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    Turner Syndrome

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    Feb.11.2025

    Turner Syndrome

    Synopsis

    Key Points

    • Turner syndrome affects females and presents with characteristic features, most commonly short stature, delayed puberty, webbed neck, shield chest, short fourth metacarpal, and/or nail hypoplasia; infants classically present with transient congenital lymphedema
    • Caused by complete or partial absence of the second sex chromosome in phenotypic females
    • History and physical examination lead to suspicion of Turner syndrome; definitive diagnosis is made with karyotype or other genetic testing
    • Early recognition and diagnosis are essential for appropriate management of growth delay and hypogonadism
    • Treatment includes somatropin to help achieve optimal adult height
    • Estrogen replacement is necessary for most adolescents and adults owing to ovarian failure due to gonadal dysgenesis; most patients are infertile
    • Screening for other associated congenital anomalies is indicated at the time of definitive diagnosis; these include cardiac (aortic coarctation and bicuspid aortic valve) and renal structural abnormalities
    • Risk of aortic dissection necessitates ongoing cardiology evaluation, including monitoring of blood pressure and periodic cardiac imaging
    • Patients with Turner syndrome are at increased risk for certain acquired medical problems, such as osteoporosis and fractures, central obesity and insulin resistance, autoimmune endocrinopathies (eg, hypothyroidism), and hearing loss; ongoing monitoring for acquired disease frequently associated with the syndrome is warranted
    • Final height is improved with somatropin treatment; assisted reproduction techniques can help with infertility
    • Prognosis is generally good; patients do have a 3-fold higher mortality rate than general population, largely owing to increased cardiovascular disease

    Urgent Action

    • Urgent cardiology evaluation is indicated for aortic dilation that may lead to aortic dissection
    • Chest pain in patients with Turner syndrome can herald aortic dissection; care should be taken to exclude this potentially devastating complication
    • In individuals with aortic dilation and/or bicuspid aortic valve, discomfort of the neck, shoulder, back, or flank, particularly if it is sudden in onset and severe, may be secondary to aortic dissection and requires immediate evaluation r1

    Pitfalls

    • Turner syndrome may go unrecognized when short stature is the only presenting symptom
    • Presence of Y chromosome material confers risk for gonadoblastoma and, without resection, gonadoblastoma can transform into malignant neoplasm
    • Hypertension, if unrecognized or untreated, can contribute to aortic dissection
    • Failure to consider aortic dissection in patients with Turner syndrome who present with chest pain
    • Risk of aortic dissection and rupture is further increased in patients who become pregnant
    • Adolescents and young adults with Turner syndrome require care in the transition to ongoing adult medical services because up to 30% of patients discontinue care as adults r2

    Terminology

    Clinical Clarification

    • Turner syndrome is characterized by complete or partial absence of the second sex chromosome in females, leading to a broad range of physical features that include short stature, gonadal failure, and cardiovascular disease r3
    • Affects 1 in 2000 to 5000 live-born females r3

    Diagnosis

    Clinical Presentation

    History

    • Timing of presentation is variable; some patients present in infancy whereas others present in childhood or adolescence
      • Lymphedema is the most common reason to consider diagnosis during infancy r4c1
      • Short stature is the most common reason to consider diagnosis during childhood and adolescence r4c2c3
      • May go unrecognized when short stature is the only presenting symptom
    • Other common symptoms include:
      • Lack of pubertal development and primary amenorrhea c4c5
      • Secondary amenorrhea c6
      • Problems with attention at school c7
      • Difficulty with math but overall intelligence within the reference range c8
      • Frequent ear infections, especially during toddler years c9c10
    • Prenatal screening findings suggestive of Turner syndrome r3r5
      • Nonspecific findings
        • Fetal edema c11
        • Nuchal cystic hygroma c12
        • Left-sided cardiac defect c13
        • Relatively short limbs c14
      • Abnormal chromosomal analysis on noninvasive prenatal testing, amniotic fluid cells, or fetal lymphocytes (percutaneous umbilical blood sampling) c15

    Physical examination

    • Findings are variable
    • General
      • Congenital transient generalized lymphedema c16
      • Hypertension c17
      • Height less than fifth percentile r6c18
      • Lack of pubertal development c19
      • Webbed neck c20
      • Low hairline c21
      • Shield chest (increased chest diameter) with widely spaced nipples c22c23
      • Heart murmur indicative of left-sided cardiac lesion c24
      • Central obesity
    • Dysmorphic facial features
      • Flat nasal bridge c25
      • Low-set ears c26
      • High-arched palate c27
      • Ptosis c28
      • Hypertelorism c29
      • Upward slanting palpebral fissures c30
      • Epicanthal folds c31
    • Extremities
      • Edema of hands and feet in infancy c32c33
      • Short fourth metacarpal c34
      • Nail hypoplasia c35
      • Cubitus valgus c36
        • Lateral deviation of the forearm from midline at the elbow joint observable with palms facing forward and arms extended
      • Multiple pigmented nevi c37

    Associated congenital anomalies

    • Endocrinologic
      • Short stature
        • Most common finding and may be only physical finding r5
        • Result of SHOX gene expression haploinsufficiency and not hGH deficiency r7c38
      • Gonadal failure
        • Ultimately affects 90% of patients, although 30% have some pubertal development r5c39
        • Caused by ovarian dysgenesis; patients have streak gonads (small amount of connective tissue with either no or few atretic ovarian follicles) c40
    • Cardiac
      • Congenital heart disease (up to 50% of patients) r4r8c41
        • Elongated transverse aortic arch (up to 50% of patients) r9c42
        • Bicuspid aortic valve (30% of patients) r4r8c43
        • Aortic coarctation (10%-18% of patients) r8r10c44
        • Other lesions
          • Aortic stenosis c45
          • Partial anomalous pulmonary venous connection c46
          • Mitral valve prolapse c47
          • Atrial septal or ventricular septal defect c48c49
          • Hypoplastic left side of heart c50
          • Coronary artery abnormalities c51
      • Cardiac conduction and repolarization abnormalities are more common in patients with Turner syndrome r11
        • Accelerated atrioventricular conduction r11c52
        • T-wave abnormalities c53
        • Newer research suggests that QTc prolongation is not more prevalent in persons with Turner syndrome compared with the general population r1
    • Renal
      • Structural abnormalities (30%-40% of patients) r12r13
        • Collecting-system malformations c54
        • Horseshoe kidney c55
        • Other renal positioning abnormalities c56
    • Ophthalmologic r5
      • Strabismus (25%-35% of patients) r14c57
      • Hyperopia (25%-35% of patients) r14c58
      • Cataracts c59
      • Nystagmus c60
      • Red-green color blindness c61
    • Otologic
      • External ear deformities (20%-62% of patients) r15
      • Recurrent otitis media (24%-48% of patients) r15
      • Hearing loss ( 36%-84% of patients) r15
    • Skeletal
      • Congenital hip dislocation in infants c62
      • Madelung deformity of wrist (carpus curvus) c63

    Causes and Risk Factors

    Causes

    • Caused by loss of all or part of X chromosome, including tip of short arm r6c64
      • 50% of patients have monosomy (45,X) r16c65
      • 20% to 30% of patients have mosaicism r16r17c66
        • 45,X/46,XX
        • 45,X/46,XY
        • 45,X/47,XXX
      • 20% to 30% of patients have structural anomalies of an X chromosome r5
        • Isochromosome X c67
        • Deletions of long or short arm of chromosome X c68
        • Ring chromosome X c69
        • Translocations c70
      • Y chromosome is present in up to 6% of patients with Turner syndrome; an additional 3% of patients have a cryptic marker chromosome, which is sometimes derived from Y chromosome material r17

    Risk factors and/or associations

    Sex
    • Affects only phenotypic females r5c71
    Genetics
    • Short stature and various skeletal anomalies associated with Turner syndrome are caused, in part, by haploinsufficiency of SHOX gene located on the X chromosome at locus Xp22.33 (OMIM *312865r19) r18

    Diagnostic Procedures

    Primary diagnostic tools

    • History and physical examination c72
      • Timing of presentation is variable
        • Some patients are designated high-risk via noninvasive prenatal testing with confirmatory invasive diagnostic testing r1
        • Some patients present in the neonatal period with transient congenital lymphedema and/or a variable constellation of classic physical features associated with the syndrome
        • Others present in childhood with short stature and growth failure
        • Additional patients present in adolescence with delayed puberty and primary amenorrhea
        • Some adults with previously undiagnosed Turner syndrome present with secondary amenorrhea
    • Karyotype testing is necessary for diagnosis c73
    • Obtain baseline screening for associated congenital anomalies at time of diagnosis r1c74

    Laboratory

    • If noninvasive prenatal testing indicates a high likelihood of Turner syndrome, confirmatory invasive diagnostic testing is recommended r1
      • If a pregnant patient does not wish for invasive diagnostic testing, the clinician may offer karyotyping for maternal sex chromosome aneuploidies r1
      • All prenatal diagnoses should be confirmed with postnatal blood karyotype r1
    • Karyotype with 30-cell analysis of lymphocytes in metaphase r1r5c75
      • False-negative peripheral blood lymphocyte analysis can occur; different cell lines in the same patient can carry a different distribution of molecular mosaicism (eg, 46,XX peripheral blood lymphocyte karyotype and 45,X fibroblast karyotype in the same individual) r20
        • In patients with highly suggestive clinical features of Turner syndrome but normal peripheral 30-cell karyotype, obtain skin fibroblast karyotype to exclude Turner syndrome
        • Incidental presence of 45,X cell population without clinical findings is not considered Turner syndrome r11
        • Presence of one X chromosome and a deletion distal to Xq24 on the other X chromosome is not considered Turner syndrome r1
        • Less than 5% 45,X mosaicism in females older than 50 years is not considered Turner syndrome r1
    • When a rapid test result is needed, other methods (eg, microarray, fluorescence in situ hybridization, polymerase chain reaction) can be used as a first line test, with karyotype as a second line confirmatory test r1
    • Fluorescence in situ hybridization analysis for Y chromosome material c76
      • Y chromosome material may be present in up to 5% of patients, and an additional 3% may have a marker chromosome (a chromosome fragment of X or Y origin) r4
      • Screen for Y chromosome material if marker chromosome is identified on karyotype analysis or if signs of virilization develop r1r4
        • Some experts advocate testing all patients with 45,X karyotype for Y chromosome material r17
      • Use fluorescent in situ hybridization analysis with X- and Y-specific DNA probes to evaluate for Y chromosome mosaicism r4

    Differential Diagnosis

    Most common

    • Noonan syndrome r21c77d1
      • Presents in both pediatric males and females with short stature, dysmorphic facies with downward slanting palpebral fissures, ptosis, hypertelorism, low-set ears, webbed neck, and congenital heart disease
      • Pubertal development is usually normal in females but may be delayed in males
      • Karyotype is normal
      • Diagnosis based on clinical criteria and genetic testing for mutations associated with Noonan syndrome

    Treatment

    Goals

    • Promote growth with goal of attaining height within reference range for age, puberty at normal age, and eventual adult height within reference range r5
    • Manage any congenital abnormalities associated with the disease (eg, renal, cardiac, endocrine)
    • Monitor for any disease manifestations commonly associated with the syndrome (eg, hypothyroidism, hearing loss)

    Disposition

    Recommendations for specialist referral

    • Multidisciplinary team approach to patient care is optimal at diagnosis,r22 leading to continued coordinated multidisciplinary evaluation every 1 to 2 years after transition to adult care r1r4
    • Refer all patients to cardiologist for ECG, cardiac imaging (echocardiogram or MRI), and regular cardiology follow-up r4r23
    • Urgently refer to cardiologist for evaluation any patient with aortic dilation that could lead to aortic dissection
    • Refer all patients at time of diagnosis to endocrinologist to address growth and hGH replacement issues, puberty and estrogen replacement issues, and thyroid function test abnormalities, as well as for regular endocrine follow-up r4
    • Refer all patients during adolescence to an obstetrician/gynecologist to discuss risks associated with pregnancy and likelihood of infertility r4
    • Refer to reproductive endocrinologist to discuss fertility options, such as controlled ovarian stimulation and oocyte cryopreservation in postmenarchal females r1
    • Refer to geneticist/genetic counselor before pregnancy r1
    • Patients who achieve pregnancy require referral to a high-risk obstetrician owing to the risk of worsening aortic dissection and rupture during pregnancy
    • Refer to surgeon or urologist for prophylactic gonadectomy if Y chromosome material is present
    • Refer all patients to audiologist for hearing screen at the time of diagnosis and for further audiology screening throughout adulthood
    • Refer to otolaryngologist if patient has recurrent otitis media or hearing loss
    • Refer all patients to ophthalmologist for evaluation of potential eye abnormalities and ongoing monitoring for the development of ocular abnormalities
    • Refer to nephrologist if patient has structural abnormality of kidney or collecting system
    • Refer to orthopedic surgeon if patient develops scoliosis or kyphosis
    • Refer to gastroenterologist for positive celiac screen result, persistently elevated liver function test results, concern for cirrhosis, or clinical suspicion for inflammatory bowel disease
    • Refer to psychologist if patient needs support, especially with social isolation and coping with infertility issues

    Treatment Options

    Growth promotion

    • Start somatropin treatment as soon as growth failure, short stature, or likelihood of short stature is identified r1r3
      • Leads to greater final adult stature, decrease in central obesity, improved glucose tolerance, and increase in lean body mass
      • Optimal timing not established r5
        • Most patients start somatropin around age 2 years r1r3
        • Treatment is initiated and managed by endocrinologist as soon as growth failure is detected (apparent with decreasing height percentiles on reference growth curve) r1
      • Short stature and various skeletal anomalies associated with Turner syndrome are caused, in part, by haploinsufficiency of SHOX gene located on the X chromosome at locus Xp22.33 (OMIM #312865r19), usually not a specific deficiency in hGH itself r24
        • Rarely, patients will have concomitant hGH deficiency, as evidenced by lack of hGH secretion following provocative testing; however, in patients with Turner syndrome, the hGH–insulinlike growth factor binding protein axis is disturbed r24
    • Continue treatment with somatropin until growth plates have fused and little growth potential remains, usually at bone age of 14 years or older, or growth velocity less than 2 cm/year r1r4
    • Monitor and plot growth every 6 months to make sure that patient is maintaining height percentile equal to or greater than the pretreatment height percentile r1
    • Measure insulin-like growth factor 1 annually; should be in the normal range for age, pubertal stage, and sex r1
      • Reduce somatropin dose if persistently high insulin-like growth factor 1 values are detected r1
    • If an individual with short stature and remaining growth potential is diagnosed with Turner syndrome at older than 12 years, initiate treatment with low-dose 17β-estradiol (E2) simultaneously with somatropin r1

    Puberty induction

    • Estrogen therapy is indicated in patients in whom spontaneous puberty does not occur (most patients with Turner syndrome) or in patients who develop premature gonadal failure later in life
      • High luteinizing hormone and follicle-stimulating hormone levels with low estradiol levels at time of normal puberty indicate gonadal failure
    • Start estrogen therapy between 11 and 12 years of age, after follicle-stimulating hormone has been elevated on at least 2 sequential measurements, to allow for normal pace of puberty r1
      • Estrogen replacement is unlikely to inhibit somatropin treatment effects on final height r4r5
    • Low-dose estrogen is recommended initially and gradually increased over 2 to 4 years with the goal of achieving estradiol concentrations of 100 to 150 pg/mL at full adult replacement r1r5
      • Treatment is generally initiated and managed by endocrinologist
    • Administer estradiol via transdermal route when possible, with oral estradiol as second choice r1
      • Transdermal estradiol is preferred, owing to lower risk of thrombosis compared with oral estrogen dosing r4
      • Ethinyl estradiol has more risks but is better than no treatment r1
    • Monitor breast development, height, uterine lining (via ultrasonography), bone density, and serum estradiol concentrations while patient is taking estrogen r1
    • Add cyclic progesterone once breakthrough bleeding occurs r1
      • Usually after approximately 18 to 24 months of unopposed estrogen exposure r1
    • Continue estrogen and progesterone replacement in adulthood for prevention of osteoporosis and to reduce risk for atherosclerosis
      • Combination oral contraceptive pill is a convenient alternative once adult estrogen doses are reached
    • At the usual age of menopause (approximately 50-55 years old) reevaluate for possible continued lower dose of estradiol and progesterone r1
      • Decision to continue hormonal replacement is then made on an individual basis r25
    • Hormone replacement therapy should be continued in the presence of liver function abnormalities r1
      • Estrogen therapy is not contraindicated in patients with elevated liver enzyme levels r26
      • Benign elevations in liver function test results are common in patients with Turner syndrome and are of unknown significance

    Monitoring and management of acquired diseases frequently associated with Turner syndrome

    • Osteoporosis
      • Treat with appropriate dietary intake of calcium and vitamin D, weight-bearing activity, and estrogen replacement r1
    • Gonadectomy for patients with Y chromosome material r1
    • Bacterial endocarditis prophylaxis recommended if an underlying cardiac anomaly is present that places patient at risk for endocarditis based on the American Heart Association guidelines r27r28
      • Most Turner syndrome patients do not fall under the criteria requiring antibiotic prophylaxis unless patient has unrepaired cyanotic congenital heart disease or a prosthetic valve
    • Aggressive control of blood pressure with β-adrenergic blocker, angiotensin receptor blocker, or both is recommended when aortic dilation is present r1r4r23
      • Target blood pressure goal is low end of reference range r1
      • Consider treatment of patients who have a dilated aorta even if they are not hypertensive r1
      • Administer treatment per pediatric or adult guidelines for hypertension if patients do not have a dilated aorta r1
    • Middle ear disease management
      • Administer antibiotic treatment for acute bacterial otitis media as for a high-risk population per local treatment guidelines and repeat examination to ensure resolution r1
      • Place tympanostomy tubes at the early stages of chronic or recurrent middle ear disease in childhood (as for a high-risk population) r1
      • Tympanostomy tube insertion and/or hearing aid placement should be performed rapidly for conductive hearing loss due to middle ear disease in childhood r1
      • Provide counseling for balance and vestibular problems in adults with sensorineural hearing loss; refer to appropriate specialists for vestibular testing and compensatory training if concerns are identified r1

    Drug therapy

    • Recombinant growth hormone
      • Somatropin c78
        • Somatropin (Recombinant rhGH) Solution for injection; Children: 45 to 50 mcg/kg/dose subcutaneously once daily, initially. Adjust dose based on growth response and insulin-like growth factor 1 concentrations. Max: 68 mcg/kg/day.
    • Hormone replacement therapies
      • Estradiol c79
        • Transdermal
          • Biweekly
            • Estradiol Transdermal patch - biweekly; Children and Adolescents 11 to 17 years†: 6.25 mcg/24 hours transdermally twice weekly, initially. Increase the dose gradually over 2 to 4 years to mimic the normal process of puberty. Max: 200 mcg/24 hours transdermally twice weekly. Continue treatment for reproductive life.
            • Estradiol Transdermal patch - biweekly; Adults: 37.5 to 50 mcg/24 hours transdermally twice weekly, initially. Adjust dose as needed to control symptoms. Max: 200 mcg/24 hours transdermally twice weekly. Continue treatment for reproductive life.
          • Weekly
            • Estradiol Transdermal patch - weekly; Children and Adolescents 11 to 17 years†: 6.25 to 7 mcg/24 hours transdermally once weekly, initially. Increase the dose gradually over 2 to 4 years to mimic the normal process of puberty. Max: 200 mcg/24 hours transdermally once weekly. Continue treatment for reproductive life.
            • Estradiol Transdermal patch - weekly; Adults: 25 mcg/24 hours transdermally once weekly, initially. Adjust dose as needed to control symptoms. Max: 200 mcg/24 hours transdermally once weekly. Continue treatment for reproductive life.
        • Oral
          • Estradiol Oral tablet; Children and Adolescents 11 to 17 years†: 0.25 mg PO once daily, initially. Increase the dose gradually over 2 to 4 years to mimic the normal process of puberty. Max: 4 mg/day. Continue treatment for reproductive life.
          • Estradiol Oral tablet; Adults: 1 to 2 mg PO once daily, initially. Adjust dose as needed to control symptoms. Max: 4 mg/day. Continue treatment for reproductive life.
      • Progesterone c80
        • Progesterone Oral capsule; Adolescents: 200 mg PO once daily for 10 to 12 sequential days of every 28-day cycle. Adjust dose proportionately to estrogen dose as needed. Max: 300 mg PO once daily for 12 days/month. Continue treatment for reproductive life.
        • Progesterone Oral capsule; Adults: 200 mg PO once daily for 10 to 12 sequential days of every 28-day cycle. Adjust dose proportionately to estrogen dose as needed. Max: 300 mg PO once daily for 12 days/month. Continue treatment for reproductive life.
    • Combined estrogen and progestin contraceptives
      • Ethinyl estradiol with drospirenone
        • Drospirenone, Ethinyl Estradiol Oral tablet, Inert Oral tablet; Adolescents: 3 mg drospirenone; 0.03 mg ethinyl estradiol PO once daily for 21 days, followed by 7 days of inert, inactive tablets as for routine contraception. Continue treatment for reproductive life.
        • Drospirenone, Ethinyl Estradiol Oral tablet, Inert Oral tablet; Adults: 3 mg drospirenone; 0.02 to 0.03 mg ethinyl estradiol PO once daily for 21 days, followed by 7 days of inert, inactive tablets as for routine contraception. Continue treatment for reproductive life.
      • Ethinyl estradiol with levonorgestrel
        • Levonorgestrel, Ethinyl Estradiol Oral tablet; Adolescents: 0.05 to 0.15 mg levonorgestrel; 0.03 to 0.04 mg ethinyl estradiol PO once daily for 21 days, followed by 7 days of inert, inactive tablets as for routine contraception. Continue treatment for reproductive life.
        • Levonorgestrel, Ethinyl Estradiol Oral tablet; Adults: 0.05 to 0.15 mg levonorgestrel; 0.02 to 0.03 mg ethinyl estradiol PO once daily for 21 days, followed by 7 days of inert, inactive tablets as for routine contraception. Continue treatment for reproductive life.
      • Ethinyl estradiol with norethindrone
        • Ethinyl Estradiol, Norethindrone Oral tablet; Adolescents: 0.4 to 1 mg norethindrone; 0.035 mg ethinyl estradiol PO once daily for 21 days, followed by 7 days of inert, inactive tablets as for routine contraception. Continue treatment for reproductive life.
        • Ethinyl Estradiol, Norethindrone Oral tablet; Adults: 0.4 to 1 mg norethindrone; 0.035 mg ethinyl estradiol PO once daily for 21 days, followed by 7 days of inert, inactive tablets as for routine contraception. Continue treatment for reproductive life.

    Nondrug and supportive care

    Lymphedema

    • Treat with compression garments, lymphatic massage, and referral to specialists in lymphedema care r1

    Psychological support r5c81

    • Age-appropriate discussions about implications of diagnosis, especially regarding infertility
    • Support to enhance self-esteem and avoid social isolation
      • Local and national Turner syndrome organizations offer patient-oriented materials and support groups r1

    Educational support r5c82

    • Perform comprehensive psychoeducational evaluation
    • Early intervention for dyslexia or attention-deficit/hyperactivity disorder, which may interfere with academic performance
    • Classroom accommodations to assist with potential visual-spatial issues and slower processing speed

    Facilitate transition to adult care r2c83

    • Adolescent and young adult females with Turner syndrome require care in the transition to ongoing adult medical services, given the increased risk for cardiovascular disease, osteoporosis, autoimmune disease (eg, celiac disease, hypothyroidism), glucose intolerance, and dyslipidemia r2
      • Up to 30% of patients discontinue care as adults r2
    • Continuation of estrogen replacement therapy is necessary to reduce risks of cardiovascular disease and osteoporosis associated with premature ovarian failure
    • Continued monitoring for adult disease frequently associated with Turner syndrome is warranted

    Provide family support and anticipatory guidance c84c85

    • Web-based resources are available r29

    Fertility counseling

    • Refer to a fertility specialist when developmentally appropriate for the patient r1
    • Controlled ovarian stimulation and oocyte cryopreservation should be offered in postmenarchal females with fertility potential as the primary fertility preservation option r1

    Provide appropriate anticipatory guidance regarding physical activity in patients with Turner syndrome

    • Healthy lifestyles including exercise should be encouraged to address modifiable risk factors of cardiovascular disease r1
    • Individuals with a mild to moderately dilated aorta (Z of 2.5-3.5) may participate in low and moderate static and dynamic competitive sports, but intense weight-training should be avoided r1
    • Individuals with moderate to severely dilated aorta (Z more than 3.5) should not participate in any competitive sports, intense weight-training, or physical activities with risk of contact injury to the chest r1
    Procedures
    Prophylactic gonadectomy c86c87
    General explanation
    • Ultrasonography and/or MRI imagingr31 is performed to locate testicular tissue and ovaries; removal is usually accomplished by laparoscopic approach r30
      • Testicle-like gonads can be located in any pelvic anatomic location, usually pelvis, inguinal canal, or labia majora
      • Streak gonads can be located in the ovarian fossa
    • Consider preservation of follicles or oocytes to retain future reproductive potential r11
    • Hysterectomy is not indicated
    Indication
    • Patients with Turner syndrome who have detectable Y chromosome material in genome (owing to increased risk of gonadoblastoma/dysgerminoma) r1r4r11
    • Requires individualized decision-making about the timing of gonadectomy/salpingo-oophorectomy, weighing the risk of malignancy against the potential benefit of gonadal function and fertility r1

    Comorbidities c88

    Special populations

    • Pregnant patients
      • Absolute contraindications to pregnancy in patients with Turner syndrome r1r4
        • Aortic dilation with a body surface area–adjusted aortic size index greater than 2 cm/m², ORr1
        • Individuals with severe subaortic or aortic valve stenosis or significant valve disease and reduced cardiac function r1
      • Risk of aortic dissection and rupture is further increased in patients who become pregnant; close monitoring of aortic diameter and blood pressure control are essential
      • Before conception r4
        • Patients require careful assessment and counseling
        • Cardiac MRI or CT should be performed at least once within 2 years before planned pregnancy or assisted reproductive methods and repeated closer to pregnancy if recommended by a cardiovascular specialist r1
      • Individuals with mosaicism (45,X/46,XX) who become pregnant spontaneously should be offered prenatal diagnostic testing r1
      • Low-risk patients (eg, no aortic dilation, bicuspid aortic valve, aortic coarctation, hypertension, or rapid aortic diameter increase) should have a transthoracic echocardiogram at least once during gestation, ideally around 20 weeks r1
      • If aortic dilation or any other risk factor for dissection exists (eg, bicuspid aortic valve, aortic coarctation, hypertension, rapid aortic diameter increase), patient should:
        • Have individualized peripartum cardiovascular care by a multidisciplinary team that includes a maternal-fetal medicine specialist and a cardiologist with expertise in managing patients with Turner syndrome, preferably in a center with expertise in aortic surgery and Turner syndrome r1
        • Have a transthoracic echocardiogram at least once every 12 weeks during pregnancy, or more frequently on an individualized basis r1
      • All pregnant patients with Turner syndrome must have tight blood pressure control to a target of less than 130/80 mm Hg during the peripartum period r1
        • Antihypertensive therapies and low-dose aspirin for the prevention of adverse pregnancy outcomes due to preeclampsia and related hypertensive disorders should be administered according to current clinical practice guidelines r1
      • Cardiac MRI without contrast medium should be performed during pregnancy if a transthoracic echocardiogram raises suspicion of rapid aortic dilation or if any areas of the aorta previously known to be dilated cannot be visualized r1
      • If a patient has rapid aortic dilation (more than 3 mm compared with preconception imaging), consider timely prophylactic aortic valve replacement r1
      • Cesarean section is the preferred delivery modality in patients with severe aortic dilation or history of aortic dissection r1
      • Obtain initial postpartum cardiac imaging 2 to 6 weeks after delivery in individuals with severe aortic dilation or a history of aortic dissection r1
        • These high-risk patients should have an additional follow-up cardiology visit as well r1
      • Postpartum cardiac imaging may be obtained 4 to 6 months after delivery in females with less-severe aortic disease before resuming routine follow-up intervals r1

    Monitoring

    • Ophthalmic
      • After initial comprehensive ophthalmologic examination between 6 to 12 months (or at time of diagnosis), follow up for new concerns or if initial evaluation is abnormal r1
    • Otologic
      • Perform annual otoscopy for middle ear disease, including effusion and cholesteatoma, annually during childhood and as needed if symptoms develop r1
      • Perform annual tympanometry up to age 5 years r1
      • Age-appropriate behavioral audiometric evaluation should be conducted: r1
        • Every 2 to 3 years during childhood and adolescence, starting as soon as developmentally able (age 1-2 years)
        • Every 5 years in adults and any time decreased hearing is suspected
    • Dental
      • Dental care recommended at least annually from first tooth eruption r1
      • Orthodontic evaluation is recommended when adult teeth present r1
    • Cardiac
      • Lifelong cardiac follow-up is recommended, even in patients without cardiovascular disease r23
      • Obtain blood pressure annually r1c89
      • Normal cardiovascular system and blood pressure at last assessment:
        • Cardiac imaging (echocardiogram or MRI) at diagnosis, at appearance of hypertension, at transition to adult clinic, and before attempting pregnancy r1
          • Echocardiogram for younger patients c90
          • MRI for adolescents and adults (when no sedation is needed) c91
        • In absence of issues after initial screening, transthoracic echocardiography should be done at age 9 to 11 years and then every 5 to 10 years as an adult r1
      • Cardiovascular abnormality present or individuals contemplating pregnancy: r4
        • Increased frequency of monitoring is recommended, including patients with the following:
          • Aortic dilation (eg, aortic size index more than 2 cm/m²) r4
          • Elongated transverse aortic arch
          • Hypertension
          • Rapid increase in aortic diameter ( eg, more than 3 mm in a year)
          • Bicuspid aortic valve
          • Aortic coarctation
        • Frequency of monitoring and treatment should be determined by cardiologist
      • Lipid profile at age of initial screening recommended by country-specific guidelines or at transition to adult care, and repeated every 3 years r1
        • Diagnosis and treatment of hyperlipidemia in Turner syndrome should be based on the appropriate pediatric or adult clinical guidelines for the general population r1
    • Growth r5c92
      • Plot and follow patient growth on Turner syndrome–specific growth charts beginning at age 2 years r3
      • Patients receiving somatropin treatment require periodic monitoring of insulin-like growth factor 1 levels (approximately annually) and growth parameters as coordinated and managed by endocrinologist r1
      • Monitor growth-promoting treatment by measuring height at least every 6 months r1
    • Endocrine
      • Evaluate for diabetes with measurement of hemoglobin A1c or fasting glucose every 1 to 2 years starting at age 10 to 12 years, or sooner if symptoms of diabetes develop r1
      • In females with Turner syndrome diagnosed with diabetes, assess diabetes autoantibodies to determine the type of diabetes r1
      • Screen for hypothyroidism with measurement of thyroid-stimulating hormone every 1 to 2 years starting at age 2 years; continue annually through adulthood, with more frequent testing if new symptoms develop r1
        • If thyroid stimulating hormone level is elevated, test for antithyroid antibodies r1
    • Gastrointestinal
      • Monitor liver enzyme levels (ALT at minimum) every 1 to 2 years, starting at age 10 years r1
      • AST, gamma-glutamyl transferase, and alkaline phosphatase should also be monitored every 1 to 2 years in adults r1
      • If liver enzyme levels are elevated at least twice the upper limit of normal, reassessment is recommended, as fluctuation is common r1
        • Persistent liver function abnormalities warrant further investigation and referral to a gastroenterologist r1
    • Renal
      • Obtain laboratory testing or repeat imaging if there are new renal or urinary concerns, such as urinary tract infections and hypertension r1
      • Obtain annual urinalysis for proteinuria in all individuals with critical renal anomalies r1
    • Hematologic
      • Obtain a complete blood count to evaluate for anemia every 1 to 2 years in adolescents and adults r1
    • Orthopedic
      • Perform annual physical examination to evaluate for scoliosis until skeletal maturity r1
      • Perform routine screening for vitamin D deficiency using a serum 25 (OH) vitamin D level concentration between 9 and 11 years of age and every 2 to 3 years thereafter; treat with standard vitamin D supplement as necessary r1
      • Obtain a DXA scan after completion of growth but before age 21 years, and every 5 to 10 years throughout adulthood r1
    • Psychosocial and educational
      • Integrate cognitive/neuropsychological evaluations and behavioral/social/emotional screenings into the care of individuals with Turner syndrome across the lifespan r1
      • Perform age-appropriate evaluation for educational/learning deficiencies if indicated by declining school performance r1
    • Gynecologic
      • Measure follicle-stimulating hormone and antimüllerian hormone at age 8 to 9 years and then yearly until 11 to 12 years r1
      • During estrogen therapy, monitor breast development, height, uterine lining, bone density, and serum estradiol concentrations r1
    • Autoimmune
      • Monitor for symptoms of autoimmune conditions (eg, celiac disease, psoriasis, vitiligo, inflammatory bowel diseases); provide counseling and further workup as needed if symptoms arise r1
      • Test for celiac disease with tissue transglutaminase antibodies in asymptomatic individuals starting at age 2 years and subsequently every 2 to 5 years r1
        • Perform triggered testing immediately if gastrointestinal symptoms, poor growth, weight loss, osteoporosis, skin changes, anemia, and/or other symptoms develop r1

    Complications and Prognosis

    Complications

    • Acquired disease
      • Cardiovascular disease
        • Aortic dissection or rupture c93c94
          • Occurs at median age of 30 to 35 years in 0.6% to 1.4% of patients r4
          • Chest pain in patients with Turner syndrome can herald aortic dissection; take care to exclude this potentially devastating complication
          • Females with aortic dilation and/or bicuspid aortic valve should seek prompt evaluation if they experience acute symptoms consistent with aortic dissection (eg, discomfort in chest, neck, shoulder, back, flank), particularly if onset is sudden and severe r1
          • Usually preceded by aortic dilation c95
            • Patients with aortic size index of 2 to 2.5 cm/m² or more are at highest risk for aortic dissection r4r32
            • Aortic dilation occurs in up to 30% of patients r4
          • Uncommonly (less than 10% of cases) occur without prior risk factors (eg, bicuspid aortic valve, aortic coarctation, hypertension) r4
          • Body surface area-adjusted aortic size index of greater than 2 cm/m² or any significant cardiac abnormality as an absolute contraindication to pregnancy owing to high risk of death from aortic dissection in the perinatal period r4
        • Hypertension c96c97
          • Found in 25% of teens and 40% to 60% of adults r33
          • Idiopathic in many cases r23r25
          • Often systolic and nocturnal r4
          • If unrecognized or untreated, can contribute to aortic dissection r23
        • Dyslipidemia and increased risk for atherosclerosis predisposing to coronary artery disease and cerebrovascular disease r5r23c98c99
        • ECG abnormalities c100c101
          • Common in adults with disease; abnormalities are often independent of structural defects and include the following: r4
            • Right-axis deviation
            • T-wave abnormalities
            • Accelerated AV conduction
      • Autoimmune
        • Autoimmune thyroid disease
          • Hypothyroidism affects 25% of patients r34c102
          • Hyperthyroidism affects 2.5% of patients r34c103
        • Celiac disease c104
          • Affects 4% to 6% of patients r35
        • Inflammatory bowel disease c105
          • Affects 4% of patients r36
            • Crohn disease c106
            • Ulcerative colitis c107
            • Chronic diarrhea of unknown cause c108
      • Otologic
        • Recurrent otitis media r16c109c110
          • Affects more than half of infants and children with Turner syndrome and may result in conductive hearing loss r16
          • Patients at increased risk for cholesteatoma formation
        • Hearing loss
          • Progressive sensorineural hearing loss in up to 90% of patients by age 45 years r37c111
            • Clinically significant in 60% of those affected; hearing aids required in 27% of patients r37
        • Increased risk of cholesteatoma c112
      • Malignancy
        • Gonadoblastoma c113
          • 5% to 30% risk if Y chromosome material is present r4
          • May transform into malignant germ cell neoplasm (dysgerminoma) r5
          • Prophylactic gonadectomy is recommended in patients with any Y chromosome material in their genome
      • Musculoskeletal
        • Scoliosis affects 10% to 20% of patients r38c114
        • Kyphosis affects up to 50% of patients r39c115
        • Osteoporosis c116
          • Increased risk for developing osteoporosis
            • May be related to previous inadequate estrogen replacement r5
          • Increased risk of fractures
      • Endocrine
        • Metabolic
          • Development of insulin resistance and type 2 diabetes is common r5c117c118
          • Increased frequency of central obesity/abdominal adiposity c119
          • Increased risk of dyslipidemia c120
        • Ovarian failure and fertility c121c122
          • Spectrum of gonadal dysgenesis/hypogonadism is found in Turner syndrome patients r40c123
            • Most have no pubertal development but up to 30% have spontaneous puberty r5r40
              • Secondary amenorrhea, irregular menstrual cycles, and premature ovarian failure are common among patients who develop spontaneous puberty
            • Spontaneous pregnancy is rare r40
              • Pregnancy-related complications are significant, with a reported 2% or higher risk of death from aortic dissection or rupture during pregnancy r41
              • Pregnancy is possible with oocyte donation and embryo transfer
              • Oocyte preservation is possible in patients with Turner syndrome mosaicism
      • Hepatic disease
        • In patients with Turner syndrome, 44% to 80% have liver function test results outside the reference range r26r42c124
        • Commonly elevated liver enzyme levels have an unclear relationship with chronic liver disease; if cirrhosis is suspected, refer to a gastroenterologist for further evaluation and management
        • Cirrhosis is 5 times more common in patients with Turner syndrome r43c125
      • Ophthalmologic
        • Congenital and acquired ocular abnormalities are common
      • Dermatologic
        • Increased prevalence of benign pilomatricoma (up to 2.6% of patients) r44c130
          • Pilomatricoma is an otherwise uncommon tumor arising from follicular hair cells
      • Neurocognitive deficits r16
        • Visuospatial organization problems c131
        • Selective nonverbal skill impairments
          • Problems with mathematics c132
        • Psychomotor deficits
        • Attention problems
          • Attention-deficit/hyperactivity disorder c134
      • Depression r45c135
        • Adolescents and adults with Turner syndrome are at risk; adults seem to have the highest risk
    • Other

    Prognosis

    • Mortality is 3 times higher than in the general population due largely to increased cardiovascular disease r46
    • Patients treated with somatropin can achieve adult height within reference range r47
      • Patients treated with somatropin are, on average, 7.2 cm taller than untreated patients after 5.7 years r48
      • Without somatropin, final adult stature is about 21 cm shorter than in healthy female adults r47
      • Health-related quality-of-life scores do not differ between somatropin-treated and untreated groups r49
    • Pregnancy can be achieved through in vitro fertilization with oocyte donation, but risk of death from aortic dissection or rupture during a pregnancy is 2% or higher r41

    Screening and Prevention

    Screening

    • Screening for associated congenital anomalies r5
      • Patients who are diagnosed with Turner syndrome prenatally should have:
        • Fetal echocardiogram r1
        • Detailed fetal ultrasonography r1
        • Genetic counseling provided to parents r1
      • After birth but before discharge, neonates with Turner syndrome should have:
        • Transthoracic echocardiography at day 2 to day 3 of life, sooner if congenital heart disease is suspected, even if fetal echocardiogram or postnatal clinical examination findings were normal r1
          • If transthoracic echocardiogram is not possible, obtain 4-extremity blood pressure, pulse oximetry, palpation of femoral pulses, cardiac auscultation, and ECG before discharge, followed by outpatient transthoracic echocardiogram within the first weeks of life r1
        • A comprehensive physical examination with particular attention to hip stability and lymphedema
        • Renal ultrasonography (regardless of prenatal imaging results)
        • Prefeeding blood glucose levels in the first 48 hours of life, and ensure that the infant is euglycemic before discharge r1
        • A newborn hearing screen r1
        • Counseling on, and monitoring for, feeding difficulties and poor weight gain in the first year of life r1
        • Screening for orthopedic anomalies (eg, scoliosis, genu valgum, Madelung deformity)
      • Older infants diagnosed with Turner syndrome should have:
        • Transthoracic echocardiography at the time of the diagnosis; cardiac MRI is recommended as soon as feasible without general anesthesia r1
        • Clinical evaluation for hip dislocation for patients aged 0 to 4 years; if examination is inconclusive, obtain plain radiograph of hips to exclude possible subclinical dislocation c136
        • Screening for orthopedic anomalies (eg, scoliosis, genu valgum, Madelung deformity)
        • Strabismus evaluation on physical examination in patients aged 4 months to 5 years r14
      • All patients, including adults, upon initial diagnosis with Turner syndrome should have: c137
        • Cardiac imaging for coarctation of the aorta and other cardiac defects r1r23
          • 4-extremity blood pressure measurements and assessment of peripheral pulse quality c138
          • Cardiac echocardiogram for younger patients c139
          • Cardiac MRI for adolescents and adults (when no sedation is needed) c140
        • ECG for prolonged QTc and other cardiac conduction abnormalities r1
        • Screening for orthopedic anomalies (eg, scoliosis, genu valgum, Madelung deformity) r1c141
        • Hearing evaluation by audiologist r1c142
        • Eye examination by ophthalmologist c143
        • Thyroid function tests with thyroid-stimulating hormone level and free thyroxine level for patients aged 4 years or older c144
        • Celiac screen with tissue transglutaminase IgA antibodies for patients aged 2 years or older r1c145
        • Educational and psychosocial evaluations for patients aged 4 years or older c146
        • Orthodontic evaluation if adult teeth are present c147
        • Evaluation of ovarian function with physical examination, luteinizing hormone, follicle-stimulating hormone, and estradiol levels for patients aged 8 to 9 years or older r1c148c149c150
        • Liver function tests and measuring fasting blood glucose, lipids, CBC, creatinine, and BUN for patients aged 10 years or older c151
        • Bone mineral density scan for patients aged 18 years or older c152

    Prevention c153

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