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Turner syndrome (TS) is defined by partial or complete absence of a sex chromosome. Little is known about the phenotype of individuals with TS mosaic with trisomy X (45,X/47,XXX or 45,X/46,XX/47,XXX) (~3% of TS). We compared the diagnostic, perinatal, medical, and neurodevelopmental comorbidities of mosaic 45,X/47,XXX (n = 35, 9.4%) with nonmosaic 45,X (n = 142) and mosaic 45,X/46,XX (n = 66). Females with 45,X/47,XXX had fewer neonatal concerns and lower prevalence of several TS‐related diagnoses compared with 45,X; however the prevalence of neurodevelopmental and psychiatric diagnoses were not different. Compared to females with 45,X/46,XX, the 45,X/47,XXX group was significantly more likely to have structural renal anomalies (18% vs. 3%; p = 0.03). They were twice as likely to have congenital heart disease (32% vs. 15%, p = 0.08) and less likely to experience spontaneous menarche (46% vs. 75% of those over age 10, p = 0.06), although not statistically significant. Congenital anomalies, hypertension, and hearing loss were primarily attributable to a higher proportion of 45,X cells, while preserved ovarian function was most associated with a higher proportion of 46,XX cells. In this large TS cohort, 45,X/47,XXX was more common than previously reported, individuals were phenotypically less affected than those with 45,X, but did have trends for several more TS‐related diagnoses than individuals with 45,X/46,XX. [ABSTRACT FROM AUTHOR]

There is a paucity of research on the experiences of parents of children with trisomy X (47,XXX). Increased prenatal diagnoses associated with advances in noninvasive prenatal screening necessitate a better understanding of how trisomy X impacts family systems. This qualitative investigation aimed to describe the lived experience of parents of young daughters with prenatally identified trisomy X to guide genetic counseling. Semi‐structured qualitative interviews were conducted via teleconferencing with parents (n = 11) of girls with trisomy X, ages 6–44 months. A descriptive phenomenological approach was used to code transcripts for significant statements and reduce data into themes describing the experience of receiving a diagnosis of trisomy X and the experience of early parenting in this population. Participants described an emotional journey of adapting to prenatally identified trisomy X. Four descriptive themes included two related, yet distinct, life stages: Negative Diagnostic Experience and a Hopeful Early Childhood, as well as two ongoing experiences: Persistent Ambiguity and Coping with and Adapting to Uncertainty. Results suggest providers should carefully consider word choice and timing in delivery of diagnosis, and genetic counseling should provide expectant parents with current research specific to trisomy X, facilitate connections with other parents of young girls with trisomy X, introduce developmental monitoring approaches, and be prepared to support families with a range of emotional responses to the diagnosis and decisions regarding disclosure. [ABSTRACT FROM AUTHOR]

Turner syndrome (TS) is a genetic condition occurring in ~1 in 2000 females characterized by the complete or partial absence of the second sex chromosome. TS research faces similar challenges to many other pediatric rare disease conditions, with homogenous, single‐center, underpowered studies. Secondary data analyses utilizing electronic health record (EHR) have the potential to address these limitations; however, an algorithm to accurately identify TS cases in EHR data is needed. We developed a computable phenotype to identify patients with TS using PEDSnet, a pediatric research network. This computable phenotype was validated through chart review; true positives and negatives and false positives and negatives were used to assess accuracy at both primary and external validation sites. The optimal algorithm consisted of the following criteria: female sex, ≥1 outpatient encounter, and ≥3 encounters with a diagnosis code that maps to TS, yielding an average sensitivity of 0.97, specificity of 0.88, and C‐statistic of 0.93 across all sites. The accuracy of any estradiol prescriptions yielded an average C‐statistic of 0.91 across sites and 0.80 for transdermal and oral formulations separately. PEDSnet and computable phenotyping are powerful tools in providing large, diverse samples to pragmatically study rare pediatric conditions like TS. [ABSTRACT FROM AUTHOR]

Inspiring New Science to Guide Healthcare in Turner Syndrome (InsighTS) Registry is a national, multicenter registry for individuals with Turner syndrome (TS) designed to collect and store validated longitudinal clinical data from a diverse cohort of patients with TS. Herein, we describe the rationale, design, and approach used to develop the InsighTS registry, as well as the demographics of the initial participants to illustrate the registry's diversity and future utility. Multiple stakeholder groups have been involved from project conceptualization through dissemination, ensuring the registry serves the priorities of the TS community. Key features of InsighTS include recruitment strategies to facilitate enrollment of participants that appropriately reflect the population of individuals with TS receiving care in the US, clarity of data ownership and sharing, and sustainability of this resource. The registry gathers clinical data on diagnosis, treatment, comorbidities, health care utilization, clinical practices, and quality of life with the goal of improving health outcomes for this population. Future directions include multiple patient‐centered clinical‐translational research projects that will use the InsighTS platform. This thorough and thoughtful planning will ensure InsighTS is a valuable and sustainable resource for the TS community for decades to come. [ABSTRACT FROM AUTHOR]

Sex chromosome aneuploidies (SCAs) are collectively common conditions caused by carriage of a sex chromosome dosage other than XX for females and XY for males. Increases in sex chromosome dosage (SCD) have been shown to have an inverted‐U association with height, but we lack combined studies of SCA effects on height and weight, and it is not known if any such effects vary with age. Here, we study norm‐derived height and weight z‐scores in 177 youth spanning 8 SCA karyotypes (XXX, XXY, XYY, XXXX, XXXY, XXYY, XXXXX, and XXXXY). We replicate a previously described inverted‐U association between mounting SCD and height, and further show that there is also a muted version of this effect for weight: both phenotypes are elevated until SCD reaches 4 for females and 5 for males but decrease thereafter. We next use 266 longitudinal measures available from a subset of karyotypes (XXX, XXY, XYY, and XXYY) to show that mean height in these SCAs diverges further from norms with increasing age. As weight does not diverge from norms with increasing age, BMI decreases with increasing age. These findings extend our understanding of growth as an important clinical outcome in SCA, and as a key context for known effects of SCA on diverse organ systems that scale with body size. [ABSTRACT FROM AUTHOR]

Objectives: The availability of cell‐free (cf) DNA as a prenatal screening tool affords an opportunity for non‐invasive identification of sex chromosome aneuploidy (SCA). The aims of this longitudinal study were to investigate the evolution and frequency of both invasive prenatal diagnostic testing, using amniocentesis and chorionic villus sampling (CVS), and the detection of SCA in cfDNA samples from a large unselected cohort in Northern Italy. Methods: The results of genetic testing from CVS and amniotic fluid samples received from public and private centers in Italy from 1995 to 2021 were collected. Chromosomal analysis was performed by routine Q‐banding karyotype. Regression analyses and descriptive statistics were used to determine population data trends regarding the frequency of prenatal diagnostic testing and the identification of SCA, and these were compared with the changes in indication for prenatal diagnostic tests and available screening options. Results: Over a period of 27 years, there were 13 939 526 recorded births and 231 227 invasive procedures were performed, resulting in the prenatal diagnosis of 933 SCAs. After the commercial introduction of cfDNA use in 2015, the frequency of invasive procedures decreased significantly (P = 0.03), while the frequency of prenatal SCA detection increased significantly (P = 0.007). Between 2016 and 2021, a high‐risk cfDNA result was the indication for 31.4% of detected sex chromosome trisomies, second only to advanced maternal age. Conclusions: Our findings suggest that the inclusion of SCA in prenatal cfDNA screening tests can increase the prenatal diagnosis of affected individuals. As the benefits of early ascertainment are increasingly recognized, it is essential that healthcare providers are equipped with comprehensive and evidence‐based information regarding the associated phenotypic differences and the availability of targeted effective interventions to improve neurodevelopmental and health outcomes for affected individuals. © 2023 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Sex chromosome aneuploidies (SCAs), including 47,XXY, 47,XXX, 47,XYY, and supernumerary variants, occur collectively in approximately one of 500 live births. Clinical phenotypes are highly variable resulting in previous ascertainment rates estimated to be only 10%–25% during a lifetime. Historically, prenatal SCA diagnoses were incidental findings, accounting for ≤10% of cases, with the majority of diagnoses occurring postnatally during evaluations for neurodevelopmental, medical, or infertility concerns. The initiation of noninvasive prenatal screening (NIPS) in 2012 and adoption into standardized obstetric care provides a unique opportunity to significantly increase prenatal ascertainment of SCAs. However, the impact NIPS has had on ascertainment of SCAs is understudied, particularly for those who may defer diagnostic testing until after birth. This study evaluates the timing of diagnostic testing following positive NIPS in 152 infants with SCAs and potential factors influencing this decision. Eighty‐seven (57%) elected to defer diagnostic testing after a positive NIPS until birth, and 8% (7/87) of those confirmed after birth were found to have discordant results on postnatal diagnostic testing, most of which would have influenced genetic counseling. [ABSTRACT FROM AUTHOR]

Many non‐invasive prenatal testing (NIPT) platforms screen for sex chromosome aneuploidy (SCA) and SCA analysis is generally included in Australia where NIPT is available as a self‐funded test. Little is known about the experience of receiving an NIPT result indicating an increased chance of SCA. This study aimed to explore the experiences of people who received this result and their perspectives on the information, care, and support they received from healthcare practitioners (HCPs). Semi‐structured interviews were conducted with people who received an NIPT result indicating an increased chance of SCA and continued their pregnancy. Most participants only had contact with a genetic counselor after receiving their result. Transcribed data were analyzed using rigorous thematic analysis to identify important patterns and themes. Participants (18 women, 2 male partners) described embarking on NIPT, primarily based on advice from their HCP and without much consideration. Consequently, participants expressed feeling unprepared for the unanticipated complexity of their NIPT result and were faced with making a time‐sensitive decision about a condition they had not previously considered. While more pre‐test information was desired, timely access to genetic counseling post‐test assisted with adjustment to the result. These findings suggest that routinization of NIPT may be compromising informed decision‐making, resulting in unpreparedness for an increased chance result. Given the increasing uptake and expanding scope of NIPT, resources should be dedicated to educating HCPs offering NIPT and ensuring timely access to genetic counseling post‐result. With appropriate funding, genetics services may be able to play a central role in offering information and support to both people who undertake NIPT and their HCPs ordering the testing. Implementing a publicly funded screening program in Australia could assist with standardizing prenatal screening care pathways and consequently better access to appropriate resources. [ABSTRACT FROM AUTHOR]

Students with sex chromosome aneuploidies (SCAs) are at increased risk for learning disabilities and often require individualized supports in the school setting. Parents of students with rare disorders such as SCAs possess a unique understanding of their child's educational experiences and play a crucial role in the development of successful school support plans. This international survey study aimed to inductively capture parent perspectives on educational needs and supports for students with SCAs. Parents of youth with SCAs ages 5‐21 years (n = 305) provided free‐text responses to open‐ended questions about their child's education. Qualitative content analysis using a bioecological systems framework resulted in three overarching themes. Overall, parents identified multiple factors related to the SCA diagnosis that act as barriers to learning, a strong need for school‐based social and emotional supports, and elusive or incomplete educational support plans. Based on these findings, we recommend developing robust family‐school partnerships, increased collaboration between the school and the child's medical team, and acknowledgement of the significant role the genetic condition plays in the educational experiences of students with SCAs. Specific suggestions for school support plans for students with SCAs are explored, such as providing school‐based behavioral health supports and explicit teaching of executive function strategies. [ABSTRACT FROM AUTHOR]

Objective: The present study aimed to evaluate the efficacy of a non‐invasive prenatal test (NIPT) in the detection of the sex chromosome aneuploidies (SCAs) at our prenatal diagnosis centre. Methods: Among a cohort of 34,717 pregnancies, maternal plasma samples from our prenatal diagnosis centre were subject to analysis of SCAs using NIPT detection. Pregnant women with NIPT positive results of SCAs were recommended to undergo an invasive prenatal diagnosis (i.e. karyotyping and fluorescence in situ hybridization) to validate the prediction value of NIPT. Results: From 34,717 clinical pregnancies, 229 (0.66%) pregnancies were identified with SCAs. Of these, 78 (34.1%) cases were positive for 45,X and 151 (65.9%) cases comprised a sex chromosome trisomy. Of the 229 positive NIPT results, 193 (84.3%) cases had accepted an invasive diagnosis involving karyotyping analysis of the amniotic fluid, which confirmed 67 cases (34.7%) as true positive, as well as 126 cases (65.3%) as false positive. The positive predictive values were 23.07%, 50%, 36% and 27.27% respectively. The remaining 36 (15.7%) cases declined a prenatal diagnosis. The termination rates of 45,X, 47,XXY, 47,XXX and 47,XYY were 20.5%,46%,12.9% and 11.5% respectively. Conclusions: NIPT demonstrated a lower accuracy in predicting monosomy X than sex chromosome trisomies. After invasive testing, the fetal chromosome with 45,X and 47,XXY were terminated more often than those with 47,XXX, 47,XYY. Because NIPT is a screening test, false positive/negative cases exist, and pre‐ and post‐test counselling is essential for informing patients about the benefits and limitations of the test. Confirmatory testing of abnormal results is recommended prenatally or after birth, and the importance of confirmatory testing and benefits of early diagnosis should be addressed. [ABSTRACT FROM AUTHOR]

Eight years have passed since noninvasive prenatal testing (NIPT) was clinically evaluated and data on NIPT for trisomy 21, 18 and 13 were collected. The data revealed that NIPT is more accurate than conventional first‐trimester screening. However, there is still insufficient data regarding the clinical use of NIPT results in detecting sex chromosome aneuploidies or whole‐genome regions. NIPT is already being used as a clinical screening method globally. However, it is an unconfirmed diagnostic test and the results must be interpreted with caution as they may yield false negatives, false positives or inconclusive results. Therefore, the aim of this review is to highlight the current status of information, including the different methodologies, shortcomings and implications, regarding NIPT after its adoption worldwide. It is important to include genetic counseling when implementing NIPT. Going forward, the knowledge obtained to date, including the associated shortcomings, must be considered in evaluating the effectiveness of NIPT in detecting genetic abnormalities. [ABSTRACT FROM AUTHOR]

Women with Turner syndrome (TS) have a high morbidity from both medical and psychological conditions with a negative impact on quality of life (QoL). Physical activity is a modifiable behavior shown to reduce risk for these chronic medical and mental health conditions and enhance QoL in other populations. Limited research suggests that adolescents and women with TS are less likely to engage in or enjoy physical activity than peers. This mixed methods study aimed to document physical activity levels in a sample of youth with TS and explore how factors unique to TS contribute to and are affected by physical activity. A cross‐sectional sample of 21 girls (12–21 years) with TS and their parents (n = 21) completed standardized questionnaires to quantify habitual physical activity (3‐day physical activity recall) and QoL (PROMIS) and participated in individual interviews focused on their experience with physical activity. Quantitative and qualitative results were synthesized using a phenomenological mixed methods approach. Results indicate that our sample engaged in less physical activity than peers and only 19% met recommendations for 1 hr per day of moderate‐to‐vigorous physical activity. Parents reported significant problems with peer relationships and psychological stress, and peer relationships scores correlated with physical activity. Reported barriers to physical activity included physical and psychosocial complications related to TS as well as unique developmental considerations specific to adolescence. Quantitative and qualitative results supported that structured fitness options embedded into routines enhanced activity levels. Results were compiled into specific recommendations for clinical care and areas of future research. [ABSTRACT FROM AUTHOR]

Despite affecting in 1 in every 1000 females, remarkably little is known about trisomy X syndrome (47,XXX), especially among older adults who are undiagnosed. In this study, we aimed to determine the prevalence of 47,XXX among females enrolled in the Million Veterans Program (MVP; mean age 50.2 ± 13.6 years), and compare broad health outcomes between females with 47,XXX and 46,XX matched controls. We identified 61 females with an additional X chromosome, corresponding to a prevalence of 103 per 100,000 females; 27.9% had been clinically diagnosed. Females with 47,XXX had taller stature (+6.1 cm, p < 0.001), greater rate of outpatient encounters (p = 0.026), higher odds of kidney disease (odds ratio [OR] = 12.3; 95% confidence interval [CI] 2.9-51.8), glaucoma (OR = 5.1; 95% CI 1.5-13.9), and congestive heart failure (OR = 5.6; 95% CI 1.4-24.2), and were more likely to be unemployed (p = 0.008) with lower annual income (p = 0.021) when compared with 46,XX controls of the same age and genetic ancestry. However, there were no differences in the rates of other encounter types, Charlson Comorbidity Index, all other medical and psychological diagnoses, military service history or quality of life metrics. In conclusion, in this aging and predominately undiagnosed sample, 47,XXX conferred few differences when compared with matched controls, offering a more reassuring perspective to the trisomy X literature., (© 2024 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Turner Syndrome (TS; 45,X) is a sex chromosome aneuploidy associated with deficits in social interaction, for which clinical care guidelines have recently recommended trialling a social skills training intervention. The present study aimed to gather preliminary evidence to support a training programme for young women. Methods: Semi‐structured interviews and psychometric questionnaires about social ability were administered to young women with TS aged 16 to 25 years old (n=17) and their parents (n=20). Interview transcripts were analysed using thematic analysis. Results: Although young women with TS experienced a "wide range of social competencies," they attributed social challenges to "personal and contextual factors." The magnitude of these challenges to social integration intensified during adolescence. They felt increasingly "out of sync" with their peers. They also considered their social abilities to be better than their parents did; on a scale of autistic traits (rated by parents), half had mild to severe autistic traits. Most expressed interest in taking part in a social skills programme. Conclusion: Young women with TS are aware they experience difficulties in social communication, and they express interest in improving their social skills. Accordingly, social skills training during adolescence would be welcomed by them and their families. Any intervention should take account of their feelings of social dislocation arising from hearing difficulties together with limited recognition, and slow processing, of social cues. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study is to evaluate if language and executive functioning deficits in individuals with the 47,XXY chromosomal pattern contribute to emotion regulation problems and related symptoms of psychopathology. Methods: A group of 26 adult men with 47,XXY completed measures of cognitive emotion regulation strategies, neurocognitive functioning, and symptoms of psychopathology. Results: Atypical emotion regulation strategies were found in the XXY group, with increased expression of emotions (69%), avoiding (65%), distraction seeking (54%), and passive coping (54%). More difficulties in mental flexibility and attention regulation, and speeded responding were associated with more pronounced emotion expression (emotional outbursts). Emotion regulation problems were associated with symptoms of anxiety, depression, thought problems, and hostility. Conclusion: This study has identified emotion regulation as a potential target for treatment and intervention, with a specific focus on executive functions in the management of emotions in individuals with 47,XXY. [ABSTRACT FROM AUTHOR]

