Publications by authors named "Isabelle Touitou"

107 Publications

Mevalonate Kinase-Associated Diseases: Hunting for Phenotype-Genotype Correlation.

J Clin Med 2021 Apr 7;10(8). Epub 2021 Apr 7.

Department of Medical Genetics, Rare Diseases and Personalized Medicine, Rare and Autoinflammatory Diseases Unit, CHU, 34295 Montpellier, France.

Mevalonate kinase-associated diseases (MKAD) are caused by pathogenic mutations in the mevalonate kinase gene () and encompass several phenotypically different rare and hereditary autoinflammatory conditions. The most serious is a recessive systemic metabolic disease called mevalonic aciduria, and the most recently recognized is disseminated superficial actinic porokeratosis, a dominant disease limited to the skin. To evaluate a possible correlation between genotypes and (1) the different MKAD clinical subtypes or (2) the occurrence of severe manifestations, data were reviewed for all patients with variants described in the literature (N = 346), as well as those referred to our center (N = 51). The genotypes including p.(Val377Ile) (homozygous or compound heterozygous) were more frequent in mild systemic forms but were also sometimes encountered with severe disease. We confirmed that amyloidosis was more prevalent in patients compound heterozygous for p.(Ile268Thr) and p.(Val377Ile) than in others and revealed new associations. Patients homozygous for p.(Leu264Phe), p.(Ala334Thr) or compound heterozygous for p.(His20Pro) and p.(Ala334Thr) had increased risk of severe neurological or ocular symptoms. All patients homozygous for p.(Leu264Phe) had a cataract. The variants associated with porokeratosis were relatively specific and more frequently caused a frameshift than in patients with other clinical forms (26% vs. 6%). We provide practical recommendations focusing on phenotype-genotype correlation in MKAD that could be helpful for prophylactic management.
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http://dx.doi.org/10.3390/jcm10081552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067830PMC
April 2021

TNFR1-d2 carrying the p.(Thr79Met) pathogenic variant is a potential novel actor of TNFα/TNFR1 signalling regulation in the pathophysiology of TRAPS.

Sci Rep 2021 Feb 18;11(1):4172. Epub 2021 Feb 18.

INSERM U1183, CHU Saint Eloi, IRMB, Univ Montpellier, 80 Avenue Augustin Fliche, 34295, Montpellier Cedex 5, France.

Binding of tumour necrosis factor α (TNFα) to its receptor (TNFR1) is critical for both survival and death cellular pathways. TNFα/TNFR1 signalling is complex and tightly regulated at different levels to control cell fate decisions. Previously, we identified TNFR1-d2, an exon 2-spliced transcript of TNFRSF1A gene encoding TNFR1, whose splicing may be modulated by polymorphisms associated with inflammatory disorders. Here, we investigated the impact of TNFRSF1A variants involved in TNFR-associated periodic syndrome (TRAPS) on TNFR1-d2 protein expression and activity. We found that TNFR1-d2 could be translated by using an internal translation initiation codon and a de novo internal ribosome entry site (IRES), which resulted in a putative TNFR1 isoform lacking its N-terminal region. The kinetic of assembly of TNFR1-d2 clusters at the cell surface was reduced as compared with full-length TNFR1. Although co-localized with the full-length TNFR1, TNFR1-d2 neither activated nuclear factor (NF)-κB signalling, nor interfered with TNFR1-induced NF-κB activation. Translation of TNFR1-d2 carrying the severe p.(Thr79Met) pathogenic variant (also known as T50M) was initiated at the mutated codon, resulting in an elongated extracellular domain, increased speed to form preassembled clusters in absence of TNFα, and constitutive NF-κB activation. Overall, TNFR1-d2 might reflect the complexity of the TNFR1 signalling pathways and could be involved in TRAPS pathophysiology of patients carrying the p.(Thr79Met) disease-causing variant.
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http://dx.doi.org/10.1038/s41598-021-83539-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893027PMC
February 2021

First report of MEFV gene duplication in a patient with familial Mediterranean fever.

Clin Exp Rheumatol 2020 Sep-Oct;38 Suppl 127(5):129-130. Epub 2020 Dec 10.

CHU Montpellier, University of Montpellier, Department of Medical Genetics, Rare Diseases and Personalized Medicine, Rare and Autoinflammatory Diseases Unit, CEREMAIA Reference Centre, Montpellier, and IRMB, University of Montpellier, INSERM, CHU Montpellier, France.

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February 2021

Correspondance on 'Clinical characteristics and genetic analyses of 187 patients with undefined autoinflammatory diseases'.

Ann Rheum Dis 2020 Dec 9. Epub 2020 Dec 9.

AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Hopitaux Universitaires Pitie Salpetriere-Charles Foix, Paris, France.

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http://dx.doi.org/10.1136/annrheumdis-2020-219566DOI Listing
December 2020

Phenotypic Associations of PSTPIP1 Sequence Variants in PSTPIP1-Associated Autoinflammatory Diseases.

J Invest Dermatol 2021 May 18;141(5):1141-1147. Epub 2020 Nov 18.

Department of Medical Genetics, Rare Diseases and Personalized Medicine, Rare and Auto Inflammatory Diseases Unit, CEREMAIA, CHU Montpellier, University of Montpellier, Montpellier, France; Cellules souches, plasticité cellulaire, médecine régénératrice et immunothérapies, INSERM, University of Montpellier, Montpellier, France.

Pathogenic variants in the PSTPIP1 gene cause pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. They were also identified in a broad spectrum of phenotypes. As their interpretation is sometimes challenging, we discuss the genotype-phenotype association in PSTPIP1-associated autoinflammatory diseases (PAIDs) in light of a recent consensus classification of variant pathogenicity. Only 7 of 39 (18%) of the PSTPIP1 variants found in all reported cases and our national reference center (161 patients [114 probands]) were pathogenic. They were clearly associated with PAPA and PSTPIP1-associated myeloid-related proteinemia inflammatory syndrome (PAMI), reflecting a variable clinical expression of PAIDs.
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http://dx.doi.org/10.1016/j.jid.2020.08.028DOI Listing
May 2021

INSAID Variant Classification and Eurofever Criteria Guide Optimal Treatment Strategy in Patients with TRAPS: Data from the Eurofever Registry.

J Allergy Clin Immunol Pract 2021 Feb 9;9(2):783-791.e4. Epub 2020 Nov 9.

National Amyloidosis Centre, UCL Division of Medicine, Royal Free Campus, University College London, London, United Kingdom. Electronic address:

Background: TNF receptor-associated periodic syndrome (TRAPS) is a rare autoinflammatory disease caused by dominant mutation of the TNF super family receptor 1A (TNFRSF1A) gene. Data regarding long-term treatment outcomes are lacking.

Objective: To assess correlations of genotype-phenotypes in patients with TRAPS, as defined by the International Study Group for Systemic Autoinflammatory Diseases (INSAID) classification and Eurofever criteria, with treatment responses.

Methods: Data from 226 patients with variants of the TNFRSF1A gene and enrolled in the Eurofever registry were classified according to the INSAID classification in groups A (pathogenic or likely pathogenic variants), B (variants of uncertain significance or not classified variants), and C (benign or likely benign variants) and screened for Eurofever criteria.

Results: In group A (127 of 226 patients, 56%), all fulfilled Eurofever criteria and 20 of 127 patients (16%) developed AA amyloidosis. In group B (78 of 226 patients, 35%), 40 of 78 patients (51%) did not fulfill Eurofever criteria, displaying a lower incidence of abdominal pain (P < .02) and higher efficacy rate of on-demand nonsteroidal anti-inflammatory drugs (P < .02) and colchicine (P < .001). Group C (21 of 226 patients, 9%) presented a milder disease (P < .02) and none fulfilled Eurofever criteria. Anti-IL-1 drugs were the most frequently used in patients fulfilling Eurofever criteria, with the highest efficacy rate (>85% complete response). No patients on anti-IL-1 treatments developed AA amyloidosis, and 7 women with a history of failure to conceive had successful pregnancies.

Conclusion: Anti-IL-1 drugs are the best maintenance treatment in patients with TRAPS. The diagnosis of TRAPS should be considered very carefully in patients of group B not fulfilling Eurofever criteria and group C, and colchicine may be preferable as the first maintenance treatment.
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http://dx.doi.org/10.1016/j.jaip.2020.10.053DOI Listing
February 2021

Pregnancy after oocyte donation in a patient with NLRP7 gene mutations and recurrent molar hydatidiform pregnancies.

J Assist Reprod Genet 2020 Sep 26;37(9):2273-2277. Epub 2020 Jun 26.

Centre Hospitalier Amiens Sud, Amiens Cedex 1, France.

