Immunodysregulation Polyendocrinopathy Enteropathy X-Linked Syndrome (IPEX)

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Immune dysfunction, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a lethal syndrome first described as a unique entity by Powell et al in 1982. [1] It most commonly manifests with early onset, insulin-dependent diabetes mellitus; severe watery diarrhea, often with accompanying failure to thrive; and dermatitis. Other clinical features are more variable in their expression. [1, 2, 3]

Most affected children die within the first 2 years of life. IPEX syndrome is an X-linked recessive disorder with exclusive expression in males. The identification of mutations in the forkhead box protein 3 (FOXP3) gene associated with IPEX syndrome and a murine model has generated a considerable amount of interest and research. [2, 3] This has also extended into the therapeutic spectrum, with new immunosuppressive regimens and use of hematopoietic stem cell transplantation (HSCT).

IPEX syndrome is one of the monogenic autoimmune diseases, such as Wiskott-Aldrich syndrome and autoimmune lymphoproliferative syndrome (ALPS). A potential murine model was identified in mice suffering from Scurfy syndrome. Using information gathered from these mice, researchers mapped the forkhead box protein 3 (FOXP3) gene to Xp11.23-Xq13.3. [1, 2, 4] This is a genetic region also closely associated with the WASP gene responsible for Wiskott-Aldrich syndrome. The FOXP3 gene is part of a family of genes that are strongly associated with normal immune responses and thymic development. [5]

FOXP3 has recently been linked with the development of immunosuppressive CD4+ CD25+ regulatory T cells, which form in the thymus and represent a subset (5-10%) of the helper CD4+ T cells. [6] These cells have been noted in previous studies to dampen immune responses, including in the setting of autoimmune diseases. [7] When the FOXP3 gene is absent or dysfunctional, this specific subset of regulatory T-cells (Treg) fails to develop normally, though variable function has been noted in more recent studies. [8, 9] Although the role of Tregs in self-tolerance and immune homeostasis is of critical importance, the mechanism by which they exert these effects has not been fully elucidated. [5, 6]

More recent studies have uncovered links between FOXP3 dysfunction and an inflammatory helper T-cell subtype (Th17), as well as loss of peripheral B-cell tolerance. [10, 11] Ongoing research seeks to better characterize the full extent and implications of these and other manifestations of immune dysregulation.

Although patients with IPEX syndrome share many of the same core clinical and immune manifestations of the disease, the expressed phenotypes vary. Elevated immunoglobulin E (IgE) and immunoglobulin A (IgA) levels and eosinophilia have been noted but are not universally present in affected individuals. Neutrophil activity and complement levels are generally normal, although neutropenia has been reported. [6] Similarly, levels of immunoglobulin G (IgG) and immunoglobulin M (IgM) can be normal but are often slightly depressed in older individuals, likely as a result of protein loss from their enteropathy. [2]

Other clinical effects are also variably present, with some patients demonstrating thrombocytopenia, lymphadenopathy, tubular nephropathy, hypothyroidism, and alopecia in addition to the more common triad of dermatitis, insulin-dependent diabetes, and enteropathy. Although not fully understood, the presence of diabetes appears to be related to inflammatory destruction of the islet cells, supported by the histologic presence of lymphocytic infiltrates of the pancreas. [3, 12] In terms of the enteropathy seen in IPEX syndrome, a celiac-like pattern with villous-blunting is noted along with a similar lymphocytic infiltrate. [13] The cutaneous manifestations are most often eczematous but can also take on a spongiotic psoriasiform appearance histologically. [14]

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The available literature consistently states that IPEX syndrome is a rare condition with unknown incidence, with no proposed estimates. Some sources suggest that the incidence may be higher than anticipated due to misdiagnosed cases and subsequent underreporting. [3, 15]

Children who do not receive treatment usually die within the first 2 years of life. Sepsis and complications from failure to thrive are the most common causes of death. [6]

In those patients who developed sepsis, enterococcal, staphylococcal, and candidal species as well as cytomegalovirus were the most commonly identified infectious agents. [5] Enterococcal and staphylococcal species have also been predominant in complications of immunosuppressive treatment, including catheter-associated infections, peritonitis, pneumonitis, and septic arthritis. [3]

Hematopoietic stem cell transplantation (HSCT) is an option, and increased success has been noted with “reduced-intensity” conditioning protocols. However, HSCT in patients with IPEX syndrome has met with significant complications and death rates, which may be increased compared with patients undergoing the procedure for other conditions. [3, 6, 16]

No difference in the incidence of IPEX syndrome among individuals of different races is known.

Only males have been noted to be affected in this X-linked recessive process. Obligate carrier females have all been healthy in cases reviewed in the literature. The female IPEX syndrome carriers do not appear to be subject to disease manifestation related to a skewed pattern of lyonization or inactivation of the unaffected X-chromosome. [3]

The disease manifests shortly after birth and, in most cases, in the first 3-4 months of life. Because the condition is rare, no large scale studies or reports have been completed to aid further delineation of the age-related characteristics of IPEX syndrome. [1, 6]

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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].

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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].

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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].

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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.

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.

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.

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.

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.

Immunodysregulation Polyendocrinopathy Enteropathy X-Linked Syndrome (IPEX)

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