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Introduction: Aortic abnormalities contribute to increased morbidity and mortality of women with Turner syndrome (TS). Impaired aortic stiffness may prove to have clinical prognostic value in TS as is the case in other diseases such as Marfan syndrome, diabetes and hypertension. Additionally, the parental origin of the X chromosome in TS may influence aortic stiffness., Objective: To assess the relation between X chromosome parental origin and aortic stiffness in TS patients., Methods: Twenty-four subjects with TS participated in this cross-sectional study at a tertiary care centre. The parental origin of the X chromosome was determined. Cardiac-gated multidetector computerized tomography (MDCT) was performed and distensibility of the ascending aorta (AA), a measure of aortic stiffness, was calculated., Results: Fourteen women were Xm (maternal origin) and 10 were Xp (paternal origin) for their inheritance of the single X chromosome. Age, body size, blood pressure and AA areas were similar in the two groups. However, the calculated AA distensibility was significantly lower in the Xm group (2·8 ± 1·1 mm/Hg) than in the Xp group (4·1 ± 1·5 mm/Hg); P < 0·05. Conclusion This study demonstrates that TS subjects that inherit their single X chromosome from their mother (Xm) have a significantly stiffer aorta compared with the TS with a paternally originating X chromosome (Xp), consistent with a potentially greater risk for cardiovascular complications. These findings suggest that parental chromosomal analysis and aortic stiffness measurements would be useful for the risk assessment and clinical management of TS patients., (Published 2014. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Congenital heart disease (CHD) is a cardinal feature of X chromosome monosomy, or Turner syndrome (TS). Haploinsufficiency for gene(s) located on Xp have been implicated in the short stature characteristic of the syndrome, but the chromosomal region related to the CHD phenotype has not been established., Design: We used cardiac MRI to diagnose cardiovascular abnormalities in four non-mosaic karyotype groups based on 50-metaphase analyses: 45,X (n=152); 46,X,del(Xp) (n=15); 46,X,del(Xq) (n=4); and 46,X,i(Xq) (n=14) from peripheral blood cells., Results: Bicuspid aortic valves (BAV) were found in 52/152 (34%) 45,X study subjects and aortic coarctation (COA) in 19/152 (12.5%). Isolated anomalous pulmonary veins (APV) were detected in 15/152 (10%) for the 45,X study group, and this defect was not correlated with the presence of BAV or COA. BAVs were present in 28.6% of subjects with Xp deletions and COA in 6.7%. APV were not found in subjects with Xp deletions. The most distal break associated with the BAV/COA trait was at cytologic band Xp11.4 and ChrX:41,500 000. One of 14 subjects (7%) with the 46,X,i(Xq) karyotype had a BAV and no cases of COA or APV were found in this group. No cardiovascular defects were found among four patients with Xq deletions., Conclusions: The high prevalence of BAV and COA in subjects missing only the X chromosome short arm indicates that haploinsufficiency for Xp genes contributes to abnormal aortic valve and aortic arch development in TS.

Background: Turner Syndrome (TS) is due to X chromosome monosomy and affects ~1 per 2500 females at birth. The major features are short stature and primary ovarian failure. Short stature and monosomy for a maternal X chromosome have been implicated in impaired functionality in adult life; however, data on adult outcomes in TS are limited. In this study we evaluated the influence of adult height and parental origin of the single X chromosome on education, employment, and marital outcomes among women with TS., Methods: This was a cross-sectional study of 240 women (25-67 years old) with TS participating in an intramural National Institutes of Health (NIH) study. Parental origin of the single X chromosome was determined by genotyping proband and parental genomic DNA. Information on education, employment, and family status was self reported. Normative data was obtained from the U.S. Bureaus of Census and Labor and Statistics., Results: Seventy percent of the TS group had a baccalaureate degree or higher, compared with 30% of U.S. women (p<0.0001). Eighty percent of the TS group was employed compared with 70% of the U.S. female population. Approximately 50% of the TS group had ever married, compared with 78% of the general female population (p<0.0001). Height and parental origin of the single normal X chromosome had no association with education, employment, or marital status., Conclusion: Women with TS currently achieve education and employment levels higher than the female U.S. population but are less likely to marry. Neither adult height nor parental origin of the single X chromosome influenced outcomes in education, employment, or marriage.

