Turner syndrome

The strength of the association between Turner syndrome and short stature is such that idiopathic short stature alone is a major diagnostic indication.

When Turner syndrome is diagnosed in early life, growth hormone therapy can decrease the degree of short stature. The effects of growth hormone therapy are at their strongest during the first year of treatment and taper off over time. In some cases oxandrolone, a steroid with a relatively mild masculinizing effect, may be used alongside growth hormone. The addition of oxandrolone to a Turner syndrome treatment regimen adds around to the final height. Oxandrolone is used particularly often in girls diagnosed later in their growth period, due to the reduced impact of growth hormone alone in this population. However, oxandrolone use runs the risk of delayed breast development, voice deepening, increased body hair, or clitoromegaly. Lymphedema (swelling) of the hands and feet is common at birth and sometimes persistent throughout the lifespan.

A number of the external manifestations of Turner syndrome are focused on the limbs, hands, and feet. Lymphedema at birth is one of the classic features of the syndrome; though it often resolves during toddlerhood, recurrence in later life is frequent, often without apparent cause. Cases where the retained X chromosome was inherited from the mother more often experience lymphedema than those where it was from the father. As a consequence of lymphedema's effects on nail anatomy, females with Turner syndrome frequently have small, hypoplastic, upturned nails. Their fingers are shorter and the hands are broad. Their feet are puffy, thicker, and swollen. Shortened metacarpal bones, particularly the fourth metacarpal, are a frequent finding. The body shape of individuals with Turner syndrome is frequently quite broad and stocky, as the growth deficiency is more pronounced in the length of bones than in their width. Scoliosis is common in Turner syndrome, and is seen in 40% of girls without growth hormone treatment. The underlying etiology of neck webbing is related to prenatal blood flow issues, and even in populations without Turner's has broad health consequences; the rate of congenital heart disease in webbed neck is 150-fold higher than in the general population, while the feature is also associated with reduced height and minor developmental impairments. and in the case of Turner's may be a consequence of fetal lymphedema.

Coronary artery disease onsets earlier in life in women with Turner syndrome compared to controls, and mortality from cardiac events is increased. This is thought to be in part a function of the relationship between Turner syndrome and obesity; women with Turner syndrome have a higher percentage of body fat for their weight than control women, and their short stature makes weight control more difficult. Though coronary artery disease is frequently thought a disease of older adults, young women with Turner syndrome are more likely to develop the disease than their 46,XX peers. Treatment recommendations for women with Turner syndrome and coronary artery disease are as in the general population, but as Turner's increases the risk of type 2 diabetes, women with insulin resistance must weigh up the benefits of prophylactic or early statin treatment with the risk of Type II diabetes. Non-alcoholic fatty liver disease is increased in prevalence in Turner syndrome, likely related in part to both conditions' associations with obesity. Hepatic vascular diseases are also seen in the syndrome as an aspect of Turner syndrome's broader vascular, aortic and cardiac impacts. Primary biliary cholangitis is more common in 45,X0 than 46,XX women. An unclear association exists between estrogen replacement therapy and liver dysfunction in Turner syndrome; some studies imply estrogen therapy worsens such conditions, while others imply improvement.

thumb|left|upright=0.75|Duplicated ureter

Kidney issues, such as horseshoe kidney, are sometimes observed in Turner syndrome. Serious complications of the kidney anomalies associated with Turner syndrome are rare, although there is some risk of issues such as obstructive uropathy, where the flow of urine from the kidneys is blocked.). In one study, 34 Turner syndrome girls without overt evidence of these tumors were found at preventative surgery to have a gonadoblastoma (7 cases), dysgerminoma (1 case), or non-specific in situ gonadal neoplasm (1 case). Turner syndrome girls with this sSMC otherwise have typical features of the Turner syndrome except for a minority who also have hirsutism and/or clitoral enlargement. Surgical removal of the gonads has been recommended to remove the threat of developing these sSMC-associated neoplasms. Turner syndrome individuals with an sSMC that lacks the SRY gene are not at an increased risk of developing these cancers. This hearing loss is progressive; at the age of 40, women with Turner syndrome have equivalent hearing loss to 46,XX women aged 60, on average. Cohort studies imply hearing loss may be more common in women who also have metabolic syndrome. The high prevalence of sensorineural hearing loss in Turner syndrome appears to be related to SHOX deficiency. Nearly half of cases have hyperopia or myopia, usually mild. Strabismus, or misalignment of the eye, occurs in around one-fifth to one-third of girls with Turner syndrome. As with strabismus outside the Turner's context, it may be treated with glasses, patching, or surgical correction. Esotropia, where the eye turns inwards, is more common than exotropia, where it turns outwards. Ptosis, or a drooping eyelid, is a common facial manifestation of Turner syndrome; it usually has no appreciable impact on vision, but severe cases may limit visual range and require surgical correction. Inflammatory bowel disease is also common, while the prevalence of type 1 diabetes is unclear, though appears increased.

