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Conditions

Familial periodic fever syndromes

Familial periodic fever syndromes are inherited autoinflammatory conditions characterised by recurrent, self-limiting episodes of fever and systemic inflammation – often involving serosal, synovial or cutaneous tissues – in the absence of infection or autoantibody production.

Overview

‘Familial periodic fever syndromes’ is a term that describes the classical monogenic autoinflammatory conditions that cause recurrent, episodic, self-limiting fevers with serositis. These typically manifest in childhood and include:

  • familial Mediterranean fever (FMF);
  • TNF receptor-associated periodic syndrome (TRAPS); and
  • mevalonate kinase deficiency (MKD), which is also known as hyper IgD syndrome (HIDS).

Cryopyrin-associated periodic syndromes and related inflammasomopathies (CAPS) are considered separately.

Clinical features

Clinical features of FMF

FMF typically presents with episodes of fever and serositis, although clinical features may be variable even within families with the same genetic variant. Typically, patients will experience symptoms before their 10th birthday, though some adult-onset cases have been described.

Features include:

  • fever lasting typically 12–72 hours, which:
    • resolves spontaneously; and
    • varies in frequency;
  • serositis, including:
    • peritonitis and pleuritis (often presenting as abdominal pain);
    • synovitis (presenting as acute monoarthritis of the knee, ankle or hip); and
    • pericarditis (rare);
  • rash (erysipelas-like, erythematous, tender lesions, usually on the lower limbs);
  • myalgia;
  • potentially being triggered by menstruation, emotional stress or physical exertion;
  • being responsive to colchicine (typically, episodic features reduce in frequency); and
  • AA amyloidosis, particularly without treatment. Atypical forms may present with AA amyloidosis without any other features.

Clinical features of TRAPS

Clinical features of TRAPS include:

  • fever lasting typically one to four weeks, which:
    • resolves spontaneously; and
    • typically has a monthly frequency;
  • migratory myalgia;
  • periorbital oedema, which is associated with conjunctivitis;
  • serositis (often presenting as abdominal pain);
  • arthralgia; and
  • longer-term risk of AA amyloidosis.

Clinical features of MKD

Clinical features of MKD include:

  • fever lasting typically three to seven days, which:
    • resolves spontaneously; and
    • typically has a frequency of every four to six weeks;
  • lymphadenopathy, which:
    • is usually cervical; and
    • may be accompanied by splenomegaly;
  • peritonitis (often presenting as abdominal pain);
  • arthralgia and myalgia;
  • ulceration, typically oral or genital;
  • characteristic laboratory features, such as elevated IgD;
  • mevalonic acid in urine during febrile episodes; and
  • wide spectrum of disease, from:
    • hyper-IgD syndrome (mild periodic fever); to
    • mevalonic aciduria (a severe form with predominant neurodegenerative disease, presenting with developmental delay, cerebellar ataxia and dysmorphic features, poor growth and eye features including retinal dystrophy, cataracts and uveitis).

Genomics

FMF

FMF is caused by biallelic variants in the MEFV gene, located on chromosome 16p13.3. MEFV codes for pyrin, which functions as an immune sensor. Disease-causing genetic variants in MEFV lead to pyrin malfunction and subsequent inflammation due to uncontrolled IL-1β and IL-18 release and pyroptosis. Pyroptosis is a form of controlled cell death triggered by inflammasomes in response to intracellular pathogens. In monogenic familial periodic fever syndromes, pyroptosis is triggered inappropriately.

FMF is the most common autoinflammatory syndrome worldwide, with a prevalence as high as 1 in 1,000 in Mediterranean populations, particularly in those with Sephardic Jewish and Turkish heritage. The majority of cases follow an autosomal recessive mode of inheritance, with no disease present in carriers. However, in about 20% of cases, monoallelic variants appear to cause disease with autosomal dominant inheritance.

Well-characterised founder missense variants have been described in FMF and account for up to two-thirds of cases:

  • M694V (exon 10) – biallelic variants are associated with severe phenotypes;
  • M680I (exon 10);
  • V726A (exon 10);
  • M694I (exon 10); and
  • E148Q (exon 2) – may be a reduced penetrance variant.

In addition to missense variants, rare pathogenic variants include small deletions and splice-site variants that disrupt pyrin function.

TRAPS

TRAPS is an autosomal dominant condition caused by monoallelic variants in the TNFRSF1A gene, which encodes tumour necrosis factor receptor 1 (TNFR1). Pathogenic variants lead to misfolded versions of the receptor, causing intracellular accumulation and triggering the pyrin inflammasome and pyroptosis.

Disease-causing variants in TNFRSF1A are mostly found in the extracellular domain of TNFR1, where they disrupt protein folding. They include:

  • T50M – the most common variant, associated with a severe form of the condition;
  • C30S, C33G, C52R, C73W – associated with a more severe clinical phenotype and a higher risk of AA amyloidosis;
  • R92Q; and
  • C96R.

