Turner Syndrome

Turner Syndrome (Gonadal Dysgenesis; 45,X)

Pathophysiology TS is caused by complete or partial loss of one X chromosome and affects ~ 1 in 2500 women. Approximately one-half of women with TS have a 45,X karyotype, ~20% have 45,X/46,XX mosaicism, and the remainder have structural abnormalities of the X chromosome such as X fragments, isochromosomes, rings, or Y chromosome material. The clinical features of TS result from haploinsufficiency of multiple X chromosomal genes (e.g., short stature homeobox, SHOX), either directly or through effects on autosomal gene expression. However, imprinted genes are also proposed to be affected when the inherited X has different parental origins.

Clinical Features TS is characterized by female external genitalia, short stature, hypergonadotropic hypogonadism, infertility, and other phenotypic features. Infants may present with lymphedema, nuchal folds, low hairline, or left-sided cardiac defects or later in childhood with unexplained growth failure or delayed puberty. Although limited spontaneous pubertal development occurs in up to 30% of girls with TS (10%, 45,X; 60%, 45,X/46XX) and up to 20% have menarche, the vast majority of women with TS develop complete ovarian insufficiency. Therefore, this diagnosis should be considered in all women who present with primary or secondary amenorrhea and elevated gonadotropin levels.

TREATMENT:

The management of girls and women with TS requires a multidisciplinary approach to address many potentially affected organ systems according to TS practice guidelines. Individuals require long-term monitoring by an experienced cardiologist to follow congenital heart defects (CHDs)(30%)(bicuspid aortic valve, 30-50%; coarctation of the aorta, 30%; aortic root dilation, 5%), antibiotic prophylaxis for dental or surgical procedures, and serial magnetic resonance imaging (IMR) of aortic root dimensions , as progressive aortic root dilation is associated with increased risk of aortic dissection. Individuals found to have congenital renal and urinary tract malformations (30%) are at risk for urinary tract infections, hypertension, and nephrocalcinosis. Hypertension can occur independently of cardiac and renal malformations and should be monitored and treated as in other patients with essential hypertension. Regular assessments of thyroid function, weight, dentition, hearing, speech, vision, and educational issues should be performed during childhood. Counseling about long-term growth and fertility issues sould be provided. Patient support groups are active throughout the world and can play an invaluable role.

Short stature is common, and untreated final height rarely exceeds 150 cm in nonmosaic 45,X TS. Recombinant growth hormone has been used in an attempt to increase growth, sometimes with oxandrolone in older children. Girls with evidence of ovarian insufficiency require estrogen replacement to induce breast and uterine development, support growth, and maintain bone mineralization. Most physicians now initiate low-dose estrogen therapy to induce puberty at an age-appropriate time (~11 years). Doses of estrogen are increased gradually to allow development over a 2 -to 4-year period. Progestins are added later to regulate withdrawal bleeds. A very small percentage of women with TS have had spontaneous pregnancy, whereas others have achieved successful pregnancy after ovum donation and in vitro fertilization, but the risks of cardiac complications are high, and expert counseling and management are needed. Long-term follow-up of women with TS includes careful surveillance of sex hormone replacement and reproductive function, bone mineralization, cardiac function and aortic root dimensions, blood pressure, weight and glucose tolerance, hepatic and lipid profiles, thyroid function, skin examination, and hearing. This service is provided by a dedicated TS clinic in some centers.

45,X/46,XY MOSAICISM

The phenotype of individuals with 45,X/46,XY mosaicism (sometimes called mixed gonadal dysgenesis) can vary considerably. Some have a predominantly female phenotype and testes, and the diagnosis is made incidentally after amniocentesis or during investigation of infertility. In practice, most newborns referred for assessment have atypical genitalia and variable comatic referred for assessment have atypical genitalia and variable somatic features. There is often marked asymmetry, with a streak gonad and hemiuterus on one side and a partially descended dysgenetic testis and hemiscrotum on the other side. Many children are raised as boys, but in some children, sex designation (whether to raise the baby as male or female) must be decided by parents and the multidisciplinary team. In these children, gender identity may be harder to predict. There is an increased risk of germ cell cancer (GCC), up to 35% in intraabdominal gonads, so prophylactic removal of intraabdominal gonads is usually considered. Individuals raised as males often have reconstructive surgery for hypospadias and removal of dysgenetic or streak gonads if the gonads cannot be brought down into the scrotum. Scrotal testes can be preserved but require regular examination  for tumor development and sonography at the time of puberty. Biopsy for carcinoma in situ is recommended in adolescence, and testosterone supplementation may be required to support androgenization in puberty or if low testosterone is detected in adulthood. As 45,X/46XY mosaicism can be associated with other features (e.g., cardiac, renal), individuals should be monitored according to TS guidelines. Infertility is typical, but non-azoospermia or focal spermatogenesis has been reported, highlighting the importance of individualized approaches to management.