenterol Hepatol. 2007 Nov;5(11):1282-90.]
• Ruemmele FM, Moes N, de Serre NP, Rieux-Laucat F, Goulet O. Clinical and molecular aspects of autoimmune enteropathy and immune dysregulation, polyendocrinopathy autoimmune enteropathy X-linked syndrome. Curr Opin Gastroenterol. 2008 Nov;24(6):742-8.
  
• 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. 2009 Jan;22(1):95-102.
• Martin BA, Kerner JA, Hazard FK, Longacre TA. Evaluation of intestinal biopsies for pediatric enteropathy: a proposed immunohistochemical panel approach. Am J Surg Pathol. 2014 Oct;38(10):1387-95. doi: 10.1097. PubMed PMID: 25188866.