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PubMed1999

SHOX: pseudoautosomal homeobox containing gene for short stature and dyschondrosteosis.

A growth gene has been postulated, on the basis of genotype-phenotype correlations in patients with sex chromosome aberrations, to exist on the short-arm pseudoautosomal region (PAR1) of the sex chromosomes. Recently, Rao et al. have identified a novel homeobox containing gene, SHOX (short stature homeobox containing gene), from the distal part of PAR1, by means of a positional cloning method. SHOX is most strongly expressed in bone marrow fibroblasts, implying that SHOX plays a positive role in bone growth and development. In addition, SHOX is expressed from an inactive X chromosome, as well as an active X and a normal Y chromosome, suggesting that SHOX escapes X-inactivation and exerts the dosage effect in sex chromosome aberrations. Mutational analysis of SHOX was done in about 400 patients with idiopathic short stature, identifying three types of heterozygous nonsense and missense mutations. Furthermore, fluorescence in situ hybridization analysis of SHOX was performed in six Japanese families with dyschondrosteosis, demonstrating microdeletions involving SHOX in all the patients. The results indicate that SHOX is responsible for short stature and dyschondrosteosis.

Chromosome Mapping↗
PubMed2002

Deletions of the homeobox gene SHOX (short stature homeobox) are an important cause of growth failure in children with short stature.

Short stature, with an incidence of 3 in 100, is a fairly frequent disorder in children. Idiopathic short stature refers to patients who are short due to various unknown reasons. Mutations of a human homeobox gene, SHOX (short stature homeobox), have recently been shown to be associated with the short stature phenotype in patients with Turner syndrome and most patients with Léri-Weill dyschondrosteosis. This study addresses the question of the incidence and type of SHOX mutations in patients with short stature. We analyzed the SHOX gene for intragenic mutations by single strand conformation polymorphism, followed by sequencing, in 750 patients and for complete gene deletions by fluorescence in situ hybridization in 150 patients (total, 900 patients). This is the largest group of patients with short stature studied to date for SHOX mutations. All patients had a normal karyotype, and their height for chronological age were below the third percentile or minus 2 SD of national height standards. All were without obvious skeletal features reminiscent of the Leri-Weill syndrome at the time of diagnosis. Silent, missense, and nonsense mutations and a small deletion in the coding region of SHOX were identified in 9 of the 750 patients analyzed for intragenic mutations. Complete gene deletions were detected in 3 of the 150 patients studied for gene deletions. At least 3 of the 9 intragenic mutations were judged to be functional based upon the genotype- phenotype relationship for the parents and normal control individuals. We conclude that SHOX mutations have been detected in 2.4% of children with short stature. The spectrum of SHOX mutations is biased, with the vast majority leading to complete gene deletions. The prevalence of short stature due to SHOX gene mutations among children with short stature appears to be similar to that of GH deficiency or Turner syndrome. Family studies of the children with SHOX mutations often reveal older family members with same mutation who exhibit mild skeletal features reminiscent of the Turner syndrome, such as high-arched palate, short neck, abnormal auricular development, cubitus valgus, genu valgum, short fourth metacarpals, and Madelung deformity.

Adolescent↗
PubMedDate not supplied

Short stature and dysmorphology associated with defects in the SHOX gene.

Since its discovery in 1997, knowledge about the SHOX gene ( Short stature HOmeoboX-containing gene) has rapidly advanced. Although originally described as causing idiopathic short stature, SHOX mutations are also responsible for growth retardation in Léri-Weill dyschondrosteosis, Langer mesomelic dysplasia and Turner syndrome. Furthermore, SHOX has a broad functional scope and leads to a variety of different morphological-skeletal stigmata associated with these syndromes. This article reviews clinical and molecular data associated SHOX gene defects. Functional ongoing studies are expected to improve our understanding of the SHOX gene as comprising part of a genetic process responsible for normal growth and bone development.

Arm Bones↗
PubMed2000

The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome.

Turner syndrome is characterized by short stature and is frequently associated with a variable spectrum of somatic features including ovarian failure, heart and renal abnormalities, micrognathia, cubitus valgus, high-arched palate, short metacarpals and Madelung deformity. Madelung deformity is also a key feature of Leri-Weill syndrome. Defects of the pseudoautosomal homeobox gene SHOX were previously shown to lead to short stature and Leri-Weill syndrome, and haploinsufficiency of SHOX was implicated to cause the short stature phenotype in Turner syndrome. Despite exhaustive searches, no direct murine orthologue of SHOX is evident. SHOX is, however, closely related to the SHOX2 homeobox gene on 3q, which has a murine counterpart, Og12x. We analysed SHOX and SHOX2 expression during human embryonic development, and referenced the expression patterns against those of Og12x. The SHOX expression pattern in the limb and first and second pharyngeal arches not only explains SHOX -related short stature phenotypes, but also for the first time provides evidence for the involvement of this gene in the development of additional Turner stigmata. This is strongly supported by the presence of Turner-characteristic dysmorphic skeletal features in patients with SHOX nonsense mutations.

