Familial Mediterranean fever

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Familial Mediterranean fever is an inherited condition characterized by recurrent episodes of painful inflammation in the abdomen, chest, or joints. These episodes are often accompanied by fever and sometimes a rash or headache. Occasionally inflammation may occur in other parts of the body, such as the heart; the membrane surrounding the brain and spinal cord; and in males, the testicles. In about half of affected individuals, attacks are preceded by mild signs and symptoms known as a prodrome. Prodromal symptoms include mildly uncomfortable sensations in the area that will later become inflamed, or more general feelings of discomfort.

The first episode of illness in familial Mediterranean fever usually occurs in childhood or the teenage years, but in some cases, the initial attack occurs much later in life. Typically, episodes last 12 to 72 hours and can vary in severity. Episodes generally occur once a month, and in affected women of reproductive age, attacks often correspond with menstruation or ovulation. However, the length of time between episodes can range from days to years. During these periods, affected individuals usually have no signs or symptoms related to the condition. However, without treatment to help prevent attacks and complications, a buildup of protein deposits (amyloidosis) in the body's organs and tissues may occur, especially in the kidneys, which can lead to kidney failure.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Familial Mediterranean fever is caused by variants (also known as mutations) in the MEFV gene. The MEFV gene provides instructions for making a protein called pyrin (also known as marenostrin), which is found in white blood cells. This protein is involved in the immune system, helping to regulate the process of inflammation. Inflammation occurs when the immune system sends signaling molecules and white blood cells to a site of injury or disease to fight microbial invaders and facilitate tissue repair. When this process is complete, the body stops the inflammatory response to prevent damage to its own cells and tissues.

Variants in the MEFV gene reduce the activity of the pyrin protein, which disrupts control of the inflammation process. An inappropriate or prolonged inflammatory response can result, leading to fever and pain in the abdomen, chest, or joints.

Normal variations in the SAA1 gene may modify the course of familial Mediterranean fever. Some evidence suggests that a particular version of the SAA1 gene (called the alpha variant) increases the risk of amyloidosis among people with familial Mediterranean fever.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Familial Mediterranean fever is usually inherited in an autosomal recessive pattern, which means both copies of the MEFV gene in each cell have variants. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition. Research shows that about one-third of people with familial Mediterranean fever have a single MEFV gene variant, though most experts believe there is a second variant somewhere else in the gene that has not been detected by genetic testing.

In rare cases, this condition appears to be inherited in an autosomal dominant pattern. An autosomal dominant inheritance pattern describes cases in which one copy of the altered gene in each cell is sufficient to cause the disorder. In autosomal dominant inheritance, affected individuals often inherit the variant from one affected parent.

However, another mechanism is believed to account for some cases of familial Mediterranean fever that were originally thought to be inherited in an autosomal dominant pattern. A gene variant that occurs frequently in a population may result in a disorder with autosomal recessive inheritance appearing in multiple generations in a family, a pattern that mimics autosomal dominant inheritance. If one parent has familial Mediterranean fever (with variants in both copies of the MEFV gene in each cell) and the other parent is an unaffected carrier (with a variant in one copy of the MEFV gene in each cell), it may appear as if the affected child inherited the disorder only from the affected parent. This appearance of autosomal dominant inheritance when the pattern is actually autosomal recessive is called pseudodominance.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Familial Mediterranean fever primarily affects populations originating in the Mediterranean region, particularly people of Armenian, Arab, Turkish, or Jewish ancestry. The disorder affects 1 in 200 to 1,000 people in these populations. It is less common in other populations.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abdominal pain · Very frequent (99-80%)

An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) and perceived to originate in the abdomen.

Arthralgia · Very frequent (99-80%)

Joint pain.

Constipation · Very frequent (99-80%)

Infrequent or difficult evacuation of feces.

Fever · Very frequent (99-80%)

Body temperature elevated above the normal range.

Myalgia · Very frequent (99-80%)

Pain in muscle.

Nausea and vomiting · Very frequent (99-80%)

Nausea is a commonly encountered symptom that has been defined as an unpleasant painless subjective feeling that one will imminently vomit. Vomiting has been defined as the forceful expulsion of the contents of the stomach, duodenum, or jejunum through the oral cavity. While nausea and vomiting are often thought to exist on a temporal continuum, this is not always the case. There are situations when severe nausea may be present without emesis and less frequently, when emesis may be present without preceding nausea.

Arthritis · Frequent (79-30%)

Inflammation of a joint.

Asthenia · Frequent (79-30%)

A state characterized by a feeling of weakness and loss of strength leading to a generalized weakness of the body.

Other findings in the same source

From: Orphanet

Additional reported features include Chest pain (Frequent (79-30%)); Diarrhea (Frequent (79-30%)); Erysipelas (Frequent (79-30%)); Erythema (Frequent (79-30%)); Fatigue (Frequent (79-30%)); Hyperfibrinogenemia (Frequent (79-30%)); Hypoesthesia (Frequent (79-30%)); Increased total leukocyte count (Frequent (79-30%)); Irritability (Frequent (79-30%)); Oral leukoplakia (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Familial Mediterranean fever is Rheumatology, with a rheumatologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Are the findings inflammatory, structural or due to another mechanism?
• Is there evidence that other organs need assessment?
• How will function and any treatment-related risks be monitored?

Treatment discussions and follow-up

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.