SHOX mutations in idiopathic short stature and Leri-Weill dyschondrosteosis: frequency and phenotypic variability

Summary 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. Pati...

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Published in:Clinical endocrinology (Oxford) 2007-01, Vol.66 (1), p.130-135
Main Authors: Jorge, Alexander A. L., Souza, Silvia C., Nishi, Miriam Y., Billerbeck, Ana E., Libório, Débora C. C., Kim, Chong A., Arnhold, Ivo J. P., Mendonca, Berenice B.
Format: Article
Language:English
Subjects:
Adult
Biological and medical sciences
Blotting, Southern
Case-Control Studies
Chi-Square Distribution
Child
Consensus Sequence
DNA Mutational Analysis
Endocrinopathies
Female
Fundamental and applied biological sciences. Psychology
Gene Frequency
Genes, Homeobox
Growth Disorders - genetics
Homeodomain Proteins - genetics
Humans
In Situ Hybridization, Fluorescence
Male
Medical sciences
Osteochondrodysplasias - genetics
Pedigree
Phenotype
Point Mutation
Short Stature Homeobox Protein
Vertebrates: endocrinology
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Summary:Summary 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. Patients  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. Conclusion  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.
ISSN:0300-0664
1365-2265
DOI:10.1111/j.1365-2265.2006.02698.x