AMH and other markers of ovarian function in patients with Turner syndrome - a single center experience of transition from pediatric to gynecological follow up.

Turner syndrome (TS) is a chromosomal disorder that affects about 1 in 2500 female births and is characterized by the partial or complete absence of the second X chromosome. Depending on karyotype, TS is associated with primary ovarian insufficiency (POI). Approximately 50% of girls with a mosaic 45, X/46, XX karyotype may enter puberty spontaneously, but only 5-10% of women with TS achieve pregnancy without egg donation. In this review, we will evaluate the clinical use of markers of ovarian function in TS patients. Based on longitudinal studies of serum concentrations of reproductive hormones as well as ovarian morphology in healthy females and patients with TS, we will evaluate how they can be applied in a clinical setting. This is important when counseling patients and their families about future ovarian function essential for pubertal development and fertility. Furthermore, we will report on 20 years of experience of transition from pediatric to gynecological and adult endocrinological care in our center at Rigshospitalet, Copenhagen, Denmark.

Sex chromosome aneuploidies give rise to changes in the circular RNA profile: A circular transcriptome-wide study of Turner and Klinefelter syndrome across different tissues.

Purpose: The landscape of circular RNAs (circRNAs), an important class of non-coding RNAs that regulate gene expression, has never been described in human disorders of sex chromosome aneuploidies. We profiled circRNAs in Turner syndrome females (45,X; TS) and Klinefelter syndrome males (47,XXY; KS) to investigate how circRNAs respond to a missing or an extra X chromosome. Methods: Samples of blood, muscle and fat were collected from individuals with TS (n = 33) and KS (n = 22) and from male (n = 16) and female (n = 44) controls. CircRNAs were identified using a combination of circRNA identification pipelines (CIRI2, CIRCexplorer2 and circRNA_finder). Results: Differential expression of circRNAs was observed throughout the genome in TS and KS, in all tissues. The host-genes from which several of these circRNAs were derived, were associated with known phenotypic traits. Furthermore, several differentially expressed circRNAs had the potential to capture micro RNAs that targeted protein-coding genes with altered expression in TS and KS. Conclusion: Sex chromosome aneuploidies introduce changes in the circRNA transcriptome, demonstrating that the genomic changes in these syndromes are more complex than hitherto thought. CircRNAs may help explain some of the genomic and phenotypic traits observed in these syndromes.

Coronary plaque burden in Turner syndrome a coronary computed tomography angiography study.

Turner syndrome (TS) is associated with coronary artery disease (CAD), an important cause of premature death in TS. However, the determinants of CAD in women with TS remain unknown. In a cross-sectional study design, 168 women without clinical evidence of CAD (115 with TS and 53 without TS) were assessed for the presence and volume of subclinical CAD using coronary CT angiography. Karyotype, the presence of congenital heart defects and conventional cardiovascular risk factors were also registered. Comparative analyses were performed (1) between women with and without TS and (2) in the TS group, between women with and without subclinical CAD. The prevalence of CAD, in crude and adjusted analyses, was not increased for women with TS (crude prevalence: 40 [35%] in TS vs. 25 [47%] in controls, p = 0.12). The volume of atherosclerosis was not higher in women with TS compared with controls (median and interquartile range 0 [0-92] in TS vs. 0 [0-81]mm3 in controls, p = 0.29). Among women with TS, women with subclinical CAD were older (46 ± 13 vs. 37 ± 11 years, p < 0.001), had higher blood pressure (systolic blood pressure 129 ± 16 vs. 121 ± 16 mmHg, p < 0.05) and were more frequently diagnosed with type 2 diabetes (5 [13%] vs. 2 [3%], p < 0.05). Karyotype or congenital heart defects were not associated with subclinical CAD. Some women with TS show early signs of CAD, however overall, not more than women without TS. Conventional cardiovascular risk factors were the principal determinants of CAD also in TS, and CAD prevention strategies should be observed.ClinicalTrial.gov Identifier: NCT01678261 ( https://clinicaltrials.gov/ct2/show/NCT01678261 ).

Sex Hormone Replacement Therapy in Turner Syndrome: Impact on Morbidity and Mortality.

CONTEXT: The long-term effects of female hormone replacement therapy (HRT) in Turner syndrome (TS) are unknown. OBJECTIVE: To examine morbidity, mortality and medicinal use in TS and the impact of HRT in 45,X women. DESIGN AND SETTING: National cohort study, following all TS individuals ever diagnosed in Denmark from 1977 to 2014. PATIENTS AND METHODS: In the Danish Cytogenetic Central Registry, we identified 1156 females diagnosed with TS from 1960 to 2014, and, subsequently, Statistics Denmark randomly identified 115 577 age-matched female controls. TS women and their matched controls were linked with person-level data from the National Patient Registry and the Medication Statistics Registry, and they were compared concerning mortality, hospitalizations, and medical prescriptions. Among 329 45,X women, 44 had never been HRT treated, and 285 had been treated at some point. HRT treated women were compared with untreated concerning mortality, hospitalizations, and medical prescriptions. RESULTS: Endocrine and cardiovascular mortality and morbidity were significantly increased in TS compared with the matched controls. Comparing HRT treated with nontreated 45,X women, we found a similar mortality (hazard ratio 0.83, 95% confidence interval 0.38-1.79). Among the HRT-treated 45,X women, we found a significantly lower use of antihypertensives, antidiabetics, and thyroid hormones and significantly reduced hospitalization rates for stroke and osteoporotic fractures. CONCLUSION: Women with TS have an increased overall mortality and morbidity. HRT seems to have a beneficial effect on endocrine conditions, hypertension, and stroke in women with 45,X karyotype, with no clear impact on mortality.

Care of adult women with Turner syndrome: the state of affairs in Germany.

In this commentary, we discuss the state of affairs concerning the clinical care of females with Turner syndrome (TS) in Germany. TS is a rare disease and new international guidelines describe an appropriate setup for optimal clinical care. Several countries have implemented a program with centralized adult Turner syndrome clinics, which are now found in France, Denmark, the Netherlands, Sweden, parts of England and possibly other countries, but hitherto not in Germany. Such an approach should ensure the availability of high quality multi-disciplinary care for all women with TS to be treated and to detect all the conditions that have been associated with TS, which typically appear at odd times during the lifetime of a female with TS. Care should be offered at no added cost for the patient, and treatment with relevant drugs should be available at reasonable cost for the individual patient. Currently, it is quite problematic that many female sex hormone preparations are not available at low cost in a number of countries. Additional problems include supply chain issue which lead to patients not being able to buy their usual drug for a certain period of time. We think it is timely that countries improve the care for individuals with rare conditions, such as TS.

Recognition and management of adults with Turner syndrome: From the transition of adolescence through the senior years.

Turner syndrome is recognized now as a syndrome familiar not only to pediatricians and pediatric specialists, medical geneticists, adult endocrinologists, and cardiologists, but also increasingly to primary care providers, internal medicine specialists, obstetricians, and reproductive medicine specialists. In addition, the care of women with Turner syndrome may involve social services, and various educational and neuropsychologic therapies. This article focuses on the recognition and management of Turner syndrome from adolescents in transition, through adulthood, and into another transition as older women. It can be viewed as an interpretation of recent international guidelines, complementary to those recommendations, and in some instances, an update. An attempt was made to provide an international perspective. Finally, the women and families who live with Turner syndrome and who inspired several sections, are themselves part of the broad readership that may benefit from this review.

Turner syndrome: mechanisms and management.

Turner syndrome is a rare condition in women that is associated with either complete or partial loss of one X chromosome, often in mosaic karyotypes. Turner syndrome is associated with short stature, delayed puberty, ovarian dysgenesis, hypergonadotropic hypogonadism, infertility, congenital malformations of the heart, endocrine disorders such as type 1 and type 2 diabetes mellitus, osteoporosis and autoimmune disorders. Morbidity and mortality are increased in women with Turner syndrome compared with the general population and the involvement of multiple organs through all stages of life necessitates a multidisciplinary approach to care. Despite an often conspicuous phenotype, the diagnostic delay can be substantial and the average age at diagnosis is around 15 years of age. However, numerous important clinical advances have been achieved, covering all specialty fields involved in the care of girls and women with Turner syndrome. Here, we present an updated Review of Turner syndrome, covering advances in genetic and genomic mechanisms of disease, associated disorders and multidisciplinary approaches to patient management, including growth hormone therapy and hormone replacement therapy.

Impaired aortic distensibility and elevated central blood pressure in Turner Syndrome: a cardiovascular magnetic resonance study.

BACKGROUND: Women with Turner Syndrome have an increased risk for aortic dissection. Arterial stiffening is a risk factor for aortic dilatation and dissection. Here we investigate if arterial stiffening can be observed in Turner Syndrome patients and is an initial step in the development of aortic dilatation and subsequent dissection. METHODS: Fifty-seven women with Turner Syndrome (48 years [29-66]) and thirty-six age- and sex-matched controls (49 years [26-68]) were included. Distensibility, blood pressure, carotid-femoral pulse wave velocity (PWV), the augmentation index (Aix) and central blood pressure were determined using cardiovascular magnetic resonance, a 24-h blood pressure measurement and applanation tonometry. Aortic distensibility was determined at three locations: ascending aorta, transverse aortic arch, and descending aorta. RESULTS: Mean aortic distensibility in the descending aorta was significantly lower in Turner Syndrome compared to healthy controls (P = 0.02), however, this was due to a much lower distensibility among Turner Syndrome with coarctation, while Turner Syndrome without coarctation had similar distensibility as controls. Both the mean heart rate adjusted Aix (31.4% vs. 24.4%; P = 0.02) and central diastolic blood pressure (78.8 mmHg vs. 73.7 mmHg; P = 0.02) were higher in Turner Syndrome compared to controls, and these indices correlated significantly with ambulatory night-time diastolic blood pressure. The presence of aortic coarctation (r = - 0.44, P = 0.005) and a higher central systolic blood pressure (r = - 0.34, P = 0.03), age and presence of diabetes were inversely correlated with aortic distensibility in TS. CONCLUSION: Aortic wall function in the descending aorta is impaired in Turner Syndrome with lower distensibility among those with coarctation of the aorta, and among all Turner Syndrome higher Aix, and elevated central diastolic blood pressure when compared to sex- and age-matched controls. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov ( #NCT01678274 ) on September 3, 2012.

