INTRODUCTION — Turner syndrome is an important cause of short stature in girls and of primary or secondary amenorrhea in adolescents. It is caused by loss of part or all of an X chromosome .
This topic will review the management of children and adolescents with this disorder. Treatment varies with the age of the patient and includes therapy for the short stature and estrogen deficiency, as well as identifying and managing the associated congenital anomalies and related comorbidities or complications (table 1) .
The clinical manifestations and diagnosis of Turner syndrome and management in adults are reviewed separately. (See "Clinical manifestations and diagnosis of Turner syndrome" and "Management of Turner syndrome in adults".)
PRENATAL MANAGEMENT — Cases of Turner syndrome sometimes are discovered incidentally during chorionic villus sampling or amniocentesis done for either advanced maternal age or for suspicion about congenital anomalies noted on fetal ultrasonography. Ultrasound findings that may be seen in a fetus with Turner syndrome include increased nuchal translucency, a good marker for fetal chromosomal defects, cystic hygroma, or fetal hydrops . Finding a 45,X karyotype in a fetus with a large cystic hygroma or hydrops confirms the diagnosis of Turner syndrome . In such cases, the likelihood for spontaneous abortion is high.
When a diagnosis of Turner syndrome is entertained prenatally, the parents should be provided detailed genetic counseling. Parents may, on their own, consider termination of the pregnancy, often prompted by their review of information available on the internet. Reliable genetic counseling may be challenging because it can be difficult to predict the exact phenotype of girls with prenatally diagnosed Turner syndrome. Retrospective studies suggest that many girls, and particularly those with 45,X/46,XX mosaicism , may have a milder phenotype than those diagnosed on the basis of clinical suspicion [5,6]. It is important that some of the counseling be provided by health care professionals with direct experience caring for Turner syndrome patients throughout childhood and adolescence; these are often pediatric endocrinologists. Such clinicians are best suited to answer questions about available treatments and prognosis related to the Turner syndrome comorbidities (see "Sonographic findings associated with fetal aneuploidy", section on 'Monosomy X (Turner syndrome)'). Finally, advanced methods of noninvasive prenatal testing using molecular sequencing may raise the possibility of Turner syndrome (either in the fetus or the mother), and additional testing plus genetic counseling will be needed. At this time, there is not enough evidence to recommend the routine use of noninvasive prenatal testing to diagnose Turner syndrome prenatally, whether performed by sequencing or single-nucleotide polymorphism array analysis of cell-free fetal deoxyribonucleic acid (DNA) from maternal blood. (See "Prenatal screening for common aneuploidies using cell-free DNA".)
DISCLOSURE OF THE DIAGNOSIS — Providers should counsel parents about how to disclose diagnostic and other health-related information in a timely, caring, and age-appropriate manner. This is of great importance to the overall mental and physical health of the patient.
Many patients report that their Turner syndrome diagnosis or other important information was inappropriately withheld from them. In a study conducted in the United States, approximately one-third of patients with Turner syndrome reported that their families or health care providers had withheld all or part of the Turner syndrome diagnosis . In particular, several patients were not informed of the infertility associated with the diagnosis. A guide to disclosure prepared by the Turner Syndrome Foundation is available online.
MONITORING AND MANAGING COMORBIDITIES — A comprehensive initial evaluation and subsequent monitoring are recommended for each of the following issues, as outlined in the tables (table 2A-B) [8,9]. Whenever possible, patients should be cared for in a multidisciplinary clinic dedicated to Turner syndrome or at least by a team of specialists with such expertise.
Cardiovascular anomalies — Congenital heart defects may occur in 23 to 50 percent of Turner syndrome patients. They are the most frequent cause of early mortality in this population. The incidence of such defects is higher in patients harboring a 45,X karyotype compared with those who have X chromosome mosaicism or structural X chromosome defects. The spectrum of cardiovascular comorbidities associated with Turner syndrome and guidance for monitoring and management are summarized in a statement from the American Heart Association . An approach to screening for cardiovascular anomalies is shown in the table (table 2A).
Initial evaluation — At the time of diagnosis, all infants and children with Turner syndrome should have a comprehensive cardiovascular evaluation by a pediatric cardiologist, including the following [8,9]:
●Measurements of blood pressure in both the upper and lower extremities.
●Electrocardiography (ECG) to assess for conduction abnormalities (eg, prolonged QTc interval). (See "Clinical manifestations and diagnosis of Turner syndrome", section on 'Conduction abnormalities'.)
●Cardiac imaging – Echocardiography is performed to evaluate for structural abnormalities such as coarctation of the aorta, bicuspid aortic valve, or partial anomalous pulmonary venous return. We suggest cardiac magnetic resonance (CMR) imaging as soon as the patient is old enough to tolerate the procedure without general anesthesia (typically around 12 years of age) . CMR is valuable for both screening and surveillance, especially to detect abnormalities such as a dilated ascending aorta, an elongated transverse aortic arch (as well as other aortic phenotypes with milder aortic arch hypoplasia), and partial anomalous pulmonary venous return. Other cardiovascular anomalies in Turner syndrome are outlined in the table and reviewed separately (table 1) [8,9,11].
Ideally, all patients with Turner syndrome, and especially those with identified cardiac anomalies, should have ongoing follow-up care with a cardiologist, preferably one who has expertise in congenital heart disease. (See "Clinical manifestations and diagnosis of Turner syndrome", section on 'Cardiovascular disease'.)
Management of specific cardiovascular abnormalities — Specific management issues are:
●Patients with coarctation of the aorta usually require corrective surgery. Management of coarctation of the aorta is discussed in detail separately. (See "Management of coarctation of the aorta".)
●For those with a prolonged QTc interval, drugs that prolong QTc interval should be avoided (eg, antiarrhythmic drugs, certain nonsedating antihistamines [eg, terfenadine and astemizole], certain antimicrobials [eg, macrolide and fluoroquinolone antibiotics, metronidazole, some antifungal agents, and antiretroviral drugs], certain psychotropic medications [eg, haloperidol], certain gastric motility agents [eg, cisapride], and others) (table 3). (See "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".)
