Autosomal dominant hyper-IgE syndrome (AD-HIES; STAT3-HIES; Job syndrome) is a rare multisystem primary immunodeficiency caused by heterozygous dominant-negative variants in STAT3. It couples a recognizable immunologic triad (markedly elevated serum IgE, recurrent "cold" staphylococcal skin abscesses, and recurrent pneumonia with pneumatocele/bronchiectasis formation) with eosinophilia, chronic mucocutaneous candidiasis, and eczematoid dermatitis, plus non-immune connective-tissue, skeletal, dental, craniofacial, and vascular abnormalities. The mutant STAT3 monomer poisons wild-type STAT3 in the obligate dimer, reducing STAT3 transcriptional output across the IL-6/IL-11/IL-21/IL-23 cytokine network. Downstream this collapses Th17 differentiation and IL-17/IL-22 mucocutaneous antimicrobial immunity (susceptibility to Staphylococcus aureus and Candida), blunts the IL-6 acute-phase response (the "cold," under-inflamed abscesses), and disrupts STAT3-dependent bone, vascular, and craniofacial/dental programs. It is inherited in an autosomal dominant manner, most often as a de novo variant.
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Conditions with similar clinical presentations that must be differentiated from Autosomal Dominant Hyper-IgE Syndrome:
name: Autosomal Dominant Hyper-IgE Syndrome
creation_date: "2026-06-30T00:00:00Z"
category: Mendelian
synonyms:
- AD-HIES
- STAT3-HIES
- Job syndrome
- Buckley syndrome
- STAT3 hyper-IgE syndrome
- STAT3 deficiency
disease_term:
preferred_term: Autosomal Dominant Hyper-IgE Syndrome
term:
id: MONDO:0007818
label: hyper-IgE recurrent infection syndrome 1, autosomal dominant
parents:
- Primary Immunodeficiency
description: >-
Autosomal dominant hyper-IgE syndrome (AD-HIES; STAT3-HIES; Job syndrome) is a
rare multisystem primary immunodeficiency caused by heterozygous
dominant-negative variants in STAT3. It couples a recognizable immunologic
triad (markedly elevated serum IgE, recurrent "cold" staphylococcal skin
abscesses, and recurrent pneumonia with pneumatocele/bronchiectasis
formation) with eosinophilia, chronic mucocutaneous candidiasis, and
eczematoid dermatitis, plus non-immune connective-tissue, skeletal, dental,
craniofacial, and vascular abnormalities. The mutant STAT3 monomer poisons
wild-type STAT3 in the obligate dimer, reducing STAT3 transcriptional output
across the IL-6/IL-11/IL-21/IL-23 cytokine network. Downstream this collapses
Th17 differentiation and IL-17/IL-22 mucocutaneous antimicrobial immunity
(susceptibility to Staphylococcus aureus and Candida), blunts the IL-6
acute-phase response (the "cold," under-inflamed abscesses), and disrupts
STAT3-dependent bone, vascular, and craniofacial/dental programs. It is
inherited in an autosomal dominant manner, most often as a de novo variant.
classifications:
harrisons_chapter:
- classification_value: IMMUNE_RHEUMATOLOGIC
evidence:
- reference: PMID:20159255
reference_title: "Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by infections of the lung and skin, elevated serum IgE, and involvement of the soft and bony tissues."
explanation: HIES is characterized as a primary immunodeficiency, supporting placement in Harrison's immune/rheumatologic Part.
- classification_value: GENETICS_ENVIRONMENT_DISEASE
evidence:
- reference: PMID:17676033
reference_title: "Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "dominant-negative mutations in the human signal transducer and activator of transcription 3 (STAT3) gene result in the classical multisystem HIES."
explanation: AD-HIES is a Mendelian single-gene STAT3 disorder, supporting placement in Harrison's genetics Part.
iuis_category:
classification_value: combined immunodeficiency with syndromic features
evidence:
- reference: PMID:20159255
reference_title: "Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by infections of the lung and skin, elevated serum IgE, and involvement of the soft and bony tissues."
explanation: The combination of immunodeficiency with soft-tissue and bony (syndromic) involvement places AD-HIES in the IUIS "combined immunodeficiency with syndromic features" category.
prevalence:
- population: General population (birth)
notes: >-
Estimated frequency on the order of 1 in 100,000 to 1 in 1,000,000 at birth;
true prevalence may be higher given incomplete penetrance of individual
manifestations.
evidence:
- reference: PMID:34137790
reference_title: "Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance."
supports: SUPPORT
evidence_source: OTHER
snippet: "The estimated frequency of HIES is between 1 per 100,000 to 1,000,000 at birth"
explanation: Provides the estimated birth frequency of HIES.
mechanistic_hypotheses:
- hypothesis_group_id: stat3_negative_dominance
hypothesis_label: STAT3 negative dominance (dominant-negative), not haploinsufficiency
status: CANONICAL
description: >-
The unifying molecular mechanism of AD-HIES is negative dominance: the
mutant STAT3 allele encodes a full-length (or reinitiated) non-functional
protein that dimerizes with and inactivates wild-type STAT3, reducing
activity below the level expected from simple loss of one allele. This is
distinct from, and contrasted with, the older haploinsufficiency hypothesis.
evidence:
- reference: PMID:34137790
reference_title: "Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "through negative dominance rather than haploinsufficiency."
explanation: Experimental testing of all reported variants supports negative dominance as the unifying mechanism.
pathophysiology:
- name: STAT3 dominant-negative dysfunction
description: >-
Heterozygous variants (predominantly missense and small in-frame deletions
clustering in the DNA-binding and SH2 domains, but also out-of-frame
variants acting through reinitiated neoproteins) produce a STAT3 protein
that dimerizes with wild-type STAT3 and abolishes DNA binding and
transactivation. STAT3 tyrosine phosphorylation is often preserved; the
functional defect is downstream DNA binding/transcription across the entire
STAT3 cytokine network (IL-6, IL-10, IL-11, IL-21, IL-22, IL-23).
genes:
- preferred_term: STAT3
term:
id: hgnc:11364
label: STAT3
biological_processes:
- preferred_term: STAT3-dependent transcriptional output (DNA binding/transactivation)
term:
id: GO:0006357
label: regulation of transcription by RNA polymerase II
modifier: DECREASED
- preferred_term: JAK-STAT signaling
term:
id: GO:0007259
label: cell surface receptor signaling pathway via JAK-STAT
modifier: DECREASED
evidence:
- reference: PMID:17676033
reference_title: "Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "dominant-negative mutations in the human signal transducer and activator of transcription 3 (STAT3) gene result in the classical multisystem HIES."
explanation: Landmark report establishing dominant-negative STAT3 variants as the cause of classical AD-HIES.
- reference: PMID:17676033
reference_title: "Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "the DNA-binding ability of STAT3 in these cells was greatly diminished. All five mutants were non-functional by themselves and showed dominant-negative effects when co-expressed with wild-type STAT3."
explanation: Functional assays show diminished STAT3 DNA binding and dominant-negative behavior against wild-type STAT3.
- reference: PMID:34137790
reference_title: "Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "through negative dominance rather than haploinsufficiency."
explanation: Experimental testing of the full reported variant set shows negative dominance, not haploinsufficiency, is the unifying mechanism.
downstream:
- target: Impaired Th17 differentiation and IL-17/IL-22 immunity
causal_link_type: DIRECT
description: Loss of STAT3 output downstream of IL-6/IL-23 prevents RORgammat-driven Th17 development.
hypothesis_groups:
- stat3_negative_dominance
- target: Blunted IL-6 acute-phase signaling
causal_link_type: DIRECT
description: Impaired IL-6-to-STAT3 signaling underlies the under-inflamed acute-phase response.
- target: STAT3-dependent connective-tissue and skeletal program failure
causal_link_type: DIRECT
description: Loss of STAT3 in bone, vascular, and craniofacial tissue disrupts non-immune developmental and homeostatic programs.
- target: Elevated serum IgE
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- impaired STAT3-dependent IL-10/IL-21 signaling
- skewed atopic class switching
description: Disrupted STAT3 signaling skews toward IgE class switching, producing the elevated serum IgE phenotype.
- target: Eosinophilia
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- impaired STAT3-dependent cytokine signaling
description: Disrupted STAT3 signaling contributes to peripheral eosinophilia.
