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OBJECTIVE: To define the molecular basis of familial Mediterranean fever (FMF) in patients with only 1 mutation in the MEFV gene. METHODS: Genetic analysis was performed in 20 FMF patients, including full sequencing of complementary DNA (cDNA) samples and multiplex ligation-dependent probe amplification analysis. In patients with first-degree relatives with FMF, haplotype analysis was also performed. RESULTS: A second mutation was found in 2 patients. In the other 18 patients, we could not identify additional mutations, large genomic deletions, or duplications. Analysis of single-nucleotide polymorphisms along the cDNA ruled out a lack of expression of 1 of the alleles. In 2 of the 3 families in which more than 1 sibling had FMF, we showed that the affected siblings inherited a different MEFV allele from the parent who did not have the MEFV mutation. CONCLUSION: These findings are highly consistent with the existence of a clinical phenotype among some patients who are heterozygous for FMF and could explain the vertical transmission in some families. A single mutation in the MEFV gene may be much more common than was previously thought and may include up to 25% of patients who are diagnosed as having FMF. [ABSTRACT FROM AUTHOR]

Aim: To examine the clinical significance of thrombocytosis (platelets > 500 × 10 9 /L) in admitted children with an influenza-like illness., Methods: We performed a database analysis consisting of patients evaluated at our medical centers with an influenza-like illness between 2009 and 2013. We included paediatric patients and examined the association between platelet count, respiratory viral infections, and admission outcomes (hospital length of stay and admission to the paediatric intensive care unit) using regression models adjusting for multiple variables., Results: A total of 5171 children were included in the study cohort (median age 0.8 years; interquartile range, 0.2-1.8; 58% male). Younger age, and not the type of viral infection, was associated with a high platelet count (p < 0.001). Elevated platelet count independently predicted admission outcomes (p ≤ 0.05). The presence of thrombocytosis was associated with an increased risk for a prolonged length of stay (odds ratio = 1.2; 95% Confidence interval = 1.1 to 1.4; p = 0.003) and admission to the paediatric intensive care unit (odds ratio = 1.5; 95% Confidence interval = 1.1 to 2.0; p = 0.002)., Conclusion: In children admitted with an influenza-like illness, a high platelet count is an independent predictor of admission outcomes. Platelet count may be used to improve risk assessment and management decisions in these paediatric patients., (© 2023 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Objectives: To identify predictors of a severe clinical course of multisystem inflammatory syndrome in children (MIS-C), as defined by the need for inotropic support., Methods: This retrospective study included patients diagnosed with MIS-C (according to the CDC definition) in nine Israeli and one US medical centre between July 2020 and March 2021. Univariate and multivariate regression models assessed odds ratio (OR) of demographic, clinical, laboratory and imaging variables during admission and hospitalization for severe disease., Results: Of 100 patients, 61 (61%) were male; mean age 9.65 (4.48) years. Sixty-five patients were hypotensive, 44 required inotropic support. Eleven patients with MIS-C fulfilled Kawasaki disease diagnostic criteria; 87 had gastrointestinal symptoms on admission. Echocardiographic evaluation showed 10 patients with acute coronary ectasia or aneurysm, and 37 with left ventricular dysfunction. In a univariate model, left ventricular dysfunction was associated with severe disease [OR 4.178 (95% CI 1.760, 9.917)], while conjunctivitis [OR 0.403 (95% CI 0.173, 0.938)] and mucosal changes [OR 0.333 (95% CI 0.119, 0.931)] at admission were protective. Laboratory markers for a severe disease course were low values of haemoglobin, platelets, albumin and potassium; and high leukocytes, neutrophils, troponin and brain natriuretic peptide. In multivariate analysis, central nervous system involvement and fever >39.5°C were associated with severe disease. Mucosal involvement showed 6.2-fold lower risk for severe disease. Low haemoglobin and platelet count, and elevated C-reactive protein and troponin levels were identified as risk factors for severe disease., Conclusion: Key clinical and laboratory parameters of MIS-C were identified as risk factors for severe disease, predominantly during the disease course and not at the time of admission; and may prompt close monitoring, and earlier, more aggressive treatment decisions. Patients presenting with a Kawasaki-like phenotype were less likely to require inotropic support., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Importance: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency affecting both children and adults. DADA2 is among the more common monogenic autoinflammatory diseases, with an estimate of more than 35 000 cases worldwide, but currently, there are no guidelines for diagnostic evaluation or management., Objective: To review the available evidence and develop multidisciplinary consensus statements for the evaluation and management of DADA2., Evidence Review: The DADA2 Consensus Committee developed research questions based on data collected from the International Meetings on DADA2 organized by the DADA2 Foundation in 2016, 2018, and 2020. A comprehensive literature review was performed for articles published prior to 2022. Thirty-two consensus statements were generated using a modified Delphi process, and evidence was graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence., Findings: The DADA2 Consensus Committee, comprising 3 patient representatives and 35 international experts from 18 countries, developed consensus statements for (1) diagnostic testing, (2) screening, (3) clinical and laboratory evaluation, and (4) management of DADA2 based on disease phenotype. Additional consensus statements related to the evaluation and treatment of individuals with DADA2 who are presymptomatic and carriers were generated. Areas with insufficient evidence were identified, and questions for future research were outlined., Conclusions and Relevance: DADA2 is a potentially fatal disease that requires early diagnosis and treatment. By summarizing key evidence and expert opinions, these consensus statements provide a framework to facilitate diagnostic evaluation and management of DADA2.