Sex chromosomes are advantageous to mammals, allowing them to adopt a genetic rather than environmental sex determination system. However, sex chromosome evolution also carries a burden, because it results in an imbalance in gene dosage between females (XX) and males (XY). This imbalance is resolved by X dosage compensation, which comprises both X chromosome inactivation and X chromosome upregulation. X dosage compensation has been well characterized in the soma, but not in the germ line. Germ cells face a special challenge, because genome wide reprogramming erases epigenetic marks responsible for maintaining the X dosage compensated state. Here we explain how evolution has influenced the gene content and germ line specialization of the mammalian sex chromosomes. We discuss new research uncovering unusual X dosage compensation states in germ cells, which we postulate influence sexual dimorphisms in germ line development and cause infertility in individuals with sex chromosome aneuploidy. [ABSTRACT FROM AUTHOR]

47,XXY (KS) occurs in 1:650 male births, though less than 25% are ever identified. We assessed stability of neurocognitive features across diverse populations and quantified factors mediating outcome. Forty‐four boys from the Netherlands (NL) and 54 boys from the United States (US) participated. The Wechsler Intelligence Scales assessed intellectual functioning; the ANT program evaluated cognitive function; and the CBCL assessed behavioral functioning. ANOVA was used for group comparisons. Hierarchical regressions assessed variance explained by each independent variable: parental education, timing of diagnosis, testosterone, age, and nationality. Parental education, timing of diagnosis, and hormonal treatment all played an important role in neurocognitive performance. The observed higher IQ and better attention regulation in the US group as compared to the NL group was observed with decreased levels of behavioral problems in the US group. Cognitive measures that were different between the NL and US groups, i.e., attention regulation and IQ scores, were also significantly influenced by external factors including timing of diagnosis, testosterone treatment, and parental education. On the ANT, a cognitive phenotype of 47,XXY was observed, with similar scores on 9 out of the 10 ANT subtests for the NL and US groups. This study lays additional features to the foundation for an algorithm linking external variables to outcome on various neurodevelopmental measures. [ABSTRACT FROM AUTHOR]

Aim According to the published work, pregnancy termination rates due to prenatal diagnosis of fetal sex chromosome aneuploidies (SCA) vary widely. Some potentially modifiable and non-modifiable factors have been reported to be associated with parental decision. This study aimed to evaluate the rate of pregnancy termination for fetal SCA and the factors influencing parents' decisions in Hong Kong. Methods This was a 21-year retrospective cohort study of parents' decisions following prenatal diagnosis of SCA. Univariate and multivariate analyses for the association between demographic factors, prenatal factors, or counseling provided and decision-making were conducted. Results The study included 399 pregnancies with prenatal diagnosis of SCA and the overall termination rate was 55.6% (91.7%, 48.0%, 23.4%, 4.8%, and 22.7% for 45,X, 47,XXY, 47,XXX, 47,XYY, and mosaicism, respectively). Pregnancies with ultrasound abnormalities were associated with higher termination rates than pregnancies with normal ultrasound findings (91.3% vs 28.3%, P < 0.0001). From multivariate regression analysis on 226 pregnancies with normal ultrasound examination, a higher likelihood to terminate was found in pregnancies affected by 45,X and 47,XXY (adjusted odds ratio, 4.72, P < 0.0001). Increased maternal age and history of infertility were associated with lower likelihood to terminate (adjusted odds ratio, 0.9, P = 0.012; and 5.12, P = 0.038, respectively). The pregnancy termination rate declined over time. Conclusion A significant correlation was found between the termination of SCA-affected pregnancy and the presence of fetal sonographic abnormalities, type of SCA, maternal age, and presence of infertility. [ABSTRACT FROM AUTHOR]

Objectives: To review clinical validation or implementation studies of maternal blood cell-free (cf) DNA analysis and define the performance of screening for fetal trisomies 21, 18 and 13 and sex chromosome aneuploidies (SCA).Methods: Searches of PubMed, EMBASE and The Cochrane Library were performed to identify all peer-reviewed articles on cfDNA testing in screening for aneuploidies between January 2011, when the first such study was published, and 31 December 2016. The inclusion criteria were peer-reviewed study reporting on clinical validation or implementation of maternal cfDNA testing in screening for aneuploidies, in which data on pregnancy outcome were provided for more than 85% of the study population. We excluded case-control studies, proof-of-principle articles and studies in which the laboratory scientists carrying out the tests were aware of fetal karyotype or pregnancy outcome. Pooled detection rates (DRs) and false-positive rates (FPRs) were calculated using bivariate random-effects regression models.Results: In total, 35 relevant studies were identified and these were used for the meta-analysis on the performance of cfDNA testing in screening for aneuploidies. These studies reported cfDNA results in relation to fetal karyotype from invasive testing or clinical outcome. In the combined total of 1963 cases of trisomy 21 and 223 932 non-trisomy 21 singleton pregnancies, the weighted pooled DR and FPR were 99.7% (95% CI, 99.1-99.9%) and 0.04% (95% CI, 0.02-0.07%), respectively. In a total of 563 cases of trisomy 18 and 222 013 non-trisomy 18 singleton pregnancies, the weighted pooled DR and FPR were 97.9% (95% CI, 94.9-99.1%) and 0.04% (95% CI, 0.03-0.07%), respectively. In a total of 119 cases of trisomy 13 and 212 883 non-trisomy 13 singleton pregnancies, the weighted pooled DR and FPR were 99.0% (95% CI, 65.8-100%) and 0.04% (95% CI, 0.02-0.07%), respectively. In a total of 36 cases of monosomy X and 7676 unaffected singleton pregnancies, the weighted pooled DR and FPR were 95.8% (95% CI, 70.3-99.5%) and 0.14% (95% CI, 0.05-0.38%), respectively. In a combined total of 17 cases of SCA other than monosomy X and 5400 unaffected singleton pregnancies, the weighted pooled DR and FPR were 100% (95% CI, 83.6-100%) and 0.004% (95% CI, 0.0-0.08%), respectively. For twin pregnancies, in a total of 24 cases of trisomy 21 and 1111 non-trisomy 21 cases, the DR was 100% (95% CI, 95.2-100%) and FPR was 0.0% (95% CI, 0.0-0.003%), respectively.Conclusions: Screening by analysis of cfDNA in maternal blood in singleton pregnancies could detect > 99% of fetuses with trisomy 21, 98% of trisomy 18 and 99% of trisomy 13 at a combined FPR of 0.13%. The number of reported cases of SCA is too small for accurate assessment of performance of screening. In twin pregnancies, performance of screening for trisomy 21 is encouraging but the number of cases reported is small. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Klinefelter syndrome (XXY) is a common yet significantly underdiagnosed condition with considerable medical, psychological and social implications. Many health care providers lack familiarity with XXY, resulting in medical management challenges and a limited understanding of the personal impact of the condition. Genetic counselors benefit from understanding the challenges adolescents and men with XXY face to effectively address their medical and psychosocial needs. The purpose of this study was to understand the impact of living with XXY as an adolescent or an adult. Individuals aged 14 to 75 years with self-reported XXY were recruited from online support networks to complete a web-based survey that included open-ended questions. Open-ended responses were coded and analyzed thematically ( n = 169 to 210 for each open-ended question). Over half of respondents to the open-ended questions reported challenges in finding health care providers who are knowledgeable about XXY, with many describing an extensive diagnostic odyssey and relief when receiving a diagnosis. Individuals sought support coping with the challenges they face and acknowledgement of the positive aspects of XXY. Recommendations are made for how genetic counseling can enhance quality of life for individuals living with XXY. [ABSTRACT FROM AUTHOR]

