Turner syndrome

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

all patients: at diagnosis

1st line – surveillance and preventive care

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1st line –

surveillance and preventive care

A careful history, a meticulous physical examination, and a peripheral white blood cell karyotype are crucial in making an accurate diagnosis of Turner syndrome.

The main aims of treatment include optimization of height, induction and maintenance of pubertal development, treatment of ongoing ovarian hormone deficiency, and screening for and treatment of comorbidities or complications. Much of the excess morbidity and mortality may be prevented by early diagnosis and effective screening for these conditions.

Timely initiation of preventive treatments, including appropriate estrogen therapy, healthy diet and exercise, statin treatment for individuals with high risk for ischemic heart disease, and surveillance and treatment of congenital heart defects, is mandatory.

Annual screening should be carried out, including thyroid function tests for autoimmune hypothyroidism, LFTs to screen for "Turner hepatitis," BP measurements for hypertension, fasting glucose to identify patients with diabetes mellitus (fasting glucose and HbA1c to identify patients likely to develop diabetes), lipids to monitor dyslipidemia, and hearing screen to identify those with sensorineural or other types of deafness. Tissue transglutaminase IgA (if normal IgA levels) should be measured every 3 to 5 years to screen for celiac disease. Baseline bone mineral density should be assessed at the transition to adult care and reevaluated at menopause or sooner if indicated.

with poor growth

Plus – GH until growth velocity is less than 2 cm/year or earlier if patient is satisfied with height

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Plus –

GH until growth velocity is less than 2 cm/year or earlier if patient is satisfied with height

Treatment recommended for ALL patients in selected patient group

Short stature and poor growth are often the primary symptoms.

Recombinant human growth hormone (GH), also known as somatropin, is often considered to enhance adult height. The goal is to help girls achieve a height sufficient to prevent disability and enable them to function independently (e.g., drive a car), as well as promoting social integration.

Treatment should be started at time of diagnosis until growth velocity is less than 2 cm/year or adequate height is obtained.

Treatment effect is monitored by the growth response and insulin-like growth factor 1 (IGF-1) levels, which should be maintained below the upper limit of normal.

Failure of a good growth response is commonly due to hypothyroidism, celiac disease, or noncompliance.

Adverse effects over a 4- to 5-year follow-up include increased intracranial pressure, slipped capital femoral epiphyses, scoliosis, pancreatitis, and possibly an increased onset of type 1 diabetes.[34]

Primary options

somatropin (recombinant): dose depends on brand used; consult specialist for guidance on dose

Consider – oxandrolone

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Consider –

oxandrolone

Treatment recommended for SOME patients in selected patient group

The major impediment to successful GH treatment is late diagnosis, which is not uncommon.

For girls diagnosed very late with only a small time window for treatment, or for those who cannot obtain GH, some pediatric endocrinologists add oxandrolone, a nonaromatizable oral androgen, to GH treatment to promote linear growth.[35][38] Oxandrolone treatment usually promotes a few centimeters of additional height.[36][37] However, it can, even at low doses, inhibit breast development and cause virilization due to its androgenic effects.[36][37]

Primary options

oxandrolone: 0.03 mg/kg/day orally

with pubertal delay/arrest (age >12 years)

Plus – low-dose estrogen

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Plus –

low-dose estrogen

Treatment recommended for ALL patients in selected patient group

The aim is to induce pubertal development on a par with peers and as physiologically as possible. This also ensures that the girls experience the salutary effects of estrogen on bone and other tissues, and undergo optimal psychosocial adjustment to their condition.

Treatment includes gradually increasing doses of estrogen therapy, and then estrogen combined with cyclic progesterone treatment.

Treatment is begun if no spontaneous breast development has occurred by the age of 11-12 years and serum follicle-stimulating hormone is elevated.

If potential for linear growth remains (patient may be already on GH treatment), low dose with a slower increase in dose should be continued until an optimum height is achieved. Higher doses bring growth to an end. The bone age should be monitored and, if found to be advancing rapidly, the dosage should be reduced.

If there is no potential for further growth or if there is no evidence of a rapidly advancing bone age, the dose of estradiol is increased gradually, over approximately 2 years, to a full adult dose of 75-100 mcg or until vaginal bleeding occurs.

Lower doses of estradiol (to initiate puberty) can be achieved by cutting a transdermal patch into smaller pieces. However, only the matrix formulation can be cut safely without affecting the drug dose delivered.[44]

Primary options

estradiol transdermal: 0.025 mg/24 hour patch weekly or twice weekly depending on brand used

Secondary options

estradiol: 0.5 to 2 mg orally once daily

Consider – cyclic progesterone

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Consider –

cyclic progesterone

Treatment recommended for SOME patients in selected patient group

Cyclic progesterone is added to estrogen therapy once there is breakthrough bleeding or when the patient is on a full adult dose of estrogen treatment to induce menstruation. Treatment for the last 2 weeks of a 3-month cycle is also an option.

Primary options

progesterone micronized: 100-200 mg orally once daily on the last 10 days of the menstrual cycle

with congenital cardiac anomalies

Plus – cardiovascular assessment and evaluation for surgery

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Plus –

cardiovascular assessment and evaluation for surgery

Treatment recommended for ALL patients in selected patient group

Aortic coarctation and bicuspid aortic valves are the most common abnormalities. Other cardiac abnormalities include partial anomalous pulmonary veins, left heart hypoplasia, and a dilated aorta. Prevalence of cardiovascular defects is much higher in those with clear evidence of fetal lymphedema, such as neck webbing.

