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High incidence of SHOX anomalies in individuals with short stature.

ABSTRACT: OBJECTIVE: To study the SHOX gene and the PAR1 region in individuals with short stature. METHODS: The study involved 56 cases of dyschondrosteosis and 84 cases of idiopathic short stature (ISS). The study was designed to determine the following: the prevalence of SHOX anomalies in ISS; the frequency of Madelung deformity in individuals with SHOX anomalies; and the value of a family history of short stature in deciding whether to test for the SHOX gene. RESULTS: 54 SHOX anomalies were observed, including 42 (68%) in the dyschondrosteosis group and 12 (15%) in the ISS group. The high frequency of SHOX anomalies in the ISS group can be explained by the large proportion of boys in this group, reflecting the difficulty in diagnosing dyschondrosteosis in young boys. Clinical evidence of Madelung deformity in six parents of ISS individuals emphasised the importance of family evaluation. Among the 54 SHOX anomalies, 33 PAR1 deletions were identified encompassing the SHOX gene (62%), one partial intragenic deletion (2%), nine deletions located downstream of the SHOX gene (16%), and 11 point mutations (20%). CONCLUSIONS: These data emphasise the value of using microsatellite markers located within and downstream of the SHOX gene.

SUBMITTER: Huber C

PROVIDER: S-EPMC2564573 | biostudies-literature | 2006 Sep

REPOSITORIES: biostudies-literature

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High incidence of SHOX anomalies in individuals with short stature.

Huber C C Rosilio M M Munnich A A Cormier-Daire V V

Journal of medical genetics 20060405 9

<h4>Objective</h4>To study the SHOX gene and the PAR1 region in individuals with short stature.<h4>Methods</h4>The study involved 56 cases of dyschondrosteosis and 84 cases of idiopathic short stature (ISS). The study was designed to determine the following: the prevalence of SHOX anomalies in ISS; the frequency of Madelung deformity in individuals with SHOX anomalies; and the value of a family history of short stature in deciding whether to test for the SHOX gene.<h4>Results</h4>54 SHOX anomali ...[more]

PMID: 16597678

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Project description:BackgroundSHOX mutations have previously been described as causes of Léri-Weill dyschondrosteosis (LWD), Langer mesomelic dysplasia (LMD), and idiopathic short stature. The loss of X chromosome-Turner syndrome or mosaic 45,X/46,XX or 46,XY-also leads to the heterozygous loss of SHOX in patients with short stature only or with features similar to LWD. The aim of this study was to assess the efficacy of the targeted screening for SHOX variants, which involved different methods in the laboratory analysis of short stature. We determined the significance and positive predictive value of short stature for the detection of SHOX variants.MethodsTargeted screening for variants in SHOX involving MLPA, sequencing, karyotyping and FISH was performed in the short stature cohort (N = 174) and control cohort (N = 91). The significance of short stature and particular characteristics for the detection of SHOX variants was determined by Fisher's exact test, and the probability of SHOX mutation occurrence was calculated using a forward/stepwise logistic regression model.ResultsIn total, 27 and 15 variants influencing SHOX were detected in the short stature and control cohorts, respectively (p > 0.01). Sex chromosome aberrations and pathogenic CNV resulting in diagnosis were detected in eight (4.6%) and five (2.9%) patients of the short stature group and three (3.3%) and one (1.1%) individuals of the control group. VUS variants were discovered in 14 (8.0%) and 11 (12.1%) individuals of the short stature and control groups, respectively. MLPA demonstrated the detection rate of 13.22%, and it can be used as a frontline method for detection of aberrations involving SHOX. However, only mosaicism of monosomy X with a higher frequency of monosomic cells could be reliably discovered by this method. Karyotyping and FISH can compensate for this limitation; their detection rates in short stature group were 3.55% and 13.46% (N = 52), respectively. FISH proved to be more effective than karyotyping in the study as it could reveal cryptic mosaics in some cases where karyotyping initially failed to detect such a clone. We suggest adding FISH on different tissue than peripheral blood to verify sex-chromosome constitution, especially in cases with karyotypes: 45,X; mosaic 45,X/46,XX or 46,XY; 46,Xidic(Y) detected from blood; in children, where mosaic 45,X was detected prenatally but was not confirmed from peripheral blood. The correlation of short stature with the occurrence of SHOX mutations was insignificant and short stature demonstrates a low positive predictive value-15.5% as unique indicator for SHOX mutations. The typical skeletal signs of LWD, including Madelung deformity and disproportionate growth, positively correlate with the findings of pathogenic SHOX variants (p < 0.01) by Fisher's exact test but not with the findings of VUS variants in SHOX which are more prevalent in the individuals with idiopathic short stature or in the individuals with normal height.

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High incidence of SHOX anomalies in individuals with short stature.

Publications

High incidence of SHOX anomalies in individuals with short stature.

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