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The enlarging clinical genetic and population spectrum of tumor necrosis factor receptorassociated periodic syndrome.

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ARTHRITIS & RHEUMATISM
Vol. 46, No. 8, August 2002, pp 2181–2188
DOI 10.1002/art.10429
© 2002, American College of Rheumatology
The Enlarging Clinical, Genetic, and Population Spectrum of
Tumor Necrosis Factor Receptor–Associated
Periodic Syndrome
Catherine Dodé,1 Marc André,2 Thierry Bienvenu,1 Pierre Hausfater,3 Christophe Pêcheux,4
Jacques Bienvenu,5 Jean-Claude Lecron,6 Philippe Reinert,7 Daniel Cattan,8
Jean-Charles Piette,3 Marie-France Szajnert,9 Marc Delpech,1 Gilles Grateau,10
and the French Hereditary Recurrent Inflammatory Disorder Study Group
Objective. To characterize the frequency, clinical
signs, and genotypic features of tumor necrosis factor
receptor–associated periodic syndrome (TRAPS) in a
series of 394 patients of various ethnic origins who have
recurrent inflammatory syndromes.
Methods. Sequencing of the coding region of the
TNFRSF1A gene was performed in 128 patients in whom
there was a high suspicion of TRAPS, and denatured
high-performance liquid chromatography was used to
systematically screen for TNFRSF1A in 266 patients
with recurrent inflammatory syndrome and no or only 1
Mediterranean fever gene (MEFV) mutation.
Results. TNFRSF1A mutations were found in 28
(7.1%) of 394 unrelated patients. Nine (32%) of the 28
patients had a family history of recurrent inflammatory
syndromes. In 13 patients, the length of the attack of
inflammation was fewer than 5 days. Three of the
mutations (Y20H, L67P, and C96Y) were novel. Two
mutations, R92Q and (mainly) P46L, found in 12 and 10
patients, respectively, had lower penetrance compared
with other mutations. TNFRSF1A mutations were found
in patients of various ethnic origins, including those at
risk for familial Mediterranean fever (FMF): Armenians, Sephardic Jews, and especially Arabs from Maghreb. Only 3 (10.7%) of the 28 patients had amyloidosis.
Conclusion. TRAPS is an underdiagnosed cause
of recurrent inflammatory syndrome. Its presence in the
population of persons of Mediterranean ancestry and
the short duration of the attacks of inflammation can
lead to a fallacious diagnosis of FMF. Because an
accurate diagnosis in patients with recurrent inflammatory syndromes is crucial for proper clinical management and treatment, genetic screening for TNFRSF1A is
warranted.
The French Hereditary Recurrent Inflammatory Disorder
Study Group is supported by grants from INSERM and by
l’Association Française contre les Myopathies.
1
Catherine Dodé, PhD, Thierry Bienvenu, PhD, Marc
Delpech, MD, PhD: Hôpital Cochin, Institut Cochin, and Institut
fédéritif de recherche, de l’INSERM, Université Paris V, Paris,
France; 2Marc André, MD: Hôpital Gabriel Montpied, ClermontFerrand, France; 3Pierre Hausfater, MD, Jean-Charles Piette, MD:
Hôpital de la Pitié, Paris, France; 4Christophe Pêcheux, BSc: Hôpital
Cochin, Paris, France; 5Jacques Bienvenu, PharmD: Centre hospitalier
Lyon-sud, Pierre-Bénite, France; 6Jean-Claude Lecron, MD: Institut
fédéritif de recherche CNRS 59, Poitiers, France; 7Philippe Reinert,
MD: Hôpital Intercommunal, Créteil, France; 8Daniel Cattan, MD:
Centre Hospitalier de Villeneuve Saint-Georges, Villeneuve SaintGeorges, France; 9Marie-France Szajnert, PhD: Institut Cochin and
Institut fédéritif de recherche, de l’INSERM, Université Paris V, Paris,
France; 10Gilles Grateau, MD: Institut Cochin and Institut fédéritif de
recherche, de l’INSERM, Université Paris V, and l’Hôtel-Dieu,
Assistance-Publique Hôpitaux de Paris, Paris, France.
