Severe TNF Receptor–Associated Periodic Syndrome Due to 2 TNFRSF1A Mutations Including a New F60V Substitution

doi:10.1053/j.gastro.2005.09.014

Gastroenterology

Volume 130, Issue 1, January 2006, Pages 172-178

Presented in part at United European Gastroenterology Week, Prague, Czech Republic, September 25–29, 2004.

https://doi.org/10.1053/j.gastro.2005.09.014 Get rights and content

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.

Section snippets

Case Report

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

Discussion

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%).¹⁰ In another study by Dode et al,¹² 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 (//fmf.igh.cnrs.fr/infevers

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Cited by (19)

IL-1 mediated autoinflammatory diseases: the “classic” hereditary recurrent fever syndromes and the inflammasomopathies
2020, Stiehm's Immune Deficiencies: Inborn Errors of Immunity
The genetically defined Mendelian autoinflammatory diseases are a group of immune dysregulatory conditions that present with systemic and organ-specific “sterile” inflammation with clinical features that include fever, rashes arthritis/arthralgia, serositis, meningitis, and inner ear, eye, bone, and/or gut inflammation. The pattern of organ inflammation in the various conditions often allows a specific diagnosis on clinical grounds. At the onset, autoinflammatory conditions can resemble infections or hematopoietic malignancies, warranting a careful work-up. While the genetic discovery of the initial “classic” autoinflammatory diseases was pioneered by the discovery of IL-1 mediated autoinflammatory diseases that pointed to dysregulation of the IL-1 activating inflammasomes, more recent work pointed to the dysregulation of additional innate immune pathways that regulate other pro-inflammatory cytokines, including Type-I IFN, IL-18, NFκB activation through ubiquitylation defects and IL-17 activation in keratinocytes. The subsequent chapters review many genetically defined autoinflammatory syndromes identified since the classic inflammatory disorders were described. This chapter describes the spectrum of diseases that are caused by monogenic defects that regulate the activity of 4 human IL-1β activating inflammasomes including the three “classic” hereditary periodic fever syndromes of familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), and mevalonate kinase deficiency (MKD)/hyperimmunoglobulinemia D with periodic fever syndrome (HIDS); the cryopyrin associated periodic syndromes (CAPS) that comprise the clinical continuum of neonatal-onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS); and diseases caused by dysregulation of other IL-1 activating inflammasomes, NLRC4-associated autoinflammatory diseases (NLRC4-AID), NLRP1-associated auto-inflammation with arthritis and dyskeratosis (NAIAD) and NLRP12-Associated Autoinflammatory Disorder (NLRP12AD).
Targeting the inflammasome in rheumatic diseases
2016, Translational Research
Citation Excerpt :
The disease manifests as recurrent fevers, acute abdominal pain, myalgias, and arthritis. Ocular involvement including conjunctivitis and anterior uveitis is seen in roughly half of patients.123-125 IL-1 inhibition is currently the most successful targeted therapy in autoinflammatory disorders, and is used in the treatment of CAPS, colchicine-resistant FMF, TRAPS, HIDS, and DIRA.126
Activation of the inflammasome, a protein complex responsible for many cellular functions, including the activation of the proinflammatory cytokines interleukin (IL)-1β and IL-18, has been identified as a key participant in many rheumatic diseases including autoimmune, inflammatory, and autoinflammatory syndromes. This review will discuss the recent advances in understanding the role of this complex in various rheumatic diseases. Furthermore, it will focus on available therapies, which directly and indirectly target the inflammasome and its downstream cytokines to quiet inflammation and possibly dampen autoimmune processes.
Classic Autoinflammatory Diseases: Monogenic Autoinflammatory Diseases Caused by Defects in CIAS1, MEFV, TNFRSF1A, MVK, and PSTPIP1
2014, Stiehm's Immune Deficiencies
Monogenic autoinflammatory diseases are a group of immune dysregulatory conditions that present with “excessive” inflammation and clinically cause fever, rashes arthritis/arthralgia, serositis, meningitis, and inner ear, eye, bone, and/or gut inflammation. The pattern of organ inflammation in the various conditions often allows a specific diagnosis on clinical grounds. At the onset, autoinflammatory conditions can resemble infections or hematopoietic malignancies, warranting a careful work-up. Effective treatment options for several of these conditions, including colchicine in FMF and anticytokine therapies, and mainly anti IL-1 blocking therapies in other conditions, can halt the progression or development of inflammation-mediated organ damage and thus make an early diagnosis in these conditions imperative. The subsequent five chapters, Chapters 25–29, describe the currently known monogenic autoinflammatory syndromes. This chapter describes the group of cryopyrin associated periodic syndromes (CAPS) that comprise the clinical continuum of neonatal onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS); the three classic hereditary “periodic fever syndromes” of familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), and mevalonate kinase deficiency/hyperimmunoglobulinemia D with periodic fever syndrome or mevalonate kinase deficiency (HIDS/MKD); and the pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome.
Monogenic autoinflammatory diseases: Concept and clinical manifestations
2013, Clinical Immunology
Citation Excerpt :
