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1. Characterization and prevalence of severe primary IGF1 deficiency in a large cohort of French children with short stature

Author: G. Pinto, M. Le Merrer, A Colmenares, C Thalassinos, K Lambot-Juhan, C Pauwels, Hélène Crosnier, A. Simon, Hanane Latrech, Jean-Claude Souberbielle, Michel Polak, Valérie Cormier-Daire, Jacques Beltrand, Geneviève Baujat, R Teissier, I. Flechtner, and Dinane Samara-Boustani
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Percentile, Adolescent, Pediatric endocrinology, Hearing Loss, Sensorineural, Endocrinology, Diabetes and Metabolism, Severity of Illness Index, Short stature, Cohort Studies, Young Adult, Endocrinology, Prevalence, Humans, Medicine, Insulin-Like Growth Factor I, Child, Prospective cohort study, Growth Disorders, business.industry, Infant, Newborn, Infant, General Medicine, medicine.disease, Body Height, Idiopathic short stature, Child, Preschool, Etiology, Small for gestational age, Female, Observational study, France, medicine.symptom, business
Abstract: ObjectiveThe prevalence of severe primary IGF1 deficiency (IGFD) is unclear. IGFD must be identified promptly as treatment with recombinant human IGF1 (rhIGF1) is now available. Our objective was to characterize and assess the prevalence of severe primary IGFD in a large cohort of patients evaluated for short stature at a pediatric endocrinology unit in France.DesignObservational study in a prospective cohort.MethodsConsecutive patients referred to our unit between 2004 and 2009 for suspected slow statural growth were included. Patients were classified into eight etiological categories. IGFD was defined by height ≤−3 SDS, serum IGF1 levels ResultsOut of 2546 patients included, 337 (13.5%) were born small for gestational age and 424 (16.9%) had idiopathic short stature. In these two categories, we identified 30 patients who met our criterion for IGFD (30/2546, 1.2%). In these 30 patients, we assessed the response to IGF1 generation test, time course of IGF1 levels, and efficiency of GH replacement therapy. The results indicated that only four of the 30 children were definite or possible candidates for rhIGF1 replacement therapy.ConclusionThe prevalence of severe primary IGFD defined using the standard criterion for rhIGF1 treatment was 1.2%, and only 0.2% of patients were eligible for rhIGF1 therapy.
Published: 2014
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2. Three-dimensional helical computed tomography in prenatal diagnosis of fetal skeletal dysplasia

Author: Jelena Martinovic, Bruno Carbonne, Caroline Elie, M.-C. Aubry, Valérie Cormier-Daire, G. Macé, Yves Dumez, Alexandra Benachi, M. Le Merrer, Pascale Sonigo, Marie Gonzales, and Francis Brunelle
Subjects: medicine.medical_specialty, Fetus, Pregnancy, Radiological and Ultrasound Technology, business.industry, Ultrasound, Obstetrics and Gynecology, Prenatal diagnosis, Autopsy, Retrospective cohort study, General Medicine, medicine.disease, Reproductive Medicine, Dysplasia, Micromelia, medicine, Radiology, Nuclear Medicine and imaging, Radiology, business
Abstract: Objectives (1) To study the use and diagnostic value, as a complement to ultrasound, of helical computed tomography (helical CT) to differentiate normal fetuses from cases of skeletal dysplasia; (2) to define the most relevant indications for helical CT; and (3) to evaluate its diagnostic performance with respect to radiological criteria considered discriminatory. Methods This was a retrospective study from 2005 to 2008 in 67 pregnant women who underwent helical CT after 26 weeks of gestation for suspected fetal skeletal dysplasia due to fetal shortened long bones on ultrasound (≤ 10thpercentile), either alone or associated with other bone abnormalities. The results were compared with pediatric examinations in 41 cases and with fetal autopsy findings after elective termination of pregnancy in the others. Results Helical CT had a sensitivity of 82%, specificity of 91% and positive and negative predictive values of 90% and 83%, respectively, for diagnosis of fetal skeletal dysplasia. An etiological diagnosis that had not been suspected at ultrasound was specified in 15% of cases and diagnoses suspected at ultrasound were confirmed in 24% and discounted in 43% of cases. The prevalence of skeletal dysplasia was increased in cases of micromelia < 3rd percentile or if there was a combination of bone signs. Helical CT showed 69% sensitivity in identifying individual predefined pathological bone signs which were confirmed on fetal autopsy findings. Conclusion Helical CT is a key examination, in combination with ultrasound, in the diagnosis of fetal skeletal dysplasia from 26 weeks of gestation. It should be reserved for cases with severe micromelia below the 3rd percentile and for those with micromelia ≤ 10th percentile associated with another bone sign. A checklist of discriminatory signs is proposed. Copyright © 2012 ISUOG. Published by John Wiley & Sons Ltd.
Published: 2013
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3. Les tests génétiques à l’heure de la deuxième révision des lois de bioéthique

Author: M. Le Merrer, Dominique Stoppa-Lyonnet, Dominique Bonneau, Marie Gonzales, Sylvie Manouvrier, Hagay Sobol, Sandrine Marlin, P. Malzac, Sylvie Odent, Jean-Michel Dupont, Damien Sanlaville, and Ferechté Razavi
Subjects: medicine.medical_specialty, medicine.diagnostic_test, business.industry, Medical screening, Prenatal diagnosis, Late onset, General Medicine, Bioethics, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Family medicine, medicine, Genomic medicine, 030212 general & internal medicine, Population screening, business, Genetic testing
Abstract: This article focuses on six questions raised by genetic testing in human: (1) the use of genetic tests, (2) information given to relatives of patients affected with genetic disorders, (3) prenatal and preimplantatory diagnosis for late onset genetic diseases and the use of pangenomic tests in prenatal diagnosis, (4) direct-to-consumer genetic testing, (5) population screening in the age of genomic medicine and (6) incidental findings when genetic testing are used.
Published: 2010
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4. Autosomal dominant spondylocarpotarsal synostosis syndrome: Phenotypic homogeneity and genetic heterogeneity

Author: Antoine Hamel, C Le Caignec, M. Le Merrer, Sébastien Jacquemont, Valérie Cormier-Daire, Bertrand Isidor, T. Lefrancois, and Albert David
Subjects: Adult, Male, Clinodactyly, Filamins, Genetic counseling, Biology, Compound heterozygosity, Short stature, Contractile Proteins, Genetics, medicine, Humans, FLNB, Child, Genetics (clinical), Genes, Dominant, Tarsal synostosis, Genetic heterogeneity, Microfilament Proteins, Tarsal Bones, Hand Deformities, Synostosis, medicine.disease, Spine, Pedigree, Radiography, Phenotype, Mutation, Female, medicine.symptom
Abstract: Spondylocarpotarsal synostosis syndrome (SCT) (OMIM 272460), originally thought to be a failure of normal spine segmentation, is characterized by progressive fusion of vertebras and associates unsegmented bars, scoliosis, short stature, carpal and tarsal synostosis. Cleft palate, sensorineural or mixed hearing loss, joint limitation, clinodactyly, and dental enamel hypoplasia are variable manifestations. Twenty-five patients have been reported. Thirteen affected individuals were siblings from six families and four of these families were consanguineous. In four of those families, Krakow et al. [Krakow et al. (2004) Nat Genet 36:405-410] found homozygosity or compound heterozygosity for mutations in the gene encoding FLNB. This confirmed autosomal recessive inheritance of the disorder. We report on two new patients (a mother and her son) representing the first case of autosomal dominant inheritance. These patients met the clinical and radiological criteria for SCT and did not present any features which could exclude this diagnosis. Molecular analysis failed to identify mutations in NOG and FLNB. SCT is therefore, genetically heterogeneous. Both dominant and autosomal recessive forms of inheritance should be considered during genetic counseling.
Published: 2008
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5. Untreated growth hormone deficiency with extremely short stature, bone dysplasia, cleft lip–palate and severe mental retardation in a 26-year-old man with a de novo unbalanced translocation t(1;12)(q24;q24)

Author: Laurence Faivre, Nathalie Marle, Frédéric Huet, A. Danino, Patrick Callier, C. Thauvin-Robinet, Francine Mugneret, G. Malka, S. Falcon-Eicher, M. Le Merrer, Alice Masurel-Paulet, J. Borgnon, and A.L. Mosca
Subjects: Adult, Male, medicine.medical_specialty, Cleft Lip, Chromosomal translocation, Biology, Short stature, Translocation, Genetic, Growth hormone deficiency, Molecular cytogenetics, Intellectual Disability, Internal medicine, Genetics, medicine, Humans, Growth Disorders, In Situ Hybridization, Fluorescence, Genetics (clinical), Bone Diseases, Developmental, Chromosomes, Human, Pair 12, Cytogenetics, Karyotype, General Medicine, medicine.disease, Cleft Palate, Developmental disorder, Endocrinology, Chromosomes, Human, Pair 1, Dysplasia, Growth Hormone, Karyotyping, medicine.symptom
Abstract: We report on a 26-year-old patient presenting with extremely short stature (height 72cm, weight 6.5kg, OFC 42.5cm), facial dysmorphism, cleft lip--palate, severe mental retardation and de novo 1q24.2--q25.2 and 12q24.31 interstitial deletion. He was the only child of non-consanguineous parents and his birth length was 43cm. He had severe feeding difficulties and required enteral nutrition until the age of 3 years. Standard cytogenetic analysis showed an apparently balanced de novo translocation t(1;12)(q24;q24). Endocrine studies at 11 years of age for severe growth retardation revealed multiple pituitary hormone deficiency with severe growth hormone deficiency, but the child was untreated because of associated mental retardation. At 26 years of age, he could not walk or speak and had no signs of puberty. Investigations revealed spondylo-epi-metaphyseal dysplasia with severe osteoporosis, enlarged aorta when compared to the patient's size and apparently normal pituitary development. High resolution karyotype showed a 1q24-q25 deletion, and comparative genomic hybridization studies confirmed the 1q interstitial deletion. FISH studies of both breakpoints using PACs and BACs enabled us to further characterize the 1q interstitial deletion (1q24.2-1q25.2) and also revealed a 12q24.31 interstitial microdeletion. This case is compared with previously reported patients with similar deletions, but the untreated pituitary deficiency could also be responsible in part for the severity of the growth deficiency. This observation is of interest for two reasons. First, these deletions could be a clue in the search for a gene responsible for growth hormone deficiency/midline defects. Second, it shows the importance of molecular cytogenetics in the study of de novo apparently balanced translocation with abnormal phenotype.
Published: 2007
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6. Étiologie des craniosténoses

Author: D. Renier, Eric Arnaud, Daniel Marchac, and M. Le Merrer
Subjects: Pediatrics, medicine.medical_specialty, Text mining, business.industry, Etiology, Medicine, Dysostosis, Surgery, Neurology (clinical), business, medicine.disease, Craniosynostosis
Published: 2006
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7. Radiologie et maladies osseuses constitutionnelles : nomenclatures, classification et approche diagnostique

Author: G. Kalifa, M. Le Merrer, S. Ferey, and Christine Hall
Subjects: business.industry, Medicine, business
Published: 2006
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8. New insights in congenital bowing of the femora

Author: M. Le Merrer, Valérie Cormier-Daire, David Geneviève, and Arnold Munnich
Subjects: medicine.medical_specialty, Pathology, business.industry, Kyphomelic dysplasia, SOX9, medicine.disease, Osteochondrodysplasia, STUVE-WIEDEMANN SYNDROME, Campomelic dysplasia, Endocrinology, Dysplasia, Bent bone dysplasia, Internal medicine, Genetics, medicine, SOX9 Transcription Factor, business, Genetics (clinical)
Abstract: The aim of this study is to review the clinical, radiological and molecular findings of the bent bone dysplasia group including Stuve-Wiedemann syndrome due to LIFR mutations, Compomelic dysplasia due to SOX9 mutations and Kyphomelic dysplasia with no known molecular bases.
Published: 2004
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9. Genome-wide screening using automated fluorescent genotyping to detect cryptic cytogenetic abnormalities in children with idiopathic syndromic mental retardation

Author: Florence Molinari, M. Le Merrer, Odile Raoul, Nigel P. Carter, Laurence Colleaux, Richard Redon, Valérie Cormier-Daire, Delphine Bacq, Arnold Munnich, Jeanne Amiel, Marlène Rio, Marguerite Prieur, Damien Sanlaville, Michel Vekemans, Guntram Borck, M-C de Blois, and Stanislas Lyonnet
Subjects: Genetics, 0303 health sciences, medicine.medical_specialty, education.field_of_study, 030305 genetics & heredity, Population, Cytogenetics, Chromosomal rearrangement, Biology, Subtelomere, medicine.disease, Genome, Uniparental disomy, 03 medical and health sciences, medicine, Microsatellite, education, Genotyping, Genetics (clinical), 030304 developmental biology
Abstract: Mental retardation (MR) is the most common developmental disability, affecting approximately 2% of the population. The causes of MR are diverse and poorly understood, but chromosomal rearrangements account for 4-28% of cases, and duplications/deletions smaller than 5 Mb are known to cause syndromic MR. We have previously developed a strategy based on automated fluorescent microsatellite genotyping to test for telomere integrity. This strategy detected about 10% of cryptic subtelomeric rearrangements in patients with idiopathic syndromic MR. Because telomere screening is a first step toward the goal of analyzing the entire genome for chromosomal rearrangements in MR, we have extended our strategy to 400 markers evenly distributed along the chromosomes to detect interstitial anomalies. Among 97 individuals tested, three anomalies were found: two deletions (one in three siblings) and one parental disomy. These results emphasize the value of a genome-wide microsatellite scan for the detection of interstitial aberrations and demonstrate that automated genotyping is a sensitive method that not only detects small interstitial rearrangements and their parental origin but also provides a unique opportunity to detect uniparental disomies. This study will hopefully contribute to the delineation of new contiguous gene syndromes and the identification of new imprinted regions.
Published: 2004
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10. Atypical findings in Kabuki syndrome: Report of 8 patients in a series of 20 and review of the literature

Author: M. Le Merrer, Arnold Munnich, Jeanne Amiel, A. Urtizberea, Stanislas Lyonnet, Marion Gérard, Damien Sanlaville, David Geneviève, Valérie Cormier-Daire, and Géraldine Viot
Subjects: Pediatrics, medicine.medical_specialty, Optic nerve coloboma, business.industry, Vitiligo, Hypoglycemia, medicine.disease, CHARGE syndrome, Pseudarthrosis, Cerebellar vermis atrophy, Intellectual disability, Genetics, medicine, business, Kabuki syndrome, Genetics (clinical)
Abstract: Kabuki syndrome (KS) is a rare multiple congenital anomaly/mental retardation syndrome with an estimated frequency of 1/32,000 in Japan. Five major criteria delineate KS namely postnatal short stature, skeletal anomalies, moderate mental retardation, dermatoglyphic anomalies, and a characteristic facial dysmorphism. Here we report on a series of 20 sporadic KS patients and we focus on some rare and atypical features that we have observed: chronic and/or severe diarrhea (4/20) including celiac disease, diaphragmatic defects (3/20), pseudarthrosis of the clavicles (2/20), vitiligo (2/20), and persistent hypoglycemia (2/20). Other occasional findings were severe autoimmune thrombopenia, cerebellar vermis atrophy, and myopathic features. Interestingly, one of our KS patients presented with a clinical overlap with CHARGE syndrome (right eye microphtalmia with optic nerve coloboma, VSD, bilateral cryptorchidism, and severe deafness). Because these features are more frequent in our series than previously described, we propose to carefully investigate these manifestations during KS patient survey in an attempt to determine their real frequency and in order to improve clinical management.
Published: 2004
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11. Maladie des exostoses multiples après 40 ans d’évolution : à propos d’un cas

Author: M. El Guedj, Laurence Legeai-Mallet, A.M Zagdanski, Dominique Farge, M Le Merrer, G Délépine, and J Rambeloarisoa
Subjects: Gynecology, medicine.medical_specialty, Multiple cartilaginous exostosis, business.industry, Hereditary multiple exostoses, Gastroenterology, Internal Medicine, medicine, business, medicine.disease, Osteochondrodysplasia
Abstract: Resume Introduction. – La maladie des exostoses multiples est une affection osteocartilagineuse hereditaire de type autosomique dominant, genetiquement heterogene, dont la prevalence est estimee a 1/50 000 dans les pays occidentaux. Sa complication classique, peu frequente (environ 2 %) mais grave, est la degenerescence maligne. Au moins 3 locus differents, correspondant aux genes codant EXT 1, EXT 2 et EXT 3, sont impliques dans cette maladie. Exegese. – Le patient, âge de 45 ans, est suivi depuis 15 ans a la suite de la resection d’un chondrosarcome tres bien differencie de grade I, developpe a partir d’une exostose iliaque droite posterieure. Les lesions radiologiques sont restees relativement stables et la mutation genetique qui en est responsable a ete identifiee dans la serie EXT 1, l’analyse aux autres locus etant en cours. Conclusion. – Le cas de notre patient illustre les donnees cliniques, radiologiques et genetiques recentes concernant la maladie des exostoses multiples avec une longue survie apres resection d’une exostose degeneree. L’aboutissement de l’analyse genetique permet de progresser dans la comprehension de la physiopathologie de la maladie.
Published: 2002
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12. Automated fluorescent genotyping detects 10% of cryptic subtelomeric rearrangements in idiopathic syndromic mental retardation