Molar pregnancies are benign trophoblastic diseases associated with a risk of malignant transformation. If aetiology remains mostly unknown, the risk of recurrent molar pregnancy is around 1.5% after one molar pregnancy and around 25% after 2 molar pregnancies. In the later situation, genetic mutations have been described, increasing hugely this risk. In case of mutations, probability to obtain a normal pregnancy is estimated around 1.8%. We report the case of a Caucasian 30-year-old woman whose previous five spontaneous pregnancies had a negative outcome: a spontaneous miscarriage and then 4 complete hydatidiform moles. Genetic testing revealed that the patient carried two heterozygous mutations in the NLRP7 gene (c.2982-2A > G and Y318CfsX7). According to this, counselling was conducted to advocate for oocyte donation in order to obtain a normal pregnancy. This technique enabled a complication-free, singleton pregnancy that resulted in a healthy term live birth of a 2900 g female. Few months after delivery, the patient presented a new complete hydatidiform mole. Women presented with mutations in the NLRP7, KHDC3L or PADI6 genes are unlikely to obtain normal pregnancies, with a major risk of reproductive failure. In such a context, oocyte donation may be the best option. Only 4 normal pregnancies and deliveries have been published in this situation through this technique to our knowledge.
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http://dx.doi.org/10.1007/s10815-020-01861-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492304PMC
September 2020

Clinical and Molecular Spectrum of Nonsyndromic Early-Onset Osteoarthritis.

Arthritis Rheumatol 2020 10 25;72(10):1689-1693. Epub 2020 Aug 25.

Université de Montpellier, Centre Hospitalier Universitaire Montpellier, CLAD Sud Languedoc-Roussillon, Montpellier, France.

Objective: Osteoarthritis (OA) is the most common joint disease worldwide. The etiology of OA is varied, ranging from multifactorial to environmental to monogenic. In a condition called early-onset OA, OA occurs at an earlier age than is typical in the general population. To our knowledge, there have been no large-scale genetic studies of individuals with early-onset OA. The present study was undertaken to investigate causes of monogenic OA in individuals with nonsyndromic early-onset OA.

Methods: The study probands were 45 patients with nonsyndromic early-onset OA who were referred to our skeletal disease center by skeletal dysplasia experts between 2013 and 2019. Criteria for early-onset OA included radiographic evidence, body mass index ≤30 kg/m , age at onset ≤50 years, and involvement of ≥1 joint site. Molecular analysis was performed with a next-generation sequencing panel.

Results: We identified a genetic variant in 13 probands (29%); the affected gene was COL2A1 in 11, ACAN in 1, and SLC26A2 in 1. After familial segregation analysis, 20 additional individuals were identified. The mean ± SD age at onset of joint pain was 19.5 ± 3.9 years (95% confidence interval 3-47). Eighteen of 33 subjects (55%) with nonsyndromic early-onset OA and a genetic variant had had at least 1 joint replacement (mean ± SD age at first joint replacement 41 ± 4.2 years; mean number of joint replacements 2.6 per individual), and 21 (45%) of the joint replacement surgeries were performed when the patient was <45 years old. Of the 20 patients age >40 years, 17 (85%) had had at least 1 joint replacement.

Conclusion: We confirmed that COL2A1 is the main monogenic cause of nonsyndromic early-onset OA. However, on the basis of genetic heterogeneity of early-onset OA, we recommend next-generation sequencing for all individuals who undergo joint replacement prior to the age of 45 years. Lifestyle recommendations for prevention should be implemented.
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http://dx.doi.org/10.1002/art.41387DOI Listing
October 2020

C-reactive protein and ART outcomes: a systematic review.

Hum Reprod Update 2020 09;26(5):753-773

Univ Montpellier, Développement Embryonnaire Précoce Humain et Pluripotence, INSERM 1203, Montpellier, France.

Background: A dynamic balance between pro- and anti-inflammatory factors contributes to regulating human female reproduction. Chronic low-grade inflammation has been detected in several female reproductive conditions, from anovulation to embryo implantation failure. C-reactive protein (CRP) is a reliable marker of inflammation that is extensively used in clinical practice. Recent studies quantified CRP in the serum of infertile women undergoing ART and suggested its potential for the prediction of ART reproductive outcomes.

Objective And Rationale: The first objective of this systematic review of the available literature was to evaluate the association between pre-implantation circulating CRP concentration and pregnancy rates in women undergoing ART. The second objective was to describe serum CRP concentration changes after early embryo implantation. The changes in circulating CRP throughout the ART cycle, clinical implications of CRP quantification for the management of women undergoing ART, and future therapeutic options will also be discussed.

Search Methods: The MEDLINE database was systematically searched from inception to March 2019 using the following key words: (C-reactive protein) AND (assisted reproductive techniques OR ovulation induction OR insemination OR in vitro fertilization). Only articles in English were considered. Studies were selected based on title and abstract. The full text of potentially relevant articles was retrieved and assessed for inclusion by two reviewers (S.B. and S.H.). The protocol was registered in the International prospective register of systematic reviews (PROSPERO; registration number: CRD148687).

Outcomes: In total, 10 studies were included in this systematic review. Most of these studies reported lower circulating CRP values before the window of implantation and higher circulating CRP values during the peri-implantation period in women with successful ART outcome (biochemical or clinical pregnancy) compared to women without a successful outcome. Several lifestyle factors and/or drugs that reduce the concentration of circulating CRP significantly improve ART outcomes. Subgroup analyses according to female BMI and baseline circulating CRP concentration are highly recommended in future analyses.

Wider Implications: These findings highlight a possible detrimental impact of preconception high circulating CRP concentration on ART outcomes. However, the biochemical or clinical pregnancy rate endpoints used in the studies examined here are insufficient (there were no data on live birth outcome), and the impact of major variables that can influence CRP and/or ART, for example maternal age, BMI, number of transferred embryos, and use of anti-inflammatory drugs, were not considered in the analyses. CRP quantification may be a potential marker of ART outcome, but its predictive value still needs to be investigated in large prospective studies. In future, the quantification of circulating CRP before starting ART could help to identify patients with a poor ART prognosis, leading to ART cycle cancellation or to preconception treatment to minimize the medical risks and costs.
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http://dx.doi.org/10.1093/humupd/dmaa012DOI Listing
September 2020

Clinical and pathological dermatological features of deficiency of adenosine deaminase 2: A multicenter, retrospective, observational study.

J Am Acad Dermatol 2020 Dec 10;83(6):1794-1798. Epub 2020 Apr 10.

Sorbonne Université, Faculté de Médecine, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Service de médecine interne, Centre de référence des maladies auto-inflammatoires et des amyloses d'origine inflammatoire (CEREMAIA), Paris, France.

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http://dx.doi.org/10.1016/j.jaad.2020.03.110DOI Listing
December 2020

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

Clin Chem 2020 04;66(4):525-536

Department of Medical Genetics, Rare Diseases and Personalized Medicine, Reference Center CEREMAIA, CHU Montpellier, University of Montpellier, Montpellier, France.

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.
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http://dx.doi.org/10.1093/clinchem/hvaa024DOI Listing
April 2020

Growth charts in Kabuki syndrome 1.

Am J Med Genet A 2020 03 26;182(3):446-453. Epub 2019 Dec 26.

Service de Génétique, Hôpital Saint Pierre, GH Sud Réunion, Ile de la Réunion, Saint Pierre, France.

Kabuki syndrome (KS, KS1: OMIM 147920 and KS2: OMIM 300867) is caused by pathogenic variations in KMT2D or KDM6A. KS is characterized by multiple congenital anomalies and neurodevelopmental disorders. Growth restriction is frequently reported. Here we aimed to create specific growth charts for individuals with KS1, identify parameters used for size prognosis and investigate the impact of growth hormone therapy on adult height. Growth parameters and parental size were obtained for 95 KS1 individuals (41 females). Growth charts for height, weight, body mass index (BMI) and occipitofrontal circumference were generated in standard deviation values for the first time in KS1. Statural growth of KS1 individuals was compared to parental target size. According to the charts, height, weight, BMI, and occipitofrontal circumference were lower for KS1 individuals than the normative French population. For males and females, the mean growth of KS1 individuals was -2 and -1.8 SD of their parental target size, respectively. Growth hormone therapy did not increase size beyond the predicted size. This study, from the largest cohort available, proposes growth charts for widespread use in the management of KS1, especially for size prognosis and screening of other diseases responsible for growth impairment beyond a calculated specific target size.
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http://dx.doi.org/10.1002/ajmg.a.61462DOI Listing
March 2020

PSMB10, the last immunoproteasome gene missing for PRAAS.

J Allergy Clin Immunol 2020 03 26;145(3):1015-1017.e6. Epub 2019 Nov 26.

IRMB, Univ Montpellier, INSERM, CHU Montpellier, Montpellier, France; Department of Medical Genetics, Rare Diseases and Personalized Medicine, Rare and Autoinflammatory Diseases Unit, CHU Montpellier, Univ Montpellier, Montpellier, France.

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http://dx.doi.org/10.1016/j.jaci.2019.11.024DOI Listing
March 2020

Positive Impact of Expert Reference Center Validation on Performance of Next-Generation Sequencing for Genetic Diagnosis of Autoinflammatory Diseases.

J Clin Med 2019 10 18;8(10). Epub 2019 Oct 18.

Cellules souches, plasticité cellulaire, médecine régénératrice et immunothérapies, INSERM, University Montpellier, Department of Medical Genetics, Rare Diseases and Personalized Medicine, CEREMAIA, CHU Montpellier, 34295 Montpellier, France.