●Antimicrobial prophylaxis is not required for most Turner syndrome patients with heart valve disease, including those with bicuspid aortic valve. This is based on the 2007 American Heart Association guidelines on the prevention of bacterial endocarditis, which recommend that only patients with the highest risk for the development of endocarditis receive antimicrobial prophylaxis .
Monitoring for aortic dilatation — Repeat imaging with echocardiography and/or CMR is suggested periodically throughout life to monitor for the development and/or progression of ascending aortic dilation. Aortic dissection or rupture is an important cause of death in women with Turner syndrome, and the risk is predicted by a dilated ascending aorta (measured as the aortic diameter, normalized for body surface area with Turner syndrome-specific Z-scores or standard deviation [SD] units). Patients with known aortic dilation and those with risk factors for dissection (eg, hypertension, coarctation of the aorta, and/or bicuspid aortic valve) should undergo more frequent monitoring (algorithm 1) . However, routine surveillance is suggested for all women with Turner syndrome since aortic dissection can occur even in the absence of these risk factors. The protocol for women 16 years and older, and for those considering pregnancy, is discussed separately. Unfortunately, despite increased efforts, it appears that more than one-half of individuals with Turner syndrome are not adequately informed about the need for ongoing monitoring, even in the absence of cardiovascular symptomatology . (See "Management of Turner syndrome in adults", section on 'Cardiovascular health'.)
If aortic dilatation is identified, patients should be evaluated to optimize medical treatment, as outlined in a statement from the American Heart Association . Because hypertension is common in Turner syndrome, maintaining normal blood pressure may lower the risk of acute aortic events [14-16]. Management may include beta blockers, exercise restriction, and aggressive blood pressure control. Management of aortic dilatation is generally similar to the approach taken for patients with Marfan syndrome and other genetic aortopathies; clinical trials in individuals with Turner syndrome are lacking. (See "Management of Marfan syndrome and related disorders".)
Prophylactic antihypertensive therapy may be started early in the course because aortic dissection may also occur earlier (at smaller aortic dimensions) in Turner syndrome than in nonsyndromic patients with aortic dilatation . Elective surgical repair may be an option for some patients, particularly if aortic dilation is rapidly expanding (ie, an increase of >+1 in Turner syndrome-specific Z-scores or an absolute increase of >+0.5 cm in one year). The techniques used and perioperative care are similar to those used for other patients with aortic dilatation and dissection. (See 'Hypertension' below and "Management of Marfan syndrome and related disorders" and "Management of thoracic aortic aneurysm in adults".)
Any complaint of chest pain should be evaluated urgently by a specialist because it may be a symptom of early dissection. (See "Clinical features and diagnosis of acute aortic dissection".)
Hypertension — Blood pressure should be monitored at every clinical visit. It is important to measure blood pressure manually because automatic blood pressure monitoring often results in falsely high readings.
Hypertension is common in Turner syndrome, although little has been documented about the diagnosis of hypertension in this population . A prevalence as high as 30 percent in children and 60 percent in adults has been suggested. This was confirmed in a group of Turner syndrome girls compared with a large cohort of healthy girls: The former had significantly higher diastolic and systolic blood pressures than did the reference population, with the diastolic measurements remaining higher even when corrected for body mass index. More than one-half of the Turner syndrome group had at least one blood pressure reading above the hypertension threshold . Turner syndrome patients are more likely to have transiently elevated blood pressure measurements in the office ("white coat hypertension") due to their increased level of anxiety compared with normal peers. (See "Clinical manifestations and diagnosis of Turner syndrome", section on 'Hypertension'.)
If hypertension develops, it should be treated vigorously, including lifestyle modification and weight management. Early recognition of and treatment for systemic hypertension is particularly important for patients with Turner syndrome because of their increased risk for cardiovascular events. Patients should also be carefully evaluated for causes of hypertension such as kidney disease, obstructive uropathy, and coarctation of the aorta.
Most experts suggest starting therapy for blood pressures that are persistently in the hypertensive range and targeting a low-normal blood pressure . Hypertension is defined as blood pressure >130/80 mmHg for adults and children >13 years, or >95th percentile for younger children (table 4) [19,20]. Initial therapy usually consists of beta-adrenergic receptor blockers, unless otherwise contraindicated, due to their favorable effect on aortic dilatation in Marfan syndrome, although evidence in Turner syndrome is limited [8,9,17]. Angiotensin-converting enzyme (ACE) inhibitors are a reasonable alternative. (See "Nonemergent treatment of hypertension in children and adolescents", section on 'Antihypertensive drugs'.)
Cognitive function and learning disabilities — Neuropsychology and allied behavioral health services should be integrated into the care for girls and women with Turner syndrome . This includes annual developmental and behavioral screenings until adulthood, with referrals as needed. Simple screening tools are also available for anxiety, one of the more common mood disorders observed in Turner syndrome girls, and can even be applied easily by nonmental health care providers who may see these girls in the office on a more frequent basis . In addition, neuropsychologic assessments should be performed at key transitional stages in schooling, such as entry into elementary, middle, and high school. Any learning or performance issues identified should be addressed with appropriate academic and occupational adjustments. Educational needs should be reevaluated periodically, depending on initial results and school performance (see "Specific learning disorders in children: Educational management"). A review of the many neurocognitive features observed in individuals with Turner syndrome provides practical recommendations for the treatment of psychological and behavioral difficulties, as well as specific considerations for educational support for the school-aged child with Turner syndrome .
Most individuals with Turner syndrome have normal intelligence, but girls with a small ring X chromosome have a higher risk for significant intellectual disability. This is due to the ring X missing the X-inactivation site XIST at Xq13.2. The result is functional disomy of certain Xp loci that should normally be inactivated but instead leads to an atypical Turner syndrome phenotype . Other patients with Turner syndrome may have attention hyperactivity deficit disorder (ADHD) and difficulties with visual-spatial organization, social cognition, and nonverbal problem-solving tasks such as mathematics. (See "Clinical manifestations and diagnosis of Turner syndrome", section on 'Psychologic and educational issues'.)
Tympanometry and audiology — Regular monitoring of hearing, including serial audiology evaluations, is recommended throughout life, with an audiology evaluation every three years in children and every five years in adults .
Children with Turner syndrome have high rates of conductive hearing problems due to recurrent otitis media and middle ear effusions, resulting from abnormalities of the Eustachian tubes and cranial base . Progressive sensorineural hearing loss develops by adulthood in more than 50 percent of patients. (See "Clinical manifestations and diagnosis of Turner syndrome", section on 'Hearing and ear abnormalities' and "Management of Turner syndrome in adults", section on 'Audiology testing'.)
Scoliosis and kyphosis — Surveillance for scoliosis and kyphosis is important throughout childhood and especially during adolescence [8,9]. At a minimum, surveillance should include a physical examination for scoliosis (visual inspection and bend-forward test) annually and every six months during growth hormone therapy, with a consideration for additional radiographic assessment around school entry (five to six years of age) and during mid-puberty (12 to 14 years of age), or when concerns arise. (See "Adolescent idiopathic scoliosis: Clinical features, evaluation, and diagnosis", section on 'Scoliosis examination'.)
Scoliosis may progress or manifest itself during growth hormone therapy. The presence of scoliosis or kyphosis does not preclude growth hormone therapy but warrants close monitoring during therapy, sometimes with the assistance of orthopedic specialists [8,9]. (See "Clinical manifestations and diagnosis of Turner syndrome", section on 'Short stature and skeletal anomalies' and "Adolescent idiopathic scoliosis: Management and prognosis", section on 'Indications for referral'.)
Renal anomalies and urinary tract infections — Patients should undergo renal ultrasonography at the time that Turner syndrome is diagnosed to identify congenital malformations of the renal/urinary system, which are present in approximately 30 to 40 percent of patients. If structural abnormalities are identified, patients should be evaluated by a nephrologist or urologist and monitored clinically for urinary tract infection. The presence of an abnormality of the collecting system increases the risk for urinary tract infections, although most patients do not have any long-term issues with recurrent infections. (See "Clinical manifestations and diagnosis of Turner syndrome", section on 'Renal anomalies'.)
Ophthalmology — An ophthalmologic examination is recommended at the time of diagnosis of Turner syndrome (starting in the second year of life) and every three years thereafter due to risks for strabismus, amblyopia, and ptosis [8,9]. (See "Clinical manifestations and diagnosis of Turner syndrome", section on 'Ocular abnormalities'.)
Edema — Edema in Turner syndrome is usually due to lymphatic hypoplasia. Lymphedema of the hands and feet at birth usually remits substantially but not always completely. Anecdotal reports describe worsening of some of the edema coinciding with the institution of either growth hormone therapy or estrogen supplementation. When present in the upper and/or lower extremities in children or adults, it can be controlled in most cases with support stockings, lymphatic drainage massage therapy, and physical therapy. Some patients may benefit from referral to a lymphedema treatment center. Vascular surgery aimed at the correction of the lymphedema is rarely indicated. Use of diuretics does not help and is not warranted.
Celiac disease — Screen for celiac disease by measuring tissue transglutaminase immunoglobulin A antibodies (tTG-IgA; usually combined with total IgA), beginning in early childhood (around two years of age) and repeating every two years throughout childhood [8,9]. During early adulthood, screening should be repeated if symptoms suggestive of celiac disease arise. The risk of celiac disease is modestly increased in Turner syndrome, with approximately 4 to 6 percent of patients affected. (See "Clinical manifestations and diagnosis of Turner syndrome", section on 'Autoimmune disorders'.)
Autoimmune thyroiditis — Screen for autoimmune thyroiditis by measuring thyroid-stimulating hormone and free or total thyroxine (T4) annually beginning around four years of age [8,9]. The prevalence of autoimmune thyroid disorders increases with advancing age. Hypothyroidism develops in approximately 15 percent of adolescents and 25 to 30 percent of adults, while up to 50 percent of adults have thyroid autoantibodies . (See "Clinical manifestations and diagnosis of Turner syndrome", section on 'Autoimmune disorders'.)
Liver disease — Screen for liver disease by measuring alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGTP), and alkaline phosphatase annually after 10 years of age. Abnormalities in these measures are common in patients with Turner syndrome, perhaps due to metabolic syndrome and obesity and/or autoimmunity. Patients with persistent aminotransferase elevations (eg, greater than twice the upper limit of normal) should be further evaluated for other causes of liver disease and/or referred to a hepatologist. Although liver enzymes may remain elevated throughout childhood and in the adolescent years, they may improve or resolve with estrogen replacement therapy . (See "Clinical manifestations and diagnosis of Turner syndrome", section on 'Abnormal liver enzymes'.)
Metabolic syndrome — Because Turner syndrome youth have beta cell dysfunction due to both reduced insulin secretion and sensitivity, screening for hyperglycemia by measuring hemoglobin A1c, with or without fasting glucose, should be done annually beginning at 10 years of age . Screen for dyslipidemia by measuring a lipid panel annually if at least one cardiovascular disease risk factor is present . (See "Clinical manifestations and diagnosis of Turner syndrome", section on 'Metabolic syndrome and diabetes mellitus'.)
Vitamin D deficiency — Screen for vitamin D deficiency by measuring serum 25-hydroxyvitamin D between 9 and 11 years of age and every two to three years thereafter . Maintaining recommended serum concentrations of 25-hydroxyvitamin D is important because girls and women with Turner syndrome have an increased risk of fracture even if they have normal bone mineral density. In a nationwide survey, there was no difference in fracture prevalence in younger women with Turner syndrome compared with controls . On the other hand, the location of their fractures differed, and, after controlling for age, impaired balance was associated with an increased fracture risk. This may be an underrecognized risk factor for fracture in this population. Patients should further be counseled to ingest the recommended amount of calcium in the diet or by taking supplements. Bone mineral density assessment is not needed during the childhood years; such assessment should begin when patients reach adult estradiol replacement doses (late adolescence or early adulthood). (See "Clinical manifestations and diagnosis of Turner syndrome", section on 'Osteoporosis and bone health' and "Vitamin D insufficiency and deficiency in children and adolescents".)
Gonadoblastoma risk — Screen for Y chromosome mosaicism in any Turner syndrome patient who has marker chromosome elements (sex chromosome material of uncertain origin) detected on the karyotype or who develops virilization. This is because Y chromosome mosaicism is associated with an increased risk for gonadoblastoma. Routine molecular search for Y chromosome-derived DNA is not necessary in Turner syndrome patients without marker chromosome elements or virilization. (See "Clinical manifestations and diagnosis of Turner syndrome", section on 'Y chromosome mosaicism'.)
If Y chromosome material is detected, affected patients should still undergo prophylactic removal of the gonads (oophorectomy or salpingo-oophorectomy), even if they appear to be streak gonads [9,28]. Hysterectomy is not recommended to preserve the possibility of pregnancy using donor oocytes . Streak gonads do not need to be explored or removed in patients without Y chromosome mosaicism.
MANAGEMENT OF SHORT STATURE
Monitoring growth — Short stature, sometimes combined with a disproportionately wide torso that results in a stocky appearance, is the most common clinical feature of Turner syndrome. For monitoring growth, the height of patients with Turner syndrome should be plotted on growth curves specific for this disorder. These growth curves show height percentiles for untreated patients with Turner syndrome, as well as height percentiles for the general female population (figure 1) [30,31].
Note that growth hormone testing is not indicated, because patients with Turner syndrome do not have growth hormone deficiency despite their short stature. Nonetheless, growth hormone therapy in pharmacologic doses improves growth.
Growth hormone therapy — Most patients with Turner syndrome should be treated with growth hormone therapy to maximize their adult height and improve body composition.
●Indications and timing – Recombinant human growth hormone therapy should be initiated as soon as the height of a girl with Turner syndrome falls below the 5th percentile for age on the normal female growth chart, which usually occurs between two and five years of age [8,9,32]. Young patients with particularly slow height velocity may benefit from starting growth hormone even earlier (ie, before the height falls below the 5th percentile). The clinician should monitor how the patient's growth compares with the expected growth based on the mid-parental (target) height and expected target height growth curve. Significant deviation from the expected growth curve is always reason for concern and should prompt assessment of superimposed secondary causes of growth failure and/or earlier intervention.
●Dosing – In the United States, a typical initial dose of growth hormone is approximately 50 mcg/kg/day (0.35 to 0.375 mg/kg/week), given once daily by subcutaneous injection. Patients with Turner syndrome are typically treated with somewhat higher doses of growth hormone compared with patients with growth hormone deficiency; doses of growth hormone up to 67 mcg/kg/day have been used. Growth hormone therapy should be continued until little growth potential remains (eg, bone age exceeds 13.5 to 14 years and growth slows to less than 2.5 cm per year). (See "Treatment of growth hormone deficiency in children".)
Because this dosing scheme is based on body weight, the growth hormone dose may be excessive if the child is overweight. To avoid this problem, we suggest measuring serum concentrations of insulin-like growth factor 1 (IGF-1) at least annually . The growth hormone dose can then be adjusted as needed to maintain IGF-1 concentrations below +2 standard deviations (SD) above the mean for age and/or Tanner stage of pubertal development but ideally above the mean (approximately +1 SD). This is because a prolonged elevation of IGF-1 (eg, >+3 SD) may be associated with toxicity, while a low IGF-1 suggests that the dose of growth hormone may be insufficient and may not achieve an optimal growth response. IGF-1-based dose titration of growth hormone therapy is extrapolated from management of children with other growth disorders, such as idiopathic short stature or growth hormone deficiency, and the efficacy of this approach for Turner syndrome has not been established.
Alternatively, growth hormone dosing in Turner syndrome patients can be calculated based on body surface area (using 1.33 mg/m2/day as a starting point). This approach may be most appropriate for the Turner syndrome patients beyond 9 to 10 years of age, when they are more likely to be overweight and, therefore, body weight-based dosing is more likely to lead to overdosing .
In other countries, slightly lower doses are used. In Europe, a typical dose is 1.3 to 1.4 mg/m2/day (approximately 40 to 50 mcg/kg/day, or 4.0 to 4.3 international units/m2/day), and in Australasia. 4.5 to 9.5 mg/m2/week, administered in divided doses seven days/week. Higher growth hormone doses are not routinely recommended, but an increase in the growth hormone dose may be considered in girls with very poor height prognosis, while staying within the authority-approved dose range and following careful discussion of potential risks and benefits.
●Efficacy – Initiation of recombinant human growth hormone at a young age (four to six years) often permits attainment of normal adult height. This was illustrated in several studies:
•The dose response to growth hormone therapy was evaluated in a trial of 68 young girls (mean age between six and seven years) with Turner syndrome who were randomly assigned to three different regimens of growth hormone (figure 2), starting at approximately 45 mcg/kg/day, with some groups escalating to doses as high as approximately 90 mcg/kg/day during the first few years of therapy . In long-term follow-up of 60 participants, 83 percent reached a normal adult height (ie, more than -2 SD) . Escalating the growth hormone dose over time to approximately 67.5 mcg/kg/day achieved a mean additional height gain of 5.3 cm (figure 3). These height outcomes were achieved after an average treatment duration of 8.6 years. Similar results were reported from an observational registry of 344 patients with Turner syndrome treated with growth hormone .
•The efficacy of low-dose estradiol as an adjunct to growth hormone therapy was evaluated in a placebo-controlled trial in which girls 5 to 12.5 years of age were randomized to treatment with growth hormone at a dose of 0.1 mg/kg body weight three times a week, with or without low-dose ethinyl estradiol orally (starting dose 25 ng/kg/day), or with corresponding placebos . The group treated with growth hormone alone achieved a mean adult height of 148 cm, which was 0.78 SD (approximately 5 cm) greater than those treated with double placebo. The group treated with ethinyl estradiol as well as growth hormone grew an additional 2.1 cm in height. In this study, the height increment attributable to growth hormone therapy was less than in some of the other studies [34,36], perhaps because treatment was started at a later age and the dose of growth hormone was lower than is typically used.
•Effects of very early initiation of growth hormone were evaluated in a prospective, randomized, open-label clinical trial in 88 girls with Turner syndrome aged nine months to four years of age . The subjects were treated with growth hormone (50 mcg/kg/day; n = 45) or were not treated (n = 43) for two years. The between-group difference at the end of the study was 1.6±0.6 SD (p <0.0001). This study confirmed that early growth hormone treatment can correct growth failure and normalize height in infants and toddlers with Turner syndrome. Long-term follow-up of these patients showed that, although the earlier-treated girls were taller throughout childhood, their near-adult height outcome was not significantly different than those whose treatment was initiated later (ie, the initial control group) .
Together, the findings from these studies demonstrate that early initiation of growth hormone therapy is important to achieve clinically significant increments in height and that higher doses (eg, above 45 mcg/kg/day) yield additional benefit . We do not recommend the routine use of very low-dose estradiol in prepubertal children (ie, before approximately 11 years of age), because its effects on height are modest (an additional 2.1 cm) and this may be insufficient to justify its use. It is possible that such very low-dose estradiol therapy may also improve bone mineralization, memory, and cognitive function, but these outcomes require additional investigation . (See 'Benefits of hormonal therapy' below.)
In addition to its effect on longitudinal bone growth, growth hormone therapy may have beneficial effects on body composition. In a cross-sectional study of girls with Turner syndrome, growth hormone therapy increased lean body mass and decreased body fat . These changes were independent of estrogen exposure. Growth hormone therapy does not appear to have a deleterious effect on blood pressure, left ventricular function, or aortic diameter [42-44]. Adverse effects of growth hormone therapy, including intracranial hypertension, slipped capital femoral epiphysis, and pancreatitis are uncommon but perhaps slightly more prevalent than in children who are treated with growth hormone for indications other than Turner syndrome . (See "Treatment of growth hormone deficiency in children", section on 'Adverse effects of growth hormone therapy'.)
Finally, it is unclear whether benefits of growth hormone therapy on adult height will affect the overall health-related quality of life (HRQoL). Improved height is often the basis of parents' decision to initiate growth hormone therapy and is also endorsed as important by most girls with Turner syndrome. However, in one study of adult women with Turner syndrome, growth hormone treatment was not associated with improved HRQoL, despite a mean 5.7 cm gain in adult height . This finding does not preclude an effect of growth hormone on HRQoL, since many girls experience significant improvement in adult height with growth hormone therapy compared with their untreated height projections and because HRQoL is compromised by the effects of multiple other comorbidities of Turner syndrome. The introduction of novel therapeutic approaches (eg, long-acting growth hormone compounds) in the future may further impact the outcome of growth-promoting therapies in Turner syndrome.
Strategies for severe short stature — In girls 10 to 12 years of age with severe short stature (ie, unlikely to reach the 5th percentile for the adult general female population), one may consider delaying pubertal induction, in combination with high-dose growth hormone therapy (eg, growth hormone dose up to 67 mcg/kg/day) . Delaying pubertal induction may improve height outcome in some individuals by postponing fusion of the epiphyses, which is triggered by estradiol. If this approach is chosen, monotherapy with growth hormone is continued and estradiol is started closer to 14 years, rather than the standard 11 to 12 years of age. This permits additional growth before epiphyses fuse. However, delayed pubertal induction appears to have, at best, a modest effect on adult height. This was shown in a trial in which delaying pubertal induction from age 12 to 14 years was associated with a 2.7 cm increase in adult height, which was not statistically significant (95% CI -0.8 to 6.1 cm; n = 56) [47,48].
Oxandrolone, an anabolic steroid, in combination with growth hormone, improves height velocity in girls with Turner syndrome. Through its androgenic effects, oxandrolone increases protein synthesis, lean body mass, and bone mineral density. In a randomized trial, adjunctive oxandrolone (added to growth hormone therapy at age 9 to 10 years and titrated to no more than 0.05 mg/kg/day) significantly increased adult height by 4.1 cm (95% CI 1.6-6.6) compared with growth hormone alone . Other trials comparing oxandrolone plus growth hormone with growth hormone alone show a mean difference of 2.7 cm, in favor of adjunctive oxandrolone. Oxandrolone was generally continued until 11 to 12 years of age, when estradiol therapy was initiated .
However, regulatory approval for oxandrolone was withdrawn by the US Food and Drug Administration in 2023. This was due to reporting of substantial side effects including liver failure and liver cell tumors . Most of the available data was from use of oxandrolone in adults with chronic infections, after severe trauma, for the relief of the osteoporosis-associated bone pain, or to promote weight gain after weight loss following surgery. Review is underway by some of the manufacturers of oxandrolone to evaluate if these reported adverse effects are also observed when oxandrolone is used to promote growth in girls with Turner syndrome.
Of note, a systematic review did not detect such adverse effects in girls with Turner syndrome up to 18 years of age but noted low certainty for these outcomes because of limited sample size . An update of the 2017 Clinical Practice Guideline on the care of patients with Turner syndrome  is expected to be published in 2024. This should provide additional information about potential adverse effects of oxandrolone in girls with Turner syndrome.
INDUCTION OF PUBERTY — Primary hypogonadism is one of the most common features of Turner syndrome, as demonstrated by lack of pubertal development and primary amenorrhea or pubertal arrest with secondary amenorrhea in approximately 90 percent of Turner syndrome individuals. Because of the broad range of gonadal dysfunction, it can be difficult to predict which girls will have absence of puberty and which will have spontaneous thelarche or even menarche. However, serum anti-müllerian hormone (AMH) concentrations appear to be useful for predicting future ovarian function. (See "Clinical manifestations and diagnosis of Turner syndrome", section on 'Ovarian failure'.)
Monitoring during childhood — Pubertal development should be assessed with serial examinations throughout childhood and adolescence. Estradiol replacement therapy usually should be initiated if there is no evidence of breast development by 11 to 12 years of age .
In addition, we measure serum follicle-stimulating hormone (FSH) and AMH, around 10 or 11 years of age, to help estimate ovarian function, detect impending ovarian failure, and predict the need for estradiol replacement. AMH is a reasonably sensitive marker of prepubertal follicular development and can be used to assess ovarian function throughout childhood . In one study, serum AMH was detectable in 22 percent of all Turner syndrome patients (10 percent in 45,X versus 77 percent in 45,X/46,XX) and those with detectable concentrations of AMH were more likely to experience spontaneous puberty (odds ratio 19.3) and menarche (odds ratio 47.6) [52,53]. Additional studies confirmed that AMH concentrations are associated with karyotype, presence of spontaneous pubertal development, and both LH and FSH levels in girls with Turner syndrome .