Incomplete penetrance with variable phenotypic severity is seen in TRAPS.

More rarely, loss-of-function variants in TNFRSF1A are described.

MKD

MKD is a rare autosomal recessive condition caused by biallelic genetic variants in MVK. These lead to a deficiency of mevalonate kinase, an enzyme required for cholesterol metabolism. This causes a reduction in geranylgeranyl pyrophosphate (GGPP), a protein required for post-translation modification of the essential molecular switch RhoA. RhoA is critical for appropriate activation of the pyrin inflammasome.

Pathogenic variants in MVK cause a loss of function in the resulting enzyme. Damaging missense and protein-truncating variants are both described in relation to disease, but protein-truncating variants typically cause mevalonic aciduria, a rare, early-onset metabolic condition. Residual activity of mevalonate kinase correlates with the severity of clinical features and age of onset, although variability can occur.

Diagnosis

FMF

Both clinical features and confirmatory genomic testing are required for a diagnosis of FMF. Clinical diagnosis is based on patients meeting the Tel-Hashomer criteria, which stipulate two major features or one major and two minor features for a definitive diagnosis, and one major and one minor for a probable diagnosis. Supportive criteria are also provided.

The major features are:

  • recurrent febrile attacks accompanied by peritonitis, synovitis or pleuritis;
  • AA-amyloidosis without predisposing disease; and
  • favourable response to continuous colchicine treatment.

The minor features are:

  • recurrent febrile attacks;
  • erysipelas-like erythema; and
  • FMF in a first-degree relative.

Despite being well characterised, genetic interpretation of MEFV variants may be challenging due to a large number of variants of unknown significance and the fact that patients with one disease-causing variant may occasionally express the disease phenotype. A trial of colchicine therapy may provide supportive evidence if genomic testing is inconclusive.

TRAPS

A diagnosis of TRAPS may be made in patients presenting with suggestive clinical features, as listed above, alongside molecular confirmation of a pathogenic genetic variant in TNFRSF1A.

Laboratory and imaging tests can help support the diagnosis. They may show:

  • elevated inflammatory markers (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), ferritin) during episodic flares; and
  • raised white cell count (leukocytosis).

MKD

A diagnosis of MKD may be made in patients presenting with suggestive clinical features, as listed above, alongside molecular confirmation of biallelic pathogenic genetic variants in MVK. Note that:

  • urinary mevalonate acid is high in patients, particularly during inflammatory episodes; and
  • mevalonate kinase activity may be measured to determine disease extent.

For information about testing in relation to the above conditions, see ‘Child with a suspected autoinflammatory condition‘.

Familial periodic fever syndromes may be identified before any symptoms appear; for example, through the Generation Study. Confirmation of the diagnosis will require referral to autoinflammatory or specialist rheumatology services. Please refer to the local pathway for your region for this condition.

Inheritance and genetic counselling

FMF is predominantly an autosomal recessive condition, although autosomal dominant forms have been described. It is mostly seen in patients with Mediterranean or Middle Eastern origin, with prevalence in these communities as high as 1 in 300. Affected individuals may have variable clinical features and incomplete penetrance has been described.

TRAPS and MVK are rarer genetic conditions; TRAPS in an autosomal dominant condition and MVK is inherited in an autosomal recessive pattern.

  • If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
    • 1-in-4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected;
    • 1-in-2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
    • 1-in-4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.
  • Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with a pathogenic variant.
    • The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%).
    • Incomplete penetrance can occur (that is, not everyone who has the variant develops the disease).

A family history should be taken, and parents and other potentially affected family members should be identified and screened as appropriate.

If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

Management

Familial periodic fever syndromes are rare, complex conditions and are best managed by a multidisciplinary autoinflammatory and/or specialist rheumatology service. Treatment is aimed at controlling inflammation and preventing life-threatening complications, such as amyloidosis.

In FMF, the initial first-line treatment is colchicine, a drug that blocks inflammasome assembly and reduces neutrophil chemotaxis. Treatment is life-long and in >95% of patients, frequency of periodic fevers is reduced, as is the risk of amyloidosis.

In patients where colchicine is ineffective, the following IL-1 inhibitors have been shown to be effective:

  • canakinumab: an anti-IL-1β monoclonal antibody;
  • anakinra: recombinant IL-1 receptor antagonist; and
  • rilonacept: an IL-1 fusion protein that binds IL-1.

In contrast with FMF, patients with TRAPS and MVK are usually unresponsive to colchicine and IL-I inhibitors are preferred in patients over two years old.

Mild or intermittent inflammatory symptoms may be treated with steroid-sparing agents, such as non-steroidal anti-inflammatory agents or corticosteroids.

Familial periodic fever syndromes may be identified before any symptoms appear; for example, through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 13/11/2025
  • Next review due: 13/11/2027
  • Authors: Dr Jesmeen Maimaris
  • Reviewers: Dr Eleanor Hay