INTRODUCTION — The term IPEX is an acronym for:
IPEX is a rare, often fatal, X-linked monogenic immune dysregulatory disorder that typically presents during infancy with a triad of enteropathy, autoimmune endocrinopathy, and dermatitis (MIM #304790). The pathogenesis, epidemiology, clinical manifestations, diagnosis, and management of IPEX will be discussed in this topic review.
PATHOGENESIS — The defining feature of IPEX is regulatory T cell impairment leading to immune dysregulation manifesting as autoimmune disease with allergic inflammation.
The phenotype of IPEX was first described in 1982, and the first genetic mutations in FOXP3 (then known as JM2) were identified in 2000 [1-4]. IPEX was previously designated X-linked polyendocrinopathy, immune dysfunction, and diarrhea (XPID) and X-linked autoimmunity and allergic dysregulation (XLAAD) [2,3,5].
IPEX is caused by mutations in the gene for the transcription factor FOXP3 (FOXP3). Multiple different mutations have been identified . FOXP3 is a member of the forkhead box P (FOXP) family of transcription factors and is fundamental to the function of a subset of T lymphocytes known as regulatory T cells (Tregs) . Tregs exhibit potent immune suppressive effects and thereby play a fundamental role in immune homeostasis, particularly with respect to tolerance . In addition to modulating autoimmune and allergic inflammation, Tregs also appear to be involved in transplantation tolerance . Penetrance of FOXP3 mutations is variable, and asymptomatic family members with mutations have been identified in some families .
Patients who present with a similar phenotype but without mutations in FOXP3 are described as "IPEX-like."
Overview of T regulatory cells — The suppressive actions of Tregs govern autoimmunity and atopy [8,10,11]. CD4+ Tregs comprise 5 to 10 percent of the CD4+ T cell population and include natural Tregs derived from the thymus and adaptive or induced Tregs from the peripheral lymphoid tissues. (See "Normal B and T lymphocyte development", section on 'Regulatory T cells (Tregs)'.)
Unique subsets of Tregs appear to utilize different functional mechanisms, including cell contact-mediated cytotoxicity, competitive sequestration of interleukin (IL)-2, and cytokine-mediated inhibition via IL-10 or transforming growth factor-beta (TGF-beta) [12-15]. Investigations using a mouse model suggest that FOXP3+ Tregs may also modulate autoreactive B cell populations .
The expansion of Tregs appears to be a natural consequence of the human immune response [17-19]. However, in vitro, Tregs are anergic and proliferate poorly. Tregs require IL-2 to survive and exert their suppressive functions. However, they do not produce IL-2, and therefore, they are dependent upon its production by other types of CD4+ T cells. (See "Normal B and T lymphocyte development", section on 'Regulatory T cells (Tregs)'.)
Normal function of FOXP3 — FOXP3 is a member of the FOXP family of transcription factors. The gene is located on chromosome Xp11.23. It encodes a 431 amino acid protein with multiple, well-described functional domains (figure 1). In addition to the forkhead DNA-binding domain that interacts with the IL-2 promoter and other target genes, FOXP3 also contains an N-terminal proline-rich domain, which regulates transcription. A zinc finger motif may be involved in protein-DNA interactions, while a leucine zipper domain mediates homo- and heterodimerization with FOXP3 and other FOXP transcription factors. Methylation of C-phosphate-G sites (CpG methylation) and other epigenetic changes appear to be important in FOXP3 isoform expression . A general discussion of transcription factors is found separately. (See "Basic genetics concepts: DNA regulation and gene expression", section on 'Transcription'.)
There is overwhelming evidence that FOXP3 plays a fundamental role in the differentiation of CD4+ Tregs and that high levels of FOXP3 expression are directly linked to the suppressive capacity of these cells . However, in vitro overexpression of human FOXP3 in conventional T cells is not sufficient to induce potent immune suppression, indicating that other factors (in addition to FOXP3 expression) are required to optimize suppression [20-23]. Importantly, the suppressive function in human FOXP3-deficient cells can be partially restored in vitro with manipulation of metabolic pathways via mTOR inhibitors [24,25]. Similar results are obtained in murine models that specifically interfere with aerobic glycolysis .
Mutations in FOXP3 — IPEX is due to loss-of-function mutations in FOXP3. These mutations result in quantitative or functional deficiencies of Tregs and thereby cause autoimmune disease and allergic inflammation [2-4,26-28]. A large number of mutations have been described, many of which are familial, although sporadic cases have been reported [29-32]. Disease-causing mutations have been described in each of the main coding regions, demonstrating that each functional domain is essential to the normal function of FOXP3 (figure 1)[6,33,34]. Equally important are mutations in noncoding regions, which can also cause IPEX. However, there is no clear genotype-phenotype correlation [5,28,31,35-37].
Mouse model — A naturally occurring mutation of the FOXP3 gene in mice causes the fatal autoimmune and inflammatory disorder called scurfy. This X-linked recessive lymphoproliferative disease has many of the clinical and molecular features of IPEX in humans. Scurfy is characterized by multiorgan lymphocytic infiltration and cytokine dysregulation due to unregulated T cell activity .
In scurfy mice, a frameshift mutation omits the forkhead domain of the gene product and demonstrates that a fully functional protein is essential for immune homeostasis. The phenotype can also be induced in knockout models and via hypomorphic mutations in FOXP3 [12,22,39-41]. As the physical manifestations of scurfy are due to the lack of functional Tregs, the phenotype of these mice can be reversed by bone marrow reconstitution, adoptive transfer of an enriched CD25+ T cell population, or the introduction of a FOXP3 transgene [42,43].
EPIDEMIOLOGY — IPEX is a rare, X-linked disorder that classically presents in infancy. Published reports of patients with IPEX are limited, and therefore, the prevalence and incidence are unknown. Moreover, retrospective analysis suggests many cases may have been under-reported or misdiagnosed [5,44,45]. A retrospective study of the incidence of neonatal diabetes in Australia identified 1 case of IPEX in 10 cases of neonatal diabetes contained in the national registry data from 1989 to 2007, and thus, these data provide an estimate of the incidence of IPEX at 1 in 1,609,490 . Most patients present in early infancy, and miscarriage due to fetal-onset IPEX has been reported . Ameliorated phenotypes may present later in life [6,48].
Family history may or may not be present, as mutations may be familial or sporadic. A history of infantile demise in maternal male relatives is suggestive of an X-linked disease process such as IPEX .
In multiple large familial cohorts with varying mutations in FOXP3, female carriers do not appear to be at increased risk for autoimmune, allergic, or oncologic disease [3,30,37,50].
CLINICAL MANIFESTATIONS — The classic presentation of IPEX is a male infant with the following triad of disorders :
●Failure to thrive with severe chronic diarrhea due to an autoimmune enteropathy
●Autoimmune endocrinopathy (neonatal type 1 diabetes or thyroiditis)
●Dermatitis, usually eczematous
Most affected children have failure to thrive. Additionally, patients with IPEX may have immune-mediated cytopenias, other manifestations of autoimmunity, severe food allergies, nephritis, and exaggerated responses to infections (table 1). These conditions are variable among patients, and ameliorated phenotypes have been described. At times, only one of the hallmark features may be present [51,52]. While in most cases the disease becomes clinically apparent at neonatal age or during the first year of life, development of the disease in fetal life  or conversely, delayed onset [48,52], have also been demonstrated.
Fluctuations in disease activity — Acute exacerbations of autoimmunity and/or allergic inflammation are referred to as "disease flares" and may be triggered by infections, vaccinations, or dietary allergens. In this respect, patients with IPEX are similar to those with systemic lupus erythematosus or other autoimmune diseases. The signs and symptoms that comprise a disease flare can vary among different patients and may vary from episode to episode for a given patient. Typical manifestations of disease flares include acute worsening of chronic diarrhea, exacerbations or new manifestations of dermatitis, cytopenias, and/or refractory hyperglycemia in the setting of diabetes mellitus.
Immune dysregulation — Manifestations of IPEX are due to immune dysregulation leading to autoimmune disease and allergic inflammation. Tissue from patients with enteropathies and endocrinopathies are characterized by lymphocytic infiltrates with or without associated autoantibodies. Allergic inflammation manifests as eczema, food allergies, eosinophilia, and elevated total and antigen-specific immunoglobulin (Ig)E .
Allergic and autoimmune disease processes may interact. As an example, both the characteristic enteropathy and dermatitis may have concurrent active autoimmune and allergic features. Additionally, exposure to known food allergens may cause a flare of enteropathy, endocrinopathy, or dermatitis.
Gastrointestinal manifestations — A common presentation of IPEX in infancy is chronic intractable diarrhea with failure to thrive. In addition to the characteristic autoimmune enteropathy, IPEX patients may have multiple gastrointestinal manifestations of autoimmune and/or allergic inflammation.
●IPEX typically presents with severe watery diarrhea that can be mucoid or bloody and can be life-threatening. This diarrhea frequently worsens if the affected infant is switched from breastfeeding to formula and may improve with dietary modification.
●Metabolic derangements can result from profound dehydration and malabsorption, including hypernatremic dehydration, metabolic acidosis, renal insufficiency, weight loss, and failure to thrive. Protein-losing enteropathy may also be present . (See "Overview of the causes of chronic diarrhea in children in resource-abundant settings" and "Neonatal hyperglycemia" and "Approach to the child with metabolic acidosis".)
●Grossly, the bowel may demonstrate loss of the normal architecture, ulcerations, and hyperemic mucosa. The small bowel is typically most significantly affected, although the colon may demonstrate similar findings. Biopsy findings in IPEX and other autoimmune enteropathies vary and include villous atrophy, crypt hyperplasia or abscesses, and an extensive mixed cellular infiltrate, notably lymphocytic infiltrates of the bowel mucosa (picture 1). These lesions are not specific for IPEX and resemble those in other immune-mediated enteropathies, such as graft-versus-host, celiac disease, and other autoimmune enteropathies .
●Severe food allergies are common. These are typically associated with antigen-specific IgE, although non-IgE-mediated conditions similar to food protein-induced enterocolitis syndrome have also been described. IPEX patients may develop increased diarrhea and/or dermatitis, as well as other manifestations of disease flare following ingestion of dietary allergens. Typical manifestations of IgE-mediated food allergy, such as acute urticaria, vomiting, or anaphylaxis, may also occur.
●Autoimmune hepatitis is frequently seen in conjunction with autoimmune enteropathy, although the hepatosplenomegaly characteristic of mouse models is rarely present in humans .
Endocrinopathies — Early-onset autoimmune endocrinopathies, typically diabetes and/or thyroiditis, are hallmark features of IPEX. IPEX is a leading cause of permanent neonatal diabetes due to autoimmunity [46,54-57].
●Type 1 diabetes is most common, and onset is generally during the first year of life. Hyperglycemia may be present at birth. Disease progression results in the complete immune-mediated destruction of islet cells. These patients may or may not have detectable anti-islet cell antibodies in addition to lymphocytic infiltration of the pancreas [5,58].
●Thyroiditis may result in either hypo- or hyperthyroidism, although hypothyroidism with elevated antithyroid antibodies is most common [5,32].
●Other immune endocrinopathies are uncommon. However, atypical findings of growth hormone deficiency and hypoadrenalism have been described .
Skin findings — The third component of the IPEX triad is dermatitis, which typically consists of an eczematous rash (ie, atopic dermatitis) that ranges from mild to severe (picture 2) [60,61]. The presence of atopic dermatitis correlates with elevated levels of serum IgE and peripheral blood eosinophilia . The rash typically appears in early infancy, and its appearance may be concurrent with the onset of clinical manifestations of enteropathy and endocrinopathy.
Other skin findings may include diffuse erythema, alopecia universalis, psoriasiform rashes, painful fissurary cheilitis, and pemphigoid nodularis. Most are characterized by lymphocytic infiltrates that may respond to treatment with topical corticosteroids or other immunomodulators [32,60-62].
Hematologic disorders — About one-half of the patients demonstrate evidence of immune-mediated cytopenias, and patients frequently have associated autoantibodies. Coombs-positive hemolytic anemia, autoimmune thrombocytopenia, and autoimmune neutropenia are most common . (See "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis" and "Immune thrombocytopenia (ITP) in children: Clinical features and diagnosis" and "Immune neutropenia".)
Infectious diseases — Increased susceptibility and exaggerated responses to infections have been observed in IPEX patients since the original report . Over one-half of a 50 patient cohort had significant infections, including sepsis, meningitis, pneumonia, and osteomyelitis . Overall, the most commonly reported pathogens are enterococcal and staphylococcal species, cytomegalovirus, and Candida .
Several factors may contribute to the vulnerability of IPEX patients to infection, including the following:
●Compromised barrier functions of the skin and gut
●Immune suppressive therapy
In several patients, infection occurred prior to commencing immune suppressive agents, and patients may experience fewer infections when disease control is obtained with appropriate immune suppression [32,65].
Infections can also trigger flares of autoimmunity, even if the infection is relatively minor. As with patients with systemic lupus erythematosus and other autoimmune diseases, infections can mimic disease flares in patients with IPEX and thereby cause a diagnostic dilemma [66,67]. This complexity may confound decisions regarding the appropriate diagnosis and management. (See 'Management of acute medical events' below.)
Renal disease — Renal disease is reported in up to one-third of patients [32,68-70]. Interstitial nephritis is the most frequent disorder, and other findings range from mild hematuria and proteinuria to rapidly-progressive glomerulonephritis. Renal disease may also be worsened and/or induced by treatment with calcineurin inhibitors. On histology, renal involvement may appear as immune complex deposition in a membranous-like pattern and/or interstitial nephritis . (See "Clinical manifestations and diagnosis of acute interstitial nephritis" and 'Immune suppression' below.)
Neurologic abnormalities — Developmental delay is common and may be a sequela of chronic failure to thrive since infancy. Seizures are also reported in some patients, usually associated with metabolic derangements resulting from severe diarrhea or diabetes.
Pulmonary disease — Patients with IPEX may suffer from acute respiratory distress syndrome . Infection-related pulmonary disease is well-described in IPEX patients. Viral and other pneumonias are reported, and Pneumocystis jirovecii may follow the initiation of immune suppressive therapy [65,73].
In contrast, primary lung involvement in IPEX patients remains less characterized, although interstitial lung disease has been observed anecdotally in some patients . In addition, there is a report of a child with IPEX and allergic bronchopulmonary aspergillosis . Primary lung disease is a feature of the murine model and is characterized by both perivascular and interstitial lymphocytic and mixed inflammatory cell infiltrates [76,77]. However, these findings have not been validated in studies of patients with IPEX.
EVALUATION AND DIAGNOSIS — IPEX should be considered in any male infant presenting with chronic intractable diarrhea with failure to thrive and/or infantile onset of type 1 diabetes. The presence of dermatitis, autoimmune cytopenias, or thyroiditis further supports the diagnosis but is not required. The diagnosis is established by mutational analysis of the FOXP3 gene.
Approach to an infant with suspected IPEX
●Infants with suggestive signs and symptoms should be evaluated in consultation with a clinical immunologist familiar with IPEX and the other diseases listed in the differential diagnosis. Referral to a pediatric tertiary care center is highly advised. (See 'Differential diagnosis' below.)
●If hospitalized, infants with possible IPEX should be placed in isolation and managed similarly to a severely immunocompromised patient, as even minor infections can trigger significant flares of autoimmune and allergic disease. Blood products should be leukodepleted (in part to prevent dysregulated host immune activation due to allostimulation), cytomegalovirus-negative, and irradiated. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management" and "Approach to the ill-appearing infant (younger than 90 days of age)".)
Preliminary studies — The initial evaluation for IPEX requires extensive laboratory testing (table 2).
●Complete blood count – The complete blood count with differential typically demonstrates eosinophilia and may demonstrate neutropenia, anemia, or thrombocytopenia. If cytopenias are present, studies for antibody-mediated disease should be conducted including direct and indirect Coombs test and antineutrophil and antiplatelet antibodies.
●Serum glucose and anti-islet antibodies – Serum glucose should be monitored, given the high association with type 1 diabetes mellitus. Studies should be sent for anti-islet antibodies, although direct T cell pancreatic infiltration in the absence of anti-islet antibodies has been described. (See "Prediction of type 1 diabetes mellitus" and "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults".)
●Thyroid function and antithyroid antibodies – Abnormalities in thyroid function may be accompanied by elevated antithyroid antibodies. (See "Pathogenesis of Hashimoto's thyroiditis (chronic autoimmune thyroiditis)".)
●Antienterocyte antibodies – When present, antienterocyte antibodies confirm the diagnosis of autoimmune enteropathy . Additionally, gut and kidney antigen-specific (autoimmune enteropathy-related-75 [AIE-75]) and anti-goblet cell antibodies have also been associated with autoimmune enteropathies, including IPEX [53,68,79]. Anti-AIE-75 antibodies may be more specific to IPEX, while anti-villin antibodies can also be detected in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) . (See 'Other rare syndromes' below.)
●Immunoglobulins – Most patients with IPEX have significantly elevated total and antigen-specific IgE, and more than one-half of the patients also have elevated IgA [27,32]. Serum IgG and IgM levels are generally normal. However, hypogammaglobulinemia may be seen, particularly in association with protein-losing enteropathy [37,81].
●Food hypersensitivity testing – Hypersensitivity to food antigens may be a feature of IPEX or a competing diagnosis. IgE-mediated food allergy is common in IPEX [3,37]. In patients with concurrent dermatitis, serum testing for allergen-specific IgE is generally preferred to skin prick testing to evaluate for the presence of food-specific IgE. Evaluation for non-IgE-mediated food allergy, including food protein-induced enterocolitis and celiac disease, should also be considered. (See "Diagnostic evaluation of IgE-mediated food allergy" and "Food protein-induced allergic proctocolitis of infancy" and "Diagnosis of celiac disease in adults".)
●Lymphocyte subsets and proliferation assays – Lymphocyte subsets are nondiagnostic but should be performed to exclude a primary immunodeficiency syndrome. B and T cell subsets are normal in most IPEX patients. Similarly, mitogen and antigen stimulation studies typically demonstrate normal lymphoproliferative responses. There are reports of cytokine dysregulation consistent with skewing toward a T helper type 2 response, including low interferon-gamma (IFN-gamma) and elevated IL-4 levels . (See "Laboratory evaluation of the immune system", section on 'Defects in cellular immunity'.)
Advanced investigations — If preliminary studies are suggestive of IPEX, then further testing is recommended (table 2):
●Endoscopy with intestinal biopsy – Endoscopy with intestinal biopsy is required to characterize small bowel enteropathies. Staining biopsy samples for FOXP3 is available at some research institutions and has been suggested as a potential diagnostic tool for IPEX . (See 'Gastrointestinal manifestations' above.)
●Skin biopsy – The skin rashes associated with IPEX are typically eczematous, although other unusual dermatologic conditions have been described. Biopsy specimens demonstrating lymphocyte infiltration may be required to characterize the process as autoimmune disease. (See 'Skin findings' above.)
●Regulatory T cell immunophenotyping and functional studies – Quantitative analysis via flow cytometry and fluorescence-activated cell sorting (FACS), as well as functional assays of regulatory T cells (Tregs), are indicated, although these tests are only available at selected research institutions .
The CD4+CD25+FOXP3+ cell population of the patient should be compared with that of an age-matched healthy control subject. CD4+ Tregs normally comprise approximately 5 to 10 percent of the CD4+ T cell population, although more precise age-specific standards have not been established for children or adults. Cells identified as CD4+CD25+CD127low correlate well with the CD4+CD25+FOXP3+ population [84-86]. However, the two populations should not be considered identical, and CD4+CD25+CD127low may be found in some IPEX patients with profoundly decreased FOXP3 expression due to hypomorphic mutations [87,88]. Absence of CD4+FOXP3+ cells confirms a Treg cell deficiency and is consistent with a loss-of-function mutation in FOXP3. Additionally, absence of CD4+CD25+ cells confirms a diagnosis of CD25 deficiency. (See 'IPEX-like syndromes' below.)
However, detection of CD4+FOXP3+ cells does not rule out IPEX, as missense mutations may result in present but either partially functioning or nonfunctional FOXP3 protein [26,28,89]. Functional studies of Tregs, such as cell suppression assays, can help corroborate the hypomorphic nature of some FOXP3 mutations. Various methods have been described [35,90].
Therefore, when the clinical picture is consistent with IPEX, gene sequencing of FOXP3 should be performed, regardless of the results of FACS analysis.
Diagnosis — Definitive diagnosis requires gene sequencing to identify a mutation in FOXP3. Testing is commercially available and should be obtained when the clinical picture and other investigations are consistent with a diagnosis of IPEX.
DIFFERENTIAL DIAGNOSIS — Several other disorders can mimic IPEX or components of the IPEX phenotype.
IPEX-like syndromes — IPEX-like syndromes share the clinical manifestations of IPEX, including enteropathy, autoimmune endocrinopathy, and dermatitis, although the clinical findings and age of presentation are more variable, and females can also be affected. In a cohort of over 100 patients with the IPEX phenotype, more than one-half lacked mutations in the gene for the transcription factor FOXP3 (FOXP3) . The underlying defect in these patients is generally unknown, although IPEX-like features have been associated with several novel genetic syndromes . Newer techniques may be better able to delineate the role of quantitative defects in regulatory T cell (Treg) populations.
●CD25/IL2RA deficiency – CD25, the alpha chain of the IL-2 receptor (IL2RA), is a cell surface marker found on both Treg and activated T cells. The IL-2R alpha and beta chains combine with the common gamma chain to form the high-affinity IL-2R on T cells, B cells, natural killer (NK) cells, and monocytes. IL-2 production and expression of IL-2R are stimulated by antigen binding to the T cell receptor (TCR). IL-2 is involved in the growth and differentiation of cytotoxic and regulatory T cells and NK cells and optimization of T cell help to B cells for antibody production. Of the IPEX-like syndromes, CD25/IL2RA deficiency was the first to be well-characterized [91,92]. (See "Normal B and T lymphocyte development".)
At least five patients have been described with homozygous pathogenic variants in the interleukin 2 receptor alpha (IL2RA) gene located on chromosome 10p15.1 (MIM #147730) [92-97]. One patient had a phenotype resembling IPEX with onset of chronic diarrhea and diabetes mellitus and CMV pneumonia at six weeks of age . Serum immunoglobulins were elevated, and lymphocyte populations initially appeared normal. Over the ensuing eight years, he exhibited asthma, recurrent otitis media, sinusitis and pneumonia, eczema, lymphadenopathy and hepatosplenomegaly, hypothyroidism, and autoimmune anemia and neutropenia .
Another patient had a SCID-like presentation at 6 months of age with increased susceptibility to bacterial, viral, and fungal infections including CMV pneumonia, persistent oral and esophageal candidiasis, and failure to thrive partly due to chronic diarrhea from adenoviral gastroenteritis [92,93]. He developed extensive infiltration and inflammation of several tissues with autoreactive T cells. Lymphadenopathy and hepatosplenomegaly became more prominent with age. He had extremely few T and B cells in the circulation, and the T cells did not respond to mitogens in vitro. He underwent successful allogeneic hematopoietic cell transplantation (HCT) at three years of age.
A third patient had recurrent infections and primary biliary cholangitis . A fourth patient had follicular bronchiolitis with lymphocyte hyperplasia, eczema, and recurrent infections . A fifth patient presented in the first year of life with severe diarrhea with villous atrophy and eczema and went on to develop cytomegalovirus (CMV) infection, bullous pemphigoid, autoimmune thyroiditis, eczema, alopecia, and lymphadenopathy .
●STAT5b deficiency – A female patient with severe growth hormone resistance due to a deficiency in signal transducer and activator of transcription 5b (STAT5b) also demonstrated an IPEX-like syndrome. In addition to a homozygous missense mutation at STAT5b, she had significantly diminished FOXP3 expression, absence of functional CD4+ Tregs, and decreased levels of CD25 expression . Patients with this disorder have profound growth failure and may present with chronic mucocutaneous candidiasis (CMCC), CMV infection, and lung disease [99,100].
●STAT1 mutations – A small number of children with dominant gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1) and an IPEX-like syndrome have been described . They presented with a broad range of clinical problems reminiscent of IPEX, including polyendocrinopathy, enteropathy, and dermatitis. More specifically, CMCC, disseminated fungal infections, arterial aneurysms, thyroid autoimmunity, short stature, and squamous cell cancers were noted. Treg cell numbers and function were normal in these children. (See "Chronic mucocutaneous candidiasis", section on 'Signal transducer and activator of transcription (STAT1) dysfunction'.)
●LRBA mutations – A nonsense mutation in the gene encoding lipopolysaccharide (LPS)-responsive beige-like anchor (LRBA) has been identified in a patient with an IPEX-like syndrome who presented with type 1 diabetes and chronic enteropathy . More broadly, LRBA (also known as CVID8) deficiency is associated with both Treg cell deficiency and with defective Treg cell function . LRBA deficiency is associated with lymphopenia and hypogammaglobulinemia. Patients with LRBA deficiency exhibit autoantibody production and dysregulated expansion of circulating T follicular helper cells, consistent with defective T follicular Treg cell function . Expression of cytotoxic T lymphocyte-associated protein 4 (CTLA4) on the surface of Tregs is profoundly decreased, which may contribute to disease pathogenesis.
●CTLA4 mutations – Heterozygous loss-of-function mutations in CTLA4 have been described in individuals suffering from autoimmune cytopenias, enteropathy, and infiltration of different tissues with lymphocytes (eg, lungs and gastrointestinal tract). In addition, patients have recurrent infections, hypogammaglobulinemia, autoimmunity, an age-dependent decrease in B cells, and the accumulation of CD21low autoreactive B cells. Treg cell numbers are preserved, although their suppressive functions are decreased [103,104]. Some parents and relatives who carry the same mutations are asymptomatic, indicating that additional genetic, epigenetic, or environmental triggers may be required for the disease to manifest itself fully.
●STAT3 gain-of-function mutation – At least 19 individuals from diverse families have been reported with heterozygous germline gain-of-function mutations in STAT3, which are associated with defects in phosphorylation of STAT1, STAT5, and Tregs. Clinical features include infections, autoimmune-mediated lung, gastrointestinal, hepatic, and endocrine disease (including early-onset type 1 diabetes), autoimmune cytopenias, as well as short stature and lymphadenopathy. Patients have been described as IPEX-like, autoimmune lymphoproliferative syndrome (ALPS)-like, and STAT5b deficiency-like [105-107].
●DOCK8 deficiency – Dedicator of cytokinesis 8 (DOCK8) mutations can result in an IPEX-like phenotype with severe eczema and chronic diarrhea, as described in a report of three patients . DOCK8 deficiency is classified as autosomal recessive hyper-IgE syndrome and results in combined immunodeficiency due to impaired memory T and B cell function and defects in CD8 and natural killer cell function. Affected individuals have recurrent infections, autoimmune disease, including hepatitis and vasculitis, and allergic inflammation with elevated IgE and eosinophilia. (See "Combined immunodeficiencies: Specific defects", section on 'DOCK8 deficiency'.)
Enteropathies of infancy — The differential diagnosis of an infant with intractable diarrhea includes unusual presentations of common illnesses (ie, infections, food-sensitive enteropathies). The autoimmune enteropathies and other considerations are less common . Celiac disease is of particular interest, given its association with type 1 diabetes and thyroiditis . Rare genetic conditions to consider include microvillus inclusion disease or enteroendocrine cell dysgenesis [111,112]. Inflammatory bowel disease is also a consideration, although it usually affects older children. However, very early-onset inflammatory bowel disease is increasingly recognized and often associated with monogenic mutations in genes associated with immune function, including FOXP3 . (See "Gastrointestinal manifestations in primary immunodeficiency" and "Approach to chronic diarrhea in children >6 months in resource-abundant settings" and "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children" and "Clinical presentation and diagnosis of inflammatory bowel disease in children" and "Genetic factors in inflammatory bowel disease".)
Eosinophilic enteropathies — The eosinophilic enteropathies can manifest in infancy and childhood with malabsorption, eczema, food allergy, eosinophilia, and elevated total and specific IgE. Eczema and other manifestations of atopy may also be present. Eosinophilic enteropathies may be distinguished from autoimmune enteropathies by the presence of a predominantly eosinophilic rather than lymphocytic infiltrate in the gastrointestinal mucosa on biopsy. However, treatment with systemic glucocorticoids prior to biopsy may significantly reduce the eosinophilic infiltrate and complicate diagnosis. (See "Eosinophilic gastrointestinal diseases".)
