Wissler syndrome

Immune MONDO:0006018 Pathograph 24 Autoinflammatory Disease Inflammatory Arthritis

A rheumatic syndrome characterized by recurrent high fever, polymorphous exanthemas, arthralgia/arthritis, neutrophilic leukocytosis, and a markedly elevated systemic inflammatory response (CRP, ESR, ferritin). First described as "subsepsis allergica" by Wissler and Fanconi in the 1940s, the entity is now widely regarded as a variant within the Still's disease continuum (systemic juvenile idiopathic arthritis and adult-onset Still's disease) rather than a true allergic process; no Mendelian causative gene has been identified, and the disorder is classified as an autoinflammatory syndrome driven by innate immune (monocyte/macrophage and neutrophil) hyperactivation with downstream IL-1β, IL-6, and IL-18 signalling.

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8
Pathophys.
12
Phenotypes
24
Pathograph
7
Medical Actions
5
Differentials
⚙

Pathophysiology

8
Innate immune activation by PAMPs/DAMPs
An infectious or sterile inflammatory trigger engages pattern-recognition receptors (PRRs) on monocytes and tissue macrophages, initiating the monocyte/macrophage hyperactivation characteristic of the Still's disease spectrum to which Wissler-Fanconi syndrome is now considered to belong.
monocyte CL:0000576 macrophage CL:0000235
pattern recognition receptor signaling pathway GO:0002221 inflammatory response GO:0006954 ↑ INCREASED cytokine-mediated signaling pathway GO:0019221
Downstream
NLRP3 inflammasome activation and IL-1β/IL-18 maturation PRR engagement provides signal 1 for inflammasome priming and signal 2 for assembly.
Show evidence (3 references)
PMID:36090971 SUPPORT Human Clinical
"Regarding the activation mechanisms of monocytes/macrophages in AOSD, in addition to type II interferon (IFN) stimulation, several pathways have recently been identified, such as the pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs)-pattern..."
Identifies PAMP/DAMP-PRR signalling as the canonical upstream trigger of monocyte/macrophage activation in adult-onset Still's disease, the condition that current literature equates with Wissler-Fanconi syndrome.
PMID:41737969 SUPPORT Human Clinical
"Recognition of the Wissler-Fanconi variant and early ferritin testing can prevent diagnostic delay and enable prompt, effective immunosuppressive therapy."
Recent case literature explicitly frames Wissler-Fanconi as a variant of adult-onset Still's disease, justifying application of Still's disease pathophysiology to this entity.
PMID:38756937 SUPPORT Human Clinical
"sJIA and AOSD are rare autoinflammatory disorders that have similar pathophysiological and clinical features."
Confirms that the Still's disease continuum (sJIA + AOSD), to which Wissler-Fanconi syndrome is now ascribed, is a single autoinflammatory entity sharing innate-immune-driven pathophysiology.
NLRP3 inflammasome activation and IL-1β/IL-18 maturation
PAMP/DAMP signalling in monocytes and macrophages assembles the NLRP3 inflammasome, activating caspase-1 and converting pro-IL-1β and pro-IL-18 into their mature, secreted forms — a core innate-immune mechanism shared across the Still's disease spectrum.
monocyte CL:0000576 macrophage CL:0000235
NLRP3 inflammasome complex assembly GO:0044546 ↑ INCREASED interleukin-1 beta production GO:0032611 ↑ INCREASED interleukin-18 production GO:0032621 ↑ INCREASED
Downstream
Systemic pro-inflammatory cytokine cascade Mature IL-1β and IL-18 propagate paracrine signalling and trigger IL-6 production, driving systemic inflammation.
Show evidence (2 references)
PMID:36090971 SUPPORT Human Clinical
"These stimulations on monocytes/macrophages cause activation of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain (NLRP) 3 inflammasomes, which trigger capase-1 activation, resulting in conversion of pro-IL-1β and pro-IL-18 into mature forms."
Establishes NLRP3 inflammasome→caspase-1→IL-1β/IL-18 as the canonical mechanism downstream of PAMP/DAMP signalling in AOSD.
PMID:37446301 SUPPORT Human Clinical
"key mediator of autoinflammatory diseases associated with the development of macrophage activation syndrome (MAS), including systemic juvenile idiopathic arthritis and adult-onset Still's disease."
IL-18 produced downstream of inflammasome activation is a recognised key mediator of the Still's disease spectrum, supporting this node's mechanistic role.
Systemic pro-inflammatory cytokine cascade
Mature IL-1β, IL-18, and downstream IL-6 produced by activated monocytes/macrophages drive a systemic acute-phase response with fever, leukocyte mobilisation, and synthesis of acute-phase reactants (CRP, serum amyloid A, ferritin) in the liver. This cascade underlies the validated efficacy of IL-1 and IL-6 pathway inhibitors in Still's disease.
macrophage CL:0000235 hepatocyte CL:0000182
interleukin-1-mediated signaling pathway GO:0070498 ↑ INCREASED interleukin-6 production GO:0032635 ↑ INCREASED positive regulation of inflammatory response GO:0050729
Downstream
Neutrophil hyperactivation and NET formation
Th1/Th17 adaptive immune hyperactivation
Vascular endothelial activation and cutaneous vasculitis IL-1β and TNF directly upregulate endothelial adhesion molecules and procoagulant gene expression.
Cardiac serositis
Recurrent high fever
Erythrocyte sedimentation rate
C-reactive protein
Hyperferritinemia
Show evidence (2 references)
PMID:36090971 SUPPORT Human Clinical
"IL-1β and IL-18 produced by activated monocytes/macrophages contribute to various clinical features in AOSD."
Connects mature inflammasome cytokines to the multi-system clinical phenotype of AOSD/Still's disease.
PMID:39317417 SUPPORT Human Clinical
"The optimal therapeutic strategy relies on early use of interleukin (IL-1 or IL-6 inhibitors"
EULAR/PReS consensus that IL-1 and IL-6 are core therapeutic targets in Still's disease confirms these cytokines as the dominant inflammatory drivers.
Neutrophil hyperactivation and NET formation
Pro-inflammatory cytokines drive marked neutrophilia with neutrophil predominance and release of neutrophil extracellular traps (NETs), which feed back to amplify monocyte/macrophage activation and contribute to cutaneous and small-vessel inflammation.
neutrophil CL:0000775
neutrophil migration GO:1990266 ↑ INCREASED neutrophil extracellular trap formation GO:0140645 ↑ INCREASED
Downstream
Leukocytosis Cytokine-driven neutrophilic leukocytosis is the haematologic hallmark of the syndrome.
Vascular endothelial activation and cutaneous vasculitis
Vasculitis in the skin
Show evidence (2 references)
PMID:36090971 SUPPORT Human Clinical
"Hyperactivation of macrophages and neutrophils along with low activation of natural killer (NK) cells in innate immunity"
Identifies neutrophil hyperactivation as a core innate-immune feature of AOSD/Still's disease.
PMID:27843372 SUPPORT Human Clinical
"white blood cell count (21,000 cells per µL, >95% neutrophils and 28 bands)"
Case-level demonstration of marked neutrophilic leukocytosis with bandemia in a patient meeting Wissler-Fanconi criteria.
Th1/Th17 adaptive immune hyperactivation
In addition to innate immune drive, hyperactivation of Th1 and Th17 effector populations and a relative deficit of regulatory T cells contribute to chronic auto-inflammation and synovial involvement.
CD4-positive, alpha-beta T cell CL:0000624 T-helper 17 cell CL:0000899
T-helper 1 type immune response GO:0042088 ↑ INCREASED positive regulation of interleukin-17 production GO:0032740 adaptive immune response GO:0002250
Downstream
Synovial inflammation
Show evidence (1 reference)
PMID:36090971 SUPPORT Human Clinical
"hyperactivation of Th1 and Th17 cells, whereas low activation of regulatory T cells (Tregs) in acquired immunity are involved in the pathogenic process of AOSD."
Establishes Th1/Th17 hyperactivation and Treg deficit as the adaptive-immune limb of AOSD/Still's pathogenesis.
Synovial inflammation
Cytokine- and Th17-driven inflammation of synovial tissue produces the characteristic migratory polyarthralgia and arthritis of the disease.
synovial cell CL:0000214 macrophage CL:0000235
chronic inflammatory response GO:0002544
Downstream
Arthralgia
Arthritis
Show evidence (2 references)
PMID:8150635 SUPPORT Human Clinical
"This rare disease is characterized by four typical symptoms: polymorphous exanthemas, recurrent high fever, leucocytosis and arthralgia."
Arthralgia is a defining feature of Wissler-Fanconi syndrome, consistent with synovial inflammation.
PMID:27843372 PARTIAL Human Clinical
"The patient had migratory polyarthritis and polymorphic maculopapular rash on the back and lower extremities for 4 months."
Documents the migratory polyarthritis attributable to synovial inflammation in a Wissler-Fanconi case.
Vascular endothelial activation and cutaneous vasculitis
Cytokine-driven endothelial activation produces a polymorphous exanthem that can show histologic urticarial / leukocytoclastic vasculitis on skin biopsy. Renal microvascular involvement with intravascular coagulation can manifest as transient microscopic hematuria.
endothelial cell CL:0000115 neutrophil CL:0000775
positive regulation of inflammatory response GO:0050729 leukocyte migration GO:0050900
Downstream
Exanthem
Vasculitis in the skin
Microscopic hematuria
Show evidence (2 references)
PMID:27843372 SUPPORT Human Clinical
"A dermatologist biopsied the rash. According to a dermatopathologist, the findings were consistent with urticarial vasculitis."
Provides histopathologic confirmation of cutaneous vasculitis as the substrate of the Wissler-Fanconi exanthem.
PMID:3572917 SUPPORT Human Clinical
"Renal biopsy findings were compatible with intravascular coagulation."
Documents a microvascular intravascular coagulation pattern on renal biopsy, providing the proximate mechanism for hematuria.
Cardiac serositis
Pericardial and myocardial inflammation can complicate the disease, ranging from sterile pericarditis with effusion to chronic pericardio-myocarditis progressing to refractory heart failure in rare cases.
macrophage CL:0000235
inflammatory response GO:0006954 ↑ INCREASED
Downstream
Pericardial effusion
Pericarditis
Myocarditis
Congestive heart failure
Show evidence (2 references)
PMID:3092775 SUPPORT Human Clinical
"The long-term evolution is marked by recurrent febrile exacerbations, sometimes complicated by pericardo-myocarditis which usually resolves without sequellae."
Pericardo-myocarditis is a recognised, mechanism-relevant complication of Wissler-Fanconi syndrome.
PMID:27843372 SUPPORT Human Clinical
"Computed tomography scan of the chest ruled out pulmonary embolism and revealed a pericardial effusion."
Imaging documentation of pericardial effusion in a Wissler-Fanconi case.
⬡