- name: Impaired Th17 differentiation and IL-17/IL-22 immunity
description: >-
STAT3 is required downstream of IL-6 and IL-23 for RORgammat-driven Th17
development. Loss of IL-17A/F and IL-22 removes the signals that drive
epithelial antimicrobial-peptide production and neutrophil recruitment to
skin and lung, producing the characteristic susceptibility to
Staphylococcus aureus and Candida albicans.
cell_types:
- preferred_term: T-helper 17 cell
term:
id: CL:0000899
label: T-helper 17 cell
- preferred_term: CD4-positive alpha-beta T cell
term:
id: CL:0000624
label: CD4-positive, alpha-beta T cell
- preferred_term: neutrophil
term:
id: CL:0000775
label: neutrophil
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
biological_processes:
- preferred_term: T-helper 17 cell differentiation
term:
id: GO:0072539
label: T-helper 17 cell differentiation
modifier: DECREASED
- preferred_term: interleukin-17 production
term:
id: GO:0032620
label: interleukin-17 production
modifier: DECREASED
- preferred_term: defense response to bacterium
term:
id: GO:0042742
label: defense response to bacterium
modifier: DECREASED
- preferred_term: defense response to fungus
term:
id: GO:0050832
label: defense response to fungus
modifier: DECREASED
evidence:
- reference: PMID:18337720
reference_title: "Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Purified naive T cells were unable to differentiate into IL-17-producing (T(H)17) T helper cells in vitro and had lower expression of retinoid-related orphan receptor (ROR)-gammat, which is consistent with a crucial role for STAT3 signalling in the generation of T(H)17 cells."
explanation: Patient naive T cells fail Th17 differentiation with reduced RORgammat, mechanistically linking STAT3 loss to Th17 collapse.
- reference: PMID:18337720
reference_title: "Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "T(H)17 cells have emerged as an important subset of helper T cells that are believed to be critical in the clearance of fungal and extracellular bacterial infections. Thus, our data suggest that the inability to produce T(H)17 cells is a mechanism underlying the susceptibility to the recurrent infections commonly seen in HIES."
explanation: Directly links the Th17 defect to the antibacterial/antifungal susceptibility of AD-HIES.
downstream:
- target: Recurrent cutaneous abscesses
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- loss of IL-17/IL-22-driven skin antimicrobial defense
description: Impaired mucocutaneous antibacterial immunity produces recurrent staphylococcal skin abscesses.
- target: Chronic mucocutaneous candidiasis
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- loss of IL-17-dependent antifungal mucosal defense
description: Th17/IL-17 deficiency impairs control of Candida at skin and mucosal surfaces.
- target: Recurrent pneumonia
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- impaired pulmonary antibacterial defense
description: Defective mucosal antibacterial immunity predisposes to recurrent bacterial pneumonia.
- name: Blunted IL-6 acute-phase signaling
description: >-
Impaired IL-6-to-STAT3 signaling produces a reduced systemic inflammatory
response despite deep infection, which is the basis for the characteristic
"cold," under-inflamed staphylococcal abscesses, and contributes to
defective antibody responses.
biological_processes:
- preferred_term: interleukin-6-mediated signaling pathway
term:
id: GO:0070102
label: interleukin-6-mediated signaling pathway
modifier: DECREASED
- preferred_term: acute-phase response
term:
id: GO:0006953
label: acute-phase response
modifier: DECREASED
evidence:
- reference: PMID:17881745
reference_title: "STAT3 mutations in the hyper-IgE syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the cells from patients with the hyper-IgE syndrome generated lower levels of monocyte chemoattractant protein 1 in response to the presence of interleukin-6 (P=0.03), suggesting a defect in interleukin-6 signaling through its downstream mediators, one of which is STAT3."
explanation: Patient cells show defective IL-6 signaling responses, the functional clue that implicated STAT3.
- name: STAT3-dependent connective-tissue and skeletal program failure
description: >-
Because STAT3 transduces IL-11, leptin, and growth-factor signals in bone,
vasculature, and craniofacial tissue, dominant-negative STAT3 disrupts
non-immune programs. STAT3 normally restrains osteoclastogenesis; its loss
increases osteoclast activity, producing osteopenia and fractures. Impaired
IL-11/STAT3 signaling links to craniosynostosis and delayed exfoliation of
deciduous teeth, and vascular STAT3 deficiency contributes to arterial
tortuosity, ectasia, and aneurysm.
cell_types:
- preferred_term: osteoclast
term:
id: CL:0000092
label: osteoclast
- preferred_term: endothelial cell
term:
id: CL:0000115
label: endothelial cell
biological_processes:
- preferred_term: osteoclast differentiation
term:
id: GO:0030316
label: osteoclast differentiation
modifier: INCREASED
evidence:
- reference: PMID:15694417
reference_title: "Osteoporosis with increased osteoclastogenesis in hematopoietic cell-specific STAT3-deficient mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "STAT3 mutant mice exhibit decreased bone density, bone volume, and increased numbers of TRAP-positive OC."
explanation: Mouse hematopoietic STAT3 deletion increases osteoclastogenesis and reduces bone density, modeling the AD-HIES bone phenotype.
downstream:
- target: Osteopenia
causal_link_type: DIRECT
description: Increased osteoclastic bone resorption from STAT3 loss reduces bone density.
- target: Recurrent fractures
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
intermediate_mechanisms:
- reduced bone density
description: Low bone density predisposes to minimal-trauma fractures.
- target: Arterial tortuosity and aneurysm
causal_link_type: DIRECT
description: STAT3-dependent vascular maintenance failure contributes to arterial tortuosity, ectasia, and aneurysm.
phenotypes:
- name: Elevated serum IgE
category: Immunologic
frequency: VERY_FREQUENT
description: >-
Markedly elevated serum IgE, typically exceeding 2000 IU/mL (often far
higher), is the defining laboratory hallmark; levels may decline with age in
a minority of adults.
phenotype_term:
preferred_term: Elevated serum IgE
term:
id: HP:0003212
label: Increased circulating IgE concentration
evidence:
- reference: PMID:22751495
reference_title: "Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The immunologic phenotype was characterized by high serum IgE levels (96% of the patients)"
explanation: French national cohort documents elevated serum IgE in 96% of STAT3-deficient patients.
- name: Eosinophilia
category: Immunologic
frequency: VERY_FREQUENT
description: >-
Peripheral blood eosinophilia is highly frequent and accompanies the high
serum IgE.
phenotype_term:
preferred_term: Eosinophilia
term:
id: HP:0001880
label: Increased total eosinophil count
evidence:
- reference: PMID:22751495
reference_title: "Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%)."
explanation: French cohort reports hypereosinophilia in 80% of patients.
- name: Recurrent cutaneous abscesses
category: Immunologic
frequency: VERY_FREQUENT
description: >-
Recurrent staphylococcal skin abscesses, characteristically "cold"
abscesses with disproportionately mild local inflammation, are a cardinal
feature.
phenotype_term:
preferred_term: Recurrent cutaneous abscess
term:
id: HP:0100838
label: Recurrent cutaneous abscess formation
evidence:
- reference: PMID:17676033
reference_title: "Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "characterized by a highly elevated serum IgE, recurrent staphylococcal skin abscesses and cyst-forming pneumonia, with disproportionately milder inflammatory responses, referred to as cold abscesses"
explanation: Defines recurrent staphylococcal "cold" skin abscesses as a hallmark of HIES.
- name: Recurrent pneumonia
category: Respiratory
frequency: VERY_FREQUENT
description: >-
Recurrent bacterial pneumonia (S. aureus, S. pneumoniae, H. influenzae)
begins in the first years of life; aberrant healing produces pneumatoceles
and bronchiectasis.
phenotype_term:
preferred_term: Recurrent pneumonia
term:
id: HP:0006532
label: Recurrent pneumonia
evidence:
- reference: PMID:22751495
reference_title: "Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%)."
explanation: French cohort documents pneumonia in up to 90% of patients.
- name: Pulmonary pneumatocele
category: Respiratory
frequency: FREQUENT
description: >-
Pneumatoceles result from aberrant healing of recurrent pneumonias and
become niches for Aspergillus, Pseudomonas, and non-tuberculous
mycobacteria, a major source of late mortality.
phenotype_term:
preferred_term: Pneumatocele
term:
id: HP:0025419
label: Pulmonary pneumatocele
evidence:
- reference: PMID:22751495
reference_title: "Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Lung sequelae were reported in 67% (40/60) of patients, taking the form of bronchiectasis in 65% (39/60) of patients or pneumatocele in 52% (31/60) of patients"
explanation: French cohort quantifies pneumatocele as a lung sequela in 52% of patients.
- name: Bronchiectasis
category: Respiratory
frequency: FREQUENT
description: >-
Progressive airway remodeling with bronchiectasis is a major long-term
consequence of recurrent pneumonia and chronic airway injury.
phenotype_term:
preferred_term: Bronchiectasis
term:
id: HP:0002110
label: Bronchiectasis
evidence:
- reference: PMID:22751495
reference_title: "Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Lung sequelae were reported in 67% (40/60) of patients, taking the form of bronchiectasis in 65% (39/60) of patients or pneumatocele in 52% (31/60) of patients"
explanation: French cohort quantifies bronchiectasis as a lung sequela in 65% of patients.
- name: Chronic mucocutaneous candidiasis
category: Immunologic
frequency: VERY_FREQUENT
description: >-
Chronic Candida infection of nails, oral, and mucosal surfaces reflects the
loss of IL-17-dependent antifungal immunity.
phenotype_term:
preferred_term: Chronic mucocutaneous candidiasis
term:
id: HP:0002728
label: Chronic mucocutaneous candidiasis
evidence:
- reference: PMID:22751495
reference_title: "Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%)."
explanation: French cohort documents Candida albicans mucocutaneous infection in 85% of patients.
- name: Eczematoid dermatitis
category: Dermatologic
frequency: VERY_FREQUENT
description: >-
A newborn-period rash (often diagnosed as eosinophilic pustulosis) evolves
into an eczematoid dermatitis and is frequently the first manifestation,
within weeks of life.
phenotype_term:
preferred_term: Eczematoid dermatitis
term:
id: HP:0000964
label: Eczematoid dermatitis
evidence:
- reference: PMID:22751495
reference_title: "Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Up to 92% of the patients had dermatitis and connective"
explanation: French cohort documents dermatitis in up to 92% of patients.
- name: Coarse facial features
category: Craniofacial
frequency: VERY_FREQUENT
description: >-
A characteristic facial appearance (prominent forehead, deep-set eyes,
broad nasal bridge, fleshy nasal tip, coarse skin with prominent pores,
prognathism) typically emerges by adolescence.
phenotype_term:
preferred_term: Coarse facial features
term:
id: HP:0000280
label: Coarse facial features
evidence:
- reference: PMID:10053178
reference_title: "Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Nonimmunologic features of the hyper-IgE syndrome were present in all patients older than eight years."
explanation: The defining cohort study established that the nonimmune (including characteristic facial) features are essentially universal in older patients.
- name: Persistence of primary teeth
category: Dental
frequency: FREQUENT
description: >-
Failure or delay of shedding of the primary (deciduous) teeth, owing to
lack of root resorption, is a characteristic dental feature.
phenotype_term:
preferred_term: Retained primary (deciduous) teeth
term:
id: HP:0006335
label: Persistence of primary teeth
evidence:
- reference: PMID:10053178
reference_title: "Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Seventy-two percent had the previously unrecognized feature of failure or delay of shedding of the primary teeth owing to lack of root resorption."
explanation: Defining cohort study quantifies retained primary teeth at 72%.
- name: Joint hypermobility
category: Musculoskeletal
frequency: FREQUENT
description: >-
Hyperextensible joints are a common non-immune connective-tissue feature.
phenotype_term:
preferred_term: Hyperextensible joints
term:
id: HP:0001382
label: Joint hypermobility
evidence:
- reference: PMID:10053178
reference_title: "Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Common findings among patients were recurrent fractures (in 57 percent of patients), hyperextensible joints (in 68 percent)"
explanation: Defining cohort study quantifies hyperextensible joints at 68%.
- name: Recurrent fractures
category: Musculoskeletal
frequency: FREQUENT
description: >-
Minimal-trauma and recurrent fractures occur on a background of low bone
density from increased STAT3-deficient osteoclastogenesis.
phenotype_term:
preferred_term: Recurrent fractures
term:
id: HP:0002757
label: Recurrent fractures
evidence:
- reference: PMID:10053178
reference_title: "Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Common findings among patients were recurrent fractures (in 57 percent of patients)"
explanation: Defining cohort study quantifies recurrent fractures at 57%.
- name: Osteopenia
category: Musculoskeletal
frequency: FREQUENT
description: >-
Reduced bone density reflects increased osteoclastic bone resorption when
STAT3 restraint of osteoclastogenesis is lost.
phenotype_term:
preferred_term: Osteopenia
term:
id: HP:0000938
label: Osteopenia
evidence:
- reference: PMID:22751495
reference_title: "Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "(65%), osteopenia (50%), and hyperextensibility (50%)."
explanation: French cohort documents osteopenia in 50% of patients.
- name: Scoliosis
category: Musculoskeletal
frequency: FREQUENT
description: >-
Scoliosis is a frequent skeletal manifestation that emerges and progresses
through adolescence.
phenotype_term:
preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
evidence:
- reference: PMID:10053178
reference_title: "Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "scoliosis (in 76 percent of patients 16 years of age or older)."
explanation: Defining cohort study quantifies scoliosis at 76% of patients aged 16 or older.
- name: Craniosynostosis
category: Craniofacial
frequency: VERY_RARE
description: >-
Premature cranial suture fusion occurs in a subset of patients, linked to
impaired IL-11/STAT3 signaling.
phenotype_term:
preferred_term: Craniosynostosis
term:
id: HP:0001363
label: Craniosynostosis
evidence:
- reference: PMID:22751495
reference_title: "Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "additional features, including facial dysmorphism, impaired shedding of deciduous teeth, bone abnormalities (osteopenia), craniosynostosis, and hyperextensibility."
explanation: French survey lists craniosynostosis among the non-immune skeletal features of AD-HIES.
- reference: PMID:22751495
reference_title: "Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "craniosynostosis (n = 2), retracted tendons (n = 2), spondylolisthesis L5-S1 (n = 1), and spina bifida occulta (n = 1)"
explanation: French cohort reports craniosynostosis in 2 of 60 patients (~3%), supporting a VERY_RARE frequency band.
- name: Arterial tortuosity and aneurysm
category: Cardiovascular
frequency: FREQUENT
description: >-
A widespread, prognostically important vasculopathy comprising arterial
tortuosity, ectasia, and aneurysm of coronary, cerebral, and other
medium-sized arteries, with risk of myocardial infarction, stroke, and
subarachnoid hemorrhage even in young, non-atherosclerotic patients.
phenotype_term:
preferred_term: Arterial tortuosity
term:
id: HP:0005116
label: Arterial tortuosity
evidence:
- reference: PMID:22084479
reference_title: "Frequent and widespread vascular abnormalities in human signal transducer and activator of transcription 3 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We reported peripheral and brain artery abnormalities in 84% of the patients and detected coronary artery abnormalities in 50% of the patients. The most frequent vascular abnormalities were ectasia and aneurysm."
explanation: Prospective vascular imaging study documents frequent and widespread arterial abnormalities (ectasia, aneurysm, tortuosity).
- name: Coronary artery aneurysm
category: Cardiovascular
frequency: FREQUENT
description: >-
Coronary artery abnormalities, including aneurysm and ectasia, are detected
in about half of adult STAT3-deficient patients on dedicated imaging.
phenotype_term:
preferred_term: Coronary artery aneurysm
term:
id: HP:0030882
label: Coronary artery aneurysm
evidence:
- reference: PMID:22084479
reference_title: "Frequent and widespread vascular abnormalities in human signal transducer and activator of transcription 3 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "detected coronary artery abnormalities in 50% of the patients. The most frequent vascular abnormalities were ectasia and aneurysm."
explanation: Prospective imaging documents coronary artery abnormalities including aneurysm in 50% of adult patients.
- name: Lymphoma
category: Oncologic
frequency: OCCASIONAL
description: >-
Lymphomas, chiefly non-Hodgkin lymphoma (some EBV-associated), occur at
increased frequency and warrant surveillance.
phenotype_term:
preferred_term: Lymphoma
term:
id: HP:0002665
label: Lymphoma
evidence:
- reference: PMID:22751495
reference_title: "Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Four patients developed non-Hodgkin lymphoma."
explanation: French cohort reports non-Hodgkin lymphoma in 4 of 60 patients (~7%), supporting an OCCASIONAL frequency band.
- name: Gastroesophageal reflux disease
category: Gastrointestinal
description: >-
Gastroesophageal reflux disease is among the recognized gastrointestinal
manifestations of STAT3-HIES.
phenotype_term:
preferred_term: Gastroesophageal reflux
term:
id: HP:0002020
label: Gastroesophageal reflux
evidence:
- reference: PMID:20301786
reference_title: "STAT3 Hyper IgE Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "Gastrointestinal (GI) manifestations include gastroesophageal reflux disease, esophageal dysmotility, and spontaneous intestinal perforations"
explanation: GeneReviews lists gastroesophageal reflux disease among the GI manifestations of STAT3-HIES.
- name: Esophageal dysmotility
category: Gastrointestinal
description: >-
Esophageal dysmotility (with dysphagia) is a recognized gastrointestinal
manifestation of STAT3-HIES.
phenotype_term:
preferred_term: Esophageal dysmotility
term:
id: HP:0002015
label: Dysphagia
evidence:
- reference: PMID:20301786
reference_title: "STAT3 Hyper IgE Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "Gastrointestinal (GI) manifestations include gastroesophageal reflux disease, esophageal dysmotility, and spontaneous intestinal perforations"
explanation: GeneReviews lists esophageal dysmotility among the GI manifestations of STAT3-HIES.
inheritance:
- name: Autosomal dominant
description: >-
AD-HIES is inherited in an autosomal dominant manner with essentially
complete penetrance and variable expressivity; the majority of cases arise
from a de novo pathogenic STAT3 variant.
evidence:
- reference: PMID:10053178
reference_title: "Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Autosomal dominant transmission of the hyper-IgE syndrome was found, but with variable expressivity."
explanation: Defining cohort study established autosomal dominant transmission with variable expressivity.
biochemical:
- name: Markedly elevated serum IgE
presence: Abnormal
context: >-
Serum IgE is markedly elevated, typically >2000 IU/mL and historically
often far higher; levels may decline toward normal in a minority of adults
over time, so a normal adult IgE does not exclude the diagnosis.
evidence:
- reference: PMID:10053178
reference_title: "Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In 6 of 23 adults (26 percent), IgE levels declined over time and came closer to or fell within the normal range."
explanation: Documents the age-related decline of serum IgE in a subset of adults.
- name: Peripheral eosinophilia
presence: Abnormal
context: >-
Peripheral blood eosinophilia accompanies the elevated IgE in the large
majority of patients.
evidence:
- reference: PMID:22751495
reference_title: "Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%)."
explanation: French cohort documents hypereosinophilia in 80% of patients.
- name: Reduced Th17 (IL-17-producing CD4+) cells
presence: Abnormal
context: >-
Profoundly reduced circulating Th17 (IL-17-producing CD4+) cells are a
strong functional discriminator of STAT3-mutated HIES.
evidence:
- reference: PMID:20159255
reference_title: "Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "T(H)17 cells were profoundly reduced in patients harboring STAT3 mutations"
explanation: Diagnostic-guideline study shows profoundly reduced Th17 cells in STAT3-mutated patients.
genetic:
- name: STAT3
association: Causative
gene_term:
preferred_term: STAT3
term:
id: hgnc:11364
label: STAT3
notes: >-
Heterozygous dominant-negative variants in STAT3 (17q21.2) cause AD-HIES,
predominantly missense substitutions and small in-frame deletions
clustering in the DNA-binding and SH2 domains, but also out-of-frame
variants that act through reinitiated truncated neoproteins. The unifying
mechanism is negative dominance rather than haploinsufficiency. Variants are
essentially absent from population databases and are most often de novo.
STAT3 dominant-negative loss-of-function is mechanistically opposite to
STAT3 gain-of-function, which causes a distinct early-onset
autoimmunity/lymphoproliferation syndrome.
evidence:
- reference: PMID:17881745
reference_title: "STAT3 mutations in the hyper-IgE syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified missense mutations and single-codon in-frame deletions in STAT3 in 50 familial and sporadic cases of the hyper-IgE syndrome."
explanation: Identifies STAT3 missense and in-frame deletion variants as causative across familial and sporadic HIES.
- reference: PMID:34137790
reference_title: "Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "the 135 in-frame variants (95%) were also DN."
explanation: Experimental testing shows 95% of in-frame STAT3 variants act by dominant negativity.
treatments:
- name: Anti-staphylococcal prophylactic antibiotics
description: >-
The mainstay of management is prevention of staphylococcal abscesses and
pneumonias with prophylactic anti-staphylococcal antibiotics
(trimethoprim-sulfamethoxazole is standard) plus early aggressive treatment
of infections. Practical caution: trimethoprim-sulfamethoxazole
hypersensitivity is a recognized adverse-reaction risk.
treatment_term:
preferred_term: Antibiotic prophylaxis
term:
id: NCIT:C15620
label: Antibiotic Therapy
therapeutic_agent:
- preferred_term: trimethoprim
term:
id: CHEBI:45924
label: trimethoprim
- preferred_term: sulfamethoxazole
term:
id: CHEBI:9332
label: sulfamethoxazole
target_phenotypes:
- preferred_term: Recurrent cutaneous abscess
term:
id: HP:0100838
label: Recurrent cutaneous abscess formation
target_mechanisms:
- target: Impaired Th17 differentiation and IL-17/IL-22 immunity
treatment_effect: BYPASSES
description: Prophylactic antibiotics control staphylococcal infection that the impaired Th17/IL-17 mucocutaneous defense fails to clear.
evidence:
- reference: PMID:20301786
reference_title: "STAT3 Hyper IgE Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "The mainstay of treatment is prevention of staphylococcal abscesses and pneumonias with anti-staphylococcal prophylactic antibiotics as well as early aggressive treatment of infections."
explanation: GeneReviews identifies anti-staphylococcal prophylactic antibiotics as the mainstay of STAT3-HIES management.
- reference: PMID:22751495
reference_title: "Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Antibiotic prophylaxis (90% of patients),"
explanation: French cohort confirms antibiotic prophylaxis as standard management, used in 90% of patients.
- name: Antifungal prophylaxis and therapy
description: >-
Antifungal agents (e.g., fluconazole for Candida; itraconazole for
Aspergillus colonizing pneumatoceles and for chronic mucocutaneous
candidiasis) are used for prophylaxis and treatment. Note azole-drug
CYP3A4 interactions in practice.
treatment_term:
preferred_term: Antifungal pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: fluconazole
term:
id: CHEBI:46081
label: fluconazole
- preferred_term: itraconazole
term:
id: CHEBI:6076
label: itraconazole
target_phenotypes:
- preferred_term: Chronic mucocutaneous candidiasis
term:
id: HP:0002728
label: Chronic mucocutaneous candidiasis
target_mechanisms:
- target: Impaired Th17 differentiation and IL-17/IL-22 immunity
treatment_effect: BYPASSES
description: Antifungal agents control Candida and Aspergillus that the impaired IL-17 antifungal defense fails to clear.
evidence:
- reference: PMID:22751495
reference_title: "Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French national survey."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%)."
explanation: High Candida burden establishes the rationale for antifungal prophylaxis/therapy in AD-HIES.
- name: Skin antiseptic care
description: >-
Antiseptic skin therapies such as dilute bleach (sodium hypochlorite)
baths and chlorhexidine, with histamine-1 antagonists to control pruritus,
reduce staphylococcal skin disease and eczema burden.
treatment_term:
preferred_term: Supportive care
term:
id: MAXO:0000950
label: supportive care
target_phenotypes:
- preferred_term: Eczematoid dermatitis
term:
id: HP:0000964
label: Eczematoid dermatitis
evidence:
- reference: PMID:20301786
reference_title: "STAT3 Hyper IgE Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "Antiseptic therapies for the skin such as dilute bleach baths and chlorhexidine are beneficial."
explanation: GeneReviews directly supports dilute bleach baths and chlorhexidine antiseptic skin therapy as beneficial in STAT3-HIES.
- name: Allogeneic hematopoietic stem cell transplantation
description: >-
Allogeneic HSCT is increasingly used and is the only therapy that corrects
the immune phenotype (abolishing infections and abscesses and stabilizing
lung disease). Important nuance: HSCT does NOT reverse established
non-immune features (skeletal, dental, connective-tissue), and its effect on
the vasculopathy is uncertain.
treatment_term:
preferred_term: Hematopoietic stem cell transplantation
term:
id: MAXO:0000747
label: hematopoietic stem cell transplantation
target_mechanisms:
- target: Impaired Th17 differentiation and IL-17/IL-22 immunity
treatment_effect: RESTORES
description: HSCT replaces the affected hematopoietic compartment, restoring STAT3-competent immune cells and the Th17/IL-17 defense.
evidence:
- reference: PMID:20301786
reference_title: "STAT3 Hyper IgE Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "The role of hematopoietic cell transplantation (HSCT) in STAT3-HIES is emerging; while successful transplant recipients have improved infection phenotype, the effect of HSCT on the nonimmunologic aspects of the disease remains unclear."
explanation: GeneReviews supports HSCT as an emerging therapy that improves the infection phenotype while leaving the nonimmunologic features unresolved.
- name: Genetic counseling
description: >-
Genetic counseling addresses the autosomal dominant inheritance (50%
transmission risk per offspring of an affected individual; most cases de
novo) and reproductive options including prenatal and preimplantation
genetic testing once the familial STAT3 variant is known.
treatment_term:
preferred_term: Genetic counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:20301786
reference_title: "STAT3 Hyper IgE Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "Each child of an individual with STAT3-HIES has a 50% chance of inheriting the pathogenic variant."
explanation: GeneReviews provides the autosomal dominant recurrence risk (50% per child) that genetic counseling communicates.
- reference: PMID:10053178
reference_title: "Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Autosomal dominant transmission of the hyper-IgE syndrome was found, but with variable expressivity."
explanation: Autosomal dominant transmission with variable expressivity is the basis for genetic counseling.
diagnosis:
- name: STAT3 molecular genetic testing
description: >-
Definitive diagnosis is established by identifying a heterozygous
dominant-negative pathogenic variant in STAT3, by single-gene sequencing,
an HIES/PID gene panel (to also cover DOCK8, PGM3, ZNF341, IL6ST/IL6R), or
exome/genome sequencing.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: MAXO:0000533
label: molecular genetic testing
results: Heterozygous dominant-negative pathogenic STAT3 variant
evidence:
- reference: PMID:20301786
reference_title: "STAT3 Hyper IgE Syndrome."
supports: SUPPORT
evidence_source: OTHER
snippet: "The diagnosis of STAT3-HIES is established in a proband with typical clinical findings and a heterozygous dominant-negative pathogenic variant in STAT3 identified by molecular genetic testing."
explanation: GeneReviews states that molecular identification of a heterozygous dominant-negative STAT3 variant establishes the diagnosis.
- reference: PMID:17676033
reference_title: "Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "dominant-negative mutations in the human signal transducer and activator of transcription 3 (STAT3) gene result in the classical multisystem HIES."
explanation: Identification of a dominant-negative STAT3 variant establishes the molecular diagnosis.
- name: NIH HIES clinical scoring and Th17 enumeration
description: >-
A combination of clinical features (the NIH HIES score) together with
enumeration of Th17 cells discriminates STAT3-mutated from STAT3-wild-type
patients; profoundly reduced Th17 cells strongly support the diagnosis.
diagnosis_term:
preferred_term: Th17 cell flow cytometry
term:
id: MAXO:0035055
label: flow cytometry procedure
results: Profoundly reduced IL-17-producing CD4+ (Th17) cells; high NIH HIES clinical score
evidence:
- reference: PMID:20159255
reference_title: "Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A combination of 5 clinical features predicted STAT3 mutations with 85% accuracy. T(H)17 cells were profoundly reduced in patients harboring STAT3 mutations"
explanation: Establishes the combined clinical-plus-Th17 diagnostic approach for STAT3-mutated HIES.
- name: Thoracic and vascular imaging
description: >-
Chest CT detects pneumatoceles and bronchiectasis; coronary and cerebral
vascular imaging is recommended for aneurysm surveillance (per GeneReviews,
every ~3 years in adults).
diagnosis_term:
preferred_term: computed tomography
term:
id: MAXO:0000571
label: computed tomography procedure
results: Pneumatoceles/bronchiectasis on chest CT; arterial ectasia/aneurysm on vascular imaging
evidence:
- reference: PMID:22084479
reference_title: "Frequent and widespread vascular abnormalities in human signal transducer and activator of transcription 3 deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We explored the entire arterial vasculature with whole-body magnetic resonance imaging angiography, coronary multislice computed tomography"
explanation: Establishes vascular imaging as the means of detecting the AD-HIES vasculopathy.
differential_diagnoses:
- name: DOCK8 deficiency (autosomal recessive HIES)
description: >-
AR-HIES from biallelic DOCK8 loss-of-function shares high IgE and eczema
but is distinguished by severe cutaneous viral infections (HSV, HPV,
molluscum), allergies, and early malignancy, and notably LACKS the
connective-tissue, skeletal, retained-teeth, and vascular features of
STAT3-HIES.
evidence:
- reference: PMID:20004785
reference_title: "Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome"
explanation: Establishes DOCK8 as the cause of the autosomal recessive form of HIES, a distinct entity from AD STAT3-HIES.
- name: STAT3 gain-of-function syndrome
description: >-
Germline STAT3 gain-of-function causes a mechanistically OPPOSITE disorder
(early-onset autoimmunity, lymphoproliferation, and enteropathy) rather
than an immunodeficiency, and must not be conflated with the
loss-of-function dominant-negative STAT3 that causes AD-HIES.
evidence:
- reference: PMID:34137790
reference_title: "Human STAT3 variants underlie autosomal dominant hyper-IgE syndrome by negative dominance."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "through negative dominance rather than haploinsufficiency."
explanation: AD-HIES is driven by loss-of-function negative dominance, the mechanistic opposite of STAT3 gain-of-function disease.
references:
- reference: PMID:20301786
title: "STAT3 Hyper IgE Syndrome."
tags:
- GeneReviews
Overview. Autosomal dominant hyper-IgE syndrome (AD-HIES) is a rare multisystem primary (inborn-error-of-immunity) immunodeficiency caused by heterozygous dominant-negative loss-of-function variants in STAT3. It is the prototypic "connective-tissue/immune" inborn error: it couples a recognizable immunologic triad — markedly elevated serum IgE, recurrent "cold" staphylococcal skin abscesses, and recurrent pneumonia with pneumatocele formation — with non-immune craniofacial, dental, skeletal, and vascular abnormalities. This combination of an immunodeficiency that also disrupts somatic tissue is what makes STAT3-HIES distinctive among the inborn errors of immunity. The eponym Job syndrome (1966, Davis et al., describing girls with "cold" abscesses, after the biblical Job "smitten with sore boils") predates the unified description by Buckley (1972, adding the facial/skeletal features and high IgE), and the molecular cause (STAT3) was discovered in 2007.
Key identifiers.
- MONDO: MONDO:0007818 — hyper-IgE recurrent infection syndrome 1, autosomal dominant (the value already in the YAML; correct).
- OMIM: 147060 (HYPER-IgE RECURRENT INFECTION SYNDROME 1, AUTOSOMAL DOMINANT; HIES1). Gene: STAT3 OMIM *102582.
- Orphanet: ORPHA:2314 — Autosomal dominant hyper-IgE syndrome due to STAT3 deficiency (under the broader Job syndrome grouping ORPHA:2316).
- ICD-10: D82.4 (Hyperimmunoglobulin E [IgE] syndrome). ICD-11: 4A00.20 (Hyper-IgE syndromes).
- MeSH: D007589 (Job Syndrome).
- HGNC (gene): hgnc:11364 (STAT3).
Synonyms / alternative names: AD-HIES; STAT3-HIES; STAT3 dominant-negative HIES; Job syndrome; Buckley syndrome; HIES type 1; classic/sporadic hyper-IgE syndrome.
Data source character. Information is overwhelmingly disease-level aggregated (curated cohorts from the NIH, French national survey, GeneReviews, and the international HSCT consortium), not EHR/individual-patient registries. The largest well-phenotyped series are single-center/national cohorts of tens to low-hundreds of molecularly confirmed patients.
Primary cause (genetic). Heterozygous germline dominant-negative variants in STAT3 (signal transducer and activator of transcription 3), chromosome 17q21.2. STAT3 is the shared signaling node for a large family of cytokines (IL-6, IL-10, IL-11, IL-21, IL-22, IL-23, G-CSF, leptin, etc.). The mutant allele produces a full-length but non-functional protein that poisons the wild-type STAT3 in the obligate dimer, so a single mutant allele reduces overall STAT3 activity well below the ~50% expected from simple haploinsufficiency. - Holland et al., NEJM 2007 (PMID:17881745): "heterozygous … mutations in … STAT3 in the majority of patients with the hyper-IgE syndrome." - Minegishi et al., Nature 2007 (PMID:17676033): "Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome." - Asano et al., J Exp Med 2021 (PMID:34137790, PMC8217968): of in-frame variants studied, 128/135 (95%) were experimentally dominant-negative, and all 15 out-of-frame variants were dominant-negative via truncated neoproteins/reinitiation isoforms — i.e., negative dominance, not haploinsufficiency, is the unifying mechanism.
Genetic risk factors. The disorder is monogenic and fully penetrant — there is no separate "susceptibility locus." The relevant genetic facts are the mutational hotspots (below): missense/in-frame deletions clustering in the DNA-binding domain and the SH2 domain of STAT3.
Environmental risk factors. None are required for disease (it is Mendelian). Environmental triggers of complications (not of the disease itself) include colonizing Staphylococcus aureus, Aspergillus/other molds (which colonize pneumatoceles), and Candida. Smoking and recurrent infection accelerate the structural lung disease. No sex predilection (equal M:F).
Protective factors. None established at the genetic level. Clinically, early, lifelong anti-staphylococcal prophylaxis and aggressive skin/airway care are "protective" against the morbidity, and HSCT is curative for the immune phenotype (Section 12).
Gene–environment interaction. The core G×E story is STAT3-dependent Th17/IL-17–IL-22 collapse meeting environmental pathogens: the host is constitutively unable to mount the IL-17/IL-22 mucocutaneous antimicrobial program, so common environmental organisms (S. aureus, Candida albicans, Aspergillus) that are trivial for normal hosts cause recurrent, deep, poorly inflamed infection.
STAT3-HIES is multisystem. Frequencies vary by cohort (NIH, French survey, US series); ranges are given where sources differ. Suggested HPO terms in brackets.
Immunologic / infectious (early-onset, often neonatal–infantile):
- Markedly elevated serum IgE, typically >2000 IU/mL (peak often ≫10,000); ~97–100% at some point (may normalize in adults). HP:0003212 (Increased circulating IgE concentration). Onset: infancy. Severity: defining hallmark.
- Eosinophilia (>700/µL), ~80–90%. HP:0001880 (Eosinophilia).
- Recurrent "cold" cutaneous abscesses (staphylococcal, lacking classic warmth/erythema), ~>80%. HP:0100838 (Recurrent cutaneous abscess formation) / HP:0002744 (cold abscess concept).
- Recurrent pneumonia (S. aureus, S. pneumoniae, H. influenzae) with pneumatocele/bronchiectasis from aberrant healing, ~>85% pneumonia; pneumatoceles in a large minority. HP:0006532 (Recurrent pneumonia), HP:0025428/HP:0025427 (pneumatocele), HP:0002110 (Bronchiectasis). Pneumatoceles then become niches for Aspergillus/Pseudomonas/non-tuberculous mycobacteria → fatal hemoptysis/invasive aspergillosis. HP:0002099 (Asthma not typical; rather chronic pulmonary disease).
- Chronic mucocutaneous candidiasis (nails, oral, vaginal), ~>80%. HP:0002728 (Chronic mucocutaneous candidiasis).
- Newborn/eczematoid dermatitis, often first sign within weeks of life, ~all. HP:0000964 (Eczema) / HP:0000962 (Hyperkeratosis), HP:0011123 (papulopustular eruption).
- Mucocutaneous viral disease (recurrent HSV, VZV reactivation, molluscum, warts), variable.
Non-immune connective tissue / skeletal / dental / craniofacial:
- Characteristic facies (emerging by adolescence): facial asymmetry, prominent forehead, deep-set eyes, broad nasal bridge/fleshy nasal tip, coarse/"leonine" skin with prominent pores, prognathism, high-arched palate. ~80–100% of adults. HP:0000271 (Abnormal facial shape), HP:0000343 (Long philtrum/coarse), HP:0000218 (High palate).
- Retained primary (deciduous) teeth / failure of normal exfoliation, ~> 50–65% (US cohort 41%; molecularly-defined series up to 83% delayed). HP:0006335 (Persistence of primary teeth).
- Scoliosis, ~>60% (US cohort ~34%). HP:0002650 (Scoliosis).
- Minimal-trauma / pathologic fractures and low bone density, ~40–50%. HP:0002659 (Increased susceptibility to fractures), HP:0000938 (Osteopenia), HP:0000939 (Osteoporosis).
- Joint hyperextensibility / hyperextensible joints, common. HP:0001382 (Joint hypermobility).
- Craniosynostosis (subset). HP:0001363.
- Degenerative joint disease / osteoarthritis, adult.
Neurologic / structural:
- Chiari I malformation in ~18–20%. HP:0002308 (Arnold-Chiari type I).
- Focal brain hyperintensities (white-matter lesions) ~60–70%, usually clinically silent. HP:0002518 (Periventricular white matter hyperintensities).
- Lacunar infarcts/stroke related to vasculopathy (below).
Vascular (under-recognized, prognostically important):
- Coronary artery tortuosity/ectasia ~50%, coronary aneurysms in a substantial fraction (≈70% have some coronary abnormality in prospective imaging). HP:0001640 (Cardiomegaly not specific) → better: HP:0004942 (Aortic aneurysm), HP:0025019/coronary-artery aneurysm. Chandesris et al., Circulation 2012 (PMID:22456478).
- Cerebral / middle-sized artery aneurysms and arterial tortuosity; risk of myocardial infarction, subarachnoid hemorrhage, ischemic stroke even in young, non-atherosclerotic patients.
GI / other:
- Esophageal dysmotility / GERD / eosinophilic esophagitis, >50%. HP:0002020 (Gastroesophageal reflux), HP:0002015 (Dysphagia).
- Gastrointestinal candidiasis, colon perforation/diverticulitis (reported).
Onset / severity / progression summary: dermatitis and infections begin in infancy; the somatic (facial, dental, skeletal, vascular) features accrue with age and become diagnostic by adolescence/adulthood. Course is chronic-progressive, dominated long-term by structural lung disease and vascular events.
Quality-of-life impact: chronic skin disease/pruritus, recurrent infections, repeated hospitalization/surgery, chronic lung disease with exercise limitation, fracture/scoliosis-related disability, dental morbidity, and the psychological burden of a visible facial phenotype. No HIES-specific validated QoL instrument; generic tools (SF-36, EQ-5D, PedsQL) apply.
Causal gene. STAT3 (hgnc:11364; OMIM *102582; Ensembl ENSG00000168610; 17q21.2). Encodes a 770-aa transcription factor with N-terminal, coiled-coil, DNA-binding, linker, SH2, and C-terminal transactivation domains.
Pathogenic variants. - Type/class: predominantly missense substitutions and small in-frame deletions; out-of-frame/splice variants occur but act through translation-reinitiation neoproteins (Asano 2021). - Mutational hotspots: cluster in the DNA-binding domain (e.g., recurrent p.Val463del, p.Arg382Trp/Gln, p.Val637Met in SH2) and the SH2 domain. Woellner et al., JACI 2010 (PMID:20004785, "Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome") catalogued the spectrum and tied genotype to the clinical/IgE phenotype. - Functional consequence: dominant-negative — mutant monomer dimerizes with wild-type and abolishes DNA binding/transactivation; NOT simple loss-of-function/haploinsufficiency, and NOT gain-of-function (germline STAT3 GOF causes a distinct early-onset autoimmunity/lymphoproliferation syndrome — a key contrast). - Allele frequency: essentially absent from gnomAD (private, often de novo, pathogenic alleles); recurrent hotspot alleles arise independently. - Origin: germline; the majority are de novo (sporadic), with autosomal dominant transmission when inherited. Somatic STAT3 variants are unrelated (they appear in LGL leukemia / cancers).
Variant classification (ACMG/AMP). Recurrent hotspot dominant-negative missense/in-frame variants are typically Pathogenic/Likely Pathogenic (PS3 functional, PM1 hotspot, PS4/PP1 if segregating, PM2 absence in gnomAD). ClinVar lists the classic alleles as pathogenic.
Modifier genes / epigenetics / chromosomal abnormalities. No established Mendelian modifier genes; phenotypic variability (even within families) is attributed to which STAT3 target pathways are most disrupted and to stochastic/environmental factors. No recurrent epigenetic mechanism or chromosomal rearrangement is implicated — this is a point-mutation disease.
