Familial Mediterranean Fever

Also known as: recurrent polyserositis

The symptoms and severity vary among affected individuals. Amyloidosis, which can result in renal failure, is a life threatening complication that can be prevented by colchicine treatment.

Presentation

  • The majority of affected individuals present within the first decade or two of life.
  • Episodes typically last for 48-72 hrs (peak 12 hrs.).
  • Symptoms can recur after days/months/years.
  • Fever – may be the only symptom, particularly during early childhood– temperature rises rapidly to 38-40 degrees Celsius.
  • Abdominal pain is experienced by 90% of affected individuals.
  • Patients with FMF frequently have symptoms consistent with appendicitis or cholecystitis and commonly undergo appendectomies and cholecystectomies, as the abdominal symptoms of FMF are not recognized as such.
  • Pleuritic chest pain (occurs in >50% cases) – sudden onset of an acute, one-sided febrile pleuritis, which resolves rapidly.
  • Pericarditis may develop.
  • Joint pain – the episodes may resemble gout in their acute onset and intensity. Often triggered by minor trauma or effort, such as prolonged walking. Hip, knee, ankles, and wrists are the
  • joints most commonly affected.
  • Joints are normal between attacks, permanent damage is unusual.
  • Erysipelas-like rash (10-20%) below the knees.
  • Myalgia.
  • Pelvic pain in women (due to PID); scrotal pain in men (inflammation of tunica vaginalis).
  • Vasculitis – HSP, polyarteritis nodosa and Bechets disease are more common with in individuals with FMF.

Please click on the titles to open and close the following information sections.

  • FMF is associated with mutations in MEFV (Mediterranean fever) gene located on the short arm of chromosome 16.
  • MEFV gene codes for a protein – pyrin that is expressed mostly in neutrophils. The exact function of pyrin is unknown, but it appears to be an inhibitor of chemotactic factor (C5a) or interleukin-8.
  • Individuals with normal pyrin function have the ability to deactivate the target chemotactic factor when it is produced in response to an inflammatory stimulus. Patients with FMF lack this ability, resulting in uninhibited activity of the chemotactic factor and episodes of inflammation (with accompanying fever) in the peritoneum, joints and pleura.
  • The inflammation is accompanied by excess production of serum amyloid A protein (SAA) in the blood, which can begin to become lodged in the kidneys and other organs in the form of AA amyloidosis.
  • Estimates of MEFV mutation carrier frequency in the Ashkenazi Jewish (AJ) population vary (research reports range from 1:135 up to as high as 1:6) – this suggests that different mutations have different penetrance.
  • Disease incidence in the AJ population is estimated to be at least 1:75,000.
  • In different Sephardic Jewish (SJ) populations, the carrier frequency for the MEFV mutation is estimated to be between 1:16 and 1:6, with an approximate disease incidence of 1:200-1000.
  • There are many different possible mutations in the MEFV gene – the most severe mutations tend to be common in SJ populations whist the milder mutations are more common in the AJ population.
  • Other groups know to be affected by FMF include: the Armenian population – carrier frequency of 1:7 and disease incidence of 1:500; and the Turkish population with an estimated disease incidence of 1:1000.

The current criteria for diagnosis of FMF are the Tel Hashomer clinical criteria:

  • Fever plus either one or more major signs and one minor sign; or two minor signs below:

Major signs:

  • Abdominal pain.
  • Chest pain.
  • Joint pain.
  • Skin eruption.

Minor signs:

  • Increased erythrocyte sedimentation rate (ESR).
  • Leukocytosis.
  • Elevated serum concentration of fibrinogen.

Other supporting evidence includes:

  • During an attack – increased acute phase proteins (CRP and fibrinogen); increased ESR; raised WCC.
  • Proteinuria – as sign amyloidosis (renal biopsy may be required to confirm diagnosis.
  • For unclear reasons, haematuria occurs in 5% of patients.
  • Synovial fluid will show inflammatory picture .

An FMF diagnosis can be confirmed through genetic testing.

Gene specific:

  • Genetic testing is available for FMF.
  • Symptomatic patients with at least one MEFV mutation should be considered to have FMF.  Most patients with FMF have mutations in both of their FMF genes.

Treatment is symptomatic and supportive:

  • Treatment of an acute episode is supportive – hydration, analgesia, treatment of febrile and inflammatory episodes with nonsteroidal anti-inflammatory drugs (NSAIDs).
  • The key to treatment is prevention – colchicine is a safe drug that should be taken life-long, with very few exceptions, as a prophylactic treatment. It is highly effective in reducing the frequency of attacks, and extremely effective in preventing the risk of developing amyloidosis.
  • Anakinra and other injectable drugs that block interleukin-1 are very effective preventative treatments in the small proportion of patients who cannot tolerate or do not respond adequately to colchicine.
  • NSAIDs are the mainstay of treatment for arthritis.
  • Myalgia can be managed with prednisolone.
  • Patients who are compliant with daily colchicine can expect to have a normal lifespan if colchicine is started before amyloidosis develops.
  • AA amyloidosis is eventually common in untreated individuals, especially in Jews of North African origin. It presents with a persistent, heavy proteinuria leading to nephrotic syndrome and progressive nephropathy leading to end-stage renal disease. The prevalence of amyloidosis varies by ethnicity, genotype and gender.
  • One third of patients with amyloidosis develop renal vein thrombosis.
  • Approximately 5% of patients with FMF develop chronic arthritis, sometimes leading to destructive arthritis of the hips or knees, necessitating joint replacements.
  • Approximately 10% patients with chronic arthritis develop seronegative spondyloarthropathy.
  • Infertility and miscarriage (secondary to PID) – approximately one third of female patients with FMF are infertile, and 20-30% pregnancies result in fetal loss.
  • For children exhibiting features of FMF, suggested initial referral would be to a paediatrician. For patient of Jewish origin it is valuable to note ancestry as this may impact the specific mutations needing investigation.
  • On-going management for patients diagnosed with FMF may be via a specialist centre for Amyloidosis, such as the one at Royal free (see link below):

Information for physicians making a referral to the Royal Free Hospital specialist centre

  • Families may benefit from referral to a clinical genetics department to establish carrier status in other family members as appropriate.
FMF Support Group – Yahoo Group

An online support group for individuals and their families who are affected by Familial Mediterranean fever (FMF).

Stop CAID Now  (Stop Childhood Autoinflammatory Diseases Now)

This USA based charity aims to educate, raise awareness, and fund researchers who are committed to finding a cure for CAIDs.

Ariella’s Story

Click on the link above to watch a short personal story of someone affected by FMF.

GeneReviews: www.ncbi.nlm.nih.gov/books/NBK1227/

OMIM: #249100

Written by: Dr Jacky Megitt, Jnetics researcher.
Approved by: Professor Philip N Hawkins, Clinical Director of the National Amyloidosis Centre, Royal Free Hospital
Last review: 8.1.2015

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