Aim: The major clinical manifestations multisystem inflammatory syndrome in children (MIS-C) are fever, gastrointestinal and cardiac. The aim of this study was to describe MIS-C in a series of patients who presented primarily with cervical manifestations., Methods: We retrospectively reviewed medical records of all patients who met the Centers for Disease Control and Prevention and World Health Organization MIS-C diagnostic criteria treated at Hadassah-Hebrew University Medical Center between April 2020 and September 2021., Results: Of 37 children diagnosed with MIS-C (median age: 10.2 years, range 1.5-18 years, 20 male) five, 13.5% (median age: 14.4 years, range 9.2-17.5 years) presented with cervical symptoms mimicking neck infections. One was hospitalised with a working diagnosis of retropharyngeal abscess, and four with acute cervical lymphadenitis that did not respond to early antibiotic treatment. All developed full MIS-C phenotype., Conclusion: MIS-C may present as cervical inflammation. An ill-appearing child with symptoms and/or signs of cervical inflammation should be evaluated for clinical and laboratory features of MIS-C, thereby facilitating prompt treatment of this potentially fatal disorder., (© 2022 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Introduction: Since the development of COVID-19 vaccines, more than 4.8 billion people have been immunized worldwide. Soon after vaccinations were initiated, reports on cases of myocarditis following the second vaccine dose emerged. This study aimed to report our experience with adolescent and young adults who developed post-COVID-19 vaccine myocarditis and to compare these patients to a cohort of patients who acquired pediatric inflammatory multisystem syndrome (PIMS/PIMS-TS) post-COVID-19 infection., Methods: We collected reported cases of patients who developed myocarditis following COVID-19 vaccination (Pfizer mRNA BNT162b2) from all pediatric rheumatology centers in Israel and compared them to a cohort of patients with PIMS., Results: Nine patients with post-vaccination myocarditis were identified and compared to 78 patients diagnosed with PIMS. All patients with post-vaccination myocarditis were males who developed symptoms following their second dose of the vaccine. Patients with post-vaccination myocarditis had a shorter duration of stay in the hospital (mean 4.4 ± 1.9 vs. 8.7 ± 4.7 days) and less myocardial dysfunction (11.1% vs. 61.5%), and all had excellent outcomes as compared to the chronic changes among 9.2% of the patients with PIMS., Conclusion: The clinical course of vaccine-associated myocarditis appears favorable, with resolution of the symptoms in all the patients in our cohort.

