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 phenotypegenotype 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.
18 Sep 2014 - 20 Sep 2014