Familial Mediterranean Fever, Type 1 Diabetes
MAKALE #1671 © Yazan Prof.Dr.Mehmet Emre ATABEK | Yayın Ekim 2008 | 4,608 Okuyucu
CASE REPORT
Familial Mediterranean Fever AssociatedWith Type 1 Diabetes
Association or Coincidence?
Mehmet Emre Atabek, MD,* Ozgur Pirgon, MD,* Ahmet Sert, MD,* and Ugur Arslan, MD†
Abstract:
Familial Mediterranean fever, also known as a periodic
disease or recurrent polyserositis, is an autosomal-recessive disorder
characterized by recurrent attacks of fever, synovitis, peritonitis, or
pleuritis. In patients presenting with typical clinical features and
with an appropriate ethnic origin, the diagnosis can be made without
genetic confirmation. The discovery of the MEFV gene has led to a
molecular approach to diagnosis, aiming at improving the global
diagnosis of the disease. Some diseases, mainly vasculitides, seem to
be more common in familial Mediterranean fever. The “decreased
antiinflammatory response” hypothesis and other putative mechanisms
(cytokines) in familial Mediterranean fever can also take a
predisposing and facilitating role in type 1 diabetes autoimmune
pathogenicity. We describe a previously unreported association
between familial Mediterranean fever and type 1 diabetes in a
9-year-old girl.
Key Words:
type 1 diabetes, familial Mediterranean fever,
autoimmunity
(
The Endocrinologist 2006;16: 133–135)
F
amilial Mediterranean fever (FMF) is the most frequent
periodic syndrome characterized by recurrent attacks of
polyserositis. Fever, abdominal pain, chest pain, and arthritis/
arthralgia are the leading symptoms. The cause of the disease
is unknown. Recent genetic studies have shown that the gene
for FMF is located on chromosome 16p.
1,2 The diagnosis of
FMF is usually made on clinical grounds, typically when
recurrent attacks of abdominal pain, fever, and arthritis are
observed in a patient with an appropriate ethnic background
and family history.
3 So far, there are no specific diagnostic
laboratory tests for FMF.
FMF is an autosomal-recessive disorder affecting several
ethnic groups in the Middle East and in Mediterranean
countries (Armenians, Arabs, Jews, and Turks).
4 The prevalence
reaches a high of one in 200 individuals; one in 256 to
one in 500 in non-Ashkenazi Jews and one in 1073 in the
Turkish population.
5,6 Carrier rates for FMF mutations may
be as high as 1:3 in some populations, suggesting that the
disease is underdiagnosed.
Type 1 diabetes results from the destruction of beta
cells by an autoimmune attack. Type 1 diabetes, like most
other autoimmune diseases, presents a nosologic difficulty:
an autoimmune process perpetrates the damage, but we usually
cannot assign the onset of the disease to a specific factor
or factors. Indeed, too many causative factors seem to be
implicated in autoimmune diseases. The association between
type 1 diabetes and FMF or FMF and type 1 diabetes has not
yet been determined. The case presented here is the first
demonstration of heterozygous for the M680I mutation in a
patient with type 1 diabetes mellitus.
CASE REPORT
The subject was a 9-year-old girl who had applied to our
clinic for her diabetic ketoacidosis 11 months ago. She had been
followed up with the diagnosis of type 1 diabetes mellitus for 2
months and had used an insulin regimen (1 U/kg per day)
throughout this period. However, she had been evaluated owing
to recurrent abdominal pain since the fourth year of her life in
other clinics, suggesting recurrent urinary infections recurred at
a maximum frequency of once a month. She was assessed again
2 months later with identical symptoms and findings, fever up to
40°C, and severe abdominal pain. Her sedimentation rate was
elevated during these attacks, but the examination exhibited
normal findings and the episodes resolved over 2 days. Extensive
investigation failed to reveal any infective, inflammatory,
immunologic, or malignant cause. Physical and laboratory examination
findings were normal blood pressure, no edema,
serum albumin 4.6 mg/dL, and serum creatinine 0.9 mg/dL.
Serum antistreptolysin O titer and complement levels were
within normal ranges.
The parents were nonconsanguineous; however, her
mother, uncle, and grandfather (who have symptoms) had
been diagnosed with FMF (Fig. 1). To confirm the clinical
diagnosis, DNA samples from our patient and her parents
were analyzed for known FMF gene (MEFV) mutations on
chromosome 16. The mutation, M680I, was identified in the
patient and her parents (Fig. 2).
From the *Departments of *Paediatric Endocrinology and †Molecular
Microbiology, School of Medicine, Selcuk University, Konya, Turkey.
Reprints: Mehmet Emre Atabek, MD, Selcuk Universitesi Meram Tip
Fakultesi, Cocuk Sagligi ve Hastaliklari, 42080 Konya, Turkey. E-mail:
meatabek@hotmail.com.
Copyright © 2006 by Lippincott Williams & Wilkins
ISSN: 1051-2144/06/1603-0133
DOI: 10.1097/01.ten.0000217875.07954.6e
The Endocrinologist
• Volume 16, Number 3, June 2006 133
Denaturing gradient gel electrophoresis was done to
screen the mutations in exon 10. Complimentary methods
were used for the most frequent mutations: amplification
refractory mutation system for M694V and M694I and restriction
fragment length polymorphism for R761H, V762A,
and M680I. Mutations in exon 2 (E148Q, E167D, and T267I)
were studied by RFLP (ABI Prism 310; Genetic Analyzer).
Although the subject could be shown to be heterozygous
for a single known MEFV mutation, the dramatic
cessation in her symptoms was managed with colchicine
treatment. The patient has been treated with colchicine (0.5–
1.5 mg/d) as well as the intensive insulin treatment since
being diagnosed with FMF.
DISCUSSION
FMF is the prototype of a group of inherited inflammatory
disorders. The diagnosis of FMF has until recently
been based on clinical signs alone and can be difficult in mild
or atypical forms of the disease. The discovery of the MEFV
gene has led to a molecular approach to diagnosis, aiming at
improving the global diagnosis of the disease. The value of
the molecular approach has been established in patients with
a high suspicion of clinical diagnosis and who satisfied
proposed criteria.
7,8 The 5 most common mutations are
M694V (most common among Jews, Turks, and Armenians),
M680I (more common among Armenians), M694I (more
common among Arabs), E148Q (most common European
mutation and Turkish carriers; associated with mild phenotype),
and V726A (associated with mild phenotype).
4 We
diagnosed FMF by her clinical findings and molecular analysis
demonstrating the M680I mutation in our patient.
Until recently, the exact biochemical and molecular
basis for FMF was unknown, and several hypotheses were
suggested. The fact that FMF has clinical manifestations
resembling those of systemic lupus erythematosus raises the
possibility of an underlying autoimmune pathogenesis.
9 Certain
vasculitides, for example, Henoch-Scho¨nlein purpura and
polyarteritis nodosa, are more frequent among patients with
FMF. However, FMF does not respond to steroids and other
immunosuppressive medications, and autoantibodies have
not been found.
10
MEFV maps to chromosome 16p and encodes a 781-
amino acid protein, called pyrin or marenostrin that is expressed
mainly in neutrophils and myeloid bone marrow
precursors. This protein functions as a transcriptional regulator
of inflammation in granulocytes.
11 It is proposed that
pyrin acts to repress a proinflammatory molecule or a transcriptional
“upregulator” of an antiinflammatory protein. Defective
pyrin probably results in inflammatory events, increased
leukocyte migration to serosal sites, and inappropriate
and prolonged response to inflammatory stimuli.
12,13 MEFV is
expressed specifically in the primary cellular effectors and regulators
of inflammation. Gene expression is controlled by cytokine-
mediated pathways in the inflammatory cascade.
14 Centola
et al suggested that MEFV was a downstream element in
cytokine-induced regulatory cascade. Because mutations in
MEFV result in a dysregulation of the inflammatory response,
this was hypothesized early that MEFV was likely to be an
inflammatory regulator.
15 Recently, pyrin, the product of
MEFV, was shown to interact with ASC (apoptosis-associated
speck-like protein containing a caspase recruitment domain) and
modulate ASC-induced apoptosis.
16 Basu et al suggested that an
early low-grade inflammatory process reflected by elevated
levels of prostaglandin F2
and IL-6 is involved in type 1
diabetes.
17 Thus, cytokine-mediated inflammatory pathways are
significantly related to type 1 diabetes. Consistent with these
ideas, FMF attacks are characterized by serosal inflammation
rich in PMNL leukocytes and activation of a definite cytokine
network, and recurrent attacks in our patient might be triggered
a cytokine-induced apoptosis in beta cells.
The other hypothesis and putative mechanisms for FMF
are FMF-associated chronic antigenemia, free radical mediated
chromosome damage, or some other FMF-related immunologic
mechanism such as relative bone marrow plasmocytosis,
T-cell dysfunction, and lymphocytotoxins.
3,18 Whether
or not the underlying mechanism (the “decreased antiinflammatory
response” hypothesis) is immunologically mediated and
whether or not type 1 diabetes occurs in FMF because of those
inflammatory changes may be revealed by further experience.
All the mechanisms proposed here are speculative. Whatever the
M680I
M680I
M680I
The patient with type
1 diabetes
M680I
FIGURE 1.
MEFV mutations were found in compound heterozygosity
with the mutation M680I in Turkish family with
clinical syndromes characteristic for familial Mediterranean
fever.
FIGURE 2. The mutation, M680I, was detected in the diabetic
patient. G
3C transversion at nucleotide 2040 that results in
substitution of isoleucine for methionine (black arrow).
Atabek et al
The Endocrinologist
• Volume 16, Number 3, June 2006
© 2006 Lippincott
134 Williams & Wilkins
immune dysregulation is in FMF, however, it could be involved
in the autoimmune process that leads to type 1 diabetes.
FMF has not previously been reported in association
with type 1 diabetes mellitus. The association between FMF
and type 1 diabetes could arise from a simple cooccurrence.
However, presence of the clinical symptoms or signs of FMF
before the presentation of diabetes suggests that diabetes in
this case could be a manifestation of FMF rather than a
coincidence. It is tempting to speculate that an MEFV mutation
may be a risk factor for the development of type 1
diabetes mellitus. Further studies are needed to test this
hypothesis.
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The Endocrinologist
• Volume 16, Number 3, June 2006 Familial Mediterranean Fever and Diabetes
© 2006 Lippincott Williams & Wilkins
135
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