Author: Catherine Ozilou, Arnold Munnich, Jeanne Amiel, Catherine Turleau, Valérie Cormier-Daire, S. Romana, M-C de Blois, Michel Vekemans, P. Gosset, Laurence Colleaux, Stanislas Lyonnet, M. Le Merrer, Odile Raoul, Solange Heuertz, Marguerite Prieur, Marlène Rio, Florence Molinari, Service de Génétique Médicale [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Handicaps génétiques de l'enfant (Inserm U393), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)
Subjects: Male, Proband, MESH: Genotype, Chromosome Segregation, Gene Duplication, MESH: Child, Gene duplication, MESH: Syndrome, MESH: In Situ Hybridization, Fluorescence, Child, In Situ Hybridization, Fluorescence, Genetics (clinical), Gene Rearrangement, Genetics, 0303 health sciences, MESH: Genetic Testing, medicine.diagnostic_test, MESH: Gene Duplication, 030305 genetics & heredity, Chromosome Mapping, Syndrome, Telomere, MESH: Fluorescent Dyes, Subtelomere, Uniparental disomy, Pedigree, Female, Original Article, Chromosome Deletion, medicine.medical_specialty, Genotype, MESH: Pedigree, MESH: Gene Rearrangement, MESH: Chromosome Deletion, MESH: Chromosome Segregation, Biology, Sensitivity and Specificity, MESH: Intellectual Disability, 03 medical and health sciences, Intellectual Disability, MESH: Uniparental Disomy, MESH: Polymorphism, Genetic, medicine, Humans, Genetic Testing, Genotyping, Fluorescent Dyes, 030304 developmental biology, Genetic testing, Polymorphism, Genetic, MESH: Humans, Cytogenetics, Gene rearrangement, Uniparental Disomy, medicine.disease, MESH: Male, MESH: Sensitivity and Specificity, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Microsatellite Repeats, MESH: Telomere, MESH: Chromosome Mapping, MESH: Female, Microsatellite Repeats
Abstract: International audience; Recent studies have shown that cryptic unbalanced subtelomeric rearrangements contribute to a significant proportion of idiopathic syndromic mental retardation cases. Using a fluorescent genotyping based strategy, we found a 10% rate of cryptic subtelomeric rearrangements in a large series of 150 probands with severe idiopathic syndromic mental retardation and normal RHG-GTG banded karyotype. Fourteen children were found to carry deletions or duplications of one or more chromosome telomeres and two children had uniparental disomy. This study clearly shows that fluorescent genotyping is a sensitive and cost effective method that not only detects cryptic subtelomeric rearrangements but also provides a unique opportunity to detect uniparental disomies. We suggest giving consideration to systematic examination of subtelomeric regions in the diagnostic work up of patients with unexplained syndromic mental retardation.
Published: 2002
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13. Dysmorphism, variable overgrowth, normal bone age, and severe developmental delay: a 'Sotos-like' syndrome?

Author: Robin M. Winter, Stanislas Lyonnet, Arnold Munnich, Jeanne Amiel, Louise C. Wilson, Valérie Cormier-Daire, M. Le Merrer, and Laurence Faivre
Subjects: Pediatrics, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Sotos syndrome, Birth weight, Macrocephaly, Bone age, medicine.disease, Uniparental disomy, Hypotonia, Endocrinology, Internal medicine, Overgrowth syndrome, Genetics, medicine, Amniocentesis, medicine.symptom, business, Genetics (clinical)
Abstract: Sotos syndrome (MIM 117550) is an overgrowth syndrome first described by Sotos et al 1 in 1964 with over 200 cases reported to date. The syndrome is characterised by pre- and postnatal overgrowth, macrocephaly, advanced bone age, and distinctive facial features.2 In a review of 79 patients diagnosed as Sotos syndrome, Cole and Hughes3 showed that the overall gestalt was as efficient as clinical and radiological criteria for the diagnosis. The vast majority of cases are sporadic. Concordant and discordant monozygotic twins have been reported.4,5 In rare instances, familial cases with autosomal dominant or autosomal recessive inheritance have been suspected and chromosomal rearrangements have also been reported.4,6 However, the aetiology of Sotos syndrome remains unknown. A hypothalamic origin was first suspected but extensive endocrinological testing failed to show significant anomalies. More recently, chromosomal uniparental disomy has been ruled out.7 Here, we report on five unrelated cases with a Sotos facial gestalt, severe developmental delay, moderate to absent overgrowth, and normal bone age. We propose a separate Sotos-like syndrome. ### Case 1 Case 1, a male, was the third child of healthy, non-consanguineous parents, aged 31 and 33 years at the time of birth. The mother's height was 1.57 m (25th centile) and the father's 1.72 m (between the 25th and 50th centile). Amniocentesis was performed for at risk maternal serum screening and fetal chromosomes were normal 46,XY. Bilateral vesicoureteral reflux was diagnosed prenatally and surgically repaired at 9 months of age. He was born at term with normal birth parameters (birth weight 3360 g, 25th centile; length 51 cm, 50th centile; OFC 35 cm, 50th centile). He had hypotonia and psychomotor delay (sat at 12 months, walked at 24 months, no words at 24 months). He was first investigated at 9 months; hypsarrythmia was diagnosed and …
Published: 2002
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14. Arthrogryposis multiplex congenita and Cerebellopontine Ischemic Lesions in Sibs: Recurrence of Prenatal Disruptive Brain Lesions with Different Patterns of Expression?

Author: M. Le Merrer, Dominique Mahieu-Caputo, Y. Martinovic, Laurent Salomon, Pascale Sonigo, Marie-Cécile Aubry, Marc Dommergues, Yves Dumez, and Férechté Encha-Razavi
Subjects: Adult, Embryology, Pathology, medicine.medical_specialty, Gestational Age, Prenatal diagnosis, Ultrasonography, Prenatal, Brain Ischemia, Pregnancy, Cerebellum, Pons, Prenatal Diagnosis, medicine, Humans, Radiology, Nuclear Medicine and imaging, Family history, Arthrogryposis, Fetus, Arthrogryposis multiplex congenita, business.industry, Brain, Obstetrics and Gynecology, General Medicine, medicine.disease, Magnetic Resonance Imaging, Hypoplasia, Pediatrics, Perinatology and Child Health, Female, Multiple pterygium syndrome, medicine.symptom, Abnormality, Tomography, X-Ray Computed, business
Abstract: Arthrogryposis multiplex congenita (AMC) is a heterogeneous group of disorders in which prolonged decrease or absence of fetal movements results in a series of deformational anomalies. The rate of recurrence ranges from 25% in some recessive forms of myogenic arthrogryposis or of primary anterior horn cell loss, to less than 1% in anoxic-ischaemic damage. Cerebral clastic processes are considered as sporadic. We report on a non-consanguineous family in which the first child was affected by AMC and the following pregnancy was terminated because cerebellum hypoplasia was suspected at ultrasound and confirmed by fetal magnetic resonance imaging. Post-mortem findings demonstrated pontocerebellar ischaemic-haemorrhagic injuries. The occurrence of these neurologic abnormalities in the same family suggests a common mechanism, which might correspond to a same genetic defect with different patterns of expression. This is the first prenatal report suggesting that an ‘ischaemic’ process, usually recognised as sporadic could in fact be due to an inherited abnormality. Careful prenatal follow-up of third-trimester fetal brain development may be required in pregnant women with a family history of AMC.
Published: 2002
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15. Unexpected high frequency of skeletal dysplasia in idiopathic short stature and small for gestational age patients

Author: K. Lambot-Juhan, Ana Colmenares, M. Le Merrer, Isabelle Flechtner, Michel Polak, R Teissier, Graziella Pinto, Jacques Beltrand, Valérie Cormier-Daire, Albane Simon, Z Ajaltouni, Caroline Thalassinos, Geneviève Baujat, C Pauwels, and Dinane Samara-Boustani
Subjects: Male, Pediatrics, medicine.medical_specialty, Adolescent, Skeletal survey, Endocrinology, Diabetes and Metabolism, Limb Deformities, Congenital, Context (language use), Hypochondroplasia, Dwarfism, Osteochondrodysplasias, Bone and Bones, Cohort Studies, Endocrinology, medicine, Prevalence, Humans, Prospective Studies, Prospective cohort study, Child, Hospitals, Teaching, Referral and Consultation, Growth Disorders, Family Health, Bone Diseases, Developmental, Fetal Growth Retardation, business.industry, Genetic Variation, Infant, General Medicine, medicine.disease, Hospitals, Pediatric, Idiopathic short stature, Dysplasia, Child, Preschool, Infant, Small for Gestational Age, Lordosis, Small for gestational age, Female, France, business, Cohort study
Abstract: ObjectiveTo assess the prevalence of skeletal dysplasias (SDs) in patients with idiopathic short stature (ISS) or small for gestational age (SGA) status.SettingRare Endocrine/Growth Diseases Center in Paris, France.DesignA prospective study on consecutive patients with ISS and SGA enrolled from 2004 to 2009.MethodWe used a standardized workup to classify patients into well-established diagnostic categories. Of 713 patients with ISS (n=417) or SGA status (n=296), 50.9% underwent a skeletal survey. We chose patients labeled normal or with a prepubertal slowdown of growth as a comparison group.ResultsDiagnoses were ISS (16.9%), SGA (13.5%), normal growth (24.5%), transient growth rate slowing (17.3%), endocrine dysfunction (12%), genetic syndrome (8.9%), chronic disease (5.1%), and known SD (1.8%). SD was found in 20.9% of SGA and 21.8% ISS patients and in only 13.2% in our comparison group. SD prevalence was significantly higher in the ISS group than in the comparison group, especially (50%) for patients having at least one parent whose height was ConclusionSD may explain more than 20% of cases of growth retardation ascribed to ISS or SGA, and this proportion is higher when parental height is
Published: 2014

16. The Molecular Basis of X-Linked Spondyloepiphyseal Dysplasia Tarda

Author: D. Chitayat, Jozef Gecz, William G. Cole, Stephen P. Robertson, Solange Heuertz, David L. Rimoin, Arnold Munnich, Ravi Savarirayan, B.G. Kousseff, I. A. Glass, George E. Tiller, John C. Mulley, Bernhard Zabel, M. Le Merrer, Agi K. Gedeon, Hirofumi Ohashi, and L. Tranebjaerg
Subjects: Spondyloepiphyseal dysplasia, Genetic Markers, Male, X Chromosome, Genetic Linkage, Nonsense mutation, DNA Mutational Analysis, Molecular Sequence Data, Biology, medicine.disease_cause, Osteochondrodysplasias, Frameshift mutation, 03 medical and health sciences, Exon, Structure-Activity Relationship, 0302 clinical medicine, medicine, Ethnicity, Genetics, Missense mutation, Humans, Genetics(clinical), Genetic Testing, RNA, Messenger, Genetics (clinical), X chromosome, 030304 developmental biology, 0303 health sciences, Mutation, Bone Development, Polymorphism, Genetic, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, Racial Groups, Membrane Transport Proteins, Exons, Articles, medicine.disease, Osteochondrodysplasia, Body Height, 3. Good health, Phenotype, Haplotypes, Carrier Proteins, 030217 neurology & neurosurgery, Transcription Factors
Abstract: The X-linked form of spondyloepiphyseal dysplasia tarda (SEDL), a radiologically distinct skeletal dysplasia affecting the vertebrae and epiphyses, is caused by mutations in the SEDL gene. To characterize the molecular basis for SEDL, we have identified the spectrum of SEDL mutations in 30 of 36 unrelated cases of X-linked SEDL ascertained from different ethnic populations. Twenty-one different disease-associated mutations now have been identified throughout the SEDL gene. These include nonsense mutations in exons 4 and 5, missense mutations in exons 4 and 6, small (2–7 bp) and large (>1 kb) deletions, insertions, and putative splicing errors, with one splicing error due to a complex deletion/insertion mutation. Eight different frameshift mutations lead to a premature termination of translation and account for >43% (13/30) of SEDL cases, with half of these (7/13) being due to dinucleotide deletions. Altogether, deletions account for 57% (17/30) of all known SEDL mutations. Four recurrent mutations (IVS3+5G→A, 157–158delAT, 191–192delTG, and 271–275delCAAGA) account for 43% (13/30) of confirmed SEDL cases. The results of haplotype analyses and the diverse ethnic origins of patients support recurrent mutations. Two patients with large deletions of SEDL exons were found, one with childhood onset of painful complications, the other relatively free of additional symptoms. However, we could not establish a clear genotype/phenotype correlation and therefore conclude that the complete unaltered SEDL-gene product is essential for normal bone growth. Molecular diagnosis can now be offered for presymptomatic testing of this disorder. Appropriate lifestyle decisions and, eventually, perhaps, specific SEDL therapies may ameliorate the prognosis of premature osteoarthritis and the need for hip arthroplasty.
Published: 2001
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17. Linkage exclusion and mutational analysis of thenoggingene in patients with fibrodysplasia ossificans progressiva (FOP)

Author: M. Le Merrer, Eileen M. Shore, Michel Fardeau, Y Y Shugart, James T. Triffitt, David L. Glaser, J. M. Connor, Roger Smith, J. A. Urtizberea, Frederick S. Kaplan, George J. Feldman, and Meiqi Xu
Subjects: Genetics, animal structures, Genetic disorder, Locus (genetics), Single-strand conformation polymorphism, Biology, medicine.disease, Germline mutation, Bone morphogenetic protein 4, Genetic linkage, Fibrodysplasia ossificans progressiva, embryonic structures, medicine, Noggin, Genetics (clinical)
Abstract: Fibrodysplasia ossificans progressiva (FOP) is an extremely rare and disabling genetic disorder characterized by congenital malformation of the great toes and by progressive heterotopic endochondral ossification in predictable anatomical patterns. Although elevated levels of bone morphogenetic protein 4 (BMP4) occur in lymphoblastoid cells and in lesional cells of patients with FOP, mutations have not been identified in the BMP4 gene, suggesting that the mutation in FOP may reside in a BMP4-interacting factor or in another component of the BMP4 pathway. A powerful antagonist of BMP4 is the secreted polypeptide noggin. A recent case report described a heterozygous 42-bp deletion in the protein-coding region of the noggin gene in a patient with FOP. In order to determine if noggin mutations are a widespread finding in FOP, we examined 31 families with 1 or more FOP patients. Linkage analysis with an array of highly polymorphic microsatellite markers closely linked to the noggin gene was performed in four classically-affected multigenerational FOP families and excluded linkage of the noggin locus to FOP (the multipoint lod score was -2 or less throughout the entire range of markers). We sequenced the noggin gene in affected members of all four families, as well as in 18 patients with sporadic FOP, and failed to detect any mutations. Single-strand conformation polymorphism (SSCP) analysis of 4 of these patients plus an additional 9 patients also failed to reveal any mutations. Among the samples analyzed by SSCP and DNA sequencing was an independently obtained DNA sample from the identical FOP patient previously described with the 42-bp noggin deletion; no mutation was detected. Examination of the DNA sequences of 20 cloned noggin PCR products, undertaken to evaluate the possibility of a somatic mutation in the noggin gene which could be carried by a small subset of white blood cells, also failed to detect the presence of the reported 42-bp deletion. We conclude that mutations in the coding region of noggin are not associated with FOP.
Published: 2000
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18. Genitopatellar syndrome: a new condition comprising absent patellae, scrotal hypoplasia, renal anomalies, facial dysmorphism, and mental retardation

Author: Stanislas Lyonnet, Arnold Munnich, M. Le Merrer, Valérie Cormier-Daire, M. L. Chauvet, and Marie-Louise Briard
Subjects: Microcephaly, Nasal bridge, business.industry, Brachydactyly, Short Report, Anatomy, medicine.disease, Hypoplasia, Pulmonary hypoplasia, Agenesis, Genetics, medicine, Genitopatellar syndrome, business, Agenesis of the corpus callosum, Genetics (clinical)
Abstract: We report on the association of absent patellae, genital and renal anomalies, dysmorphic features, and mental retardation in seven children (six boys and one girl) belonging to five unrelated families. Flexion deformities of the knees and hips with club feet and absent patellae were consistently observed and scrotal hypoplasia and cryptorchidism were present in all boys (6/6). Dysmorphic features included a coarse face, a large nose with a high nasal bridge, and microcephaly. Other features included renal anomalies (multicystic kidneys or hydronephrosis, 7/7), agenesis of the corpus callosum (4/7), swallowing difficulties, micrognathia (4/7), and pulmonary hypoplasia (3/7). Bilateral hypoplasia of the ischia and brachydactyly were also consistently observed (5/5). In two out of seven cases, prenatal ultrasound detection of microcephaly and renal anomalies led to termination of the pregnancy at 27 weeks. Three children died during the first years of life and the remaining two who survived exhibit severe developmental delay. High resolution cytogenetic studies performed on lymphocytes or fibroblasts or both were normal in all cases. Recurrence in two families suggests an autosomal recessive mode of inheritance. We propose that this unusual association, similar to that observed in a 4 year old boy by Goldblatt et al, represents a new syndrome distinct from previously reported hypoplastic patella syndromes. Keywords: patella; genital anomalies; renal anomalies; mental retardation
Published: 2000
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19. A Novel Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Mutation in Jansen’s Metaphyseal Chondrodysplasia1

Author: Ernestina Schipani, Caroline Silve, Kah Yin Loke, Harald Jüppner, J.L. Hunzelman, M. Le Merrer, Craig B. Langman, and M J Dillon
Subjects: medicine.medical_specialty, Mutation, Parathyroid hormone receptor, Endocrinology, Diabetes and Metabolism, Biochemistry (medical), Clinical Biochemistry, Parathyroid hormone, Biology, medicine.disease_cause, medicine.disease, Biochemistry, Osteochondrodysplasia, Jansen's metaphyseal chondrodysplasia, Endocrinology, Ion homeostasis, Internal medicine, medicine, Missense mutation, Receptor, hormones, hormone substitutes, and hormone antagonists
Abstract: Two heterozygous PTH/PTH-related peptide (PTHrP) receptor missense mutations were previously identified in patients with Jansen’s metaphyseal chondrodysplasia (JMC), a rare form of short limb dwarfism associated with hypercalcemia and normal or undetectable levels of PTH and PTHrP. Both mutations, H223R and T410P, resulted in constitutive activation of the cAMP signaling pathway and provided a plausible explanation for the abnormalities in skeletal development and mineral ion homeostasis. In the present study we analyzed genomic DNA from four additional sporadic cases with JMC to search for novel activating mutations in the PTH/PTHrP receptor, to determine the frequency of the two previously identified missense mutations, H223R and T410P, and to determine whether different mutations present with different severity of the disease. The H223R mutation was identified in three novel JMC patients and is, therefore, to date the most frequent cause of JMC. In the fourth patient, a novel heterozygous missense muta...
Published: 1999
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20. Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia

Author: S. Bahabri, Andrea Superti-Furga, Jamil Al-Alami, J K Herd, W. Van Hul, Jean Roudier, H Rezai-Delui, M. Le Merrer, Wafaa M. Suwairi, J R Hurvitz, D Holderbaum, Hatem El-Shanti, Richard M. Pauli, Eric Legius, E Van Hul, and Matthew L. Warman
Subjects: Male, Pathology, medicine.medical_specialty, Adolescent, Molecular Sequence Data, Population, Biology, Osteochondrodysplasias, Bone and Bones, Immediate early protein, Immediate-Early Proteins, CCN Intercellular Signaling Proteins, Nephroblastoma Overexpressed Protein, Skeletal disorder, Proto-Oncogene Proteins, Genetics, medicine, Humans, CCN protein, Growth Substances, education, Oncogene Proteins, education.field_of_study, Cartilage homeostasis, Connective Tissue Growth Factor, Intracellular Signaling Peptides and Proteins, Hand, medicine.disease, Radiography, CTGF, Cartilage, Haplotypes, Dysplasia, Mutation, Intercellular Signaling Peptides and Proteins, Chromosomes, Human, Pair 6
Abstract: Members of the CCN (for CTGF, cyr61/cef10, nov) gene family encode cysteine-rich secreted proteins with roles in cell growth and differentiation1. Cell-specific and tissue-specific differences in the expression and function of different CCN family members suggest they have non-redundant roles. Using a positional-candidate approach, we found that mutations in the CCN family member WISP3 are associated with the autosomal recessive skeletal disorder progressive pseudorheumatoid dysplasia (PPD; MIM 208230). PPD is an autosomal recessive disorder that may be initially misdiagnosed as juvenile rheumatoid arthritis2,3,4,5. Its population incidence has been estimated at 1 per million in the United Kingdom4, but it is likely to be higher in the Middle East and Gulf States6. Affected individuals are asymptomatic in early childhood2,3. Signs and symptoms of disease typically develop between three and eight years of age. Clinically and radiographically, patients experience continued cartilage loss and destructive bone changes as they age2,3,4,5,6,7, in several instances necessitating joint replacement surgery by the third decade of life. Extraskeletal manifestations have not been reported in PPD. Cartilage appears to be the primary affected tissue, and in one patient, a biopsy of the iliac crest revealed abnormal nests of chondrocytes and loss of normal cell columnar organization in growth zones5. We have identified nine different WISP3 mutations in unrelated, affected individuals, indicating that the gene is essential for normal post-natal skeletal growth and cartilage homeostasis.
Published: 1999
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21. Ostéogenèse imparfaite, annonce du diagnostic (classification clinique et génétique)

Author: Valérie Cormier-Daire, M. Le Merrer, Geneviève Baujat, and A.-S. Lebre
Subjects: Nosology, medicine.medical_specialty, Pediatrics, Osteogenesis imperfecta, business.industry, Public health, Pediatrics, Perinatology and Child Health, medicine, medicine.disease, business, Osteochondrodysplasia
Published: 2008
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22. Progressive osseous heteroplasia

Author: F. Cartault, H. Testart, Frederick S. Kaplan, Liliane Boccon-Gibod, M. Le Merrer, and J. A. Urtizberea
Subjects: musculoskeletal diseases, Pathology, medicine.medical_specialty, Candidate gene, integumentary system, Ossification, business.industry, Genetic disorder, medicine.disease, Progressive osseous heteroplasia, Connective tissue disease, Genetic linkage, Fibrodysplasia ossificans progressiva, medicine, Orthopedics and Sports Medicine, Surgery, Osteodystrophy, medicine.symptom, business
Abstract: We report a case of progressive osseous heteroplasia in a female infant who had progressive ossification of the skin and deep connective tissues. Isolated dermal ossification is present in her father and younger sister suggesting an autosomal dominant mode of inheritance with variable expressivity or possible somatic mosaicism. This report of a family with progressive osseous heteroplasia contributes to the understanding of this uncommon genetic disorder, which must be distinguished from fibrodysplasia ossificans progressiva and Albright’s hereditary osteodystrophy. The paucity of familial cases of progressive osseous heteroplasia currently limits the use of a genome-wide linkage analysis, but linkage exclusion analysis with promising candidate genes is a possibility.
Published: 1998
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23. Trigonocéphalie: formes isolées, associées et syndromiques. Étude génétique d'une série de 278 patients

Author: E. Lajeunie, M. Le Merrer, Dominique Renier, Daniel Marchac, and Eric Arnaud
Subjects: Gynecology, medicine.medical_specialty, business.industry, Pediatrics, Perinatology and Child Health, medicine, business, Infant newborn
Abstract: Resume A partir d'une serie de 1 833 craniostenoses, les auteurs analysent 278 observations de trigonocephalies. La prevalence de la trigonocephalie est evaluee a 1/15 000 nouveau-nes. Patients et methodes Tous les patients porteurs d'une synostose de la suture metopique ont ete selectionnes, en excluant les cas ou d'autres sutures etaient egalement atteintes. L'âge au moment du diagnostic allait de 15 jours a 15 ans. Le diagnostic de trigonocephalie etait fait sur l'examen clinique et les radiographies du crâne. La recherche de malformations associees etait fondee sur la clinique, la tomodensitometrie crânienne (et/ou l'IRM), les radiographies du squelette et l'echographie abdominale. Autant que possible, une etude du caryotype etait realisee lorsqu'une malformation associee etait decouverte. L'etude familiale etait faite par contact direct ou, plus rarement, par telephone. Les observations ont ete divisees en trois groupes : groupe 1, les trigonocephalies isolees ; groupe 2, les cas avec malformations associees mais sans syndromes repertories ; et groupe 3, les syndromes repertories. Resultats Il y avait 213 garcons et 65 filles, donnant un sex-ratio de 3,3. Une enquete familiale etait disponible dans 216 cas. L'âge maternel moyen etait de 29,6 ans et l'âge paternel moyen etait de 32,2 ans a la naissance des enfants, ce qui correspond aux moyennes nationales. On comptait 18 grossesses multiples (7,9 %). Trois des six paires de jumeaux monozygotes etaient concordantes pour la craniostenose. On denombrait 13 cas de trigonocephalies familiales (6 %). Dans un seul cas, la transmission etait verticale ; tous les autres comportaient des germains atteints avec des parents indemnes. Onze des formes familiales correspondaient a des trigonocephalies isolees ; les deux autres etaient des formes syndromiques. Sur 53 caryotypes obtenus, neuf revelaient des anomalies, qui portaient sur les chromosomes 7, 9, 11 ou 13. Le groupe 1 comportait 208 observations. Le groupe 2 regroupait 53 cas : les malformations associees etaient uniques dans 32 cas et affectaient surtout le cœur (12 cas), les extremites (six cas), l'encephale (cinq cas) et l'appareil genito-urinaire (quatre cas). Elles etaient multiples dans 21 cas, le plus souvent a la fois viscerales et des extremites (15 cas). Certaines de ces associations pourraient correspondre a des syndromes encore non decrits. Dix-sept syndromes, dont neuf syndromes chromosomiques, representaient le groupe 3. Onze de ces syndromes presentaient des malformations multiples. Une exposition in utero a l'acide valproique etait retrouvee dans deux cas du groupe 1, cinq cas du groupe 2 et un cas du groupe 3.
Published: 1998
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24. Identification of fifteen novel mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in European patients with severe hypophosphatasia

Author: R Puddu, JM Rival, Peter Freisinger, S Peyramaure, F. Muller, H. Plauchu, J. L. Serre, P Bussière, J Godard, Andrea Superti-Furga, B. Simon-Bouy, M. Le Merrer, Renaud Touraine, F Kaper, J F Oury, Rolf E. Brenner, Agnès Taillandier, and Etienne Mornet
Subjects: Genetics, Mutation, Base Sequence, Hypophosphatemia, Nonsense mutation, Hypophosphatasia, Gene mutation, Biology, Alkaline Phosphatase, medicine.disease, medicine.disease_cause, Polymerase Chain Reaction, Europe, Genetic marker, Prenatal Diagnosis, medicine, Humans, Alkaline phosphatase, Missense mutation, Gene, Polymorphism, Single-Stranded Conformational, Genetics (clinical), DNA Primers
Abstract: Hypophosphatasia is an inherited disorder characterised by defective bone mineralisation and deficiency of serum and tissue liver/bone/kidney alkaline phosphatase (L/B/K ALP) activity. We report the characterisation of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutations in a series of 13 European families affected by perinatal, infantile or childhood hypophosphatasia. Eighteen distinct mutations were found, only three of which had been reported previously in North American and Japanese populations. Most of the 15 new mutations were missense mutations, but we also found two mutations affecting donor splice sites and a nonsense mutation. A missense mutation in the last codon of the putative signal peptide probably affects the final maturation of the protein. Despite extensive sequencing of the gene and its promotor region, only one mutation was identified in two cases, one of which was compatible with a possible dominant effect of certain mutations and the putative role of polymorphisms of the TNSALP gene. In 12 of the 13 tested families, genetic diagnosis was possible by characterisation of the mutations or by use of polymorphisms as genetic markers. Hypophosphatasia diagnosis was assigned in two families where clinical, laboratory and radiographic data were unclear and prenatal diagnosis was performed in one case. The results also show that severe hypophosphatasia is due to a very large spectrum of mutations in European populations with no prevalent mutation and that genetic diagnosis of the disease must be performed by extensive analysis of the gene.
Published: 1998
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25. Clinical homogeneity of the St�ve-Wiedemann syndrome and overlap with the Schwartz-Jampel syndrome type 2

Author: M. Le Merrer, Stanislas Lyonnet, P. Maroteaux, Arnold Munnich, Andrea Superti-Furga, A. Giedion, P de Lonlay, Pierre Rustin, Anne-Lise Delezoide, and Valérie Cormier-Daire
Subjects: Pediatrics, medicine.medical_specialty, Muscle Hypotonia, Muscular hypotonia, Respiratory distress, business.industry, Schwartz–Jampel syndrome, Dysostosis, Consanguinity, medicine.disease, Osteochondrodysplasia, Camptodactyly, Endocrinology, Internal medicine, medicine, medicine.symptom, business, Genetics (clinical)
Abstract: The Stuve-Wiedemann syndrome (SWS) is a rare disorder characterized by respiratory distress, hyperthermic episodes, and early lethality and radiologically by bowing of the long bones with internal cortical thickening and large metaphyses. We report findings in 8 new patients suggesting that this syndrome is clinically homogeneous. All patients had feeding and swallowing difficulties, respiratory insufficiency, abnormal appearance, muscle hypotonia, and postnatal short stature. Recurrent episodes of unexplained fever occurred in all and were the cause of death in 6 of 8 cases. Parental consanguinity and sib recurrence suggest autosomal recessive inheritance. The clinical, radiological, and histological similarities between our patients with SWS and those with the recently delineated "neonatal" Schwartz-Jampel syndrome (SJS type 2) lead us to suggest that SWS and SJS type 2 may be a single entity.
Published: 1998
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26. Novel recurrent nonsense mutation causing neurofibromatosis type 1 (NF1) in a family segregating both NF1 and Noonan syndrome

Author: H Lakhdar, Claude Houdayer, Dominique Vidaud, Michel Vidaud, Michel Bahuau, S Giraud, Stanislas Lyonnet, B Assouline, D Récan, M. Le Merrer, and C Blanchet-Bardon
Subjects: Genetics, congenital, hereditary, and neonatal diseases and abnormalities, biology, Nonsense mutation, Genetic disorder, Locus (genetics), medicine.disease, Neurofibromin 1, Exon, Genetic linkage, biology.protein, medicine, Noonan syndrome, Neurofibromatosis, Genetics (clinical)
Abstract: Neurofibromatosis type 1 (NF1), a genetic disorder with neuroectodermal involvement, demonstrates phenotypic overlap in some patients with Noonan syndrome (NS), ultimately resulting in the so-called neurofibromatosis-Noonan syndrome (NF-NS). A strong association of the two phenotypic traits was recently illustrated by a four-generation family, although NF1 and NS were eventually demonstrated to segregate independently on the basis of polymorphic DNA markers [Bahuau et al., 1996: Am J Med Genet 66:347-355]. Identification of the causal NF1 mutation seemed a prerequisite to further dissecting this singular familial association. Using the protein truncation assay, a nonsense mutation (C2446T-->R816X) of the neurofibromin gene was evidenced. This mutation occurred on a CpG dinucleotide within exon 16 and 5' to the GAP domain-specifying region of the gene. R816X creates a recognition site for endonuclease HphI, absent in 2 individuals with NS only. Screening 184 unrelated NF1 patients, three novel occurrences of the mutation were found in individuals diagnosed with classical NF1. Based on the assumption of genotype-phenotype correlation in these individuals, clinical and molecular analyses of this four-generation family demonstrated that the NF-NS phenotype was additive, being the result of both classical NF1 and NS. This particular observation also suggests the presence of an NS locus on 17q, which might be of interest for further linkage studies.
Published: 1998
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27. Common Mutations in the Fibroblast Growth Factor Receptor 3 (FGFR 3) Gene Account for Achondroplasia, Hypochondroplasia and Thanatophoric Dwarfism

