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IPEX Syndrome

Synonym: Immunodeficiency, Polyendocrinopathy, and Enteropathy X-Linked Syndrome

, MD, PhD, , PhD, and , MD.

Author Information

Initial Posting: ; Last Update: July 19, 2018.

Summary

Clinical characteristics.

IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome is characterized by systemic autoimmunity, typically beginning in the first year of life. Presentation is most commonly the clinical triad of watery diarrhea, endocrinopathy (most commonly insulin-dependent diabetes mellitus) and eczematous dermatitis. Most children have other autoimmune phenomena including cytopenias, autoimmune hepatitis or nephropathy; lymphadenopathy, splenomegaly, alopecia, arthritis, and lung disease related to immune dysregulation have all been observed. Fetal presentation of IPEX includes hydrops, echogenic bowel, skin desquamation, IUGR, and fetal akinesia. Without aggressive immunosuppression or bone marrow transplantation, the majority of affected males die within the first one to two years of life from metabolic derangements, severe malabsorption, or sepsis; a few with a milder phenotype have survived into the second or third decade of life.

Diagnosis/testing.

Diagnosis is established in a male proband with typical clinical findings and by the identification of a hemizygous pathogenic variant in FOXP3. Affected females have not been reported; female carriers of a pathogenic variant do not have clinical findings.

Management.

Treatment of manifestations: Bone marrow transplantation (BMT) offers the only potential cure for IPEX syndrome. When done at the time of no or mild organ impairment, there is improved resolution of autoimmunity, especially when compared with non-transplanted individuals under chronic immunosuppressive therapy. T cell-directed immune suppression (i.e., sirolimus, cyclosporin A, or tacrolimus), either alone or in combination with steroids, is considered first-line therapy; granulocyte colony stimulating factor (G-CSF) for autoimmune neutropenia; rituximab for pemphigus nodularis and other autoantibody-mediated disease; nutritional support; standard treatment of diabetes mellitus and autoimmune thyroid disease; topical therapies for dermatitis.

Prevention of secondary complications: Prophylactic antibiotic therapy for those with autoimmune neutropenia or recurrent infections; aggressive management of dermatitis with topical steroids and anti-inflammatory agents to prevent infection.

Surveillance: Monitoring with lab tests for evidence of autoimmune disease every 3-6 months; frequent monitoring of growth parameters, nutritional intake, and stooling patterns; monitor for drug side effects if under immunosuppression related to bone marrow transplantation.

Evaluation of relatives at risk: If the family-specific pathogenic variant is known, FOXP3 molecular genetic testing in at-risk males immediately after birth to permit early diagnosis and BMT before significant organ damage occurs; otherwise, monitoring of at-risk males for symptoms to enable early diagnosis and treatment.

Genetic counseling.

IPEX syndrome is inherited in an X-linked manner. The risk to sibs of the proband depends on the carrier status of the mother. If the mother of the proband is a carrier, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant are carriers and will not be affected. Affected males pass the pathogenic variant to all of their daughters and none of their sons. Carrier testing for at-risk relatives, prenatal testing for pregnancies at risk, and preimplantation diagnosis are possible for families in which the pathogenic variant has been identified.

Diagnosis

The term IPEX is an acronym for immune dysregulation, polyendocrinopathy, enteropathy, X-linked.

Suggestive Findings

IPEX syndrome should be suspected in males with the following clinical triad, family history, and suggestive laboratory findings.

Clinical triad

  • Enteropathy that manifests as chronic watery diarrhea. Onset is typically in the first months of life; villous atrophy with a mononuclear cell infiltrate (activated T cells) in the lamina propria is the most common finding in biopsy.
  • Endocrinopathy, most commonly type 1 diabetes mellitus with onset in the first months or years of life. Autoimmune thyroid disease leading to hypothyroidism or hyperthyroidism has also been observed [Wildin et al 2002, Gambineri et al 2003].
  • Dermatitis, most commonly eczematous presenting within the first months of life, although prenatal skin desquamation has been reported [Louie et al 2017]. Erythroderma, exfoliative dermatitis, psoriasis-like lesions, and pemphigus nodularis have also been observed [Nieves et al 2004, McGinness et al 2006].

Family history

  • Consistent with X-linked inheritance
  • Note: Lack of a family history consistent with X-linked inheritance does not preclude the diagnosis.