Adult↗
PubMed2006

Expression of the short stature homeobox gene Shox is restricted by proximal and distal signals in chick limb buds and affects the length of skeletal elements.

SHOX is a homeobox-containing gene, highly conserved among species as diverse as fish, chicken and humans. SHOX gene mutations have been shown to cause idiopathic short stature and skeletal malformations frequently observed in human patients with Turner, Leri-Weill and Langer syndromes. We cloned the chicken orthologue of SHOX, studied its expression pattern and compared this with expression of the highly related Shox2. Shox is expressed in central regions of early chick limb buds and proximal two thirds of later limbs, whereas Shox2 is expressed more posteriorly in the proximal third of the limb bud. Shox expression is inhibited distally by signals from the apical ectodermal ridge, both Fgfs and Bmps, and proximally by retinoic acid signaling. We tested Shox functions by overexpression in embryos and micromass cultures. Shox-infected chick limbs had normal proximo-distal patterning but the length of skeletal elements was consistently increased. Primary chick limb bud cell cultures infected with Shox showed an initial increase in cartilage nodules but these did not enlarge. These results fit well with the proposed role of Shox in cartilage and bone differentiation and suggest chick embryos as a useful model to study further the role of Shox in limb development.

Amino Acid Sequence↗
PubMed2005

The phenotype of short stature homeobox gene (SHOX) deficiency in childhood: contrasting children with Leri-Weill dyschondrosteosis and Turner syndrome.

OBJECTIVE: To evaluate the growth disorder and phenotype in prepubertal children with Leri-Weill dyschondrosteosis (LWD), a dominantly inherited skeletal dysplasia, and to compare the findings from girls with Turner syndrome (TS). STUDY DESIGN: We studied the auxologic and phenotypic characteristics in 34 prepubertal LWD subjects (ages 1 to 10 years; 20 girls, 14 boys) with confirmed short stature homeobox-containing gene (SHOX) abnormalities. For comparative purposes, we evaluated similar physical and growth parameters in 76 girls with TS (ages 1 to 19 years) and 24 girls with LWD (ages 1 to 15 years) by using data collected from the postmarketing observational study, GeNeSIS. RESULTS: In the clinic sample LWD subjects, height standard deviation score ranged from -5.5 to +0.1 (-2.3 +/- 1.3, girls and -1.8 +/- 0.6, boys). Wrist changes related to Madelung deformity were present in 18 of 34 (53%) LWD subjects. In comparing the LWD and TS populations in the GeNeSIS sample, Madelung deformity, increased carrying angle, and scoliosis were more prevalent in the LWD population, whereas high arched palate was similarly prevalent in the two populations. CONCLUSIONS: Short stature is common in both LWD (girls and boys) and TS (girls). Clinical clues to the diagnosis of SHOX haploinsufficiency in childhood include short stature, short limbs, wrist changes, and tibial bowing.

Adolescent↗
PubMed2001

Short stature homeobox-containing gene deletion screening by fluorescence in situ hybridisation in patients with short stature.

UNLABELLED: The short stature homeobox-containing gene (SHOX) on the short arm of the X and Y chromosomes is an important determining factor of stature phenotype. Absence of the SHOX gene is a main cause for short stature in patients with Turner syndrome. Mutations of the SHOX gene can also be responsible for Léri-Weill syndrome (dyschondrosteosis). The aim of this study was to determine the frequency of SHOX deletions in short stature children and to delineate indications for SHOX deletion screening. Out of 50 probands, 35 had idiopathic short stature, 12 cases showed additional anomalies of the forearms (in particular Madelung deformity) and three patients were affected by a congenital heart defect. Chromosomal investigations with fluoresence in situ hybridisation did not reveal a SHOX deletion in any patient with idiopathic short stature. In five of the 12 patients (41.7%) with anomalies of the forearms, a SHOX deletion on one sex chromosome could be detected. No deletion was observed in the three cases with additional heart defects. CONCLUSION: The frequency of short stature homeobox-containing gene deletions in patients with idiopathic short stature appears to be very low and does not require a fluorescence in situ hybridisation analysis. Short stature in association with anomalies of the forearms such as Madelung deformity makes a deletion more probable and therefore screening for such deletions is recommended in these cases.

Adolescent↗
PubMed2000

Mutations in short stature homeobox containing gene (SHOX) in dyschondrosteosis but not in hypochondroplasia.

Dyschondrosteosis (DCO) and hypochondroplasia (HCH) are common skeletal dysplasias characterized by disproportionate short stature. The diagnosis of these conditions might be difficult to establish especially in early childhood. Point mutations and deletions of the short stature homeobox containing gene (SHOX) are detected in DCO and idiopathic short stature with some rhizomelic body disproportion, whereas mutations in the fibroblast growth factor receptor 3 (FGFR3) gene are found in 40-70% of HCH cases. In this study, we performed mutational analysis of the coding region of the SHOX gene in five DCO and 18 HCH patients, all of whom tested negative for the known HCH-associated FGFR3 mutations. The polymorphic CA-repeat analysis, direct sequencing and Southern blotting were used for detection of deletions and point mutations. The auxological and radiological phenotype of these patients was carefully determined. Three novel mutations in DCO patients were found: (1) a deletion of one base (de1272G) (according to GenBank accession nos. Y11536, Y11535), resulting in a premature stop codon at position 75 of the amino acid sequence; (2) the transversion C485G resulting in the substitution Leu132Val; and (3) the transversion G549T causing an Arg153Leu substitution. These substitutions segregate with the DCO phenotype and affect evolutionarily conserved homeodomain residues, based on a comparison of homeobox containing proteins in 13 species. Moreover, these changes were not found in 80 unrelated, unaffected individuals. This strongly suggests that these mutations are pathogenic. The phenotype of our patients with DCO and HCH varied from mild to severe shortness and body disproportion. These results further support clinical and genetic heterogeneity of dyschondrosteosis and hypochondroplasia.

Amino Acid Sequence↗
PubMed2003

Longitudinal auxological study in a female with SHOX (short stature homeobox containing gene) haploinsufficiency and normal ovarian function.

OBJECTIVE: To report on auxological data in the combination of SHOX (short stature homeobox containing gene) haploinsufficiency and normal ovarian function. DESIGN: Longitudinal auxological study in a 14 Year 9 Month old Japanese girl with Leri-Weill dyschondrosteosis accompanied by mesomelic short stature, who had a submicroscopic pseudoautosomal deletion involving SHOX, and pubertal development of an almost average tempo. METHODS: Auxological data were assessed by the age-matched standards for Japanese females. RESULTS: The standard deviation scores (SDSs) for height, leg length (LL), and arm span remained below the normal range from childhood and worsened during puberty, whereas those for sitting height (SH) remained within the normal range and stayed almost constant throughout the observation period. Consequently, the SDSs for SH/LL ratio remained above the normal range from childhood and deteriorated during puberty. The decreased pubertal height gain was caused by a diminished pubertal height spurt and abrupt growth cessation shortly after menarche. The SDSs for hand length and palm length remained within the normal range but decreased during puberty, and those for head circumference remained within the normal range and stayed almost constant throughout the observation period. CONCLUSIONS: The results suggest that, in individuals with SHOX haploinsufficiency and normal ovarian function, auxological abnormalities related to mesomelia are evident from childhood and worsen further during puberty because of the skeletal maturing effects of ovarian estrogens.

Adolescent↗
PubMed2002

Trisomy of the short stature homeobox-containing gene (SHOX), resulting from a duplication-deletion of the X chromosome.

The Turner syndrome (TS) is a complex disorder associated with almost invariant short stature and gonadal dysgenesis, as well as a variety of other major organ malformations. Recently, a homeobox-containing gene entitled short-stature homeobox-containing gene (SHOX), was isolated from a minimal short stature gene interval from the pseudoautosomal region of Xp (and Yp). Together with the demonstrable escape of SHOX from X-inactivation, this suggested SHOX to be a strong candidate gene for the short stature component of TS, and as SHOX haploinsufficiency appears to be the molecular basis of a mesomelic short statured skeletal dysplasia (Leri-Weill syndrome), this suggested that SHOX protein expression levels may confer a dosage effect on human stature. However, in this communication we report a normal statured female with gonadal dysgenesis, due to the inheritance of a recombinant duplication-deletion X-chromosome. The karyotype of the proband was 46,X,rec(X)dup(Xp)inv(X)(p11.22q21.2)mat and fluorescent in situ hybridization of her metaphases with a SHOX cosmid confirmed the proband to be trisomic for SHOX. This communication suggests the relationship between levels of SHOX expression and human stature to be more complex than envisaged previously. The presence of normal stature in our patient rather than tall stature is likely to represent the natural variation seen in patients with transcription factor disorders.