The rash can be macular, edematous or urticarial [72] but can also be reticular or serpiginous [69]. Half of the patients have ocular manifestations presenting with recurrent conjunctivitis or anterior uveitis [67,72]. Periorbital edema is a feature that may suggest the diagnosis of TRAPS when consistent with the other clinical findings [72].
The objective of this review is to describe the clinical manifestations of the growing spectrum of monogenic autoinflammatory diseases including recently described syndromes. The autoinflammatory diseases can be grouped based on clinical findings: 1. the three classic hereditary “periodic fever syndromes”, familial Mediterranean Fever (FMF); TNF receptor associated periodic syndrome (TRAPS); and mevalonate kinase deficiency/hyperimmunoglobulinemia D and periodic fever syndrome (HIDS); 2. the cryopyrin associated periodic syndromes (CAPS), comprising familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID) or CINCA, and; 3. pediatric granulomatous arthritis (PGA); 4. disorders presenting with skin pustules, including deficiency of interleukin 1 receptor antagonist (DIRA); Majeed syndrome; pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome; deficiency of interleukin 36 receptor antagonist (DITRA); CARD14 mediated psoriasis (CAMPS), and early-onset inflammatory bowel diseases (EO-IBD); 5. inflammatory disorders caused by mutations in proteasome components, the proteasome associated autoinflammatory syndromes (PRAAS) and 6. very rare conditions presenting with autoinflammation and immunodeficiency.
Tumor necrosis factor receptor associated periodic fever syndrome with photographic evidence of various skin disease and unusual phenotypes: Case report and literature review
2012, Seminars in Arthritis and Rheumatism
Citation Excerpt :
In fact, 45% of the patient cohort had abdominal surgery for acute abdominal pain, and 10% later presented with necrotic bowel (16). Intestinal pseudo-obstruction, episodes of acute abdominal pain with sterile purulent peritonitis and recurrent right upper quadrant pain have also been reported (18-20). Recurrent pericarditis has been reported in 4 cases in a study (21) and it can be an atypical presentation of TRAPS (15).
To report a case of tumor necrosis factor receptor associated periodic fever syndrome (TRAPS) with unusual clinical phenotypes and a systematic review.
The relevant English literature of TRAPS was searched using the keywords TRAPS, autoinflammatory disease, and gene mutation. Original and review articles were reviewed and the clinical scenarios were exemplified with a case report.
A 58-year-old Jewish woman with Eastern European Ashkenazic background presented with photographic evidence of various skin disease, including previously unreported vesicles and alopecia, as well as other systemic manifestations. The complaints of urinary foreign bodies prompted a discovery of ureteral strictures with atypia perhaps from autoinflammation. A R92Q gene mutation of TNFRSFA1 was detected. The clinical manifestations of this disease are protean and its pathogenesis is complex, involving the interaction of wild-type and mutated gene products, innate immune system, and proinflammatory cytokines. Glucocorticoid and anticytokine therapy is generally efficacious but some cases remain refractory to the current treatment.
TRAPS is a systemic autoinflammatory disease with variable clinical phenotypes associated with gene mutations. Recognition of the unusual phenotypes may enhance early accurate diagnosis.
What's new in autoinflammatory diseases?
2008, Revue de Medecine Interne
Le terme d’auto-inflammation a initialement été créé pour définir le groupe des maladies génétiques mendéliennes caractérisées par des signes inflammatoires récurrents. Le cœur de ce groupe est constitué par les fièvres récurrentes héréditaires. Ce groupe s’est maintenant élargi à d’autres maladies inflammatoires héréditaires de type mendélien, mais aussi à d’autres maladies dont la composante génétique porte sur le domaine de l’immunité innée.
La mise en évidence que la cryopyrine, produit du gène CIAS1/PYPPAF1/NALP3/NLRP3, dont les mutations sont associées à certains syndromes mendéliens (syndrome de Mückle-Wells et chronic infantile neurological cutaneous and articular (CINCA), urticaire familiale au froid), est un des facteurs majeurs de la régulation de la production de l’interleukine-1 au sein d’un complexe multiprotéique appelé inflammasome. Cette donnée a transformé nos connaissances des mécanismes de l’immunité innée.
La part croissante et la meilleure compréhension des mécanismes liés à l’immunité au sein des maladies inflammatoires invitent à reconsidérer la nosologie de ce vaste groupe en distinguant deux pôles : un pôle où prédominent les mécanismes auto-immuns et un pôle où les mécanismes auto-inflammatoires jouent le plus grand rôle.
The concept of auto-inflammation was initially coined to define the group of mendelian disorders characterized by recurrent inflammatory symptoms. The core of this group mainly consists of hereditary recurrent fevers, which has been lately enlarged to other inflammatory mendelian disorders as well as to some sporadic diseases with a genetic component relevant to innate immunity.
Cryopyrin, the product of the CIAS1/PYPPAF1/NALP3/NLRP gene, whose mutations underline some mendelian syndromes (Mückle-Wells and chronic infantile neurological cutaneous and articular (CINCA), familial cold urticaria) can now be considered as a major factor of the regulation of interleukin-1 production within the multiprotein complex called inflammasome. This discovery has lit up our view of innate immunity.
The contribution of the innate immunity mechanisms in inflammatory disorders have led to a new look to the current nosology of this vast group of diseases and to suggest a classification with two poles. The first would be defined by the predominance of auto-inflammation, whereas in the second one auto-immunity predominates.

