title: 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.
authors.affiliation: Paediatric Endocrinology Unit, Karolinska Hospital, Stockholm, Sweden. Giedre.Grigelioniene@kbh.ki.se
authors.forename: G
authors.initials: G
authors.lastname: Grigelioniene
authors.forename: J
authors.initials: J
authors.lastname: Schoumans
authors.forename: L
authors.initials: L
authors.lastname: Neumeyer
authors.forename: A
authors.initials: A
authors.lastname: Ivarsson
authors.forename: O
authors.initials: O
authors.lastname: Eklöf
authors.forename: O
authors.initials: O
authors.lastname: Enkvist
authors.forename: P
authors.initials: P
authors.lastname: Tordai
authors.forename: I
authors.initials: I
authors.lastname: Fosdal
authors.forename: A G
authors.initials: AG
authors.lastname: Myhre
authors.forename: O
authors.initials: O
authors.lastname: Westphal
authors.forename: N O
authors.initials: NO
authors.lastname: Nilsson
authors.forename: M
authors.initials: M
authors.lastname: Elfving
authors.forename: I
authors.initials: I
authors.lastname: Ellis
authors.forename: B M
authors.initials: BM
authors.lastname: Anderlid
authors.forename: I
authors.initials: I
authors.lastname: Fransson
authors.forename: I
authors.initials: I
authors.lastname: Tapia-Paez
authors.forename: M
authors.initials: M
authors.lastname: Nordenskjöld
authors.forename: L
authors.initials: L
authors.lastname: Hagenäs
authors.forename: J P
authors.initials: JP
authors.lastname: Dumanski
mesh_terms: D015139:Blotting, Southern; D001827:Body Height / Q000235:genetics*; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D010009:Osteochondrodysplasias / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D000074122:Short Stature Homeobox Protein; D013577:Syndrome
chemical_list: D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein