fmf
TRANSCRIPT
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/