Autoimmune Polyendocrine Syndrome Type 1

Mendelian MONDO:0009411 Pathograph 27 Show in embeddings browser Autoimmune polyendocrinopathy Primary immunodeficiency Monogenic autoimmune disease

Autoimmune polyendocrine syndrome type 1 (APS-1/APECED) is a rare autosomal recessive disorder caused by loss-of-function mutations in the AIRE (autoimmune regulator) gene. AIRE is essential for thymic expression of tissue-restricted antigens, enabling negative selection of autoreactive T cells. Its deficiency leads to failure of central immune tolerance, resulting in multi-organ autoimmune destruction. The classic clinical triad consists of chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency (Addison disease), though the phenotypic spectrum is much broader, including type 1 diabetes, autoimmune hepatitis, and ectodermal dystrophy.

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1
Inheritance
4
Pathophys.
20
Phenotypes
27
Pathograph
1
Genes
3
Variants
4
Medical Actions
2
Differentials
2
Datasets
1
Deep Research
🏷

Classifications

IUIS Category
immune dysregulation
👪

Inheritance

1
Autosomal Recessive HP:0000007
Autosomal recessive inheritance
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Pathophysiology

4
AIRE Deficiency and Thymic Tolerance Failure
AIRE (autoimmune regulator) is a transcription factor expressed in medullary thymic epithelial cells (mTECs). It drives ectopic expression of tissue-restricted self-antigens (TRAs) in the thymus, enabling negative selection of autoreactive T cells. Loss-of-function mutations in AIRE abolish this promiscuous gene expression, allowing autoreactive T cells to escape thymic deletion and enter the periphery.
medullary thymic epithelial cell CL:0002365 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves medullary thymic epithelial cell (CL:0002365). CL:0002365 is a cell type from the Cell Ontology.
AIRE hgnc:360 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves AIRE (hgnc:360). hgnc:360 is a gene from the HUGO Gene Nomenclature Committee.
T cell negative selection GO:0043383 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves T cell negative selection, annotated with negative T cell selection (GO:0043383). GO:0043383 is a biological process from the Gene Ontology. thymic T cell selection GO:0045061 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves thymic T cell selection (GO:0045061). GO:0045061 is a biological process from the Gene Ontology.
medulla of thymus UBERON:0002124 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in medulla of thymus (UBERON:0002124). UBERON:0002124 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Organ-Specific Autoimmune Destruction Escaped autoreactive T cells attack multiple endocrine and non-endocrine organs.
Anti-Cytokine Autoantibody Production Failure of central tolerance leads to B cell production of anti-cytokine autoantibodies.
Show evidence (2 references)
PMID:12376594 SUPPORT Model Organism
"Aire-deficient thymic medullary epithelial cells showed a specific reduction in ectopic transcription of genes encoding peripheral antigens."
Seminal study demonstrating that AIRE drives ectopic expression of peripheral tissue-restricted antigens in thymic medullary epithelial cells, and that its absence causes autoimmunity.
PMID:34790633 SUPPORT Human Clinical
"AIRE deficiency impairs immune tolerance in the thymus and results in the peripheral escape of self-reactive T lymphocytes and the generation of several cytokine- and tissue antigen-targeted autoantibodies."
Review confirms that AIRE deficiency impairs thymic tolerance and allows autoreactive T cell escape.
Anti-Cytokine Autoantibody Production
APS-1 patients produce high-titer neutralizing autoantibodies against type I interferons (IFN-alpha, IFN-omega), IL-17A, IL-17F, and IL-22. Anti-IL-17/IL-22 antibodies impair mucocutaneous antifungal immunity, explaining the susceptibility to chronic mucocutaneous candidiasis. Anti-IFN antibodies are nearly universal and serve as a diagnostic biomarker.
cytokine-mediated signaling pathway GO:0019221 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cytokine-mediated signaling pathway (GO:0019221). GO:0019221 is a biological process from the Gene Ontology. defense response to fungus GO:0050832 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased defense response to fungus (GO:0050832). GO:0050832 is a biological process from the Gene Ontology.
Downstream
Chronic Mucocutaneous Candidiasis Anti-IL-17/IL-22 autoantibodies cripple Th17-mediated mucosal antifungal defense.
Show evidence (3 references)
PMID:20123959 SUPPORT Human Clinical
"Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC."
Multicenter study quantifying anti-cytokine autoantibody prevalence in APS-1 patients.
PMID:27588307 SUPPORT Human Clinical
"All but one patient had anti-IFN-ω autoantibodies, including 4 of 5 patients without biallelic AIRE mutations."
NIH cohort demonstrating near-universal anti-IFN-omega autoantibodies in APS-1.
PMID:27588307 SUPPORT Human Clinical
"Autoantibodies against IL-22 and IL-17F , but not IL-17A, were significantly associated with the time to development of CMC"
In the American APECED cohort, anti-IL-22 and anti-IL-17F (but not anti-IL-17A) autoantibody titers correlated with the timing of CMC onset, supporting their causal role in impaired mucocutaneous antifungal defense.
Chronic Mucocutaneous Candidiasis
Chronic mucocutaneous candidiasis (CMC) is often the earliest manifestation of APS-1, typically appearing in infancy or early childhood. It results from neutralizing autoantibodies against IL-17A, IL-17F, and IL-22 that cripple Th17-mediated antifungal defense at mucosal surfaces. Candida albicans colonizes oral mucosa, nails, and skin, causing recurrent and persistent infection.
T-helper 17 cell CL:0000899 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T-helper 17 cell (CL:0000899). CL:0000899 is a cell type from the Cell Ontology.
defense response to fungus GO:0050832 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased defense response to fungus (GO:0050832). GO:0050832 is a biological process from the Gene Ontology.
Show evidence (1 reference)
PMID:20123959 SUPPORT Human Clinical
"We conclude that IL-22 and IL-17F are key natural defenders against CMC and that the immunodeficiency underlying CMC in both patient groups has an autoimmune basis."
Demonstrates that CMC in APS-1 is caused by autoantibodies neutralizing Th17 cytokines IL-22 and IL-17F.
Organ-Specific Autoimmune Destruction
Autoreactive T cells that escape thymic deletion target multiple endocrine and non-endocrine organs. Autoimmune attack on the parathyroid glands causes hypoparathyroidism; destruction of the adrenal cortex causes Addison disease; and pancreatic beta cell autoimmunity can lead to type 1 diabetes. The pattern and timing of organ involvement is variable even within the same family, suggesting stochastic and environmental modifiers.
CD8-positive, alpha-beta T cell CL:0000625 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD8-positive, alpha-beta T cell (CL:0000625). CL:0000625 is a cell type from the Cell Ontology.
T cell mediated cytotoxicity GO:0001913 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves T cell mediated cytotoxicity (GO:0001913). GO:0001913 is a biological process from the Gene Ontology.
Downstream
Hypoparathyroidism
Primary Adrenal Insufficiency
Primary Hypogonadism
Type 1 Diabetes Mellitus
Hashimoto Thyroiditis
Autoimmune Hepatitis
Alopecia
Vitiligo
Nail Dystrophy
Dental Enamel Hypoplasia
Intestinal Malabsorption
Keratoconjunctivitis
Asplenia
Urticarial Eruption
Pneumonitis
Pernicious Anemia
Autoimmune Gastritis
Growth Hormone Deficiency
Tubulointerstitial Nephritis
Show evidence (2 references)
PMID:35690244 SUPPORT Human Clinical
"APS-1 is often accompanied by hypogonadism, type 1 diabetes, autoimmune thyroiditis, vitiligo, alopecia, asplenia, pneumonitis, gastritis, pernicious anemia, and intestinal dysfunction, nephritis, and hepatitis."
Review documenting the broad spectrum of organ-specific autoimmune manifestations in APS-1.
PMID:27588307 SUPPORT Human Clinical
"Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjögren's-like syndrome, uncommon entities in European APECED cohorts, affected 40%-80% of American cases."
NIH cohort revealing that non-endocrine autoimmune manifestations are more common in American APS-1 patients than previously recognized.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autoimmune Polyendocrine Syndrome Type 1 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

20
Blood 1
Pernicious Anemia OCCASIONAL Macrocytic anemia HP:0001972 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pernicious anemia, annotated with Macrocytic anemia (HP:0001972). HP:0001972 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35690244 SUPPORT Human Clinical
"APS-1 is often accompanied by hypogonadism, type 1 diabetes, autoimmune thyroiditis, vitiligo, alopecia, asplenia, pneumonitis, gastritis, pernicious anemia, and intestinal dysfunction, nephritis, and hepatitis."
Pernicious anemia listed among APS-1 manifestations.
Cardiovascular 2
Asplenia OCCASIONAL HP:0001746 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Asplenia (HP:0001746). HP:0001746 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35690244 SUPPORT Human Clinical
"APS-1 is often accompanied by hypogonadism, type 1 diabetes, autoimmune thyroiditis, vitiligo, alopecia, asplenia, pneumonitis, gastritis, pernicious anemia, and intestinal dysfunction, nephritis, and hepatitis."
Asplenia listed among APS-1 manifestations.
Urticarial Eruption FREQUENT HP:0001025 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Urticaria (HP:0001025). HP:0001025 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27588307 SUPPORT Human Clinical
"Urticarial eruption, intestinal dysfunction, and enamel hypoplasia were prominent among early manifestations."
Urticarial eruption identified as prominent early manifestation in NIH APS-1 cohort.
Digestive 3
Autoimmune Hepatitis FREQUENT HP:0012115 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmune hepatitis, annotated with Hepatitis (HP:0012115). HP:0012115 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27588307 SUPPORT Human Clinical
"Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjögren's-like syndrome, uncommon entities in European APECED cohorts, affected 40%-80% of American cases."
Hepatitis affected 40-80% of American APS-1 patients in the NIH cohort.
Intestinal Malabsorption OCCASIONAL HP:0002024 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intestinal malabsorption, annotated with Malabsorption (HP:0002024). HP:0002024 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27588307 SUPPORT Human Clinical
"Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjögren's-like syndrome, uncommon entities in European APECED cohorts, affected 40%-80% of American cases."
Intestinal dysfunction is common in American APS-1 patients.
Autoimmune Gastritis FREQUENT HP:0005263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmune gastritis, annotated with Gastritis (HP:0005263). HP:0005263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27588307 SUPPORT Human Clinical
"biopsy-proven gastritis was seen in 17 patients (48.6%)"
Biopsy-proven autoimmune gastritis affected 48.6% of the American APECED cohort.
Endocrine 6
Hypoparathyroidism VERY_FREQUENT HP:0000829 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoparathyroidism (HP:0000829). HP:0000829 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34790633 SUPPORT Human Clinical
"APECED features a classic triad of characteristic clinical manifestations consisting of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and primary adrenal insufficiency (Addison's disease)."
Confirms hypoparathyroidism as part of the classic APECED triad.
Primary Adrenal Insufficiency VERY_FREQUENT HP:0000846 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Primary adrenal insufficiency, annotated with Adrenal insufficiency (HP:0000846). HP:0000846 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34790633 SUPPORT Human Clinical
"APECED features a classic triad of characteristic clinical manifestations consisting of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and primary adrenal insufficiency (Addison's disease)."
Adrenal insufficiency confirmed as classic triad component.
Primary Hypogonadism FREQUENT HP:0000135 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Primary hypogonadism, annotated with Hypogonadism (HP:0000135). HP:0000135 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35690244 SUPPORT Human Clinical
"APS-1 is often accompanied by hypogonadism, type 1 diabetes, autoimmune thyroiditis, vitiligo, alopecia, asplenia, pneumonitis, gastritis, pernicious anemia, and intestinal dysfunction, nephritis, and hepatitis."
Review lists hypogonadism among the common APS-1 manifestations.
Type 1 Diabetes Mellitus OCCASIONAL Type I diabetes mellitus HP:0100651 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Type 1 diabetes mellitus, annotated with Type I diabetes mellitus (HP:0100651). HP:0100651 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35690244 SUPPORT Human Clinical
"APS-1 is often accompanied by hypogonadism, type 1 diabetes, autoimmune thyroiditis, vitiligo, alopecia, asplenia, pneumonitis, gastritis, pernicious anemia, and intestinal dysfunction, nephritis, and hepatitis."
Type 1 diabetes listed among APS-1 manifestations.
Hashimoto Thyroiditis OCCASIONAL HP:0000872 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hashimoto thyroiditis (HP:0000872). HP:0000872 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35690244 SUPPORT Human Clinical
"APS-1 is often accompanied by hypogonadism, type 1 diabetes, autoimmune thyroiditis, vitiligo, alopecia, asplenia, pneumonitis, gastritis, pernicious anemia, and intestinal dysfunction, nephritis, and hepatitis."
Autoimmune thyroiditis listed among APS-1 manifestations.
Growth Hormone Deficiency OCCASIONAL Reduced circulating growth hormone concentration HP:0034323 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth hormone deficiency, annotated with Reduced circulating growth hormone concentration (HP:0034323). HP:0034323 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27588307 SUPPORT Human Clinical
"growth hormone (GH) deficiency (17.1%)"
Growth hormone deficiency affected 17.1% of the American APECED cohort.
Eye 1
Keratoconjunctivitis OCCASIONAL Keratitis HP:0000491 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Keratoconjunctivitis, annotated with Keratitis (HP:0000491). HP:0000491 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28137823 SUPPORT Human Clinical
"This is a retrospective review of 10 patients with APS-1. The patients were treated with topical tacrolimus 0.01% solution"
Clinical series of 10 APS-1 patients with keratitis requiring treatment, directly demonstrating keratitis as a recognized APS-1 manifestation.
Genitourinary 1
Tubulointerstitial Nephritis OCCASIONAL HP:0001970 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tubulointerstitial nephritis (HP:0001970). HP:0001970 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27588307 SUPPORT Human Clinical
"asplenia (8.6%), and tubulointerstitial nephritis (5.7%)"
Tubulointerstitial nephritis affected 5.7% of the American APECED cohort.
Head and Neck 1
Dental Enamel Hypoplasia FREQUENT HP:0006297 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Enamel hypoplasia (HP:0006297). HP:0006297 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27588307 SUPPORT Human Clinical
"Urticarial eruption, intestinal dysfunction, and enamel hypoplasia were prominent among early manifestations."
Enamel hypoplasia identified as a prominent early manifestation in the NIH APS-1 cohort.
Immune 1
Chronic Mucocutaneous Candidiasis VERY_FREQUENT HP:0002728 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic mucocutaneous candidiasis (HP:0002728). HP:0002728 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20123959 SUPPORT Human Clinical
"In autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED, or autoimmune polyendocrine syndrome 1), CMC is often the first sign"
Confirms CMC as frequently the first clinical manifestation of APS-1.
Integument 3
Alopecia FREQUENT HP:0001596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Alopecia (HP:0001596). HP:0001596 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35690244 SUPPORT Human Clinical
"APS-1 is often accompanied by hypogonadism, type 1 diabetes, autoimmune thyroiditis, vitiligo, alopecia, asplenia, pneumonitis, gastritis, pernicious anemia, and intestinal dysfunction, nephritis, and hepatitis."
Alopecia listed among common APS-1 manifestations.
Vitiligo OCCASIONAL HP:0001045 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vitiligo (HP:0001045). HP:0001045 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35690244 SUPPORT Human Clinical
"APS-1 is often accompanied by hypogonadism, type 1 diabetes, autoimmune thyroiditis, vitiligo, alopecia, asplenia, pneumonitis, gastritis, pernicious anemia, and intestinal dysfunction, nephritis, and hepatitis."
Vitiligo listed among APS-1 manifestations.
Nail Dystrophy FREQUENT HP:0008404 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nail dystrophy (HP:0008404). HP:0008404 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31905445 SUPPORT Human Clinical
"Various autoimmune diseases and ectodermal abnormalities are also commonly associated with the syndrome."
Nail dystrophy is an ectodermal abnormality commonly associated with APS-1/APECED (the E and D in the acronym stand for Ectodermal Dystrophy).
Respiratory 1
Pneumonitis OCCASIONAL Interstitial pneumonitis HP:0006515 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Interstitial pneumonitis (HP:0006515). HP:0006515 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:27588307 SUPPORT Human Clinical
"Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjögren's-like syndrome, uncommon entities in European APECED cohorts, affected 40%-80% of American cases."
Pneumonitis is a significant non-endocrine manifestation in American APS-1 patients.
PMID:27588307 SUPPORT Human Clinical
"A single 14-year-old patient in our cohort died (mortality, 2.9%) from pneumonitis-related"
Autoimmune pneumonitis carries life-threatening potential; a cohort patient died of pneumonitis-related respiratory failure.
PMID:27588307 SUPPORT Human Clinical
"BPIFB1 was highly sensitive, whereas KCNRG lacked sensitivity but was 100% specific"
Autoantibodies against BPIFB1 and KCNRG were significantly associated with time to development of pneumonitis in the APECED cohort; BPIFB1 was a highly sensitive and KCNRG a 100%-specific serologic marker.
🧬

Genetic Associations

1
AIRE (Causal)
Gene: AIRE hgnc:360 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is AIRE (hgnc:360). hgnc:360 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal Recessive
Show evidence (5 references)
PMID:9398839 SUPPORT Human Clinical
"Two mutations, a C-->T substitution that changes the Arg 257 (CGA) to a stop codon (TGA) and an A-->G substitution that changes the Lys 83 (AAG) to a Glu codon (GAG), were found in this novel gene in Swiss and Finnish APECED patients."
Original positional cloning paper identifying AIRE as the APECED gene with specific mutations.
PMID:27588307 SUPPORT Human Clinical
"Most patients were compound heterozygous; the most common AIRE mutation was c.967_979del13."
NIH cohort confirms c.967_979del13 as the most common AIRE mutation in American patients.
PMID:34790633 SUPPORT Other
"carry homozygous p.R257X, p.R139X, p.Y85C, and p.R203X mutations, respectively"
Review documents the population-specific founder alleles (Finnish p.R257X, Sardinian p.R139X, Persian Jewish p.Y85C, Sicilian p.R203X) behind the founder-effect epidemiology.
+ 2 more references
Variants (3)
R257X (c.769C>T)
Nonsense mutation in exon 6, the most common AIRE mutation worldwide and a Finnish founder mutation. Creates a premature stop codon truncating the protein before the second PHD domain.
R139X (c.415C>T)
Nonsense mutation in exon 3 common in Sardinian patients. Truncates the protein within the SAND domain.
13bp deletion (c.967_979del13)
Frameshift deletion in exon 8, common in British and North American patients.
💊

Medical Actions

4
Hormone Replacement Therapy
Action: hormone replacement therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is hormone replacement therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: hydrocortisone NCIT:C555 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses hydrocortisone, annotated with Therapeutic Hydrocortisone (NCIT:C555). NCIT:C555 is a therapeutic agent from the NCI Thesaurus. fludrocortisone CHEBI:50885 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses fludrocortisone (CHEBI:50885). CHEBI:50885 is a therapeutic agent from Chemical Entities of Biological Interest. insulin CHEBI:5931 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses insulin, annotated with insulin (human) (CHEBI:5931). CHEBI:5931 is a therapeutic agent from Chemical Entities of Biological Interest.
Replacement of deficient hormones is the mainstay of treatment: calcium and vitamin D for hypoparathyroidism, hydrocortisone and fludrocortisone for adrenal insufficiency, insulin for diabetes, and sex hormones for hypogonadism.
Show evidence (1 reference)
PMID:31905445 SUPPORT Human Clinical
"The treatment of APS-1 includes hormone replacement and symptom control."
Case report confirms hormone replacement as a mainstay of APS-1 treatment.
Antifungal Therapy
Action: antifungal therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antifungal therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: fluconazole CHEBI:46081 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses fluconazole (CHEBI:46081). CHEBI:46081 is a therapeutic agent from Chemical Entities of Biological Interest.
Chronic or intermittent antifungal therapy (fluconazole, itraconazole) for management of chronic mucocutaneous candidiasis.
Show evidence (1 reference)
PMID:34790633 SUPPORT Other
"Acute episodes of mucosal candidiasis respond well to induction therapy for four weeks"
Review of APECED management documents azole induction therapy for acute mucosal candidiasis episodes.
Immunosuppressive Therapy
Action: immunosuppressive therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immunosuppressive therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: azathioprine CHEBI:2948 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses azathioprine (CHEBI:2948). CHEBI:2948 is a therapeutic agent from Chemical Entities of Biological Interest. cyclosporin A CHEBI:4031 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cyclosporin A (CHEBI:4031). CHEBI:4031 is a therapeutic agent from Chemical Entities of Biological Interest.
Immunosuppression (e.g., azathioprine, mycophenolate, cyclosporine) may be needed for severe autoimmune manifestations such as autoimmune hepatitis or enteropathy.
Show evidence (1 reference)
PMID:34790633 SUPPORT Other
"autoimmune hepatitis responds clinically and biochemically to immunomodulatory treatment. Azathioprine-based or"
Review documents immunomodulatory (azathioprine-based) treatment of the severe non-endocrine autoimmune manifestations such as autoimmune hepatitis.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Genetic counseling for family members given the autosomal recessive inheritance pattern. Early identification of at-risk siblings allows for surveillance and early intervention.
Show evidence (1 reference)
PMID:35690244 SUPPORT Human Clinical
"Analysis of the AIRE gene is the main diagnostic method for early detection of APS-1 and the choice of methods for its treatment. Timely genetic counseling makes it possible to identify the disease early, prescribe appropriate treatment and prevent serious complications."
Review highlights genetic counseling as important for early APS-1 detection.
🌍

Environmental Factors

1
Candida albicans Exposure
Ubiquitous fungal exposure triggers chronic mucocutaneous candidiasis in the context of impaired Th17 immunity due to anti-IL-17/IL-22 autoantibodies.
Show evidence (2 references)
PMID:34455138 SUPPORT Human Clinical
"Chronic mucocutaneous candidiasis (CMC) is one of the earliest and most frequent clinical manifestations of autosomal recessive autoimmune polyendocrine syndrome type 1 (APS-1), a monogenic inborn error of immunity caused by deleterious variants of the autoimmune regulator (AIRE) gene."
Establishes that candidiasis is among the earliest and most frequent manifestations of this syndrome, which is what makes an otherwise ubiquitous fungal exposure a disease-relevant one here.
PMID:20123958 SUPPORT Human Clinical
"We found high titers of autoantibodies (auto-Abs) against IL-17A, IL-17F, and/or IL-22 in the sera of all 33 patients tested"
Primary data for the host side of this entry's claim: neutralizing autoantibodies against IL-17A, IL-17F and IL-22 were present in every one of 33 patients tested, which is the impaired Th17 immunity that lets the exposure produce chronic infection.
🔬

Biochemical Markers

2
Anti-Interferon Autoantibodies (Increased)
Show evidence (1 reference)
PMID:27588307 SUPPORT Human Clinical
"All but one patient had anti-IFN-ω autoantibodies, including 4 of 5 patients without biallelic AIRE mutations."
Near-universal anti-IFN-omega autoantibodies in the NIH APS-1 cohort confirms diagnostic utility.
Anti-IL-17/IL-22 Autoantibodies (Increased)
Show evidence (1 reference)
PMID:20123959 SUPPORT Human Clinical
"Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC."
Large multicenter study quantifying anti-IL-17 and anti-IL-22 autoantibody prevalence in APS-1.
🔬

Diagnosis

3
Clinical Diagnostic Dyad (Classic Triad Criteria)
Clinical diagnosis rests on developing any two of the classic triad (chronic mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency). In the American NIH cohort the dyad was reached at a mean of 7.38 years, and expanded criteria adding urticarial eruption, intestinal dysfunction, and enamel hypoplasia would accelerate diagnosis by about four years.
Show evidence (3 references)
PMID:27588307 SUPPORT Human Clinical
"Developing any two of these classic triad manifestations establishes the diagnosis."
States the classic dyad-based clinical diagnostic criterion.
PMID:27588307 SUPPORT Human Clinical
"Development of a classic diagnostic dyad was delayed at mean 7.38 years."
Quantifies the diagnostic delay under classic-triad criteria, the motivation for the expanded criteria.
PMID:27588307 SUPPORT Human Clinical
"Incorporation of these new manifestations into American diagnostic criteria would accelerate diagnosis by approximately 4 years and potentially prevent life-threatening endocrine complications."
Supports the expanded diagnostic criteria incorporating early non-triad manifestations.
Anti-Interferon-Omega Autoantibody Testing
Neutralizing anti-IFN-omega autoantibodies are a highly sensitive and specific serologic marker, positive in 97% of the NIH cohort including most patients without detectable biallelic AIRE mutations, and are especially useful when sequencing is uninformative.
Show evidence (2 references)
PMID:27588307 SUPPORT Human Clinical
"Testing for anti–IFN-ω autoantibodies upon clinical suspicion may be helpful for diagnosis, as 97% of our patients had such autoantibodies, which are known to be highly prevalent and specific for APECED"
Directly supports anti-IFN-omega autoantibody testing as a diagnostic tool.
PMID:27588307 SUPPORT Human Clinical
"All but one patient had anti-IFN-ω autoantibodies, including 4 of 5 patients without biallelic AIRE mutations."
Shows the marker remains positive in most patients without detectable biallelic AIRE mutations, where sequencing alone would miss the diagnosis.
AIRE Molecular Genetic Testing
Sequencing of AIRE confirms the diagnosis and guides family counseling, but 15-20% of patients carry large deletions, monoallelic variants, or even wild-type AIRE despite a clinically indistinguishable phenotype, so serology complements sequencing.
Show evidence (2 references)
PMID:35690244 SUPPORT Human Clinical
"Analysis of the AIRE gene is the main diagnostic method for early detection of APS-1"
Identifies AIRE gene analysis as the main diagnostic method.
PMID:27588307 SUPPORT Human Clinical
"Between 15% and 20% of patients carry large AIRE deletions, heterozygous AIRE mutations, or even fully wild-type AIRE"
Documents the sequencing-negative fraction that makes serologic confirmation necessary.
📈

Progression

2
Early childhood presentation (candidiasis and non-triad manifestations)
Age: Infancy to ~7 years
Chronic mucocutaneous candidiasis is typically the earliest manifestation. In the American NIH cohort, urticarial eruption, intestinal dysfunction, and enamel hypoplasia were also prominent early, often preceding any classic triad dyad (which was reached at a mean of 7.38 years).
Show evidence (2 references)
PMID:20123959 SUPPORT Human Clinical
"In autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED, or autoimmune polyendocrine syndrome 1), CMC is often the first sign"
CMC is documented as frequently the first manifestation.
PMID:27588307 SUPPORT Human Clinical
"Urticarial eruption, intestinal dysfunction, and enamel hypoplasia were prominent among early manifestations."
The NIH cohort identifies the adjunct-triad manifestations as prominent early features of the disease course.
Childhood-adolescence accrual of endocrinopathies and organ autoimmunity
Age: Childhood through adulthood
Hypoparathyroidism and adrenal insufficiency typically develop during childhood, and organ-specific autoimmune manifestations continue to accumulate lifelong; most patients develop several non-triad manifestations before a classic diagnostic dyad is reached.
Show evidence (2 references)
PMID:27588307 SUPPORT Human Clinical
"Eighty percent of patients developed a median of 3 non-triad manifestations before a diagnostic dyad."
Documents progressive accrual of manifestations preceding the classic diagnostic dyad.
PMID:27588307 SUPPORT Human Clinical
"We found a dramatic expansion of disease manifestations, with 23 clinical entities seen in varying frequencies (5.7%–91.4%; Figure 1A and Table 1)"
Documents the breadth of multi-organ manifestations that accumulate over the disease course in the NIH cohort.
📊

Prevalence

1
General (worldwide)
Point Prevalence 0.5–1.0 per 100,000 1–9 per 1,000,000
APS-1 is very rare worldwide. Higher prevalence in genetically isolated populations including Finnish (1:25,000), Sardinian (1:14,400), and Iranian Jewish (1:9,000) communities due to founder effects.
Show evidence (3 references)
PMID:35690244 SUPPORT Human Clinical
"The prevalence rate is highest in genetically isolated populations (up to 1:6500-1:9000)."
Review confirms high prevalence in isolated populations.
PMID:34790633 SUPPORT Other
"highest prevalence has been reported in Finnish, Sardinian,"
Review names the Finnish and Sardinian founder populations as carrying the highest prevalence, supporting the founder-effect note.
PMID:34790633 SUPPORT Other
"United States, the prevalence of APECED is estimated between 1:100,000–1:300,000"
Supports the very low general-population prevalence outside founder populations.
⚖️