At the time of initial diagnosis, no matter what age, a comprehensive cardiovascular evaluation needs to be done by a specialist in congenital heart disease and appropriate treatment started.[29] A functionally bicuspid valve as a result of complete or partial fusion of the right and left coronary leaflets is seen in 30% of asymptomatic patients, and poses a risk for infection, valve deterioration, and aortic dilation and dissection.[16]

Congenital cardiovascular defects constitute the major source of premature mortality in Turner syndrome. Children with cardiac abnormalities should be transferred later to an adult congenital heart disease clinic in view of clear ongoing morbidity and mortality associated with the defects.

ONGOING

all patients: after establishment of cyclical bleeding

1st line – ovarian HRT

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1st line –

ovarian HRT

Oral or transdermal estrogen therapy should be used for hypoestrogenism, to reduce osteoporosis, cardiovascular disease, urogenital atrophy, and improve quality of life.[39]

Women with Turner syndrome should normally continue on HRT after induction and development of puberty. HRT should continue until about 50 years of age, after which further estrogen therapy may be given depending on individuals' risk/benefit considerations.[40]

Estrogen should be combined with progestogen therapy (administered continuously or cyclically) to prevent endometrial hyperplasia and cancer.[39]

For women seeking to prevent pregnancy, combined hormonal contraceptives are more effective than estrogen hormone therapy. A levonorgestrel intrauterine device is another acceptable option.[39]

Low bone mass should be managed with estrogen replacement hormone therapy, adequate calcium in diet, normal vitamin D levels, and weight-bearing activities, not bisphosphonates.[39]

Risk of not using ovarian HRT for young women with premature ovarian failure includes severe premature osteoporosis.[Figure caption and citation for the preceding image starts]: Importance of estrogen therapy in young adults with Turner syndrome (TS): X-ray figure A shows near collapse of T11, diffuse osteoporosis, and dorsal kyphosis in a woman with TS who discontinued HRT at age 18 years. Figure B shows normal spinal architecture and bone health in another woman with TS, age 30 years, who has taken HRT consistently since age 12.8 yearsFrom the personal collection of Carolyn Bondy, MS, MD (NIH study) [Citation ends]. com.bmj.content.model.Caption@2530da0b

Primary options

estradiol transdermal: 0.025 to 0.100 mg/24 hour patch weekly or twice weekly depending on brand used

and

progesterone micronized: 100-200 mg orally once daily on the last 10 days of the menstrual cycle, cycles may also be scheduled for every 1-3 months; or 100 mg orally once daily continuously

Secondary options

estradiol: 1-2 mg orally once daily

and

progesterone micronized: 100-200 mg orally once daily on the last 10 days of the menstrual cycle, cycles may also be scheduled for every 1-3 months; or 100 mg orally once daily continuously

Consider – breast implants

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Consider –

breast implants

Treatment recommended for SOME patients in selected patient group

Girls who have prominent signs of fetal lymphedema and hypoplastic nipples may not achieve adequate breast development with estrogen treatment and may require breast implants.

Consider – monitoring + education on reproductive issues

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Consider –

monitoring + education on reproductive issues

Treatment recommended for SOME patients in selected patient group

Most women with Turner syndrome are infertile, but spontaneous menses and pregnancies may occur in 2% to 3%. There is increased incidence of a fetus with aneuploidy when women with TS use their own oocytes. Pregnancy exacerbates underlying metabolic, hypertensive, and cardiovascular problems and may be catastrophic for women with Turner syndrome; therefore, girls over the age of 10 years need close monitoring with regard to potential fertility and education on reproductive issues and sexual behaviors.

Given that fertility in women with TS declines rapidly with age, offering fertility treatment at a young age should be considered.[3] Young women with mosaic TS should be counseled about the possibility of controlled ovarian hyperstimulation and oocyte cryopreservation, but routine oocyte retrieval is not recommended in girls aged <12 years.[3] Women with Turner syndrome may be interested in pregnancy via assisted reproduction using donor oocytes. Such pregnancies may have an unusually high risk for maternal death from aortic dissection or rupture, and from pre-eclampsia and its complications.[41][42]

Very stringent prepregnancy screening and patient education as to risks are imperative prior to attempting assisted reproduction for women with Turner syndrome.[43] The American Heart Association and International Turner Syndrome Consensus Group have made recommendations for management of pregnant women with TS; this should be undertaken by a multidisciplinary team, including a maternal-fetal medicine specialist and cardiologist with appropriate expertise.[3][29]

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Turner syndrome

Treatment algorithm

all patients: at diagnosis

surveillance and preventive care

GH until growth velocity is less than 2 cm/year or earlier if patient is satisfied with height

Primary options

oxandrolone

Primary options

low-dose estrogen

Primary options

Secondary options

cyclic progesterone

Primary options

cardiovascular assessment and evaluation for surgery

all patients: after establishment of cyclical bleeding

ovarian HRT

Primary options

Secondary options

breast implants

monitoring + education on reproductive issues