Turner syndrome in children and adolescents: Management

INTRODUCTION — 

Turner syndrome (TS) is an important cause of short stature in females and of primary or secondary amenorrhea in adolescents. It is diagnosed based on characteristic clinical features and a blood karyotype demonstrating loss of part or all of one of the X chromosomes [1].

This topic will review the management of children and adolescents with this condition. Treatment varies with the age of the patient and includes therapy for short stature and estradiol deficiency as well as identifying and managing the associated congenital anomalies and related comorbidities or complications (table 1) [2].

The clinical manifestations and diagnosis of TS and management in adults are reviewed separately. (See "Turner syndrome: Clinical manifestations and diagnosis" and "Management of Turner syndrome in adults".)

PRENATAL MANAGEMENT — 

The diagnosis of TS may be suspected after noninvasive prenatal testing (of cell-free deoxyribonucleic acid [DNA]), an abnormal combined first-trimester screen, or abnormal fetal ultrasound. The diagnosis may be confirmed by chorionic villous sampling, amniocentesis, or cordocentesis. (see "Prenatal screening for common fetal aneuploidies: Cell-free DNA test" and "Turner syndrome: Clinical manifestations and diagnosis", section on 'Diagnosis of Turner syndrome'). Up to 42 percent of fetuses with TS are being diagnosed prenatally via first trimester screening [3]. Because the prevalence of cardiac anomalies may be quite high, depending on the karyotype, a fetal echocardiogram should always be performed a when a diagnosis of TS is ascertained prenatally.

Genetic counseling should be provided before and after prenatal testing. If possible, the counseling should be provided by health care professionals with direct experience caring for patients with TS throughout childhood and adolescence (eg, pediatric endocrinologists). Such clinicians are best suited to answer questions about available treatments and prognoses of comorbidities. Genetic counseling may be challenging because of the difficulty of predicting the specific phenotype for an individual diagnosed with TS prenatally [4]. However, retrospective case series suggest that 45,X/46,XX mosaicism may be associated with a milder phenotype [5,6]. (See "Turner syndrome: Clinical manifestations and diagnosis", section on 'Most common features'.)

DISCUSSION OF THE DIAGNOSIS — 

We counsel parents and other caregivers about how to discuss the TS diagnosis and related health information with children in a timely, caring, and developmentally appropriate manner.

Many patients report that their TS diagnosis or other important information was inappropriately withheld from them. In a study conducted in the United States, approximately one-third of patients with TS reported that their families or health care providers had withheld all or part of the diagnosis [7]. Several patients were not informed that they might be infertile, which caused significant distress. 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 table (table 2) [8,9]. Whenever possible, patients should be cared for in a multidisciplinary clinic dedicated to TS or at least by a team of specialists with experience in the care of youth with TS.

Neonates

●Confirm diagnosis – For patients in whom prenatal testing is suggestive of TS, we perform diagnostic postnatal chromosomal testing to confirm the diagnosis. (See "Turner syndrome: Clinical manifestations and diagnosis", section on 'Confirmatory diagnostic testing'.)

●Evaluate for comorbidities – We also evaluate for comorbidities that may cause health concerns in the neonatal period:

•Blood glucose monitoring – Because of the link between TS and hyperinsulinemic hypoglycemia [10] (likely caused by haploinsufficiency of the KDM6A gene located on Xp11.3), we typically perform prefeeding blood glucose monitoring in all newborns with known or highly suspected TS throughout the first 48 hours of life, following institution-specific protocols for infants at risk of hypoglycemia. In institutions where no protocols are established, guidelines have been developed by the American Association of Pediatrics, Pediatric Endocrine Society, and other professional societies (table 3) [11]. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia", section on 'Timing of glucose screening'.)

•Cardiovascular assessment – We conduct a thorough cardiac examination and echocardiogram to identify congenital heart defects such as coarctation of the aorta. (See 'Initial evaluation' below.)

•Kidney ultrasound – We perform an ultrasound to identify congenital abnormalities of the kidney and urinary tract. (See 'Kidney anomalies and urinary tract infections' below.)

Infants, children, and adolescents

Cardiovascular anomalies — Congenital heart defects are the most frequent cause of early mortality in this population. The incidence of such defects is higher in patients with a 45,X karyotype compared with those who have X chromosome mosaicism or structural X chromosome defects. (See "Turner syndrome: Clinical manifestations and diagnosis", section on 'Cardiovascular abnormalities'.)

An approach to screening for cardiovascular anomalies is shown in the table (table 2).

Initial evaluation — At the time of diagnosis, all infants, children, and adolescents with TS should have a comprehensive cardiovascular evaluation by a pediatric cardiologist, which should include the following [8,9,12]:

●Blood pressure – In both the upper and lower extremities to screen for coarctation of the aorta.

●Electrocardiogram (ECG) – To screen for congenital heart disease, arrhythmia, or conduction abnormality.

●Echocardiogram – To evaluate for structural abnormalities, such as coarctation of the aorta, bicuspid aortic valve, and hypoplastic left heart syndrome.

●Cardiac magnetic resonance (CMR) – When the patient is old enough to tolerate the procedure without general anesthesia (typically around 12 years of age) [9]. 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 TS are outlined in the table and reviewed separately (table 1) [8,9,13]. (See "Turner syndrome: Clinical manifestations and diagnosis", section on 'Cardiovascular abnormalities'.)

