Shanlee M. Davis

Context: Treatment with growth hormone is effective in improving height outcomes in children with Turner syndrome. However, poor adherence—often influenced by daily injection burden—may compromise treatment outcomes. Lonapegsomatropin is a prodrug, administered once weekly, that provides sustained release of somatropin. Objective: To evaluate the efficacy and safety of lonapegsomatropin in children with Turner syndrome. Design: New InsiGHTS is a phase 2 dose-ranging trial (ClinicalTrials.gov: NCT05690386). Setting: This trial was conducted across 19 centers in the United States. Participants: This trial enrolled and dosed 49 prepubertal children with Turner syndrome. Interventions: Randomization was 1:1:1:1 to receive once-weekly lonapegsomatropin (0.24, 0.30, or 0.36 mg hGH/kg/week) or daily somatropin (0.35 mg/kg/week). Main Outcome Measure: The primary efficacy endpoint was annualized height velocity (AHV) at week 26. Secondary efficacy endpoints included AHV at week 52 and change from baseline in height standard deviation score (SDS) at weeks 26 and 52. Results: At week 26, AHV was comparable between lonapegsomatropin starting dose cohorts (range: 9.23 to 10.36 cm/year) and the somatropin cohort (10.86 cm/year). At week 52, AHV was comparable between pooled lonapegsomatropin cohorts (9.05 cm/year) and the somatropin cohort (9.04 cm/year), with mean gains in height SDS of 0.60 and 0.67, respectively. Lonapegsomatropin was well tolerated with a safety profile similar to somatropin. Conclusions: Across evaluated doses, lonapegsomatropin treatment demonstrated comparable efficacy, safety, and tolerability to somatropin after 1 year, supporting development of lonapegsomatropin as a once-weekly treatment option for short stature in children with Turner syndrome.

Background: 47,XXY/Klinefelter syndrome is associated with high rates of obesity, metabolic syndrome, type 2 diabetes, and cardiovascular disease. Objective: This study compared cardiorespiratory fitness (CRF) in adolescents and young adults (AYA) with and without XXY and investigated the relationship between CRF and other biomarkers of cardiometabolic health. We hypothesized that CRF would be lower in XXY compared to healthy male controls. Materials and Methods: This cross‐sectional analysis included AYA with non‐mosaic 47,XXY ( n = 56) and 46, XY male controls ( n = 37) without hypertension, diabetes, or exercise restrictions. Participants completed graded exercise testing with oxygen consumption (VO ₂ ) measured continuously. The primary outcome was VO ₂ peak, with secondary outcomes including other CRF test parameters at maximal exertion and at the anaerobic threshold; as well as the prevalence of chronotropic incompetence defined as failure to achieve ≥85% of age‐predicted maximal heart rate during maximal exercise. Body composition completed via dual‐energy X‐ray absorptiometry (DXA), habitual physical activity, and serum biomarkers including lipids, hemoglobin A1c, hematocrit, and total testosterone were explored as covariates. Results: Compared with controls, CRF was markedly reduced in XXY despite similar effort, with 24% lower peak VO ₂ (31.2 ± 8.3 vs. 41.2 ± 7.9 mL/kg/min, p < 0.001). Chronotropic incompetence was more common in XXY (30.4% vs. 8.1%, p = 0.018) and associated with lower VO ₂ peak. Anaerobic threshold occurred earlier and at lower oxygen consumption in XXY. Individuals with XXY had higher adiposity with 7.0 ± 1.3% greater body fat for a given BMI, and in multivariable models, percent fat mass was the only independent predictor of VO ₂ peak ( p < 0.001). CRF was not associated with testosterone treatment status nor testosterone concentrations. Discussion: AYA with XXY demonstrated reduced CRF and earlier anaerobic threshold compared with controls, indicating diminished physiologic reserve. Higher adiposity and presence of chronotropic incompetence were associated with lower fitness, suggesting multifactorial mechanisms. These results support the need for prospective studies and targeted exercise‐based interventions to improve cardiometabolic health in this population. Conclusions: AYA with XXY have markedly reduced CRF driven primarily by excess adiposity, identifying an underrecognized target for early intervention to reduce cardiometabolic risk.

Background: 48,XXYY syndrome is a rare sex chromosome aneuploidy (SCA) characterized by neurodevelopmental deficits and medical comorbidities. The limited information available in the literature is almost exclusively limited to postnatally diagnosed cases. This study aims to describe the early medical and developmental features of prenatally identified 48,XXYY infants, with comparisons to 47,XYY, 47,XXY cohorts, and typical populations, as well as previously reported postnatally diagnosed 48,XXYY cases. Methods: The eXtraordinarY Babies Study prospectively follows children prenatally identified to be at high risk for SCA with annual medical and neurodevelopmental evaluations. Data presented herein include the prevalence of medical conditions, developmental milestones, developmental and adaptive functioning assessment scores, and therapy utilization in participants confirmed to have 48,XXYY. Comparisons were made between this cohort and the typical population, infants with 47,XYY and 47,XXY also enrolled in the eXtraordinarY Babies Study, and a 2008 cohort of individuals postnatally identified 48,XXYY. Results: Infants with 48,XXYY exhibited a range of early medical features, including high rates of feeding and GI disorders (breastfeeding difficulties, gastroesophageal reflux, and eosinophilic esophagitis), allergic disorders (food allergies and environmental allergies), and hypotonia. Developmental and adaptive functioning scores indicated delays in motor, communication, and social domains, with nearly all infants receiving speech therapy, physical and/or occupational therapy. Comparisons with the 47,XYY and 47,XXY cohorts revealed more medical and developmental challenges in the 48,XXYY group, however there was variability and some overlap with both the general population and sex chromosome trisomy conditions. Additionally, comparison to the 2008 postnatally identified 48,XXYY cohort indicated that while prenatal diagnosis allowed for earlier intervention, developmental outcomes in the first years of life were similar between the two groups. Conclusions: 48,XXYY diagnosed prenatally facilitates early monitoring, anticipatory guidance, and proactive referrals for medical evaluations and intervention, given developmental delays and medical challenges are more common in infancy and early childhood compared to the general population and trisomy SCAs. These findings provide valuable insights for genetic counselors and healthcare providers, emphasizing the spectrum of medical and developmental findings and importance of early and proactive care to support individual outcomes. Prospective study of this prenatally identified cohort will provide important natural history and phenotypic variability in XXYY, as well as identification of predictors of health and developmental outcomes.

BACKGROUND AND OBJECTIVES: Although tall stature is commonly associated with 47,XXY/Klinefelter syndrome (KS), detailed childhood growth patterns are not well-defined. This study aimed to develop KS-specific growth charts for stature-for-age, weight-for-age, weight-for-length (0–24 months), and body mass index (BMI)-for-age (2–18 years). METHODS: We conducted a population-based secondary analysis using clinical data from 6 US pediatric centers. The cohort included 1279 males aged younger than 20 years with a diagnosis of KS and at least 1 outpatient measurement of height and/or weight. Nonparametric quantile regression was used to model age-related growth trajectories. RESULTS: A median of 6 longitudinal growth data points per individual contributed to the creation of KS-specific curves. Key differences from standard reference growth charts included the following: (1) approximately 20% of boys with KS aged younger than 4 years were below the 5th percentile for height, whereas approximately 25% exceeded the 95th percentile by late childhood; (2) height velocity increased in midchildhood (after age 6 years), but without a distinct pubertal growth spurt; and (3) BMI distribution was broader, with approximately 10% of individuals below the 5th percentile and approximately 25% above the 95th percentile. CONCLUSIONS: Boys with KS demonstrate distinct and variable growth trajectories compared with the general population. These KS-specific growth charts offer a valuable clinical tool for monitoring growth, guiding anticipatory counseling, and identifying atypical development patterns.

Sex chromosome aneuploidies (SCAs), including Klinefelter syndrome (47,XXY), Turner syndrome (45,X), XYY syndrome, trisomy X (47,XXX), and rarer tetrasomies and pentasomies, affect approximately 1 in 400 births and are associated with a wide range of developmental, cognitive, and physical health outcomes. While clinical research on SCAs has expanded over the past two decades, it is unclear whether the populations included in these studies reflect the demographic diversity of those affected. Assessing representation is critical to ensuring research findings are generalizable and applicable to diverse patient populations. We conducted a systematic review of global clinical research on SCAs published in English between January 2004 and May 2024. Searches were performed in Ovid MEDLINE ALL, Embase, and Web of Science. Studies were included if they enrolled ≥ 10 participants and excluded if they were case reports, reviews, or meta‐analyses. We extracted data from 1474 studies on geographic location, participant karyotypes, and demographic metrics, including race, ethnicity, and socioeconomic status (SES) reported. Trends in demographic reporting were examined over time and by geographic region. For US‐based studies reporting race/ethnicity, we compared pooled participant demographics to national census data. SCA research is concentrated within a small number of geographic areas, primarily in Europe (51.4%) and the United States (23.6%). Reporting rates of race or ethnicity for US papers increased over the 20‐year observation period, with an average increase of 1.5% ± 0.4% per year ( p = 0.003), peaking in 2024 with 61.4% of US‐based papers presenting demographics. When reported, studies consistently overrepresented White non‐Hispanic ( p < 0.001) and college‐educated ( p < 0.001) participants relative to US census benchmarks. This systematic review reveals persistent gaps in the demographic reporting and representation of participants in SCA research. Even in the United States, where population diversity is high, published studies do not reflect the expected racial, ethnic, and socioeconomic makeup of affected individuals. To ensure that research findings are equitable and clinically relevant, future studies should adopt standardized demographic reporting and prioritize inclusive enrollment strategies to reflect the full spectrum of individuals with SCAs.

Individuals with Turner syndrome (TS) are known to be at increased risk for neurodevelopmental disorders (NDD) and mental health (MH) conditions, but data from large, population‐based pediatric samples remain limited. We examined the prevalence of NDD and MH diagnoses among youth with TS ( N = 2145) compared to matched female controls ( N = 8580) across six US pediatric health systems. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using generalized estimating equations. Youth with TS had significantly higher odds of an NDD diagnosis (24.2% vs. 11.9%; OR 2.37, 95% CI 2.11–2.67), particularly for speech‐language, motor, learning, and attentional disorders. Increased odds were also observed for autism spectrum disorder (ASD) and intellectual developmental disorder (IDD), though these remained relatively uncommon. In contrast, MH diagnoses, such as anxiety and mood disorders, were not more prevalent in TS compared to controls (17.3% vs. 18.5%; OR 0.92, 95% CI 0.81–1.05). These findings support the need for proactive neurodevelopmental screening in TS and raise important questions about the recognition and documentation of MH conditions in this population. Additional research is warranted to understand whether MH symptoms are underdiagnosed, present differently, or emerge later in development in youth with TS.

Sex chromosome aneuploidies (SCAs) are a family of genetic disorders that result from an atypical number of X and/or Y chromosomes. SCAs are the most common chromosomal abnormality, affecting ~1/400 live births, yet are often underdiagnosed, leading to over‐representation of more severely impacted individuals in many clinical studies. In addition to this ascertainment bias, existing work in SCAs has also been limited by low geographic and demographic diversity. To address these limitations, we have created the Generating Advancements with Longitudinal Analysis in X and Y variations (GALAXY) Registry. Through prioritizing sustainability, transparency, and minimizing participant burden, the overarching goal of the GALAXY Registry is to improve health outcomes for individuals with SCAs by serving as an infrastructure for future SCA research based on a large, heterogeneous, and longitudinal sample. To date, GALAXY has accrued 335 verified SCA participants with an average accrual of 11.2 participants/month (6.7 47,XXY, 1.9 47,XXX, 2.0 47,XYY, 3.2 48,XXYY, 1.8 48,XXXY, and 1.3 Other). Demographic data between those identified to have SCA prenatally (predominantly cell‐free DNA screening) differ from those diagnosed postnatally for insurance status, age at enrollment, genetic test type, and reason for SCA diagnosis. Next steps include targeted recruitment of underrepresented groups (e.g., non‐47,XXY karyotypes, older adults, minoritized individuals), extraction of medical record data into the registry, international expansion, and continued engagement with the SCA community. As a collaboration between clinician investigators and the SCA community, the GALAXY Registry is a powerful resource for future patient‐centered clinical research.

