Clinical Guidance

There are currently no genotype-phenotype correlations. The same genotype can present with variable severity in different individuals, even within the same family . 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 infants, but also in individuals who survive into adolescence . Within the cohort of affected individuals with extremely early onset of symptoms (24 hours of life), the types of variants and their position within the gene vary . FOXP3 missense variants can result in FOXP3 expression resulting in normal regulatory T cell (Treg) enumeration by flow cytometry but abnormal Treg function .

Source: GeneReviews — "IPEX Syndrome"

Diagnostic Criteria

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

Source: GeneReviews — "IPEX Syndrome"

Differential Diagnosis

IPEX syndrome is classified by the International Union of Immunological Societies (IUIS) as an inborn error of immunity that results in immune dysregulation due to absent or defective regulatory T cells (Treg) . Autoimmunity is the primary clinical manifestation. Among the ten unique disorders with Treg dysfunction, LRBA deficiency, CTLA4 haploinsufficiency, CD25 deficiency, FERMT1 deficiency, BACH2 deficiency, IKAROS GOF (gain of function), and CD122 deficiency have the most clinical overlap with IPEX syndrome . Other inborn errors of immunity without Treg dysfunction, including immune dysregulation with colitis, can also mimic IPEX syndrome . In addition to immune dysregulation disorders, monogenic forms of neonatal diabetes that are clinically evident soon after birth can present similarly to IPEX syndrome. These conditions are most commonly associated with pancreatic defects and lack autoimmune manifestations . Similarly, intrinsic defects of the intestinal microvilli have clinical presentations consistent with enteropathy with malabsorption and diarrhea but are not immune mediated . See for these and other considerations in the differential diagnosis. Table 2. Syndromes of Known Genetic Cause to Consider in the Differential Diagnosis of IPEX Syndrome

Management Guidelines

Evaluations Following Initial Diagnosis

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

Table 3.

IPEX Syndrome: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Gastrointestinal

| Nutrition assessment incl serum electrolyte levels, calcium, magnesium, zinc, serum albumin, pre-albumin | The majority of persons will require discontinuation of enteral feeding initiation of TPN.

Hepatic assessment | Incl serum AST, ALT, GGT, total bilirubin, assessment of hepatic autoantibodies

Small bowel biopsy incl specific staining for Treg | To assess response to treatment

Endocrine

| • Glucose tolerance test

• Hemoglobin A1c

• Thyroid function tests

• Autoantibodies to pancreatic islet antigens thyroid antigens

|

Dermatologic

| Eval of any skin lesions | Should incl biopsy for histology

Clinical Guidance

Immune activation (e.g., by immunizations or severe infections) has been reported to cause worsening or exacerbation of disease symptoms . It is generally best practice to withhold immunizations until after HSCT, if possible.

Source: GeneReviews — "IPEX Syndrome"

Therapies Under Investigation

HSCT carries the risk of significant morbidity and mortality, and suitable donors are not always available. For these and other reasons, IPEX syndrome is an excellent candidate for treatment with gene therapy. However, one major hurdle is the need to regulate the expression of FOXP3 on mature T cells; thus, hematopoietic stem cells are not the ideal target for gene delivery. An alternative approach has been to convert CD4+ T cells from individuals with IPEX syndrome using lentivirus vectors that carry normal FOXP3. Lentiviral delivery of exogenous FOXP3 cDNA is accomplished under the constitutive promoter to achieve conversion of FOXP3 mutated cells to normal functioning regulatory T cells (Treg) in vivo.

Source: GeneReviews — "IPEX Syndrome"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended.

Table 5.

IPEX Syndrome: Recommended Surveillance

System/Concern | Evaluation | Frequency

Enteropathy

| Monitor growth, nutritional intake, stooling patterns. | At each visit

Endocrinopathy

| • Glucose tolerance test

• Hemoglobin A1c

• Thyroid function tests

| Every 3-6 mos

Dermatitis

| Skin exam | At each visit

Immune dysregulation

| • Complete blood count

• BUN, creatinine

• Urinalysis

• Serum AST, ALT

| Every 3-6 mos

ALT = alanine transferase; AST = aspartate transferase; BUN = blood urea nitrogen

Source: GeneReviews — "IPEX Syndrome"