Clinical Burden

High
APS-1 is a lifelong multisystem autoimmune disease: NIH-cohort patients accumulated manifestations spanning 23 distinct clinical entities across endocrine and non-endocrine organs, require lifelong hormone replacement and multidisciplinary surveillance, and face life-threatening complications (hypocalcemic seizures, adrenal crises, fulminant hepatitis, and pneumonitis-related respiratory failure, which caused the one cohort death).
Show evidence (2 references)
PMID:27588307 SUPPORT Human Clinical
"A single 14-year-old patient in our cohort died (mortality, 2.9%) from pneumonitis-related"
Documents disease-related mortality in the prospective cohort, supporting the HIGH burden level.
PMID:27588307 SUPPORT Human Clinical
"Incorporation of these new manifestations into American diagnostic criteria would accelerate diagnosis by approximately 4 years and potentially prevent life-threatening endocrine complications."
The life-threatening endocrine complications of delayed diagnosis (hypocalcemic seizures, adrenal crises) contribute to the HIGH burden assessment.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Autoimmune Polyendocrine Syndrome Type 1:

IPEX Syndrome (FOXP3, peripheral tolerance defect)
Overlapping Features IPEX is the key mechanistic contrast to APS-1: it is caused by FOXP3 mutations abolishing regulatory T cell function (a PERIPHERAL-tolerance defect), whereas APECED is a CENTRAL (thymic) tolerance defect caused by AIRE mutations. IPEX is X-linked, presents in male infants with the enteropathy-diabetes-eczema triad, and lacks the APECED triad of candidiasis, hypoparathyroidism and Addison disease.
Show evidence (1 reference)
PMID:19410687 SUPPORT Other
"Mutations in the FOXP3 gene interfere with Treg cell development and cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome."
Identifies the FOXP3/Treg (peripheral tolerance) mechanism of IPEX, distinguishing it from the AIRE-driven central tolerance failure of APS-1.
Thymoma-Associated Chronic Mucocutaneous Candidiasis
Overlapping Features Thymoma patients can develop the same neutralizing anti-Th17-cytokine autoantibodies and chronic mucocutaneous candidiasis as APECED patients, without AIRE mutations; thymoma is the main acquired mimic of the anti-cytokine autoimmunity of APS-1.
Show evidence (1 reference)
PMID:20123959 SUPPORT Human Clinical
"We independently found autoantibodies against these Th17-produced cytokines in rare thymoma patients with CMC."
Documents thymoma as an acquired phenocopy producing the same anti-IL-17/IL-22 autoantibodies and candidiasis.
📊

Related Datasets

2
The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1 geo:GSE225460
Background: Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood. Methods: We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues.
human BULK RNA SEQ n=8
PMID:38810185
Identified by GEO DataSets index search for Autoimmune Polyendocrine Syndrome Type 1 (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
Tregs in autoimmune polyendocrine syndrome type I geo:GSE243061
Autoimmune polyendocrine syndrome type 1 (APS-1) relies on failures both in central and peripheral tolerance. A decreased number of regulatory T cells (Tregs) is repeatedly reported, and Tregs based therapy could therefore be considered. We have used a single cell transcriptomic approach to characterize Tregs sorted from blood.
human SINGLE CELL RNA SEQ n=8
PMID:38632993
Identified by GEO DataSets index search for Autoimmune Polyendocrine Syndrome Type 1 (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
{ }

