Familial Mediterranean Fever

Naeim Ehtesham

Disease characteristics (Clinical Description)

Common manifestations

Recurrent fever during early childhood may be the only manifestation of FMF

Abdominal attacks

Articular attacks

Pleural attacks

Pericarditis

Rash

Amyloidosis

Molecular Genetics

Gene Symbol Chromosomal

Locus

Protein Name

MEFV 16p13.3 Pyrin

Simplified view of the pathogenesis

Inheritance

FMF is an autosomal recessive disease

A patient with only one mutation is a carrier and should not display the disease

phenotype

MEFV heterozygous genotypes produce a phenotype intermediate between

that of homozygous affected individuals and homozygous wild-type unaffected

individuals

How a genetic carrier can express the phenotype?

Ruled out several possible explanations, such as loss of expression of one

allele

A single mutation can cause unexpected inflammation in the setting of a

number of polymorphisms in genes encoding relevant proinflammatory

cytokines

Cont…

Although disease severity, are influenced by the MEFV pathogenic variants themselves, intra- and

interfamilial clinical differences suggest that these parameters are also influenced by other genes

(outside the MEFV locus)

However, in these individuals, detection of a single pathogenic variant appears to be sufficient in the

presence of clinical symptoms for the diagnosis of FMF and the initiation of a trial of colchicine

Prevalence

FMF predominantly affects populations living in the Mediterranean region,

especially North African Jews, Armenians, Turks, and Arabs

1 in 5 Mediterranean descent have FMF gene , but 1 in 200 have FMF

The pathogenic variant c.2080A>G(p.Met694Val) is found in more than 90%

of affected Jewish persons of North African origin.

FMF is also seen (although in much lower numbers) in many other countries,

where it shows considerable variability in severity and type of manifestations

Differential Diagnosis

Differential diagnosis in a child referred with fever

Diagnosis/testing

The minimal (and most 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

Cont…

Major signs

Abdominal pain

Chest pain

Joint pain

Skin eruption

cont…

Minor signs

Increased erythrocyte sedimentation rate (ESR)

Normal values:

Men age <50 years: <15 mm/h

Men age 50-85 years: <20 mm/h

Women age <50 years: <20 mm/h

Women age 50-85 years: <30 mm/h

Leukocytosis

Normal values: 4.5 to 11.0 times 103µL (4.5-11.0 x 10-9L)

Elevated serum concentration of fibrinogen

Normal values: 200-400 mg/dL (2.00-4.00 g/L)

Flowchart to guide requests for MEFV mutation

analysis

Algorithm to guide diagnosis and treatment

decisions after MEFV genotype analysis

Treatment and management

The treatment of patients with FMF is aimed at suppressing the inflammation,

as indicated by laboratory measures such as CRP levels, and providing an

acceptable quality of life

colchicine is efficient in preventing the development of amyloidosis in the

majority of the patients who are compliant with the drug

Indeed, the mainstay of treatment for FMF is colchicine, which is effective not

only in controlling the attacks but also in preventing secondary amyloidosis

Cont…

The follow up of patients with FMF should include the management of

possible complications that arise from chronic inflammation

For example, quality of life will be impaired in patients with frequent attacks,

and thus depression might ensue

In untreated patients, uncontrolled inflammation can result in splenomegaly,

growth retardation, decreased bone density, premature atherosclerosis and,

ultimately, secondary amyloidosis

Frequent attacks might also lead to female or male infertility owing to

adhesions in reproductive organs

Cont…

Patients with FMF are considered to be resistant to colchicine if they continue

to have >1 attack per month and have elevated CRP and SAA levels in between

the attacks (during the attack-free period).

In patients resistant to colchicine, anti-IL-1 treatment has proven beneficial in

suppressing clinical and laboratory measures of inflammation

Genetic counseling

For autosomal recessive FMF: In general,

both parents of an affected individual with

biallelic MEFV pathogenic variants are

unaffected heterozygotes. However, in

populations with a high carrier rate and/or

a high rate of consanguineous marriages, it

is possible that one or both parents have

biallelic pathogenic variants and are

affected

Symptomatic heterozygotes have also been

reported. Thus, it is appropriate to consider

molecular genetic testing of the parents of

the proband to establish their genetic

status. If both parents are heterozygotes,

the risk to sibs of inheriting two pathogenic

variants and being affected is 25%

Carrier testing for at-risk relatives and

prenatal testing for pregnancies at

increased risk are possible if the MEFV

pathogenic variants in the family are

known

Refrences

A clinical guide to autoinflammatory diseases: familial Mediterranean fever

and next-of-kin , Ozen, S. & Bilginer, Y. Nat. Rev. Rheumatol. 10, 135–147

(2014)

http://www.ncbi.nlm.nih.gov/gtr/

http://www.ncbi.nlm.nih.gov/omim/

http://www.ncbi.nlm.nih.gov/books/NBK1116/