Measurement of FSH or luteinizing hormone (LH) has less utility than AMH in predicting gonadal function in girls with Turner syndrome. In most girls with ovarian failure over the age of 10 years, FSH will be elevated (into the menopausal range) . In the past, mainly measurements of FSH (and, to a lesser extent, LH) were used to predict gonadal dysfunction in children with Turner syndrome. Although prepubertal girls with Turner syndrome tend to have higher FSH values than healthy girls, there is considerable overlap, especially because FSH varies with age in healthy children . FSH concentrations tend to be higher in girls with 45,X karyotype compared with those with mosaicism. In girls with ovarian failure (which typically begins in utero), LH and FSH levels are elevated after birth (mini-puberty of infancy) and decline during mid-childhood, only to rise again in the peripubertal years [55,56], or at the time of loss of previously normal ovarian function. Undetectable inhibin B concentrations have also been reported to predict ovarian failure in Turner syndrome individuals [55,56].
Estradiol therapy — Ultimately, almost all girls with Turner syndrome need supplementation with exogenous estradiol. This includes the 15 to 20 percent of girls with Turner syndrome who experience spontaneous puberty, which may persist for some time but which usually is followed by primary ovarian insufficiency (premature ovarian failure) . The objective of estradiol replacement therapy is to mimic the normal progression of puberty while maximizing growth potential with minimal risk. Later, cyclic progestins are added to the regimen to induce cyclic uterine bleeding and prevent endometrial hyperplasia.
Dose and timing — Estradiol therapy usually should be initiated around 11 to 12 years of age if gonadotropins are elevated or AMH is low (see 'Strategies for severe short stature' above). Beginning treatment with low-dose estradiol around 11 to 12 years of age permits a normal timing and pace of puberty without compromising adult height . Some investigators suggest estradiol at an earlier age and at a very low dose [37,40]. However, the potential benefits and risks of this approach have not been sufficiently established to warrant routine use. Growth hormone and estradiol may be given together until epiphysial fusion occurs, after which the growth hormone is stopped. If oxandrolone was used in conjunction with growth hormone, it should be discontinued when estradiol treatment is started. (See 'Strategies for severe short stature' above.)
Estradiol replacement is usually begun at doses between one-tenth to one-eighth of the adult replacement dose. The dose is increased incrementally at approximately six-month intervals to simulate normal pubertal progression until adult dosing is reached over a two- to three-year period (table 5) [8,9]:
●The initial dose of estradiol should thus be low, eg, part of a transdermal estradiol patch at 3.125 to 6.25 mcg daily (or even just applied overnight to deliver approximately one-half this dose), or micronized 17-beta estradiol at 0.25 mg daily by mouth [8,9,51]. Depot estradiol at 0.2 to 0.4 mg intramuscularly monthly can be an alternative but is not often the patient's choice [51,58]. Some clinicians use an estradiol gel; potential disadvantages of this approach are that the gel is more difficult to dose in a small amount for pubertal induction, and there are only limited data concerning its use in Turner syndrome girls . Moreover, gel preparations may be inadvertently transferred to other children or pets, causing adverse effects.
When using transdermal estradiol patches, the lowest doses are achieved by cutting a matrix estradiol patch accordingly; the cutting technique cannot be used for a reservoir-type patch, as this would make the entire dose available at once.
●The dose should be increased gradually during the following 18 months to two years to a young adult dose. A typical adult dose is a transdermal estradiol patch (100 mcg/day) applied weekly or twice weekly. This dose is also roughly equivalent to 2 mg of oral micronized estradiol, approximately 10 mcg of oral ethinyl estradiol, or 1.25 mg of oral conjugated equine estrogen. Clinicians treating adult Turner syndrome patients can interchange between these formulations, but the transdermal route is preferred, as discussed in the following section [8,9]. Most clinicians increase the dose every four to six months, with some variation based on the patient's clinical response (table 5). For girls whose epiphyses are still open, it may be useful to advance the estradiol dose more slowly to maximize growth potential. Some clinicians choose to measure serum estradiol concentrations and adjust the dose to a normal range for the patient's age, but the utility of this approach has not been demonstrated. The individual responsiveness to even small doses of estradiol is variable and also needs to be taken into account when escalating the estradiol replacement.
The rationale for the gradual increase in estradiol dose is to mimic normal puberty and breast development. Although there are no available clinical data, many clinicians feel that this approach results in more normal breast development than when high doses are initiated. However, some girls do not think that their breast development is optimal even after appropriate estradiol therapy. This is hard to prove but could be due to poor development of breast anlage, widely spaced nipples, and the shield chest.
Route of administration — The best choice at this time is to use transdermal estradiol if the patient is willing and able to use this dose form. The transdermal estradiol is administered via a patch, which can be cut to deliver a reduced dose for young patients, as outlined above. Potential advantages of transdermal administration compared with oral estrogens include:
●More physiologic delivery, ie, into the systemic, rather than the hepatic, circulation. Bypassing the hepatic first-pass metabolism avoids stimulating production of coagulation factors and steroid- and thyroxine (T4)-binding proteins.
●Lower risk for venous thromboembolism due to avoiding hepatic first-pass metabolism.
●Ability to measure serum estradiol and, therefore, adjust the dose to achieve a normal concentration.
●Higher insulin-like growth factor 1 (IGF-1) concentrations, with possible improvement in metabolism.
●Improved blood pressure control (less activation of the renin-angiotensin system).
●Possibly improved uterine growth.
●Increased bone mineral accrual.
Studies comparing oral versus transdermal estradiol demonstrate a less physiologic estrogen milieu with the oral preparations, although the metabolic responses were similar [60,61]. The benefits of use of transdermal estradiol preparations should be balanced against the potential for poorer treatment adherence compared with oral estrogens .
We generally avoid conjugated estrogens altogether, if possible, given the advantages of the other preparations. Many adult patients with Turner syndrome prefer combination estrogen-progestin contraceptives for hormone replacement and, for some patients, the added convenience may improve treatment adherence. In this case, improved adherence to combination estrogen-progestin contraceptives may outweigh their additional risks compared with transdermal estrogens.
