The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
Review Article
Medical Progress
H EREDITARY P ERIODIC F EVER
JOOST P.H. DRENTH, M.D., PH.D.,
AND JOS W.M. VAN DER MEER, M.D., PH.D.
P
ERIODIC fever is defined as recurrences of
fever that last from a few days to a few weeks,
separated by symptom-free intervals of vari-
able duration. This pattern of fever can be caused by
recurrent infections or neoplastic disorders but also
by noninfectious inflammatory disorders.1 It is im-
portant to review the medical history carefully in pa-
tients with recurrent febrile attacks. Patients with
periodic fever that persists for more than two years
rarely have infections or malignant disorders. Attacks
with a predictable course and a similar set of symp-
toms, along with a family history of such attacks,
may suggest the presence of a noninfectious form of
periodic fever. Although numerous disorders, such as
juvenile rheumatoid arthritis, adult-onset Still’s dis-
ease, Crohn’s disease, and Behçet’s syndrome, can
cause periodic fever, this article will focus on hered-
itary periodic fever syndromes. We will review the clin-
ical, genetic, and molecular aspects of familial Medi-
terranean fever, the hyper-IgD syndrome, and the
tumor necrosis factor (TNF) receptor–associated pe-
riodic syndrome.
FAMILIAL MEDITERRANEAN FEVER
Clinical Features
In 1908, Janeway and Mosenthal described a Jew-
ish girl who had episodic abdominal pain and fever.
Although additional cases were described subsequent-
ly,2 it took nearly half a century to establish this dis-
order as familial Mediterranean fever.3,4 The condition
is characterized by short attacks of serositis (peritoni-
tis, pleuritis, or arthritis) and fever.5 About 90 per-
cent of patients have their first attack before the age
of 20 years.6 Attacks of familial Mediterranean fever
unfold suddenly, and the symptoms persist for only
a short time (6 to 96 hours) (Fig. 1A).
From the Department of Medicine, Division of Gastroenterology and
Hepatology (J.P.H.D.), and the Division of General Internal Medicine
(J.W.M.M.), University Medical Center St. Radboud, Nijmegen, the Neth-
erlands. Address reprint requests to Dr. Drenth at the Department of Med-
icine, Division of Gastroenterology and Hepatology, University Medical
Center St. Radboud, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands,
or at joostphdrenth@cs.com.
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Abdominal pain of one or two days’ duration oc-
curs in 95 percent of patients,5 most of whom present
with an acute abdomen, although some patients have
only mild abdominal pain without overt peritonitis.7
Monoarthritis, with effusions of the knee, ankle, or
wrist joints, is the sole manifestation of an attack in
75 percent of patients. Chronic destructive arthritis
and migratory polyarthritis are rare. Chest pain due
to unilateral pleuritis is reported in 30 percent of
patients5; pericarditis occurs in less than 1 percent.8
Young male patients (less than 20 years of age) may
present with acute scrotal swelling and tenderness.9
Erysipelas-like skin lesions on the shins or feet, con-
sidered to be a specific clinical finding for the dis-
ease, are present in 7 to 40 percent of patients.10 Se-
vere, protracted myalgia of the legs is an uncommon
symptom of familial Mediterranean fever.
Characteristically, the above-mentioned symptoms
are accompanied by fever, but patients may present
with fever alone. AA amyloidosis is regarded as the
main complication of the disease, and amyloid depos-
its are found mainly in the kidneys but also in the
gastrointestinal tract, liver, and spleen and eventually
in the heart, testes, and thyroid. The prevalence of
amyloidosis varies according to the population; it is
high among Sephardic Jews and low among Ash-
kenazi Jews.11
Genetic and Epidemiologic Features
Familial Mediterranean fever is an autosomal re-
cessive disease. It is the most prevalent periodic fever
syndrome, affecting more than 10,000 patients world-
wide. Familial Mediterranean fever predominantly
affects people from the Mediterranean basin, includ-
ing Sephardic Jews, Arabs, Turks, and Armenians. The
disorder is unusual in other populations, but it has
been described in Greeks, Italians, Cubans, and Bel-
gians.12 The frequency of the susceptibility gene var-
ies widely; it is very high among Armenians (ratio of
persons with the gene to those without it, 1:7)13 and
Sephardic Jews (1:5 to 1:16)14,15 but is much lower
in Ashkenazi Jews (1:135).
Laboratory Findings
There is no specific biologic marker of familial
Mediterranean fever that is clinically available. Affect-
ed patients lack a specific protease, normally present
in serosal fluids, that can inactivate both interleukin-
8 and the chemotactic complement factor 5a inhibitor,
but the test for this protease is used only in research
settings.16 Nonspecific findings include increases in
inflammatory mediators, such as serum amyloid A,
fibrinogen, and C-reactive protein, during febrile at-
 MED ICA L PROGR ES S

