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). ... 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).
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 ... 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.