Women with uncontrolled hypertension or risk factors for venous thromboembolism should receive lower replacement doses of estradiol rather than estrogen-progestin contraceptives. Treatment is best individualized depending on the clinical situation, but the goal should first be to attempt using the transdermal preparations, primarily because of the lower risk for thromboembolic events. Based on a meta-analysis of many observational trials, women treated with oral estrogens have twice the risk for thromboembolic events compared with those treated with transdermal estradiol . In addition, a large prospective study confirmed that transdermal estradiol did not increase the relative risk for thromboembolism .
Adjunctive progestins — Girls receiving estradiol must be given cyclic progestin therapy to minimize the risk of endometrial hyperplasia and perhaps also for irregular bleeding and endometrial cancer (see "Menopausal hormone therapy: Benefits and risks"). Progestin therapy should begin after a maximum of approximately two years of estradiol monotherapy (typically around 13 or 14 years of age) or when vaginal breakthrough bleeding first occurs [8,9]. It is usually given as micronized progesterone at a dose of 200 mg daily for 10 to 12 days (eg, days 1 to 12 of each calendar month), which is associated with a low risk for the development of venothrombotic episodes . Medroxyprogesterone acetate 10 mg daily for 12 days is an appropriate alternative.
Benefits of hormonal therapy — Estradiol therapy effectively induces and maintains sexual development and improves uterine length and volume. In addition, estrogen therapy contributes to growth and height outcome when combined with growth hormone therapy (figure 3) [35,37,65] and improves bone mineralization and peak bone mass [66,67]. Early and consistent estradiol replacement may also have benefits on cardiovascular outcomes, as indicated by improvements in the lipid profile and reduced aortic stiffness [68,69], and may also improve liver enzyme abnormalities .
In addition, preliminary evidence suggests that gonadal hormone replacement may have beneficial effects on cognitive function and learning disabilities:
●Estrogen replacement appears to have some benefits on cognitive function in preadolescent girls, but its effects in older individuals are unclear . In a study of girls ages seven to nine years with Turner syndrome, low doses of ethinyl estradiol (25 ng/kg/day) improved verbal and nonverbal memory when compared with placebo . No effect on other verbal abilities or attention was seen. A similar report in slightly older girls suggested that estrogen replacement improved nonverbal processing speed and motor function .
●Androgen replacement (oxandrolone), in combination with growth hormone, has been used in selected patients with severe short stature but has been withdrawn from the market by the US Food and Drug Administration due to concerns about adverse effects (see 'Strategies for severe short stature' above). The possibility that oxandrolone might have benefit on certain aspects of cognitive function in girls with Turner syndrome has been investigated, but the small sample sizes of the studies preclude any definitive conclusions [74,75].
Adverse effects — Abnormal uterine bleeding occurs in approximately one-third of girls during pubertal induction with transdermal estrogen preparations, including prolonged, heavy, or intermenstrual bleeding . Abnormal uterine bleeding is more likely if progestin therapy is started later (after >18 months of unopposed estrogen), is given as micronized progesterone in doses <200 mg, is given less often than on a monthly basis, or if there is noncompliance.
CRYOPRESERVATION OF OVARIAN TISSUE OR OOCYTES — Cryopreservation of ovarian tissue and/or oocytes from selected preadolescent or adolescent girls with Turner syndrome is under investigation as a technique that might permit reproduction later in life . The use of these techniques is limited to girls with evidence of ovarian function. Follicle yield varies by genotype and is highest in girls with 45,X/46,XX mosaic genotypes and much lower in those with 45,X genotypes .
Cryopreservation of oocytes is an established fertility technique, but its use in Turner syndrome is limited to girls with mosaicism whose ovarian function persists through puberty [9,79]. Guidelines recommend against oocyte retrieval before 12 years of age . The first live birth using cryopreserved oocytes in a woman with mosaic Turner syndrome has been reported . This approach may therefore become an option for fertility preservation in selected individuals. However, pregnancy puts women with Turner syndrome at risk for cardiovascular events, most importantly, aortic dissection. (See "Fertility preservation: Cryopreservation options", section on 'Cryopreservation' and "Clinical manifestations and diagnosis of Turner syndrome", section on 'Pregnancy and cardiovascular risk'.)
Cryopreservation of cortical ovarian tissue is an experimental technique that has been used to preserve primordial follicles in ovarian tissue from adult women without Turner syndrome, and a case report describes its use in a prepubertal girl without Turner syndrome . The efficacy of this approach in Turner syndrome is unproven, but it might be applied to prepubertal girls with Turner syndrome with declining ovarian reserve who cannot wait until puberty to undergo oocyte cryopreservation. A combination of serum follicle-stimulating hormone (FSH), inhibin B, anti-müllerian hormone (AMH), and antral follicle counts on pelvic ultrasound can be used to select candidates for each cryopreservation technique, as outlined in the algorithm (algorithm 2) . (See "Female infertility: Evaluation", section on 'Assessment of ovarian reserve' and "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery", section on 'Fertility preservation'.)
For girls with ovarian function, consultation with a fertility expert (eg, reproductive endocrinologist) may be helpful to discuss prognosis and fertility options. Early referral (eg, during childhood) would be needed for consideration of ovarian tissue cryopreservation.
Parents should be aware that even if the cryopreservation procedure is successful, future pregnancy may not be advisable, because of the excess risk of mortality due to aortic complications such as dilatation and dissection. However, use of a gestational carrier allows a woman the option of using her own oocytes. (See "Management of Turner syndrome in adults", section on 'Management of fertility and pregnancy'.)
Although available guidelines recommend counseling regarding infertility, fertility preservation, and pregnancy risks in patients with Turner syndrome , this counseling is not always occurring. This was illustrated in a medical record review of over 460 young women with Turner syndrome who received care at academic medical centers . Documentation of fertility counseling was noted for 67 percent of families but in only 27 percent of individual Turner syndrome patients. Only 10 percent of Turner syndrome patients were referred to a reproductive specialist to discuss fertility preservation. Spontaneous menarche occurred in 58 patients (17 percent) aged nine years and older, but only 24 (41 percent) of these patients were referred to a fertility specialist . Patients receiving care at a multidisciplinary clinic were more likely to receive fertility and/or pregnancy counseling.
