ESPE Abstracts (2014) 82 P-D-1-1-145

Genotype-Phenotype Relationship in Patients with SHOX Region Rearrangements Detected by MLPA in the French Population

Julie Augera, Amandine Baptisteb, Gaëlle Thierryc, Jean-Marc Costad, Mélanie Amouyale, Marie-Laure Kottlerf, Renaud Touraineg, Marine Lebrung, Bruno Leheupa, Sébastien Schmittc, Valérie Cormier-Daireh, Nicolas De Rouxe, Caroline Elieb & Jean-Paul Bonnefonth


aService de Médecine Infantile et Génétique Clinique, Centre Hospitalier Universitaire de Nancy, et U954, Université de Lorraine, Vandoeuvre les Nancy, France; bUnité de Recherche clinique/Centre d’Investigation Clinique Paris Centre, Groupe Hospitalier Universitaire Necker-Enfants Malades, Paris, France; cCHU Nantes, Service de Génétique Médicale, Nantes, France; dUnité de Génétique Moléculaire, Laboratoire Cerba, Saint-Ouen l’Aumône, France; eLaboratoire de Biochimie–Hormonologie, Hopital Robert Debré, Université Paris Diderot, Paris, France; fService de Génétique, CHU de Caen, INSERM U1075, Caen, France; gService de Génétique, CHU de Saint-Etienne, Saint-Etienne, France; hUniversité Paris Descartes, IHU IMAGINE et Sce de Génétique Médicale, GH Necker Enfants Malades, Paris, France


Background: SHOX and enhancer regions on PAR1 disorders have variable phenotypic consequences such as idiopathic short stature (ISS) and Leri-Weill Dyschondrosteosis (LWD).

Objective and hypotheses: The aim of this observational multicentric study was to describe phenotypes and genotypes of a large population with mutation on SHOX and adjacent regions and to identify a possible phenotype–genotype correlation.

Method: Phenotypes and genotypes were collected between 2009 and 2013 in seven French laboratories using multiplex ligation-dependant PCR analysis (MLPA) routinely for diagnostic. Sequencing was performed to detect point mutation when MLPA was normal and the clinical description in favor of LWD.

Results: 205 index cases (IC; 74% females) and 100 related cases (RC; 26% females) where diagnosed with SHOX anomalies, 91.3% with LWD. Median age at diagnosis was 11.7 years in IC (Q1: 9.0; Q3: 15.9) and 38 years in RC (Q1: 14.1; Q3: 43.8). Median height SDS was −2.2 in IC (Q1: −2.9; Q3: −1.7) and −1.8 in RC (Q1: 2.4; Q3: −0.8). Girls were diagnosed earlier than boys (12.7 vs 15.2 years, P=0.04), were shorter (−2.4 S.D. vs −2.0 S.D., P=0.007) and presented more frequently with Madelung deformity (78.2 vs 21.7%, P=0.0004). Genetic anomalies were: 40.3% SHOX+/−PAR1 deletions, 33.7% PAR1 deletions, 5.9% PAR1 duplications, 2.0% SHOX+PAR1 duplications, and 18% point mutations. In girls, deletions were more frequently associated with Madelung deformity, short forearm and radiologic anomalies than duplications (P=0.02, P=0.006, and P=0.008 respectively).

Conclusion: Our study is biological relevant since MLPA allows an easy access of patients to SHOX anomalies diagnosis before sequencing and allows identification of duplications and clinical relevant since we show that phenotypes in boys are less severe than in girls.