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1. Multi-locus imprinting disturbance (MLID): interim joint statement for clinical and molecular diagnosis

Author

Deborah J. G. Mackay, Gabriella Gazdagh, David Monk, Frederic Brioude, Eloise Giabicani, Izabela M. Krzyzewska, Jennifer M. Kalish, Saskia M. Maas, Masayo Kagami, Jasmin Beygo, Tiina Kahre, Jair Tenorio-Castano, Laima Ambrozaitytė, Birutė Burnytė, Flavia Cerrato, Justin H. Davies, Giovanni Battista Ferrero, Olga Fjodorova, Africa Manero-Azua, Arrate Pereda, Silvia Russo, Pierpaola Tannorella, Karen I. Temple, Katrin Õunap, Andrea Riccio, Guiomar Perez de Nanclares, Eamonn R. Maher, Pablo Lapunzina, Irène Netchine, Thomas Eggermann, Jet Bliek, and Zeynep Tümer

Subjects
Differentially methylated regions, DMR, Multi-locus imprinting disturbance, MLID, Imprinting disorder, Clinical diagnosis, Medicine, Genetics, QH426-470
Abstract

Abstract Background Imprinting disorders are rare diseases resulting from altered expression of imprinted genes, which exhibit parent-of-origin-specific expression patterns regulated through differential DNA methylation. A subgroup of patients with imprinting disorders have DNA methylation changes at multiple imprinted loci, a condition referred to as multi-locus imprinting disturbance (MLID). MLID is recognised in most but not all imprinting disorders and is also found in individuals with atypical clinical features; the presence of MLID often alters the management or prognosis of the affected person. Some cases of MLID are caused by trans-acting genetic variants, frequently not in the patients but their mothers, which have counselling implications. There is currently no consensus on the definition of MLID, clinical indications prompting testing, molecular procedures and methods for epigenetic and genetic diagnosis, recommendations for laboratory reporting, considerations for counselling, and implications for prognosis and management. The purpose of this study is thus to cover this unmet need. Methods A comprehensive literature search was conducted resulting in identification of more than 100 articles which formed the basis of discussions by two working groups focusing on clinical diagnosis (n = 12 members) and molecular testing (n = 19 members). Following eight months of preparations and regular online discussions, the experts from 11 countries compiled the preliminary documentation and determined the questions to be addressed during a face-to-face meeting which was held with the attendance of the experts together with four representatives of patient advocacy organisations. Results In light of available evidence and expert consensus, we formulated 16 propositions and 8 recommendations as interim guidance for the clinical and molecular diagnosis of MLID. Conclusions MLID is a molecular designation, and for patients with MLID and atypical phenotypes, we propose the alternative term multi-locus imprinting syndrome. Due to the intrinsic variability of MLID, the guidelines underscore the importance of involving experts from various fields to ensure a confident approach to diagnosis, counselling, and care. The authors advocate for global, collaborative efforts in both basic and translational research to tackle numerous crucial questions that currently lack answers, and suggest reconvening within the next 3–5 years to evaluate the research advancements and update this guidance as needed.

Published
2024
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2. Screening of patients born small for gestational age with the Silver-Russell syndrome phenotype for DLK1 variants

Author

Aurélie Pham, Frédéric Brioude, Marilyne Le Jules Fernandes, Marie-Laure Sobrier, Eloise Giabicani, Irène Netchine, and Delphine Mitanchez

Subjects
Genetics, Chromosome 7 (human), Silver–Russell syndrome, Calcium-Binding Proteins, Infant, Newborn, Membrane Proteins, Chromosome, Biology, medicine.disease, Phenotype, Article, Silver-Russell Syndrome, Infant, Small for Gestational Age, Mutation, medicine, Humans, Small for gestational age, Female, Imprinting (psychology), Allele, Genomic imprinting, Genetics (clinical)
Abstract

Silver–Russell syndrome (SRS) is a rare imprinting disorder associated with prenatal and postnatal growth retardation. Loss of methylation (LOM) on chromosome 11p15 is observed in 40 to 60% of patients and maternal uniparental disomy (mUPD) for chromosome 7 (upd(7)mat) in ~5 to 10%. Patients with LOM or mUPD 14q32 can present clinically as SRS. Delta like non-canonical Notch ligand 1 (DLK1) is one of the imprinted genes expressed from chromosome 14q32. Dlk1-null mice display fetal growth restriction (FGR) but no genetic defects of DLK1 have been described in human patients born small for gestational age (SGA). We screened a cohort of SGA patients with a SRS phenotype for DLK1 variants using a next-generation sequencing (NGS) approach to search for new molecular defects responsible for SRS. Patients born SGA with a clinical suspicion of SRS and normal methylation by molecular testing at the 11p15 or 14q32 loci and upd(7)mat were screened for DLK1 variants using targeted NGS. Among 132 patients, only two rare variants of DLK1 were identified (NM_003836.6:c.103 G > C (p.(Gly35Arg) and NM_003836.6: c.194 A > G p.(His65Arg)). Both variants were inherited from the mother of the patients, which does not favor a role in pathogenicity, as the mono-allelic expression of DLK1 is from the paternal-inherited allele. We did not identify any pathogenic variants in DLK1 in a large cohort of SGA patients with a SRS phenotype. DLK1 variants are not a common cause of SGA.

