title: Chondrodysplasia with multiple dislocations: comprehensive study of a series of 30 cases.
abstract: The group of chondrodysplasia with multiple dislocations includes several entities, characterized by short stature, dislocation of large joints, hand and/or vertebral anomalies. Other features, such as epiphyseal or metaphyseal changes, cleft palate, intellectual disability are also often part of the phenotype. In addition, several conditions with overlapping features are related to this group and broaden the spectrum. The majority of these disorders have been linked to pathogenic variants in genes encoding proteins implicated in the synthesis or sulfation of proteoglycans (PG). In a series of 30 patients with multiple dislocations, we have performed exome sequencing and subsequent targeted analysis of 15 genes, implicated in chondrodysplasia with multiple dislocations, and related conditions. We have identified causative pathogenic variants in 60% of patients (18/30); when a clinical diagnosis was suspected, this was molecularly confirmed in 53% of cases. Forty percent of patients remain without molecular etiology. Pathogenic variants in genes implicated in PG synthesis are of major importance in chondrodysplasia with multiple dislocations and related conditions. The combination of hand features, growth failure severity, radiological aspects of long bones and of vertebrae allowed discrimination among the different conditions. We propose key diagnostic clues to the clinician.
authors.affiliation: Department of Genetics, INSERM UMR1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker Enfants Malades (AP-HP), Paris, France.|Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Ranza
authors.affiliation: Department of Genetics, INSERM UMR1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker Enfants Malades (AP-HP), Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Huber
authors.affiliation: Department of Genetics, INSERM UMR1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker Enfants Malades (AP-HP), Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Levin
authors.affiliation: Department of Genetics, INSERM UMR1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker Enfants Malades (AP-HP), Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Baujat
authors.affiliation: Plateforme de génomique, Fondation IMAGINE, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Bole-Feysot
authors.affiliation: Plateforme de Bioinformatique, Université Paris Descartes, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Nitschke
authors.affiliation: Plateforme de Bioinformatique, Université Paris Descartes, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Masson
authors.affiliation: School of Medicine, Department of Pediatrics, Pediatric Genetics Unit, Acibadem University, Istanbul, Turkey.
authors.forename: Y
authors.initials: Y
authors.lastname: Alanay
authors.affiliation: Department of Pediatrics, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.
authors.forename: L
authors.initials: L
authors.lastname: Al-Gazali
authors.affiliation: Génétique Médicale, Hôpital Jean Verdier, Bondy, France.
authors.forename: P
authors.initials: P
authors.lastname: Bitoun
authors.affiliation: Génétique Clinique, Hôpital Jeanne de Flandre, Lille, France.
authors.forename: O
authors.initials: O
authors.lastname: Boute
authors.affiliation: Division of Medical genetics, Department of Pediatrics, CHU Sainte Justine and University of Montreal, Montreal, Quebec, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Campeau
authors.affiliation: Département de Génétique Médicale, Hôpital Arnaud de Villeneuve, Montpellier, France.
authors.forename: C
authors.initials: C
authors.lastname: Coubes
authors.affiliation: Medical Genetics, St George's Healthcare NHS Trust, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: McEntagart
authors.affiliation: Department of Pediatric Genetics, Marmara University Medical School, Istanbul, Turkey.
authors.forename: N
authors.initials: N
authors.lastname: Elcioglu
authors.affiliation: Centre de Référence Anomalies du Développement et Syndromes Malformatifs et FHU TRANSLAD, CHU de Dijon et Université de Bourgogne, Dijon, France.
authors.forename: L
authors.initials: L
authors.lastname: Faivre
authors.affiliation: Department of Medical Genetics, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey.
authors.forename: A
authors.initials: A
authors.lastname: Gezdirici
authors.affiliation: Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK.
authors.forename: D
authors.initials: D
authors.lastname: Johnson
authors.affiliation: Akdeniz University School of Medicine, Division of Pediatric Genetics, Antalya, Turkey.
authors.forename: E
authors.initials: E
authors.lastname: Mihci
authors.affiliation: Akdeniz University School of Medicine, Division of Pediatric Genetics, Antalya, Turkey.
authors.forename: B G
authors.initials: BG
authors.lastname: Nur
authors.affiliation: Unité de Génétique Clinique, Hopital Robert Debré, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Perrin
authors.affiliation: Génétique Médicale, Hôpital Sud, Rennes, France.
authors.forename: C
authors.initials: C
authors.lastname: Quelin
authors.affiliation: University Medical Center, Wilhelmina Childrens Hospital, Utrecht, the Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Terhal
authors.affiliation: Cerrahpasa Medical Faculty, Department of Pediatric Genetics, Istanbul University, Istanbul, Turkey.
authors.forename: B
authors.initials: B
authors.lastname: Tuysuz
authors.affiliation: Department of Genetics, INSERM UMR1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker Enfants Malades (AP-HP), Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Cormier-Daire
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009139:Musculoskeletal Abnormalities / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D010009:Osteochondrodysplasias / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D011859:Radiography; D000073359:Exome Sequencing
keywords: chondrodysplasia; genotype-phenotype correlation; joint dislocations; proteoglycans; targeted NGS