Individuals with Turner syndrome (TS) are known to be at increased risk for neurodevelopmental disorders (NDD) and mental health (MH) conditions, but data from large, population-based pediatric samples remain limited. We examined the prevalence of NDD and MH diagnoses among youth with TS (N = 2,145) compared to matched female controls (N = 8,580) across six U.S. pediatric health systems. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using generalized estimating equations. Youth with TS had significantly higher odds of an NDD diagnosis (24.2% vs. 11.9%; OR 2.37, 95% CI 2.11–2.67), particularly for speech-language, motor, learning, and attentional disorders. Increased odds were also observed for autism spectrum disorder (ASD) and intellectual developmental disorder (IDD), though these remained relatively uncommon. In contrast, MH diagnoses, such as anxiety and mood disorders, were not more prevalent in TS compared to controls (17.3% vs. 18.5%; OR 0.92, 95% CI 0.81–1.05). These findings support the need for proactive neurodevelopmental screening in TS and raise important questions about the recognition and documentation of MH conditions in this population. Additional research is warranted to understand whether MH symptoms are underdiagnosed in youth with TS or emerge later in development.

Background Sex chromosome aneuploidies (SCAs), including Klinefelter syndrome (47,XXY), Turner syndrome (45,X), XYY syndrome, trisomy X (47,XXX), and rarer tetrasomies and pentasomies, affect approximately 1 in 400 births and are associated with a wide range of developmental, cognitive, and physical health outcomes. While clinical research on SCAs has expanded over the past two decades, it is unclear whether the populations included in these studies reflect the demographic diversity of those affected. Assessing representation is critical to ensuring research findings are generalizable and applicable to diverse patient populations. Methods We conducted a systematic review of global clinical research on SCAs published in English between January 2004 and May 2024. Searches were performed in Ovid MEDLINE® ALL, Embase, and Web of Science. Studies were included if they enrolled ≥10 participants and excluded if they were case reports, reviews, or meta-analyses. We extracted data from 1,474 studies on geographic location, participant karyotypes, and demographic metrics, including race, ethnicity, and socioeconomic status (SES) reported. Trends in demographic reporting were examined over time and by geographic region. For U.S.-based studies reporting race/ethnicity, we compared pooled participant demographics to national census data. Results SCA research is concentrated within a small number of geographic areas, primarily in Europe (51.4%) and the U.S. (23.6%). Reporting rates of race or ethnicity for U.S. papers increased over the 20-year observation period, with an average increase of 1.5% ± 0.4% per year (p = 0.003), peaking in 2024 with 61.4% of U.S.-based papers presenting demographics. When reported, studies consistently overrepresented non-Hispanic White (pConclusions This systematic review reveals persistent gaps in the demographic reporting and representation of participants in SCA research. Even in the U.S., where population diversity is high, published studies do not reflect the expected racial, ethnic, and socioeconomic makeup of affected individuals. To ensure that research findings are equitable and clinically relevant, future studies should adopt standardized demographic reporting and prioritize inclusive enrollment strategies to reflect the full spectrum of individuals with SCAs.

Objectives: Hypergonadotropic hypogonadism is a characteristic clinical manifestation of Turner syndrome (TS). While up to 30 and 20 % of people with TS will have spontaneous thelarche and menarche respectively, there is a lack of evidence to predict who will retain sufficient ovarian function to achieve these outcomes. The aim of this study was to determine if follicle-stimulation hormone (FSH) and/or luteinizing hormone (LH) concentrations measured in infancy would accurately predict later spontaneous thelarche or menarche. Methods: Patients with a diagnosis of Turner syndrome with FSH and/or LH clinically measured prior to three years of age and now ≥10 years of age with documented pubertal assessment were included (n=33). Differences in infant gonadotropin values were determined for patients with vs. without spontaneous thelarche/menarche using Kruskal-Wallis tests. The optimal threshold of infant LH and FSH to predict spontaneous thelarche and menarche was then determined by maximizing the sum of sensitivity and specificity. Results: The prevalence of spontaneous thelarche and menarche were 21.2 and 15.2 % respectively. An infant LH value greater than 0.5 mIU/mL predicted lack of spontaneous thelarche with an estimated accuracy of 94 % and lack of spontaneous menarche with an estimated accuracy of 96 %. An infant FSH value greater than 37.4 mIU/mL predicted lack of lack of spontaneous thelarche with an accuracy of 97 % and lack of spontaneous menarche with an accuracy of 100 %. Conclusions: Infant gonadotropin concentrations accurately predict spontaneous later thelarche and menarche for persons with TS.