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

Abstract

Dyschondrosteosis (DCO; also called Léri-Weill syndrome) is a skeletal dysplasia characterised by disproportionate short stature because of mesomelic shortening of the limbs. Madelung deformity is a feature of DCO that is distinctive, variable in expressivity and frequently observed. Mutations of the SHOX (short stature homeobox-containing) gene have been previously described as causative in DCO. Isolated Madelung deformity (IMD) without the clinical characteristics of DCO has also been described in sporadic and a few familial cases but the genetic defect underlying IMD is unknown. In this study, we have examined 28 probands with DCO and seven probands with IMD for mutations in the SHOX gene by using polymorphic CA-repeat analysis, fluorescence 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 showed 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. Sixteen unrelated DCO families had SHOX gene deletions. Four novel DCO-associated mutations were found in different families. In two additional DCO families, the previously described nonsense mutation (Arg195Stop) was detected. We conclude that mutations in the SHOX gene are the major factor in the pathogenesis of DCO. In a female proband with severe IMD and her unaffected sister, we detected an intrachromosomal duplication of the SHOX gene.

PAR1 deletions downstream ofSHOX are the most frequent defect in a Spanish cohort of Léri-Weill dyschondrosteosis (LWD) probands

“…In previous reports, SHOX deletions and mutations were identified in ~40-80% of LWD cases (Falcinelli et al, 2002;Flanagan et al, 2002;Cormier-Daire et al, 2001;Grigelioniene et al, 2001;Schneider et al, 2005). Since previous studies did not include the screening of PAR1 deletions downstream of SHOX, we set out to determine the mutation rate and the distribution of mutations in 26 Spanish LWD probands including the screening of this new class PAR1 deletions downstream of SHOX.…”

Clinical and Radiological Characteristics of 22 Children with SHOX Anomalies and Familial Short Stature Suggestive of Léri-Weill Dyschondrosteosis

“…Short Stature HomeoboX (SHOX) gene anomalies are found in 60–100% of dyschondrosteosis cases [2,3,4,5,6,7]. The SHOX gene is located on the distal part of the pseudoautosomic region (PAR), common to X and Y chromosomes.…”

Short stature and dysmorphology associated with defects in the SHOX gene

“…In the majority of pertinent studies, SHOX gene deletions or mutations have been detected in about 2% of children with ISS and this prevalence would imply a population prevalence of at least 1 in 2000 children. Clas- Taken together, the data of some recent studies 22,25,31 indicate that the growth deficit caused by SHOX defects in patients with Léri-Weill dyschondrosteosis is approximately 2SDS, which is not as severe as that encountered in other osteodysplasias or in Turner syndrome. This observation suggests that there may be other genessuch as the lymphogenic gene(s) mapped to a ~9 Mb region between DMD and MAOA loci on Xp chromosomethat are responsible for the impaired development of soft tissue, visceral and skeletal abnormalities and shortness.…”

“…Two identical point mutations, c.674C>T 1,9,15,22,25,26 and c.599G>C [RR Project HD, GDFN HD, www.shox.uni-hd.de], have been described in patients with either ISS or LWD. This finding suggests that SHOX haploinsufficiency can lead to different clinical phenotypes.…”