Necrosis Factor Receptor-associated Periodic Fever Research Articles

A rare missense p.C125Y mutation in the TNFRSF1A gene identified in a Chinese family with tumor necrosis factor receptor-associated periodic fever syndrome.

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare autosomal dominant disorder with a low incidence in Asia. The most frequent clinical manifestations include fever, rash, myalgia, joint pain and abdominal pain. Misdiagnosis rates are high because of the clinical and genetic variability of the disease. The pathogenesis of TRAPS is complex and yet to be fully defined. Early genetic diagnosis is the key to precise treatment. In this study, a Chinese family with suspected TRAPS were analyzed by genome-wide SNP genotyping, linkage analysis and targeted sequencing for identification of mutations in causative genes. To study the pathogenicity of the identified gene mutation, we performed a conservation analysis of the mutation site and protein structure analysis. Flow cytometry was used to detect TNFRSF1A shedding and quantitative real-time PCR were used to assess the activation of unfolded protein response (UPR) in the mutation carriers and healthy individuals. A typical TRAPS family history, with a pattern of autosomal dominant inheritance, led to the identification of a rare mutation in the TNFRSF1A gene (c.G374A [p.Cys125Tyr]) with unknown significance. The patient responded well to corticosteroids, and long-term therapy with colchicine effectively reduced the inflammatory attacks. No amyloid complications occurred during the 6-year follow-up. In silico protein analysis showed that the mutation site is highly conversed and the mutation prevents the formation of intrachain disulfide bonds in the protein. Despite a normal shedding of the TNFRSF1A protein from stimulated monocytes in the TRAPS patients with p.C125Y mutation, the expression of CHOP and the splicing of XBP1 was significantly higher than healthy controls, suggesting the presence of an activation UPR. This is the first report of a Chinese family with the rare p.C125Y mutation in TNFRSF1A. The p.C125Y mutation does not result in aberrant receptor shedding, but instead is associated with an activated UPR in these TRAPS patients, which may provide new insights into the pathogenesis of this rare mutation in TRAPS.

Periodic Fever in Children: A Report of Three Unusual Cases

Introduction: Periodic fever syndrome (PFS) is a rare monogenic autoinflammatory disease group. The innate immune system abnormalities have a characteristic onset and spontaneous inflammation without any infectious or autoimmune trigger. It differs from autoimmune disorders (e.g., systemic lupus erythematosus (SLE)) occurring due to a defect in the adaptive immune system with auto-antibodies. Case Presentation: The clinical features of three patients presented with a periodic pattern of fever and a different constellation of symptoms were investigated. The final diagnosis of Periodic fever syndrome was reached based on standard diagnostic criteria and genetic testing. All three cases were observed to present with recurrent fever episodes at an interval of 6 - 12 weeks, 3 - 4 weeks, and one month, respectively. The first patient, presenting with a diffuse erythematous plaque-like lesion along the calf with severe calf pain and tenderness with signs of meningeal irritation, was diagnosed with a tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS) like phenotype. The genetic panel was negative in this case. The second patient presenting with recurrent pharyngitis, cervical adenitis, and tonsillitis unresponsive to antibiotics was diagnosed with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. The last patient presenting with recurrent monoarthritis, hepatosplenomegaly, and a positive Mediterranean fever (MEFV) gene mutation was diagnosed with familial Mediterranean fever (FMF). All three patients had normal growth and development. Conclusions: Although periodic fever syndrome was an uncommon entity, it was recommended that this syndrome should be considered when a patient presented with recurring fever episodes with a characteristic constellation of symptoms.

The Fever Mystery: Unraveling Tumor Necrosis Factor Receptor-associated Periodic Fever Syndrome as the Instigator of Secondary Renal Amyloidosis

ABSTRACT Secondary renal amyloidosis is a well-known complication that often follows chronic infections and rheumatological conditions. However, its association with tumor necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS) is considerably less common and remains poorly understood. Here, we present an interesting case report of a patient diagnosed with secondary renal amyloidosis secondary to TRAPS.

