Severe TNF Receptor–Associated Periodic Syndrome Due to 2 TNFRSF1A Mutations Including a New F60V Substitution
2006; Elsevier BV; Volume: 130; Issue: 1 Linguagem: Inglês
10.1053/j.gastro.2005.09.014
ISSN1528-0012
AutoresStephan Haas, Peter Lohse, Wilhelm H. Schmitt, Ralf Hildenbrand, Mevlüt Karaorman, Manfred V. Singer, Ulrich Böcker,
Tópico(s)Immune Cell Function and Interaction
ResumoTumor necrosis factor receptor–associated periodic syndrome (TRAPS) is typically characterized by episodic fever, myalgia, skin rash, conjunctivitis, and abdominal cramps. Recently, mutations in the TNFRSF1A gene on chromosome 12p13 encoding tumor necrosis factor receptor type 1 have been linked to this autoinflammatory syndrome. We report the case of a 29-year-old white woman who experienced periodic inflammatory manifestations with fever up to 40°C, leukocytosis, and elevation of C-reactive protein level (>100 mg/L) in conjunction with acute peritonitis of unknown origin since the age of 19 years. The patient had undergone 2 laparotomies with appendectomy and left hemicolectomy. Familial Mediterranean fever was excluded by sequencing of the MEFV gene. In view of the possibility of TRAPS, sequence analysis of the TNFRSF1A gene was also performed. The patient carried a novel T→G substitution in exon 3, leading to the replacement of phenylalanine by valine at amino acid position 60 (F60V), as well as the common R92Q low-penetrance mutation, encoded by exon 4. Upon the next flare, the patient started corticosteroid therapy, resulting in complete relief and normalization of elevated C-reactive protein levels. To the best of our knowledge, we report the first case of compound heterozygosity for 2 TNFRSF1A gene mutations, including a novel one that causes a severe form of TRAPS that responds to anti-inflammatory treatment. A history of recurrent sterile peritonitis should prompt genotyping for periodic fever syndromes. Tumor necrosis factor receptor–associated periodic syndrome (TRAPS) is typically characterized by episodic fever, myalgia, skin rash, conjunctivitis, and abdominal cramps. Recently, mutations in the TNFRSF1A gene on chromosome 12p13 encoding tumor necrosis factor receptor type 1 have been linked to this autoinflammatory syndrome. We report the case of a 29-year-old white woman who experienced periodic inflammatory manifestations with fever up to 40°C, leukocytosis, and elevation of C-reactive protein level (>100 mg/L) in conjunction with acute peritonitis of unknown origin since the age of 19 years. The patient had undergone 2 laparotomies with appendectomy and left hemicolectomy. Familial Mediterranean fever was excluded by sequencing of the MEFV gene. In view of the possibility of TRAPS, sequence analysis of the TNFRSF1A gene was also performed. The patient carried a novel T→G substitution in exon 3, leading to the replacement of phenylalanine by valine at amino acid position 60 (F60V), as well as the common R92Q low-penetrance mutation, encoded by exon 4. Upon the next flare, the patient started corticosteroid therapy, resulting in complete relief and normalization of elevated C-reactive protein levels. To the best of our knowledge, we report the first case of compound heterozygosity for 2 TNFRSF1A gene mutations, including a novel one that causes a severe form of TRAPS that responds to anti-inflammatory treatment. A history of recurrent sterile peritonitis should prompt genotyping for periodic fever syndromes. Hereditary periodic fever syndromes are characterized by recurrent fever episodes and at present include the following 4 disease entities.1Drenth J.P. van der Meer J.W. Hereditary periodic fever.N Engl J Med. 2001; 345: 1748-1757Crossref PubMed Scopus (389) Google Scholar, 2Grateau G. Clinical and genetic aspects of the hereditary periodic fever syndromes.Rheumatology (Oxford). 2004; 43: 410-415Crossref PubMed Scopus (58) Google Scholar (1) Familial Mediterranean fever (FMF; OMIM 249100) is an autosomal recessive disorder found primarily in populations of eastern Mediterranean descent that results from mutations in the MEFV gene. (2) Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS; OMIM 260020) represents a rare autosomal recessive autoinflammatory disease caused by a deficiency of mevalonate kinase due to mutations in the MEVK gene. (3) Muckle–Wells syndrome (OMIM 191900), familial cold urticaria (OMIM 120100), and the chronic infantile neurologic cutaneous and articular syndrome (OMIM 607115) are 3 autosomal dominant inherited disorders with overlapping phenotypic features that are the consequence of mutations in the CIAS1 