Author: Laurence Legeai-Mallet, J. Bonaventure, Pierre Maroteaux, Arnold Munnich, F. Rousseau, and M. Le Merrer
Subjects: musculoskeletal diseases, Genetics, Thanatophoric dysplasia, Endocrinology, Diabetes and Metabolism, Dwarfism, Hypochondroplasia, Gene mutation, Biology, Fibroblast growth factor receptor 3, medicine.disease, Endocrinology, Skeletal disorder, Fibroblast growth factor receptor, Pediatrics, Perinatology and Child Health, medicine, Missense mutation, Achondroplasia, Genetics (clinical)
Abstract: The mapping of the achondroplasia locus to the short arm of chromosome 4 and the subsequent identification of a recurrent missense mutation (G380R) in the fibroblast growth factor receptor 3 (FGFR-3) gene has been followed by the detection of common FGFR-3 mutations in two clinically related disorders: thanatophoric dwarfism (types I and II) and hypochondroplasia. The relative clinical homogeneity of achondroplasia was substantiated by demonstration of its genetic homogeneity as more than 98% of all patients hitherto reported exhibit mutations in the transmembrane receptor domain. Although most hypochondroplasia cases were accounted for by a recurrent missense substitution (N540K) in the first tyrosine kinase (TK 1) domain of the receptor, a significant proportion (40%) of our patients did not harbor the N540K mutation and three hypochondroplasia families were not linked to the FGFR-3 locus, thus supporting clinical heterogeneity of this condition. In thanatophoric dwarfism (TD), a recurrent FGFR-3 mutation located in the second tyrosine kinase (TK 2) domain of the receptor was originally detected in 100% of TD II cases, our series seven distinct mutations in three different protein domains were identified in 25 of 26 TD I patients, suggesting that TD, like achondroplasia, is a genetically homogenous skeletal disorder.
Published: 1997
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28. Animal models of Osteogenesis Imperfecta and craniofacial development

Author: A Marchadier, M Goldberg, Agnès Kamoun-Goldrat, and M Le Merrer
Subjects: Nosology, Pathology, medicine.medical_specialty, business.industry, Dentinogenesis imperfecta, Genetic disorder, medicine.disease, Skull, medicine.anatomical_structure, Osteogenesis imperfecta, Brittle bones, Wormian bones, Medicine, Craniofacial, business
Abstract: Introduction Osteogenesis imperfecta (OI) is a human genetic disorder of increased bone fragility and low bone mass. Severity varies widely, ranging from intrauterine fractures and perinatal lethality to very mild forms without fractures. There is variable association of typical extra skeletal manifestations with the disorder, including blue sclera, dentinogenesis imperfecta, hyperlaxity of ligaments and skin, hearing impairment and the presence of Wormian bones on skull radiography1. The most widely used classification of OI distinguished four clinical types2. The most relevant clinical characteristic of all OI t-ypes is bone fragility, the severity of which increases in the order type I < type IV < type III < type II. It is now w-idely recognized that there may be m-any more types of OI than those class-ified by Sillence et al. Some forms of congenital brittle bones have been considered OI and have been added as types V, VI and VII3–5. There is still no perfect consensus about the definition of OI. Plotkin recently proposed defining OI as syndromes resulting from mutations in either COL1A1 or COL1A2 genes, and to group all other syndromes with congenital brittle bones as ‘syndromes resembling OI (SROI)’, pending the identification of their causal mutations6. In the new Nosology and Classification of the Genetic Skeletal disorders7, OI is declined in several forms depending on the severity of the phenotype, whatever the mode of the transmission or the gene involved. We first review the genetic mutations implicated in the eight different types of OI, then, the craniofacial consequences of OI mutations are summarized. * Corresponding author Email: mgoldberg.goldberg004@gmail.com
Published: 2013
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29. Possible genetic heterogeneity in the Saethre-Chotzen syndrome

Author: M. Le Merrer, N de Parseval, H. W. Ma, D. Renier, Arnold Munnich, and Elizabeth Lajeunie
Subjects: Genetic Markers, Male, Genetics, Disease gene, Genetic Linkage, Genetic heterogeneity, Chromosome Mapping, Locus (genetics), Acrocephalosyndactylia, Biology, medicine.disease, Genetic analysis, Pedigree, Child, Preschool, medicine, Humans, Female, Saethre–Chotzen syndrome, Gene, Chromosomes, Human, Pair 7, Genetics (clinical), Genes, Dominant
Abstract: Saethre-Chotzen syndrome is an autosomal dominant acrocephalosyndactyly syndrome whose gene has been assigned to chromosome 7p. Cytogenetic and linkage analyses have enabled the interval encompassing the disease gene to be delimited to a short region of chromosome 7p15.3-p21.2. Based on the genetic analysis of three unreported families, we confirm the location of the disease gene(s) in the interval defined by loci D7S664 and D7S493 (Zmax = 4.78 at [symbol: see text] = 0 at the D7S488 locus) but fail to decide whether one or more disease-causing genes map in this genetic interval.
Published: 1996
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30. Genetic mapping of Xp22.12–p22.31, with a refined localization for spondyloepiphyseal dysplasia (SEDL)

Author: M. Le Merrer, Pierre Maroteaux, Marie-Claude Hors-Cayla, A. Smahi, Solange Heuertz, and Andrew O.M. Wilkie
Subjects: Male, Recombination, Genetic, Spondyloepiphyseal dysplasia, Genetics, X Chromosome, Genetic Linkage, Chromosome Mapping, Biology, Osteochondrodysplasias, medicine.disease, Osteochondrodysplasia, Short stature, Human genetics, Pedigree, Gene mapping, Genetic marker, medicine, Humans, Microsatellite, Female, medicine.symptom, Genetics (clinical), X chromosome
Abstract: Spondyloepiphyseal dysplasia tarda (SEDL) is an X-linked recessive disorder characterized in affected males by short stature resulting from a growth defect of the vertebral bodies. We have extended our earlier studies by analyzing 15 families with newly identified microsatellite DNA markers; analysis of recombination events with these markers indicates that the gene responsible for SEDL is located in Xp22 between DXS 16 and DXS 987 on an interval spanning approximately 2 Mb.
Published: 1995
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31. Acral dysostosis dyserythropoiesis syndrome

Author: Pierre Maroteaux, Philippe Parent, M. Le Merrer, Valérie Cormier-Daire, and R. Girot
Subjects: Male, Ineffective erythropoiesis, Congenital dyserythropoietic anaemia, medicine.medical_specialty, Foot Deformities, Congenital, Macrocytosis, medicine.disease_cause, Pelvis, Fingers, Depigmentation, medicine, Humans, Abnormalities, Multiple, Anemia, Dyserythropoietic, Congenital, business.industry, Infant, Dysostosis, Toes, medicine.disease, Dermatology, Surgery, Radiography, medicine.anatomical_structure, Polysyndactyly, Pediatrics, Perinatology and Child Health, Female, Syndactyly, Bone marrow, Congenital disease, medicine.symptom, business, Hand Deformities, Congenital
Abstract: The term congenital dyserythropoietic anaemia (CDA) designates a group of rare but well defined erythrocytic disorders. Type I is defined by macrocytosis and megaloblastic changes of the bone marrow cells. Two unrelated children with CDA are described with associated defects: absence of nails and short or absent phalanges, polysyndactyly of the fourth metacarpal. One of them had also areas of depigmentation.The association of congenital dyserythropoietic anaemia with morphological defects of hands and feet is suggested to constitute a new syndrome caused by a single morphogenetic gene.
Published: 1995
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32. Mainzer-Saldino syndrome is a ciliopathy caused by mutations in the IFT140 gene

Author: Nora Shannon, M. Le Merrer, Heleen H. Arts, Emilie Filhol, Isabelle Perrault, Machteld M. Oud, Albane A. Bizet, Sylvain Hanein, Arnold Munnich, Véronique Baudouin, Jean-Claude Kaplan, Corinne Antignac, F Collins, V. Cormier Daire, PL Beales, Sophie Saunier, Mustafa A. Salih, Eduardo Silva, Christine Pietrement, Jean-Michel Rozet, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Néphropathies héréditaires et rein en développement (UMR_S 983), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Clinical Genetics, Westmead Hospital [Sydney], Division of Pediatric Neurology, King Khalid University Hospital, Department of Ophthalmology, Universidade de Coimbra [Coimbra], Service de Néphrologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Department of Human Genetics, Radboud University Medical Center [Nijmegen]-Faculty of Medical Sciences, Clinical Genetics Service, Nottingham University Hospitals NHS Trust - City Hospital Campus, Service de Pédiatrie, Centre Hospitalier Universitaire de Reims (CHU Reims)-American Memorial Hospital (Reims), Molecular Medicine Unit, University College of London [London] (UCL)-Institute of Child Health, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Néphropathies héréditaires et rein en développement ( UMR_S 983 ), CHU Necker - Enfants Malades [AP-HP]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Assistance publique - Hôpitaux de Paris (AP-HP), Westmead Hospital, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Centre Hospitalier Universitaire de Reims ( CHU Reims ) -American Memorial Hospital (Reims), University College of London [London] ( UCL ) -Institute of Child Health, and BMC, Ed.
Subjects: Bone development, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 01 natural sciences, Ciliopathies, 03 medical and health sciences, Intraflagellar transport, MAINZER-SALDINO SYNDROME, 0103 physical sciences, medicine, lcsh:QH573-671, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Gene, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetics, 0303 health sciences, 010304 chemical physics, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, lcsh:Cytology, Cilium, Cell Biology, medicine.disease, Human genetics, Ciliopathy, Oral Presentation, sense organs
Abstract: Ciliopathies is an emerging class of genetic disorders due to altered cilia assembly, maintenance or function. Syndromic ciliopathies affecting bone development have been classified as skeletal ciliopathies. Mutations in genes encoding components of the intraflagellar transport (IFT) complex A, that drives retrograde ciliary transport, are a major cause of skeletal ciliopathies. Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal cone-shaped epiphyses, chronic renal failure and early-onset severe retinal dystrophy.
Published: 2012