Source YAML

click to show 
name: Autoimmune Polyendocrine Syndrome Type 1
creation_date: "2026-04-22T00:00:00Z"
category: Mendelian
synonyms:
- APECED
- APS-1
- Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
- Whitaker syndrome
description: >
  Autoimmune polyendocrine syndrome type 1 (APS-1/APECED) is a rare autosomal
  recessive disorder caused by loss-of-function mutations in the AIRE
  (autoimmune regulator) gene. AIRE is essential for thymic expression of
  tissue-restricted antigens, enabling negative selection of autoreactive T
  cells. Its deficiency leads to failure of central immune tolerance, resulting
  in multi-organ autoimmune destruction. The classic clinical triad consists of
  chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal
  insufficiency (Addison disease), though the phenotypic spectrum is much
  broader, including type 1 diabetes, autoimmune hepatitis, and ectodermal
  dystrophy.
disease_term:
  preferred_term: autoimmune polyendocrine syndrome type 1
  term:
    id: MONDO:0009411
    label: autoimmune polyendocrine syndrome type 1
parents:
- Autoimmune polyendocrinopathy
- Primary immunodeficiency
- Monogenic autoimmune disease
classifications:
  iuis_category:
    classification_value: immune dysregulation
    notes: >-
      IUIS 2022 phenotypic classification Table 4 (diseases of immune
      dysregulation); APS-1/APECED is a canonical immune-dysregulation IEI.
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee."
      explanation: >-
        APS-1 is classified under IUIS Table 4 (immune dysregulation) in the
        IUIS phenotypic IEI nosology.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
prevalence:
- population: General (worldwide)
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_low: 0.5
  rate_high: 1.0
  percentage: 1 in 100,000-200,000
  notes: >-
    APS-1 is very rare worldwide. Higher prevalence in genetically isolated
    populations including Finnish (1:25,000), Sardinian (1:14,400), and
    Iranian Jewish (1:9,000) communities due to founder effects.
  evidence:
  - reference: PMID:35690244
    reference_title: "Autoimmune polyendocrine syndrome type 1: Clinical manifestations, pathogenetic features, and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence rate is highest in genetically isolated populations (up to 1:6500-1:9000)."
    explanation: Review confirms high prevalence in isolated populations.
  - reference: PMID:34790633
    reference_title: "Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      highest prevalence has been reported in Finnish, Sardinian,
    explanation: >-
      Review names the Finnish and Sardinian founder populations as carrying
      the highest prevalence, supporting the founder-effect note.
  - reference: PMID:34790633
    reference_title: "Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      United States, the prevalence of APECED is estimated between
      1:100,000–1:300,000
    explanation: >-
      Supports the very low general-population prevalence outside founder
      populations.
progression:
- phase: Early childhood presentation (candidiasis and non-triad manifestations)
  age_range: Infancy to ~7 years
  notes: >-
    Chronic mucocutaneous candidiasis is typically the earliest manifestation.
    In the American NIH cohort, urticarial eruption, intestinal dysfunction, and
    enamel hypoplasia were also prominent early, often preceding any classic
    triad dyad (which was reached at a mean of 7.38 years).
  evidence:
  - reference: PMID:20123959
    reference_title: "Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED, or autoimmune polyendocrine syndrome 1), CMC is often the first sign"
    explanation: CMC is documented as frequently the first manifestation.
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Urticarial eruption, intestinal dysfunction, and enamel hypoplasia were prominent among early manifestations."
    explanation: >-
      The NIH cohort identifies the adjunct-triad manifestations as prominent
      early features of the disease course.
- phase: Childhood-adolescence accrual of endocrinopathies and organ autoimmunity
  age_range: Childhood through adulthood
  notes: >-
    Hypoparathyroidism and adrenal insufficiency typically develop during
    childhood, and organ-specific autoimmune manifestations continue to
    accumulate lifelong; most patients develop several non-triad manifestations
    before a classic diagnostic dyad is reached.
  evidence:
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eighty percent of patients developed a median of 3
      non-triad manifestations before a diagnostic dyad.
    explanation: >-
      Documents progressive accrual of manifestations preceding the classic
      diagnostic dyad.
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We found a dramatic expansion of disease manifestations, with
      23 clinical entities seen in varying frequencies (5.7%–91.4%; Figure 1A and Table 1)
    explanation: >-
      Documents the breadth of multi-organ manifestations that accumulate over
      the disease course in the NIH cohort.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    APS-1 is a lifelong multisystem autoimmune disease: NIH-cohort patients
    accumulated manifestations spanning 23 distinct clinical entities across
    endocrine and non-endocrine organs, require lifelong hormone replacement and
    multidisciplinary surveillance, and face life-threatening complications
    (hypocalcemic seizures, adrenal crises, fulminant hepatitis, and
    pneumonitis-related respiratory failure, which caused the one cohort
    death).
  evidence:
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A single 14-year-old patient in our cohort died (mortality, 2.9%) from pneumonitis-related"
    explanation: >-
      Documents disease-related mortality in the prospective cohort,
      supporting the HIGH burden level.
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Incorporation of these new manifestations into American diagnostic criteria
      would accelerate diagnosis by approximately 4 years and potentially prevent
      life-threatening endocrine complications.
    explanation: >-
      The life-threatening endocrine complications of delayed diagnosis
      (hypocalcemic seizures, adrenal crises) contribute to the HIGH burden
      assessment.
pathophysiology:
- name: AIRE Deficiency and Thymic Tolerance Failure
  description: >
    AIRE (autoimmune regulator) is a transcription factor expressed in
    medullary thymic epithelial cells (mTECs). It drives ectopic expression
    of tissue-restricted self-antigens (TRAs) in the thymus, enabling
    negative selection of autoreactive T cells. Loss-of-function mutations
    in AIRE abolish this promiscuous gene expression, allowing autoreactive
    T cells to escape thymic deletion and enter the periphery.
  cell_types:
  - preferred_term: medullary thymic epithelial cell
    term:
      id: CL:0002365
      label: medullary thymic epithelial cell
  locations:
  - preferred_term: medulla of thymus
    term:
      id: UBERON:0002124
      label: medulla of thymus
  biological_processes:
  - preferred_term: T cell negative selection
    term:
      id: GO:0043383
      label: negative T cell selection
  - preferred_term: thymic T cell selection
    term:
      id: GO:0045061
      label: thymic T cell selection
  genes:
  - preferred_term: AIRE
    term:
      id: hgnc:360
      label: AIRE
  evidence:
  - reference: PMID:12376594
    reference_title: "Projection of an immunological self shadow within the thymus by the aire protein."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Aire-deficient thymic medullary epithelial cells showed a specific reduction in ectopic transcription of genes encoding peripheral antigens."
    explanation: Seminal study demonstrating that AIRE drives ectopic expression of peripheral tissue-restricted antigens in thymic medullary epithelial cells, and that its absence causes autoimmunity.
  - reference: PMID:34790633
    reference_title: "Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AIRE deficiency impairs immune tolerance in the thymus and results in the peripheral escape of self-reactive T lymphocytes and the generation of several cytokine- and tissue antigen-targeted autoantibodies."
    explanation: Review confirms that AIRE deficiency impairs thymic tolerance and allows autoreactive T cell escape.
  downstream:
  - target: Organ-Specific Autoimmune Destruction
    description: Escaped autoreactive T cells attack multiple endocrine and non-endocrine organs.
  - target: Anti-Cytokine Autoantibody Production
    description: Failure of central tolerance leads to B cell production of anti-cytokine autoantibodies.
- name: Anti-Cytokine Autoantibody Production
  description: >
    APS-1 patients produce high-titer neutralizing autoantibodies against
    type I interferons (IFN-alpha, IFN-omega), IL-17A, IL-17F, and IL-22.
    Anti-IL-17/IL-22 antibodies impair mucocutaneous antifungal immunity,
    explaining the susceptibility to chronic mucocutaneous candidiasis.
    Anti-IFN antibodies are nearly universal and serve as a diagnostic
    biomarker.
  biological_processes:
  - preferred_term: cytokine-mediated signaling pathway
    term:
      id: GO:0019221
      label: cytokine-mediated signaling pathway
    modifier: DECREASED
  - preferred_term: defense response to fungus
    term:
      id: GO:0050832
      label: defense response to fungus
    modifier: DECREASED
  evidence:
  - reference: PMID:20123959
    reference_title: "Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC."
    explanation: Multicenter study quantifying anti-cytokine autoantibody prevalence in APS-1 patients.
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All but one patient had anti-IFN-ω autoantibodies, including 4 of 5 patients without biallelic AIRE mutations."
    explanation: NIH cohort demonstrating near-universal anti-IFN-omega autoantibodies in APS-1.
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autoantibodies against IL-22 and IL-17F , but not IL-17A, were significantly associated with the time to development of CMC"
    explanation: In the American APECED cohort, anti-IL-22 and anti-IL-17F (but not anti-IL-17A) autoantibody titers correlated with the timing of CMC onset, supporting their causal role in impaired mucocutaneous antifungal defense.
  downstream:
  - target: Chronic Mucocutaneous Candidiasis
    description: Anti-IL-17/IL-22 autoantibodies cripple Th17-mediated mucosal antifungal defense.
    causal_link_type: DIRECT
- name: Chronic Mucocutaneous Candidiasis
  description: >
    Chronic mucocutaneous candidiasis (CMC) is often the earliest
    manifestation of APS-1, typically appearing in infancy or early
    childhood. It results from neutralizing autoantibodies against IL-17A,
    IL-17F, and IL-22 that cripple Th17-mediated antifungal defense at
    mucosal surfaces. Candida albicans colonizes oral mucosa, nails, and
    skin, causing recurrent and persistent infection.
  cell_types:
  - preferred_term: T-helper 17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  biological_processes:
  - preferred_term: defense response to fungus
    term:
      id: GO:0050832
      label: defense response to fungus
    modifier: DECREASED
  evidence:
  - reference: PMID:20123959
    reference_title: "Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that IL-22 and IL-17F are key natural defenders against CMC and that the immunodeficiency underlying CMC in both patient groups has an autoimmune basis."
    explanation: Demonstrates that CMC in APS-1 is caused by autoantibodies neutralizing Th17 cytokines IL-22 and IL-17F.
- name: Organ-Specific Autoimmune Destruction
  description: >
    Autoreactive T cells that escape thymic deletion target multiple
    endocrine and non-endocrine organs. Autoimmune attack on the
    parathyroid glands causes hypoparathyroidism; destruction of the
    adrenal cortex causes Addison disease; and pancreatic beta cell
    autoimmunity can lead to type 1 diabetes. The pattern and timing of
    organ involvement is variable even within the same family, suggesting
    stochastic and environmental modifiers.
  cell_types:
  - preferred_term: CD8-positive, alpha-beta T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: T cell mediated cytotoxicity
    term:
      id: GO:0001913
      label: T cell mediated cytotoxicity
  evidence:
  - reference: PMID:35690244
    reference_title: "Autoimmune polyendocrine syndrome type 1: Clinical manifestations, pathogenetic features, and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "APS-1 is often accompanied by hypogonadism, type 1 diabetes, autoimmune thyroiditis, vitiligo, alopecia, asplenia, pneumonitis, gastritis, pernicious anemia, and intestinal dysfunction, nephritis, and hepatitis."
    explanation: Review documenting the broad spectrum of organ-specific autoimmune manifestations in APS-1.
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjögren's-like syndrome, uncommon entities in European APECED cohorts, affected 40%-80% of American cases."
    explanation: NIH cohort revealing that non-endocrine autoimmune manifestations are more common in American APS-1 patients than previously recognized.
  downstream:
  - target: Hypoparathyroidism
    causal_link_type: DIRECT
  - target: Primary Adrenal Insufficiency
    causal_link_type: DIRECT
  - target: Primary Hypogonadism
    causal_link_type: DIRECT
  - target: Type 1 Diabetes Mellitus
    causal_link_type: DIRECT
  - target: Hashimoto Thyroiditis
    causal_link_type: DIRECT
  - target: Autoimmune Hepatitis
    causal_link_type: DIRECT
  - target: Alopecia
    causal_link_type: DIRECT
  - target: Vitiligo
    causal_link_type: DIRECT
  - target: Nail Dystrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Dental Enamel Hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intestinal Malabsorption
    causal_link_type: DIRECT
  - target: Keratoconjunctivitis
    causal_link_type: DIRECT
  - target: Asplenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Urticarial Eruption
    causal_link_type: DIRECT
  - target: Pneumonitis
    causal_link_type: DIRECT
  - target: Pernicious Anemia
    causal_link_type: DIRECT
  - target: Autoimmune Gastritis
    causal_link_type: DIRECT
  - target: Growth Hormone Deficiency
    causal_link_type: DIRECT
  - target: Tubulointerstitial Nephritis
    causal_link_type: DIRECT
phenotypes:
- category: Endocrine
  name: Hypoparathyroidism
  description: >
    Autoimmune destruction of parathyroid glands leading to hypocalcemia.
    One of the classic triad components, typically presenting in childhood.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypoparathyroidism
    term:
      id: HP:0000829
      label: Hypoparathyroidism
  evidence:
  - reference: PMID:34790633
    reference_title: "Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "APECED features a classic triad of characteristic clinical manifestations consisting of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and primary adrenal insufficiency (Addison's disease)."
    explanation: Confirms hypoparathyroidism as part of the classic APECED triad.
- category: Endocrine
  name: Primary Adrenal Insufficiency
  description: >
    Autoimmune destruction of the adrenal cortex (Addison disease). Second
    most common endocrine manifestation, typically presenting in childhood
    or adolescence.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Primary adrenal insufficiency
    term:
      id: HP:0000846
      label: Adrenal insufficiency
  evidence:
  - reference: PMID:34790633
    reference_title: "Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "APECED features a classic triad of characteristic clinical manifestations consisting of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and primary adrenal insufficiency (Addison's disease)."
    explanation: Adrenal insufficiency confirmed as classic triad component.
- category: Immunological
  name: Chronic Mucocutaneous Candidiasis
  description: >
    Chronic Candida infection of oral mucosa, nails, and skin due to
    impaired Th17-mediated antifungal immunity. Often the earliest clinical
    manifestation.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Chronic mucocutaneous candidiasis
    term:
      id: HP:0002728
      label: Chronic mucocutaneous candidiasis
  evidence:
  - reference: PMID:20123959
    reference_title: "Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED, or autoimmune polyendocrine syndrome 1), CMC is often the first sign"
    explanation: Confirms CMC as frequently the first clinical manifestation of APS-1.
- category: Endocrine
  name: Primary Hypogonadism
  description: >
    Autoimmune destruction of gonadal tissue leading to primary ovarian or
    testicular failure. More common in females.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Primary hypogonadism
    term:
      id: HP:0000135
      label: Hypogonadism
  evidence:
  - reference: PMID:35690244
    reference_title: "Autoimmune polyendocrine syndrome type 1: Clinical manifestations, pathogenetic features, and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "APS-1 is often accompanied by hypogonadism, type 1 diabetes, autoimmune thyroiditis, vitiligo, alopecia, asplenia, pneumonitis, gastritis, pernicious anemia, and intestinal dysfunction, nephritis, and hepatitis."
    explanation: Review lists hypogonadism among the common APS-1 manifestations.
- category: Endocrine
  name: Type 1 Diabetes Mellitus
  description: >
    Autoimmune destruction of pancreatic beta cells causing insulin-dependent
    diabetes.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Type 1 diabetes mellitus
    term:
      id: HP:0100651
      label: Type I diabetes mellitus
  evidence:
  - reference: PMID:35690244
    reference_title: "Autoimmune polyendocrine syndrome type 1: Clinical manifestations, pathogenetic features, and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "APS-1 is often accompanied by hypogonadism, type 1 diabetes, autoimmune thyroiditis, vitiligo, alopecia, asplenia, pneumonitis, gastritis, pernicious anemia, and intestinal dysfunction, nephritis, and hepatitis."
    explanation: Type 1 diabetes listed among APS-1 manifestations.
- category: Endocrine
  name: Hashimoto Thyroiditis
  description: >
    Autoimmune thyroiditis (Hashimoto disease) leading to hypothyroidism.
    The predominant form of thyroid autoimmunity in APS-1.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hashimoto thyroiditis
    term:
      id: HP:0000872
      label: Hashimoto thyroiditis
  evidence:
  - reference: PMID:35690244
    reference_title: "Autoimmune polyendocrine syndrome type 1: Clinical manifestations, pathogenetic features, and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "APS-1 is often accompanied by hypogonadism, type 1 diabetes, autoimmune thyroiditis, vitiligo, alopecia, asplenia, pneumonitis, gastritis, pernicious anemia, and intestinal dysfunction, nephritis, and hepatitis."
    explanation: Autoimmune thyroiditis listed among APS-1 manifestations.
- category: Hepatic
  name: Autoimmune Hepatitis
  description: >
    Autoimmune inflammation of the liver, which can be severe and
    life-threatening. Requires monitoring of liver function tests.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Autoimmune hepatitis
    term:
      id: HP:0012115
      label: Hepatitis
  evidence:
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjögren's-like syndrome, uncommon entities in European APECED cohorts, affected 40%-80% of American cases."
    explanation: Hepatitis affected 40-80% of American APS-1 patients in the NIH cohort.
- category: Dermatological
  name: Alopecia
  description: >
    Autoimmune hair loss ranging from patchy alopecia areata to total
    alopecia universalis.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Alopecia
    term:
      id: HP:0001596
      label: Alopecia
  evidence:
  - reference: PMID:35690244
    reference_title: "Autoimmune polyendocrine syndrome type 1: Clinical manifestations, pathogenetic features, and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "APS-1 is often accompanied by hypogonadism, type 1 diabetes, autoimmune thyroiditis, vitiligo, alopecia, asplenia, pneumonitis, gastritis, pernicious anemia, and intestinal dysfunction, nephritis, and hepatitis."
    explanation: Alopecia listed among common APS-1 manifestations.
- category: Dermatological
  name: Vitiligo
  description: >
    Autoimmune destruction of melanocytes causing patchy depigmentation of
    the skin.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Vitiligo
    term:
      id: HP:0001045
      label: Vitiligo
  evidence:
  - reference: PMID:35690244
    reference_title: "Autoimmune polyendocrine syndrome type 1: Clinical manifestations, pathogenetic features, and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "APS-1 is often accompanied by hypogonadism, type 1 diabetes, autoimmune thyroiditis, vitiligo, alopecia, asplenia, pneumonitis, gastritis, pernicious anemia, and intestinal dysfunction, nephritis, and hepatitis."
    explanation: Vitiligo listed among APS-1 manifestations.
- category: Dermatological
  name: Nail Dystrophy
  description: >
    Dystrophic changes of fingernails and toenails, part of the ectodermal
    dystrophy component.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Nail dystrophy
    term:
      id: HP:0008404
      label: Nail dystrophy
  evidence:
  - reference: PMID:31905445
    reference_title: "A novel compound heterozygous mutation of the AIRE gene in a patient with autoimmune polyendocrine syndrome type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Various autoimmune diseases and ectodermal abnormalities are also commonly associated with the syndrome."
    explanation: Nail dystrophy is an ectodermal abnormality commonly associated with APS-1/APECED (the E and D in the acronym stand for Ectodermal Dystrophy).
- category: Dermatological
  name: Dental Enamel Hypoplasia
  description: >
    Defective enamel formation as part of the ectodermal dystrophy, leading
    to pitting and discoloration of permanent teeth.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Enamel hypoplasia
    term:
      id: HP:0006297
      label: Enamel hypoplasia
  evidence:
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Urticarial eruption, intestinal dysfunction, and enamel hypoplasia were prominent among early manifestations."
    explanation: Enamel hypoplasia identified as a prominent early manifestation in the NIH APS-1 cohort.
- category: Gastrointestinal
  name: Intestinal Malabsorption
  description: >
    Autoimmune enteropathy causing malabsorption, chronic diarrhea, and
    nutrient deficiencies.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Intestinal malabsorption
    term:
      id: HP:0002024
      label: Malabsorption
  evidence:
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjögren's-like syndrome, uncommon entities in European APECED cohorts, affected 40%-80% of American cases."
    explanation: Intestinal dysfunction is common in American APS-1 patients.
- category: Ophthalmological
  name: Keratoconjunctivitis
  description: >
    Autoimmune keratitis and conjunctivitis that can lead to corneal damage
    and vision impairment.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Keratoconjunctivitis
    term:
      id: HP:0000491
      label: Keratitis
  evidence:
  - reference: PMID:28137823
    reference_title: "Topical tacrolimus solution in autoimmune polyglandular syndrome-1-associated keratitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is a retrospective review of 10 patients with APS-1. The patients were treated with topical tacrolimus 0.01% solution"
    explanation: Clinical series of 10 APS-1 patients with keratitis requiring treatment, directly demonstrating keratitis as a recognized APS-1 manifestation.
- category: Hematological
  name: Asplenia
  description: >
    Functional asplenia due to autoimmune splenic atrophy, increasing risk
    of encapsulated bacterial infections.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Asplenia
    term:
      id: HP:0001746
      label: Asplenia
  evidence:
  - reference: PMID:35690244
    reference_title: "Autoimmune polyendocrine syndrome type 1: Clinical manifestations, pathogenetic features, and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "APS-1 is often accompanied by hypogonadism, type 1 diabetes, autoimmune thyroiditis, vitiligo, alopecia, asplenia, pneumonitis, gastritis, pernicious anemia, and intestinal dysfunction, nephritis, and hepatitis."
    explanation: Asplenia listed among APS-1 manifestations.
- category: Dermatological
  name: Urticarial Eruption
  description: >
    Periodic urticarial rash, a newly recognized non-endocrine manifestation
    that is particularly common in American APS-1 patients and often
    presents early in the disease course.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Urticaria
    term:
      id: HP:0001025
      label: Urticaria
  evidence:
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Urticarial eruption, intestinal dysfunction, and enamel hypoplasia were prominent among early manifestations."
    explanation: Urticarial eruption identified as prominent early manifestation in NIH APS-1 cohort.
- category: Pulmonary
  name: Pneumonitis
  description: >
    Autoimmune interstitial pneumonitis (bronchiolitis with lymphocytic
    infiltration) with potential for progressive lung disease and
    life-threatening respiratory failure. Autoantibodies against BPIFB1 and
    KCNRG are associated with its development.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Interstitial pneumonitis
    term:
      id: HP:0006515
      label: Interstitial pneumonitis
  evidence:
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis, and Sjögren's-like syndrome, uncommon entities in European APECED cohorts, affected 40%-80% of American cases."
    explanation: Pneumonitis is a significant non-endocrine manifestation in American APS-1 patients.
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A single 14-year-old patient in our cohort died (mortality, 2.9%) from pneumonitis-related"
    explanation: Autoimmune pneumonitis carries life-threatening potential; a cohort patient died of pneumonitis-related respiratory failure.
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BPIFB1 was highly sensitive, whereas KCNRG lacked sensitivity but was 100% specific"
    explanation: Autoantibodies against BPIFB1 and KCNRG were significantly associated with time to development of pneumonitis in the APECED cohort; BPIFB1 was a highly sensitive and KCNRG a 100%-specific serologic marker.
- category: Hematological
  name: Pernicious Anemia
  description: >
    Autoimmune destruction of gastric parietal cells leading to vitamin B12
    malabsorption and megaloblastic anemia.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Pernicious anemia
    term:
      id: HP:0001972
      label: Macrocytic anemia
  evidence:
  - reference: PMID:35690244
    reference_title: "Autoimmune polyendocrine syndrome type 1: Clinical manifestations, pathogenetic features, and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "APS-1 is often accompanied by hypogonadism, type 1 diabetes, autoimmune thyroiditis, vitiligo, alopecia, asplenia, pneumonitis, gastritis, pernicious anemia, and intestinal dysfunction, nephritis, and hepatitis."
    explanation: Pernicious anemia listed among APS-1 manifestations.
- category: Gastrointestinal
  name: Autoimmune Gastritis
  description: >
    Autoimmune (lymphocytic/atrophic) gastritis with chronic antral
    inflammation and lymphoplasmacytic infiltration of the lamina propria.
    It is the antecedent lesion to intrinsic-factor loss and vitamin B12
    deficiency (pernicious anemia) and is biopsy-proven in nearly half of
    American APECED patients.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Autoimmune gastritis
    term:
      id: HP:0005263
      label: Gastritis
  evidence:
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biopsy-proven gastritis was seen in 17 patients (48.6%)"
    explanation: Biopsy-proven autoimmune gastritis affected 48.6% of the American APECED cohort.
- category: Endocrine
  name: Growth Hormone Deficiency
  description: >
    Autoimmune destruction of pituitary somatotrophs causing growth hormone
    deficiency, a recognized but less common APS-1 endocrinopathy that
    typically presents in childhood.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Growth hormone deficiency
    term:
      id: HP:0034323
      label: Reduced circulating growth hormone concentration
  evidence:
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "growth hormone (GH) deficiency (17.1%)"
    explanation: Growth hormone deficiency affected 17.1% of the American APECED cohort.
- category: Renal
  name: Tubulointerstitial Nephritis
  description: >
    Autoimmune tubulointerstitial nephritis, an uncommon non-endocrine
    manifestation that can impair renal function.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Tubulointerstitial nephritis
    term:
      id: HP:0001970
      label: Tubulointerstitial nephritis
  evidence:
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "asplenia (8.6%), and tubulointerstitial nephritis (5.7%)"
    explanation: Tubulointerstitial nephritis affected 5.7% of the American APECED cohort.
biochemical:
- name: Anti-Interferon Autoantibodies
  notes: >
    Neutralizing autoantibodies against type I interferons (IFN-alpha,
    IFN-omega) are found in virtually all APS-1 patients and serve as
    a highly sensitive diagnostic biomarker.
  presence: Increased
  evidence:
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All but one patient had anti-IFN-ω autoantibodies, including 4 of 5 patients without biallelic AIRE mutations."
    explanation: Near-universal anti-IFN-omega autoantibodies in the NIH APS-1 cohort confirms diagnostic utility.
- name: Anti-IL-17/IL-22 Autoantibodies
  notes: >
    Neutralizing autoantibodies against IL-17A, IL-17F, and IL-22 are
    strongly associated with chronic mucocutaneous candidiasis in APS-1
    patients.
  presence: Increased
  evidence:
  - reference: PMID:20123959
    reference_title: "Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC."
    explanation: Large multicenter study quantifying anti-IL-17 and anti-IL-22 autoantibody prevalence in APS-1.
genetic:
- name: AIRE
  gene_term:
    preferred_term: AIRE
    term:
      id: hgnc:360
      label: AIRE
  association: Causal
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  variants:
  - name: R257X (c.769C>T)
    description: >
      Nonsense mutation in exon 6, the most common AIRE mutation
      worldwide and a Finnish founder mutation. Creates a premature
      stop codon truncating the protein before the second PHD domain.
  - name: R139X (c.415C>T)
    description: >
      Nonsense mutation in exon 3 common in Sardinian patients. Truncates
      the protein within the SAND domain.
  - name: 13bp deletion (c.967_979del13)
    description: >
      Frameshift deletion in exon 8, common in British and North American
      patients.
  evidence:
  - reference: PMID:9398839
    reference_title: "Positional cloning of the APECED gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two mutations, a C-->T substitution that changes the Arg 257 (CGA) to a stop codon (TGA) and an A-->G substitution that changes the Lys 83 (AAG) to a Glu codon (GAG), were found in this novel gene in Swiss and Finnish APECED patients."
    explanation: Original positional cloning paper identifying AIRE as the APECED gene with specific mutations.
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients were compound heterozygous; the most common AIRE mutation was c.967_979del13."
    explanation: NIH cohort confirms c.967_979del13 as the most common AIRE mutation in American patients.
  - reference: PMID:34790633
    reference_title: "Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      carry homozygous p.R257X, p.R139X, p.Y85C, and p.R203X
      mutations, respectively
    explanation: >-
      Review documents the population-specific founder alleles (Finnish
      p.R257X, Sardinian p.R139X, Persian Jewish p.Y85C, Sicilian p.R203X)
      behind the founder-effect epidemiology.
  - reference: PMID:35690244
    reference_title: "Autoimmune polyendocrine syndrome type 1: Clinical manifestations, pathogenetic features, and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "APS-1 occurs because of mutations in the autoimmune regulator (AIRE) gene, leading to a disrupted mechanism of normal antigen expression, the formation of abnormal clones of immune cells, and autoimmune damage to various organs."
    explanation: Review confirming AIRE mutations as causative of APS-1.
  - reference: CGGV:assertion_c8a4a9cc-050b-46dc-b24a-af6a53517274-2024-11-07T170000.000Z
    reference_title: "AIRE / autoimmune polyendocrine syndrome type 1 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "AIRE | HGNC:360 | autoimmune polyendocrine syndrome type 1 | MONDO:0009411 | AR | Definitive"
    explanation: ClinGen classifies the AIRE-autoimmune polyendocrine syndrome type 1 gene-disease relationship as definitive with autosomal recessive inheritance.
environmental:
- name: Candida albicans Exposure
  description: >
    Ubiquitous fungal exposure triggers chronic mucocutaneous candidiasis in
    the context of impaired Th17 immunity due to anti-IL-17/IL-22
    autoantibodies.
  evidence:
  - reference: PMID:34455138
    reference_title: "Candidiasis in patients with APS-1: low IL-17, high IFN-γ, or both?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chronic mucocutaneous candidiasis (CMC) is one of the earliest and most frequent clinical manifestations of autosomal recessive autoimmune polyendocrine syndrome type 1 (APS-1), a monogenic inborn error of immunity caused by deleterious variants of the autoimmune regulator (AIRE) gene."
    explanation: >-
      Establishes that candidiasis is among the earliest and most frequent
      manifestations of this syndrome, which is what makes an otherwise
      ubiquitous fungal exposure a disease-relevant one here.
  - reference: PMID:20123958
    reference_title: "Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found high titers of autoantibodies (auto-Abs) against IL-17A, IL-17F, and/or IL-22 in the sera of all 33 patients tested"
    explanation: >-
      Primary data for the host side of this entry's claim: neutralizing
      autoantibodies against IL-17A, IL-17F and IL-22 were present in every one
      of 33 patients tested, which is the impaired Th17 immunity that lets the
      exposure produce chronic infection.
diagnosis:
- name: Clinical Diagnostic Dyad (Classic Triad Criteria)
  description: >-
    Clinical diagnosis rests on developing any two of the classic triad (chronic
    mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency). In
    the American NIH cohort the dyad was reached at a mean of 7.38 years, and
    expanded criteria adding urticarial eruption, intestinal dysfunction, and
    enamel hypoplasia would accelerate diagnosis by about four years.
  evidence:
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Developing any two of these classic triad manifestations establishes the diagnosis."
    explanation: States the classic dyad-based clinical diagnostic criterion.
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Development of a classic diagnostic dyad was delayed at mean 7.38 years."
    explanation: >-
      Quantifies the diagnostic delay under classic-triad criteria, the
      motivation for the expanded criteria.
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Incorporation of these new manifestations into American diagnostic criteria
      would accelerate diagnosis by approximately 4 years and potentially prevent
      life-threatening endocrine complications.
    explanation: >-
      Supports the expanded diagnostic criteria incorporating early non-triad
      manifestations.
- name: Anti-Interferon-Omega Autoantibody Testing
  description: >-
    Neutralizing anti-IFN-omega autoantibodies are a highly sensitive and
    specific serologic marker, positive in 97% of the NIH cohort including most
    patients without detectable biallelic AIRE mutations, and are especially
    useful when sequencing is uninformative.
  evidence:
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Testing for anti–IFN-ω autoantibodies upon clinical suspicion may be helpful for diagnosis, as 97% of
      our patients had such autoantibodies, which are known to be highly prevalent and specific for APECED
    explanation: >-
      Directly supports anti-IFN-omega autoantibody testing as a diagnostic
      tool.
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All but one patient had anti-IFN-ω autoantibodies, including 4 of 5 patients without biallelic AIRE mutations."
    explanation: >-
      Shows the marker remains positive in most patients without detectable
      biallelic AIRE mutations, where sequencing alone would miss the
      diagnosis.
- name: AIRE Molecular Genetic Testing
  description: >-
    Sequencing of AIRE confirms the diagnosis and guides family counseling, but
    15-20% of patients carry large deletions, monoallelic variants, or even
    wild-type AIRE despite a clinically indistinguishable phenotype, so
    serology complements sequencing.
  evidence:
  - reference: PMID:35690244
    reference_title: "Autoimmune polyendocrine syndrome type 1: Clinical manifestations, pathogenetic features, and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of the AIRE gene is the main diagnostic method for early detection of APS-1"
    explanation: Identifies AIRE gene analysis as the main diagnostic method.
  - reference: PMID:27588307
    reference_title: "Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Between 15% and 20% of
      patients carry large AIRE deletions, heterozygous AIRE mutations, or even fully wild-type AIRE
    explanation: >-
      Documents the sequencing-negative fraction that makes serologic
      confirmation necessary.
differential_diagnoses:
- name: IPEX Syndrome (FOXP3, peripheral tolerance defect)
  description: >-
    IPEX is the key mechanistic contrast to APS-1: it is caused by FOXP3
    mutations abolishing regulatory T cell function (a PERIPHERAL-tolerance
    defect), whereas APECED is a CENTRAL (thymic) tolerance defect caused by
    AIRE mutations. IPEX is X-linked, presents in male infants with the
    enteropathy-diabetes-eczema triad, and lacks the APECED triad of
    candidiasis, hypoparathyroidism and Addison disease.
  evidence:
  - reference: PMID:19410687
    reference_title: "TH17 cells and regulatory T cells in primary immunodeficiency diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mutations in the FOXP3 gene interfere with Treg cell development and cause
      immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.
    explanation: >-
      Identifies the FOXP3/Treg (peripheral tolerance) mechanism of IPEX,
      distinguishing it from the AIRE-driven central tolerance failure of
      APS-1.
- name: Thymoma-Associated Chronic Mucocutaneous Candidiasis
  description: >-
    Thymoma patients can develop the same neutralizing anti-Th17-cytokine
    autoantibodies and chronic mucocutaneous candidiasis as APECED patients,
    without AIRE mutations; thymoma is the main acquired mimic of the
    anti-cytokine autoimmunity of APS-1.
  evidence:
  - reference: PMID:20123959
    reference_title: "Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We independently
      found autoantibodies against these Th17-produced cytokines in rare thymoma
      patients with CMC.
    explanation: >-
      Documents thymoma as an acquired phenocopy producing the same
      anti-IL-17/IL-22 autoantibodies and candidiasis.
treatments:
- name: Hormone Replacement Therapy
  description: >
    Replacement of deficient hormones is the mainstay of treatment: calcium
    and vitamin D for hypoparathyroidism, hydrocortisone and
    fludrocortisone for adrenal insufficiency, insulin for diabetes, and sex
    hormones for hypogonadism.
  treatment_term:
    preferred_term: hormone replacement therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: hydrocortisone
      term:
        id: NCIT:C555
        label: Therapeutic Hydrocortisone
    - preferred_term: fludrocortisone
      term:
        id: CHEBI:50885
        label: fludrocortisone
    - preferred_term: insulin
      term:
        id: CHEBI:5931
        label: insulin (human)
  evidence:
  - reference: PMID:31905445
    reference_title: "A novel compound heterozygous mutation of the AIRE gene in a patient with autoimmune polyendocrine syndrome type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The treatment of APS-1 includes hormone replacement and symptom control."
    explanation: Case report confirms hormone replacement as a mainstay of APS-1 treatment.
- name: Antifungal Therapy
  description: >
    Chronic or intermittent antifungal therapy (fluconazole, itraconazole)
    for management of chronic mucocutaneous candidiasis.
  treatment_term:
    preferred_term: antifungal therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: fluconazole
      term:
        id: CHEBI:46081
        label: fluconazole
  evidence:
  - reference: PMID:34790633
    reference_title: "Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute episodes of mucosal candidiasis respond well to
      induction therapy for four weeks
    explanation: >-
      Review of APECED management documents azole induction therapy for acute
      mucosal candidiasis episodes.
- name: Immunosuppressive Therapy
  description: >
    Immunosuppression (e.g., azathioprine, mycophenolate, cyclosporine) may
    be needed for severe autoimmune manifestations such as autoimmune
    hepatitis or enteropathy.
  treatment_term:
    preferred_term: immunosuppressive therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: azathioprine
      term:
        id: CHEBI:2948
        label: azathioprine
    - preferred_term: cyclosporin A
      term:
        id: CHEBI:4031
        label: cyclosporin A
  evidence:
  - reference: PMID:34790633
    reference_title: "Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      autoimmune hepatitis responds clinically and biochemically
      to immunomodulatory treatment. Azathioprine-based or
    explanation: >-
      Review documents immunomodulatory (azathioprine-based) treatment of the
      severe non-endocrine autoimmune manifestations such as autoimmune
      hepatitis.
- name: Genetic Counseling
  description: >
    Genetic counseling for family members given the autosomal recessive
    inheritance pattern. Early identification of at-risk siblings allows
    for surveillance and early intervention.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:35690244
    reference_title: "Autoimmune polyendocrine syndrome type 1: Clinical manifestations, pathogenetic features, and management approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of the AIRE gene is the main diagnostic method for early detection of APS-1 and the choice of methods for its treatment. Timely genetic counseling makes it possible to identify the disease early, prescribe appropriate treatment and prevent serious complications."
    explanation: Review highlights genetic counseling as important for early APS-1 detection.
datasets:
- accession: geo:GSE225460
  title: The Role of Interferon-γ in Autoimmune Polyendocrine Syndrome Type 1
  description: 'Background: Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood. Methods: We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues.'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 8
  publication: PMID:38810185
  notes: Identified by GEO DataSets index search for Autoimmune Polyendocrine Syndrome Type 1 (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE243061
  title: Tregs in autoimmune polyendocrine syndrome type I
  description: Autoimmune polyendocrine syndrome type 1 (APS-1) relies on failures both in central and peripheral tolerance. A decreased number of regulatory T cells (Tregs) is repeatedly reported, and Tregs based therapy could therefore be considered. We have used a single cell transcriptomic approach to characterize Tregs sorted from blood.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 8
  publication: PMID:38632993
  notes: Identified by GEO DataSets index search for Autoimmune Polyendocrine Syndrome Type 1 (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
📚

