TNF Receptor-Associated Periodic Syndrome — Structured Data

AI-optimized single page. All data for TNF Receptor-Associated Periodic Syndrome in dense, structured format. Last updated: 2026-03-30.

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Key Statistics

Total reported cases: 1,000
Mean onset age: 4 years
Onset range: 1–63 years
Sex ratio (M:F): 1.1:1
Diagnostic delay: ~5 years
Discovered: 1982 (L.M. Williamson)
Prevalence: <1/1,000,000
Classification: autoinflammatory, monogenic
Pathophysiology: partially understood
Treatment status: effective options available
Genetic basis: well characterised
Aliases: TRAPS, Familial Hibernian Fever, TNFRSF1A-associated periodic syndrome, TNF Receptor-Associated Periodic Fever Syndrome, Periodic Fever, Familial, Autosomal Dominant

Symptoms (12)

Symptom	Frequency	Severity	Category	Description
Recurrent prolonged fever	88%	cardinal	systemic	Febrile episodes lasting 1–4 weeks (longer than FMF), recurrent at irregular intervals. Temperature often >39°C. Median 70 symptomatic days per year.
Migratory myalgia	80%	cardinal	musculoskeletal	Distinctive centrifugal migratory muscle pain, typically moving distally along a limb over hours to days. Often accompanied by overlying erythematous skin changes. A hallmark feature that helps distinguish TRAPS from other periodic fevers.
Abdominal pain	75%	major	gastrointestinal	Severe abdominal pain during febrile episodes, sometimes mimicking surgical abdomen. Caused by peritoneal inflammation (sterile peritonitis). More frequent in paediatric onset (84% in children vs 25% in adults).
Periorbital edema	40%	cardinal	ophthalmic	Swelling around the eyes, often unilateral. A distinctive clinical feature that helps differentiate TRAPS from other autoinflammatory diseases. Included in Eurofever classification criteria.
Migratory erythematous rash	70%	major	dermatologic	Erythematous, often tender, migratory skin patches overlying areas of myalgia. Not urticarial (unlike Schnitzler or CAPS). Histology shows perivascular mononuclear infiltrate.
Arthralgia / arthritis	65%	major	musculoskeletal	Joint pain affecting large joints, sometimes with frank arthritis. Non-destructive. Typically coincides with febrile episodes.
Pleurisy / chest pain	40%	major	respiratory	Pleuritic chest pain from serositis. May present with pleural effusion. Part of the serosal inflammation spectrum in TRAPS.
Pericarditis	30%	major	cardiovascular	Present in ~30% of TRAPS patients. Can be the presenting feature, particularly in adults. More responsive to corticosteroids than to colchicine. 6% of idiopathic recurrent pericarditis patients may carry TNFRSF1A mutations.
Conjunctivitis / periorbital inflammation	45%	major	ophthalmic	Eye redness and inflammation, often unilateral. May occur with periorbital edema. Characteristic of TRAPS attacks.
Elevated CRP / acute phase reactants	95%	major	laboratory	Markedly elevated CRP and ESR during attacks. Serum amyloid A (SAA) often extremely high, predisposing to AA amyloidosis. Normalises between episodes in some patients.
Elevated serum amyloid A (SAA)	85%	major	laboratory	SAA is often extremely elevated during attacks, sometimes >1000 mg/L. Persistent SAA elevation is a risk factor for AA amyloidosis. Key monitoring biomarker.
Lymphadenopathy	20%	minor	systemic	Enlarged lymph nodes during febrile episodes. More commonly described in paediatric patients.

Molecular Pathway (9 molecules)