Objective: To measure components of the circulating transforming growth factor β (TGFβ) system in patients with Turner syndrome (TS) compared to relevant controls and to ascertain correlation with endocrine and cardiovascular parameters., Methods: TGFβ1, TGFβ2 and endoglin (a vascular TGF receptor component) were measured using enzyme-linked immunoassays in the sera of 40 subjects with TS and 40 healthy volunteer women. The cardiovascular phenotype in TS subjects was extensively characterized by cardiac magnetic resonance (MR) and echo., Results: TGFβ1 levels were about 3-fold higher in TS while TGFβ2 levels were about 3.5-fold higher in controls (P<0.000 1 for both). Soluble endoglin levels were 25% higher in TS (P<0.000 1). Variation in TGFβ system components was not explained by age, blood pressure, platelet count, thyroid function, body proportions or cardiovascular phenotype., Conclusion: There is profound perturbation of the TGFβ system evident in the circulation of individuals with TS.

Background: Women with X-chromosome monosomy or Turner syndrome (TS) are at increased risk for aortic dilation and dissection. To better understand the pathology and develop tools to monitor the risk of aortic disease, we investigated N-terminal pro-brain natriuretic peptide (BNP) (NT-proBNP) levels in women with TS and healthy female controls., Methods: We evaluated NT-proBNP levels in women with karyotype-proven TS and healthy female volunteers in relation to ascending aortic diameter and descending aortic diameter measured by cardiovascular magnetic resonance imaging., Results: The NT-proBNP levels were strongly and positively correlated with ascending aortic diameter and descending aortic diameter in both cohorts. The TS group (n = 114, age 37.4 ± 12 yr) had greater body surface area-indexed aortic diameters and higher NT-proBNP levels than the control group (n = 27, age 46.4 ± 11 years): 88.3 ± 62.7 versus 53.5 ± 35 pg/mL, P = .0003. Within the TS group, NT-proBNP levels were higher in those with dilated ascending aorta (n = 42, 112.4 ± 75.7 pg/mL) compared with those with normal aortic dimensions (n = 72, 74.2 ± 49 pg/mL, P = .0014). Abnormally high NT-pro BNP levels were seen in 3 of 4 TS women who presented with previously undetected aortic aneurysm and/or dissection., Conclusions: The NT-proBNP levels are positively associated with aortic diameters in women with and without TS, suggesting a role for BNP in arterial wall homeostasis. Further study is necessary to determine whether NT-proBNP measurement may be used to monitor aortic diameter and/or detect aortic pathology in individuals at risk for aortic disease., (Published by Mosby, Inc.)

The higher prevalence of autoimmune diseases in women compared to men could be due to effects of ovarian hormones, pregnancy and/or the presence of a second X chromosome. To elucidate the role of these factors, we investigated the prevalence and spectrum of autoimmune diagnoses in women with primary ovarian insufficiency associated with X chromosome monosomy (Turner syndrome, TS, n = 244) and women with karyotypically normal (46,XX) primary ovarian insufficiency (POI, n = 457) in a prospective study, conducted at the National Institutes of Health. We compared the study group prevalence to normative data for the U.S. population of women. Chronic lymphocytic (Hashimoto's) thyroiditis (HT) occurred in 37% of women with TS vs. 15% with POI (P < 0.0001); HT prevalence in both ovarian insufficiency groups significantly exceeded that in U.S. population of women (5.8%). Inflammatory bowel (IBD, 4%) and celiac disease (CD, 2.7%) were significantly increased in TS, but not in POI. No other autoimmune diagnosis, including Graves' disease or Type 1 diabetes appears to be significantly increased in either group. Women with TS had higher pro-inflammatory IL6 and TGF β1 levels (p < 0.0001 for both), and lower anti-inflammatory IL10 and TGF β2 levels (p < 0.005 for both) compared to POI and to normal volunteers. Lifetime estrogen exposure and parity were significantly lower in TS compared to POI, which were in turn lower than the general population of women. The finding that lymphocytic thyroiditis is greatly increased in both women with TS and POI suggests that factors associated with ovarian insufficiency per se promote this form of autoimmunity. The absence of a normal second X-chromosome further contributes to increased autoimmunity in TS., (Published by Elsevier Ltd.)

The present observations are derived from 273 girls and women aged 7-40 years participating in the National Institutes of Health natural history study of Turner syndrome (TS) in the interval 2001-2011. There was a higher percentage of GH use among individuals in the pediatric age group (7-17, n = 118, 83%) compared to young adult women with prior GH use (18-40, n = 155, 61%). The major factor in this divergence seems to be a trend toward earlier diagnosis of TS in the younger age group. We find a striking association between history of GH use and lower total body and abdominal fat mass in young adults with TS approximately one decade after discontinuation of GH treatment. The interpretation of this observation is limited by the fact that our study subjects were not randomly assigned to GH treatment. There may be a bias involving poor health care, childhood obesity, delayed diagnosis, absent GH treatment and persistent adult obesity. Further studies on the socioeconomic factors implicated in patterns of GH use and non-use for girls with TS are needed to illuminate this important issue.

Objective: To identify and characterize otolaryngologic markers for the early diagnosis of Turner syndrome (TS)., Study Design: Prospective cohort survey., Setting: Clinical Center of the National Institutes of Health (NIH)., Patients: Ninety-one females, 7-61 years old (average=28.7 y), enrolled in a multidisciplinary study of karyotype-phenotype correlations in TS., Main Outcome Measures: Age at diagnosis, X chromosome karyotype, history of chronic or recurrent otitis media (OM), sensorineural hearing loss (SNHL), palate dysmorphism, pinna deformity, pterygium colli, low posterior hairline, low-set ears, and micrognathia., Results: Sixty-nine (76%) patients had a history of chronic or recurrent OM, 62 (68%) had a dysmorphic palate, 57 (63%) had SNHL, and 90 (99%) had one or more of these findings. 83 (91%; average age at diagnosis=9.4 y) had one or more external craniofacial signs: pinna abnormalities, pterygium colli, low-set ears, micrognathia or a low posterior hairline. Eight patients (average age at diagnosis=13.2 y) had no external craniofacial signs, although seven (88%) of these eight patients had a history of chronic or recurrent OM, dysmorphic palate or SNHL. The age at diagnosis was not significantly different between groups with or without external craniofacial signs (P=0.126)., Conclusions: PATIENTS with mild or incompletely penetrant TS phenotypes often present with otitis media, hearing loss, or both before the diagnosis of TS is established. Palatal dysmorphism, including ogival morphology, is another otolaryngologic marker for TS. Prompt recognition of these manifestations of TS could hasten its diagnosis and appropriate medical care.

Background: Turner syndrome (TS) is caused by the absence or fragmentation of the second sex chromosome. An increased risk of diabetes mellitus (DM) has consistently been noted, but the specific phenotype and genetic etiology of this trait are unknown., Methods: In a prospective study, we examined the prevalence of DM in adult participants in an intramural National Institutes of Health (NIH) TS study. Results were analyzed with respect to karyotype, age, body mass index (BMI), and autoimmune indices. Insulin sensitivity and secretion were compared in age- and BMI-matched euglycemic women with TS and healthy female controls. We compared gene expression profiles in lymphocytes from differentially affected TS groups., Results: Type 2 DM was present in 56 of 224 (25%) of the women with TS; type 1 DM was found in only one woman (<0.5%). DM was more prevalent among women with an isoXq chromosome compared to X monosomy (40.0 vs. 17.3%; P = 0.004). Euglycemic women with TS (n = 72; age, 33 +/- 12 yr; BMI, 23 +/- 3 kg/m(2)) had significantly higher glycemic and lower insulin responses to OGTT, with insulin sensitivity similar to controls. Gene expression profiles comparing 46,X,i(X)q vs. 45,X groups showed a significant increase in Xq transcripts and in potentially diabetogenic autosomal transcripts in the isoXq group., Conclusion: Type 2 DM associated with deficient insulin release is significantly increased among women with monosomy for the X-chromosome but is increased even more among women with monosomy for Xp coupled with trisomy for Xq. These data suggest that haploinsufficiency for unknown Xp genes increases risk for DM and that excess dosage of Xq genes compounds the risk.

Background: Individuals with Turner syndrome (TS) are at increased risk for impaired glucose tolerance and diabetes mellitus. It is unknown whether pharmacological GH treatment commonly used to treat short stature in TS alters this risk., Objective: Our objective was to compare adiposity and glucose tolerance in GH-treated vs. untreated girls with TS., Methods: In a cross sectional study, GH-treated girls with TS (n = 76; age 13.6 +/- 3.7 yr) were compared to girls with TS that never received GH (n = 26; age 13.8 +/- 3.5 yr). Protocol studies took place in the NIH Clinical Research Center from 2001-2006 and included oral glucose tolerance tests, body composition analysis by dual-energy x-ray absorptiometry, and abdominal fat quantification by magnetic resonance imaging. GH was not given during testing., Results: Total body fat (35 +/- 8 vs. 28 +/- 8%, P < 0.0001), sc abdominal fat (183 vs. 100 ml, P = 0.001), and intraabdominal fat (50 vs. 33 ml, P < 0.0001) were significantly greater in untreated girls. Fasting glucose and insulin were similar, but the response to oral glucose was significantly impaired in the untreated group (28 vs. 7% with impaired glucose tolerance, P = 0.006). A specific excess of visceral fat and insulin resistance was apparent only in postpubertal girls that had never received GH. GH-treated girls demonstrated lower adiposity compared with untreated girls for an average of 2 yr after discontinuation of GH., Conclusions: Abdominal adiposity is significantly lower and glucose tolerance significantly better in GH-treated vs. untreated girls with TS, suggesting that beneficial effects upon body composition and regional fat deposition outweigh transient insulin antagonism associated with GH administration.

Bone health is a major lifelong concern in caring for women and girls with Turner syndrome (TS). There is an approximately 25% increase in fracture risk most of which is related to medium or high impact trauma. The long bones, especially of the forearm are predominantly affected. This fact may be due to a selective cortical bone deficiency in TS which is unrelated to hypogonadism. In addition, lack of adequate estrogen replacement can lead to trabecular bone deficiency and increase in vertebral compression fractures after age 45. Evaluation of bone density by dual X-ray absorptiometry (DEXA) is important, however, it should be used judiciously in TS in view of its inherent tendency to underestimate the bone density of people with short stature. Bone size-independent methods, such as QCT or volumetric transformation of DEXA data should be used in individuals shorter than 150 cm. Achieving optimal bone density is of critical importance for fracture prevention in TS, and should be pursued by timely introduction of hormone replacement therapy, adequate dose of estrogens during the young adult life, optimal calcium and vitamin D intake and regular physical exercise. In addition, other measures to prevent fall and trauma should be considered, including optimizing hearing and vision, avoiding contact sports and exercise to improve coordination.

Objectives: Turner syndrome is the most common sex chromosome disorder in females, and is caused by a total or partial deletion of one X chromosome. The purpose of this study was to describe the auditory phenotype in a large group of individuals with Turner Syndrome, with analysis focusing on hearing loss and age, as well as the phenotypic relationship to karyotype variation., Design: Our analysis of auditory function was part of a large-scale, natural history study in which clinical and genetic factors related to Turner syndrome were examined. This ascertainment avoids the bias inherent in studies of patients referred to audiology or otolaryngology specialty clinics. Analysis included data from 200 females with Turner syndrome ranging in age from 7 to 61 yr (mean=27.9 yr)., Results: We observed hearing loss in approximately one-half of females with Turner syndrome, and report on a common, previously unlabeled audiometric configuration found in 24% of ears tested. Our cross-sectional design revealed an observable deterioration in hearing loss above the averaged rate of age-related hearing loss seen in an otologically screened, standardized population. Karyotype analysis revealed air conduction thresholds that were significantly poorer in the 46, XdelXp and 46, XiXq groups than in the 46, XdelXq group., Conclusions: This natural history study provides a more representative description of the auditory phenotype associated with Turner syndrome than previous studies that may have been biased by the method of ascertainment. Correlative analysis of Turner syndrome-specific hearing loss features with karyotype revealed that air conduction threshold elevations are associated with loss of the p arm of chromosome X. Our cross-sectional data indicate a loss of hearing sensitivity at an accelerated rate beyond a normal age-related decline, which warrants continued audiologic monitoring in all females with Turner syndrome regardless of a history of normal hearing.

Objective: To evaluate uterine development of women with Turner syndrome (TS) receiving conventional medical care., Study Design: In a cross-sectional study we used ultrasonography for uterine evaluation in 86 women with TS 18 to 45 years of age participating in an intramural NIH study, and who had abnormal karyotypes in >70% of white blood cells. Outcomes were uterine dimensions and shape. Information on hormone treatment was obtained by personal interview., Results: Twenty-five percent had a mature in size and shape uterus, and 31% had an immature uterus, with the remainder in a transitional category. Twenty percent of all participants were not taking hormone replacement therapy (HRT) in the preceding year. The majority on treatment were taking conjugated estrogens (CE) or oral contraceptives (OC). Factors associated with uterine maturity were history of spontaneous puberty and duration and type of HRT, with estradiol-based treatment being the most effective. The age at starting HRT was not a critical factor., Conclusions: Women with TS may develop a normal uterus even at a late start of HRT given adequate duration of treatment and regardless of karyotype.

Objective: To determine whether cardiac dimensions were different in girls with Turner syndrome (TS) who received growth hormone (GH) compared with those who did not receive GH., Study Design: This retrospective, cross-sectional study analyzed echocardiograms in 86 females with TS divided into GH-treated (n = 67) and untreated (n = 19) groups. The subjects all participated in the National Institutes of Health protocol between 2001 and 2006., Results: The average age was 16.2 years (range, 10 to 25 years), and average duration of GH treatment was 4.4 years (range, 1 to 14 years). The GH-treated group was taller by approximately 7 cm (P = .004), but cardiac dimensions normalized to body surface area (BSA), including septal and posterior wall thickness and left ventricular (LV) mass and internal diameters, did not differ significantly between the 2 groups. The fractional shortening index was similar in the 2 groups. Multiple regression analyses indicated that BSA, but not duration of GH treatment, predicted LV dimensions in girls with TS., Conclusions: GH treatment of girls with TS increases stature but does not disproportionately affect cardiac dimensions.

Certain behavioral and metabolic aspects of Turner syndrome (TS) are attributed to X-chromosome genomic imprinting. To investigate the possible contribution of imprinting to the physical features of the TS phenotype in live-born individuals, we genotyped the single normal X-chromosome in subjects with TS who all underwent a comprehensive evaluation as part of the NIH genotype-phenotype protocol. All had physical examinations, auxological measurements and imaging of the renal and cardiovascular systems. Absolute height and height as a percent of predicted height was the same in X(M) (n = 56) and X(P) (n = 23) subjects that had reached final height and were not growth hormone treated. Interestingly, adult height was significantly correlated with maternal but not paternal heights in both X(M) and X(P) groups. Neck webbing was found in 35% of the X(M) (n = 133) and 22% of the X(P) (n = 50) groups (P = 0.11). Renal anomalies were present in 24% of X(M) and 25% of X(P) groups (P = 0.9). Bicuspid aortic valve was found in 26% of X(M) and 24% of X(P) groups (P = 0.83), and any cardiovascular anomaly (abnormal aortic valve, aortic coarctation, elongated transverse aortic arch, anomalous pulmonary venous connection, left superior vena cava) affected 55% of X(M) and 52% of X(P) groups. Thus, we found no evidence for X-linked genomic imprinting effects on stature or lymphatic, renal or cardiovascular development in TS. Our sample size was sufficient to exclude such effects within 95% confidence limits. We did demonstrate a selective maternal effect on final stature that was independent of X-chromosome origin, suggesting potential autosomal imprinting effects on growth revealed by X monosomy.

Background: Many girls with Turner syndrome (TS) are treated with GH to increase adult height. In addition to promoting longitudinal bone growth, GH has effects on bone and body composition., Objective: The objective was to determine how GH treatment affects bone mineral density (BMD) and body composition in girls with TS., Method: In a cross-sectional study, we compared measures of body composition and BMD by dual energy x-ray absorptiometry, and phalangeal cortical thickness by hand radiography in 28 girls with TS who had never received GH and 39 girls who were treated with GH for at least 1 yr. All girls were participants in a National Institutes of Health (NIH) Clinical Research Center (CRC) protocol between 2001 and 2006., Results: The two groups were similar in age (12.3 yr, sd 2.9), bone age (11.5 yr, sd 2.6), and weight (42.8 kg, sd 16.6); but the GH-treated group was taller (134 vs. 137 cm, P = 0.001). The average duration of GH treatment was 4.2 (sd 3.2) yr (range 1-14 yr). After adjustment for size and bone age, there were no significant differences in BMD at L1-L4, 1/3 radius or cortical bone thickness measured at the second metacarpal. However, lean body mass percent was higher (P < 0.001), whereas body fat percent was lower (P < 0.001) in the GH-treated group. These effects were independent of estrogen exposure and were still apparent in girls that had finished GH treatment at least 1 yr previously., Conclusions: Although GH treatment has little effect on cortical or trabecular BMD in girls with TS, it is associated with increased lean body mass and reduced adiposity.

Background: We recently reported that electrocardiographic abnormalities are common in adults with monosomy X (Turner syndrome), but this issue has not been investigated in girls with Turner syndrome., Patients and Methods: We analyzed electrocardiograms in 78 girls with Turner syndrome and 50 age-matched control girls. The girls with Turner syndrome had additional cardiac and metabolic evaluations., Results: Girls with Turner syndrome were more likely to demonstrate > or = 1 electrocardiographic findings including right axis deviation, right ventricular hypertrophy, accelerated atrioventricular conduction, T-wave abnormalities, and a prolonged rate-corrected QT interval. The right-sided findings were associated with partial anomalous pulmonary venous connection, but the etiology of the other findings remains unknown. The rate-corrected QT interval was significantly longer in girls with Turner syndrome (431 +/- 22 vs 407 +/- 21 milliseconds). Twenty-eight girls with Turner syndrome but only 2 controls had a rate-corrected QT interval above the reference range. We found no correlation between body habitus, cardiac dimensions, or metabolic parameters and the rate-corrected QT interval duration in girls with Turner syndrome., Conclusions: Cardiac conduction and repolarization abnormalities seem to affect both young girls and adults with Turner syndrome equally, suggesting that electrophysiologic defects are intrinsic to the syndrome and indicating that electrocardiogram analysis should be included in evaluating and monitoring even the youngest patients with Turner syndrome. Attention to the rate-corrected QT interval is important, because some common medications may further prolong this interval and increase the risk of arrhythmias.

This review highlights recent developments in the detection and management of congenital heart disease and osteoporosis in patients with monosomy X, or Turner syndrome (TS). Magnetic resonance angiography (MRA) using gadolinium as a contrast agent demonstrates a higher prevalence and greater diversity of congenital cardiovascular defects than previously recognized in TS. Almost 50% of girls and women with TS have marked tortuosity or ectasia of the aortic arch, suggesting that these individuals may be at greater risk for aneurysm formation or dissection and therefore require closer monitoring. MRA also reveals that major venous anomalies are common in TS, with partial anomalous pulmonary venous return and persistent left superior vena cava each found in about 13% of patients. MR imaging even without contrast is a valuable complement to routine cardiac ultrasound in detecting abnormalities of the aortic valve. Abnormal electrocardiographic findings, including prolongation of the QTc interval, have recently been documented in many individuals with TS. Conduction and repolarization abnormalities have not been associated with congenital anatomic defects and are as common in young girls as adults. The clinical significance of these electrophysiological findings is unknown at present, but attention to the ECG in TS is important, particularly in monitoring the QTc when prescribing drugs associated with QT prolongation. Patients with TS are at high risk for osteoporosis as a result of premature ovarian failure and intrinsic bone abnormalities specific to the syndrome. Low cortical bone mineral density (BMD) is apparent in prepubertal girls, and it remains low in adults, independent of estrogen treatment and other hormonal factors. The low mineralization of cortical bone in TS may be associated with a small increased fracture risk, but no treatments are known to increase cortical bone mineral content in TS. Trabecular BMD is normal in TS women who have received continuous estrogen treatment from their mid-teens, although areal densitometry scores may be misleadingly low in very small patients. However, young women with ovarian failure who have not received estrogen treatment for extended periods of time are at high risk for osteoporosis of trabecular bone of the spine, with associated compression fractures and height loss. Therefore, judicious management of estrogen therapy to prevent osteoporosis while minimizing estrogen-associated adverse events is a challenging aspect of care for girls and women with TS.

Background: In recent years many girls with Turner syndrome (TS) have been treated with supraphysiological doses of GH to increase adult height. In addition to promoting statural growth, GH may have direct effects on the cardiovascular system., Objective: We sought to determine whether GH treatment affects aortic diameter in girls with TS because there is an increased risk for aortic dilation and dissection in this syndrome., Methods: In a retrospective, cross-sectional study, we compared ascending and descending aortic diameters measured by magnetic resonance imaging in GH-treated (n = 53) vs. untreated (n = 48) patients with TS participating in a National Institutes of Health protocol between 2001 and 2004., Results: The average duration of GH treatment was 4.7 with se 0.4 yr (range 2-11 yr). The two groups were similar in age and weight, but GH-treated subjects were on average 8 cm taller (P = 0.002). The diameter of the ascending aorta was increased by 7.3% and descending aorta by 8.9% in the GH-treated group. However, after correction for age, height, weight, and presence of bicuspid aortic valve and coarctation, using a multiple regression, neither history of GH treatment nor the length of GH treatment had an effect on the aortic diameter. Weight (P = 0.02), height (P = 0.001), and presence of bicuspid aortic valve (P = 0.0001) were associated with larger ascending aortic diameter, whereas age (P = 0.008), height (P = 0.02), and history of coarctation (P = 0.006) were associated with larger descending aortic diameter., Conclusions: GH treatment of girls with TS does not seem to affect ascending or descending aortic diameter above the increase related to the larger body size.

Anatomic anomalies of the cardiovascular system occur in approximately 50% of individuals with Turner syndrome (TS), with the specific genetic cause(s) for the heart defects still unknown. Because congenital heart disease may be associated with conduction system abnormalities, we compared electrocardiograms (ECGs) in 100 women with TS and 100 age-matched female controls. Women with TS were significantly more likely to demonstrate left posterior fascicular block (p < 0.005), accelerated AV conduction (p < 0.006), and T wave abnormalities (p < 0.006). The PR interval was significantly shorter (137 +/- 17 vs. 158 +/- 18 ms, p < 0.0001) and the rate-corrected QT interval (QTc) significantly longer in women with TS than in controls (423 +/- 19 ms vs. 397 +/- 18 ms; p < 0.0001). Twenty-one women with TS but no controls had a QTc greater than 440 ms. We found no statistically significant relation between body habitus, cardiac dimensions, evidence of congenital heart disease, or metabolic parameters and the incidence of ECG abnormalities or QTc duration in TS. Cardiac conduction and repolarization abnormalities appear to be intrinsic features of TS, suggesting that deletion of the second sex chromosome has more profound effects on the cardiovascular system than previously recognized, and that ECG analysis should be included in evaluating and monitoring patients with Turner syndrome.

Objectives: Turner syndrome (TS) is associated with congenital cardiovascular defects (CCVDs), most commonly bicuspid aortic valve (BAV) and aortic coarctation (COARC), congenital renal anomalies, and fetal lymphedema. It has been theorized that compressive or obstructive effects of fetal lymphedema may actually cause cardiovascular and renal dysmorphogenesis in TS. The objective of this study was to determine whether there is a specific association between a history of fetal lymphedema and CCVDs in monosomy X, or TS, independent of karyotype or general severity of the phenotype., Methods: This was a prospective study of 134 girls and women who have TS (mean age: 30 years) and were clinically evaluated for evidence of fetal lymphedema, classified as central (signified by the presence of neck webbing) or peripheral (current or perinatal, or dysplastic fingernails). The presence of BAV and/or COARC was detected by magnetic resonance imaging combined with echocardiography, and renal anomalies were determined by ultrasound., Results: There is a strong association between developmental central lymphedema, signified by neck webbing, and the presence of BAV (chi2 = 10) and COARC (chi2 = 8). The association between webbed neck and CCVDs was independent of karyotype. There was, in contrast, no significant association between renal anomalies and webbed neck or CCVDs., Conclusions: The strong, statistically significant association between neck webbing and the presence of BAV and COARC in TS suggests a pathogenetic connection between fetal lymphatic obstruction and defective aortic development. The presence of neck webbing in TS should alert the clinician to the possibility of congenital cardiovascular defects.

In a previous report, preliminary data showed a significant reduction in cortical bone mineral density (BMD) in women with Turner syndrome that had been treated with GH compared with women with Turner syndrome that had not been treated. To clarify this point, we have investigated the effects of GH treatment at multiple sites in this case-control, cross-sectional study. There were 23 women per group, who were similar in age, height, body mass index, estrogen use, and ethnic makeup. Median age (range) at start and duration of GH treatment was 9 (3-17) and 5 (2-9) yr, respectively. GH-treated women had a slightly greater ( approximately 8%, P = 0.03) width of the radial shaft, but otherwise there were no significant differences between groups in bone dimensions or BMD at the distal radius, lumbar spine, or femoral neck. Furthermore, regression analysis in a linear model including independent variables of age, age at diagnosis, body mass index, presence of spontaneous puberty, and GH use confirmed that GH use did not contribute to variation in BMD.

Background: Turner syndrome (TS) is associated with aortic coarctation and dissection; hence, echocardiographic evaluation of all patients is currently recommended. X-ray angiography in clinically symptomatic patients has suggested a range of other vascular anomalies, but the true prevalence of such lesions in TS is unknown. To better understand the prevalence and pathogenesis of cardiovascular defects in TS, we prospectively evaluated a group of asymptomatic adult volunteers with TS using magnetic resonance (MR) angiography., Methods and Results: A total of 85 adults with TS and 27 normal female adult volunteers underwent gadolinium-enhanced 3D MR angiography. A high prevalence of aortic anomalies was seen in women with TS, including elongation of the transverse arch (49%), aortic coarctation (12%), and aberrant right subclavian artery (8%). Venous anomalies were also prominent, including persistent left superior vena cava (13%) and partial anomalous pulmonary venous return (13%). None of these anomalies were found in healthy female controls. The constellation of elongation of the transverse arch, aortic coarctation, and persistent left superior vena cava was significantly associated with women with TS. Neck webbing and increased thoracic anterior-to-posterior dimension diameters were strong predictors for arterial and venous anomalies., Conclusions: Thoracic vascular anomalies are common in TS, occurring in approximately 50% of a group not preselected for cardiovascular disease. The highly significant association between neck webbing, increased chest diameter, and these vascular anomalies suggests that in utero, centrally localized lymphatic obstruction may contribute to these cardiovascular deformities in TS. Improved recognition of these often-undetected vascular lesions may be important for identification of patients in need of closer cardiovascular monitoring.

An increased prevalence of impaired glucose homeostasis (IGH) and diabetes mellitus is reported in monosomy X, or Turner syndrome (TS). To determine whether IGH is an intrinsic feature of this syndrome, independent of obesity or hypogonadism, we compared results of a standard oral glucose challenge in age- and body mass index-matched women with TS and with karyotypically normal premature ovarian failure (POF). Fasting glucose levels were normal in both groups, but glucose values after oral glucose challenge were higher in TS [2-h glucose, 135 +/- 36 mg/dl (7.5 +/- 2.0 mmol/liter) in TS and 97 +/- 18 mg/dl (5.4 +/- 1.0 mmol/liter) in POF; P < 0.0001]. Glucose-stimulated insulin secretion was lower in TS; e.g. the initial insulin response (DeltaI/DeltaG(30)) was decreased by 60% compared with POF (P < 0.0001). We also compared responses to a standard iv glucose tolerance test in women with TS and in age- and body mass index-matched normal women and found that the insulin area under the curve was 50% lower in women with TS (P = 0.003). Insulin sensitivity measured by the quantitative insulin sensitivity check index was higher in women with TS compared with both control groups. Thus, IGH is not secondary to obesity or hypogonadism in TS, but it is a distinct entity characterized by decreased insulin secretion, suggesting that haploinsufficiency for X-chromosome gene(s) impairs beta-cell function and predisposes to diabetes mellitus in TS.

Women with Turner syndrome (TS) are at risk for osteoporosis from ovarian failure and possibly from haploinsufficiency for bone-related X-chromosome genes. To establish whether cortical or trabecular bone is predominantly affected, and to control for the ovarian failure, we studied forearm bone mineral density (BMD) in 41 women with TS ages 18-45 yr and in 35 age-matched women with karyotypically normal premature ovarian failure (POF). We measured BMD at the 1/3 distal radius (D-Rad(1/3); predominantly cortical bone) and at the ultradistal radius (UD-Rad; predominantly trabecular bone) by dual x-ray absorptiometry. Women with TS had lower cortical BMD compared with POF (D-Rad(1/3) Z-score = -1.5 +/- 0.8 for TS and 0.08 +/- 0.7 for POF; P < 0.0001). In contrast, the primarily trabecular UD-Rad BMD was normal in TS and not significantly different from POF (Z-score = -0.62 +/- 1.1 for TS and -0.34 +/- 1.0 for POF; P = 0.26). The difference in cortical BMD remained after adjustment for height, age of puberty, lifetime estrogen exposure, and serum 25-hydroxyvitamin D (P = 0.0013). Cortical BMD was independent of serum IGF-I and -II, PTH, and testosterone in TS. We conclude that there is a selective deficiency in forearm cortical bone in TS that appears independent of ovarian hormone exposure and is probably related to X-chromosome gene(s) haploinsufficiency.

Purpose: To determine whether women with Turner syndrome who were treated with estrogen were more likely to have osteoporosis and fractures., Methods: Areal bone density at the lumbar spine and femoral neck was measured in 40 adult women with Turner syndrome and 43 age-matched healthy women using dual-energy X-ray absorptiometry. Histories of estrogen treatment and fractures were obtained by structured personal interviews., Results: Mean (+/- SD) areal bone density was significantly lower at the lumbar spine (0.87 +/- 0.11 g/cm(2) vs. 0.98 +/- 0.10 g/cm(2), P <0.001) and femoral neck (0.68 +/- 0.07 g/ cm(2) vs. 0.83 +/- 0.08 g/cm(2), P <0.001) in women with Turner syndrome than in controls. The diagnostic criterion for osteoporosis (T-score <-2.5) was met by 8 women with Turner syndrome (20%) with scores at the lumbar spine and by 3 (8%) with scores at the femoral neck. All women diagnosed with osteoporosis were less than 150 cm in height. Areal bone density correlated significantly with height (lumbar spine: R(2) = 0.3, P <0.001; femoral neck: R(2) = 0.4, P <0.001). Adjustments for skeletal size reduced the differences between the groups as well as the number of women diagnosed with osteoporosis (e.g., from 8 to 2 women based on lumbar spine scores). The prevalence and type of fractures were similar in the two groups., Conclusions: The prevalence of osteoporosis and bone fractures is not increased significantly in women with Turner syndrome who are treated with standard estrogen therapy. Women less than 150 cm in height are likely to be misdiagnosed with osteoporosis when areal bone density is measured, unless adjustments for body size are made.

Abstract: Apparent demineralization of the skeleton has been noted in females with Turner syndrome (TS) since the first descriptions of the disorder. Studies, using quantitative methods to measure areal bone mineral density (BMD) in TS, have often been confounded by small skeletal size and variable exposure to estrogen. Recent studies taking bone size into account suggest that BMD at skeletal sites of predominantly trabecular bone, e.g., the lumbar spine and ultra distal radius, is normal in women that have used estrogen consistently. However, these women have significantly lower than normal BMD at skeletal sites with predominantly cortical bone, e.g., the radial shaft and femoral neck. It is unknown whether the reduction in cortical BMD is an intrinsic feature of TS perhaps related to haploinsufficiency for SHOX or another X-linked gene, or due to deficient estrogen exposure during childhood and adolescence, and whether this cortical bone deficit increases fracture risk. Current recommendations to begin low dose estrogen treatment in the early teens may clarify these issues. Wide use of bisphosphonates to treat low BMD in young women with TS is not warranted since these agents have little if any effect on cortical bone while trabecular bone has excellent response to estrogens. [Copyright &y& Elsevier]