An extra X chromosome among adult women in the Million Veteran Program: A more benign perspective of trisomy X.

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.

Incidence, prevalence, age at diagnosis, and mortality in individuals with 45,X/46,XY mosaicism: A population-based registry study.

PURPOSE: To assess the population-based incidence, prevalence, and age at diagnosis of individuals with 45,X/46,XY mosaicism (and associated variants) and describe the associated mortality pattern. In addition, a systematic literature review of papers providing prevalence data of 45,X/46,XY mosaicism was performed. METHODS: A population-based epidemiological study of all individuals diagnosed with 45,X/46,XY mosaicism between 1960 and 2019. Mortality was analyzed using data from the Danish Causes of Death Register. One-hundred randomly age- and sex-matched general population controls per case were identified for comparison. RESULTS: One-hundred-thirty-seven males and 46 females with 45,X/46,XY mosaicism were identified. The apparent prevalence was 5.6 per 100,000 liveborn males and 2.1 per 100,000 liveborn females. The incidence of males with 45,X/46,XY increased during the study (P > .0001) but was stable for females (P = .4). Males were significantly older than females when diagnosed (median age = 29.1, interquartile range: 3.4-41.3) years versus 13.3 (interquartile range: 2.1-19.1) years, P = .002). All-cause mortality was doubled in males with 45,X/46,XY (Hazard Ratio = 2.0, 95% confidence interval: 1.2-3.3) and quadrupled in females (Hazard Ratio = 4.0, confidence interval: 2.0-7.9). CONCLUSION: The apparent population-based prevalence of males and females with 45,X/46,XY is 5.6 and 2.1 per 100,000 liveborn males and females, respectively. Diagnosis of males with 45,X/46,XY males is increasing. 45,X/46,XY mosaicism is associated with an increased all-cause mortality.

Development and validation of a computable phenotype for Turner syndrome utilizing electronic health records from a national pediatric network.

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.

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.

Neuropsychological and mental health concerns in a multicenter clinical sample of youth with turner syndrome.

Clinical practice guidelines for individuals with Turner syndrome (TS) recommend screening for neuropsychological concerns (NC) and mental health concerns (MHC). However, current provider screening and referral patterns for NC and MHC are not well characterized. Additionally, prevalence of and risk factors for NC and MHC vary across studies. This multicenter chart review study examined the prevalence, risk factors for, and management of NC and MHC in a cohort of 631 patients with TS from three pediatric academic medical centers. NC and/or MHC were documented for 48.2% of patients. Neuropsychological evaluation recommendations were documented for 33.9% of patients; 65.4% of the sample subsequently completed these evaluations. Mental health care recommendations were documented in 35.0% of records; subsequent documentation indicated that 69.7% of these patients received such services. Most notably, rates of documented MHC, NC, and related referrals differed significantly by site, suggesting the need for standardized screening and referral practices. TS diagnosis in early childhood was associated with an increased risk of NC. Spontaneous menarche was associated with increased risk of MHC. Younger age at growth hormone initiation was associated with both increased risk of isolated NC and co-occurring NC and MHC. Mosaic karyotype was associated with decreased risk of NC and MHC.

Noninvasive prenatal screening (NIPS) results for participants of the eXtraordinarY babies study: Screening, counseling, diagnosis, and discordance.

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.

Hepatic abnormalities in youth with Turner syndrome.

BACKGROUND & AIMS: Liver disease in children with Turner Syndrome (TS) is poorly understood relative to associated growth, cardiac and reproductive complications. This study sought to better characterize hepatic abnormalities in a large national cohort of youth with TS. METHODS: Using electronic health record data from PEDSnet institutions, 2145 females with TS were matched to 8580 females without TS on eight demographic variables. Outcomes included liver enzymes (AST and ALT) stratified as normal, 1-2 times above the upper limit of normal (ULN), 2-3 times ULN and >3 times ULN, as well as specific liver disease diagnoses. RESULTS: Fifty-eight percent of youth with TS had elevated liver enzymes. Patients with TS had higher odds of enzymes 1-2 times ULN (OR: 1.7, 95% CI: 1.4-1.9), 2-3 times ULN (OR: 2.7, 95% CI: 1.7-3.3) and >3 times ULN (OR: 1.7, 95% CI: 1.3-2.2). They also had higher odds of any liver diagnosis (OR: 2.4, 95% CI: 1.7-3.3), fatty liver disease (OR: 1.9, 95% CI: 1.1-3.2), hepatitis (OR: 3.7, 95% CI: 1.9-7.1), cirrhosis/fibrosis (OR: 5.8, 95% CI: 1.3-25.0) and liver tumour/malignancy (OR: 4.8, 95% CI: 1.4-17.0). In a multinomial model, age, BMI and presence of cardiovascular disease or diabetes significantly increased the odds of elevated liver enzymes in girls with TS. CONCLUSIONS: Youth with TS have higher odds for elevated liver enzymes and clinically significant liver disease compared with matched controls. These results emphasize the need for clinical screening and additional research into the aetiology and treatment of liver disease in TS. LAY SUMMARY: Turner Syndrome, a chromosomal condition in which females are missing the second sex chromosome, is often associated with short stature, infertility and cardiac complications. Liver abnormalities are less well described in the literature. In this study, nearly 60% of youth with TS have elevated liver enzymes. Furthermore, patients with TS had a diagnosis of liver disease more often than patients without TS. Our results support the importance of early and consistent liver function screening and of additional research to define mechanisms that disrupt liver function in paediatric TS females.

