Although the ZED’s location and specific activity make it a promising candidate as a discrete SHOX limb enhancer, several reports of copy number variations (CNVs) in LWD and ISS patients implicate other genomic regions in the cis-regulation of SHOX. Three ISS families/patients have been reported with non-coding deletions upstream of SHOX37,50 and another study reported a homozygous >500 kb downstream deletion in members of a consanguineous family with LWD51. This evidence concerns the gene SHOX and Leri-Weill dyschondrosteosis.