A Familial Mediterranean Fever B Hyper-IgD Syndrome

41 Serositis (peritonitis), 41 Cervical lymphadenopathy,
vomiting, arthritis, erythematous macules,
erysipelas-like skin lesions abdominal pain, vomiting,
Body Temperature (°C)

arthralgia
40
40

Body Temperature (°C)

39
39
38

38
37

36 37
0 1 2 3
Day
36
0 1 2 3 4 5 6 7 8 9

Jan. Feb. Mar. Apr. May June July Aug. Sept. Oct. Nov. Dec. Day

Figure 1. Temporal Patterns of Fever and Associated Clinical

Findings in a Patient with Familial Mediterranean Fever (Panel
A), a Patient with the Hyper-IgD Syndrome (Panel B), and a Pa- Jan. Feb. Mar. Apr. May June July Aug. Sept. Oct. Nov. Dec.
tient with the Tumor Necrosis Factor (TNF) Receptor–Associat-
ed Periodic Syndrome (Panel C).
Each panel shows the temperature during an attack of fever in
a hospitalized patient and the symptoms that accompanied the
febrile attack. The bar graph below each curve shows the num- C TNF-Receptor–Associated Periodic Syndrome
ber of attacks that the patient had in a year, when they oc-
curred, and their approximate duration. The patient with the 41 Conjunctivitis, erythematous skin lesions,
myalgia and arthralgia, abdominal pain
Body Temperature (°C)

TNF-receptor–associated periodic syndrome had long attacks

twice in one year, whereas the patient with familial Mediterra- 40
nean fever and the patient with the hyper-IgD syndrome had
shorter but more frequent attacks.
39

38

tacks.17 Proteinuria (more than 0.5 g of protein per
24 hours) in patients with familial Mediterranean fe-
ver is highly suggestive of amyloidosis.7
Pathogenesis and Molecular Genetic Features
After familial Mediterranean fever was mapped to
the short arm of chromosome 16,18 two independent
groups were able to clone the gene (MEFV).19,20 The
protein (pyrin, or marenostrin) encoded by MEFV
contains 781 amino acids and has a molecular weight
of 86,000. MEFV is predominantly expressed in my-
eloid cells, and its expression is up-regulated during
myeloid differentiation. Inflammatory mediators such
as interferon-g and tumor necrosis factor are also ef-
fective stimuli for expression of the gene.21 The pre-
cise function of pyrin is still unclear. It is mainly ex-
pressed in the cytoplasm of mature neutrophils and
monocytes and is thought to regulate neutrophil-
mediated inflammation.21 At least 28 mutations in the
MEFV gene have been described, most of which are
37
36
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Day
Jan. Feb. Mar. Apr. May June July Aug. Sept. Oct. Nov. Dec.
clustered in one exon (Fig. 2).22 Two common mis-
sense mutations are M694V (occurring in 20 to 67
percent of cases) and V726A (in 7 to 35 percent);
their prevalence varies according to the population
tested.23,24 Founder effects in familial Mediterranean
fever have been established, and it is believed that
the V726A and M694V mutations originated in com-
mon ancestors who lived some 2500 years ago in the

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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

1 2 3 4 5 6 7 8 9 10

E148Q M680I M694V V726A

V694I
M694I

Figure 2. Structure of the Gene for Familial Mediterranean Fever (MEFV ).

