Analysis of short stature homeobox-containing gene (SHOX) and auxological phenotype in dyschondrosteosis and isolated Madelung deformity

Dyschondrosteosis (DCO; also called Leri-Weill syndrome) is a skeletal dysp lasia characterised by disproportionate short stature because of mesomelic shortening of the limbs. Madelung deformity is a feature of DCO that is dis tinctive, variable in expressivity and frequently observed. Mutations of th e SHOX (short stature homeobox-containing) gene have been previously descri bed as causative in DCO. Isolated Madelung deformity (IMD) without the clin ical characteristics of DCO has also been described in sporadic and a few f amilial cases but the genetic defect underlying IMD is unknown. In this stu dy, we have examined 28 probands with DCO and seven probands with IMD for m utations in the SHOX gene by using polymorphic CA-repeat analysis, fluoresc ence in situ hybridisation (FISH), Southern blotting, direct sequencing and fibre-FISH analyses. This was combined with auxological examination of the probands and their family members. Evaluation of the auxological data show ed a wide intra- and interfamilial phenotype variability in DCO. Out of 28 DCO probands, 22 (79%) were shown to have mutations in the SHOX gene. Sixte en unrelated DCO families had SHOX gene deletions. Four novel DCO-associate d mutations were found in different families. In two additional DCO familie s, the previously described nonsense mutation (Arg195Stop) was detected. We conclude that mutations in the SHOX gene are the major factor in the patho genesis of DCO. In a female proband with severe IMD and her unaffected sist er, we detected an intrachromosomal duplication of the SHOX gene.