Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 724276006; ORPHA: 37042; DO: 0090110;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp11.23 | Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked | 304790 | X-linked recessive | 3 | FOXP3 | 300292 |
A number sign (#) is used with this entry because X-linked immunodysregulation, polyendocrinopathy, and enteropathy (IPEX) is caused by mutation in the FOXP3 gene (300292) on chromosome Xp11.
IPEX is an X-linked recessive immunologic disorder characterized by onset in infancy of severe diarrhea due to enteropathy, type 1 diabetes mellitus, and dermatitis. Other features may include hypothyroidism, autoimmune hemolytic anemia, thrombocytopenia, lymphadenopathy, hepatitis, and nephritis. The disorder may be fatal before age 2 years if not aggressively treated. Long-term therapeutic options include immunosuppression and hematopoietic stem cell transplantation (review by d'Hennezel et al., 2012).
Powell et al. (1982) described a 'new' X-linked syndrome in a large kindred in which 8 males in 3 generations connected through females had various combinations of intractable diarrhea, eczema, hemolytic anemia, diabetes mellitus, or thyroid autoimmunity. Exaggerated responses to viral infections were noted. Only 2 of the 8 survived the first decade. Death in infancy or early childhood occurred in 11 additional males in the kindred; these occurred with infections or shortly after immunizations. B-cell function, T-cell numbers, polymorph chemotaxis, and complement concentrations were normal.
Satake et al. (1993) described a Japanese family in which 2 brothers and their maternal uncle suffered from a presumably X-linked autoimmune enteropathy with hemolytic anemia and polyendocrinopathy. Two of the boys died from severe diarrhea accompanied by total or subtotal intestinal villous atrophy. The third affected male showed the same symptoms and had circulating IgG antibodies against enterocytes, but his condition improved dramatically and he became well following the use of cyclosporin A (CSA).
Peake et al. (1996) reported the cases of 4 related male infants who presented with neonatal diabetes mellitus, immune dysregulation with extremely high concentrations of immunoglobulin E, and intractable diarrhea. All of the infants were from 1 family, and all of them died. They had an exfoliative skin eruption and frequent infections. The diabetes was insulin-dependent and very difficult to regulate. One of the patients sustained a cardiac arrest 10 minutes after he was 'introduced to a branched chain amino acid supplement.' He was believed to have had an anaphylactic reaction to the formula. Necropsy showed apparent agenesis of the islets of Langerhans, a normal exocrine pancreas, normal small bowel, generalized mild to moderate lymphoid hyperplasia, and low-grade, nonspecific hepatitis. In a second case, the child died at 19 months of age from overwhelming sepsis. A third boy died at 10 weeks of age. Postmortem examination showed no macroscopic abnormalities; microscopic specimens were not available for interpretation. The same disorder may have been described by Meyer et al. (1970). Two brothers had absent islet cells, neonatal IDDM, diarrhea, and failure to thrive. One brother had numerous infections (including fungal infections, thigh abscess, and discharging ears) and died at 4 months; the other died at 32 days, also of infection. The mother had 10 brothers who died of unknown causes in infancy, and a healthy sister. Some of the features were similar to those of Omenn syndrome (603554), but diabetes does not occur in that disorder which is inherited as an autosomal recessive. The disorder in this family appeared to be X-linked recessive. The 4 affected males occurred in separate sibships in 3 generations, connected through presumably carrier females.
Goulet et al. (1998) studied the clinical and histopathologic features of 47 infants with intractable diarrhea and villous atrophy of varying degrees, dividing them into 2 groups, with or without lamina propria mononuclear cell infiltration. Of the 24 patients with an infiltrate, 12 had extraintestinal manifestations of autoimmunity, including arthritis, diabetes, nephrotic syndrome, dermatitis, anemia, thrombocytopenia, and tended to have a later onset of diarrhea (median, 5 months of age) with larger volumes.
Additional families were reported by Roberts and Searle (1995) and Di Rocco and Marta (1996). Most of the affected males developed autoimmune phenomena and immunologic abnormalities within the first 6 months of life, and most died within the first year of life. Immunologic abnormalities were highly variable, 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 in this family survived beyond the age of 2 years.