The MEFV gene consists of 10 exons (coding regions). Exon 2 and exon 10 are the largest and most mutation-rich regions of the
MEFV gene, but mutations have also been reported in exons 3, 5, and 9. Most mutations in the gene are missense mutations in
which one amino acid has been replaced with another in the MEFV gene product, pyrin (marenostrin). The most common mutations
in the MEFV gene are M694V (replacement of methionine with valine at codon 694) and V726A (replacement of valine with alanine
at codon 726). Because familial Mediterranean fever is autosomal recessive, two MEFV mutations must be present in order for the
disease to develop. Most genetic laboratories screen only for the most common mutations in exon 10 and in some cases for the
E148Q mutation (replacement of glutamine for glutamic acid at codon 148) in exon 2 as well.

Middle East.20 The relatively high frequency of the
gene might suggest that carrier status for these muta-
tions may have conferred a heightened resistance to
a pathogen that has not yet been identified. It is well
established that the M694V mutation is associated
with a more severe phenotype than the V726A mu-
tation and that homozygosity for M694V carries a
higher risk of amyloidosis.25,26 Apart from MEFV
mutations, it appears that polymorphisms in the
gene for serum amyloid A increase the susceptibility
to renal amyloidosis and that polymorphisms in a
gene for the major-histocompatibility-complex class
Ia chain influence the severity of the disease.27,28
Treatment
Since 1972, colchicine has been the first-line treat-
ment for patients with familial Mediterranean fever,
and its efficacy has been established in two con-
trolled clinical trials.29,30 Colchicine prevents febrile
attacks in 60 percent of patients and significantly re-
duces the number of attacks in another 20 to 30
percent.6 The lack of efficacy in approximately 5 to
10 percent of patients may be due in part to non-
compliance. The average dose in adults is 1 mg daily,
but if there is no response, the dose may be increased
to 2 mg or even 3 mg. Most patients tolerate this
regimen, but diarrhea or abdominal pain may devel-
op, necessitating a reduction in the dose. Side effects
such as myopathy, neuropathy, and leukopenia are
rare and occur mainly in patients with renal or liver
impairment. Colchicine does not stop an established
attack, and diclofenac (75 mg administered intramus-
cularly) may be used for pain relief. Compliance is
very important, because the discontinuation of col-
chicine may result in an attack within a few days. Pre-
liminary data suggested that interferon alfa might be
useful in aborting febrile attacks, but a double-blind
trial failed to confirm its efficacy.31,32 Other agents
have limited efficacy, but anecdotal experience sug-
gests that prazosin may be useful.33
Prognosis
The prognosis for patients with familial Mediter-
ranean fever is determined mainly by the presence or
absence of AA amyloidosis; in its absence, life ex-
pectancy is normal. Before the introduction of col-
chicine, amyloidosis occurred in 60 percent of affect-
ed patients who were over 40 years of age, and it was
the main cause of death in such patients.34 Treatment
with colchicine greatly altered the prognosis by ar-
resting amyloidosis and reversing proteinuria. Even
if colchicine therapy does not prevent febrile attacks,
it will prevent amyloidosis.35
Diagnostic Strategy
It is important to take a thorough medical history
and obtain all the details of a typical attack. Since ex-
amination of the patient between attacks usually re-
veals no abnormalities, examination during an attack
is crucial. Familial Mediterranean fever is a clinical