View all citing articles on Scopus

¹: S.L.H. and P.L. contributed equally to this study.

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Gastroenterology

Section snippets

Case Report

Discussion

References (27)

Linkage of familial Hibernian fever to chromosome 12p13

Am J Hum Genet

Gene localization for an autosomal dominant familial periodic fever to 12p13

Am J Hum Genet

Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes

Cell

The tumor-necrosis-factor receptor-associated periodic syndromenew mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers

Am J Hum Genet

Autosomal-dominant periodic fever with AA amyloidosisnovel mutation in tumor necrosis factor receptor 1 gene

Kidney Int

Gene localization for an autosomal dominant familial periodic fever to 12p13

Am J Hum Genet

Hereditary periodic fever

N Engl J Med

Clinical and genetic aspects of the hereditary periodic fever syndromes

Rheumatology (Oxford)

Familial Hibernian fever

Q J Med

Infeversan evolving mutation database for auto-inflammatory syndromes

Hum Mutat

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

Shedding of tumor necrosis factor receptors by activated human neutrophils

J Exp Med

Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes

Arthritis Rheum

Cited by (19)

IL-1 mediated autoinflammatory diseases: the “classic” hereditary recurrent fever syndromes and the inflammasomopathies

Targeting the inflammasome in rheumatic diseases

Classic Autoinflammatory Diseases: Monogenic Autoinflammatory Diseases Caused by Defects in CIAS1, MEFV, TNFRSF1A, MVK, and PSTPIP1

Monogenic autoinflammatory diseases: Concept and clinical manifestations

Tumor necrosis factor receptor associated periodic fever syndrome with photographic evidence of various skin disease and unusual phenotypes: Case report and literature review

What's new in autoinflammatory diseases?

Case reportSevere TNF Receptor–Associated Periodic Syndrome Due to 2 TNFRSF1A Mutations Including a New F60V Substitution

Section snippets

Case Report

Discussion

Am J Hum Genet

Am J Hum Genet

Cell

Am J Hum Genet

Kidney Int

Am J Hum Genet

Hereditary periodic fever

N Engl J Med

Clinical and genetic aspects of the hereditary periodic fever syndromes

Rheumatology (Oxford)

Familial Hibernian fever

Q J Med

Infeversan evolving mutation database for auto-inflammatory syndromes

Hum Mutat

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

Shedding of tumor necrosis factor receptors by activated human neutrophils

J Exp Med

Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes

Arthritis Rheum

Case report
Severe TNF Receptor–Associated Periodic Syndrome Due to 2 TNFRSF1A Mutations Including a New F60V Substitution