Clinical Practice Guidelines for the Care of Girls and Women with Turner Syndrome.

Turner syndrome affects 50 per 100,000 females, affects multiple organs through all stages of life, necessitating multidisciplinary care. This guideline extends previous ones and includes important new advances, within diagnostics and genetics, estrogen treatment, fertility, co-morbidities, and neurocognition and neuropsychology. Exploratory meetings were held in 2021 in Europe and US culminating with a consensus meeting in Aarhus, Denmark in June 2023. Prior to this, eight groups addressed important areas in TS care: 1) diagnosis and genetics, 2) growth, 3) puberty and estrogen treatment, 4) cardiovascular health, 5) transition, 6) fertility assessment, monitoring, and counselling, 7) health surveillance for comorbidities throughout the lifespan, and 8) neurocognition and its implications for mental health and well-being. Each group produced proposals for the present guidelines, which were meticulously discussed by the entire group. Four pertinent questions were submitted for formal GRADE (Grading of Recommendations, Assessment, Development and Evaluation) evaluation with systematic review of the literature. The guidelines project was initiated by the European Society for Endocrinology and the Pediatric Endocrine Society, in collaboration with members from the European Society for Pediatric Endocrinology, the European Society of Human Reproduction and Embryology, the European Reference Network on Rare Endocrine Conditions, the Society for Endocrinology, and the European Society of Cardiology, Japanese Society for Pediatric Endocrinology, Australia and New Zealand Society for Pediatric Endocrinology and Diabetes, Latin American Society for Pediatric Endocrinology, Arab Society for Pediatric Endocrinology and Diabetes, and the Asia Pacific Pediatric Endocrine Society. Advocacy groups appointed representatives for pre-meeting discussions and the consensus meeting.

Bicuspid Aortic Valve Disease With Early Onset Complications: Characteristics And Aortic Outcomes.

Bicuspid aortic valve (BAV) is the most common congenital heart malformation in adults but can also cause childhood-onset complications. In multicenter study, we found that adults who experience significant complications of BAV disease before age 30 are distinguished from the majority of BAV cases that manifest after age 50 by a relatively severe clinical course, with higher rates of surgical interventions, more frequent second interventions, and a greater burden of congenital heart malformations. These observations highlight the need for prompt recognition, regular lifelong surveillance, and targeted interventions to address the significant health burdens of patients with early onset BAV complications.

Practice Patterns and Barriers to Vascular Genetic Testing Among Vascular Surgeons.

INTRODUCTION: Engaging patients living with or at risk of aortic dissection via the Aortic Dissection Collaborative, physician education in vascular genetics was identified as a research priority. We surveyed vascular surgeons to characterize practice patterns, motivations, and barriers regarding aortopathy genetic testing. METHODS: An anonymous 27-question survey was distributed on social media platforms between November and December 2022. Domains included demographics, vascular genetic education, testing attitudes and utilization, and experience in treating patients with genetic vascular aortopathies. The analysis included summary statistics and unpaired t-test to compare responses by interest in incorporating testing and practice type. RESULTS: A total of 171 vascular surgeons from 15 countries responded to the survey (23% trainees). Over half received vascular genetics education during training (59%), and most (86%) were interested in incorporating genetic testing into their practice. Academic surgeons were more likely to have cared for a patient with a known genetic aortopathy over the past year than surgeons in hospital-based and private practices (83% vs. 56% vs. 27%; P < 0.01), to have ever made a referral to a medical geneticist (78% vs. 51% vs. 9%; P < 0.01), and have access to genetic counselors or geneticists (66% vs. 46% vs. 0%; P < 0.01). Barriers to genetic testing were rated as more significant by surgeons in nonacademic practices, with top barriers being insurance coverage of testing, cost of genetic testing, and access to genetic counselors. Evidence-based professional society guidelines were the strongest rated motivating factor for testing incorporation among respondents. CONCLUSIONS: Vascular surgeon attitudes are not major barriers to incorporating genetic testing for patients with aortopathies; however, practical challenges regarding genetic testing and counseling are barriers to implementation especially for vascular surgeons in nonacademic practices. Future efforts should focus on evidence-based society guidelines, continuing medical education to increase adoption, and facilitating access to genetic counseling.

X-linked genetic associations in sporadic thoracic aortic dissection.

