Identification of short stature caused by SHOX defects and therapeutic effect of recombinant human growth hormone.

Point mutations or complete deletions of SHOX, the short-stature homeobox-containing gene on the pseudoautosomal region of the sex chromosomes (Xp22 and Yp11.3), were recently reported in one family with idiopathic short stature and in several families with Leri-Weill syndrome (dyschondrosteosis). The missing SHOX is also thought to attribute to the growth failure in Turner syndrome. For testing the frequency of defects of SHOX in unexplained growth failure and recombinant human GH (rhGH) as a possible growth-promoting agent, we selected 68 children with idiopathic short stature. These probands had heights below -2.0 SD score for age, normal target heights, no significant bone age retardations, no endocrine abnormalities, no skeletal diseases, and no other organic diseases. No mutations were detected by single-strand conformational polymorphism analysis of the PCR-amplified SHOX. The analysis of three microsatellite DNA markers of the pseudoautosomal region, including one located on the 5' untranslated region of SHOX-exon 1, identified a 15-yr-old girl who carried a mutation in the form of a complete SHOX deletion. This girl who had a normal karyotype presented with mild mesomelic shortening of the forearms and lower legs. We treated two children with short stature on the basis of a SHOX point mutation (C674T) with rhGH at a dose of 1.0 IU/kg body weight-week in accordance with the regimen used in Turner syndrome. During the first 12 months of treatment, these two children (5.9- and 8.4-yr-old) showed an excellent growth spurt with a growth rate of 9.5 and 9.4 cm/yr, respectively. Growth of the lower extremities was weaker than in the trunk and arms. Our data suggest that short stature due to SHOX deletions is not a rare entity. Growth-promoting therapy with rhGH was effective with regard to height gain, but a tendency to disproportionate growth was apparent. In cases of unexplained growth failure, especially if associated with any mild skeletal disproportions, genetic analysis of SHOX should be considered.