Clinical phenotype and management of individuals with mosaic monosomy X with Y chromosome material stratified by genital phenotype.

Individuals mosaic for monosomy X and a cell line with Y chromosome material can have genitalia that appear phenotypical female, male, or ambiguous. Those with this karyotype and typical female genitalia are diagnosed with Turner syndrome; however, this definition specifically excludes those with genitalia other than typical female. There is limited information on whether medical and neurodevelopmental risks are similar among individuals with monosomy X and Y chromosome material across genital phenotypes. This multicenter retrospective study compared comorbidities and clinical management in individuals with monosomy X and Y material and male/ambiguous genitalia to those with typical female genitalia. Electronic medical records for all patients with monosomy X and Y material (n = 76) at two large U.S. pediatric centers were abstracted for predetermined data and outcomes. Logistic regression was used to compare the two phenotypic groups adjusting for site and duration of follow-up. The male/ambiguous genitalia group was just as likely to have congenital heart disease (RR 1.0, 95%CI [0.5-1.9]), autoimmune disease (RR 0.6 [0.2-1.3]), and neurodevelopmental disorders (RR 1.4 [0.8-1.2]) as those with female genitalia. Despite similar risks, they were less likely to receive screening and counseling. In conclusion, individuals with monosomy X and Y chromosome material have similar medical and neurodevelopmental risks relative to individuals with Turner syndrome regardless of genitalia, but there are notable differences in clinical management.

Minipuberty in Klinefelter syndrome: Current status and future directions.

Klinefelter syndrome is highly underdiagnosed and diagnosis is often delayed. With the introduction of non-invasive prenatal screening, the diagnostic pattern will require an updated description of the clinical and biochemical presentation of infants with Klinefelter syndrome. In the first months of life, the hypothalamic-pituitary-gonadal (HPG)-axis is transiently activated in healthy males during the so-called minipuberty. This period represents a "window of opportunity" for evaluation of the HPG-axis before puberty and without stimulation tests. Infants with Klinefelter syndrome present with a hormonal surge during the minipuberty. However, only a limited number of studies exist, and the results are contradictory. Further studies are needed to clarify whether infants with Klinefelter syndrome present with impaired testosterone production during the minipuberty. The aim of this review is to describe the clinical and biochemical characteristics of the neonate and infant with Klinefelter syndrome with special focus on the minipuberty and to update the clinical recommendations for Klinefelter syndrome during infancy.

Morbidity in Klinefelter syndrome and the effect of testosterone treatment.

Klinefelter syndrome (KS; 47,XXY) is the most common sex chromosome abnormality in males (150 per 100,000 males). The condition leads to hypergonadotropic hypogonadism and ever since the condition was described approximately 80 years ago, testosterone treatment has been the cornerstone in care for individuals with KS. However, KS is associated with an array of health-related and socioeconomic challenges and it is becoming progressively clear that proper care for boys and men with KS reaches far beyond simply supplementing with testosterone. There are no widely implemented guidelines for KS care, and studies investigating crucial aspects of testosterone treatment in individuals with KS, including both beneficial and potentially adverse effects, have only begun to emerge during the last decades. For this descriptive review, we present an overview of literature describing health-related outcomes of testosterone treatment in KS and outline the clinical applications of testosterone treatment in KS. Collectively, beneficial effects of testosterone treatment on overall health in KS are described with few apparent adverse effects. However, larger randomized studies in adult and pediatric patients are warranted to elucidate key aspects of treatment. We stress the implementation of centralized multidisciplinary clinics and the need for a dedicated international guideline to ensure optimal care of boys and men with KS.

Testicular function in boys with 47,XYY and relationship to phenotype.

