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.

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.

• Males with a somewhat milder/atypical disease phenotype can present at older ages [Ge et al 2017, Hwang et al 2018].
• Fetal presentation of IPEX includes hydrops, echogenic bowel, skin desquamation, IUGR, and fetal akinesia. There may be a family history of pregnancy loss [Rae et al 2015, Vasiljevic et al 2015, Xavier-da-Silva et al 2015, Reichert et al 2016, Louie et al 2017, Shehab et al 2017].

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], and 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:

• One heterozygous female had an expression level of FOXP3 mRNA intermediate between the very low level observed in her affected son and the normal level in a control [Bennett et al 2001].
• One heterozygous female has monogenic diabetes mellitus [Alkorta-Aranburu et al 2014].
• X-chromosome inactivation studies performed on one heterozygous female demonstrated that normal and pathogenic variant FOXP3 alleles are equally expressed in peripheral blood mononuclear cells [Tommasini et al 2002]. However, subsequent studies of the FOXP3+ regulatory T cell population (CD4+/CD25+) demonstrated a selective advantage for cells utilizing the normal X chromosome, resulting in complete skewing of X chromosome usage in this cell subset [Di Nunzio et al 2009].
• Recurrent miscarriage of male fetuses has been reported [Rae et al 2015, Vasiljevic et al 2015, Xavier-da-Silva et al 2015, Reichert et al 2016, Louie et al 2017, Shehab et al 2017].