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

Juvenile neuropsychiatric systemic lupus erythematosus: identification of novel central neuroinflammation biomarkers

International audienceIntroduction Juvenile systemic lupus erythematosus (j-SLE) is a rare chronic autoimmune disease affecting multiple organs. Ranging from minor features, such as headache or mild cognitive impairment, to serious and life-threatening presentations, j-neuropsychiatric SLE (j-NPSLE) is a therapeutic challenge. Thus, the diagnosis of NPSLE remains difficult, especially in pediatrics, with no specific biomarker of the disease yet validated. Objectives To identify central nervous system (CNS) disease biomarkers of j-NPSLE. Methods A 5-year retrospective tertiary reference monocentric j-SLE study. A combination of standardized diagnostic criteria and multidisciplinary pediatric clinical expertise was combined to attribute NP involvement in the context of j-SLE. Neopterin and interferon-alpha (IFN-α) protein levels in cerebrospinal fluid (CSF) were assessed, together with routine biological and radiological investigations. Results Among 51 patients with j-SLE included, 39% presented with j-NPSLE. J-NPSLE was diagnosed at onset of j-SLE in 65% of patients. No specific routine biological or radiological marker of j-NPSLE was identified. However, CSF neopterin levels were significantly higher in active j-NPSLE with CNS involvement than in j-SLE alone ( p = 0.0008). Neopterin and IFN-α protein levels in CSF were significantly higher at diagnosis of j-NPSLE with CNS involvement than after resolution of NP features (respectively p = 0.0015 and p = 0.0010) upon immunosuppressive treatment in all patients tested ( n = 10). Both biomarkers correlated strongly with each other ( R s = 0.832, p < 0.0001, n = 23 paired samples). Conclusion CSF IFN-α and neopterin constitute promising biomarkers useful in the diagnosis and monitoring of activity in j-NPSLE

TNF-Receptor Associated Periodic Syndrome (TRAPS) (une maladie rare)

PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Enhanced chickenpox exanthema in vaccine injection site

Exacerbation of viral exanthema has been described after different types of aggression. We report a case of enhanced chickenpox exanthema occurring in the vaccination site of an otherwise healthy boy. Specific local inflammatory modifications may explain the increased number of varicella skin lesions on the site of a previous vaccine-induced inflammation

Neurological manifestations in mevalonate kinase deficiency: A systematic review

International audienceIntroduction: Mevalonate kinase deficiency (MKD) is a monogenic auto-inflammatory disease. Its manifestations range from partial MKD to mevalonic aciduria (MVA). All patients display a periodic fever, and MVA patients additionally exhibit severe neurological involvement. The objective of this work was to describe neurological manifestations of MKD. Methods: A systematic literature review was performed from January 1990 to January 2022. Forty-five patients from 18 case reports and five cohort studies were included in the analysis. Results: In cohort studies, the most-reported manifestations were headaches (41%) and fatigue (31%). Serious involvements including ataxia and developmental delay were described less than 1% of patients but 22-31% of case reports. They consistently appeared in the first years of life. Retinal dystrophy was frequently reported (31%) in case reports. Other manifestations, including uveitis, aseptic meningitis, and stroke remained rare. Discussion: Severe neurological manifestations are rare in MKD but are responsible for major functional disabilities. They are present at onset and never appear at follow-up of patients with mild MKD. Conversely, headaches and fatigue are frequent symptoms that should be investigated. Visual examinations should be performed on the appearance of visual symptoms. The efficacy of anti-IL-1β therapy on neurological manifestations should be further investigated

How to favour efficient networking of teams working in the field of rare diseases? Experience of the CeRéMAI reference centre for auto-inflammatory diseases

