International periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome cohort: description of distinct phenotypes in 301 patients

Objectives. The aims of this study were to describe the clinical features of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) and identify distinct phenotypes in a large cohort of patients from different countries. Methods. We established a web-based multicentre cohort through an international collaboration within the periodic fevers working party of the Pediatric Rheumatology European Society (PReS). The inclusion criterion was a diagnosis of PFAPA given by an experienced paediatric rheumatologist participating in an international working group on periodic fever syndromes. Results. Of the 301 patients included from the 15 centres, 271 had pharyngitis, 236 cervical adenitis, 171 oral aphthosis and 132 with all three clinical features. A total of 228 patients presented with additional symptoms (131 gastrointestinal symptoms, 86 arthralgias and/or myalgias, 36 skin rashes, 8 neurological symptoms). Thirty-one patients had disease onset after 5 years and they reported more additional symptoms. A positive family history for recurrent fever or recurrent tonsillitis was found in 81 patients (26.9%). Genetic testing for monogenic periodic fever syndromes was performed on 111 patients, who reported fewer occurrences of oral aphthosis or additional symptoms. Twenty-four patients reported symptoms (oral aphthosis and malaise) outside the flares. The CRP was >50 mg/l in the majority (131/190) of the patients tested during the fever. Conclusion. We describe the largest cohort of PFAPA patients presented so far. We confirm that PFAPA may present with varied clinical manifestations and we show the limitations of the commonly used diagnostic criteria. Based on detailed analysis of this cohort, a consensus definition of PFAPA with better-defined criteria should be propose

FMF revisited

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Diagnostic dilemma in autoinflammatory disease in two patients: does the name matter?

The systemic autoinflammatory diseases are inflammatory disorders characterized by uncontrolled inflammation of the innate immune system. A common monogenic autoinflammatory disease is familial Mediterranean fever (FMF), associated with mutations in the MEFV gene. Another autoinflammatory disease group is cryopyrin-associated periodic syndromes (CAPS), which are characterized by urticarial rash and mutations of the gene NLRP. Systemiconset juvenile idiopathic arthritis (soJIA) is classified as a multifactorial autoinflammatory disease. We report two cases of systemic autoinflammatory disease with homozygous E148Q mutation in the FMF gene. They had unusual features, such as urticarial rash, non-erysipeloid erythema, lymphadenopathy, and hepatosplenomegaly, and neurological findings in one. These patients met the "definition" criteria for FMF with two mutations in the MEFV gene. They fit the "description" criteria for CAPS with their fever, urticaria, and other clinical features. They also met the "classification" criteria for soJIA, with the fever, rash, arthritis, and accompanying systemic features

Combined Mutation And Rearrangement Screening by Quantitative PCR High-Resolution Melting: Is It Relevant for Hereditary Recurrent Fever Genes?

The recent identification of genes implicated in hereditary recurrent fevers has allowed their specific diagnosis. So far however, only punctual mutations have been identified and a significant number of patients remain with no genetic confirmation of their disease after routine molecular approaches such as sequencing. The possible involvement of sequence rearrangements in these patients has only been examined in familial Mediterranean fever and was found to be unlikely. To assess the existence of larger genetic alterations in 3 other concerned genes, MVK (Mevalonate kinase), NLRP3 (Nod like receptor family, pyrin domain containing 3) and TNFRSF1A (TNF receptor superfamily 1A), we adapted the qPCR-HRM method to study possible intragenic deletions and duplications. This single-tube approach, combining both qualitative (mutations) and quantitative (rearrangement) screening, has proven effective in Lynch syndrome diagnosis. Using this approach, we studied 113 unselected (prospective group) and 88 selected (retrospective group) patients and identified no intragenic rearrangements in the 3 genes. Only qualitative alterations were found with a sensitivity similar to that obtained using classical molecular techniques for screening punctual mutations. Our results support that deleterious copy number alterations in MVK, NLRP3 and TNFRSF1A are rare or absent from the mutational spectrum of hereditary recurrent fevers, and demonstrate that a routine combined method such as qPCR-HRM provides no further help in genetic diagnosis. However, quantitative approaches such as qPCR or SQF-PCR did prove to be quick and effective and could still be useful after non contributory punctual mutation screening in the presence of clinically evocative signs