Levy-Lahad and Wildin (2001) described 2 premature male sibs and 1 maternal half brother with intrauterine growth retardation/failure to thrive, an inflammatory enteropathy presenting as bowel hypomobility with mucosal erosion and relatively primitive-appearing gut epithelium, endocrinopathy (neonatal diabetes mellitus in 2, hypothyroidism in 1, and parathyroid hormone resistance in 1), and thrombocytopenia and coagulopathy in 2. All died by 5 months 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. Dermatitis or eczema was also common. Less common features included thyroid disease (3 patients), hemolytic anemia (3 patients), thrombocytopenia (2 patients), and hepatitis (3 patients). Immunologic studies before immunosuppressive treatment showed normal white blood cell counts and normal immunoglobulin levels, except in 1 patient who had intestinal protein loss. Most patients had increased serum IgE and eosinophilia, and many had serum autoantibodies despite immunosuppressive therapy. There was variable severity: 3 patients with null mutations or mutations in functional domains had a severe form of the disease, whereas patients with splicing mutations had a less severe form. However, there was no correlation between FOXP3 protein expression and disease severity, since nonfunctional mutant proteins were expressed at normal levels. Gambineri et al. (2008) suggested that patients who present in infancy with autoimmune enteropathy or diabetes should be screened for FOXP3 mutations.
Congenital Absence of Islets of Langerhans
Jonas et al. (1991) reported the cases of 2 unrelated male infants who presented in the first days of life with brittle insulin-dependent diabetes mellitus and subsequently developed severe secretory diarrhea with stool volumes of more than 100 ml/kg/day. No etiology or effective therapy was discovered for the diarrhea and both infants succumbed to septicemia, malnutrition, and poor control of hyperglycemia. At autopsy, both were found to have absence of islets of Langerhans in the pancreas and diffuse dysplastic changes in the mucosa of the small and large intestine. The entire alimentary tract in each case was lined by epithelia more typical of foregut mucosa: secretory-like glands, absent crypts of Lieberkuhn, and absent villi. One of the infants was Asian and one Caucasian. Meyer et al. (1970) described congenital IDDM due to hypoplastic pancreas in 2 infant brothers who had 10 maternal uncles who had died in infancy of unknown causes. Dodge and Laurence (1977) described congenital IDDM and absent islets in a male infant who died on the second day of life and whose brother was likewise very small for dates and died at the age of 40 days.
Eisenbarth and Gottlieb (2004) compared the features of 3 autoimmune polyendocrine syndromes: autoimmune polyendocrine syndrome type I (240300); autoimmune polyendocrine syndrome type II, or Schmidt syndrome (269200); and X-linked polyendocrinopathy with immune dysfunction and diarrhea.
Seidman et al. (1990) had reported the successful treatment of autoimmune enteropathy with cyclosporin A (CSA). In the Japanese family described by Satake et al. (1993), 1 of the 3 affected males became well following the use of CSA, although he showed the same symptoms as the others and had circulating IgG antibodies against enterocytes. Satake et al. (1993) stated that a patient in the family reported by Powell et al. (1982) developed autoimmune diabetes mellitus and was successfully treated with CSA.
Supportive therapy with total parenteral nutrition, insulin, and blood transfusions is beneficial in patients with IPEX, and prolonged immunosuppressive therapy with steroids and cyclosporin has been attempted. Nevertheless, the prognosis is poor and most reported cases have been fatal. Baud et al. (2001) performed transplantation of allogeneic bone marrow from an HLA-identical family member in a Moroccan boy with IPEX. A brother had died at the age of 4.5 months from intractable diarrhea, thrombocytopenia, insulin-dependent diabetes mellitus, and ichthyosiform dermatitis. The proband had onset of persistent secretory diarrhea at the age of 4 weeks. Insulin-dependent diabetes mellitus was diagnosed at 2.5 months of age. Ichthyosis had been observed 2 weeks after birth. It became a widespread exfoliative skin eruption that responded partially to emollients and hydrocortisone cream. Hemolytic anemia was diagnosed at the age of 4 weeks. The patient was found to carry the F371C mutation in the FOXP3 gene (300292.0003), inherited from his mother. Bone marrow transplantation from his HLA-identical sister who did not have the F371C mutation was performed at the age of 4 months. On day 19, analysis of sex chromosomes by fluorescence in situ hybridization showed that 95% of white cells were of the female XX genotype. Diarrhea improved and stools were normal 1 month after transplantation. Two weeks later, enteral feeding was successfully reinstated. Six months after bone marrow transplantation, the patient's diet was normal and was associated with a normal intestinal transit time. Duodenal, jejunal, and colonic biopsies showed normal tissues with recovered villous architecture and mucous membranes. Insulin therapy was stopped 7 days before bone marrow transplantation, the pretransplantation conditioning regimen having been associated with progressive improvement in blood glucose control. In this case, bone marrow transplantation was followed by a complete remission. The conditioning regimen, consisting of intravenous rabbit anti-T-lymphocyte globulin, oral busulfan, and intravenous cyclophosphamide, controlled most of the clinical and biologic features of the disease, including the diarrhea, hyperglycemia, and dermatitis. Engraftment probably facilitated a sustained remission, and the patient remained in clinical and biologic remission for more than 2 years after bone marrow transplantation. Unexplained rapidly progressive hemophagocytic syndrome, which proved fatal, occurred 29 months after bone marrow transplantation, when the child was nearly 3 years of age. Baud et al. (2001) stated that there were only 3 known long-term survivors of this disease (Powell et al., 1982; Satake et al., 1993; Seidman et al., 1990; Wildin et al., 2001).