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Autoimmune Polyendocrine Syndrome Type 1. Core disease mechanisms, molecul...
Asta Scientific Corpus Retrieval 20 citations 2026-04-22T23:11:41.689310

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Autoimmune Polyendocrine Syndrome Type 1. Core disease mechanisms, molecul...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] Autoimmune polyglandular syndrome type 1 and eye damage

  • Authors: L. Khamnueva, T. Iureva, L. S. Andreeva, E. Chugunova
  • Year: 2021
  • Venue: Acta Biomedica Scientifica
  • URL: https://www.semanticscholar.org/paper/9ff5215092b3849c233dcc2d4064ad4eaa96db73
  • DOI: 10.29413/abs.2021-6.6-1.3
  • Summary: This review presents the accumulated experimental and clinical data on the development of eye damage of autoimmune nature in APS type 1, as well as the laboratory and instrumental methods used for diagnosing the disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.580) > Autoimmune polyendocrine syndrome type 1 (APS type 1) is a disease characterized by a variety of clinical manifestations resulting from the involvement of multiple endocrine and non-endocrine organs in the pathological process. APS type 1 is a rare genetically determined disease with autosomal recessive inheritance. Mutations in the autoimmune regulator gene (AIRE) lead to a disruption of the mechanism of normal antigen expression and the formation of abnormal clones of immune cells, and can cause autoimmune damage to organs. Within APS type 1, the most common disorders are primary adrenal insufficiency, hypoparathyroidism, and chronic candidiasis. Some understudied clinical manifestations of APS type 1 are autoimmune pathological processes in the eye: keratoconjunctivitis, dry eye syndrome, iridocyclitis, retinopathy, retinal detachment, and optic atrophy. This review presents the accumulated experimental and clinical data on the development of eye damage of autoimmune nature in APS type 1, as well as the laboratory and instrumental methods used for diagnosing the disease. Changes in the visual organs in combination with clinical manifestations of hypoparathyroidism, adrenal insufficiency and candidiasis should lead the clinical doctor to suspect the presence of APS type 1 and to examine the patient comprehensively. Timely genetic counselling will allow early identifi cation of the disease, timely prescription of appropriate treatment and prevention of severe complications.