This study supports training in genetic counseling for obstetricians and adoption of a multidisciplinary approach in the counseling process following prenatal diagnosis of sex chromosome aneuploidy. [ABSTRACT FROM AUTHOR]

The most common sex chromosome aneuploidy, Klinefelter syndrome (KS), is associated with primary gonadal failure and increased morbidity and mortality from cardiometabolic disorders in adulthood. Children with KS also have a high prevalence of metabolic syndrome (MetS) features. To assess the relationship of gonadal and cardiometabolic function in children with KS, we evaluated serum hormones [gonadotropins, inhibin B (INHB), anti-mullerian hormone (AMH), total testosterone (TT)], and features of MetS (waist circumference, fasting lipid panel, fasting blood glucose (FBG), and blood pressure) in 93 pre-pubertal boys with KS age 4–12 years (mean 7.7 ± 2.5 years). The cohort was grouped by age and tanner stage, and biomarkers were compared to normal ranges. A total of 80% of this pre-pubertal cohort had ≥1 feature of metabolic syndrome (MetS) and 11% had ≥3 features of MetS. Risk of MetS was independent of age and body mass index. Sertoli cell dysfunction was common with 18% having an INHB below the normal range. A low INHB was associated with higher FBG, triglycerides, LDL, and lower HDL (p < 0.05). An INHB <50 ng/dL yielded a sensitivity of 83% and a specificity of 79% for having ≥3 features of MetS. INHB and AMH positively correlated with each other (p < 0.001), and high AMH was protective of MetS. TT was below the lower limit of normal in 49% of subjects, with mean values significantly lower than expected (3.3 ng/dL vs. 4.9 ng/dL, p < 0.0001), however, no convincing relationship between TT and MetS was seen. In conclusion, gonadal and cardiometabolic dysfunction are prevalent in pre-pubertal boys with KS. Although the relationship of testosterone deficiency and MetS is well-known, this study is the first to report an association between impaired Sertoli cell function and cardiometabolic risk. [ABSTRACT FROM AUTHOR]

To date, the disclosure of a sex chromosome aneuploidy (SCA) diagnosis to an affected individual has not been explored. This study aimed to assess the timing and content revealed to an affected child by his or her parent(s), resources accessed in preparation, parental feelings of preparedness, common parental concerns, and recommendations for disclosure approaches. Two online surveys were created: 1) for parents of a child with a diagnosis and 2) for individuals with a diagnosis. One-hundred thirty-nine parent surveys (XXY n = 68, XXX n = 21, XYY n = 9, other SCAs n = 41) and 67 individual surveys (XXY n = 58, XXX n = 9) were analyzed. Parents most frequently discussed the topics of learning disabilities (47 %) and genetics (45 %) with their child during the initial disclosure. A significantly greater proportion of parent respondents reported feeling prepared vs. unprepared for disclosure, regardless of their child's diagnosis (z-test of proportions, all p's < 0.001). Both prepared and unprepared parents most frequently accessed resources such as websites, support groups, and discussion with the child's physician prior to disclosure, with unprepared parents accessing fewer resources ( M = 2.0 ± 1.41) than prepared parents [ M = 2. ± 1.56; t(101) =−2.02, p < 0.05]. Common parental concerns included making the conversation age-appropriate, discussing infertility, and possible impact on the child's self-esteem. Both parent and individual respondents endorsed being honest with the child, disclosing the diagnosis early and before puberty, and discussing the diagnosis gradually over time. These results provide recommendations for parents, and suggest benefits from additional resources and supports to alleviate concerns when approaching diagnosis disclosure. [ABSTRACT FROM AUTHOR]