Personal non-commercial use only

ABSTRACT. Objective. To put forward a new concept -Blau arteritis, a form of large-vessel vasculitis phenotypically related to Takayasu disease but genetically and clinically part of an expanded phenotype of Blau syndrome. Methods. We provide a clinical description of a new case and summarize previously published cases of arteritis associated with Blau syndrome. Genetic testing was performed by direct sequencing of exon 4 of the NOD2 gene. Results. The case described and those reviewed from the literature demonstrate the emerging phenotype of Takayasu-like arteritis in patients with Blau syndrome. Although most patients described to date depict an otherwise classic Blau syndrome phenotype, the current case was atypical in that the predominant features were arteritic. A novel substitution, G464W, in a highly conserved position near the nucleotide oligomerization domain of the NOD2 protein is also described. Blau syndrome is a monogenic granulomatous disease characterized in its most typical form by a triad of exuberant polyarthritis, uveitis, and granulomatous dermatitis 1 . It is caused by single amino acid substitutions at or near the NACHT domain of NOD2 2 . Although its systemic expression is well recognized after the descriptions of the expanded phenotype of Blau syndrome 3,4 , large-vessel vasculitis remains one of its serious and yet underrecognized manifestations if not actively sought by the treating physician. We describe an 8-year-old girl with symptomatic Takayasu-like arteritis and cardiomyopathy against the background of Blau syndrome with a G464W substitution in NOD2. We reported a similar case in 1989 5 , while others have observed arteritis among children with both sporadic and familial Blau phenotype before the mutation was known MATERIALS AND METHODS A girl, now 11 years old, from rural India, presented to us for the first time at 18 months of age, with bilateral knee effusions of a few months' duration in the absence of rash, uveitis, or systemic features. From the age of 1 month she had had recurrent and unexplained episodes of fever. Her antinuclear antibody result was negative. With a working diagnosis of oligoarticular juvenile arthritis she was administered intraarticular steroids, to which she responded well. She was lost to followup for almost 6 years thereafter. At the age of 8 years, she presented with gradually progressive dyspnea and palpitations of 3 months' duration. She had not thrived, and at this stage she weighed 17.2 kg and her height was 113 cm. There were no systemic features but joint examination showed "boggy synovitis" of the right elbow and knee. Cardiovascular examination showed an irregular pulse with a pulsatile precordium and evidence of congestive heart failure. A rhythm strip on electrocardiography showed ventricular extra beats. The echocardiogram revealed dilated ventricles, generalized hypokinesia with an ejection fraction of 20%, mild tricuspid and aortic regurgitation, and abnormal echogenicity within the wall of the left ventricle. With oligoarticular arthritis in a setting of dilated cardiomyopathy, elevated erythrocyte sedimentation rate, and family history of recurrent unexplained fevers in her mother, a diagnosis of early-onset sarcoidosis was considered. Her eye examination continued to be normal and all biopsies requiring sedation were deferred because of poor cardiac function. Oral methotrexate 10 mg/m 2 and corticosteroids 2 mg/kg were initiated in addition to decongestive treatment consisting of digitalis, diuretics, and captopril. She showed a gradual but steady improvement in effort tolerance, although her ejection fraction on electrocardiography did not mirror her clinical improvement. One and a half years later on a routine followup she was found to be hypertensive. Her carotid pulsations were decreased and a renal bruit was detected. Antihypertensive treatment was instituted and a compute

Personal non-commercial use only

ABSTRACT. Objective. To put forward a new concept -Blau arteritis, a form of large-vessel vasculitis phenotypically related to Takayasu disease but genetically and clinically part of an expanded phenotype of Blau syndrome. Methods. We provide a clinical description of a new case and summarize previously published cases of arteritis associated with Blau syndrome. Genetic testing was performed by direct sequencing of exon 4 of the NOD2 gene. Results. The case described and those reviewed from the literature demonstrate the emerging phenotype of Takayasu-like arteritis in patients with Blau syndrome. Although most patients described to date depict an otherwise classic Blau syndrome phenotype, the current case was atypical in that the predominant features were arteritic. A novel substitution, G464W, in a highly conserved position near the nucleotide oligomerization domain of the NOD2 protein is also described. Blau syndrome is a monogenic granulomatous disease characterized in its most typical form by a triad of exuberant polyarthritis, uveitis, and granulomatous dermatitis 1 . It is caused by single amino acid substitutions at or near the NACHT domain of NOD2 2 . Although its systemic expression is well recognized after the descriptions of the expanded phenotype of Blau syndrome 3,4 , large-vessel vasculitis remains one of its serious and yet underrecognized manifestations if not actively sought by the treating physician. We describe an 8-year-old girl with symptomatic Takayasu-like arteritis and cardiomyopathy against the background of Blau syndrome with a G464W substitution in NOD2. We reported a similar case in 1989 5 , while others have observed arteritis among children with both sporadic and familial Blau phenotype before the mutation was known MATERIALS AND METHODS A girl, now 11 years old, from rural India, presented to us for the first time at 18 months of age, with bilateral knee effusions of a few months' duration in the absence of rash, uveitis, or systemic features. From the age of 1 month she had had recurrent and unexplained episodes of fever. Her antinuclear antibody result was negative. With a working diagnosis of oligoarticular juvenile arthritis she was administered intraarticular steroids, to which she responded well. She was lost to followup for almost 6 years thereafter. At the age of 8 years, she presented with gradually progressive dyspnea and palpitations of 3 months' duration. She had not thrived, and at this stage she weighed 17.2 kg and her height was 113 cm. There were no systemic features but joint examination showed "boggy synovitis" of the right elbow and knee. Cardiovascular examination showed an irregular pulse with a pulsatile precordium and evidence of congestive heart failure. A rhythm strip on electrocardiography showed ventricular extra beats. The echocardiogram revealed dilated ventricles, generalized hypokinesia with an ejection fraction of 20%, mild tricuspid and aortic regurgitation, and abnormal echogenicity within the wall of the left ventricle. With oligoarticular arthritis in a setting of dilated cardiomyopathy, elevated erythrocyte sedimentation rate, and family history of recurrent unexplained fevers in her mother, a diagnosis of early-onset sarcoidosis was considered. Her eye examination continued to be normal and all biopsies requiring sedation were deferred because of poor cardiac function. Oral methotrexate 10 mg/m 2 and corticosteroids 2 mg/kg were initiated in addition to decongestive treatment consisting of digitalis, diuretics, and captopril. She showed a gradual but steady improvement in effort tolerance, although her ejection fraction on electrocardiography did not mirror her clinical improvement. One and a half years later on a routine followup she was found to be hypertensive. Her carotid pulsations were decreased and a renal bruit was detected. Antihypertensive treatment was instituted and a compute