Address correspondence and reprint requests to Gilles Grateau, MD, Service de Médecine Interne, l’Hôtel-Dieu, 1 Place du
Parvis Notre-Dame, 75181 Paris Cedex 04, France. E-mail:
gilles.grateau@htd.ap-hop-paris.fr.
Submitted for publication November 11, 2001; accepted in
revised form April 16, 2002.
Hereditary recurrent inflammatory disorders are
characterized by repeated attacks of fever and organlocalized inflammation affecting mainly the abdomen,
thorax, musculoskeletal system, and skin (1). These
disorders comprise 4 main nosologic entities. Two of
them, familial Mediterranean fever (FMF; OMIM no.
249100) (2) and hyperimmunoglobulinemia D syndrome
(HIDS; OMIM no. 260920) (3), are transmitted via the
autosomal-recessive mode. The other 2, tumor necrosis
factor receptor superfamily 1A–associated periodic syn2181
2182
DODÉ ET AL
drome (TRAPS; previously described in several families
under different names, including FMF-like syndrome
with amyloidosis [OMIM no. 134610], autosomaldominant periodic fever [OMIM no. 170300, changed to
OMIM no. 142680], familial Hibernian fever [OMIM
no. 142680], and familial periodic fever [OMIM no.
142680]) (4,5) and Muckle-Wells syndrome (OMIM no.
191000) (6), are transmitted via the autosomal-dominant
mode. The genetic abnormalities underlying FMF,
HIDS, and TRAPS have previously been characterized
(7–11), and a gene responsible for the Muckle-Wells
syndrome and familial cold urticaria, localized at chromosome 1q44, was recently discovered (12,13).
The gene encoding the TNFRSF1A
(TNFRSF1A) recently was shown to underlie most
autosomal-dominant recurrent fevers (11). Fewer than
100 persons, most of northern European origin, have
thus far been shown to carry TNFRSF1A mutations, all
of which were in the first or second extracellular domains of TNFRSF1A (11,14–20).
We now report clinical and genetic features in a
series of patients with TRAPS who had various ethnic
origins, including Mediterranean. The presentations of
these patients varied considerably in terms of family
history and clinical manifestations. Three new mutations
in the extracellular domain of the TNFRSF1A gene were
discovered.
PATIENTS AND METHODS
Molecular-level diagnosis of the 3 genetically characterized forms of hereditary recurrent inflammatory syndrome
began with FMF in November 1997 and is now performed
routinely in our laboratory. The main clinical data (age, sex,
origin of both parents, consanguinity, family history, age at
onset of inflammatory attacks, duration of attacks, organ
involvement, frequency of attacks, splenomegaly, amyloidosis,
and efficacy of colchicine and other drugs) have been prospectively registered on a standard form. Routine molecular diagnosis of TRAPS in our laboratory began in 1999, with the
discovery of the C30S TNFRSF1A mutation in a patient with a
typical form of TRAPS (14). Routine diagnosis of HIDS began
after we identified the MVK gene as the gene responsible for
HIDS.
We searched for TNFRSF1A mutations in 394 patients,
including 128 patients in whom the suspicion of TRAPS was
high based on familial and clinical data and whose blood
samples were referred to our laboratory for TNFRSF1A analysis, and 266 patients in whom there was clinical suspicion of
FMF and who had no or only 1 MEFV mutation. DNA from
the latter group of patients underwent mutation screening (see
below). A group of Caucasian and Maghrebian subjects
(Maghreb is the area comprising the countries of Morocco,
Algeria, and Tunisia) who served as controls were also tested
for some of the mutations, using the screening or restriction
fragment length polymorphism method.
DNA extraction. Genomic DNA was isolated from the
patient’s peripheral blood leukocytes using standard procedures (21).
Mutation analysis in the MEFV gene (GenBank accession no. Y14441). A search for the mutations presented in exon
10 between codons 663 and 771 (including the 4 most frequent
mutations, namely M680I, M694V, M694I, and V726A), and
for mutation E148Q in exon 2 was conducted using the
procedure previously described (14).
Mutation analysis in the TNFRSF1A gene (GenBank
accession no. M75866). A search for mutations in the
TNFRSF1A gene was conducted in patients who were heterozygous or had no MEFV mutations. Polymerase chain
reaction (PCR) amplification of the complete coding region of
the TNFRSF1A gene was performed as previously described
(14). Direct sequencing of the PCR products was carried out
using the same primers as those used in the PCR.
Denaturing high-performance liquid chromatography
(dHPLC) analysis. The search for TNFRSF1A mutations
presented in exons 2, 3, and 4 was performed using dHPLC
scanning on an automated HPLC instrument, using the
WAVE DNA fragment analysis system (Transgenomic, Santa
Clara, CA) (22). Exons 2, 3, and 4 were PCR amplified using
the experimental conditions described above. The stationary
phase was 2 ␮m of nonporous alkylated poly(styrenedivinylbenzene) particles packed into a 50 ⫻ 4.6–mm directinject column (Transgenomic). The mobile phase was 0.1M of
triethylammonium acetate (TEAA) buffer (pH 7.0) containing
0.1 mM EDTA. DNA was eluted within a linear acetonitrile
gradient consisting of buffer A, 0.1M TEAA, and buffer B,
0.1M TEAA in 25% acetonitrile. WaveMaker software was
used to predict the mean melting temperature of each PCR
fragment and the appropriate linear acetonitrile gradient
necessary to distinguish heteroduplexes and homoduplexes
(23). The temperature required for successful resolution of
heteroduplex molecules was adjusted experimentally by
injecting and running PCR products at increasing mobilephase temperatures, usually in 1–2°C increments, starting at
50°C, until a significant decrease in retention (⬃1 minute)
was observed. The dHPLC gradient conditions were 60°C
for exon 2 and 64°C for exons 3 and 4, with acetonitrile
gradients of 52–64%, 48–60%, and 50–62% of buffer B,
respectively.
Restriction analysis for TNFRSF1A mutations. Restriction analysis was performed for the 2 new mutations, P46L
and R92Q, located in exons 3 and 4, respectively. Exon 3 and
exon 4 were PCR amplified and digested for at least 3 hours at
37°C with the appropriate restriction endonucleases (Stu I for
P46L and Nci I for R92Q), using the manufacturer’s instructions (Biolab, Barcelona, Spain). The P46L mutation creates a
Stu I restriction site, and the R92Q abolishes an Nci I
restriction site. PCR products were visualized on 2% agarose
gels stained with ethidium bromide.
Measurement of serum IgD levels. IgD levels in plasma
from patients with TRAPS were determined using a previously
described procedure (24).
CLINICAL AND GENETIC SPECTRUM OF TRAPS
2183
Table 1. Distribution of TNFRSF1A mutations in patients with a
high suspicion of TRAPS (group 1) and patients with clinical suspicion
of FMF (group 2)*
Population (n)
Measurement of TNF receptors and TNF␣ levels. The
levels of TNF receptors and TNF␣ were determined in plasma,
as previously described (14).
Mutation (no.)
Group 1
Caucasian (76)
C30R (1)
T50M (1)
L67P (1)
R92Q (2)
C96Y (1)
Y20H (1)
P46L (1)
R92Q (2)
(10)
Other (52)
Total (128)
Group 2
Caucasian (87)
P46L (2)
R92Q (4)
P46L (7)
T50M (1)
R92Q (4)
(18)
Other (179)
Total (266)
* TRAPS ⫽ tumor necrosis factor receptor–associated periodic syndrome; FMF ⫽ familial Mediterranean fever.
RESULTS
At our laboratory, which is a referral center for
molecular analysis of hereditary recurrent inflammatory
disorders, 2,200 patients with a clinical suspicion of this
type of disorder have been evaluated since 1997. Patients in the current study were examined by physicians
of many medical specialties, who were involved in the
French network for the study of hereditary recurrent
inflammatory disorders (see Appendix A). In the first
group of patients (n ⫽ 128), 10 were found to have a
TNFRSF1A mutation (Y20H, C30R, P46L, T50M, L67P,
R92Q [4 patients], C96Y). In the second group of
patients (n ⫽ 266), 18 were found to have a TNFRSF1A
mutation (P46L [9 patients], T50M, R92Q [8 patients])
Table 2. Clinical data from 28 genetically independent patients with a TNFRSF1A mutation*
Mutation
L67P
Y20H
C96Y
T50M
T50M
C30R
R92Q
R92Q
R92Q
R92Q
R92Q
R92Q
R92Q
R92Q
R92Q
R92Q
R92Q
R92Q
P46L
P46L
P46L
P46L
P46L
P46L
P46L
P46L
P46L
P46L
Ethnic
origin
French
Se/P-I
Czech
Kabylian
French
French/Sp
French
French
Ashk/French
Sa/Si
French/R
French
Dutch
Arab
Arab
Arab
Arab
Arm
French
Por
Arab
Arab
Arab
Arab
Kabylian
Arab
Arab
Arab
Duration
Age, Age at onset No. of
of
Family years/ of attacks,
attacks
attacks, Abdominal
history sex
years
per month
days
signs
⫹
⫹
–
⫹
⫹
⫹
⫹
–
⫹
–
–
–
⫹
–
–
–
–
⫹
–
–
–
–
–
–
–
–
–
–
16/M
49/F
31/F
37/F
25/M
33/F
44/M
26/F
4/M
37/M
32/F
12/F
35/M
47/M
35/F
42/M
30/M
15/M
67/F
49/F
33/F
6/F
42/M
46/M
42/M
50/F
7/M
40/F
1
14
5
21
1
15
27
5
2
22
15
9
6
29
33
36
26
7
63
48
25
3
35
40
2
20
2
10
1
Variable
2
⬍1
1
⬎2
2
⬎2
1
⬍1
2
2
⬍1
3
4
Unknown
1–2
1–2
4
1
⬍1
⬎2
⬍1
⬍1
1–2
⬍1
⬍1
1–2
Thoracic
signs
Arthritis
7
Pain
–
2–4
Pain
–
Unknown
Pain
–
1–4
Pain
–
3–21
Pain
–
7–14
Pain
⫹
1–3
Pain
⫹
1
Pain
⫹
3
Pain
⫹
Unknown
–
Pericarditis
2
–
⫹
Unknown
–
–
15–20
⫹
–
15–20
⫹
–
2
Lumbar pain
–
5
–
⫹
Unknown
–
–
3–5
⫹
–
⬎7
–
Pericarditis
14
–
–
4
–
⫹
2–3
⫹
⫹
1
⫹
–
Unknown
⫹
–
14
⫹
–
7
⫹
–
3
⫹
–
Unknown
⫹
–
–
–
⫹
–
⫹
⫹
⫹
⫹
–
–
–
–
–
–
–
–
–
–
–
–
⫹
⫹
⫹
⫹
⫹
–
⫹
⫹
Skin
rash
Urticaria
ELE, thigh
–
–
–
Erythema
Urticaria
Erythema
–
–
–
⫹
–
–
–
–
–
⫹
–
–
–
ELE
–
–
ELE
–
–
–
Amyloid, Colchicine Steroid
by biopsy
use
use
–
Kidney
Kidney
–
–
–
–
–
–
–
–
–
Kidney
–
–
–
–
–
–
–
–
–
–
–
–
Kidney†
–
–
–
⫹
⫹
⫹
⫹
⫹
⫹
–
–
–
⫹
–
⫹
–
–
⫹
–
⫹
–
–
–
⫹
–
–
⫹
–
–
–
⫹
⫹
⫹
–
⫹
⫹
–
⫹
–
⫹
–
–
⫹
–
–
–
–
⫹
⫹
–
–
–
⫹
⫹
–
⫹
⫹
–
* Se ⫽ Sephardic; P ⫽ Polish; I ⫽ Italian; ELE ⫽ erysipelas-like eruption; Sp ⫽ Spanish; Ashk ⫽ Ashkenazi; Sa ⫽ Sardinian; SI ⫽ Sicilian; R ⫽
Russian; Arm ⫽ Armenian; Por ⫽ Portuguese.
† The patient had a long history of Crohn’s disease.
2184
DODÉ ET AL
attacks (40°C) accompanied by abdominal pain and
urticaria.
Y20H is a new mutation (Figure 1) found in a
family of mixed Sephardic Jewish and Polish/Italian
origin (Family B; see Figure 2). Daily colchicine therapy
did not prevent recurrence of attacks, but glucocorticoids, when taken at the beginning of the attacks,
seemed to shorten their duration. Proteinuria developed
when the patient was age 44 years, and a renal biopsy
revealed amyloid. The patient continued to receive
colchicine and glucocorticoids, and renal disease progressed slowly. Five years later, the serum creatinine
level was 15 mg/dl.
The third new mutation, C96Y (Figure 1), was
found in a 31-year-old Czech woman who had disease of
26 years’ duration and in whom type AA amyloidosis
developed at age 25 years.
Clinical features of patients with T50M or C30R
TNFRSF1A mutations. The T50M mutation was previously reported to be associated with TRAPS (11). We
found it again in 2 families, 1 French (Family C, Figure
Figure 1. New TNFRSF1A mutations: Y20H, L67P, C96Y. A, Sequence analysis of exon 2 (Y20H), exon 3 (L67P), and exon 4 (C96Y)
mutations. Arrows indicate the TAT3 CAT (Y20H), CTC3 CCC
(L67P), and TGT3 TAT (C96Y) substitutions. B, Three-dimensional
structure of the mutated TNFRSF1A proteins (top) compared with
normal ones (bottom), obtained by homology with the normal
TNFRSF1A crystal structure using the Swiss-Model automated modeling server (http://www.expasy.ch/spdbv/) and the Geno D modeling
server. The amino acid involved in the mutation is shown in pink.
Amino acids interacting with the mutated amino acids by hydrogen
bonding are shown in blue. C76 involved in the cysteine disulfide
bridge with C96 is shown in green. Hydrogen bonds are represented
with green broken lines.
(Table 1). The main clinical signs of TRAPS in the
patients in this series are summarized in Table 2.
Clinical features of patients with novel
TNFRSF1A mutations. The new L67P mutation (Figure
1) was found in a family of French origin. The proband
(III-1, Family A; see Figure 2) and many relatives
presented before age 5 years with recurrent febrile
Figure 2. Pedigrees of 8 families (families A–H) with tumor necrosis
factor receptor–associated periodic syndrome. Open shapes represent
healthy individuals, solid shapes represent individuals affected with the
mutation, shaded shapes represent asymptomatic carriers of the
mutation, and shapes with slashes represent deceased individuals.
Boxes ⫽ males, circles ⫽ females.
CLINICAL AND GENETIC SPECTRUM OF TRAPS
2) and 1 Kabylian (Family D, Figure 2). Kabylians are
inhabitants of a mountainous area in Algeria and are not
of Arab origin; FMF is also prevalent in these populations. In the French family, the 25-year-old proband
(II-2) had a life-long history of recurrent febrile attacks.
Enlarged lymph nodes were frequently observed both
during and between attacks. IgD levels of the proband
were above the normal range, at 21.8 mg/dl (normal ⬍14
mg/dl), and IgA levels were increased at 4.2 gm/liter.
This patient was thought to have HIDS and was included
in the series of 50 patients described by Drenth et al in
1994 (3). Daily administration of colchicine did not
succeed in reducing the number of attacks. Glucocorticoids, taken at the beginning of the attacks, seemed to
diminish their severity, but daily long-term treatment did
not prevent recurrent attacks.
The proband (I-5) of the Kabylian family, a
37-year-old woman, was thought to have FMF. She did
not appear to respond to colchicine, although observance of the treatment was not perfect.
The C30R mutation was previously reported to
be associated with TRAPS. We found it in a 33-year-old
woman of French/Spanish origin. Her disease is poorly
controlled with a daily steroid regimen.
Patients with the R92Q TNFRSF1A mutation.
The recently described R92Q mutation was found in 12
unrelated patients, including 4 with a family history of
recurrent inflammatory disease. The proband of one of
the French families is a 44-year-old man (I-2, Family E;
Figure 2). Prominent signs and symptoms during his
attacks included abdominal pain, thoracic pain, skin rash
mainly on the trunk, and unique behavioral changes such
as irritability. Although the patient took colchicine regularly, he considered it to be ineffective. His 15-year-old
daughter (II-1) was thought to be affected because of a
1-week episode of unexplained fever after pelvic surgery
for recurrent abdominal pain and recurrent cervical
pain; she, like her father, also experienced transient
mood changes. DNA sequencing revealed she was homozygous for the R92Q mutation.
A Dutch patient (III-5, Family F; Figure 2)
experienced periodic fever beginning at age 6 years. At
age 25 years, he developed a nephrotic syndrome, and
AA amyloidosis was diagnosed. Colchicine was not
helpful in preventing the attacks. Renal failure occurred
at age 29 years, and he was treated with regular hemodialysis until he received a kidney transplant at age 33
years. Following the transplant, his attacks completely
disappeared, and he is still alive and well.
The R92Q mutation was found in 4 other patients
of French origin, all of whom presented with sporadic
2185
disease. In one of these patients, a 26-year-old woman
with a life-long history of recurrent fever, we measured
the levels of TNF␣ and its soluble receptors during an
inflammatory attack: the TNF␣ serum level was high at
49 pg/ml (normal level ⬍13), whereas the levels of
soluble TNFR1 and TNFR2 were also high at 9.6 ng/ml
(normal 2–5.5) and 8.8 ng/ml (normal 0.4–1.7), respectively.
The R92Q mutation was also found in patients of
Mediterranean origin (Sardinian/Sicilian, Maghrebian,
Armenian) who were at risk for FMF. A 15-year-old
Armenian boy had recurrent inflammatory attacks of 5
days’ duration accompanied by abdominal pain, which
started at age 7 years. He had been treated with corticosteroids and cyclophosphamide for nephrosis since age 3
years. Colchicine treatment did not completely prevent
recurrent attacks. His father also had intermittent inflammatory attacks. A diagnosis of FMF was made, and
the heterozygous V726A mutation was found in the
MEFV gene in both the patient and his father. A search
for a mutation in the TNFRSF1A gene was performed,
and the R92Q mutation was found in both patients. One
Maghrebian patient met the criteria for Behçet’s disease.
Overall, the R92Q mutation was found in 6 of 160
symptomatic Caucasian patients (allele frequency 1.8%)
without the MEFV mutation and was not found in 78
control subjects. In the population of Maghreb origin,
R92Q was found in 6 of 148 patients (allele frequency
2.0%) and was not found in 52 control subjects.
Patients with the P46L TNFRSF1A mutation.
The P46L mutation was found in 10 unrelated patients,
8 of whom were of Arab or Kabylian origin. In 2
patients, the disease was considered to be potentially
familial, because several family members had clinical
signs that could be compatible with TRAPS. However,
the P46L mutation was not linked to clinical signs in
either family (Figure 2, Families G and H). One of the
Maghrebian patients has a long history of Crohn’s
disease and amyloidosis.
Overall, the P46L mutation was found in 2 of 163
symptomatic Caucasian patients (allele frequency ⬍1%)
and was not found in 61 control subjects. P46L was
found in 8 of 148 patients of Maghrebian origin (allele
frequency 2.7%) and in 3 of 52 control subjects (allele
frequency 2.9%). In all patients bearing the P46L mutation, the complete coding region was sequenced, and
no sequence variation other than P46L was found.
DISCUSSION
We have identified 28 genetically unrelated patients with TRAPS, who had strikingly different clinical
2186
presentations. All 28 patients have missense mutations
in the first 2 N-terminal cysteine-rich domains (CRD1
and CRD2) of the extracellular part of TNFRSF1A. At
this time, 19 mutations have been reported: 11 in CRD1
(H22Y, C29F, C30S, C30R, C33Y, C33G, Y38C, P46L,
T50M, C52F, and c.193-14G⬎A) and 8 in CRD2 (C55S,
S86P, C70Y, C70R, C88R, C88Y, R92P, and R92Q)
(11,14–20).
We now report 3 novel mutations in patients with
TRAPS, 1 in CRD1 (Y20H) and 2 in CRD2 (L67P and
C96Y) (Figure 1). One of these new mutations (C96Y)
affects cysteine residue, which disrupts one of the highly
conserved intrachain disulfide bonds. The Y20H mutation affects a residue that plays a crucial role in the
spatial structure of the receptor. The Y20 amino acid is
highly conserved among the family of extracellular CRD
receptors. It has been shown that in the crystal structure
of soluble TNFRSF1A, Tyr20 points in toward conserved
Thr50. One hydrogen bond between Y20 and D42 is lost
when Y20 is mutated to histidine (Figure 1B). It has
already been shown that in patients with TRAPS, the
T50 residue mutated into methionine (T50M) (11). The
L67P mutation does not seem to involve important
structural modifications in terms of hydrogen bonding or
hydrophobicity (data not shown). It is possible that such
a mutation can modify some interactions with ligands of
TNFRSF1A and/or be implicated in clustering of the
receptor.
