IPEX E31.0

IPEX syndrome is a very rare recessive X-linked polyorganic autoimmune syndrome with a severe clinical course, associated with mutations in the FOXP3 gene and characterized by severe autoimmunolgically induced diarrhea in infancy. Chronic enteropathy is combined with diabetes mellitus type 1, pruriginous psoriasiform or exfoliative dermatitis, and other autoimmune phenomena: autoimmune hypothyroidism, autoimmune hemolytic anemia, thrombocytopenia, lymphadenopathy, hepatitis, and nephritis.

IPEX syndrome mainly affects males.

This is due to mutations in the FOXp3 gene, which is located on chromosome Xp11.23. The coding gene "FOXP3 gene" is X-chromosmal, in humans localized in gene locus Xp11.23. The transcription factor FOXP3 encoded by this gene belongs to the group of "forkhead/winged-helix family of transcriptional regulators". As a transcription factor, FOXP3 is central in the development of regulatory T cells and is expressed by CD4+/CD25+ regulatory T cells, which play a central role in the maintenance of immune homeostasis.

Clinically, the first enteritic symptoms of IPEX syndrome usually occur in the first months of life. They may cause the infants not to gain weight (failure to thrive).

Initial symptoms are severe autoimmune enteropathy with refractory secretory diarrhea leading to malabsorption, electrolyte disturbances, and developmental disorders. Other symptoms include vomiting, ileus, gastritis, or colitis. Other autoimmune endocrinopathies present with type 1 diabetes mellitus and/or thyroiditis (hypo- or hyperthyroidism). On the skin, there is generalized pruriginous dermatitis, sometimes lichenoid, sometimes psoriasiform or resembling atopic dermatitis.Furthermore, erythrodermic exfoliative dermatitis has been described. More rarely, alopecia or onychodystrophy occurs.

Furthermore, pneumonitis, hepatitis, nephritis, myositis, splenomegaly and lymphadenopathy, hematological symptoms such as thrombocytopenia, hemolytic anemia or neutropenia.

Untreated, the disease is often fatal. Bone marrow transplantation is an important therapeutic option. Satake et al. 1993 reported the successful treatment of autoimmune enteropathy with cyclosporine A (CSA). In the Japanese family described by them, one of the three affected men became well after using CSA, although he showed the same symptoms as the others and had circulating IgG antibodies to enterocytes.

The disease can be fatal before the age of 2 years if not treated aggressively. Long-term treatment options include immunosuppression and hematopoietic stem cell transplantation (review by d'Hennezel et al., 2012).

The term polyendocrinopathy is used in the context of IPEX syndrome because affected individuals may develop multiple autoimmune disorders of the endocrine glands. Diabetes mellitus, type 1 is an autoimmune disorder of the pancreas and is the most common endocrine disorder in people with IPEX syndrome.

Powell et al (1982) described in a large kindred, a polyautoimmunologic syndrome with chronic diarrhea, dermatitis, hemolytic anemia, diabetes mellitus, or thyroid autoimmunity. High susceptibility to viral infections was noted. Only 2 of the 8 patients survived the first decade. Death in infancy or early childhood occurred due to infection in 11 male family members (also after vaccination). Lab.: B-cell functions, number of T cells, chemotaxis, and complement concentrations were normal.

Satake et al (1993) described a Japanese family in which two brothers and their maternal uncle suffered from a presumed X-linked autoimmune enteropathy with hemolytic anemia and polyendocrinopathy. Two of the boys died of severe diarrhea accompanied by total or subtotal intestinal villous atrophy. The third affected boy had the same symptoms and circulating IgG antibodies to enterocytes. He recovered after administration of cyclosporine A.

Peake et al (1996) reported the cases of four related male infants who presented with neonatal diabetes mellitus, immune dysregulation with extremely high levels of immunoglobulin E, and intractable diarrhea. All infants were from one family, and all died. They had severe exfoliative dermatitis and frequent infections. The diabetes was insulin-dependent and very difficult to control. Necropsy revealed agenesis of the islets of Langerhans, a normal exocrine pancreas, a normal small intestine, generalized mild to moderate lymphoid hyperplasia, and low-grade nonspecific hepatitis. A second child died of sepsis at 19 months of age. A third boy died at 10 weeks of age.

Meyer et al (1970) described two brothers with absent islet cells, neonatal IDDM, diarrhea, and failure to thrive. One brother suffered from numerous infections (including fungal infections, thigh abscess, and otitis media) and died at 4 months of age; the other died at 32 days of age, also from infection. The mother had 10 brothers who died in infancy for unknown reasons and one healthy sister. Clinically, the symptomatology resembled Omenn syndrome (603554), but diabetes is not found in this syndrome.

Goulet et al (1998) studied the clinical and histopathological features of 47 infants with intractable diarrhea and villous atrophy of varying degrees and divided them into two groups: with or without infiltration of the lamina propria with mononuclear cells. Of the 24 patients with infiltration of the lamina propria, 12 had extraintestinal manifestations of autoimmunity, including arthritis, diabetes, nephrotic syndrome, dermatitis, anemia, thrombocytopenia; they tended to have a later onset of diarrhea (median, 5 months) with larger volumes.

Roberts and Searle (1995) and Di Rocco and Marta (1996) described several patients with multiple autoimmune phenomena and immunologic abnormalities within the first 6 months of life. Most died within the first year of life. The immunologic abnormalities varied widely, but intermittent eosinophilia and elevated IgE levels were documented in several patients.

Ferguson et al (2000) identified a family with a similar X-linked disorder characterized by autoimmunity and variable immunodeficiency. Affected males developed autoimmune endocrinopathy (type I diabetes mellitus and/or hypothyroidism), enteropathy characterized by villous atrophy, chronic dermatitis, and variable immunodeficiency. Only 1 affected male patient survived to 2 years of age.

Gambineri et al (2008) reported the clinical features of 14 unrelated male patients with genetically confirmed IPEX syndrome. All patients presented with symptoms in the first year of life, mainly severe watery diarrhea due to enteropathy and/or hyperglycemia or ketoacidosis due to diabetes mellitus. Pronounced dermatitic manifestations occurred frequently. Thyroid disease (3 patients), hemolytic anemia (3 patients), thrombocytopenia (2 patients), and hepatitis (3 patients) occurred less frequently. Immunologic examinations before immunosuppressive treatment showed normal leukocyte counts and normal immunoglobulin levels, except in one patient who had intestinal protein loss. Most patients had elevated serum IgE and eosinophilia, and many had serum autoantibodies despite immunosuppressive therapy. The severity was variable: 3 patients with null mutations or mutations in functional domains had a severe form of the disease, whereas patients with splice mutations had a less severe form. However, there was no correlation between FOXP3 protein expression and disease severity, as nonfunctional mutant proteins were expressed at normal levels.

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