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 MED ICA L PROGR ES S

diagnosis, and the diagnostic criteria have been val-
idated.36 If a patient has a characteristic medical his-
tory and belongs to an ethnic group with a high prev-
alence of the disorder, the diagnosis is not difficult to
make (Table 1). However, the diagnostic criteria were
validated in a population with a very high prevalence
of familial Mediterranean fever, and it is not known
whether the reported sensitivity and specificity (99
percent in both cases) apply to other populations.
Since the MEFV gene has been cloned, it is pos-
sible to establish a molecular diagnosis of familial
Mediterranean fever, but there are some limitations.
Genetic laboratories usually screen for the five most
frequent mutations (M694V, V726A, V680I, E148Q,
and V694I), and those that are more rare will be
missed. Furthermore, MEFV mutations occur on both
alleles in only 70 percent of typical cases.37 In the re-
maining 30 percent, only one mutation or none can
be detected, even after sequencing.12 There is also
evidence of nonpenetrance (i.e., two mutant MEFV
alleles in the absence of clinical disease). Despite
these limitations, molecular testing can be used as a
confirmatory test in cases in which there is a high in-
dex of suspicion. Whether or not the results are posi-
tive, treatment with colchicine is warranted in symp-
tomatic cases.25,26,29,30
HYPER-IgD SYNDROME
Clinical Features
The hyper-IgD syndrome was recognized as a sep-
arate entity in 198438; the disorder has also been de-
scribed as a variant of Still’s disease39,40 or as etio-
cholanolone fever.41 Patients with the hyper-IgD syn-
drome have recurrent attacks of fever that usually
start before the end of the first year of life.42 An at-
tack is heralded by chills, followed by a sharp rise in
body temperature, and lasts for four to six days, with
gradual defervescence (Fig. 1B). It can be provoked by
vaccination, minor trauma, surgery, or stress. Cervi-
cal lymphadenopathy and abdominal pain with vom-
iting, diarrhea, or both almost always accompany the
attack. Symptoms that are common include hepato-
splenomegaly, headache, arthralgias, arthritis of large
joints, erythematous macules and papules, and even
petechia and purpura (Fig. 3).43 A minority of pa-
tients report painful, aphthous ulcers in the mouth
or vagina. After an attack, patients are free of symp-
toms, although skin and joint symptoms disappear
slowly. The attacks generally recur every four to six
weeks, but the interval between them can vary sub-
stantially in an individual patient and from one pa-
tient to another.
Genetic and Epidemiologic Features
The hyper-IgD syndrome is inherited as an auto-
somal recessive trait, and half the patients with this
syndrome have affected siblings.44 The frequency of
the susceptibility gene is low (ratio of persons with
the gene to those without it, 1:350), which is why
the disorder is not observed in the parents or off-
spring of affected patients. The hyper-IgD syndrome
registry in Nijmegen, the Netherlands, currently has

TABLE 1. DISTINCTIVE FEATURES OF FAMILIAL MEDITERRANEAN FEVER, THE HYPER-IgD

SYNDROME, AND THE TUMOR NECROSIS FACTOR (TNF) RECEPTOR–ASSOCIATED
PERIODIC SYNDROME.*

FAMILIAL TNF-RECEPTOR–
MEDITERRANEAN HYPER-IgD ASSOCIATED PERIODIC
FEATURE FEVER SYNDROME SYNDROME

Ancestry Jewish, Turkish, Dutch, French Scottish, Irish

Armenian, Arab
Familial transmission† Horizontal Horizontal Vertical
Age at onset (yr) <20 <1 <20
Typical duration of attack <2 4–6 >14
(days)
Symptoms other than fever Serositis, scrotal involve- Prominent cervical Conjunctivitis, localized
ment, erysipelas-like lymphadenopathy myalgia
erythema
Laboratory findings Low C5a inhibitor in High serum IgD Low serum type 1 TNF
serosal fluids (>100 IU/ml) receptor (<1 ng/ml)
Gene MEFV Gene for mevalo- Gene for type 1 TNF
nate kinase receptor
Protein Pyrin (marenostrin) Mevalonate kinase Type 1 TNF receptor
Therapy Colchicine None available Corticosteroids,
etanercept

*The features that are helpful in the diagnostic evaluation are shown. The presence or absence of
a particular feature does not rule out the diagnosis.
†Horizontal transmission denotes disease in one or more siblings of an affected patient, and vertical
transmission disease in one or both parents or in one or more uncles or aunts.

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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
Figure 3. Petechiae and Purpura on the Lower Right Leg during
a Febrile Attack in a Patient with the Hyper-IgD Syndrome.
The skin lesions disappeared a week after the end of the attack.
The clinical findings in this patient (Patient 30 in the hyper-IgD
syndrome registry in Nijmegen, the Netherlands) have been
described in detail elsewhere.42
clinical data on more than 170 published and un-
published cases worldwide (information is available
at http://www.hids.net). Most patients with the hy-
per-IgD syndrome are white and are from western
European countries; some 60 percent are either Dutch
or French.
Laboratory Findings
The hyper-IgD syndrome is diagnosed on the ba-
sis of characteristic clinical findings and continuous-
ly high IgD values (more than 100 IU per milliliter).
However, IgD values may be normal in very young
patients (those less than three years old),45 and per-
sistently low levels were reported in a patient with
typical clinical findings and the genotype for the
syndrome.46 In siblings with the disease, there may
be marked differences in IgD levels, with very high
values in one sibling but low values in another.47
More than 80 percent of patients have high IgA lev-
els in conjunction with high IgD levels.45,48 During
an attack, there is a brisk acute-phase response, with
leukocytosis, high levels of serum C-reactive protein
and serum amyloid A, and activation of the cytokine
network.49 Elevated urinary excretion of neopterin,
a marker of an activated cellular immune response,
reflects disease activity.50
Pathogenesis and Molecular Genetic Features
A recent genome-wide search established the link-
age of the susceptibility gene for the hyper-IgD syn-
drome to the long arm of chromosome 12.51 This
information, along with the fortuitous detection of
mevalonic acid in a urine sample obtained during a
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febrile attack in a patient with the hyper-IgD syn-
drome, led to the identification of mutations in the
gene for mevalonate kinase as the cause of the syn-
drome.46,51 Mevalonate kinase is a key enzyme in the
cholesterol metabolic pathway and follows 3-hydroxy-
3-methylglutaryl–coenzyme A reductase (Fig. 4).52
In patients with the hyper-IgD syndrome, the activ-
ity of mevalonate kinase is reduced to 5 to 15 per-
cent of normal; as a result, serum cholesterol levels
are slightly reduced, and during attacks, urinary ex-
cretion of mevalonic acid is slightly elevated.
Most patients are compound heterozygotes for
missense mutations in the gene for mevalonate ki-
nase. One mutation, V377I, is present in more than
80 percent of patients; the other mutations are less
frequent.47,52 The V377I mutation results in a slight
reduction of the stability of recombinant human me-
valonate kinase protein and in the catalytic activity
of the enzyme.53 Less than 1 percent of patients have
a complete deficiency of mevalonate kinase, which is
associated with mevalonic aciduria, a rare inherited
disorder characterized by developmental delay, failure
to thrive, hypotonia, ataxia, myopathy, and cataracts.
In mevalonic aciduria, the disease-associated muta-
tions are mainly clustered within a specific region of
the protein.54,55 How a deficiency of mevalonate ki-
nase is linked to an inflammatory periodic fever syn-
drome is not yet known.
Treatment
No uniformly successful treatment of the hyper-
IgD syndrome is available. There are anecdotal reports
of a benefit of treatment with corticosteroids, intra-
venous immune globulin, colchicine, or cyclosporine
in some cases, but these approaches have failed in
others.42 In a recent double-blind, randomized, cross-
over trial involving six patients, treatment with tha-
lidomide failed to reduce the disease activity.56 A tri-
al of simvastatin is under way.
Prognosis
Patients with the hyper-IgD syndrome have fe-
brile attacks throughout their lives, although the fre-
quency of attacks is highest in childhood and ado-
lescence. Patients may be free of attacks for months
or even years. Amyloidosis has not been reported in
association with the hyper-IgD syndrome. As a rule,
attacks of arthritis do not lead to joint destruction,
but there are exceptions.
Diagnostic Strategy
A clinical assessment should be the first step in di-
agnosing the hyper-IgD syndrome (Table 1). Hyper-
IgD syndrome almost always develops in infancy. If
a patient presents with symptoms suggestive of the
syndrome, IgD and IgA should be measured. If both
are elevated, the diagnosis can be made. For confir-
mation, we recommend screening for the V377I mu-
 MED IC A L PROGR ES S

Acetyl-CoA + acetoacetyl-CoA
O OH O

HO S-CoA HMG-CoA

O HMG-CoA reductase
OH
Defect in the
HO OH Mevalonate hyper-IgD
syndrome
O Mevalonate kinase
OH

