Spiliotis reason can be found to have a karyotype performed in order to investigate the possibility of the presence of TS (Nielsen and Wohlert 1991). Growth Girls with TS are born with intrauterine growth retardation and they exhibit growth failure during early childhood as early as 1 year of age. The growth delay worsens during puberty, because of the absence of the pubertal growth spurt, resulting in a strikingly short adult height approximately 20 cm. shorter than the mean adult height of normal women. Spontaneous puberty occurs in 10% to 20% of the girls with TS accompa- nied by a small pubertal growth spurt but prepubertal growth and ﬁnal adult height in these cases are similar to those of TS girls without spontaneous puberty (Massa et al 1990). In the past, it was thought that the etiology of the short stature in TS was due to a reduction in spontaneous growth hormone (GH) secretion. This was because 24-hour (24 h) GH studies in girls from the age of 9 to 20 years of age showed decreased mean 24 h GH concentrations (Lyon et al 1985). After the observation though that estradiol ampliﬁes the neuroendocrine regulation of pulsatile GH release in normal pubertal girls (Ho et al 1987) it became evident that this decrease in the 24 h GH concentrations in the pubertal- aged TS girls was due to their lack of estradiol. Estrogen replacement therapy in pubertal-aged TS girls normalizes the 24 h integrated concentrations of GH, but the growth deﬁcit is still present in these girls (Zadik et al 1992). The growth impairment in the majority of TS individuals therefore, is not due to GH deﬁciency although a small minority of TS girls may manifest classic GH deﬁciency (abnormal GH concentrations after pharmacologic provocation) in addition to their abnormal karyotype. Pharmacologic provocation tests though, are not recommended unless the girl’s growth is clearly abnormal relative to that expected for TS determined by plotting lengths and heights on TS-speciﬁc growth curves (Rongen-Westerlaken et al 1997; Bondy 2007). Despite the fact that GH deﬁciency is not usually pres- ent in TS, the GH – insulin-like growth factor (IGF) – IGF binding protein (IGFBP) axis is disturbed. Increased IGFBP- 3 proteolytic activity has been found in adult TS combined with low levels of circulating free IGF-I and increased levels of free IGF-II. Normal formation of the 150 kDa IGFBP-3 ternary complex ( acid-labile subunit (ALS), IGF-I and IGFBP-3) is also disrupted in TS, together with decreased levels of intact IGFBP-1,- 2, and -4, and decreased bioactive IGF-I. These occur despite the presence of normal immuno- reactive levels of total IGF-I, IGFBP-1, -2, -3 and -4 and ALS 1178 (Gravholt et al 2001). A sex hormone dependent IGFBP-3 protease (serine protease) seems to lead to destabilization of the 150 kDa IGFBP-3 ternary complex in TS since hormone replacement therapy (HRT) with estrogen causes a marked reduction in IGFBP-3 proteolysis, suggesting modulation of the protease by sex hormones. Concurrently after HRT in TS, free IGF-II decreases while free IGF-I remains unchanged. The binary complex of IGF-I and IGFBP-1 increases in response to HRT, the proteolysis of IGFBP-3 normalizes, and accordingly leads to normalization of ternary complex formation (Gravholt et al 2006). In 1997, haploinsufﬁciency for the short stature homeobox- containing gene (SHOX) was found to also contribute to the marked short stature found in TS (Rao et al 1997; Rao et al 2001). The SHOX gene is located on the distal end of the X and Y chromosomes at Xp22.3 and Yp11.3 in the pseudoau- tosomal region 1 (Marchini et al 2004; Munns et al 2004). It is essential for the regulation of chondrocyte proliferation and differentiation and it encodes a cell-type speciﬁc nuclear tran- scriptional activator, primarily expressed in osteogenic cells (Rao et al 2001). SHOX acts as a repressor of growth plate fusion since it is speciﬁcally expressed in the growth plate in hypertrophic chondrocytes undergoing apoptosis (Marchini et al 2004; Munns et al 2004). The haploinsufﬁciency of the SHOX gene may lead to premature growth plate fusion in the distal limbs in TS and it inﬂuences the short stature of XO females since two copies of this gene are required for normal height (Blaschke 2006). Individuals with SHOX deﬁciency have variable degrees of growth impairment with or without a spectrum of skeletal anomalies (Blum et al 2007). A wide spectrum of abnormalities are associated with mutations or deletions of the SHOX gene ranging from short stature without dysmorphic abnormalities to a form of short stature characterized by disproportionate shortening of the forearms and lower legs, cubitus valgus, Madelung deformity, short fourth metacarpals and high-arched palate (Binder et al 2003). This skeletal anomaly is typically observed in patients with Leri-Weill syndrome and to a lesser degree in TS patients (Ogata 1993). It is noteworthy to add though, that the degree of short stature observed with simple haploinsufﬁciency for the SHOX gene is not as severe as that observed in TS patients suggesting that haploinsufﬁciency for additional genes located on the short arm of the X chromosome also contribute to the growth retardation seen in TS (Ogata et al 1993; Zinn et al 2000; Rosenfeld 2007). A recent study suggests that haploinsufﬁciency of one or more genes in Xp22.3, the distal 8.3 megabases (Mb) of the X chromosome, is also responsible for the TS neurocognitive Therapeutics and Clinical Risk Management 2008:4(6)