Immunodeficiency Search

FAMILIAL MEDITERRANEAN FEVER

SUMMARY

1. Familial Mediterranean Fever (FMF) is the most common periodic fever syndrome. This autosomal recessive disease mainly affects populations from the eastern Mediterranean area (Armenians, Jews, Turks, North Africans, Greeks, Italians).

2. Clinically, patients begin to experience episodic attacks of fever (lasting 12-72 hours) starting in childhood. The fever is usually accompanied by the following clinical features:

-Elevated CRP/ESR
-Arthritis and arthralgias
-Abdominal pain from peritonitis (90%)
-Erythematous raised painful rash on the lower extremities mimicking cellulitis (7-40%)
-Pleuritis causing painful breathing (15-30%)
-Polyarteritis nodosa, Henoch-Schonlein purpura, orchitis, aseptic meningitis, and pericarditis have also been associated with FMF

3. Despite the short duration of actual febrile episodes, there is evidence that patients suffer from subclinical inflammation between attacks.

4. Mutations in the MEFV gene cause FMF. MEFV codes for the protein pyrin that is expressed exclusively in cells of myeloid lineage. Pyrin is a major regulatory component of the inflammasome (which activates pro-IL-1 beta and pro-IL18 to IL-1 beta and IL18). One possible mechanism of action for Pyrin is that it acts as an inhibitor of the cryopyrin (NALP3) inflammasome thus preventing excessive inflammation.

5. The most serious complication from FMF is the development amyloid deposition in various organs (particularly in the kidneys). Renal amyloidosis can result in eventual end-stage renal disease.

6. The diagnosis is suggested by the characteristic clinical features and by the ethnic background of patients. MEFV gene sequencing provides a definitive diagnosis.

7. FMF is treated with the use of lifelong prophylactic colchicine (1-2 mg/day). This therapy can decrease the number of febrile attacks and also reduce the risk of amyloidosis from 25-40% to less than 1%. Colchicine is not helpful in aborting an acute febrile attack once it has started. Guidelines for initial colchicine dosing (available in 0.6mg tablets in the United States):

3. ATM is involved in the regulation of both non-homologous end joining (NHEJ) and homologous recombination (HR) - the two major DSB repair pathways. Defects in the NHEJ pathway can also lead to radiosensitive SCID (the NHEJ repair machinery includes DNA-PKcs, Artemis, DNA ligase IV, and Cernunnos).

4. Clinically, patients with A-T typically walk normally by 1 year of life. However, ataxia often develops around the second year of life and patients are generally wheelchair bound after 10 years of age. Other neurologic abnormalities include oculomotor apraxia, dysarthria, and choreoathetosis. Patients develop progressive difficulty with eating and swallowing, which increases the risk for aspiration in older patients.

5. Telangiectasia on the bulbar conjunctiva, ear pinna, and nose develops several years after the development of ataxia (around 3 to 5 years of age).

6. Patients suffer from recurrent sinopulmonary infections at high frequency. However, opportunistic infections or other invasive infections are typically not observed. Dysfunctional swallowing and aspiration can contribute to the development of pulmonary infections.

7. The immunodeficiency found in A-T is characterized by both humoral and cell-mediated abnormalities. It should be noted that some patients have mild or no immunodeficiency. Humoral Abnormalities include decreased IgG, IgA, IgE and decreased IgG subclasses. Serum IgM levels are normal or elevated. Decreased specific antibody responses may be present. T cell Abnormalities include T cell lymphopenia and decreased in vitro proliferation to mitogens.

-Children <5 yo: Starting dose 0.6mg/day
-Children 5-10 yo: Starting dose 1.2 mg/day
-Children >10yo: Starting dose 1.8 mg/day

-Colchicine should be gradually increased by 0.3 mg to achieve control of febrile episodes (maximum dose of 2.4mg/day). For patients with nephrotic syndrome, prevention of disease progression requires higher dosing (1.8 2.4 mg/day).

OVERVIEW

The periodic fever syndromes encompass a group of autoinflammatory disorders characterized by recurrent fevers and inflammation in the absence of infectious triggers. Familial Mediterranean Fever (FMF) is the most common periodic fever syndrome.

FMF is an autosomal recessive disease which mainly affects populations from the eastern Mediterranean area (Armenians, Jews, Turks, North Africans, Greeks, Italians). Clinically, patients begin to experience episodic attacks of fever (lasting 12-72 hours) starting in childhood. The fever is usually accompanied by the following clinical features:

Despite the short duration of actual febrile episodes, there is evidence that patients suffer from subclinical inflammation between attacks. The most serious complication from FMF is the development amyloid deposition in various organs (particularly in the kidneys). Renal amyloidosis can gradually progress from proteinuria to end-stage renal disease.

PATHOGENESIS

Mutations in the MEFV gene cause FMF. MEFV codes for the protein pyrin that is expressed exclusively in cells of myeloid lineage. Pyrin is a major regulatory component of the inflammasome (which activates pro-IL-1 beta and pro-IL18 to IL-1 beta and IL18). One possible mechanism of action for Pyrin is that it acts as an inhibitor of the cryopyrin (NALP3) inflammasome thus preventing excessive inflammation.

DIFFERENTIAL DIAGNOSIS

1.Hyper IgD Syndrome

2.Mevalonic Aciduria

3.TRAPS

4.Crypopyrin associated periodic fevers (muckle wells, FCAS, NOMID)

5.PFAPA

EVALUATION

The diagnosis of FMF should be suspected for patients who have episodic fevers without an infectious source and are of a high risk ethnicity. Other types of periodic fevers syndromes should also be considered in the differential diagnosis.

Step 1: Screening Studies

-C reactive protein / Erythrocyte sedimentation rate
-BUN/Creatinine and Urine Protein

-CRP and ESR are often elevated during and between attacks.

-Renal function and urine protein should be checked to screen for potential renal disease from amyloid deposition.

Step 2: Genetic confirmation

-MEFV gene sequencing

-This is the definitive test for establishing a diagnosis of FMF and is commercially available (Gene Dx).

MANAGEMENT

FMF is treated with the use of lifelong prophylactic colchicine (0.6-2.4 mg/day). The exact mechanism of action of this drug in FMF is not understood but may be related to suppression of neutrophil function. This therapy can decrease the number of febrile attacks and also reduce the risk of amyloidosis from 25-40% to less than 1%. Colchicine can cause gastrointestinal side-effects such as nausea and diarrhea at higher doses (this can be alleviated by a temporary reduction in the dosing). Colchicine is not helpful for aborting a febrile episode once an acute attack has started. Colchicine is safe for use in children and during pregrancy.

Guidelines for starting colchicine dosing: available in 0.6mg tablets in the United States

-Children <5 yo: Starting dose 0.6mg/day
-Children 5-10 yo: Starting dose 1.2 mg/day
-Children >10yo: Starting dose 1.8 mg/day

** Colchicine should be gradually increased by 0.3 mg to achieve control of febrile episodes (maximum dose of 2.4mg/day). For patients with nephrotic syndrome, prevention of disease progression requires higher dosing (1.8 2.4 mg/day).

RESOURCES

Diagnostic Resources

1. Gene Dx: gene sequencing for MEFV.

A sample submission and informed consent form is required.

Testing typically takes 6 - 8 weeks.

www.genedx.com/services/dis_cg.php

Phone 301-519-2100 FAX 301-519-2892

Literature Resources

1. Gattorno 2008

Diagnosis and management of autoinflammatory diseases in childhood (review)

2. Saatci 1997

FMF in 606 children risk and prognostic factors for amyloidosis