Monitoring with cardiac imaging — All patients with TS, especially those with identified cardiac anomalies, should have ongoing follow-up care with a cardiologist, preferably with expertise in congenital heart disease. Repeat imaging with echocardiography and/or CMR imaging is suggested periodically throughout life to monitor for the development and/or progression of ascending aortic dilatation. Aortic dissection or rupture is an important cause of death in women with TS, and the risk is predicted by measuring the ascending aortic diameter. Because patients with TS are typically smaller than their general population peers, the measured aortic diameter should be indexed according to body size [9]. Evaluating the ascending aorta can be achieved by using a calculated Z-score, the aortic height index (ie, aortic diameter divided by body length), or the aortic size index (ie, aortic diameter divided by body surface area [BSA]). Although there is still not enough evidence to recommend one indexing approach over another, the aortic height index seems to have the best predictive value [14,15]. Please refer to the TS clinical practice guidelines for additional information on the approach to screening for aortic dilatation.

Patients with known aortic dilatation and those with risk factors for dissection (eg, hypertension, coarctation of the aorta, and/or bicuspid aortic valve) should undergo more frequent monitoring [9]. However, routine surveillance is suggested for all patients with TS since aortic dissection can occur even in the absence of these risk factors. Despite increased efforts, many individuals with TS are not adequately informed about the need for ongoing monitoring, even in the absence of cardiovascular symptomatology [16]. The protocol for patients 15 years and older and those considering pregnancy is discussed separately. (See "Management of Turner syndrome in adults", section on 'Cardiovascular health'.)

Management of specific cardiovascular abnormalities — TS is associated with several cardiac manifestations. (See "Turner syndrome: Clinical manifestations and diagnosis", section on 'Cardiovascular abnormalities'.)

Management is individualized to the clinical concerns, which may include:

●Aortic dilatation – If aortic dilatation is identified, prophylactic intervention should be considered, especially if hypertension is present [12,17]. Maintaining normal blood pressure may lower the risk of acute aortic events [18-20]. Management may include beta blockers, exercise restriction, and/or more aggressive blood pressure control.

Prophylactic antihypertensive therapy may be started early in the course because aortic dissection may also occur earlier (at smaller aortic dimensions) in TS than in patients with aortic dilatation in the general population [9]. Elective surgical repair may be an option for some patients, particularly if aortic diameter is rapidly expanding (ie, an increase of >+1 in TS-specific Z-scores or an absolute increase of >+0.5 cm in one year). The techniques and perioperative care are similar in patients with TS and all other patients with aortic dilatation or dissection. (See 'Hypertension' below 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".)

●Coarctation of the aorta – 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".)

●Bicuspid aortic valve – Antimicrobial prophylaxis is not required for most patients with TS and 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 should receive antimicrobial prophylaxis [21].

Although prolonged QT interval was previously thought to be more common in TS, a crossover study measuring the corrected QT (QTc) interval in more than 300 pediatric and adult patients with TS demonstrated no increased prevalence of QTc abnormalities [22]. Therefore, we do not counsel patients with TS and normal ECG to take special precautions (eg, avoidance of QT-prolonging medications) [9]. In addition, because individuals with TS are known to have a higher resting heart rate, the calculation of the QTc interval should be performed using the Hodges formula [23].

Hypertension — Hypertension is common in TS. 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. Please refer to the TS clinical practice guidelines for additional information on the management of hypertension.

●Diagnosis – Elevated blood pressure (prehypertension) and hypertension are diagnosed and evaluated using the same criteria in patients with TS as in pediatric patients without TS. Hypertension is defined as blood pressure >130/80 mmHg for adults and children >13 years or >95^th percentile for younger children (table 4) [24,25]. (See "Turner syndrome: Clinical manifestations and diagnosis", section on 'Elevated blood pressure and hypertension' and "Hypertension in children and adolescents: Evaluation" and "Hypertension in children and adolescents: Evaluation", section on 'Initial evaluation'.)

●Treatment – If hypertension develops, it should be treated immediately with lifestyle modification and weight management. Medication is indicated in some patients. Early recognition of and treatment for systemic hypertension are particularly important for patients with TS because of their increased risk for aortic dilatation and other cardiovascular events. Patients should also be carefully evaluated for causes of hypertension that are part of the TS phenotype such as kidney disease, obstructive uropathy, and coarctation of the aorta.

Treatment of hypertension for patients with TS without a dilated aorta is the same as in pediatric patients without TS. Most experts suggest starting medical therapy for high blood pressure when measurements are in the hypertensive range on multiple measurements, ideally over multiple days [18,24-28]. The goal is to achieve a low-normal blood pressure. (See "Hypertension in children and adolescents: Nonemergency treatment", section on 'Details on specific antihypertensive drugs'.)

Patients with TS found to have aortic dilatation should be managed intensively by cardiologists. (See 'Management of specific cardiovascular abnormalities' above and "Management of Turner syndrome in adults", section on 'Aortic dilatation'.)