In the last few months the world has witnessed a global pandemic due to severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection causing coronavirus disease 2019 (COVID-19). Obviously, this pandemic affected individuals differently, with a significant impact on populations considered to be at high-risk. One such population, was assumed to be patients with primary genetic defect involving components or pathways of the immune system. While human immunity against COVID-19 is not fully understood, it is, so far, well documented, that both adaptive and innate cells have a critical role in protection against SARS-CoV-2. Here, we aimed to summarize the clinical and laboratory data on primary immunodeficiency (PID) patients in Israel, who were tested positive for SARS-CoV-2, in order to estimate the impact of COVID-19 on such patients. Data was collected from mid-February to end-September. During this time Israel experienced two "waves" of COVID-19 diseases; the first, from mid-February to mid-May and the second from mid-June and still ongoing at the end of data collection. A total of 20 PID patients, aged 4 months to 60 years, were tested positive for SARS-CoV-2, all but one, were detected during the second wave. Fourteen of the patients were on routine monthly IVIG replacement therapy at the time of virus detection. None of the patients displayed severe illness and none required hospitalization; moreover, 7/20 patients were completely asymptomatic. Possible explanations for the minimal clinical impact of COVID-19 pandemic observed in our PID patients include high level of awareness, extra-precautions, and even self-isolation. It is also possible that only specific immune pathways (e.g. type I interferon signaling), may increase the risk for a more severe course of disease and these are not affected in many of the PID patients. In some cases, lack of an immune response actually may be a protective measure against the development of COVID-19 sequelae., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Marcus, Frizinsky, Hagin, Ovadia, Hanna, Farkash, Maoz-Segal, Agmon-Levin, Broides, Nahum, Rosenberg, Kuperman, Dinur-Schejter, Berkun, Toker, Goldberg, Confino-Cohen, Scheuerman, Badarneh, Epstein-Rigbi, Etzioni, Dalal and Somech.)

The deubiquitinase OTULIN removes methionine-1 (M1)-linked polyubiquitin signals conjugated by the linear ubiquitin chain assembly complex (LUBAC) and is critical for preventing TNF-driven inflammation in OTULIN-related autoinflammatory syndrome (ORAS). Five ORAS patients have been reported, but how dysregulated M1-linked polyubiquitin signalling causes their symptoms is unclear. Here, we report a new case of ORAS in which an OTULIN-Gly281Arg mutation leads to reduced activity and stability in vitro and in cells. In contrast to OTULIN-deficient monocytes, in which TNF signalling and NF-κB activation are increased, loss of OTULIN in patient-derived fibroblasts leads to a reduction in LUBAC levels and an impaired response to TNF Interestingly, both patient-derived fibroblasts and OTULIN-deficient monocytes are sensitised to certain types of TNF-induced death, and apoptotic cells are evident in ORAS patient skin lesions. Remarkably, haematopoietic stem cell transplantation leads to complete resolution of inflammatory symptoms, including fevers, panniculitis and diarrhoea. Therefore, haematopoietic cells are necessary for clinical manifestation of ORAS Together, our data suggest that ORAS pathogenesis involves hyper-inflammatory immune cells and TNF-induced death of both leukocytes and non-haematopoietic cells., (© 2019 MRC Laboratory of Molecular Biology. Published under the terms of the CC BY 4.0 license.)

Background: Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease., Methods: Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed., Results: Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia., Conclusion: Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment., Trial Registration: ClinicalTrials.gov NCT01724580 and NCT02974595., Funding: This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.

Objectives: Cryopyrin associated periodic syndromes (CAPS) comprise a spectrum of autoinflammatory disorders of varying severity caused by mutations in the NLRP3 gene. The NLRP3-Q703K allele has been reported both as a functional polymorphism and as a low penetrance mutation., Methods: To describe the clinical phenotype of subjects with the Q703K allele and to report the frequency of this allele among patients with autoinflammatory symptoms and healthy controls. To this end, a cohort of 10 ethnically-matched controls per each Q703K-carrying patient, was composed., Results: Ninety patients suspected of harboring a systemic autoinflammatory disease (SAID), exclusive of FMF, were referred to our center for genotyping between 2012 and 2015. Fourteen of them (15.5%) were found to carry the Q703K allele, compared to 22 of 130 (16.9%) healthy, ethnically matched controls., Conclusions: The similar carrier rate of the NLRP3-Q703K allele among patients with manifestations of a SAID and an ethnically matched control group suggest that this variant, does not determine the clinical phenotype. This reiterates the importance of testing a control group to avoid erroneously attributing a causative role to a gene polymorphism.

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.

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.

Background: Alopecia areata (AA) is an autoimmune disease resulting in hair loss with devastating psychosocial consequences. Despite its high prevalence, there are no FDA-approved treatments for AA. Prior studies have identified a prominent interferon signature in AA, which signals through JAK molecules., Methods: A patient with AA was enrolled in a clinical trial to examine the efficacy of baricitinib, a JAK1/2 inhibitor, to treat concomitant CANDLE syndrome. In vivo, preclinical studies were conducted using the C3H/HeJ AA mouse model to assess the mechanism of clinical improvement by baricitinib., Findings: The patient exhibited a striking improvement of his AA on baricitinib over several months. In vivo studies using the C3H/HeJ mouse model demonstrated a strong correlation between resolution of the interferon signature and clinical improvement during baricitinib treatment., Interpretation: Baricitinib may be an effective treatment for AA and warrants further investigation in clinical trials.

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.

Severe congenital neutropenia as well as primary myelofibrosis are rare in infancy. Elucidation of the underlying mechanism is important because it extends our understanding of the more common adult forms of these disorders. Using homozygosity mapping followed by exome sequencing, we identified a Thr224Asn mutation in the VPS45 gene in infants from consanguineous families who suffered from life-threatening neutropenia, which was refractory to granulocyte CSF, from defective platelet aggregation and myelofibrosis. The mutation segregated in the families, was not present in controls, affected a highly conserved codon, and apparently destabilized the Vps45 protein, which was reduced in the patients' leukocytes. Introduction of the corresponding mutation into yeast resulted in reduced cellular levels of Vps45 and also of the cognate syntaxin Tlg2, which is required for membrane traffic through the endosomal system. A defect in the endosomal-lysosomal pathway, the homologous system in humans, was suggested by the absence of lysosomes in the patients' fibroblasts and by the depletion of α granules in their platelets. Importantly, accelerated apoptosis was observed in the patients' neutrophils and bone marrow. This is the first report of a Vps45-related disease in humans, manifesting by neutropenia, thrombasthenia, myelofibrosis, and progressive bone marrow failure.

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.

The year 2012-2013 has been a fertile one in the area of FMF inquiry. Recent studies have led to further insight into the possible mechanisms whereby pyrin mutations might cause the auto-inflammatory phenotype that is characteristic of FMF. Evidence-based guidelines for diagnosis of FMF, including the role of genetic testing, have become available. Risks for colchicine resistance have been partially defined, and a randomised, controlled trial showing efficacy of an interleukin-1 antagonist for treatment of colchicine-resistant or intolerant FMF patients was reported. In this review, we summarise these and other salient findings from the recent FMF literature, and discuss their significance for the clinician.

CEACAM1 (biliary glycoprotein-1, CD66a) was reported as a strong clinical predictor of poor prognosis in melanoma. We have previously identified CEACAM1 as a tumor escape mechanism from cytotoxic lymphocytes. Here, we present substantial evidence in vitro and in vivo that blocking of CEACAM1 function with a novel monoclonal antibody (MRG1) is a promising strategy for cancer immunotherapy. MRG1, a murine IgG1 monoclonal antibody, was raised against human CEACAM1. It recognizes the CEACAM1-specific N-domain with high affinity (K(D) ~ 2 nmol/L). Furthermore, MRG1 is a potent inhibitor of CEACAM1 homophilic binding and does not induce any agonistic effect. We show using cytotoxicity assays that MRG1 renders multiple melanoma cell lines more vulnerable to T cells in a dose-dependent manner, only following antigen-restricted recognition. Accordingly, MRG1 significantly enhances the antitumor effect of adoptively transferred, melanoma-reactive human lymphocytes using human melanoma xenograft models in severe combined immunodeficient/nonobese diabetic (SCID/NOD) mice. A significant antibody-dependent cell cytotoxicity response was excluded. It is shown that MRG1 reaches the tumor and is cleared within a week. Importantly, approximately 90% of melanoma specimens are CEACAM1(+), implying that the majority of patients with melanoma could be amenable to MRG1-based therapy. Normal human tissue microarray displays limited binding to luminal epithelial cells on some secretory ducts, which was weaker than the broad normal cell binding of other anticancer antibodies in clinical use. Importantly, MRG1 does not directly affect CEACAM1(+) cells. CEACAM1 blockade is different from other immunomodulatory approaches, as MRG1 targets inhibitory interactions between tumor cells and late effector lymphocytes, which is thus a more specific and compartmentalized immune stimulation with potentially superior safety profile., (©2012 AACR)

The last two years have been marked by many studies trying to better characterize the clinical features of FMF in children and proposal of new treatment for those who are resistant to colchicine. In addition, many studies tried to address the potential effect of genetic modifiers on FMF and the potential effect of MEFV mutations on other inflammatory diseases. The main points arose from these studies include a breakthrough in the therapeutic approach for FMF and the lack of consistency regarding the reciprocal effect of MEFV mutations on other diseases and the effect of genetic modifiers on FMF. The highlights of these studies, their potential clinical implications and the unmet needs, which are still to be addressed, are summarised in this review.

