Rheumatology 2004;43:410–415
Advance Access publication 24 February 2004
doi:10.1093/rheumatology/keh157
Review
Clinical and genetic aspects of the hereditary periodic
fever syndromes
G. Grateau
Hereditary periodic fever syndromes are a group of diseases characterized by intermittent bouts of clinical inflammation with
focal organ involvement, mainly of the abdomen, musculoskeletal system and skin. The most frequent is familial Mediterranean
fever, which affects patients of Mediterranean descent all over the world. Three other types have recently been characterized
clinically and genetically. A thorough diagnosis is warranted, as clinical and therapeutic management is specific for each of
these diseases. The underlying mechanisms of these inflammatory diseases appear to be specific for each type, involving so far
unknown proteins, and have already opened new avenues in our understanding of the inflammatory response.
KEY WORDS: Amyloidosis, Tumour necrosis factor (TNF), TNF inhibitors, Hereditary fever, Familial Mediterranean fever (FMF), TNF
receptor-associated periodic syndrome (TRAPS), Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS), Muckle–Wells
syndrome, Familial cold urticaria (FCU), Familial cold autoinflammatory syndrome (FCAS), Chronic infantile neurological cutaneous
and articular (CINCA) syndrome.
The familial hereditary periodic fever syndromes consist of a
unique group of diseases with permanent genetic defects and
intermittent clinical symptoms [1]. The genetic nature of the defect,
together with the inflammatory character of the symptoms, has led
recently to the alternative name of ‘autoinflammatory syndromes’.
Clinical symptoms are often deceptive. Attacks of fever lasting a
couple of days, possibly accompanied by abdominal pain, are not
uncommon. This explains in part why these diseases have not been
recognized until recently. Four syndromes presenting mainly as
intermittent bouts of inflammatory symptoms have now been
clinically and genetically characterized (Table 1). The best known
of the group remains familial Mediterranean fever (FMF), but
three other entities have now been identified: TNF receptor superfamily 1A-associated periodic fever syndrome (TRAPS), hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS),
and the most recently recognized entity, which includes Muckle–
Wells syndrome, familial cold autoinflammatory syndrome/
familial cold urticaria (FCAS/FCU) and the chronic infantile
neurological cutaneous and articular/neonatal onset multisystemic
inflammatory disease (CINCA/NOMID) syndrome. Thorough
diagnosis, which now relies on combined clinical and genetic
data, is warranted because of the specific clinical and therapeutic
management of each of these four syndromes. Inflammatory (AA)
amyloidosis remains a severe complication of these disorders, apart
from HIDS.
periodicity (i.e. regularity) and their frequency varies considerably,
from one attack every year up to an attack every week. (iii) Clinical
signs are accompanied by blood inflammation. Blood samples
for neutrophil count and CRP or SAA determination must be
taken during that attack or within 24 h after the end of the attack.
(iv) The familial nature of the disease is obvious, with a recessive or
dominant mode of transmission. A detailed analysis of these
points, together with consideration of the patient’s ethnicity, helps
in reaching a more thorough diagnosis. The diagnosis of hereditary
periodic fever syndrome may be simple when all characteristic
points are present. By contrast, diagnosis may remain difficult for
an atypical form.
Familial Mediterranean fever
FMF (OMIM 249100) is the most frequent of the hereditary
recurrent inflammatory disorders. It is a disease which affects
populations of Mediterranean descent: Arabs from the East as well
as from the West, Armenians, Turks, non-Ashkenazi and other
Jews, Druzes, Lebanese, Italians, Greeks and others. Among nonAshkenazi Jews, Turks and Arabs from the East, the frequency of
heterozygotes for MEFV, the gene responsible for FMF, is greater
than 1/5 in the general population [2–4]. Its high prevalence
explains the pseudodominant mode of inheritance observed in
these populations [5].
The core of hereditary periodic fever syndromes
Hereditary fever syndromes are rare diseases and they should be
considered only in the presence of a typical association, as follows.
(i) A fever attack is accompanied by specific signs: abdominal pain,
musculoskeletal involvement and skin rash are the most frequent.
(ii) Inflammatory attacks are intermittent, but without true
FMF attacks
Age at onset of FMF is before 5 yr in two-thirds of patients. Fever,
which is constant, is typically associated with signs of acute serosal
inflammation: peritonitis (95%, range 89–96%), pleuritis (45%,
33–53%), scrotitis (3%) and pericarditis (1%). Large joints are also
Service de médecine interne, L’Hôtel-Dieu, Assistance publique-hôpitaux de Paris, 1 place du parvis Notre-Dame, 75181 Paris cedex 04 and Laboratoire de
Génétique et physiopathologie des maladies inflammatoires et musculaires, INSERM U567, Institut Cochin, Paris, France.