33. Fourth meeting of the European Neurological Society 25–29 June 1994 Barcelona, Spain

Author: H. Hattig, C. Delli Pizzi, M. C. Addonizio, Michelle Davis, A. R. Giovagnoli, L. Florensa, M. Roth, J. de Kruijk, Francisco Lacruz, Ph. Dewailly, A. Toygar, C. Avendano, P.P. De Deyn, J. F. Hurtevent, F. Lomeila, T. W. Wong, Gordon T. Plant, M. Bud, H. J. Willison, DH Miller, D. W. Langdon, R. Cioni, J. Servan, A. Kaygisiz, E. Racadot, D. B. Schens, E. Picciola, L. Falip, C. Bouchard, J. Jotova, A. Jorge-Santamaria, P. Misra, A. Dufour, C. P. Panagopoulos, A. Venneri, B. Sredni, B. Angelard, M. Janelidze, M. Carreno, J. Obenberger, J. Pouget, H. W. Moser, R. Kaufmann, J. A. Molina, D. Linden, A. Martin Urda, E. Uvestad, A. Krone, J. P. Cochin, J. Mallecourt, A. Cambon-Thomsen, K. Violleau, P. Osschmann, A. M. Durocher, E. Bussaglia, D. M. Danielle, H. Efendi, C. Van Broeckhoven, K. G. Jordan, W. Rautenberg, C. Iniguez, J. M. Delgado, Graham Watson, M. Lawden, Gareth J. Barker, K. Stiasny, James T. Becker, G. Campanella, E. Peghi, A. Poli, A. Haddad, T. Yamawaki, Giacomo P. Comi, S. Sotgiu, B. Ersmark, A. Pomes, M. Ziegler, P. Ferrante, P. Ruppi, H. KuÇukoglu, R. Bouton, U. K. Rinne, P. Vieregge, M. Dary, P. Giunti, Peter J. Goadsby, S. Jung, E. Secor, A. Steinberg, N. Vila, M. A. Hernandez, M. Cursi, A. Enqelhardt, A. Engelhardt, J. Veitch, F. Di Silverio, F. Arnaud, B. Neundörfer, R. Brucher, Dominique Caparros-Lefebvre, B. Meyer, Marianne Dieterich, M. H. Snidaro, R. Gomez, R. Cerbo, M. Ragno, J. M. Vance, S. Nemni, A. Caliskan, F. Barros, I. Velcheva, D. Ceballos-Baumann, V. Barak, A. Avila, N. Antonova, F. Resche, S. Pappata, L. Varela, S. R. Silveira Santos, A. Cammarota, L. Naccache, Y. Nara, E. Tournier-Lasserves, R. Mobner, T. Chase, A. Ensenyat, J. Ulrich, G. Giegerich, M. Rother, M. Revilla, N. Nitschke, K. Honczarenko, E. Basart Tarrats, J. Blin, B. Jacob, J. Santamaria, S. Knezevic, J. L. Castillo, M. Antem, J. Colomer, O. Busse, Didier Hannequin, S. Carrier, J. B. Ruidavets, C. Rozman, J. Bogoussslavsky, J. Pascual Calvet, E. Monros, J. M. Polo, M. Zucconl, Javier Muruzabal, R. R. Allen, R. Rivolta, K. Haugaard, A. Nespolo, K. Hoang-Xuang, G. Bussone, T. Avramidis, E. Corsini, Christiana Franke, T. Vinogradova, H. Boot, K. Vestergaard, G. H. Jansen, N. Argentino, M. Raltzig, W. Linssen, Mark B. Pepys, P. Roblot, L. Lauritzen, E. Fainardi, D. Morin, T. X. Arbizu Urdiain, J. Wollenhaupt, S. Bostantjopoulou, G. Pavesi, A. D. Forman, Giovanni Fabbrini, D. Jean, J. J. Archelos, M. I. Blanchs, M. Del Gobbo, Anna Carla Turconi, Ch. Derouesné, Elio Scarpini, A. Visbeck, P. Castejon, J. P. Renou, F. Mounier-Vehier, G. Potagas, Ch. Duyckaerts, A. Filla, R. Schneider, G. Ronen, K. Nagata, J. P. Vedel, A. Henneberg, G. van Melle, C. Baratti, H. Knott, M. C. Prevett, A. Bes, B. Metin, Jos V. Reempts, L. Martorell, Mefkure Eraksoy, H. O. Handwerker, D. S. Younger, O. Oktem, D. Frongillo, C. Soriano-Soriano, L. Niehaus, F. Zipp, A. Tartaro, S Newman, R. H. Browne, P. Davous, R. Sanchez, M. Muros, M. E. Kornhuber, A. Lavarone, M. Mohr, M. R. Garcia, S. Russell, H. Kellar-Wood, M. R. Tola, B. Ostermeyer, Ch. Tzekov, K. Sartor, E. B. Ringelstein, P. P. Gazzaniga, Paul Krack, H. Fidaner, H. Rico, T. Dbaiss, F. Alameda, E. Torchiana, L. Rumbach, I. Charques, J. M. Bogaard, C. D. Frith, L. J. Rappelle, R. Brenner, A. Joutel, K. Fuxe, G. HÄcker, M. J. Blaser, J. Valls-SolÇ, G. Ulm, M. Alberdi, A. Bock, F. W. Bertelsmann, U. Wieshmann, J. Visa, J. R. Lupski, D. D'Amico, L. M. P. Ramos, A. A. Vanderbark, R. Horn, M. Warmuth, Dietmar Kühne, Mark S. Palmer, C. Ehrenheim, E. Canga, S. Viola, O. Scarpino, P. Naldi, R. Almeida, A. A. Raymond, J. Gamez, Stephan Arnold, A. DiGiovanni, J. Dalmau, C. C. Chari, H. F. Beer, J. C. Koetsier, J. Iriarte, E. Yunis, J. Casadevall, E. Le Guern, E. Stenager, S. R. Benbadis, J. M. Warter, F. Burklin, I. Theodorou, L. Johannesen, G. A. Graveland, X. Leclerc, I. Vecchio, L. Ozelius, G. Nicoletti, R. K. Gherardi, E. Esperet, M. L. Delodovici, F. Cattin, F. Paiau, Giorgio Sacilotto, C. A. J. Broere, D. Chavdarov, J. P. Willmer, C. H. Hawkes, Th. Naegele, E. Ellie, E. Dartigues, M. J. Guardiola, S. Hesse, Z. Levic, Marco Rovaris, P. Saugeir-Veber, B. A. Yaqub, H. F. Durwen, R. Larumbe, J. Ballabrina, M. Sendtner, J. Röther, M. Horstink, C. Kluglein, M.P. Montesi, H. Apaydin, J. Montoya, E. Waubant, Ch. Verellen-Dunoulin, A. Nicolai, J. Lopez-Delval, R. Lemon, G. Cantinho, E. Granieri, A. Zeviani, Wolfgang H. Oertel, U. Ficola, V. Di Piero, V. Fragola, K. Sabev, M. V. Guitera, I. Turki, F. Bolgert, P. Ingrand, J. M. Gobernado, L. M. E. Grimaldi, S. Baybas, B. Eymard, Y. Rolland, Y. Robitaille, Ta. Pampols, P. J. Koehler, A. Carroacedo, J. Vilchez, S. Di Vittorio, I. R. Rise, T. Nagy, M. Kuffner, E. Palazzini, A. Ott, J. Pruim, T. X. Arbizu, E. Manetti, C. Cervera, S. Felber, G. Gursoy, J. Scholz, G. A. Buscaino, M. S. Chen, A. Pascual, J. Hazan, J. U. Gajda, J. G. Cea, G. Bottini, G. Damalik, F. Le Doze, G. Bonaldi, J. M. Hew, C. Messina, A. M. Kennedy, J. M. Carney, N. M. F. Murray, M. Parent, M. Koepp, V. Dimova, D. De Leo, K. Jellinger, G. Salemi, S. Mientus, M. L. Hansen, F. Mazzucchelli, J. Vieth, M. Mauri, E. Bartels, L. Johannsen, C. Humphreys, J. Emile, D. N. Landon, E. Kansu, R. Sanchez-Pernaute, Rsj Frackowiak, M. Gonzalez Torres, L. Oller, C. Machedo, J. Kother, M. Billiard, H. Durak, T. Schindler, A. Frank, A. Uncini, A. Sbriccoli, C. Farinas, D. W. Paty, N. Fast, A. T. Zangaladze, A. Kerkhofs, J. M. Pino Garcia, I. De la Fuente, B. Marini, L. Gomez, I. Rubio, Alessandra Bardoni, C. Brodie, P. Acin, U. Sliwka, S. A. Hawkins, S. Tardieu, F. Vitullo, J. M. Pereira Monteino, R. Gagliardi, T. Jezewski, A. Cano, T. Lempert, F. Abad Alegria, G. Rotondo, D. Ince, C. Martinez Parra, Y. Huang, H. Luders, Y. Steinvil, F. G. A. Van Der Meche, R. Bianchi, A. Sanchez, T. Sevilla, J. M. Ketelslegers, A. Domzal-Stryga, M. Pandolfo, M. O. Josse, K. W. Neff, I. Blanco, G. W. Bruyn, O. W. Witte, J. L. Thibault, G. Andersen, J. Pariset, A. Marcone, R. J. M. Lane, A. Hofman, M. Verin, T. Matilla, P. Bedoucha, J. Roche, M. Lai, M. Collard, A. Ugarte, F. Gallecho, D. Silbersweig, C. Kennard, J. P. Azulay, T. W. Ho, P. L. I. Dellemijn, R. Girardello, F. Baas, B. Voss, F. Rozenberg, E. M. Brocker, V. Stanev, A. A. J. Soeterboek, A. Marra, A. Rey, E. Ertem, M. Sawradewicz-Rybak, J. De Keyser, P. Cavallari, F. Proust, Y. Chevalier, H. C. Hansen, D. Leys, C. A. Davie, K. Hoang-Xuan, C. Bairati, H. van Crevel, Thomas T. Warner, B. Bompais, A. Dobbeleir, T Campbell, C. Macko, C. J. M. Klijn, M. Dussallant, T. P. Berlit, W. Rozenbaum, M. J. van den Bent, W. A. Rocca, M. Muller, H. Hundemer, U. Zifko, M. Campera, F. Drislane, D. Ranoux, T. M. Kloss, Anil Kumar, I. Ruolt, C. Bargnani, B. Marescau, N. A. Losseff, S. Notermans, B. Kint, E. T. Burke, C. Aykut, J. Matias Guiu, P. Maquet, T. Drogendijk, M. Leone, K. von Ammon, M. Pepeliarska, C. Prados, L. DiGiamberardino, T. Logtenberg, G. Lenoir, I. Castaldo, Damhaut, M. Radionova, G. Sirabian, R. Navon, Giovanni Antonini, K. Al Moutaery, E. Chamas, R. Schönhuber, M. Giannini, B. Debilly, I. Labatut, H. Henon, J. A. Egido, M. Baudrimont, J. N. Lorenzo, J. E. C. Bromberg, R. Antonacci, J. J. Vilchez, T. Moulin, B. Rautenstrauss, Giovanni Meola, J. Noth, S Mammi, P. Laforet, F. Lopez, C. Gehring, S. Bort, G. Rancurel, D. Decamps, S. Kostadinova, Y. Shapira, B. Neundoerfer, D. Chavrot, M. Solimena, J. P. Salier, W. Deberdt, R. Hoff-Jörgensen, A. Messina, S. Meairs, G. Rosoklija, E. Nelis, I. Bertran, C. Ertekin, J. Lohmeyer, Mitermayer Galvao dos Reis, L. Calo, E. Maccagnano, A. P. Hays, J. Verlooy, M. G. Forno, T. Blanco, L. Bail, Gabriella Silvestri, J. Montero, F. Bertrand, R. T. Ghnassia, C. Besses, T. Sereghy, F. Shalit, G. Bogliun, S. Braghi, St. Baykouchev, C. Franke, A. Lasa, L. C. Archard, J. Kriebel, S. Shaunak, M. Nocito, Alexander Tsiskaridze, E. Manfredini, T. Seigal, David G. Gadian, M. Barlas, J. D. Degos, C. Seeber, J. Caemert, J. L. Mas, R. B. Pepinsky, M. G. D'Angelo, N. Baumann, S. Yorifuji, H. P. Endtz, M. A. Cassatella, R. A. C. Hughes, V. Golzi, A. Bittencourt, A. Ferreira, M. Sanson, C. Alper, M. Vermeulen, M. A. A. van Walderveen, E. Alexiou, C. H. Lucas, M. Fiorelli, Y. N. Debbink, R. Gil, S. Congia, T. Banerjee, J. M. Bouchard, A. N. Pinto, A. Ceballos-Baumann, G. Grollier, P. I. M. Schmitz, M. D. Catata, N. Lahat, N. S. Rao, P. Papathanasopoulos, J. Valls-Solé, D. Claus, G. Schroter, A. Castro, C. Videbaek, R. Martinez Dreke, A. D. Platts, M. Hermesl, A. C. PeÇanha-Martins, M. Cardoso Silva, P. Masnou, M. J. A. Tanner, Ch. Confavreux, B. Mishu, H. Rasmussen, L. Valenciano, Carlo Pozzilli, S. W. Li, V. Salzman, Y. Vashtang, Massimo Franceschi, M. Severo, G. Deuschl, S. Setien, G. Mariani, A. Protti, J. Castillo, M. J. B. Taphoorn, M. Frontali, I. Milonas, D. Decoq, J. A. Navarro, S. Castellvi-Pel, C. Ertikin, M. Urtasun, Y. Lajat, B. E. Kendall, E. Verdu, B. Gueguen, E. Boisen, R. Couderc, A Danek, JM Stevens, F. Nicoli, L. Feltri, M. L. Vazquez-Andre, J. A. Morgan-Hughes, L. D'Angelo, F. Y. Liew, L. F. Pascual, J. Patrignani Ochoa, Vittorio Martinelli, J. Cophignon, L. Zhang, S. Martin, J. F. Meder, H. C. Buschmann, L. Bertin, J. van Gijn, A. Barreiro, A. Cools, C. Leon, A. Berod, E. A. Anllo, E. Zanette, L. Petrov, R. Barona, B. Gallicchio, P. J. Cozzone, N. Diederich, G. Cancel, L. Schelosky, P. Orizaola, K. Yulug, S. Ozer, Valeria A. Sansone, B. Guiraud-Chaumeil, K. Voigt, P. Labauge, M. Eoli, J. Zhu, J. Aguirre, M. Ferrarini, B. Zyluk, E. Planas, A. Cadilha, C. Tortorella, H. Bismuth, C. E. Counsell, A. Laun, A. Ferlini, Rio J. Montalban, N. Biary, L. Becker, M. Fardeau, M. Poloni, V. M. S. de Bruin, C. Fornada, J. Barros, E. Ganzmann, E. Touze, D. Wallach, J. Peila, H. Fujimura, M. T. Iba-Zizen, G. Macchi, C. Villoslada, R. Gouider, Ph. Rondepierre, P. Grummich, P. Chiodi, C. Conte, M. Michels, P. Annunziata, G. Semana, C. Sommer, J. Vajsar, D. Zekin, J. Kulisevsky, David G. Munoz, B. Jacotot, M. Magoni, A. Luxen, T. Garcia-Silva, S. Di Cesare, Christophe Tzourio, M. Gomori, I. Picomell, L. Santoro, F. Villa, Giovanni Pennisi, T. Ribalta, J. M. Molto, L. Marzorati, P. Loiseau, F. Gemignani, A. Gironell, J. Wissel, A. Prusinski, F. Cailloux, P. Villanueva-Hemandez, P. Cozzone, T. Del Ser, J. Sans-Sabrafen, M. Zappia, P. W. A. Willems, G. Tchernia, D. Gardeur, R. Bauer, F. Palomo, H. Metz, S. Lamoureux, C. Chastang, I. Reinhard, A. Goldfarb, S. Harder, Jordi Río, C. Ozkara, E. Tekinsoy, P. Vontobell, J. De Recondo, M. Rabasa, L. Lacomblez, F. Boon, Dgt Thomas, V. Palma, Renato Mantegazza, A. Dervis, M. Nueckel, B. YalÇinerner, I. Duran, G. Dalla Volta, A. Zubimendi, J. Pinheiro, A. Marbini, Xavier Montalban, H. Wekerle, X. Pereira Monteino, F. Crespo, F. Koskas, N. Battistini, C. Ruiz, H. Offner, J. de Pommery, P. Kanovsky, J. Y. Barnett, J. Pardo, G. Tomei, R. Rene, H. M. Lokhorst, P. Thajeb, H. Bilgin, D. McGehee, R. Fahsold, L. Morgante, Katie Sidle, C. Delwaide, M. N. Diaye, P. H. Rice, A. Creange, C. Sabev, K. Stephan, K. WeilBenborn, G. Magnani, L. Grymonprez, F. Cardellach, M. Kaps, N. G. Meco, F. Vega, V. Bonifati, A. Desomer, M. Baldy-Moulinier, G. Kvale, F. J. Authier, B. Yegen, T. Ho, J. M. Rozet, E. A. Cabanis, L. Bruce, L. Ambrosoli, M. A. Petrella, M. Hernandez, P. Timmings, H. B. van der Worp, F. Mahieux, A. Urbano-Marquez, D. A. Krendel, A. A. Garcia, R. Divari, R. Michalowicz, M. R. Piedmonte, M. Bondavalli, M. Zanca, P. F. Ippel, Onofre Combarros, B. Tavitian, E. Hirsch, I. Anastasopoulos, A. Roses, A. Köhler, P. Vienna, V. Timmerman, P. Sergi, F. Cornelio, A. Di Pasquale, R. Verleger, S. Castellvirel, J. Proano, B. van Moll, F. Rubio, W. Hacke, I. Lavenu, L. Zetta, M. W. Tas, N. Bittmann, M. Bonamini, O. R. Hommes, V. Dousset, N. Afsar, S. Belal, R. R. Myers, J. Goes, Giuseppe Vita, E. Clementi, V. G. Karepov, M. Jueptner, A Vincent, P. Emmrich, Th. Heb, A. Caballo, J. Gallego, T. Mokrusch, C. Perla, L. Gebuhrer, O. Titlbach, Alessandro Prelle, A. Czlonkowska, M. Russo, D. Hadjiev, T. S. Chkhikvishvili, M. Oehlschlager, G. Becker, I. Günther, E. N. Stenager, J. Garcia Agundez, J. Casademont, J. Batlle, S. Podobnik-Sarkanji, C. Alonso-Villaverde, B. Delaguillaume, B. Genc, B. Mazoyer, A. Rodriguez-Al-barino, Ch. Hilger, B. Ferrero, R. Price, W. Grisold, L. Fuhry, D. Oulbani, D. Ewing, A. Petkov, W. Walther, A. Gokyigit, John Newsom-Davis, J. Tayot, D. Seliak, G. Pelliccioni, D. Campagne, K. Kessler, F. Boureau, D. Perani, J. P. N'Guyen, N. Tchalucova, B. A. Antin-Ozerkis, C. Lacroix, B. D. Aronovich, I. H. Jenkins, E. A. dos Reis, M. Hortells, H. M. Meinck, H. Ch. Buschmann, S. C. J. M. Jacobs, T. Wetter, P. Creissard, N. Martinez, J. Weidenfeldl, H. J. Sturenburg, G. Damlacik, V. Gracia, J. C. Turpin, A. Pou-Serradell, J. P. Vincent, T. Gagoshidze, U. Ozkutlu, M. McLeod, K. Siegfried, I. Tchaoussoglou, J. Hildebrand, S. Kowalska, M. C. Picot, G. Galardin, L. Crevits, F. Andreetta, S. Larumbe-Lobalde, G. de la Sierra, J. C. Alvarez-Cermeno, R. J. Seitz, P. L. Oey, L. Ptacek, A. M. J. Paans, A. Wirrwar, A. Schmied, J. Uilchez, H. Tounsi, D. Hipola, V. Avoledo, Y. Hirata, P. Vermersch, T. M. Aisonobe, J. Valls-SoIè, H. Staunton, J. Dichgans, R. Karabudak, I. Dones, G. Porta, E. Janssens, Maria Martinez, J. M. Fernandez-Real, R. Villagra, Y. Yoshino, C. Kabus, K. Schimrigk, I. Girard-Buttaz, F. Piccoli, F. Aichner, P. Zuchegna, S. M. Al Deeb, F. Bono, N. Busquets, A. Jobert, Patrizia Ciscato, M. Martin, L. Polman, S. Darbra, V. Le Cam-Duchez, F. Baldissera, B. Baykan-Kurt, D. Guez, M. Bratoeva, H. Matsui, M. Mila, H. Perron, L. Bjorge, G. Husby, Steven T. DeKosky, D. R. Cornblath, J. M. Gabriel, J. J. Poza, Y. Wu, A. Toscano, R. P. Kleyweg, J. Kuhnen, S. O. Confort-Gouny, A. Barcelo, A. M. Conti, C. Fiol, C. Steichen-Wiehn, J. Rodes, M. Cavenaile, C. Vedeler, M. Drlicek, C. Argentino, M. L. Peris, A. Cervello, A. Z. GinaÏ, S. Yancheva, D. Passingham, S. Aoba, D. L. Lopez, T. Rechlin, K. Sonka, L. Grazzi, V. Folnegovic-Smalc, Maurizio Moggio, S. Rivaud, F. G. I. Jennekens, C. H. Hartard, H. Meierkord, G. Stocklin, M. D. Catala, W. C. McKay, E. Salmon, C. Navarro, I. Pastor, L. Canafoglia, M. De Braekeleer, P. K. Thomas, C. Mocellini, C. Pierre-Jerome, M. C. Dalakas, P. Pollak, M. Levivier, Niall Quinn, G. E. Rivolta, Z. Tunca, H. Zeumer, J. Garcia Tena, St. Guily, P. Gaudray, Johannes Kornhuber, V. Petrunjashev, R. Montesanti, R. J. Abbott, H. Petit, G. Kiteva-Trencevska, F. Carletto, C. Ramo, I. M. Pino, P. Beau, G. F. Mennuni, F. Moschian, F. Meneghini, B. Zdziarska, B. Fontaine, C. Stephens, G. Meco, K. Reiners, G. Badlan, M. Sessa, I. Degaey, S. M. Hassan, C. Albani, F. Caroeller, M. Schroeder, G. Savettieri, A. Novelletto, R. Kurita, P. Oschmann, I. Plaza, M. Oliveres, Simone Spuler, A. Molins, M. Schwab, J. R. Kalden, C. P. Gennaula, Y. Baklan, O. Picard, J. M. Léger, B. Mokri, E. Ghidoni, M. Jacob, D. Deplanque, W. JÄnisch, C. De Andres, P. De Deyn, G. Guomundsson, B. Herron, J. Barado, J. L. Gastaut, Guglielmo Scarlato, F. Poron, Nicola Jones, H. Teisserenc, C. P. Hawkins, A. J. Steck, H. C. Chandler, S. Blanc, J. H. Faiss, Jm. Soler Insa, I. Sarova-Ponchas, M. Malberin, A. Sackmann, G. De Vuono, K. Kaiser-Rub, K. Badhia, E. Szwabowska-Orzeszko, S. Ramm, C. Jodice, G. Franck, J. Marta-Moreno, R. Sciolla, C. Fritz, A. Attaccalite, F. Weber, E. Neuman, M. Cannata, A. Rodriguez, I. Nachainkin, R. Raffaele, T. S. Yu, N. Losseff, E. Fabrizio, C. Khati, M. Keipes, M. P. Ortega, M. Ramos-Alvarez, E. Brambilla, A. Tarasov, K. H. Wollinsky, O. B. Paulson, F. Boller, G. Bozzato, H. Wagnur, R. Canton, D. Testa, E. Kutluaye, M. Calopa, D. Smadja, G. Malatesta, F. Baggi, A. Stracciari, G. Daral, G. Avanzini, J. Perret, J. Arenas, P. Boon, I. Gomes, A. Vortmeyer, P. Cesaro, S. Venz, E. Bernd Ringelstein, N. Milani, D. Laplane, P. Seibel, E. Tournier-Lasserve, Alexis Brice, L. Motti, E. Wascher, R. J. Abbot, F. Miralles, A. Turon, P. De Camilli, G. Luz, G. C. Guazzi, S. Tekin, F. Lesoin, T. Kryst, N. Lannoy, F. Gerstenbrand, S. Ballivet, H. A. M. van Diemen, J. Lopez-ArLandis, P. Bell, A. Silvani, M. A. Garcia, S. Vorstrup, D. Langdon, S. Ueno, B. Sander, V. Ozurk, C. Gurses, P. Berlit, J. M. Martinez-Lage, M. Treacy, S. O. Rodiek, S. Cherninkova, J. Grimaud, P. Marozzi, K. Hasert, S. Goldman, S. H. Ingwersen, A. Taghavy, T. Roig, R. Harper, I. Sarova-Pinchas, Anthony H.V. Schapira, R. Lebtahi, A. Vidaller, B. Stankov, D. Link, J. p. Malin, V. Petrova, Ludwig Kappos, J. L. Ochoa, T. Torbergsen, M. Carpo, M. Donato, Simon Shorvon, J. Mieszkowski, J. Perez-Serra, Raymond Voltz, G. Comi, S. Rafique, A. Perez-Sempere, N. Khalfallah, S. Bailleul, M. Borgers, S. Banfi, S. Mossman, A. Laihinen, G. Filippini, R. A. Grunewald, E. Stern, H. D. Herrmann, A. G. Droogan, P. Xue, A. Grilo, L. La Mantia, J. H. J. Wokke, S. Pizzul, Kie Kian Ang, S. Rapaport, W. Szaplyko, B. Romero, P. Brunet, A. 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Navasa, J. Ballabriga, G. Broggi, T. Gudeva, C. Rose, J. Vion-Dury, J. A. Gastaut, J. Pniewski, Nicola J. Robertson, G. Kohncke, M. Billot, S. Gok, E. Castellli, F. Denktas, P. Bazzi, F. Spinelli, I. F. Moseley, C. D. Mardsen, B. Barbiroli, O. M. Koriech, A. Miller, Hiroaki Yoshikawa, F. X. Borruat, J. Zielasek, P. Le Coz, J. Pascual, A. Drouet, L. T. Giron, F. Schondube, R. Midgard, M. Alizadeh, M. Liguori, Lionel Ginsberg, L. Harms, C. Tilgner, G. Tognoni, F. Molteni, Mar Tintoré, M. Psylla, C. Goulon-Goeau, M. V. Aguilar, Massimo Filippi, K. H. Mauritz, Thomas V. Fernandez, C. Basset, S. Rossi, P. Meneses, B. Jandolo, T. Locatelli, D. Shechtcr, C. Magnani, R. Ferri, Bruno Dubois, J. M. Warier, S. Berges, F. Idiman, M. Schabet, R. R. Diehl, P. D'aurelio, M. Musior, Reinhard Hohlfeld, P. Smeyers, M. Olivé, A. Riva, C. A. Broere, N. Egund, S. Franceschetti, V. Bonavita, Nicola Canal, E. Timmermans, M. Ruiz, S. Barrandon, G. Vasilaski, B. Deweer, L. Galiano, S. F. T. M. de Bruijn, L. Masana, A. Goossens, B. Heye, K. Lauer, Heinz Gregor Wieser, Stephen R. Williams, B. Garavaglia, A. P. Sempere, F. Grigoletto, P. Poindron, R. Lopez-Pajares, I. Leite, T. A. McNell, C. Caucheteur, J. M. Giron, A. D. Collins, P. Freger, J. Sanhez Del Rio, D. A. Harn, K. Lindner, S. S. Scherer, G. Serve, M. Juncadella, X. Estivill, R. Binkhorst, M. Anderson, B. Tekinsoy, C. Sagan, T. Anastopoulos, G. Japaridze, S. Guillou, F. Erminio, Jon Sussman, P. G. Oomes, D. S. Rust, S. Mascheroni, O. Berger, M. Peresson, K. V. Toyka, T. W. Polder, M. Huberman, B. Arpaci, H. Ramtami, I. Martinez, Ph. Violon, P. P. Gazzaniga Pozzill, R. Ruda, P. Auzou, J. Parker, S. P. Morrissey, Jiahong Zhu, F. Rotondi, P. Baron, W. Schmid, P. Doneda, M. Spadaro, M. C. Nargeot, I. Banchs, J.S.P. van den Berg, R. Ferrai, M. Robotti, M. Fredj, Pedro M. Rodríguez Cruz, B. Erne, D. G. Piepgras, M. C. Arne-Bes, J. Escudero, C. Goetz, A. R. Naylor, M. Hallett, O. Abramsky, E. Bonifacio, L. E. Larsson, R. Pellikka, P. Valalentino, D. Guidetti, B. Buchwald, C. H. Lücking, D. Gauvreau, F. Pfaff, A. Ben Younes-Chennoufi, R. Kiefer, R. Massot, K. A. Hossmann, L. Werdelin, P. J. Baxter, U. Ziflo, S. Allaria, C. D. Marsden, M. Cabaret, S. P. Mueller, E. Calabrese, R. Colao, S. I. Bekkelund, M. Yilmaz, O. Oktem-Tanor, R. Gine, M. E. Scheulen, J. Beuuer, A. Melo, Z. Gulay, M. D. Have, C. Frith, D. Liberati, J. Gozlan, P. Rondot, Ch. Brunholzl, M. Pocchiari, J. Pena, L. Moiola, C. Salvadori, A. Cabello, T. Catarci, S. Webb, C. Dettmers, N. A. Gregson, Alexandra Durr, F. Iglesias, U. Knorr, L. Ferrini-Strambi, F. Kruggel, P. Allard, A. Coquerel, P. Genet, F. Vinuels, C. Oberwittler, A. Torbicki, P. Leffers, B. Renault, B. Fauser, C. Ciano, G. Uziel, J. M. Gibson, F. Anaya, C. Derouesné, C. N. Anagnostou, M. Kaido, W. Eickhoff, G. Talerico, M. L. Berthier, A. Capdevila, M. Alons, D. Rezek, E. Wondrusch, U. Kauerz, D. Mateo, M. A. Chornet, Holon, N. Pinsard, I. Doganer, E. Paoino, H. Strenge, C. Diaz, J. R. Brasic, W. Heide, I. Santilli, W. M. Korn, D. Selcuki, M. J. Barrett, D. Krieger, T. Leon, T. Houallah, M. Tournilhac, C. Nos, D. Chavot, F. Barbieri, F. J. Jimenez-Jimenez, J. Muruzabal, K. Poeck, A. Sennlaub, L. M. Iriarte, L. G. Lazzarino, C. Sanz, P. A. Fischer, S. D. Shorvon, R. Hoermann, F. Delecluse, M. Krams, O. Corabianu, F. H. Hochberg, Christopher J. Mathias, B. Debachy, C. M. Poser, L. Delodovici, A. Jimenez-Escrig, F. Baruzzi, F. Godenberg, D. Cucinotta, P. J. Garcia Ruiz, K. Maier-Hauff, P. R. Bar, R. Mezt, R. Jochens, S. Karakaneva, C. Roberti, E. Caballero, Joseph E. Parisi, M. Zamboni, T. Lacasa, B. Baklan, J. C. Gautier, J. A. Martinez-Matos, W. Pollmann, G. Thomas, L. Verze, E. Chleide, R. Alvarez Sala, I. Noel, E. Albuisson, O. Kastrup, S. I. Rapoport, H. J. Braune, H. Lörler, M. Le Merrer, A. Biraben, S. Soler, S. J. Taagholt, U. Meyding-Lamadé, K. Bleasdale-Barr, Isabella Moroni, Y. Campos, J. Matias-Guiu, G. Edan, M. G. Bousser, John B. Clark, J. Garcia de Yebenes, N. K. Olsen, P. Hitzenberger, S. Einius, Aj Thompson, Ch. J. Vecht, T. Crepin-Leblond, Klaus L. Leenders, A. Di Muzio, L. Georgieva, René Spiegel, K. Sabey, D. Ménégalli, J. Meulstee, U. Liszka, P. Giral, C. Sunol, J. M. Espadaler, A. D. Crockar, K. Varli, G. Giraud, P. J. Hülser, A. Benazzouz, A. Reggio, M. Salvatore, K. Genc, M. Kushnir, S. Barbieri, J. Ph. Azulay, M. Gianelli, N. Bathien, A. AlMemar, F. Hentati, I. Ragueneau, F. Chiarotti, R. C. F. Smits, A. K. Asbury, F. Lacruz, B. Muller, Alan J. Thompson, Gordon Smith, K. Schmidt, C. Daems Monpeun, Juergen Weber, A. Arboix, G. R. Fink, A. M. Cobo, M. Ait Kaci Ahmed, E. Gencheva, Israel-Biet, G. Schlaug, P. De Jonghe, Philip Scheltens, K. Toyka, P. Gonzalez-Porque, A. Cila, J. M. Fernandez, P. Augustin, J. Siclia, S. Medaglini, D. E. Ziogas, A. Feve, L. Kater, G. J. E. Rinkel, D. Leppert, Rüdiger J. Seitz, S. Ried, C. Turc-Carel, G. Smeyers, F. Godinho, M. Czygan, M. Rijntjes, E. Aversa, M. Frigo, Leif Østergaard, J. L. Munoz Blanco, A. Cruz-Matinez, J. De Reuck, C. Theillet, T. Barroso, V. Oikonen, Florence Lebert, M. Kilinc, C. Cordon-Cardon, G. Stoll, E. Thiery, F. Pulcinelli, J. Solski, M. Schmiegelow, L. J. Polman, P. Fernandez-Calle, C. Wikkelso, M. Ben Hamida, M. Laska, E. Kott, W. Sulkowski, C. Lucas, N. M. Bornstein, D. Schmitz, M. W. Lammers, A. de Louw, R. J. S. Wise, P. A. van Darn, C. Antozzi, P. Villanueva, P. H. E. Hilkens, C. Constantin, W. Ricart, A. Wolf, M. Gamba, P. Maguire, Alessandro Padovani, B. M. Patten, Marie Sarazin, H. Ackermann, L. Durelli, S. Timsit, Sebastian Jander, B. W. Scheithauer, G. Demir, J. P. Neau, P. Barbanti, A. Brand, N. AraÇ, V. Fischer-Gagnepain, R. Marchioli, G. Serratrice, C. Maugard-Louboutin, G. T. Spencer, D. Lücke, G. Mainardi, K. Harmant Van Rijckevorsel, G. B. Creel, R. Manzanares, Francesco Fortunato, A. May, J. Workman, K. Johkura, E. Fernandez, Carlo Colosimo, L. Calliauw, L. Bet, Félix F. Cruz-Sánchez, M. Dhib, H. Meinardi, F. Carrara, J. Kuehnen, C. Peiro, H. Lassmann, K. Skovgaard Olsen, A. McDonald, L. Sciulli, A. Cobo, A. Monticelli, B. Conrad, J. Bagunya, J. Benitez, V. Desnizza, B. Dupont, O. Delrieu, D. Moraes, J. J. Heimans, F. Garcia Rio, M. Matsumto, A. Fernandez, R. Nermni, R. Chalmers, M. J. Marchau, F. Aguado, P. Velupillai, P. J. Martin, P. Tassan, V. Demarin, A. Engelien, T. Gerriets, Comar, J. L. Carrasco, J. P. Pruvo, A. Lopez de Munain, D. Pavitt, J. Alarcon, Chris H. Polman, B. Guldin, N. Yeni, Hartmut Brückmann, N. Wilczak, H. Szwed, R. Causaran, G. Kyriazis, M. E. Westarp, M. Gasparini, N. Pecora, J. M. Roda, E. Lang, V. Scaioli, David R. Fish, D. Caputo, O. Gratzl, R. Mercelis, A. Perretti, G. Steimetz, I. Link, C. Rigoletto, A. Catafau, G. Lucotte, M. Buti, G. Fagiolari, A. Piqueras, C. Godinot, J. C. Meurice, Erodriguez J. Dominigo, F. Lionnet, H. Grzelec, David J. Brooks, P. M. G. Munro, F. X. Weilbach, M. Maiwald, W. Split, B. Widjaja-Cramer, V. Ozturk, J. Colas, E. Brizioli, J. Calleja, L. Publio, M. Desi, R. Soffietti, P. Cortinovis-Tourniaire, E. F. Gonano, G. Cavaletti, S. Uselli, K. Westerlind, H. Betuel, C. O. Dhiver, H. Guggenheim, M. Hamon, R. Fazio, P. Lehikoinen, A. Esser, B. Sadzot, G. Fink, Angelo Antonini, D. Bendahan, V. Di Carlo, G. Galardi, A. F. Boller, M. Aksenova, Del Fiore, V. de la Sayette, H. Chabriat, A. Nicoletti, A. Dilouya, M. L. Harpin, E. Rouillet, J. Stam, A. Wolters, M. R. Delgado, Eduardo Tolosa, G. Said, A. J. Lees, L. Rinaldi, A. Schulze-Bonhage, MA Ron, C. Lefebvre, E. W. Radü, R. Alvarez, M. L. Bots, P. Reganati, S. Palazzi, A. Poggi, N. J. Scolding, V. Sazdovitch, T. Moreau, E. Maes, M. A. Estelies, P. Petkova, Jose-Felix Marti-Masso, G De La Meilleure, N. Mullatti, M. Rodegher, N. C. Notermans, T. A. T. Warner, S. Aktan, J. P. Louboutin, L. Volpe, C. Scheidt, W. Aust, C. M. Wiles, U. Schneider, S. K. Braekken, W. R. Willems, K. Usuku, Peter M. Rothwell, C. Talamon, M. L. Sacchetti, A. Codina, M. H. Marion, A. Santoro, J. Roda, A. Bordoni, D. J. Taylor, S. Ertas, H. H. Emmen, J. Vichez, V. BesanÇon, R. E. Passingham, M. L. Malosio, A. Vérier, M. Bamberg, A. W. Hansen, E. Mostacero, G. Gaudriault, Marie Vidailhet, B. Birebent, K. Strijckmans, F. Giannini, T. Kammer, I. Araujo, J. Nowicki, E. Nikolov, A. Hutzelmann, R. Gherardi, J. Verroust, L. Austoni, A. Scheller, A. Vazquez, S. Matheron, H. Holthausen, J. M. Gerard, M. Bataillard, S. Dethy, V. H. Patterson, V. Ivanez, N. P. Hirsch, F. Ozer, M. Sutter, C. Jacomet, M. Mora, Bruno Colombo, A. Sarropoulos, T. H. Papapetropoulos, M. Schwarz, D. S. Dinner, N. Acarin, B. Iandolo, J. O. Riis, P. R. J. Barnes, F. Taroni, J. Kazenwadel, L. Torre, A. Lugaresi, I. L. Henriques, S. Pauli, S. Alfonso, Pedro Quesada, A. S. T. Planting, J. M. Castilla, Thomas Gasser, M. Van der Linden, A. Alfaro, E. Nobile-Orazio, G. Popova, W. Vaalburg, F. G. A. van der Mech, L. Williams, F. Medina, J. P. Vernant, J. Yaouanq, B. Storch-Hagenlocher, A. Potemkowski, R. Riva, M. H. Mahagne, M. Ozturk, Ve. Drory, N. Konic, C. Jungreis, A. Pou Serradell, J. L. Gauvrit, G. J. Chelune, S. Hermandez, T. Dingus, L. Hewer, Ch. Koch, M. N. Metz-Lutz, G. Parlato, M. Sinaki, Charles Pierrot-Deseilligny, H. C. Diener, J. Broeckx, J. Weill-Fulazza, M. L. Villar, M. Rizzo, O. Ganslandt, C. Duran, N. A. Fletcher, G. Di Giovacchino, Susan T. Iannaccone, C. Kolig, N. Fabre, H. A. Crockard, Rita Bella, M. Tazir, E. Papagiannuli, K. Overgaard, Emma Ciafaloni, I. Lorenzetti, F. Viader, P. A. H. Millac, I. Montiel, L. H. Visser, M. Palomar, P. L. Murgia, H. Pedersen, Rafael Blesa, S. Seddigh, W. O. Renier, I. Lemahieu, H. M. L. Jansen, L. Rosin, J. Galofre, K. Mattos, M. Pondal, G. M. Hadjigeorgiou, D. Francis, L. Cantin, D. Stegeman, M. Rango, A. B. M. F. Karim, S. Schraff, B. Castellotti, I. Iriarte, E. Laborde, T. J. Tjan, R. Mutani, D. Toni, B. Bergaasco, J. G. Young, C. Klotzsch, A. Zincone, X. Ducrocq, M. Uchuya, O. J. Kolar, A. Quattrone, T. Bauermann, Nereo Bresolin, J. Vallée, B. C. Jacobs, A. Campos, Werner Poewe, J. A. Villanueva, A. W. Kornhuber, A. Malafosse, E. Diez-Tejedor, G. Jungreia, M. J. A. Puchner, A. Komiyama, O. Saribas, V. Volpini, L. Geremia, S. Bressi, A. Nibbio, Timothy E. Bates, T. z. Tzonev, E. Ideman, G. A. Damlacik, G. Martino, G. Crepaldi, T. Martino, Kjell Någren, E. Idiman, D. Samuel, J. M. Perez Trullen, Y. van der Graaf, J. O. Thorell, M. J. M. Dupuis, E. Sieber, R. D'Alessandro, C. Cazzaniga, J. Faiss, A. Tanguy, A. Schick, I. Hoksergen, A. Cardozo, R. Shakarishvili, G. K. Wennlng, J. L. Marti-Vilalta, J. Weissenbach, I. L. Simone, Amalia C. Bruni, Darius J. Adams, C. Weiller, A. Pietrangeli, F. Croria, C. Vigo-Pelfrey, Patricia Limousin, A. Ducros, G. Conti, O. Lindvall, E. Richter, M. Zuffi, A. Nappo, T. Riise, J. Wijdenes, M. J. Fernandez, J. Rosell, P. Vermersh, S. Servidei, M. S. C. Verdugo, F. Gouttiere, W. Solbach, M. Malbezin, I. S. Watanabe, A. Tumac, W. I. McDonald, D. A. Butterfield, P. P. Costa, F. deRino, F. Bamonti, J. M. Cesar, C. H. Lahoz, I. Mosely, M. Starck, M. H. Lemaitre, K. M. Stephan, S. Tex, R. Bokonjic, I. Mollee, L. Pastena, M. Gutierrez, F. Boiler, M. C. Martinez-Para, M. Velicogna, O. Obuz, A. Grinspan, M. Guarino, L. M. Cartier, E. Ruiz, D. Gambi, S. Messina, M. Villa, Michael G. Hanna, J. Valk, Leone Pascual, M. Clanet, Z. Argov, B. Ryniewicz, E. Magni, B. Berlanga, K. S. Wong, C. Gellera, C. Prevost, F. Gonzalez-Huix, R. Petraroli, J. E. G. Benedikz, I. Kojder, C. Bommelaer, L. Perusse, M. R. Bangioanni, Guy M. McKhann, A. Molina, C. Fresquet, E. Sindern, Florence Pasquier, M. J. Rosas, M. Altieri, O. Simoncini, M. Koutroumanidis, C. A. F. Tulleken, M. Dary-Auriol, S. Oueslati, H. Kruyer, I. Nishisho, C. R. Horning, A. Vital, G. V. Czettritz, J. Ph. Neau, B. Mihout, A. Ameri, M. Francis, S. Quasthoff, D. Taussig, S. Blunt, P. Valentin, C. Y. Gao, O. Heinzlef, H. d'Allens, C. Coudero, M. Erfas, G. Borghero, P. J. Modrego Pardo, M. C. Patrosso, N. L. Gershfeld, P. A. J. M. Boon, O. Sabouraud, M. Lara, J. Svennevig, G. L. Lenzi, A. Barrio, H. Villaroya, JosÇ M. Manubens, O. Boespflug-Tanguy, M. Carreras, D. A. Costiga, J. P. Breux, S. Lynn, C. Oliveras Ley, A. G. Herbaut, J. Nos, C. Tornali, Y. A. Hekster, J. L. Chopard, J. M. Manubens, P. Chemouilli, A. Jovicic, F. Dworzak, S. Smirne, S. E. Soudain, B. Gallano, D. Lubach, G. Masullo, G. Izquierdo, A. Pascual Leone Pascual, A. Sessa, V. Freitas, O. Crambes, L. Ouss, G. W. Van Dijk, P. Marchettini, P. Confalonieri, M. Donaghy, A. Munnich, M. Corbo, and M. E. L. van der Burg
Subjects: Neurology, business.industry, Media studies, Library science, Medicine, Neurology (clinical), business
Published: 1994
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34. X–linked spastic paraplegia and Pelizaeus–Merzbacher disease are allelic disorders at the proteolipid protein locus

