Short Stature, Idiopathic, X-Linked

A number sign (#) is used with this entry because some cases of short stature are associated with variations in the pseudoautosomal genes SHOX (312865) or SHOXY (400020).

Mutations in the SHOX gene also cause Leri-Weill dyschondrosteosis (127300) and Langer mesomelic dysplasia (249700). In addition, haploinsufficiency of the SHOX gene is associated with short stature in Turner syndrome.

Description

Idiopathic short stature is usually defined as a height below the third percentile for chronological age or minus 2 standard deviations (SD) of national height standards in the absence of specific causative disorders (Rao et al., 1997).

For a discussion of genetic heterogeneity of quantitative trait loci for stature, see STQTL1 (606255).

Clinical Management

Blum et al. (2007) determined the efficacy of growth hormone (GH; 139250) in treating short stature associated with SHOX gene deficiency (SHOX-D). This large, randomized, multicenter clinical trial in subjects with SHOX-D showed marked, significant, GH-stimulated increases in height velocity and height SDS during the 2-year study period. The efficacy of GH treatment in subjects with SHOX-D was equivalent to that seen in subjects with Turner syndrome. The authors concluded that GH is effective in improving the linear growth of patients with various forms of SHOX-D.

Mapping

Ballabio et al. (1989) did an extensive study of 27 patients with interstitial and terminal deletions involving the distal short arm of the X chromosome. The patients had various syndromes as isolated entities or associated in various combinations as contiguous gene syndromes. The use of cDNA and genomic probes from the Xpter-p22 region allowed Ballabio et al. (1989) to identify 12 different deletion intervals. A putative pseudoautosomal gene affecting height was assigned to the pseudoautosomal region (PAR) of Xp, distal to surface antigen MIC2 (313470). One of their patients had the XXY chromosome constitution of Kallmann syndrome (308700), associated with an X/Y translocation and a presumed deletion in PAR of both Xp and Yp. Rather than the usual increase in height of Kallmann syndrome, the patient was 155 cm tall. Furthermore, both affected males and heterozygous females with terminal deletions of Xp displayed short stature. Ballabio et al. (1989) suggested that these observations confirmed those of Zuffardi et al. (1982), who noted short stature in patients with terminal deletions of the X and Y chromosomes.

Pointing out that short stature is consistently found in persons with terminal deletions of Xp, Henke et al. (1991) attempted to refine a localization of the putative locus affecting height by analysis of 2 patients with partial monosomy of the pseudoautosomal region at the molecular level. Of 8 pseudoautosomal probes used, 3 were new markers positioned on the pseudoautosomal map by pulsed field gel electrophoresis. Their findings suggested that a locus affecting height maps within a region of about 1.5 Mb distal to the DXS406 locus and proximal to the DXS405 locus, a region that contains 2 CpG islands. Ogata et al. (1992) described a Japanese girl with short stature and a terminal deletion of Xp distal to DXYS15. Their findings supported the mapping of 1 or more growth genes to the PAR. Cytogenetic studies showed that the rearranged X chromosome was formed by breakage at Xq26 and the transfer of the Xq fragment onto the tip of Xp. The abnormal X was always late replicating. Since the abnormal X chromosome was missing only about 700 kb of DNA from the PAR distal to DXYS15, Ogata et al. (1992) proposed that the growth gene was present in that region, where it can be assumed to escape inactivation and exert a dosage effect. Ogata et al. (1992) also described a Japanese boy and his mother with an interstitial deletion in Xp22.3 and reviewed the correlation between genotype and stature in 6 cases of partial monosomy of the PAR. The results indicated that the region from DXYS20 to DXYS15 is a critical region for the putative growth gene(s). Ogata et al. (1995) described a girl with isolated short stature and an inverted duplication of Xp21.3-p22.33. Molecular studies showed deletion of the PAR distal to DXYS15.

By fluorescence in situ hybridization studies of 4 patients with X-chromosomal rearrangements, 2 with normal height and 2 with short stature, Rao et al. (1997) narrowed the critical 'short stature interval' to a 270-kb region within PAR1.

Deng et al. (2002) performed genomewide linkage analysis on a sample of 53 pedigrees containing 1,249 sib pairs, 1,098 grandparent-grandchildren pairs, 1,993 avuncular pairs, and 1,172 first-cousin pairs. The study suggested several genomic regions linked with variation in height, including Xp22 at the marker DXS1060 (2-point lod score of 1.95). Deng et al. (2002) observed that the SHOX gene, which had been related to idiopathic familial short stature, was located in the Xp22 region.

Molecular Genetics

Rao et al. (1997) identified a 170-kb DNA interval within the PAR1 that was deleted in 36 individuals with short stature and different rearrangements on Xp22 or Yp11.3. This deletion was not detected in any of the relatives with normal stature or in a further 30 individuals with rearrangements on Xp22 or Yp11.3 with normal height. The authors identified and isolated the SHOX gene within this region. In 1 of 91 individuals with idiopathic short stature, Rao et al. (1997) identified a functionally significant mutation in the SHOX gene (312865.0001).

Shanske et al. (1999) found a Y;13 translocation in a 10-year-old boy with idiopathic short stature. Southern blot analysis using cDNA probes indicated that most of the pseudoautosomal region, including the SHOX gene, was lost as a result of the translocation. They concluded that haploinsufficiency for this gene was responsible for the growth failure in the patient. Treatment with recombinant growth hormone resulted in greatly improved growth velocity.

Rappold et al. (2002) investigated the incidence and type of SHOX mutations in 900 patients with short stature. All patients had a normal karyotype, and their heights for chronologic age were below the 3rd percentile or -2 SD of national height standards. All were without obvious skeletal features reminiscent of 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. The authors concluded that 2.4% of children with short stature have SHOX mutations and that the spectrum of mutations is biased, with the vast majority leading to complete gene deletions.

Morizio et al. (2003) identified deletion of the SHOX gene in 4 (7.1%) of 56 patients with idiopathic short stature. None of the patients had skeletal abnormalities.

In a study of 140 children with idiopathic short stature, Binder et al. (2003) sought to determine the prevalence of SHOX mutations and to give an unbiased characterization of the haploinsufficiency phenotype of such children. SHOX haploinsufficiency caused by a SHOX deletion was confirmed in 3 probands (2%), all females, who carried a de novo deletion through loss of the paternal allele. Their auxologic data revealed a significant shortening of arms and legs in the presence of a low-normal sitting height when compared with the other 137 children tested. Therefore, the extremities-trunk ratio (sum of leg length and arm span, divided by sitting height) for total height was significantly lower in the 3 SHOX haploinsufficient probands in comparison with the whole group. All children with SHOX haploinsufficiency exhibited at least 1 characteristic radiologic sign of Leri-Weill dyschondrosteosis in their left-hand radiography, namely, triangularization of the distal radial epiphysis, pyramidalization of the distal carpal row, or lucency of the distal ulnar border of the radius. Binder et al. (2003) concluded that it is rational to limit SHOX mutation screening to children with an extremities-trunk ratio less than 1.95 +/- 0.5 height (m) and to add a critical judgment of the hand radiography.

Deletions of the SHOX Downstream Regulatory Domain

By comparative genetic analysis, Sabherwal et al. (2007) identified 8 highly conserved noncoding DNA elements (CNE2 to CNE9) within a 200-kb interval, located between 48 and 215 kb downstream of the SHOX gene, and functional analysis showed that CNE4, CNE5, and CNE9 had cis-regulatory activity in the developing limbs of chicken embryos. Sabherwal et al. (2007) stated that their findings indicated that the deleted region in the affected families contains several distinct elements that regulate SHOX expression in the developing limb, and noted that deletion of these elements in humans with both SHOX genes intact generates a phenotype apparently indistinguishable from that of patients with mutations in the SHOX coding region.

Chen et al. (2009) analyzed copy number variation in the pseudoautosomal region of the sex chromosomes in 735 individuals with idiopathic short stature (ISS) and in 58 patients with Leri-Weill syndrome. They identified 31 microdeletions in the pseudoautosomal region in ISS patients, 8 of which involved only enhancer CNEs (CNE7, CNE8, and CNE9) residing at least 150 kb centromeric to the SHOX gene. In the Leri-Weill patients, 29 microdeletions were identified, 13 of which involved CNEs and left the SHOX gene intact. These deletions were not found in 100 controls. Chen et al. (2009) concluded that enhancer deletions in the SHOX downstream region are a relatively frequent cause of growth failure in patients with idiopathic short stature and Leri-Weill syndrome.

Benito-Sanz et al. (2012) identified a recurrent 47.5-kb deletion in the pseudoautosomal region 1 (PAR1) downstream of the SHOX gene (312865.0016) in 19 of 124 probands with Leri-Weill dyschondrosteosis (15.3%) and 11 of 576 probands with idiopathic short stature (300582) (1.9%). The deletion did not include any of the SHOX enhancer elements known at that time. Conservation analysis of the deleted region followed by chromosome conformation capture and luciferase reporter assays demonstrated the presence of an evolutionarily conserved region (ECR1) that acted as a novel orientation- and position-independent SHOX enhancer.

Turner Syndrome

Relevant to the earlier work on these short stature genes is the work of Ellison et al. (1996, 1997), who reported the isolation of the SHOX gene from the PAR which they suggested might be involved in the short stature of Turner syndrome. Ellison et al. (1996, 1997) named the gene PHOG for 'pseudoautosomal homeobox-containing osteogenic gene'. Turner syndrome is presumably the result of haploinsufficiency of certain genes on the X chromosome. Gene dosage considerations led to the prediction that the genes implicated are those that escape X inactivation and have functional Y homologs. Among the genes possessing these characteristics are those residing in the PAR. Genes in the PAR that are dosage sensitive probably contribute to the short stature observed in Turner syndrome.