Introduction: Familial Mediterranean fever (FMF) is an autosomal recessive disease, caused by mutations in the FMF gene MEFV (MEditerranean FeVer). It has a large phenotypic diversity even in patients with similar genotypes. Despite evidence that environmental factors (EFs) and genetic factors, including MEFV mutations (such as M694V, E148Q) and background modifier genes (MGs), affect the clinical manifestations of FMF, the relative contribution of each remains unknown., Methods: To investigate the relative contribution of environmental and genetic factors to the phenotype of FMF, we compared the intra-pair clinical concordance of 10 mono and 7 dizygotic twins with FMF. The part played by EFs was determined by the phenotypic discordance of the monozygous twins, and the MGs effect was determined by deducing the environmental effect, computed for MZ twins, from the phenotypic discordance of the dizygous twins., Results: The mean±SD of intra-pair concordance was higher in the MZ than in DZ twin group (88.1±13.2 vs. 70.7±14.1 respectively, P value<0.05). Based on the concordance in clinical manifestations in MZ and DZ twins, the environmental effect on the phenotype of FMF is estimated as 11.9%±6.6% and the MGs effect as 17.4%±15.5% in average., Conclusions: In FMF the phenotype is affected by MEFV mutations, MGs and EFs in an estimated ratio of about 6:1.5:1 respectively., (Copyright © 2011 Elsevier B.V. All rights reserved.)

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.

Objective: To evaluate the outcome of pregnancies in women with familial Mediterranean fever (FMF) who are taking colchicine, and to reconsider the justification for amniocentesis in these women., Methods: The outcome of 179 pregnancies in a group of women with FMF taking colchicine was compared with the outcome of 197 pregnancies in women with FMF who did not take colchicine during pregnancy and with 312 pregnancies in another cohort of healthy pregnant women of similar age and ethnicity., Results: There was no difference in the 3 groups regarding early abortions, late abortions, or congenital malformations. There was a mild trend towards a better outcome for the colchicine-treated group but these results did not reach statistical significance., Conclusion: Treatment with colchicine during pregnancy in patients with FMF is beneficial in controlling the disease while not affecting the outcome of the pregnancy; therefore there is no justification for recommending amniocentesis in women taking colchicine solely because of this treatment.

Familial Mediterranean fever (FMF) is a disease caused by mutations in the MEditerranean FeVer gene (MEFV), and in Israel it most commonly affects Jews of North African extraction, in whom the mutation carrier rate is as high as 1 in 5. To assess the protective as well as the modulating affect of MEFV mutation carriage on various inflammatory disease states, we sought to define the frequency of MEFV mutations in Israeli Jewish individuals of various ethnicities, including those with low frequency of FMF, which were not in the focus of our attention hitherto. A total of 163 adults of Bucharian, Turkish, Georgian, Yemenite and Bulgarian origin comprised the study group. The prevalence of the most frequent MEFV mutations in the Israeli Jewish population, namely: M694V, V726A and E148Q, was assessed. The association of mutation carriage with a personal history of FMF-like phenomena, as well as various inflammatory and non-inflammatory diseases, was evaluated. A high MEFV mutation frequency was found among Jews of Bucharian, Georgian and Bulgarian origin (20%), whereas intermediate and low rates were detected in Jews of Turkish and Yemenite extraction (14 and 8%, respectively). FMF-like manifestations and related diseases were observed more often in MEFV mutation carriers than in their counterparts. MEFV mutation frequency, directly assessed by DNA analysis, exceeds the rate calculated from disease prevalence in Israeli Jewish individuals originated from ethnicities with a low prevalence of FMF. MEFV mutation carriage in this subgroup is associated with various inflammatory disorders.