title: SHOX mutations in idiopathic short stature and Leri-Weill dyschondrosteosis: frequency and phenotypic variability.
abstract: OBJECTIVE
  The frequency of SHOX mutations in children with idiopathic short stature (ISS) has been found to be variable. We analysed the SHOX gene in children with ISS and Leri-Weill dyschondrosteosis (LWD) and evaluated the phenotypic variability in patients harbouring SHOX mutations.
  
  
  METHODS
  Sixty-three ISS, nine LWD children and 21 affected relatives.
  
  
  METHODS
  SHOX gene deletion was evaluated by fluorescence in situ hybridization (FISH), Southern blotting and segregation study of polymorphic marker. Point mutations were assessed by direct DNA sequencing.
  
  
  RESULTS
  None of the ISS patients presented SHOX deletions, but two (3.2%) presented heterozygous point mutations, including the novel R147H mutation. However, when ISS patients were selected by sitting height : height ratio (SH/H) for age > 2 SD, mutation frequency detection increased to 22%. Eight (89%) LWD patients had SHOX deletions, but none had point mutations. Analysis of the other relatives in the families carrying SHOX mutations identified 14 children and 17 adult patients. A broad phenotypic variability was observed in all families regarding short stature severity and Madelung deformities. However, the presence of disproportional height, assessed by SH/H, was observed in all children and 82% of adult patients, being the most common feature in our patients with SHOX mutations.
  
  
  CONCLUSIONS
  Patients with SHOX mutations present a broad phenotypic variability. SHOX mutations are very frequent in LWD (89%), in opposition to ISS (3.2%) in our cohort. The use of SH/H SDS as a selection criterion increases the frequency of SHOX mutation detection to 22% and should be used for selecting ISS children to undergo SHOX mutation molecular studies.
authors.affiliation: Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42, Disciplina de Endocrinologia, Hospital das Clinicas, SP, Brazil. alexj@usp.br
authors.forename: Alexander A L
authors.initials: AA
authors.lastname: Jorge
authors.forename: Silvia C
authors.initials: SC
authors.lastname: Souza
authors.forename: Miriam Y
authors.initials: MY
authors.lastname: Nishi
authors.forename: Ana E
authors.initials: AE
authors.lastname: Billerbeck
authors.forename: Débora C C
authors.initials: DC
authors.lastname: Libório
authors.forename: Chong A
authors.initials: CA
authors.lastname: Kim
authors.forename: Ivo J P
authors.initials: IJ
authors.lastname: Arnhold
authors.forename: Berenice B
authors.initials: BB
authors.lastname: Mendonca
mesh_terms: D000328:Adult; D015139:Blotting, Southern; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D002648:Child; D016384:Consensus Sequence; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D005801:Genes, Homeobox; D006130:Growth Disorders / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D010009:Osteochondrodysplasias / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D000074122:Short Stature Homeobox Protein
chemical_list: D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein