Tumour Necrosis Factor Receptor-associated Periodic Fever Syndrome Research Articles

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.

Joint impact of key air pollutants on COVID-19 severity: prediction based on toxicogenomic data analysis

Considering that some researchers point to a possible influence of air pollution on COVID-19 transmission, severity, and death rate, the aim of our in silico study was to determine the relationship between the key air pollutants [sulphur dioxide (SO), carbon monoxide (CO), 2particulate matter (PMx), nitrogen dioxide (NO2), and ozone (O3)] and COVID-19 complications using the publicly available toxicogenomic analytical and prediction tools: (i) Comparative Toxicogenomic Database (CTD) to identify genes common to air pollutants and COVID-19 complications; (ii) GeneMANIA to construct a network of these common and related genes; (iii) ToppGene Suite to extract the most important biological processes and molecular pathways; and (iv) DisGeNET to search for the top gene-disease pairs. SO2, CO, PMx, NO2, and O3 interacted with 6, 6, 18, 9, and 12 COVID-19-related genes, respectively. Four of these are common for all pollutants (IL10, IL6, IL1B, and TNF) and participate in most (77.64 %) physical interactions. Further analysis pointed to cytokine binding and cytokine-mediated signalling pathway as the most important molecular function and biological process, respectively. Other molecular functions and biological processes are mostly related to cytokine activity and inflammation, which might be connected to the cytokine storm and resulting COVID-19 complications. The final step singled out the link between the CEBPA gene and acute myelocytic leukaemia and between TNFRSF1A and TNF receptor-associated periodic fever syndrome. This indicates possible complications in COVID-19 patients suffering from these diseases, especially those living in urban areas with poor air quality.

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.

Current Therapeutic Options for the Main Monogenic Autoinflammatory Diseases and PFAPA Syndrome: Evidence-Based Approach and Proposal of a Practical Guide.

Monogenic autoinflammatory diseases are rare conditions caused by genetic abnormalities affecting the innate immunity. Previous therapeutic strategies had been mainly based on results from retrospective studies and physicians' experience. However, during the last years, the significant improvement in their genetic and pathogenic knowledge has been accompanied by a remarkable progress in their management. The relatively recent identification of the inflammasome as the crucial pathogenic mechanism causing an aberrant production of interleukin 1β (IL-1β) in the most frequent monogenic autoinflammatory diseases led to the introduction of anti–IL-1 agents and other biologic drugs as part of the previously limited therapeutic armamentarium available. Advances in the treatment of autoinflammatory diseases have been favored by the use of new biologic agents and the performance of a notable number of randomized clinical trials exploring the efficacy and safety of these agents. Clinical trials have contributed to increase the level of evidence and provided more robust therapeutic recommendations. This review analyzes the treatment of the most frequent monogenic autoinflammatory diseases, namely, familial Mediterranean fever, tumor necrosis factor receptor–associated periodic fever syndrome, hyperimmunoglobulin D syndrome/mevalonate kinase deficiency, and cryopyrin-associated periodic syndromes, together with periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis syndrome, which is the most common polygenic autoinflammatory disease in children, also occurring in adult patients. Finally, based on the available expert consensus recommendations and the highest level of evidence of the published studies, a practical evidence-based guideline for the treatment of these autoinflammatory diseases is proposed.

Tumor necrosis factor receptor–associated periodic syndrome in a pediatric patient: A genetic diagnosis

Periodic fevers are characterized by flares in inflammatory symptoms that punctuate general good health. There are clinical classification criteria in place to aid in the diagnosis of several hereditary recurrent fever syndromes and one nonhereditary syndrome. 1 Gattorno M. Hofer M. Federici S. et al. Eurofever Registry and the Paediatric Rheumatology International Trials Organisation (PRINTO). Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis. 2019; 78: 1025-1032 Crossref PubMed Scopus (182) Google Scholar Differential diagnosis in this case included syndromes such as the following: 1.Familial Mediterranean fever 2.Tumor necrosis factor receptor–associated periodic fever syndrome (TRAPS) 3.Mevalonate kinase deficiency 4.Cryopyrin-associated periodic syndromes 5.Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA)

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.

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.

What's new in autoinflammation?

The pathogenesis of autoinflammatory diseases has shed light on the concept of inflammation in general and on our understanding of the role of the innate immune system. The autoinflammatory diseases have a large spectrum with varying features of inflammation. The most common autoinflammatory diseases are those associated with periodic fevers. The delay in diagnosis of these four common diseases (familial Mediterranean fever, cryopyrin-associated periodic fever syndrome, mevalonate kinase deficiency, and TNF receptor-associated periodic fever syndrome) results in secondary amyloidosis of the kidney. The new work towards classification criteria for these diseases is presented. Recently a group of autoinflammatory diseases that are associated with vasculitis have also been identified. These are stimulators of interferon genes (STING)-associated vasculopathy of infancy (SAVI), which is a monogenic defect associated with excessive activity in interferon alpha and deficiency of adenosine deaminase 2, which is characterized by a polyarteritis nodosa-like picture. These monogenic diseases are now in our differential diagnosis of vasculitides. Secondary amyloidosis is a complication of autoinflammatory diseases. Understanding the inflammatory mechanisms in these diseases has led to the use of targeted biologics for this complication. It is hoped that enlightening the mechanisms underlying these monogenic autoinflammatory diseases will also teach us about the pathways in common diseases.

Inositol-Requiring Enzyme 1-Mediated Downregulation of MicroRNA (miR)-146a and miR-155 in Primary Dermal Fibroblasts across Three TNFRSF1A Mutations Results in Hyperresponsiveness to Lipopolysaccharide.

Tumor necrosis factor (TNF)-receptor-associated periodic fever syndrome (TRAPS) is a rare monogenic autoinflammatory disorder characterized by mutations in the TNFRSF1A gene, causing TNF-receptor 1 (TNFR1) misfolding, increased cellular stress, activation of the unfolded protein response (UPR), and hyperresponsiveness to lipopolysaccharide (LPS). Both microRNA (miR)-146a and miR-155 provide negative feedback for LPS-toll-like receptor 2/4 signaling and cytokine production, through regulation of nuclear factor kappa B (NF-κB). In this study, we hypothesized that proinflammatory cytokine signaling in TRAPS downregulates these two miRs, resulting in LPS-induced hyperresponsiveness in TRAPS dermal fibroblasts (DFs), irrespective of the underlying genetic mutation. Primary DF were isolated from skin biopsies of TRAPS patients and healthy controls (HC). TNFR1 cell surface expression was measured using immunofluorescence. DF were stimulated with LPS, interleukin (IL)-1β, thapsigargin, or TNF, with and without inositol-requiring enzyme 1 (IRE1) inhibitor (4u8C), following which miR-146a and miR-155 expression was measured by RT-qPCR. IL-1β, IL-6, and TNF secretion was measured by enzyme-linked immunosorbent assays, and baseline expression of 384 different miRs was assessed using microfluidics assays. TNFR1 was found to be expressed on the surface of HC DF but expression was deficient in all samples with TRAPS-associated mutations. HC DF showed significant dose-dependent increases in both miR-146a and miR-155 expression levels in response to LPS; however, TRAPS DF failed to upregulate either miR-146a or miR-155 under the same conditions. This lack of miR-146a and miR-155 upregulation was associated with increased proinflammatory cytokine production in TRAPS DF in response to LPS challenge, which was abrogated by 4u8C. Incubation of HC DF with IL-1β led to downregulation of miR-146a and miR-155 expression, which was dependent on IRE1 enzyme. We observed global dysregulation of hundreds of other miRs at baseline in the TRAPS DF. In summary, these data suggest a mechanism whereby IL-1β, produced in response to activation of the UPR in TRAPS DF, downregulates miR-146a and miR-155, by inducing IRE1-dependent cleavage of both these miRs, thereby impairing negative regulation of NF-κB and increasing proinflammatory cytokine production.

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.

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.

Tumor Necrosis Factor Receptor Associated Periodic Fever Syndrome with Photographic Evidence of Various Skin Disease and Unusual Phenotypes: Case Report and Literature Review

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.