immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome

Summary

immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome (MONDO:0010580) is a disease caused by FOXP3 (GenCC Definitive), with 4 cohort genes and 5 clinical trials. Top therapeutic interventions include melphalan.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FOXP3 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 387
• Phenotypes (HPO): 60
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		195	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

60 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0002960	Autoimmunity	Very frequent (80-99%)
HP:0000818	Abnormality of the endocrine system	Frequent (30-79%)
HP:0000964	Eczematoid dermatitis	Frequent (30-79%)
HP:0001531	Failure to thrive in infancy	Frequent (30-79%)
HP:0001891	Iron deficiency anemia	Frequent (30-79%)
HP:0002242	Abnormal intestine morphology	Frequent (30-79%)
HP:0003111	Abnormal blood ion concentration	Frequent (30-79%)
HP:0003212	Increased circulating IgE level	Frequent (30-79%)
HP:0005208	Secretory diarrhea	Frequent (30-79%)
HP:0007473	Crusting erythematous dermatitis	Frequent (30-79%)
HP:0011123	Inflammatory abnormality of the skin	Frequent (30-79%)
HP:0012393	Allergy	Frequent (30-79%)
HP:0025379	Anti-thyroid peroxidase antibody positivity	Frequent (30-79%)
HP:0031401	Reduced proportion of CD4-negative, CD8-negative, alpha-beta regulatory T cells	Frequent (30-79%)
HP:0100646	Thyroiditis	Frequent (30-79%)
HP:0100651	Type I diabetes mellitus	Frequent (30-79%)
HP:0000821	Hypothyroidism	Occasional (5-29%)
HP:0001025	Urticaria	Occasional (5-29%)
HP:0001581	Recurrent skin infections	Occasional (5-29%)
HP:0001875	Decreased total neutrophil count	Occasional (5-29%)
HP:0001890	Autoimmune hemolytic anemia	Occasional (5-29%)
HP:0001904	Neutropenia in presence of anti-neutropil antibodies	Occasional (5-29%)
HP:0001970	Tubulointerstitial nephritis	Occasional (5-29%)
HP:0001973	Autoimmune thrombocytopenia	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002024	Malabsorption	Occasional (5-29%)
HP:0002098	Respiratory distress	Occasional (5-29%)
HP:0002205	Recurrent respiratory infections	Occasional (5-29%)
HP:0002719	Recurrent infections	Occasional (5-29%)
HP:0002901	Hypocalcemia	Occasional (5-29%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Occasional (5-29%)
HP:0002917	Hypomagnesemia	Occasional (5-29%)
HP:0003073	Hypoalbuminemia	Occasional (5-29%)
HP:0003765	Psoriasiform dermatitis	Occasional (5-29%)
HP:0004326	Cachexia	Occasional (5-29%)
HP:0006515	Interstitial pneumonitis	Occasional (5-29%)
HP:0008066	Abnormal blistering of the skin	Occasional (5-29%)
HP:0008404	Nail dystrophy	Occasional (5-29%)
HP:0012115	Hepatitis	Occasional (5-29%)
HP:0012578	Membranous nephropathy	Occasional (5-29%)
HP:0030909	Anti-liver cytosolic antigen type 1 antibody positivity	Occasional (5-29%)
HP:0031085	Decreased prealbumin level	Occasional (5-29%)
HP:0031104	Insulin receptor antibody positivity	Occasional (5-29%)
HP:0031123	Recurrent gastroenteritis	Occasional (5-29%)
HP:0000100	Nephrotic syndrome	Very rare (<1-4%)
HP:0000836	Hyperthyroidism	Very rare (<1-4%)
HP:0001287	Meningitis	Very rare (<1-4%)
HP:0001596	Alopecia	Very rare (<1-4%)
HP:0001744	Splenomegaly	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome
Mondo ID	MONDO:0010580
MeSH	C580192
OMIM	304790
Orphanet	37042
DOID	DOID:0090110
ICD-11	1060287444
NCIT	C131009
SNOMED CT	237618001
UMLS	C0342288
MedGen	83339
GARD	0001850
Is cancer (heuristic)	no

