The enlarging clinical genetic and population spectrum of tumor necrosis factor receptorassociated periodic syndrome.код для вставкиСкачать
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: firstname.lastname@example.org. 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. 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