Whole exome sequencing in childhood-onset lupus frequently detects single gene etiologies.

BACKGROUND: Systemic lupus erythematosus (SLE) comprise a diverse range of clinical manifestations. To date, more than 30 single gene causes of lupus/lupus like syndromes in humans have been identified. In the clinical setting, identifying the underlying molecular diagnosis is challenging due to phenotypic and genetic heterogeneity. METHODS: We employed whole exome sequencing (WES) in patients presenting with childhood-onset lupus with severe and/or atypical presentations to identify cases that are explained by a single-gene (monogenic) cause. RESULTS: From January 2015 to June 2018 15 new cases of childhood-onset SLE were diagnosed in Edmond and Lily Safra Children's Hospital. By WES we identified causative mutations in four subjects in five different genes: C1QC, SLC7A7, MAN2B1, PTEN and STAT1. No molecular diagnoses were established on clinical grounds prior to genetic testing. CONCLUSIONS: We identified a significant fraction of monogenic SLE etiologies using WES and confirm the genetic locus heterogeneity in childhood-onset lupus. These results highlight the importance of establishing a genetic diagnosis for children with severe or atypical lupus by providing accurate and early etiology-based diagnoses and improving subsequent clinical management.

Progressive Pseudorheumatoid Dysplasia resolved by whole exome sequencing: a novel mutation in WISP3 and review of the literature.

BACKGROUND: Progressive pseudorheumatoid dysplasia (PPRD) is a rare autosomal-recessive, non-inflammatory arthropathy, shown to be caused by mutations in the WNT1-inducible signaling pathway protein 3 (WISP3) gene. Although several hundred cases were reported worldwide, the diagnosis remains challenging. Subsequently, the syndrome is often unrecognized and misdiagnosed (for instance, as Juvenile Idiopathic Arthritis), leading to unnecessary procedures and treatments. The objective of the current study was to identify the molecular basis in a family with PPRD and describe their phenotype and course of illness. PATIENTS AND METHODS: We present here a multiply affected consanguineous family of Iraqi-Jewish descent with PPRD. The proband, a 6.5 years old girl, presented with bilateral symmetric bony enlargements of the 1st interphalangeal joints of the hands, without signs of synovitis. Molecular analysis of the family was pursued using Whole Exome Sequencing (WES) and homozygosity mapping. RESULTS: WES analysis brought to the identification of a novel homozygous missense mutation (c.257G > T, p.C86F) in the WISP3 gene. Following this diagnosis, an additional 53 years old affected family member was found to harbor the mutation. Two other individuals in the family were reported to have had similar involvement however both had died of unrelated causes. CONCLUSION: The reported family underscores the importance of recognition of this unique skeletal dysplasia by clinicians, and especially by pediatric rheumatologists and orthopedic surgeons.

High-dose aspirin for Kawasaki disease: outdated myth or effective aid?

OBJECTIVES: To compare the efficacy and safety of intravenous immunoglobulin (IVIG) plus high-dose aspirin (HDA) vs. IVIG plus low-dose aspirin (LDA) for the treatment of Kawasaki disease, with an emphasis on coronary artery outcomes. METHODS: This study was a retrospective, medical record review of paediatric patients with Kawasaki disease comparing 6 centres that routinely used HAD for initial treatment and 2 that used LDA in 2004-2013. Treatment response and adverse events were compared. The primary outcome measure was the occurrence of coronary aneurysm at the subacute or convalescent stage. RESULTS: The cohort included 358 patients, of whom 315 were initially treated with adjunctive HDA and 43 with LDA. There were no demographic differences between the groups. Coronary aneurysms occurred in 10% (20/196) of the HDA group and 4% (1/24) of the LDA group (p=0.34). Equivalence tests indicate it is unlikely that the risk of coronary aneurysm in LDA exceeds HDA by more than 3.5%. There were no significant between-group differences in the need for glucocorticoid pulse therapy or disease recurrence. Coronary ectasia rate and hospitalisation time were significantly greater in the HDA group. Adverse events were similar in the two groups. CONCLUSIONS: We found no significant clinical benefit in using IVIG+HDA in Kawasaki disease compared to IVIG+LDA. The use of adjunctive HDA in this setting should be reconsidered.

Familial Mediterranean fever.

