The Role of SHOX Gene in Short Stature of Turner Syndrome and Its Variant
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SHOX gene is located on the edge of each short/p arm sex chromosome called the pseudoautosomal region-1 (PARI) plays as a dindomental role on controling chondrocyte differentation and apoptosis in the growth plate. Longitudinal growth is determined by environmental, hormonal and genetic factors. Short stature is defiened as a stature is defined as a standing height below the third percentile according to Tunner et al. Short stature affects approximately 2% of Children. Tuner syndrome is the most common genetic disorder in female characterized by the absence od all or post of a normal second X chromasome, effecting 1:2500 live-born female babies Short stature and avarian failure is the main clinical feature. The objective of this study is to elucidate the implication of SHOX gene in dhort of Turner Syndrome and its variant. Puposive sampling was performed to recruit female with short stature after informed consent ogreement. Female with growth teratement history and chronic diseases was exluded from this study. Cytogenetics testting was done for all sample by G-banding method, in routine karyotyping. We report 9 female with short stature which cytogenetically and clinically diagnosed as Turner Syndrome Four cases is classic Turner syndromr with standing height is below third percentile, there cases are 45,X/46,X, i(Xq) with standing height is below third percentile, one case is 46,XX45,X (80%) with standing height is below third percentile, and the rest is 46,XX/45,X(20%) with. SHOX gene haplonsufficiency is strongly indicated the cause of shoet stature in Turner SyndromeKeywords:
Pseudoautosomal region
Idiopathic short stature
Tall Stature
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Objective: SHOX gene mutations constitute one of the genetic causes of short stature.The clinical phenotype includes variable degrees of growth impairment, such as Langer mesomelic dysplasia (LMD), Léri-Weill dyschondrosteosis (LWD) or idiopathic short stature (ISS).The aim of this study was to describe the clinical features and molecular results of SHOX deficiency in a group of Turkish patients who had skeletal findings with and without short stature.Methods: Forty-six patients with ISS, disproportionate short stature or skeletal findings without short stature from 35 different families were included.SHOX gene analysis was performed using Sanger sequencing and multiplex ligation-dependent probe amplification analysis.Results: Three different point mutations (two nonsense, one frameshift) and one whole SHOX gene deletion were detected in 15 patients from four different families.While 4/15 patients had LMD, the remaining patients had clinical features compatible with LWD.Madelung's deformity, cubitus valgus, muscular hypertrophy and short forearm were the most common phenotypic features, as well as short stature.Additionally, hearing loss was detected in two patients with LMD. Conclusion:This study has presented the clinical spectrum and molecular findings of 15 patients with SHOX gene mutations or deletions.SHOX deficiency should be especially considered in patients who have disproportionate short stature or forearm anomalies with or without short stature.Although most of the patients had partial or whole gene deletions, SHOX gene sequencing should be performed in suspected cases.Furthermore, conductive hearing loss may rarely accompany these clinical manifestations.
Idiopathic short stature
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The term idiopathic short stature (ISS) refers to patients who are short due to various unknown reasons. Although it is clear that multiple factors contribute to final height, genetic factors play a crucial role. Mutations of a human homeobox gene, short stature homeobox-containing (SHOX) gene, have been shown to be associated with the short stature phenotype in patients with Turner syndrome, most patients with Leri-Weill dyschondrosteosis and some cases of ISS. The prevalence of SHOX anomalies in subjects previously recognized as having ISS has been estimated at 2.4% in a large series of ISS individuals. This review focuses on the functional properties of the SHOX gene and its linkage to ISS.
Idiopathic short stature
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Haploinsufficiency
Pseudoautosomal region
Idiopathic short stature
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Deficiency of the short stature homeobox-containing (SHOX) gene is a frequent cause of short stature in children (2–15%). Here, we report 7 siblings with SHOX deficiency due to a point mutation in the SHOX gene. Index case was a 3-year-old male who presented for evaluation of short stature. His past medical history and birth history were unremarkable. Family history was notable for multiple individuals with short stature. Physical exam revealed short stature, with height standard deviation score (SDS) of −2.98, as well as arm span 3 cm less than his height. His laboratory workup was noncontributory for common etiologies of short stature. Due to significant familial short stature and shortened arm span, SHOX gene analysis was performed and revealed patient is heterozygous for a novel SHOX gene mutation at nucleotide position c.582. This mutation is predicted to cause termination of the SHOX protein at codon 194, effectively causing haploinsufficiency. Six out of nine other siblings were later found to also be heterozygous for the same mutation. Growth hormone was initiated in all seven siblings upon diagnosis and they have demonstrated improved height SDS.
Haploinsufficiency
Arm span
Idiopathic short stature
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Idiopathic short stature
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DLX5
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SHOX 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.Targeted 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.In 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.
Idiopathic short stature
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We report on an 11-yr-old boy with short stature and Turner skeletal features. Chromosome analysis revealed a 46,X,r(Y)(p11.3q11.2) karyotype, and FISH analysis showed loss of the Short stature homeobox containing gene (SHOX) from the ring Y chromosome. The results are consistent with the association of SHOX haploinsufficiency with short stature and Turner skeletal features, and suggest the importance of SHOX analysis in boys with Turner-like skeletal phenotype.
Haploinsufficiency
Idiopathic short stature
Ring chromosome
DLX5
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The short stature homeobox-containing(SHOX) gene,located in the short-arm pseudoautosomal region (PAR1) of the sex chromosomes,is one of the recently discovered genes,which is related to short stature.Its encoded protein,as a transcription activator,plays an important role in the regulation of growth.It has now been confirmed that the human SHOX gene mutation can cause Leri-Weill syndrome,Turner syndrome,idiopathic short stature growth and its related characteristic skeletal deformities.This review makes a summary about SHOX gene defects,its clinical phenotype and treatment.
Pseudoautosomal region
Idiopathic short stature
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