Periodic Fever Syndromes: TRAPS, Mevalonate Kinase Deficiency, CAPS and PFAPA

A child or adult runs a high fever, feels ill for days, recovers completely, and then does it again. When no infection explains the pattern, the cause can be one of a small group of conditions in which the body's first-line inflammatory defenses switch on with no real target. This page covers four of them: tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD, formerly called hyperimmunoglobulin D syndrome), cryopyrin-associated periodic syndromes (CAPS), and periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA). The first three are inherited and rare, and all three can damage organs over time. The fourth is the common one, has no single known gene, and usually fades on its own during childhood. The fifth well-known member of the family has its own page: Familial Mediterranean Fever.

Table of Contents

  1. What These Conditions Share
  2. Tumor Necrosis Factor Receptor-Associated Periodic Syndrome
  3. Mevalonate Kinase Deficiency
  4. Cryopyrin-Associated Periodic Syndromes
  5. Periodic Fever, Aphthous Stomatitis, Pharyngitis and Adenitis
  6. How They Are Told Apart
  7. The Eurofever and PRINTO Classification Criteria
  8. Trial Results in the Inherited Syndromes
  9. Steroid Responses in the Childhood Syndrome
  10. The Tonsil Surgery Trials
  11. Amyloidosis: The Long-Term Risk
  12. Limits of the Evidence
  13. Key Research Papers
  14. Connections
  15. Featured Videos

What These Conditions Share

Researchers call these diseases autoinflammatory. A 2009 report in the New England Journal of Medicine gave a working definition: inflammation without evidence of infection, without high levels of autoantibodies and without self-attacking T cells. That separates them from autoimmune diseases such as lupus, where the immune system's targeted arm has learned to attack the body.

Two chemical messengers run through this family. In cryopyrin-associated periodic syndromes, gene variants cause overproduction of interleukin-1 beta, a signal that drives fever and inflammation. In tumor necrosis factor receptor-associated periodic syndrome, the fault lies in a receptor for tumor necrosis factor, yet the drugs with the strongest trial results block interleukin-1. In mevalonate kinase deficiency, the fault starts in a metabolic pathway rather than in an immune gene at all.

Blood tests during an attack usually show a surge of inflammatory proteins, including C-reactive protein and serum amyloid A. The second of these matters most over the long run, because serum amyloid A is the raw material of AA amyloidosis, the organ-damaging complication described further down this page.

Tumor Necrosis Factor Receptor-Associated Periodic Syndrome

Gene. The cause was reported in 1999: mutations in the gene for the 55 kDa tumor necrosis factor receptor, now called TNFRSF1A, found in seven families. The inheritance is autosomal dominant, so one altered copy is enough. In the original work, soluble receptor levels in the blood were about half of normal, and the researchers proposed that the receptor was not being cleared from the cell surface properly. A 2020 review describes the mechanism as still unclear, with misfolded receptor building up inside cells as a leading idea alongside defective shedding of the receptor.

Age and attacks. The largest series, 158 patients from the Eurofever/EUROTRAPS registry, reported a median age at first symptoms of 4.3 years, although 9.1% of patients first presented after age 30. Attacks were recurrent in 88%. Patients spent a median of 70 days a year with symptoms. A 2020 review describes the episodes as prolonged.

Symptoms. Among patients with clearly disease-causing variants, the registry recorded fever in 88%, limb pain in 85%, abdominal pain in 74%, rash in 63% and eye problems in 45%. Children were more likely than adults to have swollen lymph nodes, swelling around the eyes and abdominal pain.

The R92Q question. The commonest variant in that registry was R92Q, at 34% of cases, followed by T50M at 10%. A family history was present in only 19% of people with R92Q, against 64% of those with other variants. A later Eurofever analysis of 361 patients found that people with R92Q resembled those with syndrome of undifferentiated recurrent fever more than those with classical disease, with fewer affected relatives, less migratory rash and less amyloidosis; its authors concluded that these patients no longer fit this diagnosis. A French registry study of 101 patients labeled with the disease found a pathogenic or likely pathogenic variant in only 69%, named R92Q as the main variant of uncertain significance, and estimated a minimum French prevalence of about 1 in 1,156,711.

Mevalonate Kinase Deficiency

Gene. Two papers published side by side in 1999 traced the disease to MVK, the gene for mevalonate kinase, an enzyme in the pathway that makes isoprenoids. Inheritance is autosomal recessive, so a person needs two altered copies. One of the 1999 groups found raised mevalonic acid in patients' urine during severe fever episodes but not between them. A 2016 review states that the amount of enzyme activity left largely determines severity. The two named forms sit at opposite ends of that range: the milder hyperimmunoglobulin D syndrome and the severe mevalonic aciduria, which can also bring facial and body differences and brain abnormalities.

Age and attacks. The Eurofever series of 114 patients reported a median age at onset of 0.5 years and an average of 12 episodes a year. A separate international series of 103 patients found the same early start, a median first attack at 6 months, and a median gap of 9.9 years between onset and diagnosis. Attacks became less frequent with age, yet half of the patients over 20 still had six or more a year.

Symptoms. Of the 114 patients, 112 had gastrointestinal symptoms, 102 swollen lymph nodes, 99 skin or mouth involvement and 89 muscle or joint symptoms. Headache was reported in 43, a cerebellar syndrome in 2 and intellectual disability in 4. One patient had macrophage activation syndrome, a dangerous overactivation of immune cells. Most patients were well between attacks, but 10% to 20% had ongoing symptoms such as fatigue.

The old name was misleading. Immunoglobulin D levels were normal in 22% of the 103 patients in the international series, so a normal result does not exclude the disease. A single-center study of 61 patients tested urine mevalonic acid instead: sensitivity was 92% and specificity 90%, with a negative predictive value of 98%. Its authors wrote that the disease is very unlikely with normal excretion but cannot be ruled out completely, and that a positive result still needs gene analysis to confirm it.

Cryopyrin-Associated Periodic Syndromes

Gene. A 2001 paper found the responsible gene, then called CIAS1 and now NLRP3, which encodes the protein cryopyrin. A 2021 review describes the result: heterozygous variants lead to excess activity of the inflammasome, a protein complex inside cells, and overproduction of interleukin-1 beta. The milder forms run in families in a dominant pattern. In the severe form, parental DNA tested in a 2002 study showed no mutation in any of the four children whose parents could be checked, which supports a new mutation arising in the child.

Three points on one spectrum.

Organ involvement. The Eurofever series of 136 patients reported a median age at onset of 9 months and a median follow-up of 15 years. Neurological involvement appeared in 40%, with severe complications in 12%. Eye involvement appeared in 71% and hearing loss from nerve damage in 42%. Thirty-one different mutations were recorded. Rare variants and onset before 6 months of age were associated with more severe neurological disease and hearing loss.

Periodic Fever, Aphthous Stomatitis, Pharyngitis and Adenitis

No single known gene. The syndrome was first described in 1987 in 12 children, as a sporadic illness with attacks every 4 to 6 weeks. The cause is still described as unknown in reviews and in the 2019 Cochrane review. The Eurofever group classes it as non-hereditary, yet family histories do appear: 26.9% of 301 patients in an international cohort had a relative with recurrent fever or recurrent tonsillitis.

Age and frequency. A population-based Swedish study of 336 children found first symptoms before age 5 in almost 90%, with fewer than 3% presenting after age 10. It estimated a yearly incidence of 0.86 per 10,000 children under 18 and 2.6 per 10,000 children under 5. Adults are also described: a 2017 study enrolled 74 adults and proposed separate diagnostic criteria for them.

The clockwork pattern. Several series report nearly the same timing. A 1999 registry of 94 children recorded episodes of 4.8 days recurring every 28 days, with a peak temperature of 40.5 degrees C. A 2010 review of 105 children recorded 4.1 days and 29.8 days. A 2026 series of 1,211 patients recorded a median of 4.0 days and an interval of 30.0 days.

Symptoms vary more than the name suggests. In the 301-patient cohort, 271 had pharyngitis, 236 had swollen neck glands and 171 had mouth ulcers, but only 132 had all three. A further 228 had additional symptoms, including 131 with gastrointestinal complaints, 86 with joint or muscle pain and 36 with rash. C-reactive protein exceeded 50 mg/L in 131 of the 190 tested during a fever.

Outcome. The original report and the 1999 registry both recorded no long-term after-effects. In the 1999 registry, 34 of the 83 children followed up no longer had episodes, and in the remainder the episodes came less often over time. In the 105-child review, 20% resolved spontaneously, after a mean of 33.2 months, while 63% were still having episodes at the end of the study. A 2026 Finnish case-control study surveyed 98 former patients and 490 controls 5 to 16 years after diagnosis. Atopy was the only chronic condition significantly more common (14.3% versus 7.9%), and its authors concluded that long-term illness was otherwise not raised.

How They Are Told Apart

No single test separates all four. The published series point to several features that, taken together, help distinguish them:

Two other conditions on this site overlap with this list. Familial Mediterranean Fever is the other classic inherited recurrent fever. Adult-onset Still's Disease is not inherited in this way and has a daily fever pattern rather than separate attacks.

The Eurofever and PRINTO Classification Criteria

Classification criteria are built to sort patients consistently, mainly for research. The Eurofever Registry group published two rounds of them, the second with the Paediatric Rheumatology International Trials Organisation (PRINTO).

2015, clinical scores. From 1,215 consecutive patients, the group evaluated 518 with confirmed genetic disease (291 familial Mediterranean fever, 74 mevalonate kinase deficiency, 86 tumor necrosis factor receptor disease, 67 cryopyrin disease), plus 199 patients with the childhood syndrome as comparison patients. In an independent validation set, the area under the curve, a measure of how well a score separates groups where 1.0 is perfect, was 0.95 for tumor necrosis factor receptor disease, 0.96 for mevalonate kinase deficiency and 0.99 for the cryopyrin group.

2019, genetic and clinical sets. A panel of 25 clinicians and 8 geneticists, blinded to each patient's diagnosis, reviewed 360 random registry patients and reached consensus on 281 (78%). A consensus meeting then chose two sets of criteria for each inherited fever, one combining genetic and clinical findings and one using clinical findings alone, plus new criteria for the childhood syndrome. The four inherited-fever sets showed sensitivity of 0.94 to 1 and specificity of 0.95 to 1. For the childhood syndrome, sensitivity was 0.97 and specificity 0.93. Testing in an independent group of 1,018 patients gave accuracy from 0.81 to 0.98. This page reports those performance figures from the published abstract and does not reproduce the item-by-item checklists.

Other criteria. A separate 2017 set for cryopyrin-associated periodic syndromes requires raised inflammatory markers plus at least two of six features: hives-like rash, cold-triggered episodes, hearing loss from nerve damage, muscle and joint symptoms, chronic meningitis without infection, and skeletal abnormalities. Tested on 284 cases and 837 controls, it reached 81% sensitivity and 94% specificity. The 2017 adult criteria for the childhood syndrome reached 93.4% sensitivity and 91.7% specificity against adults with fever of unknown origin.

Trial Results in the Inherited Syndromes

The canakinumab CLUSTER trial

CLUSTER, published in 2018, randomly assigned patients with genetically confirmed disease, at the time of a flare, to canakinumab 150 mg or placebo every 4 weeks. Canakinumab is an antibody against interleukin-1 beta. The main outcome was resolution of the flare with no new flare up to week 16.

Infections were the most frequent adverse events among patients on canakinumab: 313.5, 148.0 and 173.3 per 100 patient-years in the three groups in the same order. Serious infections occurred at 13.7, 0.0 and 6.6 per 100 patient-years.

Cryopyrin-associated periodic syndromes

Canakinumab. A 2009 randomized withdrawal trial gave 35 patients canakinumab 150 mg, and 34 (97%) had a complete response. Of the 31 who then entered the randomized stage, all 15 kept on canakinumab every 8 weeks stayed in remission, while 13 of 16 on placebo (81%) flared. Suspected infections were more common on canakinumab (P=0.03), and two serious adverse events occurred, one urinary-source sepsis and one episode of vertigo.

Rilonacept. Two sequential placebo-controlled studies enrolled 47 adults with familial cold autoinflammatory syndrome or Muckle-Wells syndrome. The trial gave 160 mg weekly by injection. Group mean symptom scores fell 84% on rilonacept and 13% on placebo (P<0.0001), and the commonest adverse events were injection site reactions. A 72-week open-label extension reported multi-symptom flare days falling from a mean of 7.3 to 0.6.

Anakinra. A 2006 study gave 18 patients with the severe neonatal form 1 to 2 mg per kilogram daily. All 18 responded rapidly, median serum amyloid A fell from 174 to 8 mg per liter, and in the 11 in whom the drug was withdrawn at three months, relapse followed within days. A later cohort of 26 patients treated for at least 36 months reported that central nervous system inflammation stayed suppressed and hearing was mostly stable or improved at up to 5 years, but that bone lesions progressed and doses needed to rise. A separate safety report on 43 patients recorded 1,233 adverse events, a yearly rate of 7.7 per patient, and 24 serious events in 14 patients, mostly infections such as pneumonia and gastroenteritis. All resolved, and no patient stopped permanently because of an adverse event.

Tumor necrosis factor receptor-associated periodic syndrome outside CLUSTER

Before CLUSTER, the evidence came from small open studies. Anakinra at 1.5 mg per kilogram daily produced a prompt response in all 5 patients in a 2008 report, and when it was withdrawn from the children, the disease relapsed after a mean of 5.6 days. In a 2017 open-label study of 20 patients, 19 (95%) reached the main response on canakinumab, with a median of 4 days to clinical remission. All relapsed when the drug was withdrawn, at a median of 91.5 days. Etanercept, which blocks tumor necrosis factor itself, reduced symptoms in a dose-dependent way in a 15-patient open study but did not fully normalize symptoms or inflammatory markers, and patients stayed on it for a median of 3.3 years.

Mevalonate kinase deficiency outside CLUSTER

In a small observational study of on-demand anakinra, started at the first symptoms of an attack, 8 of 12 treated attacks showed at least a 50% shorter duration, without any change in how often attacks came. One of the two patients with mevalonic aciduria had a partial remission on continuous treatment, and the other had no response. A 6-patient crossover trial of simvastatin, testing whether blocking an earlier step of the same pathway would help, reduced urinary mevalonic acid in all patients and febrile days in 5 of 6, which its authors called preliminary evidence. In the 103-patient series, 24.4% responded to high-dose prednisone, and 33.3% to anakinra or etanercept.

Registries and recommendations

A 2013 analysis of 496 Eurofever patients plus the literature concluded that interleukin-1 blockade is confirmed for cryopyrin-associated periodic syndromes, and that on-demand steroids are probably a valid strategy in the childhood syndrome, mevalonate kinase deficiency and tumor necrosis factor receptor disease. The 2015 SHARE recommendations, a European expert consensus, accepted 20 recommendations on therapy and 14 on monitoring, with at least 80% agreement among the experts. The RELIANCE registry of 168 patients on canakinumab in routine care reported that about 70% stayed in remission. In its cryopyrin group, serious infections and serious adverse drug reactions were more common at higher than the recommended starting dose.

Steroid Responses in the Childhood Syndrome

A short steroid course is the best-known feature of treatment, reported from the very first description in 1987. In the 105-child review, individual episodes usually resolved with one oral dose of prednisolone of about 1 mg per kilogram. A 2006 series of 54 children found that a mean of 0.6 mg per kilogram per day was enough. The 1,211-patient series in 2026 reported that prednisone aborted episodes within a median of 3.0 hours.

The same reports record the drawback. The interval between attacks shortened in 50% of the patients who used prednisolone in the 105-child review. In the 2026 series, 54.2% had shorter intervals after prednisone, 38.2% had no change and 7.6% had longer ones, and 29.0% of those given a single low dose had a return of symptoms within 24 to 72 hours. All of these figures come from observational series rather than placebo-controlled trials.