[2] Diabetes and Atypical Autoimmune Polyglandular Syndrome Type 3: A Paediatric Case Report

  • Authors: I. Rutigliano, P. Maccarone, M. Sacco, D. Torres, S. Pedicelli
  • Year: 2020
  • Venue: Biomedical Journal of Scientific & Technical Research
  • URL: https://www.semanticscholar.org/paper/80dd20b7bc3b07e6545c07d3e5f2b6a243f945cf
  • DOI: 10.26717/bjstr.2020.29.004772
  • Summary: Type 1 Diabetes (T1DM) is an autoimmune disease and children affected by T1DM are at higher risk of other autoimmune diseases, including cancer and stroke.
  • Evidence snippets:
  • Snippet 1 (score: 0.543) > Type 1 Diabetes (T1DM) is an autoimmune, multifactorial, disease caused by beta cells destruction induced by immune response [1]. The pathophysiology of T1DM is still unclear but genetic predisposition is a landmark of this condition. HLA and non-HLA genes are involved in the risk of autoimmunity onset and many of these genes are shared by different autoimmune settings; thus, children affected by T1DM are at increased risk of other autoimmune comorbidities [2,3].In particular, T1DM could be part of autoimmune polyglandular syndrome cluster. > In 1980 Neufled and Blizzard proposed a classification of the autoimmune polyendocrine syndromes (APS) Table 1 [4]. These conditions are characterized by lack of self-tolerance and by induction of immune responses directed against self-structures with the coexistence, in the same patient, of more than one autoimmune disease [5]. The term polyendocrine is not completely appropriate, because several non-endocrine scenarios could be part of the clinical picture of these autoimmune syndromes [5,6]. > Here, we report the case of a girl affected by APS type 3 and the course of the different diseases' diagnosis in her young life. Treatment was started with methylprednisolone in bolus for three days at dosage of 10 mg/kg/die, followed by oral prednisone at 1 mg/kg/die for one month and then tapered in the following weeks. She had no good response with this first line therapy with persistent high proteinuria levels (703.57 mg/24 h). Second line therapy was started with cyclophosphamide at the dose of 2 mg/kg/die for three months, during corticosteroid tapering, with progressive reduction of proteinuria (402.5 mg/24 h, 242.1 mg/24 h).

[3] A novel compound heterozygous mutation of the AIRE gene in a patient with autoimmune polyendocrine syndrome type 1

  • Authors: Junghwan Suh, H. Choi, A. Kwon, H. Chae, Jin-Sung Lee et al.
  • Year: 2019
  • Venue: Annals of Pediatric Endocrinology & Metabolism
  • URL: https://www.semanticscholar.org/paper/538a1e71c9e24405c15b00133e08e9e2aa00b9b4
  • DOI: 10.6065/apem.2019.24.4.248
  • PMID: 31905445
  • PMCID: 6944864
  • Citations: 3
  • Summary: The case of a 10-year-old Korean girl with APS-1 due to a novel compound heterozygous mutation of the AIRE gene, where the main clinical manifestations were adrenal insufficiency and chronic mucocutaneous candidiasis is reported.
  • Evidence snippets:
  • Snippet 1 (score: 0.539) > Autoimmune polyendocrine syndrome type 1 (APS-1), or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare, autosomal recessive autoimmune disease caused by a mutation of the autoimmune regulator (AIRE) gene. The main symptom triad in APS-1 comprises chronic mucocutaneous candidiasis, adrenal insufficiency, and hypoparathyroidism. Various autoimmune diseases and ectodermal abnormalities are also commonly associated with the syndrome. The treatment of APS-1 includes hormone replacement and symptom control. It is important to monitor such patients for clinical manifestations of their disease through regular follow-up. We report the case of a 10-year-old Korean girl with APS-1 due to a novel compound heterozygous mutation of the AIRE gene. This patient's main clinical manifestations were adrenal insufficiency and chronic mucocutaneous candidiasis. The patient had a previously known pathogenic variant of c.1513delG (p.Ala505ProfsTer16), and a newly discovered variant of c.1360dupC (p.His454ProfsTer50).

[4] Search for Genetic Predictors of Adult Autoimmune Polyendocrine Syndrome in Monozygotic Twins

  • Authors: Marina Yukina, A. Larina, E. Vasilyev, E. Troshina, D. A. Dimitrova
  • Year: 2021
  • Venue: Clinical Medicine Insights. Endocrinology and Diabetes
  • URL: https://www.semanticscholar.org/paper/88aaac9d3e7d26c1779aef9f543110ac853421c5
  • DOI: 10.1177/11795514211009796
  • PMID: 33953634
  • PMCID: 8058797
  • Citations: 3
  • Summary: The article presents the case of isolated Addison’s disease and APS type 2 in monozygotic twins with a revealed compound heterozygosity in the candidate gene VTCN1.
  • Evidence snippets:
  • Snippet 1 (score: 0.536) > Autoimmune polyendocrine syndromes (APS) are a heterogeneous group of diseases characterized by the presence of autoimmune dysfunction of 2 or more endocrine glands and other non-endocrine organs. The components of the syndrome can manifest throughout life: in childhood—APS type 1 (the juvenile type) and in adulthood—APS type 2, 3, and 4 (the adult types). Adult types of APS are more common in clinical practice. It is a polygenic disease associated with abnormalities in genes encoding key regulatory proteins of the major histocompatibility complex (MHC). The search of for candidate genes responsible for mutations in adult APS is continuing. Genetic predisposition is insufficient for the manifestation of the APS of adults, since the penetrance of the disease, even among monozygotic twins, does not approach 100% (30–70%). The article presents the case of isolated Addison’s disease and APS type 2 in monozygotic twins with a revealed compound heterozygosity in the candidate gene VTCN1.

[5] Autoimmune polyendocrine syndrome type 2 in children: a case report and literature review

  • Authors: Yahong Liu, Fei Wang, Lijuan Zhang, Hongxia Zhang, Yanfang Zhu
  • Year: 2025
  • Venue: BMC Pediatrics
  • URL: https://www.semanticscholar.org/paper/7b92a470911f0a47c2814ef7ebdee3c459a2fb76
  • DOI: 10.1186/s12887-025-05697-3
  • PMID: 40316945
  • PMCID: 12046904
  • Citations: 3
  • Summary: This case of a 3-year-old girl diagnosed with autoimmune polyendocrine syndrome type 2 represents the youngest reported patient of APS-2 at the time of diagnosis, as well as the shortest documented interval between the onset of autoimmune disorders affecting distinct endocrine glands.
  • Evidence snippets:
  • Snippet 1 (score: 0.531) > Autoimmune polyendocrine syndrome (APS) is a clinical disorder characterized by the loss of immune tolerance, leading to dysfunction in multiple endocrine glands. According to the latest disease classification, APS is categorized into three main subtypes: APS-1, APS-2, and IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome. APS-2 is defined by the presence of at least two autoimmune endocrine disorders, such as type 1 diabetes mellitus, autoimmune thyroiditis, or Addison’s disease. APS-2 typically manifests later than APS-1, with onset most commonly occurring in early adulthood. However, pediatric cases involving a combination of autoimmune thyroid disease, type 1 diabetes mellitus, and myasthenia gravis, are extremely rare. This article reported the case of a 3-year-old girl diagnosed with autoimmune polyendocrine syndrome type 2 (APS-2). The patient initially presented with hyperthyroidism and exophthalmos and was subsequently diagnosed with type 1 diabetes mellitus and myasthenia gravis. To our knowledge, this case represents the youngest reported patient of APS-2 at the time of diagnosis, as well as the shortest documented interval between the onset of autoimmune disorders affecting distinct endocrine glands. Through a retrospective analysis, we comprehensively reviewed the phenotypic characteristics of APS-2 and explored its potential immune mechanisms. This article aims to provide clinicians with a valuable reference case to enhance early recognition and facilitate the implementation of targeted prevention and treatment strategies.

[6] Immune Checkpoint Blockade Anti–PD-L1 as a Trigger for Autoimmune Polyendocrine Syndrome

  • Authors: G. Lanzolla, A. Coppelli, M. Cosottini, S. Del Prato, C. Marcocci et al.
  • Year: 2019
  • Venue: Journal of the Endocrine Society
  • URL: https://www.semanticscholar.org/paper/a6e6815222fa063ff276df837668b4eedbcb83dd
  • DOI: 10.1210/js.2018-00366
  • PMID: 30746508
  • PMCID: 6364624
  • Citations: 51
  • Influential citations: 1
  • Summary: A link exists between HLA haplotypes, gene variants involved in immune checkpoint molecule expression, and increased susceptibility to autoimmune endocrinopathies, and additional studies are needed to identify susceptible patients and adapt therapy to each patient.
  • Evidence snippets:
  • Snippet 1 (score: 0.524) > Abstract Context The programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) pathway is a key regulator in T-cell activation and tolerance, limiting effector T-cell function in peripheral tissues. Atezolizumab, an anti–PD-L1 monoclonal antibody, is approved for treatment of some types of advanced cancer. Its main treatment-related adverse events are immune related, such as thyroid dysfunction and hypophysitis. Autoimmune endocrinopathy can occur as isolated manifestations; only a few cases of autoimmune polyendocrine syndromes have been reported thus far. Case We report a case of polyendocrine syndrome type 2, characterized by Addison disease (AD), type 1 diabetes mellitus (T1DM), accompanied by hypophysitis, in a patient treated with atezolizumab. Testing was positive for 21-hydroxylase and pituitary antibodies and negative for islet cells antibodies. HLA typing revealed DRB104 and DQB103 haplotypes, which are associated with increased susceptibility to T1DM and AD. Conclusion The type and severity of immune-related adverse events in polyendocrine syndrome type 2 are different and depend on the monoclonal antibody used. Although the numerous molecular mechanisms inducing autoimmune endocrine diseases are still unclear, a link exists between HLA haplotypes, gene variants involved in immune checkpoint molecule expression, and increased susceptibility to autoimmune endocrinopathies. Additional studies are needed to identify susceptible patients and adapt therapy to each patient.

[7] Identifying a Common Autoimmune Gene Core as a Tool for Verifying Biological Significance and Applicability of Polygenic Risk Scores

  • Authors: Victoria S Shchekina, Nikita Aleksandrovich Batashkov, A. Maznina, J. Krupinova, V. Bogdanov et al.
  • Year: 2026
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/cf658a97de9166afe9055c8c9251b46847759973
  • DOI: 10.3390/ijms27010543
  • PMID: 41516417
  • PMCID: 12786532
  • Summary: Clustering of PRS based on used genes showed that clusters of ADs remained consistent across all chosen PRS sizes, concluding that PRS size does not have an impact on biological relevance.
  • Evidence snippets:
  • Snippet 1 (score: 0.523) > Autoimmune diseases (ADs) are conditions resulting from an abnormal response of the adaptive immune system in which it mistakenly targets healthy, functional tissues of the organism as if they were foreign [1]. Over 100 types of autoimmune diseases have been identified [2]. Monogenic autoimmune diseases, such as Autoimmune polyendocrine syndrome type 1 and IPEX syndrome, result from pathogenic mutations in single genes (AIRE and FOXP3, respectively) that disrupt the function of the corresponding proteins [3]. Polygenic autoimmune diseases have several common features that are caused by a complex interplay of genetic and environmental factors [4]. These diseases arise from variations in multiple genes, often involving immune-related genes, such as the HLA region, and their onset can be influenced by multiple factors, such as gender (can be triggered during pregnancy or due to a disbalance of sex hormones) [2] and environmental triggers (infections, toxins, stress, and diet). Infections often act as triggers for autoinflammatory processes in genetically susceptible individuals through various mechanisms, such as activation of innate immune responses, molecular mimicry, and T-cell activation [5]. Despite these associations, the exact mechanisms of polygenic AD development are still unclear. Common pathophysiological mechanisms include dysregulation of the immune system, chronic inflammation, and epigenetic changes influenced by external factors. Clinically, these diseases often present with overlapping symptoms such as fatigue, joint pain, or organ-specific inflammation and progress in episodes, typically being challenging to diagnose and treat [6]. > An overlap of two or more autoimmune diseases commonly manifests in a single patient [7]. Type 1 diabetes (T1D) is commonly associated with autoimmune thyroid diseases, such as Addison's disease, celiac disease, Hashimoto's thyroiditis, and Graves' disease. Other ADs may also be associated with each other, particularly Sjögren's syndrome with systemic lupus erythematosus and systemic sclerosis [8]. These conditions co-occur in 17-30% of cases.

[8] Clinical case of demyelynating polyneuropathy of patient with autoimmune polyendocrine syndrome

  • Authors: Y. Solovyova, N. Nekrasova, A.V. Stromylo, L. V. Tykhonova
  • Year: 2024
  • Venue: Psychiatry Neurology and Medical Psychology
  • URL: https://www.semanticscholar.org/paper/90ea19335f73af7d28018ea87f743a15ab5e16ea
  • DOI: 10.26565/2312-5675-2024-25-10
  • Summary: The clinical case of autoimmune polyendocrine syndrome described in this article is very representative because of the presence of combination of immune system dysfunction and the impact of glucose toxicity phenomenon on NS.
  • Evidence snippets:
  • Snippet 1 (score: 0.517) > Background. The function of a nervous system (NS) has a strong correlation with a somatic state of each individual. Therefore, somatoneurology as a new branch of medicine appeared. Nowadays due to pathophysiological researches we possess the knowledge of mechanisms on NS damage at the background of diseases of endocrine, cardiovascular, digestive, respiratory and other systems. Nevertheless, practically all these processes are difficult to be separated in each case of illness because of the complexity of their simultaneous interaction and polymorphism of clinical symptoms. Autoimmune diseases are worth special attention due to their chameleon-like way of progressing when different organ systems get involved with new exacerbations. Moreover, the pathogenesis of NS damage at the background of autoimmunisation is not only connected with the response of nervous tissue on inflammation and demyelination, but it’s also a result of multiorgan disfunction – a consequence of their autoimmune disruption. According to the mentioned fact the clinical case of autoimmune polyendocrine syndrome described in this article is very representative because of the presence of combination of immune system dysfunction (what is a potential trigger of demyelination) and the impact of glucose toxicity phenomenon on NS (a symptom of diabetes mellitus caused by autoimmune pancreatitis). To sum up with, studying somatoneurological features of autoimmune diseases is a relevant topic for practitioners at the «century of autoimmune diseases». > Purpose – to describe the clinical case of polyneuropathy at the background of autoimmune polyendocrine syndrome. > Materials and Methods. The results of objective examination and data of instrumental and laboratory tests protocols made at «Kharkiv Regional Clinical Hospital» were used. > Results. Polyneuropathic type of nervous system damage was verified due to electroneuromyographic examination and the scale «Neuropathy Impairment Score of Lower Limbs» (NIS-LL). The efficiency of combined therapy with «Nerviplex», «Dialipon» and «Gabapentin» was demonstrated in this case. > Conclusions. Autoimmune diseases can lead to nervous tissue damage due to different pathophysiological mechanisms, including the direct impact on it with the processes of inflammation and

[9] A Rare Case of Refractory Epilepsy Associated With Brain Calcifications and Mucocutaneous Candidiasis

  • Authors: P. Dubey, P. Rao, P. Naphade
  • Year: 2025
  • Venue: Cureus
  • URL: https://www.semanticscholar.org/paper/08b2b56a78dcc35d8ca029a07e86084ba52cd5b3
  • DOI: 10.7759/cureus.83507
  • PMID: 40470404
  • PMCID: 12135895
  • Summary: A 23-year-old female with a history of abnormal body movement associated with posturing and transient loss of consciousness, along with a history of recurrent oral ulceration, itchy patches over intertriginous areas, and pigmentation of skin is presented.
  • Evidence snippets:
  • Snippet 1 (score: 0.512) > Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare and complex primary immunodeficiency disorder. The classic clinical triad of APS-1 includes chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency [1,2]. While the overall prevalence of APS-1 is estimated at 10 cases per million people, certain populations, such as Iranian Jews and Finns, exhibit higher rates [3,4,5]. Clinically, APS-1 presents with significant variability and is characterized by autoimmune dysfunction affecting both endocrine organs (including the parathyroids, adrenal glands, thyroid, gonads, and pituitary) as well as non-endocrine tissues (such as the skin, hair, liver, kidneys, lungs, eyes, and intestines [6,7]. > Autoimmune polyglandular syndrome type 1 arises from a failure in central immune tolerance, which leads to the development of autoimmunity. Since the identification of the AIRE gene, significant progress has been made in unraveling the underlying mechanisms of this condition. AIRE is predominantly expressed in medullary thymic epithelial cells and encodes a DNA-binding protein known as the autoimmune regulator. This protein plays a crucial role in promoting the expression of a wide range of tissue-specific antigens within the thymus. By exposing developing T cells to these antigens, the immune system is able to eliminate potentially self-reactive cells through negative selection. When AIRE is defective or absent, this screening process is impaired, allowing autoreactive T cells to bypass deletion and enter the peripheral circulation, where they can contribute to autoimmune disease [8].

[10] Limbal stem cell deficiency secondary to vitrectomy in the context of an autoimmune polyendocrine syndrome type

  • Authors: Francesc March de Ribot, Anna March de Ribot, J. Núñez Pérez, Joshua M. Huang, Jordan J. Huang et al.
  • Year: 2025
  • Venue: American Journal of Ophthalmology Case Reports
  • URL: https://www.semanticscholar.org/paper/75838aa2866020fd0dd5b65c8f63d07d9d37848b
  • DOI: 10.1016/j.ajoc.2025.102421
  • PMID: 40978286
  • PMCID: 12446495
  • Summary: It is proposed that surgical trauma near the limbus and damage to the corneal sub‐basal nerve plexus during vitrectomy may result in the development of limbal stem cell deficiency in a predisposed eye, as postulated in this patient with an APS.
  • Evidence snippets:
  • Snippet 1 (score: 0.511) > Autoimmune polyendocrine syndromes (APS) are a group of rare diseases characterized by immune activity against more than one endocrine organ. However, non-endocrine organs can be affected due to the loss of immunologic tolerance. APS can be differentiated as polyendocrine syndrome type 1 (APS-1), monogenic and aggressive, and polyendocrine syndrome type 2 (APS-2), polygenic and appearing later in life with more benign forms. APS may present across a broad age spectrum, from infancy to advanced age, with considerable heterogeneity in clinical manifestations and frequency. This variability is influenced by both genetic predisposition and environmental factors, often observed even among individuals within the same family. The pathogenesis is typically insidious, characterized by the presence of circulating autoantibodies and progressive lymphocytic infiltration of target tissues, which may culminate in organ dysfunction and eventual failure. 1,2 PS-1 is a rare autosomal recessive disease caused by autoimmune regulator gene (AIRE) mutations with T-cell-mediated loss of immune tolerance, presenting in some cases with autoantibodies targeting proteins with key functions in the affected endocrine organs. It is characterized by a minimum of two of three main components during infancy: chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency (Addison's disease). The two most common ocular manifestation of APS-1 include keratoconjunctivitis with dry eye and retinal degeneration. 3,4 Findings within the keratopathy phenotype may vary greatly, and are typically bilateral, ranging from a mild superficial keratitis, to epithelial ulcerations, stromal opacities, and/or severe stromal scarring. One potential complication of this may be the development of a limbal stem cell deficiency. 3,4 In contrast, the retinopathy phenotype is primarily characterized by changes to the retinal pigment epithelium (RPE).

[11] The “polyglandular crisis” behind recurrent hyponatremia: misdiagnosis of a case of autoimmune polyglandular syndrome type 2 and clinical lessons learned

  • Authors: Manli Yan, Hai Wu, Jingyu Deng, Yiting Wang, Haoyue Huang et al.
  • Year: 2026
  • Venue: Frontiers in Immunology
  • URL: https://www.semanticscholar.org/paper/963c27fccb4171b455854864bb733e0b5e3efe0c
  • DOI: 10.3389/fimmu.2026.1744295
  • PMID: 41659856
  • PMCID: 12872557
  • Summary: The case of APS type 2 (APS-2) in an adult female, characterized predominantly by emaciation, fatigue, palpitations, and notably, refractory hyponatremia is reported, highlighting the importance of dynamic monitoring of multiple glandular functions, enhancing clinicians’ recognition of this syndrome, and multidisciplinary collaboration to improve patient outcomes and reduce delays caused by misdiagnosis.
  • Evidence snippets:
  • Snippet 1 (score: 0.503) > Autoimmune polyendocrine syndrome (APS) (1) is a group of clinical syndromes caused by genetic dysfunction of the immune system, which can manifest as simultaneous or sequential dysfunction of multiple endocrine or non-endocrine glands (2). > Based on pathogenesis and clinical characteristics, APS can be classified into type 1 (APS-1), type 2 (APS-2), and IPEX syndrome (3). APS-1 is more common in children and is mainly caused by mutations in the AIRE gene (4), which lead to immune tolerance defects and abnormal clonal proliferation of immune cells. The classic triad of APS-1 includes chronic mucocutaneous candidiasis, primary adrenocortical insufficiency, and hypoparathyroidism (4,5). APS-2 occurs more frequently in adults (6) and is usually associated with certain HLA haplotypes, such as HLA-DR3 and HLA-DR4 (6). Its typical manifestations (7) include autoimmune adrenal insufficiency, autoimmune thyroid disease, and type 1 diabetes mellitus, and it may also be accompanied by various other autoimmune disorders. > The clinical manifestations of APS are highly complex and heterogeneous (8), with significant individual differences in the types of glands affected, the extent of glandular dysfunction, and the specific symptoms presented. Early-stage APS often lacks distinctive features, making misdiagnosis or missed diagnosis common and potentially leading to delays in treatment and increased healthcare costs. Here, we report a case of APS-2 admitted to Guangdong Provincial Hospital of Traditional Chinese Medicine in March 2022, in which emaciation, fatigue, and palpitations were the initial presentations, with refractory hyponatremia as a prominent feature. By reviewing the patient's repeated misdiagnoses and treatment course and analyzing relevant literature, this article aims to enhance clinical awareness of the syndrome's diversity and the importance of early recognition, thereby promoting standardized diagnosis and management.

[12] Cutaneous vasculitis in patients with autoimmune polyendocrine syndrome type 1: report of a case and brief review of the literature

  • Authors: N. Improda, D. Capalbo, E. Cirillo, Manuela Cerbone, A. Esposito et al.
  • Year: 2014
  • Venue: BMC Pediatrics
  • URL: https://www.semanticscholar.org/paper/e1f9ed511cf6e0334026ccd67b22ed4c00b21676
  • DOI: 10.1186/1471-2431-14-272
  • PMID: 25361846
  • PMCID: 4286916
  • Citations: 15
  • Summary: This case suggests that cutaneous vasculitis may represent a first sign of autoimmune polyendocrine syndrome type 1 and children presenting with unexplained vasculitic skin rash should be followed-up in order to early identify APS 1.
  • Evidence snippets:
  • Snippet 1 (score: 0.501) > Autoimmune polyendocrine syndrome type 1 (APS 1), also known as autoimmune polyendocrinopathy-candidiasisectodermal dystrophy (APECED), is a rare autosomal recessive disease caused by pathogenic variants in the autoimmune regulator (AIRE) gene. AIRE encodes for the homonymous protein, AIRE, which acts as a regulator of the process of gene transcription and is involved in the mechanisms of deletional central (and presumably peripheral) tolerance. AIRE deficiency leads to the escape and extra-thymic spreading of autoreactive T-cell clones: this creates the basis for the onset of the autoimmune attack against several tissue-specific self-antigens [1]. > The clinical diagnosis of APS 1 is defined by the presence of at least two components of the classic triad, which is given by chronic mucocutaneous candidiasis (CMC), chronic idiopathic hypoparathyroidism (HPT) and Addison disease (AD). The disease generally begins in childhood and CMC is the first component appearing by five years of age, followed by HPT and then by AD. Other endocrine and non-endocrine components, such as hypergonadotropic hypogonadism, hypothyroidism, type 1 diabetes, gastrointestinal dysfunction, autoimmune hepatitis, asplenia and various ectodermal abnormalities (interstitial keratitis, alopecia, vitiligo, nail dystrophy and dental enamel hypoplasia), may occur with a different prevalence [2][3][4][5]. In addition to ectodermal features, which are quite common features of the disease, APS 1 patients may experience other types of skin alterations. Indeed, in a restricted number of cases a maculopapular, or morbilliform, or urticaria-like skin rash, eventually accompanied by fever, splenomegaly and arthralgia, has been reported [2,3,[6][7][8][9][10][11][12][13][14][15][16

[13] Biomarkers of Mercury Exposure in the Amazon

  • Authors: Nathália Santos Serrão de Castro, M. Lima
  • Year: 2014
  • Venue: BioMed Research International
  • URL: https://www.semanticscholar.org/paper/c206729d43837c1a94bb84c81183aef7d37bc250
  • DOI: 10.1155/2014/867069
  • PMID: 24895619
  • PMCID: 4020561
  • Citations: 10
  • Summary: The general aspects involved with each biomarker that was studied in the Amazon region are introduced in order to contextualize the reader and add information about the Amazonian life style and health that may be considered for future studies.
  • Evidence snippets:
  • Snippet 1 (score: 0.492) > Autoimmune diseases (AID) comprise a class of clinical outcomes associated with an imbalance of the discrimination between self and nonself. The biological mechanisms associated with AID are poorly comprehended, but some general events can unleash the disease, such as pathogenic mechanisms, inflammation response, autophagy, and diet [29][30][31]. > Genetic predisposition can contribute to the susceptibility to developing an AID. The hereditary studies and the discoveries of the molecular basis of AID have evolved and some researchers have already associated some genetic factors, such as the autoimmune polyendocrine syndrome type 1 (APS-1) and multiple sclerosis (MS), to disease development. The development of APS1, formerly autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is attributed to the loss of function mutation and dysregulation of the AIRE gene [32][33][34]. This gene codifies an autoimmune regulator protein (AIRE), which is a transcriptional factor that controls the expression of selfantigens in the thymus [35]. Different from APS1, multiple genes have been linked with the development of MS [36]. Among them, polymorphisms in the Human Leukocyte Antigen (HLA) class II genes have been extensively investigated [37][38][39]. Exposure to sunlight coupled with the intake of vitamin D has emerged as a factor to be involved with the development of MS and the advances in neuroepigenetic studies provide new clues about the plasticity and phenotype of the disease [40][41][42][43]. In spite of the progress of immunogenetics, no single gene has been identified as the main cause of the development of an AID. It is believed that AID is a conjunction of multiple genes working simultaneously to produce autoreactivity. Moreover, environmental triggers may play an important role in AID and, in conjunction with the genetic background, may determine the disease phenotype.

[14] In Search for the Missing Link in APECED-like Conditions: Analysis of the AIRE Gene in a Series of 48 Patients

  • Authors: A. Fierabracci, E. Belcastro, Elena Carbone, Olivia Pagliarosi, A. Palma et al.
  • Year: 2022
  • Venue: Journal of Clinical Medicine
  • URL: https://www.semanticscholar.org/paper/a2740213a93d9a1254bc7f589e0b82654b97d3e5
  • DOI: 10.3390/jcm11113242
  • PMID: 35683627
  • PMCID: 9181695
  • Citations: 5
  • Summary: The results of this genetic analysis emphasize the need to look for additional genetic determinants playing in concert with AIRE polymorphisms, which will help to improve the diagnostic workup and ensure a precision medicine approach to targeted therapies in APECED-like patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.488) > Autoimmune diseases are a heterogeneous group of disorders of the immune system.Environmental factors, family history and/or genetic susceptibility underlie their etiopathogenesis [1].These disorders are due to a loss of tolerance to self-proteins or autoantigens that can be organ specific or systemic [2].Organ-specific autoimmune diseases are due to target cell destruction determined by autoreactive T lymphocytes and can cluster in the same individual revealing various preferential associations; this is the case of polyendocrine autoimmune syndrome Type I (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome (APECED)), Type II and immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome [3].Indeed, although phenotypically different and confirmed by different diagnostic procedures, autoimmune disorders can share similar immune and genetic defects, a phenomenon called 'autoimmune tautology' [2], i.e., the cooccurrence of polyautoimmunity or multiple autoimmune syndrome (MAS) and familiarity for autoimmunity [4]. > Clinical observation has further highlighted that autoimmunity can even share some common characteristics and mechanisms with other conditions that initially were considered independent polar opposites.Indeed, this was suggested by the high prevalence of autoimmune manifestations in primary immunodeficiencies (PID) and the observation that autoimmunity may even be the first manifestation [5]. > Identifying susceptibility genes for these complex phenotypes and unraveling their putative effects in their etiopathogenesis is a relevant issue.Further increased awareness and use of genetic screening of confirmatory functional studies, together with immunological markers, can lead to a precision medicine workup for early specific diagnosis in highly vulnerable patient categories [6]. > Both purely autoimmune conditions and PIDs can exhibit defects in central and peripheral tolerance influenced by mutations in genes that regulate immunological tolerance [5].

[15] A partial form of AIRE deficiency underlies a mild form of autoimmune polyendocrine syndrome type 1

  • Authors: B. Oftedal, A. Berger, Øyvind Bruserud, Yael Goldfarb, André Sulen et al.
  • Year: 2023
  • Venue: The Journal of Clinical Investigation
  • URL: https://www.semanticscholar.org/paper/58c03a4375e8b65a44eba1fe42dd4879e37565bb
  • DOI: 10.1172/JCI169704
  • PMID: 37909333
  • PMCID: 10617782
  • Citations: 6
  • Influential citations: 1
  • Summary: The data illustrate an association between AIRE activity and the severity of autoimmune disease, with implications for more common autoimmune diseases associated with AIRE variants, such as primary adrenal insufficiency, pernicious anemia, type 1 diabetes, and rheumatoid arthritis.
  • Evidence snippets:
  • Snippet 1 (score: 0.484) > Autoimmune polyendocrine syndrome type 1 (APS-1) is caused by mutations in the autoimmune regulator (AIRE) gene. Most patients present with severe chronic mucocutaneous candidiasis and organ-specific autoimmunity from early childhood, but the clinical picture is highly variable. AIRE is crucial for negative selection of T cells, and scrutiny of different patient mutations has previously highlighted many of its molecular mechanisms. In patients with a milder adult-onset phenotype sharing a mutation in the canonical donor splice site of intron 7 (c.879+1G>A), both the predicted altered splicing pattern with loss of exon 7 (AireEx7–/–) and normal full-length AIRE mRNA were found, indicating leaky rather than abolished mRNA splicing. Analysis of a corresponding mouse model demonstrated that the AireEx7–/– mutant had dramatically impaired transcriptional capacity of tissue-specific antigens in medullary thymic epithelial cells but still retained some ability to induce gene expression compared with the complete loss-of-function AireC313X–/– mutant. Our data illustrate an association between AIRE activity and the severity of autoimmune disease, with implications for more common autoimmune diseases associated with AIRE variants, such as primary adrenal insufficiency, pernicious anemia, type 1 diabetes, and rheumatoid arthritis.

[16] Late-Onset Isolated Corticotrope Deficiency in a Woman with Down Syndrome

  • Authors: I. Oueslati, M. Ben Jemaa, M. Yazidi, F. Chaker, M. Chihaoui
  • Year: 2021
  • Venue: Case Reports in Endocrinology
  • URL: https://www.semanticscholar.org/paper/9c47406f6240fdab53843aade23bbf658ae8608a
  • DOI: 10.1155/2021/5562831
  • PMID: 34007493
  • PMCID: 8100382
  • Citations: 1
  • Summary: A case of an isolated corticotrope deficiency diagnosed at the age of 33 years in a woman with Down syndrome, which may be induced by autoimmune mechanism in similar to other disorders of patients with Down syndrome is reported.
  • Evidence snippets:
  • Snippet 1 (score: 0.482) > 's disease are the commonest. ese patients are also more predisposed to develop early-onset type 1 diabetes, Addison disease, celiac disease, alopecia areata, chronic autoimmune hepatitis, and primary sclerosing cholangitis [12]. According to many authors, these patients share clinical features, such as autoimmune manifestations and specific autoantibodies, with patients suffering from autoimmune polyendocrine syndrome type 1 [13]. > is syndrome results from inactivating mutations in the autoimmune regulator (AIRE) gene, located on chromosome 21. e AIRE acts as a transcriptional regulator that promotes immunological central tolerance by inducing the ectopic thymic expression of many tissue-specific antigens [14]. Its mutations are associated with a huge spectrum of phenotypes. Two major forms were identified. e classical autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APCED) is an autosomal recessive disease defined by the presence of at least two of the major components including chronic mucocutaneous candidiasis, chronic hypoparathyroidism, and autoimmune Addison's disease [15]. e nonclassical form is caused by dominant heterozygous mutations mainly in the first plant homeodomain (PHD1) zinc finger of AIRE and is characterized by late-onset, milder phenotype, and reduced penetrance [15]. e pituitary involvement in autoimmune polyendocrine syndrome type 1 is a rare condition. Growth hormone deficiency, central diabetes insipidus, gonadotropin deficiency, and ACTH deficiency were reported. > In patients with Down syndrome, Skogberg et al. demonstrated that the AIRE gene is overexpressed, which may alter thymic selection processes and affect the susceptibility for autoimmune diseases [13]. On the contrary, other authors reported that the level of AIRE expression in the thymus of patients with Down syndrome is reduced [16,17]. > Corticotrope cells are often the first to be affected in lymphocytic hypophysitis, and adult isolated corticotrope

[17] A Functional Alternative Splicing Mutation in AIRE Gene Causes Autoimmune Polyendocrine Syndrome Type 1

  • Authors: Junyu Zhang, Hongbin Liu, Zhiyuan Liu, Y. Liao, Luo Guo et al.
  • Year: 2013
  • Venue: PLoS ONE
  • URL: https://www.semanticscholar.org/paper/de936b913b09761caa8187b66af5eaf247d4615e
  • DOI: 10.1371/journal.pone.0053981
  • PMID: 23342054
  • PMCID: 3540864
  • Citations: 30
  • Influential citations: 1
  • Summary: This study represents the first functional characterization of the alternatively spliced AIRE mutation that may explain the pathogenetic role in APS-1 and potentially compromised the recognition of the splice donor of intron 3.
  • Evidence snippets:
  • Snippet 1 (score: 0.475) > Autoimmune polyendocrine syndrome type 1 (APS-1, OMIM 240300), formerly known as Autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy (APECED), is a rare but devastating primary immunodeficiency disorder, which usually manifests during childhood and adolescence [1,2]. Clinical diagnosis for APS-1 typically requires the presence of at least two of the three hallmark conditions: chronic mucocutaneous candidiasis, hypoparathyroidism and Addison's disease [2]. Mutations in autoimmune regulator (AIRE) gene have been linked to APS-1 [3,4]. The AIRE gene encodes a 57 kDa transcription regulator of 545 amino acids involved in regulating autoimmunity by promoting the ectopic expression and presentation of tissuerestricted antigens during T-cell development in the thymus [5]. AIRE protein contains several distinct domains, such as a potential bipartite nuclear localization signals (NLS) consisting of amino acids 110-114 and 131-133, four interspersed LXXLL motifs, two plant homeodomain (PHD) fingers, caspase-recruitment domain (CARD), and SAND (named after Sp100, AIRE-1, NucP41/75, DEAF-1) domain [3,4,6,7]. Consistent with these features, the AIRE protein is localized predominantly in the nucleus, where it potentially modulates the transcription of a variety of genes by interacting with specific DNA sequences and/or acting through epigenetic mechanisms [5,6,8]. > Patients with APS-1 also routinely exhibit additional autoimmune diseases, including type 1 diabetes mellitus, hypothyroidism, vitiligo, alopecia, autoimmune hepatitis, pernicious anemia, and asplenism [9]. The range of these secondary disorders is broad and variable, affected siblings carrying the same mutations can develop divergent spectrums of autoimmune disorders [10].

[18] On type 1 diabetes mellitus pathogenesis

  • Authors: S. Paschou, N. Papadopoulou-Marketou, G. Chrousos, C. Kanaka-Gantenbein
  • Year: 2017
  • Venue: Endocrine Connections
  • URL: https://www.semanticscholar.org/paper/b5152d55833c335afe30a8dc8204f1418cbf33e8
  • DOI: 10.1530/EC-17-0347
  • PMID: 29191919
  • PMCID: 5776665
  • Citations: 198
  • Influential citations: 6
  • Summary: Genetic, environmental and immunologic factors that destroy β cells of the endocrine pancreas and lead to insulin deficiency are presented, which reflects the large percentage of β cells that need to be destroyed before overt diabetes become evident.
  • Evidence snippets:
  • Snippet 1 (score: 0.467) > Presentation of autoantigens in both the thymus and the periphery to negatively select and delete T lymphocytes that are highly reactive (central and peripheral immune tolerance, respectively) is a very important regulatory mechanism of autoimmunity. The AIRE protein (autoimmune regulator) is mainly expressed in the epithelial and dendritic cells of the thymus marrow. It is a transcription factor which controls the expression of many specific autopeptides (8). Patients with mutations in the AIRE gene, located on the long arm of the chromosome 21 (21q22.3), exhibit autoimmune polyendocrine syndrome 1 (APS 1), also known as APECED syndrome, which is the acronym of its main clinical manifestations, polyendocrine autoimmunity (Addison's disease, hypoparathyroidism, T1DM), candidiasis and ectodermal dystrophy (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy -APECED). The presence of T1DM in patients with AIRE mutations (less frequent of course than in APS 2) demonstrates that the expression and presentation of relevant autoantigens (insulin, GAD, IA-2) in the thymus are under the surveillance of this transcription factor (21,22).

[19] Autoimmunity and Genetic Syndromes: A Focus on Down Syndrome

  • Authors: M. Ferrari, S. Stagi
  • Year: 2021
  • Venue: Genes
  • URL: https://www.semanticscholar.org/paper/0796d39809e74381c0923aa4a4afa3b875e9cd84
  • DOI: 10.3390/genes12020268
  • PMID: 33668420
  • PMCID: 7918365
  • Citations: 30
  • Influential citations: 3
  • Summary: This short review aims to report the current literature regarding the genetic, immune, and environmental factors that have been proposed as the possible underlying mechanism of autoimmunity in individuals with DS, with the intent to provide insight for a comprehensive understanding of these diseases in genetic syndromes.
  • Evidence snippets:
  • Snippet 1 (score: 0.466) > Autoimmunity commonly features many well-known genetic conditions, such as Turner syndrome (TS), Trisomy 21 or Down syndrome (DS), and 22q11.2 deletion syndrome (22q11.2DS) [1]. The susceptibility toward this disorder has been recently investigated for many other genetic syndromes, such as Kabuki, Noonan, and Klinefelter [2][3][4][5]. In these patients, virtually all autoimmune disorders have been described, in particular thyroid disorders and celiac disease, in addition to alopecia, vitiligo, type 1 diabetes, juvenile idiopathic arthritis, and systemic lupus erythematosus (SLE). Several mechanisms have been attributed to the etiology of autoimmunity, including genetic or acquired defects of immune regulatory pathways, impaired apoptosis, and molecular mimicry to viral or bacterial antigens [5]. Although the exact mechanisms underlying autoimmune diseases are still elusive, it appears as though a pathogenic inflammatory response by self-antigen-specific T cells is frequently involved [1]. Given the common association between autoimmunity and chromosomal aberrations, many efforts have been made with the intent of identifying possible underlying mechanisms and perhaps also provide insights for a better understanding of other clinical aspects related to genetic syndromes. Among the many genetic alterations, DS was one of the first to be studied in relation to autoimmunity. In fact, as early as 1969, an association between DS (at the time defined as Mongolism) and autoimmune thyroiditis was observed [6]. Since that time, much progress has been made in defining Genes 2021, 12, 268 2 of 10 the main features of this syndrome and associated autoimmune complications; however, many questions still need to be answered. In this short review, we aim to report the current literature regarding mechanisms underlying autoimmunity and its main clinical outcomes, providing, where possible, recommendations for early identification, follow up, and monitoring of these disorders in DS.

[20] Autoimmune hepatitis in genetic syndromes: A literature review

  • Authors: A. Capra, E. Chiara, S. Briuglia
  • Year: 2021
  • Venue: World Journal of Hepatology
  • URL: https://www.semanticscholar.org/paper/60dffb45c6a2cec3b2a3f11536ce56f91689de36
  • DOI: 10.4254/wjh.v13.i10.1328
  • PMID: 34786169
  • PMCID: 8568577
  • Citations: 6
  • Summary: It is suggested that when a patient presents a clinical picture of cryptogenic chronic hepatitis, that is unexplained, it is useful to explore differential diagnosis of AIH associated with genetic syndrome, that could be useful for pathogenetic hypothesis and clinical approach to genetic syndrome.
  • Evidence snippets:
  • Snippet 1 (score: 0.464) > Autoimmune polyendocrinopathy syndromes: The term APS refers to a group of rare endocrine diseases characterized by autoimmune activity against more than one endocrine organ, with possible additional involvement of non-endocrine organs. > Autoimmunity is typically directed against different target antigens in different tissues. The two more common autoimmune polyendocrine syndromes, APS type 1 and type 2, have a strong genetic background and have Addison's disease as a major feature. The group furthermore includes APS type 3 and type 4. > The APS type 1 is a rare recessive autosomal disease, also named APECED syndrome (OMIM 240300), and related to AIRE gene mutations. Because of a founder effect, APECED is particularly prevalent in Finland (1:25000) but is observed worldwide with variable prevalence [15]. Diagnosis is classically based on presence of at least two out of three "majors" criterions of Whitaker's triad (chronic mucocutaneous candidiasis, autoimmune hypoparathyroidism and adrenal insufficiency or Addison disease). AIRE gene (21q22.3), coding for the AIRE transcription factor, is involved in immune tolerance mechanisms and contributes to the negative selection of autoreactive T lymphocytes in the thymus, lymph nodes and spleen. AIH and hepatitis as an APECED component may be distinguished on the basis of a different autoantibody profile. The anti-LM antibodies are specific of AIH, which develops in individuals with APECED. > The major target autoantigen of anti-LM antibodies has been documented as the CYP1A2 [8,12,14]. In the considered period, we have found four papers reporting in all six patients with APECED syndrome and AIH, that is non-endocrine complication [7,[16][17][18]. > The girl described by Huibregtse et al [7] had homozygous 967-979del13bp mutation. Meloni et al [17] described a longitudinal cohort study in which AIH was seen in 27% of their APS1 Sardinian patients.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.