More data are necessary to evaluate the feasibility and efficacy of oocyte and ovarian tissue cryopreservation in girls with Turner syndrome. Oocyte cryopreservation after controlled ovarian stimulation (as in in vitro fertilization) may be an option in (mainly mosaic) adolescents with Turner syndrome who continue to have functional ovaries. Cryopreservation of ovarian tissue may work best if the girl is between 12 to 16 years of age, has mosaic Turner syndrome, develops puberty spontaneously, and maintains normal FSH and AMH concentrations.
TRANSITION TO ADULT CARE — The transition period is a crucial period during the health care management of the Turner syndrome patient. Loss to follow-up is common, leading to insufficient monitoring of comorbidities and lack of estrogen therapy or other interventions [84,85]. Providers must take this opportunity to address the many medical and nonmedical aspects of health, including a comprehensive health evaluation [9,86]. The communication and counseling should be tailored to the patient's maturity level and is ideally achieved by a multidisciplinary team.
A toolkit to assist with the transition to adult care was developed by the Endocrine Society in 2016 and includes forms for assessing patient readiness, knowledge and skills, general recommendations to the adult-care provider, and a summary of screening recommendations .
Important issues to discuss with the patient during the transition period include:
●Potential long-term complications of Turner syndrome, especially cardiovascular disease and hearing loss, and need for ongoing monitoring.
●Reproductive issues, including fertility options and potential risks of pregnancy. (See "Clinical manifestations and diagnosis of Turner syndrome", section on 'Pregnancy and cardiovascular risk' and "Management of Turner syndrome in adults", section on 'Management of fertility and pregnancy'.)
●Strategies and resources for managing learning difficulties, which, if present, continue into adult life. These resources may include educational consulting and support and vocational counseling .
●Resources for psychosocial support. The team should specifically encourage the patient to engage with Turner syndrome support groups for emotional support and to help empower the patient to stay engaged with their health maintenance . (See 'Resources and information' below.)
MORTALITY — Overall mortality rates in patients with Turner syndrome are increased approximately threefold when compared with the general population, with the greatest excess mortality in older adulthood . Noncongenital cardiovascular disease accounts for approximately 40 percent of deaths. These observations highlight the importance of preventive measures and careful monitoring for complications in both children and adults with Turner syndrome. (See "Management of Turner syndrome in adults", section on 'Mortality'.)
RESOURCES AND INFORMATION — Information and support for patients and their families can be obtained from:
●Turner Syndrome Society of the United States – 1-800-365-9944
●Turner Syndrome Foundation – 1-800-594-4585
●Turner Syndrome Society of Canada – 1-800-465-6744
●Turner Syndrome Support Society (United Kingdom) – +44-0141-952-8006
A patient/family version of the Turner Syndrome clinical practice guideline is available at the Turner Syndrome Society website .
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Turner syndrome".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Turner syndrome (The Basics)")
SUMMARY AND RECOMMENDATIONS
•Evaluation and monitoring – All infants and children with Turner syndrome should have a comprehensive cardiovascular evaluation by a pediatric cardiologist, including measurements of blood pressure in both the upper and lower extremities, electrocardiography (ECG), and echocardiography. We suggest cardiac magnetic resonance (CMR) imaging in older girls and women, mainly to monitor for dilation of the ascending aorta. Repeat imaging should be performed every five years during childhood and adolescence and more often if aortic dilatation or other pathology is detected (table 2A). (See 'Cardiovascular anomalies' above.)
•Aortic dissection – Aortic dissection is an important cause of death in women with Turner syndrome. The risk is predicted by a dilated ascending aorta, although dissection may occur at any point along the aorta. Patients with known aortic dilation and those with risk factors for dissection (eg, hypertension, coarctation, and/or bicuspid aortic valve) should have frequent monitoring (algorithm 1). Management of patients with aortic dilatation may include beta blockers, exercise restriction, and aggressive blood pressure control, similar to management of this issue in patients with Marfan syndrome. (See 'Monitoring for aortic dilatation' above and "Management of Marfan syndrome and related disorders".)
●Other comorbidities – Monitoring for other important health issues is outlined in the table (table 2B). During childhood, monitoring focuses on learning disabilities, conductive and sensorineural hearing impairment, scoliosis, and autoimmune disease (thyroiditis and celiac disease). (See 'Monitoring and managing comorbidities' above.)
•Prevalence – Short stature is the most common clinical feature of Turner syndrome. Mean adult height is 20 cm below the mean female population if not treated with growth hormone. (See 'Management of short stature' above.)
•Growth hormone therapy – We recommend starting recombinant human growth hormone therapy as soon as the height of a girl with Turner syndrome falls below the 5th percentile for age, which usually occurs between two and five years of age, rather than later initiation of growth hormone therapy (Grade 1B). Young patients with particularly slow height velocity may benefit from starting growth hormone even earlier. Height can be normalized in most patients with Turner syndrome but requires somewhat higher doses of growth hormone compared with standard doses used for growth hormone deficiency. Individualized dosing is essential. (See 'Growth hormone therapy' above.)
•Prevalence – Most individuals with Turner syndrome have primary hypogonadism (ovarian failure), as demonstrated by lack of pubertal development and primary amenorrhea and/or pubertal arrest. All patients should be provided counseling regarding infertility, fertility preservation, and pregnancy risks. (See 'Cryopreservation of ovarian tissue or oocytes' above.)
•Estradiol therapy – For most patients, low-dose estradiol therapy should be started around age 11 to 12 years of age to permit a normal timing and pace of puberty, without compromising adult height. Estradiol replacement is usually begun at doses between one-tenth and one-eighth of the adult replacement dose and then increased gradually during the next two to four years (table 5). Transdermal estradiol preparations are preferred. To optimize breast development, we suggest continuing estradiol monotherapy for up to two years before adding progestins (Grade 2C). (See 'Induction of puberty' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Paul Saenger, MD, MACE, who contributed to an earlier version of this topic review.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