Also known as: autoimmune enteropathy type 1 · autoimmunity-immunodeficiency syndrome X-linked · autoimmunity-immunodeficiency syndrome, X-linked · diabetes mellitus, congenital insulin-dependent, with fatal secretory diarrhea · diabetes mellitus, congenital insulin-dependent, with fatal secretory diarrhoea · diarrhea, polyendocrinopathy, fatal infection syndrome, X-linked · DMSD · enteropathy, autoimmune, with hemolytic Anaemia and polyendocrinopathy · IDDM secretory diarrhea syndrome · IDDM secretory diarrhoea syndrome · IDDM-secretory diarrhea syndrome · IDDM-secretory diarrhoea syndrome · Iddm-secretory diarrhoea syndrome · immune dysfunction and diarrhea syndrome · immune dysfunction and diarrhoea syndrome · immune dysregulation, polyendocrinopathy, and enteropathy X-linked syndrome · Immunodysregulation, polyendocrinopathy and enteropathy X-linked · IMMUNODYSREGULATION, polyendocrinopathy, and enteropathy, X-linked · immunodysregulation, polyendocrinopathy, and enteropathy, X-linked · immunodysregulation, polyendocrinopathy, and enteropathy, X-linked, X-linked recessive (+8 more)

Data availability: 387 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › autoimmune disorder of endocrine system › immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome

Related subtypes (12): type 1 diabetes mellitus, autoimmune thyroid disease, autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome, autoimmune pancreatitis, autoimmune hepatitis, autoimmune polyendocrinopathy, autoimmune hypoparathyroidism, insulin autoimmune syndrome, IgG4-related sclerosing cholangitis, lymphocytic hypophysitis, autoimmune oophoritis, autoimmune primary ovarian failure

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

387 retrieved; paginated sample, class counts are floors:

156 uncertain significance, 120 likely benign, 32 conflicting classifications of pathogenicity, 27 pathogenic, 22 benign, 12 benign/likely benign, 11 likely pathogenic, 5 pathogenic/likely pathogenic, 1 pathogenic/likely risk allele, 1 pathogenic/likely pathogenic/likely risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
2425881	NC_000023.10:g.(?46466387)(50659607_?)del	AKAP4	Pathogenic	criteria provided, single submitter
1098427	NM_014009.4(FOXP3):c.224C>T (p.Pro75Leu)	FOXP3	Pathogenic	no assertion criteria provided
11407	NM_014009.4(FOXP3):c.1189C>T (p.Arg397Trp)	FOXP3	Pathogenic	criteria provided, multiple submitters, no conflicts
11408	NM_014009.4(FOXP3):c.1290_*12delinsTG (p.Pro431fs)	FOXP3	Pathogenic	no assertion criteria provided
11409	NM_014009.4(FOXP3):c.1112T>G (p.Phe371Cys)	FOXP3	Pathogenic	no assertion criteria provided
11410	NM_014009.4(FOXP3):c.1150G>A (p.Ala384Thr)	FOXP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11411	NM_014009.4(FOXP3):c.1293_1294del (p.Ter432ThrextTer?)	FOXP3	Pathogenic	no assertion criteria provided
11413	NM_014009.4(FOXP3):c.751_753del (p.Glu251del)	FOXP3	Pathogenic	criteria provided, multiple submitters, no conflicts
11414	NM_014009.4(FOXP3):c.227del (p.Leu76fs)	FOXP3	Pathogenic	criteria provided, single submitter
11415	NM_014009.4(FOXP3):c.1117_1118delinsGC (p.Phe373Ala)	FOXP3	Pathogenic	no assertion criteria provided
11417	FOXP3, 543C-T	FOXP3	Pathogenic	no assertion criteria provided
11418	NM_014009.4(FOXP3):c.3G>A (p.Met1Ile)	FOXP3	Pathogenic	no assertion criteria provided
11419	NM_014009.4(FOXP3):c.1099T>C (p.Phe367Leu)	FOXP3	Pathogenic	criteria provided, single submitter
1436074	NM_014009.4(FOXP3):c.2T>A (p.Met1Lys)	FOXP3	Pathogenic	criteria provided, single submitter
1460125	NM_014009.4(FOXP3):c.736-2A>T	FOXP3	Pathogenic	criteria provided, single submitter
1505816	NM_014009.4(FOXP3):c.1087A>G (p.Ile363Val)	FOXP3	Pathogenic	criteria provided, single submitter
1685829	NM_014009.4(FOXP3):c.1234del (p.Glu412fs)	FOXP3	Pathogenic	criteria provided, single submitter
211046	NM_014009.4(FOXP3):c.727del (p.Glu243fs)	FOXP3	Pathogenic	criteria provided, single submitter
2675750	NM_014009.4(FOXP3):c.1110G>A (p.Met370Ile)	FOXP3	Pathogenic	criteria provided, single submitter
282065	NM_014009.4(FOXP3):c.1015C>G (p.Pro339Ala)	FOXP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3724235	NM_014009.4(FOXP3):c.906del (p.Asp303fs)	FOXP3	Pathogenic	criteria provided, single submitter
379222	NM_014009.4(FOXP3):c.1190G>A (p.Arg397Gln)	FOXP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
435255	NM_014009.4(FOXP3):c.1222G>A (p.Val408Met)	FOXP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4710758	NM_014009.4(FOXP3):c.816+7G>C	FOXP3	Pathogenic	criteria provided, single submitter
4710759	NM_014009.4(FOXP3):c.816+5G>A	FOXP3	Pathogenic	criteria provided, single submitter
4732563	NM_014009.4(FOXP3):c.711_712del (p.Glu237fs)	FOXP3	Pathogenic	criteria provided, single submitter
4763913	NM_014009.4(FOXP3):c.766A>G (p.Met256Val)	FOXP3	Pathogenic	criteria provided, single submitter
499890	NM_014009.4(FOXP3):c.748_750del (p.Lys250del)	FOXP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
575607	NM_014009.4(FOXP3):c.210+1G>T	FOXP3	Pathogenic	criteria provided, single submitter
578790	NM_014009.4(FOXP3):c.694T>G (p.Cys232Gly)	FOXP3	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
FOXP3	Definitive	X-linked	immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FOXP3	Orphanet:37042	Immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome
CCDC22	Orphanet:7	3C syndrome
AKAP4	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FOXP3	HGNC:6106	ENSG00000049768	Q9BZS1	Forkhead box protein P3	gencc,clinvar
CCDC22	HGNC:28909	ENSG00000101997	O60826	Coiled-coil domain-containing protein 22	clinvar
AKAP4	HGNC:374	ENSG00000147081	Q5JQC9	A-kinase anchor protein 4	clinvar
GAGE2A	HGNC:4099	ENSG00000189064	Q6NT46	G antigen 2A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FOXP3	Forkhead box protein P3	Transcriptional regulator which is crucial for the development and inhibitory function of regulatory T-cells (Treg).
CCDC22	Coiled-coil domain-containing protein 22	Component of the commander complex that is essential for endosomal recycling of transmembrane cargos; the Commander complex is composed of composed of the CCC subcomplex and the retriever subcomplex.
AKAP4	A-kinase anchor protein 4	Major structural component of sperm fibrous sheath.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	2.1×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FOXP3	Transcription factor	no		Fork_head_dom, Znf_C2H2_type, TF_fork_head_CS_2
CCDC22	Other/Unknown	no		CCDC22, CCDC22_CC, CCDC22_N
AKAP4	Other/Unknown	no		SPHK1-interactor_AKAP_110, AKAP_110_C, RII-bd_1
GAGE2A	Other/Unknown	no		GAGE_fam, GAGE

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
parotid gland	1
skeletal muscle tissue of rectus abdominis	1
granulocyte	1
leukocyte	1
monocyte	1
left testis	1
male germ cell	1
sperm	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FOXP3	155	tissue_specific	marker	buccal mucosa cell, parotid gland, skeletal muscle tissue of rectus abdominis
CCDC22	258	ubiquitous	yes	granulocyte, monocyte, leukocyte
AKAP4	62	tissue_specific	marker	sperm, male germ cell, left testis
GAGE2A	90		marker	male germ line stem cell (sensu Vertebrata) in testis, right testis, testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FOXP3	4,306
CCDC22	1,910
GAGE2A	1,375
AKAP4	1,149

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CCDC22	O60826	4
FOXP3	Q9BZS1	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GAGE2A	Q6NT46	66.09
AKAP4	Q5JQC9	53.52

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 4 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RUNX1 regulates transcription of genes involved in WNT signaling	1	951.7×	0.004	FOXP3
RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)	1	571.0×	0.004	FOXP3
Neddylation	1	23.7×	0.070	CCDC22
Post-translational protein modification	1	9.6×	0.127	CCDC22
Metabolism of proteins	1	6.2×	0.155	CCDC22

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of peripheral T cell tolerance induction	1	5617.3×	0.004	FOXP3
CD4-positive, CD25-positive, alpha-beta regulatory T cell lineage commitment	1	2808.7×	0.004	FOXP3
establishment of endothelial blood-brain barrier	1	2808.7×	0.004	FOXP3
negative regulation of chronic inflammatory response	1	1872.4×	0.004	FOXP3
transforming growth factor beta1 production	1	1872.4×	0.004	FOXP3
isotype switching to IgE isotypes	1	1872.4×	0.004	FOXP3
negative regulation of isotype switching to IgE isotypes	1	1872.4×	0.004	FOXP3
tolerance induction to self antigen	1	1404.3×	0.004	FOXP3
regulation of T cell anergy	1	1404.3×	0.004	FOXP3
T cell anergy	1	1404.3×	0.004	FOXP3
obsolete negative regulation of CREB transcription factor activity	1	1404.3×	0.004	FOXP3
regulation of isotype switching to IgG isotypes	1	1404.3×	0.004	FOXP3
response to rapamycin	1	1404.3×	0.004	FOXP3
positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation	1	1123.5×	0.004	FOXP3
immature T cell proliferation in thymus	1	1123.5×	0.004	FOXP3
positive regulation of T cell anergy	1	936.2×	0.004	FOXP3
positive regulation of transforming growth factor beta1 production	1	936.2×	0.004	FOXP3
positive regulation of immature T cell proliferation in thymus	1	936.2×	0.004	FOXP3
negative regulation of T cell cytokine production	1	802.5×	0.005	FOXP3
negative regulation of interleukin-4 production	1	802.5×	0.005	FOXP3
myeloid cell homeostasis	1	702.2×	0.005	FOXP3
regulatory T cell differentiation	1	702.2×	0.005	FOXP3
negative regulation of interleukin-5 production	1	624.1×	0.005	FOXP3
CD4-positive, alpha-beta T cell proliferation	1	624.1×	0.005	FOXP3
negative regulation of T-helper 17 cell differentiation	1	624.1×	0.005	FOXP3
negative regulation of CD4-positive, alpha-beta T cell proliferation	1	468.1×	0.006	FOXP3
negative regulation of defense response to virus	1	432.1×	0.006	FOXP3
negative regulation of interleukin-17 production	1	351.1×	0.007	FOXP3
negative regulation of activated T cell proliferation	1	351.1×	0.007	FOXP3
negative regulation of immune response	1	351.1×	0.007	FOXP3

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 4

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FOXP3	0	0
CCDC22	0	0
AKAP4	0	0
GAGE2A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
FOXP3	4	Binding:4
CCDC22	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	FOXP3, CCDC22, AKAP4, GAGE2A

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
FOXP3	4	—
CCDC22	1	—
AKAP4	0	—
GAGE2A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	3
PHASE1	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT07284641	PHASE2	RECRUITING	Hematopoietic Stem Cell Transplantation (HSCT) for Common Variable Immunodeficiency (CVID) and Other Autoimmune Manifestations of Primary Immune Regulatory Disorders (PIRD)
NCT01998633	PHASE2	COMPLETED	Reduced Intensity Conditioning for Hemophagocytic Syndromes or Selected Primary Immune Deficiencies (BMT CTN 1204)
NCT05241444	PHASE1	RECRUITING	CD4^LVFOXP3 in Participants With IPEX
NCT04902807	Not specified	RECRUITING	Conception of a Diagnosis, Prognosis and Therapeutic Decision Tool for Patients With Autoimmunity and Inflammation

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MELPHALAN	4	1