Trisomy X, the presence of an extra X chromosome in females (47, XXX), is a relatively common but under-recognized chromosomal disorder associated with characteristic cognitive and behavioral features of varying severity. The objective of this study was to determine whether there were neuroanatomical differences in girls with Trisomy X that could relate to cognitive and behavioral differences characteristic of the disorder during childhood and adolescence. MRI scans were obtained on 35 girls with Trisomy X (mean age 11.4, SD 5.5) and 70 age- and sex-matched healthy controls. Cognitive and behavioral testing was also performed. Trisomy X girls underwent a semi-structured psychiatric interview. Regional brain volumes and cortical thickness were compared between the two groups. Total brain volume was significantly decreased in subjects with Trisomy X, as were all regional volumes with the exception of parietal gray matter. Differences in cortical thickness had a mixed pattern. The subjects with Trisomy X had thicker cortex in bilateral medial prefrontal cortex and right medial temporal lobe, but decreased cortical thickness in both lateral temporal lobes. The most common psychiatric disorders present in this sample of Trisomy X girls included anxiety disorders (40%), attention-deficit disorder (17%) and depressive disorders (11%). The most strongly affected brain regions are consistent with phenotypic characteristics such as language delay, poor executive function and heightened anxiety previously described in population-based studies of Trisomy X and also found in our sample. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives To evaluate the performance of a massively parallel sequencing ( MPS)-based test in detecting fetal sex chromosome aneuploidy ( SCA) and to present a comprehensive clinical counseling protocol for SCA-positive patients. Methods This was a retrospective study in a large patient cohort of 5950 singleton pregnancies which underwent MPS-based testing as a prenatal screening test for trisomies 21, 18 and 13, with X and Y chromosomes as secondary findings, in Southwest Hospital in China. MPS-based SCA-positive women were offered the choice of knowing whether their SCA results were positive and those who did commenced a two-stage post-test clinical counseling protocol. In Stage 1, general information about SCA was given, and women were given the option of invasive testing for confirmation of findings; in Stage 2, those who had chosen to undergo invasive testing were informed about the specific SCA affecting their fetus and their management options. Results Thirty-three cases were classified as SCA-positive by MPS-based testing. After Stage 1 of the two-stage post-test clinical counseling session, 33 (100%) of these pregnant women chose to know the screening test results, and 25 (75.76%) underwent an invasive diagnostic procedure and karyotype analysis, in one of whom karyotyping failed. In thirteen cases, karyotyping confirmed the MPS-based test results (two X0 cases, seven XXX cases, three XXY cases and one XYY case), giving a positive predictive value of 54.17% (13/24 cases confirmed by karyotyping). After post-test clinical counseling session Stage 2, seven women chose to terminate the pregnancy: one X0 case, two XXX cases, the three XXY cases and the single XYY case. Six women decided to continue with pregnancy: one X0 case and five XXX cases. Conclusion Our study showed the feasibility of clinical application of the MPS-based test in the non-invasive detection of fetal SCA. Together with a two-stage post-test clinical counseling protocol, it leads to a well-informed decision-making procedure. Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Congenital heart defects (CHDs) are common malformations, affecting four to eight per 1,000 total births. Conotruncal defects are an important pathogenetic subset of CHDs, comprising nearly 20% of the total. Although both environmental and genetic factors are known to contribute to the occurrence of conotruncal defects, the causes remain unknown for most. To identify novel candidate genes/loci, we used array comparative genomic hybridization to detect chromosomal microdeletions/duplications. From a population base of 974,579 total births born during 1999-2004, we screened 389 California infants born with tetralogy of Fallot or d-transposition of the great arteries. We found that 1.7% (5/288) of males with a conotruncal defect had sex chromosome aneuploidy, a sevenfold increased frequency (relative risk = 7.0; 95% confidence interval 2.9-16.9). We identified eight chromosomal microdeletions/duplications for conotruncal defects. From these duplications and deletions, we found five high priority candidate genes ( GATA4, CRKL, BMPR1A, SNAI2, and ZFHX4). This is the initial report that sex chromosome aneuploidy is associated with conotruncal defects among boys. These chromosomal microduplications/deletions provide evidence that GATA4, SNAI2, and CRKL are highly dosage sensitive genes involved in outflow tract development. Genome wide screening for copy number variation can be productive for identifying novel genes/loci contributing to non-syndromic common malformations. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The article presents oral abstracts on intellectual disability research to be presented at the 2010 Society for the Study of Behavioural Phenotypes (SSBP) Annual Scientific Meeting including a study on language impairments and fragile X syndrome (FXS), influence of the parent-of-origin of the supernumerary X chromosome on autistic and schizotypal symptom profiles in Klinefelter syndrome (KS), and the causal effect of seizures on learning and memory and social behaviour phenotypes.

This study investigated parental decision-making to terminate or continue a pregnancy after prenatal diagnosis of a chromosomal abnormality among a sample of patients in Southeast Turkey. Between 2004 and 2007, 1068 amniocentesis tests were performed in the Medical Biology and Genetic Department Laboratory at Dicle University. Aneuploidy was found in 38 cases (3.56%). Genetic counseling was provided for the couples that received abnormal results, and they were later interviewed and asked if they had continued or interrupted the pregnancy after the diagnosis. When confronted with autosomal aneuploidy in which a severe prognosis was expected, 85% of cases decided to terminate the pregnancy. When confronted with sex chromosome aneuploidy with a low risk of an abnormal clinical phenotype 60% of cases decided to continue the pregnancy. Among the diagnoses with aneuploidy, pregnancy was continued in 21.1% of cases due to religious beliefs regardless of whether there was a low or severe risk of an abnormal clinical phenotype. These findings indicate that both severity of abnormality and religiosity play an important role in genetic counseling patients’ decision-making processes and outcomes in Turkey. In addition, the findings suggest the need for legislation that reduces the differences in approaches between the physicians and institutions regarding parental decision-making to terminate or continue a pregnancy in our country. [ABSTRACT FROM AUTHOR]

Incidence of sex chromosome aneuploidy in men is as high as 1:500. The predominant conditions are an additional Y chromosome (47,XYY) or an additional X chromosome (47,XXY). Behavioral studies using animal models of these conditions are rare. To assess the role of sex chromosome aneuploidy on sexual behavior, we used mice with a spontaneous mutation on the Y chromosome in which the testis-determining gene Sry is deleted (referred to as Y−) and insertion of a Sry transgene on an autosome. Dams were aneuploid (XXY−) and the sires had an inserted Sry transgene (XY Sry). Litters contained six male genotypes, XY, XYY−, XX Sry, XXY− Sry, XY Sry and XYY− Sry. In order to eliminate possible differences in levels of testosterone, all of the subjects were castrated and received testosterone implants prior to tests for male sex behavior. Mice with an additional copy of the Y− chromosome (XYY−) had shorter latencies to intromit and achieve ejaculations than XY males. In a comparison of the four genotypes bearing the Sry transgene, males with two copies of the X chromosome (XX Sry and XXY− Sry) had longer latencies to mount and thrust than males with only one copy of the X chromosome (XY Sry and XYY− Sry) and decreased frequencies of mounts and intromissions as compared with XY Sry males. The results implicate novel roles for sex chromosome genes in sexual behaviors. [ABSTRACT FROM AUTHOR]

Klinefelter syndrome (KS) has not typically been associated with mental retardation (MR), however, in recent years a growing body of evidence suggested that KS boys often experience language deficits and academic difficulties. In this study, we screened DNA samples from 1205 patients originally referred for fragile X syndrome (FRAX) testing, because of MR of unknown etiology and detected 8 KS patients. A similar number of males in the same age group were found to have FRAX; 3 of them had a family history of FRAX. Based on these findings, KS might be the most common cause of MR of unknown etiology among prepubertal males. Because of the significant benefits of early recognition and treatment of KS, we emphasize the importance of cytogenetic testing of all prepubertal males with cognitive impairment even without dysmorphic features. [ABSTRACT FROM AUTHOR]

A defined genetic syndrome with neurobehavioral components offers an unusual paradigm for the correlation of genetic defects with neurodevelopmental abnormalities. The power of the combination of detailed behavioral, neuroanatomical, and genetic studies has been demonstrated in studies of other conditions involving the sex chromosomes, such as Fragile X syndrome (Mazzocco [2000] Ment Retard Develop Disabil Res Rev. 6:96–106) and Turner syndrome (Ross [2000] Ment Retard Develop Disabil Res Rev. 6:135–141). Although the behavioral and neurologic difficulties that have been identified in Klinefelter syndrome (KS) are in most cases milder than the consequences of many other genetic syndromes, the deficits in KS cause significant morbidity, representing a more common, but poorly understood, subtype of those with learning disabilities. Both as children and as adults, KS subjects appear to offer a powerful genetic model for the study of language and language-based learning disabilities. Although it has been proposed that the language-based learning difficulties of KS boys are similar to those of nonaneuploidic dyslexics [Bender et al., 1986; Geschwind et al., 1998], this is not yet well established. The co-morbid frontal-executive dysfunction observed in KS is also a likely contributor to learning difficulties and, perhaps, social cognition, in many KS patients. It is also proposed that altered left-hemisphere functioning, whether causing, or due to, altered functional and anatomical cerebral dominance, is at the core of KS subjects' language problems. Although X chromosomal loci can provide only part of the picture, the study of KS subjects, a population with a relatively homogeneous etiology for dyslexia/dysphasia and frontal-executive dysfunction, offers many advantages over such a study in the general population, in which both dyslexia and attentional disorders are quite genetically heterogeneous [Decker and Bender, 1988; Pennington, 1990; Grigorenko et al., 1997; Geschwind et al., 1998]. Furthermore, the interaction of genetic factors and hormonal influences in the cognitive phenotypes described remains an unexplored area for future investigation. MRDD Research Reviews 2000;6:117-124. © 2000 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

This essay describes the author's reflections as a contemporary artist who was the sister of a woman with Turner syndrome. She reflects on the process of creating a painting which is literally about X and 0, but conveys deeper artistic and personal themes., (© 2021 Wiley Periodicals LLC.)

Klinefelter syndrome (KS) occurs in 1:600 males and is associated with high morbidity and mortality due to diabetes and cardiovascular disease. Up to 50% of men with KS have metabolic syndrome, a cluster of features conferring increased risk for diabetes and cardiovascular disease. These cardiometabolic (CM) risk features have not been studied in adolescents with KS. The objective of this cohort study was to compare CM risk features in adolescents with KS to controls matched for sex, age, and BMI z score. Fifty males with KS (age 10-17 years) were well-matched to male controls (n = 50) for age (14.0 ± 1.7 vs. 14.0 ± 1.5 years) and BMI z score (0.3 ± 1.3 vs. 0.4 ± 1.2). Three CM risk features were present in 30% of adolescents with KS compared to 12% of controls (RR 2.5, 95% CI 1.1-5.9, p = .048). The KS group had significantly lower HDL cholesterol (p = .006), higher triglycerides (p < .001), and greater waist circumference percentile (p < .001). Despite a normal BMI, the prevalence of CM risk features was very high in adolescents with KS, particularly for central adiposity and dyslipidemia. The pathophysiology of this metabolic profile independent of obesity needs further investigation to facilitate prevention of the high morbidity of cardiovascular disease and diabetes in this population. ClinicalTrials.gov identifiers: NCT01585831 and NCT02723305., (© 2020 Wiley Periodicals, Inc.)

Sex chromosome aneuploidies (SCAs) are the most commonly occurring aneuploidies in children with a collective prevalence rate of 1 in 500 live births. Prior research has documented SCAs are associated with an increased risk for early expressive language and gross motor delays, learning disorders, ADHD, autism spectrum disorder, anxiety, and executive function problems. Although SCAs have been historically underdiagnosed in young children, recent advances in noninvasive prenatal testing have resulted in an increasing nationwide cohort of infants with confirmed diagnoses. Consequently, early childhood support systems must prepare for an influx of children with known risks for associated developmental delays and potential school problems. This national survey aimed to update our understanding of current early childhood intervention services for young children with SCA in the United States and to describe parent perspectives and priorities. Descriptive statistics, chi-square tests, and logistic regression models controlling for parent education revealed a majority of respondents reported receiving public early childhood intervention services with speech therapy as the most common service. There were significant differences in early childhood intervention services by timing of diagnosis (prenatal vs. postnatal), number of sex chromosomes (trisomy vs. tetra/pentasomy), and geographic location. Parents described interventions as desirable and effective yet also difficult to obtain due to issues with the SCA phenotype, lack of provider knowledge, and challenges navigating the intervention systems. Results support the need for enhanced provider training in SCAs, policy change for early childhood intervention qualification criteria for SCA conditions, and collaboration between medical and early childhood settings., (© 2020 Wiley Periodicals, Inc.)

While the most common Sex Chromosome Aneuploidy (SCA) is 47,XXY, other variations, such as 48,XXYY, are less studied, perhaps due to its rarity. 48,XXYY occurs with an estimated prevalence of 1:18,000-40,000 male births. This SCA is associated with a variety of complex physical, psychological, and neuroanatomical findings. The purpose of this integrative review is to summarize the available evidence related to 48,XXYY and identify gaps in the literature. This study utilized integrative review and PRISMA-guided methodology to search six databases for information pertaining to 48,XXYY. There were no exclusion criteria related to design methodology, given the paucity of available research. Among 397 articles reviewed for potential inclusion, 30 articles remained after inclusion and exclusion criteria were applied. Seven of these articles concentrated solely on participants with 48,XXYY. Literature was summarized into categories of physical phenotype, psychosocial, behavioral, neurocognitive, and brain function. Clinical description of 48,XXYY has evolved over time to develop a deeper understanding of this complex disorder. Large gaps remain, especially a lack of experimental studies, clinical guidelines, and treatments. Additionally, few studies explore methodologies such as interviews or self-report surveys in this population. 48,XXYY presents with a wide spectrum of physical, psychological, and neurocognitive symptoms, and frequently requires complex interdisciplinary care. In order to better understand this disorder and to appropriately treat the individuals affected by it, future research should focus on experimental studies and research that utilizes a variety of methods, including participant interviews and patient-report surveys., (© 2020 Wiley Periodicals, Inc.)

The most common sex chromosome aneuploidies (SCA) (47, XXY; 47, XYY; 47, XXX) frequently result in a milder phenotype than autosomal aneuploidies. Nevertheless, these conditions are highly variable and more symptomatic phenotypes may require significant clinical involvement, including specialty care. While historically most individuals with mild phenotypes remained undiagnosed during their lifetime, the increasing use of genetic testing in clinical care has increased the prenatal and postnatal diagnosis of SCAs. These genetic tests are frequently ordered by nongenetic providers who are also responsible for delivering the diagnosis. We surveyed parents of children (n = 308) to evaluate their experience of receiving a diagnosis and their support needs. The majority (73.3%) received the diagnosis from a nongenetic medical provider. Following a prenatal diagnosis parents reported experiencing depression, anxiety, and less optimism than those receiving a postnatal diagnosis. Few parents reported receiving materials explaining their child's condition that they found to be up-to-date, accurate, and unbiased. The frequently negative reported experiences of parents at time of diagnosis suggests more educational opportunities should be provided for nongenetic providers in order to become more informed about these conditions and communicate the diagnosis in a way parents experience as supportive., (© 2020 Wiley Periodicals, Inc.)

One of the two X chromosomes in females is epigenetically inactivated, thereby compensating for the dosage difference in X-linked genes between XX females and XY males. Not all X-linked genes are completely inactivated, however, with 12% of genes escaping X chromosome inactivation and another 15% of genes varying in their X chromosome inactivation status across individuals, tissues or cells. Expression of these genes from the second and otherwise inactive X chromosome may underlie sex differences between males and females, and feature in many of the symptoms of XXY Klinefelter males, who have both an inactive X and a Y chromosome. We review the approaches used to identify genes that escape from X-chromosome inactivation and discuss the nature of their sex-biased expression. These genes are enriched on the short arm of the X chromosome, and, in addition to genes in the pseudoautosomal regions, include genes with and without Y-chromosomal counterparts. We highlight candidate escape genes for some of the features of Klinefelter syndrome and discuss our current understanding of the mechanisms underlying silencing and escape on the X chromosome as well as additional differences between the X in males and females that may contribute to Klinefelter syndrome., (© 2020 The Authors. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals, LLC.)

Background: We evaluated the performance of a cell‐free DNA (cfDNA) prenatal screening assay for trisomies 21, 18, and 13, and sex chromosome aneuploidies (SCAs) among a population of pregnant women that included both those at average and high risk. Methods: Specimen collection, cfDNA extraction, massively parallel sequencing, and bioinformatics analysis were conducted per laboratory protocol. Assay results, concordance with pregnancy outcomes, and performance characteristics were evaluated. Results: A total 75,658 specimens from 72,176 individual pregnant women were received. Technical reasons accounted for 288 (0.4% of all received samples) tests not performed. In the final analysis cohort (N = 69,794), 13% of pregnancies were considered at average risk and 87% at high risk. Mean gestational age at specimen collection was 15.1 weeks. Of the 69,794 unique pregnancies, 1,359 (1.9%) had positive test results. Among the results with confirmed outcomes, PPV for trisomies 21, 18, and 13 was 98.1%, 88.2%, and 59.3%, respectively; the PPV was 69.0% for SCAs and 75.0% for microdeletions. Overall, PPV was 87.2%, sensitivity was 97.9%, and specificity was 99.9%. Conclusion: This cfDNA prenatal screening assay provides highly accurate discrimination between affected and unaffected pregnancies among a population of pregnant women at average and high risk for fetal genetic abnormalities. This study demonstrates that this cfDNA prenatal screening assay, QNatal® Advanced™, provides highly accurate discrimination between affected and unaffected pregnancies among a population of pregnant women at average or high risk for fetal genetic abnormalities. This has significant implications for patient care in the general obstetrical population. Increased understanding of assay performance facilitates improved clinical care and appropriate medical management for all patients. [ABSTRACT FROM AUTHOR]

Although XO mice do not show many of the overt phenotypic features of Turner syndrome (TS; 45,X or XO), mice and humans share different classes of genes on the X chromosome that are more or less likely to cause TS phenotypes. Based on the evolutionary history of the sex chromosomes, and the pattern of dosage balancing among sex chromosomal and autosomal genes in functional gene networks, it is possible to prioritize types of X genes for study as potential causes of features of TS. For example, X-Y gene pairs are among the most interesting because of the convergent effects of X and Y genes that both are likely to prevent the effects of TS in XX and XY individuals. Many of the high-priority genes are shared by mouse and human X chromosomes, but are easier to study in genetically tractable mouse models. Several mouse models, used primarily for the study of sex differences in physiology and disease, also produce XO mice that can be investigated to understand the effects of X monosomy. Using these models will lead to the identification of specific X genes that make a difference when present in one or two copies. These studies will help to achieve a better appreciation of the contribution of these specific X genes to the syndromic features of TS., (© 2019 Wiley Periodicals, Inc.)

Individuals with Turner syndrome (TS) have a higher morbidity and mortality compared to the general population. Diabetes and cardiovascular disease are the major contributors to this burden. Precursors to diabetes and cardiovascular disease make up what is known as metabolic syndrome, including abdominal obesity, hypertension, dyslipidemia, and elevated fasting glucose. These features of poor cardiometabolic health are also prevalent among women with TS. Youth with TS also exhibit many of these features, indicating that the pathogenesis of these cardiometabolic conditions may begin early in life. The etiology of the increased risk of cardiometabolic conditions in TS is likely multifactorial, involving genetics, epigenetics, hypogonadism, medical comorbidities, medications, and lifestyle. Counseling for the increased risk of cardiometabolic diseases as well as efforts to prevent or lower this risk should be routinely provided in the care of all patients with TS. Clinical practice guidelines are now available to guide screening and treatment of cardiometabolic conditions in girls and women with TS., (© 2019 Wiley Periodicals, Inc.)

Sex chromosome constitution varies in the human population, both between the sexes (46,XX females and 46,XY males), and within the sexes (e.g., 45,X and 46,XX females, and 47,XXY and 46,XY males). Coincident with this genetic variation are numerous phenotypic differences between males and females, and individuals with sex chromosome aneuploidy. However, the molecular mechanisms by which sex chromosome constitution impacts phenotypes at the cellular, tissue, and organismal levels remain largely unexplored. Thus, emerges a fundamental question connecting the study of sex differences and sex chromosome aneuploidy syndromes: How does sex chromosome constitution influence phenotype? Here, we focus on Turner syndrome (TS), associated with the 45,X karyotype, and its synergies with the study of sex differences. We review findings from evolutionary studies of the sex chromosomes, which identified genes that are most likely to contribute to phenotypes as a result of variation in sex chromosome constitution. We then explore strategies for investigating the direct effects of the sex chromosomes, and the evidence for specific sex chromosome genes impacting phenotypes. In sum, we argue that integrating the study of TS with sex differences offers a mutually beneficial alliance to identify contributions of the sex chromosomes to human development, health, and disease., (© 2019 Wiley Periodicals, Inc.)