Adolescent↗
PubMed2006

Unique deletion in exon 5 of SHOX gene in a patient with idiopathic short stature.

BACKGROUND/AIM: It is known that haploinsufficiency for the SHOX gene (short-stature homeobox gene on the X chromosome) is responsible for short stature in Turner syndrome and Leri-Weill dyschondrogenesis, and it has been reported that it is responsible for upwards of 1 in 50 cases of idiopathic short stature. SHOX haploinsufficiency is also associated with various radiographic abnormalities, such as coarse trabecular pattern, short metacarpals/metatarsals with metaphyseal flaring, altered osseous alignment at the wrist, radial/tibial bowing, triangularization of the radial head, abnormal tuberosity of the humerus, and an abnormal femoral neck. Shortening and bowing of the radius and dorsal dislocation of the distal ulna characterize the Madelung deformity. These characteristic findings led us to do a study assessing the predictive value of certain radiographic features in association with genetic markers of idiopathic short stature. METHODS: Here we describe a case of a Hispanic male with idiopathic short stature and Madelung deformity with a novel mutation in the SHOX gene. RESULTS: Additional studies revealed a strong family history of short stature and the same SHOX mutation segregating from the mother. CONCLUSION: This case resulted in the description of a novel mutation in exon 5 (M202delA) and suggests the importance of screening for SHOX mutations in patients with idiopathic short stature with subtle radiographic abnormalities, including the components of the Madelung deformity in their bone age films.

Adolescent↗
PubMed2006

Evidence for involvement of the vitamin D receptor gene in idiopathic short stature via a genome-wide linkage study and subsequent association studies.

Stature is a highly heritable trait under both polygenic and major gene control. We aimed to identify genetic regions linked to idiopathic short stature (ISS) in childhood, through a whole genome scan in 92 families each with two affected children with ISS, including constitutional delay of growth and puberty and familial short stature. Linkage analysis was performed for ISS, height and bone age retardation. Chromosome 12q11 showed significant evidence of linkage to ISS and height (maximum non-parametric multipoint LOD scores 3.18 and 2.31 at 55-58 cM, between D12S1301 and D12S1048), especially in sister-sister pairs (LOD score of 1.9 for ISS in 22 pairs). These traits were also linked to chromosomes 1q12 and 2q36. The region on chromosome 12q11 had previously shown significant linkage to adult stature in several genome scans and harbors the vitamin D receptor gene, which has been associated with variation in height. A single nucleotide polymorphism (SNP) (rs10735810, FokI), which leads to a functionally relevant alteration at the protein level, showed preferential transmission of the transcriptionally more active G-allele to affected children (P=0.04) and seems to be responsible for the observed linkage (P=0.05, GIST test). Bone age retardation showed moderate linkage to chromosomes 19p11-q11 and 7p14 (LOD scores 1.69 at 57 cM and 1.42 at 50 cM), but there was no clear overlap with linkage regions for stature. In conclusion, we identified significant linkage, which might be due to a functional SNP in the vitamin D receptor (VDR) gene and could be responsible for up to 34% of ISS cases in the population.

Adolescent↗
PubMed2006

Growth hormone is effective in treatment of short stature associated with short stature homeobox-containing gene deficiency: Two-year results of a randomized, controlled, multicenter trial.

BACKGROUND: The short stature homeobox-containing gene, SHOX, located on the distal ends of the X and Y chromosomes, encodes a homeodomain transcription factor responsible for a significant proportion of long-bone growth. Patients with mutations or deletions of SHOX, including those with Turner syndrome (TS) who are haplo-insufficient for SHOX, have variable degrees of growth impairment, with or without a spectrum of skeletal anomalies consistent with dyschondrosteosis. OBJECTIVE: Our objective was to determine the efficacy of GH in treating short stature associated with short stature homeobox-containing gene deficiency (SHOX-D). DESIGN AND METHODS: Fifty-two prepubertal subjects (24 male, 28 female; age, 3.0-12.3 yr) with a molecularly proven SHOX gene defect and height below the third percentile for age and gender (or height below the 10th percentile and height velocity below the 25th percentile) were randomized to either a GH-treatment group (n = 27) or an untreated control group (n = 25) for 2 yr. To compare the GH treatment effect between subjects with SHOX-D and those with TS, a third study group, 26 patients with TS aged 4.5-11.8 yr, also received GH. Between-group comparisons of first-year and second-year height velocity, height sd score, and height gain (cm) were performed using analysis of covariance accounting for diagnosis, sex, and baseline age. RESULTS: The GH-treated SHOX-D group had a significantly greater first-year height velocity than the untreated control group (mean +/- se, 8.7 +/- 0.3 vs. 5.2 +/- 0.2 cm/yr; P < 0.001) and similar first-year height velocity to GH-treated subjects with TS (8.9 +/- 0.4 cm/yr; P = 0.592). GH-treated subjects also had significantly greater second-year height velocity (7.3 +/- 0.2 vs. 5.4 +/- 0.2 cm/yr; P < 0.001), second-year height sd score (-2.1 +/- 0.2 vs.-3.0 +/- 0.2; P < 0.001) and second-year height gain (16.4 +/- 0.4 vs. 10.5 +/- 0.4 cm; P < 0.001) than untreated subjects. CONCLUSIONS: This large-scale, randomized, multicenter clinical trial in subjects with SHOX-D demonstrates marked, highly significant, GH-stimulated increases in height velocity and height SDS during the 2-yr study period. The efficacy of GH treatment in subjects with SHOX-D was equivalent to that seen in subjects with TS. We conclude that GH is effective in improving the linear growth of patients with various forms of SHOX-D.

Body Height↗
PubMed2002

Growth pattern and body proportion in a female with short stature homeobox-containing gene overdosage and gonadal estrogen deficiency.

OBJECTIVE: To report on growth pattern and body proportion in the combination of short stature homeobox-containing gene (SHOX) overdosage and gonadal estrogen deficiency. DESIGN: Auxological studies in a 20-year-old Japanese female with 45,X[28]/46,X,psu idic(X)(q28)[72], gonadal estrogen deficiency, and SHOX duplication on the idic(X) chromosome, who received sex steroid replacement therapy from 16 years 8 months of age. METHODS: Growth pattern and body proportion were assessed by the age-matched standards for Japanese females. RESULTS: She continued to grow with a mean height velocity of 5.0 cm/year between 8 and 12 years of age and 4.4 cm/year between 12 and 16 years 8 months of age, and ceased to grow shortly after the replacement therapy. The standard deviation score (SDS) for height was -0.9, -1.4, +0.7 and +0.8 at 8, 12, 16 years 8 months and 20 years of age respectively. She showed a unique change in body proportion in her middle teens. At 8, 12, 16 years 8 months and 20 years of age, the SDS for sitting height (SH) was -0.8, -1.1, -0.9 and -0.6 respectively, the SDS for leg length (LL) was -1.2, -1.4, +1.1 and +1.4 respectively, and the SDS for SH/LL ratio was +0.6, +0.4, -1.6 and -1.7 respectively. CONCLUSIONS: The results provide further support for the notion that the combination of SHOX overdosage and gonadal estrogen deficiency permits continued growth with a roughly constant height velocity throughout the pubertal period of normal children, and suggest that the height gain in that period is primarily ascribed to the LL increase, as expected from SHOX expression in the distal limb bones.

Adult↗
PubMed2005

Shox2-deficient mice exhibit a rare type of incomplete clefting of the secondary palate.

The short stature homeobox gene SHOX is associated with idiopathic short stature in humans, as seen in Turner syndrome and Leri-Weill dyschondrosteosis, while little is known about its close relative SHOX2. We report the restricted expression of Shox2 in the anterior domain of the secondary palate in mice and humans. Shox2-/- mice develop an incomplete cleft that is confined to the anterior region of the palate, an extremely rare type of clefting in humans. The Shox2-/- palatal shelves initiate, grow and elevate normally, but the anterior region fails to contact and fuse at the midline, owing to altered cell proliferation and apoptosis, leading to incomplete clefting within the presumptive hard palate. Accompanied with these cellular alterations is an ectopic expression of Fgf10 and Fgfr2c in the anterior palatal mesenchyme of the mutants. Tissue recombination and bead implantation experiments revealed that signals from the anterior palatal epithelium are responsible for the restricted mesenchymal Shox2 expression. BMP activity is necessary but not sufficient for the induction of palatal Shox2 expression. Our results demonstrate an intrinsic requirement for Shox2 in palatogenesis, and support the idea that palatogenesis is differentially regulated along the anteroposterior axis. Furthermore, our results demonstrate that fusion of the posterior palate can occur independently of fusion in the anterior palate.

Animals↗
PubMed2001

Analysis of short stature homeobox-containing gene ( SHOX) and auxological phenotype in dyschondrosteosis and isolated Madelung deformity.

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.

Blotting, Southern↗