PURPOSE OF REVIEW: Familial Mediterranean fever (FMF) is the oldest and most common of the hereditary autoinflammatory diseases (AIDs). A large body of information has been accumulated over recent years on the pathophysiology, diagnosis and treatment of these diseases. The purpose of this review is to bring an up-to-date summary of the clinic manifestations, diagnostic criteria and treatment of FMF. RECENT FINDINGS: An overview of the pathophysiologic basis of FMF as part of the AID is discussed. Over the last year, attempts to establish new criteria for childhood FMF, new guidelines for treatment and follow-up of disease and novel treatment for FMF were made. A comparison of the different disease severity scores for research purposes suggests that a new score is needed. New evidence for antiinterleukin-1 blockade as a new treatment modality is described. SUMMARY: New diagnostic criteria, disease severity score, treatment and follow-up guidelines have been proposed, and need validation in the next several years.

Behçet's disease and cerebral sinus vein thrombosis in children: a case study and review of the literature.

OBJECTIVES: Central nervous system (CNS) involvement, one of the most severe manifestations of Behçet's disease (BD), is uncommon in children. Because it is rare, the clinical features of this disease in children are not well characterised. Here we describe a teenager with BD which was disclosed following an episode of cerebral sinus vein thrombosis (CSVT) and review the available literature on children with CSVT associated with BD. METHODS: A 12-year-old boy who presented with CSVT is described and the relevant literature, based on a Medline search from 1966 to January 2015 is reviewed. RESULTS: Twenty-three well-documented reports of children with CSVT and BD are described. This manifestation affected mainly males (61%) with a mean age of 12 years (range 4-18). BD was first diagnosed simultaneously or following CSVT in the majority of cases (75%). Multiple sinuses were involved in 30% of the cases. Thrombosis of additional large vessel was identified in 5 of the 23 children. The most common presenting symptom and signs were headache (91%), lasting more than 3 days in most cases (75%), followed by papilledema (43%), seizures (17%), and personality changes (9%). A mixed pattern of CNS involvement including both parenchymal involvement and CSVT, was demonstrated in only two patients (9%). Management of CSVT differed between reports. CONCLUSIONS: CSVT in children is a rarely reported manifestation of BD and has a characteristic clinical picture of a teenage boy presenting with prolonged headache, with no previous diagnosis of BD. A therapeutic approach has not been established yet.

Seasonality of birth of patients with juvenile idiopathic arthritis.

OBJECTIVES: The aim of this study was to determine the seasonality of month of birth (MOB) in children with juvenile idiopathic arthritis (JIA) as compared to the general population. METHODS: Cosinor analysis was used to analyse MOB rhythmicity in 558 children with JIA from a simple rheumatology clinic compared with the MOB pattern of the general population in Israel (n=1.040558). Statistical differences between groups were also analysed by non-parametrical tests. RESULTS: Patients with JIA showed different patterns from that of the general population. A rhythmic pattern of 12 months was found in the MOB patterns of JIA patients. This rhythm with a peak between November to March and a nadir in summer was a mirror image of the rhythmic pattern observed for MOB of the healthy population. Males showed a pattern with combined rhythm of 8 and 6 months with peaks in winter, while females' MOB pattern showed no rhythmicity. Testing different JIA subtypes, only the patients with the enthesitis-related arthritis (ERA) subtype showed rhythmicity in MOB. Rhythmicity patterns were different for males and females, and differed according to several disease characteristics. CONCLUSIONS: The observed pattern of MOB in JIA patients is distinctive and different from that in the healthy population supporting the hypothesis that autoimmune process may begin in utero or in the perinatal period due to seasonal environmental pathogenic agents.

Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy.

BACKGROUND: Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood. METHODS: We carried out exome sequencing in persons from multiply affected families of Georgian Jewish or German ancestry. We performed targeted sequencing in additional family members and in unrelated affected persons, 3 of Georgian Jewish ancestry and 14 of Turkish ancestry. Mutations were assessed by testing their effect on enzymatic activity in serum specimens from patients, analysis of protein structure, expression in mammalian cells, and biophysical analysis of purified protein. RESULTS: In all the families, vasculitis was caused by recessive mutations in CECR1, the gene encoding adenosine deaminase 2 (ADA2). All the Georgian Jewish patients were homozygous for a mutation encoding a Gly47Arg substitution, the German patients were compound heterozygous for Arg169Gln and Pro251Leu mutations, and one Turkish patient was compound heterozygous for Gly47Val and Trp264Ser mutations. In the endogamous Georgian Jewish population, the Gly47Arg carrier frequency was 0.102, which is consistent with the high prevalence of disease. The other mutations either were found in only one family member or patient or were extremely rare. ADA2 activity was significantly reduced in serum specimens from patients. Expression in human embryonic kidney 293T cells revealed low amounts of mutant secreted protein. CONCLUSIONS: Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression. (Funded by the Shaare Zedek Medical Center and others.).

Evidence-based recommendations for the practical management of Familial Mediterranean Fever.

AIM: Familial Mediterranean Fever (FMF) is the most common recurrent autoinflammatory fever syndrome. Still, many issues-e.g.: colchicine dosage adjustment, maximum dosage of colchicine in children and adults, definition of colchicine resistance, alternative treatment solutions in colchicine-resistant patients, and genetic screening for asymptomatic siblings-have not yet been standardized. The current paper aims at summarizing consensus recommendations to approach these issues. METHODS: A literature review concerning these practical management questions was performed through PubMed. On the basis of this analysis, expert recommendations were developed during a consensus meeting of caregivers from France and Israel. RESULTS: A patient experiencing more than four FMF attacks a year needs colchicine dose adjustment. In case of persistent attacks (≥6 per year) in patients with maximum doses of colchicine (2 mg in children; 3 mg in adults), alternative treatment to colchicine with IL1 inhibitors should be considered. Routine genetic testing for MEFV mutations in asymptomatic siblings of an index case is not recommended. CONCLUSION: This is a first attempt to resolve practical questions in the daily management of FMF patients.

Pentraxin 3 is a marker of early joint inflammation in patients with juvenile idiopathic arthritis.

Pentraxin 3 (PTX3) is an acute phase protein produced in different body tissues. The aims of this study were to characterize PTX3 secretion in synovial fluid (SF) of juvenile idiopathic arthritis (JIA) patients and to analyze the correlation of PTX3 levels in SF with clinical characteristics and the course of the disease. SF-PTX3 levels were measured in a cohort of 75 consecutive JIA patients followed in a single center. Patients' clinical characteristics, disease course, and therapies were analyzed for their correlation with SF-PTX3 levels. A synovial cell line was used to study the kinetics of PTX3 secretion by synoviocytes. SF-PTX3 levels varied over a wide range. Elevated SF-PTX3 levels were detected in patients who subsequently required treatment with disease-modifying antirheumatic drugs during the follow-up period. SF-PTX3 levels were found to be inversely correlated with the length of time from onset of joint swelling. No correlation was found between synovial and serum PTX3 or C-reactive protein (CRP). Following in vitro stimulation of synovial cell line with TNFa or IL1, the secretion of PTX3 increases transiently in the first 48-72 h. A similar increase was obtained in patients' synovial fluids but not with IL6. Higher SF-PTX3 levels were found when tested closer to arthritis exacerbation and 48-72 h after in vitro stimulation of cells from a synovial cell line, implying that PTX3 plays a role in early stages of inflammation. Higher SF-PTX3 levels were associated with several clinical features reflecting disease severity and prognostic data. Measuring SF-PTX3 levels may help in providing a more focused and patient-adjusted treatment.

Chronic chilblains: the clinical presentation and disease course in a large paediatric series.

OBJECTIVES: Children often present during winter with painful, red-purple swollen fingers and/or toes, usually misdiagnosed as Raynaud's phenomenon. Pernio, or chronic chilblains, is a localised inflammatory lesion of the skin resulting from an abnormal response to cold. The aim of this study was to better characterise the clinical presentation of chronic chilblains in children. METHODS: This is a single-centre retrospective study of patients referred to our paediatric rheumatology clinic with cold, purple, and painful hands. Patients were identified from the paediatric rheumatology clinic database, at the Safra Children Hospital, Israel. Data of the clinical presentation, physical findings, laboratory investigations and the course of the disease were extracted from the patients' charts and analysed. RESULTS: A total of 33 patients (27 females, sex ratio 4.5:1) were identified. Patients age at presentation was 13.5±2.1, and disease duration was 2.0±1.0 winters. Patients presented with prolonged capillary refill time (100%) and abnormal modified Allen test (75.6%). Fingers swelling was the most common finding (81.8%), followed by proximal interphalangeal joint (PIPs) swelling (63.6%), skin ulceration (54.5%), and dry, irritated skin (45.5%). Nailfold capillary microscopy was normal in all patients. The only abnormal laboratory test was the test for anti-nuclear factor (ANA) in 25%. CONCLUSIONS: We report a large series of children with a unique symptomatology consisting in chronic chilblains.

Colchicine is a safe drug in children with familial Mediterranean fever.