Author: Odile Boespflug-Tanguy, Jean-Michel Rozet, Arnold Munnich, Dominique Bonneau, M. Le Merrer, R. Gil, and Pascale Saugier-Veber
Subjects: Male, Candidate gene, X Chromosome, Proteolipid protein 1, Genetic Linkage, Proteolipids, Molecular Sequence Data, Locus (genetics), Biology, Gene mapping, immune system diseases, Genetics, medicine, Humans, Point Mutation, Allele, Alleles, DNA Primers, Paraplegia, Base Sequence, Paraplegin, Chromosome Mapping, Pelizaeus–Merzbacher disease, Diffuse Cerebral Sclerosis of Schilder, medicine.disease, Pedigree, nervous system diseases, Xq28, Phenotype, Mutation, Female, lipids (amino acids, peptides, and proteins)
Abstract: Three forms of X-linked spastic paraplegia (SPG) have been defined. One locus (SPG 1) maps to Xq28 while two clinically distinct forms map to Xq22 (SPG2). A rare X-linked dysmyelinating disorder of the central nervous system, Pelizaeus-Merzbacher disease (PMD), has also been mapped to Xq21-q22, and is caused by mutations in the proteolipid protein gene (PLP) which encodes two myelin proteins, PLP and DM20. While narrowing the genetic interval containing SPG2 in a large pedigree, we found that PLP was the closest marker to the disease locus, implicating PLP as a possible candidate gene. We have found that a point mutation (His139Tyr) in exon 3B of an affected male produces a mutant PLP but a normal DM20, and segregates with the disease (Zmax = 6.63, theta = 0.00). It appears, therefore, that SPG2 and PMD are allelic disorders.
Published: 1994
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35. Diagnostic prénatal des anomalies du squelette et des membres

