Familiar Mediterranean Fever

FMF ( Familiar Mediterranean Fever ) is a hereditary inflammatory disorder that affects groups of patients originating from around the mediterranean Sea. It is prominently present in :

* Ashkenazi Jewish people (descended from Eastern European Jewish people and also including most European and American Jewish people) have a prevalence of 1 case per 73,000 population, with a gene frequency of 1:135.
* Sephardic Jewish people (descended from Jewish people who were expelled from Spain, largely to North Africa, and also including other Middle Eastern Jewish populations) have a prevalence of 1 case per 250-1000 population, with a gene frequency of 1:8-16.
* Armenian persons (based on epidemiology among Armenian populations in Lebanon and Southern California) have an estimated prevalence of 1 case per 500 population and a gene frequency of 1:7.
* Turkish people (from one study) may have a prevalence of approximately 1 case per 1000 population.
* Arabic people (from one study) may have a prevalence of 1 case per 2600 population in children and a gene frequency of 1:50.

There are seven types of attacks. 90% of all patients have their first attacks before they are 20 years old. Most attacks involve:

1- Abdominal attacks featuring abdominal pain affecting the whole abdomen with all signs of acute abdomen. They occur in 95% of all patients and may lead to unnecessary laparotomy. Incomplete attacks, with local tenderness and normal blood tests, have been reported.
2 - Joints attacks occurring in large joints, mainly of the legs. Usually, only one joint is affected. 75% of all FMF patients experience Joint attacks.
3 - Chest attacks with pleuritis(inflammation of the pleural lining) and pericarditis (inflammation of the pericardium). Pleuritis occurs in 40%, but pericarditis is rare.
4 - Scrotal attacks due to inflammation of the tunica vaginalis. This occurs in up to 5% and may be mistaken for acute scrotum (i.e. testicular torsion)
5 - Myalgia
6 - Erysipeloid
7 - Fever without any reason

FMF is a recessive genetic disease likely caused by missense and nonsense mutations in the MEFV gene that is located on the short arm of chromosome 16. This gene codes for the protein known as pyrin or marenostrin. This was discovered in 1997 by two different groups, each working independently - the French FMF Consortium and the International FMF Consortium Various mutations of this gene lead to FMF, although some mutations cause a more severe picture than others.

* Multiple mutations are located on the MEFV gene. Most of the mutations are in exon 10 of the gene between amino acids 680 and 761. One mutation in exon 1 at amino acid 148 may represent as many as one quarter of the known mutations.
* Although certain mutations are more common in particular ethnic groups, patients usually inherit different mutations from each parent.
* Homozygotes for M694V (valine for methionine at position 694) may experience more severe disease and may be more likely to develop amyloidosis.
* Patients with V726A (alanine for valine at position 726) may be less likely to develop amyloidosis.

The preeminent feature of FMF is the paroxysm, the classic onset of which occurs without warning. The paroxysms usually last 48-96 hours, with peak intensity occurring within the first 12 hours. A plateau with resolution follows, usually occurring more slowly than the onset of symptoms.

* Fever
* Temperatures rise rapidly to 38-40°C (100.4-104°F). Temperature increases may occur before other manifestations.
* In mild attacks, fever may be the only manifestation.
* Peritoneal symptoms
* Almost all patients with FMF experience abdominal episodes. Patients develop abdominal pain that may progress to peritonitis, resembling a surgical abdomen.
* Patients frequently have symptoms consistent with appendicitis or cholecystitis, and they frequently have appendectomies and cholecystectomies because the abdominal episodes of FMF are not recognized as such.
* The symptoms may also mimic renal colic.
* Often, patients develop constipation during the attack and diarrhea after the attack resolves.
* Pleural and pericardial symptoms
* The frequency of pleural and pericardial attacks varies among ethnic groups, with 25-80% of patients reporting pleuritic episodes.
* Effusions may occasionally occur. Pericarditis may develop, but tamponade and constrictive pericarditis are rare.
* The rate of synovial symptoms varies from 25-75% in reported series. The episodes may resemble gout in their acute onset and intensity. Knees, ankles, and wrists are the joints most commonly affected. An arthritis that resembles seronegative spondyloarthritis may also occur.
* The joints are normal between attacks, and permanent damage does not usually occur.
* Arthritic symptoms tend to last several days longer than abdominal symptoms. Episodes can be protracted.
* Arthritis may be the only manifestation. FMF should be considered in patients with a family history of FMF or who live in an endemic area.
* As many as 50% of patients report erysipelaslike rashes on the lower extremities, particularly below the knees.
* Rash and fever may be the only manifestations of attacks.
* Recent descriptions more often include reports of severe myalgia lasting 3-6 weeks. These episodes do not respond to colchicine therapy.
* Symptoms are consistent with fibromyalgia.
* Pelvic symptoms: Female patients may have episodes of pelvic inflammatory disease.
* Scrotal attacks: In males, inflammation of the tunica vaginalis testis may mimic episodes of torsion of the testis.
* Vasculitis: An increased frequency of Henoch-Schönlein purpura and polyarteritis nodosa is reported in persons with FMF, even in children. Behçet disease is also more common.
* In a patient of the appropriate ethnic group, the typical progression is proteinuria, followed by nephrotic syndrome, and, inevitably, death from renal failure.
* One third of patients with amyloidosis may develop renal vein thrombosis. Nephrotic syndrome is reported in patients as young as 14 years. Despite the frequency and extent of amyloid deposits in the renal system, deposits in other organs are only rarely reported as significant.
* Prolonged survival resulting from colchicine therapy, dialysis, and renal transplantation allows additional manifestations of amyloidosis to develop. Some patients have intestinal involvement, which may lead to malabsorption and death.
* Some patients with a family history of FMF may present with amyloid nephropathy without ever having experienced an amyloid attack. Furthermore, some patients with otherwise typical FMF may develop renal failure without previous proteinuria.
* Temperatures can reach as high as 40°C (104°F), but, in most cases, rapid defervescence occurs within 12 hours.
* A boardlike or surgical abdomen is present with typical findings of peritonitis (ie, abdominal tenderness, decreased bowel sounds). Splenomegaly is common in response to the inflammation. Patients with pleural involvement may have shallow breathing and chest-wall tenderness, but friction rubs are rare.
* Joints show typical inflammatory changes, with warmth, erythema, or swelling.
* A well-demarcated, erythematous, warm rash, particularly below the knee, ranging from 15-50 cm2 may develop and be accompanied by swelling.
* Patients with painful myalgia syndrome may have tender muscles.
* Patients with symptoms mimicking pelvic inflammatory syndrome may experience pain upon cervical motion and may develop tender, enlarged ovaries.
* Unilateral, erythematous, and tender swelling of the scrotum occurs in scrotal attacks. The typical manifestations of Behçet disease and Henoch-Schönlein purpura may be observed.
* Amyloidosis is usually asymptomatic, with hypertension reported in 35% of patients late in the disease. Renal vein thrombosis may develop and manifests as loin pain.

Since the 1970s, colchicine, has been shown to decrease attack frequency in FMF patients. The exact way in which colchicine suppresses attacks is unclear. While this agent is not without side-effects (such as abdominal pain and muscle pains, it may markedly improve quality of life in patients. The dosage is typically 1-2 mg a day. Development of amyloidosis is delayed with colchicine treatment. Interferon is being studied as a therapeutic modality.v