Genetic markers in clinical subtypes of juvenile idiopathic arthritis

Poster presentatationInternational audienc

TNFRSF1A-pR92Q variant identifies a subset of patients more similar to systemic undifferentiated recurrent fever than TNF receptor-associated periodic syndrome

Objectives: To describe the clinical phenotype and response to treatment of autoinflammatory disease (AID) patients with the TNFRSF1A-pR92Q variant compared to patients with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) due to pathogenic mutations in the same gene and patients diagnosed with other recurrent fever syndromes including periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) and syndrome of undefined recurrent fever (SURF). Methods: Clinical data from pR92Q variant associated AID, classical TRAPS, PFAPA and SURF patients were obtained from the Eurofever registry, an international, multicentre registry enabling retrospective collection of data on AID patients. Results: In this study, 361 patients were enrolled, including 77 pR92Q variant, 72 classical TRAPS, 152 PFAPA and 60 SURF patients. pR92Q carriers had an older age of disease onset than classical TRAPS and PFAPA patients. Compared to pR92Q variant patients, classical TRAPS patients had more relatives affected and were more likely to have migratory rash and AA-amyloidosis. Despite several differences in disease characteristics and symptoms between pR92Q variant and PFAPA patients, part of the pR92Q variant patients experienced PFAPA-like symptoms. pR92Q variant and SURF patients showed a comparable clinical phenotype. No major differences were observed in response to treatment between the four patient groups. Steroids were most often prescribed and effective in the majority of patients. Conclusions: Patients with AID carrying the TNFRSF1A-pR92Q variant behave more like SURF patients and differ from patients diagnosed with classical TRAPS and PFAPA in clinical phenotype. Hence, they should no longer be diagnosed as having TRAPS and management should differ accordingly

ISSAID/EMQN Best Practice Guidelines for the Genetic Diagnosis of Monogenic Autoinflammatory Diseases in the Next-Generation Sequencing Era

Abstract Background Monogenic autoinflammatory diseases are caused by pathogenic variants in genes that regulate innate immune responses, and are characterized by sterile systemic inflammatory episodes. Since symptoms can overlap within this rapidly expanding disease category, accurate genetic diagnosis is of the utmost importance to initiate early inflammation-targeted treatment and prevent clinically significant or life-threatening complications. Initial recommendations for the genetic diagnosis of autoinflammatory diseases were limited to a gene-by-gene diagnosis strategy based on the Sanger method, and restricted to the 4 prototypic recurrent fevers (MEFV, MVK, TNFRSF1A, and NLRP3 genes). The development of best practices guidelines integrating critical recent discoveries has become essential. Methods The preparatory steps included 2 online surveys and pathogenicity annotation of newly recommended genes. The current guidelines were drafted by European Molecular Genetics Quality Network members, then discussed by a panel of experts of the International Society for Systemic Autoinflammatory Diseases during a consensus meeting. Results In these guidelines, we combine the diagnostic strength of next-generation sequencing and recommendations to 4 more recently identified genes (ADA2, NOD2, PSTPIP1, and TNFAIP3), nonclassical pathogenic genetic alterations, and atypical phenotypes. We present a referral-based decision tree for test scope and method (Sanger versus next-generation sequencing) and recommend on complementary explorations for mosaicism, copy-number variants, and gene dose. A genotype table based on the 5-category variant pathogenicity classification provides the clinical significance of prototypic genotypes per gene and disease. Conclusions These guidelines will orient and assist geneticists and health practitioners in providing up-to-date and appropriate diagnosis to their patients

Classification criteria for autoinflammatory recurrent fevers.

BACKGROUND: Different 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 syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA. METHODS: Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients\u27 diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria. RESULTS: The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98). CONCLUSION: Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity