The Journal of Clinical Endocrinology & Metabolism 92(1):10 –25 Copyright 2007 by The Endocrine Society CLINICAL PRACTICE GUIDELINE
Care of Girls and Women with Turner Syndrome: A
Guideline of the Turner Syndrome Study Group

Carolyn A. Bondy for the The Turner Syndrome Consensus Study Group* National Institutes of Health, National Institute of Child Health and Human Development, Bethesda, Maryland 20892 Objectives: The objective of this work is to provide updated guide-
Conclusions: We suggest that parents receiving a prenatal diagnosis
lines for the evaluation and treatment of girls and women with Turner of TS be advised of the broad phenotypic spectrum and the good quality of life observed in TS in recent years. We recommend thatmagnetic resonance angiography be used in addition to echocardiog- Participants: The Turner Syndrome Consensus Study Group is a
raphy to evaluate the cardiovascular system and suggest that pa- multidisciplinary panel of experts with relevant clinical and research tients with defined cardiovascular defects be cautioned in regard to experience with TS that met in Bethesda, Maryland, April 2006. The pregnancy and certain types of exercise. We recommend that puberty meeting was supported by the National Institute of Child Health and should not be delayed to promote statural growth. We suggest a unrestricted educational grants from pharmaceutical companies.
comprehensive educational evaluation in early childhood to identifypotential attention-deficit or nonverbal learning disorders. We sug- Evidence: The study group used peer-reviewed published informa-
gest that caregivers address the prospect of premature ovarian failure tion to form its principal recommendations. Expert opinion was used in an open and sensitive manner and emphasize the critical impor- tance of estrogen treatment for feminization and for bone healthduring the adult years. All individuals with TS require continued Consensus: The study group met for 3 d to discuss key issues. Brea-
monitoring of hearing and thyroid function throughout the lifespan.
kout groups focused on genetic, cardiological, auxological, psycholog- We suggest that adults with TS be monitored for aortic enlargement, ical, gynecological, and general medical concerns and drafted recom- hypertension, diabetes, and dyslipidemia. (J Clin Endocrinol
mendations for presentation to the whole group. Draft reports were Metab 92: 10 –25, 2007)
available for additional comment on the meeting web site. Synthesisof the section reports and final revisions were reviewed by e-mail andapproved by whole-group consensus.
TURNERSYNDROME(TS)affectsapproximatelyonein represent the experts’ consensus judgments given the best 2500 live-born females (1). This disorder presents the information available. The paper is divided into sections clinician with a challenging array of genetic, developmental, addressing 1) diagnostic issues, 2) congenital cardiovascular endocrine, cardiovascular, psychosocial, and reproductive disease, 3) growth and development, 4) psychological and issues. There have been important advances in each of these educational issues, and 5) TS in adulthood.
arenas since publication of the previous recommendationsfor the care of girls and women with TS (2). This paper is Diagnostic Issues
based on the proceedings of a multidisciplinary international conference sponsored by the National Institute of Child The diagnosis of TS requires the presence of characteristic Health and Human Development (NICHD) in April 2006.
physical features in phenotypic females (3, 4) coupled with Discussions at this conference and the ensuing recommen- complete or partial absence of the second sex chromosome, dations have been based upon recent, peer-reviewed scien- with or without cell line mosaicism (5). Individuals with a tific publications. However, there are very few TS studies 45,X cell population but without clinical features are not that would qualify as guidance for evidence-based recom- considered to have TS. Phenotypic males are also excluded mendations, and hence most of the following guidelines from the diagnosis of TS, regardless of karyotype. Whetherto diagnose individuals with sex chromosome structural ab-normalities as having TS requires clinical judgment. Abnor- First Published Online October 25, 2006
* For a list of members of The Turner Syndrome Consensus Study
malities such as ring X and Xq isochromosomes are common in patients with classic TS features, and many of these pa- Abbreviations: BAV, Bicuspid aortic valve; BMD, bone mineral den- tients have phenotypes indistinguishable from that of pa- sity; ECG, electrocardiogram; FISH, fluorescence in situ hybridization; tients with apparently nonmosaic monosomy X (45,X) (5).
MRI, magnetic resonance imaging; OM, otitis media; PAPVC, partial Patients with small distal short arm deletions (Xp-) including anomalous pulmonary connection; TS, Turner syndrome.
the SHOX gene frequently have short stature and other TS- JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the en-

associated skeletal anomalies, but most are at low risk of docrine community.
ovarian failure and should generally not be diagnosed with Bondy • Care of Girls and Women with Turner Syndrome J Clin Endocrinol Metab, January 2007, 92(1):10 –25 TS if band Xp22.3 is not deleted (6). Individuals with dele- postdiagnostic counseling need to be fully informed about tions of the long arm distal to Xq24 frequently have primary the prognosis, complications, and quality of life of individ- or secondary amenorrhea without short stature or other TS uals affected with TS as well as of recent advances in man- features (7); the diagnosis of premature ovarian failure is agement. The clinical spectrum of TS is much broader and often less severe than that described in many textbooks.
Prenatal counseling should always involve discussion of thevariability of features, the likelihood of short stature and ovarian failure, and their management. It should be empha- Sex chromosome abnormalities are increasingly detected sized that most individuals with TS have intelligence scores prenatally by chorionic villous sampling or amniocentesis, in the normal range, although they may have specific types and genetic counseling before any prenatal diagnostic pro- of learning disabilities. Most adults with TS function well cedure should always include discussion of the possibility of and independently. Girls and women in one study indicated detecting them. Certain ultrasound findings indicate an in- that struggling with their infertility was the greatest chal- creased likelihood of TS. Increased nuchal translucency on lenge they faced in adapting to a life with TS (18). Speaking ultrasound is frequently seen in TS but may also be observed with children and adults with TS and their families is im- in autosomal trisomy syndromes. The presence of cystic hy- portant for prospective parents faced with a decision about gromas make the diagnosis of TS more likely (8). Other pregnancy and can be facilitated by support organizations, ultrasound findings suggestive of TS are coarctation of the e.g. Turner Syndrome Societies.
aorta and/or left-sided cardiac defects, brachycephaly, renalanomalies, polyhydramnios, oligohydramnios, and growthretardation (9). Abnormal triple or quadruple maternal se- rum screening (␣-fetoprotein, human chorionic gonadotro- All individuals with suspected TS (see below) should have pin, inhibin A, and unconjugated estriol) may also suggest a karyotype performed. A standard 30-cell karyotype is rec- the diagnosis of TS (10). Ultrasound and maternal serum ommended by the American College of Medical Genetics and screening are not diagnostic, and to make a prenatal diag- identifies at least 10% mosaicism with 95% confidence (19), nosis of TS, karyotype confirmation is obligatory.
although additional metaphases may be counted or fluores- The postnatal outcome and constitutional karyotype of cence in situ hybridization (FISH) studies performed if there individuals with prenatally diagnosed sex chromosome is a strong suspicion of undetected mosaicism (20). The cy- monosomy are uncertain, especially in mosaic cases. There- togeneticist should be consulted in this case. Although a fore, chromosomes should be reevaluated postnatally in all peripheral blood karyotype is usually adequate, if there is a cases. The degree of mosaicism detected prenatally is not strong clinical suspicion of TS, despite a normal blood karyo- generally predictive of the severity of the TS phenotype (11, type, a second tissue, such as skin, may be examined.
12). In general, any of the features of TS may be seen with Testing for Y chromosome material should be performed virtually any of the common chromosome constitutions (5).
in any TS patient (or fetus) with a marker chromosome (a sex Nonmosaic 45,X fetuses with pleural effusion or cystic hy- chromosomal fragment of unknown origin, i.e. X vs. Y). This groma often spontaneously abort (13). Nevertheless, a 45,X can be achieved by DNA studies or FISH using a Y centro- karyotype, even with ultrasound evidence of cystic hygroma, meric probe, supplemented as necessary by short- and long- lymphedema, and effusions, is compatible with delivery of arm probes. The presence of virilization in a TS patient should prompt a search for a gonadal, adrenal, or midline Many pregnancies diagnosed prenatally with TS are cur- tumor as well as investigation of the karyotype for Y mate- rently terminated (14, 15). Decisions regarding pregnancy rial. The prevalence and clinical significance of cryptic Y termination are difficult; thus, it is critical that the best avail- material detected only by FISH or DNA analysis in patients able information be provided to parents. Although uphold- without virilization or a marker chromosome needs addi- ing personal choice about reproduction is a widely embraced tional investigation. False positives may be a problem with ethical principle, decisions to terminate a fetus with TS highly sensitive PCR-based Y detection methods (21).
should never be based upon misunderstood or unbalanced The patient and/or her parents should be informed of the information (16). Many studies providing genotype-pheno- finding of Y chromosome material with the utmost sensitiv- type correlations are subject to considerable ascertainment ity regarding gender identity issues to minimize psycholog- bias. Individuals with 45,X mosaicism detected because of an ical harm. The presence of Y chromosome material is asso- abnormal antecedent ultrasound study are more likely to ciated with an approximately 12% risk of a gonadoblastoma, have clinical TS than those with 45,X mosaicism detected according a recent analysis of pooled data (22). Gonadoblas- incidentally by screening on the basis of advanced maternal tomas may transform into malignant germ cell neoplasms; age (11, 12), which itself is not associated with an increased hence, the current recommendation is for laparoscopic, pro- incidence of TS (17). Outcomes of incidentally detected 45,X/ phylactic gonadectomy (22). It is often assumed that gonads 46,XX mosacism are difficult to predict prenatally, but high- in patients with TS and Y chromosome mosaicism have no resolution ultrasound often provides useful prognostic in- reproductive potential, but spontaneous pregnancies in such formation. Not unexpectedly, prenatally diagnosed children women have been reported (23, 24). Thus, preservation of tend to be less affected than those diagnosed postnatally on follicles or oocytes may be a future option for some patients undergoing gonadectomy. The gene responsible for gonado- Physicians and genetic counselors involved in pre- and blastoma has not been identified, but mapping data indicate J Clin Endocrinol Metab, January 2007, 92(1):10 –25 Bondy • Care of Girls and Women with Turner Syndrome that it is distinct from SRY, the male sex-determining gene mas caused the cardiovascular defects by compressing out- (25, 26). Routine testing for SRY or the presence of Y chro- flow tracts (33). This view remains speculative, however, and mosome material in 45,X individuals without masculiniza- it seems equally possible that haploinsufficiency for the same tion is not clinically warranted at present.
X-linked gene(s) impairs both lymphatic and vasculardevelopment.
Several recent imaging studies have investigated the prev- alence of aortic coarctation and BAV in large groups of girls The diagnosis of TS should be considered in any female and women with TS (34, 36 –38). These studies suggest that with unexplained growth failure or pubertal delay or any on average, approximately 11% have coarctation and ap- constellation of the following clinical findings: edema of the proximately 16% have BAV. Aortic coarctation and BAV are hands or feet, nuchal folds, left-sided cardiac anomalies, each almost 4-fold more frequent in patients with webbed especially coarctation of the aorta or hypoplastic left heart, necks, e.g. 37% of patients with neck webbing have a BAV low hairline, low-set ears, small mandible, short stature with compared with 12% in those without webbing (34). It is growth velocity less than the 10th percentile for age, mark- important to note that coarctation may not be detected in edly elevated levels of FSH, cubitus valgus, nail hypoplasia, infancy and may be first diagnosed in older children or hyperconvex uplifted nails, multiple pigmented nevi, char- adults, and magnetic resonance imaging (MRI) studies fre- acteristic facies, short fourth metacarpal, high arched palate, quently identify cases missed by echocardiography (39 – 43).
The presence of an abnormal aortic valve is usually clinicallysilent in young patients and detected only as a result of screening (44). The risks associated with BAV in TS are prob- Under-diagnosis and delayed diagnosis of TS remains a ably similar to those for nonsyndromic cases. The abnormal problem (27). Importantly, early detection permits identifi- valve is at risk for infective endocarditis, and over time, it cation of cardiovascular system malformations such as bi- may deteriorate leading to clinically significant aortic steno- cuspid aortic valve that require treatment to prevent com- sis or regurgitation. The BAV is also associated with aortic plications. Moreover, early diagnosis facilitates prevention wall abnormalities, including ascending aortic dilation, an- or remediation of growth failure, hearing problems, and eurysm formation, and aortic dissection (45, 46).
learning difficulties. Finally, it may be possible in future Recent studies suggest a broader spectrum of cardiovas- years to prevent infertility in some individuals with TS by cular system abnormalities in TS than previously recognized.
harvesting eggs or ovarian tissue for cryopreservation from Magnetic resonance angiographic screening studies of girls while they still have viable follicles (28). PCR-based asymptomatic individuals with TS have identified a high screening methods to detect sex chromosome aneuploidy are prevalence of vascular anomalies of uncertain clinical sig- feasible (29) but have not yet been validated on a newborn nificance (39 – 42). Almost 50% have an unusual angulation population sample. If and when molecular screening for TS and elongation of the aortic arch termed elongated transverse is offered, positive findings will need karyotype confirma- arch by Ho et al. (42). By itself the elongated transverse arch tion, an infrastructure for follow-up and treatment of the does not appear to be clinically significant, but there is con- patients with sex chromosome abnormalities, and support cern that it may reflect an abnormal aortic wall prone to services to help parents and caregivers deal with the uncer- dilation and perhaps dissection. Additional vascular anom- tainties inherent in this type of diagnosis. By extrapolation alies found in magnetic resonance angiographic studies in- from experience with prenatal diagnosis, it is highly likely clude partial anomalous pulmonary connection (PAPVC) that newborn screening will also identify sex chromosome and persistent left superior vena cava, each affecting ap- abnormalities of no clinical consequence in some phenotyp- proximately 13% (42) vs. less than 1% in the general popu- ically normal individuals; this risk must be weighed against lation. PAPVC in TS frequently involves the left upper the benefit of early detection of TS and other X-chromosome pulmonary vein, which is less common than the typical right- sided presentation in the general population, and makesechocardiographic detection more challenging. Whether thisdefect is clinically significant depends upon the degree of the Cardiovascular System
Frequency and type of congenital defects There seems to be a generalized dilation of major vessels The most serious, life-threatening consequences of X-chro- in women with TS, including the brachial and carotid arteries mosome haploinsufficiency involve the cardiovascular sys- as well as the aorta. The distal extent of this dilated vascu- tem. This is most apparent during fetal development, where lopathy is unknown. Estrogen deficiency contributes to major defects in cardiac and aortic development result in a greater intima medial thickness and altered arterial wall dy- very high mortality for fetuses with a 45,X karyotype (30 –32).
namics but not to the increased caliber of vessels (50, 51).
Fetuses with cardiovascular failure almost always demon-strate obstructed jugular lymphatics with nuchal cystic hy-gromas. These hygromas resolve as the lymphatics open later in gestation, but residual postnatal webbing of the neck pre- Adults with TS have a high prevalence of electrocardio- dicts defects such as bicuspid aortic valve (BAV) and aortic graphic conduction and repolarization abnormalities. Right coarctation in surviving individuals with TS (33–35). This axis deviation, T wave abnormalities, accelerated AV con- association led to the hypothesis that the fetal cystic hygro- duction, and QTc prolongation are significantly more com- Bondy • Care of Girls and Women with Turner Syndrome J Clin Endocrinol Metab, January 2007, 92(1):10 –25 mon in women with TS than normal, age-matched controls should visualize the aortic valve well and provide additional (52). Right axis deviation may be associated with underlying important information about smaller arteries as well as the PAPVC, but the other findings appear independent of ana- distal aortic arch and descending aorta. It is important to note tomic defects (52). These data and the recent observations of that these different modalities may not be directly compa- an unusual resting tachycardia that begins in utero (53) and rable, and use of a single imaging technique for ongoing evidence of impaired sympathovagal tone (54) suggest that monitoring is preferred. All individuals with TS should un- there may be an intrinsic defect in autonomic regulation of dergo cardiac magnetic resonance imaging at an age when the cardiovascular system in TS. The clinical significance of the study may be performed without sedation. This should these recent observations is unclear, but additional monitor- be performed at a center with appropriate technical expertise ing of electrocardiograms (ECGs) in TS seems warranted.
to screen for abnormalities of the aortic arch and descendingaorta. If a younger child needs additional imaging on clinical grounds, MRI is an excellent choice even if sedation is A major concern in TS remains the rare but often fatal occurrence of aortic dilation, dissection, or rupture in rela- In addition to screening for anatomic defects, it is impor- tively young individuals. Dissecting aortic aneurysm in TS is tant to evaluate the blood pressure and ECG in all newly usually associated with additional risk factors including diagnosed patients. Hypertension affects about 25% of girls BAV or other abnormalities of the aortic valve, coarctation or and a larger percentage of adults with TS (46, 56, 57). Sys- dilatation of the aorta, and systemic hypertension (45, 55, temic hypertension is an important risk factor for aortic di- 164). Systemic hypertension is common in TS and therefore lation and dissection. Therefore, blood pressure should be may be the most important treatable risk factor for aortic monitored frequently on a regular basis and treated vigor- enlargement and dissection (46, 164). However, a few cases ously in all patients with TS. If the baseline ECG reveals a do not clearly document the established risk factors, raising significantly prolonged QTc, then medications that might the possibility that the vasculopathy of TS alone may pre- further prolong the QT should be avoided.
dispose to dissection. The International Turner SyndromeDissection Registry has been established in association GH treatment and the cardiovascular system with the Turner Syndrome Society of the United States to To increase adult stature, most girls with TS are now better understand this serious problem (http://www.turner- treated with GH (see Medical Care for the Child with TS below).
Two echocardiography studies reported normal left ventric-ular morphology and function in GH-treated girls with TS (58, 59), and two recent MRI studies found no deleterious All newly diagnosed individuals need a baseline evalua- effect of GH treatment on aortic diameter (60) or compliance tion by a cardiologist familiar with the spectrum of cardio- vascular issues encountered in TS (Table 1). This shouldinclude two-dimensional and color Doppler echocardiogra- phy done in the context of the clinical examination and a For the patient that has no identified cardiovascular de- baseline ECG. A comprehensive postnatal echocardiogram fects after a comprehensive evaluation, routine pediatric care should be evaluated by a pediatric cardiologist in all infants is advised, with continued monitoring of blood pressure, and diagnosed with TS, even in those who had an apparently a reassessment of the cardiovascular system around the time normal fetal echocardiogram. Echocardiography is usually of transitioning from pediatric to adult care, including MRI, effective in infants and children but may be limited in some as mentioned above. For normotensive adults with TS who adults because of abnormal thoracic shape or obesity. It is have no underlying cardiovascular disease, the frequency or essential that all aortic valve leaflets be clearly visualized to even the need for continued echocardiographic monitoring exclude significant abnormalities. If echocardiography is in- is unclear, but it seems prudent to reevaluate aortic dimen- adequate, computed tomography or cardiac MRI should be performed in a center with expertise in these techniques and Patients that do have significant cardiovascular defects TABLE 1. Cardiovascular screening and monitoring algorithm for girls and women with TS
Screening: All patients at time of diagnosis Evaluation by cardiologist with expertise in congenital heart diseaseComprehensive exam including blood pressure in all extremitiesAll require clear imaging of heart, aortic valve, aortic arch, and pulmonary veins ● Echocardiography is usually adequate for infants and young girls ● MRI and echo for older girls and adults Monitoring: Follow-up depends on clinical situation For patients with apparently normal cardiovascular system and age-appropriate blood pressure ● Reevaluation with imaging at timely occasions, e.g. at transition to adult clinic, before attempting pregnancy, or with appearance of hypertension. Girls that have only had echocardiography should undergo MRI when old enough to cooperate with the procedure ● Otherwise, imaging about every 5–10 yr For patients with cardiovascular pathology, treatment and monitoring determined by cardiologist J Clin Endocrinol Metab, January 2007, 92(1):10 –25 Bondy • Care of Girls and Women with Turner Syndrome need continued monitoring by a cardiologist, with frequency of monitoring determined by the individual circumstances.
Spontaneous or assisted pregnancy in TS should be un- Patients with (isolated) hypertension can usually be cared for dertaken only after thorough cardiac evaluation. Alarming by a pediatrician or internist, but aortic dimensions need to reports of fatal aortic dissection during pregnancy and the be determined on a regular basis in these patients. Patients postpartum period have raised concern about the safety of or parents of girls that are considered at increased risk for pregnancy in TS (65). If pregnancy is being considered, pre- aortic dilatation or dissection because of the presence of a conception assessment must include cardiology evaluation BAV, coarctation, or hypertension should be educated about with MRI of the aorta. A history of surgically repaired car- this risk, the need for compliance with medical monitoring diovascular defect, the presence of BAV, or current evidence and treatment, and the possible presenting symptoms, e.g. of aortic dilatation or systemic hypertension should probably chest or back pain. Patients with multiple risk factors (BAV, be viewed as relative contraindications to pregnancy. For dilated aortic root, and hypertension) that put them at high those who become pregnant, close cardiology involvement risk for aortic deterioration might want to consider carrying throughout pregnancy and the postpartum period is medical information in their wallet or on a bracelet alerting medical personnel to the aortic disease. Such patients alsoneed to be counseled about pregnancy and appropriate ex- ercise programs that do not stress the cardiovascular system.
The adult with TS or parents of TS children must be informed In general, heart-healthy exercise (66), in which regular that prophylactic antibiotics should be given before tooth or moderate aerobic activity is emphasized, should be encour- aged in individuals with TS. Highly competitive sports andvery strenuous or isometric exercises are associated withmarked increases in heart rate and blood pressure that may have adverse effects on individuals with a dilated aortic root.
Therefore, eligibility for competitive sports for all those with Normal ascending aortic diameter is related to body size TS should be determined by a cardiologist after a compre- and age. Because most individuals with TS are small, one hensive cardiac evaluation that includes recent MRI of the would expect their aortic diameter to be smaller than the aorta. Extreme exertion should be discouraged in individuals average for age-matched control females, but in general it is with significant aortic enlargement. The experts polled on larger (43, 46). All measurements of the aorta should be done this issue agreed that aortic enlargement in TS may be de- at the end of systole. The ascending aorta should be mea- fined as an aortic sinus of Valsalva or ascending aorta, body sured at the level of the annulus at the hingepoints of the size-adjusted Z-score greater than 2 plus evidence of increas- valve, at the level of the sinuses of Valsalva perpendicular to ing Z-score on a subsequent imaging study of the aorta, or the ascending aorta long axis, and at the ascending aorta 10 a single Z-score greater than 3. In those cases, participation mm above the sino-tubular junction. Normative data for in competitive sports is contraindicated.
aortic diameters as a function of body surface area are avail-able (62). Additional measurements that are not as well stan- Medical Care for the Child with TS
dardized include measurement of the transverse aortic archand the descending aorta.
Once the diagnosis of TS is made, patients should be re- Data on aortic diameters normalized to body surface area ferred, if at all possible, to a center with expertise in TS and for adults with TS are available (46), and a range of absolute a multidisciplinary approach to treatment. Optimally, mem- diameters from both echo and MRI for women with TS and bers of the pediatric care team should include specialists in age-matched controls are also available (43). Review of these pediatric endocrinology, audiology, genetics, cardiology, data (including echocardiographic ascending aorta diame- dermatology, development, nephrology, occupational ther- ters measured at the annulus and MRI diameters measured apy, ophthalmology, orthopedic surgery, otolaryngology, at the level of the bifurcation of the pulmonary arteries) psychology, and speech therapy. Suggested guidelines for suggests that unadjusted values greater than 28 –32 mm will evaluation of newly diagnosed individuals with TS are sum- identify patients with diameters greater than 95% of controls, marized in Table 2, and a summary of the suggested schedule which would clearly be abnormal for women with TS who for ongoing care is given in Table 3.
are generally smaller. When aortic root enlargement is found,medical therapy and serial imaging are recommended. Ag- gressive control of blood pressure should aim for low-normal Abnormalities of cardiovascular and lymphatic develop- values. Because many individuals with TS demonstrate noc- ment are found in most TS fetuses that fail to survive the first turnal hypertension, 24-h monitoring may be helpful in ob- trimester (31, 32). For those girls that survive, the residua of taining optimal control (54, 63). In hypertensive patients with the fetal lymphedema and cystic hygromas are peripheral aortic root enlargement who also have resting tachycardia, lymphedema and webbed neck, the principal keys to diag- ␤-adrenergic receptor blockade is an excellent therapeutic nosis in the newborn period. The lymphedema seen at birth option. ␤-Blockers have been shown to reduce the rate of usually resolves by 2 yr of age without therapy. However, aortic dilation and dissection in Marfan syndrome (64), al- lymphedema may occur or reoccur at any age and may be though efficacy in treating aortic dilatation in TS has not yet associated with the initiation of salt-retaining therapies such as GH or estrogen. Some children and adolescents may re- Bondy • Care of Girls and Women with Turner Syndrome J Clin Endocrinol Metab, January 2007, 92(1):10 –25 TABLE 2. Screening at diagnosis of TS in children and adults
pyelogram is also used for screening, even more abnormal- ities will be identified, but these tend to be clinically insig-nificant (71). All girls with TS should have a renal ultrasound study performed at diagnosis. Structural malformations of Cardiovascular evaluation by specialistaRenal ultrasound the kidney occur more frequently in 45,X TS, whereas col- lecting-system malformations occur more frequently in those with mosaic/structural X karyotypes. In a recent study (69), Evaluation for knowledge of TS; referral to support groups no patient with a normal baseline ultrasound developed Evaluation for growth and pubertal development renal disease during a follow-up period averaging 6 yr.
However, some of those with malformations developed hy- Eye exam by pediatric ophthalmologist (if age Ն 1) pertension and urinary tract infections.
Thyroid function tests (T , TSH) and celiac screen (TTG Ab) Educational/ psychosocial evaluationsOrthodontic evaluation (if age Ն 7) Abnormalities of the external ocular adnexa including epi- Thyroid function tests (T , TSH) and celiac screen (TTG Ab) canthal folds, ptosis, hypertelorism, and upward slanting palpebral fissures are common in TS (72). Red-green color deficiency is present in approximately 8% of the population, Evaluation of ovarian function/estrogen replacement a percentage similar to that found in males. Most impor- tantly, strabismus and hyperopia (farsightedness) each occur in 25–35% of these children, putting them at high risk for BUN, Blood urea nitrogen; CBC, complete blood count; Cr, creat- amblyopia. To promote early detection and treatment and inine; FBG, fasting blood glucose; LFTs, liver function tests.
prevent visual loss, children with TS should be evaluated bya pediatric ophthalmologist at 12–18 months of age in ad- quire support stockings and elevation for treatment. Com- dition to receiving routine ophthalmological evaluations by plete decongestive physiotherapy, a four-step process in- volving skin and nail care, massage for manual lymphdrainage, compression bandaging, and a subsequent reme- dial exercise regimen (67) is recommended for those with Hearing problems and ear malformations are common in more significant lymphedema (68). Long-term diuretic use TS and correlate with karyotype (73, 74). There is a high should be avoided because of its marginal efficacy and prob- prevalence of OM that may result from an abnormal rela- lems with fluid and electrolyte imbalance. Vascular surgery tionship between the eustachian tube and middle ear, a con- should be avoided. Families can be directed toward The sequence of abnormal cranial base anatomy. As the result of National Lymphedema Network (http://www.lymphnet.
OM, conductive hearing loss is common in young girls with TS (75). Although a more significant issue in adulthood,progressive sensorineural hearing loss with a unique dip in the 1.5- to 2-kHz region and/or a high frequency loss (above Congenital malformations of the urinary system are 8 kHz) may present as early as 6 yr of age and necessitate the present in 30 – 40% of patients with TS (69, 70). By ultrasound, collecting-system malformations are found most frequently Heightened surveillance for middle ear effusions should (ϳ20%), followed by horseshoe kidneys (ϳ10%) and malro- occur in girls with TS until at least 7– 8 yr of age, and longer tation and other positional abnormalities (ϳ5%). If an iv for those with a history of OM. Evaluation should includeotoscopic examination, preferably pneumatic otoscopy, tym- TABLE 3. Ongoing monitoring in TS
panometry, or both on at least an annual basis. Therapy forOM in girls with TS should be managed aggressively because of the significant impact that hearing loss can have on speech Cardiological evaluation as indicateda and language development and the risk of cholesteatoma Blood pressure annuallyENT and audiology every 1–5 yr formation in those with persistent otorrhea. TS girls should be evaluated for persistence of middle ear fluid approxi- mately 6 –10 wk after an episode of acute OM to document whether the effusion has cleared. Girls that have middle ear Liver and thyroid screening annuallyCeliac screen every 2–5 yr effusions persisting longer than 3 months or recurrent epi- sodes of acute (suppurative) OM should be referred to an otolaryngology specialist. Common surgeries for recurrent OM and airway problems include tympanostomy tube place- ment, tonsillectomy, and adenoidectomy. Removal of the Liver and thyroid screening annuallyCeliac screen as indicated adenoids may exacerbate palatal dysfunction and negatively Age-appropriate evaluation of pubertal development and influence quality of speech, factors that must be taken into Girls or women diagnosed with TS at an older age should J Clin Endocrinol Metab, January 2007, 92(1):10 –25 Bondy • Care of Girls and Women with Turner Syndrome be referred to an audiologist at the time of diagnosis. For upper chest) rather than an intrinsic difference in healing those with a history of OM or hearing loss, audiological evaluations are recommended annually or as per their au-diologist. In older girls and women with TS with no historyof hearing loss, audiological surveillance is warranted every 2–3 yr.The assiduous treatment of ear-nose-throat problems Short stature is probably the most common, readily rec- in childhood and avoiding additional potential injuries to the ognizable clinical feature of TS. Much of the deficit in height inner ear may reduce the risk of hearing loss.
is caused by haploinsufficiency of the short-stature ho-meobox-containing gene (SHOX) located within the Xp- terminal, pseudoautosomal region of the X chromosome (87).
It affects virtually all individuals with TS and results in an Distinct craniofacial features in TS include a flattened cra- average adult stature 20 cm shorter than their target height nial base angle, a marked reduction in posterior cranial base (88, 89). The typical growth pattern in TS is characterized by length, and a retrognathic face (76). The maxilla is generally mild intrauterine growth retardation, slow growth during narrow with a high, arched palate, whereas the mandible infancy, delayed onset of the childhood component of tends to be wide and micrognathic. The prevalence of distal growth, growth failure during childhood, and the absence of molar occlusion, anterior and lateral open bite, and lateral crossbite are significantly increased (77). Abnormalities in Skeletal abnormalities encompass more than poor linear tooth development and morphology include early eruption growth. Disproportionate growth causes many girls with TS of the secondary teeth, simple crown morphology, thinner to appear stocky, with a wide body and relatively large hands enamel, less dentine, and short roots (78). Girls with TS are and feet (90). In addition, developmental abnormalities of also at greater risk for root resorption, which can lead to tooth individual bones account for many common findings such as loss, especially during orthodontic treatment. It is recom- short neck, cubitus valgus, genu valgum, and short fourth mended that all girls with TS see a pediatric dental specialist metacarpals. Madelung deformity of the wrist, although of- by the age of 2 yr and an orthodontist no later than age 7 yr.
ten mentioned in connection with TS, is actually rather in- Because GH treatment can alter craniofacial proportions, all frequent (91). Infants with TS have an increased risk of con- girls with TS treated with GH should receive periodic orth- genital hip dislocation. Girls with TS have higher risks for odontic follow-up (79). Prophylactic antibiotics should be scoliosis and kyphosis than the general population; 10 –20% used before dental procedures in TS with known cardiac of girls with TS develop scoliosis, and kyphosis and/or ver- tebral wedging also appears to be more common (92, 93). Thelatter may be quite difficult to appreciate clinically, and both problems can progress with rapid growth. Phalangeal bone Individuals with TS clearly have increased risk for auto- density has been reported to be normal during childhood immune thyroiditis and celiac disease. Autoimmune thyroid disease is common during childhood in TS and has beenreported as early as 4 yr of age (80, 81). In a recent study, 24% of 84 children with TS (0 –19 yr old) who were followedlongitudinally (mean duration, 8 yr) developed hypothy- The goals of growth-promoting therapies are to attain a roidism and 2.5% developed hyperthyroidism (80). Gener- normal height for age as early as possible, progress through ally, there are no overt clinical symptoms of hypothyroidism.
puberty at a normal age, and attain a normal adult height.
Although thyroid antibodies identify patients at high risk, all The centerpiece of growth-promoting therapy is GH, which patients with TS should be screened annually for autoim- increases growth velocity and final adult stature. Girls with TS generally have a normal GH secretory pattern (95). Pro- vocative GH testing should be performed only in those The risk of celiac disease is increased in TS, with 4 – 6% of whose growth is clearly abnormal relative to that expected individuals affected (82). As recommended by North Amer- for TS, determined by plotting lengths and heights on TS- ican Society for Pediatric Gastroenterology, Hepatology, and specific growth curves (88, 89, 96, 97).
Nutrition guidelines (83), TS girls should be screened by It is well established that GH therapy is effective in in- measurement of tissue transglutaminase IgA antibodies. Pe- creasing final adult height. However, the magnitude of the riodic screening should begin at age 4 and be repeated every benefit has varied greatly depending upon study design and 2–5 yr. If HLA typing is performed, individuals without DQ2 treatment parameters. In the first randomized controlled trial or DQ8 need no additional antibody measurements.
to follow GH-treated TS subjects to final height (98), theCanadian GH Advisory Committee corroborated the in-creases in adult stature reported by studies with historical controls (99 –102). In the Canadian study, girls with TS (aged An increased number of acquired melanocytic nevi is seen 7–13 yr) who were randomized to receive GH (0.3 mg/kg⅐wk; in TS (84), but the risk for melanoma does not appear to be maximum weekly dose, 15 mg) achieved a final adult stature increased (85). A reputed propensity toward keloid forma- 7.2 cm taller than the control group after an average of 5.7 yr.
tion may be a reflection more of the sites at which individuals Factors predictive of taller adult stature include a relatively with TS commonly undergo plastic surgery (head, neck, and tall height at initiation of therapy, tall parental heights, Bondy • Care of Girls and Women with Turner Syndrome J Clin Endocrinol Metab, January 2007, 92(1):10 –25 young age at initiation of therapy, a long duration of therapy, more rapid skeletal maturation. Therapy may be continued until a satisfactory height has been attained or until little The optimal age for initiation of GH treatment has not been growth potential remains (bone age Ն 14 yr and growth established. Preliminary data from the Toddler Turner velocity Ͻ 2 cm/yr). GH therapy should be directed by a Study, in which 88 girls between the ages of 9 months and pediatric endocrinologist and the child monitored at inter- 4 yr (mean age, 2.0 yr) were randomized to GH or no GH vals of 3– 6 months. Evaluation for orthopedic problems as therapy, indicate that GH therapy is effective beginning as well as growth velocity should be part of the regular physical early as 9 months of age (109). In addition, the safety profile examination. Development of scoliosis or kyphosis does not appears to be similar to that observed in older TS children.
necessarily preclude GH therapy; however, close collabora- Treatment with GH should be considered as soon as growth tion with an orthopedic surgeon is required.
failure (decreasing height percentiles on the normal curve) isdemonstrated and its potential risks and benefits have beendiscussed with the family.
GH therapy in the United States is generally initiated at the Absent pubertal development is one of the most com- FDA-approved dose of 0.375 mg/kg⅐wk. This is most effec- mon clinical features of TS, although up to 30% or more of tive when given daily and customarily administered in the girls with TS will undergo some spontaneous pubertal evening. The dose can be adapted according to the patient’s development (112, 113), and 2–5% may achieve sponta- growth response and IGF-I levels. Growth prediction models neous pregnancy (114). Ultimately, over 90% of individ- may be helpful in determining the potential effects of uals with TS will have gonadal failure. Before initiation of changes in dosing (103). Doses substantially higher than estrogen therapy, serum gonadotropin levels should be those approved by the FDA (0.054 mg/kg⅐d ϭ 0.162 IU/ determined to exclude the possibility of delayed sponta- kg⅐d ϭ ϳ4.8 IU/m2⅐d) produce a relatively small gain in final height, although there is no apparent increase in short-term When estrogen therapy is required to induce pubertal adverse events (110). For example, in a study by the Dutch development, the form, dosing, and timing should reflect the Working Group, the mean gain in final height in groups process of normal puberty (Table 4). Delaying estrogen ther- treated with 4 IU/m2⅐d (0.045 mg/kg⅐d), 6 IU/m2⅐d and 8 apy until 15 yr of age to optimize height potential, as pre- IU/m2⅐d averaged 11.9 Ϯ 3.6, 15.7 Ϯ 3.5, and 16.9 Ϯ 5.2 cm, viously recommended (115), seems unwarranted. This em- respectively (99). However, when GH was given at the higher phasis on stature tends to undervalue the psychosocial doses, IGF-I levels were often above the normal range, and importance of age-appropriate pubertal maturation and may ideally, prolonged exposure to elevated IGF-I levels should be deleterious to bone and other aspects of the child’s health be avoided because of theoretical concern about potential (116 –118). Furthermore, recent evidence suggests that some treatment regimens using estradiol that begin replacement at For girls below approximately 9 yr of age, therapy is usu- the age of 12 yr permit a normal pace of puberty without ally started with GH alone. In older girls, or those with interfering with the positive effect that GH has on final adult extreme short stature, consideration can be given to using higher doses of GH and adding a nonaromatizable anabolic Many forms of estrogen are available, and oral estrogens steroid, such as oxandrolone (100). The dose of oxandrolone have been most often used. However, both transdermal and should be 0.05 mg/kg⅐d or less, and liver enzymes should be injectable depot forms of estradiol may be more physiolog- monitored. Higher doses are likely to result in virilization ical alternatives (116, 119 –121). Low-dose estradiol therapy (clitoral enlargement, acne, lowering of the voice, etc.) and can be initiated as early as 12 yr of age. Replacement is TABLE 4. Ovarian hormone replacement treatment in TS
Monitor for spontaneous puberty by Tanner staging and Low-dose estrogen treatment may not inhibit GH-enhanced If no spontaneous development and FSH elevated, begin low Equivalent initial E2 doses: depot (im) E2, 0.2– 0.4 mg/month; transdermal E2, 6.25 ␮g dailya; micronized E2,0.25 mg daily by mouth Gradually increase E2 dose over about 2 yr (e.g. 14, 25, 37, Usual adult daily dose is 100 –200 ␮g transdermal E2, 2– 4 50, 75, 100, 200 ␮g daily via patch) to adult dose mg micronized E2, 20 ␮g EE2, 1.25–2.5 mg CEE Begin cyclic progesterone treatment after 2 yr of estrogen or Oral micronized progesterone best option at present; usual adult dose is 200 mg/d on d 20 –30 of monthly cycle or d100 –120 of 3-month cycle Continue full doses at least until age 30 because normally Some women may prefer using oral or transdermal estrogen levels are highest between age 15 and 30 yr contraceptive for HRT; monitor endometrial thickness The lowest estrogen dose providing full protection vs. Monitor osteoporosis risk factors, diet, exercise; obtain BMD and begin regular screening mammography by age 45 yr Decision on estrogen use based on same considerations as recommendations may need updating in near future CEE, Conjugated equine estrogens; E2, estradiol; EE2, ethinyl estradiol; HRT, hormone replacement treatment.
a The lowest-dose commercially available E2 transdermal patches deliver 14 and 25 ␮g daily; it is not established whether various means of dose fractionation (e.g. administering a quarter patch overnight or daily or administering whole patches for 7–10 d per month) are equivalent.
J Clin Endocrinol Metab, January 2007, 92(1):10 –25 Bondy • Care of Girls and Women with Turner Syndrome usually begun at one tenth to one eighth of the adult re- for a selective impairment in nonverbal skills and, as a group, placement dose and then increased gradually over a period score lower on performance than on verbal subsections of of 2– 4 yr. The following are equivalent doses that achieve standardized intelligence tests (124). In school, these impair- estradiol levels in the normal range for young adult women: ments are manifested as math, visuospatial, and executive oral estradiol, 2 mg/d; transdermal estradiol, 0.1 mg/d; and function deficits (125). Slowed response time is observed injectable estradiol cypionate, 2.5 mg/month. To allow for across each of these three domains (126). The specific neu- normal breast and uterine development, it seems advisable ropsychological deficits include four interacting areas of to delay the addition of progestin at least 2 yr after starting functioning: visual-spatial organization deficits (e.g. diffi- estrogen or until breakthrough bleeding occurs. The use of culty with direction sense), difficulty with social cognition oral contraceptive pills to achieve pubertal development is (e.g. failure to appreciate subtle social cues), difficulty with best avoided, because the synthetic estrogen doses in most problem solving (e.g. mathematics), and motor deficits (124, formulations are too high and the typical synthetic progestin 126 –128). Some of these deficits may be improved by hor- may interfere with optimal breast and uterine development.
monal therapy at the time of puberty (129). A higher than It is important to educate the patient that estrogen replace- expected rate of attention deficit disorder diagnoses (i.e. 24%) ment is usually required until the time of normal menopause is reported in school-age girls (130). Drawing from the to maintain feminization and prevent osteoporosis (118).
broader field of educational research, it is possible that ed- During the process of pubertal development, it is impor- ucational intervention directed at learning or attentional dif- tant to engage the patient in a gradual discussion about how ficulties may offer additional benefits. Despite variable de- TS and its treatment may impact her sexual development and grees and areas of learning difficulties, as a group, girls and function and reproductive potential. In addition, when ap- women with TS excel at verbal skills and many adults with propriate, counseling for the prevention of sexually trans- TS have university-level education (131–133).
mitted diseases (and unwanted pregnancy for those withendogenous ovarian function) should also be provided.
Overall, behavioral function is normal in girls with TS.
The transition from pediatric to adult health care should However, there may be an increased risk for social isolation, occur at the completion of growth and puberty during late- stage adolescence (usually by age 18 yr). However, the tran- Girls with TS typically have a female pattern of gender sition should be initiated as a staged process. Beginning at identity, but adolescent and adult women with TS achieve approximately age 12, the center of care should be shifted sexual milestones later than their peers and are less likely to incrementally from the parent to the adolescent with TS. The marry (136, 137). It is unclear whether this delayed sexual health care focus also shifts from maximizing height to in- activity reflects some underlying genetic or hormonal influ- ducing feminization, counseling the adolescent with TS ence on behavior or the timing of puberty. Recent studies do about the evolving impact of her condition into adulthood not support the influence of height (137, 138) as influential on and promoting the development of independent self-care dating and initiation of sexual activities, but the role of phys- ical anomalies is unclear. The developmental process is likely Transition is an appropriate time to assess individual risks affected by treatments with GH and estrogen that potentially for potential adult morbidities and promote healthy life- influence the child’s perception of herself.
styles. To help ensure adequate bone mineral accrual, girlswith TS are encouraged to have calcium intake of more than Psychosocial function in adults with TS 1000 mg of elemental calcium daily in the preteen years and1200 –1500 mg daily after 11 yr of age. This will generally Young, GH-treated adults on average have normal self- require oral supplementation. Counseling as to healthy eat- perceived physical and mental health, but some women ex- ing and exercise habits and maintaining a healthy weight are perience decreased self-esteem, mostly in the context of so- essential. During late-stage transition, the pediatric endocri- cial functioning (139). Adult height does not appear to impact nologist should engage the transition patient in developing adult quality of life (117, 139). Formal psychiatric evaluation an adult care plan in close collaboration with her new health of 100 adult volunteers with TS participating in a National care provider to help assure that they will continue to receive Institutes of Health natural history study revealed no in- the careful monitoring that they need to optimize adult crease in major psychiatric diagnoses other than depression and anxiety-related disorders, which were higher than thosereported from a community-based sample but similar tothose reported in women from a general gynecological clinic Psychological and Educational Issues
sample (140). Women with TS report significantly higher Cognitive and educational performance levels of shyness and social anxiety and reduced self-esteem The majority of individuals with TS have normal intelli- compared with normal menstruating women but similar to gence, although patients with a small ring X-chromosome karyotypically normal women with premature ovarian fail- clearly have an increased risk of mental retardation (122).
ure, suggesting that the experience of ovarian failure and These individuals may have a severe phenotype with fea- infertility contribute to psychosocial dysfunction (138). Sup- tures atypical for TS, apparently due to failure of small rings porting this view, these same women with TS reported in to inactivate (123). Individuals with TS have an increased risk open-ended interviews that dealing with premature ovarian Bondy • Care of Girls and Women with Turner Syndrome J Clin Endocrinol Metab, January 2007, 92(1):10 –25 failure and loss of fertility was the most difficult part of process of transition should take place over a period of 2–3 yr during the late pubertal period as described above andshould involve an adult endocrinologist and a gynecologist with expertise in premature ovarian failure. A multidisci- Significant psychosocial risks are associated with TS, in- plinary team including specialists in endocrinology, cardi- cluding cognitive, social, and behavioral components. Plans ology, hearing and ear-nose-throat, infertility/gynecology, for both medical and psychological intervention should be and psychology may be developed at a tertiary care center.
developed so as to reinforce and support the individual’s The agenda for such a specialist service should be developed self-esteem and to ensure that individuals remain in the in partnership between medical professionals and Turner mainstream of social, educational, and employment activi- support groups. Regrettably, late diagnosis of TS, even in ties. Many of these issues are discussed in patient-oriented adults, is still a problem. No matter what the age of the material available through the Turner Syndrome Society of patient, a full workup with assessment of congenital mal- the United States (www.turner-syndrome-us.org) and from formations should be performed, including all screening other local and national TS organizations (e.g. Magic Foun- tests recommended for younger patients (Table 2).
dation, www.magicfoundation.org). Early involvement in a Upon transfer to an adult care clinic, the young woman TS support group should be encouraged.
with TS should undergo a comprehensive medical evalua- A comprehensive psycho-educational evaluation is rec- tion, addressing not only the specific problems associated ommended immediately preceding school entry or at the with TS but also screening for osteoporosis, hypertension, time of TS diagnosis. Evaluations may need to be repeated diabetes, and dyslipidemia, which are increased in TS (143).
during primary school if indicators of academic difficulties All medical problems present during childhood should be emerge. Children with TS may also have other conditions; as followed in adults, especially congenital cardiovascular is- for all children, if evidence of other difficulties emerge (such sues, thyroid and celiac disease, and hearing loss (Table 3).
as dyslexia or attention deficit), evaluation and treatment Annual medical history and general physical evaluation should be encouraged. As with documentation of learning should be performed, including blood pressure, heart aus- disability in any child, classroom accommodations and mod- cultation, clinical evaluation of thyroid size and function, ifications may be necessary and could be considered at any breast examination, and Pap smear. As in children, regular age as needed. For example, in view of the slower processing otological examination is important, because about 60% of speeds observed in girls with TS, untimed testing may be adults with TS experience senorineural hearing loss. The appropriate. In many cases, it may be useful to refer children hearing loss is progressive but tends to occur more rapidly and their families to educational specialists to facilitate de- after about 35 yr of age, leading to early presbyacusis (146).
velopment of coping strategies, such as reliance on relatively Hearing aids are frequently necessary. Otological screening superior verbal skills to mediate problem solving. In child- should be conducted at least every 2–3 yr in patients who are hood, parents should be alerted to possible peer issues and asymptomatic and have previous documented normal hear- educated about strategies to deal with difficulties such as ing and more frequently as indicated for those with estab- lished hearing loss or new symptoms of hearing loss.
Age-appropriate pubertal induction is recommended be- Many of the problems of adult life in patients with TS are cause of potential long-lasting psychosocial implications of compounded by obesity (147, 148), partly because of low delayed pubertal development. Discussions should be initi- physical fitness and a sedentary lifestyle (149, 150). Lifestyle ated regarding sexuality and reproductive options at age- education with advice on diet and exercise must be included appropriate levels. It is sometimes difficult for adult care- in a program of prevention of diabetes, osteoporosis, and givers to address the ramifications of a TS diagnosis, hypertension. Women with TS should aim to have a body especially infertility. However, it is important to address mass index less than 25 kg/m2 and a waist/hip ratio less than these issues in an honest and open manner, because secret- 0.80. Any exercise program should be developed with con- keeping may have unintended negative consequences and sideration of individual skeletal or cardiovascular problems, actually amplify the problems for girls and young women and a physical rehabilitation specialist or trainer may be of (141). Age-appropriate social interactions should be encour- great value in designing individualized programs for pa- aged. Finally, attention should be given to career and voca- tional planning and preparation for transition to living in-dependently, starting in adolescence. Learning disabilitiescan be a major impediment to emancipation from family and to career enhancement, although many women with TS do Laboratory testing of women with TS should be carried out at 1- to 2-yr intervals and include measurements of usualscreening tests, such as hemoglobin, white blood cell count, Medical Care for Adults with TS
renal function (creatinine and blood urea nitrogen), but Medical follow-up and estrogen replacement therapy should especially include fasting blood glucose lipid profile, Adult women with TS require careful medical follow-up.
liver enzymes, TSH, and total or free T4.
Early medical intervention may decrease the substantially Recommendations for breast evaluation, self-examination, increased morbidity (142, 143) and mortality (144, 145) and and mammography are the same as for the general improve the quality of life of women with TS. Ideally, the J Clin Endocrinol Metab, January 2007, 92(1):10 –25 Bondy • Care of Girls and Women with Turner Syndrome cals are not recommended for treating osteopenia in young Liver enzymes, especially ␥-glutamyl transferase, alanine women with TS, because reduced cortical BMD in TS is not amino transferase, aspartate amino transferase, and alkaline proven to lead to increased fractures and bisphosphonates phosphatase, are commonly raised in women with TS, but have not been shown to be effective in enhancing cortical their relationship to chronic liver disease is unknown (148, BMD in TS. Furthermore, these agents may blunt treatment 151). Hepatitis serology can be checked if indicated, although with newer modalities in the future and are contraindicated the prevalence of viral hepatitis is not raised in TS. Usually, in women who might attempt pregnancy. For women with elevated liver enzymes do not progress to overt hepatic dis- confirmed osteoporosis, especially those at risk for fracture, ease, but regenerative nodular hyperplasia and other archi- or who have already sustained a low-impact fracture, the tectural abnormalities or biliary lesions are seen on biopsy, usual medical treatment for osteoporosis is indicated.
as is portal hypertension, which should be treated accordingto hepatology guidelines (152). Estrogen treatment is not Risk factors for coronary artery disease associated with adverse effects on the liver and usually low- In addition to their burden of congenital cardiovascular ers liver enzymes in TS and thus is not contraindicated in disease, women with TS are at increased risk for atheroscle- patients that have elevated liver enzymes (151). If elevated rosis. Hypertension affects as many as 50% of young adult liver enzymes persist for more than 6 –12 months, an ultra- patients. Blood pressure should therefore be closely moni- sound should be performed to rule out hepatic steatosis. If tored and hypertension treated vigorously (57, 63, 150). In- steatosis is not present and liver enzymes remain elevated or creased heart rate and altered autonomic innervation of the increase, a hepatology consult may be obtained with con- heart are common in TS (54). Type 2 diabetes is common in sideration of biopsy guided by the use of hepatic ultrasound TS. An oral glucose tolerance test uncovers impaired glucose with assessment of blood flow by Doppler. Potentially hepa- tolerance or diabetes in more than 50% of cases, usually toxic drugs such as statins and glitazones have to be pre- associated with an insulin secretory defect in TS (57, 157).
scribed with caution in affected patients.
Insulin sensitivity may be normal in many patients but re-duced in those with obesity or a strong family history of type 2 diabetes. Often, the diabetes is relatively mild and respon-sive to weight loss or monotherapy.
Although congenital structural anomalies of the kidney Low-density lipoprotein cholesterol and triglycerides are are found in about 30% of TS patients, renal function is elevated, and lipid particle size is reduced in women with TS usually normal, with the only common complication being compared with age and body-mass-index-matched women urinary infections related to obstruction. Thus, individuals with karyotypically normal ovarian failure (158, 159), sug- with known renal collecting-system anomalies may require gesting that the X chromosome deletion per se, apart from the more frequent screening for urinary tract infections.
effects of premature ovarian failure, is associated withdyslipidemia.
Fractures are increased in older patients with TS, but these patients may not have received optimal estrogen treatment As indicated in the pediatrics section, screening for thyroid in the past. Most studies using dual-energy x-ray absorpti- and celiac diseases may continue throughout adult life (Table ometry find decreased bone mineral density (BMD) (149, 3) because of an increased risk of developing overt disease 153), but small size may lead to underestimation of BMD by dual-energy x-ray absorptiometry (154). When adjusted forsize, women that have received appropriate estrogen treat-ment usually have normal BMD in trabecular bone, e.g. the spine (149, 154). However, there seems to be an intrinsic, It is recommended that women with TS receive cyclical estrogen-independent deficit in cortical bone in TS (149, 155, estrogen and progestin. Sufficient estrogen should be pre- 156). A baseline BMD should be obtained at the initial visit scribed to prevent the symptoms, signs, and sequelae of in the adult clinic, with follow-up depending on the initial estrogen deficiency. An estrogen dose equivalent to 2 mg result. If the BMD is normal (adjusting for size), additional estradiol daily suffices for most adult women with TS, but evaluation need not take place until age 40 –50 yr or when the individual requirements may vary from 1– 4 mg/d. Ideally, patient plans to discontinue estrogen treatment. If BMD is natural estradiol and progesterone, rather than analogs, low in a young woman with TS, one needs to investigate and should be delivered by transdermal or transmembranous treat possible contributory factors such estrogen replacement routes so as to mimic age-appropriate physiological patterns noncompliance, tobacco use, excessive alcohol use, possible as closely as possible. However, regimens that meet each celiac disease, or vitamin D deficiency. Proper estrogen treat- individual woman’s tolerance and preference vary widely, ment improves BMD and is the mainstay of bone protection.
and the most important consideration is that women actually Adequate calcium and vitamin D intake is essential, because take ovarian hormone replacement. This is critical because many women have low levels of vitamin D. Weight-bearing the risk of clinically significant osteoporosis with spontane- exercise is very important in achieving and maintaining ous fractures is very high in young women with TS not taking estrogen (132). As with other women receiving estrogen re- Bisphosphonates or other antiosteoporotic pharmaceuti- placement therapy, pelvic ultrasonography and endometrial Bondy • Care of Girls and Women with Turner Syndrome J Clin Endocrinol Metab, January 2007, 92(1):10 –25 biopsy should be considered when abnormal vaginal bleed- additional risks associated with multiple pregnancies. An ing occurs. Androgen concentrations are reduced in many embryo cryopreservation program is therefore essential. Un- women with TS (160), and androgen substitution therapy der optimal conditions, spontaneous vaginal delivery is an may be of value in some instances. This is an area that needs acceptable option. Cesarean section, however, is often em- additional investigation. The duration of estrogen therapy ployed because of a narrow pelvis. Adoption is an option for should be individualized, and readjustment of dosage or many women with TS, and the use of surrogate mothers is discontinuation should occur at the age of normal Cryopreservation of ovarian tissue and immature oocytes Fertility and family-planning issues New data have emerged during the last years showing that Although a few patients with TS achieve spontaneous adolescents with only few signs of spontaneous puberty may pregnancy, most are infertile. Various assisted reproductive still have ovaries with follicles (28). The possibility of using techniques are now available for achieving pregnancy. Re- cryopreserved ovarian tissue and immature oocytes, ob- cent studies show that women with TS become pregnant as tained before regression of the ovaries occurs in childhood, easily as women with other types of infertility and carry their is currently under intensive investigation, and results seem pregnancies to term without an increased miscarriage rate promising (28). Although only a research tool at present, this (161, 162); however, they do have an increased rate of ma- technique may provide the possibility of pregnancy with the ternal complications (65). First, because of their small size, many women with TS need to deliver by cesarean section.
Second, hypertension and diabetes are common in TS preg- nancy (162). Most critically, the risk for dilatation and dis- This consensus statement arose from an interdisciplinary section of the aorta appears to increase during pregnancy meeting of geneticists, pediatricians, cardiologists, internists, (65). Karnis et al. (65) also found that only approximately 50% behavioral health specialists, and gynecologists involved of women in the United States had a cardiac workup before with the care of and clinical research on patients with TS. Our fertility treatment. Before contemplating spontaneous or as- goal was to address new information and experience that has sisted pregnancy, individuals with TS need a complete med- accrued in the past 5– 6 yr since the last international work- ical evaluation. Particular attention should be paid to the shop with regard to practical implications for the diagnosis cardiovascular system, and echocardiography, ECG, and and care of individuals with TS. The first issue was the high MRI need to be performed before any attempt at pregnancy.
elective abortion rate for incidentally diagnosed 45,X and Women with cardiovascular issues (BAV, dilated aorta, or 45,X/mosaic fetuses (14, 15), which seemed at odds with history of coarctation), as described above, are best counseled recent reports of a normal quality of life for individuals against attempted pregnancy (163). In addition, thyroid sta- receiving current medical care (117, 131, 133). Another paper tus and glucose tolerance should be monitored. All preg- reviewing care for individuals with TS, in general agreement nancies should be followed by a multidisciplinary team, with this article, has appeared during the review process including high-risk pregnancy specialists, endocrinologists, (165). It was clear that the content of prenatal counseling on and cardiologists, generally at a tertiary care facility.
the significance of such a karyotype for expectant parentsneeds updating and needs inclusion of TS patient and parent groups. Participants were in favor of the initiation of new- Women with TS who have spontaneous menstrual cycles born screening for TS, with the caveat that a suitable infra- and ovulate normally should receive counseling on the tim- structure to provide educational and psychological support ing of pregnancies: because of the risk of premature ovarian for families must be established. An expanded view of con- failure, pregnancies should not be postponed without good genital cardiovascular disease in TS led to the recommen- reason, and the possibility of oocyte or embryo cryopreser- dation for diagnostic cardiovascular MRI study for all pa- vation; the risk of miscarriage and chromosomal abnormal- tients and increased focus on regular monitoring of systemic ities in the offspring; and the possibility of prenatal genetic blood pressure and aortic diameter in children and adults.
Concerns have been raised about cardiovascular risks asso-ciated with pregnancy in TS and inadequate medical eval-uation before conception (163), hence new cautions for in- dividuals with existing cardiovascular issues. GH treatment Oocyte or embryo donation can be used to achieve preg- has now been proven to increase adult height (98), although nancy in patients with TS who do not have functional ovaries whether this effect confers an advantage to adults with TS (161). Special attention should be given to appropriate prep- has not been proven (117). Because growth appears to con- aration of the uterus. This requires adequate hormone re- tinue apace with the gradual introduction of estradiol, pu- placement therapy for 1–2 yr before oocyte or embryo trans- bertal development generally should not be delayed to fur- fer to increase the size of and improve the blood flow in the ther increase adult height. Pubertal delay may exacerbate the uterus. Adequate uterine preparation has to be performed (4, negative psychosocial impact of early ovarian failure, asso- 6, or 8 mg of 17␤-estradiol and a gestagen), and optimally, ciated with excessive shyness and social anxiety, delayed the thickness of the endometrium should be 7 mm. Ideally, sexual debut, and decreased marriage rate. The increased only one embryo should be transferred at a time to avoid the frequency of nonverbal learning and attention deficit disor- J Clin Endocrinol Metab, January 2007, 92(1):10 –25 Bondy • Care of Girls and Women with Turner Syndrome ders in girls with TS mandates comprehensive testing at an of Medicine, Farmington, CT; Paul Saenger, M.D., Department of Pe- early age so as to implement appropriate educational plans diatrics, Montefiore Medical Center, Bronx, NY; Peter Schmidt, M.D., in a timely manner. The care of adults with TS has received National Institute of Mental Health, Bethesda, MD; Mike Silberbach,M.D., Doernbecher Children’s Hospital, Portland, OR; Virginia Sybert, less attention than the treatment of children, and many seem M.D., Division of Dermatology, University of Washington School of to be falling through the cracks with inadequate cardiovas- Medicine, Seattle, WA; Daniel L. Van Dyke, Ph.D., Mayo Clinic, Roch- cular evaluation (166) and estrogen treatment (167).
ester, MN; and Andrew Zinn, M.D., Ph.D., McDermott Center for Hu- Last, it is important to recognize that the recommendations man Growth and Development and Department of Internal Medicine,The University of Texas Southwestern Medical Center, Dallas, TX.
in this document are based on the authors’ best judgments Section Chair or Cochairs were Andrew Zinn, Genetics; Mike Silber- given the current level of medical knowledge. There are bach and Angela Lin, Cardiology; Marsha Davenport, Growth and De- many questions that remain unanswered regarding care for velopment; Judy Ross, Psychosocial and Educational Development; and girls and women with TS, such as identifying the optimal age Gerard Conway and Claus H. Gravholt, Adult and Gynecological Care.
of initiation and duration of GH treatment, specific inter- We thank Duane Alexander, M.D., Director, NICHD, for his faithful support of research aimed at improving the lives of girls and women ventions for attention and perceptual deficits, the best with TS. We appreciate the generous participation in clinical research by method of ovarian hormone replacement across the lifespan, families of girls with TS and girls and women with TS. We acknowledge and the most effective monitoring for osteoporosis and car- expert advice from Alan DeCherney, M.D., NICHD, NIH; Harry Dietz, M.D., Johns Hopkins, Baltimore, MD; Andrew Griffith, National Insti-tute of Deafness and Other Communication Disorders, NIH; Vincent Ho,M.D., Uniformed Services University of the Health Sciences and NIHClinical Center, Bethesda, MD; and Jacquelyn Noonan, M.D., University Acknowledgments
of Kentucky. We acknowledge the support for the Wellness for Girls and * The Turner Syndrome Consensus Study Group includes the fol- Women with Turner Syndrome Conference generously provided by the lowing: Carolyn Bondy, M.D., Conference and Writing Committee National Institute of Child Health, Genentech, Eli Lilly, Novo-Nordisk, Chair, Developmental Endocrinology Branch, National Institute of Child Health and Human Development (NICHD), National Institutes ofHealth (NIH); Neus Baena, M.D., Genetics Laboratory, Corporacio San- Received June 27, 2006. Accepted October 6, 2006.
itaria Parc Tauli, Institut Universitari Parc Tauli-UAB, Sabadell, Spain; Address all correspondence and requests for reprints to: Carolyn Vladimir K. Bakalov, M.D., Developmental Endocrinology Branch, Bondy, M.D., Developmental Endocrinology Branch, National Institute NICHD, NIH; Barbara Bowles Biesecker, M.S., National Human Ge- of Child Health and Human Development, National Institutes of Health, nome Research Institute, NIH; Jean-Claude Carel, M.D., Endocrinologie Bethesda, Maryland 20892. E-mail: bondyc@mail.nih.gov.
Diabe´tologie Pe´diatrique and Institut National de la Sante´ et de la This work is based on the proceedings of an international, multidis- Recherche Me´dicale U690, Hoˆpital Robert Debre´, Paris, France; Gerard ciplinary meeting, “Wellness for Girls and Women with Turner Syn- Conway, M.D., Department of Endocrinology, Middlesex Hospital, drome,” sponsored by the National Institute of Child Health, Bethesda, Mortimer Street, London, UK; Marsha Davenport, M.D., Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC; Disclosure: C.A.B. has nothing to disclose.
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Stability profiles of drug products extended beyond labeled expiration dates

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