Cognitive function and learning disabilities — Most individuals with TS have normal intelligence, although patients with a small ring X chromosome may have a higher risk for intellectual disability [29]. Learning disabilities are common in TS, including attention deficit hyperactivity disorder (ADHD) and difficulties with visual-spatial processing, executive function, and social cognition. This results in a typical neurocognitive profile characterized by a discrepancy between relatively strong verbal intellectual abilities and impaired nonverbal and visual-spatial reasoning abilities. This may be observed as early as the toddler years in patients with TS. Neuropsychology and allied behavioral health services should be integrated into the care for all patients with TS [9]. This includes annual developmental and behavioral screenings until adulthood, with referrals as needed. Simple screening tools are also available for anxiety, a common mood disorder in TS, and can even be applied easily by nonmental health care providers more frequently [30]. (See "Turner syndrome: Clinical manifestations and diagnosis", section on 'Neuropsychologic concerns'.)

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 TS 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 TS [31].

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 [9].

Children with TS 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 [32]. Progressive sensorineural hearing loss develops by adulthood in more than 50 percent of patients. (See "Management of Turner syndrome in adults", section on 'Audiology testing' and "Turner syndrome: Clinical manifestations and diagnosis", section on 'Hearing and ear abnormalities'.)

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 midpuberty (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 first appear 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 "Turner syndrome: Clinical manifestations and diagnosis", section on 'Short stature' and "Adolescent idiopathic scoliosis: Management and prognosis", section on 'Indications for referral'.)

Kidney anomalies and urinary tract infections — Patients should undergo kidney ultrasonography at diagnosis to identify congenital malformations of the kidney/urinary collecting system. If structural abnormalities are identified, patients should be evaluated by a nephrologist or urologist and may require ongoing monitoring for urinary tract infections. (See "Turner syndrome: Clinical manifestations and diagnosis", section on 'Anatomical findings'.)

Ophthalmologic concerns — We perform (if feasible) a detailed ophthalmologic examination between 6 and 12 months of age or at diagnosis if older than 12 months [9]. Follow-up eye examination is required if abnormalities are present or new problems occur [8,9]. (See "Turner syndrome: Clinical manifestations and diagnosis", section on 'Anatomical findings'.)

Edema — Edema in TS 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 estradiol supplementation. When present in the 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 improve edema and is not warranted [9].

Gonadoblastoma risk — We screen for Y chromosome mosaicism in any patient with TS who has marker chromosome elements (sex chromosome material of uncertain origin) or a small ring chromosome detected on the karyotype, or who presents with/develops virilization. This is because Y chromosome mosaicism can be associated with an increased risk for gonadoblastoma with or without malignant transformation. Routine molecular search for Y chromosome-derived DNA is not necessary in TS patients [33]. (See "Turner syndrome: Clinical manifestations and diagnosis", section on 'Features associated with Y chromosome mosaicism'.)

If Y chromosome material is detected, we engage in collaborative decision-making discussions with the patient (if possible) and their parents/caregivers to determine whether the patient will be monitored clinically or undergo prophylactic removal of the gonads (oophorectomy or salpingo-oophorectomy). The first approach is recommended in the TS clinical practice guidelines, though prophylactic gonadectomy was recommended previously [9,33]. However, some still recommend prophylactic gonadectomy at diagnosis and find deferring is an unsafe approach based on observations that gonadoblastoma has been demonstrated, on rare occasion, in very young children [34]. Hysterectomy is not recommended to preserve the possibility of pregnancy using donor oocytes [35]. Streak gonads do not need to be explored or removed in patients without Y chromosome mosaicism.

Laboratory monitoring in children and adolescents — Routine laboratory monitoring for some TS-associated comorbidities is recommended, as outlined in the table (table 2) [9].

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); repeat screening every two to five years throughout childhood and with new symptoms [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 TS, with approximately 3 to 7 percent of patients affected. (See "Turner syndrome: Clinical manifestations and diagnosis", section on 'Comorbidities'.)

Autoimmune thyroiditis — Screen for autoimmune thyroiditis by measuring thyroid-stimulating hormone annually beginning around two 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 [36]. (See "Turner syndrome: Clinical manifestations and diagnosis", section on 'Comorbidities'.)

Liver disease — Screen for liver disease by measuring alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGTP), and alkaline phosphatase once in childhood and around peripuberty and every one to two years thereafter. Abnormalities in these measures are common in patients with TS, perhaps due to metabolic syndrome, 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 estradiol replacement therapy [9]. (See "Turner syndrome: Clinical manifestations and diagnosis", section on 'Comorbidities'.)

Metabolic syndrome — Youth with TS are at greater lifetime risk of developing type 2 diabetes than the general population due to impaired insulin secretion and/or sensitivity. As a result, screening for hyperglycemia by measuring hemoglobin A1C (with or without fasting glucose) should begin around 10 years of age [37]. Screening every one to two years and with new symptoms is appropriate thereafter. Screen for dyslipidemia by measuring a lipid panel annually if at least one cardiovascular disease risk factor is present (per local recommendations) and during transition [9]. (See "Turner syndrome: Clinical manifestations and diagnosis", section on 'Comorbidities'.)

Vitamin D deficiency — We 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 [9]. Alternatively, universal vitamin D supplementation may be advised rather than laboratory assessment.

Maintaining recommended serum concentrations of 25-hydroxyvitamin D is important because individuals with TS 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 patients with TS compared with controls [38]. 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 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 "Vitamin D insufficiency and deficiency in children and adolescents" and "Turner syndrome: Clinical manifestations and diagnosis", section on 'Comorbidities'.)

MANAGEMENT OF SHORT STATURE

Monitoring growth — Short stature is the most common clinical feature of TS. To monitor growth, measurements should be plotted on TS-specific growth charts. These growth curves show height percentiles for patients with TS not treated with growth hormone and height percentiles for the general female population (figure 1) [39,40].

We do not perform growth hormone stimulation testing because patients with TS do not have growth hormone deficiency despite their short stature. Nonetheless, growth hormone therapy in pharmacologic doses improves growth.

Growth hormone therapy — Our practice is to offer growth hormone therapy to most patients with TS and short stature to maximize adult height and improve body composition.

●Indications and timing – We initiate recombinant human growth hormone therapy as soon as the height of a patient with TS falls below the 5^th percentile for age on the growth chart for girls in the general population. This usually occurs between two and five years of age [8,9,41].

Younger patients with particularly poor height velocity may benefit from starting growth hormone even earlier (ie, before the height falls below the 5^th percentile). We monitor how the patient's growth compares with the expected growth based on the midparental (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. We continue growth hormone therapy until growth is complete or nearly complete (eg, bone age exceeds 13.5 to 14 years and growth slows to less than 2.5 cm per year). (See "Growth hormone deficiency in children: Treatment".)

●Dosing

•Initial – In the United States, a typical initial dose of recombinant human growth hormone is approximately 45 to 50 mcg/kg/day (0.35 to 0.375 mg/kg/week) given once daily by subcutaneous injection. Patients with TS are typically treated with higher doses of growth hormone than patients with growth hormone deficiency.

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 per week. Using body surface area (BSA) rather than weight-based dosing may be needed in patients with a body mass index (BMI) >90^th percentile to prevent excessive dosing [42].

Growth hormone doses >50 mcg/kg/day are not routinely recommended but may be considered in patients with very poor height prognosis if the dose is below the product-specific maximum dose and only after a careful discussion of potential risks and benefits. For example, growth hormone dosing up to 0.067 mg/kg/day has been approved for specific growth hormone preparations in certain regions of the world.

●Dose titration – The growth hormone dose is often titrated based on a review of growth response during clinical visits and laboratory assessment of insulin-like growth factor-1 (IGF-1). Because the initial 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 IGF-1 at least annually [9]. 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.

The use of IGF-1-based dose titration of growth hormone in TS is extrapolated from the management of children with other growth disorders, such as idiopathic short stature or growth hormone deficiency. However, the efficacy of this approach for TS has not been established. In particular, data are inconsistent regarding the correlation between growth response and growth hormone-treated IGF-1 concentrations among individuals with TS. Furthermore, although epidemiologic studies have raised concerns about an association between elevated IGF-1 and neoplasia, no evidence exists for such an association in TS [43]. (See "Growth hormone deficiency in children: Treatment", section on 'Dose adjustment based on IGF-1 response'.)

●Formulations – Daily growth hormone is well studied in patients with TS and therefore remains the preferred formulation for treatment in this population [9]. Although long-acting growth-hormone preparations are approved for treatment of growth-hormone deficiency in the general population, data from randomized controlled trials of these agents in individuals with TS are not available. One retrospective study found that outcomes in patients with TS treated with long-acting growth hormone were comparable to those in patients with TS treated with daily growth hormone, with respect to safety and efficacy [44]. Additional trials with long-acting growth hormone preparations are underway.

●Effect on height – Initiation of recombinant human growth hormone at a young age (four to six years) often permits attainment of normal adult height.

This has been illustrated in several studies:

The impact of growth hormone dose on growth in this population was evaluated in a trial of 68 children (mean age six to seven years) with TS who were randomly assigned to three different regimens of growth hormone (figure 2). The starting dose was approximately 45 mcg/kg/day, with some patients being treated with doses as high as approximately 90 mcg/kg/day during the first few years of therapy [45]. In long-term follow-up of 60 participants, 83 percent reached a normal adult height (ie, >-2 SD) [46]. 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 TS treated with growth hormone [47].

Effects of very early initiation of growth hormone were evaluated in a prospective, randomized, open-label clinical trial in 88 children with TS aged nine months to four years of age [41]. The patients 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 TS, an effect that lasts until pubertal induction. However, long-term follow-up of these patients showed that although the earlier-treated children were taller throughout childhood, their near-adult height outcome was not significantly different from those in whom treatment was initiated later (ie, the initial control group). This was attributed to lapses in growth hormone treatment after the toddler period in the treatment group and similar lifetime exposure to growth hormone between the two groups [48].

Together, these findings suggest early initiation of growth hormone (nine months to <4 years of age) does not improve adult height outcomes compared with initiation after age four years. However, earlier initiation (age two to four years) may be beneficial if adherence to treatment is maintained [48]. In addition, higher growth hormone doses (eg, above 45 mcg/kg/day) may yield additional benefits in selected patients [49].

●Effect on body composition – 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 youth with TS, growth hormone therapy increased lean body mass and decreased body fat [50]. 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 [51-53]. Adverse effects of growth hormone therapy, including benign intracranial hypertension and slipped capital femoral epiphysis, are uncommon but perhaps slightly more prevalent than in children who are treated with growth hormone for indications other than TS [54]. (See "Growth hormone deficiency in children: Treatment", section on 'Adverse effects of growth hormone therapy'.)