Suggestive laboratory findings. No laboratory findings specifically identify affected individuals. Evidence of immune dysregulation manifested by the following is suggestive of IPEX syndrome:

  • Elevated serum concentration of IgE (immunoglobulin E) and in some cases, IgA
  • Eosinophilia
  • Autoimmune anemia, thrombocytopenia, and/or neutropenia
  • Autoantibodies to pancreatic islet antigens, thyroid antigens, small bowel mucosa, and other autoantigens
  • Decreased numbers of FOXP3-expressing T cells in peripheral blood determined by flow cytometry – although FOXP3 levels in regulatory T cells (Treg) can be normal in some cases

Establishing the Diagnosis

Male proband. The diagnosis of IPEX syndrome is established in a male proband with the typical clinical findings and by the identification of a hemizygous pathogenic variant in FOXP3 by molecular genetic testing (see Table 1).

Female proband. Affected females have not been reported. Carrier status is determined by identification of a heterozygous pathogenic variant in FOXP3 by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of IPEX syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with enteropathy, endocrinopathy and/or immune dysregulation or those in whom the diagnosis of IPEX syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of IPEX syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of FOXP3 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants. If no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
    Note: (1) Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis. (2) Disease-associated variants have been reported in the 5’UTR (c.-7G>T) and the 3’UTR (c.*876A>G and c.*876A>G). Since the 3’UTR variants are further 3’ than typically included in sequencing assays, the assay design may need to be modified to include these variants.
  • A multigene panel that includes FOXP3 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by enteropathy, endocrinopathy, or immune dysregulation or when the diagnosis of IPEX syndrome is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in IPEX Syndrome

Gene 1Test MethodProportion of Pathogenic Variants 2 Detectable by This Method
FOXP3Sequence analysis 3,4~99%
Gene-targeted deletion/duplication analysis 51 reported 6
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

A deletion of the noncoding exon 1 has been reported [Torgerson et al 2007]; however, no systematic data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

Males

IPEX syndrome is generally considered to be a syndrome of neonatal enteropathy [Ruemmele et al 2004] and neonatal polyendocrinopathy [Dotta & Vendrame 2002] found in males.

Presentation. The most common presentation of IPEX syndrome is severe watery diarrhea, type 1 insulin-dependent diabetes mellitus, thyroiditis, and dermatitis in males younger than age one year. This disorder is frequently accompanied by other autoimmune phenomena.

Enteropathy. The enteropathy of IPEX syndrome, often the first sign, is present in virtually all affected individuals. Even in those with milder disease, the diarrhea typically begins in the first six to12 months of life. Watery diarrhea, which may at times also have mucus and blood, leads to malabsorption, failure to thrive, and cachexia, often requiring the use of total parenteral nutrition (TPN) [Bacchetta et al 2018]. Exocrine pancreatic insufficiency has been observed in some cases [Gambineri et al 2008, Scaillon et al 2009], which may worsen the diarrhea. Other gastrointestinal manifestations include colitis [Lucas et al 2007] and gastritis [Gambineri et al 2008, Scaillon et al 2009]. Food allergies are common [Torgerson et al 2007].

Endocrinopathy is present in the majority of affected individuals. Type 1 diabetes mellitus, often with onset in the first months of life, is the most common endocrine manifestation [Gambineri et al 2008, Rubio-Cabezas et al 2009]. Thyroid disease (thyroiditis with either hypothyroidism [more common] or hyperthyroidism) is also frequently present [Wildin et al 2002, Gambineri et al 2003, Gambineri et al 2008, Rubio-Cabezas et al 2009].

Dermatitis. The dermatitis is most frequently eczematous, but psoriasiform and ichthyosiform dermatitis have been reported as well. Other dermatologic manifestations include painful chelitis and skin lesions related to food allergies. Rare cutaneous symptoms include pemphigoid nodularis and epidermolysis bullosa acquisita [Nieves et al 2004, McGinness et al 2006, Halabi-Tawil et al 2009, Bis et al 2015].

