Myhre and LAPS syndromes : clinical and molecular review of 32 patients. C. Michot1, C. Le Goff1, A. Afenjar2, A. S. Brooks3, P. M. Campeau4, A. Destree5, M. Di Rocco6, D. Donnai7, R. Hennekam8, D. Heron9, S. Jacquemont10, P. Kannu11, A. E. Lin12, S. Manouvrier-Hanu13, S. Mansour14, S. Marlin15, R. McGowan16, H. Murphy7, A. Raas-Rothschild17, M. Rio1, M. Simon3, I. Stolte-Dijkstra18, J. R. Stone19, Y. Sznajer20, J. Tolmie21, J. van den Ende22, N. Van der Aa22, T. van Essen18, A. Verloes23, V. Cormier-Daire1 1) INSERM U781, Department of Genetics, Paris Descartes University - Sorbonne Paris Cité, Institut IMAGINE, Necker Enfants Malades Hospital, Paris, France; 2) Department of Neuropediatry, Centre de Référence Maladies Rares "anomalies du développement et syndromes malformatifs- Ile de France", Armand-Trousseau CHU, Paris, France; 3) Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands; 4) Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, USA; 5) Department of Human Genetics, Institute of Pathology and Genetics, Gosselies, Belgium; 6) Unit of Rare Diseases, Department of Pediatrics, Gaslini Institute, Genoa, Italy; 7) Genetic Medicine University of Manchester, Manchester Academic Health Science Centre, St Marys Hospital, Manchester, M13 9WL, UK; 8) Department of Pediatrics H7-236, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; 9) Genetics and cytogenetics Departement, GRC-upmc, Pitié-Salpétrière CHU, Paris, France; 10) Department of Genetics, CHUV, CH-1011 Lausanne, Vaud, Switzerland; 11) Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Canada; 12) Medical Genetics, Massachussets General Hospital for Children, Boston, Massachusetts; 13) Department of Clinical Genetics, University Hospital, Lille, France; 14) Clinical Genetics, St George's Healthcare NHS Trust, Tooting, London SW17 0QT, UK; 15) Genetic and Medical Embryology unit, Centre de Référence des Surdités Génétiques, Armand-Trousseau CHU, Paris, France; 16) North Scotland Regional Genetics Service, Clinical Genetics Centre, Ashgrove House, Foresterhill, Aberdeen, UK; 17) Institute of Human Genetics, Meir Medical Center, Kfar Saba, Israel; 18) Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 19) Department of Pathology, Massachussets General Hospital for Children, Boston, Massachusetts; 20) Center for Human Genetics, Cliniques Universitaires St-Luc - UCL B 1200 Brussels, Belgium; 21) Ferguson-Smith Department of Clinical Genetics, Yorkhill Hospital, Glasgow, UK; 22) Department of Medical Genetics, University and University Hospital Antwerp, Edegem, Belgium; 23) Clinical Genetics Functionnal Unit, Department of Genetics, Robert Debré CHU,Paris, France.

   Myhre syndrome is characterized by short stature, brachydactyly, dysmorphic facial features, pseudomuscular hypertrophy, joint limitation and hearing loss. We previously identified SMAD4 mutations as the cause of Myhre syndrome. More recently, 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 better define the clinical spectrum of SMAD4 mutations. 17 females and 15 males, ranging in age from 8 to 48 years, were included in the study. Among them, 30 cases were diagnosed with Myhre syndrome and 2 with LAPS. The entire SMAD4 coding sequence was analyzed by Sanger sequencing. Details of clinical and radiological features were collected from a questionnaire completed by each referring physician. All patients displayed a typical facial gestalt, thickened skin, joint limitation and pseudomuscular hypertrophy. Growth retardation was common (22/32 - 68.7%) and was variable in severity (-5.5 to -2 SD). Intellectual deficiency of mild to moderate degree was observed in 28/32 (87.5%) and associated with behavioral troubles in 18 cases (56.2%). Significant health concerns included obesity (n=11), arterial hypertension (n=9), bronchopulmonary insufficiency (n=7), laryngotracheal stenosis (n=5) and pericarditis (n=3). Early death occurred in 4 patients (at 9, 19, 22 and 28 years). 29 patients (90%) had a de novo heterozygous SMAD4 mutation, including both patients with LAPS. In 27 cases, mutation affected Ile 500 and in 2 cases Arg 496. The three patients without SMAD4 mutations had typical findings of Myhre syndrome. We conclude that Myhre and LAPS syndromes are a unique clinically homogenous condition with life threatening complications in the course of the disease, supporting specific management recommendations. Our identification of SMAD4 mutations in 29/32 cases confirms that SMAD4 is the major gene responsible for Myhre syndrome. The finding of the Ile 500 change in SMAD4 in the majority of cases and of a significant increase in paternal age may suggest a mechanism of protein-driven selfish selection in sperm.

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