Short Stature Homeobox-Containing (SHOX) Gene Deficiency: Genetics and Growth Response to Growth Hormone Treatment in Comparison with Turner Syndrome

Abstract

Listen

Translate article

Short stature, affecting approximately 2–3% of children, is one of the most frequent conditions in childhood for which clinical attention is sought from pediatric endocrinologists. Many genes are required for normal longitudinal growth, but to date mutations in these genes account for only a small proportion of the short stature cases. Mutations or deletions of the short stature homeobox-containing gene (SHOX) and its associated regulatory regions are found relatively frequently in children with short stature. The SHOX gene is located in the pseudoautosomal region 1 (PAR1) of the short arms of the X and Y chromosomes and encodes a homeodomain transcription factor involved in the regulation of growth of the limbs. The clinical phenotype of SHOX haploinsufficiency includes variable degrees of growth impairment with or without obvious mesomelia of the limbs (middle segment shortening, i.e., of the forearms and lower legs), from disproportionate short stature (as seen in Leri–Weill syndrome and Turner syndrome) to apparent “idiopathic” short stature devoid of dysmorphic signs. Recombinant human growth hormone (GH) was first approved for use in patients with Turner syndrome around 1991 in Europe (depending on country) and 1996 in the USA. Subsequently, GH was demonstrated to be effective in improving the growth of patients with isolated SHOX deficiency during a 2-year randomized, controlled clinical trial; the study demonstrated similar efficacy in patients with Leri–Weill and Turner syndromes. Furthermore, retrospective analysis of adult (final) heights of GH-treated patients with isolated SHOX deficiency and Turner syndrome revealed comparable height gain for both groups; patients with SHOX deficiency and Turner syndrome attained final heights in the normal range (above –2 standard deviation scores (SDS)). On the basis of the randomized clinical trial data, GH has been approved by regulatory authorities in the USA, Europe, and subsequently in other countries for the treatment of short stature in subjects with SHOX deficiency.