Molecule	Role	Expression change	Evidence level	Targeted by	Explanation
TNFR1 (TNFRSF1A)	Mutated receptor — primary disease gene product	Misfolded / ER-retained	established	—	TNFR1 is the 55 kDa type 1 TNF receptor encoded by TNFRSF1A. In TRAPS, missense mutations in the extracellular cysteine-rich domains cause protein misfolding, ER retention, and abnormal disulfide-linked oligomerisation. The mutant receptor does not function normally on the cell surface but instead potentiates inflammation from within the ER.
TNF-α	Ligand for TNFR1 — upstream trigger	Elevated during attacks	established	Etanercept (partial)	TNF-α is the principal ligand for TNFR1. In TRAPS, autocrine TNF secretion and wild-type TNFR1 on the cell surface amplify inflammation. Paradoxically, anti-TNF monoclonal antibodies (infliximab) can worsen disease, while soluble receptor mimetic etanercept has partial efficacy.
NF-κB	Transcription factor — inflammatory amplifier	Constitutively activated	established	—	ER-retained mutant TNFR1 constitutively activates NF-κB signalling, driving transcription of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α. NF-κB activation occurs via both canonical and non-canonical pathways.
MAPK pathway	Signalling cascade — enhanced by mutant TNFR1	Hyperactivated	strong	—	MAPK phosphorylation is enhanced in TRAPS patient cells upon LPS stimulation. Mitochondrial ROS drive increased MAPK activation, which in turn promotes pro-inflammatory cytokine production. This represents a TNF-independent mechanism of inflammation.
Mitochondrial ROS	Oxidative stress mediator — inflammasome activator	Elevated	strong	—	TRAPS cells exhibit elevated baseline mitochondrial reactive oxygen species. These ROS enhance NLRP3 inflammasome activation and drive IL-1β and other pro-inflammatory cytokine production. Antioxidants can reduce inflammatory output in vitro, suggesting ROS as a potential therapeutic target.
IL-1β	Key effector cytokine	Elevated	established	Anakinra, Canakinumab	IL-1β is the convergent downstream effector driving TRAPS symptoms. Despite being a TNF receptor disease, IL-1β blockade (anakinra, canakinumab) is far more effective than anti-TNF therapy. Mitochondrial ROS and ER stress both activate NLRP3 inflammasome → caspase-1 → IL-1β processing.
IL-6	Pro-inflammatory cytokine — acute phase driver	Elevated	moderate	Tocilizumab	IL-6 is elevated in TRAPS and drives acute phase responses including CRP and SAA production. Tocilizumab (anti-IL-6R) has shown efficacy in case reports when IL-1 and TNF blockade failed, supporting a pathogenic role for IL-6.
NLRP3 inflammasome	Inflammasome sensor — activated by mitochondrial ROS	Hyperactivated	strong	—	The NLRP3 inflammasome is activated downstream of mitochondrial ROS generation in TRAPS. NLRP3 assembles with ASC and activates caspase-1, which cleaves pro-IL-1β into active IL-1β. Unlike CAPS, there are no NLRP3 mutations — the inflammasome is activated by upstream signals from the misfolded TNFR1.
Serum Amyloid A (SAA)	Acute phase protein — amyloid precursor	Markedly elevated	established	—	SAA is produced by the liver in response to IL-6 and IL-1β. Persistent SAA elevation is the direct precursor to AA amyloidosis, the most serious TRAPS complication. SAA levels are a key monitoring biomarker and treatment target.

Genetic Findings (4)

Gene	Variant	Type	Frequency in disease	Significance	Also found in
TNFRSF1A	Cysteine-disrupting mutations (multiple)	germline	~27% of Eurofever patients	High-penetrance pathogenic variants. Disrupt disulfide bonds in CRD1/CRD2 of the TNFR1 extracellular domain. Associated with severe phenotype and high amyloidosis risk (24% vs 2% for non-cysteine).	—
TNFRSF1A	T50M (p.Thr79Met)	germline	~10% of Eurofever patients	Most common high-penetrance pathogenic variant. Affects a conserved hydrogen bond critical for protein folding in CRD1. Despite not disrupting a cysteine, carries high disease penetrance and amyloidosis risk similar to cysteine mutations.	—
TNFRSF1A	R92Q (p.Arg121Gln)	germline	~34% of Eurofever patients (most common variant overall)	Low-penetrance variant of uncertain pathogenic significance. Present in 1.2–4% of healthy Caucasians. Associated with milder disease, shorter episodes, less familial aggregation (19% vs 64%), and higher spontaneous resolution rates. Classified as INSAID Group B (uncertain significance).	Multiple sclerosis (Occasional co-occurrence reported)
TNFRSF1A	P46L (p.Pro75Leu)	germline	Low-penetrance, uncertain pathogenicity	Another low-penetrance variant. Found at high frequency in sub-Saharan West African populations. Clinical significance debated — may be a benign polymorphism in some ethnic backgrounds.	—

Treatment Evidence Matrix (7 treatments)