Monogenic autoinflammatory diseases (AIDs) are caused by variants in genes that regulate innate immunity. The current diagnostic performance of targeted next-generation sequencing (NGS) for AIDs is low. We assessed whether pre-analytic advice from expert clinicians could help improve NGS performance from our 4 years of experience with the sequencing of a panel of 55 AIDs genes. The study included all patients who underwent routine NGS testing between September 2014 and January 2019 at the laboratory of autoinflammatory diseases (Montpellier, France). Before March 2018, all medical requests for testing were accepted. After this time, we required validation by a reference center before NGS: the positive advice could be obtained after a face-to-face consultation with the patient or presentation of the patient's case at a multidisciplinary staff meeting. Targeted NGS resulted in an overall 7% genetic confirmation, which is consistent with recent reports. The diagnostic performance before and after implementation of the new pre-requisite increased from 6% to 10% ( = 0.021). Our study demonstrated, for the first time, the beneficial effect of a two-step strategy (clinical expert advice, then genetic testing) for AIDs diagnosis and stressed the possible usefulness of the strategy in anticipation of the development of pan-genomic analyses in routine settings.
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http://dx.doi.org/10.3390/jcm8101729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832712PMC
October 2019

Current practices for the genetic diagnosis of autoinflammatory diseases: results of a European Molecular Genetics Quality Network Survey.

Eur J Hum Genet 2019 10 11;27(10):1502-1508. Epub 2019 Jun 11.

INSERM, Department of Medical Genetics, Rare Diseases and Personalized Medicine, University of Montpellier, CEREMAIA, CHU Montpellier, Montpellier, France.

Monogenic autoinflammatory disorders (AIDs) are rare diseases caused by variants in genes regulating the innate immune system. The identification of the first four genes responsible for the prototype group of hereditary recurrent fevers prompted the development of genetic diagnosis, followed by external quality assessment and guidelines for the interpretation of sequence variants in these diseases. Recent changes in the diagnosis of genetic diseases, namely the implementation of next-generation sequencing (NGS), lead to discovery of the new genes associated with at least 40 novel AIDs, which revolutionized patient care and prognosis. However, these rapid advances resulted in nonstandardized molecular strategies that can influence genetic diagnosis and reporting of results. In order to assess factors, which may have an impact on performance and quality of results in the NGS era, we carried out an online survey among member laboratories of the European Molecular Genetics Quality Network, which highlighted different strategies being used and identified pitfalls that deserve discussion and improvement.
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http://dx.doi.org/10.1038/s41431-019-0439-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777449PMC
October 2019

Classification criteria for autoinflammatory recurrent fevers.

Ann Rheum Dis 2019 08 24;78(8):1025-1032. Epub 2019 Apr 24.

Division of Medicine, UCL Medical School, Royal Free Campus, National Amyloidosis Centre, London, UK.

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' 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.
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http://dx.doi.org/10.1136/annrheumdis-2019-215048DOI Listing
August 2019

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

J Pediatr 2019 06 27;209:12-16.e1. Epub 2019 Mar 27.

AP-HP, CHU de Bicetre, Pediatric Rheumatology, CEREMAIA, Le Kremlin Bicetre, Bicetre, France. Electronic address:

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http://dx.doi.org/10.1016/j.jpeds.2019.02.039DOI Listing
June 2019

Comment on: Familial Mediterranean fever: breaking all the (genetic) rules.

Authors:
Isabelle Touitou

Rheumatology (Oxford) 2020 02;59(2):452

Stem cells, Cellular Plasticity, Regenerative Medicine and Immunotherapies, INSERM, University of Montpellier, France.

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http://dx.doi.org/10.1093/rheumatology/kez086DOI Listing
February 2020

A single nucleotide polymorphism of IL6-receptor is associated with response to tocilizumab in rheumatoid arthritis patients.

Pharmacogenomics J 2019 08 16;19(4):368-374. Epub 2019 Jan 16.

Clinical Immunology and Osteoarticular Diseases Therapeutic Unit, Lapeyronie University Hospital, Montpellier, France.

Biological disease-modifying anti-rheumatic drugs (bDMARDs) have changed care of patients with rheumatoid arthritis (RA). However, bDMARDs are costly, can lead to serious infections, and induce a sustained remission in only 30% of RA patients. In this study, we sought to determine if the clinical response to treatment with Tocilizumab (TCZ), an IL-6 inhibitor, varied with genetic background. The efficacy of TCZ was assessed using the European League Against Rheumatism (EULAR) response criteria, measured after 3 months of treatment in two samples of French RA patients (TOCI and ROC studies). Single nucleotide polymorphisms (SNPs) in 21 candidate genes were genotyped using KasPar method (LGC-genomics, UK) and then analyzed to determine their contribution to variation in the response to treatment. One hundred twenty-three patients in the TOCI group (79.8%) and 48 patients in the ROC group (80%) experienced good or moderate EULAR response. The clinical response to treatment was associated with SNP genotype in the gene IL6R, with patients with the homozygous AA-genotype for rs12083537 (IL6R) showing a significantly better response than homozygous or heterozygous patients with the G allele [TOCI: 87.5% of responders for AA genotype vs. 72.2% for AG or GG genotype (p = 0.018); ROC patients: 89.2% of responders for AA genotype vs. 65.2% for AG or GG genotype, p = 0.044]. A meta-analysis combining data from the two cohorts confirmed the lower response rate in patients carrying a copy of the G allele (OR (95% CI) = 0.35 (0.16-0.61), p = 0.001). No association was found with any of the other SNPs tested.
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http://dx.doi.org/10.1038/s41397-019-0072-6DOI Listing
August 2019

New data in causes of autoinflammatory diseases.