Morbidity, Mortality, and Socioeconomics in Females With 46,XY Disorders of Sex Development: A Nationwide Study.

Context: Little is known about long-term health outcomes in phenotypic females with 46,XY disorders of sex development (XY females), and the socioeconomic profile has not been described in detail. Objective: To describe morbidity, mortality, and socioeconomic status in XY females in a comparison to the general population. Design: Nationwide registry study with complete follow-up. Setting: Uniform public health care system. Participants: A total of 123 XY females karyotyped in Denmark during 1960 to 2012 and a randomly selected age-matched control cohort of 12,300 females and 12,300 males from the general population. Main Outcome Measures: Overall mortality and morbidity as well as cause-specific morbidity; medicine use and socioeconomics (education, income, cohabitation, motherhood, and retirement). Results: Compared with female controls, overall morbidity was increased in XY females [hazard ratio (HR), 1.72; 95% confidence interval (CI), 1.43 to 2.08] but not when excluding diagnoses associated with the specific disorder of sex development (DSD) diagnosis or pregnancy and birth (HR, 1.13; CI, 0.93 to 1.37). Mortality was similar to controls (HR, 0.79; CI, 0.35 to 1.77). Cohabitation (HR, 0.44; CI, 0.33 to 0.58) and motherhood (HR, 0.10; CI, 0.05 to 0.18) were reduced in XY females but education (HR, 0.92; CI, 0.61 to 1.37) was similar to controls. Income was higher than among controls in the older years. Conclusions: Morbidity was not increased in XY females when excluding diagnoses associated to the DSD condition per se. Judged on education and income, XY females perform well in the labor market. However, DSD seems to impact on the prospects of family life.

Incidence, Prevalence, Diagnostic Delay, and Clinical Presentation of Female 46,XY Disorders of Sex Development.

CONTEXT: The prevalence of phenotypic females with a 46,XY karyotype is low, thus current knowledge about age and clinical presentation at diagnosis is sparse even for the most frequent conditions, androgen insensitivity syndrome (AIS), and gonadal dysgenesis. OBJECTIVE: To estimate incidence, prevalence, age at diagnosis, and clinical presentation at diagnosis in 46,XY females. DESIGN AND SETTING: A nationwide study covering all known females with a 46,XY karyotype in Denmark since 1960. The diagnosis of 46,XY disorder of sex development (DSD) was determined by medical record evaluation, data from the Danish National Patient Registry, and genetic testing, if available. PATIENTS: A total of 166 females registered as 46,XY females in the Danish Cytogenetic Central Registry were identified. RESULTS: A total of 124 females were classified as having 46,XY DSD, 78 with AIS and 25 with gonadal dysgenesis, whereas the remaining subjects had a variety of different diagnoses. The prevalence of 46,XY females was 6.4 per 100 000 live born females, and for AIS and gonadal dysgenesis, it was 4.1 and 1.5 per 100 000, respectively. Median age at diagnosis was 7.5 years (95% confidence interval, 4.0-13.5; range, 0-34 y) in AIS and 17.0 years (95% confidence interval, 15.5-19.0; range, 0-28 y) in gonadal dysgenesis (P = .001). Clinical presentation was dependent on cause of DSD. CONCLUSIONS: The first estimate on prevalence of 46,XY females is 6.4 per 100 000 live born females. The presentation of AIS and gonadal dysgenesis is distinctly different, with AIS being diagnosed during childhood and gonadal dysgenesis during pubertal years. The presenting phenotype is dependent on the cause of 46,XY DSD.

Coronary artery anomalies in Turner Syndrome.

BACKGROUND: Congenital heart disease, primarily involving the left-sided structures, is often seen in patients with Turner Syndrome. Moreover, a few case reports have indicated that coronary anomalies may be more prevalent in Turner Syndrome than in the normal population. We therefore set out to systematically investigate coronary arterial anatomy by computed tomographic coronary angiography (coronary CTA) in Turner Syndrome patients. METHODS: Fifty consecutive women with Turner Syndrome (mean age 47 years [17-71]) underwent coronary CTA. Patients were compared with 25 gender-matched controls. RESULTS: Coronary anomaly was more frequent in patients with Turner Syndrome than in healthy controls [20% vs. 4% (p = 0.043)]. Nine out of ten abnormal cases had an anomalous left coronary artery anatomy (absent left main trunk, n = 7; circumflex artery originating from the right aortic sinus, n = 2). One case had a tubular origin of the right coronary artery above the aortic sinus. There was no correlation between the presence of coronary arterial anomalies and karyotype, bicuspid aortic valve, or other congenital heart defects. CONCLUSION: Coronary anomalies are highly prevalent in Turner Syndrome. The left coronary artery is predominantly affected, with an absent left main coronary artery being the most common anomaly. No hemodynamically relevant coronary anomalies were found.