The P46L and R92Q mutations were recently
reported in patients with TRAPS, as well as in control
populations (⬃1% of control chromosomes) (18). The
investigators also demonstrated that P46L reduced
TNFRSF1A shedding in monocytes, and found R92Q in
7 of 135 patients with early arthritis. They therefore
concluded that P46L and R92Q are low-penetrance
mutations rather than polymorphisms. In our series, the
R92Q mutation was not found in control populations
but was present in both symptomatic and asymptomatic
patients with TRAPS. Therefore, we estimated that
R92Q is a mutation with incomplete penetrance. Only
the P46L mutation was present in the control Maghrebian population, with an allele frequency of 2.9%. The
P46L mutation was found mainly in patients with sporadically occurring disease and was sometimes associated with atypical signs, such as pericarditis. Thus, the
P46L mutation can be considered either a lowpenetrance mutation or a polymorphism that facilitates
inflammatory diseases.
In our series, clinical signs differed from those
considered typical of TRAPS, as described for familial
Hibernian fever (5). Age at onset appears to vary
DODÉ ET AL
considerably. In 2 patients, the disease began in the first
year of life as recurrent unexplained inflammatory attacks. Conversely, in 1 patient, the disease began at age
63 years and featured recurrent pericarditis. In many
patients, the duration of inflammatory attacks was less
than 4 days, although TRAPS attacks are usually considered to last longer than 1 week (frequently as long as
2–3 weeks). In a recent series, patients with TRAPS
were selected on the basis of attacks lasting longer than
1 week. In our series, the duration of crises was closer to
that of FMF attacks; therefore, the duration of attacks of
inflammation cannot be used as a diagnostic argument
for TRAPS.
Although none of the clinical manifestations of
TRAPS described thus far can be considered completely
specific, orbital edema and the stereotypic cellulitis-like
subcutaneous inflammation on the upper limbs (moving
distally) are usually thought to be the most characteristic
signs (5,14). Only 1 patient, who had the novel Y20H
mutation, reported recurrent episodes of orbital swelling; the same patient also reported cellulitis-like episodes on the thigh. Skin lesions observed in 3 other
patients were rather nonspecific, as described by Toro et
al (25). Abdominal signs continue to be the most prominent characteristic of inflammatory attacks. In 2 patients, recurrent pericarditis was the only sign of disease.
Recurrent pericarditis is an entity in search of etiologic
factors (26). As demonstrated in a large series of patients with FMF (27), recurrent pericarditis was rare
(occurring in 27 [0.7%] of 4,000 patients) and was
seldom isolated. TRAPS should probably be added to
the list of potential causes of recurrent pericarditis of
undetermined origin.
In our series, 2 patients had intriguing clinical
signs. In 1 patient, pain was essentially restricted to the
lumbar region, and the association with fever led to an
initial diagnosis of pyelonephritis. The attacks were of
short duration (2–4 days), and their recurrence in the
absence of an identified infection made the diagnosis of
pyelonephritis uncertain. In the other patient, recurrent
episodes of fever of longer duration (15–21 days) accompanied by lumbar pain were revealed to be caused by
aseptic abscesses of the psoas.
The finding of high IgD levels in one of the
families with the T50M mutation contributed to an
erroneous diagnosis of HIDS. The same error can
probably be found retrospectively in the original description of HIDS by Van der Meer et al (28). In fact, in the
current series, a patient who had recurrent inflammatory
attacks but no enlarged lymph nodes had a family history
CLINICAL AND GENETIC SPECTRUM OF TRAPS
(both parents) of autosomal-dominant disease complicated by amyloidosis, all of which suggests a diagnosis of
TRAPS rather than HIDS. High IgD levels have been
reported in other inflammatory conditions, including
FMF; elevated levels were reported in 13% of a group of
80 FMF patients (29). This highlights the fact that even
in the context of hereditary recurrent inflammatory
syndromes, an increase in the serum IgD level is not
specific for HIDS.
Amyloidosis is the most severe complication of
TRAPS, as it is in FMF. Amyloidosis has been observed
in several families with TRAPS, representing 14% of all
patients reported (5,11,16–18). Four patients in our
series had biopsy-proven amyloidosis. One patient, bearing the R92Q mutation, has a familial form of inflammatory disease and amyloidosis. Two others, bearing the
C96Y and Y20H mutations, respectively, had sporadic
disease. The fourth patient had a long history of Crohn’s
disease and amyloidosis and also bears the P46L mutation. In the entire population of patients with TRAPS
reported before this series, cysteine substitution, compared with noncysteine substitution, was considered to
be a risk factor for amyloidosis (18). The present series
confirms that noncysteine substitutions can also be associated with the development of amyloidosis. Because
of the wide variability in the clinical presentation of
TRAPS, especially in patients with the R92Q mutation,
development of amyloidosis probably depends on other
modifier genes, such as SAA1 alleles, as has been shown
for Armenian patients affected with FMF (30), or a
novel polymorphism at the 5⬘-flanking region of SAA1
in Japanese patients with rheumatoid arthritis (31).
The case of the fourth patient with amyloidosis in
our series raises the question of the role of the
TNFRSF1A gene mutation in the pathogenesis of inflammatory bowel disease. Crohn’s disease seems to be
more frequent and more severe in patients with FMF
than in the general population (32). The role of TNF in
the pathogenesis of Crohn’s disease and the potent
effect of anti-TNF drugs in alleviating some of its
manifestations have recently been highlighted, which
strengthens the possible link between TNFRSF1A gene
mutations and Crohn’s disease (33). It has recently been
suggested that the R92Q mutation may be associated
with early arthritis (18). Further studies are required to
ascertain the association of TNFRSF1A gene mutations
with Crohn’s disease, with or without aseptic abscesses
(34), as well as with Behçet’s disease (which we observed
in 1 patient) and to elucidate its mechanisms.
Finally, our data provide important new insights
into the population affected by TRAPS. As was recently
2187
pointed out, most of the reported families with TRAPS
are of Irish and/or Scottish descent, although families of
various ethnic origins (French, Dutch, Belgian, Puerto
Rican, African American, Mexican, Italian, Portuguese,
Ashkenazi, Arab) have also been described (14,16,18).
None of the patients in our current series is of Irish or
Scottish descent. Moreover, some of them belong to
populations of Mediterranean origin (Sardinian/Sicilian,
Sephardic Jewish, Armenian, and especially Arab or
Kabylian from Maghreb). The C70R mutation was recently found in an Israeli Arab patient (20). In these
populations, where FMF is highly prevalent, TRAPS can
mimic FMF, resulting in inaccurate management and
therapy. This argues for establishing a thorough clinical
and genetic diagnosis in the presence of an hereditary
recurrent inflammatory disorder, even in populations
with a high prevalence of FMF.
In conclusion, we wish to highlight the more
relevant data from our report. First, the clinical presentation of TRAPS can differ from the typical description
of the disease, especially in terms of duration of attacks,
which can be close to what is observed in FMF. Second,
populations affected by the disease include those of
Mediterranean origin; this point is crucial, because
TRAPS in these populations may be confused with
FMF. Third, for some of these mutations, penetrance is
incomplete, and a sporadic presentation of the disease
occurs frequently. Fourth, the potential association of
TNFRSF1A mutations and rheumatic and/or inflammatory bowel diseases offers new clues for elucidating their
mechanisms.
APPENDIX A: THE FRENCH HEREDITARY
RECURRENT INFLAMMATORY DISORDER
STUDY GROUP
Contributors to the French Hereditary Recurrent Inflammatory Disorder Study Group include M. Alcalay, MD, R.
Amira, MD, Z. Amoura, MD, O. Aumaı̂tre, MD, P. Babinet,
MD, N. Chalumeau, MD, J. P. Clauvel, MD, L. David, MD, M.
Dervichian, MD, D. Goldfain, MD, E. Hachulla, MD, PhD,
P. Y. Hatron, MD, B. P. C. Hazenberg, MD, G. Hayem, MD,
S. Herson, MD, M. Horackova, MD, I. Kone-Paut, MD, J. P.
Latrive, MD, M. Lémann, MD, D. Malka, MD, F. Martinez,
MD, J. Ninet, MD, A. M. Prieur, MD, T. Papo, MD, I. Royer,
MD, H. Sauvé-Martin, MD, A. Sefiani, MD, I. Touitou, MD,
PhD.
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