phenotype which includes impaired visual-spatial abilities (Zinn et al 2007). This interval includes the 2.6 Mb Xp-Yp pseudoautosomal region (PAR1) but the study suggests that haploinsufﬁciency of the SHOX gene does not cause TS neurocognitive phenotype. Psychosocial status Another view advocated by some researchers, is that the abnormal adult height in women with TS is a complex quali- tative trait associated with additional genes that have not yet been identiﬁed, and with aneuploidy or other forms of chro- mosomal imbalance, as is present in chromosomal disorders such as Down’s syndrome (Haverkamp et al 1999). Growth hormone therapy Treatment of the short stature in TS has been historically based on psychosocial issues since it is not evident that there is an advantageous organic health beneﬁt by being taller with TS. Psychological studies of children with TS report that their short stature is most often associated with social competence. Shorter TS children are less competent socially and at a greater risk of social impairment with social isola- tion and social ineptitude probably because of teasing and stigmatization by their peers (Rovet et al 1994). Recombinant human GH (hGH) therapy is now routinely used to treat the growth impediment in girls with TS although many studies have shown varied results. Comparisons of the studies of the ﬁnal adult heights (FHA) of women with TS who were treated with hGH show height gains after treatment ranging from no signiﬁcant increase over the projected adult height (PAH) (Dacou-Voutetakis et al 1998), signiﬁcant increases of 5 cm or more over the PAH (Taback et al 1996; Chu et al 1997; Carel et al 1998; Plotnick et al 1998; Rosenfeld et al 1998; Chernausek et al 2000; Ranke et al 2000; Reiter et al 2001; Quigley et al 2002; van Pareren et al 2003; Massa et al 2003; The Canadian Growth Hormone Advisory Committee 2005) to a mean height gain over the PAH of up to 16 cm using a higher dose of hGH (∼0.630 mg/kg/week) (Sas et al 1999a). The multicenter Canadian study (The Canadian Growth Hormone Advisory Committee 2005) employed a parallel, randomized control group that received no hGH and was followed to adult height showing a mean height gain due to GH of +7.2 cm. Also, the largest TS study to date which included 5500 TS patients, of which 1146 TS patients were treated to adult height using an hGH dose of 0.28 ± 0.08 mg/kg/week, reported a height SDS at the beginning of hGH treatment of –3.1 ± 0.9 and at adult height an SDS of –2.3 ± 1.1 (Ranke et al 2007). Therapeutics and Clinical Risk Management 2008:4(6) GH and Turner syndrome To overcome the retarded growth in TS patients most studies have shown that high doses of hGH are needed induc- ing sometimes “acromegalic” levels of IGF-I, suggesting the presence of GH or IGF-I resistance in the bones (Van Pareren et al 2003; Bannink et al 2006a). Which hGH dose to use is still an issue of debate but recombinant hGH therapy is usu- ally started at the recommended dose of 0.375 mg/kg/week divided into daily injections which is the dose approved by the US Food and Drug Administration (Bondy 2007). Growth hormone treatment though in higher doses, as mentioned above, has been shown to enhance growth even more in girls with TS but this many times leads to abnormally high IGF-I levels. Since the long-term effects of exceedingly high IGF-I concentrations during the growth period are not known and there is a theoretical potential of increasing the risk of cancer this should be avoided (Sas et al 1999a; Bannink et al 2006a; Park et al 2004; Ranke et al 2007). Factors that seem to be most predictive of taller adult stature in TS individuals are related to the following: (1) taller mean parental height, (2) taller height at initiation of therapy, (3) the response to hGH during the ﬁrst year of therapy, (4) mean dose of hGH/week, (5) taller height at the start of puberty and (6) age at the start of puberty (Wilson et al 1991; Welse et al 1993; Carel et al 1997; Hofman et al 1997; Ranke et al 2000; Reiter et al 2001; Quigley et al 2002; Bondy 2007; Ranke et al 2007; Rosenfeld 2007). Some compounding factors that may explain the vari- ability in the response of TS girls to hGH therapy are genomic imprinting and certain polymorphisms present in these girls. A recent study revealed that 72% of nonmosaic 45,X girls retain a maternal X whereas 86% of nonmosaic 46,X,i(Xq) girls carry an intact paternal X chromosome. By using a linear model which included age and height at the initiation of hGH therapy, the girls with a maternal X were shown to have a greater mean height gain than those with a paternal X. Interestingly, girls with a maternal X also had a smaller chance of having sensorineural hearing loss than the girls with a paternal X (Hamelin et al 2006). Also a pro- tein polymorphism of the GH receptor (GHR) based on the genomic deletion of exon 3 (d3-GHR) has been linked to a signiﬁcantly higher increment in height velocity of TS girls after the ﬁrst year of treatment with high-dose recombinant hGH (Binder et al 2006). The optimal age of initiation of hGH therapy is still not well established. Most physicians start hGH when the height drops well below the 5th percentile on the growth chart, which is usually on the average around the age of 9 years (Saenger et al 1996). This results in a situation though where the TS 1179