Thyroid disease is common in Turner syndrome. Hypothyroidism is prevalent; 30%–50% of women with Turner syndrome have Hashimoto's disease, where the thyroid gland is slowly destroyed by an autoimmune reaction from the immune system. By age 50, half of women with Turner syndrome have subclinical or clinical hypothyroidism. Women with isochromosome Xq are more likely to develop autoimmune thyroid disease than women with other forms of Turner syndrome. 6% of women with Turner syndrome have regular menstrual cycles; the rest experience primary or secondary amenorrhea or other menstrual dysfunction.

In girls with Turner syndrome who do not experience spontaneous puberty, exogenous estrogen is used to induce and maintain feminization. Estrogen replacement is recommended to begin at around age 11–12, although some parents prefer to delay the induction of puberty in girls with lower social and emotional preparedness. The dose of estrogen in induced puberty begins at 10% of adult estrogen levels and is steadily increased at six-month intervals, with a full adult dose attained two to three years after the beginning of treatment. Estrogen replacement may interfere with growth hormone therapy, due to the closing effects of estrogen on growth plates; individuals must weigh up their preferences for taller height versus greater feminization.

Early in gestation, fetuses with Turner syndrome have a normal number of gametes in their developing ovaries, but this starts decreasing rapidly as early as 18 weeks of pregnancy; by birth, girls with the condition have markedly reduced follicular counts. Women with Turner syndrome who wish to raise families but are incapable of conception with their own oocytes have the options of adoption or of pregnancy with donor eggs; the latter has a comparable success rate to donor pregnancy in women with 46,XX karyotypes.

Usually, estrogen replacement therapy is used to spur the growth of secondary sexual characteristics at the time when puberty should onset. While very few women with Turner syndrome menstruate spontaneously, estrogen therapy requires a regular shedding of the uterine lining ("withdrawal bleeding") to prevent its overgrowth. Withdrawal bleeding can be induced monthly, like menstruation, or less often, usually every three months, if the patient desires. Estrogen therapy does not make a woman with nonfunctional ovaries fertile, but it plays an important role in assisted reproduction; the health of the uterus must be maintained with estrogen if an eligible woman with Turner Syndrome wishes to use IVF (using donated oocytes).

Especially in mosaic cases of Turner syndrome that contains Y-chromosome (e.g., 45,X/46,XY) due to the risk of development of ovarian malignancy (most common is gonadoblastoma) gonadectomy is recommended. Turner syndrome is characterized by primary amenorrhoea, premature ovarian failure (hypergonadotropic hypogonadism), streak gonads and infertility (however, technology (especially oocyte donation) provides the opportunity of pregnancy in these patients). Failure to develop secondary sex characteristics (sexual infantilism) is typical.

Cognition

Neurodevelopmental

Individuals with Turner syndrome have normal intelligence. Verbal IQ is usually higher than performance IQ; one review of thirteen studies found an average verbal IQ of 101 compared to an average performance IQ of 89.

People with Turner syndrome demonstrate relative strengths in verbal skills, but may exhibit weaker nonverbal skills – particularly in arithmetic, select visuospatial skills, and processing speed. They have difficulties with directional sense, visualization of three-dimensional shapes, properties of shapes, and symmetry and may have dyscalculia. Turner syndrome does not typically cause intellectual disability or impair cognition. However, learning difficulties are common among women with Turner syndrome, particularly a specific difficulty in perceiving spatial relationships, such as nonverbal learning disorder. This may also manifest itself as a difficulty with motor control or with mathematics. While it is not correctable, in most cases it does not cause difficulty in daily living. Most Turner syndrome patients are employed as adults and lead productive lives.

Also, a rare variety of Turner syndrome, known as "Ring-X Turner syndrome", has about a 60% association with intellectual disability. This variety accounts for around 2–4% of all Turner syndrome cases.

Psychological

Social difficulties appear to be an area of vulnerability for girls with Turner Syndrome. Counseling affected individuals and their families about the need to carefully develop social skills and relationships may prove useful in advancing social adaptation. Women with Turner syndrome may experience adverse psychosocial outcomes which can be improved through early intervention and the provision of appropriate psychological and psychiatric care. Although Turner syndrome constitutes a chronic medical condition, with possible physical, social, and psychological complications in a woman's life, hormonal and estrogen replacement therapy, and assisted reproduction, are treatments that can be helpful for Turner syndrome patients and improve their quality of life. Research shows a possible association between age at diagnosis and increased substance use and depressive symptoms.