gene. (4) Tumor necrosis factor (TNF) receptor–associated periodic syndrome (TRAPS; OMIM 142680) is also dominantly inherited and was originally termed familial Hibernian fever.3Williamson L.M. Hull D. Mehta R. Reeves W.G. Robinson B.H. Toghill P.J. Familial Hibernian fever.Q J Med. 1982; 51: 469-480PubMed Google Scholar In concurrence with fever, abdominal pain is a characteristic feature of patients with TRAPS, FMF, and HIDS.1Drenth J.P. van der Meer J.W. Hereditary periodic fever.N Engl J Med. 2001; 345: 1748-1757Crossref PubMed Scopus (389) Google Scholar In addition, arthralgia and/or arthritis are frequently found in periodic fever syndromes. A further common feature is the occurrence of variable types of rashes such as urticaria, erythema, or maculopapular lesions, depending on the type of periodic syndrome. Whereas periorbital edema and conjunctivitis may be present in patients with TRAPS, the lower limbs are rarely affected by erysipelas-like skin lesions in patients with FMF. The age of onset of periodic fever syndrome is highly variable.1Drenth J.P. van der Meer J.W. Hereditary periodic fever.N Engl J Med. 2001; 345: 1748-1757Crossref PubMed Scopus (389) Google Scholar In chronic infantile neurologic cutaneous and articular syndrome, rash and neurologic symptoms are already observed in neonates. In HIDS, the diagnosis is typically made before the age of 1 year, whereas attacks of abdominal pain in FMF usually commence before the age of 20 years. In contrast, the age of onset in TRAPS varies between 2 weeks and 53 years. The prognosis of patients with periodic fever syndromes is determined mainly by the presence or absence of amyloidosis with the exception of HIDS, where development of amyloidosis is rare. FMF is the best-known hereditary periodic fever syndrome with the highest prevalence, whereas TRAPS has the highest prevalence among the periodic fever syndromes with autosomal dominant inheritance. In patients with TRAPS, more than 60 pathogenic mutations and polymorphisms in the TNFRSF1A gene encoding the 55-kilodalton TNF receptor (also termed TNFR1, p55-TNFR, TNF receptor superfamily 1A, TNFRSF1, or CD120a) have been identified4Touitou I. Lesage S. McDermott M. Cuisset L. Hoffman H. Dode C. Shoham N. Aganna E. Hugot J.P. Wise C. Waterham H. Pugnere D. Demaille J. Sarrauste de Menthiere C. Infevers an evolving mutation database for auto-inflammatory syndromes.Hum Mutat. 2004; 24: 194-198Crossref PubMed Scopus (233) Google Scholar (http://fmf.igh.cnrs.fr/infevers/). The gene is located on chromosome 12p13 and codes for a protein containing 4 cysteine-rich extracellular domains (CRD1–4), each stabilized by 3 cysteine-cysteine disulfide bonds, a transmembrane region, and a large intracellular domain.5McDermott M.F. Ogunkolade B.W. McDermott E.M. Jones L.C. Wan Y. Quane K.A. McCarthy J. Phelan M. Molloy M.G. Powell R.J. Amos C.I. Hitman G.A. Linkage of familial Hibernian fever to chromosome 12p13.Am J Hum Genet. 1998; 62: 1446-1451Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 6Mulley J. Saar K. Hewitt G. Ruschendorf F. Phillips H. Colley A. Sillence D. Reis A. Wilson M. Gene localization for an autosomal dominant familial periodic fever to 12p13.Am J Hum Genet. 1998; 62: 884-889Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar TNFRSF1 is widely expressed on various cell types, including leukocytes. Cellular responses to TNF-α are physiologically controlled and limited by TNFRSF1 shedding. Serin proteases and metalloproteinases inactivate the receptor by enzymatic cleavage between residues Asn172 and Val173 of the extracellular portion, thus preventing further TNF-α receptor binding.7Gullberg U. Lantz M. Lindvall L. Olsson I. Himmler A. Involvement of an Asn/Val cleavage site in the production of a soluble form of a human tumor necrosis factor (TNF) receptor. Site-directed mutagenesis of a putative cleavage site in the p55 TNF receptor chain.Eur J Cell Biol. 1992; 58: 307-312PubMed Google Scholar, 8Porteu F. Nathan C. Shedding of tumor necrosis factor receptors by activated human neutrophils.J Exp Med. 1990; 172: 599-607Crossref PubMed Scopus (373) Google Scholar Shed soluble TNFRSF1 (sTNFRSF1) attenuates TNF-α effects by competitively inhibiting the binding of TNF-α to its receptor. Several missense mutations affect disulfide bonds of the extracellular cysteine-rich domains (mainly CRD1 and CRD2 encoded by exons 2–4), resulting in impairment of receptor shedding and leading to uncontrolled cellular activation by TNF-α and diminished inactivation due to reduced levels of sTNFRSF1.9McDermott M.F. Aksentijevich I. Galon J. McDermott E.M. Ogunkolade B.W. Centola M. Mansfield E. Gadina M. Karenko L. Pettersson T. McCarthy J. Frucht D.M. Aringer M. Torosyan Y. Teppo A.M. Wilson M. Karaarslan H.M. Wan Y. Todd I. Wood G. Schlimgen R. Kumarajeewa T.R. Cooper S.M. Vella J.P. Amos C.I. Mulley J. Quane K.A. Molloy M.G. Ranki A. Powell R.J. Hitman G.A. O’Shea J.J. Kastner D.L. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes.Cell. 1999; 971: 133-144Abstract Full Text Full Text PDF Scopus (1081) Google Scholar However, a growing number of disease-associated TNFRSF1 mutations are described with no apparent defect in receptor shedding. In addition, accumulating data also indicate that TRAPS may be a polygenic disease entity that is not only caused by mutations in the TNFRSF1A gene.10Aksentijevich I. Galon J. Soares M. Mansfield E. Hull K. Oh H.H. Goldbach-Mansky R. Dean J. Athreya B. Reginato A.J. Henrickson M. Pons-Estel B. O’Shea J.J. Kastner D.L. The tumor-necrosis-factor receptor-associated periodic syndrome new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers.Am J Hum Genet. 2001; 69: 301-314Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar, 11Aganna E. Hammond L. Hawkins P.N. Aldea A. McKee S.A. van Amstel H.K. Mischung C. Kusuhara K. Saulsbury F.T. Lachmann H.J. Bybee A. McDermott E.M. La Regina M. Arostegui J.I. Campistol J.M. Worthington S. High K.P. Molloy M.G. Baker N. Bidwell J.L. Castaner J.L. Whiteford M.L. Janssens-Korpola P.L. Manna R. Powell R.J. Woo P. Solis P. Minden K. Frenkel J. Yague J. Mirakian R.M. Hitman G.A. McDermott M.F. Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes.Arthritis Rheum. 2003; 48: 2632-2644Crossref PubMed Scopus (161) Google Scholar In intervals of a few weeks to months, a 29-year-old German woman had experienced recurrent fever attacks of variable intensity since the age of 19 years with fever up to 40°C that lasted 3–7 days. These episodes were accompanied by persistent, noncolic, ill-defined abdominal pain without diarrhea and by generalized myalgia and arthralgia (most prominently of the hips, knees, and ankles), followed by spontaneous and complete resolution. No conjunctivitis, periorbital edema, or other skin alterations were noted during these episodes. The patient was unaware of any precipitating factors such as infections or stressful events. During a severe attack in 1994, the patient underwent a laparoscopy. The peritoneum appeared slightly inflamed, and an acute peritonitis of unknown etiology was stated. Histologic specimens were not obtained. Purulent peritoneal fluid proved to be sterile microbiologically. Three years later, the patient again experienced an episode of severe abdominal pain, and a corpus luteum cyst of the right ovary was laparoscopically removed. Moreover, in the resected specimen, endometriosis was histologically diagnosed. In July 2001, acute abdominal pain was attributed to acute appendicitis and a laparoscopic appendectomy was performed. However, macroscopically and histologically, the appendix was only mildly inflamed. In June 2003, the patient was referred to the outpatient clinic of the Department of Medicine II of the University of Heidelberg at Mannheim. Inflammatory bowel disease, irritable bowel syndrome, and postoperative adhesions were diagnostically considered. The workup included upper endoscopy, colonoscopy, and magnetic resonance imaging enteroclysis. The examinations yielded no pathologic alterations. Celiac disease and eosinophilic colitis were ruled out. Wireless capsule endoscopy revealed small superficial ileal ulcerations compatible with Crohn’s disease but not accessible for histology, and the patient was put on mesalazine (1 g 3 times daily). In August 2003, the patient presented with an acute abdomen with all signs and symptoms of acute peritonitis in conjunction with leukocytosis (13.6 ×109 cells/L) and marked elevation of C-reactive protein levels (335 mg/dL), resulting in an exploratory laparotomy. During this procedure, the whole left colon was found to be heavily inflamed with a thick yellow exudate coating the peritoneal surfaces. Pus was visible in the Douglas space. The patient, then 28 years old, received a left hemicolectomy and a protective ileostoma. Histologically, a purulent peritonitis was demonstrated with an inflammatory infiltrate in the pericolic fat tissue, reaching the muscularis propria. The submucosa showed marked edema, whereas a significant inflammatory infiltrate was lacking. The mucosa was intact without any ulceration (Figure 1). Swabs from the peritoneal cavity did not verify a bacterial or fungal