Biological disease-modifying antirheumatic drugs in the main monogenic autoinflammatory diseases treatment. Experience of application in rheumatological practice

Objective: to assess the frequency of prescription, efficacy and tolerability of biological disease-modifying antirheumatic drugs (bDMARDs) therapy in patients with major monogenic autoinflammatory diseases (mAID) according to the Federal Rheumatology Center clinical practice. Patients and methods. From 2008 to 2020 years, 158 patients with mAID were included in the study, 53 of whom were prescribed bDMARDs: 12 patients had Familial Mediterranean Fever (FMF); 26 – Cryopyrin-Associated Periodic Syndromes (CAPS), including 21 patients with MuckleWells Syndrome (MWS) and 5 – with Chronic Infantile Onset Neurologic Cutaneous Articular / Neonatal Onset Multisystem Inflammatory Disease (CINCA/NOMID), 12 patients had Tumor necrosis factor (TNF) receptor-Associated Periodic Fever Syndrome (TRAPS) and 3 – Hyper-Immunoglobulinemia D-syndrome (HIDS/MKD). Among all these patients 25 were male and 28 female, aged 1.5 to 44 years, 45 were children (under 18) and 8 adults. Interleukin 1 inhibitors (iIL1) were prescribed in accordance with the following scheme: canakinumab – subcutaneously 2–5 mg/kg or 150 mg per injection, every 4–8 weeks; anakinra – subcutaneously 1–5 mg/kg or 100 mg/day, daily. Etanercept (ETC) was injected subcutaneously 0.4–0.8 mg/kg 1–2 times a week, and adalimumab (ADA) was injected subcutaneously 20–40 mg once every 2 weeks. Tocilizumab (TCZ) was administered intravenously, 8–12 mg/kg once every 2–4 weeks. The duration of the disease at the time of treatment initiation ranged from 1 to 44 years. The duration of bDMARDs therapy in patients with mAID ranged from 1 month to 12 years.Results and discussion. From 158 patients with mAID, in 53 (33.5%) bDMARDs were administered. They were used more often in patients with CAPS (56.6%), and less often – in TRAPS (26.4%), FMF (28.3%) and HIDS/MKD (5.7%). iIL1 were the most frequently prescribed bDMARDs (90.6%): canakinumab (in 38 patients) and anakinra (in 10), they were mainly used in patients with CAPS, in 2/3 of patients with TRAPS, HIDS/MKD and colchicine-resistant FMF. During the first days of iIL1 treatment, all patients with mAID showed a statistically significant clinical improvement: normalization of general condition, emotional recovery, relief of fever, disappearance of rash, decrease in the severity of lymphadenopathy and hepatosplenomegaly, relief or significant positive dynamics of eye symptoms, subjective improvement in hearing and audiogram (with dynamic control in patients with CAPS), decrease in the level of acute phase markers (in all cases). In 7 patients with CAPS, who received anakinra, after a positive response was achieved, switching to canakinumab was performed, which maintained the full effectiveness of therapy. TCZ (in 7 patients) and inhibitors of tumor necrosis factor α (iTNFα) – ADA (in 3) and ETC (in 4), – were used less frequently. iTNFα were more often prescribed to FMF patients with a complete response to treatment. Tolerability of bDMARD therapy was satisfactory in all patients.Conclusion. Currently, iIL1 are the first line of therapy among biological agents for mAID, especially in patients with CAPS. If they are ineffective or intolerant in certain situations, alternative bDMARDs (iTNFα and IL6 inhibitors) can also be used, but this issue needs further study.

Growth Parameters of Turkish Children With an Autoinflammatory Disease Before and After Canakinumab Treatment

To evaluate the effect of canakinumab on growth parameters of patients with autoinflammatory diseases. This retrospective study included Colchicine resistant familial Mediterranean fever (FMF), Mevalonate kinase deficiency (MKD), Tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), Deficiency of adenosine deaminase 2 (DADA2) patients treated with canakinumab for at least six consecutive months. Eleven patients with FMF, 9 with MKD, 3 with TRAPS, and 1 with DADA2 were included. The median age (range) at diagnosis and drug initiation was 6.06 (1.45-16.06) years and 9.72 (1.82-19.11) years, respectively. The mean weight, height, and BMI SD scores significantly increased after canakinumab. There were significant improvements in laboratory parameters and disease activities. However, growth parameters after the drug did not differ according to gender, the duration of diagnostic delay, and age at the diagnosis. Canakinumab seems to have a positive effect on growth in patients with autoinflammatory diseases by controlling disease activity and inflammation.

Otoinflamatuar Periyodik Ateş Sendromları

Otoinflamatuar periyodik ateş sendromları, bulguları çoğunlukla çocukluk çağında başlayan, tekrarlayan ateş ve inflamasyon atakları ile karakterize doğal immün sistem bozukluğu sonucu ortaya çıkan hastalıklar grubudur. Ailevi Akdeniz ateşi (AAA) Türkiye gibi Akdeniz ülkelerinde en sık görülen periyodik ateş sendromudur. Diğer herediter otoinflamatuar periyodik ateş sendromları nadir hastalıklar olarak sınıflandırılmaktadır. Bu derlemede; AAA, tümör nekroz faktör (TNF) reseptörü ilişkili periyodik ateş sendromu (TRAPS), mevalonat kinaz (MVK) eksikliği, kriyopirin ilişkili periyodik ateş sendromu (CAPS) ve periyodik ateş, aftöz stomatit, farenjit ve adenit (PFAPA) sendromunun klinik özellikleri, önerilen sınıflandırma kriterleri ve tedavi seçenekleri değerlendirilmiştir.

Autoinflammatory diseases in childhood, part 1: monogenic syndromes.

Autoinflammatory diseases constitute a family of disorders defined by aberrant stimulation of inflammatory pathways without involving antigen-directed autoimmunity. They may be divided into monogenic and polygenic types. Monogenic autoinflammatory syndromes are those with identified genetic mutations, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency or hyperimmunoglobulin D syndrome, cryopyrin-associated periodic fever syndromes (CAPS), pyogenic arthritis pyoderma gangrenosum and acne (PAPA) syndrome, interleukin-10 and interleukin-10 receptor deficiencies, adenosine deaminase 2 deficiency and pediatric sarcoidosis. Those without an identified genetic mutation are known as polygenic and include systemic-onset juvenile idiopathic arthritis, idiopathic recurrent acute pericarditis, Behçet syndrome, chronic recurrent multifocal osteomyelitis and inflammatory bowel disease among others. Autoinflammatory disorders are defined by repeating episodes or persistent fever, rash, serositis, lymphadenopathy, arthritis and increased acute phase reactants, and thus may mimic infections clinically. Most monogenic autoinflammatory syndromes present in childhood. However, because of their infrequency, diverse and nonspecific presentation, and the relatively new genetic recognition, diagnosis is usually delayed. In this article, which is Part 1 of a two-part series, the authors update monogenic autoinflammatory diseases in children with special emphasis on imaging features that may help establish the correct diagnosis.

Neurological manifestations of autoinflammatory diseases in Chinese adult patients

ObjectiveSystemic autoinflammatory diseases (SAIDs) are a group of disorders characterized by a dysregulation of innate immune system leading to multi-systemic inflammation. We aim to assess the neurological manifestations of Chinese adult patients with SAIDs. MethodsEighty adult patients (≥16 years) were diagnosed as SAIDs from April 2015 to June 2019, at the center of adult autoinflammatory diseases, Department of Rheumatology, Peking Union Medical College Hospital. Clinical and genetic features of these patients were collected. All patients underwent neurologic, ophthalmologic and otolaryngologic evaluation. ResultsTotally 31 out of 80 (38.8%) patients had neurological manifestations, including 14 familial Mediterranean fever (45.2%), 6 NLRP3-associated autoinflammatory disease (19.4%), 5 tumor necrosis factor receptor-associated periodic fever syndrome (16.1%), 5 NLRP12-associated autoinflammatory disease (16.1%), and 1 Yao syndrome (3.2%). Twenty patients (64.5%) were adult-onset. The median time of diagnosis delay was 11.7 years (0.5–50 years). The common neurological damage included headache (28 patients, 90.3%), sensorineural hearing loss (6, 19.4%), dizziness (4, 12.9%), cerebral infarction/hemorrhage (4, 12.9%), chronic aseptic meningitis (3, 9.7%), intracranial hypertension (3, 9.7%), papilledema (3, 9.7%), optic neuritis (2, 6.5%), and hydrocephalus (1, 3.2%). Severe neurological damage was observed in 8 patients (25.8%), including brain atrophy, hydrocephalus, complete hearing loss, chronic aseptic meningitis and optic neuritis. ConclusionNeurological damage was diverse in SAIDs patients. Neurological symptoms should be fully realized by physicians, in not only pediatric but also adult patients with SAIDs. CSF analysis and brain images should be performed promptly. Early diagnosis and appropriate treatment are essential to avoid irreversible neurological complications.

Clinical and genetic features of Chinese adult patients with tumour necrosis factor receptor-associated periodic fever syndrome

TNF receptor-associated periodic fever syndrome (TRAPS) is an autosomal dominant systemic autoinflammatory disease caused by mutations of TNF receptor superfamily member 1 A (TNFRSF1A) gene. TRAPS has hardly been reported in the Chinese population. We aimed to characterize the clinical and genetic features of Chinese adult patients with TRAPS. Nine adult patients (≥16 years) were diagnosed during April 2015 to June 2019, at the Department of Rheumatology, Peking Union Medical College Hospital. Clinical and genetic features of these patients were evaluated and compared with those from Japan and Europe. The median age of disease onset was 3 (0.5-38.5) years old, and adult-onset was observed in two (22.2%) patients. The median time of diagnosis delay was 16.5 (1.5-50.5) years. One patient had a family history of TRAPS. The frequent symptoms were fever (nine, 100%), rash (seven, 77.8%), arthralgia/arthritis (five, 55.6%) and abdominal pain (five, 55.6%). Only two (22.2%) patients had periorbital oedema. Nine TNFRSF1A gene variants were detected, including C58R, G65E, F89L, C99G, V202G, V202D, c.769-23T>C, S290I and c.*64T>C. Rash was more frequently seen in Chinese than in Japanese and European patients, while chest pain and amyloidosis occurred less frequently. This is the first and largest case series of TRAPS in Chinese adult patients. Two novel TNFRSF1A variants, S290I and V202G, have been identified. The different clinical manifestations of our patients compared with those from Japan and Europe might be related to their TNFRSF1A variants.

Classification criteria for autoinflammatory recurrent fevers

BackgroundDifferent diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)—familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic...

Phenotypes and genotypes of Chinese adult patients with systemic autoinflammatory diseases

ObjectiveWe aimed to characterize the phenotypes and genotypes of Chinese adult patients with systemic autoinflammatory diseases (SAIDs). MethodsWe prospectively evaluated clinical and genetic features of 92 adult patients (≥16 years) suspected of SAIDs in the period from April 2015 to October 2017, at the adult SAIDs center, Peking Union Medical College Hospital. The definite diagnosis of each disease was deemed to be present if both clinical phenotypes and genetic confirmation were met. Clinical manifestations of these patients were compared with those from the pediatric populations and patients from other countries. ResultsA final diagnosis of SAIDs was reached in 50 patients, including 13 familial Mediterranean fever (FMF), 10 NLRP12-associated autoinflammtory disease (NLRP12-AID), 7 NLRP3-associated autoinflammatory disease (NLRP3-AID), 5 tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), 3 Blau syndrome, 3 Yao syndrome (YAOS) and 9 periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA). First disease onset during adulthood was observed in 30 patients, and the final diagnosis was delayed with a median time of 9 years. Adult monogenic SAIDs patients usually carried low-penetrance mutations and all gene variants were presented as heterozygosis or compound heterozygosis. Frequencies of clinical manifestations in Chinese adult SAIDs patients were similar with adult patients in other countries, but different from pediatric populations. ConclusionsFMF, NLRP3-AID, and NLRP12-AID are relatively common monogenic SAIDs in Chinese adults. Adult-onset SAIDs may be related to the presence of low-penetrance mutations, characterized by nonspecific, incomplete or atypical disease patterns compared with child-onset SAIDs, leading to a delay of diagnosis.

TNFRSF1A gene variant identified in a boy with recurrent episodes of fever

Introduction. Fever of unknown origin is an important diagnostic challenge. Although rare, periodic fever syndromes may often present with a chronic or recurrent febrile condition with a variable temporal pattern of occurrence. Although clinical characteristics often indicate the syndrome in question, there are many atypical forms, and the genotype?phenotype relationship is highly complex, warranting in many cases the designation of a ?syndrome spectrum? rather than a syndrome per se. The aim of this paper was to present a boy with recurrent fever of unknown origin. Case outline. We hereby present a boy with recurrent fever of unknown origin who was by clinically guided partial exome sequencing found to have a heterozygous variant 434A>G in the TNFRSF1A gene, otherwise connected with tumor necrosis factor receptor-associated periodic fever syndrome. The patient responded well to short courses of glucocorticoids and is no longer subjected to unnecessary antibiotic treatment he had frequently received in the past. Conclusion. Periodic fever syndromes should be kept in mind as a differential diagnostic possibility in children with fever of unknown origin.

Vasculitis and vasculitis-like manifestations in monogenic autoinflammatory syndromes.

Monogenic autoinflammatory syndromes are a rare group of disorders characterized by periodic episodes of systemic inflammation of endogenous origin. Sometimes, these diseases may present with features akin to vasculitis. We conducted a literature review on such vasculitic manifestations in described monogenic autoinflammatory syndromes utilizing the Online Mendelian Inheritance in Man (OMIM), Medline, and Scopus databases. Our search identified that Familial Mediterranean fever (FMF) can manifest with features of either small, medium, large, or variable-vessel vasculitis. Stimulator of interferon gene (STING)-associated vasculopathy of infancy (SAVI) is an interferonopathy that can mimic the presentation of medium-vessel or small-vessel vasculitis, whereas deficiency of adenosine deaminase 2 (DADA2) is another such mimic of medium-vessel vasculitis, associated in a significant number of patients with features of immunodeficiency. Occasional reports exist of vasculitic manifestations in tumor necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS) and chronic infantile neurologic cutaneous and articular disorder (CINCA), whereas mevalonate kinase deficiency can also mimic the presentation of small- or medium-vessel vasculitis. Clinicians should be aware of the possibility of autoinflammatory disease presenting as vasculitis to diagnose and treat the same appropriately.

Autoinflammatory Diseases with Periodic Fevers.

One purpose of this review was to raise awareness for the new autoinflammatory syndromes. These diseases are increasingly recognized and are in the differential diagnosis of many disease states. We also aimed to review the latest recommendations for the diagnosis, management, and treatment of these patients. Familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), and hyperimmunoglobulinemia D and periodic fever syndrome/mevalonate kinase deficiency (HIDS/MVKD) are the more common autoinflammatory diseases that are characterized by periodic fevers and attacks of inflammation. Recently much collaborative work has been done to understand the characteristics of these patients and to develop recommendations to guide the physicians in the care of these patients. These recent recommendations will be summarized for all four diseases. FMF is the most common periodic fever disease. We need to further understand the pathogenesis and the role of single mutations in the disease. Recently, the management and treatment of the disease have been nicely reviewed. CAPS is another interesting disease associated with severe complications. Anti-interleukin-1 (anti-IL-1) treatment provides cure for these patients. TRAPS is characterized by the longest delay in diagnosis; thus, both pediatricians and internists should be aware of the characteristic features and the follow-up of these patients. HIDS/MVKD is another autoinflammatory diseases characterized with fever attacks. The spectrum of disease manifestation is rather large in this disease, and we need further research on biomarkers for the optimal management of these patients.