Pathograph

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

Phenotypes

12
Blood 2
Leukocytosis FREQUENT Increased total leukocyte count HP:0001974
Show evidence (1 reference)
PMID:8150635 SUPPORT
"This rare disease is characterized by four typical symptoms: polymorphous exanthemas, recurrent high fever, leucocytosis and arthralgia."
The abstract lists leukocytosis as a typical symptom of Wissler-Fanconi syndrome.
Anemia OCCASIONAL Anemia HP:0001903
Anemia of chronic inflammation; documented in case-level laboratory data.
Show evidence (1 reference)
PMID:27843372 PARTIAL Human Clinical
"hemoglobin (9.3 g/dL, normal: 10.1–14.5 g/dL)"
Case-level hemoglobin documents anemia in a patient meeting Wissler-Fanconi criteria.
Cardiovascular 3
Pericarditis VERY_RARE Pericarditis HP:0001701
Show evidence (1 reference)
PMID:3092775 PARTIAL
"The long-term evolution is marked by recurrent febrile exacerbations, sometimes complicated by pericardo-myocarditis which usually resolves without sequellae."
The abstract notes pericardo-myocarditis as a complication during the course of disease.
Myocarditis VERY_RARE Myocarditis HP:0012819
Show evidence (1 reference)
PMID:3092775 PARTIAL
"The long-term evolution is marked by recurrent febrile exacerbations, sometimes complicated by pericardo-myocarditis which usually resolves without sequellae."
The abstract reports pericardo-myocarditis as a complication of Wissler-Fanconi syndrome.
Congestive heart failure VERY_RARE Congestive heart failure HP:0001635
Show evidence (1 reference)
PMID:3092775 SUPPORT
"The authors report a case with chronic pericardo-myocarditis progressing over a 7 year period to refractory congestive cardiac failure."
The case report documents progression to refractory congestive heart failure.
Genitourinary 1
Microscopic hematuria VERY_RARE Microscopic hematuria HP:0002907
Show evidence (1 reference)
PMID:3572917 PARTIAL
"We describe a case of persistent microscopic hematuria as initial finding in incomplete Still's disease or Wissler-Fanconi syndrome."
The case report documents microscopic hematuria as a presenting sign.
Immune 1
Exanthem FREQUENT Exanthem HP:4000054
Show evidence (1 reference)
PMID:8150635 SUPPORT
"This rare disease is characterized by four typical symptoms: polymorphous exanthemas, recurrent high fever, leucocytosis and arthralgia."
The abstract lists polymorphous exanthemas as a typical symptom of Wissler-Fanconi syndrome.
Metabolism 1
Recurrent high fever FREQUENT Recurrent fever HP:0001954
Show evidence (1 reference)
PMID:8150635 SUPPORT
"This rare disease is characterized by four typical symptoms: polymorphous exanthemas, recurrent high fever, leucocytosis and arthralgia."
The abstract lists recurrent high fever as a typical symptom of Wissler-Fanconi syndrome.
Musculoskeletal 1
Arthritis FREQUENT Arthritis HP:0001369
Migratory polyarthritis reported in case presentations.
Show evidence (1 reference)
PMID:27843372 PARTIAL
"A middle-aged female presented to the emergency department with shortness of breath and chest pain associated with fever, polyarthritis, and had a chronic polymorphic rash on the back and lower extremities."
The case report documents polyarthritis as part of the clinical presentation.
Constitutional 1
Arthralgia FREQUENT Arthralgia HP:0002829
Show evidence (1 reference)
PMID:8150635 SUPPORT
"This rare disease is characterized by four typical symptoms: polymorphous exanthemas, recurrent high fever, leucocytosis and arthralgia."
The abstract lists arthralgia as a typical symptom of Wissler-Fanconi syndrome.
Other 2
Pericardial effusion VERY_RARE Pericardial effusion HP:0001698
Show evidence (1 reference)
PMID:27843372 SUPPORT Human Clinical
"Computed tomography scan of the chest ruled out pulmonary embolism and revealed a pericardial effusion."
Imaging directly documents pericardial effusion as a complication of Wissler-Fanconi syndrome.
Vasculitis in the skin OCCASIONAL Vasculitis in the skin HP:0200029
Histologic substrate of the polymorphous exanthem on biopsy.
Show evidence (1 reference)
PMID:27843372 SUPPORT Human Clinical
"A dermatologist biopsied the rash. According to a dermatopathologist, the findings were consistent with urticarial vasculitis."
Skin biopsy in a Wissler-Fanconi case showed histologic urticarial vasculitis.
💊

Medical Actions

7
Nonsteroidal anti-inflammatory drugs
Action: NSAID therapy MAXO:0000221
Agent: naproxen NCIT:C680
NSAIDs can reduce fever and inflammatory symptoms.
Show evidence (1 reference)
PMID:27843372 PARTIAL
"A combination of nonsteroidal anti-inflammatory drugs and steroids achieved complete remission."
The case report documents remission with NSAID therapy.
Corticosteroids
Action: corticosteroid agent therapy MAXO:0000640
Systemic corticosteroids (e.g., prednisolone) used as part of combination regimens to control inflammation.
Show evidence (2 references)
PMID:27843372 PARTIAL
"A combination of nonsteroidal anti-inflammatory drugs and steroids achieved complete remission."
The case report notes complete remission with steroids plus NSAIDs.
PMID:1210460 PARTIAL
"In the present case the disease could successfully be controlled using imuran in combination with corticosteroids."
The abstract indicates corticosteroids were part of successful therapy.
Dapsone
Action: Pharmacotherapy NCIT:C15986
Agent: dapsone NCIT:C415
Dapsone was used alongside NSAIDs and corticosteroids in a reported case.
Show evidence (1 reference)
PMID:27843372 PARTIAL
"A combination of naproxen, dapsone, and prednisolone therapy resulted in significant improvement of the patient’s arthralgias and rash."
The case report documents improvement with dapsone as part of combination therapy.
Azathioprine
Action: immunosuppressive therapy Ontology label: Pharmacotherapy NCIT:C15986
Agent: azathioprine NCIT:C290
Immunosuppressive therapy used in combination with corticosteroids.
Show evidence (1 reference)
PMID:1210460 PARTIAL
"In the present case the disease could successfully be controlled using imuran in combination with corticosteroids."
The abstract reports successful control with azathioprine (imuran) plus steroids.
IL-1 inhibitor (anakinra / canakinumab)
Action: Pharmacotherapy NCIT:C15986
Agent: anakinra NCIT:C38717 canakinumab NCIT:C80971
IL-1 pathway blockade (anakinra, the recombinant IL-1 receptor antagonist, or canakinumab, an anti-IL-1β monoclonal antibody) targets the inflammasome–IL-1β axis that drives the Still's disease spectrum to which Wissler-Fanconi syndrome is now ascribed. EULAR/PReS recommends early use of IL-1 (or IL-6) inhibitors in Still's disease.
Mechanism Target:
INHIBITS NLRP3 inflammasome activation and IL-1β/IL-18 maturation — IL-1 receptor blockade (anakinra) and IL-1β neutralization (canakinumab) directly inhibit downstream signalling from the activated inflammasome.
INHIBITS Systemic pro-inflammatory cytokine cascade — IL-1 pathway blockade abrogates the IL-1-driven fever, acute-phase response, and ferritin elevation.
Show evidence (2 references)
PMID:39317417 SUPPORT Human Clinical
"The optimal therapeutic strategy relies on early use of interleukin (IL-1 or IL-6 inhibitors"
International consensus guideline endorses early IL-1 inhibitor use in Still's disease, the spectrum to which Wissler-Fanconi syndrome belongs.
PMID:38302170 SUPPORT Human Clinical
"Evidence supports TCZ, ANK, and CNK therapy for AOSD."
Meta-analysis confirms efficacy of anakinra (ANK) and canakinumab (CNK) in adult-onset Still's disease.
IL-6 inhibitor (tocilizumab)
Action: Pharmacotherapy NCIT:C15986
Agent: tocilizumab NCIT:C84217
IL-6 receptor blockade with tocilizumab targets the IL-6-driven acute phase response (fever, CRP, ferritin) and is recommended alongside IL-1 inhibitors as a first-line biologic for Still's disease.
Mechanism Target:
INHIBITS Systemic pro-inflammatory cytokine cascade — IL-6R blockade interrupts hepatic acute-phase protein synthesis and IL-6-mediated febrile signalling.
Show evidence (2 references)
PMID:39317417 SUPPORT Human Clinical
"The optimal therapeutic strategy relies on early use of interleukin (IL-1 or IL-6 inhibitors"
International consensus guideline endorses early IL-6 inhibitor use in Still's disease.
PMID:38302170 SUPPORT Human Clinical
"For bDMARDs, tocilizumab (TCZ), anakinra (ANK), and canakinumab (CNK) had the most available data."
Meta-analysis identifies tocilizumab as a primary biologic with supporting efficacy data in adult-onset Still's disease.
Anti-TNF biologic therapy
Action: Pharmacotherapy NCIT:C15986
Agent: adalimumab NCIT:C65216
Anti-TNF therapy (e.g., adalimumab) has been used after diagnostic re-classification in a reported Wissler-Fanconi case who later met criteria for adult-onset Still's disease and rheumatoid arthritis.
Show evidence (1 reference)
PMID:27843372 PARTIAL Human Clinical
"She is currently doing well on on adalimumab, methotrexate, and prednisone for rheumatoid arthritis"
Documents anti-TNF (adalimumab) as part of long-term therapy in a case meeting Wissler-Fanconi criteria after rediagnosis within the Still's-RA spectrum.
🔬

Biochemical Markers

4
Erythrocyte sedimentation rate (Elevated)
Show evidence (1 reference)
PMID:27843372 PARTIAL
"Blood sample analysis revealed high levels of CRP (42.9 mg/dL, normal: 0–0.3), erythrocyte sedimentation rate (113 mm/h normal: 2–20)"
The case report documents markedly elevated ESR, supporting a systemic inflammatory state.
C-reactive protein (Elevated)
Show evidence (1 reference)
PMID:27843372 PARTIAL
"Blood sample analysis revealed high levels of CRP (42.9 mg/dL, normal: 0–0.3), erythrocyte sedimentation rate (113 mm/h normal: 2–20)"
The case report documents markedly elevated CRP as part of the inflammatory syndrome.
Hyperferritinemia (Elevated)
Show evidence (2 references)
PMID:27843372 SUPPORT Human Clinical
"Ferritin was significantly high at 29,349 ng/mL (normal: 10–291 ng/mL)."
Documents markedly elevated ferritin (~100× upper limit of normal) in a Wissler-Fanconi case, consistent with the hyperferritinemic Still's spectrum.
PMID:41737969 SUPPORT Human Clinical
"Recognition of the Wissler-Fanconi variant and early ferritin testing can prevent diagnostic delay and enable prompt, effective immunosuppressive therapy."
Recent literature explicitly emphasises ferritin testing as a diagnostic anchor for the Wissler-Fanconi variant.
Neutrophilic leukocytosis (Elevated)
Show evidence (1 reference)
PMID:27843372 SUPPORT Human Clinical
"white blood cell count (21,000 cells per µL, >95% neutrophils and 28 bands)"
Case-level data show marked neutrophilic predominance with bandemia, despite negative cultures (i.e. neutrophilia in absence of infection).
🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Wissler syndrome:

Sepsis Not Yet Curated MONDO:1040015
Overlapping Features Early Wissler-Fanconi presentations can be difficult to distinguish from septicemia.
Distinguishing Features
  • Repeated blood and urine cultures can be negative despite high fever and leukocytosis.
Show evidence (2 references)
PMID:8150635 SUPPORT
"In the early stages it is difficult to differentiate from septicaemia."
The abstract notes early overlap with septicemia.
PMID:27843372 SUPPORT
"Urine and multiple blood cultures were negative."
The case report documents negative cultures despite systemic inflammatory presentation.
Acute rheumatic fever Not Yet Curated MONDO:0017767
Overlapping Features Considered in the differential diagnosis because of overlapping febrile inflammatory presentations.
Show evidence (1 reference)
PMID:27843372 SUPPORT
"Features of Wissler-Fanconi syndrome can be found in a differential diagnosis that includes true sepsis, acute rheumatic fever, rheumatoid arthritis, and adult onset Still’s disease."
The case report explicitly lists acute rheumatic fever as part of the differential diagnosis.
Rheumatoid arthritis MONDO:0008383
Overlapping Features Inflammatory arthritis with systemic features can overlap with Wissler-Fanconi syndrome.
Show evidence (1 reference)
PMID:27843372 SUPPORT
"Features of Wissler-Fanconi syndrome can be found in a differential diagnosis that includes true sepsis, acute rheumatic fever, rheumatoid arthritis, and adult onset Still’s disease."
The case report explicitly lists rheumatoid arthritis as part of the differential diagnosis.
Adult-onset Still's disease Not Yet Curated MONDO:0019355
Overlapping Features Shares fever, rash, leukocytosis, and arthralgia; some authors consider Wissler-Fanconi syndrome related.
Show evidence (2 references)
PMID:27843372 SUPPORT
"Features of Wissler-Fanconi syndrome can be found in a differential diagnosis that includes true sepsis, acute rheumatic fever, rheumatoid arthritis, and adult onset Still’s disease."
The case report explicitly lists adult-onset Still's disease as part of the differential diagnosis.
PMID:8150635 SUPPORT
"This syndrome has sometimes been considered equivalent to or an initial stage of Still's disease (juvenile rheumatoid arthritis) progressing to degenerative arthritis in many patients, whereas other authors have classified it as a separate entity with good prognosis."
The abstract notes debated overlap with Still's disease.
Autoimmune polyendocrine syndrome type 1 MONDO:0009411
Overlapping Features Reported in a case with subsepsis allergica; included as a differential context.
Show evidence (1 reference)
PMID:2233764 PARTIAL
"A 10.6 year old Turkish girl developed + the signs of a polyglandular autoimmune syndrome (PGA) type I since her first year of age."
The report describes a patient with type I polyglandular autoimmune syndrome alongside subsepsis allergica.
{ }

Source YAML

click to show 
name: Wissler syndrome
creation_date: '2026-01-27T22:32:20Z'
updated_date: '2026-04-27T00:00:00Z'
category: Immune
description: >-
  A rheumatic syndrome characterized by recurrent high fever, polymorphous
  exanthemas, arthralgia/arthritis, neutrophilic leukocytosis, and a markedly
  elevated systemic inflammatory response (CRP, ESR, ferritin). First
  described as "subsepsis allergica" by Wissler and Fanconi in the 1940s, the
  entity is now widely regarded as a variant within the Still's disease
  continuum (systemic juvenile idiopathic arthritis and adult-onset Still's
  disease) rather than a true allergic process; no Mendelian causative gene
  has been identified, and the disorder is classified as an autoinflammatory
  syndrome driven by innate immune (monocyte/macrophage and neutrophil)
  hyperactivation with downstream IL-1β, IL-6, and IL-18 signalling.
disease_term:
  term:
    id: MONDO:0006018
    label: Wissler syndrome
  preferred_term: Wissler syndrome
parents:
- Autoinflammatory Disease
- Inflammatory Arthritis
synonyms:
- Wissler-Fanconi syndrome
- Subsepsis allergica
- Subsepsis hyperergica
pathophysiology:
- name: Innate immune activation by PAMPs/DAMPs
  description: >-
    An infectious or sterile inflammatory trigger engages pattern-recognition
    receptors (PRRs) on monocytes and tissue macrophages, initiating the
    monocyte/macrophage hyperactivation characteristic of the Still's disease
    spectrum to which Wissler-Fanconi syndrome is now considered to belong.
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: pattern recognition receptor signaling pathway
    term:
      id: GO:0002221
      label: pattern recognition receptor signaling pathway
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: cytokine-mediated signaling pathway
    term:
      id: GO:0019221
      label: cytokine-mediated signaling pathway
  evidence:
  - reference: PMID:36090971
    reference_title: Activation mechanisms of monocytes/macrophages in adult-onset Still disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regarding the activation mechanisms of monocytes/macrophages in AOSD, in addition to type II interferon (IFN) stimulation, several pathways have recently been identified, such as the pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs)-pattern recognition receptors (PRRs) axis, and neutrophil extracellular traps (NETs)-DNA."
    explanation: >-
      Identifies PAMP/DAMP-PRR signalling as the canonical upstream trigger
      of monocyte/macrophage activation in adult-onset Still's disease, the
      condition that current literature equates with Wissler-Fanconi
      syndrome.
  - reference: PMID:41737969
    reference_title: "When Fever Defies Diagnosis: Wissler-Fanconi Syndrome as an Atypical Presentation of Adult-Onset Still's Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recognition of the Wissler-Fanconi variant and early ferritin testing can prevent diagnostic delay and enable prompt, effective immunosuppressive therapy."
    explanation: >-
      Recent case literature explicitly frames Wissler-Fanconi as a variant
      of adult-onset Still's disease, justifying application of Still's
      disease pathophysiology to this entity.
  - reference: PMID:38756937
    reference_title: Diagnosing and Treating Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still's Disease as Part of the Still's Disease Continuum.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sJIA and AOSD are rare autoinflammatory disorders that have similar pathophysiological and clinical features."
    explanation: >-
      Confirms that the Still's disease continuum (sJIA + AOSD), to which
      Wissler-Fanconi syndrome is now ascribed, is a single autoinflammatory
      entity sharing innate-immune-driven pathophysiology.
  downstream:
  - target: NLRP3 inflammasome activation and IL-1β/IL-18 maturation
    causal_link_type: DIRECT
    description: >-
      PRR engagement provides signal 1 for inflammasome priming and signal 2
      for assembly.
- name: NLRP3 inflammasome activation and IL-1β/IL-18 maturation
  description: >-
    PAMP/DAMP signalling in monocytes and macrophages assembles the NLRP3
    inflammasome, activating caspase-1 and converting pro-IL-1β and pro-IL-18
    into their mature, secreted forms — a core innate-immune mechanism shared
    across the Still's disease spectrum.
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: NLRP3 inflammasome complex assembly
    term:
      id: GO:0044546
      label: NLRP3 inflammasome complex assembly
    modifier: INCREASED
  - preferred_term: interleukin-1 beta production
    term:
      id: GO:0032611
      label: interleukin-1 beta production
    modifier: INCREASED
  - preferred_term: interleukin-18 production
    term:
      id: GO:0032621
      label: interleukin-18 production
    modifier: INCREASED
  evidence:
  - reference: PMID:36090971
    reference_title: Activation mechanisms of monocytes/macrophages in adult-onset Still disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These stimulations on monocytes/macrophages cause activation of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain (NLRP) 3 inflammasomes, which trigger capase-1 activation, resulting in conversion of pro-IL-1β and pro-IL-18 into mature forms."
    explanation: >-
      Establishes NLRP3 inflammasome→caspase-1→IL-1β/IL-18 as the canonical
      mechanism downstream of PAMP/DAMP signalling in AOSD.
  - reference: PMID:37446301
    reference_title: "IL-18 in Autoinflammatory Diseases: Focus on Adult Onset Still Disease and Macrophages Activation Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "key mediator of autoinflammatory diseases associated with the development of macrophage activation syndrome (MAS), including systemic juvenile idiopathic arthritis and adult-onset Still's disease."
    explanation: >-
      IL-18 produced downstream of inflammasome activation is a recognised
      key mediator of the Still's disease spectrum, supporting this node's
      mechanistic role.
  downstream:
  - target: Systemic pro-inflammatory cytokine cascade
    causal_link_type: DIRECT
    description: >-
      Mature IL-1β and IL-18 propagate paracrine signalling and trigger IL-6
      production, driving systemic inflammation.
- name: Systemic pro-inflammatory cytokine cascade
  description: >-
    Mature IL-1β, IL-18, and downstream IL-6 produced by activated
    monocytes/macrophages drive a systemic acute-phase response with fever,
    leukocyte mobilisation, and synthesis of acute-phase reactants
    (CRP, serum amyloid A, ferritin) in the liver. This cascade underlies
    the validated efficacy of IL-1 and IL-6 pathway inhibitors in Still's
    disease.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: interleukin-1-mediated signaling pathway
    term:
      id: GO:0070498
      label: interleukin-1-mediated signaling pathway
    modifier: INCREASED
  - preferred_term: interleukin-6 production
    term:
      id: GO:0032635
      label: interleukin-6 production
    modifier: INCREASED
  - preferred_term: positive regulation of inflammatory response
    term:
      id: GO:0050729
      label: positive regulation of inflammatory response
  evidence:
  - reference: PMID:36090971
    reference_title: Activation mechanisms of monocytes/macrophages in adult-onset Still disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IL-1β and IL-18 produced by activated monocytes/macrophages contribute to various clinical features in AOSD."
    explanation: >-
      Connects mature inflammasome cytokines to the multi-system clinical
      phenotype of AOSD/Still's disease.
  - reference: PMID:39317417
    reference_title: EULAR/PReS recommendations for the diagnosis and management of Still's disease, comprising systemic juvenile idiopathic arthritis and adult-onset Still's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The optimal therapeutic strategy relies on early use of interleukin (IL-1 or IL-6 inhibitors"
    explanation: >-
      EULAR/PReS consensus that IL-1 and IL-6 are core therapeutic targets
      in Still's disease confirms these cytokines as the dominant
      inflammatory drivers.
  downstream:
  - target: Neutrophil hyperactivation and NET formation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - IL-1β and IL-6 drive granulopoiesis and neutrophil demargination, producing the marked neutrophilic leukocytosis.
  - target: Th1/Th17 adaptive immune hyperactivation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - IL-18 is a potent Th1 polariser and IL-6 promotes Th17 differentiation, linking the innate cytokine cascade to adaptive immune skewing.
  - target: Vascular endothelial activation and cutaneous vasculitis
    causal_link_type: DIRECT
    description: IL-1β and TNF directly upregulate endothelial adhesion molecules and procoagulant gene expression.
  - target: Cardiac serositis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Systemic IL-1β/IL-6/IL-18 signalling extends to pericardial and myocardial serosal surfaces, where it drives sterile inflammation.
  - target: Recurrent high fever
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - IL-1β/IL-6 acting on hypothalamic temperature regulation.
  - target: Erythrocyte sedimentation rate
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - IL-6-driven hepatic acute-phase protein (fibrinogen) synthesis.
  - target: C-reactive protein
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - IL-6 induction of hepatocyte CRP transcription.
  - target: Hyperferritinemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - IL-1β/IL-18 driven activation of macrophage ferritin synthesis.
- name: Neutrophil hyperactivation and NET formation
  description: >-
    Pro-inflammatory cytokines drive marked neutrophilia with neutrophil
    predominance and release of neutrophil extracellular traps (NETs), which
    feed back to amplify monocyte/macrophage activation and contribute to
    cutaneous and small-vessel inflammation.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: neutrophil migration
    term:
      id: GO:1990266
      label: neutrophil migration
    modifier: INCREASED
  - preferred_term: neutrophil extracellular trap formation
    term:
      id: GO:0140645
      label: neutrophil extracellular trap formation
    modifier: INCREASED
  evidence:
  - reference: PMID:36090971
    reference_title: Activation mechanisms of monocytes/macrophages in adult-onset Still disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hyperactivation of macrophages and neutrophils along with low activation of natural killer (NK) cells in innate immunity"
    explanation: Identifies neutrophil hyperactivation as a core innate-immune feature of AOSD/Still's disease.
  - reference: PMID:27843372
    reference_title: "Wissler-Fanconi syndrome and related diagnoses: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "white blood cell count (21,000 cells per µL, >95% neutrophils and 28 bands)"
    explanation: Case-level demonstration of marked neutrophilic leukocytosis with bandemia in a patient meeting Wissler-Fanconi criteria.
  downstream:
  - target: Leukocytosis
    causal_link_type: DIRECT
    description: Cytokine-driven neutrophilic leukocytosis is the haematologic hallmark of the syndrome.
  - target: Vascular endothelial activation and cutaneous vasculitis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - NET-derived DNA and granule contents activate endothelium and amplify perivascular neutrophil-mediated injury.
  - target: Vasculitis in the skin
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Perivascular neutrophil infiltration with leukocytoclasis manifests histologically as urticarial vasculitis.
- name: Th1/Th17 adaptive immune hyperactivation
  description: >-
    In addition to innate immune drive, hyperactivation of Th1 and Th17
    effector populations and a relative deficit of regulatory T cells
    contribute to chronic auto-inflammation and synovial involvement.
  cell_types:
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  - preferred_term: T-helper 17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  biological_processes:
  - preferred_term: T-helper 1 type immune response
    term:
      id: GO:0042088
      label: T-helper 1 type immune response
    modifier: INCREASED
  - preferred_term: positive regulation of interleukin-17 production
    term:
      id: GO:0032740
      label: positive regulation of interleukin-17 production
  - preferred_term: adaptive immune response
    term:
      id: GO:0002250
      label: adaptive immune response
  evidence:
  - reference: PMID:36090971
    reference_title: Activation mechanisms of monocytes/macrophages in adult-onset Still disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hyperactivation of Th1 and Th17 cells, whereas low activation of regulatory T cells (Tregs) in acquired immunity are involved in the pathogenic process of AOSD."
    explanation: Establishes Th1/Th17 hyperactivation and Treg deficit as the adaptive-immune limb of AOSD/Still's pathogenesis.
  downstream:
  - target: Synovial inflammation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Th17-derived IL-17 and IL-1β/IL-6 from activated monocytes drive synovitis.
- name: Synovial inflammation
  description: >-
    Cytokine- and Th17-driven inflammation of synovial tissue produces the
    characteristic migratory polyarthralgia and arthritis of the disease.
  cell_types:
  - preferred_term: synovial cell
    term:
      id: CL:0000214
      label: synovial cell
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: chronic inflammatory response
    term:
      id: GO:0002544
      label: chronic inflammatory response
  evidence:
  - reference: PMID:8150635
    reference_title: "[Wissler's allergic subsepsis]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This rare disease is characterized by four typical symptoms: polymorphous exanthemas, recurrent high fever, leucocytosis and arthralgia."
    explanation: Arthralgia is a defining feature of Wissler-Fanconi syndrome, consistent with synovial inflammation.
  - reference: PMID:27843372
    reference_title: "Wissler-Fanconi syndrome and related diagnoses: a case report."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient had migratory polyarthritis and polymorphic maculopapular rash on the back and lower extremities for 4 months."
    explanation: Documents the migratory polyarthritis attributable to synovial inflammation in a Wissler-Fanconi case.
  downstream:
  - target: Arthralgia
    causal_link_type: DIRECT
  - target: Arthritis
    causal_link_type: DIRECT
- name: Vascular endothelial activation and cutaneous vasculitis
  description: >-
    Cytokine-driven endothelial activation produces a polymorphous exanthem
    that can show histologic urticarial / leukocytoclastic vasculitis on skin
    biopsy. Renal microvascular involvement with intravascular coagulation
    can manifest as transient microscopic hematuria.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: positive regulation of inflammatory response
    term:
      id: GO:0050729
      label: positive regulation of inflammatory response
  - preferred_term: leukocyte migration
    term:
      id: GO:0050900
      label: leukocyte migration
  evidence:
  - reference: PMID:27843372
    reference_title: "Wissler-Fanconi syndrome and related diagnoses: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A dermatologist biopsied the rash. According to a dermatopathologist, the findings were consistent with urticarial vasculitis."
    explanation: Provides histopathologic confirmation of cutaneous vasculitis as the substrate of the Wissler-Fanconi exanthem.
  - reference: PMID:3572917
    reference_title: Hematuria as presenting sign in Wissler-Fanconi syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Renal biopsy findings were compatible with intravascular coagulation."
    explanation: Documents a microvascular intravascular coagulation pattern on renal biopsy, providing the proximate mechanism for hematuria.
  downstream:
  - target: Exanthem
    causal_link_type: DIRECT
  - target: Vasculitis in the skin
    causal_link_type: DIRECT
  - target: Microscopic hematuria
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Glomerular microvascular intravascular coagulation, as documented on renal biopsy.
- name: Cardiac serositis
  description: >-
    Pericardial and myocardial inflammation can complicate the disease,
    ranging from sterile pericarditis with effusion to chronic
    pericardio-myocarditis progressing to refractory heart failure in rare
    cases.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:3092775
    reference_title: "[Fatal form of pericardo-myocarditis in Wissler-Fanconi syndrome]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The long-term evolution is marked by recurrent febrile exacerbations, sometimes complicated by pericardo-myocarditis which usually resolves without sequellae."
    explanation: Pericardo-myocarditis is a recognised, mechanism-relevant complication of Wissler-Fanconi syndrome.
  - reference: PMID:27843372
    reference_title: "Wissler-Fanconi syndrome and related diagnoses: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Computed tomography scan of the chest ruled out pulmonary embolism and revealed a pericardial effusion."
    explanation: Imaging documentation of pericardial effusion in a Wissler-Fanconi case.
  downstream:
  - target: Pericardial effusion
    causal_link_type: DIRECT
  - target: Pericarditis
    causal_link_type: DIRECT
  - target: Myocarditis
    causal_link_type: DIRECT
  - target: Congestive heart failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Chronic refractory pericardio-myocarditis with progressive ventricular dysfunction.
phenotypes:
- name: Recurrent high fever
  category: Systemic
  frequency: FREQUENT
  severity: High
  phenotype_term:
    preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
  evidence:
  - reference: PMID:8150635
    reference_title: "[Wissler's allergic subsepsis]."
    supports: SUPPORT
    snippet: "This rare disease is characterized by four typical symptoms: polymorphous exanthemas, recurrent high fever, leucocytosis and arthralgia."
    explanation: The abstract lists recurrent high fever as a typical symptom of Wissler-Fanconi syndrome.
- name: Exanthem
  category: Dermatological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Exanthem
    term:
      id: HP:4000054
      label: Exanthem
  evidence:
  - reference: PMID:8150635
    reference_title: "[Wissler's allergic subsepsis]."
    supports: SUPPORT
    snippet: "This rare disease is characterized by four typical symptoms: polymorphous exanthemas, recurrent high fever, leucocytosis and arthralgia."
    explanation: The abstract lists polymorphous exanthemas as a typical symptom of Wissler-Fanconi syndrome.
- name: Arthralgia
  category: Musculoskeletal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  evidence:
  - reference: PMID:8150635
    reference_title: "[Wissler's allergic subsepsis]."
    supports: SUPPORT
    snippet: "This rare disease is characterized by four typical symptoms: polymorphous exanthemas, recurrent high fever, leucocytosis and arthralgia."
    explanation: The abstract lists arthralgia as a typical symptom of Wissler-Fanconi syndrome.
- name: Leukocytosis
  category: Hematologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Leukocytosis
    term:
      id: HP:0001974
      label: Increased total leukocyte count
  evidence:
  - reference: PMID:8150635
    reference_title: "[Wissler's allergic subsepsis]."
    supports: SUPPORT
    snippet: "This rare disease is characterized by four typical symptoms: polymorphous exanthemas, recurrent high fever, leucocytosis and arthralgia."
    explanation: The abstract lists leukocytosis as a typical symptom of Wissler-Fanconi syndrome.
- name: Microscopic hematuria
  category: Renal
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Microscopic hematuria
    term:
      id: HP:0002907
      label: Microscopic hematuria
  evidence:
  - reference: PMID:3572917
    reference_title: "Hematuria as presenting sign in Wissler-Fanconi syndrome."
    supports: PARTIAL
    snippet: "We describe a case of persistent microscopic hematuria as initial finding in incomplete Still's disease or Wissler-Fanconi syndrome."
    explanation: The case report documents microscopic hematuria as a presenting sign.
- name: Arthritis
  category: Musculoskeletal
  frequency: FREQUENT
  notes: Migratory polyarthritis reported in case presentations.
  phenotype_term:
    preferred_term: Arthritis
    term:
      id: HP:0001369
      label: Arthritis
  evidence:
  - reference: PMID:27843372
    reference_title: "Wissler-Fanconi syndrome and related diagnoses: a case report."
    supports: PARTIAL
    snippet: "A middle-aged female presented to the emergency department with shortness of breath and chest pain associated with fever, polyarthritis, and had a chronic polymorphic rash on the back and lower extremities."
    explanation: The case report documents polyarthritis as part of the clinical presentation.
- name: Pericarditis
  category: Cardiovascular
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Pericarditis
    term:
      id: HP:0001701
      label: Pericarditis
  evidence:
  - reference: PMID:3092775
    reference_title: "[Fatal form of pericardo-myocarditis in Wissler-Fanconi syndrome]."
    supports: PARTIAL
    snippet: "The long-term evolution is marked by recurrent febrile exacerbations, sometimes complicated by pericardo-myocarditis which usually resolves without sequellae."
    explanation: The abstract notes pericardo-myocarditis as a complication during the course of disease.
- name: Myocarditis
  category: Cardiovascular
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Myocarditis
    term:
      id: HP:0012819
      label: Myocarditis
  evidence:
  - reference: PMID:3092775
    reference_title: "[Fatal form of pericardo-myocarditis in Wissler-Fanconi syndrome]."
    supports: PARTIAL
    snippet: "The long-term evolution is marked by recurrent febrile exacerbations, sometimes complicated by pericardo-myocarditis which usually resolves without sequellae."
    explanation: The abstract reports pericardo-myocarditis as a complication of Wissler-Fanconi syndrome.
- name: Congestive heart failure
  category: Cardiovascular
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:3092775
    reference_title: "[Fatal form of pericardo-myocarditis in Wissler-Fanconi syndrome]."
    supports: SUPPORT
    snippet: "The authors report a case with chronic pericardo-myocarditis progressing over a 7 year period to refractory congestive cardiac failure."
    explanation: The case report documents progression to refractory congestive heart failure.
- name: Pericardial effusion
  category: Cardiovascular
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Pericardial effusion
    term:
      id: HP:0001698
      label: Pericardial effusion
  evidence:
  - reference: PMID:27843372
    reference_title: "Wissler-Fanconi syndrome and related diagnoses: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Computed tomography scan of the chest ruled out pulmonary embolism and revealed a pericardial effusion."
    explanation: Imaging directly documents pericardial effusion as a complication of Wissler-Fanconi syndrome.
- name: Vasculitis in the skin
  category: Dermatological
  frequency: OCCASIONAL
  notes: Histologic substrate of the polymorphous exanthem on biopsy.
  phenotype_term:
    preferred_term: Urticarial vasculitis
    term:
      id: HP:0200029
      label: Vasculitis in the skin
  evidence:
  - reference: PMID:27843372
    reference_title: "Wissler-Fanconi syndrome and related diagnoses: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A dermatologist biopsied the rash. According to a dermatopathologist, the findings were consistent with urticarial vasculitis."
    explanation: Skin biopsy in a Wissler-Fanconi case showed histologic urticarial vasculitis.
- name: Anemia
  category: Hematologic
  frequency: OCCASIONAL
  notes: Anemia of chronic inflammation; documented in case-level laboratory data.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:27843372
    reference_title: "Wissler-Fanconi syndrome and related diagnoses: a case report."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "hemoglobin (9.3 g/dL, normal: 10.1–14.5 g/dL)"
    explanation: Case-level hemoglobin documents anemia in a patient meeting Wissler-Fanconi criteria.
biochemical:
- name: Erythrocyte sedimentation rate
  presence: Elevated
  biomarker_term:
    preferred_term: Elevated erythrocyte sedimentation rate
    term:
      id: HP:0003565
      label: Elevated erythrocyte sedimentation rate
  evidence:
  - reference: PMID:27843372
    reference_title: "Wissler-Fanconi syndrome and related diagnoses: a case report."
    supports: PARTIAL
    snippet: "Blood sample analysis revealed high levels of CRP (42.9 mg/dL, normal: 0–0.3), erythrocyte sedimentation rate (113 mm/h normal: 2–20)"
    explanation: The case report documents markedly elevated ESR, supporting a systemic inflammatory state.
- name: C-reactive protein
  presence: Elevated
  biomarker_term:
    preferred_term: Elevated circulating C-reactive protein concentration
    term:
      id: HP:0011227
      label: Elevated circulating C-reactive protein concentration
  evidence:
  - reference: PMID:27843372
    reference_title: "Wissler-Fanconi syndrome and related diagnoses: a case report."
    supports: PARTIAL
    snippet: "Blood sample analysis revealed high levels of CRP (42.9 mg/dL, normal: 0–0.3), erythrocyte sedimentation rate (113 mm/h normal: 2–20)"
    explanation: The case report documents markedly elevated CRP as part of the inflammatory syndrome.
- name: Hyperferritinemia
  presence: Elevated
  notes: >-
    Markedly elevated serum ferritin is a key shared feature of the Still's
    disease spectrum and a recommended early diagnostic test in suspected
    Wissler-Fanconi syndrome.
  biomarker_term:
    preferred_term: Increased circulating ferritin concentration
    term:
      id: HP:0003281
      label: Increased circulating ferritin concentration
  evidence:
  - reference: PMID:27843372
    reference_title: "Wissler-Fanconi syndrome and related diagnoses: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ferritin was significantly high at 29,349 ng/mL (normal: 10–291 ng/mL)."
    explanation: Documents markedly elevated ferritin (~100× upper limit of normal) in a Wissler-Fanconi case, consistent with the hyperferritinemic Still's spectrum.
  - reference: PMID:41737969
    reference_title: "When Fever Defies Diagnosis: Wissler-Fanconi Syndrome as an Atypical Presentation of Adult-Onset Still's Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recognition of the Wissler-Fanconi variant and early ferritin testing can prevent diagnostic delay and enable prompt, effective immunosuppressive therapy."
    explanation: Recent literature explicitly emphasises ferritin testing as a diagnostic anchor for the Wissler-Fanconi variant.
- name: Neutrophilic leukocytosis
  presence: Elevated
  notes: Marked neutrophil-predominant leukocytosis with bandemia.
  biomarker_term:
    preferred_term: Neutrophilia in absence of infection
    term:
      id: HP:0410258
      label: Neutrophilia in absence of infection
  evidence:
  - reference: PMID:27843372
    reference_title: "Wissler-Fanconi syndrome and related diagnoses: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "white blood cell count (21,000 cells per µL, >95% neutrophils and 28 bands)"
    explanation: Case-level data show marked neutrophilic predominance with bandemia, despite negative cultures (i.e. neutrophilia in absence of infection).
progression:
- phase: Onset (SNOMEDCT:77374008)
  age_range: Childhood to adulthood
  evidence:
  - reference: PMID:8150635
    reference_title: "[Wissler's allergic subsepsis]."
    supports: SUPPORT
    snippet: "A 20-year-old female patient with the typical signs of Wissler's subsepsis allergica (Wissler-Fanconi syndrome) is described."
    explanation: This case report documents onset in a young adult.
  - reference: PMID:1210460
    reference_title: "[A further case of Wissler's allergic subsepticemia in an adult]."
    supports: SUPPORT
    snippet: "A further case of subsepsis allergica Wissler in a 35-year-old woman is reported."
    explanation: This report documents adult-onset disease.
  - reference: DOI:10.1007/978-3-642-94912-8_6
    supports: SUPPORT
    snippet: "Zunächst haben nur die Pädiater die Krankheit gesehen, neuerdings sind aber auch Fälle bei Erwachsenen bekanntgegeben worden"
    explanation: The abstract notes that early reports were pediatric, with adult cases reported later.
- phase: Chronic (SNOMEDCT:90734009)
  notes: Recurrent febrile exacerbations with possible cardiac complications.
  evidence:
  - reference: PMID:3092775
    reference_title: "[Fatal form of pericardo-myocarditis in Wissler-Fanconi syndrome]."
    supports: SUPPORT
    snippet: "The long-term evolution is marked by recurrent febrile exacerbations, sometimes complicated by pericardo-myocarditis which usually resolves without sequellae."
    explanation: The abstract summarizes recurrent febrile exacerbations and possible cardiac complications over time.
notes: |
  Early publications largely originated from continental Europe, particularly Germany, France, and Italy. At the time of the review, the disease was not recognized in the English-speaking literature.
differential_diagnoses:
- name: Sepsis
  description: Early Wissler-Fanconi presentations can be difficult to distinguish from septicemia.
  distinguishing_features:
  - Repeated blood and urine cultures can be negative despite high fever and leukocytosis.
  disease_term:
    preferred_term: infectious disease with sepsis
    term:
      id: MONDO:1040015
      label: infectious disease with sepsis
  evidence:
  - reference: PMID:8150635
    reference_title: "[Wissler's allergic subsepsis]."
    supports: SUPPORT
    snippet: "In the early stages it is difficult to differentiate from septicaemia."
    explanation: The abstract notes early overlap with septicemia.
  - reference: PMID:27843372
    reference_title: "Wissler-Fanconi syndrome and related diagnoses: a case report."
    supports: SUPPORT
    snippet: "Urine and multiple blood cultures were negative."
    explanation: The case report documents negative cultures despite systemic inflammatory presentation.
- name: Acute rheumatic fever
  description: Considered in the differential diagnosis because of overlapping febrile inflammatory presentations.
  disease_term:
    preferred_term: rheumatic fever
    term:
      id: MONDO:0017767
      label: rheumatic fever
  evidence:
  - reference: PMID:27843372
    reference_title: "Wissler-Fanconi syndrome and related diagnoses: a case report."
    supports: SUPPORT
    snippet: "Features of Wissler-Fanconi syndrome can be found in a differential diagnosis that includes true sepsis, acute rheumatic fever, rheumatoid arthritis, and adult onset Still’s disease."
    explanation: The case report explicitly lists acute rheumatic fever as part of the differential diagnosis.
- name: Rheumatoid arthritis
  description: Inflammatory arthritis with systemic features can overlap with Wissler-Fanconi syndrome.
  disease_term:
    preferred_term: rheumatoid arthritis
    term:
      id: MONDO:0008383
      label: rheumatoid arthritis
  evidence:
  - reference: PMID:27843372
    reference_title: "Wissler-Fanconi syndrome and related diagnoses: a case report."
    supports: SUPPORT
    snippet: "Features of Wissler-Fanconi syndrome can be found in a differential diagnosis that includes true sepsis, acute rheumatic fever, rheumatoid arthritis, and adult onset Still’s disease."
    explanation: The case report explicitly lists rheumatoid arthritis as part of the differential diagnosis.
- name: Adult-onset Still's disease
  description: Shares fever, rash, leukocytosis, and arthralgia; some authors consider Wissler-Fanconi syndrome related.
  disease_term:
    preferred_term: adult-onset Still disease
    term:
      id: MONDO:0019355
      label: adult-onset Still disease
  evidence:
  - reference: PMID:27843372
    reference_title: "Wissler-Fanconi syndrome and related diagnoses: a case report."
    supports: SUPPORT
    snippet: "Features of Wissler-Fanconi syndrome can be found in a differential diagnosis that includes true sepsis, acute rheumatic fever, rheumatoid arthritis, and adult onset Still’s disease."
    explanation: The case report explicitly lists adult-onset Still's disease as part of the differential diagnosis.
  - reference: PMID:8150635
    reference_title: "[Wissler's allergic subsepsis]."
    supports: SUPPORT
    snippet: "This syndrome has sometimes been considered equivalent to or an initial stage of Still's disease (juvenile rheumatoid arthritis) progressing to degenerative arthritis in many patients, whereas other authors have classified it as a separate entity with good prognosis."
    explanation: The abstract notes debated overlap with Still's disease.
- name: Autoimmune polyendocrine syndrome type 1
  description: Reported in a case with subsepsis allergica; included as a differential context.
  disease_term:
    preferred_term: autoimmune polyendocrine syndrome type 1
    term:
      id: MONDO:0009411
      label: autoimmune polyendocrine syndrome type 1
  evidence:
  - reference: PMID:2233764
    reference_title: "[Subsepsis allergica in a patient with type I polyglandular autoimmune syndrome]."
    supports: PARTIAL
    snippet: "A 10.6 year old Turkish girl developed + the signs of a polyglandular autoimmune syndrome (PGA) type I since her first year of age."
    explanation: The report describes a patient with type I polyglandular autoimmune syndrome alongside subsepsis allergica.
treatments:
- name: Nonsteroidal anti-inflammatory drugs
  description: NSAIDs can reduce fever and inflammatory symptoms.
  treatment_term:
    preferred_term: NSAID therapy
    term:
      id: MAXO:0000221
      label: NSAID therapy
    therapeutic_agent:
    - preferred_term: naproxen
      term:
        id: NCIT:C680
        label: Naproxen
  evidence:
  - reference: PMID:27843372
    reference_title: "Wissler-Fanconi syndrome and related diagnoses: a case report."
    supports: PARTIAL
    snippet: "A combination of nonsteroidal anti-inflammatory drugs and steroids achieved complete remission."
    explanation: The case report documents remission with NSAID therapy.
- name: Corticosteroids
  description: Systemic corticosteroids (e.g., prednisolone) used as part of combination regimens to control inflammation.
  treatment_term:
    preferred_term: corticosteroid agent therapy
    term:
      id: MAXO:0000640
      label: corticosteroid agent therapy
  evidence:
  - reference: PMID:27843372
    reference_title: "Wissler-Fanconi syndrome and related diagnoses: a case report."
    supports: PARTIAL
    snippet: "A combination of nonsteroidal anti-inflammatory drugs and steroids achieved complete remission."
    explanation: The case report notes complete remission with steroids plus NSAIDs.
  - reference: PMID:1210460
    reference_title: "[A further case of Wissler's allergic subsepticemia in an adult]."
    supports: PARTIAL
    snippet: "In the present case the disease could successfully be controlled using imuran in combination with corticosteroids."
    explanation: The abstract indicates corticosteroids were part of successful therapy.
- name: Dapsone
  description: Dapsone was used alongside NSAIDs and corticosteroids in a reported case.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dapsone
      term:
        id: NCIT:C415
        label: Dapsone
  evidence:
  - reference: PMID:27843372
    reference_title: "Wissler-Fanconi syndrome and related diagnoses: a case report."
    supports: PARTIAL
    snippet: "A combination of naproxen, dapsone, and prednisolone therapy resulted in significant improvement of the patient’s arthralgias and rash."
    explanation: The case report documents improvement with dapsone as part of combination therapy.
- name: Azathioprine
  description: Immunosuppressive therapy used in combination with corticosteroids.
  treatment_term:
    preferred_term: immunosuppressive therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: azathioprine
      term:
        id: NCIT:C290
        label: Azathioprine
  evidence:
  - reference: PMID:1210460
    reference_title: "[A further case of Wissler's allergic subsepticemia in an adult]."
    supports: PARTIAL
    snippet: "In the present case the disease could successfully be controlled using imuran in combination with corticosteroids."
    explanation: The abstract reports successful control with azathioprine (imuran) plus steroids.
- name: IL-1 inhibitor (anakinra / canakinumab)
  description: >-
    IL-1 pathway blockade (anakinra, the recombinant IL-1 receptor antagonist,
    or canakinumab, an anti-IL-1β monoclonal antibody) targets the
    inflammasome–IL-1β axis that drives the Still's disease spectrum to which
    Wissler-Fanconi syndrome is now ascribed. EULAR/PReS recommends early
    use of IL-1 (or IL-6) inhibitors in Still's disease.
  target_mechanisms:
  - target: NLRP3 inflammasome activation and IL-1β/IL-18 maturation
    treatment_effect: INHIBITS
    description: IL-1 receptor blockade (anakinra) and IL-1β neutralization (canakinumab) directly inhibit downstream signalling from the activated inflammasome.
  - target: Systemic pro-inflammatory cytokine cascade
    treatment_effect: INHIBITS
    description: IL-1 pathway blockade abrogates the IL-1-driven fever, acute-phase response, and ferritin elevation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anakinra
      term:
        id: NCIT:C38717
        label: Anakinra
    - preferred_term: canakinumab
      term:
        id: NCIT:C80971
        label: Canakinumab
  evidence:
  - reference: PMID:39317417
    reference_title: EULAR/PReS recommendations for the diagnosis and management of Still's disease, comprising systemic juvenile idiopathic arthritis and adult-onset Still's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The optimal therapeutic strategy relies on early use of interleukin (IL-1 or IL-6 inhibitors"
    explanation: International consensus guideline endorses early IL-1 inhibitor use in Still's disease, the spectrum to which Wissler-Fanconi syndrome belongs.
  - reference: PMID:38302170
    reference_title: Systematic Review and Metaanalysis of Pharmacological Interventions in Adult-Onset Still Disease and the Role of Biologic Disease-Modifying Antirheumatic Drugs.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Evidence supports TCZ, ANK, and CNK therapy for AOSD."
    explanation: Meta-analysis confirms efficacy of anakinra (ANK) and canakinumab (CNK) in adult-onset Still's disease.
- name: IL-6 inhibitor (tocilizumab)
  description: >-
    IL-6 receptor blockade with tocilizumab targets the IL-6-driven acute
    phase response (fever, CRP, ferritin) and is recommended alongside IL-1
    inhibitors as a first-line biologic for Still's disease.
  target_mechanisms:
  - target: Systemic pro-inflammatory cytokine cascade
    treatment_effect: INHIBITS
    description: IL-6R blockade interrupts hepatic acute-phase protein synthesis and IL-6-mediated febrile signalling.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tocilizumab
      term:
        id: NCIT:C84217
        label: Tocilizumab
  evidence:
  - reference: PMID:39317417
    reference_title: EULAR/PReS recommendations for the diagnosis and management of Still's disease, comprising systemic juvenile idiopathic arthritis and adult-onset Still's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The optimal therapeutic strategy relies on early use of interleukin (IL-1 or IL-6 inhibitors"
    explanation: International consensus guideline endorses early IL-6 inhibitor use in Still's disease.
  - reference: PMID:38302170
    reference_title: Systematic Review and Metaanalysis of Pharmacological Interventions in Adult-Onset Still Disease and the Role of Biologic Disease-Modifying Antirheumatic Drugs.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For bDMARDs, tocilizumab (TCZ), anakinra (ANK), and canakinumab (CNK) had the most available data."
    explanation: Meta-analysis identifies tocilizumab as a primary biologic with supporting efficacy data in adult-onset Still's disease.
- name: Anti-TNF biologic therapy
  description: >-
    Anti-TNF therapy (e.g., adalimumab) has been used after diagnostic
    re-classification in a reported Wissler-Fanconi case who later met
    criteria for adult-onset Still's disease and rheumatoid arthritis.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: adalimumab
      term:
        id: NCIT:C65216
        label: Adalimumab
  evidence:
  - reference: PMID:27843372
    reference_title: "Wissler-Fanconi syndrome and related diagnoses: a case report."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "She is currently doing well on on adalimumab, methotrexate, and prednisone for rheumatoid arthritis"
    explanation: Documents anti-TNF (adalimumab) as part of long-term therapy in a case meeting Wissler-Fanconi criteria after rediagnosis within the Still's-RA spectrum.