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Turner Syndrome (TS) is a developmental disorder caused by partial or complete loss of one sex chromosome. Bicuspid aortic valve and other left-sided congenital heart lesions (LSL), including thoracic aortic aneurysms and acute aortic dissections, are 30-50 times more frequent in TS than in the general population. In 454 TS subjects, we found that LSL are significantly associated with reduced dosage of Xp genes and increased dosage of Xq genes. We also showed that genome-wide copy number variation is increased in TS and identify a common copy number variant (CNV) in chromosome 12p13.31 that is associated with LSL with an odds ratio of 3.7. This CNV contains three protein-coding genes (SLC2A3, SLC2A14, and NANOGP1) and was previously implicated in congenital heart defects in the 22q11 deletion syndrome. In addition, we identified a subset of rare and recurrent CNVs that are also enriched in non-syndromic BAV cases. These observations support our hypothesis that X chromosome and autosomal variants affecting cardiac developmental genes may interact to cause the increased prevalence of LSL in TS. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

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.)

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.

Objective: Menopause is associated with increased visceral adiposity and reduced insulin sensitivity. It remains unclear whether these changes are due primarily to ovarian failure or aging. The aim of this study was to clarify the impact of ovarian failure on body composition and insulin sensitivity in young women., Design: In a cross-sectional study, we compared main outcome measures (body mass index, body composition by dual-energy x-ray absorptiometry, and insulin sensitivity by Quantitative Insulin Sensitivity Check Index) in three groups: women with 46,XX premature ovarian failure (POF), women with premature ovarian failure associated with 45,X or Turner syndrome (TS), and normal control women (NC). Participants were enrolled in National Institutes of Health Clinical Center protocols between years 2000 and 2005., Results: Mean body mass index (+/- SD) was lower in women with POF (n = 398): 24.3 +/- 5 kg/m versus 27.8 +/- 7 for women with TS (n = 131) and 26.6 +/- 4 for controls (n = 73) (both P < 0.001). Only 33% of women with POF were overweight or obese, compared with 56% of those with TS and 67% of NC women (P < 0.0001 for both). Despite less obesity, women with POF had lower insulin sensitivity (0.367 +/- 0.03) compared with those with TS (0.378 +/- 0.03, P = 0.003) and NC women (0.376 +/- 0.03, P = 0.04). In groups selected for similar age and body mass index, women with POF (n = 89), women with TS (n = 48), and NC women (n = 40) had similar total body and trunk adiposity. After adjustment for age and truncal adiposity, women with POF had significantly lower insulin sensitivity than women with TS (P = 0.03) and NC women (P = 0.049)., Conclusions: In contrast to observations in middle-aged postmenopausal women, ovarian failure in young women is not associated with increased total or central adiposity. In fact, women with TS were similar to NC women, whereas women with POF were leaner. The lower insulin sensitivity observed in women with POF deserves further investigation.

Context and Objective: Men typically have a more atherogenic lipid profile than women characterized by higher low-density lipoprotein (LDL) cholesterol and triglyceride levels and reduced lipid particle size, contributing to a greater risk for coronary disease. To determine whether X-chromosomal gene dosage affects lipid metabolism independent of sex steroid effects, we compared lipid profiles in age- and body mass-matched young women with ovarian failure, differing only in X-chromosome dosage., Design, Setting, and Patients: Women with premature ovarian failure associated with monosomy X or Turner syndrome (TS, n = 118) were compared with women with 46,XX premature ovarian failure (n = 51) in an in-patient clinical research center unit at the National Institutes of Health. These women were normally on estrogen replacement treatment but discontinued the estrogen 2 wk before study., Major Outcomes: Fasting lipid levels and nuclear magnetic resonance lipid particle profiles in the two study groups were the major outcomes., Results: Average age and body mass were similar in the two groups of women, but LDL cholesterol (P = 0.001) and triglyceride levels (P = 0.0005) were higher in the TS group. Also among women with TS, average LDL particle size was reduced (P < 0.0001) and LDL particle concentration increased, with a 2-fold increase in the smallest particle categories (P < 0.0001). Whereas total high-density lipoprotein cholesterol levels were similar, high-density lipoprotein particle size was significantly smaller in women with TS, compared with women with premature ovarian failure (P < 0.0001)., Conclusions: Women with 45,X with ovarian failure exhibit a distinctly more atherogenic lipid profile than 46,XX women with ovarian failure, suggesting that the second X-chromosome contributes to a more salutary lipid profile in normal women, independent of sex steroid effects.

Presents a letter to the editor concerning a study of lipid profiles in women with primary ovarian failure.

Presents the authors' reply to a reader's letter to the editor about a study of lipid metabolism in women and offers criticism of the research methods.