Development of the autoinflammatory disease damage index (ADDI)

ObjectivesAutoinflammatory diseases cause systemic inflammation that can result in damage to multiple organs. A validated instrument is essential to quantify damage in individual patients and to compare disease outcomes in...

Living with Tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS)

TRAPS is a genetic disorder characterised by recurrent attacks of fever, abdominal and muscle pain and rash, most common in patients of northern European origin.1 Very little is known about the patient experience with TRAPS.

Abnormal Motility Associated With Tumor Necrosis Factor Receptor-Associated Periodic Fever Syndrome

Introduction: Tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS) is a rare autosomal dominant condition with mutations in the TNFRSF1A gene encoding for the tumor necrosis factor receptor 1 (TNFR1) and is commonly associated with gastroenterological related symptoms. An NIH cohort of 53 patients with TRAPS reported that 92% of patients with TRAPS present with abdominal pain. The pathophysiology of TRAPS may be a defective shedding of the mutant TNFR1 receptor. Lack of shedding of this receptor leads to decreased neutralization of serum TNF and to increased proinflammatory signaling. The motility profile of patients with this syndrome has not been delineated. We present a 62-year-old female with a history of acute gastroenteritis 5 years prior to presentation, marking the beginning of persistent GI symptoms including postprandial abdominal pain, constipation, myalgias, nausea, progressive weight loss and fever of unknown origin diagnosed with TRAPS. GI evaluation including colonoscopy showed microscopic colitis and EGD was otherwise negative. Other motility evaluation done such as breath testing showed small bowel overgrowth. Gastric emptying study supported a diagnosis of gastroparesis. As her GI symptoms progressed, a 6-hour antroduodenal manometry was performed showing a disorganized motility pattern in the interdigestive (fasting) state consistent with a visceral neuropathy. Despite treatment with several prokinetics and antibiotics for overgrowth and pseudoobstruction, the patient continued to deteriorate and required TPN for nutritional support. She later developed neurologic symoptoms including tremors and was referred to neurology team for further evaluation. After evaluations for familial mediterranean fever and other neurologic causes of her dysmotility were ruled out, she was worked up for hereditary fever syndrome which prompted genomic studies revealing the patient had a R121Q variant in the TNFRSF1A gene. This variant is also referred to R92Q which is the accurate location in the mature, processed protein. She was then started on immunosupressives. To our knowledge this is the first case that describes a motility disorder in a patient with TRAPS. Our patient’s complicated medical course sheds light into some of the GI symptoms associated with TRAPS and the importance of early diagnosis in these patients before the onset of profound malnutrition.

FRI0545 Treatment with anti IL-1 and Infectious Complications in Paediatric Patients with Systemic Juvenile Idiophatic Arthritis and Autoinflammatoy Diseases

BackgroundPaediatric patients with rheumatic diseases have a higher risk of infections. The treatment with anti-IL 1 drugs (anakinra/canakinumab) can increase the occurrence of infectious diseasesObjectivesThe aim of this study is...

Mutations in the TNFRSF1A, CEBPE and ELANE genes in a Congenital Cyclic Neutropenia Patient: A New Syndrome?

Abstract 11Cyclic neutropenia (CyN) is a hematologic disorder in which blood cell counts particularly granulocytic neutrophil numbers show cycles at 21 day intervals. The majority of CyN patients (ca 90 %) harbor inherited mutations in the ELANE gene. Intriguingly, same ELANE mutations are present in two different hematologic syndromes: congenital as well as in cyclic neutropenias. It is unclear how mutation in the same gene cause congenital or cyclic neutropenia. We aimed to identify genes which are exclusively mutated in cyclic or in congenital neutropenia additionaly to the ELANE gene mutations. Recently, we found in congenital neutropenia patients additional to ELANE mutations inherited mutations in for example the G6PC3 gene or the HAX1 gene (Germeshausen, M., et al, Haematologica 2010). This suggests cooperating effects of different defective intracellular signaling pathways and excludes that mutated ELANE alone is responsible for the pathogenesis of congenital or cyclic neutropenia.To identify gene mutations causing cyclic neutropenia in association with ELANE mutation, we performed whole genome sequencing using Complete Genomics technology (Complete Genomics. Inc, Mountain View, CA.) of a family with an affected CyN patient. The CyN patient harbors sporadic heterozygous ELANE mutation (c.761C>G p.W241L) and her family consists of a healthy brother and healthy parents. We identified a novel heterozygous point mutation in the tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A) gene (c.664C>T; p.R121Q) in the affected patient and her mother. This mutation was confirmed by Sanger sequencing. The TNFRSF1A gene encodes p55 subunit of the TNFa receptor (TNFR1) and intriguingly this gene is known to be frequently mutated in patients with Tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), a disease clinically similar to cyclic neutropenia. TRAPS is an autosomal dominant disorder characterized by episodes of fever, inflammation and periodical changes in the neutrophil counts. Functional studies in patients with TRAPS described heterogenous effects of different TNFRSF1A mutations on the surface expression and PMA-induced clevage of TNFR1 on the neutrophilic granulocytes and monocytes. In our CyN patient we measured elevated mRNA levels of TNFR1 on neutrophils, in comparison to her healthy family members and unrelated healthy individuals. However, we detected diminished surface expression of the TNFR1 protein, but elevated PMA-induced receptor shedding in the affected CyN patient, in comparison to healthy individuals, as assessed by estimation of soluble TNFR1 in supernatants of PMA-stimulated neutrophils.We also identified in the same patient and her father a second novel heterozygous point mutation in the CEBPE gene (c.636C>A; p.L155M), which was also confirmed by Sanger sequencing. This C>A substitution changes CTG to ATG creating a new start site for translation of a novel isoform of C/EBPε protein. C/EBPε is a myeloid-specific transcription factor playing an important role in granulopoiesis. Mutations in the CEBPE gene have been described in patients with neutrophil-specific granule deficiency (SGD).In summary, we identified additional to the ELANE mutation two novel mutations in a CyN patient, one in the TNFRSF1A gene inherited from the mother, another in the CEBPE gene inherited from the father. Mutations in both genes are already described in patients with TRAPS (periodic fever syndrome) and granulocyte abnormalities, respectively. These mutations in association with the ELANE gene mutation may contribute to the pathogenesis of cyclic neutropenia in this patient. Whether the combination of these three mutations might be responsible for a subgroup of CyN patients remains to be investigated. Disclosures:No relevant conflicts of interest to declare.

Autoinflammatory syndromes and cellular responses to stress: pathophysiology, diagnosis and new treatment perspectives

The term 'autoinflammatory disease' was first proposed in 1999 to encompass some of the distinct clinicopathologic features of a group of monogenic conditions, characterised by recurrent episodes of inflammation, without high-titre autoantibodies or antigen-specific T cells. It was subsequently observed that several of these conditions were caused by mutations in proteins involved in the innate immune response, including, among others, components of the NLRP3 inflammasome, cytokine receptors (tumour necrosis factor receptor 1 (TNFR1)) and receptor antagonists (interleukin 1 receptor antagonist (IL-1RA)). More recently, additional mechanisms linking innate immune-mediated inflammation with a variety of cellular processes, including protein misfolding, oxidative stress and mitochondrial dysfunction, have been recognised to play a role in the pathogenesis of some monogenic autoinflammatory conditions, and also in more common diseases such as type 2 diabetes (T2D), previously perceived as a metabolic disorder, but reclassified as a chronic inflammatory condition. NLRP3 inflammasome activation is induced by islet amyloid polypeptides (IAPPs) in T2D and this condition may, in future, be more commonly treated with targeted anti-cytokine therapies. Caspase 1 activation and release of IL-1β/IL-1 family members is central to the pathogenesis of many autoinflammatory syndromes, as evidenced by the effectiveness of anti-IL-1 biologics in treating these disorders. However, many patients continue to experience symptoms of chronic inflammation, and it will be necessary to translate discoveries on the immunopathology of these conditions into more effective therapies. For example, in tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), the pathogenesis may vary with each mutation and therefore future approaches to treatment of individual patients will require a more tailored approach based on genetic and functional studies.