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Familial Mediterranean fever at the millennium. Clinical spectrum,
ancient mutations, and a survey of 100 American referrals to the National
Institutes of Health.
Samuels J, Aksentijevich I, Torosyan Y, Centola M, Deng Z, Sood
R, Kastner DL.
Arthritis and Rheumatism Branch, National Institute of Arthritis
and Musculoskeletal and Skin Diseases, National Institutes of Health,
Bethesda, Maryland 20892-1820, USA.
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Medicine (Baltimore) 1998 Jul;77(4):268-97 Abstract quote
Regarded as the most common and best understood of the hereditary periodic
fever syndromes, familial Mediterranean fever (FMF) is a recessively
inherited disease of episodic fever with some combination of severe
abdominal pain, pleurisy, arthritis, and a characteristic ankle rash.
The flares typically last for up to 3 days at a time, and most patients
are completely asymptomatic between attacks; if untreated with prophylactic
colchicine, some patients later develop amyloidosis and renal failure.
The recent cloning of the FMF gene on the short arm of chromosome 16p,
and the subsequent finding that its tissue expression is limited to
granulocytes, has helped to explain the dramatic accumulation of neutrophils
at the symptomatic serosal sites; the wild-type gene likely acts as
an upregulator of an anti-inflammatory molecule or as a downregulator
of a pro-inflammatory molecule. For nearly half a century, FMF was thought
to cluster primarily in non-Ashkenazi Jews, Arabs, Armenians, and Turks,
although the screening of the 8 known mutations in an American cohort
has identified substantial numbers of people from the Ashkenazi Jewish
and Italian populations in the United States who also have this disease.
Nevertheless, the symptoms often go unrecognized and patients remain
undiagnosed for years, not receiving the highly efficacious colchicine
therapy; their histories often include multiple laparotomies, laparoscopies,
and psychiatric evaluations.
The combinations of clinical manifestations among FMF patients are
quite heterogeneous, but our American cohort did not establish any connections
between individual mutations and specific clinical pictures--as is seen
in other diseases like cystic fibrosis, in which distinct genotypes
target certain organ systems. Specifically, the data from our American
series are insufficient to evaluate the hypothesis that the M694V/M694V
genotype confers a more severe phenotype, or increases the risk of amyloidosis;
but both our data and the recent literature (160) indicate that amyloidosis
can occur in FMF patients with only 1 copy, or no copies, of the M694V
mutation. It appears that specific MEFV mutations are probably not the
sole determinants of phenotype, and that unknown environmental factors
or modifying genes act as accomplices in this disease. Although we hope
the discovery of the FMF gene will allow the diagnosis of FMF to become
genetically accurate, the reality is that both clinical and genetic
tools must still be used together unless mutations are identified on
both of a patient's chromosomes. Physicians should be careful not to
rule out the diagnosis in patients of high-risk ethnic backgrounds just
because of atypical clinical features, as our data indicate that MEFV
mutations are sometimes demonstrable in such patients. At the same time,
physicians cannot yet rely solely on a genetic diagnosis because we
have not yet identified a sufficient spectrum of mutations, and it is
not currently feasible to examine every patient's full DNA sequence
for the entire gene; screening an ethnically consistent and clinically
positive patient for the 8 known mutations frequently identifies a mutation
on only 1 chromosome, and genetic analysis of other classic cases will
often reveal none of the 8 mutations.
Still, our data suggest that ethnic background is an important predictor
of finding 1 of the presently known mutations, and the knowledge of
ancestries atypical for FMF can suggest the diagnosis of other hereditary
periodic fever syndromes. As the list of FMF-associated MEFV mutations
is expanded, and/or new sequencing technologies permit more rapid screening,
the value and interpretation of genetic testing for FMF will become
more straightforward. Moreover, as the pathophysiology of this disorder
becomes less of a hypothesis and more of an understood entity, it is
likely that treatment options will broaden beyond the use of daily prophylactic
colchicine.
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The clinical patterns of myalgia in children with familial Mediterranean
fever.
Majeed HA, Al-Qudah AK, Qubain H, Shahin HM.
Department of Pediatrics, Faculty of Medicine, University of Jordan.
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Semin Arthritis Rheum 2000 Oct;30(2):138-43 Abstract quote
OBJECTIVES: To study the frequency and clinical patterns of myalgia
in a defined group of children with familial Mediterranean fever (FMF).
METHODS: A prospective 4-year (September 1995-September 1999) study
of children with FMF seen in the pediatric FMF clinic of Jordan University
teaching hospital. Diagnosis of FMF was made according to published
criteria. Once the diagnosis of FMF and myalgia was made, details about
myalgia were collected by interview with the child and his/her parents
and entered into a special study form.
RESULTS: Of 264 children with FMF seen over the study period, 65 (25%)
developed myalgia. Three clinical patterns of myalgia were identified:
the spontaneous pattern, the exercise-induced pattern, and the protracted
febrile myalgia syndrome (PFMS), seen in 8%, 81%, and 11% of patients,
respectively. The three patterns differed in the severity of pain, height
of fever, and duration of the episode. In 33 children with the exercise-induced
myalgia, in which response to colchicine could be reliably assessed,
a favorable response was achieved in 97%. Three children with the PFMS
had a dramatic response to corticosteroids.
CONCLUSIONS: Myalgia in children with FMF is common and can follow
three different clinical patterns.
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Familial Mediterranean fever--renal involvement by diseases other
than amyloid.
Tekin M, Yalcinkaya F, Tumer N, Cakar N, Kocak H, Ozkaya N, Gencgonul
H.
Ankara University Faculty of Medicine, Turkey.
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Nephrol Dial Transplant 1999 Feb;14(2):475-9 Abstract quote
BACKGROUND: In patients with familial Mediterranean fever (FMF) renal
involvement is usually in the form of AA amyloidosis. There is increasing
evidence that renal involvement may be due to diseases other than amyloid
as well.
METHODS: Amongst 302 children with FMF we observed and followed 28
with typical clinical and laboratory features of vasculitis. The diagnosis
of FMF was established according to the Tel Hashomer criteria.
RESULTS: Polyarteritis nodosa, protracted febrile attacks and Henoch-Schonlein
purpura were diagnosed in 4, 13, and 11 patients, respectively. The
presentation was often difficult to distinguish from FMF attacks, but
protracted febrile attacks lasting several weeks, hypertension, thrombocytosis,
and dramatic responses to corticosteroid therapy that were observed
in many cases were different from what is observed in classical FMF.
CONCLUSIONS: We suggest that FMF, perhaps as a consequence of impaired
control of inflammatory responses, predisposes to vasculitis with renal
involvement.
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