IPEX Syndrome and Related Disorders (Tregopathies)

Immune dysregulation beginning in the neonatal period or infancy, caused by loss of function of the FOXP3 transcription factor in regulatory T lymphocytes, with autoimmune enteropathy, early-onset type 1 diabetes and dermatitis; autosomal tregopathies (CD25, CD122, LRBA and DEF6 deficiencies, CTLA-4 insufficiency, STAT3 gain of function, BACH2, IKAROS gain of function, FERMT1) and other IPEX-like disorders form part of the differential diagnosis.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

1.1. From the 1982 family to the FOXP3 gene

IPEX syndrome was first described in 1982 by Powell and colleagues in a family in which boys died in the first year of life with intractable diarrhoea, diabetes and eczema, and in which exacerbations were associated with vaccination or severe infections; genetic characterisation came almost twenty years later [1, 6]. In 2000, Chatila and colleagues described XLAAD syndrome, an X-linked recessive disorder with multisystem autoimmunity, early-onset type 1 diabetes and severe atopy (eczema, food allergy, eosinophilic inflammation), and used a positional-candidate approach to identify mutations in JM2, at Xp11.23, a gene encoding a protein with a forkhead domain: a splice-junction variant producing transcripts lacking the forkhead domain and an in-frame 3-base-pair deletion in the leucine zipper domain [28]. In January 2001, two consecutive Nature Genetics articles demonstrated that mutations in FOXP3, the human orthologue of the gene mutated in the scurfy mouse, cause the syndrome: Bennett and colleagues built on previous linkage to the Xp11.23-Xq13.3 interval [29], and Wildin and colleagues, who called the disease X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome, found four non-polymorphic mutations, all in the forkhead/winged-helix domain of scurfin, suggesting impaired DNA binding [30].

In subsequent years, recognition that FOXP3 is the master regulator of CD4+CD25+ regulatory T lymphocytes made IPEX syndrome the human model of loss of Treg-mediated peripheral tolerance [1, 31]. In 2005, Bindl and colleagues reported the first successful use of sirolimus in three patients, attributing its effectiveness to a mechanism of action different from that of calcineurin inhibitors [32]. In 2007, Caudy and colleagues described a patient with an IPEX phenotype, normal FOXP3 and CD25 deficiency (IL2RA, autosomal recessive), and proposed that every patient with an IPEX phenotype and normal FOXP3 should undergo IL2RA testing; the concept of IPEX-like syndrome thus emerged [33]. Human CTLA4 haploinsufficiency was described simultaneously in 2014 [34, 35], and in 2015 LRBA deficiency was linked to CTLA-4 loss and response to abatacept [36], giving rise to mechanism-directed therapies in this family of disorders.

1.2. Nomenclature and classification

The acronym IPEX summarises the three dominant manifestations and the mode of inheritance: immune dysregulation, polyendocrinopathy and enteropathy, X-linked [1]. The synonyms XLAAD and XPID and the designation autoimmune enteropathy type 1 refer to the same entity [1, 2]. The Oxford clinical genetics reference book places the syndrome within the group of immune dysregulation disorders with autoimmunity, alongside autoimmune lymphoproliferative syndrome (ALPS) and autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) [37]. In the IUIS classification of inborn errors of immunity (IEI), IPEX syndrome belongs to primary immune regulatory disorders (PIRD), within the subgroup of Treg defects [1, 38]. The 2024 update, published in 2025, encompasses 508 genes and 17 phenocopies, with 67 new monogenic defects since June 2022 [11]; according to Iyengar and colleagues' interpretation, the list of Treg defects in that update includes FOXP3 (X-linked), IL2RA, IL2RB, LRBA, DEF6, NBEAL2 and FERMT1 (autosomal recessive), and CTLA4, STAT3 gain of function, BACH2 and IKZF1 gain of function (autosomal dominant) [11, 12].

The term “IPEX-like” denotes patients with the clinical presentation of IPEX and normal FOXP3; 20 to 30% of patients with clinical IPEX have no FOXP3 variant [7]. Chatila and colleagues propose the designation “tregopathies” for the group of monogenic disorders in which the primary or secondary defect affects Treg generation, stability or function [7]. In the Florence and Seattle cohort, the genes identified in IPEX-like patients were divided into those primarily affecting Treg generation or function (IL2RA, STAT5B, CTLA4) and those affecting them secondarily (LRBA, STAT3 and STAT1 gain of function) [8]. FERMT1 deficiency, known in dermatology as Kindler syndrome (described by Kindler in 1954), entered the list because epithelial kindlin-1 activates integrin αvβ6, which releases active TGF-β1 and induces Treg at barriers [12]. Kennedy-Batalla and colleagues' review of Treg in inborn errors of immunity lists FERMT1 deficiency among these disorders, with the Treg phenotype not assessed [39].

1.3. Definition of the entities covered

IPEX syndrome is defined by the presence of a hemizygous pathogenic or likely pathogenic FOXP3 variant in a male individual, usually with early-onset enteropathy, endocrinopathy and dermatitis [1]. Atypical forms include onset after the first year, single-organ involvement, mild severity or predominance of rare manifestations such as interstitial lung disease or nephritis [7, 40]. Autosomal tregopathies and IPEX-like phenocopies (CD25, CD122, LRBA, DEF6 and STAT5B deficiencies, CTLA-4 insufficiency, STAT1 and STAT3 gain of function, BRIDA, IKAROS gain of function and FERMT1 deficiency) are addressed as differential diagnoses, with their own data in sections 2, 3, 6 and 7 wherever they differ from IPEX. Hyper-IgE syndromes due to STAT3 loss of function, DOCK8 deficiency and combined and humoral immunodeficiencies in general are part of the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. The FOXP3 gene and protein

FOXP3 is located at Xp11.23 and encodes the forkhead box P3 protein (UniProt Q9BZS1; HGNC:6106), a transcription factor of the forkhead/winged-helix family [1, 3]. The reference transcript is NM_014009.4, confirmed as MANE Select in VariantValidator, with protein NP_054728.2 [4]. The protein has four functional regions: a proline-rich N-terminal domain with repressive and autoinhibitory functions, required for interaction with RORα and RORγt; a central C2H2 zinc finger and leucine zipper, responsible for dimerisation and protein–protein interactions; and a C-terminal DNA-binding forkhead (FKH) domain containing a putative nuclear localisation signal [1, 7]. There are two main isoforms, the full-length form (FL, with 11 coding exons) and the isoform lacking exon 2 (Δ2 or ΔE2), expressed in approximately equal proportions in normal T cells [8].

FOXP3 is expressed mainly in lymphoid tissues (thymus, spleen and lymph nodes) and, within these, in CD4+CD25+ Treg [1]. In mice, it is required for Treg development and suppressive function; in humans, it is not expressed under basal conditions in CD4+CD25− or CD8+ T cells, but is transiently induced by T-cell activation, with as yet unknown significance in effector cells [1]. FOXP3 regulates hundreds of target genes: it activates CTLA4, IL2RA and TNFRSF18 and represses IL2 and IFNG, in cooperation with partners such as RUNX1, the acetyltransferase KAT5 (TIP60) and HDAC7 [3].

2.2. Regulatory T lymphocytes and mechanisms of suppression

In healthy individuals, 5 to 7% of CD4+ T cells have Treg properties; thymic Treg (Helios+) are distinguished from peripherally induced Treg, and the usual phenotype is CD4+CD25(high)FOXP3(high)CD127(low) [8]. Suppression occurs through contact, via CTLA-4, which removes the CD80 and CD86 ligands from antigen-presenting cells by transendocytosis; through inhibitory cytokines (IL-10 and TGF-β); and through IL-2 consumption via CD25, which acts as a “sink” for this cytokine [8, 41]. CD25 maintains Treg, CD103 directs their trafficking and CTLA-4 executes their function [8]. The Treg-specific demethylated region (TSDR), located within conserved non-coding sequence 2 (CNS2) of FOXP3, is fully demethylated in thymic Treg and methylated in activated effector cells and other cells, making it an epigenetic lineage marker [9].

2.3. Disease mechanism

Pathogenic FOXP3 variants act through loss of function: they alter mRNA stability, protein function or intracellular localisation [1]. The consequence is not simply a lack of Treg. Borna and colleagues showed that patients with IPEX, unlike those with APECED, have expanded autoreactive T cells originating from both effector cells and Treg themselves; some expanded Treg lose CD25 and FOXP3 (instability) and acquire effector-like function with Th2 skewing, reproduced in cells with CRISPR-Cas9-mediated FOXP3 inactivation [42]. In carrier mothers and a patient after HSCT, Treg with non-mutated FOXP3 prevented accumulation of autoreactive effectors and unstable Treg [42]. In patients with typical IPEX (n=6) and atypical or asymptomatic IPEX (n=9), Narula and colleagues described a consistent increase in cells with demethylated TSDR, more marked in typical IPEX, already present in still-asymptomatic carriers of a pathogenic variant and increasing with progression, accompanied by a plasma signature of macrophage activation and Th2 polarisation (CCL22, CCL17, CCL15, IL-13; TNF-α, IL-1A, IL-8, soluble FasL, CXCL9) [43]. The expansion of cells with demethylated TSDR corresponds to mutant Treg that have lost their identity [7].

The epithelial barrier contributes to the disease. Anti-enterocyte autoantibodies target harmonin and villin, and villin expression in the small intestine and renal proximal tubules has been proposed to explain the association between enteropathy and nephropathy [7]. Elevated IgE and food allergies reflect failure of oral tolerance [7]. Severe infections are not attributed to an intrinsic immune defect, but to impaired intestinal and skin barrier function, malnutrition, central venous catheters and immunosuppression [1, 31].

2.4. Variant spectrum and nomenclature

Most pathogenic variants are missense variants or small in-frame deletions; they cluster in the FKH domain but also occur in the leucine zipper and N-terminal domain, at conserved residues [1, 8]. In the international cohort of 96 patients, 33 previously published and 21 novel variants were distributed throughout the gene, with FKH as a hotspot [6]. In the Florence and Seattle cohort, 44 distinct variants (9 novel) accounted for 88 patients from 66 families, and five recurrent variants accounted for approximately 35% of families (23/66) [8]. Rayes and colleagues count more than 187 pathogenic variants described in IPEX and approximately 300 mutations in patients with an IPEX phenotype [9]. Outside the coding region, the c.-7G>T variant in the 5' UTR, c.*876A>G in the 3' UTR and a deletion of non-coding exon 1 in a patient presenting with severe food allergy have been described [1, 44]. Polyadenylation signal mutations (AAUAAA→AAUGAA, that of the original family, and AAUAAA→AAUAAG), located approximately 798 to 883 base pairs downstream of the stop codon, accounted for 11 patients from 3 families, up to 12% of IPEX patients in the cohort; they produce unstable mRNA with very low expression and fall outside standard sequencing approaches [8]. In 2026, the first deep intronic variant (c.968-207A>G, intron 9), creating pseudoexons, was described [45].

The literature before 2010 sometimes uses the protein designation without a prefix (p.R337Q, p.A384T) and the former gene name (JM2) [8, 28]. Interpretation requires caution: the synonymous variant c.543C>T, at the first base of exon 5, was present in 3.5% of 200 chromosomes from multiethnic controls and produced fewer than 5% incorrectly spliced transcripts, and c.112G>T p.(Ala38Ser) was found in approximately half the asymptomatic men in the family; both were reclassified as non-pathogenic [8].

2.5. Genotype–Phenotype Correlation, Penetrance and Modifiers

There is no genotype–phenotype correlation useful for clinical decision-making: the same genotype produces variable severity, even within the same family, and frameshift variants with no predicted FKH domain have been described both in non-viable fetuses and in survivors into adolescence [1, 49]. In the cohort of 96 patients, the number of initial symptoms and age at onset did not depend on the mutation site, and the effects predicted by PolyPhen-2 and PROVEAN did not correlate with the severity score or survival [6]. In patients with onset within the first 24 hours of life, variant type and position vary [50]. Some descriptive trends exist: in the cohort of 173 patients, 10-year survival was 87.5% with in-frame deletions (n=11), 78% with splicing variants (n=14), 67% with missense (n=43) and frameshift variants (n=6), and 19% with polyadenylation signal variants (n=11); the complete triad was more frequent with in-frame deletions (83%) and frameshift variants (67%) [8]. All patients with complete loss of FOXP3 protein have the severe, early-onset classical form [9]. Six patients with frameshift variants in exon 2, who lose only the full-length isoform, had IPEX in five cases, without a significant phenotypic difference [7, 8].

Missense variants may preserve FOXP3 expression and a normal Treg count by flow cytometry, with abnormal suppressive function [1, 51]. Mouse models carrying patient variants (published designations in the protein numbering used by the authors, not mapped to NM_014009.4) show that only R337Q causes multiorgan autoimmunity on its own; R51Q, C168Y, K199del, R309Q and F324L cause it only on a susceptible genetic background, and the absence of MyD88 or a germ-free environment attenuates inflammation at interfaces, but not systemic autoimmunity [7]. Heterogeneity thus results from variant type, genetic background and environment. Penetrance in hemizygous boys is not complete in the clinical sense: in the international cohort, one patient with a familial variant was asymptomatic at 6 years and two did not require immunosuppression [6].

2.6. Allelic Disorders and Female Carriers

No other phenotype is known to be associated with germline FOXP3 variants [1]. Heterozygous females have normal Treg differentiation and are asymptomatic, because Tregs expressing the normal allele have a competitive advantage and X-inactivation becomes skewed only in this population, remaining random in other lymphocyte lineages [1, 7, 9]. One carrier mother in the Florence and Seattle cohort had type 1 diabetes, an isolated finding [8]. Common polymorphisms in IL2RA (susceptibility to type 1 diabetes and multiple sclerosis) and BACH2 (genome-wide association study associations with autoimmunity) do not constitute Mendelian disease [52, 53].

2.7. Genetics of Autosomal Tregopathies and Phenocopies

The mechanism shared by CTLA-4 insufficiency and LRBA and DEF6 deficiencies is a lack of functional CTLA-4 in Tregs, which makes these conditions almost clinically indistinguishable and provides a rationale for mechanistic replacement with CTLA-4-Ig (abatacept) [36, 41, 56]. In STAT1 gain of function, Janus kinase (JAK) inhibition is rational only for gain-of-function variants and worsens loss-of-function variants [58]. Activating somatic STAT5B variants (p.Asn642His) in T/NK neoplasms and the STAT5B-RARA fusion in promyelocytic leukaemia should not be confused with germline variants [26]. In IKZF1, gain of function contrasts with loss of function or haploinsufficiency, which causes B-cell deficiency and predisposition to acute lymphoblastic leukaemia [7].

3. Clinical Spectrum and Manifestations by System

3.1. Age at Onset and Presentation

In boys, IPEX syndrome is considered a cause of neonatal enteropathy and neonatal polyendocrinopathy [1]. In the 2012 natural history study by Barzaghi and colleagues, cited by GeneReviews, 95% of patients developed disease within the first year of life and 50% by the first month [1, 59]. The 2018 retrospective international cohort, comprising 96 patients with a FOXP3 variant from 38 centres, provides the best quantitative description: median age at onset of 2 months (birth to 11.3 years), 41% in the first month, 46% between 1 month and 1 year, 10% after the first year and 3% with unknown age; the median interval between onset and genetic diagnosis was 14 months, with a maximum of 23.9 years, and the number of diagnoses per year was increasing [6]. The classical triad (enteropathy, type 1 diabetes and eczema) predominated in the 39 patients with neonatal onset; after the first month, gastrointestinal involvement and eczema predominated, rather than diabetes; failure to thrive was sometimes the sole initial manifestation after the first month, and after the first year disease could begin with nephropathy or hepatitis [6]. The most common presentation is a boy under 1 year with malabsorption and severe watery diarrhoea, type 1 diabetes, thyroiditis and dermatitis [1].

3.2. Fetal and Perinatal Presentation

Disease may begin in utero, with cases reported from the 18th week of gestation [7]. Findings include hydrops, hyperechogenic bowel, skin desquamation, intrauterine growth restriction and fetal akinesia, sometimes with a history of recurrent pregnancy losses involving male fetuses [1, 49, 50]. GeneReviews reproduces images of prenatal skin desquamation published by Louie and colleagues, who described novel variants in fetuses with hyperechogenic bowel and desquamation on ultrasound [1, 49]. A dysmorphology reference textbook includes FOXP3 among genes associated with the fetal akinesia phenotype (Pena–Shokeir sequence), a listing consistent with the akinesia described in fetuses with IPEX, but without case descriptions in the textbook itself [60]. The São Paulo group included IPEX syndrome among inborn errors of immunity with fetal or perinatal manifestations [61].

3.3. Enteropathy

Enteropathy is frequently the first symptom and is present in virtually all patients; even in mild forms, diarrhoea begins between 6 and 12 months [1]. It consists of watery diarrhoea, sometimes with mucus and blood, with loss of villous architecture, leading to failure to thrive and cachexia [1, 31]. In the Florence and Seattle comparison, enteropathy was present in 97% of IPEX patients, with mean onset at 7.8 months, and failure to thrive in 75% [8]. Histology shows changes resembling graft-versus-host disease (GVHD) in most patients, lymphocytic infiltrates, goblet cell depletion and anti-enterocyte antibody deposition [1]. In the international cohort, biopsies showed simultaneous involvement of multiple segments (small intestine more than colon, stomach and oesophagus), a polymorphic infiltrate predominantly comprising lymphocytes and eosinophils, villous atrophy as a hallmark, ulcers, crypt hyperplasia and abscesses, and four patients had intestinal or gastric metaplastic lesions and one had gastric dysplasia [6]. Gastric adenocarcinoma has been described in a young person with IPEX [7]. Some patients have exocrine pancreatic insufficiency, colitis or gastritis [1, 62].

3.4. Endocrinopathy

Type 1 diabetes, frequently beginning in the first few months, is the most common endocrine manifestation [1, 63]. In the cohort of 173 patients, endocrinopathy was present in 65% of IPEX patients and type 1 diabetes in 49%, with mean onset at 27 months, and thyroid disease in 26% [8]. Thyroiditis is frequent, with hypothyroidism more common than hyperthyroidism [1, 64]. In the international cohort, autoimmune thyroiditis occurred in 15 of 96 patients over the course of disease [6]. Rubio-Cabezas and colleagues described clinical heterogeneity in patients with FOXP3 variants who presented with permanent neonatal diabetes [63]. Twelve patients in the international cohort had diabetes-associated autoantibodies without diabetes [6].

3.5. Skin

Dermatitis is predominantly eczematous, but may also be psoriasiform or ichthyosiform; painful cheilitis, erythroderma, exfoliative dermatitis and food allergy lesions may occur, and, rarely, nodular pemphigoid and acquired epidermolysis bullosa [1, 65]. Skin involvement occurred in 89% of IPEX patients in the cohort of 173, with eczema or exfoliative dermatitis in 85%, erythroderma in 8% and alopecia in 11% [8]. The disrupted skin barrier provides a portal of entry for infections [1].

3.6. Other Autoimmune and Inflammatory Manifestations

Over the course of disease, the international cohort of 96 patients recorded nephropathy in 33 (autoimmune or secondary to malnutrition and drugs: stones, nephrocalcinosis, isolated proteinuria, nephrotic syndrome or glomerulonephritis, tubulopathy, interstitial nephritis), autoimmune haemolytic anaemia in 25, thrombocytopenia in 13, neutropenia in 6, hepatitis in 19, food allergies in 13, arthritis in 8, alopecia in 8 and lymphadenopathy in 9 [6]. Neurological findings of uncertain relationship to FOXP3 were also recorded in 16 patients (peripheral neuropathy, myopathy or hypotonia, hemidiaphragmatic paralysis, eosinophilic meningitis, neurodevelopmental delay, seizures and benign intracranial hypertension) [6]. Membranous nephropathy, interstitial nephritis and, rarely, minimal change disease, autoimmune hepatitis, splenomegaly due to lymphoproliferation and interstitial lung disease due to immune dysregulation are part of the spectrum described in GeneReviews [1]. The frequency of haematological (42%), renal (28%), hepatic (20%), pulmonary (23%) and neurological (24%) manifestations was similar between IPEX and IPEX-like disease in the cohort of 173 patients [8].

3.7. Allergy, IgE and Eosinophilia

IgE was elevated in 92% of IPEX patients versus 49% of IPEX-like patients, and above 1000 IU/mL in 59% versus 25.5%, with values sometimes exceeding 10,000 IU/mL; food allergy was present in 36% of IPEX patients and 11% of IPEX-like patients [8]. Eosinophilia is frequent, and food allergies or intolerances confirmed by specific IgE or skin tests are common [1]. Torgerson and colleagues described severe food allergy as the presenting feature of IPEX, caused by a deletion in a non-coding region [44].

3.8. Infections

Gastrointestinal, skin and respiratory infections are common, and invasive infections (sepsis, meningitis, pneumonia, osteomyelitis) affect a significant number of patients [1]. The most frequent organisms are Staphylococcus, Enterococcus, cytomegalovirus (CMV) and Candida [1, 65]. In the cohort of 173 patients, 47% of those with IPEX had severe infections (Staphylococcus 23%, Candida 19%, CMV 10%), which the authors interpreted mainly as a complication of intensive and prolonged immunosuppression [8]. Many infections occur before treatment and are related to malnutrition, central catheters and barrier loss [1].

3.9. Atypical Forms

Atypical presentations include onset later in childhood, single-organ or mild disease, and predominance of rare manifestations [1, 40]. In the Turkish Hacettepe cohort, comprising 12 patients from 9 families with 6 variants, median age at diagnosis was 2.5 years (0.3 to 22), and class IV lupus nephritis, a severe combined immunodeficiency-like immunophenotype (CD3+ 4% [100/µL], CD4+ 3%, CD8+ 1%, CD19+ 81%, NK 13%) and isolated hypogammaglobulinaemia persisting for years were described [66]. Lorenzini and colleagues described a patient with the c.210+1G>T variant, loss of FOXP3 expression, food allergy, eczema and severe infections, without chronic diarrhoea or polyendocrinopathy, with CD4 lymphopenia (markedly reduced naive cells), low IgG2, IgA and IgM, elevated IgE, eosinophilia and probably neutralising anti-IL-6 autoantibodies, in a presentation resembling hyper-IgE syndromes [48]. In the Indian tregopathy series, the two IPEX patients had autoimmune cytopenia and nephritis or nephropathy, manifestations considered uncommon [12].

3.10. Untreated Natural History and Treated Disease

Without effective immunosuppression or HSCT, most boys die within the first 1 to 2 years from metabolic disturbances, severe malabsorption or sepsis; milder phenotypes have allowed survival into the second or third decade, but are rare [1]. Data on treated disease differ. In the international cohort, estimated overall survival at 15 years was 73.2% after HSCT (n=58) and 86.8% with chronic immunosuppression (n=34), but under immunosuppression survival fell to 65.1% at 24 years and disease-free survival progressively declined [6]. In the cohort of 173 patients, survival from birth was 65% at 10 years and 52% at 30 years in IPEX patients [8]. Section 11 details these data by treatment modality.

3.11. Clinical Spectrum of Autosomal Tregopathies and Phenocopies

The cohort of 173 patients with an IPEX phenotype identified no major clinical features distinguishing IPEX from IPEX-like disease: IPEX patients had more food allergy, eczema, type 1 diabetes and the complete triad, whereas IPEX-like patients had more thyroid disease and cardiovascular abnormalities [8].

Source: Florence and Seattle cohort, 88 IPEX and 85 IPEX-like patients [8].

CD25 deficiency. Onset is early, with an IPEX-like triad, but greater susceptibility to viral (severe CMV), bacterial and fungal infections (oesophageal candidiasis), cytopenias, lymphoproliferation, follicular bronchiolitis and congenital diarrhoea [1, 7]. Goudy and colleagues described severe autoimmune enteritis, viral infection and lymphoproliferation predominantly involving activated CD8+ cells, with FOXP3+ Tregs still present [52]. Alzubedy and colleagues described two siblings with severe enteropathy, eczema, respiratory infections, failure to thrive, allergy, hypergammaglobulinaemia, CD4/CD8 inversion and absent CD25, and counted 13 cases published since 1997 [16]. GeneReviews, using earlier data, reported 3 individuals [1].

CD122 deficiency. Early IPEX-like autoimmunity (enteropathy, autoimmune haemolytic anaemia, dermatitis), susceptibility to herpesviruses, Epstein–Barr virus (EBV) and CMV, hypergammaglobulinaemia with elevated IgG and IgE, and antinuclear antibodies; endocrinopathy is uncommon; 8 individuals described [1, 7].

CTLA-4 insufficiency. In the cohort of 133 carriers from 54 families (45 variants, 28 novel), 90 were affected, giving a clinical penetrance of at least 67%; median age at onset was 11 years, with cases up to 50 years; affected individuals had hypogammaglobulinaemia (84%), lymphoproliferation (73%), respiratory manifestations (68%), autoimmune cytopenias (62%), gastrointestinal (59%) and neurological manifestations (29%), T-, B- and NK-cell lymphopenia, and mortality of 16% (15 patients) [18]. Schubert and colleagues considered 8 of 19 adult carriers unaffected [35]. 8 lymphomas and 3 gastric cancers were described in the cohort of 133, with EBV association in 6 patients with malignancy [18]; in an analysis of 131 affected carriers, malignancies occurred in 17 (12.9%), more than half associated with EBV [41]. Lymphoid or granulomatous infiltrates occur in the intestine, lung, brain, skin, liver and kidney, and more than 200 patients have been described [7].

LRBA deficiency. In a series of 22 genetically confirmed patients, immune dysregulation was present in 95%, organomegaly in 86%, recurrent infections in 71% and hypogammaglobulinaemia in 57%; T cells were normal in 81%, but Tregs were reduced in 73% [67]. A systematic review of 109 cases found autoimmunity in 82%, enteropathy in 63%, splenomegaly in 57% and pneumonia in 49% [21]. Onset is earlier (preschool age) than in CTLA-4 insufficiency, the phenotype ranges from IPEX-like to ALPS-like disease and common variable immunodeficiency (CVID), and deafness, renal dysfunction and T2-FLAIR lesions on MRI have been described [7]. A Turkish study described LRBA deficiency as more severe than CTLA-4 insufficiency in a cohort of 98 patients [68].

DEF6 deficiency. Seven patients from 3 families with autoimmunity (predominantly haemolytic anaemia), inflammation, enteropathy, EBV-associated lymphoproliferation and lymphoma, with T-cell lymphopenia, low switched B cells and expansion of FOXP3+CD25− cells [7, 56].

STAT3 gain of function. In the international cohort of 191 patients from 33 countries (72 variants), median age at onset was 2.3 years and at diagnosis 12 years; lymphoproliferation occurred in 73%, increased double-negative T cells in 83% of those tested, autoimmune cytopenias in 67%, infections in 72%, cellular immunodeficiency in 37% and humoral immunodeficiency in 51%, together with failure to thrive, enteropathy, skin involvement, lung involvement (interstitial lung disease in 43%), endocrinopathy, arthritis, hepatitis, neurological involvement, vasculopathy and renal involvement; overall survival was 88% [22]. Short stature distinguishes it from IPEX [1]. The entity was delineated by Milner and colleagues in 2015, with early-onset lymphoproliferation and autoimmunity [69].

STAT1 gain of function. In the cohort of 274 patients from 167 families and 40 countries, chronic mucocutaneous candidiasis (CMC) affected 98% (median onset at 1 year), bacterial infections 74%, viral infections 38%, invasive fungal infections 10% and mycobacterial infections 6%; autoimmunity affected 37% (hypothyroidism 22%, type 1 diabetes 4%, cytopenias 4%), and predictors of poor prognosis were invasive infections (25%), cerebral aneurysms (6%) and cancer (6%) [24]. The Orphanet name of the entity (“autoimmune enteropathy and endocrinopathy with susceptibility to chronic infections”) reflects the IPEX-like phenotype, but the spectrum is dominated by CMC [23].

STAT5B deficiency. The recessive form causes severe and progressive postnatal growth failure, profound IGF-1 deficiency with normal or elevated GH and no response to exogenous GH, increased prolactin, eczema, elevated IgE, autoimmunity (thyroiditis, cytopenias, juvenile arthritis, coeliac-like enteropathy) and potentially fatal lymphocytic interstitial lung disease; the dominant-negative form is milder, with short stature, eczema and elevated IgE, without severe immune complications [7, 26].

BRIDA, IKAROS gain of function, FERMT1 and NBEAL2 deficiencies. BRIDA presents with colitis in infancy, immunoglobulin deficiency, intestinal inflammation, pulmonary infiltrates and a CVID phenotype, with incomplete penetrance [7, 27]. IKAROS gain of function combines prominent autoimmunity and dysregulation, atopy, plasma cell proliferation (IgG4-related disease) and normal or increased B lymphocytes and immunoglobulins [7]. Null FERMT1 variants cause skin blistering shortly after birth, skin atrophy, pigmentary changes, photosensitivity, haemorrhagic mucositis, periodontitis, oesophageal stenosis and, rarely, fulminant infantile colitis; in the Indian series, two infants with colitis, blistering and Gram-negative sepsis entered the differential diagnosis of neonatal IPEX [12]. Autoimmune retinopathy has been described in a patient with FERMT1 deficiency [70]. NBEAL2 deficiency combines grey platelet syndrome, splenomegaly, progression to myelofibrosis, autoimmunity, EBV reactivation and haemophagocytic lymphohistiocytosis (HLH), with 50% survival in the series summarised by Iyengar and colleagues [12].

4. Clinical Recognition and Warning Signs

4.1. When to Suspect the Diagnosis

In the fetal period, suspicion arises with hydrops, hyperechogenic bowel, skin desquamation, growth restriction or akinesia in a male fetus, particularly if there have been previous pregnancy losses involving male fetuses [1, 49]. In newborns and infants, signs that should prompt investigation are intractable watery diarrhoea requiring parenteral nutrition, neonatal diabetes or diabetes in the first few months, severe eczematous or exfoliative dermatitis, erythroderma, thyroiditis and autoimmune cytopenias, especially when two or more coexist [1, 6]. Diabetes diagnosed before 6 months raises the differential diagnosis of monogenic neonatal diabetes; prenatal diagnosis in neonatal diabetes is performed mainly for syndromic forms, such as IPEX or Wolcott–Rallison syndrome, which may be fatal in childhood [71]. After the first month, isolated failure to thrive may be the first manifestation, and after the first year disease may begin with nephropathy or hepatitis [6].

In older children, adolescents and adults, suspicion focuses on atypical forms and autosomal tregopathies: multiorgan autoimmunity with enteropathy, cytopenias, lymphoproliferation, hypogammaglobulinaemia or lymphocytic infiltration of organs, as occurs in CTLA-4 insufficiency (median onset at 11 years) and STAT3 gain of function (median onset at 2.3 years, diagnosis at 12) [18, 22]. An adult diagnosed with CVID and autoimmunity may have LRBA deficiency: GeneGuidance describes a patient with rheumatoid arthritis, followed by a CVID-like presentation, diagnosed at 49 years using a 264-gene panel [72].

4.2. Family History

In X-linked inheritance, there is no father-to-son transmission; affected boys may occur on the maternal side (brothers, sons of maternal aunts, maternal uncles), together with male fetal losses [1]. Absence of a family history does not exclude the diagnosis, because de novo cases and maternal mosaicism occur [1, 73]. Consanguinity points towards autosomal recessive forms (IL2RA, IL2RB, LRBA, DEF6, STAT5B, FERMT1), and a dominant family history with incomplete penetrance is compatible with CTLA4 or BACH2 [18, 27].

4.3. Emergency Signs

Emergencies include dehydration and hypovolaemic shock due to secretory diarrhoea (volumes reaching 60 to 250 mL/kg/day in the case in section 10), diabetic ketoacidosis, sepsis in a patient with a central catheter and parenteral nutrition, severe autoimmune cytopenias and respiratory failure [1, 9, 74]. Immune activation (vaccination or severe infection) has been associated with exacerbations since the original description [1]. In a transplant recipient, graft failure and GVHD require immediate contact with the transplant centre [6].

4.4. Newborn Screening

There is no population-based newborn screening for IPEX syndrome. The TSDR assay is DNA-based, is little affected by processing, can be performed on dried blood spots from the newborn screening card, and is already accredited under ISO 15189 in Europe for IPEX diagnosis [9]. In the case in section 10, TSDR measured retrospectively on the screening card was normal at birth and already elevated at 2 weeks, before symptoms, suggesting a possibility of early detection that has not been assessed in population studies [9].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

IPEX syndrome is diagnosed in a male proband with suggestive clinical findings by identification of a hemizygous pathogenic or likely pathogenic FOXP3 variant; the two classes are equivalent for clinical decision-making under ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) guidance, and a hemizygous variant of uncertain significance (VUS) neither establishes nor excludes the diagnosis [1]. In females, a heterozygous variant establishes carrier status; no affected women have been described [1]. GeneReviews also describes diagnosis in a boy with typical clinical findings, absent Tregs in blood or tissues and reduced FOXP3+ T cells on flow cytometry, with the caveat that these may be normal [1]. The ESID registry working definitions (a registry with more than 25,000 patients) provide clinical criteria for classification of inborn errors of immunity without a genetic diagnosis or with a VUS; they support registry classification and therapeutic decisions and do not replace molecular diagnosis [75].

5.2. Suggestive Laboratory Findings

No laboratory finding is specific [1]. Suggestive findings are elevated IgE (sometimes also IgA), eosinophilia, autoimmune haemolytic anaemia, thrombocytopenia or neutropenia, autoantibodies against islet, thyroid and small intestinal mucosal antigens, and reduced FOXP3+ T cells in peripheral blood [1]. T-, B- and NK-lymphocyte counts and proliferation to mitogens are generally normal and do not aid diagnosis [1, 8]. In the international cohort, anti-enterocyte, anti-harmonin or anti-villin autoantibodies were positive in 33 of 42 tested patients with enteropathy (negative in 9), and anti-harmonin positivity led to diagnosis in a patient with isolated gastritis; histological and serological markers are indicative only when interpreted alongside clinical findings [6]. In the Turkish cohort, 8 of 12 patients had low Tregs (CD4+CD127−/lowCD25+FOXP3+) and all had low FOXP3 expression [66].

5.3. Treg Flow Cytometry and Its Limitations

Flow cytometry in 41 IPEX patients, 34 IPEX-like patients and 75 controls showed a significantly lower percentage of FOXP3+ cells among CD4+ cells in IPEX and IPEX-like disease; expression was very low or absent with in-frame deletions, frameshift variants or polyadenylation signal variants, and variable with missense and splicing variants [8]. Two missense variants (p.E323K and p.S390N) were associated with a markedly elevated percentage of FOXP3+ cells, probably with poor function, and expression level did not correlate with severity [8]. A normal FOXP3+ Treg count or expression does not exclude IPEX, because missense variants may preserve the protein while altering its function [1, 3, 51]. In the international cohort, the proportion of Tregs by flow cytometry was available in only a few patients and FOXP3 expression varied widely [6]. Flow cytometry also guides the diagnosis of IPEX-like disorders: in CD25 deficiency, the percentage of CD4+FOXP3+ cells may be normal despite absent CD25, making CD25 staining essential [8]; however, a variant preserving the epitope may not abolish staining, and molecular confirmation remains necessary [52]. In CTLA-4 insufficiency, Tregs are normal or slightly reduced (functional defect), and in STAT1 and STAT3 gain of function they are variable [8].

5.4. TSDR Quantification

The percentage of cells with demethylated TSDR is increased in IPEX regardless of protein expression [9, 43]. The ratio between FOXP3 TSDR demethylation and CD4 demethylation (%TSDR/CD4) distinguishes patients from controls and corrects spurious values caused by lymphopenia, and remains elevated even with normal or low phenotypic Tregs [9]. There are limitations: overlap with controls complicates interpretation in some cases; in the presence of a novel VUS without clinical manifestations, measurement should be repeated, because onset may be late or mild; and, in a symptomatic patient with a pathogenic variant, normal values may reflect lymphopenia due to prolonged immunosuppression [9]. The test is stable across paediatric and adult ages [9].

5.5. Molecular Testing

The GeneReviews strategy begins with FOXP3 sequencing (missense, nonsense and splicing variants and small insertions and deletions) and, if negative, targeted deletion and duplication analysis; alternatively, a multigene panel including FOXP3 and differential diagnosis genes is used, or exome or genome sequencing when the phenotype is not informative [1]. Gambineri and colleagues proposed a molecular flowchart based on clinical phenotype and immunological markers, and acknowledged that single-gene sequencing had been superseded by next-generation sequencing panels and exome sequencing [8].

Source: GeneReviews Table 1 [1, 44]. The 99% represents the proportion of variants detectable by sequencing among probands with a known variant, not the clinical sensitivity of the test in a patient with suspected IPEX.

The limitations of testing should be stated in the request and report. Variants in the 3' UTR, including the polyadenylation signal, are not included in most assays and may require a specific design; in the cohort of 173 patients, they accounted for up to 12% of IPEX patients [1, 8]. Deep intronic variants escape Sanger sequencing, panels and exome sequencing: in the patient with c.968-207A>G, FOXP3 sequencing (coding region and essential splice sites) in 2005 was negative, and the variant was only detected decades later on a 331-gene panel performed in his sisters, at depths of 59× and 11× [45]. In that case, the variant was absent from gnomAD v4.1.0, splicing predictors were discordant (SpliceAI 0.67; Pangolin 0.2; MaxEntScan +350%; SPiP negative), and RNA from the sisters’ activated T cells, with emetine to inhibit nonsense-mediated decay, showed two pseudoexons of 106 and 125 base pairs in 16% and 13% of reads (3% and 2% without emetine); the variant was classified as likely pathogenic, without a minigene assay [45]. The authors note that the molecular diagnostic rate for IEIs remains below 50% and recommend genome sequencing with splicing predictors and RNA studies when suspicion persists [45]. Deletions and duplications require a dedicated method [1]. A negative result excludes neither IPEX nor a tregopathy.

The report should specify the gene, transcript with version (NM_014009.4), variant in HGVS notation at DNA and protein levels, zygosity (hemizygous in boys, heterozygous in women) and ACMG/AMP class [1, 4]. For a VUS, useful investigations include familial segregation (including asymptomatic men in the family, who allowed p.(Ala38Ser) to be excluded), Treg flow cytometry, TSDR, RNA studies and, where available, functional assays [8, 9, 45].

5.6. Tests Targeting Autosomal Tregopathies

5.7. Practical Algorithm

5.8. Prenatal and Preimplantation Diagnosis

When the familial variant is known, prenatal diagnosis in chorionic villi or amniocytes and preimplantation genetic testing are possible [1, 37]. Prenatal mutation analysis is performed only when the proband’s variant is known [37]. Ultrasound may show signs of fetal IPEX, but its sensitivity is unknown [1, 49].

6. Differential Diagnosis

6.1. Principles

The differential diagnosis of IPEX syndrome comprises three groups: other tregopathies, which share the mechanism; inborn errors of immunity without a primary Treg defect that cause autoimmunity, enteropathy or eczema with elevated IgE; and non-immune disorders causing neonatal diabetes or congenital diarrhoea [1]. In the cohort of 173 patients, 85 (49.1%) had normal FOXP3, and genetic testing (a 50-gene panel in Italy; Sanger sequencing of STAT5B, STAT1, STAT3, IL2RA, CTLA4, LRBA, TTC7A and TTC37 in Seattle) found 25 variants in 21 patients (25%) in 9 genes: LRBA, STAT1 gain of function (4 variants in the DNA-binding domain), STAT3 gain of function (4), CTLA4 (2 extracellular missense variants), IL2RA (2 homozygous variants in the sushi domains), STAT5B (with IGF deficiency), DOCK8 (3 siblings), TTC7A and TTC37; STAT1 and STAT3 gain of function accounted for 38% (8/21) of IPEX-like variants [8]. In the Indian series of 26 tregopathies, there were 13 LRBA deficiencies, 5 CTLA-4 insufficiencies, 2 IPEX cases, 2 CD25 deficiencies, 2 STAT3 gain-of-function cases and 2 FERMT1 deficiencies, with median onset at 4.25 years, median diagnostic delay of 2 years and autoimmune cytopenia as the most common presentation [12].

6.2. Comparative Table

6.3. Main Differential Diagnoses

Autosomal tregopathies are the closest differential diagnoses because they reproduce multiorgan autoimmunity and enteropathy; later age at onset, hypogammaglobulinaemia, lymphoproliferation and organ infiltration point towards CTLA4 and LRBA, short stature towards STAT3 gain of function and STAT5B, CMC towards STAT1 gain of function, and severe viral infection towards IL2RA and IL2RB [1, 8]. In IPEX-like patients with Treg gene defects, autoimmune cytopenias were present in all patients with CTLA4 and LRBA, 75% of patients with LRBA had lymphadenopathy or hepatosplenomegaly, severe infections clustered in CD25 deficiency, STAT5B deficiency and STAT1 gain of function, and food allergy was absent [8]. Very high IgE favours IPEX: above 1000 IU/mL in 59% of IPEX patients and 25.5% of IPEX-like patients (p=0.0005) [8]. Hypogammaglobulinaemia is associated mainly with LRBA, STAT3 gain of function and CTLA4 [8].

Among inborn errors without a primary Treg defect, APECED is distinguished by CMC and ectodermal dysplasia, ALPS by chronic lymphoproliferation with double-negative T cells, Omenn syndrome by combined immunodeficiency with erythroderma and eosinophilia, and DOCK8 deficiency by cutaneous viral infections in the context of hyper-IgE [1, 37]. An atypical form of IPEX may mimic these disorders: a severe combined immunodeficiency-like immunophenotype, isolated hypogammaglobulinaemia and a hyper-IgE-like presentation with anti-IL-6 autoantibodies have all been described with FOXP3 variants [48, 66]. IL-10 receptor deficiency causes very early severe colitis, but is not a tregopathy because the targets are innate cells [7].

Non-immune causes of neonatal diabetes (KCNJ11, ABCC8, INS, GCK, PDX1, GATA6, PTF1A and 6q24 transient diabetes) lack autoimmunity, and distinguishing them has direct therapeutic implications [1, 71]. Congenital epithelial enteropathies (tufting enteropathy, microvillus inclusion disease, trichohepatoenteric syndrome) cause intractable diarrhoea without immune infiltration [1]. GeneReviews also mentions pancreatic β-cell agenesis with neonatal diabetes and autoimmune polyendocrine syndrome type II, without a known genetic aetiology [1]. In females, an IPEX-like presentation immediately points towards autosomal forms, because no affected women with a FOXP3 variant have been described [1].

7. Treatments and Risk Management Strategies

7.1. General Principles

Treatment of IPEX syndrome has two successive objectives: to control inflammation and its metabolic and nutritional consequences, and to cure the disease with HSCT before irreversible organ damage occurs [1, 10]. GeneGuidance summarises the evidence in one sentence: immunosuppression is the bridge to transplantation, not the destination [3]. No drug is authorised for IPEX syndrome or tregopathies in the USA or the European Union (EU), and there are no randomised trials; recommendations rest on retrospective observational cohorts, case series and expert opinion [3, 6]. All drugs used in IPEX syndrome and tregopathies are prescribed off-label, and the doses described come from labels for other indications, centre protocols or published series.

7.2. Evaluation Following Diagnosis

Source: GeneReviews Table 3 [1].

7.3. Support by Manifestation

Enteropathy and nutrition. Fluid intake must be monitored and fluids replaced to maintain intravascular volume, allowing for insensible losses through damaged skin; almost all patients require nutritional support with TPN, an elemental formula or a low-carbohydrate formula, continued until immunosuppression allows intestinal function to recover [1]. In the international cohort, 19 of 34 patients receiving chronic immunosuppression required enteral or parenteral support for months or years, with a median of 4 hospital admissions per year (0 to 7) [6]. Strict control of hyperglycaemia is essential [1].

Endocrinopathy. Type 1 diabetes is treated with insulin and carbohydrate management, and autoimmune thyroid disease with standard treatment [1].

Skin. Dermatitis is treated with systemic T-cell-directed immunosuppression and topical agents (corticosteroids, tacrolimus, emollients); severe dermatitis responds to topical corticosteroids, topical tacrolimus and dupilumab, with support from a wound care specialist [1, 77, 78]. Intensive treatment of dermatitis prevents infections through the impaired skin barrier [1].

Cytopenias and autoantibodies. In autoimmune neutropenia, granulocyte colony-stimulating factor (G-CSF) may improve counts; in nodular pemphigoid and other autoantibody-mediated diseases, rituximab (anti-CD20) has been effective [1]. The sources consulted do not provide IPEX-specific doses of G-CSF or rituximab.

Infections and immunoglobulin. In autoimmune neutropenia, recurrent infections associated with severe eczema, and patients with a central venous catheter and TPN, antibiotic prophylaxis may reduce severe complications; treatment antimicrobials follow the usual indications [1]. Immunoglobulin replacement was beneficial in a patient with hypogammaglobulinaemia and infections [48]. The Mumbai protocol for tregopathies treated with sirolimus does not use routine antibiotic prophylaxis [12].

7.4. Immunosuppression

Observational outcomes. In the international cohort, 34 patients were treated with immunosuppression alone (median starting age 1.5 years; median follow-up 4 years): systemic corticosteroids were used in 25, with benefit in 56%, almost always in combination; calcineurin inhibitors (ciclosporin or tacrolimus) in 20, with benefit in 40%; rapamycin (sirolimus) in 15, with improvement in autoimmunity in 67%, and, as monotherapy, 8 of 10 patients improved and 6 of 8 entered remission; azathioprine was beneficial in 36%; corticosteroids combined with a calcineurin inhibitor or another immunosuppressant rarely led to remission (1/12); monoclonal antibodies (anti-TNF-α, anti-CD20, abatacept), almost always added to other treatment, provided benefit in 52%, with sustained remission in 2 of 8 [6]. Malnutrition fell from 74% (25/34) to 29% and intractable diarrhoea from 76% to 20% (both P<0.001), but only 10 of 34 patients achieved complete control of autoimmunity, 24 retained manifestations (mainly enteropathy) and 11 developed new manifestations under immunosuppression (type 1 diabetes in 4, thyroiditis in 3, cytopenia in 2, hepatitis in 2, and enteropathy, adrenal insufficiency and arthritis in 1 each) [6]. The authors concluded that rapamycin should be the preferred immunosuppressant, as it appeared superior to calcineurin inhibitors [6]. In the cohort of 173 patients, most responded at least transiently to corticosteroids combined with ciclosporin, tacrolimus or sirolimus, and the response to corticosteroids alone was marginal [8].

Sirolimus. Sirolimus suppresses effector T cells while allowing Treg development and function, and is considered first-line treatment, as monotherapy or in combination; it is effective when tacrolimus has failed or proved toxic [1, 32]. Passerini and colleagues treated 6 patients with different variants and observed that clinical and histological improvement accompanied partial restoration of Treg function, regardless of FOXP3 expression or Treg frequency, with increased GITR (TNFRSF18) and EBI3 in Tregs, a FOXP3-independent mechanism [79]. GeneReviews specifies doses adjusted to levels of 8 to 12 ng/mL and notes that early use may reverse endocrinopathy [1]. In a patient with severe gastrointestinal involvement, vomiting and diarrhoea prevented therapeutic levels from being achieved with the only available formulation, the oral one [9]. The Mumbai centre’s off-label protocol for tregopathies uses sirolimus as the first choice in all tregopathies except STAT3 gain of function (for which a JAK inhibitor is preferred) and FERMT1 deficiency [12].

Sirolimus dosing. There is no authorised dose for IPEX syndrome; the reference is the published protocol of the Mumbai centre, and the US label serves for comparison. In the protocol, sirolimus is started at 2 mg/m²/day orally, with a target trough level of about 10 ng/mL; levels are measured 7 to 10 days after initiation and after each dose change [12]. In the same series, one patient with IPEX started 2 mg/m²/day (level 9 ng/mL), reduced to 1 mg/m²/day (4 ng/mL) and then discontinued because of recurrent respiratory infections and a severe oral ulcer, and one patient with CD25 deficiency went from 2 to 3 mg/m²/day (10.8 ng/mL), developed pneumonia, and returned to 2 mg/m²/day with levels of 5.6 to 6.28 ng/mL [12]. The 10 ng/mL target of this protocol lies within the 8 to 12 ng/mL range given by GeneReviews [1, 12].

The US label defines the proportional adjustment rule, new dose = current dose × (target concentration / current concentration), and, when the level needs to be raised, an additional loading dose equal to 3 × (new maintenance − current maintenance); because of the long half-life, each new dose is maintained for 7 to 14 days before any further adjustment, and the trough is re-measured 3 to 4 days after a loading dose [80]. The maximum dose on any one day is 40 mg, and a loading dose exceeding this is divided over 2 days; the drug is taken once daily, consistently with or consistently without food, tablets are not crushed, chewed or split, and the oral solution is intended for those unable to swallow them (equivalence between formulations has been demonstrated only for 2 mg) [80]. Maintenance is reduced by about one third in mild to moderate hepatic impairment and by about half in severe impairment, without changing the loading dose, and is not adjusted in renal impairment; target values depend on the assay method (chromatography or immunoassay), which are not interchangeable [80]. Compared with the label, the tregopathy protocol differs in its body-surface-area calculation in children younger than 13 years, in whom safety has not been established, in the absence of a described loading dose and in a target intermediate between those for lymphangioleiomyomatosis and for transplantation [12, 80].

The European summary of product characteristics (SmPC) for Rapamune® agrees with the US label on the starting dose in adult kidney transplantation (single oral loading dose of 6 mg, then 2 mg/day), on adult lymphangioleiomyomatosis (2 mg/day, trough measured at 10 to 20 days and maintained between 5 and 15 ng/mL), on the proportional adjustment rule, on the additional loading dose and on the 40 mg maximum on any one day, but differs on three points: in the initial phase of transplantation with ciclosporin the target trough is 4 to 12 ng/mL and, after ciclosporin withdrawal, 12 to 20 ng/mL, without the 16 to 24 ng/mL band for the first year; the reduction of about half of the maintenance dose applies only to severe hepatic impairment, with levels every 5 to 7 days until 3 stable values are obtained; and there is no paediatric posology, because safety and efficacy below 18 years have not been established, compared with 13 years in the US label, which includes the 1 mg/m²/day calculation for those weighing less than 40 kg [80, 81]. The tregopathy protocol in children therefore falls outside the conditions of both labels [12, 80, 81].

Sirolimus monitoring includes serum levels and renal function surveillance, because sirolimus and tacrolimus are nephrotoxic; chronic use is associated with toxicity, tachyphylaxis and susceptibility to opportunistic infections, reducing long-term benefit in most patients [1]. In the Mumbai protocol, baseline assessment includes immunology, full blood count, renal and liver function, autoimmunity and fasting triglycerides and cholesterol; levels are measured 7 to 10 days after initiation and after each change, and full blood count, liver and renal function, electrolytes and lipids monthly until stabilisation and then every 2 to 3 months; a response usually emerges within 1 to 2 months, and the most common adverse effects were upper respiratory tract infections and hypertriglyceridaemia, the latter treated without discontinuing the drug [12]. The US label carries a boxed warning about increased susceptibility to infections and the possible development of lymphoma and other malignancies under immunosuppression, recommends level monitoring in all patients, particularly with strong CYP3A4 inducers or inhibitors and in hepatic impairment, and states that safety and efficacy are not established below 13 years; animal data indicate that it may cause fetal harm [80].

Calcineurin inhibitors. Tacrolimus and ciclosporin are alternatives when sirolimus is not feasible or is insufficient, and are associated with nephrotoxicity and a need for level monitoring [1, 6]. In the USA, tacrolimus (Prograf®) is authorised for prophylaxis of rejection in kidney, liver, heart and lung transplantation in adults and children, and ciclosporin (Neoral®) for kidney, liver and heart transplantation, severe rheumatoid arthritis and severe psoriasis in adults; use in IPEX is off-label, and the sources consulted provide no validated paediatric doses for this disease [82, 83].

Calcineurin inhibitor dosing. The sources consulted on IPEX syndrome and tregopathies do not give doses or target levels of tacrolimus or ciclosporin for this disease; the following doses come from the US labels and correspond to other indications (solid organ transplantation, rheumatoid arthritis and psoriasis), so their application to IPEX syndrome is an extrapolation [82, 83].

The tacrolimus label states that children generally require higher doses than adults, that this requirement decreases with age, that level monitoring is recommended and that, in liver, heart or lung recipients with pre-existing renal impairment, the lower end of the dose range should be used; lower doses may be needed in severe hepatic impairment (Child-Pugh ≥10) [82]. Neoral® has greater bioavailability than Sandimmune®, the two formulations are neither bioequivalent nor interchangeable without supervision, the daily dose is always divided into two doses at regular times in relation to meals, and grapefruit should be avoided because it increases ciclosporin concentrations [83]. The ciclosporin label states that transplant recipients from 1 year of age have received it without unusual adverse effects, but that safety and efficacy have not been established below 18 years in arthritis and psoriasis [83].

The Portuguese SmPCs differ from the US labels in some values. For Prograf®, the initial oral dose in children is 0.30 mg/kg/day in two doses in both liver and kidney transplantation (in adults, 0.10–0.20 mg/kg/day in liver and 0.20–0.30 mg/kg/day in kidney transplantation), with no maximum dose defined in the SmPC, which adjusts the dose by levels; children generally require doses 1.5 to 2 times higher than adults to achieve similar levels, and troughs have ranged from 5 to 20 ng/mL (liver) or 10 to 20 ng/mL (kidney and heart) in the initial phase and from 5 to 15 ng/mL during maintenance, measured about 12 hours after dosing; no adjustment is needed in renal impairment, with monitoring of renal function because of the nephrotoxic potential [84]. For Sandimmun Neoral®, the dose in solid organ transplantation is 10 to 15 mg/kg in two doses, started within the 12 hours before surgery and maintained for 1 to 2 weeks, with reduction to a maintenance dose of about 2 to 6 mg/kg/day (3 to 6 mg/kg initially when combined with other immunosuppressants); in psoriasis and atopic dermatitis the starting dose is 2.5 mg/kg/day with a maximum of 5 mg/kg/day, above the 4 mg/kg/day of the US label, and in nephrotic syndrome the paediatric dose is 6 mg/kg/day [83, 85]. The SmPC does not recommend use in children younger than 16 years outside transplantation and nephrotic syndrome, owing to lack of experience, so use in IPEX syndrome is off-label in both jurisdictions [85].

Monitoring and safety of calcineurin inhibitors. The labels of both drugs carry a boxed warning on increased susceptibility to infection and the risk of lymphoma and other malignancies, particularly of the skin, a risk that depends on the intensity and duration of immunosuppression rather than on the agent chosen; in Epstein–Barr virus-seronegative children, the tacrolimus label recommends monitoring serology because of the risk of post-transplant lymphoproliferative disorder, and both require live vaccines to be avoided [82, 83]. With tacrolimus, whole-blood level monitoring is complemented by surveillance of renal and hepatic function, blood glucose (new-onset diabetes), potassium and magnesium, blood pressure and neurological examination, because neurotoxicity may extend to posterior reversible encephalopathy syndrome; the most frequent reactions in transplant trials were renal dysfunction, hypertension, diabetes, fever, tremor, hyperglycaemia, leucopenia, anaemia, diarrhoea, paraesthesia, hyperkalaemia, hypomagnesaemia and hyperlipidaemia, and the label adds myocardial hypertrophy, pure red cell aplasia and thrombotic microangiopathy; combination with sirolimus is not recommended in liver and heart transplantation because of an increase in serious reactions, which is relevant when combining the two drugs is considered in this disease [82]. With ciclosporin, the main reactions are renal dysfunction, tremor, hirsutism, hypertension and gingival hyperplasia, with nephrotoxicity described in about a quarter of kidney recipients and glomerular capillary thrombosis as a rare complication [83]. For non-transplant indications, which are closest to use in this disease, the US label sets out a specific schedule: two blood pressure and two creatinine measurements before starting, then creatinine, urea, full blood count, uric acid, potassium, magnesium, lipids and blood pressure every 2 weeks for the first 3 months and monthly if the patient is stable; a creatinine rise of 25% or more above baseline is repeated within 2 weeks and, if sustained, requires a dose reduction of 25 to 50%, as does a rise of 50% or more or any other clinically relevant laboratory change; if creatinine does not return to within 25% of baseline after two reductions, the drug is discontinued, and sustained hypertension is treated first by reducing the dose [83]. The Portuguese SmPC requires bilirubin and liver function tests before starting, lipids, magnesium, potassium and uric acid before and periodically, and regular monitoring of blood pressure and renal function, and considers occasional measurement of blood levels sufficient outside transplantation, reserving it for pharmacokinetic interactions and unexpected clinical responses [85]. Both drugs are CYP3A substrates: grapefruit and potent inhibitors increase concentrations and potent inducers reduce them, so any change in these co-medications requires repeat level measurement [82, 83].

Adjuncts. Azathioprine, mycophenolic acid and methotrexate were used as adjuncts in the international cohort, as were mesalazine, sulfasalazine and 6-mercaptopurine [1, 6]. Corticosteroids combined with an immunosuppressant rarely led to remission in this cohort [6].

7.5. Haematopoietic Stem Cell Transplantation

HSCT is the only potentially curative treatment for IPEX syndrome [1]. Classical myeloablative conditioning was associated with high transplant-related mortality, so most centres moved to reduced-intensity conditioning, with better overall survival [1]. GeneReviews reports overall survival of 77.5% at 15 years after HSCT and similar survival with matched related, matched unrelated, cord blood or haploidentical donors [1]; the international cohort, the primary source for the series, estimated 73.2% at 15 years [6]. Diabetes and thyroiditis established before transplantation generally persist, whereas other manifestations regress; Yamauchi and colleagues described recovery from insulin deficiency after very early HSCT, suggesting that endocrine reversibility depends on early intervention [1, 86]. Survival and outcomes are better when transplantation is performed earlier, before irreversible organ damage [87–89].

In the international cohort, 58 patients underwent transplantation (7 had a second transplant and 1 a third): median age 1.4 years (1 month to 18.8 years), median follow-up 2.7 years; 54 had received prior immunosuppression, with improvement in 27; conditioning was of reduced intensity in 33 of 58; donors were matched related in 31, matched unrelated in 21, haploidentical in 5 and mismatched related in 1; the source was bone marrow in 35, peripheral blood in 12 and cord blood in 13; 49 received antithymocyte globulin or alemtuzumab; GVHD prophylaxis was mainly ciclosporin with mycophenolate or corticosteroids [6]. Neutrophil recovery occurred at a median of 16 days and platelet recovery at 20; T-cell reconstitution by the first year occurred in 22 of 33, proliferation to mitogens became positive in 20 of 29 (median 14.5 months) and independence from intravenous immunoglobulin in 30 of 45 (median 7 months); transplant-related toxicity occurred in 11 (19%) and multiple infections in 46 (85%) [6]. Acute GVHD occurred in 19 of 58 (33%), grade III–IV in 9, and chronic GVHD in 6 of 52 survivors beyond 100 days (10%); differences by serotherapy and donor type were not significant [6]. Chimerism was complete in 31 of 53 and mixed in 18, with similar remission rates (54% and 50%); in 3 of 9 patients with mixed chimerism in remission, Tregs were 100% donor-derived, highlighting the importance of lineage-specific chimerism; graft failure occurred in 4 of 53 [6]. Mixed chimerism also occurred after myeloablative conditioning [6].

The determinant of outcome was clinical status before transplantation. The organ involvement score (0 to 5 points: intractable diarrhoea, malnutrition, liver dysfunction, respiratory impairment and renal dysfunction, one point each) was the only variable with a significant effect on survival after HSCT: outcomes were worse with 3 to 5 points than with 0 to 2 (P=0.002); with 0 to 2 points, survival was good regardless of conditioning, and with 3 to 5, myeloablative conditioning was better than reduced-intensity conditioning; patients under 1 year with a high score had poorer outcomes, and 16 of 21 patients under 1 year were at or below the 3rd weight centile [6]. The authors recommend optimising clinical status before transplantation and transplanting before progression, in patients with low scores and stable condition [6]. Regimens used in the cohort were, in the myeloablative group, busulfan with cyclophosphamide, busulfan above 14 mg/kg or with a cumulative area under the curve of 80 to 90 mg·h/L with fludarabine, or treosulfan; and, in the reduced-intensity group, fludarabine with non-myeloablative doses of busulfan, treosulfan or melphalan, or minimal-intensity regimens [6].

In the cohort of 173 patients, 40 IPEX and 15 IPEX-like patients underwent transplantation; 9 IPEX patients (22.5%) and 1 IPEX-like patient died after transplantation; survivors had resolution of enteropathy and skin lesions, pre-existing diabetes persisted and food allergy resolved in one child [8]. A Colombian case documents the feasibility of haploidentical transplantation with post-transplant cyclophosphamide: an infant with intrauterine growth restriction, neonatal diabetes, secretory diarrhoea, hypothyroidism and severe fungal and bacterial infections had fully recovered nutritionally and immunologically by 320 days [90].

7.6. Transplantation Guidelines

The updated guidelines from the EBMT (European Society for Blood and Marrow Transplantation) Inborn Errors Working Party and ESID, published in May 2026, replace the 2021 edition [10, 91]. They classify indications into four categories: standard of care (severe combined immunodeficiency, familial HLH, IL-10 receptor deficiency, Wiskott–Aldrich syndrome and chronic granulomatous disease in many patients); clinical option (all inborn errors demonstrably curable by HSCT, with a complex decision weighing natural history, genotype–phenotype correlation, quality of life, disease burden, comorbidities, age, donor, risks including fertility, alternatives and family motivation); developmental (diseases with experience limited to isolated cases, such as some PIRDs, and situations in which incomplete correction is expected because of extra-haematopoietic manifestations); and generally not recommended (thymic epithelial defects, ataxia-telangiectasia) [10]. The guideline does not name IPEX syndrome or FOXP3 in its indication tables, and places PIRDs in general in the developmental category and inborn errors curable by transplantation in the clinical option category [10]. For PIRDs, it recommends controlling inflammation as far as possible before considering transplantation, acknowledges that the role of biotherapies and targeted immunosuppressants (definitive treatment or bridging therapy) remains to be clarified, and emphasises that complete remission is not always possible and should not delay transplantation [10]. Pre-transplant comorbidities are the main predictor of outcome, supporting intervention before irreversible damage occurs [10].

Regarding the donor, survival with a matched unrelated donor is similar to that achieved with a matched sibling, but an HLA-identical sibling remains the first choice, and the guideline recommends screening family donors for the same genetic defect (affected individuals or carriers), particularly in diseases with late or variable onset [10]. This recommendation applies to sisters carrying FOXP3 variants and relatives with incompletely penetrant CTLA4 variants, an extrapolation that the guideline does not explicitly make for IPEX syndrome. The case reported by Gaufryau and colleagues illustrates the issue: the patient underwent transplantation at 7 years from an HLA-identical sister whose carrier status was discovered only decades later, and died 47 days afterwards with severe GVHD, without the authors attributing GVHD to that fact [45]. The guideline also details haploidentical platforms (αβ T-cell and CD19 depletion, or post-transplant cyclophosphamide), in which the main determinant of outcome was pre-transplant comorbidity rather than the platform, with greater toxicity and acute GVHD with post-transplant cyclophosphamide and more adenoviraemia, primary graft failure and second transplantation with αβ depletion; describes six conditioning protocols (A to F) with mandatory busulfan monitoring; and recommends a calcineurin inhibitor with methotrexate or mycophenolate for GVHD prophylaxis with unmanipulated grafts, considering the evidence insufficient for routine abatacept or vedolizumab use [10].

7.7. Mechanism-Directed Therapies in Autosomal Tregopathies

In disorders lacking functional CTLA-4 (CTLA-4 insufficiency, LRBA and DEF6 deficiencies), abatacept, a CTLA4-Ig fusion protein, replaces the missing function; it controls disease but does not cure it, and requires continued administration [19, 56]. In the international cohort of 173 CTLA4 variant carriers followed between 2014 and 2020 (2624 months from diagnosis), 123 (71%) were treated; abatacept, rituximab, sirolimus and corticosteroids reduced severity, particularly cytopenias and lymphocytic infiltration of the intestine, lung and central nervous system; immunoglobulin replacement was effective in preventing infections; splenectomy for cytopenia produced a sustained response in only 4 of 16 (25%); and HSCT cured 13 of 18 (72%) [19]. In the Turkish cohort of 98 patients (63 with LRBA deficiency and 35 with CTLA-4 insufficiency), followed for a median of 5 years with six-monthly assessment, 58 patients received abatacept as initial or rescue treatment, with sustained complete control in 46 (79.3%) and no serious adverse effects, whereas 72.1% of the 61 patients who had started with conventional immunosuppressants had partial or no control; the 12 patients who did not respond to abatacept had longer-standing disease and more organs involved, and survival probabilities were similar between transplantation and abatacept [68]. In a prospective cohort of 22 patients with LRBA deficiency, 18 were treated with abatacept for a mean of 3.4 years, with long-term benefit in 16; control of lymphoproliferation and chronic diarrhoea preceded that of cytopenias, and weekly or fortnightly administration was better than monthly administration [92]. In 76 patients with LRBA deficiency from 29 centres, the IDDA (immune deficiency and dysregulation activity) score was lower in transplant survivors (P=0.005), and also with abatacept or sirolimus and with residual LRBA expression [76]. A longitudinal multi-omic analysis showed that abatacept increases thymic output, expands naive T and B cells, reduces memory T cells and CD21-low B cells, and reverses most transcriptomic and proteomic abnormalities, with more severe dysregulation in LRBA deficiency than in CTLA-4 insufficiency [93]. A 2025 review concludes that abatacept and sirolimus have the greatest efficacy in controlling these diseases and that HSCT is the only curative option [94].