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MEFV gene analysis in PFAPA

The PFAPA syndrome is a chronic disease of unknown etiology characterized by Periodic episodes of high Fever accompanied by Aphthous stomatitis, Pharyngitis, and cervical Adenitis, sometimes associated with headache and/ or abdominal or joint pain. 1-3 This syndrome belongs to the group of recurrent fever syndromes, which includes systemic onset juvenile rheumatoid arthritis, cyclic neutropenia, and the group of hereditary fevers, ie, familial Mediterranean fever (FMF), hyperimmunoglobinemia D syndrome (HIDS), TNF receptor-1-associated syndromes (TRAPS), Muckle-Wells syndrome (MWS), and familial cold urticaria (FCU). 2 As with other recurrent fevers, the diagnosis of this disease is difficult to establish because: (a) none of the clinical symptoms is pathognomonic of PFAPA; (b) there is no specific biologic abnormality; and (c) the symptomatology may mimic other recurrent fevers. However, regarding the latter point, molecularly-based diagnostic tests are now available for several of the hereditary recurrent fevers: MEFV gene analysis has been proved to provide an objective diagnostic criterion for FMF 4 ; HIDS has been shown to result from mutations in the mevalonate kinase gene 5,6 ; mutations in the gene encoding the tumor necrosis factor receptor-type 1 (TNFRSF1A) have been identified in patients with TRAPS 7 ; more recently, it has been shown that MWS and FCU are both related to mutations in the CIAS1 gene. 8,9 The phenotypic similarities between PFAPA and FMF prompted us to test the involvement of MEFV in PFAPA. Indeed, given the recent demonstration that different hereditary inflammatory disorders may be related to mutations in a single gene, eg, mutations in CIAS1 and NOD2 accounting for MWS or FCU, 8,9 and Crohn's disease or Blau syndrome, 10,11 respectively, one cannot exclude the possibility that, depending on the nature of the molecular defect, the MEFV gene may be involved in clinically related diseases. We have, therefore, searched for MEFV mutations in six unrelated children with PFAPA by means of an exhaustive molecular analysis of all coding sequences and intronic boundaries. 4 All patients met the clinical criteria for FMF defined by Livneh et al. 12 Among the twelve independent alleles studied, only one was found to carry a MEFV gene mutation: the M694V substitution (nucleotide 2080 ATG>GTG), which was identified in a girl of Sephardic Jewish origin, a population in which the frequency of healthy carriers for the M694V substitution reaches one sixth. Therefore, our patient may actually be a simple carrier, a hypothesis further strengthened by the fact that this patient was successfully treated with cimetidine, a drug known to be efficient in several patients with PFAPA. 13 The similar existence of MEFV mutations i

Familial Mediterranean Fever in Heterozygotes: Are We Able to Accurately Diagnose the Disease in Very Young Children?

International audienceObjective: Familial Mediterranean fever (FMF) is an autosomal-recessive autoinflammatory disease due to mutations in MEFV. Descriptions of disease manifestations among patients carrying a single mutated MEFV allele are becoming more frequent, although no data are available on the long-term outcome. We undertook this study to assess the accuracy of clinical diagnosis in children carrying a single mutated MEFV allele with symptoms of recurrent autoinflammatory disorder.Methods: We performed a retrospective single-center study of 33 patients with autoinflammatory disorders age <6 years at disease onset with 1 mutated MEFV allele. The phenotype of the patients was investigated in detail, and the clinical picture and outcome of 18 patients with an initial FMF diagnosis according to current clinical criteria were compared to those of 25 homozygous or compound heterozygous FMF patients.Results: No major differences in presenting signs or initial response to colchicine were observed between patient groups. During followup, heterozygotes had a milder disease course compared to homozygotes and were less prone than homozygotes to experience new clinical signs of FMF. At puberty, clinical signs of FMF completely disappeared in 5 of 18 heterozygotes, allowing them to discontinue colchicine without recurrence of symptoms or increases in inflammatory marker levels.Conclusion: Our data suggest that the clinical diagnosis of FMF in very young heterozygous children should be made with caution. At this young age they can present with an FMF-like disease-similar to that seen in patients carrying 2 mutated alleles-that is not necessarily predictive of life-long illness

The Changing Concepts Regarding the Mediterranean Fever Gene: Toward a Spectrum of Pyrin-Associated Autoinflammatory Diseases with Variable Heredity

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