Autoimmune disorder. Most affected individuals have other autoimmune phenomena including cytopenias (autoimmune hemolytic anemia, immune thrombocytopenia, autoimmune neutropenia [Barzaghi et al 2018], autoimmune hepatitis [López et al 2011], nephropathy (membranous nephropathy, interstitial nephritis, and rarely minimal change nephrotic syndrome) [Park et al 2015, Sheikine et al 2015]. Lymphadenopathy and splenomegaly as a result of lymphoproliferation have been reported [Ochs &Torgerson 2007, Nademi et al 2014, Bacchetta et al 2018, Barzaghi et al 2018]. Alopecia and arthritis have also been observed [Barzaghi et al 2018], as well as lung disease related to immune dysregulation [Baris et al 2014]

Infectious complications. Infections of the gastrointestinal tract, skin, and airways occur in individuals with IPEX syndrome [Bacchetta et al 2018], and severe or invasive infections including sepsis, meningitis, pneumonia, and osteomyelitis affect a significant number of subjects [Gambineri et al 2008, Barzaghi et al 2012, Barzaghi et al 2018]. Common pathogens identified were Staphylococcus, Enterococcus, cytomegalovirus, and Candida [Halabi-Tawil et al 2009, Barzaghi et al 2012]. Some infections may be secondary to immunosuppressive therapy; however, many occur prior to the initiation of treatment. Serious infections in individuals with IPEX syndrome are not thought to be due to an intrinsic immune defect but instead are typically related to poor barrier function of the gut and skin [Bacchetta et al 2018].

Survival. The outcome of classic IPEX syndrome is universally poor. Many children die within the first or second year of life from metabolic derangements, severe malabsorption, or sepsis. Although improvements in immunosuppressive regimens have prolonged survival, long-term immunosuppression did not appear to prevent morbidity due to disease progression and side effects or complications in the majority of patients [Barzaghi et al 2018].

Early bone marrow transplantation (BMT) is able to cure IPEX; some survivors are now more than ten years post transplant and doing well. If individuals develop diabetes or thyroiditis prior to BMT, these aspects of the disorder usually persist but the other signs of IPEX resolve. Survival and long-term outcomes are improved if BMT occurs at an earlier age, prior to the individual developing irreversible organ damage related to the extensive, systemic autoimmunity present in virtually all individuals with IPEX [Rao et al 2007, Burroughs et al 2010, Kucuk et al 2016].

Females

Heterozygous females are generally healthy. However, exceptions have been noted:

Genotype-Phenotype Correlations

There is currently no genotype-phenotype correlation. The same genotype can present with variable severity in different individuals, even within the same family [Seidel et al 2016].

Furthermore, it is difficult to correlate the type of pathogenic variant and outcome. Loss-of-function variants (frameshift) predicted to be missing the forkhead domain have been described in fetal-onset and nonviable cases, but also in individuals who survive into adolescence [Kobayashi et al 2001, Louie et al 2017]. In addition, within the cohort of affected individuals with extremely early onset of symptoms (<24 h of life), the types of variants and their position within the gene vary [Reichert et al 2016].

Nomenclature

IPEX syndrome may also be referred to as X-linked autoimmunity-allergic dysregulation (XLAAD) syndrome or X-linked syndrome of polyendocrinopathy, immune dysfunction, and diarrhea (XPID).

Prevalence

IPEX syndrome is rare: fewer than 300 affected individuals have been identified worldwide. No accurate estimates of prevalence have been published.

Differential Diagnosis

IPEX is classified by the International Union of Immunological Societies as a disease of immune dysregulation [Bousfiha et al 2018]. With autoimmunity as the primary clinical manifestation it shares features of other primary immune deficiencies associated with T regulatory cell dysfunction such as CD25 deficiency, CTL4 deficiency, and BACH2 deficiency. See Table 2 for these and other considerations in the differential diagnosis.

Table 2.