●Effect on health-related quality of life – It is unclear whether the benefits of growth hormone therapy on adult height affect the overall health-related quality of life (HRQoL). Improved height is often the basis of the parents'/caregivers' decision to initiate growth hormone therapy and is also endorsed as important by most adolescents with TS. However, in one study of adults with TS, growth hormone treatment was not associated with improved HRQoL despite a mean 5.7 cm gain in adult height [55]. This finding does not preclude an effect of growth hormone on HRQoL because many girls experience significant improvement in adult height with growth hormone therapy compared with their untreated height projections, and HRQoL is compromised by the effects of multiple other comorbidities of TS. Studies with novel therapeutic approaches (eg, C-natriuretic peptide analogs) may further benefit the outcome of growth-promoting therapies in TS, particularly in those patients with an initial suboptimal response to monotherapy with growth hormone.

Strategies no longer advocated — In children and adolescents with severe short stature (ie, unlikely to reach the 5^th percentile for the adult general female population), we do not use adjunctive growth-promoting approaches such as delaying pubertal induction and/or therapy with oxandrolone.

Updated TS clinical practice guidelines advise against the following:

●Use of the nonaromatizable anabolic steroid oxandrolone as an adjunctive treatment for short stature in patients with TS [9]. Prior guidance suggested use of oxandrolone in addition to growth hormone for patients with TS and severe short stature, based on evidence of additional height gain for treated patients in randomized trials [56,57]. However, the US Food and Drug Administration (FDA) withdrew regulatory approval for oxandrolone in 2023 because of reported adverse effects such as liver failure and liver cell tumors in adult patients without TS treated with oxandrolone for indications such as relief of osteoporosis-associated bone pain [58]. Oxandrolone remains unavailable in most countries.

●Delaying pubertal induction (waiting until approximately age 14 to allow for a longer period of growth before physeal fusion) [9]. This approach appears to provide, at best, a modest additional benefit to adult height. This was shown in a trial in which delaying pubertal induction from age 12 to 14 years was associated with an extra 2.7 cm increase in adult height, which was not statistically significant (95% CI -0.8 to 6.1 cm; n = 56) [56,59].

MANAGEMENT OF DELAYED OR ABSENT PUBERTY — 

Primary hypogonadism is one of the most common features of TS. Approximately 90 percent of individuals with TS have absent pubertal development and primary amenorrhea or pubertal arrest with secondary amenorrhea. (See "Turner syndrome: Clinical manifestations and diagnosis", section on 'Gonadal insufficiency'.)

Monitoring pubertal development — Pubertal development should be assessed through physical examination and measurement of serum follicle-stimulating hormone (FSH). We also measure anti-müllerian hormone (AMH) to guide decisions about fertility preservation.

●Physical examination – We monitor patients with yearly physical examinations for Tanner staging beginning around nine years of age. Prior to performing the pubertal staging examination, we take several measures to ensure patients understand and assent to an examination. We provide a clear explanation of the purpose of the examination and how it will be conducted. We offer patients the opportunity to have a chaperone present during the examination (usually a clinical staff member). (See "The pediatric physical examination: The perineum", section on 'Preparation for examination' and "Normal puberty", section on 'Pubertal changes'.)

●FSH – We measure serum FSH at approximately eight or nine years of age as it may provide information on ovarian function [60]. In most individuals with ovarian insufficiency older than 10 years, FSH will be markedly elevated [61]. However, FSH alone may be inadequate to diagnose ovarian insufficiency. Although prepubertal patients with TS tend to have higher FSH values than prepubertal females without TS, there is considerable overlap, especially because FSH varies with age in healthy children [62] (see "Clinical manifestations and diagnosis of primary ovarian insufficiency (premature ovarian failure)"). We do not routinely use inhibin B in clinical practice for monitoring of puberty [61,62].

●AMH – We consider measurement of serum AMH prepubertally but offer it annually from approximately 9 to 10 years of age if primary ovarian insufficiency (POI) has not already been established. AMH has some utility as a predictor of the likelihood of spontaneous puberty [60] and the presence of functional oocytes [63]. In one retrospective study of adolescents and adults with TS, those with detectable serum AMH were more likely to experience spontaneous puberty (odds ratio [OR] 19.3) and menarche (OR 47.6) [64]. However, there is variability in AMH assays. A single detectable AMH value is rarely useful for predicting the timing or course of puberty for an individual and does not replace long-term monitoring for pubertal development.

Estradiol therapy — Most patients with TS will require treatment with exogenous estradiol to treat hypogonadism. This includes the 15 to 30 percent of individuals with TS who experience spontaneous puberty, which may persist for a variable amount of time before premature ovarian failure occurs [65]. The goal of estradiol therapy is to mimic the normal progression of pubertal events while maximizing growth potential. Later, cyclic progestogens are added to the regimen to induce cyclic uterine bleeding and prevent endometrial hyperplasia.

When to initiate — In most patients 11 to 12 years of age with absent, delayed, or stalled puberty and elevated gonadotropins, we initiate low-dose estradiol treatment. This approach allows puberty to begin at an age-appropriate time without compromising adult height [66]. We do not initiate estradiol replacement in patients younger than this age (even at a low dose) as evidence is insufficient to support this approach [67,68].

Growth hormone and estradiol may be given together until epiphysial fusion occurs, after which we stop growth hormone.