Submitted 30 October 2003; revised version accepted 14 January 2004.
Correspondence to: G. Grateau, Service de médecine interne, L’Hôtel-Dieu, Assistance publique-hôpitaux de Paris, 1 place du parvis Notre-Dame,
75181 Paris cedex 04, France. E-mail: [email protected]
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Rheumatology Vol. 43 No. 4 ß British Society for Rheumatology 2004; all rights reserved
Hereditary periodic fever syndromes
411
TABLE 1. Characteristics of the four main types of hereditary fevers
FMF
HIDS
TRAPS
M-W_FCAS/CINCA
Mode of inheritance
Age at onset
Length of the
Access
Abdominal pain
Musculoskeletal
Chest pain
Rash
recessive
<20 years
1–4 days
recessive
childhood
3–7 days
dominant
childhood/neonatal
variable
very common (serositis)
monoarthritis
pleuritis, often unilateral
rare (<5%) erysipelas-like
on lower limbs
Other signs
pericarditis, scrotal attacks,
splenomegaly
Amyloidosis
Treatment
yes
colchicine
Chromosomal locus
Gene
Protein
16p13.3
MEFV
marenostrin/pyrin
very common
athralgias
unusual
very common (>90%)
or several types: maculopapular, papular
headache
cervical lymph nodes
hepatosplenomegaly
not reported
none effective
TNF inhibitors?
12q44
MVK
mevalonate kinase
dominant
variable
often more than 1 up
to several weeks
common
myalgias
yes
common erysipelas-like
including upper limbs
affected in more than 50% (21–76%) of patients. The most
common skin lesion is erysipelas-like erythema of the lower limbs
(25%, 12–41%) [6]. Most often only one organ is affected during
an attack. Length of the attack varies from some hours to 3 or 4
days. The attacks stop spontaneously and recur without any
regular periodicity. Their frequency varies considerably from one
patient to another and from one period of life to another for the
same patient. Chronic manifestations of the disease are rare;
examples are encapsulating peritonitis and chronic destructive
arthritis, affecting especially the hips and knees.
Diagnosis
Diagnosis of FMF relies on clinical arguments, recently helped by
genetic testing. In the typical form of FMF the diagnosis is often
obvious and the systematic use of a genetic test is questionable. At
the beginning of the disease, when clinical signs are not typical or
when the familial history is lacking, genetic testing is of great
value [7]. FMF can no longer be considered a diagnosis of
exclusion. In the clinical context of FMF, the presence of two
mutations on different alleles (homozygosity or compound
heterozygosity) makes it possible to affirm the diagnosis. When
only one mutation is present, the diagnosis is not ascertained, but
neither can it be excluded. Although five mutations account for
more than 85% of all the mutations, some rare or unknown
mutations exist. It is also likely that some heterozygous patients,
as in many recessive diseases, may have attenuated clinical signs.
It has been showed that the serum concentration of acute-phase
proteins is basically higher in heterozygotes than in controls [8].
Even so, the genetic diagnosis does not provide a final solution
for every patient, rather, it has become a powerful help in
ascertaining the diagnosis of FMF and consequently in give
the appropriate treatment, mainly in children.
orbital edema
yes
steroids
TNF inhibitors
12p13
TNFRSF1A
type 1 TNF receptor (55p)
rare
arthritis/destruction
no
urticaria/erythema
deafness–cold
sensitivity/dysmorphy
papillitis
yes
steroids
Interleukin-1 inhibitor?
1q44
CIAS1
cryopyrin
CRP and fibrinogen levels during the attack-free period, can be
calculated for each patient from their body weight and body
surface area [12]. Although colchicine intoxication remains
severe, long-term daily colchicine is a relatively safe and effective drug [13]. True non-responders to colchicine are very
uncommon; most of them are non-compliant patients. In these
patients, no treatment has proved its efficiency. Interferon has
been proposed, but early promising results have not been
confirmed [14].
What are the mechanisms of the inflammatory
response in FMF?
MEFV is a gene expressed specifically in myeloid cells. In vitro,
MEFV expression is up-regulated by a number of cytokines:
interferon , interferon and TNF-, which is more directly
involved in the mechanisms of TRAPS [15, 16]. Recent work has
opened new avenues in understanding the physiological role of
marenostrin/pyrin, the protein encoded by MEFV, and the
mechanisms of FMF. Marenostrin/pyrin has in its N-terminal
region a specific domain of 90 amino acids, the pyrin domain,
which defines a novel class of proteins [17]. It has been shown
that, by homotypic pyrin domain binding, marenostrin/pyrin can
interact with apoptotic speck protein (ASC), which mediates both
NF-B and procaspase-1 activation with associated processing
and the secretion of interleukin (IL) 1, and apoptosis [18, 19].
These interactions are highly complex and are not yet fully
elucidated. Much remains to be done to decipher the physiological
role of pyrin in myeloid cells as well as the mechanisms of the
disease. It is noteworthy that, in these experiments, diseaseassociated mutations, which are almost all located at the Cterminal part of the protein, do not modify results obtained with
the wild-type protein [20].
Treatment
Daily colchicine is an effective treatment to prevent the recurrence
of attacks and amyloidosis [9]. The usual dose of colchicine
is determined by its effect in the prevention of recurrence of
attacks and varies from 1 to 2.5 mg/day [1, 10]. Although some
controversy exists as to the adverse effects of colchicine on
sperm function, long-term use of colchicine can be considered
globally safe, including during pregnancy [11]. A recent study
suggests that in children the optimal effective colchicine dosage,
i.e. that which reduces the frequency of attacks and lowers ESR,
TRAPS: a model of cytokine receptor disease
A dominant mode of inheritance and a non-Mediterranean origin
has allowed a specific syndrome, now defined by the acronym
TRAPS, to be distinguished from FMF. ‘TRAPS’ refers to the
protein affected by the mutation in this disease: TNF receptor
superfamily type 1A (TNFRSF1A) [21].
Although TRAPS was initially described in kindreds of Nordic
origin, as emphasized by the name of familial Hibernian fever
(MIM 142680), mutations in TNFRSF1A have now been found
412
G. Grateau
in many populations, including Black Americans, Japanese and
persons of Mediterranean ancestry, among whom FMF is highly
prevalent [22–24].
TRAPS attacks
TRAPS attacks are longer than those of FMF; generally they last
at least 5 days but may persist for up to 3 weeks. However, attacks
shorter than 5 days have been reported [23, 25]. Abdominal pain
can simulate a surgical event. Skin manifestations are present in
more than three-quarters of cases. A wide spectrum of rashes may
be observed: urticaria-like rashes, plaques and patches [26]. The
most distinctive lesion, however, is an erythematous plaque of
variable size: it is swollen, has hazy edges, and is warm and tender
to palpation. Most frequently it involves the upper and lower limbs
but may also be observed on the torso. On the limbs, the rash
begins distally and migrates to the extremity during the attack.
This pseudocellulitis is often accompanied by painful myalgia,
which constitutes the other most distinctive manifestation of the
attack. In one series myalgias were present in 100% of the patients
and often heralded the onset of an attack [25]. Magnetic resonance
imaging data have suggested that subcutaneous tissue, fascia and
muscles seem to be involved during TRAPS attacks. Biopsies have
revealed that only the fascia is infiltrated by lymphocytes and
monocytes, and myositis does not occur [27]. Thoracic and scrotal
pain, arthritis, orbital oedema and conjunctivitis are also observed
in TRAPS attacks.
Genetics and mechanisms
Most TRAPS-associated mutations, including most cysteine
substitutions, are located in the two first cysteine-rich domains
(CRD) of the TNFRSF1A protein. This allows easy and comprehensive screening of the mutations [23, 24]. The status of
two sequences, R92Q and P46L, has not been completely
determined. P46L appears to be a mutation with at most low
penetrance and R92Q behaves either as a true mutation or as one
with incomplete penetrance [23, 25]. This would make a functional
test useful for the diagnosis of TRAPS. In some patients,
plasma concentrations of the soluble form of the receptor are
low or paradoxically normal during attacks, and may also be low
between attacks. This suggests a quantitative or qualitative
abnormality of the soluble form of the receptor. In some
patients a defect of receptor shedding from monocytes has been
shown, and could result in a decrease in the amount of the
soluble form [25]. However, abnormal shedding accounts for a
minority of patients with the receptor defect and other mechanisms
are needed to explain the disease in TRAPS families. Moreover, in
some families with a TRAPS-like phenotype there is a defect of
receptor shedding from monocytes and no TNFRSF1A mutations,
indicating genetic heterogeneity in autosomal dominant recurrent
fever [24].
Treatment
Colchicine does not seem to prevent the recurrence of attacks in
TRAPS patients. On the other hand, corticosteroids, when given at
the onset, can attenuate the length and severity of the attacks. In
the most severe forms of the disease, clinical signs of inflammation
are almost permanent and require daily use of corticosteroids. This
may lead to dependency, and invites the use of other antiinflammatory drugs [25]. TNF inhibitors seem to be perfectly
designed for the treatment of TRAPS. Etanercept, a TNFRSF1B
receptor–immunoglobulin fusion molecule, mimics the effect of the
normal soluble TNF receptor and thus compensates for its deficit
in TRAPS patients. Preliminary results at 6 months, at the dose
of 25 mg subcutaneously twice a week in patients who use high
doses of corticosteroids, show the efficiency of etanercept, which
induces a decrease in attack frequency and allows a decrease
in corticosteroid dose [25]. However some TRAPS patients seem
not to respond to etanercept [25, 28]. In one of these patients,
another molecule, consisting of the fusion of soluble TNFRSF1A
with an immunoglobulin, has been tested without any dramatic
effect [28].
Muckle–Wells syndrome, familial cold urticaria and
the chronic infantile neurological cutaneous and
articular (CINCA) syndrome
Although described separately, these three entities are now
grouped, as they are all associated with mutations of the gene
CIAS1 (cold-induced autoinflammatory syndrome).
Clinical features
A common sign of these diseases is a recurrent urticaria or
urticaria-like eruption. In Muckle–Wells syndrome urticaria is
associated with renal amyloidosis and nerve deafness [29]. Its mode
of inheritance is dominant autosomal. Apart from urticaria,
inflammatory attacks consist of ocular signs such as conjunctivitis,
and less frequently arthritis. Additionally, other signs are observed
in some kindreds: papillary drusen, endocrine abnormalities,
aphthous ulcers, abdominal hernias, dysmorphia, suggestive of a
certain degree of variability in clinical expression. In familial cold
urticaria, the distinctive feature is a delayed onset, most often a
few hours after exposure to a cold ambience, of urticaria with
conjunctivitis, arthralgias and a moderate fever. This explains why
it has been proposed that this variety be renamed ‘familial cold
autoinflammatory syndrome’ (FCAS) [30]. Chronic infantile
neurological cutaneous and articular (CINCA) or neonatal onset
multisystemic inflammatory disease (NOMID) is a more severe
disease with a unique neonatal onset [31]. Neonatal skin rash,
usually a non-pruriginous diffuse urticarial erythema, is associated
with a neurological and articular disease. Chronic aseptic
meningitis is responsible for headache during childhood. Cerebral
spinal fluid is sterile but contains neutrophils. Seizures, spasticity
and motor deficits have also been observed. Mental retardation
frequently appears during infancy, associated with brain atrophy.
Articular involvement consists of arthralgias and arthritis, which
are destructive and may lead to a disabling arthropathy during
infancy. Hypertrophy of the patella and growth cartilage is
characteristic. Long-bone epiphyses are also pathological. All
these associated lesions can lead to major deformations, mainly of
the knees, and to a delay in bone growth. Ocular involvement
consists of conjunctivitis, uveitis and papillitis with optic atrophy,
which can lead to blindness. Bilateral neurosensorial progressive
hearing loss may occur. A distinctive, more or less pronounced
facial dysmorphia is an almost constant feature, which gives the
patients a similar appearance. The border between Muckle–Wells
and CINCA syndromes is not clear-cut and some patients have
been diagnosed first as having Muckle–Wells syndrome and then
as having CINCA [32].
Genetics and mechanisms
The CIAS1 gene underlying Muckle–Wells syndrome, FCAS and
CINCA syndrome encodes a protein called cryopyrin/PYPAF1/
NALP3 [33]. Almost 50 mutations of CIAS1 have been described
[33–36]. The last series emphasized a relative phenotype/genotype
correlation in the whole population so far described with CIAS1
mutations. When classifying patients into three clinical groups
Hereditary periodic fever syndromes
(FCU, the mildest clinical form, MW, and CINCA, the most severe
form), there is little overlap of CIAS1 genotypes between the three
groups; overlap exists only between two contiguous groups. This
would suggest that mutations have different effects on cryopyrin
function or expression [36]. Cryopyrin has its own N-terminal
region, a typical 90 amino acid pyrin domain, and thus belongs to
the increasing pyrin family. Two other consensus domains exist in
cryopyrin: a central NACHT or nucleotide-binding site (NBS)
domain, which plays a role in protein oligomerization, and a Cterminal leucine-rich repeat (LRR), which shares some similarity
with the Toll receptor family. Clustering of these three domains
defines a new family, called PYPAF or NALP, which so far
consists of 14 members [37]. Like cryopyrin, pyrin can bind to and
interact with ASC and thus modulates ASC-dependent apoptosis,
NFB signalling and the activation of procaspase-1, with associated processing and secretion of IL-1 [38].
Treatment
There is no efficient treatment of these diseases. Colchicine
sometimes has some effect on the arthropathy of the Muckle–
Wells syndrome. Intermittent or permanent corticotherapy is
often used without modifying the course of the disease. Few data
are available on the use of novel anticytokine molecules [39].
Hyperimmunoglobulinaemia D and periodic fever syndrome:
an enzymatic disorder
Clinical features
Hyperimmunoglobulinaemia D and periodic fever syndrome or
HIDS (MIM 260920) was distinguished from FMF by the presence
of a high serum level of immunoglobulin (Ig) D in Dutch patients
[40]. The disease begins in infancy, often in the first year of life.
Inflammatory attacks of HIDS are typically 7 days long and recur
every 4–8 weeks. Focal signs in more than two-thirds of the cases
accompany fever: abdominal pain, diarrhoea, vomiting, nondestructive arthritis, various types of skin rash and painful cervical
lymphadenopathy [41].
Genetics and mechanisms
Surprisingly, it has been showed that HIDS is an enzymatic
disease. It is a moderate deficiency of the mevalonate kinase
enzyme caused by mutations in the MVK gene [42, 43]. Complete
deficiency leads to a more severe phenotype, previously known as
mevalonic aciduria, which includes morphological abnormalities
and retardation of growth and mental development. A high level of
serum IgD can no longer be considered specific for HIDS, as it has
also been observed in other inflammatory diseases, including FMF
and TRAPS [23]. The gold standard for HIDS diagnosis is
currently the biochemical demonstration of mevalonate kinase
deficiency. This can be obtained by direct measurement of the
enzyme in lymphocytes or by showing the presence of mevalonate
(the substrate of the enzyme) in the urine during the course of an
attack. Recent results help in deciphering the links between the
enzymatic defect and the inflammatory attacks. One question is
whether the inflammation is due to the accumulation of mevalonate or to the lack of its products, the isoprenoid compounds. In
vitro experiments with mononuclear cells suggest that shortage of
isoprenoid end-products contributes to increased IL-1 secretion
and subsequently to clinical inflammation, whereas excess mevalonate does not [44].
413
Treatment
NSAIDs do not relieve HIDS attacks. Corticosteroids sometimes
have a moderate effect and colchicine does not prevent recurrence
of the attacks. A recent trial has shown that thalidomide, used as
an anti-TNF agent, has no effect on HIDS attacks [45]. Preliminary results show some effect of novel anti-TNF agents, but longer
follow-up is needed [46, 47].
Hereditary periodic fever syndromes and amyloidosis
Amyloidosis remains a life-threatening complication of hereditary
periodic fever syndromes. However, as observed in other chronic
inflammatory diseases, amyloidosis does not appear in every
patient. FMF-associated amyloidosis has been investigated and
used to define some risk factors for this complication. Three
genetic factors have now been established as risk factors for the
development of AA amyloidosis in FMF. The first of these is the
MEFV genotype. Homozygosity for M694V confers a more
severe form, in terms of age at onset, frequency of attacks and
susceptibility to amyloidosis. However, this association has not
been found by one group and is not exclusive as more than 10 other
MEFV genotypes have been reported to be associated with
amyloidosis [48, 49]. The second factor is male gender. The third
factor is the SAA1 genotype: SAA1.1 homozygosity is a strong risk
factor in the populations studied so far [50]. Other genetic or
environmental factors are needed to explain FMF-associated
amyloidosis. This is particularly obvious for the Armenian
population, as amyloidosis is prevalent in Armenians living in
Armenia, whereas it was absent in those living in California even in
the precolchicine era [49]. It is likely that FMF phenotype 2, i.e.
amyloidosis occurring without previously recognized attacks, is
explained, at least in part, by subclinical inflammation, as revealed
by an increase in CRP and SAA between overt clinical attacks [51].
As is the case for FMF, in TRAPS the long-term prognosis
can be jeopardized by the development of AA amyloidosis. About
20% of the patients with TRAPS are estimated to develop this
complication [25]. Most cases of amyloidosis have been reported in
patients harbouring a cysteine residue mutation. However, this is
not exclusive, as non-cysteine mutations can be associated with
amyloidosis [23–25]. Few data are available on the effect of antiTNF agents on amyloidosis [25, 52]. By contrast to the three
entities described above, amyloidosis has not been so far reported
in HIDS, whereas the acute-phase response observed during HIDS
attacks is similar to those of other hereditary fevers. This could
suggest that a specific unique factor protects HIDS patients from
inflammatory amyloidosis.
Permanent defect versus intermittent symptoms
One of the most intriguing features of hereditary periodic fever
syndromes is the intermittent outcome of clinical inflammatory
attacks. Although many infectious, inflammatory and even
malignant diseases may present as intermittent fever, this symptom
is characteristic of hereditary periodic fever syndromes. How can
we explain intermittent symptoms when the underlying defect is
genetic, and thus permanent? Although patients with FMF report
that attacks have triggering factors, none of these can be
considered constant. More prevalent seems to be the role of
immunization and infection as a trigger of HIDS attacks [41]. This
has led to investigations of the influence of temperature on
mevalonate kinase activity in vitro and in HIDS patients. All
fibroblast cell lines from HIDS patients displayed substantially
higher mevalonate kinase activities at 30 C than at 37 C. A similar
phenomenon occurs in vivo, as mevalonate kinase activity in blood
mononuclear cells drops when HIDS patients experience febrile
attacks. These results suggest that minor elevations in temperature,
such as are induced by triggering factors, can set off a chain of
414
G. Grateau
events in which mevalonate kinase becomes progressively ratelimiting, leading to a temporary deficiency of isoprenoids and
resulting in overt inflammation and fever [53]. In fact, patients with
hereditary periodic fever syndromes have evidence of significant
inflammatory activity when they are clinically asymptomatic. This
has been shown in FMF and TRAPS patients [25, 51]. This
inflammatory activity in FMF patients is also observed in
heterozygous individuals, as stated above, and could represent
the putative acquired advantage for heterozygotes we are looking
for in order to understand the mechanisms which help to maintain
the high frequency of the disease in the affected population. What
could be (or could have been) the advantage in being heterozygous
for a marenostrin/pyrin mutation? We have to think of the great
scourges of the past, and of the future, that are infectious diseases.
Heterozygotes would be more resistant to infectious diseases,
because they are able to react against microbial aggression, with
Mycobacterium tuberculosis as the main target, with a more
intense fever and inflammatory response [54]. Although this
will be difficult to prove, marenostrin/pyrin probably controls
an important pathway of the inflammatory response and reminds
us that fever and inflammation are necessary in order to fight
against infection.
Conclusion
The population ancestry of the patient and the type of organ
involvement during the attack, mainly the abdomen, musculoskeletal apparatus and skin, provide the basis for the thorough
diagnosis of hereditary periodic fever syndrome. Biochemical and
genetic tests confirm the diagnosis. However, current genetic data
do not account for all the observed phenotypes. A survey of the
available data concerning the frequency of mutations found in
patients with an FMF phenotype in most populations affected by
FMF suggests that there is probably a second gene responsible for
the FMF-like phenotype [55, 56]. A number of dominant families
appear to be unlinked to TNFRSF1A and CIAS1, indicating the
existence of another gene responsible for these varieties [24, 57].
Better diagnosis will lead to better management of these patients—
mainly FMF patients, for whom daily colchicine is a life-saving
drug. Treatment of other forms of hereditary fever is not well
established, and this raises the more general question of how to
organize trials for rare diseases. The mechanisms of these
syndromes are beginning to be elucidated and our increasing
knowledge about them has already led to the discovery of
previously unknown pathways of the inflammatory response.
The hereditary periodic fever syndromes are thus an important
example of how rare diseases can help our understanding of the
pathogenesis of more general phenomena.
The author has declared no conflicts of interest.
Acknowledgements
Our work on hereditary periodic fever syndromes is supported
by grants (N A00047KS) from the INSERM-AFM network on
rare diseases.
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