Loss of interstitial or terminal long-arm material of the X chromosome (Xq) can result in short stature and primary or secondary ovarian failure
15). However, absence of the long arm of the X chromosome with normal stature suggests that the presence of the short arm of the X chromosome maintains the stature of the affected patient
1). Deletion involving the long arm of the X chromosome generally results in ovarian failure if the proposed critical region Xq13-q26 is involved
1). Deletion of the whole short arm of the X chromosome (Xp) in females is associated with short stature, ovarian failure, and the classic stigmata of TS. The prevalence of an Xp deletion among patients with TS is 2%
16). Patients with terminal Xp deletion have short stature and may have some somatic traits of TS; gonadal function is generally preserved
16). Women with more distal deletions [del(X)(p21.1 to p22.1 or p22.2] menstruate more often, but many are infertile or have secondary amenorrhea
17). Thus, Xp [X(pter->p21] clearly plays a role in ovarian development. Therefore, we should perform follow-up regarding fertility or occurrence of secondary amenorrhea even in a patient with distal Xp deletion, although our patient had normal puberty and menstruation in adolescence. The Xp22.3-Xp22.12 region is located at the Xp terminus and includes the
SHOX gene. The
SHOX gene is located at the very tip of the short arm of both sex chromosomes, inside the telomeric portion of pseudoautosomal region 1, containing genes that escape X inactivation. The X-linked zinc finger protein (
Zfx) is also located at Xp22.1-21.3, and is a candidate gene for short stature and ovarian failure
17). Most TS patients with Xp deletion have short stature, considering statural determinant
17). However, this patient's height was in the normal range (10th-25th percentile) from 9 years to 12 years and she experienced short stature after puberty. The exact cause of normal height during the period is unclear, and maybe because of the effect of intact Xq chromosome and early normal puberty, respectively. There are only six cases
10,11,12,13,14) about central precocious puberty in patient with TS have been reported. Five of them showing mosaic TS and one of them showing structural abnormality of one X chromosome like our patient. The mechanism is unclear, and may be the result of abnormalities in the hypothalamic feedback system with increased levels of gonadotropins, FSH surge before ovarian failure, or elevated levels of TSH by interaction between TSH and the human FSH receptor. All had normal height according to standard growth curve when diagnosed as TS, like this case. When precocious puberty is combined with TS or if midparental height is tall, the patient may have normal height and the diagnosis may be delayed
12). More studies are needed regarding the correlation between TS and central precocious puberty. With regard to thyroid autoimmunity, correlation with karyotype and phenotype shows variable results
7). In some of the studies, especially in girls with isochromosome Xq, levels of thyroid autoantibody are the highest
7,8), but in others
9), the results did not reach statistical significance.
In conclusion, we experienced a case of TS with Xp22.1 deletion presenting with short final stature, early normal puberty, and Graves disease, without short stature during puberty. We suggest that even though a patient's puberty is normal, when the final height is short and autoimmune thyroid disease is accompanied, chromosome analysis for TS should be considered. Further research about determinant factors and genes on the X chromosome in growth, ovarian function, and autoimmunity is needed. Additionally, screening karyotypically normal individuals with TS features for mutations in candidate genes is necessary.