title: Myhre and LAPS syndromes: clinical and molecular review of 32 patients.
abstract: Myhre syndrome is characterized by short stature, brachydactyly, facial features, pseudomuscular hypertrophy, joint limitation and hearing loss. We identified SMAD4 mutations as the cause of Myhre syndrome. SMAD4 mutations have also been identified in laryngotracheal stenosis, arthropathy, prognathism and short stature syndrome (LAPS). This study aimed to review the features of Myhre and LAPS patients to define the clinical spectrum of SMAD4 mutations. We included 17 females and 15 males ranging in age from 8 to 48 years. Thirty were diagnosed with Myhre syndrome and two with LAPS. SMAD4 coding sequence was analyzed by Sanger sequencing. Clinical and radiological features were collected from a questionnaire completed by the referring physicians. All patients displayed a typical facial gestalt, thickened skin, joint limitation and muscular pseudohypertrophy. Growth retardation was common (68.7%) and was variable in severity (from -5.5 to -2 SD), as was mild-to-moderate intellectual deficiency (87.5%) with additional behavioral problems in 56.2% of the patients. Significant health concerns like obesity, arterial hypertension, bronchopulmonary insufficiency, laryngotracheal stenosis, pericarditis and early death occurred in four. Twenty-nine patients had a de novo heterozygous SMAD4 mutation, including both patients with LAPS. In 27 cases mutation affected Ile500 and in two cases Arg496. The three patients without SMAD4 mutations had typical findings of Myhre syndrome. Myhre-LAPS syndrome is a clinically homogenous condition with life threatening complications in the course of the disease. Our identification of SMAD4 mutations in 29/32 cases confirms that SMAD4 is the major gene responsible for Myhre syndrome.
authors.affiliation: INSERM U781 Unit, Department of Genetics, Institut Imagine, Paris Descartes University-Sorbonne Paris Cité, Necker Enfants-Malades Hospital, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Michot
authors.affiliation: INSERM U781 Unit, Department of Genetics, Institut Imagine, Paris Descartes University-Sorbonne Paris Cité, Necker Enfants-Malades Hospital, Paris, France.
authors.forename: Carine
authors.initials: C
authors.lastname: Le Goff
authors.affiliation: INSERM U781 Unit, Department of Genetics, Institut Imagine, Paris Descartes University-Sorbonne Paris Cité, Necker Enfants-Malades Hospital, Paris, France.
authors.forename: Clémentine
authors.initials: C
authors.lastname: Mahaut
authors.affiliation: Neuropediatry Department, Centre de Référence Maladies Rares 'anomalies du développement et syndromes malformatifs - Île de France', Armand-Trousseau CHU, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Afenjar
authors.affiliation: Department of Clinical Genetics, Ersamus MC, Rotterdam, The Netherlands.
authors.forename: Alice S
authors.initials: AS
authors.lastname: Brooks
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Campeau
authors.affiliation: Department of Human Genetics, Institute of Pathology and Genetics, Gosselies, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Destree
authors.affiliation: Unit of Rare Diseases, Department of Pediatrics, Gaslini Institute, Genoa, Italy.
authors.forename: Maja
authors.initials: M
authors.lastname: Di Rocco
authors.affiliation: Manchester Academic Health Science Centre, Genetic Medicine-University of Manchester, St Mary's Hospital, Manchester, UK.
authors.forename: Dian
authors.initials: D
authors.lastname: Donnai
authors.affiliation: Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Raoul
authors.initials: R
authors.lastname: Hennekam
authors.affiliation: Genetics and Cytogenetics Department, GRC-upmc,Pitié-Salpétrière CHU, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Heron
authors.affiliation: Department of Genetics, CHUV, Vaud, Switzerland.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Jacquemont
authors.affiliation: Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Kannu
authors.affiliation: Medical Genetics, Massachussets General Hospital for Children, Boston, MA, USA.
authors.forename: Angela E
authors.initials: AE
authors.lastname: Lin
authors.affiliation: Department of Clinical Genetics, University Hospital, Lille, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Manouvrier-Hanu
authors.affiliation: Clinical Genetics, St George's Healthcare NHS Trust, London, UK.
authors.forename: Sahar
authors.initials: S
authors.lastname: Mansour
authors.affiliation: Genetic and Medical Embryology Unit, Centre de Référence des Surdités Génétiques, Armand-Trousseau CHU, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marlin
authors.affiliation: West of Scotland Regional Genetics Service, Glasgow, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: McGowan
authors.affiliation: Manchester Academic Health Science Centre, Genetic Medicine-University of Manchester, St Mary's Hospital, Manchester, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Murphy
authors.affiliation: Institute of Human Genetics, Meir Medical Center, Kfar Saba, Israel.
authors.forename: Annick
authors.initials: A
authors.lastname: Raas-Rothschild
authors.affiliation: INSERM U781 Unit, Department of Genetics, Institut Imagine, Paris Descartes University-Sorbonne Paris Cité, Necker Enfants-Malades Hospital, Paris, France.
authors.forename: Marlène
authors.initials: M
authors.lastname: Rio
authors.affiliation: Department of Clinical Genetics, Ersamus MC, Rotterdam, The Netherlands.
authors.forename: Marleen
authors.initials: M
authors.lastname: Simon
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Irene
authors.initials: I
authors.lastname: Stolte-Dijkstra
authors.affiliation: Department of Pathology, Massachussets General Hospital, Boston, MA, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Stone
authors.affiliation: Center for Human Genetics, Cliniques Universitaires St-Luc, Brussels, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Sznajer
authors.affiliation: West of Scotland Regional Genetics Service, Glasgow, UK.
authors.forename: John
authors.initials: J
authors.lastname: Tolmie
authors.affiliation: Department of Clinical Genetics, Saint-Etienne CHU, Saint-Etienne, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Touraine
authors.affiliation: Department of Medical Genetics, University and University Hospital Antwerp, Edegem, Belgium.
authors.forename: Jenneke
authors.initials: J
authors.lastname: van den Ende
authors.affiliation: Department of Medical Genetics, University and University Hospital Antwerp, Edegem, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Van der Aa
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Ton
authors.initials: T
authors.lastname: van Essen
authors.affiliation: Department of Genetics, INSERM U676, AP-HP, Robert Debré Hospital, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
authors.affiliation: INSERM U781 Unit, Department of Genetics, Institut Imagine, Paris Descartes University-Sorbonne Paris Cité, Necker Enfants-Malades Hospital, Paris, France.
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.affiliation: INSERM U781 Unit, Department of Genetics, Institut Imagine, Paris Descartes University-Sorbonne Paris Cité, Necker Enfants-Malades Hospital, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D003456:Cryptorchidism / Q000235:genetics*; D019066:Facies; D005260:Female; D005500:Follow-Up Studies; D006130:Growth Disorders / Q000235:genetics*; D006228:Hand Deformities, Congenital / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D006984:Hypertrophy / Q000235:genetics*; D008607:Intellectual Disability / Q000235:genetics*; D007592:Joint Diseases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017422:Sequence Analysis, DNA; D051901:Smad4 Protein / Q000235:genetics*; D055815:Young Adult
chemical_list: C497796:SMAD4 protein, human; D051901:Smad4 Protein