Prenatal

Despite the excellent postnatal prognosis, 99% of Turner syndrome conceptions are thought to end in miscarriage or stillbirth, and as many as 15% of all spontaneous abortions have the 45,X karyotype. Among cases that are detected by routine amniocentesis or chorionic villus sampling, one study found that the prevalence of Turner syndrome among tested pregnancies was 5.58 and 13.3 times higher, respectively, than among live neonates in a similar population.

Cause

Turner syndrome is caused by the complete or partial absence of one copy of the X chromosome in some or all the cells. The abnormal cells may have only one X (monosomy) (45,X) or they may be affected by one of several types of partial monosomy like a deletion of the short p arm of one X chromosome (46,X,del(Xp)) or the presence of an isochromosome with two q arms (46,X,i(Xq)) Turner syndrome has distinct features due to the lack of pseudoautosomal regions, which are typically spared from X-inactivation. (46,X,i(Xq)) Turner syndrome females with sSMC consisting of a partial X chromosome that does not contain the XIST gene express at least some of this sSMC's genetic material and therefore contain excesses of this material. In consequence, they have a more serious form of the Turner syndrome that ranges form moderately severe to extremely severe. The extremely severe cases have anencephaly (absence of a major portion of the brain, skull, and scalp), agenesis of the corpus callosum (lack of the thick tract of nerve fibers that connect the left and right cerebral hemispheres), and complex heart deformities. Individuals with (46,X,i(Xq)) Turner syndrome that have partial X chromosome containing sSMCs that have the XIST gene do not express this sSMC's genetic material and do not have the more severe manifestations of the syndrome.

Inheritance

In the majority of cases where monosomy occurs, the X chromosome comes from the mother. This may be due to a nondisjunction in the Mother. Meiotic errors that lead to the production of X with p arm deletions. Isochromosome X or ring chromosome X on the other hand are formed equally often by both parents.

Diagnosis

Prenatal

thumb|right|45,X [[karyotype, showing an unpaired X at the lower right]]

Turner syndrome may be diagnosed by amniocentesis or chorionic villus sampling during pregnancy.

Usually, fetuses with Turner syndrome can be identified by abnormal ultrasound findings (i.e., heart defect, kidney abnormality, cystic hygroma, ascites). In a study of 19 European registries, 67.2% of prenatally diagnosed cases of Turner syndrome were detected by abnormalities on ultrasound. 69.1% of cases had one anomaly present, and 30.9% had two or more anomalies.

An increased risk of Turner syndrome may also be indicated by abnormal triple or quadruple maternal serum screen. The fetuses diagnosed through positive maternal serum screening are more often found to have a mosaic karyotype than those diagnosed based on ultrasonographic abnormalities, and conversely, those with mosaic karyotypes are less likely to have associated ultrasound abnormalities.

A test called a karyotype, also known as a chromosome analysis, analyzes the chromosomal composition of the individual. This is the test of choice to diagnose Turner syndrome.

Treatment

As a chromosomal condition, there is no cure for Turner syndrome. However, much can be done to minimize the symptoms. While most of the physical findings are harmless, significant medical problems can be associated with the syndrome. Most of these significant conditions are treatable with surgery and other therapies including hormonal therapy.

Synthetic growth hormones, either alone or with a low dose of androgen, will increase height by several inches and probably final adult height. Growth hormone is approved by the U.S. Food and Drug Administration for treatment of Turner syndrome and is covered by many insurance plans. It can make Turner females achieve a more normal height There is evidence that this is effective, even in toddlers. A 2019 systematic review comparing effects of adding oxandrolone to growth hormone treatment to growth hormone alone has found moderate-quality evidence that the addition of oxandrolone leads to an increase in final adult height of girls with Turner syndrome. When the same review assessed the effects of adding Oxandrolone to growth hormone treatment on speech, cognition and psychological status, the results were inconclusive due to very-low quality evidence.

Epidemiology

Turner syndrome occurs in between one in 2,000 Turner syndrome accounts for about 10 percent of the total number of spontaneous abortions in the United States. In Europe, it is often called Ullrich–Turner syndrome and was sometimes called Bonnevie–Ullrich syndrome although the latter term is rarely used today. Both syndrome names acknowledge(d) that earlier cases had also been described 1930 by European doctors Kristine Bonnevie and Otto Ullrich. In Russian and Soviet literature, it is called Shereshevsky–Turner syndrome to acknowledge that the condition was first described as hereditary in 1925 by the Soviet endocrinologist , who believed that it was due to the underdevelopment of the gonads and the anterior pituitary gland and was combined with congenital malformations of internal development.

The first published report of a female with a 45,X karyotype was in 1959 by Charles Ford and colleagues in Harwell near Oxford, and Guy's Hospital in London. It was found in a 14-year-old girl with signs of Turner syndrome. In modern times, advocacy groups have played a vital role in raising awareness and offering support to those with TS, helping to reduce stigma and provide better access to medical care.