Choice of formulation — We suggest 17-beta estradiol rather than ethinyl estradiol or conjugated estrogens because 17-beta estradiol has the most favorable safety profile. We suggest transdermal rather than oral estradiol because of the more physiologic kinetics of transdermal administration and the greater ease of providing a smaller dose during early pubertal induction. However, given limited data favoring transdermal over oral estradiol for pubertal induction, patient preference should be strongly considered as a part of the treatment plan [66]. These practices are in agreement with the TS clinical practice guidelines [9]. Ethinyl estradiol is not recommended for pubertal induction [9].

●Transdermal 17-beta estradiol for most patients – Small trials suggest advantages of transdermal 17-beta estradiol, though data are limited.

•A small randomized trial comparing oral to transdermal forms of 17-beta estradiol in patients with TS demonstrated more physiologic serum estradiol concentrations in patients treated with the transdermal form [69,70]. Other studies suggest that metabolic parameters (eg, blood pressure and blood glucose) are similar in patients treated with transdermal and oral 17-beta estradiol [69,71,72].

•Transdermal 17-beta estradiol is also associated with a lower risk of venous thromboembolism when compared with oral estradiol. Other studies suggest that metabolic parameters (eg, blood pressure and blood glucose) are similar in patients treated with transdermal and oral 17-beta estradiol [69,71,72]. (See "Menopausal hormone therapy: Benefits and risks", section on 'Venous thromboembolism'.)

●Combined oral contraceptives for some – Many adult patients with TS prefer combined oral contraceptives (COCs) for hormone replacement. For some patients, the added convenience may improve treatment adherence. However, COCs may be associated with an increased risk of some cardiovascular complications. In a retrospective cohort of more than 500 youths and adults with TS, patients using combined COCs were more likely to have hypertension than those managed with other estrogen formulations [73]. We avoid COCs in individuals with uncontrolled hypertension or risk factors for venous thromboembolism. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Venous thromboembolism'.)

Dose and administration

●Dose – For patients without pubertal development, we use initial doses ranging from 3.125 to 6.25 mcg daily (table 5), lower than the starting dose for those who have Tanner stage II (or greater) breast development. (See "Delayed puberty: Approach to evaluation and management", section on 'Estradiol'.)

The dose is increased incrementally at approximately 6- to 12-month intervals to simulate normal pubertal progression until adult dosing is reached over a two- to four-year period [9,66]. The timing of dose increases may vary based on the patient's clinical response. The rationale for the gradual increase in estradiol dose is to mimic normal puberty and breast development. Several studies have demonstrated that similar regimens achieve breast development to Tanner stage II during the first three to six months and to Tanner stage IV after approximately two years [74,75]. Recommended dose-escalation strategies for 17-beta estradiol in patients undergoing pubertal induction are summarized in the TS clinical practice guidelines.

Most patients who have completed pubertal induction will be maintained on typical adult doses (eg, a transdermal estradiol patch 100 mcg/day), although more studies are required to determine the optimal dose for long-term estrogen replacement. One hundred mcg of transdermal estradiol is roughly equivalent to 2 mg of oral micronized estradiol or approximately 10 mcg of oral ethinyl estradiol [8].

●Administration – Transdermal estradiol is administered via a patch, which is placed on the skin either weekly or twice weekly. Brand names for transdermal estradiol preparations are outlined in the "estradiol" patches section of the table (table 6). Because estradiol patches are not available in the low doses required for early pubertal induction, patches must be cut to achieve the desired dose. Only matrix estradiol patches may be cut. Reservoir patches cannot be cut as this would make the entire dose available at once.

Some clinicians advise patients to apply the patch only overnight. This approach delivers lower estradiol doses and simulates the early-morning estradiol peaks observed in early puberty [9,76]. Initiation of nocturnal estradiol has resulted in timing and tempo of breast development similar to regimens that use smaller patch doses.

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. Instead, we monitor physical examination evidence of pubertal progression and growth. (See "Delayed puberty: Approach to evaluation and management", section on 'Monitoring and treatment outcomes'.)

Progesterone therapy (micronized progesterone for most)

When to initiate — In all patients being treated with estradiol for pubertal induction, we add cyclic progesterone therapy when breakthrough bleeding occurs to minimize the risk of endometrial hyperplasia. Breakthrough bleeding typically occurs 18 to 24 months after estradiol initiation, although it may start later in patients on lower estradiol doses [8,9]. Generally, if bleeding has not occurred, we initiate cyclic progesterone therapy after two years of estradiol treatment for pubertal induction. (See "Menopausal hormone therapy: Benefits and risks".)

Rationale — We use oral micronized progesterone for most patients undergoing pubertal induction to simulate the typical duration of the luteal phase. The selection of micronized progesterone is largely based on indirect evidence from postmenopausal adults, in whom combined therapy with conjugated estrogens and medroxyprogesterone resulted in a greater risk of cardiovascular disease, venous thromboembolism, and breast cancer when compared with conjugated estrogen only. Limited data in women with POI suggest a more favorable metabolic profile with micronized progesterone versus medroxyprogesterone [77]. However, limited data in youth with TS have not demonstrated a difference between these agents. As an example, in a retrospective cohort study of patients with TS treated with medroxyprogesterone acetate, levonorgestrel, or micronized progesterone, no differences were noted in blood pressure, lipid profile, fasting blood glucose, or kidney function. The study population was too small to provide information on thrombosis risk [78].

Dose — After breakthrough bleeding occurs (or two years of estradiol therapy if no bleeding occurs), we initiate micronized progesterone at a dose of 200 mg daily for 12 days (eg, days 1 to 12 of each calendar month).

A sample regimen is as follows:

●Transdermal estradiol – Available patches are changed weekly or twice weekly. Estradiol therapy is used continuously with no interruption; plus

●Micronized progesterone – Initiate on the first day of the month. Take daily for 12 days. Continue even if bleeding begins, discontinue on the 13^th day of the month. Withdrawal bleeding is expected within one week of discontinuing progesterone.

The benefit of cyclic administration of progesterone is more predictable bleeding. However, some patients prefer continuous daily combined regimens with 100 mg micronized progesterone daily. Continuous regimens may improve adherence for some patients and allow for avoidance of monthly menses and cyclic mood symptoms [9]. (See "Treatment of menopausal symptoms with hormone therapy", section on 'Progestins'.)

Benefits of hormonal therapy — Estradiol therapy effectively induces and maintains pubertal development (eg, breast development and uterine growth), positively impacts growth and height outcomes when combined with growth hormone therapy (figure 3) [46,67,79], and improves bone mineralization and peak bone mass [80,81]. Early and consistent estradiol replacement may also have benefits for cardiovascular health, as indicated by improvements in the lipid profile and reduced aortic stiffness [82,83]; it may also improve liver enzyme abnormalities [84].

Estradiol replacement appears to have some benefits on cognitive function in preadolescent patients, but its effects in older individuals are unclear [85]. In a study of patients ages seven to nine years with TS, low doses of ethinyl estradiol (25 ng/kg/day) improved verbal and nonverbal memory when compared with placebo [86]. No effect on other verbal abilities or attention was seen. A similar report in slightly older patients suggested that estradiol replacement improved nonverbal processing speed and motor function [85].

Adverse effects — Abnormal uterine bleeding occurs in approximately one-third of patients during pubertal induction with transdermal estradiol preparations, including prolonged, heavy, or intermenstrual bleeding [87]. Abnormal uterine bleeding is more likely if progesterone therapy is started later (after >18 months of unopposed estradiol), given as micronized progesterone in doses <200 mg, given less often than monthly, or if patients are not adherent to treatment. (See "Menopausal hormone therapy: Benefits and risks", section on 'Protective effect of progestins'.)

FERTILITY PRESERVATION — 

We provide counseling about options for fertility preservation and family building to all patients with TS (table 2). Please refer to the TS clinical practice guidelines for additional information on fertility preservation.

We begin counseling during peripuberty or (in some cases) earlier, even if patients are not likely to be candidates for fertility preservation procedures. The primary option for fertility preservation in youth with TS is oocyte cryopreservation, which is used routinely in the clinical care of adolescent females without TS undergoing treatment with gonadotoxic agents [88-91]. (See "Overview of cancer survivorship in adolescents and young adults" and "Overview of cancer survivorship in adolescents and young adults", section on 'Fertility'.)

Ovarian tissue cryopreservation is not routinely used for patients with TS; it is available in selected centers only on an investigational basis [92]. Generally, fertility preservation for adolescents with TS should be undertaken only by centers with expertise in caring for youth and ideally in the context of a multidisciplinary team including physicians and mental health providers who can support a collaborative decision-making process.

Oocyte cryopreservation — Our practice is to offer oocyte cryopreservation through controlled ovarian stimulation to patients with TS who are postmenarchal and of appropriate psychological maturity; they are therefore able to participate in decision-making about fertility preservation [9].

We measure anti-müllerian hormone (AMH) prior to referral for fertility preservation and use this value to set general expectations regarding the likelihood of success of oocyte retrieval [60].

In retrospective cohort studies of patients with TS undergoing oocyte retrieval, a higher percentage of 46,XX cells [93], a higher AMH, and a lower FSH [94,95] were positively associated with number of oocytes retrieved [9,96-98]. Patients with a nonmosaic 45,X karyotype may be eligible for oocyte cryopreservation; small case series of adults with TS have documented successful cryopreservation of oocytes after controlled ovarian stimulation in those with 45, X karyotype without mosaicism [99].

The first live birth using cryopreserved oocytes in an adult with mosaic TS has been reported [100]. More data are needed to understand the long-term outcomes and risks of this approach, particularly given the increased risk of aortic dissection associated with pregnancy for adults with TS. (See "Fertility preservation: Cryopreservation options", section on 'Cryopreservation' and "Management of Turner syndrome in adults", section on 'Management of fertility and pregnancy'.)

Ovarian tissue cryopreservation — Cryopreservation of cortical ovarian tissue is an experimental technique that has been used to preserve primordial follicles in ovarian tissue from adults without TS, and a case report describes its use in a prepubertal patient without TS [101]. Clinical practice guidelines recommend that this procedure be conducted only in the context of a research protocol [96]. (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'.)

Counseling — Consultation with a fertility expert (eg, reproductive endocrinology and infertility physician) may be beneficial to discuss prognosis and fertility options for many patients with TS and their families [102,103]. Counseling about fertility preservation should address both benefits and risks. Patients should be included in the discussion whenever possible [9]. Early referral (eg, during childhood) may be considered for those considering ovarian tissue cryopreservation as part of a research protocol, though challenges related to effective counseling about the implications and significant medical burden of fertility preservation procedures must be considered [9].