Other preventive options have thinner evidence. In the 105-child review, cimetidine was associated with resolution of fevers in 7 of 26 children (27%). Among 19 people needing treatment for ongoing flares after tonsillectomy in a 2025 two-center study, 15 (79%) reported improvement on cimetidine or famotidine. Those reports had no control groups. A working group of the Childhood Arthritis and Rheumatology Research Alliance, published consensus plans in 2020 covering four approaches (fever-reducing medicines, steroids to stop attacks, colchicine or cimetidine for prevention, and tonsillectomy), and stated that there is a lack of evidence-based treatment guidelines. The plans exist to allow those treatments to be compared in future studies.

The Tonsil Surgery Trials

The childhood syndrome is unusual among fever disorders in having randomized surgical trials, though all are small.

What the reviews say. The 2019 Cochrane review pooled the first two trials, 67 children in all. The risk ratio for symptoms resolving and staying resolved was 4.38, with a confidence interval from 0.64 to 30.11, wide enough to cross no effect. Episodes fell sharply (rate ratio 0.08), from about one every two months to slightly under one every two years. Certainty was rated moderate. School absence and quality of life were not measured, and the authors noted that 19 and 14 children in the surgery arms were too few to detect uncommon complications such as bleeding. Two 2025 and 2026 meta-analyses adding the tonsillotomy trial reported a risk ratio for persistent symptoms of 0.28 and an odds ratio for remission of 42.21. The second had a confidence interval from 9.34 to 190.74, and its authors called the results hypothesis-generating; its pooled effect on fever duration was not statistically significant.

Surgery compared directly with medicine. A 2026 network meta-analysis of 16 randomized and non-randomized studies with 2,048 patients found no significant difference between pooled surgical and medical management (odds ratio 1.10, confidence interval 0.21 to 5.69). The studies disagreed strongly with each other, certainty was very low, and the authors concluded that the evidence is insufficient for a reliable comparison.

Outside trials. A 2025 study of 97 patients followed for a median of 49 months after tonsillectomy reported complete resolution in 65% at one center and 35% at the other. Another 25% had milder or less frequent episodes, 23% had a remission followed by recurrence, and 4% had no change. Full response was associated with attacks that had resolved with steroids, pus on the throat, and no rash or joint and muscle pain during flares.

Amyloidosis: The Long-Term Risk

In AA amyloidosis, long-running inflammation lets serum amyloid A protein deposit in organs, most importantly the kidneys. It is a life-threatening complication of the three inherited syndromes on this page. The long-term series of the childhood syndrome above report no lasting organ after-effects.

Amyloidosis is often how the fever disease is discovered. At the UK National Amyloidosis Centre, an inherited fever had not been considered before amyloidosis in 23 of 46 patients (50%). In a French referral center series from 2012 to 2025, amyloidosis came before the diagnosis of the fever disease in 40%, particularly in diseases other than familial Mediterranean fever. In a systematic review of 41 patients with the tumor necrosis factor receptor disease and amyloidosis, it came first in 96%.

The outcomes reported are severe. In the UK series, median age at amyloidosis was 38, 11 patients (24%) already had end-stage kidney failure on arrival, another 13 developed it, and 11 (24%) died. The median time from amyloidosis to end-stage kidney failure was 3.3 years. In the French series, 46% needed a kidney transplant and mortality reached 26%. Amyloidosis came back in the transplanted kidney in 4 patients, 36% of those transplanted, in the systematic review.

Suppressing the underlying disease changed the course. In the UK series, of 37 patients whose disease was at least partly controlled, amyloid deposits regressed in 17 (46%), stayed stable in 14 (38%) and grew in 2 (5%). In the rilonacept trials, serum amyloid A fell from levels associated with risk of amyloidosis to normal. In the systematic review, of 21 biologic drug regimens with data, 10 improved kidney function, 7 stabilized it and 4 were followed by decline.

Limits of the Evidence

Key Research Papers

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  1. PubMed: tumor necrosis factor receptor-associated periodic syndrome
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  4. PubMed: tonsillectomy in periodic fever, aphthous stomatitis, pharyngitis and adenitis
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