etiology for the acute peritonitis. Nevertheless, the patient was treated postoperatively with broad-spectrum antibiotics; within 1 week, all signs and symptoms of acute peritonitis disappeared completely. In view of the recurrent fever episodes with no apparent source of infection, the presence of a hereditary periodic fever syndrome was suggestive. Serum immunoglobulin D levels were repeatedly normal, so that a hyper–immunoglobulin D syndrome appeared less likely. Consequently, a mutational screening of the MEFV and TNFRSF1A genes was initiated. Genetic analyses were conducted in the index patient and her mother after obtaining informed consent. Genomic DNA was prepared from peripheral blood mononuclear cells. Exclusion of FMF was achieved by directly sequencing all 10 exons of the MEFV gene. Exons 2–4, 6, and 7 of the TNFRSF1A gene were subsequently amplified by polymerase chain reaction. The intron-based oligonucleotides used for the analyses were as follows. Exon 2: forward 5′-TTAGATCTGCTACCCCTAAGCTTCC-3′, reverse 5′-AACTGGAAGAAGCAGAGAAAGAAGC-3′; exon 3: forward 5′-GGCTGTTGTCCCTAGCATGG-3′, reverse 5′-ACATAGACAGGCACCCACACAC-3′; exon 4: forward 5′-GATGCAGGGACAGGAGGATG-3′, reverse 5′-TGTCAGACCCACAGAATACAGGAG-3′; exons 6 and 7: forward 5′-TTCATTCTTCTGCATCAGTTCCC-3′, reverse 5′-TCCACACATGTCCATCGCAC-3′. Purification of the amplification products was performed with the QIAquick PCR purification kit (Qiagen, Hilden, Germany), and sequencing was conducted with the ABI PRISM Big Dye Terminator v3.1 Ready Reaction Cycle Sequencing Kit (Applied Biosystems, Darmstadt, Germany). Sequences were analyzed on an ABI PRISM 377 DNA sequencer (Applied Biosystems). The results were confirmed with a second blood sample. Sequence analysis of TNFRSF1A exons 2–4, 6, and 7 in the index patient revealed a heterozygous CGG to CAG missense mutation in exon 4, resulting in the substitution of amino acid 92, arginine, by glutamine (R92Q) (Figure 2). A second and hitherto unknown heterozygous TTC to GTC missense mutation was detected in exon 3 at codon 60, resulting in the replacement of the aromatic amino acid phenylalanine by an aliphatic valine (F60V) (Figure 3). This F60V mutation has not been observed in more than 400 patients analyzed. Comparison of the amino acid sequence of TNFRSF1 in 5 different species (human, mouse, rat, cat, and pig) demonstrated that phenylalanine at position 60 is completely conserved, strongly suggesting that the F60V substitution is a true mutation affecting a residue with crucial functional relevance (Figure 4).Figure 3Sequence analysis of TNFRSF1A exon 3 in the affected patient. The electropherogram shows the heterozygous T→G replacement (indicated by an arrow), which leads to the substitution of phenylalanine (TTC) by valine (GTC) at amino acid position 60.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 4Alignment of amino acid sequences encoded by exon 3 of the TNFRSF1A gene of 5 different species, demonstrating absolute sequence conservation of phenylalanine at position 60 (1, human; 2, mouse [Mus musculus]; 3, rat [Rattus norvegicus]; 4, cat [Felis catus]; 5, pig [Sus scrofa]).View Large Image Figure ViewerDownload Hi-res image Download (PPT) After the diagnosis of TRAPS was made, the patient received prednisolone with a top-down dosing schedule starting in December 2004. Initially, 40 mg of prednisolone was administered once daily and the dose was reduced by 5 mg every 5 days. During early treatment, no further overt attacks were observed, and C-reactive protein levels normalized; however, tapering of prednisolone to <20 mg daily resulted in mild abdominal symptoms, reflecting corticosteroid dependency. To answer the question whether the index patient was a compound heterozygote, the mother also underwent mutational screening of TNFRSF1A exons 3 and 4. She was without any symptoms and harbored the R92Q substitution but not the F60V replacement (Figure 5). Unfortunately, neither the patient’s father nor her brother were available for genetic testing. Alterations of the TNFRSF1A gene are infrequently found in individuals with TRAPS-like symptoms. Aksentijevich et al described 6 different amino acid substitutions and 1 splice site defect occurring in 17 of 137 unrelated patients (12.4%).10Aksentijevich I. Galon J. Soares M. Mansfield E. Hull K. Oh H.H. Goldbach-Mansky R. Dean J. Athreya B. Reginato A.J. Henrickson M. Pons-Estel B. O’Shea J.J. Kastner D.L. The tumor-necrosis-factor receptor-associated periodic syndrome new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers.Am J Hum Genet. 2001; 69: 301-314Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar In another study by Dode et al,12Dode C. Andre M. Bienvenu T. Hausfater P. Pecheux C. Bienvenu J. Lecron J.C. Reinert P. Cattan D. Piette J.C. Szajnert M.F. Delpech M. Grateau G. French Hereditary Recurrent Inflammatory Disorder Study GroupThe enlarging clinical, genetic, and population spectrum of tumor necrosis factor receptor-associated periodic syndrome.Arthritis Rheum. 2002; 46: 2181-2188Crossref PubMed Scopus (187) Google Scholar 28 of 394 unrelated patients (7.1%) carried an alteration of the TNFRSF1A gene. Overall, 64 TNFRSF1A mutations and polymorphisms have been registered in the INFEVERS database as of August 2005 (http://fmf.igh.cnrs.fr/infevers). Almost all true mutations are located in exons 2–4, which encode the 2 cysteine-rich extracellular subdomains of the receptor (CRD1 and CRD2). We report here a severely affected female patient with TRAPS with compound heterozygosity for 2 mutations in the TNFRSF1A gene: the low-penetrance R92Q substitution encoded by exon 4 and a hitherto unknown F60V exchange encoded by exon 3. Recurrent fever attacks with abdominal pain appeared since the age of 19 years in our patient and were attributed to a variety of different etiologies such as an ovarian cyst, endometriosis, appendicitis, irritable bowel syndrome, postoperative adhesions, and Crohn’s disease. The fever attacks lasted for 3–7 days with spontaneous resolution, demonstrating that the duration of symptoms is an invalid parameter to differentiate TRAPS clinically from FMF; in the majority of patients with FMF, the abdominal symptoms last 1–4 days, whereas in TRAPS the attacks are believed to last at least 5 days but may persist up to 3 weeks.2Grateau G. Clinical and genetic aspects of the hereditary periodic fever syndromes.Rheumatology (Oxford). 2004; 43: 410-415Crossref PubMed Scopus (58) Google Scholar Interestingly, skin alterations such as rash or periorbital edema were absent in this case although frequently observed in patients with TRAPS, in contrast to FMF. In one study, 84% of patients with TRAPS presented with migratory erythematous macules and patches. A total of 44% of them had conjunctivitis or periorbital edema.13Toro J.R. Aksentijevich I. Hull K. Dean J. Kastner D.L. Tumor necrosis factor receptor-associated periodic syndrome a novel syndrome with cutaneous manifestations.Arch Dermatol. 2000; 136: 1487-1494Crossref PubMed Google Scholar Apart from prominent abdominal cramping pain, arthralgia and myalgia were associated with the fever attacks in our patient. Hull et al showed that myalgia corresponded with edema in the muscle compartment and histologically with monocytic fasciitis.14Hull K.M. Wong K. Wood G.M. Chu W.S. Kastner D.L. Monocytic fasciitis a newly recognized clinical feature of tumor necrosis factor receptor dysfunction.Arthritis Rheum. 2002; 46: 2189-2194Crossref PubMed Scopus (77) Google Scholar Due to the recurrent nature of the periodic fever syndrome with some characteristic features of FMF, sequencing of the MEVF gene was performed to rule out the most prevalent form of periodic fever. However, only the subsequent analysis of the TNFRSF1A gene revealed the causative mutations in this patient. She was a heterozygous carrier of the low-penetrance R92Q mutation, which represents the most common mutation found in patients with TRAPS. Aksentijevich et al observed this substitution with a chromosomal frequency of 3.3% in individuals with TRAPS-like symptoms, whereas the prevalence in the mostly northern European controls was only 1.04%.10Aksentijevich I. Galon J. Soares M. Mansfield E. Hull K. Oh H.H. Goldbach-Mansky R. Dean J. Athreya B. Reginato A.J. Henrickson M. Pons-Estel B. O’Shea J.J. Kastner D.L. The tumor-necrosis-factor receptor-associated periodic syndrome new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers.Am J Hum Genet. 2001; 69: 301-314Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar R92Q was also the most common sequence change identified in this study, being present in 9 of the 17 index patients with confirmed mutation (53%). Aganna et al analyzed 18 families in which multiple members had symptoms compatible with TRAPS and 176 subjects with sporadic TRAPS-like symptoms and demonstrated a prevalence of 1.4%, whereas the R92Q mutation was absent in a control population, thus strongly supporting the notion that this amino acid substitution is a true pathogenic mutation rather then a benign polymorphism.11Aganna E. Hammond L. Hawkins P.N. Aldea A. McKee S.A. van Amstel H.K. Mischung C. Kusuhara K. Saulsbury F.T. Lachmann H.J. Bybee A. McDermott E.M. La Regina M. Arostegui J.I. Campistol J.M. Worthington S. High K.P. Molloy M.G. Baker N. Bidwell J.L. Castaner J.L. Whiteford M.L. Janssens-Korpola P.L. Manna R. Powell R.J. Woo P. Solis P. Minden K. Frenkel J. Yague J. Mirakian R.M. Hitman G.A. McDermott M.F. Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes.Arthritis Rheum. 2003; 48: 2632-2644Crossref PubMed Scopus (161) Google Scholar This was confirmed by the findings of Dode et al, who demonstrated this mutation in 6 of 160 symptomatic white patients (allele frequency, 1.8%) and in 6 of 148 of Arab patients with Maghreb ancestry (allele frequency, 2.0%). In control subjects, in contrast, the R92Q prevalence was 0%.15Dode C. Hazenberg B.P. Pecheux C. Cattan D. Moulin B. Barthelemy A. Gubler M.C. Delpech M. Grateau G. Mutational spectrum in the MEFV and TNFRSF1A genes in patients suffering from AA amyloidosis and recurrent inflammatory attacks.Nephrol Dial Transplant. 2002; 17: 1212-1217Crossref PubMed Scopus (34) Google Scholar Of note, no significant differences in the R92Q prevalence in white and Maghreb patients appeared to exist, so that the R92Q mutation is also present in ethnic groups predisposed to FMF. TRAPS was initially found to be prevalent in patients of northern European ancestry. In the meantime, TRAPS could be identified not only in Arab populations but also in patients from eastern Asia.16Kusuhara K. Nomura A. Nakao F. Hara T. Tumour necrosis factor receptor-associated periodic syndrome with a novel mutation in the TNFRSF1A gene in a Japanese family.Eur J Pediatr. 2004; 163: 30-32Crossref PubMed Scopus (28) Google Scholar, 17Stojanov S. Lohse P. McDermott M.F. Renner E.D. Kéry A. Mirakian R. Hammond L.J. Aganna E. Hoffmann F. Zellerer S. Belohradsky B.H. A novel TNFRSF1A Y20D missense mutation, associated with the common MEFV E148Q substitution, in a Chinese patient with clinical features of the tumor necrosis factor receptor-associated periodic syndrome (TRAPS).Rheumatology (Oxford). 2004; 43: 526-527Crossref PubMed Scopus (15) Google Scholar Interestingly, R92Q mutations were found in periodic fever syndromes other than TRAPS, resulting in a mixed clinical picture. Dode et al reported a patient with periodic fever syndrome who proved to have a mutation both in the MEFV and in the TNFRSF1A gene and did not respond to colchicine treatment.15Dode C. Hazenberg B.P. Pecheux C. Cattan D. Moulin B. Barthelemy A. Gubler M.C. Delpech M. Grateau G. Mutational spectrum in the MEFV and TNFRSF1A genes in patients suffering from AA amyloidosis and recurrent inflammatory attacks.Nephrol Dial Transplant. 2002; 17: 1212-1217Crossref PubMed Scopus (34) Google Scholar Stojanov et al presented a patient with a R92Q mutation and a MVK V377I mutation who showed HIDS- and TRAPS-associated symptoms.18Stojanov S. Lohse P. Lohse P. Hoffmann F. Renner E.D. Zellerer S. Kery A. Shin Y.S. Haas D. Hoffmann G.F. Belohradsky B.H. Molecular analysis of the MVK and TNFRSF1A genes in patients with a clinical presentation typical of the hyperimmunoglobulinemia D with periodic fever syndrome a low-penetrance TNFRSF1A variant in a heterozygous MVK carrier possibly influences the phenotype of hyperimmunoglobulinemia D with periodic fever syndrome or vice versa.Arthritis Rheum. 2004; 50: 1951-1958Crossref PubMed Scopus (39) Google Scholar Compared with mutations affecting disulfide bonds of the extracellular domains, R92Q appears to have a significantly lower penetrance12Dode C. Andre M. Bienvenu T. Hausfater P. Pecheux C. Bienvenu J. Lecron J.C. Reinert P. Cattan D. Piette J.C. Szajnert M.F. Delpech M. Grateau G. French Hereditary Recurrent Inflammatory Disorder Study GroupThe enlarging clinical, genetic, and population spectrum of tumor necrosis factor receptor-associated periodic syndrome.Arthritis Rheum. 2002; 46: 2181-2188Crossref PubMed Scopus (187) Google Scholar and can be found especially in sporadic cases of TRAPS,10Aksentijevich I. Galon J. Soares M. Mansfield E. Hull K. Oh H.H. Goldbach-Mansky R. Dean J. Athreya B. Reginato A.J. Henrickson M. Pons-Estel B. O’Shea J.J. Kastner D.L. The tumor-necrosis-factor receptor-associated periodic syndrome new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers.Am J Hum Genet. 2001; 69: 301-314Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar although segregation with disease has been described in affected families.15Dode C. Hazenberg B.P. Pecheux C. Cattan D. Moulin B. Barthelemy A. Gubler M.C. Delpech M. Grateau G. Mutational spectrum in the MEFV and TNFRSF1A genes in patients suffering from AA amyloidosis and recurrent inflammatory attacks.Nephrol Dial Transplant. 