Physicians offering fertility preservation should communicate the excess risk of mortality during pregnancy due to aortic complications such as dilatation and dissection. Therefore, even if the cryopreservation procedure is successful, future pregnancy may not be advisable. The use of a gestational carrier and other options for family building should also be included in counseling. (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 TS [104], this counseling is not always occurring. In a medical record review of over 460 young women with TS 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 patients. Only 10 percent of TS 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 [105]. Patients receiving care at a multidisciplinary clinic were more likely to receive fertility and/or pregnancy counseling.

TRANSITION TO ADULT CARE — 

The transition period is a crucial window for the health care management of patients with TS. Loss to follow-up is common, leading to insufficient monitoring of comorbidities and suboptimal adherence to medical therapies [106,107]. Providers must take this opportunity to address the many medical and nonmedical aspects of health, including a comprehensive health evaluation [9,108]. The communication and counseling should be tailored to the patient's maturity level and is ideally achieved by a multidisciplinary team (table 2).

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 [109]. Please refer to the TS clinical practice guidelines for additional information on the approach to health care transition in adolescents and young adults with TS.

Important issues to discuss with the patient during the transition period include:

●Potential long-term complications of TS (especially cardiovascular disease and hearing loss) and need for ongoing monitoring.

●Reproductive issues, including fertility options and potential risks of pregnancy. (See "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 as well as vocational counseling [31]. (See 'Cognitive function and learning disabilities' above.)

●Resources for psychosocial support. The team should specifically encourage the patient to engage with TS support groups for emotional support and to help empower the patient to stay engaged with their health maintenance [9]. (See 'Resources and information' below.)

MORTALITY — 

Overall mortality rates in patients with TS are increased approximately threefold when compared with the general population, with the greatest excess mortality in older adulthood [110]. 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 TS. (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:

●TS Society of the United States – 1-800-365-9944

●TS Foundation – 1-800-594-4585

●TS Support Society (United Kingdom) – +44-0141-952-8006

An English language summary of the 2024 TS clinical practice guidelines has been prepared for patients with TS and their families/caregivers [111]. Another version is available in Spanish [112].

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 5^th to 6^th 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 10^th to 12^th 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

●Initial evaluation – In all patients with Turner syndrome (TS), we perform a cardiac evaluation and kidney ultrasound to detect structural malformations shortly after diagnosis. In neonates, we also monitor for hypoglycemia in the first 48 hours of life using prefeed blood glucose testing. (See 'Neonates' above.)

●Cardiovascular disease

•Evaluation and monitoring – All infants and children with TS 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 adolescents and adults, mainly to monitor for dilatation of the ascending aorta. (See 'Cardiovascular anomalies' above.)

Repeat echocardiogram should be performed approximately every five years during childhood and adolescence and more often if clinically indicated (eg, aortic dilatation or other risk factors for aortic dissection such as hypertension, coarctation, and/or bicuspid aortic valve) (table 2). (See 'Cardiovascular anomalies' above.)

Management of patients with aortic dilatation may include beta blockers, exercise restriction, and aggressive blood pressure control. However, all patients with TS should have routine blood pressure monitoring and treatment. (See 'Monitoring with cardiac imaging' above and "Management of Turner syndrome in adults", section on 'Aortic dilatation'.)

●Short stature

•Prevalence – Short stature is the most common clinical feature of TS. (See 'Management of short stature' above.)

•Growth hormone therapy – For most patients with TS and short stature, we recommend recombinant human growth hormone therapy to maximize adult height and improve body composition (Grade 1B). Therapy may be initiated when the height of a patient with TS falls below the 5^th percentile for age, which usually occurs between two and five years of age, although a benefit on adult height outcome from initiating growth hormone in patients under four years of age has not been established. The dose of growth hormone used in TS is typically higher than is used for growth hormone deficiency. However, both the dose and timing of growth hormone initiation must be individualized to the patient. (See 'Growth hormone therapy' above.)

●Hypogonadism

•Prevalence – Most individuals with TS have primary hypogonadism (ovarian insufficiency), as demonstrated by lack of pubertal development, primary amenorrhea, and/or pubertal arrest. All patients should be provided counseling regarding infertility, fertility preservation, and pregnancy risks. (See 'Oocyte cryopreservation' above.)

•Estradiol therapy – For patients with TS requiring pubertal induction, we suggest starting low-dose 17-beta estradiol therapy for pubertal induction at approximately age 11 to 12 years (Grade 2C). This approach mimics the timing and pace of puberty in peers without compromising adult height. (See 'When to initiate' above.)

We prefer transdermal 17-beta estradiol, but the oral form is a reasonable alternative. We increase the dose gradually over two to four years (table 5) and add micronized progesterone at least 12 days per month starting after two years of estradiol therapy or when breakthrough bleeding occurs. (See 'Choice of formulation' above and 'Management of delayed or absent puberty' above and 'Progesterone therapy (micronized progesterone for most)' above.)

●Other comorbidities – Monitoring for other important health issues is outlined in the table (table 2). During childhood, monitoring focuses on learning disabilities, conductive and sensorineural hearing loss, scoliosis, and autoimmune diseases (thyroiditis and celiac disease). (See 'Monitoring and managing comorbidities' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Paul Saenger, MD, MACE, who contributed to an earlier version of this topic review.