Drug	Mechanism	Route	Response rate	Onset	IgM effect	Line	Explanation
Anakinra	IL-1 receptor antagonist	SC 100mg daily (adults); 1–2 mg/kg/day (children)	~90% (complete ~67%)	Hours–days	N/A	1st	IL-1 receptor antagonist that blocks both IL-1α and IL-1β signalling. Despite TRAPS being a TNF receptor disease, IL-1 blockade is the most effective treatment because the pathogenic cascade converges on IL-1β via mitochondrial ROS and NLRP3 activation. Eurofever data shows ~90% efficacy with ~67% complete remission. Can be used on-demand for milder cases or continuously for severe disease.
Canakinumab	Anti-IL-1β monoclonal antibody	SC 150mg every 4–8 weeks	45% complete (Phase III); >94% disease control (long-term)	Days–weeks	N/A	1st	Selectively neutralises IL-1β with a long half-life allowing monthly dosing. The CLUSTER Phase III RCT (De Benedetti 2018) showed 45% complete response vs 8% placebo in TRAPS. The 72-week extension demonstrated >94% achieving no/minimal disease activity with sustained treatment. FDA/EMA approved for TRAPS. No patients on canakinumab developed AA amyloidosis in the Eurofever registry.
Etanercept	Soluble TNF receptor fusion protein (TNFR2-Fc)	SC 25mg twice weekly or 50mg weekly	Partial, waning over time	Days–weeks	N/A	Alternative	Historically the first biologic used in TRAPS. NIH dose-escalation study (15 patients) showed dose-dependent symptom reduction but incomplete normalisation. Long-term efficacy wanes — median duration 3.3 years before switching. Now largely superseded by IL-1 agents. May still be considered where IL-1 agents are unavailable.
Tocilizumab	Anti-IL-6 receptor monoclonal antibody	IV 8mg/kg every 4 weeks or SC	Case reports of efficacy	Weeks	N/A	Alternative	IL-6 is elevated in TRAPS and drives SAA production. Case reports show tocilizumab can control disease when both etanercept and anakinra/canakinumab fail. First reported by Lane et al. 2011 in a patient refractory to prior biologics. Considered for refractory cases, particularly where SAA remains elevated.
Corticosteroids	Broad anti-inflammatory	Oral (prednisone/prednisolone)	Effective for acute attacks; not for long-term	Hours–days	N/A	Alternative	Corticosteroids can abort acute TRAPS attacks and were historically the mainstay of treatment. However, they do not prevent future attacks, cannot prevent AA amyloidosis, and carry cumulative toxicity with chronic use. Dose escalation is common. Now reserved for acute flare bridging while initiating IL-1 blockade.
Colchicine	Microtubule inhibitor / anti-inflammatory	Oral 0.5–1mg daily	12.5% complete response	Weeks	N/A	Alternative	AIDA Network real-life data shows colchicine monotherapy achieves complete response in only 12.5% of TRAPS patients, with partial response in 58% and no response in 29%. May be considered for patients with low-penetrance variants (INSAID Group B/C) and mild phenotypes where biologic therapy seems excessive.
Infliximab	Anti-TNF monoclonal antibody	IV infusion	Paradoxical worsening reported	—	N/A	Not recommended	Anti-TNF monoclonal antibodies can paradoxically worsen TRAPS. Four patients developed acute flares within 12 hours of infliximab infusion. Unlike etanercept (soluble receptor mimetic), infliximab crosslinks membrane TNF and may activate TNFR1 signalling. Anti-TNF monoclonal antibodies (infliximab, adalimumab) are generally not recommended in TRAPS.

Diagnostic Criteria

Eurofever/PRINTO Classification Criteria (2019)

Sensitivity: high · Specificity: high

Major criteria (all required)

Confirmatory TNFRSF1A genotype (pathogenic or likely pathogenic variant)

Minor criteria (1+ required)

Duration of episode >7 days
Migratory myalgia
Migratory erythematous rash
Periorbital edema
Affected first-degree relative

Requires confirmatory genotype PLUS at least one clinical/familial feature. Developed by a panel of 33 international experts using evidence-based methodology with 360 patients from the Eurofever Registry. Applicable to TRAPS, FMF, MKD, and CAPS. Low-penetrance variants (R92Q, P46L) are NOT considered confirmatory.

INSAID Variant Classification System (2021)

Major criteria (all required)

Group A: Pathogenic or likely pathogenic TNFRSF1A variant (cysteine mutations, T50M, etc.)
Group B: Variant of uncertain significance (R92Q, P46L, unclassified)
Group C: Benign or likely benign variant

Minor criteria (0+ required)

Classifies TNFRSF1A variants into 3 groups to guide treatment. Group A patients should receive biologic therapy; Group B may respond to colchicine; Group C rarely needs treatment. All Group A patients fulfil Eurofever criteria. 51% of Group B patients do NOT fulfil Eurofever criteria. No Group C patients fulfil Eurofever criteria. Applied to 226 patients in the Eurofever Registry.

Differential Diagnoses (6)

Condition	Key distinction	Shared features
Familial Mediterranean Fever (FMF)	FMF episodes are shorter (12–72 hours vs 1–4 weeks in TRAPS). FMF is autosomal recessive (MEFV gene). FMF responds to colchicine. No periorbital edema in FMF. FMF predominates in Mediterranean populations.	Recurrent febrile episodes, Abdominal pain / serositis, Arthralgia, Elevated acute phase reactants, Risk of AA amyloidosis
Cryopyrin-Associated Periodic Syndromes (CAPS)	CAPS is caused by NLRP3 gain-of-function mutations (not TNFRSF1A). CAPS rash is urticarial (not migratory erythematous). CAPS often has sensorineural hearing loss. CAPS episodes are shorter. Cold triggers are common in CAPS/FCAS.	Autosomal dominant inheritance, IL-1β driven pathogenesis, Responds to IL-1 blockade, Childhood onset, Elevated inflammatory markers
Mevalonate Kinase Deficiency (MKD/HIDS)	MKD is autosomal recessive (MVK gene). Elevated IgD (though not always). Episodes last 3–7 days (shorter than TRAPS). Cervical lymphadenopathy is prominent. No periorbital edema.	Recurrent febrile episodes, Abdominal pain, Arthralgia, Rash, Elevated acute phase reactants
Adult-Onset Still's Disease (AOSD)	AOSD has evanescent salmon-colored rash (not migratory erythematous). Markedly elevated ferritin (often >1000 ng/mL). AOSD is sporadic, not familial. AOSD can present with macrophage activation syndrome.	Quotidian/spiking fever, Arthralgia, Serositis, Leukocytosis, Responds to IL-1 blockade
Schnitzler Syndrome	Schnitzler requires monoclonal IgM gammopathy (absent in TRAPS). Schnitzler is acquired (adult onset, median 53 years). Schnitzler rash is urticarial (not erythematous/migratory). No genetic mutation identified.	Recurrent fever, IL-1β driven, Responds to anakinra, Elevated CRP/ESR, Autoinflammatory spectrum
Idiopathic Recurrent Pericarditis	Most recurrent pericarditis is not TRAPS-related (only ~6% carry TNFRSF1A mutations). Idiopathic recurrent pericarditis responds well to colchicine; TRAPS-related pericarditis typically does not.	Recurrent episodes of chest pain, Pericardial effusion, Elevated inflammatory markers, May respond to IL-1 blockade

Hypotheses (4)

Hypothesis	Domain	Status	Evidence score	Studies	Evidence for	Evidence against
ER retention of misfolded TNFR1 drives inflammation through the unfolded protein response (UPR), independently of TNF binding	pathogenesis	leading	75/100	15	Mutant TNFR1 forms abnormal disulfide oligomers retained in ER (Lobito 2006) UPR sensors PERK, ATF6, IRE1α activated in TRAPS cells ER stress activates NF-κB and MAPK independently of surface TNF signalling Knockin mice with TRAPS mutations show intracellular TNFR1 accumulation	Not all mutations show equal ER retention Some low-penetrance variants (R92Q) do not cause significant misfolding ER stress alone does not fully explain the periodicity of attacks
Mitochondrial ROS generation from misfolded TNFR1 activates NLRP3 inflammasome, driving IL-1β-mediated inflammation	pathogenesis	leading	70/100	10	Elevated mitochondrial ROS in TRAPS patient PBMCs and knockin mouse cells (Bulua 2011) ROS enhance LPS-driven MAPK phosphorylation and cytokine secretion Antioxidants reduce inflammatory cytokine output in TRAPS cells Explains why IL-1 blockade works better than anti-TNF in TRAPS	NLRP3 is not mutated in TRAPS — mechanism of activation is indirect Not all TRAPS mutations equally enhance ROS Antioxidant therapy not yet tested clinically
Wild-type and mutant TNFR1 act in concert from distinct cellular locations — both alleles are required for the inflammatory phenotype	pathogenesis	leading	65/100	5	Heterozygous knockin mice are hypersensitive to LPS-induced septic shock Homozygous mutant mice resemble TNFR1-deficient mice (resistant to shock) Mutant TNFR1 enhances cytokine secretion only when WT TNFR1 is present on surface Explains autosomal dominant inheritance pattern	Mechanism by which ER-retained mutant cooperates with surface WT receptor is not fully characterised Some patients with compound heterozygous mutations complicate the model
Defective TNFR1 ectodomain shedding reduces soluble receptor, leaving TNF signalling unchecked	pathogenesis	competing	35/100	8	Original finding by McDermott 1999: some mutations impair TNFR1 shedding Low soluble TNFRSF1A levels observed between attacks in some patients Metalloprotease-mediated cleavage is impaired in certain mutations Etanercept (soluble receptor mimetic) has partial efficacy	Not all TRAPS mutations show defective shedding Some mutations with normal shedding still cause disease Shedding differences are cell-type dependent, not purely mutation-dependent Cannot explain the superiority of IL-1 blockade over anti-TNF therapy