2002; 17: 1212-1217Crossref PubMed Scopus (34) Google Scholar In addition, amyloidosis and subsequent chronic renal failure may be less frequently associated with this mutation when compared with mutations affecting disulfide bonds of extracellular cysteine-rich domains. Nevertheless, chronic renal failure can be an early manifestation in patients harboring this mutation, as Dode et al reported in a patient who received a kidney transplant following renal amyloidosis at the age of 33 years.15Dode C. Hazenberg B.P. Pecheux C. Cattan D. Moulin B. Barthelemy A. Gubler M.C. Delpech M. Grateau G. Mutational spectrum in the MEFV and TNFRSF1A genes in patients suffering from AA amyloidosis and recurrent inflammatory attacks.Nephrol Dial Transplant. 2002; 17: 1212-1217Crossref PubMed Scopus (34) Google Scholar The R92Q mutant may also have a modulatory role on a variety of other inflammatory syndromes, for example, enhancing the risk of amyloidosis in patients with juvenile arthritis and increasing the risk for atherosclerosis and premature myocardial infarction.19Aganna E. Hawkins P.N. Ozen S. Pettersson T. Bybee A. McKee S.A. Lachmann H.J. Karenko L. Ranki A. Bakkaloglu A. Besbas N. Topaloglu R. Hoffman H.M. Hitman G.A. Woo P. McDermott M.F. Allelic variants in genes associated with hereditary periodic fever syndromes as susceptibility factors for reactive systemic AA amyloidosis.Genes Immun. 2004; 5: 289-293Crossref PubMed Scopus (55) Google Scholar, 20Poirier O. Nicaud V. Gariepy J. Courbon D. Elbaz A. Morrison C. Kee F. Evans A. Arveiler D. Ducimetiere P. Amarenco P. Cambien F. Polymorphism R92Q of the tumour necrosis factor receptor 1 gene is associated with myocardial infarction and carotid intima-media thickness—the ECTIM, AXA, EVA and GENIC studies.Eur J Hum Genet. 2004; 12: 213-219Crossref PubMed Scopus (41) Google Scholar Moreover, an association of the R92Q substitution with extracranial deep vein thrombosis in patients with Behçet disease was recently reported.21Amoura Z. Dode C. Hue S. Caillat-Zucman S. Bahram S. Delpech M. Grateau G. Wechsler B. Piette J.C. Association of the R92Q TNFRSF1A mutation and extracranial deep vein thrombosis in patients with Behcet’s disease.Arthritis Rheum. 2005; 52: 608-611Crossref PubMed Scopus (59) Google Scholar The mechanisms by which the R92Q mutation elicits TRAPS are still ill defined. Application of the standard in vitro shedding assays did not show a shedding defect,10Aksentijevich I. Galon J. Soares M. Mansfield E. Hull K. Oh H.H. Goldbach-Mansky R. Dean J. Athreya B. Reginato A.J. Henrickson M. Pons-Estel B. O’Shea J.J. Kastner D.L. The tumor-necrosis-factor receptor-associated periodic syndrome new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers.Am J Hum Genet. 2001; 69: 301-314Abstract Full Text Full Text PDF PubMed Scopus (293) Google Scholar and inflammatory episodes did not correspond to enhanced levels of soluble TNFRSF1 serum levels in the affected patients, suggesting that receptor function and inactivation by shedding were impaired by mechanisms not detected by the currently applied in vitro shedding assays. The second mutation in our white patient with TRAPS was found in exon 3, affecting codon 60 in the second extracellular cysteine-rich domain (CRD2) and resulting in the substitution of an aromatic phenylalanine by an aliphatic valine. None of the more than 400 other patients with TRAPS-compatible symptoms analyzed so far by us harbored this genetic defect. By comparing the TNFRSF1 amino acid sequence in 5 different species, the phenylalanine at position 60 proved to be completely conserved, indicating an important role of this amino acid in protein structure and/or function. In addition, a phenylalanine (TTC) to leucine (TTG) substitution has been described at the same amino acid position as a causal mutation in 2 members of a Scottish family diagnosed with TRAPS,11Aganna E. Hammond L. Hawkins P.N. Aldea A. McKee S.A. van Amstel H.K. Mischung C. Kusuhara K. Saulsbury F.T. Lachmann H.J. Bybee A. McDermott E.M. La Regina M. Arostegui J.I. Campistol J.M. Worthington S. High K.P. Molloy M.G. Baker N. Bidwell J.L. Castaner J.L. Whiteford M.L. Janssens-Korpola P.L. Manna R. Powell R.J. Woo P. Solis P. Minden K. Frenkel J. Yague J. Mirakian R.M. Hitman G.A. McDermott M.F. Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes.Arthritis Rheum. 