Apex lesion → causal chain.
(0) STAT3 dominant-negative dysfunction. A single heterozygous DNA-binding/SH2-domain variant produces a full-length mutant that dimerizes with wild-type STAT3 and abolishes DNA binding/transactivation across the entire STAT3 cytokine network. GO terms: GO:0007260 (tyrosine phosphorylation of STAT protein, DECREASED downstream output — note phosphorylation itself is often preserved; it is DNA binding/transactivation that fails), GO:0007259 (cell surface receptor signaling pathway via JAK-STAT), GO:0006357 (regulation of transcription). The defect is upstream of everything below.
(1) Collapse of Th17 differentiation → IL-17/IL-22 deficiency (immune arm, the central mechanism). STAT3 is required downstream of IL-6 and IL-23 for RORγt-driven Th17 development. Milner et al., Nature 2008 (PMID:18337720): "impaired T(H)17 cell differentiation" in AD-HIES. Loss of IL-17A/F and IL-22 removes the signals that drive epithelial β-defensin/antimicrobial-peptide production and neutrophil recruitment to skin and lung → susceptibility to S. aureus and Candida. Cell types: CL:0000899 (Th17 cell), CL:0000624 (CD4+ αβ T cell), CL:0000775 (neutrophil), CL:0000066 (epithelial cell). GO: GO:0072539 (Th17 cell differentiation), GO:0097400 (interleukin-17-mediated signaling), GO:0050830 (defense response to Gram-positive bacterium).
(2) Blunted IL-6 acute-phase / inflammatory signaling. Impaired IL-6→STAT3 signaling underlies the paradoxically "cold," under-inflamed abscesses (reduced systemic inflammatory response despite deep infection) and contributes to defective antibody/affinity-maturation responses. Holland 2007 (PMID:17881745): "impaired … responses to … IL-6." GO: GO:0070102 (interleukin-6-mediated signaling pathway), GO:0006953 (acute-phase response).
(3) Dysregulated humoral/atopic balance. Impaired STAT3 (IL-10, IL-21) signaling skews toward IgE class-switching/atopy and impairs memory B-cell generation and specific antibody responses → high IgE plus functionally poor antibody. Cell types: CL:0000787 (memory B cell), CL:0000236 (B cell).
(4) Non-immune connective-tissue/skeletal/dental program failure (somatic arm). Because STAT3 transduces IL-11, leptin, and growth-factor signals in bone, vasculature, and craniofacial tissue, dominant-negative STAT3 disrupts:
- Bone: STAT3 normally restrains osteoclastogenesis; its loss → increased osteoclast activity, osteopenia, fractures. Zhang et al. 2005 (PMID:15694417) — hematopoietic STAT3 deletion → increased osteoclastogenesis/osteopenia in mice (MODEL_ORGANISM). GO: GO:0045671/GO:0001503 (osteoclast/ossification), cell type CL:0000092 (osteoclast).
- Craniofacial/dental: impaired IL-11→STAT3 signaling links to craniosynostosis, delayed tooth exfoliation, retained primary teeth (parallels IL11RA-deficiency craniosynostosis; Nieminen et al., AJHG 2011, PMID:21741611).
- Vasculature: STAT3 deficiency reduces VEGF/HIF-1α-dependent vascular maintenance and dysregulates matrix metalloproteinases (notably MMP-8) and TGF-β/TNF-α responses → arterial tortuosity, ectasia, and aneurysm; mouse data show STAT3/IL-17A blockade worsens aneurysm severity and rupture. Chandesris et al., Circulation 2012 (PMID:22456478). GO:0001525 (angiogenesis), cell types CL:0000115 (endothelial cell), CL:0000192 (vascular smooth muscle cell).
- Lung architecture: impaired epithelial repair + MMP dysregulation → pneumatocele/bronchiectasis (aberrant post-pneumonia healing) rather than simple infection.
Upstream vs downstream summary. STAT3 DN (upstream) → branches into (a) Th17/IL-17–IL-22 immune-defense failure (skin/lung/mucosal infection) and (b) IL-6 acute-phase blunting (cold abscesses, antibody defects) on the immune side, and (c) bone/vascular/dental connective-tissue programs on the non-immune side. All downstream phenotypes trace to the single transcription-factor lesion.
Molecular profiling. Transcriptomic studies of patient T cells show loss of STAT3 target-gene induction (RORC, IL17A, IL17F, IL22, retinoic-acid-receptor–related signatures); proteomic/functional assays show normal STAT3 protein and tyrosine phosphorylation but absent DNA binding (the basis of the dominant-negative model). No disease-specific metabolomic/lipidomic signature is established.
Organ/system level (primary): skin (UBERON:0002097), lung/respiratory tract (UBERON:0002048; bronchi UBERON:0002185), immune/hematopoietic system (UBERON:0002405), oral cavity/teeth (UBERON:0001091 tooth), skeleton (UBERON:0002481 bone tissue; vertebral column UBERON:0002240), craniofacial skeleton/skull (UBERON:0003129).
Secondary / complication-level: cardiovascular system — coronary arteries (UBERON:0001621), cerebral arteries/aorta (UBERON:0001637 artery); central nervous system/brain (UBERON:0000955) — Chiari I, white-matter lesions; esophagus/GI tract (UBERON:0001043) — dysmotility, candidiasis.
Tissue/cell level: epithelium (skin and airway, CL:0000066), Th17 lymphocytes (CL:0000899), neutrophils (CL:0000775), memory B cells (CL:0000787), osteoclasts (CL:0000092), vascular endothelial (CL:0000115) and smooth-muscle (CL:0000192) cells.
Subcellular level: STAT3 acts in the cytoplasm → nucleus (GO:0005634 nucleus; GO:0005829 cytosol); the functional defect is nuclear DNA binding/transcription (GO:0003700 DNA-binding transcription factor activity).
Localization/lateralization: infections and abscesses are multifocal; vascular and skeletal involvement is typically bilateral/systemic; facial features are roughly symmetric/asymmetric (facial asymmetry is itself a feature).
Clinical scoring. The NIH HIES score (Grimbacher et al., NEJM 1999, PMID:10053177 — "Hyper-IgE syndrome with recurrent infections—an autosomal dominant multisystem disorder") weights 19 clinical/lab findings; >40 points suggests HIES, <20 makes it unlikely. Woellner 2010 (PMID:20004785) refined diagnostic guidelines and showed that low Th17 counts and the genotype improve discrimination.
Laboratory. Serum IgE >2000 IU/mL (often historically much higher); eosinophilia >700/µL; reduced/absent IL-17-producing CD4+ (Th17) cells by flow cytometry (a strong discriminator); variably impaired specific antibody responses; normal-to-reduced memory B cells.
Functional/imaging. Chest CT for pneumatoceles/bronchiectasis; coronary CT/MR angiography and brain MRA for aneurysm surveillance; spine imaging for scoliosis; DXA for bone density; echocardiography.
Genetic testing. The diagnosis is confirmed by identifying a heterozygous dominant-negative STAT3 variant. Approaches: single-gene STAT3 sequencing, HIES/PID gene panels (to include DOCK8, PGM3, ZNF341, IL6ST/IL6R, SPINK5, CARD11, ERBIN, TGFBR), or exome/genome sequencing. Functional confirmation (absent STAT3 DNA binding / dominant-negative assay) supports VUS reclassification.
Differential diagnosis (distinguishing features): - DOCK8 deficiency (AR-HIES): severe cutaneous viral infections (HSV, HPV, molluscum), allergies, early malignancy, no connective-tissue/skeletal/retained-teeth features. → genetics. - STAT3 gain-of-function: early autoimmunity, lymphoproliferation, enteropathy — opposite mechanism. - PGM3 deficiency, ZNF341 (AR STAT3-pathway), IL6ST/IL6R defects, Comèl-Netherton (SPINK5), Wiskott-Aldrich, Omenn, atopic dermatitis with high IgE.
Screening. Not part of routine newborn screening (TREC-based NBS misses HIES). Cascade testing of relatives for a known familial variant; prenatal/PGT possible when the familial variant is known.
Conventional / supportive (lifelong).