Syndromes to Consider in the Differential Diagnosis of IPEX Syndrome

DisorderGene(s) / Genetic
Mechanism
MOIAdditional Shared Clinical Features / Comments
Other syndromes w/neonatal diabetes mellitus6q24-related transient neonatal diabetes mellitusSee footnote 1
Pancreatic agenesis
(OMIM PS260370)
PDX1
PTF1A
AR
Heart defects, congenital, & other congenital anomalies
(OMIM 600001)
GATA6AD
Pancreatic beta cell agenesis w/neonatal diabetes mellitus
(OMIM 600089)
See footnote 2
Permanent neonatal diabetes mellitusABCC8
GCK
INS
KCNJ11
PDX1
AR
AD
Other syndromes w/polyendocrin-opathyAutoimmune polyendocrine syndrome, type I, w/ or w/out reversible metaphyseal dysplasia
(OMIM 240300)
AIREAD
AR
Autoimmune polyendocrine syndrome, type II
(OMIM 269200)
Unknown
Other syndromes w/immunodeficiency w/↓ Treg markers 3CD25 deficiency
(OMIM 606367)
IL2RAARIPEX syndrome-like clinical phenotype 4
Distinguished from IPEX syndrome by normal IgE in CD25 deficiency
STAT5B autoimmunity & immune deficiency syndrome
(OMIM 245590)
STAT5BARLow but not absent T and NK cell numbers
Distinguished by dwarfism in STAT5B deficiency 5
Immunodeficiency, common variable, 8, w/autoimmunity
(OMIM 614700)
LRBAAR
  • Autoimmune enteropathy
  • Type 1 diabetes mellitus
  • Autoimmune hypothyroidism
  • Autoimmune hemolytic anemia
Autoimmune lymphoproliferative syndrome, type V
(OMIM 616100)
CTLA4AD
  • Enteropathy
  • Autoimmune cytopenias
  • Autoimmune thyroiditis
Autoimmune disease, multisystem, infantile-onset 1 (ADMIO)
(OMIM 615952)
STAT3AD
  • Enteropathy
  • Type 1 diabetes mellitus
  • Autoimmune cytopenias
Distinguished by short stature in ADMIO 6
BACH2-related immunodeficiency and autoimmunity 7BACH2AD
  • Enteropathy
  • Chronic variable immunodeficiency
Mucosa-associated lymphoid tissue lymphoma translocation 1-related syndrome 8MALT1AR
  • Enteropathy
  • Dermatitis
Other syndromes w/immunodeficiency typically w/out ↓ Treg markersWiskott-Aldrich syndromeWASXL
  • Thrombocytopenia
  • Eczema
  • Combined immune deficiency
Omenn syndrome 9
(OMIM 603554)
DCLRE1C
RAG1
RAG2
AREosinophilia
Immunodeficiency 31C
(OMIM 614162)
STAT1AD
  • Enteropathy
  • Diabetes mellitus
  • Dermatitis
  • Autoimmune cytopenias
  • Onset in infancy or early childhood
Hyper-IgE recurrent infection syndrome (OMIM 243700)DOCK8ARAtopic dermatitis
Gastrointestinal defects & immunodeficiency syndrome
(OMIM 243150)
TTC7AAREnteropathy
Distinguished by intestinal atresias (variably present) in TTC7A deficiency 10
Autoimmune polyendocrinopathy w/candidiasis & ectodermal dystrophy (APECED)
(OMIM 240300)
AIREAD
AR
  • Endocrinopathy
  • Enteropathy
Distinguished by chronic mucocutaneous candidiasis & ectodermal dysplasia (dental enamel hypoplasia, keratopathy) in APECED
Autoimmune disease, multisystem, w/facial dysmorphism (ADMFD)
(OMIM 613385)
ITCHAR
  • Type I diabetes
  • Thyroiditis
  • Enteropathy
Distinguished by facial dysmorphisms in ADMFD
Autoimmune lymphoproliferative syndromeCASP10
FAS
FASLG
AD
AR 11
  • Hemolytic anemia
  • Thrombocytopenia
  • Splenomegaly
  • Chronic adenopathy
  • Type 1 diabetes mellitus
  • Thyroid disease
Other syndromes w/protracted diarrhea in infancy 12Microvillus inclusion disease
(OMIM 251850)
MYO5BAR
Tufting enteropathy
(OMIM 613217)
EPCAMAR
IL-10 receptor deficiency
(OMIM 613148, 612567)
IL10RA
IL10RB
ARDistinguished by severe, early-onset, fistulating enterocolitis in IL-10 receptor deficienc13
Tricohepatoenteric syndrome
(OMIM PS222470)
TTC37
SKIV2L
AR

Treg = regulatory T cell

↓ = reduced

1.

6q24-related transient neonatal diabetes mellitus is caused by overexpression of the imprinted genes at 6q24 (PLAGL1 and HYMAI).

2.

Presumed recessive disorder or imprinting defect causing an islet cell developmental defect

3.
4.