Author: M. Le Merrer, Valérie Cormier-Daire, Sylvie Manouvrier-Hanu, and V. Houfflin-Debarge
Subjects: business.industry, Medicine, business
Published: 2011
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36. X linked spastic paraplegia (SPG2): clinical heterogeneity at a single gene locus

Author: R. Gil, R Mettey, Dominique Bonneau, M. Le Merrer, C Bulteau, Jean-Michel Rozet, Arnold Munnich, and Michel Berthier
Subjects: Adult, Male, Heterozygote, congenital, hereditary, and neonatal diseases and abnormalities, X Chromosome, Adolescent, Genetic Linkage, Hereditary spastic paraplegia, Locus (genetics), Biology, Gene mapping, Genetic linkage, Genetics, medicine, Spastic, Humans, Spasticity, Child, Genetics (clinical), Recombination, Genetic, Spastic Paraplegia, Hereditary, Chromosome Mapping, Infant, medicine.disease, Pedigree, nervous system diseases, Xq28, Phenotype, Female, Allelic heterogeneity, Lod Score, medicine.symptom, Research Article
Abstract: X linked hereditary spastic paraplegia is a rare condition that has been divided into two forms (the pure spastic form and the complicated form) as a function of clinical course and severity. A gene for pure hereditary spastic paraplegia (SPG2) has been mapped to the proximal long arm of the X chromosome (Xq21) by linkage to the DXS17 locus, while a gene for a complicated form of the disease has been mapped to the distal long arm by linkage to the DXS52 locus (Xq28). Here we report on the mapping of a gene for complicated hereditary spastic paraplegia to the Xq21 region by linkage to the probe S9 at the DXS17 locus (Z = 5 at theta = 0.04) in a three generation pedigree. Multipoint linkage analysis supports the distal location of the disease gene with respect to the DXYS1-DXS17 block (cen-DXYS1-DXS3-DXS17-SPG2-tel). The observation of a complicated form of spastic paraplegia mapping to Xq21 raises the difficult issue of variable phenotypic expression, allelic heterogeneity, or even close proximity of two genes for hereditary spastic paraplegia in this region. However, since our study provides clinical evidence for intrafamilial heterogeneity in complicated X linked spastic paraplegia, the present data support the hypothesis of variable clinical expression of a single gene at the SPG2 locus, as previously suggested for SPG1. Finally, we report here what we believe to be the first evidence of clinical expression in heterozygous carriers, a feature that is relevant to genetic counselling in at risk females.
Published: 1993
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37. Sulphate transporter gene mutations in apparently isolated club foot

Author: Valérie Cormier-Daire, Céline Huber, Clotilde Penet, Arnold Munnich, S Rumeur, P Padovani, Sylvie Odent, and M. Le Merrer
Subjects: Genetic Markers, Male, Genetic Linkage, Anion Transport Proteins, Biology, Compound heterozygosity, medicine.disease_cause, Genetic determinism, Multiple epiphyseal dysplasia, Atelosteogenesis, type II, Genetics, medicine, Humans, Letters to the Editor, Child, Genetics (clinical), Mutation, Sulfates, Achondrogenesis, Membrane Transport Proteins, Biological Transport, medicine.disease, Clubfoot, Sulfate Transporters, Dysplasia, Female, Diastrophic dysplasia, medicine.symptom, Carrier Proteins
Abstract: Editor—Diastrophic dysplasia was originally ascribed to sulphate transporter gene ( DTDST ) mutations. The DTDST gene is now also known to account for a variety of bone dysplasias including diastrophic dysplasia, atelosteogenesis type II (AO2), and achondrogenesis Ib.1-3 Abnormally sulphated cartilage proteoglycans with deficient cartilage sulphate content has been reported in these conditions,4 suggesting that a variable residual DTDST activity probably accounts for the broad spectrum of clinical phenotypes at this locus.5 While a predominant founder mutation in the splice donor site of a previously undescribed 5′ untranslated exon accounts for the disease in Finland, more than 30 mutations have been reported so far world wide6 and compound heterozygosity for variably deleterious mutations probably explains the broad spectrum of clinical phenotypes at the DTDST locus.2 7 8 The R279W mutation is the most common mutation in non-Finnish patients and, apart from its original report in an AO2 patient, compound heterozygosity for this mutation has been consistently associated with a non-lethal phenotype. Recently, Superti-Furga et al 9 reported homozygosity for the R279W mutation in an adult affected with multiple epiphyseal dysplasia, normal stature, club foot, and double layered patella. Here, we add further support to this view and report on the association of apparently isolated club foot with the homozygous R279W DTDST mutation in two unrelated sibships of western French ancestry (Brittany). In family 1, dizygotic twins, a boy …
Published: 2001
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38. Fourth case of cerebral, ocular, dental, auricular, skeletal syndrome (CODAS), description of new features and molecular analysis

Author: Laurence Jonard, Françoise Denoyelle, H. Ducou Le Pointe, Marie-France Portnoï, S Chantot, Sandrine Marlin, A Mantel-Guiochon, Erea-Noel Garabedian, M. Le Merrer, and Jean-Pierre Siffroi
Subjects: Larynx, Male, Bone and Bones, Cataract, ENAMEL ANOMALY, Intellectual Disability, Genetics, Medicine, Humans, Abnormalities, Multiple, CODAS SYNDROME, Heart Atria, Congenital Malformation Syndrome, Muscle, Skeletal, Genetics (clinical), Cerebral Cortex, Epiphyseal dysplasia, business.industry, Tooth Abnormalities, Karyotype, Anatomy, Syndrome, Molecular analysis, stomatognathic diseases, medicine.anatomical_structure, Child, Preschool, Etiology, business
Abstract: Cerebral, ocular, dental, auricular, skeletal syndrome (CODAS, OMIM 600373) is a very rare congenital malformation syndrome. This clinical entity is highly distinctive and associates mental retardation, cataract, enamel abnormalities, malformations of the helix, epiphyseal and vertebral malformations, and characteristic dysmorphic features. Since 1991, only three affected children have been reported. The etiology and pattern of inheritance of CODAS syndrome still remain unknown. We describe a new sporadic case presenting with all the characteristic features of CODAS syndrome associated with previously unreported malformations of the heart, larynx, and liver. All investigations such as karyotype, metabolic screening and array CGH were normal. © 2010 Wiley-Liss, Inc.
Published: 2010

39. Stüve-Wiedemann syndrome: long-term follow-up and genetic heterogeneity

Author: M. Le Merrer, Sheila Unger, Valérie Cormier-Daire, Albert David, Ben C.J. Hamel, Andrea Superti-Furga, N Dagoneau, C Jung, Geneviève Baujat, André Mégarbané, Arnold Munnich, and M. Di Rocco
Subjects: Male, congenital, hereditary, and neonatal diseases and abnormalities, Pediatrics, medicine.medical_specialty, Leukemia Inhibitory Factor Receptor alpha Subunit, Long term follow up, Leukemia inhibitory factor receptor, Genes, Recessive, medicine.disease_cause, Osteochondrodysplasias, Genomic disorders and inherited multi-system disorders [IGMD 3], Genetic Heterogeneity, Swallowing, Genetics, Medicine, Humans, Abnormalities, Multiple, Genetics (clinical), Mutation, business.industry, Genetic heterogeneity, Dysautonomia, Syndrome, medicine.disease, STUVE-WIEDEMANN SYNDROME, body regions, Leukemia, Female, medicine.symptom, business, Functional Neurogenomics [DCN 2], Follow-Up Studies
Abstract: Stuve-Wiedemann syndrome (SWS, OMIM 601559) is a severe autosomal recessive condition caused by mutations in the leukemia inhibitory receptor (LIFR) gene. The main characteristic features are bowing of the long bones, neonatal respiratory distress, swallowing/sucking difficulties and dysautonomia symptoms including temperature instability often leading to death in the first years of life. We report here four patients with SWS who have survived beyond 36 months of age with no LIFR mutation. These patients have been compared with six unreported SWS survivors carrying null LIFR mutations. We provide evidence of clinical homogeneity of the syndrome in spite of the genetic heterogeneity.
Published: 2010
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40. Prenatal diagnosis of brachytelephalangic chondrodysplasia punctata: case report

Author: M. Alexandre, A. Benaicha, J.-M. Jouannic, Aurélia Jacquette, M. Le Merrer, Catherine Garel, H. Ducou Le Pointe, and Marc Dommergues
Subjects: musculoskeletal diseases, Adult, Male, Polyhydramnios, congenital, hereditary, and neonatal diseases and abnormalities, Pathology, medicine.medical_specialty, Chondrodysplasia Punctata, Prenatal diagnosis, Gestational Age, Ultrasonography, Prenatal, Congenital skeletal dysplasia, Pregnancy, Peroxisomal disorder, medicine, Humans, Radiology, Nuclear Medicine and imaging, Chondrodysplasia punctata, Brachytelephalangic Chondrodysplasia Punctata, Radiological and Ultrasound Technology, business.industry, Infant, Newborn, Pregnancy Outcome, Obstetrics and Gynecology, General Medicine, musculoskeletal system, medicine.disease, Osteochondrodysplasia, Reproductive Medicine, Female, sense organs, Differential diagnosis, business
Abstract: Brachytelephalangic chondrodysplasia punctata is a rare congenital skeletal dysplasia. Within the heterogeneous group of chondrodysplasia punctata, the brachytelephalangic type is noteworthy because it has a better prognosis than do the other types. We report a case of brachytelephalangic chondrodysplasia punctata diagnosed by ultrasound imaging at 30 weeks' gestation; it was associated with polyhydramnios and a normal cervical spinal canal. Imaging features are described and differential diagnosis with other forms of chondrodysplasia punctata is discussed.
Published: 2009

41. Cognitive and neuroradiological improvement in three patients with attenuated MPS I treated by laronidase

Author: Catherine Caillaud, Vassili Valayannopoulos, Nathalie Boddaert, Valérie Barbier, P. de Lonlay, and M. Le Merrer
Subjects: medicine.medical_specialty, Adolescent, Endocrinology, Diabetes and Metabolism, Mucopolysaccharidosis, Mucopolysaccharidosis I, Intelligence, Biochemistry, Mucopolysaccharidosis type I, Iduronidase, Endocrinology, Cognition, Internal medicine, Genetics, medicine, Humans, Child, Molecular Biology, Retrospective Studies, medicine.diagnostic_test, business.industry, LARONIDASE, Brain, Magnetic resonance imaging, Retrospective cohort study, medicine.disease, Magnetic Resonance Imaging, Surgery, Transplantation, Treatment Outcome, Child, Preschool, Stem cell, business
Abstract: Stem cell transplantation is not appropriate first-line treatment for attenuated phenotypes of mucopolysaccharidosis type I (MPS I). In three patients with attenuated MPSA I treated by laronidase, Patients 2 and 3 displayed significant cognitive improvement within 2years; Patients 1 and 3 displayed improvement on MRI scans of the brain.
Published: 2009

42. Molecular analysis of pericentrin gene (PCNT) in a series of 24 Seckel/microcephalic osteodysplastic primordial dwarfism type II (MOPD II) families

Author: M. Willems, Patrick Edery, M. Le Merrer, Guntram Borck, Clarisse Baumann, Dominique Martin-Coignard, Delphine Héron, Marion Gérard, Eric Bieth, Alain Verloes, Chantal Farra, Valérie Cormier-Daire, B. Leheup, Christel Thauvin-Robinet, David Geneviève, Arnold Munnich, Laurence Colleaux, Michèle Mathieu, Geneviève Baujat, and Stanislas Lyonnet
Subjects: Male, Microcephaly, Genotype, Genetic Linkage, Dwarfism, Biology, medicine.disease_cause, Frameshift mutation, Cohort Studies, 03 medical and health sciences, Consanguinity, 0302 clinical medicine, PCNT, Genetics, medicine, Missense mutation, Humans, Family, Antigens, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Mutation, Leg, Hip, medicine.disease, Hand, 3. Good health, Radiography, Seckel syndrome, Genetic Loci, Female, Growth and Development, Primordial dwarfism, 030217 neurology & neurosurgery
Abstract: Microcephalic osteodysplastic primordial dwarfism type II (MOPD II, MIM 210720) and Seckel syndrome (SCKL, MIM 210600) belong to the primordial dwarfism group characterised by intrauterine growth retardation, severe proportionate short stature, and pronounced microcephaly. MOPD II is distinct from SCKL by more severe growth retardation, radiological abnormalities, and absent or mild mental retardation. Seckel syndrome is associated with defective ATR dependent DNA damage signalling. In 2008, loss-of-function mutations in the pericentrin gene (PCNT) have been identified in 28 patients, including 3 SCKL and 25 MOPDII cases. This gene encodes a centrosomal protein which plays a key role in the organisation of mitotic spindles. The aim of this study was to analyse PCNT in a large series of SCKL-MOPD II cases to further define the clinical spectrum associated with PCNT mutations. Among 18 consanguineous families (13 SCKL and 5 MOPDII) and 6 isolated cases (3 SCKL and 3 MOPD II), 13 distinct mutations were identified in 5/16 SCKL and 8/8 MOPDII including five stop mutations, five frameshift mutations, two splice site mutations, and one apparent missense mutation affecting the last base of exon 19. Moreover, we demonstrated that this latter mutation leads to an abnormal splicing with a predicted premature termination of translation. The clinical analysis of the 5 SCKL cases with PCNT mutations showed that they all presented minor skeletal changes and clinical features compatible with MOPDII diagnosis. It is therefore concluded that, despite variable severity, MOPDII is a genetically homogeneous condition due to loss-of-function of pericentrin.
Published: 2009

43. Scalp-ear-nipple (Finlay-Marks) syndrome: a familial case with renal involvement

Author: M. Le Merrer, S Couderc, Arnold Munnich, Jeanne Amiel, Capucine Picard, Rémi Salomon, Stanislas Lyonnet, P. de Lonlay, and T Skojaei
Subjects: Familial case, medicine.medical_specialty, medicine.anatomical_structure, business.industry, Scalp, Genetics, medicine, business, Dermatology, Genetics (clinical)
Published: 1999
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44. Revisiting metatropic dysplasia: presentation of a series of 19 novel patients and review of the literature

Author: D Geneviève, P Maroteaux, M. Le Merrer, Valérie Cormier-Daire, J Feingold, and Arnold Munnich
Subjects: Adult, Male, Germline mosaicism, Dwarfism, Osteochondrodysplasias, Cricoid cartilage, Genetics, medicine, Humans, Kyphosis, Child, Kyphoscoliosis, Genetics (clinical), Genes, Dominant, Metatropic Dysplasia, business.industry, Mosaicism, Anatomy, medicine.disease, Hypoplasia, Radiography, medicine.anatomical_structure, Scoliosis, Dysplasia, Female, Presentation (obstetrics), business, Cervical vertebrae
Abstract: Metatropic dysplasia (MD-OMIM: 156530 and 250600) is a rare chondrodysplasia characterized by short limbs with limitation and enlargement of joints and usually severe kyphoscoliosis, first described in 1893. Up until now, 81 other patients have been reported. The phenotypic variability of MD has led to a classification based on radiological anomalies dividing into three different types: a lethal autosomal recessive form, an autosomal recessive non-lethal form and a non-lethal autosomal dominant form with less severe radiographs manifestations and a better clinical outcome. Here, we report on clinical and radiological features of 19 novel MD patients. We describe new radiological features, including precocious calcification of hyoid and cricoid cartilage, irregular and squared-off calcaneal bones and severe hypoplasia of the anterior portion of first cervical vertebrae. In addition, the observation of an overlap between the autosomal recessive non-lethal form and the non-lethal autosomal dominant form, the rarity of sibship recurrences and the observation of vertical transmissions of MD in the literature argue in favor of an autosomal dominant mode of inheritance for all MD types. This hypothesis is reinforced by the use of the statistical single ascertainment method that rejects the hypothesis of an autosomal recessive mode of inheritance responsible for MD. Therefore, we propose that recurrence in sibs is due to gonadal mosaicism.
Published: 2008

45. Recessive metaphyseal dysplasia without hypotrichosis. A syndrome clinically distinct from McKusick cartilage-hair hypoplasia

Author: Pierre Maroteaux, M. Le Merrer, Gérald Pierard, and Alain Verloes
Subjects: Male, Bone and Bones, Diagnosis, Differential, otorhinolaryngologic diseases, Genetics, medicine, Cartilage–hair hypoplasia, Humans, Child, Genetics (clinical), Immunodeficiency, Bone Diseases, Developmental, integumentary system, business.industry, Infant, Newborn, Infant, Anatomy, Metaphyseal dysplasia, medicine.disease, Osteochondrodysplasia, Hypoplasia, Radiography, Child, Preschool, Hypotrichosis, Female, Allelic heterogeneity, sense organs, Differential diagnosis, business, Hair, Research Article
Abstract: Among children with recessive metaphyseal dysplasia involving the knees and extremities, two types can be distinguished. In true cartilage-hair hypoplasia, as described by McKusick, many patients show clinical hair involvement and variable immunodeficiency. We present a series of six patients with the same radiological changes, but without apparent hypotrichosis. We suggest that they should be considered as having a variant form of cartilage-hair hypoplasia, with a clinically distinct phenotype, which could be as common as 'true' cartilage-hair hypoplasia among non-Amish populations. Microscopic examination of the hair may show reduction in the diameter of the hair shaft. This form of metaphyseal dysplasia may result from allelic heterogeneity.
Published: 1990
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46. Pamidronate treatment of children with moderate-to-severe osteogenesis imperfecta: a note of caution

Author: F. Guillou, G. Pinto, Georges Finidori, M. Alharbi, Jean-Claude Souberbielle, M. Le Merrer, Michel Polak, and S. Gaubicher
Subjects: Moderate to severe, Male, Pediatrics, medicine.medical_specialty, Bone density, Endocrinology, Diabetes and Metabolism, Osteocalcin, Pamidronate, Fractures, Bone, Endocrinology, Absorptiometry, Photon, Bone Density, Medicine, Humans, Prospective Studies, Amino Acids, Prospective cohort study, Child, Infusions, Intravenous, Fracture Healing, Bone Density Conservation Agents, Diphosphonates, business.industry, Osteogenesis Imperfecta, medicine.disease, Surgery, Amino acids urine, Osteogenesis imperfecta, Parathyroid Hormone, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, business
Abstract: Background/Aims: Bisphosphonates have been reported to decrease fractures related to osteogenesis imperfecta (OI). We assessed the efficacy and long-term safety of pamidronate therapy in patients with moderate-to-severe OI. Methods: We conducted an open-label uncontrolled study in 14 boys and 13 girls whose mean age was 6.8 years at baseline. Intravenous pamidronate, 1 mg/kg/day, was given for 3 consecutive days every 4 months for 2–6 years, with physical therapy and orthopedic surgery as appropriate. Mobility score, fracture rate, height, bone mineral density (BMD) and bone healing were evaluated throughout follow-up. Results: In 24 (89%) patients, the fracture rate decreased to ≤2/year and/or the mobility score improved. The remaining 3 (11%) patients continued to experience more than 2 fractures per year with mobility scores 6 months) occurred in 8 (29.6%) patients; their BMD gains, baseline age and treatment duration were not significantly different from those in the other patients. Tolerance was good. Conclusion: Pamidronate with physiotherapy and orthopedic management improved outcomes without delaying fracture healing in 19 (70%) of 27 patients. Delayed fracture healing occurred in 8/27 patients. Pamidronate should be reserved for severe OI with multiple fractures and/or flattened vertebras.
Published: 2007

47. Specific osseous spurs in a lethal form of hypophosphatasia correlated with 3D prenatal ultrasonographic images

Author: Marion Gérard-Blanluet, Etienne Mornet, A. Vergnaud, Férechté Encha-Razavi, Jean-Marc Levaillant, J. R. Blondeau, Martine Sinico, and M. Le Merrer
Subjects: musculoskeletal diseases, Pathology, medicine.medical_specialty, Hypophosphatasia, Prenatal diagnosis, Context (language use), Compound heterozygosity, Short stature, Bone and Bones, Ultrasonography, Prenatal, Imaging, Three-Dimensional, Pregnancy, Medicine, Humans, Genetics (clinical), Fetus, business.industry, Ossification, Obstetrics and Gynecology, Anatomy, medicine.disease, Alkaline Phosphatase, Fetal Diseases, Dysplasia, Female, medicine.symptom, business
Abstract: Background Hypophosphatasia is an osseous dysplasia with highly variable clinical expression, ranging from a recessive lethal prenatal type to late onset dominant short stature with premature shedding of teeth. Lethal forms of hypophosphatasia include short limb dwarfism with lack of ossification, especially on the vertebral bodies, very slender ribs and clavicles, and bowed, short lower extremities, with a bifid aspect of the diaphyses. Alkaline phosphatase is abnormally low in liver, bone, kidney and plasma. Methods We present here the prenatal images of a lethal form of hypophosphatasia, diagnosed precociously because of specific osseous spurs in a context of recurrent short limb dwarfism. Results Prenatal 3D ultrasonography has shown these spurs as early as 18 weeks. Molecular biology found compound heterozygous mutations in the gene TNSALP. Conclusion In a context of short limb dwarfism, the search for these specific osseous spurs orient strongly toward the diagnosis of lethal hypophosphatasia. Copyright © 2007 John Wiley & Sons, Ltd.
Published: 2007

48. SHOX mutations in dyschondrosteosis (Leri-Weill syndrome)

Author: V Belin, Anne Moncla, Annick Toutain, D Girlich, Michel Vekemans, Valérie Cormier-Daire, V Cusin, M. Le Merrer, Géraldine Viot, and Arnold Munnich
Subjects: Male, X Chromosome, Genotype, Molecular Sequence Data, Pseudoautosomal region, Mesomelic Dysplasia, chemical and pharmacologic phenomena, Biology, Osteochondrodysplasias, Translocation, Genetic, Short Stature Homeobox Protein, Mesomelic short stature, Y Chromosome, Mesomelia, Genetics, medicine, Humans, Léri–Weill dyschondrosteosis, In Situ Hybridization, Fluorescence, Homeodomain Proteins, Langer mesomelic dysplasia, Short stature homeobox gene, hemic and immune systems, medicine.disease, Pedigree, Mutation, Female
Abstract: Dyschondrosteosis1 (DCS) is an autosomal dominant2 form of mesomelic dysplasia with deformity of the forearm (Madelung deformity; ref. 3). Based on the observation of XY translocations (p22,q12; refs 4–6) in DCS patients, we tested the pseudoautosomal region in eight families with DCS and showed linkage of the DCS gene to a microsatellite DMA marker at the DXYS233 locus (Zmax=6.26 at θ=0). The short stature homeobox-containing gene7,8 (SHOX), involved in idiopathic growth retardation and possibly Turner short stature, maps to this region and was therefore regarded as a strong candidate gene in DCS. Here, we report large-scale deletions (in seven families) and a nonsense mutation (in one family) of SHOX in patients with DCS and show that Langer mesomelic dwarfism9 results from homozygous mutations at the DCS locus.
Published: 1998
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49. Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders

Author: M. Le Merrer, Laurence Colleaux, Richard Redon, Odile Raoul, Marguerite Prieur, Arnold Munnich, Jeanne Amiel, Damien Sanlaville, Delphine Héron, M-C de Blois, Nigel P. Carter, Valérie Cormier-Daire, Anne Philippe, Stanislas Lyonnet, Michel Vekemans, M-L Jacquemont, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Male, Genetic analysis, MESH: Child Development Disorders, Pervasive, 0302 clinical medicine, MESH: Child, Gene duplication, Chromosomes, Human, MESH: Syndrome, Child, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Genetics, 0303 health sciences, medicine.diagnostic_test, MESH: Genetic Testing, MESH: Genomics, Genomics, Syndrome, 3. Good health, Chromosome abnormality, Medical genetics, Female, Original Article, Adult, medicine.medical_specialty, Adolescent, Genetic counseling, Biology, MESH: Chromosomes, Human, 03 medical and health sciences, medicine, Humans, MESH: Chromosome Aberrations, Genetic Testing, 030304 developmental biology, Genetic testing, Chromosome Aberrations, MESH: Adolescent, MESH: Humans, MESH: Adult, medicine.disease, MESH: Male, Developmental disorder, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child Development Disorders, Pervasive, MESH: Oligonucleotide Array Sequence Analysis, Autism, MESH: Female, 030217 neurology & neurosurgery
Abstract: Background: Autism spectrum disorders (ASD) refer to a broader group of neurobiological conditions, pervasive developmental disorders. They are characterised by a symptomatic triad associated with qualitative changes in social interactions, defect in communication abilities, and repetitive and stereotyped interests and activities. ASD is prevalent in 1 to 3 per 1000 people. Despite several arguments for a strong genetic contribution, the molecular basis of a most cases remains unexplained. About 5% of patients with autism have a chromosome abnormality visible with cytogenetic methods. The most frequent are 15q11–q13 duplication, 2q37 and 22q13.3 deletions. Many other chromosomal imbalances have been described. However, most of them remain undetectable using routine karyotype analysis, thus impeding diagnosis and genetic counselling. Methods and results: 29 patients presenting with syndromic ASD were investigated using a DNA microarray constructed from large insert clones spaced at approximately 1 Mb intervals across the genome. Eight clinically relevant rearrangements were identified in 8 (27.5%) patients: six deletions and two duplications. Altered segments ranged in size from 1.4 to 16 Mb (2–19 clones). No recurrent abnormality was identified. Conclusion: These results clearly show that array comparative genomic hybridisation should be considered to be an essential aspect of the genetic analysis of patients with syndromic ASD. Moreover, besides their importance for diagnosis and genetic counselling, they may allow the delineation of new contiguous gene syndromes associated with ASD. Finally, the detailed molecular analysis of the rearranged regions may pave the way for the identification of new ASD genes.
Published: 2006
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50. A gene responsible for Ghosal hemato-diaphyseal dysplasia maps to chromosome 7q33-34

Author: Bertrand Isidor, Capucine Picard, Brigitte Bader-Meunier, Stéphane Blanche, M. Le Merrer, Valérie Cormier-Daire, M. C. De Vernejoul, David Geneviève, Arnold Munnich, Céline Huber, and Nathalie Dagoneau
Subjects: Adult, Male, Tunisia, Locus (genetics), Biology, Genome, Pathogenesis, Gene mapping, Genetics, medicine, Humans, Genetic Predisposition to Disease, Gene, Genetics (clinical), Family Health, Genome, Human, Chromosome Mapping, Infant, Osteopetrosis, Camurati-Engelmann Syndrome, medicine.disease, Human genetics, Pedigree, Dysplasia, Algeria, Child, Preschool, Female, Chromosomes, Human, Pair 7
Abstract: Ghosal hemato-diaphyseal dysplasia is a rare autosomal recessive disorder characterized by a progressive sclerosing diaphyseal dysplasia and refractory anemia. The pathogenesis and genetic bases of this syndrome remain hitherto unknown. We have performed a genome wide search in two inbred families originating from Algeria and Tunisia. Here, we report on the mapping of a disease gene to chromosome 7q33–34 (Z max = 4.21 at θ = 0 at locus D7S2513) in a 3.4 Mb defined by loci D7S2560 and AC091742. Ongoing studies will hopefully lead to identification of the disease-causing gene.
Published: 2006

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