The male predominance in sporadic thoracic aortic aneurysm and dissection (TAD) suggests that the X chromosome contributes to TAD, but this has not been tested. We investigated whether X-linked variation-common (minor allele frequency [MAF] ≥0.01) and rare (MAF <0.01)-was associated with sporadic TAD in three cohorts of European descent (Discovery: 364 cases, 874 controls; Replication: 516 cases, 440,131 controls, and ARIC [Atherosclerosis Risk in Communities study]: 753 cases, 2247 controls). For analysis of common variants, we applied a sex-stratified logistic regression model followed by a meta-analysis of sex-specific odds ratios. Furthermore, we conducted a meta-analysis of overlapping common variants between the Discovery and Replication cohorts. For analysis of rare variants, we used a sex-stratified optimized sequence kernel association test model. Common variants results showed no statistically significant findings in the Discovery cohort. An intergenic common variant near SPANXN1 was statistically significant in the Replication cohort (p = 1.81 × 10-8). The highest signal from the meta-analysis of the Discovery and Replication cohorts was a ZNF182 intronic common variant (p = 3.5 × 10-6). In rare variants results, RTL9 reached statistical significance (p = 5.15 × 10-5). Although most of our results were statistically insignificant, our analysis is the most comprehensive X-chromosome association analysis of sporadic TAD to date.

Methodological advances in patient-centered rare disease research: the UTHealth Houston Turner Syndrome Society of the United States research registry.

BACKGROUND: Many different clinical specialists provide care to patients with Turner syndrome (TS), who have highly variable clinical manifestations. Therefore, a national TS registry is essential to inform a cohesive approach to healthcare and research. In 2015, the Turner Syndrome Society of the United States (TSSUS) created the Turner Syndrome Research Registry (TSRR) to engage directly with community participants who voluntarily provide longitudinal data about their experiences with TS. TSRR projects are collaborative partnerships between people with TS, TSSUS, and researchers. RESULTS: To ensure that registry workflows conform to the data privacy choices of participants, TSSUS collaborated with UTHealth Houston in 2021 to create a new version of the TSRR that completely separates participant health data (stored at UTHealth) and personal identifiers (maintained at TSSUS). We developed an innovative Visual Basic (VB) script that, when embedded into Microsoft Outlook, redirects REDCap surveys through TSSUS to participants by matching registry IDs to participant email addresses. Additionally, the utilization of REDCap allows for portability of data as it is an open source platform. CONCLUSION: In this report, we will highlight three recent changes that more closely align the TSRR with this mission: a unique and equal collaborative partnership between UTHealth and TSSUS, an open-source platform, REDCap, that ensures data portability and compatibility across institutions, and an innovative survey routing system that retains participant confidentiality without sacrificing REDCap survey distribution capabilities to connect researchers with thousands of participants.

[Summary: International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes]. / Resumen: Consenso internacional para la nomenclatura y clasificación de la válvula aórtica bicúspide congénita y su aortopatía, con fines clínicos, quirúrgicos, intervencionistas y de investigación.

This consensus of nomenclature and classification for congenital bicuspid aortic valve and its aortopathy is evidence-based and intended for universal use by physicians (both pediatricians and adults), echocardiographers, advanced cardiovascular imaging specialists, interventional cardiologists, cardiovascular surgeons, pathologists, geneticists, and researchers spanning these areas of clinical and basic research. In addition, as long as new key and reference research is available, this international consensus may be subject to change based on evidence-based data1.

Este consenso de nomenclatura y clasificación para la válvula aórtica bicúspide congénita y su aortopatía está basado en la evidencia y destinado a ser utilizado universalmente por médicos (tanto pediatras como de adultos), médicos ecocardiografistas, especialistas en imágenes avanzadas cardiovasculares, cardiólogos intervencionistas, cirujanos cardiovasculares, patólogos, genetistas e investigadores que abarcan estas áreas de investigación clínica y básica. Siempre y cuando se disponga de nueva investigación clave y de referencia, este consenso internacional puede estar sujeto a cambios de acuerdo con datos basados en la evidencia1.

Insights From the Histopathologic Analysis of Acquired and Genetic Thoracic Aortic Aneurysms and Dissections.

OBJECTIVE: The purpose of this study was to apply contemporary consensus criteria developed by the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology to the evaluation of aortic pathology, with the expectation that the additional pathologic information may enhance the understanding and management of aortic diseases. METHODS: A scoring system was applied to ascending aortic specimens from 42 patients with heritable thoracic aortic disease and known genetic variations and from 86 patients from a single year, including patients with known genetic variations (n = 12) and patients with sporadic disease (n = 74). RESULTS: The various types of lesions of medial degeneration and the overall severity of medial degeneration overlapped considerably between those patients with heritable disease and those with sporadic disease; however, patients with heritable thoracic aortic disease had significantly more overall medial degeneration (P = .004) and higher levels of elastic fiber fragmentation (P = .03) and mucoid extracellular matrix accumulation (P = .04) than patients with sporadic thoracic aortic disease. Heritable thoracic aortic disease with known genetic variation was more prevalent in women than in men (27.2% vs 9.8%; P = .04), and women had more severe medial degeneration than men (P = .04). Medial degeneration scores were significantly lower for patients with bicuspid aortic valves than for patients with tricuspid aortic valves (P = .03). CONCLUSION: The study's findings indicate considerable overlap in the pattern, extent, and severity of medial degeneration between sporadic and hereditary types of thoracic aortic disease. This finding suggests that histopathologic medial degeneration represents the final common outcome of diverse pathogenetic factors and mechanisms.

Whole Exome Sequencing Uncovers the Genetic Complexity of Bicuspid Aortic Valve in Families with Early Onset Complications.

Bicuspid Aortic Valve (BAV) is the most common adult congenital heart lesion with an estimated population prevalence of 1%. We hypothesize that early onset complications of BAV (EBAV) are driven by specific impactful genetic variants. We analyzed whole exome sequences (WES) to identify rare coding variants that contribute to BAV disease in 215 EBAV families. Predicted pathogenic variants of causal genes were present in 111 EBAV families (51% of total), including genes that cause BAV (8%) or heritable thoracic aortic disease (HTAD, 17%). After appropriate filtration, we also identified 93 variants in 26 novel genes that are associated with autosomal dominant congenital heart phenotypes, including recurrent deleterious variation of FBN2, MYH6, channelopathy genes, and type 1 and 5 collagen genes. These findings confirm our hypothesis that unique rare genetic variants contribute to early onset complications of BAV disease.

Inspiring New Science to Guide Healthcare in Turner Syndrome: Rationale, design, and methods for the InsighTS Registry.

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.

Outcomes of cardiothoracic surgery in women with Turner syndrome.

Background: To describe short- and mid-term surgical outcomes of patients with Turner syndrome (TS) after cardiovascular interventions. Methods: All individuals >12 years of age at the time of surgical repair for cardiovascular disease (valve or coarctation repairs, aortic disease, aortic dissection) from 2002 to 2022 were eligible. The primary endpoint was complications or death within 30 days of intervention. Secondary outcomes included late complications and reinterventions within six months. Combined data from the University of Texas Health Science Center at Houston and the Turner Syndrome Society of the United States were included in the analysis. Results: We identified 22 patients who met the inclusion criterion. The median age was 46 years (range, 21-75 years), with 86% having estrogen replacement therapy. The most common medical condition was hypertension (77%), followed by hypothyroidism (59%). The most frequent indication for surgery was aortic root or ascending aortic aneurysms (68%), followed by symptomatic aortic stenosis in patients with bicuspid aortic valve (64%), coarctation of aorta (45%), and acute aortic dissection (18%). Respiratory complications were the most common (68%). Pleural effusions were the most frequent found sign on imaging studies (68%). Thoracentesis, or chest tube placement, was required in 33% (5/15). Respiratory failure requiring specific support with high flow oxygen and/or thoracentesis occurred in 36% (8/22). Conclusions: Patients with TS may be at an increased risk for postoperative complications after aortic surgery. Bicuspid aortic valve (59%) and coarctation of the aorta (45%) were the most common congenital malformations among our study group. Our study showed that respiratory complications were the most common, with pleural effusions being the most common post-surgery complication.

Hidden Y Chromosome Material and Congenital Cardiovascular Malformations in a Cohort of Turner Syndrome Patients with 45,X Blood Karyotype.

INTRODUCTION: Bicuspid aortic valve is the most common congenital cardiac malformation (CCM) in adults and is 30-50 times more frequent in Turner syndrome (TS). We hypothesize that both X and Y chromosome dosages contribute to the prevalence of CCM in TS. The recognition of genotype-phenotype correlations may improve risk stratification of patients with 45,X karyotypes who have cryptic Y chromosome mosaicism. METHODS: Utilizing data and samples from the UTHealth Turner Syndrome Research Registry, we correlated Y chromosome DNA identified by multiplex quantitative PCR and SNP microarrays with the presence of congenital heart lesions. RESULTS: We identified Y chromosome DNA in more than 10% of registry participants, including 2 participants who had no detectable Y DNA by karyotype or SNP microarray. CONCLUSIONS: There were no significant correlations between the presence of Y DNA and CCM.

Rare Genomic Copy Number Variants Implicate New Candidate Genes for Bicuspid Aortic Valve.

Bicuspid aortic valve (BAV), the most common congenital heart defect, is a major cause of aortic valve disease requiring valve interventions and thoracic aortic aneurysms predisposing to acute aortic dissections. The spectrum of BAV ranges from early onset valve and aortic complications (EBAV) to sporadic late onset disease. Rare genomic copy number variants (CNVs) have previously been implicated in the development of BAV and thoracic aortic aneurysms. We determined the frequency and gene content of rare CNVs in EBAV probands (n = 272) using genome-wide SNP microarray analysis and three complementary CNV detection algorithms (cnvPartition, PennCNV, and QuantiSNP). Unselected control genotypes from the Database of Genotypes and Phenotypes were analyzed using identical methods. We filtered the data to select large genic CNVs that were detected by multiple algorithms. Findings were replicated in cohorts with late onset sporadic disease (n = 5040). We identified 34 large and rare (< 1:1000 in controls) CNVs in EBAV probands. The burden of CNVs intersecting with genes known to cause BAV when mutated was increased in case-control analysis. CNVs intersecting with GATA4 and DSCAM were enriched in cases, recurrent in other datasets, and segregated with disease in families. In total, we identified potentially pathogenic CNVs in 8% of EBAV cases, implicating alterations of candidate genes at these loci in the pathogenesis of BAV.

Dermatological concerns for women and girls with turner syndrome.

Introduction: Turner syndrome (TS) is associated with distinct manifestations in women and girls including short stature, cardiac abnormalities, premature ovarian failure as well as dermatological features, including lymphedema, keloids, onychodystrophy, and acne. Although many dermatological concerns present during the first few decades of life, the overwhelming majority of respondents are not provided with dermatology referrals at diagnosis. Methods: This cross-sectional study utilized an author designed survey to assess self-reported dermatological manifestations, dermatology referral experience, common therapies for select dermatological conditions, as well as a validated 10-question Dermatology Life Quality Index (DLQI) to assess quality-of-life impact in women and girls with Turner syndrome. Results: In our cohort, 64% (n = 149) had been referred to a dermatologist at some point in their life time. The majority of individuals self-identified their dermatological concern (79.6%) and were referred after a dermatological concern had already occurred (90.2%). The most common dermatological findings reported were xerosis cutis (78.7%), lymphedema (73%), and more than 20 acquired melanocytic nevi (70%). The overall mean DLQI score was 3.52, indicative of a small effect on the patient's life. Onychodystrophy, history of skin biopsy, and lymphedema were statistically significant to have a higher impact on quality of life. Discussion: Our data reveal that skin conditions are highly prevalent in the TS population during the early decades of life and affirm utilizing these conditions in the TS diagnostic process, as well as emphasize the need for specialized dermatology referrals to address the detrimental impacts related to skin concerns on quality of life.

Vertebral Tortuosity Is Associated With Increased Rate of Cardiovascular Events in Vascular Ehlers-Danlos Syndrome.

Background Arterial tortuosity is associated with adverse events in Marfan and Loeys-Dietz syndromes but remains understudied in Vascular Ehlers-Danlos syndrome. Methods and Results Subjects with a pathogenic COL3A1 variant diagnosed at age <50 years were included from 2 institutions and the GenTAC Registry (National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions). Height-adjusted vertebral artery tortuosity index (VTI-h) using magnetic resonance or computed tomography angiography was calculated. Associations between VTI-h and outcomes of (1) cardiovascular events (arterial dissection/rupture, aneurysm requiring intervention, stroke), or (2) hollow organ collapse/rupture at age <50 years were evaluated using receiver operator curve analysis (using outcome by age 30 years) and mixed-effects Poisson regression for incidence rate ratios. Of 65 subjects (54% male), median VTI-h was 12 (interquartile range, 8-16). Variants were missense in 46%, splice site in 31%, and null/gene deletion in 14%. Thirty-two subjects (49%) had 59 events, including 28 dissections, 5 arterial ruptures, 4 aneurysms requiring intervention, 4 strokes, 11 hollow organ ruptures, and 7 pneumothoraces. Receiver operator curve analysis suggested optimal discrimination at VTI-h ≥15.5 for cardiovascular events (sensitivity 70%, specificity 76%) and no association with noncardiovascular events (area under the curve, 0.49 [95% CI, 0.22-0.78]). By multivariable analysis, older age was associated with increased cardiovascular event rate while VTI-h ≥15.5 was not (incidence rate ratios, 1.79 [95% CI, 0.76-4.24], P=0.185). However, VTI-h ≥15.5 was associated with events among those with high-risk variants <40 years (incidence rate ratios, 4.14 [95% CI, 1.13-15.10], P=0.032), suggesting effect modification by genotype and age. Conclusions Increased arterial tortuosity is associated with a higher incidence rate of cardiovascular events in Vascular Ehlers-Danlos syndrome. Vertebral tortuosity index may be a useful biomarker for prognosis when evaluated in conjunction with genotype and age.

Health disparities in Turner Syndrome: UTHealth Turner Syndrome Research Registry.

Aim: Turner Syndrome (TS) is caused by partial or complete absence of the second sex chromosome in a phenotypic female. TS is associated with recognizable congenital anomalies and chronic health conditions. The principal objective of this study was to evaluate the health-related knowledge and insight of participants. Methods: In 2015, we founded the UTHealth Turner Syndrome Research Registry for longitudinal follow-up of individuals with TS. Study participants were recruited from UTHealth Houston clinics and the Turner Syndrome Society of the United States. Participants completed a questionnaire about demographics, karyotype, congenital anomalies, health history, frequency of contact with care providers, and knowledge of care providers about TS. Results: Forty percent of registry participants indicated that they did not know their karyotypes. Knowledge of karyotype, which can predict clinical outcomes in TS, markedly varied by self-reported race and ethnicity but not by age. Participants also reported significant gaps in routine medical and gynecologic care. Conclusion: We identified knowledge gaps and health disparities that could benefit from improved provider and patient education.

Maternal Sex Chromosome Aneuploidy Identified through Noninvasive Prenatal Screening: Clinical Profile and Patient Experience.

OBJECTIVE: Noninvasive prenatal screening (NIPS) may incidentally identify maternal aneuploidies that have health implications. We evaluated patients' experience with counseling and follow-up diagnostic testing after NIPS flags a potential maternal sex chromosome aneuploidy (SCA). STUDY DESIGN: Patients who underwent NIPS at two reference laboratories between 2012 and 2021 and had test results that were consistent with possible or probable maternal SCA were contacted with a link to an anonymous survey. Survey topics included demographics, health history, pregnancy history, counseling, and follow-up testing. RESULTS: A total of 269 patients responded to the anonymous survey, and 83 of these individuals also completed one follow-up survey. Most received pretest counseling. A total of 80% were offered fetal genetic testing during the pregnancy, and 35% of patients completed diagnostic maternal testing. Monosomy X-related phenotypes such as short stature or hearing loss prompted follow-up testing that led to a diagnosis of monosomy X in 14 (6%) cases. CONCLUSION: Follow-up counseling and testing after a high-risk NIPS result suggestive of maternal SCA is heterogenous in this cohort and may be frequently incomplete. Health outcomes may be affected by these results and additional research could improve the provision, delivery, and quality of posttest counseling. KEY POINTS: · NIPS results showing potential SCA could have maternal health implications.. · Variations in counseling and testing after NIPS were observed for women with suspected SCA.. · Comprehensive counseling and diagnostic testing strategies are critical for these patients..