CD25 deficiency was identified in three individuals with an IPEX syndrome-like clinical phenotype [Roifman 2000, Caudy et al 2007]. In addition to autoimmunity, however, these individuals had features of severe cellular immunodeficiency with susceptibility to severe cytomegalovirus infections.

5.

Individuals with STAT5B deficiency also have a form of dwarfism related to the fact that growth hormone mediates its effects through STAT5 [Kofoed et al 2003].

6.
7.
8.
9.

Omenn syndrome is also known as familial reticuloendotheliosis with eosinophilia or severe combined immunodeficiency (SCID) with hypereosinophilia.

10.
11.

Inheritance of autoimmune lymphoproliferative syndrome (ALPS)-CASP10, of most cases of ALPS-FAS, and of some cases of ALPS-FASLG is autosomal dominant. Inheritance of most cases of ALPS-FASLG and of severe ALPS associated with biallelic FAS pathogenic variants is autosomal recessive.

12.
13.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with IPEX syndrome, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended:

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with IPEX Syndrome

Organ SystemEvaluationComment
GastrointestinalNutrition assessmentTo include serum electrolyte levels, calcium, magnesium, zinc, serum albumin & pre-albumin
Hepatic assessmentTo include serum AST, ALT, GGT, & total bilirubin & assessment of hepatic autoantibodies
Endocrine
  • Glucose tolerance test
  • HgA1C
  • Thyroid function tests
  • Autoantibodies to pancreatic islet antigens & thyroid antigens
Immunologic
  • Serum IgG, IgM, IgA, & IgE concentrations
  • Regulatory T cell numbers
DermatologicEvaluation of any skin lesionsMay include histology
Hematologic
  • Complete blood count & differential
  • Coombs test
  • Evaluation of autoimmune hypercoagulability (anti-phospholipid antibodies, lupus anticoagulant)
Renal
  • BUN, creatinine
  • Urinalysis
Miscellaneous/OtherConsultation w/clinical geneticist &/or genetic counselor

Treatment of Manifestations

Bone marrow transplantation (BMT) offers the only potential cure for IPEX syndrome. Early attempts at BMT using myeloablative conditioning regimens met with only limited success because of transplant-related mortality and other complications related to the underlying disease [Baud et al 2001]. Approaches using non-myeloablative conditioning regimens have markedly improved outcomes and survival [Burroughs et al 2007, Lucas et al 2007, Rao et al 2007]. While generally less toxic, these reduced-intensity conditioning regimens still appear to generate long-term, stable engraftment of a donor regulatory T cell population [Burroughs et al 2010, Nademi et al 2014, Barzaghi et al 2018] and, if performed in early infancy, may prevent the development of irreversible diabetes mellitus or thyroiditis [Burroughs et al 2010].

A large, multicenter long-term follow-up study suggests that bone marrow transplantation at time of no or mild organ impairment results in improved resolution of autoimmunity, especially when compared with non-transplanted individuals under chronic immunosuppressive therapy [Barzaghi et al 2012].

Table 4.

Treatment of Manifestations in Individuals with IPEX Syndrome

ManifestationTreatmentConsiderations/Other
Enteropathy of IPEX syndromeMonitor fluid intake to assure adequate intravascular volume.
Nutritional support including TPN or elemental or low-carbohydrate-containing formula is necessary in almost all individuals.
T cell-directed immune suppression (i.e., sirolimus, cyclosporin A or tacrolimus), either alone or in combination with steroidsToxicity, tachyphylaxis, & increased susceptibility to infection related to chronic use of these agents reduce their potential for long-term amelioration of symptoms in most individuals.
Sirolimus (rapamycin) as monotherapy or in combination w/other drugs 4 is considered first-line treatment; calcineurin inhibitors (e.g. tacrolimus) as an alternative 5.
  • Used successfully in individuals for whom tacrolimus was either ineffective or toxic 1
  • The ability of sirolimus to suppress effector T-cell function while allowing Treg cells to continue to develop & function offers some theoretic advantages for its use 2.
EndocrinopathyStandard treatment protocols for diabetes mellitus & autoimmune thyroid disease
Dermatitis
  • Systemic T cell-directed immune suppression
  • Topical therapies (e.g., steroids, tacrolimus, emollients) can also be beneficial.
For severe dermatitis, wound care specialist can be very helpful
Immune dysregulation
  • For autoimmune neutropenia: granulocyte colony stimulating factor (G-CSF) can improve neutrophil counts.
  • For pemphigus nodularis & other autoantibody-mediated disease: Rituximab has been effective 3.
May be beneficial

Prevention of Secondary Complications

Individuals with autoimmune neutropenia or recurrent infections resulting from severe eczema may benefit from prophylactic antibiotic therapy to decrease the risk of severe infectious complications.