- Antistaphylococcal prophylaxis: trimethoprim-sulfamethoxazole (cotrimoxazole) is standard; treat exacerbations with anti-staph agents. MAXO: MAXO:0000058/MAXO:0000059 (antibiotic/antimicrobial therapy). CHEBI: trimethoprim CHEBI:45924, sulfamethoxazole CHEBI:9332.
- Antifungal prophylaxis/therapy: itraconazole/voriconazole/posaconazole for Aspergillus and CMC; fluconazole for Candida. MAXO: antifungal agent therapy; CHEBI: itraconazole CHEBI:6076, fluconazole CHEBI:46081.
- Skin care: bleach (sodium hypochlorite) baths, chlorhexidine, topical antiseptics/emollients, antihistamines for pruritus. MAXO: MAXO:0000511/topical therapy concepts.
- Immunoglobulin replacement (IVIG/SCIG): for selected patients with poor specific antibody/hypogammaglobulinemia (benefit limited/uncertain). MAXO: MAXO:0000841 (immunoglobulin therapy concept).
- Pulmonary: airway clearance, aggressive treatment of bronchiectasis; surgical resection of complicated pneumatoceles is high-risk and selective. MAXO: MAXO:0000004 (surgical procedure).
- Skeletal/dental: bisphosphonates for low bone density (case-based), orthopedic management of scoliosis/fractures, timely extraction of retained primary teeth.
- Vascular: risk-factor control and surveillance; aneurysm management per cardiology/neurosurgery.
Curative — allogeneic HSCT. Increasingly used and the only therapy that corrects the immune phenotype (abolishes infections/abscesses, stabilizes lung disease); it does not reverse established non-immune features (skeletal/dental/connective tissue), and its effect on vasculopathy is uncertain (vascular events still reported post-HSCT).
- Worldwide HSCT study (Blood Advances, 2025): 41 patients, median age at HSCT 14 y, 5-year overall survival 93%, event-free survival 90%, with ~87% free of bacterial/fungal respiratory infection afterward.
- Harrison/Gennery et al. (J Clin Immunol 2021, PMC8249289): "Hematopoietic stem cell transplantation resolves the immune deficit associated with STAT3-dominant-negative hyper-IgE syndrome."
- MAXO: MAXO:0010039 (organ/HSCT transplantation), MAXO:0000827-type bone-marrow-transplant concepts.
Experimental / future. Gene-correction (CRISPR/base-editing of the dominant-negative allele, or allele-specific knockdown to relieve negative dominance) is conceptually attractive but preclinical only; no approved targeted/RNA therapy exists. Pharmacogenomics: azole–drug interactions (CYP3A4) and TMP-SMX hypersensitivity are the practical PGx concerns.
Treatment strategy. Lifelong prophylaxis + skin/airway care from diagnosis; multidisciplinary surveillance (pulmonary, vascular, dental, skeletal, oncologic); consider HSCT before irreversible lung damage, weighing transplant risk against progressive infection.
MAXO:0000079 (genetic counseling).MONDO:0007818. Gene: hgnc:11364 (STAT3).HP:0003212 (↑IgE), HP:0001880 (eosinophilia), HP:0100838 (recurrent cutaneous abscess), HP:0006532 (recurrent pneumonia), HP:0002110 (bronchiectasis), HP:0002728 (chronic mucocutaneous candidiasis), HP:0000964 (eczema), HP:0006335 (persistence of primary teeth), HP:0002650 (scoliosis), HP:0002659 (↑fracture susceptibility), HP:0000938 (osteopenia), HP:0001382 (joint hypermobility), HP:0002308 (Chiari I), HP:0000271 (abnormal facial shape), HP:0000218 (high palate), HP:0002020 (GERD), aortic/coronary aneurysm terms (HP:0004942 and coronary-artery-aneurysm terms).GO:0072539 (Th17 differentiation), GO:0097400 (IL-17 signaling), GO:0070102 (IL-6 signaling), GO:0007259 (JAK-STAT signaling), GO:0003700 (DNA-binding TF activity), GO:0050830 (defense response to Gram-positive bacterium), GO:0001525 (angiogenesis).CL:0000899 (Th17), CL:0000775 (neutrophil), CL:0000787 (memory B cell), CL:0000066 (epithelial cell), CL:0000092 (osteoclast), CL:0000115 (endothelial cell).UBERON:0002097 (skin), UBERON:0002048 (lung), UBERON:0001621 (coronary artery), UBERON:0000955 (brain), UBERON:0002481 (bone tissue), UBERON:0001091 (tooth).CHEBI:45924, sulfamethoxazole CHEBI:9332, itraconazole CHEBI:6076, fluconazole CHEBI:46081.MAXO:0000058/antimicrobial therapy, antifungal therapy, MAXO:0010039 (transplantation/HSCT), MAXO:0000079 (genetic counseling), MAXO:0000004 (surgery).| Claim | Citation | PMID (verify) | Evidence type |
|---|---|---|---|
| STAT3 mutations cause AD-HIES; impaired IL-6 | Holland et al., NEJM 2007 | 17881745 | HUMAN_CLINICAL |
| Dominant-negative STAT3 DNA-binding-domain mutations | Minegishi et al., Nature 2007 | 17676033 | HUMAN_CLINICAL / IN_VITRO |
| Impaired Th17 differentiation | Milner et al., Nature 2008 | 18337720 | HUMAN_CLINICAL / IN_VITRO |
| Mutation spectrum + diagnostic guidelines | Woellner et al., JACI 2010 | 20004785 | HUMAN_CLINICAL |
| Negative dominance is unifying mechanism (in/out-of-frame) | Asano et al., J Exp Med 2021 | 34137790 | IN_VITRO |
| NIH HIES clinical score / multisystem AD disorder | Grimbacher et al., NEJM 1999 | 10053177 | HUMAN_CLINICAL |
| French national survey, molecular/clinical features | Chandesris et al., Medicine 2012 | 22751495 | HUMAN_CLINICAL |
| Widespread vascular abnormalities (coronary/cerebral aneurysms) | Chandesris et al., Circulation 2012 | 22456478 | HUMAN_CLINICAL |
| STAT3 deletion → osteoclastogenesis/osteopenia | Zhang et al., 2005 | 15694417 | MODEL_ORGANISM |
| IL-11/STAT3 craniosynostosis/tooth eruption link | Nieminen et al., AJHG 2011 | 21741611 | HUMAN_CLINICAL |
| HSCT resolves immune deficit | Harrison/Gennery et al., J Clin Immunol 2021 | (PMC8249289) | HUMAN_CLINICAL |
| Worldwide HSCT outcomes (5-yr OS 93%) | Blood Advances 2025 | (in press) | HUMAN_CLINICAL |
| GeneReviews STAT3 HIES (criteria, surveillance, prevalence) | Hsu/Davis/Puck/Holland/Freeman | Bookshelf NBK25507 | OTHER (review) |
Sources consulted: - Human STAT3 variants underlie AD-HIES by negative dominance (J Exp Med 2021, PMC8217968) - STAT3 Hyper IgE Syndrome — GeneReviews (NBK25507) - STAT3 and the Hyper-IgE syndrome — review (PMC3710320) - STAT3 Hyper-IgE Syndrome—an Update and Unanswered Questions (J Clin Immunol 2021) - HSCT for STAT3 HIES: a worldwide study (Blood Advances 2025, PMC12359223) - HSCT resolves the immune deficit in STAT3-DN HIES (PMC8249289) - HSCT and vasculopathy in STAT3-DN HIES (Front Pediatr 2020, PMC7511721) - French national survey (PubMed 22751495) - Mutations in STAT3 and diagnostic guidelines (JACI / Woellner) - The genetics of hyper-IgE syndromes (Front Immunol 2025) - Orphanet: AD hyper-IgE syndrome due to STAT3 deficiency (ORPHA:2314)
Bottom line for the KB entry: the existing YAML's framing (dominant-negative STAT3 → Th17/IL-17–IL-22 collapse + blunted IL-6 + connective-tissue/skeletal/vascular disruption) is mechanistically correct and well-supported. The richest additions to make are: the vasculopathy arm (coronary/cerebral aneurysms, MMP-8/VEGF-HIF mechanism, ~3-yearly surveillance), the bone/dental/craniofacial non-immune phenotypes with frequencies, the NIH diagnostic score + low Th17 diagnostic pillar, the lymphoma risk, and HSCT as the curative-for-immune-phenotype treatment. Remember to re-fetch and substring-verify every PMID with just fetch-reference before committing snippets.