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# Familial Mediterranean fever and other hereditary autoinflammatory syndromes

Inherited diseases of the innate immune system that cause repeated bouts of fever with belly, chest or joint pain and can damage the kidneys.

Updated 2026-11-01

## Structures involved

Tap one to see what it is and open it in 3D.

- [Peritoneum](https://durgical.com/en/anatomy/peritoneum/)
- [Pleura](https://durgical.com/en/anatomy/pleura/)
- [Kidneys](https://durgical.com/en/anatomy/kidney/)
- [Pericardium](https://durgical.com/en/anatomy/pericardium/)
- [Vessels inside the kidney](https://durgical.com/en/anatomy/intrarenal-arteries-and-veins/)
- [Spleen](https://durgical.com/en/anatomy/spleen/)
- [Joint capsule](https://durgical.com/en/anatomy/articular-capsule-of-knee-joint/)
- [Skin](https://durgical.com/en/anatomy/skin/)

## Why it happens

- [Systemic effects of inflammation: fever, acute-phase proteins, leukocytosis, sepsis](https://durgical.com/en/general-pathology/systemic-effects-of-inflammation-fever-acute-phase-proteins-leukocytosis-sepsis/)
- [Mendelian inheritance: autosomal dominant, recessive and X-linked](https://durgical.com/en/general-pathology/mendelian-inheritance-autosomal-dominant-recessive-and-x-linked/)
- [Other forms of cell death: necroptosis, pyroptosis, ferroptosis](https://durgical.com/en/general-pathology/other-forms-of-cell-death-necroptosis-pyroptosis-ferroptosis/)
- [Mediators of inflammation: the table to know](https://durgical.com/en/general-pathology/mediators-of-inflammation-the-table-to-know/)
- [Fever](https://durgical.com/en/physiology/fever/)
- [Serous membranes: pleura and peritoneum](https://durgical.com/en/histology/serous-membranes-pleura-and-peritoneum/)

## What it is

Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory (periodic fever) syndrome. It causes recurrent attacks of fever with serositis (peritonitis, pleuritis), arthritis or [skin](https://durgical.com/en/anatomy/skin/) rash, lasting one to three days, with full recovery in between. Its most serious complication is AA amyloidosis of the kidney, which daily colchicine prevents. Related monogenic syndromes are TRAPS, the cryopyrin-associated periodic syndromes (CAPS) and hyper-IgD syndrome (mevalonate kinase deficiency).

## Who gets it

Most frequent in Armenian, Turkish, Arab and Jewish (especially Sephardic) populations, where it affects about 1 in 200 to 1,000 people. It is rare in Latin America, but Colombia has large communities of Lebanese, Syrian and Palestinian descent, mostly on the Caribbean coast, in whom it should be considered. About 90% of patients have their first attack before age 20.

## Causes

- FMF: mutations in the MEFV gene (chromosome 16), encoding pyrin; usually autosomal recessive
- TRAPS: mutations in TNFRSF1A (TNF receptor 1); autosomal dominant
- CAPS: mutations in NLRP3 (cryopyrin); autosomal dominant
- Hyper-IgD syndrome (mevalonate kinase deficiency): mutations in MVK; autosomal recessive

## Risk factors

- Mediterranean or Middle Eastern ancestry
- Family history of periodic fevers or amyloidosis
- Consanguinity
- For amyloidosis: no or irregular colchicine, M694V homozygosity, male sex and the SAA1 alpha/alpha genotype
- Attack triggers: stress, cold, intense exercise, menstruation, infections

## Pathophysiology

Pyrin normally restrains the inflammasome. Mutant pyrin allows excessive activation of the inflammasome in neutrophils and monocytes, releasing large amounts of interleukin-1 beta, which drives fever and neutrophil-rich inflammation of the serosal membranes, synovium and skin. Repeated surges of acute-phase serum amyloid A can deposit as AA amyloid in the kidneys, gut and other organs. Colchicine blocks neutrophil microtubules and dampens this cascade.

## Classification

- FMF: attacks of 12 to 72 hours with serositis, arthritis and erysipelas-like rash
- TRAPS: attacks often longer than a week, migratory muscle pain with overlying red rash, periorbital oedema
- CAPS (familial cold autoinflammatory syndrome, Muckle-Wells syndrome, NOMID/CINCA): cold-induced urticaria-like rash, deafness, chronic meningitis in the severe form
- Hyper-IgD syndrome (mevalonate kinase deficiency): onset in infancy, attacks of 3 to 7 days with lymph node swelling, often triggered by vaccines
- PFAPA (periodic fever, aphthous stomatitis, pharyngitis and adenitis): the most common periodic fever in children, not inherited in a simple pattern

## Symptoms and signs

- Bouts of fever lasting 1 to 3 days that recur at irregular intervals
- Severe abdominal pain with guarding (sterile peritonitis), the most common feature
- One-sided pleuritic chest pain
- Arthritis of one large joint of the leg (knee, ankle, hip)
- Erysipelas-like red, tender patch on the shin, ankle or top of the foot
- Muscle pain after exertion, scrotal swelling in boys

## Red flags

- Foamy urine, swelling or proteinuria (renal amyloidosis)
- Rising creatinine
- Abdominal pain with signs that persist beyond the usual attack (true surgical [abdomen](https://durgical.com/en/anatomy/region/abdomen/), bowel obstruction from adhesions)
- Poor growth or delayed puberty in a child
- Infertility or recurrent miscarriage linked to uncontrolled disease

## Diagnosis

**Clinical**
Diagnosis is clinical, based on short, recurrent febrile attacks with serositis, arthritis or the typical rash, normal health between attacks, ethnic background and family history (Tel-Hashomer or Livneh criteria). Improvement on a trial of colchicine supports the diagnosis.

**Tests**
During attacks: leukocytosis, raised CRP, ESR, fibrinogen and serum amyloid A, which normalise between attacks (persistent elevation suggests uncontrolled disease). Genetic testing for MEFV mutations confirms the diagnosis; gene panels for TNFRSF1A, NLRP3 and MVK when the pattern fits another syndrome; urinary mevalonic acid in attacks for hyper-IgD syndrome. Urinalysis for proteinuria at every visit; rectal, fat or [kidney](https://durgical.com/en/anatomy/kidney/) biopsy if amyloidosis is suspected.

**Imaging**
Not required for diagnosis. Abdominal ultrasound or CT during an attack may show a little free fluid and helps exclude appendicitis and other surgical causes; [chest](https://durgical.com/en/anatomy/region/chest/) X-ray may show a small pleural effusion.

## Differential diagnosis

- Acute appendicitis and other surgical abdomen (many FMF patients have an unnecessary appendectomy)
- Recurrent infections, including malaria and brucellosis
- Other periodic fevers: TRAPS, CAPS, hyper-IgD syndrome, PFAPA
- Adult-onset Still disease and systemic juvenile idiopathic arthritis
- Behçet disease and inflammatory bowel disease
- Acute intermittent porphyria (recurrent abdominal pain)

## Goal of treatment

Prevent attacks and, above all, prevent AA amyloidosis by lifelong daily treatment that keeps inflammatory markers normal between attacks.

## Treatment

**Medical**
Colchicine taken every day for life is the cornerstone of FMF: it prevents most attacks and protects against amyloidosis; it is continued in pregnancy and breastfeeding.

**Medical**
Colchicine-resistant or intolerant FMF: interleukin-1 blockers (anakinra, canakinumab or rilonacept) added to the maximum tolerated colchicine.

**Acute**
Attacks: NSAIDs, rest and hydration; colchicine does not stop an attack already under way, and recognising FMF avoids unnecessary abdominal surgery.

**Medical**
Other syndromes: interleukin-1 blockers are the treatment of choice for CAPS and are effective in TRAPS and hyper-IgD syndrome; short courses of glucocorticoids may help TRAPS attacks.

**Follow-up**
Monitoring: urine protein, creatinine and inflammatory markers between attacks, adherence and side effects of colchicine (diarrhoea, interactions with drugs such as macrolides and some statins), and growth in children.

## Drugs for this condition

- [Colchicine](https://durgical.com/en/pharmacology/colchicine/)
- [Anakinra](https://durgical.com/en/pharmacology/anakinra/)

## Complications

- AA amyloidosis with nephrotic syndrome and kidney failure
- Peritoneal adhesions and bowel obstruction
- Infertility
- Growth delay in children
- Associated vasculitis (IgA vasculitis, polyarteritis nodosa)

## Prognosis

With regular colchicine most patients live a normal life and amyloidosis is largely prevented. Without treatment, or with poor adherence, amyloidosis may lead to kidney failure, which was historically the main cause of death.

## Test yourself

Think of the answer, then tap the question to see it.

## Which gene and protein are affected in familial Mediterranean fever?

MEFV, which encodes pyrin.

## What is the most feared long-term complication of FMF and how is it prevented?

AA amyloidosis of the kidney; prevented by lifelong daily colchicine.

## How long does a typical FMF attack last?

About 12 to 72 hours, with normal health between attacks.

## Which periodic fever syndrome is characterised by cold-induced urticaria-like rash and is linked to NLRP3?

Cryopyrin-associated periodic syndrome (CAPS), such as familial cold autoinflammatory syndrome.

## Which cytokine is the main target of second-line therapy in colchicine-resistant FMF?

Interleukin-1 beta.

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## Related conditions

- [Amyloidosis](https://durgical.com/en/conditions/amyloidosis/)
- [Nephrotic syndrome](https://durgical.com/en/conditions/nephrotic-syndrome/)
- [Chronic kidney disease](https://durgical.com/en/conditions/chronic-kidney-disease/)
- [Acute appendicitis](https://durgical.com/en/conditions/acute-appendicitis/)
- [Peritonitis](https://durgical.com/en/conditions/peritonitis/)
- [Acute pericarditis](https://durgical.com/en/conditions/acute-pericarditis/)
- [Pleural effusion](https://durgical.com/en/conditions/pleural-effusion/)
- [Adult-onset Still disease](https://durgical.com/en/conditions/adult-onset-still-disease/)
- [Juvenile idiopathic arthritis](https://durgical.com/en/conditions/juvenile-idiopathic-arthritis/)
- [Behçet disease](https://durgical.com/en/conditions/behcet-disease/)
- [IgA vasculitis (Henoch–Schönlein purpura)](https://durgical.com/en/conditions/iga-vasculitis/)
- [Polyarteritis nodosa](https://durgical.com/en/conditions/polyarteritis-nodosa/)
- [Crohn disease](https://durgical.com/en/conditions/crohn-disease/)
- [Acute intermittent porphyria](https://durgical.com/en/conditions/acute-intermittent-porphyria/)

Educational information, not medical advice. For any symptom, see a health professional.

Sources: [Familial Mediterranean fever: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/familial-mediterranean-fever/) (MedlinePlus Genetics (U.S. National Library of Medicine), 2026); [Familial Mediterranean Fever - Symptoms, Causes, Treatment | NORD](https://rarediseases.org/rare-diseases/familial-mediterranean-fever/) (National Organization for Rare Disorders (NORD), 2026).

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Source: https://durgical.com/en/conditions/familial-mediterranean-fever-and-other-hereditary-autoinflammatory-syndromes/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/conditions/familial-mediterranean-fever-and-other-hereditary-autoinflammatory-syndromes/