OBJECTIVE: To identify any adverse effects of colchicine in a pediatric patients with familial Mediterranean fever (FMF). STUDY DESIGN: Clinical presentation, Mediterranean fever gene genotype, disease duration, colchicine dose, laboratory tests, and reported adverse effects in children with FMF were analyzed. RESULTS: Of the 153 patients with FMF, 22 (14.4%) developed diarrhea during a follow-up of 4 years; the colchicine dose was reduced to control this symptom in only 4 patients. In 18 (11.8%) patients, a mild transitory increase of transaminases (45-158 IU/L) was found during a follow-up of 1 year. Blood cell counts and kidney function tests were normal in all patients. No correlation was found between the adverse effects and patient's age, disease onset, treatment duration, or any of the clinical characteristics of the disease. CONCLUSION: Colchicine is a safe drug in the treatment of children with FMF, even in infancy. The only significant adverse effects are diarrhea (in a small number of patients), which can be controlled by a decrease in the colchicine dose and transitory elevation of transaminases.

Cellular interactions of synovial fluid γδ T cells in juvenile idiopathic arthritis.

The pathogenesis of juvenile idiopathic arthritis (JIA) is thought to involve multiple components of the cellular immune system, including subsets of γδ T cells. In this study, we conducted experiments to define the functional roles of one of the major synovial fluid (SF) T cell subsets, Vγ9(+)Vδ2(+) (Vγ9(+)) T cells, in JIA. We found that as opposed to CD4(+) T cells, equally high percentages (∼35%) of Vγ9(+) T cells in SF and peripheral blood (PB) produced TNF-α and IFN-γ. Furthermore, stimulation with isopentenyl pyrophosphate (IPP), a metabolite in the mevalonate pathway, which is a specific potent Ag for Vγ9Jγ1.2(+) T cells, similarly amplified cytokine secretion by SF and PB Vγ9(+) T cells. Significantly, the SF subset expressed higher levels of CD69 in situ, suggesting their recent activation. Furthermore, 24-h coculturing with SF-derived fibroblasts enhanced CD69 on the SF > PB Vγ9(+) T cells, a phenomenon strongly augmented by zoledronate, a farnesyl pyrophosphate synthase inhibitor that increases endogenous intracellular IPP. Importantly, although Vγ9(+) T cell proliferation in response to IPP was significantly lower in SF than PBMC cultures, it could be enhanced by depleting SF CD4(+)CD25(+)FOXP3(+) cells (regulatory T cells). Furthermore, coculture with the Vγ9(+) T cells in medium containing zoledronate or IPP strongly increased SF-derived fibroblasts' apoptosis. The findings that IPP-responsive proinflammatory synovial Vγ9(+) T cells for which proliferation is partly controlled by regulatory T cells can recognize and become activated by SF fibroblasts and then induce their apoptosis suggest their crucial role in the pathogenesis and control of synovial inflammation.

NOD2/CARD15 gene mutations in patients with familial Mediterranean fever.

OBJECTIVE: Familial Mediterranean fever (FMF) and Crohn's disease are autoinflammatory disorders, associated with genes (MEFV and NOD2/CARD15, respectively) encoding for regulatory proteins, important in innate immunity, apoptosis, cytokine processing, and inflammation. Although mutations in the MEFV gene were shown to modify Crohn's disease, the role of NOD2/CARD15 gene mutations in the FMF disease phenotype was never studied before. PATIENTS AND METHODS: The cohort consisted of 103 consecutive children with FMF, followed in a single referral center. NOD2/CARD15 genotypes were analyzed in all patients and 299 ethnically matched unaffected controls. Demographic data, clinical characteristics, and disease course of FMF patients with and without NOD2/CARD15 mutation were compared. RESULTS: A single NOD2/CARD15 mutation was detected in 10 (9.7%) FMF patients and 26 (8.7%) controls. No homozygous or compound heterozygous subjects were discovered in the 2 groups. FMF patients carrying a NOD2/CARD15 mutation had a higher rate of erysipelas-like erythema and acute scrotum attacks, a trend for a higher rate of colchicine resistance and a more severe disease as compared with patients without mutations. CONCLUSIONS: NOD2/CARD15 mutations are not associated with an increased susceptibility to develop FMF. Nevertheless, the presence of these mutations in FMF patients appears to be associated with a trend to a more severe disease.

T-cell compartment in synovial fluid of pediatric patients with JIA correlates with disease phenotype.

INTRODUCTION: Juvenile idiopathic arthritis (JIA) is an autoimmune disease where T cells are key players. It can be classified into two main clinical diseases: polyarticular and pauciarticular, based on the number of joints involved. Oligoarthritis, which is considered a pauciarticular subtype since it involves up to four joints upon presentation, is further divided into persistent or extended forms based on disease progression. METHODOLOGY/PRINCIPAL FINDINGS: Here we assessed the T-cell compartment in synovial fluid obtained from 33 JIA patients with active disease and correlated the analyzed parameters with the patients' clinical characteristics. The T-cell compartment was determined by the representation of T-cell receptor (TCR) repertoires and the amount of TCR excision circles (TRECs). RESULTS: Patients with polyarticular disease have more a clonal pattern of their TCR repertoire. These findings were consistent in all tested TCR-Vγ consensus primers. Similarly, patients with polyarticular disease had lower TREC levels than patients with pauciarticular disease. A predictive value of TRECs may be suggested, as lower TREC levels were observed in patients in whom disease modifying anti rheumatic drugs were initiated subsequently during the follow-up. CONCLUSION: In pediatric JIA patients, we showed an alteration in the T cells from synovial fluid, which correlated with disease phenotype, assumedly secondary to enhanced proliferation, clonal TCR restriction, and reduced T-cell production, possibly reflecting a different disease or a different course of disease progression.

Children with oligoarticular juvenile idiopathic arthritis are at considerable risk for growth retardation.

OBJECTIVE: To assess linear growth in patients with persistent oligoarticular juvenile idiopathic arthritis (JIA) treated by intra-articular corticosteroid injections (IACSI). STUDY DESIGN: Data were obtained from a retrospective review of the charts of 95 patients with persistent oligoarticular JIA (69 females). The mean age at first visit was 4.9 ± 3.4 years, with follow-up of 6 ± 3.7 years. The height SDS for chronologic age (z-score) was correlated with the clinical course of the disease and compared among patients treated by IACSI alone (group I) or by a combination of disease-modifying antirheumatic drugs (DMARDs) (group II). RESULTS: Growth retardation was found in 35.8% of patients (Δ z-score <-0.3), including 11.6% with severe growth retardation (Δ z-score <-1.0). Growth retardation was found in a smaller proportion of patients in group I (any growth retardation, 30.6%; severe growth retardation, 6.5%) than in patients in group II (any growth retardation, 44.4%; severe growth retardation, 21.2%; P < .05). Elevated erythrocyte sedimentation rate values (≥ 40 mm/1sth) indicated a significantly higher risk for growth retardation. All other clinical variables had no association with growth retardation. CONCLUSION: A significant proportion of patients with persistent oligoarticular JIA have growth retardation and a minority have severe growth retardation. Only elevated erythrocyte sedimentation rate values were proven to be a good predictor of risk for growth retardation.

GammadeltaT cells in juvenile idiopathic arthritis: higher percentages of synovial Vdelta1+ and Vgamma9+ T cell subsets are associated with milder disease.

OBJECTIVE: To analyze γδT cell subsets in peripheral blood (PB) and synovial fluid (SF) of patients with juvenile idiopathic arthritis (JIA), and to correlate γδT cell subsets with clinical characteristics. METHODS: γδT cell subsets as percentages of CD3+ T cells in samples of PB (n = 25) and SF (n = 93) were analyzed by flow cytometry in 93 JIA patients. The percentage of Vγ9+ γδT cells after 10 days of in vitro expansion with either interleukin 2 (IL-2) or isopentenyl pyrophosphate (IPP) plus IL-2 was determined. RESULTS: Both Vδ1+ and Vγ9+ γδT cell subsets were detected in SF of all patients, but only the percentage of Vδ1+ cells was higher in SF compared to PB (p < 0.01). The distribution of γδT cell subsets was similar in different JIA subgroups, whereas antinuclear antibody (ANA)-positive patients had a higher percentage of SF Vδ1+ T cells than ANA-negative patients (p < 0.01). The percentage of SF Vδ1+ T cells was inversely associated with age at onset, recurrence of synovitis, and erythrocyte sedimentation rate; and that of SF Vγ9+ T cells was inversely correlated with age at onset and was higher in patients who recovered from disease (n = 15). IPP-induced expansion of SF Vγ9+ T cells correlated with disease remission, whereas the expansion of SF Vγ9+ T cells in media with IL-2 alone was significantly greater in patients with uveitis. CONCLUSION: The percentage of Vδ1+ and Vγ9+ γδT cells among the SF T cells and their ability to respond to IPP or IL-2 correlated with specific outcomes of JIA, suggesting their role in the immunopathogenesis of this disease.

The familial Mediterranean fever gene as a modifier of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome.

OBJECTIVE: Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome is a sporadic disease, characterized by periodic attacks of inflammation. Mutations in the MEFV, the gene associated with familial Mediterranean fever (FMF), may lead to subclinical inflammation in asymptomatic carriers and modify the phenotype of some inflammatory diseases. We aimed at investigating the effect of MEFV gene mutations on disease phenotype in PFAPA. PATIENTS AND METHODS: The cohort of this ongoing prospective study consisted of 124 children with PFAPA syndrome, followed in a single referral center, who were tested for MEFV mutations. Demographic data, clinical characteristics, and disease course of 65 PFAPA patients with and 59 without MEFV mutations (M+ and M-, respectively) were compared. RESULTS: PFAPA attacks in carriers of MEFV mutations were shorter compared with patients without mutations (3.8 ± 1.7 versus 4.8 ± 1.9 days, P < 0.01). The difference was more pronounced in those carrying the M694V mutation. In M+ patients, the rates of patients with regularity of their attacks (49.2%) and oral aphthae (24.6%) were lower, compared with M- patients (74.5% and 43.9%, respectively, P < 0.05 for each of the 2 comparisons). M+ patients needed a lower corticosteroid (beclomethasone) dose to abort the attacks (0.16 ± 0.07mg/kg versus 0.19 ± 0.08, P = 0.028). No differences were observed in all other clinical and laboratory parameters, over a follow-up period of 4.3 years. CONCLUSION: In PFAPA, MEFV is a modifier gene associated with an attenuated disease severity.

Role of the R92Q TNFRSF1A mutation in patients with familial Mediterranean fever.

OBJECTIVE: To define the frequency of the R92Q tumor necrosis factor receptor-associated periodic syndrome (TRAPS) mutation in patients with familial Mediterranean fever (FMF) and to study the role of this mutation in FMF. METHODS: Ninety-two FMF patients and 250 controls were genotyped for the R92Q mutation. The frequency of R92Q was assessed among 5 groups of FMF patients. RESULTS: R92Q was found in 6% of the controls, with an especially high carrier rate among Moroccan Jews (8%). R92Q was found in 3 (3.2%) of the 92 FMF patients, 1 homozygous for the MEFV M694V mutation and 2 heterozygous for M694V. All 3 patients showed partial response to colchicine. R92Q was not found in patients unresponsive to colchicine, nor was it found in patients with amyloidosis or in patients with FMF-like disease without MEFV mutations. CONCLUSION: The frequency of the R92Q mutation in FMF patients is comparable with that of controls. Despite the fact that TRAPS and FMF share common biochemical pathways, we found no evidence for an interaction between these two genes.

Familial Mediterranean fever in children presenting with attacks of fever alone.

OBJECTIVE: Familial Mediterranean fever (FMF) is an inherited disease characterized by attacks of febrile polyserositis. In children, attacks of fever alone, or with headache and malaise, may precede other forms of attacks. Our objective was clinical and genetic characterization of FMF and its development in pediatric patients who first presented with attacks of fever alone. METHODS: Clinical characterization and MEFV genotype of all FMF patients < 16 years of age at disease onset and first presenting with attacks of fever alone were analyzed and compared for age, sex, and disease duration with matched FMF patients presenting with serositis at the onset of the disease. RESULTS: There were 814 patients with FMF in our registry. Fifty patients formed the study group and 234 patients the control group. In the study group, the first (febrile) attacks appeared at a younger age than in the control group (1.7 +/- 1.6 yrs vs 5.0 +/- 4.1 yrs, respectively; p < 0.0001), diagnosis was made earlier (4.2 +/- 2.7 yrs vs 6.7 +/- 4.1 yrs; p < 0.0001), despite a trend for a longer delay in diagnosis. In the study group, attacks were shorter (1.6 +/- 0.8 days vs 2.1 +/- 1.0 days; p = 0.023) and homozygosity to the M694V mutation was more prevalent (46% vs 31%; p = 0.03). Attack rate, colchicine dose, and the MEFV mutation carrier rates were comparable between the groups. In 40/50 (80%) of the patients with fever alone, serositis had developed over a course of 2.9 +/- 2.2 years after disease onset. CONCLUSION: FMF in young children may begin with attacks of fever alone, but it progresses to typical FMF disease over the next 2.9 +/- 2.2 years. Our study demonstrates that clinical heterogeneity at presentation is more likely to indicate a feature of a disease in development, rather than to mark distinct phenotypes of FMF.