Open Questions (5)

What triggers the periodicity of TRAPS attacks?
TRAPS patients have constant genetic mutations, yet attacks come and go. The mechanism that converts constitutive ER stress and ROS elevation into episodic febrile attacks is unknown. Environmental triggers, infections, stress, and hormonal changes are suspected but unproven.
Is R92Q truly pathogenic or a benign polymorphism with coincidental inflammatory phenotype?
R92Q is the most common TNFRSF1A variant in TRAPS patients (34%) but is also found in 1.2–4% of healthy Caucasians. Patients with R92Q have milder disease and higher spontaneous resolution. Its classification as INSAID Group B (uncertain significance) reflects genuine diagnostic ambiguity.
Why do anti-TNF monoclonal antibodies worsen TRAPS while etanercept provides partial benefit?
Infliximab and adalimumab can cause paradoxical flares in TRAPS within hours. Etanercept has partial but waning efficacy. The mechanistic difference — etanercept as soluble receptor vs infliximab crosslinking membrane TNF — is hypothesised but not proven in TRAPS-specific models.
Can early biologic treatment completely prevent AA amyloidosis in high-risk patients?
Cysteine mutations carry ~24% amyloidosis risk. The Eurofever data shows no patients on anti-IL-1 developed amyloidosis, but this is observational. A prospective study of early vs delayed biologic treatment in children with cysteine mutations is needed.
Could mitochondrial antioxidants serve as adjunctive therapy in TRAPS?
Bulua 2011 showed that pharmacological blockade of mitochondrial ROS reduces inflammatory cytokine production in TRAPS cell models. No clinical trials of antioxidants in TRAPS exist.

Complications (6)

Complication	Risk	Timeframe	Description	Monitoring
AA amyloidosis	~14% overall; ~24% with cysteine mutations; ~2% with non-cysteine mutations	Years of uncontrolled inflammation	The most severe complication of TRAPS. Chronic elevation of serum amyloid A (SAA) leads to deposition of AA amyloid fibrils, predominantly in the kidneys. Presents with proteinuria progressing to nephrotic syndrome and renal failure. In the French national series, 47% of TRAPS patients with AA amyloidosis required renal replacement therapy, with 14% mortality. AA amyloidosis preceded the TRAPS diagnosis in 96% of cases.	SAA levels every 3–6 months; annual urinalysis for proteinuria; renal function monitoring (eGFR, creatinine)
Renal failure (from AA amyloidosis)	47% of patients who develop AA amyloidosis	Progressive over months to years after amyloid deposition	End-stage renal disease from amyloid nephropathy. Biologic treatment can preserve residual renal function and prevent further progression. Some patients require dialysis or transplantation.	eGFR and creatinine every 3–6 months in patients with known AA amyloidosis; 24-hour urine protein if proteinuria detected
Growth retardation	Risk in children with chronic uncontrolled disease	Throughout childhood if inadequately treated	Chronic inflammation and recurrent corticosteroid use can impair growth in paediatric TRAPS patients. Early initiation of biologic therapy may preserve normal growth.	Regular growth monitoring (height, weight, growth velocity) in paediatric patients
Corticosteroid toxicity	High in patients requiring frequent steroid courses	Cumulative over years	Before IL-1 inhibitors, TRAPS patients often required frequent high-dose corticosteroids. Cumulative toxicity includes osteoporosis, diabetes, cushingoid features, cataracts, and growth suppression in children. This was the primary motivation for developing biologic treatments.	Bone density scans; glucose monitoring; ophthalmologic screening
Infertility	Reported in women with active uncontrolled disease	During active disease	Chronic inflammation may impair fertility. In the Eurofever registry, 7 women with a history of failure to conceive had successful pregnancies after initiation of anti-IL-1 treatment, suggesting the inflammation itself contributes to infertility.	Fertility counselling for women of reproductive age with active disease
Peritoneal adhesions	Moderate in patients with recurrent abdominal attacks	Cumulative from recurrent peritonitis	Recurrent sterile peritonitis during TRAPS attacks can lead to peritoneal adhesion formation, potentially causing bowel obstruction. Some patients undergo unnecessary exploratory laparotomy before TRAPS is diagnosed.	Clinical assessment during abdominal episodes; awareness of adhesion risk in surgical planning

Sources (1)

Ref	Authors	Title	Journal	Year	Category	Type	Grade	Link
A3	Gattorno M, Hofer M, Federici S, et al.	Classification criteria for autoinflammatory recurrent fevers (Eurofever/PRINTO)	Ann Rheum Dis	2019	diagnosis	cohort	A	DOI

Pathophysiology Narrative

TRAPS is caused by heterozygous missense mutations in the TNFRSF1A gene (chromosome 12p13), which encodes TNFR1 — the primary receptor for tumour necrosis factor. Over 170 variants have been described, most affecting the cysteine-rich extracellular domains (CRD1–CRD4) that are essential for receptor folding and TNF binding.

The pathogenesis is complex and involves multiple non-exclusive mechanisms. The original 'defective shedding' hypothesis (McDermott 1999) proposed that impaired cleavage of the TNFR1 ectodomain reduces circulating soluble receptor, leaving TNF signalling unchecked. While partly true, subsequent work revealed additional mechanisms.

Lobito et al. (2006) demonstrated that mutant TNFR1 misfolds and is retained in the endoplasmic reticulum, triggering the unfolded protein response (UPR). This ER stress activates NF-κB and MAPK signalling pathways independently of TNF binding. Simon et al. (2010) showed that wild-type and mutant TNFR1 act in concert from distinct cellular locations — the mutant from the ER, the wild-type from the cell surface — to potentiate inflammation.

Bulua et al. (2011) identified that TRAPS cells generate elevated mitochondrial reactive oxygen species (ROS), which enhance NLRP3 inflammasome activation and drive IL-1β production. This explains why IL-1 blockade is so effective despite TRAPS being a 'TNF receptor' disease — the final common pathway converges on IL-1β.

The paradox that anti-TNF monoclonal antibodies (infliximab, adalimumab) can worsen TRAPS while etanercept has partial efficacy is explained by their different mechanisms: etanercept acts as a soluble receptor mimetic, while infliximab crosslinks membrane TNF and can paradoxically activate TNFR1 signalling.

Genetic Basis Narrative

TRAPS is caused by heterozygous germline mutations in TNFRSF1A (12p13.31), encoding the 55 kDa type 1 TNF receptor. All pathogenic mutations affect the extracellular domain, which contains four cysteine-rich domains (CRDs). CRD1 mediates receptor self-assembly/homotrimerisation, while CRD2 and CRD3 are responsible for TNF ligand binding.

Mutations disrupting cysteine residues involved in disulfide bonds have higher clinical penetrance (93% vs 82% for non-cysteine) and dramatically higher amyloidosis risk (24% vs 2%). The most common high-penetrance variant is T50M (p.Thr79Met), affecting a conserved hydrogen bond critical for protein folding, found in ~10% of Eurofever registry patients.

R92Q (p.Arg121Gln) is the most frequently detected variant overall (34% of Eurofever cases) but is classified as low-penetrance. It is present in 1.2–4% of healthy Caucasians, has lower familial aggregation (19% vs 64% for other variants), and is associated with milder disease and higher rates of spontaneous resolution. Its pathogenic significance remains debated.

P46L is another low-penetrance variant, found at high frequency in sub-Saharan African populations. The INSAID classification system (pathogenic/likely pathogenic in Group A, uncertain significance in Group B, benign in Group C) has become essential for guiding treatment decisions.