Aggressive management of dermatitis with topical steroids and anti-inflammatory agents can help to prevent infections from pathogens that enter as a result of the poor barrier function of the skin.

Surveillance

Monitoring for evidence of autoimmune disease is recommended every three to six months with the following tests: complete blood count, thyroid function, HbA1c and glucose, kidney function (measurement of serum concentration of BUN, creatinine), and liver function (measurement of serum concentration of AST, ALT). Frequent monitoring of growth parameters, nutritional intake, and stooling patterns is important. If under immunosuppression of post-transplantation, monitoring for drug side effects should adhere to standard guidelines.

Agents/Circumstances to Avoid

Immune activation (e.g., by immunizations or severe infections) has been reported to cause worsening or exacerbation of disease symptoms [Powell et al 1982]. It is generally best practice to withhold immunizations until after bone marrow transplantation, if possible.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of at-risk males either prenatally or immediately after birth to enable early diagnosis and BMT and/or steroid treatment in affected males before significant organ damage occurs.

Evaluations can include:

  • Molecular genetic testing if the FOXP3 pathogenic variant in the family is known;
  • If the pathogenic variant is not known, monitoring of at-risk males for early-onset diarrhea, diabetes mellitus, thyroid dysfunction, and autoimmune hematologic manifestations.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

IPEX syndrome is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

  • The father of an affected male will not have the disorder nor will he be hemizygous for the FOXP3 pathogenic variant; therefore, he does not require further evaluation/testing.
  • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the FOXP3 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. Maternal somatic and germline mosaicism has been reported in IPEX syndrome [Lin et al 2018].
  • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a de novo FOXP3 pathogenic variant, in which case the mother is not a carrier. The percentage of affected males who have no family history of IPEX is not known.
  • Female carriers of IPEX syndrome are typically asymptomatic (see Clinical Description, Females).

Sibs of a proband. The risk to the sibs depends on the genetic status of the mother:

  • If the mother of the proband has a FOXP3 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the variant will be affected; females who inherit the variant will be heterozygous (carriers) and will typically be unaffected.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the FOXP3 pathogenic variant cannot be detected in the leukocyte DNA of the proband’s mother, the recurrence risk to sibs is slightly greater than that of the general population (though still <1%) due to the possibility of maternal germline mosaicism [Lin et al 2018].

Offspring of a proband. Affected males transmit the FOXP3 pathogenic variant to:

  • All of their daughters, who will be (heterozygotes) carriers and will typically not be affected (see Clinical Description, Females);
  • None of their sons.

Other family members. The proband's maternal aunts and their offspring may be at risk of being heterozygotes (carriers) for the pathogenic variant and the aunts' offspring, depending on their gender, may be at risk of being heterozygotes for the pathogenic variant or of being affected.

Heterozygote (Carrier) Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband.

X-chromosome inactivation is skewed only in regulatory T cells [Di Nunzio et al 2009] and is random in all other lymphocyte populations [Tommasini et al 2002]; therefore, X-chromosome inactivation studies are of limited use in carrier detection.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the FOXP3 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Diabetes Association (ADA)
    Phone: 1-800-DIABETES (800-342-2383)
    Email: AskADA@diabetes.org
  • Diabetes UK
    United Kingdom
    Phone: 0345 123 2399
    Fax: 020 7424 1001
    Email: info@diabetes.org.uk
  • International Patient Organisation for Primary Immunodeficiencies (IPOPI)
    Firside
    Main Road
    Downderry Cornwall PL11 3LE
    United Kingdom
    Phone: +44 01503 250 668
    Fax: +44 01503 250 668
    Email: info@ipopi.org
  • Jeffrey Modell Foundation/National Primary Immunodeficiency Resource Center
    747 Third Avenue
    New York NY 10017
    Phone: 866-463-6474 (toll-free); 212-819-0200
    Fax: 212-764-4180
    Email: info@jmfworld.org
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    Engesserstr. 4
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: esid-registry@uniklinik-freiburg.de
  • Latin American Society for Immunodeficiency (LASID) Registry
    Email: lagid.adm@gmail.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

IPEX Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for IPEX Syndrome (View All in OMIM)

300292FORKHEAD BOX P3; FOXP3
304790IMMUNODYSREGULATION, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED; IPEX

Gene structure. FOXP3 contains 12 exons. The first exon is untranslated and is followed by a large intron that contains key regulatory elements (particularly the Treg-specific demethylated region) that are critical for controlling which cells express the FOXP3 protein [Huehn et al 2009]. The 11 translated exons of the gene encode the FOXP3 protein. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. The majority of pathogenic variants in FOXP3 are either missense variants or small in-frame amino acid deletions. Loss-of-function variants have been described both in individuals with a neonatal presentation and others with a childhood presentation so that haploinsufficiency of FOXP3 does not appear to be lethal. The highest concentration of variants cluster within the C-terminal forkhead DNA-binding domain. Some pathogenic variants also affect the leucine zipper and an amino-terminal proline-rich domain that is involved in interactions with other key protein partners. Clustering of variants within these key functional regions of the protein demonstrates the essential role for these domains in FOXP3 function [Chatila et al 2000, Lopes et al 2006].

Normal gene product. FOXP3 encodes forkhead box protein P3 (FOXP3), a forkhead DNA-binding protein that is expressed primarily in CD4+CD25+ regulatory T cells. The protein consists of 431 amino acids and has important functional domains including:

  • An N-terminal proline-rich domain which is essential for the gene-suppressive function of FOXP3 and for interaction with other key transcription factors including RORα and RORγt [Du et al 2008, Zhou et al 2008];
  • A C2H2 zinc finger and leucine zipper (both conserved structural motifs involved in protein-protein interactions) in the central portion;
  • A forkhead DNA-binding domain at the C terminus from which it derives its name (forkhead box) [Ochs et al 2005, Lopes et al 2006]. A putative nuclear localization signal is located at the C-terminal portion of the forkhead domain [Lopes et al 2006].

Proteins bearing forkhead DNA-binding motifs comprise a large family of related DNA-binding proteins that play diverse roles in enhancing or suppressing transcription from specific binding sites. Several members of this protein family are involved in patterning and development [Gajiwala & Burley 2000]. FOXP3 is expressed primarily in lymphoid tissues (thymus, spleen, and lymph nodes), particularly in CD4+ CD25+ regulatory T lymphocytes. In mice, it is required for the development and suppressive function of this important regulatory T cell population [Fontenot et al 2003, Hori et al 2003, Khattri et al 2003, Sakaguchi 2003]. In humans, it is not expressed at baseline in CD4+CD25- or CD8+ T cells but is expressed upon T cell activation [Gavin et al 2006, Allan et al 2007]. The significance of this inducible expression in effector T cells is unknown.

Abnormal gene product. Loss of function or haploinsufficiency is the molecular mechanism of IPEX syndrome. Pathogenic alterations can affect mRNA stability, protein function, and intracellular localization. The FOXP3 protein is a transcription factor that regulates the expression of hundreds of targets, and is necessary for proper development of Treg, a population of cells responsible for tolerance of self-antigens.

A subset of the identified FOXP3 pathogenic variants have decreased function and cause a milder form of the disease [De Benedetti et al 2006, Gambineri et al 2008].

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Chapter Notes

Author History

Mark C Hannibal, MD, PhD; University of Michigan Medical School (2004-2018)
Raymond J Louie, PhD (2018-present)
John W Sleasman, MD (2018-present)
Queenie K-G Tan, MD, PhD (2018-present)
Troy Torgerson, MD, PhD; University of Washington, Seattle (2004-2018)

Revision History

  • 19 July 2018 (ha) Comprehensive update posted live
  • 27 January 2011 (me) Comprehensive update posted live
  • 12 December 2007 (me) Comprehensive update posted live
  • 27 April 2006 (cd) Revision: FOXP3 testing available clinically
  • 19 October 2004 (me) Review posted live
  • 11 February 2004 (mh) Original submission
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Bookshelf ID: NBK1118PMID: 20301297

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