ESPE Abstracts

Background: SHOX encodes a transcription factor implicated in skeletal development. Approximately 70% and ~2.5% of Leri-Weill dyschondrosteosis (LWD) and idiopathic short stature (ISS) patients, respectively, have a defect in SHOX or its regulatory regions.

Objective and hypotheses: i) To perform SHOX mutation screening in a cohort of 585 patients referred with a clinical suspicion of LWD or ISS. ii) To determine which is the SHOX mutation spectrum in an unbiased cohort.

Method: A total of 585 patients were referred for SHOX analysis during the last 16 months. Mutation screening of SHOX and its regulatory regions was performed by MLPA, HRM and Sanger sequencing. In silico pathogenicity analysis was undertaken using Alamut V2.6. Family analysis was undertaken when possible.

Results: Molecular defects in SHOX or its enhancers were identified in 75 probands (14%), 65 referred for LWD and 10 for ISS. All mutations were observed in heterozygosity except for one LWD individual who was homozygous for the common 47.5 kb PAR1 deletion. The mutation spectrum encompassed: 18 (24%) SHOX encompassing deletions, 27 (36%) PAR1 enhancer deletions (18 were the common ~47.5 kb deletion), 25 (33%) SHOX missense or splicing mutations (9 were p.A170P), 1 (1%) SHOX duplication and 4 (6%) enhancer duplications. Five of the mutations are novel: four missense and one exon 6a deletion.

Conclusion: SHOX mutations were identified in 14% of an unselected cohort of LWD and ISS referrals. SHOX mutations accounted for 59% of the mutations whilst the remaining 41% were PAR1 deletions encompassing enhancer sequences. The frequent ~47.5 kb deletion is the most common mutation (24%) in our cohort. Interesting cases include: i) The identification of the first deletion of a unique SHOX exon; and, ii) The identification of a homozygous SHOX downstream enhancer deletion in a patient with LWD, showing the variable expressivity of some SHOX alterations.

Funding: This work was supported by a MINECO grant (SAF2012-30871) and the EndoScreen project (IdiPaz and UAM).