Joint Bone Spine 2019 Oct 22;86(5):554-561. Epub 2018 Nov 22.

Centre national de référence des maladies auto-inflammatoires et de l'amylose inflammatoire (CEREMAIA), 94270 Le Kremlin-Bicêtre, France; Cellules souches, plasticité cellulaire, médecine régénératrice et immunothérapies, Inserm, Université de Montpellier, 34090 Montpellier, France; Département de génétique médicale, maladies rares et médecine personnalisée, CHU de Montpellier, 34295 Montpellier, France.

The spectrum of factors known to mediate autoinflammation has broadened recently to include not only interleukin-1 (IL-1) and interferon, but also abnormalities that impair NF-κB pathway negative regulation. The NF-κB pathway is activated upon contact of a ligand with tumor necrosis factor receptor 1 (TNFR1) and plays a pivotal role in triggering the inflammatory process by producing major cytokines such as IL-1, IL-6, and TNF. Negative regulation of the NF-κB pathway, which is essential to stop the inflammatory process, depends on the level of ubiquitination of the proteins associated with TNFR1 and of other intermediate compounds. A20 and otulin are proteins that influence the level of ubiquitination, and a deficiency in either can result in NF-κB activation with overproduction of pro-inflammatory cytokines. Similar to Behçet's disease, A20 haploinsufficiency manifests as oral and genital ulcers and, more rarely, as uveitis. However, transmission is dominant, symptom onset occurs at a younger age, and severe gastrointestinal involvement is at the forefront of the clinical picture. Clinical presentations are extremely diverse. Over their lifetime, affected patients simultaneously or sequentially experience autoinflammatory and autoimmune manifestations. Mild immune deficiency predominantly affecting humoral responses is less common. Otulin deficiency results in systemic inflammatory manifestations at a very young age, with panniculitis, lipodystrophy, and inflammatory bowel disease. The main differential diagnosis is proteasome-associated autoinflammatory syndrome. The treatment of A20 haploinsufficiency and otulin deficiency is challenging and remains unstandardized. The symptoms respond to high-dose glucocorticoid therapy. TNF antagonists and IL-1 antagonists have shown some measure of efficacy.
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http://dx.doi.org/10.1016/j.jbspin.2018.11.003DOI Listing
October 2019

Successful therapy with secukinumab in a patient with generalized pustular psoriasis carrying homozygous IL36RN p.His32Arg mutation.

Int J Dermatol 2019 Jan 14;58(1):e16-e17. Epub 2018 Nov 14.

Department of Dermatology, University Hospital of Tours, University François-Rabelais, Tours, France.

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http://dx.doi.org/10.1111/ijd.14293DOI Listing
January 2019

Reply to Sönmez et al.

Eur J Hum Genet 2018 11 11;26(11):1564-1565. Epub 2018 Sep 11.

Laboratory of Rare and Autoinflammatory Genetic Diseases and CEREMAIA, Montpellier University Hospital, Montpellier, France.

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http://dx.doi.org/10.1038/s41431-018-0242-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189082PMC
November 2018

Consensus proposal for taxonomy and definition of the autoinflammatory diseases (AIDs): a Delphi study.

Ann Rheum Dis 2018 11 12;77(11):1558-1565. Epub 2018 Aug 12.

Clinica Pediatrica e Reumatologia-PRINTO, Istituto Giannina Gaslini, Genoa, Italy.

Autoinflammatory diseases (AIDs) are a relatively new family of disorders, defined about 19 years ago. Some of them are hereditary and some are not. The names given to these diseases do not follow any systematic guidelines, and sometimes the same disorder carries several names. The aim of this study is to refine the definition of AIDs and to provide some conventions for their naming. We focused mainly on monogenetic AIDs. Delphi technique, which enables consensus among a group of experts through internet and mail communication and questionnaires, was employed. After achieving 100% consensus among six members of a steering committee, the questionnaire containing AID definitions and the agreed-upon conventions were sent to 26 physicians and researchers working in the field of AIDs in order to gain broader support for the committee's proposals. The committee proposed the following definition for AIDs: "Autoinflammatory diseases are clinical disorders caused by defect(s) or dysregulation of the innate immune system, characterized by recurrent or continuous inflammation (elevated acute phase reactants-APR) and the lack of a primary pathogenic role for the adaptive immune system (autoreactive T-cells or autoantibody production)." Several rules were defined for guiding the naming of these diseases among which are: abandoning eponyms and preferring the name of the gene over its encoded protein. The new definition for AIDs allows inclusion of clinical disorders mainly associated with defects in the innate immune system. The new conventions propose names with clinical meaning and in some cases even clues for treatment.
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http://dx.doi.org/10.1136/annrheumdis-2017-212515DOI Listing
November 2018

Mosaicism in autoinflammatory diseases: Cryopyrin-associated periodic syndromes (CAPS) and beyond. A systematic review.

Crit Rev Clin Lab Sci 2018 09 23;55(6):432-442. Epub 2018 Jul 23.

a Department of Medical Genetics, Rare Diseases and Personalized Medicine, CHU Montpellier , Stem Cells, Cellular Plasticity, Regenerative Medicine and Immunotherapies, INSERM, Univ Montpellier , Montpellier , France.

Autoinflammatory diseases (AIDs) are conditions related to defective regulation of the innate immune system. Sanger sequencing of the causative genes has long been the reference for confirming the diagnosis. However, for many patients with a typical AID phenotype, the genetic cause remains unknown. A pioneering study in 2005 demonstrated mosaicism in patients with cryopyrin-associated periodic syndromes (CAPS); the authors found somatic mosaicism in 69% of their cohort of Sanger-negative CAPS patients. We aim to address the extent to which mosaicism contributes to the etiology of AIDs and its impact on phenotype. We retrieved English-language publications reporting mosaicism in AIDs by querying PubMed with no restriction on date and we surveyed French reference centers. We provide a comprehensive clinical and genetic picture of mosaicism in AIDs. We estimate that the proportion of CAPS-like patients presenting mosaicism ranges from 0.5% to 19%. We also discuss the possible links between the proportion of mutated alleles and various clinical features. This review reevaluates the contribution of mosaic DNA variants in CAPS. Mosaicism may be more common than anticipated in other AIDs. No significant difference was demonstrated between variant allele frequency and clinical phenotype. Such knowledge has implications for the development of guidelines for genetic diagnosis, genetic counseling of affected families and effective patient care.
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http://dx.doi.org/10.1080/10408363.2018.1488805DOI Listing
September 2018

Autosomic dominant familial Behçet disease and haploinsufficiency A20: A review of the literature.

Autoimmun Rev 2018 Aug 8;17(8):809-815. Epub 2018 Jun 8.

Département de médecine interne et pneumologie, CHU de Brest, Hôpital La Cavale Blanche, Brest Cedex, France; EA 3878, GETBO, Université Bretagne Loire, Brest Cedex, France. Electronic address:

Introduction: Behçet disease (BD) is a systemic vasculitis involving vessels from any size with various clinical features. Most BD cases are multifactorial and associated with the HLA B51 antigen. In rare and severe early onset cases, dominant Mendelian transmission has been linked to mutations in the TNFAIP3 gene encoding A20. Herein, we propose a systematic review of the literature about the haploinsufficiency A20 (HA20) published cases.

Systematic Review: Our review of the 45 cases of HA20 from literature highlights the similarities and the differences between this genetic auto-inflammatory disease and classical BD. HA20 looks like BD if we consider recurrent oral (87%) and genital (67%) ulcers, arthralgia or arthritis (42%), skin involvement (53%) such as erythema nodosum or abdominal symptoms (60%) such as abdominal pain, digestive ulcers or diarrhea. However, HA20 differs from classical BD because its geographical distribution is ubiquitous, sex ratio is inversed (one man for two women), first symptoms occur in early childhood (median age = 5.5 years; interquartile range: 1-10) instead of adulthood, recurrent fever is common (62%) unlike classical BD, HLA B51 antigen is uncommon and abdominal symptoms are over-represented compared to classical BD. In addition, response to colchicine in HA20 is inconstant (24%) unlike classical BD.

Discussion/conclusion: High fever flares and digestive involvement starting in early childhood seem to be hallmarks of HA20 clinical features. Response to colchicine is unpredictable and biotherapies like anti-TNFα and anti IL1 appear to be treatments of choice, like for other auto-inflammatory diseases. Prospective description of larger cohort of HA20 cases is needed to understand better when this disease must be looked for and how to treat these patients.
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http://dx.doi.org/10.1016/j.autrev.2018.02.012DOI Listing
August 2018

A decision tree for the genetic diagnosis of deficiency of adenosine deaminase 2 (DADA2): a French reference centres experience.