2003; 48: 2632-2644Crossref PubMed Scopus (161) Google Scholar again strongly suggesting that the F60V exchange is pathogenic. Due to the fact that no blood sample of the father was available for genetic analyses, we cannot answer the question whether the F60V mutation was inherited or occurred spontaneously. However, because the mother harbored only the R92Q mutation, we can deduce that the patient carried the mutations most likely on 2 different alleles. Our patient was treated with prednisolone. Glucocorticosteroids alleviate symptoms in the majority of patients with TRAPS, but some do not respond to corticosteroids or require high amounts over a long period. Furthermore, in 1 patient, amyloidosis in the kidney graft following renal transplantation could not be prevented by combination therapy with prednisolone, cyclosporine, and azathioprine.22Jadoul M. Dode C. Cosyns J.P. Abramowicz D. Georges B. Delpech M. Pirson Y. Autosomal-dominant periodic fever with AA amyloidosis novel mutation in tumor necrosis factor receptor 1 gene.Kidney Int. 2001; 59: 1677-1682Crossref PubMed Scopus (41) Google Scholar Etanercept represents a promising and well-tolerated alternative to glucocorticosteroids in patients with TRAPS and significantly reduces the required corticosteroid dose when given in combination.23Arostegui J.I. Solis P. Aldea A. Cantero T. Rius J. Bahillo P. Plaza S. Vives J. Gomez S. Yague J. Etanercept plus colchicine treatment in a child with tumour necrosis factor receptor-associated periodic syndrome abolishes auto-inflammatory episodes without normalising the subclinical acute phase response.Eur J Pediatr. 2005; 164: 13-16Crossref PubMed Scopus (42) Google Scholar, 24Kallinich T. Briese S. Roesler J. Rudolph B. Sarioglu N. Blankenstein O. Keitzer R. Querfeld U. Haffner D. Two familial cases with tumor necrosis factor receptor-associated periodic syndrome caused by a non-cysteine mutation (T50M) in the TNFRSF1A gene associated with severe multiorganic amyloidosis.J Rheumatol. 2004; 31: 2519-2522PubMed Google Scholar, 25Drewe E. McDermott E.M. Powell P.T. Isaacs J.D. Powell R.J. Prospective study of anti-tumour necrosis factor receptor superfamily 1B fusion protein, and case study of anti-tumour necrosis factor receptor superfamily 1A fusion protein, in tumour necrosis factor receptor associated periodic syndrome (TRAPS) clinical and laboratory findings in a series of seven patients.Rheumatology (Oxford). 2003; 42: 235-239Crossref PubMed Scopus (178) Google Scholar, 26Lamprecht P. Moosig F. Adam-Klages S. Mrowietz U. Csernok E. Kirrstetter M. Ahmadi-Simab K. Schroder J.O. Gross W.L. Small vessel vasculitis and relapsing panniculitis in tumour necrosis factor receptor associated periodic syndrome (TRAPS).Ann Rheum Dis. 2004; 63: 1518-1520Crossref PubMed Scopus (66) Google Scholar Etanercept (Enbrel; Immunex, Seattle, WA) is a dimeric fusion protein comprising 2 chains of the recombinant human TNF-α receptor p75 fused with the Fc domain of human immunoglobulin G1. Etanercept is usually given subcutaneously twice weekly at a dose of 25 mg or 0.4 mg/kg. Steroid sparing is especially important in young patients, because long-term treatment with glucocorticosteroids is associated with significant morbidity. Therefore, our patient may be treated with etanercept in the near future. Data on the efficacy of infliximab, a chimeric monoclonal antibody against human TNF-α, are lacking, while colchicine, in contrast to FMF, does not seem to be effective in the majority of patients with TRAPS.15Dode C. Hazenberg B.P. Pecheux C. Cattan D. Moulin B. Barthelemy A. Gubler M.C. Delpech M. Grateau G. Mutational spectrum in the MEFV and TNFRSF1A genes in patients suffering from AA amyloidosis and recurrent inflammatory attacks.Nephrol Dial Transplant. 2002; 17: 1212-1217Crossref PubMed Scopus (34) Google Scholar, 27Mulley J. Saar K. Hewitt G. Ruschendorf F. Phillips H. Colley A. Sillence D. Reis A. Wilson M. Gene localization for an autosomal dominant familial periodic fever to 12p13.Am J Hum Genet. 1998; 62: 884-889Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar In summary, we present a severely affected patient with TRAPS who is compound heterozygous for 2 mutations in the TNFRSF1A gene. Apart from the frequently found low-penetrance R92Q mutation, a novel F60V substitution in the CRD2 domain was responsible for the recurrent attacks of fever that were accompanied by arthralgia, myalgia, and especially episodes of serious abdominal pain, resulting in appendectomy and hemicolectomy. A history of recurrent sterile peritonitis should therefore prompt genotyping for periodic fever syndromes, thus preventing unnecessary diagnostic and therapeutic procedures.
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