In STAT1 and STAT3 gain of function, JAK inhibitors are the targeted treatment. In the retrospective series of 17 patients from 11 centres (11 with STAT1 and 6 with STAT3 gain of function; 16 treated with ruxolitinib and 1 with tofacitinib), 14 had significant clinical improvement: two patients dependent on parenteral nutrition became independent, lymphocytic interstitial pneumonia resolved radiologically, autoimmune cytopenias improved in 8 patients, one case of HLH entered remission before transplantation, and CMC resolved in all patients with STAT1 gain of function [95]. The authors propose immune dysregulation, organ autoimmunity, chronic autoimmune cytopenias, lymphoproliferation, refractory CMC and recurrent severe infections as indications; they describe escalation from half the target dose, with weekly increases, frequent transaminase and full blood count monitoring, quarterly surveillance for invasive viral infections and aciclovir prophylaxis; observed adverse effects were transient thrombocytopenia, transient elevations of transaminases and bilirubin, respiratory and gastrointestinal viral infections resolving with supportive care, and herpes zoster in 2 patients, prompting treatment interruption and antivirals [95]. Of the 17 patients, 4 died: 3 non-responders who were already critically ill with invasive infection or progressive lung disease, suggesting greater efficacy when the inhibitor is started before severe disease, and 1 from transplant complications [95]. In the cohort of 191 patients with STAT3 gain of function, most required five or more treatment modalities; more than 30% started with corticosteroids and progressed to steroid-sparing agents and then targeted therapy with tocilizumab (anti-IL-6R) and/or a JAK inhibitor (21%); 36 patients received a JAK inhibitor as rescue therapy, with control of cytopenias; rituximab was used in 26% of cytopenias, with a partial response in 79%; refractory interstitial lung disease improved in 8 patients treated with tocilizumab and/or a JAK inhibitor, with withdrawal of oxygen in 7; arthritis improved in 66% of 6 patients; diabetes, pulmonary fibrosis and pulmonary hypertension did not reverse [22]. In that cohort, viral infections were associated with chronic intravenous corticosteroids (57%, P<0.001), pulses (54%, P=0.035), tacrolimus (73%, P=0.018) and alemtuzumab (4/4, P=0.023), and fungal infections with mycophenolate (31%, P=0.006), without an association with tocilizumab or JAK inhibitors [22]. In STAT3 gain of function, tocilizumab produced an initial response that plateaued and subsequently required a JAK inhibitor, so combination therapy may be useful [95].

The 2026 international consensus from ESID, the EBMT Inborn Errors Working Party and ERN RITA on JAK inhibitors in inborn errors of the JAK-STAT pathway brings together a systematic review, an international retrospective cohort and patient views, and produced 51 statements through a two-round modified Delphi method in five areas: indications and contraindications, pretreatment evaluation, pharmacology and dosing, monitoring, and use in the transplantation setting; the document states that no JAK inhibitor is licensed for inborn errors of immunity and that use is off-label [96]. The full text was inaccessible, so the individual statements, doses and monitoring schedules from this consensus are not reproduced in this article.

In CD25 deficiency, HSCT was curative in published cases, with complete resolution in one patient and complete chimerism with a favourable course at 6 years in another, and sirolimus was effective and safe in one case [16, 52]. In STAT5B deficiency, growth failure is treated with recombinant IGF-1 (mecasermin), authorised in the USA for severe primary IGF-1 deficiency in children aged 2 years or older, without naming STAT5B; three treated homozygous siblings increased their growth velocity from approximately 3 cm/year to 4.8 to 7.4 cm/year over the first three years, with a height standard deviation score gain of +2.21 and +0.93 in the two older children after 6 years and −0.62 in the youngest, a response inferior to that seen in GH receptor defects; there is no specific immunological therapy [26, 97, 98]. In complete IL-2Rα deficiency and other severe tregopathies without precision therapy, HSCT is the indicated option, and low-dose IL-2 and CD25-selective IL-2 muteins are suggested as future strategies [7]. In BRIDA, immunoglobulin replacement was used in two of the three initial patients and corticosteroids improved fever and cytopenia, but not common variable immunodeficiency or pneumonitis; a patient with early lupus improved with prednisone and tofacitinib [7, 53].

7.8. Dupilumab and the Type 2 Axis in IPEX Syndrome

Dupilumab, a monoclonal antibody against the IL-4 receptor α chain, has been associated with improvement in dermatitis and type 2 manifestations in case reports of patients with IPEX [1, 77, 78]. In a 2-year-old child with dermatitis refractory to sirolimus, adding dupilumab to sirolimus and prednisone reduced the EASI (eczema area and severity index) from 24.8 to 0.4 over 8 months, with reduced Th1 and Th2 signatures in the skin and increased Tregs, CTLA-4 and CD39 [99]. In the first report of monotherapy, a boy with the p.(Ala384Thr) variant treated from 2 years of age had marked improvement in dermatitis, a rapid fall in IgE (peak 74,625 IU/mL), better growth and a reduction in respiratory hospital admissions for asthma from 3 to 0, with normalisation of plasma IL-4 and IL-13; alarmins, eosinophil mediators, Th1 cytokines and TSDR demethylation remained elevated, showing that systemic dysregulation is not corrected by blockade of the IL-4/IL-13 axis alone [74]. Dupilumab is therefore an adjunctive therapy for atopic features, not a treatment for the underlying disease. The US label covers moderate-to-severe atopic dermatitis from 6 months, with weight-based regimens, but does not include IPEX syndrome; the patient in the monotherapy report received the dose corresponding to the lowest weight band [74, 100].

7.9. Comparative Regulatory Status

The sources consulted do not include information on funding decisions or national access in Portugal (INFARMED) or Brazil (ANVISA and CONITEC) for these off-label uses.

Abatacept dosing. In CTLA-4 insufficiency and LRBA deficiency, the reference dose is that of the phase IIa ABACHAI trial in adults: 125 mg subcutaneously once weekly for 12 months, off-label [111, 112]. In the prospective LRBA deficiency cohort, weekly or fortnightly administration gave better results than monthly administration [92]. For children, the sources consulted on these disorders do not set a dose, and the comparison is made with the paediatric regimens of the US label, which correspond to other indications [101].

In GVHD prophylaxis, the label specifies Epstein–Barr virus antiviral prophylaxis before the first dose, maintained for 6 months after transplantation, and recommends considering cytomegalovirus prophylaxis; concomitant use with other biological immunosuppressants or with JAK inhibitors is not recommended [101]. The weekly ABACHAI dose matches the adult subcutaneous dose in the label; the difference lies in the indication, which is off-label in the US and the EU [101, 102, 112].

JAK inhibitor dosing. In STAT1 and STAT3 gain of function, the reference is the series of 17 patients, in which ruxolitinib was given at 0.4–2 mg/kg/day or at 15 mg/m² per dose, twice daily, with a starting dose extrapolated from paediatric myelofibrosis, and tofacitinib according to the rheumatoid arthritis label; the authors start at half the target dose and increase by 25% per week until it is reached, with adjustment in response to changes in transaminases or the full blood count [95]. The authors stress that there are no pharmacokinetic data in these disorders and that paediatric guidance is scarce [95]. In the Mumbai protocol, baricitinib, being the most accessible JAK inhibitor at the centre, is started at 2 to 4 mg/day in two doses, a dose extrapolated from the FDA recommendations for monotherapy in COVID-19 in children over 2 years, after serology for hepatitis B and C and human immunodeficiency virus (HIV), CMV and EBV PCR testing and tuberculosis screening, and with prophylaxis with co-trimoxazole, aciclovir and fluconazole; thereafter the full blood count, liver and renal function, triglycerides and blood glucose are monitored [12]. The doses in the US labels, which correspond to other indications, serve for comparison.

The ruxolitinib label requires a full blood count before initiation and every 2 to 4 weeks until the dose is stabilised, prior screening for tuberculosis, herpes simplex, herpes zoster and hepatitis B, and adjustments in GVHD for thrombocytopenia, neutropenia and bilirubin, as well as reductions in moderate-to-severe renal impairment and in hepatic impairment; in end-stage renal disease not on dialysis, use should be avoided [103]. With tofacitinib, initiation is avoided with lymphocytes <500/mm³, neutrophils <1000/mm³ or haemoglobin <9 g/dL, use in severe hepatic impairment is not recommended, and in moderate-to-severe renal impairment the paediatric dose becomes once daily [105]. Relative to the labels, the weight- or body surface area-based dosing of the Forbes series applies ruxolitinib to children under 12 years, outside the ages authorised in the US, whereas in the EU Jakavi® is indicated in acute GVHD from 28 days and in chronic GVHD from 6 months [95, 103, 104].

Dupilumab and mecasermin dosing. In IPEX syndrome there is no guideline dose for dupilumab; the patient in the monotherapy report started 200 mg subcutaneously every 4 weeks at 2 years of age, weighing about 8 kg, which corresponds to the US label regimen for atopic dermatitis between 6 months and 5 years with 5 to <15 kg [74, 100]. In STAT5B deficiency, the three siblings treated with mecasermin received increasing doses from 40 up to 110–120 µg/kg twice daily subcutaneously, within the range of the US label for severe primary IGF-1 deficiency [26, 97, 98].

Mecasermin is administered within 20 minutes before or after a meal or snack, and the dose is omitted if the child cannot eat; the label recommends monitoring of preprandial blood glucose at initiation and until a tolerated dose is established, dose reduction in the event of hypoglycaemia despite adequate intake, rotation of injection sites to prevent lipohypertrophy, and supervision of treatment by a physician experienced in severe primary IGF-1 deficiency [98].

Tocilizumab dosing. The sources consulted on STAT3 gain of function describe the use of tocilizumab, alone or with a JAK inhibitor, without stating the dose [22, 95]. The dose is therefore presented from the labels for the closest inflammatory indications, systemic and polyarticular juvenile idiopathic arthritis and, for interstitial lung disease, that of systemic sclerosis, which constitutes an extrapolation [108, 109].

The US label recommends not initiating tocilizumab with neutrophils <2000/mm³, platelets <100,000/mm³ or ALT or AST above 1.5 times the upper limit of normal, and the European SmPC advises against initiation with neutrophils <2 × 10⁹/L and defines interruptions or reductions to 4 mg/kg in the event of raised transaminases, neutropenia or thrombocytopenia; below 2 years there is no recommended posology [108, 109].

Comparison with the European SmPCs. For abatacept, the intravenous doses for rheumatoid arthritis (500, 750 and 1000 mg by weight band, about 10 mg/kg) and for polyarticular juvenile idiopathic arthritis from 6 to 17 years (10 mg/kg below 75 kg; from 75 kg, the adult regimen, not exceeding 1000 mg) and the weekly paediatric subcutaneous doses from 2 years (50, 87.5 and 125 mg by weight band) match those of the US; the European SmPC has no GVHD prophylaxis regimen, which is not an indication in the EU, and does not recommend the intravenous route below 6 years [101, 102]. For ruxolitinib, the European SmPC sets starting doses in GVHD by age: in acute GVHD, 10 mg twice daily from 12 years (versus 5 mg twice daily in the US), 5 mg twice daily from 6 to <12 years and 8 mg/m² twice daily from 28 days to <6 years; in chronic GVHD, 10 mg, 5 mg and 8 mg/m² twice daily in the same bands, the last from 6 months; reduction is by one level (from 10 to 5 mg twice daily, or from 5 mg twice daily to 5 mg once daily), and in myelofibrosis the maximum dose is 25 mg twice daily [103, 104]. This 8 mg/m² twice daily is the only body surface area-based regimen authorised for young children and lies below the 15 mg/m² per dose of the Forbes series [95, 104]. For tofacitinib, the adult doses (5 mg twice daily, not to be exceeded) and the weight-based paediatric doses from 2 years (3.2, 4 and 5 mg twice daily) match those of the US, but the European SmPC advises against initiation with lymphocytes <750/mm³ (versus <500/mm³ in the US) and with neutrophils <1200/mm³ in children, and restricts use to patients without a suitable alternative when they are 65 years or older or have cardiovascular risk or risk factors for malignancy [105, 106]. For dupilumab, the European SmPC for atopic dermatitis between 6 months and 5 years is the same as the US label (5 to <15 kg 200 mg and 15 to <30 kg 300 mg every 4 weeks, without loading), which applies to the monotherapy case described, but differs from 6 to 11 years (15 to <60 kg: 300 mg on days 1 and 15 and then 300 mg every 4 weeks, with possible increase to 200 mg every 2 weeks) and from 12 to 17 years (bands below and above 60 kg) [74, 100, 107]. For mecasermin, the European SmPC starts at 0.04 mg/kg twice daily, at the lower limit of the US starting range of 0.04–0.08 mg/kg, with the same maximum of 0.12 mg/kg twice daily, which must not be exceeded because of the risk of neoplasia, and does not recommend use below 2 years [98, 110].

7.10. Clinical Trials and Cell and Gene Therapies

These rows are not comparable: populations, designs and outcomes differ, ABACHAI is the only study with published efficacy and safety results and has no comparator arm, and the absence of a completed randomised trial (NCT03733067 withdrawn) means that the evidence for abatacept rests on observational cohorts and a single-arm trial. Reductions described in retrospective cohorts lack a randomised denominator and are subject to selection of treated patients. A ClinicalTrials.gov search on 10 October 2026 for “IPEX”, “FOXP3”, “LRBA”, “CTLA4” and STAT1/STAT3 gain of function found no other drug trials targeting IPEX syndrome beyond the two cell and gene therapy studies; an expanded-access study of itacitinib concerns a single patient with another disease, and a study called “IPEX Study” concerns intraductal pancreatic neoplasia, unrelated to the syndrome [113]. A negative search does not establish that no other studies exist.

At the preclinical level, conversion of CD4+ T cells into Treg-like cells through lentiviral FOXP3 transfer preserves a polyclonal T-cell receptor repertoire, protects against xenogeneic GVHD in FOXP3-deficient humanised mice, and does not prevent antigen responses or tumour clearance [118]. CRISPR gene correction, with insertion of cDNA into the endogenous locus and regulated expression, has been achieved in haematopoietic progenitor cells and T cells from patients with diverse variants, preserving differentiation potential [119]. In 2026, the Seattle group published the full preclinical characterisation of Tregs modified by homology-directed repair, with integration of functional FOXP3 cDNA into its own locus: integration efficiency, enrichment and expansion, off-target analysis, in vitro suppression, in vivo GVHD reversal and safety in syngeneic and humanised models, including humoral responses and control of viral infection [120]. AAV-IL-27 gene therapy improved failure to thrive in mice with mutated Foxp3, and CTLA4 correction has been demonstrated in vitro and in a mouse model, both at the preclinical stage [7]. The review by Borna, Meffre and Bacchetta describes the clinical spectrum and curative strategies under development [121, 122].

7.11. Developments in the Last Twelve Months

Between October 2025 and October 2026, the following developments can be recorded by level of evidence: published results from a single-arm trial (ABACHAI, published in September 2026) [112]; two guidelines or consensus documents (the EBMT and ESID transplantation guidelines of May 2026 and the JAK inhibitor consensus of May 2026) [10, 96]; registrations of two new trials not yet recruiting (FOXP3-T4 cell therapy in Paris and the upadacitinib basket trial in Houston) [114, 115]; preclinical characterisation of modified Tregs [120]; and case reports, including the first dupilumab monotherapy in IPEX, the first Portuguese neonatal-onset case, the first deep intronic FOXP3 variant and the description of anti-IL-6 autoantibodies in IPEX [45, 47, 48, 74]. There was no new regulatory authorisation for IPEX syndrome or tregopathies in either jurisdiction [80, 81].

7.12. Agents and Circumstances to Avoid, Pregnancy and Perioperative Care

Immune activation through vaccination or severe infection has been associated with worsening since the original description of the disease, and recommended practice is to defer vaccines, where possible, until after HSCT [1]. Abatacept should not be combined with other biological immunosuppressants or JAK inhibitors [101]. Prolonged immunosuppression increases the risk of opportunistic infection and malignancy, and in STAT3 gain of function the association between chronic intravenous corticosteroids, tacrolimus, alemtuzumab and mycophenolate and viral or fungal infections has been quantified [22, 80]. In diseases with a risk of EBV-associated lymphoma (CTLA-4 insufficiency, LRBA and DEF6 deficiencies), surveillance of lymphoproliferation and EBV and CMV viral loads is recommended, particularly under immunosuppression [18, 41]. Sirolimus may cause fetal harm according to animal data in the label, and its interaction with strong CYP3A4 inhibitors and inducers requires adjustment and level monitoring [80]. The sources consulted do not describe pregnancy, lactation or perioperative management series in patients with IPEX syndrome; decisions in these contexts follow drug labels and centre practice.

Transition to adult care has become relevant because there are long-term survivors and patients with atypical forms diagnosed in adulthood. The transplantation guidelines devote a section to adolescents and young adults: transplantation in this age range (from 15 years into the seventh decade) is increasingly frequent, with poorer outcomes in patients with a high comorbidity index, active immune dysregulation or permanent organ damage; age and donor type do not independently influence outcome, favouring a preventive approach; reduced-intensity regimens are recommended in older patients, together with attention to the increased risk of GVHD, use of the IDDA score to identify uncontrolled inflammation, and counselling on fertility, sexuality and the limits of transplantation in correcting irreversible damage [10].

8. Reproductive Options and Family Counselling

8.1. Recurrence Risks in IPEX Syndrome

Inheritance is X-linked recessive [1]. The father of an affected boy is neither affected nor hemizygous and does not require testing. In a family with more than one affected individual, the mother is an obligate carrier. A carrier mother has a 50% chance of transmitting the variant in each pregnancy: boys who inherit it are affected, with variable severity even between brothers with the same variant, and girls are carriers, with no IPEX syndrome described [1]. An affected man transmits the variant to all his daughters, who become carriers, and to none of his sons [1]. Maternal aunts and their descendants may be at risk and should be included in cascade testing [1].

In an isolated case, the mother may be a carrier, the variant may be de novo, or maternal mosaicism may be present; the proportion of cases without a family history is unknown, and maternal molecular testing is recommended [1]. When a woman has more than one affected son and the variant is not detected in leucocytes, germline mosaicism is likely; maternal somatic and germline mosaicism has been described [1, 73]. Even without a detectable variant in maternal leucocytes, recurrence risk is presumed low but higher than that in the general population [1]. Recurrent pregnancy losses involving male fetuses with hydrops or abnormal ultrasound findings should prompt consideration of IPEX syndrome as a fetal rather than maternal factor [1, 49].

8.2. Carrier Detection

Carrier detection requires prior identification of the familial variant [1]. X-inactivation studies have limited usefulness because inactivation is skewed only in Tregs and random in other lymphocyte populations [1]. Flow cytometry does not resolve the issue either: in carriers, CD4+ T cells express FOXP3 at normal levels because Tregs with the wild-type allele have a competitive advantage [9, 42]. TSDR quantification was normal in one carrier mother [9]. Conversely, Tregs from carriers were useful for RNA studies in identifying a deep intronic variant, with T-cell activation and inhibition of nonsense-mediated decay [45].

8.3. Risks in Autosomal Tregopathies

In autosomal recessive forms (CD25, CD122, LRBA, DEF6, STAT5B, NBEAL2 and FERMT1 deficiencies), the recurrence risk for siblings of a proband is 25% in each pregnancy, with asymptomatic carriers; consanguinity increases the likelihood of these diagnoses [1, 7]. In autosomal dominant forms, the central issue is incomplete penetrance: in CTLA-4 insufficiency, 90 of 133 carriers were affected, corresponding to clinical penetrance of at least 67%, with manifestations that may emerge up to 50 years, so counselling and surveillance of carrier relatives are recommended [18, 35]. In BRIDA, one carrier parent was asymptomatic but had markedly reduced memory B cells, and another developed late-onset bronchiectasis [7, 27]. In STAT3 gain of function and IKAROS gain of function, many variants are de novo, but dominant transmission has been described [7, 22].

8.4. Evaluation of Relatives at Risk

Clarifying the genetic status of boys at risk, before birth or immediately afterwards, enables early diagnosis and initiation of treatment or referral for HSCT before significant organ damage occurs [1]. This is the setting in which prognostic data are clearest, because the pre-transplant organ involvement score is the main determinant of survival [6]. When a sibling transplant is planned, the donor should be tested for the familial variant because this is a disease with variable expression; the 2026 guideline recommends screening family donors for the same genetic defect [10, 45]. The international cohort recorded a boy with a FOXP3 variant diagnosed through family history who remained asymptomatic at 6 years, showing that presymptomatic identification implies surveillance rather than necessarily immediate treatment [6].

8.5. Prenatal Diagnosis and Preimplantation Testing

When the familial variant is known, prenatal diagnosis (chorionic villi or amniocytes) and preimplantation genetic testing are possible [1]. The ideal time for counselling is before conception, and it should be offered to affected young adults, carriers and relatives at risk; GeneReviews notes that professionals and families may differ in their views on the use of these tests [1]. In neonatal diabetes, prenatal diagnosis is performed mainly for syndromic forms, such as IPEX, which may be fatal in childhood [71]. Mutation analysis in chorionic villi is performed only when the proband’s variant is known [37].

8.6. Counselling Content

Counselling should cover the nature and inheritance of the disease, variability in severity within the same family and the absence of a useful genotype–phenotype correlation, treatment options and their off-label status, the window of opportunity for transplantation, reproductive options, cascade testing on the maternal side and, in dominant tregopathies, surveillance of asymptomatic carriers [1, 6, 18]. For adolescent and young adult transplant candidates, counselling on fertility and sexuality and an explanation of the limits of transplantation in correcting established damage are also required [10]. Testing asymptomatic minors at risk is justified here by direct benefit, because it enables early diagnosis and treatment [1]. GeneReviews recommends that counselling be provided by genetics professionals and accompanied by social support and links to patient organisations [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What the Numbers Measure

IPEX syndrome is very rare and has no prevalence estimate derived from a population study. The 2024 GeneReviews reports fewer than 300 affected individuals identified worldwide and explicitly states that no accurate estimates have been published [1]. Orphanet assigns a validated worldwide point-prevalence class below 1 per 1,000,000 and recorded 195 published cases worldwide, based on the 2020 systematic review by Park and colleagues [2, 5]. The Orphanet class is an upper bound assigned to a range, not a measurement; it should not be converted into a rate per 100,000 or interpreted as incidence. The number of published cases measures the literature, not the disease: it depends on access to genetic diagnosis and the propensity to publish. The international cohort recorded an increasing number of diagnoses per year and a median interval of 14 months between onset and genetic diagnosis, with a maximum of 23.9 years, indicating persistent underdiagnosis [6].

The same cautions apply to autosomal tregopathies, whose Orphanet records are outdated relative to published cohorts: 2 cases recorded for CD25 deficiency versus 13 published by 2026; 17 for CTLA-4 insufficiency versus cohorts of 133 and 173 carriers; 23 for LRBA deficiency versus 109 cases in the 2019 systematic review and 63 in a single national cohort in 2023; and 10 for STAT5B deficiency [15–21, 25, 68]. These figures are counts from referral centres and should be treated as minima.

9.2. Geographical Distribution of Data

Published cohorts are multicentre and international, not population-based. The largest IPEX syndrome series brought together 96 patients from 38 institutions within the North American PIDTC consortium and the EBMT Inborn Errors Working Party, coordinated in Milan and Stanford [6]. The second largest included 173 patients from 143 families at two centres, Florence and Seattle, of whom 88 had a FOXP3 variant [8]. US and European data therefore dominate clinical description and outcomes.

Single-country or single-centre series illustrate regional contexts. In Turkey, the Hacettepe centre described 12 patients from 9 families with 6 FOXP3 variants, a median age at diagnosis of 2.5 years and frequent atypical presentations [66], and a Turkish multicentre cohort brought together 98 patients with LRBA deficiency or CTLA-4 insufficiency, the largest single-country series for these two disorders [68]. In India, the Mumbai centre described 26 patients with tregopathies, comprising 13 LRBA deficiencies, 5 CTLA-4 insufficiencies, 2 IPEX cases, 2 CD25 deficiencies, 2 STAT3 gain-of-function cases and 2 FERMT1 deficiencies, and a treatment protocol adapted to local drug availability [12]. In Colombia, an infant treated with haploidentical transplantation and post-transplant cyclophosphamide has been described [90]. None of these series permits estimation of prevalence; they measure the case series of referral centres.

In Portugal, Costa Branco and colleagues published in Acta Médica Portuguesa in 2026 what they describe as the first neonatal-onset IPEX syndrome case published in the country [47]. In Brazil, the São Paulo group included IPEX syndrome among inborn errors of immunity with fetal or perinatal manifestations [61], and the LASID registry is the source of Latin American data [1]. The sources consulted contain no estimates of prevalence, incidence or the number of patients diagnosed in Portugal or Brazil, which does not establish the absence of published data; European multicentre cohorts and the ESID registry provide a route to obtaining these figures.

No founder populations or founder FOXP3 variants are described in the sources consulted. Recurrence of five variants in approximately 35% of families in the Florence and Seattle cohort reflects mutational hotspots at conserved residues in the forkhead and leucine zipper domains, rather than a geographical founder effect [8].

9.3. Special Populations

Sex determines the phenotype: disease manifests in hemizygous boys, and heterozygous women are asymptomatic, with one carrier mother described as having type 1 diabetes as an isolated finding [1, 8]. In fetuses, disease may present with hydrops, akinesia and skin desquamation, and contributes to recurrent pregnancy losses involving male fetuses [1, 7, 49]. In preterm infants, the Portuguese case shows that diagnosis is possible in a newborn delivered at 30 weeks, with enteropathy, eczema, eosinophilia and transfusion-dependent cytopenias [47]. In very young infants, the transplantation guideline recommends restraint with conditioning below 8 weeks of life and adjusts fludarabine dosing by weight below 12 months [10]. In adolescents and adults, the issues are transition of care and the transplant decision in the presence of accumulated damage [10]. In the international cohort, 28% of patients receiving immunosuppression and 31% of transplant recipients had neuromotor delay or needed educational support, and many required psychological support and prolonged nutritional support, defining long-term rehabilitation and educational support needs [6].

9.4. Referral Networks, Registries and Patient Associations

The relevant European reference network is ERN RITA (European Reference Network on Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases), organised into four streams (primary immunodeficiencies, autoinflammatory diseases, autoimmune diseases and paediatric rheumatology) and coordinated by University Medical Center Utrecht; it participated in the 2026 JAK inhibitor consensus [13, 96]. Relevant registries are the ESID registry, based in Freiburg with more than 25,000 patients, and the LASID registry for Latin America [1, 75]. Patient organisations include IPOPI, the Jeffrey Modell Foundation and its primary immunodeficiency resource centre, and, for endocrine manifestations, the American Diabetes Association and Diabetes UK [1, 14]. GeneReviews also recommends links to community parent-to-parent support resources, social services and home nursing [1].

10. Illustrative Clinical Case

The following case was published in 2026 by Rayes and colleagues in the Journal of Human Immunity, with the full text available as open access [9].

A term-born, formula-fed male infant was admitted to intensive care at 4 weeks of life for hypovolaemic shock with fever, feeding intolerance and poor weight gain; weight was below the 3rd centile (standard deviation score −4.19) and length at the 3rd centile (standard deviation score −1.66). Diarrhoea was secretory and intractable, with volumes of 60 to 250 mL/kg per day, and subsequently became intermittently bloody. There was no dermatitis. He developed normocytic anaemia requiring transfusions and catheter-associated deep vein thrombosis, treated with enoxaparin, and became dependent on parenteral nutrition. Faecal calprotectin rose from 457 to 1200 and 1380 µg/g, and faecal elastase of 10 µg/g indicated severe exocrine pancreatic insufficiency. Endoscopy at 8 weeks showed severe duodenitis with villous atrophy, extensive gastritis with a mixed infiltrate including eosinophils, and loss of colonic epithelium, consistent with autoimmune enteritis and colitis [9].

At 8 weeks, IgE was 9309 IU/mL (reference up to 13), rising to 31,478 IU/mL at 20 weeks. CD4+CD25+CD127− Tregs accounted for 5.5% of CD4+ cells (reference 4.2 to 9.9%), but only 32% expressed FOXP3 (reference 55 to 81%). Soluble IL-2 receptor was 6111.5 pg/mL, IL-6 was 49.6, IL-8 was 278.1, IL-10 was 48.7, IL-18 was 1685 and CXCL9 was 9535 pg/mL, with C-reactive protein of 19.2 mg/dL. T-, B- and NK-lymphocyte counts were essentially normal, type 1 diabetes autoantibodies (anti-GAD, anti-IA-2, anti-insulin, anti-islet and anti-ZnT8) were negative, and anti-enterocyte antibodies were not requested. Rapid genome sequencing identified the novel FOXP3 c.1050C>G p.(Ile350Met) variant, a missense variant in the forkhead domain; family history was negative and the mother was a carrier [9].

Research studies documented the pathophysiology. At 17 weeks, Tregs had fallen to 1.7% of CD4+ cells and expressed Helios and TIGIT, but FOXP3 was negligible; FOXP3 was abolished in Tregs and remained at low levels in activated effector cells, together with CTLA-4, and the full-length and Δ2 isoforms were present in normal proportions (Figures 1 and 2) [9]. TSDR quantification on the newborn screening card was normal at birth and already elevated at 2 weeks, before any clinical manifestation, and remained elevated at 17 and 25 weeks, above levels in 33 adult and 11 paediatric controls; cells with demethylated TSDR appeared in effector compartments, which is not observed in controls (Figure 1) [9]. In the carrier mother, Tregs were almost all FOXP3+ and TSDR was normal, illustrating the competitive advantage of Tregs with the wild-type allele (Figure 2) [9]. Plasma profiling showed elevated type I and II interferons, IL-6, IL-1α and IL-1β, IL-17 and IL-33, and increased Th2 cytokines between 17 and 25 weeks (Figure 3) [9]. The legends of all three figures were read in the full text; the images were not opened.

Management was escalated without a response. At 9 weeks, methylprednisolone with sirolimus was started as first-line treatment, but vomiting and diarrhoea prevented therapeutic levels from being reached within two weeks because only the oral formulation was available; this was followed by intravenous tacrolimus with intravenous methylprednisolone for three weeks, with therapeutic levels but no improvement. Biopsies at 12 weeks showed no residual epithelium in the stomach or colon. Infliximab, at 14 weeks, partially reduced stool volume. At 16 weeks, obstruction developed due to progressive pyloric stenosis. Abatacept, started at 18 weeks as fourth-line treatment, produced no response. Transplantation was deferred because the patient was too ill for conditioning. He had cytomegalovirus viraemia (treated with ganciclovir and foscarnet), Staphylococcus aureus bacteraemia, rhinovirus infection and culture-negative sepsis. At 29 weeks he developed acute respiratory distress syndrome with large-volume ascites, colitis and pancreatitis, was placed on veno-venous extracorporeal membrane oxygenation at 30 weeks, and died at 32 weeks of life [9].

The authors’ discussion contextualises the variant: the Ile350 residue is conserved between mice and humans, the Ile350Asn substitution (published designation from a mouse model) causes a scurfy-like phenotype in mice, and Ile350Ala (published designation from an experimental study) causes loss of protein expression; all patients with complete loss of FOXP3 protein have the severe, early-onset classical form [9]. The treatment sequence in this case is not a routine regimen: sirolimus is the recommended first-line treatment, but this patient illustrates the practical limitation of oral absorption with severe gastrointestinal involvement, and infliximab and abatacept were used as rescue therapy outside any formal indication or recommendation for IPEX syndrome [1, 6, 9]. The outcome is consistent with data from the international cohort, in which the pre-transplant organ involvement score determines survival and very severe disease prevents timely transplantation [6].

Two other recent cases complete the spectrum. In the Portuguese case, a preterm infant born at 30 weeks with enteropathy, eczema, eosinophilia and transfusion-dependent cytopenias, in whom recurrent infections and a desquamating rash raised suspicion of an inborn error of immunity, had absent FOXP3 expression and the hemizygous pathogenic variant c.1076C>T; he was treated with corticosteroids and sirolimus and referred for transplantation [47]. In a boy from the United Arab Emirates followed at Stanford, with severe atopic dermatitis from the neonatal period refractory to topical agents, peak IgE of 74,625 IU/mL, asthma, allergies, lymphadenopathy, recurrent febrile neutropenia and type 1 diabetes at 2 years, diagnosis was made at 2 years with the p.(Ala384Thr) variant; dupilumab monotherapy improved growth, EASI and IgE and eliminated asthma admissions, but TSDR remained elevated at 3 years and 10 months despite normal Tregs with preserved FOXP3 [74].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Without effective treatment, prognosis is poor: most boys die within the first 1 to 2 years of life from metabolic disturbances, severe malabsorption or sepsis, and survival into the second or third decade is rare and limited to mild phenotypes [1]. Immunosuppression has prolonged survival, but in most patients it does not prevent morbidity from disease progression or treatment adverse effects [1, 6].

The two studies with long follow-up provide the figures. In the international cohort of 96 patients, estimated overall survival was 73.2% at 15 years after HSCT (n=58) and 86.8% (95% confidence interval: 62.8 to 95.8) at 15 years under chronic immunosuppression (n=34), a non-significant difference (P=0.055) explained by early transplant mortality: up to 15% of patients die within the first 100 days and 25% within the first 2.5 years, and after 2.5 years there was no additional mortality up to 15 years; under immunosuppression, survival falls to 65.1% (confidence interval: 18.3 to 89.7) at 24 years [6]. The quality of disease control differs: among living patients, complete resolution of autoimmunity, or persistence of diabetes alone, occurred in 56% of transplant recipients and 36% of patients receiving immunosuppression (P=0.083), and persistence or emergence of new autoimmune manifestations in 17% versus 51% (P=0.001); disease-free survival stabilises six years after transplantation and progressively declines under immunosuppression [6]. GeneReviews cites 15-year post-transplant survival of 77.5% for the same series [1]. In the cohort of 173 patients, 10-year survival was 72.8% in transplanted IPEX patients (n=38) versus 57.3% in non-transplanted patients (n=46) (p=0.02), and in IPEX-like patients 100% (n=10) versus 78% (n=68) (p<0.0001); at 30 years, survival was 52% in IPEX and 27% in IPEX-like disease, with retrospective data and loss to follow-up after 15 years [8].

The only consistent predictor is organ status before treatment. The organ involvement score (intractable diarrhoea, malnutrition, liver dysfunction, respiratory impairment and renal dysfunction) was the only variable with a significant effect on survival after HSCT (P=0.035 in the series abstract; P=0.002 in the comparison between scores of 0 to 2 and 3 to 5), and also correlated with survival under immunosuppression (P=0.0444); conditioning, donor source and age had no independent effect [6]. Diabetes and thyroiditis established before transplantation generally persist, whereas other manifestations regress, with the qualification that very early transplantation allowed recovery from insulin deficiency [1, 86]. 10-year survival by variant type in the Florence and Seattle cohort (from 87.5% for in-frame deletions to 19% for polyadenylation signal variants) is descriptive and based on small subgroups, and should not be used to predict an individual course [8].

In autosomal tregopathies, overall survival was 88% in the cohort of 191 patients with STAT3 gain of function, with 23 deaths (10 after transplantation) and a mean age at death without transplantation of 23 years (4 months to 52 years), and was associated with time to genetic diagnosis [22]. In CTLA-4 insufficiency, mortality among affected individuals was 16% in the cohort of 133 carriers [18]. In LRBA deficiency, post-transplant survival was 70.8% (17/24), with all deaths transplant-related and early, and 82.7% of non-transplanted patients were alive (43/52, aged 3 to 69 years); among the 17 transplant survivors, 12 (70.6%) were in complete or good partial remission without treatment, versus 5 of 43 (11.6%) non-transplanted patients without immunosuppression [76]. In STAT1 gain of function, transplantation has poorer outcomes: in 15 patients, primary engraftment was 74% and overall survival 40%, with frequent secondary graft failure, so it is not a routine procedure in this disease [95, 123].

11.2. Surveillance

The 3-to-6-month intervals for endocrine, haematological, renal and liver evaluation are those in GeneReviews Table 5 and are the same as those used in the treatment recommendations in section 7; sirolimus follow-up follows the frequency of the centre protocol cited in the same section [1, 12]. In disorders treated with abatacept, assessment was quarterly in the prospective LRBA deficiency cohort and six-monthly in the Turkish cohort [68, 92]. In LRBA deficiency and CTLA-4 insufficiency, the IDDA score is used to quantify disease activity over time [10, 76].

11.3. Prognosis of Individual Manifestations

Enteropathy and dermatitis are the manifestations most responsive to both immunosuppression and transplantation [6, 8]. Established diabetes and thyroiditis are generally irreversible [1]. Nephropathy and hepatitis may arise as new manifestations during immunosuppression [6]. In STAT3 gain of function, diabetes, pulmonary fibrosis and pulmonary hypertension did not reverse with targeted therapy, whereas interstitial lung disease and cytopenias improved [22]. Malignancy risk is an issue in tregopathies with CTLA-4 defects, rather than an established feature of IPEX syndrome, in which one gastric adenocarcinoma in a young person and metaplastic or dysplastic lesions in five patients in the international cohort have been reported [6, 7, 18].

12. Summary and Final Considerations

IPEX syndrome is the human disease that demonstrates the function of regulatory T lymphocytes: loss of FOXP3 function at Xp11.23 removes peripheral tolerance in the hemizygous boy and produces autoimmune enteropathy with intractable diarrhoea, type 1 diabetes and dermatitis in the first months of life, with very high IgE, eosinophilia, cytopenias, thyroiditis, nephropathy and hepatitis during the course. Median age at onset is 2 months and almost half of patients develop disease in the first month, but fetal presentations, single-organ forms and diagnoses in adolescence or adulthood occur, and median time to genetic diagnosis remained 14 months in the largest international cohort.

Diagnosis is molecular. FOXP3 sequencing identifies the variant in approximately 99% of probands with a known variant, but a negative result does not exclude disease: polyadenylation signal variants in the 3' UTR accounted for up to 12% of patients in one cohort and are not included in most assays, deletions require dedicated methods, and a deep intronic variant identified only through genome sequencing and RNA studies has already been described. Flow cytometry helps but is not decisive: missense variants may preserve FOXP3 expression and Treg numbers, with abnormal function. Quantification of the Treg-specific demethylated region is elevated in IPEX regardless of protein expression, can be performed on dried blood and is a marker of activity, with limitations due to overlap with controls and falsely normal values in lymphopenia. There is no genotype–phenotype correlation useful in practice, and severity varies within the same family.

Treatment follows a clear sequence. Nutritional and metabolic stabilisation is immediate, with parenteral nutrition in almost all patients, insulin and thyroid treatment. Sirolimus is the preferred immunosuppressant because it partially restores Treg function and has produced remission in more patients than calcineurin inhibitors, but immunosuppression is a bridge: in the international cohort, only 10 of 34 patients achieved complete control and 11 developed new manifestations under treatment. Haematopoietic stem cell transplantation is the only potentially curative therapy, with survival of 73.2% at 15 years and mortality concentrated in the first few months; pre-transplant organ status is the only consistent determinant of outcome, so the decision should be made while the patient is stable and without irreversible damage, but control of inflammation should not delay transplantation. Established diabetes and thyroiditis persist. No drug is authorised for this disease in any jurisdiction, and all prescriptions are off-label, including dupilumab, which improves atopic features without correcting systemic dysregulation. Cell therapies using CD4+ T cells corrected with FOXP3 are in phase 1 trials in Stanford and Paris, without published results.

Tregopathies and IPEX-like disorders should be considered in all cases, particularly when FOXP3 is normal, which occurs in 20 to 30% of patients with the clinical presentation: CD25 deficiency through absent surface CD25, CTLA-4 insufficiency and LRBA and DEF6 deficiencies through lymphoproliferation, hypogammaglobulinaemia and organ infiltration, STAT3 gain of function through short stature, STAT5B through growth hormone resistance, and STAT1 gain of function through chronic mucocutaneous candidiasis. The distinction has direct therapeutic consequences, because abatacept replaces missing CTLA-4 in disorders of its trafficking and JAK inhibitors control gain-of-function disorders of the JAK-STAT pathway, whereas the same inhibitors worsen loss-of-function forms. Family counselling rests on cascade testing on the maternal side, recognition of germline mosaicism and prenatal or neonatal detection of boys at risk, which is the only route to transplantation before organ injury; in dominant forms with incomplete penetrance, it requires surveillance of asymptomatic carriers and screening of family donors before transplantation.

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