Eur J Hum Genet 2018 07 23;26(7):960-971. Epub 2018 Apr 23.

Laboratory of Rare and Autoinflammatory Genetic Diseases and CEREMAIA, Montpellier University Hospital, Montpellier, France.

Deficiency of adenosine deaminase 2 (DADA2) is a recently described autoinflammatory disorder. Genetic analysis is required to confirm the diagnosis. We aimed to describe the identifying symptoms and genotypes of patients referred to our reference centres and to improve the indications for genetic testing. DNA from 66 patients with clinically suspected DADA2 were sequenced by Sanger or next-generation sequencing. Detailed epidemiological, clinical and biological features were collected by use of a questionnaire and were compared between patients with and without genetic confirmation of DADA2. We identified 13 patients (19.6%) carrying recessively inherited mutations in ADA2 that were predicted to be deleterious. Eight patients were compound heterozygous for mutations. Seven mutations were novel (4 missense variants, 2 predicted to affect mRNA splicing and 1 frameshift). The mean age of the 13 patients with genetic confirmation was 12.7 years at disease onset and 20.8 years at diagnosis. Phenotypic manifestations included fever (85%), vasculitis (85%) and neurological disorders (54%). Features best associated with a confirmatory genotype included fever with neurologic or cutaneous attacks (odds ratio [OR] 10.71, p = 0.003 and OR 10.9, p < 0.001), fever alone (OR 8.1, p = 0.01), and elevated C-reactive protein (CRP) level with neurologic involvement (OR 6.63, p = 0.017). Our proposed decision tree may help improve obtaining genetic confirmation of DADA2 in the context of autoinflammatory symptoms. Prerequisites for quick and low-cost Sanger analysis include one typical cutaneous or neurological sign, one marker of inflammation (fever or elevated CRP level), and recurrent or chronic attacks in adults.
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http://dx.doi.org/10.1038/s41431-018-0130-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018671PMC
July 2018

Large deletion in 6q associated to A20 haploinsufficiency and thoracoabdominal heterotaxy.

Ann Rheum Dis 2018 11 20;77(11):1697-1698. Epub 2018 Apr 20.

CIRI, Centre International de Recherche en Infectiologie - International Center for Infectiology Research, Lyon, France.

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http://dx.doi.org/10.1136/annrheumdis-2018-213300DOI Listing
November 2018

New workflow for classification of genetic variants' pathogenicity applied to hereditary recurrent fevers by the International Study Group for Systemic Autoinflammatory Diseases (INSAID).

J Med Genet 2018 08 29;55(8):530-537. Epub 2018 Mar 29.

Laboratory of Rare and Autoinflammatory Diseases, CHU Montpellier, Montpellier University, INSERM U1183, Montpellier, France.

Background: Hereditary recurrent fevers (HRFs) are rare inflammatory diseases sharing similar clinical symptoms and effectively treated with anti-inflammatory biological drugs. Accurate diagnosis of HRF relies heavily on genetic testing.

Objectives: This study aimed to obtain an experts' consensus on the clinical significance of gene variants in four well-known HRF genes: , , and .

Methods: We configured a MOLGENIS web platform to share and analyse pathogenicity classifications of the variants and to manage a consensus-based classification process. Four experts in HRF genetics submitted independent classifications of 858 variants. Classifications were driven to consensus by recruiting four more expert opinions and by targeting discordant classifications in five iterative rounds.

Results: Consensus classification was reached for 804/858 variants (94%). None of the unsolved variants (6%) remained with opposite classifications (eg, pathogenic vs benign). New mutational hotspots were found in all genes. We noted a lower pathogenic variant load and a higher fraction of variants with unknown or unsolved clinical significance in the gene.

Conclusion: Applying a consensus-driven process on the pathogenicity assessment of experts yielded rapid classification of almost all variants of four HRF genes. The high-throughput database will profoundly assist clinicians and geneticists in the diagnosis of HRFs. The configured MOLGENIS platform and consensus evolution protocol are usable for assembly of other variant pathogenicity databases. The MOLGENIS software is available for reuse at http://github.com/molgenis/molgenis; the specific HRF configuration is available at http://molgenis.org/said/. The HRF pathogenicity classifications will be published on the INFEVERS database at https://fmf.igh.cnrs.fr/ISSAID/infevers/.
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http://dx.doi.org/10.1136/jmedgenet-2017-105216DOI Listing
August 2018

'A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease'.

Ann Rheum Dis 2019 05 16;78(5):e35. Epub 2018 Mar 16.

Département de médecine interne et pneumologie, CHU de Brest, Hôpital La Cavale Blanche, Brest, France.

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http://dx.doi.org/10.1136/annrheumdis-2018-213347DOI Listing
May 2019