Published
2021
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3. Impact of claudin‐10 deficiency on amelogenesis: Lesson from a HELIX tooth

Author

Nicolas Obtel, Adeline Le Cabec, Thè Nghia Nguyen, Eloise Giabicani, Stijn J. M. Van Malderen, Jan Garrevoet, Aline Percot, Céline Paris, Christopher Dean, Smail Hadj‐Rabia, Pascal Houillier, Tilman Breiderhoff, Claire Bardet, Thibaud Coradin, Fernando Ramirez Rozzi, Catherine Chaussain, Bouchet, Jérôme, Pathologies, Imagerie et Biothérapies oro-faciales (URP 2496), Université Paris Cité (UPCité), Service d'Odontologie [Bretonneau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bretonneau, De la Préhistoire à l'Actuel : Culture, Environnement et Anthropologie (PACEA), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Max Planck Institute for Evolutionary Anthropology [Leipzig], Max-Planck-Gesellschaft, Deutsches Elektronen-Synchrotron [Hamburg] (DESY), De la Molécule aux Nanos-objets : Réactivité, Interactions et Spectroscopies (MONARIS), Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), The Natural History Museum [London] (NHM), University College of London [London] (UCL), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), 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), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Laboratoire de Chimie de la Matière Condensée de Paris (LCMCP), Éco-Anthropologie (EA), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Muséum national d'Histoire naturelle (MNHN), AP-HP Services de médecine bucco-dentaire, Hôpitaux Universitaires Bretonneau (CRMR phosphore et calcium, filière OSCAR et ERN Bond) and Charles Foix, FHU DDS-net, Ile de France, France, Department of Human Evolution, Max-Planck Institute for Evolutionary Anthropology, Leipzig, Germany, Centre for Human Evolution Research, Department of Earth Sciences, Natural History Museum, London, Department of Cell and Developmental Biology, University College London, CNRS ERL 8228, Centre National de la Recherche Scientifique (CNRS), Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte [CHU-Necker] (MARHEA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité, Grant/Award Number: T-JUST program (ANR-17CE14-0032-02), Université de Bordeaux: IdEx 'Investments for the Future' Program / GPR 'Human Past', Max Planck Society, and Centre National de la Recherche Scientifique

Subjects
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SHS.ARCHEO]Humanities and Social Sciences/Archaeology and Prehistory, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], General Neuroscience, [SHS.ANTHRO-BIO]Humanities and Social Sciences/Biological anthropology, enamel, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Xerostomia, General Biochemistry, Genetics and Molecular Biology, Tight Junctions, Electrolytes, History and Philosophy of Science, Amelogenesis, Strontium, apatite, renal dysfunction, Claudins, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Claudin-3, Humans, Female, ddc:500, Claudin-4, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Annals of the New York Academy of Sciences 1516(1), 197-211 (2022). doi:10.1111/nyas.14865, In epithelia, claudin proteins are important components of the tight junctions as they determine the permeability and specificity to ions of the paracellular pathway. Mutations in CLDN10 cause the rare autosomal recessive HELIX syndrome (Hypohidrosis, Electrolyte imbalance, Lacrimal gland dysfunction, Ichthyosis, and Xerostomia), in which patients display severe enamel wear. Here, we assess whether this enamel wear is caused by an innate fragility directly related to claudin-10 deficiency in addition to xerostomia. A third molar collected from a female HELIX patient was analyzed by a combination of microanatomical and physicochemical approaches (i.e., electron microscopy, elemental mapping, Raman microspectroscopy, and synchrotron-based X-ray fluorescence). The enamel morphology, formation time, organization, and microstructure appeared to be within the natural variability. However, we identified accentuated strontium variations within the HELIX enamel, with alternating enrichments and depletions following the direction of the periodical striae of Retzius. These markings were also present in dentin. These data suggest that the enamel wear associated with HELIX may not be related to a disruption of enamel microstructure but rather to xerostomia. However, the occurrence of events of strontium variations within dental tissues might indicate repeated episodes of worsening of the renal dysfunction that may require further investigations., Published by New York Acad. of Sciences, New York, NY

Published
2022
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4. Demographic Characteristics, Risk Factors, and Presenting Features of Children with Symptomatic Nutritional Rickets: A French Series

Author

Anne Lienhardt-Roussie, Claire Flot, Agnès Linglart, Justine Bacchetta, Iva Gueorguieva, Caroline Storey, Anya Rothenbuhler, Valérie Porquet-Bordes, Jean-Pierre Salles, Eloise Giabicani, and Thomas Edouard

Subjects
Male, Pediatrics, medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, Parathyroid hormone, Rickets, Nutritional Rickets, Endocrinology, Risk Factors, medicine, Vitamin D and neurology, Humans, Vitamin D, Child, Retrospective Studies, Vitamin d supplementation, Bone Density Conservation Agents, business.industry, Infant, Dilated cardiomyopathy, Retrospective cohort study, medicine.disease, Radiography, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, France, business, Pediatric population
Abstract

Aim: To describe the demographic characteristics, risk factors, and presenting features of children with symptomatic nutritional rickets in France. Methods: This is a retrospective study of 38 children diagnosed with nutritional rickets from 1998 to 2019. Results: We observed a higher frequency of rickets in males (74 vs. 26%), in young children (median age at diagnosis: 23 months; 82% were younger than 5 years), and in children with a non-Caucasian ethnic background (89%). Most children were exclusively breastfed (78%) without adequate vitamin D supplementation (89%). The most common presentations were bowed legs (63%), hypocalcemic seizures (21%), and growth retardation (11%). Approximately half (62%) of the children were hypocalcemic. The children presenting with hypocalcemic seizures were significantly younger (0.8 vs. 2.2 years; p = 0.041) and had lower total serum calcium levels (1.44 vs. 2.17 mmol/L; p < 0.0001), higher phosphatemia (1.43 vs. 1.23 mmol/L; p = 0.020), and lower 25-hydroxy vitamin D levels (3 vs. 7 ng/mL; p = 0.020) but similar parathyroid hormone levels (357 vs. 289 ng/mL; p = 0.940) compared to rickets cases who did not experience hypocalcemic seizures. A dilated cardiomyopathy was detected in 14% of the children who had undergone echocardiography. Conclusion: Nutritional rickets remains endemic in the pediatric population and its most severe forms can have life-threatening sequelae. Health practitioners need to be cognizant of these facts to raise awareness and screen high-risk populations.

Published
2020

5. Increasing knowledge in IGF1R defects: lessons from 35 new patients

Author

Laurence Perrin, Marjolaine Willems, Sylvie Rossignol, Hélène Bony-Trifunovic, Cécile Brachet, Catherine Naud-Saudreau, Frédéric Brioude, Claire Sechter, Domitille Thomas, Walid Abi Habib, Georges Gelwane, Elise Brischoux-Boucher, Laurence Berard, Virginie Steunou, Claire Jeandel, Yves Le Bouc, Muriel Houang, Irène Netchine, Eloise Giabicani, Sandra Chantot-Bastaraud, Bertrand Isidor, Salah Azzi, James Lespinasse, Isabelle Guemas, Monique Jesuran-Perelroizen, Emmanuelle Caldagues, Pierre-François Souchon, Juliette Piard, Nathalie Thibaud, Marie-Laure Cuvelier, Bich Lam, Régis Coutant, Caroline Storey, Gestionnaire, Hal Sorbonne Université, Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), UF de Génétique chromosomique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], CHU Amiens-Picardie, Children's University Hospital Queen Fabiola [Bruxelles, Belgium], Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier de Calais, Hôpital Robert Debré Paris, Hôpital Robert Debré, Université Paris Diderot - Paris 7 (UPD7), Centre Hospitalier Métropole Savoie [Chambéry], CH Bretagne Sud, Association Française des Pédiatres Endocrinologues Libéraux (AFPEL), Centre Hospitalier Universitaire de Reims (CHU Reims), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Les Hôpitaux Universitaires de Strasbourg (HUS), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CR Saint-Antoine), and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP]

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Microcephaly, 030209 endocrinology & metabolism, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Short stature, fetal growth restriction, 03 medical and health sciences, small for gestational age, 0302 clinical medicine, Growth factor receptor, Western blot, IGF1R, Internal medicine, Genetics, medicine, Genetics (clinical), Insulin-like growth factor 1 receptor, medicine.diagnostic_test, business.industry, homozygous variant, medicine.disease, Phenotype, IGF-I, body regions, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cohort, Small for gestational age, medicine.symptom, business
Abstract

BackgroundThe type 1 insulin-like growth factor receptor (IGF1R) is a keystone of fetal growth regulation by mediating the effects of IGF-I and IGF-II. Recently, a cohort of patients carrying an IGF1R defect was described, from which a clinical score was established for diagnosis. We assessed this score in a large cohort of patients with identified IGF1R defects, as no external validation was available. Furthermore, we aimed to develop a functional test to allow the classification of variants of unknown significance (VUS) in vitro.MethodsDNA was tested for either deletions or single nucleotide variant (SNV) and the phosphorylation of downstream pathways studied after stimulation with IGF-I by western blot analysis of fibroblast of nine patients.ResultsWe detected 21 IGF1R defects in 35 patients, including 8 deletions and 10 heterozygous, 1 homozygous and 1 compound-heterozygous SNVs. The main clinical characteristics of these patients were being born small for gestational age (90.9%), short stature (88.2%) and microcephaly (74.1%). Feeding difficulties and varying degrees of developmental delay were highly prevalent (54.5%). There were no differences in phenotypes between patients with deletions and SNVs of IGF1R. Functional studies showed that the SNVs tested were associated with decreased AKT phosphorylation.ConclusionWe report eight new pathogenic variants of IGF1R and an original case with a homozygous SNV. We found the recently proposed clinical score to be accurate for the diagnosis of IGF1R defects with a sensitivity of 95.2%. We developed an efficient functional test to assess the pathogenicity of SNVs, which is useful, especially for VUS.

Published
2020
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6. Diagnosis and management of postnatal fetal growth restriction

Author

Eloise Giabicani, Aurélie Pham, Frédéric Brioude, Irène Netchine, and Delphine Mitanchez

Subjects
Male, 0301 basic medicine, Genetic syndromes, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Pregnancy, Global health, medicine, Fetal growth, Humans, Epigenetics, Child, Fetal Growth Retardation, business.industry, Silver–Russell syndrome, Disease Management, medicine.disease, 030104 developmental biology, Etiology, Small for gestational age, Female, business, Perinatal period
Abstract

Fetal growth restriction (FGR) can result from multiple causes, such as genetic, epigenetic, environment, hormonal regulation, or vascular troubles and their potential interaction. The physiopathology of FGR is not yet fully elucidated, but the insulin-like growth factor system is known to play a central role. Specific clinical features can lead to the identification of genetic syndromes in some patients. FGR leads to multiple global health concerns, from the perinatal period, with higher morbidity/mortality, through infancy, with neurodevelopmental, growth, and metabolic issues, to the onset of puberty and later in life, with subfertility and elevated risks of cardiovascular and kidney diseases. Adequate follow-up and therapeutics should be offered to these patients. We first review the main molecular etiologies leading to FGR and their specificities. We then highlight the main issues that FGR can raise later in life before concluding with the proposed management of these children.

Published
2018
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7. Perinatal features of children with Silver-Russell syndrome due to 11p15 loss of methylation

Author

Diane Darneau, Eloïse Giabicani, Irène Netchine, and Aurélie Pham

Subjects
foetal growth restriction (FGR), small for gestation age (SGA), Silver–Russel syndrome, neonatal care, placental insufficiency (PI), Pediatrics, RJ1-570
Abstract

BackgroundA diagnosis of Silver–Russell syndrome (SRS), a rare imprinting disorder responsible for foetal growth restriction, is considered for patients presenting at least four criteria of the Netchine-Harbison clinical scoring system (NH-CSS). Certain items of the NH-CSS are not assessable until the age of 2 years. The objective was to determine perinatal characteristics of children with SRS to allow an early diagnosis.MethodsWe retrospectively compared the perinatal characteristics of children with SRS (n = 17) with those of newborns small for gestational age (SGA) due to placental insufficiency (PI) (n = 21).ResultsChildren with SRS showed earlier and more severely altered foetal biometry than SGA newborns due to PI. Twenty-three percent of patients with SRS showed uterine artery Doppler anomalies. SRS children were significantly smaller at birth (birth length

Published
2024
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9. Sleep disordered breathing in Silver-Russell syndrome patients: a new outcome

Author

Irène Netchine, Frédéric Brioude, Guillaume Aubertin, Eloise Giabicani, Béatrice Dubern, Eva Galliani, Michèle Boulé, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pneumologie pédiatrique [CHU Trousseau], Service de chirurgie plastique et maxillofaciale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Nutriomique UMRS 1269, and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Pediatrics, medicine.medical_specialty, Polysomnography, Excessive daytime sleepiness, Muscle hypertrophy, 03 medical and health sciences, 0302 clinical medicine, Sleep Apnea Syndromes, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Recombinant growth hormone, Child, Retrospective Studies, Chromosome 7 (human), medicine.diagnostic_test, business.industry, Sleep disordered breathing, Silver–Russell syndrome, General Medicine, Plasma levels, medicine.disease, 3. Good health, respiratory tract diseases, nervous system diseases, Sleep apnea syndrome, Silver-Russell Syndrome, Treatment Outcome, 030228 respiratory system, Child, Preschool, Growth Hormone, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, medicine.symptom, business, 030217 neurology & neurosurgery, Sleep recording
Abstract

International audience; OBJECTIVE: Imprinting disorders (ID), such as Prader-Willi syndrome (PWS), are associated with sleep-disordered breathing (SDB). No data are available for Silver-Russell syndrome (SRS), another ID that shares clinical features with PWS, although many patients describe excessive daytime sleepiness, disturbed sleep, and snoring. The aim of this study was to characterize sleep in children with SRS and to evaluate the impact of recombinant growth hormone (rGH) therapy.METHODS: We performed a retrospective analysis of sleep recordings in 40 patients with molecularly proven SRS (methylation anomaly in 11p15 [n = 32] or maternal uniparental disomy of chromosome 7 [n = 16]). Sleep recordings were either by means of polygraphy or polysomnography (PSG) (n = 16). A total of 34 patients received rGH therapy.RESULTS: We collected 61 sleep recordings. The mean apnea-hypopnea index (AHI) was 3.4 events/h (0-12.4), with a mean central AHI of 0.5 events/h (0-2.4). SDB was identified in 73.8% (n = 45) of the recordings and was severe in 4.9%. SDB was present in 86.4% of patients before rGH therapy and was severe in 13.6%. AHI worsened for 5 of 12 patients with sleep recordings before and after rGH therapy initiation, reaching mild impairment. The mean rGH dose was 32.3 μg/kg/(12.9-51.4), with a mean insulin-like growth factor 1 plasma level of 1.7 SDS (-1.9 to 6.6).CONCLUSION: Most patients with SRS present with SDB with an obstructive profile, possibly explained by narrowing of the airways and lymphoid organ hypertrophy. We recommend systematic ear-nose-throat evaluation of SRS patients and PSG if there are clinical anomalies, preferably before initiating rGH therapy, to monitor and adapt the management of patients with SDB.

Published
2018
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10. Chromosome 14q32.2 Imprinted Region Disruption as an Alternative Molecular Diagnosis of Silver-Russell Syndrome

Author

Sylvie Rossignol, Walid Abi Habib, Sophie Geoffron, Salah Azzi, Béatrice Dubern, Sandra Chantot-Bastaraud, Isabelle Oliver Petit, Thuy-Ai Vu-Hong, Marie-Noelle Dufourg, Ana Pinheiro Machado Canton, Catherine Pienkowski, Jennifer Salem, Blandine Esteva, Fanny Morice Picard, Bertrand Isidor, Nicole Philip, Frédéric Brioude, Alexandra Afenjar, Julien Thevenon, David Geneviève, Mélanie Fradin, Marlène Rio, Catherine Naud-Saudreau, Irène Netchine, Maithé Tauber, Christel Chalouhi, Tiffanny Busa, Virginie Steunou, Eloise Giabicani, Solveig Heide, Agnès Linglart, Madeleine D. Harbison, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-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), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidade de São Paulo Medical School (FMUSP), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de pédiatrie générale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], 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 ), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Montpellier, Université de Montpellier (UM), Centre hospitalier universitaire de Nantes (CHU Nantes), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Thérapie génique, Génomique et Epigénomique (U 1169), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université de Bretagne Sud - Lorient (UBS Lorient), Université de Bretagne Sud (UBS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de Génétique Médicale [CHU Necker], Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Axe 3 : organisation structurale multiéchelle des matériaux (SPCTS-AXE3), Science des Procédés Céramiques et de Traitements de Surface (SPCTS), Université de Limoges (UNILIM)-Ecole Nationale Supérieure de Céramique Industrielle (ENSCI)-Institut des Procédés Appliqués aux Matériaux (IPAM), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Ecole Nationale Supérieure de Céramique Industrielle (ENSCI)-Institut des Procédés Appliqués aux Matériaux (IPAM), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre de Référence du Syndrome de Prader-Willi, Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Unité de recherche sur les maladies cardiovasculaires et métaboliques, UMR S 1166, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité Fonctionnelle de Génétique Clinique [CHU Pitié Salpétrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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 de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'ORL et de Chirurgie Cervicofaciale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Hôpital des Enfants, CHU Toulouse [Toulouse], Institut des Procédés Appliqués aux Matériaux (IPAM), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Ecole Nationale Supérieure de Céramique Industrielle (ENSCI)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Institut des Procédés Appliqués aux Matériaux (IPAM), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Ecole Nationale Supérieure de Céramique Industrielle (ENSCI)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM), Service de Génétique et d'Embryologie Médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Unité Fonctionnelle de Génétique Clinique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Centre de référence 'Déficiences Intellectuelles de Causes Rares' - Paris-Groupe de Recherche Clinique 'Déficience Intellectuelle et Autisme' - Paris, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Ined Inserm joint unit Elfe, Hôpital Arnaud de Villeneuve, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'endocrinologie et diabétologie pédiatriques - Le Kremlin-Bicêtre, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and MAGIC Foundation

Subjects
0301 basic medicine, Oncology, Male, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Puberty, Precocious, Chromosome Disorders, Biochemistry, Pubarche, Endocrinology, Young adult, Child, 2. Zero hunger, MEG3, Syndrome, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Uniparental disomy, 3. Good health, Phenotype, Child, Preschool, DNA methylation, Intercellular Signaling Peptides and Proteins, Female, RNA, Long Noncoding, Chromosome Deletion, Adult, medicine.medical_specialty, Adolescent, Diagnosis, Differential, 03 medical and health sciences, Genomic Imprinting, Young Adult, Internal medicine, parasitic diseases, medicine, Humans, Retrospective Studies, Chromosomes, Human, Pair 14, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, Silver–Russell syndrome, Biochemistry (medical), Calcium-Binding Proteins, Chromosome, Membrane Proteins, DNA Methylation, Uniparental Disomy, medicine.disease, Silver-Russell Syndrome, 030104 developmental biology, business, Body mass index
Abstract

International audience; Context - Silver-Russell syndrome (SRS) (mainly secondary to 11p15 molecular disruption) and Temple syndrome (TS) (secondary to 14q32.2 molecular disruption) are imprinting disorders with phenotypic (prenatal and postnatal growth retardation, early feeding difficulties) and molecular overlap. Objective - To describe the clinical overlap between SRS and TS and extensively study the molecular aspects of TS. Patients - We retrospectively collected data on 28 patients with disruption of the 14q32.2 imprinted region, identified in our center, and performed extensive molecular analysis. Results - Seventeen (60.7%) patients showed loss of methylation of the MEG3/DLK1 intergenic differentially methylated region by epimutation. Eight (28.6%) patients had maternal uniparental disomy of chromosome 14 and three (10.7%) had a paternal deletion in 14q32.2. Most patients (72.7%) had a Netchine-Harbison SRS clinical scoring system ≥4/6, and consistent with a clinical diagnosis of SRS. The mean age at puberty onset was 7.2 years in girls and 9.6 years in boys; 37.5% had premature pubarche. The body mass index of all patients increased before pubarche and/or the onset of puberty. Multilocus analysis identified multiple methylation defects in 58.8% of patients. We identified four potentially damaging genetic variants in genes encoding proteins involved in the establishment or maintenance of DNA methylation. Conclusions - Most patients with 14q32.2 disruption fulfill the criteria for a clinical diagnosis of SRS. These clinical data suggest similar management of patients with TS and SRS, with special attention to their young age at the onset of puberty and early increase of body mass index.

Published
2018
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11. Chromosomal rearrangements in the 11p15 imprinted region: 17 new 11p15.5 duplications with associated phenotypes and putative functional consequences

Author

Pierre Sarda, Claudine Heinrichs, Lionel Van Maldergem, Caroline Michot, Frédéric Brioude, Véronique Trifard, Sylvie Rossignol, Bénédicte Demeer, Salah Azzi, Eloise Giabicani, Sandra Chantot-Bastaraud, Marilyn Lackmy-Port Lys, Ron S. Newfield, Irène Netchine, Madeleine D. Harbison, Boris Keren, Jean-Pierre Siffroi, Solveig Heide, Yves Le Bouc, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), 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 Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Axe 3 : organisation structurale multiéchelle des matériaux (SPCTS-AXE3), Science des Procédés Céramiques et de Traitements de Surface (SPCTS), Institut des Procédés Appliqués aux Matériaux (IPAM), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Ecole Nationale Supérieure de Céramique Industrielle (ENSCI)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Institut des Procédés Appliqués aux Matériaux (IPAM), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Ecole Nationale Supérieure de Céramique Industrielle (ENSCI)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM), 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), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale, CHU Amiens-Picardie, Hôpital Universitaire des Enfants Reine Fabiola, Université libre de Bruxelles (ULB), Service de Génétique, Université Montpellier 2 - Sciences et Techniques (UM2)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), Service d'explorations fonctionnelles [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université de Limoges (UNILIM)-Ecole Nationale Supérieure de Céramique Industrielle (ENSCI)-Institut des Procédés Appliqués aux Matériaux (IPAM), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Ecole Nationale Supérieure de Céramique Industrielle (ENSCI)-Institut des Procédés Appliqués aux Matériaux (IPAM), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Libre de Bruxelles [Bruxelles] (ULB), Laboratoire Chrono-environnement - UFC (UMR 6249) (LCE), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
Adult, Male, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Centromere, Cnv, Beckwith–Wiedemann syndrome, Biology, Molecular Imprinting, 03 medical and health sciences, Imprinting Disorder, Insulin-Like Growth Factor II, Gene Duplication, parasitic diseases, Genetics, medicine, Humans, Epigenetics, Cyclin-Dependent Kinase Inhibitor p57, Genetics (clinical), Chromosome Aberrations, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Chromosomes, Human, Pair 11, Silver–Russell syndrome, Beckwith-wiedemann Syndrome, 11p15 Duplication, Telomere, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Phenotype, Silver Russell Syndrome, Silver-Russell Syndrome, 030104 developmental biology, Cytogenetic Analysis, Mutation, Female, Genomic imprinting
Abstract

BackgroundThe 11p15 region contains two clusters of imprinted genes. Opposite genetic and epigenetic anomalies of this region result in two distinct growth disturbance syndromes: Beckwith-Wiedemann (BWS) and Silver-Russell syndromes (SRS). Cytogenetic rearrangements within this region represent less than 3% of SRS and BWS cases. Among these, 11p15 duplications were infrequently reported and interpretation of their pathogenic effects is complex.ObjectivesTo report cytogenetic and methylation analyses in a cohort of patients with SRS/BWS carrying 11p15 duplications and establish genotype/phenotype correlations.MethodsFrom a cohort of patients with SRS/BWS with an abnormal methylation profile (using ASMM-RTQ-PCR), we used SNP-arrays to identify and map the 11p15 duplications. We report 19 new patients with SRS (n=9) and BWS (n=10) carrying de novo or familial 11p15 duplications, which completely or partially span either both telomeric and centromeric domains or only one domain.ResultsLarge duplications involving one complete domain or both domains are associated with either SRS or BWS, depending on the parental origin of the duplication. Genotype-phenotype correlation studies of partial duplications within the telomeric domain demonstrate the prominent role of IGF2, rather than H19, in the control of growth. Furthermore, it highlights the role of CDKN1C within the centromeric domain and suggests that the expected overexpression of KCNQ1OT1 from the paternal allele (in partial paternal duplications, excluding CDKN1C) does not affect the expression of CDKN1C.ConclusionsThe phenotype associated with 11p15 duplications depends on the size, genetic content, parental inheritance and imprinting status. Identification of these rare duplications is crucial for genetic counselling.

Published
2018
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12. Diagnosis and management of Silver-Russell syndrome: first international consensus statement

Author

Frédéric Brioude, I. Karen Temple, Jet Bliek, Adda Grimberg, Thomas Eggermann, Gudrun E. Moore, Agnès Linglart, Klaus Mohnike, Zeynep Tümer, Edith Said, Ana Pinheiro Machado Canton, Renuka P Dias, Oluwakemi Lokulo-Sodipe, Madeleine D. Harbison, Meropi Toumba, Gerhard Binder, Béatrice Dubern, Anita C. S. Hokken-Koelega, Jennifer Salem, Deborah J G Mackay, Susan M. O’Connell, Miriam Elbracht, Irène Netchine, Justin H Davies, David Monk, Silvia Russo, Emma Wakeling, Mohamad Maghnie, Isabelle Oliver Petit, Krystyna H. Chrzanowska, Eloise Giabicani, Philip Murray, Masayo Kagami, Alexander A. L. Jorge, Tsutomu Ogata, Karen Grønskov, Pediatrics, North West london hospitals NHS Trust, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), MAGIC Foundation, Department of Clinical Genetics, University of Amsterdam [Amsterdam] (UvA), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), Clinical genetic clinic, Copenhagen University Hospital, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Service d'endocrinologie pédiatrique [CHU Bicêtre], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Fetal Growth and Developmental Group, University College of London [London] (UCL), Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, Department of Pediatrics and Medical Genetics, St. Luke's Hospital, Service de néphrologie et pédiatrie générale [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Human Genetics and Genomic Medicine group, Faculty of Medicine, Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], and Human Genetics

Subjects
0301 basic medicine, medicine.medical_specialty, Pediatrics, Internationality, Endocrinology, Diabetes and Metabolism, Gonadotropin-Releasing Hormone/therapeutic use, Human Growth Hormone/therapeutic use, MESH: Disease Management, law.invention, Gonadotropin-Releasing Hormone, 03 medical and health sciences, Endocrinology, Randomized controlled trial, law, Internal medicine, MESH: Gonadotropin-Releasing Hormone, medicine, MESH: Human Growth Hormone, Humans, Silver-Russell Syndrome/diagnosis, Motor skill, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, MESH: Humans, Human Growth Hormone, business.industry, Adrenarche, Disease Management, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Diabetes and Metabolism, Growth hormone treatment, Natural history, Silver-Russell Syndrome, 030104 developmental biology, MESH: Silver-Russell Syndrome, Speech delay, MESH: Internationality, Small for gestational age, medicine.symptom, business, Psychosocial
Abstract

International audience; This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver-Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood.

Published
2017
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13. Imprinted disorders and growth

Author

Yves Le Bouc, Eloise Giabicani, Frédéric Brioude, Irène Netchine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'explorations fonctionnelles [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Trousseau [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Beckwith-Wiedemann Syndrome, Endocrinology, Diabetes and Metabolism, Beckwith–Wiedemann syndrome, Epigenesis, Genetic, Fetal Development, MESH: Pregnancy, 0302 clinical medicine, Endocrinology, Pregnancy, MESH: Epigenesis, Genetic, Imprinting (psychology), Growth Disorders, Genetics, KCNQ1OT1, MESH: Infant, Newborn, IGF2, Syndrome de Beckwith-Wiedemann, General Medicine, MESH: Growth Disorders, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Uniparental disomy, Fetal Diseases, MESH: Fetal Diseases, MESH: Silver-Russell Syndrome, embryonic structures, Female, MESH: Beckwith-Wiedemann Syndrome, Imprinting disorders, MESH: Fetal Development, Adult, medicine.medical_specialty, MESH: Mutation, 030209 endocrinology & metabolism, Biology, Silver–Russell syndrome, Genomic Imprinting, 03 medical and health sciences, MESH: Uniparental Disomy, Internal medicine, parasitic diseases, medicine, Humans, Epigenetics, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, MESH: Humans, Infant, Newborn, MESH: Adult, Pathologies d’empreinte, Uniparental Disomy, medicine.disease, MESH: Genomic Imprinting, Silver-Russell Syndrome, CDKN1C, 030104 developmental biology, Overgrowth syndrome, Mutation, Genomic imprinting, MESH: Female, Syndrome de Silver-Russell
Abstract

International audience; Fetal growth is a complex process. Its restriction is associated with morbidity and long-term metabolic consequences. Imprinted genes have a critical role in mammalian fetal growth. Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) are two imprinting disorders with opposite fetal growth disturbance. SRS is leading to severe fetal and postnatal growth retardation with severe feeding difficulties during early childhood and long-term metabolic consequences and BWS is an overgrowth syndrome with an enhanced risk of tumors during childhood. Epigenetic (abnormal methylation at the imprinting center regions) or genetic (mutations, duplications, uniparental disomy [UPD]) including defects of imprinted genes on chromosome 11 (BWS and SRS), 7 (SRS) and more recently 14 (SRS) have been identified in these two syndromes. In humans, the 11p15 region contains genes important for the regulation of fetal and postnatal growth. This region includes two imprinted domains: the IGF2/H19 domain regulated by imprinting center region 1 (ICR1 or H19/IGF2:IG-DMR) and the CDKN1C/KCNQ1OT1 domain regulated by ICR2 (or KCNQ1OT1: TSS DMR).

Published
2017
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14. Dental pulp stem cells as a promising model to study imprinting diseases

Author

Eloïse Giabicani, Aurélie Pham, Céline Sélénou, Marie-Laure Sobrier, Caroline Andrique, Julie Lesieur, Agnès Linglart, Anne Poliard, Catherine Chaussain, and Irène Netchine

Subjects
Dentistry, RK1-715
Abstract

Abstract Parental imprinting is an epigenetic process leading to monoallelic expression of certain genes depending on their parental origin. Imprinting diseases are characterized by growth and metabolic issues starting from birth to adulthood. They are mainly due to methylation defects in imprinting control region that drive the abnormal expression of imprinted genes. We currently lack relevant animal or cellular models to unravel the pathophysiology of growth failure in these diseases. We aimed to characterize the methylation of imprinting regions in dental pulp stem cells and during their differentiation in osteogenic cells (involved in growth regulation) to assess the interest of this cells in modeling imprinting diseases. We collected dental pulp stem cells from five controls and four patients (three with Silver-Russell syndrome and one with Beckwith-Wiedemann syndrome). Methylation analysis of imprinting control regions involved in these syndromes showed a normal profile in controls and the imprinting defect in patients. These results were maintained in dental pulp stem cells cultured under osteogenic conditions. Furthermore, we confirmed the same pattern in six other loci involved in imprinting diseases in humans. We also confirmed monoallelic expression of H19 (an imprinted gene) in controls and its biallelic expression in one patient. Extensive imprinting control regions methylation analysis shows the strong potential of dental pulp stem cells in modeling imprinting diseases, in which imprinting regions are preserved in culture and during osteogenic differentiation. This will allow to perform in vitro functional and therapeutic tests in cells derived from dental pulp stem cells and generate other cell-types.

Published
2022
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15. IGF2: Development, Genetic and Epigenetic Abnormalities

Author

Céline Sélénou, Frédéric Brioude, Eloïse Giabicani, Marie-Laure Sobrier, and Irène Netchine

Subjects
IGF2, growth, Silver–Russell syndrome, Beckwith–Wiedemann syndrome, parental imprinting, Cytology, QH573-671
Abstract

In the 30 years since the first report of parental imprinting in insulin-like growth factor 2 (Igf2) knockout mouse models, we have learnt much about the structure of this protein, its role and regulation. Indeed, many animal and human studies involving innovative techniques have shed light on the complex regulation of IGF2 expression. The physiological roles of IGF-II have also been documented, revealing pleiotropic tissue-specific and developmental-stage-dependent action. Furthermore, in recent years, animal studies have highlighted important interspecies differences in IGF-II function, gene expression and regulation. The identification of human disorders due to impaired IGF2 gene expression has also helped to elucidate the major role of IGF-II in growth and in tumor proliferation. The Silver–Russell and Beckwith–Wiedemann syndromes are the most representative imprinted disorders, as they constitute both phenotypic and molecular mirrors of IGF2-linked abnormalities. The characterization of patients with either epigenetic or genetic defects altering IGF2 expression has confirmed the central role of IGF-II in human growth regulation, particularly before birth, and its effects on broader body functions, such as metabolism or tumor susceptibility. Given the long-term health impact of these rare disorders, it is important to understand the consequences of IGF2 defects in these patients.

Published
2022
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16. Roles of Type 1 Insulin-Like Growth Factor (IGF) Receptor and IGF-II in Growth Regulation: Evidence From a Patient Carrying Both an 11p Paternal Duplication and 15q Deletion

Author

Eloïse Giabicani, Sandra Chantot-Bastaraud, Adeline Bonnard, Myriam Rachid, Sandra Whalen, Irène Netchine, and Frédéric Brioude

Subjects
Beckwith-Wiedemann syndrome, IGF1 receptor, IGF-II, fetal growth restriction, imprinting disease, 11p duplication, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

We report an original association of complex genetic defects in a patient carrying both an 11p paternal duplication, resulting in the double expression of insulin-like growth factor 2 (IGF2), as reported in Beckwith-Wiedemann syndrome, and a 15q terminal deletion, including the type 1 IGF receptor gene (IGF1R), resulting in haploinsufficiency for this gene. The patient was born with measurements appropriate for her gestational age but experienced growth retardation in early childhood, allowing a better comprehension of the IGF system in the pathophysiology of growth. It is possible that IGF-II plays a key role in fetal growth, independently of IGF1R signaling, and that its role is less important in post-natal growth, leaving IGF-I and growth hormone as the main actors.

Published
2019
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17. Models for predicting the adult height and age at first menstruation of girls with idiopathic central precocious puberty.

Author

Eloïse Giabicani, Pierre Lemaire, and Raja Brauner

Subjects
Medicine, Science
Abstract

BACKGROUND:It is difficult to determine whether to treat a given girl who has idiopathic central precocious puberty (CPP) with gonadotropin-releasing hormone analog (GnRHa) in terms of adult height (AH). The objective was to provide an easy tool for predicting AH and age at first menstruation at initial evaluation to help guide the decision regarding whether to treat. METHODS:Data analysis using multiple linear regression models was performed in 134 girls with CPP. Among them 78 were given GnRHa because of low predicted AH (n=45), pubertal luteinising hormone (LH)/follicle-stimulating hormone peaks (FSH) ratio (n=50) and/or high plasma estradiol concentration (n=45). 56 girls were followed without treatment. RESULTS:In the whole population, the actual AH (162.1±5.61 cm) was similar to target height (161.7±4.91 cm) and to AH predicted by the Bayley and Pinneau method (161.9±7.98 cm). Separated models for treated and untreated girls provide very close estimations, leading to a unique formula for both groups. The AH (cm) could be calculated at the initial evaluation: 2.21 (height at initial evaluation, SD) + 2.32 (target height, SD) - 1.83 (LH/FSH peaks ratio) + 159.68. The actual AH was lower than the calculated AH by more than 1 SD (5.6 cm) in 11 girls (8.0%). The time between onset of puberty and first menstruation (in untreated girls) can be estimated with: 10.9 - 0.57 (LH/FSH peaks ratio). The formulae are available at http://www.kamick.org/lemaire/med/girls-cpp15.html. CONCLUSIONS:We established formulae that can be used at an initial evaluation to predict the AH, and the time between onset of puberty and first menstruation after spontaneous puberty. The similarity of the formulae for both groups suggests that the treatment had no significant effect on the AH. However, the criteria used to select treatment suggest that it prevents the deterioration of AH in cases with rapidly evolving form of CPP.

Published
2015
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18. Presentation of 493 consecutive girls with idiopathic central precocious puberty: a single-center study.

Author

Eloïse Giabicani, Slimane Allali, Adélaïde Durand, Julie Sommet, Ana-Claudia Couto-Silva, and Raja Brauner

Subjects
Medicine, Science
Abstract

BACKGROUND:Despite the number of reported data concerning idiopathic central precocious puberty (CPP) in girls, major questions remain including its diagnosis, factors, and indications of gonadotropin releasing hormone (GnRH) analog treatment. METHODS:A retrospective, single-center study was carried out on 493 girls with CPP. RESULTS:Eleven girls (2.2%) were aged less than 3 years. Breast development was either isolated (Group 0, n = 99), or associated with one sign, pubic hair development, growth rate greater than 2 standard deviation score (SDS) or bone age (BA) >2 years above chronological age, (Group 1, n = 187), two signs (Group 2, n = 142) or three signs (Group 3, n = 65). The interval between onset of puberty and evaluation, body mass index (BMI) SDS, plasma luteinising hormone (LH) concentrations (basal and peak) and LH/ follicle-stimulating hormone (FSH) peak ratio after GnRH test, plasma estradiol and uterus length were significantly greater in Groups 2 and 3 than in Groups 0 and 1 respectively. 211 (42.8%) patients were obese and/or had excessive weight gain during the year before puberty. Obese girls more often had BA advance of >2 years (p = 0.0004) and pubic hair development (p = 0.003) than the others. BMI did not correlate with LH or with LH/FSH peak ratio. Girls with familial history of early puberty (41.4%) had greater frequencies of pubertal LH/FSH peak ratios (p = 0.02) than the others. During the 31 years of the study, there was no increase in the frequency of CPP or variation in its characteristics. CONCLUSION:Obesity is associated with a higher BA advance and higher frequency of pubic or axillary hair development but not with LH secretion, suggesting that obesity accelerates adrenarche but not the maturation of the hypothalamic-pituitary-ovarian axis. The LH/FSH peak ratio was more frequently pubertal in girls with a familial history of early puberty, suggesting that this maturation depends on genetic factors.

Published
2013
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