HO OP Mevalonate phosphate

O
OH

HO OPP Mevalonate pyrophosphate

Isopentenyl
OPP Isopentenyl pyrophosphate adenine (DNA
replication)

OPP Geranyl pyrophosphate

OPP Farnesyl pyrophosphate

Isoprenylation of proteins

Dolichol (protein glycosylation)

Heme A (respiratory chain)

Ubiquinone (antioxidant)

Cholesterol
Steroid hormones
Membrane biogenesis
Bile acids
Lipoproteins

Figure 4. Metabolism of Mevalonate and Biosynthesis of Cholesterol in Mammalian Cells.

Mevalonate is the first committed intermediate of the cholesterol metabolic pathway. 3-Hydroxy-3-methylglutaryl (HMG)–coenzyme A
(CoA) reductase, which is the rate-limiting enzyme, can be inhibited by the administration of statins. Mevalonate kinase is the defective
enzyme in the hyper-IgD syndrome, and the defect results in an accumulation of trace amounts of mevalonate in the urine of affected
patients. The structural formulas corresponding to the intermediates in the branched pathway of cholesterol are shown at the left.

tation. If the result is negative and the clinical suspi-
cion is high, sequencing of the gene to detect other
mutations is possible. Mevalonate kinase activity can
be measured, although the procedure is time-con-
suming. Measurement of urinary mevalonic acid is
not useful, since there is only a slight elevation in the
amount excreted during an attack.
TNF-RECEPTOR–ASSOCIATED PERIODIC
SYNDROME
Clinical Features
The TNF-receptor–associated periodic syndrome
was first described in 1982 in a large Irish family and
was called familial Hibernian fever.57 The affected
family members had recurrent fever with localized

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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
myalgia and painful erythema. The autosomal dom-
inant inheritance of this disorder and its response to
corticosteroids differentiated it from familial Medi-
terranean fever.58 Although there were descriptions
of other families with autosomal dominant periodic
fever, the genetic defect had to be discovered before
it could be established that these families had the
TNF-receptor–associated periodic syndrome.59,60
Patients with this syndrome can have attacks that
last for at least one or two days, but prolonged at-
tacks (longer than one week) are common, and they
can last for weeks (Fig. 1C). Localized pain and tight-
ness of one muscle group and a migratory pattern of
the symptoms are prominent features, occurring in
more than 80 percent of patients. Abdominal pain,
sometimes colicky, is common61 and may be associat-
ed with diarrhea or constipation, nausea, and vomit-
ing. Painful conjunctivitis, periorbital edema, or both
are also common, and chest pain due to sterile pleu-
ritis or local myalgia has been reported in half of pa-
tients. During febrile attacks, painless cutaneous le-
sions may develop on the trunk or extremities and
may migrate distally. More than 60 percent of patients
have erythematous macules or edematous plaques due
to a perivascular and interstitial mononuclear-cell in-
filtrate.61 Arthralgia of large joints is common, but
arthritis is rare.58 Other symptoms include testicular
pain and headache. The prolonged attacks, conjunc-
tivitis, and localized myalgias differentiate the TNF-
receptor–associated periodic syndrome from the oth-
er syndromes of periodic fever (Table 1). Still, the
clinical manifestations of the TNF-receptor–associ-
ated periodic syndrome in an individual patient can
be surprisingly vague. Some patients notice only pe-
riodic muscular pain or periodic conjunctivitis, and
others present with fever alone.
Genetic and Epidemiologic Features
Although the most thoroughly characterized ped-
igree is a large Irish and Scottish family, the autosomal
dominant inheritance of the TNF-receptor–associated
periodic syndrome has been reported in many ethnic
groups.62 So far, more than 20 families have been
described in Australia, France, Puerto Rico, the Unit-
ed States, Finland, and the Netherlands.59,63-66
Laboratory Findings
During a typical attack, there is neutrophilia, an
increased level of C-reactive protein, and mild com-
plement activation.58 Polyclonal immunoglobulin lev-
els, particularly IgA levels, may be elevated. The IgD
level may also be elevated, but the value is almost al-
ways less than 100 IU per milliliter.58 The most dis-
criminatory laboratory finding is a low serum level
of the soluble type 1 TNF receptor.67
Pathogenesis and Molecular Genetic Features
Linkage analysis mapped the susceptibility gene
for two separate families to the short arm of chro-
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mosome 12.64,68 Positional cloning identified several
missense mutations in the gene for the type 1 TNF
receptor, which is a 55-kD cell-membrane–coupled
receptor with four cysteine-rich extracellular domains
and an intracellular motif involved in signal trans-
duction through protein–protein interaction.69 The
receptor is expressed on a large variety of cells and
allows signaling of TNF-a. A pleiotropic molecule,
TNF-a induces cytokine secretion, activation of leu-
kocytes, fever, and cachexia.70 Activation of the recep-
tor causes cleavage and shedding of its extracellular
part into the circulation, where it acts as an inhibitor
of TNF-a. At least 16 mutations in the type 1 TNF
receptor have been detected, all in the first two cys-
teine-rich subdomains of the protein spanning exons
2, 3, and 4 of the genomic sequence.63,65,71 It has been
suggested that the subsequent structural changes in
the protein interfere with receptor shedding (Fig. 5),
leading to continuous TNF-a signaling and, hence,
uncontrolled inflammation. However, this hypothe-
sis is inconsistent with the fact that at least two mu-
tations are not associated with any apparent shed-
ding defect.65
Treatment
Patients with the TNF-receptor–associated syn-
drome have responses to high doses of oral predni-
sone (more than 20 mg). There is a dramatic initial
response that wanes with time, necessitating an ac-
celeration of the dose.58 Colchicine is ineffective in
the treatment of this syndrome.64 Given the patho-
physiological features of this disorder, inhibition of
TNF signaling seemed a logical therapeutic approach.
Etanercept is a dimeric recombinant fusion protein
consisting of two copies of the soluble, extracellular
ligand-binding domain of the type 2 TNF-a recep-
tor, linked by the constant (Fc) portion of human
IgG1. The drug binds very effectively to both solu-
ble and cell-bound TNF-a and attenuates its biologic
effects. The presence of the Fc portion of IgG1 re-
sults in a relatively long elimination half-life. Treatment
with 25 mg of etanercept, given twice weekly, led to
marked improvement in six of eight patients.65 A sim-
ilar regimen reversed the nephrotic syndrome in a pa-
tient with amyloidosis.72 We found that a single course
of etanercept (25 mg given on three consecutive days)
in a patient with a severe case of the TNF-receptor–
associated periodic syndrome resulted in a remission
that lasted for six months (unpublished data).
Prognosis
The prognosis for patients with the TNF-receptor–
associated periodic syndrome is determined mainly by
the presence or absence of amyloidosis. AA amyloi-
dosis occurs in about 25 percent of affected families.62
Amyloid deposits generally lead to renal impairment,
but hepatic failure has also been noted.65 Amyloido-
sis in a patient with the TNF-receptor–associated
 MED IC A L PROGR ES S

Soluble TNF receptor Extracellular

TNF
TNF

F
TN

TN
F

TNF
P P P P

Protease Cell membrane

TNF receptor
type I
Inflammatory response
Intracellular
Normal shedding of TNF receptor

TNF
TNF
TN
F

TNF

TNF

TNF
P P P P

Inflammatory response

TNF-receptor–associated syndrome

Figure 5. Hypothesized Pathogenesis of the Tumor Necrosis Factor (TNF) Receptor–Associated Periodic
Syndrome.
Under normal conditions, activation of the TNF receptor by TNF causes the activation of a protease that
can shed the TNF receptor from the cell surface (upper panel). This process results in diminished cellular
signaling of TNF. The shed TNF receptor is cleared in the extracellular space, where it can bind free TNF
and limit the inflammatory response. It is postulated that in patients with the TNF-receptor–associated
periodic syndrome, the TNF receptor is not shed from the cell surface (lower panel). In the absence of
shedding, there is continuous signaling by TNF and, consequently, an inflammatory response.

