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1. Health-related quality of life in children and adolescents with Marfan syndrome or related disorders: a controlled cross-sectional study

Author: Thomas Edouard, Marie-Christine Picot, Fernanda Bajanca, Helena Huguet, Aitor Guitarte, Maud Langeois, Bertrand Chesneau, Philippe Khau Van Kien, Eric Garrigue, Yves Dulac, and Pascal Amedro
Subjects: Marfan syndrome, Health-related quality of life, Aerobic physical fitness, Peak oxygen consumption, Physical well-being, Psychological well-being, Medicine
Abstract: Abstract Background This cross-sectional controlled study aims to assess health-related quality of life (HRQoL) of children and adolescents with a molecular diagnosis of Marfan syndrome (MFS) or related disorders and to evaluate the factors associated with HRQoL in this population. Sixty-three children with MFS and 124 age- and sex-matched healthy children were recruited. HRQoL was assessed using the Pediatric Quality of Life Inventory (PedsQL™) generic questionnaire. The correlation between HRQoL scores and the different continuous parameters (age, body mass index, disease severity, systemic score, aortic sinus diameter, and aerobic physical capacity) was evaluated using Pearson’s or Spearman’s coefficient. A multiple linear regression analysis was performed on the two health summary self-reported PedsQL™ scores (physical and psychosocial) to identify the factors associated with HRQoL in the MFS group. Results Except for emotional functioning, all other domains of HRQoL (psychosocial and physical health, social and school functions) were significantly lower in children with MFS compared to matched healthy children. In the MFS group, the physical health summary score was significantly lower in female than in male patients (self-report: absolute difference [95%CI] = -8.7 [-17.0; -0.47], P = 0.04; proxy-report: absolute difference [95%CI] = -8.6 [-17.3; 0.02], P = 0.05) and also negatively correlated with the systemic score (self-report: R = -0.24, P = 0.06; proxy-report: R = -0.29, P = 0.03) and with the height Z-score (proxy-report: R = -0.29, P = 0.03). There was no significant difference in the physical health summary scores between the different genetic subgroups. In the subgroup of 27 patients who performed a cardiopulmonary exercise test, self- and proxy-reported physical health summary scores were highly correlated with their aerobic physical capacity assessed by peak oxygen consumption (VO2max) and ventilatory anaerobic threshold (VAT). In the multivariate analysis, the most important independent predictors of decreased physical health were increased height, decreased body mass index, decreased VAT and use of prophylactic therapy. Conclusions This study reports an impaired HRQoL in children and adolescents with MFS or related conditions, in comparison with matched healthy children. Educational and rehabilitation programs must be developed and evaluated to improve exercise capacity and HRQoL in these patients. Trial registration ClinicalTrials.gov, NCT03236571 . Registered 28 July 2017.
Published: 2024
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2. Orofacial Features, Oral Health-Related Quality of Life, and Exposure to Bullying in Osteogenesis Imperfecta: A Cross-Sectional Study

Author: Alice Broutin, Jean-Pierre Salles, Valérie Porquet-Bordes, Thomas Edouard, Frédéric Vaysse, and Emmanuelle Noirrit-Esclassan
Subjects: osteogenesis imperfecta, bullying, malocclusion, oral health-related quality of life, Pediatrics, RJ1-570
Abstract: Background/Objectives: Osteogenesis imperfecta (OI) is a rare genetic disease that is responsible for bone fragility, but also for dental malocclusions and dentinogenesis imperfecta (DI). The aim of this study was to assess whether the severity of dental malocclusion influenced the oral health-related quality of life (OHRQoL) and exposure to bullying in a paediatric OI population compared with a control group. Methods: Dental and occlusal characteristics were noted during oral and radiographic examination. The severity of malocclusion was assessed using the PAR index. P-CPQ, COHIP(34), and BCS-A questionnaires were used to evaluate, respectively, externally and self-perceived OHRQoL and bullying. Results: We included 39 patients with a mean age of 11.3 (±4.8 SD) in the OI group, and 45 patients with a mean age of 12.3 (±3.2 SD) in the control group. There were no significant differences between the two groups in terms of occlusal vertical and transverse dimensions. Patients with severe OI, presenting with bone fractures, bones deformities, and short stature, had significantly more anterior (p < 0.05) and posterior openbites (p < 0.05) and more DI (p < 0.05) compared to patients who had moderate or mild OI. Self-perceived OHRQoL was negatively impacted by the disease (p = 0.01), particularly in the domains of oral health (p < 0.05) and self-image (p < 0.001), but not by its severity. Exposure to bullying did not differ significantly between the two groups, although more patients with OI reported being teased (21.4% face to face and 7.1% online vs. 14.6% and 2.4% in the control group). Conclusion: Interventions for dental malocclusion and oral health in OI patients would help to improve their quality of life and self-image.
Published: 2024
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3. Outcomes in growth hormone-treated Noonan syndrome children: impact of PTPN11 mutation status

Author: Alexander A L Jorge, Thomas Edouard, Mohamad Maghnie, Alberto Pietropoli, Nicky Kelepouris, Alicia Romano, Martin Zenker, and Reiko Horikawa
Subjects: growth hormone, noonan syndrome, ptpn11, rasopathies, short stature, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: Introduction: Mutations in PTPN11 are associated with Noonan syndrome (NS). Although the effectiveness of growth hormone therapy (GHT) in treating sh ort stature due to NS has been previously demonstrated, the effect of PTPN11 mutation status on the long-term outcomes of GHT remains to be elucidated. Methods: This analysis included pooled data from the observational American Norditropin Studies: Web-Enabled Research Program (NCT01009905) and the randomized, double-blinded GHLIQUID-4020 clinical trial (NCT01927861). Pediatric patients with clinically diagnosed NS and confirmed PTPN11 mutation status were eligible for inclusion. The effectiveness analysis included patients who were GHT-naïve and pre-pubertal at GHT start. Growth outcomes and safety were assessed over 4 years of GHT (Norditropin®, Novo Nordisk A/S). Results: A total of 69 patients were included in the effectiveness analy sis (71% PTPN11 positive). The proportion of females was 32.7 and 30.0% in PTPN11-positive and negative patients, respectively, and mean age at GHT start was 6.4 years in both groups. Using general population reference data, after 4 years of GHT, the mean (s.d.) height SD score (HSDS) was −1.9 (1.1) and −1.7 (0.8) for PTPN11-positive and PTPN11-negative patients, respectively, with no statistical difference observed between gr oups. The mean (s.d.) change in HSDS at 4 years was +1.3 (0.8) in PTPN11-positive patients and +1.5 (0.7) in PTPN11-negative patients (no significant differences between groups). Sa fety findings were consistent with previous analyses. Conclusions: GHT resulted in improved growth outcomes over 4 years in GHT-n aïve, pre-pubertal NS patients, irrespective of PTPN11 mutation status.
Published: 2022
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4. Editorial: Endocrine aspects of Noonan syndrome and related syndromes

Author: Giorgio Radetti, Thomas Edouard, Laura Mazzanti, Marco Tartaglia, and Martin Zenker
Subjects: noonan syndrome (NS), RASopathies, growth hormone, RAS/MAPK pathway, growth, adult height, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Published: 2023
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5. Diagnostic yield of bone fragility gene panel sequencing in children and young adults referred for idiopathic primary osteoporosis at a single regional reference centre

Author: Coline Rouleau, Margaux Malorie, Corinne Collet, Valérie Porquet-Bordes, Isabelle Gennero, Sanaa Eddiry, Michel Laroche, Jean Pierre Salles, Guillaume Couture, and Thomas Edouard
Subjects: Bone mineral density, DXA, Early-onset osteoporosis, Idiopathic juvenile osteoporosis, Primary osteoporosis, Diseases of the musculoskeletal system, RC925-935
Abstract: Aim: To describe the presenting features, bone characteristics and molecular genetics in a large monocentric cohort of children and young adults with idiopathic primary osteoporosis. Methods: Sixty-six patients (19 children, 47 adults; 28 males, 38 females; age at referral: 3.8 to 65 years) diagnosed with primary osteoporosis were included in this study; patients with features of osteogenesis imperfecta or other known syndromes associated with osteoporosis were excluded. For each patient, the following data were collected by retrospective chart review: family and personal history of fracture and osteoporosis, mineral homeostasis parameters and markers of bone formation and resorption, bone mineral density (BMD) of the lumbar spine (LS-BMD), the total body less head (TB-BMD), and total hip levels (TH-BMD) measured by DXA. As part of the initial assessment process, a bone fragility gene panel sequencing was performed in all of these patients. Results: There was a higher predominance of males in the children (63%) and of females in the adults (66%) (p = 0.030). Compared to the adults, the children had a significantly lower frequency of vertebral fractures (26 vs 57%, p = 0.022) and a higher frequency of peripheral fractures (84 vs 53%; p = 0.019). Bone fragility gene panel sequencing allowed the identification of the heterozygous pathogenic variant in 27% of patients (most frequently in LRP5, WNT1 and COL1A1 or 2 genes) and the heterozygous p.(Val667Met) LRP5 variant in 11% of them. The frequency of pathogenic variants tended to be higher in the children compared to the adults without reaching statistical significance (42 vs 19%; p = 0.053). The frequency of the p.(Val667Met) LRP5 variant was similar in children and adults. No significant differences were found regarding the various clinical, biological and radiological characteristics of the patients according to genotype. Conclusion: In this study, we reported the presenting features and bone characteristics in a large cohort of children and young adults with idiopathic primary osteoporosis. Bone fragility gene panel sequencing allowed the identification of genetic variants in a significant proportion of these patients. Molecular diagnosis in these patients is important in order to be able to offer genetic counselling and organise patient management.
Published: 2022
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6. Prenatal features and neonatal management of severe hyperparathyroidism caused by the heterozygous inactivating calcium-sensing receptor variant, Arg185Gln: A case report and review of the literature

Author: Marion Aubert-Mucca, Charlotte Dubucs, Marion Groussolles, Julie Vial, Edouard Le Guillou, Valerie Porquet-Bordes, Eric Pasmant, Jean-Pierre Salles, and Thomas Edouard
Subjects: Calcimimetics, Calcium-sensing receptor, Familial hypocalciuric hypercalcemia, Neonatal severe hyperparathyroidism, Diseases of the musculoskeletal system, RC925-935
Abstract: Background: Loss-of-function variants in the calcium-sensing receptor (CASR) gene are known to be involved in a clinical spectrum ranging from asymptomatic familial hypocalciuric hypercalcemia (FHH) to neonatal severe hyperparathyroidism (NSHPT). Homozygous or compound heterozygous variants are usually responsible for severe neonatal forms, whereas heterozygous variants cause benign forms. One recurrent pathogenic variant, p.Arg185Gln, has been reported in both forms, in a heterozygous state. This variant can be a de novo occurrence or can be inherited from a father with FHH.NSHPT leads to global hypotonia, failure to thrive, typical X-ray anomalies (diffuse demineralization, fractures, metaphyseal irregularities), and acute respiratory distress which can be fatal. Phosphocalcic markers show severe hypercalcemia, abnormal urinary calcium resorption, and hyperparathyroidism as major signs.Classical treatment involves calcium restriction, hyperhydration, and bisphosphonates. Unfortunately, the disease often leads to parathyroidectomy. Recently, calcimimetics have been used with variable efficacy. Efficacy in NSHPT seems to be particularly dependent on CASR genotype. Case presentation: We describe the antenatal presentation of a male with short ribs, initially suspected having skeletal ciliopathy. At birth, he presented with NSHPT linked to the pathogenic heterozygous CASR variant, Arg185Gln, inherited from his father who had FHH. Postnatal therapy with cinacalcet was successful. Discussion: An exhaustive literature review permits a comparison with all reported cases of Arg185Gln and to hypothesize that cinacalcet efficacy depends on CASR genotype. This confirms the importance of pedigree and parental history in antenatal short rib presentation and questions the feasibility of phosphocalcic exploration during pregnancy or prenatal CASR gene sequencing in the presence of specific clinical signs. It could in fact enable early calcimimetic treatment which might be effective in the CASR variant Arg185Gln.
Published: 2021
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7. A +3 variant at a donor splice site leads to a skipping of the MYH11 exon 32, a recurrent RNA defect causing Heritable Thoracic Aortic Aneurysm and Dissection and/or Patent Ductus Arteriosus

Author: Bertrand Chesneau, Aurélie Plancke, Guillaume Rolland, Bertrand Marcheix, Yves Dulac, Thomas Edouard, Julie Plaisancié, Marion Aubert‐Mucca, Sophie Julia, Maud Langeois, Thierry Lavabre‐Bertrand, and Philippe Khau Van Kien
Subjects: genotype–phenotype correlation, heritable aortic aneurysm syndrome, MYH11, patent ductus arteriosus, splicing, Genetics, QH426-470
Abstract: Abstract Background Pathogenic variants in MYH11 are associated with either heritable thoracic aortic aneurysm and dissection (HTAAD), patent ductus arteriosus (PDA) syndrome, or megacystis‐microcolon‐intestinal hypoperistalsis syndrome (MMIHS). Methods and Results We report a family referred for molecular diagnosis with HTAAD/PDA phenotype in which we found a variant at a non‐conserved position of the 5’ donor splice site of intron 32 of MYH11 potentially altering splicing (NM_002474.3:c.4578+3A>C). Although its cosegregation with disease was observed, it remained of unknown significance. Later, aortic surgery in the proband gave us the opportunity to perform a transcript analysis. This showed a skipping of the exon 32, an RNA defect previously reported to be translated to an in‐frame loss of 71 amino acids and a dominant‐negative effect in the smooth muscle myosin rod. This RNA defect is also reported in 3 other HTAAD/PDA pedigrees. Conclusion This report confirms that among rare variants in MYH11, skipping of exon 32 is recurrent. This finding is of particular interest to establish complex genotype–phenotype correlations where some alleles are associated with autosomal dominant HTAAD/PDA, while others result in recessive or dominant visceral myopathies.
Published: 2021
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8. The Tyrosine Phosphatase SHP2: A New Target for Insulin Resistance?

Author: Céline Saint-Laurent, Laurène Mazeyrie, Mylène Tajan, Romain Paccoud, Isabelle Castan-Laurell, Philippe Valet, Thomas Edouard, Jean-Philippe Pradère, Cédric Dray, and Armelle Yart
Subjects: SH2 containing protein tyrosine phosphatase 2, Noonan syndrome, insulin resistance, macrophage, inflammation, Biology (General), QH301-705.5
Abstract: The SH2 containing protein tyrosine phosphatase 2(SHP2) plays essential roles in fundamental signaling pathways, conferring on it versatile physiological functions during development and in homeostasis maintenance, and leading to major pathological outcomes when dysregulated. Many studies have documented that SHP2 modulation disrupted glucose homeostasis, pointing out a relationship between its dysfunction and insulin resistance, and the therapeutic potential of its targeting. While studies from cellular or tissue-specific models concluded on both pros-and-cons effects of SHP2 on insulin resistance, recent data from integrated systems argued for an insulin resistance promoting role for SHP2, and therefore a therapeutic benefit of its inhibition. In this review, we will summarize the general knowledge of SHP2’s molecular, cellular, and physiological functions, explaining the pathophysiological impact of its dysfunctions, then discuss its protective or promoting roles in insulin resistance as well as the potency and limitations of its pharmacological modulation.
Published: 2022
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9. Next-Generation Sequencing Analysis Reveals Frequent Familial Origin and Oligogenism in Congenital Hypothyroidism With Dyshormonogenesis

Author: Isabelle Oliver-Petit, Thomas Edouard, Virginie Jacques, Marie Bournez, Audrey Cartault, Solange Grunenwald, and Frédérique Savagner
Subjects: high throughput molecular screening, familial origin, oligogenicity, congenital hypothyroidism, thyroid dyshormonogenesis, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract: ContextCongenital hypothyroidism (CH) is related to dyshormonogenesis in 15% to 40% of the world population and associated with homozygous or heterozygous variants in the main genes of the hormone synthesis pathway. Emerging diagnostic tools, such as next-generation sequencing (NGS), have been used to efficiently explore panels of genes and identify complex mechanisms of pathogenesis.ObjectiveWe explored 19 candidate genes known to be causative for permanent or transient CH to evaluate the role of complex gene variations in CH phenotype.Patients, Design and SettingUsing the NGS approach, we studied 65 newborns with thyroid dyshormonogenesis (TDH). New variants were assessed in silico for pathogenicity.ResultsAmong the 65 infants, 56.9% presented a variant in one or more genes of the thyroid hormone synthesis axis. We identified homozygous or compound heterozygous variants in the TG, DUOX2, TPO, or SLC5A5 genes in 10 infants and heterozygous variants in DUOX2, TG, TPO, and TSHR in 19 others. In seven cases, a heterozygous variant in the TG gene was the unique anomaly detected, but related to disturbed hormonal balance. Oligogenic variants were found in eight infants associated with severe CH and goiter in five of them.ConclusionThe systematic exploration of genes involved in thyroid hormone synthesis by NGS in TDH showed high diagnostic relevance. Oligogenic inheritance could be related to phenotypic heterogeneity and a high frequency of goiter.
Published: 2021
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10. Clinical and genetic data of 22 new patients with SMAD3 pathogenic variants and review of the literature

Author: Bertrand Chesneau, Thomas Edouard, Yves Dulac, Hélène Colineaux, Maud Langeois, Nadine Hanna, Catherine Boileau, Pauline Arnaud, Nicolas Chassaing, Sophie Julia, Guillaume Jondeau, Aurélie Plancke, Philippe Khau Van Kien, and Julie Plaisancié
Subjects: Aneurysms‐Osteoarthritis syndrome, Loeys–Dietz syndrome, SMAD3, TGFβ, Genetics, QH426-470
Abstract: Abstract Background Pathogenic SMAD3 variants are responsible for a cardiovascular phenotype, mainly thoracic aortic aneurysms and dissections. Precocious identification of the vascular risk such as aortic dilatation in mutated patients has a major impact in terms of management, particularly to avoid dissection and sudden death. These vascular damages are classically associated with premature osteoarthritis and skeletal abnormalities. However, variable expressivity and incomplete penetrance are common with SMAD3 variants. Methods To investigate the clinical variability observed within SMAD3 patients, we reviewed the phenotypic and genetic data of 22 new patients from our Centre and of 133 patients reported in the literature. From this cohort of 155 mutated individuals, we first aimed to delineate an estimated frequency of the main clinical signs associated with SMAD3 pathogenic variants and, then, to look for genotype‐phenotype correlations, mainly to see if the aortic phenotype (AP) could be predicted by the SMAD3 variant type. Results We showed, herein, the absence of correlation between the SMAD3 variant type and the occurrence of an AP in patients. Conclusion Therefore, this report brings additional data for the genotype‐phenotype correlations of SMAD3 variants and the need to explore in more detail the effects of genetic modifiers that could influence the phenotype.
Published: 2020
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11. Pituitary Stalk Interruption Syndrome from Infancy to Adulthood: Clinical, Hormonal, and Radiological Assessment According to the Initial Presentation.

Author: Céline Bar, Charline Zadro, Gwenaelle Diene, Isabelle Oliver, Catherine Pienkowski, Béatrice Jouret, Audrey Cartault, Zeina Ajaltouni, Jean-Pierre Salles, Annick Sevely, Maithé Tauber, and Thomas Edouard
Subjects: Medicine, Science
Abstract: Patients with pituitary stalk interruption syndrome (PSIS) are initially referred for hypoglycemia during the neonatal period or growth retardation during childhood. PSIS is either isolated (nonsyndromic) or associated with extra-pituitary malformations (syndromic).To compare baseline characteristics and long-term evolution in patients with PSIS according to the initial presentation.Sixty-seven patients with PSIS were included. Data from subgroups were compared: neonates (n = 10) versus growth retardation patients (n = 47), and syndromic (n = 32) versus nonsyndromic patients (n = 35).Neonates displayed a more severe hormonal and radiological phenotype than children referred for growth retardation, with a higher incidence of multiple hormonal deficiencies (100% versus 34%; P = 0.0005) and a nonvisible anterior pituitary lobe (33% versus 2%; P = 0.0017). Regular follow-up of growth might have allowed earlier diagnosis in the children with growth retardation, as decreased growth velocity and growth retardation were present respectively 3 and 2 years before referral. We documented a progressive worsening of endocrine impairment throughout childhood in these patients. Presence of extra-pituitary malformations (found in 48%) was not associated with more severe hormonal and radiological characteristics. Growth under GH treatment was similar in the patient groups and did not vary according to the pituitary MRI findings.PSIS diagnosed in the neonatal period has a particularly severe hormonal and radiological phenotype. The progressive worsening of endocrine impairment throughout childhood justifies periodic follow-up to check for additional hormonal deficiencies.
Published: 2015
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12. Accelerated estimation of coffee sensory profiles using an AI-assisted electronic tongue

Author: Gabrieli, Gianmarco, Muszynski, Michal, Thomas, Edouard, Labbe, David, and Ruch, Patrick W.
Published: 2022
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13. A +3 variant at a donor splice site leads to a skipping of the MYH11 exon 32, a recurrent RNA defect causing Heritable Thoracic Aortic Aneurysm and Dissection and/or Patent Ductus Arteriosus

Author: Marion Aubert-Mucca, Bertrand Chesneau, Maud Langeois, Aurélie Plancke, Sophie Julia, Philippe Khau Van Kien, Bertrand Marcheix, Guillaume Rolland, Yves Dulac, Julie Plaisancié, Thomas Edouard, and Thierry Lavabre-Bertrand
Subjects: Male, Proband, Pathology, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, RNA Splicing, MYH11, heritable aortic aneurysm syndrome, QH426-470, Thoracic aortic aneurysm, Clinical Reports, Young Adult, Exon, patent ductus arteriosus, splicing, Ductus arteriosus, medicine, Genetics, Humans, Allele, Ductus Arteriosus, Patent, Molecular Biology, Genetics (clinical), Clinical Report, Aortic Aneurysm, Thoracic, Myosin Heavy Chains, business.industry, Intron, Exons, genotype–phenotype correlation, medicine.disease, Aortic Dissection, medicine.anatomical_structure, Mutation, RNA splicing, RNA Splice Sites, business
Abstract: Background Pathogenic variants in MYH11 are associated with either heritable thoracic aortic aneurysm and dissection (HTAAD), patent ductus arteriosus (PDA) syndrome, or megacystis‐microcolon‐intestinal hypoperistalsis syndrome (MMIHS). Methods and Results We report a family referred for molecular diagnosis with HTAAD/PDA phenotype in which we found a variant at a non‐conserved position of the 5’ donor splice site of intron 32 of MYH11 potentially altering splicing (NM_002474.3:c.4578+3A>C). Although its cosegregation with disease was observed, it remained of unknown significance. Later, aortic surgery in the proband gave us the opportunity to perform a transcript analysis. This showed a skipping of the exon 32, an RNA defect previously reported to be translated to an in‐frame loss of 71 amino acids and a dominant‐negative effect in the smooth muscle myosin rod. This RNA defect is also reported in 3 other HTAAD/PDA pedigrees. Conclusion This report confirms that among rare variants in MYH11, skipping of exon 32 is recurrent. This finding is of particular interest to establish complex genotype–phenotype correlations where some alleles are associated with autosomal dominant HTAAD/PDA, while others result in recessive or dominant visceral myopathies., We report on a family with heritable thoracic aortic aneurysm and/or dissection with patent ductus arteriosus (FTAAD/PDA) caused by a variant leading to a skipping of the exon 32 in the MYH11 gene. This transcripts defect previously shown to lead to a strong dominant negative effect in the smooth muscle myosin rod is recurrent. It highlights some unclear genotype‐phenotype correlations suggested by literature with some alleles associated with autosomal dominant FTAAD/PDA while others result in recessive visceral myopathies.
Published: 2021

14. Opportune maintenance and predictive maintenance decision support

Author: Thomas, Édouard, Levrat, Éric, Iung, Benoit, and Cocheteux, Pierre
Published: 2009
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15. Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation

Author: Karine Duroure, Estelle Colin, Thomas Edouard, Ludovic Martin, Linda Grimaud, Lyndon Gallacher, George McGillivray, Guy Lenaers, Valérie Desquiret-Dumas, Clarisse Billon, Anne Breton, Mohammed Zarhrate, Emmanuel Mas, Dominique Bonneau, Lynn Pais, Daniel Henrion, Thomas Haaf, Reza Maroofian, Marianna Parlato, Frank M. Ruemmele, Anne-Laure Guihot, Anaïs Philippe, Ehsan Ghayoor Karimiani, Pauline E. Schneeberger, Stanislas Lyonnet, Bernadette Bègue, Bruno Moulin, Rémi Duclaux-Loras, Nicolas Cagnard, Michael Frank, Laurence Faivre, Ruben Attali, Yves Alembik, Filippo Del Bene, Kerstin Kutsche, Céline Revenu, Fabienne Charbit-Henrion, Katta M. Girisha, Aboulfazl Rad, Eyal Reinstein, Shalini S. Nayak, Barbara Vona, Nadine Cerf-Bensussan, Caroline Lekszas, Shay Tzur, Alban Ziegler, Susan M. White, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Intestinal Immunity (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de la Vision, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Ingénierie Radioprotection Sûreté Démantèlement (IRSD), Centre National de la Recherche Scientifique (CNRS), Geroscience and rejuvenation research center (RESTORE), Université de Toulouse (UT)-Université de Toulouse (UT)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Embryology and genetics of human malformation, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital de Hautepierre [Strasbourg], Nouvel Hôpital Civil de Strasbourg, Tel Aviv University (TAU), Emedgene Technologies [Tel Aviv], Murdoch Children's Research Institute (MCRI), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Kasturba Medical College, Manipal, Massachusetts Institute of Technology (MIT), University College of London [London] (UCL), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, St George's, University of London, University of Würzburg = Universität Würzburg, Fondation Princesse Grace, Fondation Maladies Rares, Harbig Family Foundation, Royal Children's Hospital Foundation, University of Tubingen (2545-1-0), Federal Ministry of Education and Research (01DQ17003 to K.K.), Indian Council of Medical Research (file no. 5/7/1508/2016 to K.M.G), National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung, and Blood Institute grant UM1 HG008900, National Human Genome Research Institute grant R01 HG009141, Victorian Government's Operational Infrastructure Support Program, ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-18-IAHU-0001,FOReSIGHT,Enabling Vision Restoration(2018), European Project: 661527,H2020,H2020-MSCA-IF-2014,NMJALS(2015), European Project: 339407,EC:FP7:ERC,ERC-2013-ADG,IMMUNOBIOTA(2014), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Autophagie infection et immunité - Autophagy Infection Immunity (APY), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Embryology and genetics of human malformation (Equipe Inserm U1163), SEGUIN, Nathalie, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Enabling Vision Restoration - - FOReSIGHT2018 - ANR-18-IAHU-0001 - IAHU - VALID, In vivo analysis of neuromuscular junction stability in zebrafish models of amyotrophic lateral sclerosis - NMJALS - - H20202015-11-16 - 2017-11-15 - 661527 - VALID, Host-microbiota interactions across the gut immune system:lessons from early onset inflammatory bowel diseases and from gnotobiotic mice - IMMUNOBIOTA - - EC:FP7:ERC2014-03-01 - 2019-02-28 - 339407 - VALID, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Connective Tissue Disorder, Loss of Heterozygosity, [SDV.GEN] Life Sciences [q-bio]/Genetics, medicine.disease_cause, IPO8, TGF-β signaling, Pathogenesis, 0302 clinical medicine, Loss of Function Mutation, Transforming Growth Factor beta, connective tissue disorder, Child, Connective Tissue Diseases, Zebrafish, Genetics (clinical), Karyopherin, chemistry.chemical_classification, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Immunity, Cellular, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Middle Aged, beta Karyopherins, Pedigree, arterial dilatation, Cell biology, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Phenotype, medicine.anatomical_structure, Cardiovascular Diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, Bone Diseases, Signal Transduction, Adult, Adolescent, Connective tissue, Biology, Importin 8, Young Adult, 03 medical and health sciences, [SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Report, Genetics, medicine, Animals, Humans, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Infant, Immune dysregulation, Loeys-Dietz syndrome, biology.organism_classification, joint hyperlaxity, chemistry, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Transforming growth factor
Abstract: International audience; Dysregulated transforming growth factor TGF-beta signaling underlies the pathogenesis of genetic disorders affecting the connective tissue such as Loeys-Dietz syndrome. Here, we report 12 individuals with bi-allelic loss-of-function variants in IPO8 who presented with a syndromic association characterized by cardio-vascular anomalies, joint hyperlaxity, and various degree of dysmorphic features and developmental delay as well as immune dysregulation; the individuals were from nine unrelated families. Importin 8 belongs to the karyopherin family of nuclear transport receptors and was previously shown to mediate TGF-beta-dependent SMADs trafficking to the nucleus in vitro. The important in vivo role of IPO8 in pSMAD nuclear translocation was demonstrated by CRISPR/Cas9-mediated inactivation in zebrafish. Consistent with IPO8's role in BMP/TGF-beta signaling, ipo8(-/-) zebrafish presented mild to severe dorso-ventral patterning defects during early embryonic development. Moreover, ipo8(-/-) zebrafish displayed severe cardiovascular and skeletal defects that mirrored the human phenotype. Our work thus provides evidence that IPO8 plays a critical and non-redundant role in TGF-beta signaling during development and reinforces the existing link between TGF-beta signaling and connective tissue defects.
Published: 2021
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16. Prenatal features and neonatal management of severe hyperparathyroidism caused by the heterozygous inactivating calcium-sensing receptor variant, Arg185Gln: A case report and review of the literature

Author: Valerie Porquet-Bordes, Marion Groussolles, Edouard Le Guillou, Charlotte Dubucs, Marion Aubert-Mucca, Eric Pasmant, Julie Vial, Jean-Pierre Salles, and Thomas Edouard
Subjects: 0301 basic medicine, Parathyroidectomy, Cinacalcet, Neonatal severe hyperparathyroidism, Familial hypocalciuric hypercalcemia, Calcimimetic, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, 030209 endocrinology & metabolism, Case Report, Diseases of the musculoskeletal system, Compound heterozygosity, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Calcium-sensing receptor, medicine, Orthopedics and Sports Medicine, Hyperparathyroidism, business.industry, Calcimimetics, medicine.disease, RC925-935, Failure to thrive, 030101 anatomy & morphology, medicine.symptom, business, medicine.drug
Abstract: Background Loss-of-function variants in the calcium-sensing receptor (CASR) gene are known to be involved in a clinical spectrum ranging from asymptomatic familial hypocalciuric hypercalcemia (FHH) to neonatal severe hyperparathyroidism (NSHPT). Homozygous or compound heterozygous variants are usually responsible for severe neonatal forms, whereas heterozygous variants cause benign forms. One recurrent pathogenic variant, p.Arg185Gln, has been reported in both forms, in a heterozygous state. This variant can be a de novo occurrence or can be inherited from a father with FHH. NSHPT leads to global hypotonia, failure to thrive, typical X-ray anomalies (diffuse demineralization, fractures, metaphyseal irregularities), and acute respiratory distress which can be fatal. Phosphocalcic markers show severe hypercalcemia, abnormal urinary calcium resorption, and hyperparathyroidism as major signs. Classical treatment involves calcium restriction, hyperhydration, and bisphosphonates. Unfortunately, the disease often leads to parathyroidectomy. Recently, calcimimetics have been used with variable efficacy. Efficacy in NSHPT seems to be particularly dependent on CASR genotype. Case presentation We describe the antenatal presentation of a male with short ribs, initially suspected having skeletal ciliopathy. At birth, he presented with NSHPT linked to the pathogenic heterozygous CASR variant, Arg185Gln, inherited from his father who had FHH. Postnatal therapy with cinacalcet was successful. Discussion An exhaustive literature review permits a comparison with all reported cases of Arg185Gln and to hypothesize that cinacalcet efficacy depends on CASR genotype. This confirms the importance of pedigree and parental history in antenatal short rib presentation and questions the feasibility of phosphocalcic exploration during pregnancy or prenatal CASR gene sequencing in the presence of specific clinical signs. It could in fact enable early calcimimetic treatment which might be effective in the CASR variant Arg185Gln.
Published: 2021

17. OVERVIEW ON OPPORTUNISTIC MAINTENANCE

Author: Thomas, Édouard, Levrat, Éric, and Iung, BenoÎt
Published: 2008
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18. Bone Health in Pediatric Patients With Crohn Disease.

Author: Rozes, Sylvana, Guilmin-Crepon, Sophie, Alison, Marianne, Thomas, Edouard, Hugot, Jean-Pierre, Viala, Jerome, and Martinez-Vinson, Christine
Published: 2021
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19. Chapter 18 - Sensory Evaluation—Profiling and Preferences

Author: Thomas, Edouard, Puget, Sabine, Valentin, Dominique, and Songer, Paul
Published: 2017
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20. Contribution of LHX4 Mutations to Pituitary Deficits in a Cohort of 417 Unrelated Patients

Author: Michel Polak, Enzo Cohen, Sophie Rose, Frédéric Brioude, Nathalie Collot, Daniela Larizza, Marie Legendre, Florence Dastot, Juliane Léger, Anne Marie Bertrand, Philippe Duquesnoy, Marie Laure Sobrier, Philippe Touraine, Mohamad Maghnie, Bruno Copin, Maïté Tauber, Irène Netchine, Serge Amselem, Isabelle Oliver-Petit, Laura González Briceño, Thomas Edouard, Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli studi di Genova = University of Genoa (UniGe), Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Référence des Maladies Endocriniennes Rares de la Croissance [APHP Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service d'endocrinologie, gynécologie et diabétologie pédiatriques [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Chirurgie Digestive et Endocrinienne [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de Diabétologie - Endocrinologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'explorations fonctionnelles [CHU Trousseau], Fondazione IRCCS Policlinico San Matteo [Pavia], Università degli Studi di Pavia = University of Pavia (UNIPV), Couvet, Sandrine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], and Societe Francaise d'Endocrinologie et Diabetologie PediatriqueFondation pour la Recherche Medicale PLP20131028838
Subjects: 0301 basic medicine, Male, Pituitary gland, MESH: Sequence Homology, Amino Acid, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Sequence Homology, Hypopituitarism, MESH: Amino Acid Sequence, medicine.disease_cause, MESH: Hypopituitarism, Biochemistry, Cohort Studies, 0302 clinical medicine, Endocrinology, MESH: Child, Child, MESH: Cohort Studies, Genetics, Sanger sequencing, Mutation, Blotting, MESH: Infant, Newborn, MESH: Transcription Factors, MESH: Follow-Up Studies, Prognosis, MESH: Infant, Ectopic Posterior Pituitary, Pedigree, Diabetes and Metabolism, [SDV] Life Sciences [q-bio], Amino Acid, medicine.anatomical_structure, Sella turcica, Child, Preschool, symbols, Female, Western, medicine.medical_specialty, MESH: Mutation, Adolescent, MESH: Pedigree, Blotting, Western, LIM-Homeodomain Proteins, 030209 endocrinology & metabolism, Context (language use), Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Prognosis, 03 medical and health sciences, symbols.namesake, Internal medicine, medicine, Humans, Immunoprecipitation, MESH: Blotting, Western, Amino Acid Sequence, Preschool, Biomarkers, Follow-Up Studies, Infant, Infant, Newborn, Sequence Homology, Amino Acid, Transcription Factors, Biochemistry (medical), MESH: Adolescent, MESH: LIM-Homeodomain Proteins, MESH: Humans, MESH: Immunoprecipitation, MESH: Child, Preschool, Heterozygote advantage, medicine.disease, Newborn, MESH: Male, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Biomarkers, MESH: Female
Abstract: Context:LHX4 encodes a LIM-homeodomain transcription factor that is implicated in early pituitary development. In humans, only 13 heterozygous LHX4 mutations have been associated with congenital hypopituitarism.Objective:The aims of this study were to evaluate the prevalence of LHX4 mutations in patients with hypopituitarism, to define the associated phenotypes, and to characterize the functional impact of the identified variants and the respective role of the 2 LIM domains of LHX4.Design and Patients:We screened 417 unrelated patients with isolated growth hormone deficiency or combined pituitary hormone deficiency associated with ectopic posterior pituitary and/or sella turcica anomalies for LHX4 mutations (Sanger sequencing). In vitro studies were performed to assess the functional consequences of the identified variants.Results:We identified 7 heterozygous variations, including p.(Tyr131*), p.(Arg48Thrfs*104), c.606+1G>T, p.Arg65Val, p.Thr163Pro, p.Arg221Gln, and p.Arg235Gln), that were associated with variable expressivity; 5 of the 7 were also associated with incomplete penetrance. The p.(Tyr131*), p.(Arg48Thrfs*104), p.Ala65Val, p.Thr163Pro, and p.Arg221Gln LHX4 variants are unable to transactivate the POU1F1 and GH promoters. As suggested by transactivation, subcellular localization, and protein-protein interaction studies, p.Arg235Gln is probably a rare polymorphism. Coimmunoprecipitation studies identified LHX3 as a potential protein partner of LHX4. As revealed by functional studies of LIM-defective recombinant LHX4 proteins, the LIM1 and LIM2 domains are not redundant.Conclusion:This study, performed in the largest cohort of patients screened so far for LHX4 mutations, describes 6 disease-causing mutations that are responsible for congenital hypopituitarism. LHX4 mutations were found to be associated with variable expressivity, and most of them with incomplete penetrance; their contribution to pituitary deficits that are associated with an ectopic posterior pituitary and/or a sella turcica defect is ∼1.4% in the 417 probands tested.
Published: 2017
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21. Growth patterns of patients with Noonan syndrome: correlation with age and genotype

Author: Sabine Baron, Jacques Weill, Catherine Arnaud, Catie Cessans, Yline Capri, Benoit Cammas, Pascal Barat, Armelle Yart, Bruno Leheup, Jean-Pierre Salles, Didier Lacombe, Virginie Ehlinger, Régis Coutant, Marc Nicolino, Thomas Edouard, Hélène Cavé, Alain Verloes, Maithé Tauber, Albert David, Centre d'Endocrinologie, Maladies Osseuses, Génétique et Gynécologie Médicale, Hôpital des Enfants, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'épidémiologie [Toulouse], CHU Toulouse [Toulouse], Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Endocrinologie pédiatrique[CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Université d'Angers (UA), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Endocrinologie Pédiatrique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'endocrinologie pédiatrique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Jeanne de Flandre [Lille], Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service d'endocrinologie pédiatrique [CHU Lyon-Hospices Civils de Lyon], Hospices Civils de Lyon (HCL), Centre de Physiopathologie Toulouse Purpan (CPTP), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], medicine.disease_cause, Gastroenterology, Body Mass Index, 0302 clinical medicine, Endocrinology, Genotype, Birth Weight, Rescues, Young adult, Child, Leopard-Syndrome, 2. Zero hunger, education.field_of_study, Noonan Syndrome, Age Factors, General Medicine, Child, Preschool, Population study, Female, Defects, KRAS, Gestation, Adult, musculoskeletal diseases, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Standards, Born, Birth weight, Population, Activation, 030209 endocrinology & metabolism, Young Adult, 03 medical and health sciences, PTPN11 SHP2 Mutations, Internal medicine, medicine, Humans, education, business.industry, Body Weight, Infant, Newborn, medicine.disease, Body Height, 030104 developmental biology, Noonan syndrome, business, Body mass index, Pathway
Abstract: BackgroundGrowth patterns of patients with Noonan syndrome (NS) were established before the involved genes were identified.ObjectiveThe goal of this study was to compare growth parameters according to genotype in patients with NS.Subjects and methodsThe study population included 420 patients (176 females and 244 males) harboring mutations in thePTPN11,SOS1,RAF1, orKRASgenes. NS-associatedPTPN11mutations (NS-PTPN11) and NS with multiple lentigines-associatedPTPN11mutations (NSML-PTPN11) were distinguished. Birth measures and height and body mass index (BMI) measures at 2, 5, 10 years, and adulthood were compared with the general population and between genotypes.ResultsPatients with NS were shorter at birth (mean birth length standard deviation score (SDS): –1.0 ± 1.4;P< 0.001) and throughout childhood than the healthy population, with height SDS being –2.1 ± 1.3 at 2 years, and –2.1 ± 1.2 at 5 and 10 years and adulthood (P< 0.001). At birth, patients withNS-PTPN11were significantly shorter and thinner than patients withNSML-PTPN11,SOS1, orKRAS. Growth retardation was significantly less severe and less frequent at 2 years in patients withNSML-PTPN11andSOS1than in patients withNS-PTPN11(P< 0.001 andP= 0.002 respectively). Patients with NS had lower BMI at 10 years (P< 0.001). No difference between genotypes was demonstrated.ConclusionDetermining the growth patterns of patients with NS according to genotype should better inform clinicians about the natural course of growth in NS so that they can optimize the follow-up and management of these patients.
Published: 2016
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22. 0362 : Marfan syndrome diagnosed during childhood: focus on cardiac events in the French database

Author: Bruno Leheup, Jean Ferrière, Guillaume Jondeau, Thomas Edouard, Sébastien Hascoët, Nicole Philip, Bertrand Chevallier, Olivier Milleron, Sylvie Odent, Yves Dulac, Chantal Stheneur, Laurence Olivier-Faivre, Sophie Dupuis-Girod, Philippe Acar, F. Arnoult, Cécile Zordan, Nathalie Blot-Souletie, Service Cardiologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre d'Endocrinologie, Maladies Osseuses, Génétique et Gynécologie Médicale, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de Génétique, Hospices Civils de Lyon (HCL)-Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Groupe Hospitalier Est, Service de cardiologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service d'explorations fonctionnelles, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Pediatrics, Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bichat, Service de pédiatrie, urgences enfants [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de référence MARFAN, Hôpital Bichat, Service pédiatrie-cardiologie, CHU Toulouse [Toulouse]-Hôpital des Enfants, CHU Toulouse [Toulouse], Hôpital des Enfants, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bichat, Service de pédiatrie, urgences enfants, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Ambroise Paré [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: Marfan syndrome, Aortic dissection, medicine.medical_specialty, Aorta, business.industry, Incidence (epidemiology), [SDV]Life Sciences [q-bio], Bentall procedure, Mechanical Aortic Valve, 030204 cardiovascular system & hematology, medicine.disease, Surgery, 03 medical and health sciences, Dissection, 0302 clinical medicine, Interquartile range, medicine.artery, medicine, 030212 general & internal medicine, business, Cardiology and Cardiovascular Medicine
Abstract: International audience; Objectives Life expectancy of patients with Marfan syndrome has increased, due to earlier diagnosis, better familial screening, regular follow-up (FU) and prophylactic aortic surgery (PASu). Incidence of events in affected patients recognized during childhood is unknown. Methods 465 patients with Marfan syndrome, diagnosed before 18y.o. were included in the French multicenter database. Cardio-vascular events (death, aortic dissection or PASu) were recorded Results A cardio-vascular event occurred in 25 patients (5.4% 95CI 3.5- 7.8%), including PASu (n=20, 4.3% 95CI 2.5-6.2%), aortic dissection (n=3, 0.6% 95CI 0.0-1.4%) and deaths (n=2, 0.4% 95CI 0.0-1.0%). 16 events (64%) occurred before 19 year-old (Median 15.0, min 2.8, interquartile 11.7-16.3; PASu n=12, deaths n=2 and dissection n= 2). An aortic surgery was performed in 23 patients (4.9%, 95CI 3.0-6.9%), including a Bentall procedure with mechanical aortic valve in 10 (43.5%), a valve sparing surgery in the remaining 13 (56.5%) and a supra-coronary graft in 4 (17.4%, dissection: n=2 and PASu: n=2). Mean age at the date of PASu was 17.1±6.5 year-old. Events occurred before or at inclusion in the database in 8 patients (32.0%) (PASu n=5, dissection n=2, death n=1). Dissection was observed before inclusion in 2 patients and during pregnancy in 1 patient. Kaplan-Meier survival estimate indicates that 95% of patients remained free from events at eighteen and 78% at thirty year-old. Conclusion Prophylactic surgery for enlarged aorta is the main cause of cardiac events in patients with Marfan syndrome diagnosed during childhood. A quarter of them have a cardiac event before thirty year-old.
Published: 2015
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23. Pituitary Stalk Interruption Syndrome from Infancy to Adulthood: Clinical, Hormonal, and Radiological Assessment According to the Initial Presentation

Author: Charline Zadro, Jean-Pierre Salles, Gwenaelle Diene, Isabelle Oliver, Béatrice Jouret, Annick Sevely, Catherine Pienkowski, Audrey Cartault, Céline Bar, Maithé Tauber, Thomas Edouard, and Zeina Ajaltouni
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Pathology, Pituitary gland, Pituitary Stalk Interruption Syndrome, Adolescent, Hormone Replacement Therapy, Pituitary Diseases, lcsh:Medicine, Hypoglycemia, Pituitary Gland, Anterior, Hormone replacement therapy (male-to-female), Humans, Medicine, Longitudinal Studies, Child, lcsh:Science, Growth Disorders, Retrospective Studies, Multidisciplinary, business.industry, lcsh:R, Infant, Newborn, Infant, Retrospective cohort study, Syndrome, medicine.disease, Magnetic Resonance Imaging, Hormones, Radiography, Treatment Outcome, medicine.anatomical_structure, Child, Preschool, Pituitary Gland, Radiological weapon, Regression Analysis, Female, lcsh:Q, Presentation (obstetrics), business, Research Article, Hormone
Abstract: Background Patients with pituitary stalk interruption syndrome (PSIS) are initially referred for hypoglycemia during the neonatal period or growth retardation during childhood. PSIS is either isolated (nonsyndromic) or associated with extra-pituitary malformations (syndromic). Objective To compare baseline characteristics and long-term evolution in patients with PSIS according to the initial presentation. Study Design Sixty-seven patients with PSIS were included. Data from subgroups were compared: neonates (n = 10) versus growth retardation patients (n = 47), and syndromic (n = 32) versus nonsyndromic patients (n = 35). Results Neonates displayed a more severe hormonal and radiological phenotype than children referred for growth retardation, with a higher incidence of multiple hormonal deficiencies (100% versus 34%; P = 0.0005) and a nonvisible anterior pituitary lobe (33% versus 2%; P = 0.0017). Regular follow-up of growth might have allowed earlier diagnosis in the children with growth retardation, as decreased growth velocity and growth retardation were present respectively 3 and 2 years before referral. We documented a progressive worsening of endocrine impairment throughout childhood in these patients. Presence of extra-pituitary malformations (found in 48%) was not associated with more severe hormonal and radiological characteristics. Growth under GH treatment was similar in the patient groups and did not vary according to the pituitary MRI findings. Conclusions PSIS diagnosed in the neonatal period has a particularly severe hormonal and radiological phenotype. The progressive worsening of endocrine impairment throughout childhood justifies periodic follow-up to check for additional hormonal deficiencies.
Published: 2015

24. LEOPARD syndrome-associated SHP2 mutation confers leanness and protection from diet-induced obesity

Author: Patrick Raynal, Karine Tréguer, Maithé Tauber, Mylène Tajan, Philippe Valet, Aurélie Batut, Sophie Le Gonidec, Marie-Adeline Marques, Armelle Yart, Thomas Edouard, Céline Saint Laurent, Claire Vinel, Jean-Pierre Salles, Oksana Kunduzova, Thomas Cadoudal, Hélène Cavé, Joffrey Pozzo, Estelle Wanecq, Simon Deleruyelle, Maëlle Vomscheid, Audrey De Rocca Serra-Nédélec, Centre d’Etudes et de Recherches en Psychopathologie et Psychologie de la Santé (CERPPS), and Université Toulouse - Jean Jaurès (UT2J)
Subjects: Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Lipolysis, MAP Kinase Kinase Kinase 1, Mice, Transgenic, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Biology, medicine.disease_cause, LEOPARD Syndrome, Short stature, Mice, Thinness, Internal medicine, medicine, Adipocytes, Animals, Insulin, Obesity, Hypertelorism, ComputingMilieux_MISCELLANEOUS, Adiposity, 2. Zero hunger, Recombination, Genetic, Mutation, Multidisciplinary, Lentivirus, Cell Differentiation, medicine.disease, Phenotype, 3. Good health, Diet, PTPN11, Insulin receptor, Disease Models, Animal, Endocrinology, PNAS Plus, Adipose Tissue, biology.protein, Body Composition, medicine.symptom, Energy Metabolism, Noonan Syndrome with Multiple Lentigines
Abstract: LEOPARD syndrome (multiple Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, sensorineural Deafness; LS), also called Noonan syndrome with multiple lentigines (NSML), is a rare autosomal dominant disorder associating various developmental defects, notably cardiopathies, dysmorphism, and short stature. It is mainly caused by mutations of the PTPN11 gene that catalytically inactivate the tyrosine phosphatase SHP2 (Src-homology 2 domain-containing phosphatase 2). Besides its pleiotropic roles during development, SHP2 plays key functions in energetic metabolism regulation. However, the metabolic outcomes of LS mutations have never been examined. Therefore, we performed an extensive metabolic exploration of an original LS mouse model, expressing the T468M mutation of SHP2, frequently borne by LS patients. Our results reveal that, besides expected symptoms, LS animals display a strong reduction of adiposity and resistance to diet-induced obesity, associated with overall better metabolic profile. We provide evidence that LS mutant expression impairs adipogenesis, triggers energy expenditure, and enhances insulin signaling, three features that can contribute to the lean phenotype of LS mice. Interestingly, chronic treatment of LS mice with low doses of MEK inhibitor, but not rapamycin, resulted in weight and adiposity gains. Importantly, preliminary data in a French cohort of LS patients suggests that most of them have lower-than-average body mass index, associated, for tested patients, with reduced adiposity. Altogether, these findings unravel previously unidentified characteristics for LS, which could represent a metabolic benefit for patients, but may also participate to the development or worsening of some traits of the disease. Beyond LS, they also highlight a protective role of SHP2 global LS-mimicking modulation toward the development of obesity and associated disorders.
Published: 2014
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25. ‘Odds algorithm'-based opportunistic maintenance for preserving component performances

Author: Levrat, Eric, Thomas, Edouard, Iung, Benoît, Thomas, Edouard, Centre de Recherche en Automatique de Nancy (CRAN), and Université Henri Poincaré - Nancy 1 (UHP)-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SPI.AUTO] Engineering Sciences [physics]/Automatic, opportunistic maintenance, Bruss algorithm, odds algorithm, decision-making, production stoppage, [SPI.AUTO]Engineering Sciences [physics]/Automatic
Abstract: 6 pages; International audience; Today, a new role for maintenance exists to enhance the eco-efficiency of the product lifecycle. The concept of “lifecycle maintenance” has emerged to stress this role leading to push, at the manufacturing stage, an innovative culture wherein maintenance activities become of equal importance to actual production activities. This equivalence requires mainly to consider the integration of both the maintenance planning and the production strategy planning to develop opportunistic maintenance tasks guaranteeing conjointly the product – production – equipment performances. In this paper, a novel approach is proposed to synchronise the maintenance planning with the production planning. The approach uses the “odds algorithm” and is based upon the theory of optimal stopping. The objective is to select, among all the production stoppages already planned, those which will be optimal to develop maintenance tasks keeping the expected product conditions. It combines criteria such as product performance and component reliability. An approach evaluation is shown on a practical example.
Published: 2007

26. Noonan syndrome-causing SHP2 mutants inhibit insulin-like growth factor 1 release via growth hormone-induced ERK hyperactivation, which contributes to short stature

Author: Mylène Tajan, Marianne Mus, Thomas Edouard, Karine Tréguer, Jean-Pierre Salles, Alexandra Montagner, Armelle Yart, Patrick Raynal, Toshiyuki Araki, M. Tauber, Philippe Valet, Audrey De Rocca Serra-Nédélec, Marie Dance, Benjamin G. Neel, Tréguer, Karine, Tajana, Mylène, Yart, Armelle, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Endocrinologie, Maladies Osseuses, Génétique et Gynécologie Médicale, Hôpital des Enfants, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Campbell Family Cancer Research Institute, University of Toronto-Ontario Cancer Institute, Laboratoire de biologie moléculaire eucaryote (LBME), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Mécanismes des cardiopathies et résistance hormonale dans le Noonan et syndrome apparentés (M2CHRNRS), Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Ontario Cancer Institute, Melanie H. Cobb, Centre d’Etudes et de Recherches en Psychopathologie et Psychologie de la Santé (CERPPS), Université Toulouse - Jean Jaurès (UT2J), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and ProdInra, Archive Ouverte
Subjects: MAPK/ERK pathway, TYROSINE-PHOSPHATASE SHP2, medicine.medical_treatment, [SDV]Life Sciences [q-bio], MESH: Insulin-Like Growth Factor I, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein tyrosine phosphatase, growth hormone insensitivity, MESH: Animals, Newborn, MESH: Janus Kinase 2, [SHS]Humanities and Social Sciences, Mice, Phosphatidylinositol 3-Kinases, Insulin-like growth factor, 0302 clinical medicine, HEIGHT, STAT5 Transcription Factor, MESH: Animals, Insulin-Like Growth Factor I, Phosphorylation, Extracellular Signal-Regulated MAP Kinases, MESH: Biometry, MESH: Extracellular Signal-Regulated MAP Kinases, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Multidisciplinary, Noonan Syndrome, ACTIVATED PROTEIN-KINASE, MOUSE MODEL, DEFECTS, Biological Sciences, [SDV] Life Sciences [q-bio], MESH: Noonan Syndrome, Signal transduction, medicine.symptom, signaling, MESH: Protein Tyrosine Phosphatase, Non-Receptor Type 11, MESH: ras Proteins, medicine.medical_specialty, MESH: Enzyme Activation, Biometry, MESH: Mutation, MESH: Rats, 030209 endocrinology & metabolism, SIGNALING PATHWAYS, PTPN11 SHP2, MUTATIONS, DELETION, MALFORMATIONS, Biology, Short stature, MESH: Mitogen-Activated Protein Kinase Kinases, MESH: Phosphoproteins, 03 medical and health sciences, Internal medicine, medicine, Animals, MESH: Mice, Adaptor Proteins, Signal Transducing, 030304 developmental biology, Mitogen-Activated Protein Kinase Kinases, Binding Sites, MESH: Phosphorylation, MESH: Proto-Oncogene Proteins c-akt, Growth factor, MESH: STAT5 Transcription Factor, Janus Kinase 2, Phosphoproteins, medicine.disease, Rats, Enzyme Activation, PTPN11, Endocrinology, Animals, Newborn, MESH: Binding Sites, MESH: Phosphatidylinositol 3-Kinases, Growth Hormone, MESH: Growth Hormone, Mutation, ras Proteins, Noonan syndrome, Proto-Oncogene Proteins c-akt
Abstract: Noonan syndrome (NS), a genetic disease caused in half of cases by activating mutations of the tyrosine phosphatase SHP2 ( PTPN11 ), is characterized by congenital cardiopathies, facial dysmorphic features, and short stature. How mutated SHP2 induces growth retardation remains poorly understood. We report here that early postnatal growth delay is associated with low levels of insulin-like growth factor 1 (IGF-1) in a mouse model of NS expressing the D61G mutant of SHP2. Conversely, inhibition of SHP2 expression in growth hormone (GH)-responsive cell lines results in increased IGF-1 release upon GH stimulation. SHP2-deficient cells display decreased ERK1/2 phosphorylation and rat sarcoma (RAS) activation in response to GH, whereas expression of NS-associated SHP2 mutants results in ERK1/2 hyperactivation in vitro and in vivo. RAS/ERK1/2 inhibition in SHP2-deficient cells correlates with impaired dephosphorylation of the adaptor Grb2-associated binder-1 (GAB1) on its RAS GTPase-activating protein (RASGAP) binding sites and is rescued by interfering with RASGAP recruitment or function. We demonstrate that inhibition of ERK1/2 activation results in an increase of IGF-1 levels in vitro and in vivo, which is associated with significant growth improvement in NS mice. In conclusion, NS-causing SHP2 mutants inhibit GH-induced IGF-1 release through RAS/ERK1/2 hyperactivation, a mechanism that could contribute to growth retardation. This finding suggests that, in addition to its previously shown beneficial effect on NS-linked cardiac and craniofacial defects, RAS/ERK1/2 modulation could also alleviate the short stature phenotype in NS caused by PTPN11 mutations.
Published: 2012
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27. Towards opportunistic maintenance

Author: Levrat, Eric, Iung, Benoît, Macchi, Marco, Thomas, Edouard, Voisin, Alexandre, Centre de Recherche en Automatique de Nancy (CRAN), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Politecnico di Milano [Milan] (POLIMI), John Andrew, Christophe Bérenguer, Lisa Jackson, and Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SPI.AUTO]Engineering Sciences [physics]/Automatic
Abstract: International audience; Today most conventional maintenance strategies are purely reactive, corrective (fixing or replacing equipment after it fails) or time-scheduled (Wang, 2002). These strategies are not well adapted to the control of the global performances of a manufacturing system (Gupta, et al., 2001). Therefore it is now necessary to move from traditional maintenance strategies towards condition-based maintenance performed only when a certain level of equipment deterioration occurs, or predictive maintenance which anticipates the appearance of a failure (Djurdjanovic, et al., 2003). This notion of anticipation becomes of true importance whenever a prognosis process is available (Iung, et al., 2005). Indeed the notion of anticipation allows the investigation of non-planned maintenance actions, which is part of what is called opportunistic maintenance. Opportunistic maintenance aims at answering the following questions: When to perform a particular maintenance action? What components should benefit from a preventive maintenance action? Which components should first benefit from a preventive maintenance intervention? The notion of opportunistic maintenance has been carefully reviewed in (Thomas, et al., 2008a). It was emphasized that the classical notion of opportunistic maintenance can cover up various realities and criteria. Moreover predictive vs. proactive maintenance strategies may generate numerous opportunities to perform non-previously-planned maintenance tasks. The notion of opportunistic maintenance currently does not allow taking advantage of those new opportunities-to-come, partly because of the lack of rigorous definitions and adapted formalisms of opportunistic maintenance
Published: 2011

28. The International Research Society of Spinal Deformities (IRSSD) and its contribution to science

Author: Carl-Eric Aubin, J. Raso, Marc A. Asher, Ian A. F. Stokes, Geoffrey R Burwell, Doug Hill, Joseph P O'Brien, Keith M. Bagnall, Alain Moreau, Hans-Rudolf Weiss, Peter Dangerfield, Nathalie Alos, Thomas Edouard, Edmond Lou, and Theodoros B Grivas
Subjects: International research, lcsh:RD701-811, lcsh:Diseases of the musculoskeletal system, lcsh:Orthopedic surgery, Computer science, Orthopedics and Sports Medicine, Engineering ethics, Review, lcsh:RC925-935
Abstract: From the time of its initial, informal meetings starting in 1980 to its formal creation in 1990, the IRSSD has met on a bi-annual basis to discuss all aspects of the spine and associated deformities. It has encouraged open discussion on all topics and, in particular, has tried to be the seed-bed for new ideas. The members are spread around the world and include people from all areas of academia as well as the most important people, the patients themselves. Most notably, application of the ideas and results of the research has always been at the forefront of the discussions. This paper was conceived with the idea of evaluating the impact made by the IRSSD over the last 30 years in the various areas and is intended to create discussion for the upcoming meeting in Montreal regarding future focus: "We are lost over the Atlantic Ocean but we are making good time."
Published: 2009

29. Maintenance decision making tool reaching a compromise between maintainability and reliability performances

Author: Iung Benoît, Thomas Edouard, Levrat Eric, Centre de Recherche en Automatique de Nancy (CRAN), and Université Henri Poincaré - Nancy 1 (UHP)-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0209 industrial biotechnology, Engineering, Compromise, media_common.quotation_subject, Performance criteria, Maintainability, Production stoppage, 02 engineering and technology, 01 natural sciences, Maintenance decision making, [SPI.AUTO]Engineering Sciences [physics]/Automatic, 010104 statistics & probability, 020901 industrial engineering & automation, Component (UML), Maintenance actions, Production (economics), 0101 mathematics, Bruss algorithm ('Odds algorithm'), Reliability (statistics), media_common, business.industry, General Medicine, Reliability engineering, Work (electrical), A priori and a posteriori, business
Abstract: International audience; An original maintenance decision making tool based upon Bruss theorem has previously been investigated by the authors to select the optimal last production stoppage convenient to operate a maintenance action on a component according to its degradation conditions. This stoppage is optimal with respect to antagonistic criteria such as maintainability and reliability combined. The approach is also opportunistic in the sense that maintenance is developed during production stoppages already planned. However the optimality with respect to the separate criteria alone has not been taken into account to find this global optimal stoppage. The present work aims at providing, for this tool, a way to eliminate stoppages a priori unacceptable for one criterion, so that this stoppage cannot be proposed as the final global solution. This will be done with the help of a maintenance expert. Case studies are presented and commented. Two criteria have been considered, namely maintainability and reliability, which are two key elements to bring together to perform a maintenance action. These criteria will also be used for emphasis on the difference between local optimal decisions and a global optimal decision.
Published: 2008
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30. List of Contributors

Author: Ardila, Juan Carlos, Barone, Paulo, Benavides, Pablo, Bertrand, Benoit, Blank, Imre, Brando, Carlos, Browning, David, Byers, Lee, Deugd, Michelle, Dunkel, Andreas, Farah, Adriana, Fogliano, Vincenzo, Folmer, Britta, Gaitán, Alvaro, Giuliano, Peter, Glabasnia, Arne, Góngora, Carmenza, Hayward, Jeffrey, Herrera, Juan Carlos, Hofmann, Thomas, Husson, Jwanro, Jones, Lawrence, Kilian, Bernard, Klatt, Christian, Lamb, Harriet, Lambot, Charles, Lingle, Ted R., Marsh, Celia, Menon, Sunalini N., Mestdagh, Frédéric, Moayyad, Shirin, Morris, Jonathan, Nadelberg, Eric, Noponen, Martin R.A., Oliveros, Carlos, Orjuela, Juan Pablo, Peñuela, Aida, Perez, Jérôme, Pietsch, Arne, Poisson, Luigi, Polit, Jaime R., Pratt, Lawrence, Puget, Sabine, Ranitzsch, Karsten, Rodriguez, Alexis, Rothgeb, Trish, Sadeghian, Siavosh, Sanders, Dean, Sanz-Uribe, Juan R., Schenker, Stefan, Smrke, Samo, Songer, Paul, Stout, Ria, Thomas, Edouard, Valentin, Dominique, von Blittersdorff, Martin, Wellinger, Marco, Wille, Chris, Wyser, Yves, Yeretzian, Chahan, and Yusianto
Published: 2017
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31. 'Odds algorithm'-based opportunity-triggered preventive maintenance with production policy

Author: Levrat Eric, Iung Benoît, Thomas Edouard, Monnin Maxime, Centre de Recherche en Automatique de Nancy (CRAN), Université Henri Poincaré - Nancy 1 (UHP)-Institut National Polytechnique de Lorraine (INPL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Automatique, de Mécanique et d'Informatique industrielles et Humaines - UMR 8201 (LAMIH), Université de Valenciennes et du Hainaut-Cambrésis (UVHC)-Centre National de la Recherche Scientifique (CNRS)-INSA Institut National des Sciences Appliquées Hauts-de-France (INSA Hauts-De-France), and IFAC
Subjects: Engineering, 0209 industrial biotechnology, Operations research, Computer science, media_common.quotation_subject, 0211 other engineering and technologies, Maintainability, 02 engineering and technology, Predictive maintenance, Maintenance decision making, [SPI.AUTO]Engineering Sciences [physics]/Automatic, 020901 industrial engineering & automation, 0502 economics and business, Maintenance actions, Synchronization (computer science), Production (economics), Quality (business), Productivity, Odds algorithm, media_common, 021103 operations research, business.industry, Planned maintenance, 05 social sciences, General Medicine, opportunistic preventive maintenance, Preventive maintenance, Proactive maintenance, Risk analysis (engineering), ‘odds algorithm' (Bruss algorithm), business, 050203 business & management
Abstract: International audience; In the field of manufacturing, the planning of opportunistic preventive maintenance actions adapted to minimise the number of unnecessary interruptions to production remains a major industrial challenge. Indeed, maintenance decisions have to be made in synchronisation with the production demands to eliminate costly unscheduled maintenance shutdowns and to improve productivity as well as quality. To confront this issue, this paper proposes an innovative approach based on the ‘odds algorithm'. The objective is to select, among all the production stoppages already planned, those which will be optimal to develop maintenance actions in time according to the degraded system state. The optimisation phase incorporates criteria such as reliability, maintainability and the duration of production stoppages. The feasibility of the approach is shown in a sample case.
Published: 2006

32. Low-cost system for ancient stamps range image acquisition.

Author: Thomas, Edouard, Fofi, David, Nicolier, Frederic, Millon, Gilles, and Seulin, Ralph
Published: 2005
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33. Ions colorés et couleurs des sels.

Author: Piccard, Jean and Thomas, Edouard
Published: 1923
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34. Électroisomérie: La formule de constitution de l'acide hyposulfureux et le véritable acide thiosulfurique (Communication préliminaire).

Author: Piccard, Jean and Thomas, Edouard
Published: 1923
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35. MFAP5 Loss-of-Function Mutations Underscore the Involvement of Matrix Alteration in the Pathogenesis of Familial Thoracic Aortic Aneurysms and Dissections

Author: Mathilde Varret, Ketty Kessler, Laurent Tosolini, Thomas Edouard, Dongchuan Guo, Ellen S. Regalado, Laurence Faivre, Marie Sylvie Gross, Mathieu Barbier, Benoît Ho-Tin-Noé, Yves Dulac, Marianne Abifadel, Sophie Dupuis-Girod, Olivier Milleron, Sylvie Odent, Guillaume Jondeau, Mélodie Aubart, Nadine Hanna, Laurent Gouya, Dianna M. Milewicz, Catherine Boileau, and Tiffany Busa
Subjects: Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Extracellular matrix component, Nonsense mutation, Haploinsufficiency, Thoracic aortic aneurysm, Pathogenesis, Contractile Proteins, Report, Genetics, medicine, Humans, Missense mutation, Genetics(clinical), Exome, Child, Genetics (clinical), Aged, Glycoproteins, Aged, 80 and over, Aortic Aneurysm, Thoracic, biology, Genetic heterogeneity, Sequence Analysis, DNA, Fibroblasts, Middle Aged, medicine.disease, Pedigree, 3. Good health, Aortic Dissection, Amino Acid Substitution, Codon, Nonsense, biology.protein, Intercellular Signaling Peptides and Proteins, Female, Elastin
Abstract: Thoracic aortic aneurysm and dissection (TAAD) is an autosomal-dominant disorder with major life-threatening complications. The disease displays great genetic heterogeneity with some forms allelic to Marfan and Loeys-Dietz syndrome, and an important number of cases still remain unexplained at the molecular level. Through whole-exome sequencing of affected members in a large TAAD-affected family, we identified the c.472CT (p.Arg158(∗)) nonsense mutation in MFAP5 encoding the extracellular matrix component MAGP-2. This protein interacts with elastin fibers and the microfibrillar network. Mutation screening of 403 additional probands identified an additional missense mutation of MFAP5 (c.62GT [p.Trp21Leu]) segregating with the disease in a second family. Functional analyses performed on both affected individual's cells and in vitro models showed that these two mutations caused pure or partial haploinsufficiency. Thus, alteration of MAGP-2, a component of microfibrils and elastic fibers, appears as an initiating mechanism of inherited TAAD.
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36. 0365 : Risk markers of cardiac events in patients with Marfan syndrome diagnosed during childhood

Author: Bertrand Chevallier, Chantal Stheneur, Philippe Acar, F. Arnoult, Guillaume Jondeau, Yves Dulac, Sébastien Hascoët, Laurence Olivier-Faivre, Jean Ferrière, Jean-Bernard Ruidavets, Sophie Dupuis-Girod, Cécile Zordan, Nicole Philip, Bruno Leheup, Thomas Edouard, Olivier Milleron, Sylvie Odent, Service pédiatrie-cardiologie, CHU Toulouse [Toulouse]-Hôpital des Enfants, CHU Toulouse [Toulouse], Centre d'Endocrinologie, Maladies Osseuses, Génétique et Gynécologie Médicale, Hôpital des Enfants, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Service de Génétique, Hospices Civils de Lyon (HCL)-Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Groupe Hospitalier Est, Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bichat, Service de pédiatrie, urgences enfants [CHU Ambroise-Paré], Hôpital Ambroise Paré [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Pediatrics, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de cardiologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'explorations fonctionnelles, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre de référence MARFAN, Hôpital Bichat, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bichat, Service de pédiatrie, urgences enfants, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Service Cardiologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Cardiovascular event, Marfan syndrome, Aortic dissection, medicine.medical_specialty, business.industry, Aortic root, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, medicine.disease, Aortic surgery, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, Internal medicine, medicine, Cardiology, cardiovascular system, In patient, 030212 general & internal medicine, business, Cardiology and Cardiovascular Medicine, Cohort study
Abstract: International audience; Objectives Risk markers of cardio-vascular events in children with Marfan syndrome remain little known. We assessed the prognostic value of aortic root z-score in patients with Marfan syndrome diagnosed during childhood. Methods From the French multicenter database, 457 patients with Marfan syndrome, diagnosed before 18 y.o., were prospectively included in this cohort study. Echocardiographic measurements of aortic root diameters were performed at each visit. We calculated the Z-score of aortic root measurements using the Bichat formula. Mean z-score was defined as the mean of the z-score (MeanZS15) calculated for each measurement before the age of 16. Results Median age at end of FU was 15.9years (interquartile 10.9-20.3). FU was complete for 69.5% of patients. Median FU was 4.6years. A cardiovascular event occurred in 17 patients (3.7%, prophylactic aortic surgery n=14, aortic dissection n=1 and deaths n=2). Survival free of cardiac events was 85.1% in patients with a meanZS15 of the Valsalva diameter
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37. La réduction de l'acide azothydrique.

Author: Piccard, Jean and Thomas, Edouard
Published: 1923
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38. Métaux catalytiques.

Author: Piccard, Jean and Thomas, Edouard
Published: 1923
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39. Remarques sur la solubilité du sulfure de cadmium.

Author: Piccard, Jean and Thomas, Edouard
Published: 1923
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40. Sequential combination of gemtuzumab ozogamicin and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia: results of a randomized phase III trial by the EORTC and GIMEMA consortium (AML-17).

Author: Amadori S, Suciu S, Stasi R, Salih HR, Selleslag D, Muus P, De Fabritiis P, Venditti A, Ho AD, Lübbert M, Thomas X, Latagliata R, Halkes CJ, Falzetti F, Magro D, Guimaraes JE, Berneman Z, Specchia G, Karrasch M, Fazi P, Vignetti M, Willemze R, de Witte T, and Marie JP
Subjects: Acute Disease, Aged, Aminoglycosides administration & dosage, Aminoglycosides adverse effects, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cytarabine administration & dosage, Cytarabine adverse effects, Drug Administration Schedule, Etoposide administration & dosage, Etoposide adverse effects, Febrile Neutropenia chemically induced, Female, Follow-Up Studies, Gemtuzumab, Humans, Induction Chemotherapy methods, Infections chemically induced, Leukemia, Myeloid diagnosis, Liver drug effects, Liver pathology, Male, Middle Aged, Mitoxantrone administration & dosage, Mitoxantrone adverse effects, Remission Induction, Survival Analysis, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid drug therapy
Abstract: Purpose: This randomized trial evaluated the efficacy and toxicity of sequential gemtuzumab ozogamicin (GO) and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia (AML)., Patients and Methods: Patients (n = 472) age 61 to 75 years were randomly assigned to induction chemotherapy with mitoxantrone, cytarabine, and etoposide preceded, or not, by a course of GO (6 mg/m(2) on days 1 and 15). In remission, patients received two consolidation courses with or without GO (3 mg/m(2) on day 0). The primary end point was overall survival (OS)., Results: The overall response rate was comparable between the two arms (GO, 45%; no GO, 49%), but induction and 60-day mortality rates were higher in the GO arm (17% v 12% and 22% v 18%, respectively). With median follow-up of 5.2 years, median OS was 7.1 months in the GO arm and 10 months in the no-GO arm (hazard ratio, 1.20; 95% CI, 0.99 to 1.45; P = .07). Other survival end points were similar in both arms. Grade 3 to 4 hematologic and liver toxicities were greater in the GO arm. Treatment with GO provided no benefit in any prognostic subgroup, with the possible exception of patients age < 70 years with secondary AML, but outcomes were significantly worse in the oldest age subgroup because of a higher risk of early mortality., Conclusion: As used in this trial, the sequential combination of GO and standard chemotherapy provides no benefit for older patients with AML and is too toxic for those age ≥ 70 years.
Published: 2013
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