Other causes of neonatal diabetes — There are several well-characterized syndromes associated with neonatal diabetes (ie, diabetes developing within the first six months of life), which can be transient, permanent, or recurrent [54-56]. IPEX is a leading cause of neonatal diabetes due to autoimmunity [56,57]. (See "Neonatal diabetes mellitus".)
Severe combined immunodeficiency — A male infant with chronic diarrhea and significant dermatitis is also a classic presentation for severe combined immunodeficiency (SCID). Omenn syndrome is most consistent with the IPEX phenotype, as it is associated with rash, eosinophilia, and elevated IgE. Additionally, graft-versus-host disease due to engraftment of maternal T cells in patients with SCID may also share clinical features with IPEX. (See "Severe combined immunodeficiency (SCID): An overview" and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis".)
Other rare syndromes
●NOMID/CINCA – Patients with neonatal-onset multisystemic inflammatory disease (NOMID) classically present in early infancy with fever, urticarial rash, aseptic meningitis, deafness, developmental delay, and arthropathy. NOMID is caused by loss-of-function mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, which encodes cryopyrin. This disorder is also known as chronic infantile neurologic cutaneous and articular (CINCA) syndrome and is reviewed separately. (See "Cryopyrin-associated periodic syndromes and related disorders", section on 'Neonatal-onset multisystem inflammatory disease'.)
●ALPS – ALPS is caused by defects in Fas, Fas ligand, or caspases 8 or 10 that interfere with programmed cell death and result in the failure to delete autoreactive clones. As with IPEX, there is diffuse autoimmune disease. However, the dominant clinical features are chronic lymphadenopathy with splenomegaly, autoimmune anemia, and thrombocytopenia. Enteropathy is rare. In addition, T cell subsets are remarkable for increased double-negative (CD4-CD8-) gamma-delta cells. (See "Apoptosis and autoimmune disease", section on 'Autoimmune lymphoproliferative syndrome'.)
●APS1 or APECED – Various autoimmune polyendocrine syndromes are well-characterized . Autoimmune polyendocrinopathy syndrome type 1 (APS1), also denoted autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is caused by defects in the autoimmune regulator (AIRE) transcription factor. Autoimmune disease results from the failure of AIRE to regulate the expression of tissue-specific antigens on thymic medullary epithelial cells. Thus, autoreactive T cells are not identified and deleted. As a result, type 1 diabetes mellitus and other endocrinopathies may be found in APS1. Unlike IPEX, APS1 is characterized by CMCC, as well as autoimmune disease of the parathyroid and adrenals. Antibodies to tryptophan hydrolase-1 appear to be present in APS1 (especially in patients with gastrointestinal dysfunction) but not in IPEX. Conversely, antibodies to autoimmune enteropathy-related-75 kDa antigen are present in patients with IPEX but not APS1 [80,81]. (See "Causes of primary adrenal insufficiency (Addison disease)", section on 'Type 1 (monogenic)'.)
MANAGEMENT OF ACUTE MEDICAL EVENTS — Infants with IPEX may present acutely ill as a result of various factors. These emergent events may comprise the initial presentation or may occur in previously diagnosed patients. Sudden decompensations may be associated with exposures to infection, immunization, dietary antigens, and/or an unknown trigger of a disease flare. The following medical emergencies may occur in patients with IPEX:
●Metabolic derangements and severe dehydration due to infantile-onset diabetes and/or enteropathy-related diarrhea
●Disease flares due to infection, immunization, dietary allergens, and/or other unknown triggers
These acute medical events require a multidisciplinary effort tailored to the specific presentation. We suggest the following:
Isolation to prevent nosocomial infections — As mentioned previously, hospitalized IPEX patients should be placed in isolation because even minor infections can trigger significant flares of autoimmune and allergic inflammation. Blood products should be cytomegalovirus-negative and irradiated. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management" and "Approach to the ill-appearing infant (younger than 90 days of age)".)
Multispecialty intensive care — Early and aggressive therapy including immune modulation is critical and should be initiated by a team of pediatric subspecialists. Supportive care generally includes fluid resuscitation, total parenteral nutrition (TPN), insulin, antimicrobials, albumin, thyroid hormone replacement, and blood products.
Increased immune suppression — Significant immune suppression may be required during acute medical events (including minor infections) to stabilize disease flares. Acute decompensations due to a disease flare generally warrants induction immune suppressive therapy for initial presentations or an increase from the patient's baseline maintenance therapy for previously diagnosed patients. (See 'Fluctuations in disease activity' above.)
However, infections can mimic disease flares in patients with IPEX and thereby cause a diagnostic dilemma. In addition, prolonged and high-dose glucocorticoid therapy in the setting of ongoing invasive infection may increase the risk of sepsis. This complexity may confound decisions regarding the appropriate diagnosis and management and resemble the conflicts encountered in the treatment of patients with rheumatologic disease and organ transplantation [66,67,113-115]. If concerns are raised regarding invasive infections, a reduction of glucocorticoid therapy to physiologic or stress dosing is advisable until this diagnosis is excluded. Generally, maintenance therapy with steroid-sparing agents is continued despite concerns of invasive infection.
Decisions regarding appropriate immune suppressive therapy during an acute illness should be individualized based upon the patient's underlying conditions, prior presentations, and objective evidence of disease flare and/or invasive infection. However, at times, empirical dosing may be warranted with vigilance for evidence of infection. Acute immune suppression is generally achieved with high-dose intravenous glucocorticoids (ie, 1 to 2 mg/kg daily).
Management of enteropathy flares — A common presentation of IPEX in infancy is chronic intractable diarrhea with failure to thrive. These infants usually require periodic hospitalization, gut rest, and nutritional support with TPN, which can be lifesaving interventions. A nutrition consult should be obtained to evaluate for malnutrition as well as vitamin and mineral deficiencies. Immune suppression is generally required to achieve sufficient improvement in the diarrhea.
Once the stooling pattern has normalized, feeds should be reintroduced slowly. Food antigens are well-described triggers of disease flares. Patients should receive either breast milk or extensively-hydrolyzed formula. (See 'Nutrition' below.)
LONG-TERM MANAGEMENT — Chronic management of patients with IPEX and "IPEX-like" syndromes typically includes a combination of intensive immune suppression and dietary modifications to avoid food allergens and optimize nutrition. As described in this section, it is unclear if immune suppression can halt progression of the disease, as controlled trials have not been performed for any of the interventions discussed. Hematopoietic cell transplantation (HCT) offers the potential for cure but has substantial risk and may not be available for all candidates.
Unfortunately, no single or combination therapy has been uniformly effective, and each has potentially devastating adverse effects. The variable success and considerable risk of each therapy render the medical decision-making process extremely complex and dependent upon unique aspects of each patient's presentation.
The literature on this rare and heterogeneous disorder consists of case reports and limited series. In 2018, a retrospective multicenter review identified 96 patients with IPEX and demonstrated similar overall survival rates for individuals managed with chronic immune suppression compared with those that underwent HCT, although there was greater mortality in the HCT group in the peritransplant period . The disease progressed in individuals managed with chronic immune suppression, resulting in lower long-term, disease-free survival.
Immune suppression — Immune suppression can be effective in ameliorating the symptoms of autoimmune and allergic disease, but it remains to be seen if it can halt disease progression . In addition, long-term use of these medications has been associated with significant adverse side effects, and growth is often compromised [5,116].
Glucocorticoids — High-dose glucocorticoids, such as prednisone, are typically used for induction therapy at the time of presentation and for management of disease flares because of their rapid onset of action.
However, the possibility of an ongoing invasive infection should be ruled out prior to initiation of high-dose glucocorticoid therapy. (See 'Infectious diseases' above and 'Management of acute medical events' above.)
Decisions regarding the timing and dosing of glucocorticoid therapy should be individualized, although typical doses range from 1 to 2 mg/kg daily. Betamethasone has been reported to be effective in some patients that do not respond adequately to prednisone or methylprednisolone therapy [73,117].
A steroid-sparing agent should be added in conjunction with glucocorticoid therapy. Once disease control is obtained, a slow glucocorticoid wean should be attempted, and the steroid-sparing agent should be continued as maintenance therapy. Multiple immune suppressive agents may be required to obtain disease control, and it may not be possible to wean the patient entirely from glucocorticoid therapies.
Steroid-sparing agents — Sirolimus and calcineurin inhibitors are the most commonly used steroid-sparing agents in the treatment of IPEX. Other immune suppressive agents have shown less efficacy.
●Sirolimus (also called rapamycin) has been associated with significant benefit when used in IPEX patients, both as monotherapy and as part of a multidrug immune suppressive regimen, although rare serious adverse effects have also been reported [6,37,63,65,73,118]. Sirolimus appears to improve the suppressive capacity of FOXP3-deficient Tregs [24,25,119,120]. In vitro studies, animal models, and clinical investigations related to solid-organ transplantation are increasingly reporting quantitative and functional increases in FOXP3+ regulatory T cells (Tregs) with the use of sirolimus in conjunction with other factors [121-124]. Although sirolimus has reduced toxicity compared with calcineurin inhibitors, its use was associated with an Epstein-Barr virus-induced lymphoma in one patient and inflammatory pneumonia in another [63,73]. However, given the apparent superior results obtained with sirolimus as compared with other immune suppressive agents, it should be considered a first-line therapy, either as monotherapy or as a part of a multidrug immune suppressive regimen.
Nutrition — Infants with possible or confirmed IPEX should be fed breast milk or extensively-hydrolyzed formula to reduce exposure to food allergens. In patients with diarrhea or failure to thrive, a nutrition consultation should assess the extent of malnutrition and evaluate for vitamin and mineral deficiencies.
If allergic sensitization to specific foods has been identified in the infant, breastfeeding mothers may need to follow a restricted diet that excludes those foods. Mothers of these infants should also be evaluated by a dietician with expertise in food allergy to ensure that the restricted diet is providing adequate nutrition for both mother and child.
Avoidance of vaccinations — All vaccinations are best avoided in patients with known or suspected IPEX, since immunizations (like infections) can trigger severe and even fatal disease flares. If vaccinations are considered essential, consultation with a clinical immunologist is strongly encouraged. Increased immune suppression will likely be required, although this may inhibit the efficacy of the vaccination.
The administration of supplemental immunoglobulin is a potentially safer alternative to vaccination in patients with IPEX who experience frequent infections or require protection against a specific infection. Intravenous immune globulin has been administered to IPEX patients without significant adverse effects. Therapy with immunoglobulin preparations containing high titers to specific pathogens (hyperimmune preparations) may also be a consideration if there is evidence of exposure to and/or ongoing infection with a specific pathogen. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management".)
Hematopoietic cell transplantation — Hematopoietic cell transplantation (HCT) is the only curative therapy available to IPEX patients. It should be offered to IPEX patients with low organ involvement pretransplant, as it promises definitive therapy with disease resolution and better quality of life as compared with chronic immune suppressive therapy. Many of the features of IPEX remit after successful transplantation, although endocrinopathies frequently persist due to permanent organ damage.
Early HCT offers the greatest potential to correct the underlying disease process and thereby minimize end-organ damage. As with severe combined immunodeficiency, patients may be more likely to survive the peri-HCT period if they are less compromised at the time of conditioning . Therefore, extensive evaluations are required to determine availability of appropriate donors and determine the optimal timing of the procedure for each individual.
Sources of stem cells have included cord blood, peripheral blood, and bone marrow from matched related and unrelated donors. Reduced-intensity conditioning regimens have been increasingly used, which offer the potential benefit of decreased myeloablation and less risk of mortality and morbidity [81,126-129]. Selective engraftment of donor CD4+CD25highFOXP3+ cells with resultant normal levels of FOXP3 expression following nonmyeloablative conditioning has proven sufficient to prevent manifestations of autoimmunity [127-130]. In the 2018 review, remission of autoimmune disease was similar in those with full or mixed chimerism .
HCT outcomes have been described in a limited number of IPEX patients, many of whom are healthy post-transplant [5,30,31,81,126-129,131-134]. In the review of 96 patients mentioned above, 58 underwent HCT, with a 15-year overall survival rate of 73.2 percent . The severity of organ impairment pretransplant was the only significant predictor of overall post-transplant survival, and this data indicates the importance of optimizing disease control pre-HCT and considering HCT before disease progression. Potential complications of HCT in IPEX patients include macrophage activation syndrome, infection, graft-versus-host disease, and growth failure [5,6,31,81,126,132,133].
Given the potential serious adverse events and the monogenic nature of IPEX, investigators are pursuing alternative approaches to HCT, including gene editing of autologous stem cells. Although gene editing is in its nascency, work using in vitro assays and in vivo animal models with FOXP3 deficiency demonstrated successful CRISPR (clustered regularly interspaced short palindromic repeats)-based gene correction with appropriate expression of FOXP3 protein in edited Tregs derived from IPEX patients . This work demonstrates feasibility of gene editing with various mutations, but at this time, it is purely investigational. Other researchers have used CRISPR technology to identify modulators of FOXP3 in murine models and speculate that these could be exploited as targets to augment Treg function . (See "Genetics: Glossary of terms" and "Overview of gene therapy for inborn errors of immunity" and "Overview of gene therapy, gene editing, and gene silencing".)
Genetic counseling — Genetic counseling should be offered to female family members of IPEX patients who may be carriers of the defective FOXP3 gene . Prenatal diagnosis can identify affected male fetuses. IPEX has also been linked to recurrent intrauterine fetal death .
PROGNOSIS — If untreated, infants with IPEX are likely to succumb in early childhood [1,5]. Despite efforts to manage the disease with immune suppressive therapy or attempts at curative therapy with hematopoietic cell transplantation, the prognosis for these patients remains poor. Although ameliorated phenotypes have been described, most reported cases have proved fatal.
Prognosis appears to be improving gradually. A 2002 report compiled clinical information for 56 patients with IPEX and "IPEX-like" processes and described only 6 patients who survived . Results from a 2007 series were more encouraging, as 28 of 51 IPEX patients were alive at the time of publication . In the 2018 review of 96 patients, overall survival was between 70 and 90 percent at 15 years, although disease-free survival was significantly lower .
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)
SUMMARY AND RECOMMENDATIONS
●IPEX (immune dysregulation, polyendocrinopathy, and enteropathy, X-linked) is a rare and potentially fatal autoimmune lymphoproliferative disorder in which regulatory T cells (Tregs) are quantitatively or functionally deficient. These defects are caused by various mutations in FOXP3, a gene encoding a transcription factor fundamental to the functional differentiation of Treg cells. (See 'Introduction' above.)
●IPEX classically presents in male infants with a triad of enteropathy, dermatitis, and autoimmune endocrinopathy (usually type 1 diabetes or thyroiditis), although there is a broad clinical spectrum, and ameliorated phenotypes may show just one of these disorders. Some patients have severe food allergy and/or immune-mediated cytopenias. (See 'Clinical manifestations' above.)
●Evaluation for IPEX should be considered in any young male infant with type 1 diabetes and/or chronic intractable diarrhea with failure to thrive. Diagnostic testing should be performed in consultation with a clinical immunologist familiar with IPEX, when possible. The diagnosis is confirmed by mutational analysis of the FOXP3 gene. (See 'Evaluation and diagnosis' above.)
●IPEX patients may deteriorate acutely due to metabolic derangements, infections, vaccinations, or exposure to dietary allergens. In this setting, IPEX patients should be admitted to an intensive care unit and isolated to prevent nosocomial infections. (See 'Management of acute medical events' above.)
●Immune suppression may need to be increased in the setting of most acute medical events, including minor infections, in order to prevent and/or control exacerbations of autoimmunity and allergic inflammation. In contrast, if invasive infection is suspected, glucocorticoids should be administered at the minimum stress doses required. (See 'Increased immune suppression' above.)
●Chronic management of patients with IPEX involves immune suppressive therapies to control autoimmune and allergic disorders combined with dietary modifications to avoid food allergens and optimize nutrition. However, immune suppression does not appear to halt disease progression.
•We suggest the use of high-dose glucocorticoid therapy as initial immune suppressive therapy and for management of disease flares (Grade 2C). Typical doses range from 1 to 2 mg/kg per day. Steroid-sparing therapy with sirolimus should be initiated simultaneously. (See 'Immune suppression' above.)
•Enteropathy associated with chronic diarrhea and failure to thrive typically requires periodic hospitalization for gut rest and total parenteral nutrition (TPN). As with other disease flares in IPEX, increased immune suppression may be required to control symptoms. (See 'Management of enteropathy flares' above.)
•We suggest that infants with possible or confirmed IPEX be breastfed or given extensively-hydrolyzed formula to reduce exposure to food allergens (Grade 2C). Breastfeeding mothers may need to avoid foods to which the infant has demonstrated sensitivities. Consultation with a dietitian is helpful to ensure that nutrition is adequate for both infant and mother.
●For patients with appropriately matched donors, low organ involvement, and the ability to tolerate the peritransplant course, hematopoietic cell transplantation (HCT) offers the potential for cure. (See 'Hematopoietic cell transplantation' above and 'Prognosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.
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