Shigeoka et al. (1993) reported that the locus for this disorder maps to Xp11.2, where the Wiskott-Aldrich syndrome gene (WAS; 301000) had been assigned. Ferguson et al. (2000) performed linkage analysis on 20 members of an affected kindred. Informative recombinations limited the region of the locus to an approximately 20-cM interval bordered by DXS1055 and DXS1196/DXS1050. Multipoint analysis demonstrated a lod score greater than 3 for the region contained between DXS8024 and DXS8031, mapping the locus to the pericentromeric region Xp11.23-q21.1. Evaluation of the WAS gene by SSCP analysis, heteroduplex analysis, and direct sequencing of the 12 exons in an affected male and 2 carrier females revealed no abnormalities. Ferguson et al. (2000) concluded that this kindred has an X-linked disorder, distinct from Wiskott-Aldrich syndrome, that results in autoimmunity and variable immunodeficiency.
By linkage analysis in a large pedigree, Bennett et al. (2000) mapped the locus for X-linked polyendocrinopathy, immune dysfunction, and diarrhea (IPEX) to a 17-cM interval defined by markers DXS8083 and DXS8107 at Xp11.23-q13.3. The maximum lod score was 3.99 with DXS1235 at theta of 0.0. No mutations were identified in the WAS gene.
Chatila et al. (2000) referred to this disorder as X-linked autoimmunity-allergic dysregulation syndrome (XLAAD). Consistent with the allergic phenotype, analysis of 2 kindreds with this disorder revealed marked skewing of patient T lymphocytes toward the Th2 phenotype. Using a positional-candidate approach, they identified in both kindreds mutations in JM2 (called by others FOXP3; 300292), which encodes a forkhead domain-containing protein. One kindred carried a splice junction mutation; the other involved an in-frame, 3-bp deletion that was predicted to impair the function of a leucine zipper dimerization domain.
Wildin et al. (2001) identified mutations in the FOXP3 gene in patients with IPEX, including those reported by Levy-Lahad and Wildin (2001). Bennett et al. (2001) also identified mutations in the FOXP3 gene in patients with IPEX. See 300292.0001-300292.0005.
In 1 of the families studied by Owen et al. (2003), the FOXP3 locus was excluded by recombination, and no FOXP3 mutations were found. The authors concluded that their data provided evidence for a nonlinked autosomal locus, suggesting genetic heterogeneity.
'Scurfy' (sf) is an X-linked recessive mouse mutant that results in lethality in hemizygous males 16 to 25 days after birth and is characterized by overproliferation of CD4+/CD8- T lymphocytes, extensive multiorgan infiltration, and elevation of numerous cytokines (Lyon et al., 1990; Clark et al., 1999). Similar to animals that lack expression of either Ctla4 (123890) or Tgf-beta (TGFB1; 190180), the pathology observed in sf mice seems to result from an inability to regulate properly CD4+/CD8- T-cell activity. By combining high-resolution genetic and physical mapping with large-scale sequence analysis, Brunkow et al. (2001) identified the gene defective in sf mice. The protein encoded by this gene, designated Foxp3, is a new member of the forkhead/winged-helix family of transcriptional regulators and is highly conserved in humans. In sf mice, a frameshift mutation results in a product lacking the forkhead domain. Genetic complementation demonstrated that the protein product of Foxp3, scurfin, is essential for normal immune homeostasis.
Patel (2001) discussed the escape from tolerance in XLAAD and in the 'scurfy' mouse. Options for treatment of the disorder are limited to immunosuppressive agents and supportive care, with death usually occurring within the first year of life. Consistent with the decreased sensitivity of scurfy T cells to cyclosporin A, cyclosporin is often not effective in controlling XLAAD. Patel (2001) referred to the observation in the scurfy mouse that normal cells can control scurfy T cells and prevent disease manifestation. Thus, using minimally toxic, nonmyeloablative conditioning regimens followed by transplantation of normal allogeneic stem cells to induce mixed chimerism may be an effective treatment strategy for XLAAD. Alternatively, XLAAD may be one of the diseases that respond well to gene therapy, since a small percentage of wildtype T cells may be sufficient to control the disease.
Wildin (2001) pointed out that the 'I' in IPEX now stands for 'immunodysregulation' rather than 'immunodeficiency' because patients have shown immunodeficiency only when taking immunosuppressive drugs.
Chatila et al. (2000) incorrectly referred to this as a 'disregulation' syndrome. They presumably meant 'dysregulation' syndrome. The prefix 'dis' refers to separation or division; the prefix 'dys,' appropriate here, refers to abnormal or deranged.
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