Short Stature due to SHOX Deficiency: Genotype, Phenotype, and Therapy

Abstract

SHOX deficiency is a frequent cause of short stature. The short stature homeobox-containing gene resides in the telomeric PAR1 region on the short arm of both sex chromosomes and escapes X inactivation. For this review, abstracts of 207 publications presented by PubMed for the search term ‘SHOX’ were screened. Heterozygote SHOX mutations (80% deletions) were detected in 2–15% of individuals with formerly idiopathic short stature, in 50–90% of individuals with Leri-Weill dyschondrosteosis, and in almost 100% of girls with Turner syndrome. Mutational analysis is primarily performed by MLPA analysis followed by gene sequencing if necessary. SHOX is a nuclear protein that binds to DNA and acts as a transcriptional activator. Orthologs are present in many vertebrates but not in rodents. Gene expression starting as early as 33 days postconception in humans is predominant in the mid portion of the buds and in the first and second pharyngeal arches. In the growth plate, hypertrophic chondrocytes express SHOX where it seems to have antiproliferative potency. The penetrance of SHOX deficiency is high, but its clinical expression is very variable becoming more pronounced with age and being more severe in females. Growth failure starts early during the first years of life and the height deficit present at preschool age seems not to deteriorate further. The mean adult height is –2.2 SDS. Auxological analysis of the body proportions (mesomelia), the presence of minor abnormalities, and the search for subtle radiographic signs are important keys to the diagnosis which has to be confirmed by genetic analysis. The growth-promoting effect of GH therapy approved for individuals with SHOX mutations seems to be equal to the effect seen in Turner syndrome.

MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature

“…Various clinical prediction rules have been proposed to select patients for testing (139,140,141,142), but the high variability of the clinical presentation limits their predictive value (5). SHOX mutations account for 2-15% of individuals presenting with ISS (143). Since usually SHOX defects are transmitted from one of the parents, physical examination of the parents is essential, including height, sitting height, arm span, forearm length, and presence of Madelung deformity.…”

Structural and numerical changes of chromosome X in patients with esophageal atresia

“…The limb and growth anomalies of the thump are different from the wrist deformity usually associated with SHOX deletions and duplications. 43,44 Furthermore, SHOX duplications are also associated with limb anomalies, for example, in Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome type 1 45 , idiopathic short stature 46 or Leri-Weill dyschondrosteosis. 43 The healthy carriers of the transmitted SHOX duplications in patients 4 and 5 seem to have the exact same duplication/rearrangement as their offspring.…”

A Rare Combination of Mosaic Ring Y Chromosome and Shox Gene Deletion in an Infertile Male

“…In this study, we present a rare combination of SHOX gene deletion in addition to the ring structure of Y chromosome in a patient who was referred to our clinic with infertility and having 46,X,r (Y) /45,X mosaicism as a result of conventional cytogenetic analysis. Olguda periferik kandan yüksek çözünür-lüklü bantlama (HRB) tekniği ile yapılan kromozom analizi sonucunda mozaik 46, X, r(Y) [13]/45, X [11] karyotipi tespit edildi (Resim 2). Eşinin karyotip analizi ise normal (46, XX) olarak gözlendi.…”