periodic syndrome places other affected family mem-
bers at high risk for this complication. Since protein-
uria is the initial manifestation of renal amyloidosis,
it is advisable to screen urine samples from affected
family members regularly by dipstick examination.
Diagnostic Strategy
The level of type 1 TNF receptor is less than 1 ng
per milliliter in most patients with the TNF-recep-
tor–associated periodic syndrome. However, the val-
ue may be normal during an attack.63 Furthermore,
in patients with renal amyloidosis, the value increas-
es because the type 1 TNF receptor is cleared by the
kidneys. Thus, molecular analysis provides the most
straightforward diagnosis. DNA sequencing of the
gene will detect any of the known mutations, but also
novel ones; this service is available in commercial lab-
oratories. Since the TNF-receptor–associated periodic
syndrome is characterized by incomplete penetrance,
not all patients with mutations will have symptoms.
FURTHER CONSIDERATIONS
Despite the discovery of the genetic defects that
cause the three types of hereditary periodic fever, the
temporal features of the clinical attacks remain un-
explained. One might speculate that the mutated pro-
tein functions adequately much of the time but that
it decompensates under stressful conditions. This ex-

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The New England Journal of Medicine
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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
planation is compatible with the clinical observa-
tions, since most patients with periodic fever have
had attacks after localized trauma or minor surgical
interventions. Other precipitating factors might be
of environmental origin, since both viral infections
and active immunizations can provoke febrile attacks
in patients with the hyper-IgD syndrome.
Apart from the three disorders we have described,
there are other periodic fever syndromes, although
they have been less well characterized. Familial cold
urticaria is a rare autosomal dominant disorder that
develops in the first year of life. Exposure to cold air
in affected patients may cause a delayed, nonpruritic,
nonurticarial maculopapular rash. The rash is some-
times associated with chills, fever, arthralgias, con-
junctivitis, myalgias, headache, and fatigue. Amyloi-
dosis develops in some patients. The Muckle–Wells
syndrome is similar to familial cold urticaria with two
exceptions: the symptoms are not triggered by expo-
sure to cold, and progressive sensorineural deafness
is frequently present. The attacks are associated with
abdominal pain and arthritis. Both familial cold ur-
ticaria and the Muckle–Wells syndrome have been
mapped to chromosome 1 (1q44).73-75 The two dis-
orders are caused by different missense mutations in
the CIAS1 gene. This novel gene encodes a protein
with a pyrin domain, a nucleotide-binding-site do-
main, and a leucine-rich repeat motif region — fea-
tures that suggest that the protein has an inflamma-
tory role.76
Children may have a syndrome of periodic fever,
aphthous stomatitis, pharyngitis, and tender cervical
adenitis.77 The disorder usually develops before the
age of five years. The episodes, which are not due to
infections, last for about four days and recur every
two to eight weeks. The prognosis for patients with
this syndrome is more favorable than that for patients
who have other periodic fever syndromes, with spon-
taneous resolution in four to eight years and no se-
quelae. Most patients have a response to a course of
prednisone (1 to 2 mg per kilogram of body weight)
given for one or two days. The serum IgD level may
be elevated, but the value is lower than that in pa-
tients with the hyper-IgD syndrome.78 A family his-
tory of the disorder is usually absent, and it is un-
clear whether there is a genetic defect.
Great progress has been made in our understand-
ing of the three well-established periodic fever syn-
dromes, and it has become easier to diagnose these
disorders (Table 1). Still, in a substantial number of
patients with periodic fever, the specific syndrome
cannot be identified. Among patients with periodic
fever of unknown origin, the chance of establishing
a diagnosis is less than 50 percent if the three main
syndromes have been ruled out.1
Dr. Drenth is an Investigator of the Royal Netherlands Academy of Arts
and Sciences.
1756 · N Engl J Med, Vol. 345, No. 24 · December 13, 2001 · www.nejm.org
The New England Journal of Medicine
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Copyright © 2001 Massachusetts Medical Society. All rights reserved.
We are indebted to Anna Simon, M.D., for her reading and crit-
ical discussion of the manuscript.
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