An additional Y chromosome occurs in ~1 in 1,000 males, resulting in the karyotype 47,XYY. The phenotype includes tall stature, hypotonia, neuropsychiatric comorbidities, and an increased risk of infertility in adulthood. Little is known about testicular function in childhood and adolescence in 47,XYY. This cross-sectional study aimed to assess testicular function serum biomarkers, including total testosterone, inhibin B, and anti-mullerian hormone (AMH), in 82 boys with XYY (11.3 ± 3.8 years) compared with 66 male controls (11.6 ± 3.8 years). The association of testicular hormones with physical features, neuropsychological phenotype, and magnetoencephalography (MEG) was assessed with multiple linear regression models. Results indicate males with XYY have significantly lower inhibin B (median 84 pg/ml vs. 109 pg/ml, p = .004) and higher AMH (median 41 ng/ml vs. 29 ng/ml, p = .011); however, testosterone, testicular volume, and stretched penile length were not different from controls. In the exploratory analysis of relationships between hormone concentrations and phenotypic assessments, higher inhibin B concentrations were positively correlated with lower BMI and better cognitive, academic, and behavioral outcomes in the XYY group. Testosterone concentrations were positively associated with better behavioral outcomes in boys with XYY. Higher testosterone and inhibin B concentrations were also associated with shorter auditory latencies measured using magnetoencephalography (MEG) in XYY. With a few exceptions, testicular hormones were not associated with phenotypic outcomes in controls. In conclusion, there is evidence of subtle impaired testicular function in boys with XYY and a newly described relationship between measures of testicular function and some aspects of the XYY phenotype.

High prevalence of cardiometabolic risk features in adolescents with 47,XXY/Klinefelter syndrome.

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.

Automated syndrome diagnosis by three-dimensional facial imaging.

PURPOSE: Deep phenotyping is an emerging trend in precision medicine for genetic disease. The shape of the face is affected in 30-40% of known genetic syndromes. Here, we determine whether syndromes can be diagnosed from 3D images of human faces. METHODS: We analyzed variation in three-dimensional (3D) facial images of 7057 subjects: 3327 with 396 different syndromes, 727 of their relatives, and 3003 unrelated, unaffected subjects. We developed and tested machine learning and parametric approaches to automated syndrome diagnosis using 3D facial images. RESULTS: Unrelated, unaffected subjects were correctly classified with 96% accuracy. Considering both syndromic and unrelated, unaffected subjects together, balanced accuracy was 73% and mean sensitivity 49%. Excluding unrelated, unaffected subjects substantially improved both balanced accuracy (78.1%) and sensitivity (56.9%) of syndrome diagnosis. The best predictors of classification accuracy were phenotypic severity and facial distinctiveness of syndromes. Surprisingly, unaffected relatives of syndromic subjects were frequently classified as syndromic, often to the syndrome of their affected relative. CONCLUSION: Deep phenotyping by quantitative 3D facial imaging has considerable potential to facilitate syndrome diagnosis. Furthermore, 3D facial imaging of "unaffected" relatives may identify unrecognized cases or may reveal novel examples of semidominant inheritance.

Cardiometabolic health in Turner syndrome.

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.

The Turner syndrome research registry: Creating equipoise between investigators and participants.

To address knowledge gaps about Turner syndrome (TS) associated disease mechanisms, the Turner Syndrome Society of the United States created the Turner Syndrome Research Registry (TSRR), a patient-powered registry for girls and women with TS. More than 600 participants, parents or guardians completed a 33-item foundational survey that included questions about demographics, medical conditions, psychological conditions, sexuality, hormonal therapy, patient and provider knowledge about TS, and patient satisfaction. The TSRR platform is engineered to allow individuals living with rare conditions and investigators to work side-by-side. The purpose of this article is to introduce the concept, architecture, and currently available content of the TSRR, in anticipation of inviting proposals to utilize registry resources.

Profound hypokalemia associated with severe diabetic ketoacidosis.

Hypokalemia is common during the treatment of diabetic ketoacidosis (DKA); however, severe hypokalemia at presentation prior to insulin treatment is exceedingly uncommon. A previously healthy 8-yr-old female presented with new onset type 1 diabetes mellitus, severe DKA (pH = 6.98), and profound hypokalemia (serum K = 1.3 mmol/L) accompanied by cardiac dysrhythmia. Insulin therapy was delayed for 9 h to allow replenishment of potassium to safe serum levels. Meticulous intensive care management resulted in complete recovery. This case highlights the importance of measuring serum potassium levels prior to initiating insulin therapy in DKA, judicious fluid and electrolyte management, as well as delaying and/or reducing insulin infusion rates in the setting of severe hypokalemia.

High Prevalence of Obstructive Sleep-Disordered Breathing in Pediatric Patients With Turner Syndrome.

OBJECTIVE: Girls with Turner syndrome (TS) often have features that have been associated with obstructive sleep-disordered breathing (oSDB). However, little is known about oSDB in TS. Herein, we aimed to characterize oSDB in young patients with TS and identify associated risk factors. STUDY DESIGN: Retrospective cross-sectional study. SETTING: Tertiary care pediatric hospital. METHODS: We reviewed medical records for patients diagnosed with TS seen at our institution between October 1, 2007 and December 31, 2019 with the first outpatient visit before age 6 years. The prevalence of oSDB was compared to the general pediatric population with 1-sample binomial proportion tests. Clinical characteristics were compared between those diagnosed with oSDB and those without oSDB, and risk factors for oSDB were identified. RESULTS: Of 151 patients with TS, 73 (48%) were diagnosed with oSDB which is 4-fold higher than the general pediatric population (12%, P < 0.0001). In the multivariable model, adenoid, tonsillar, and inferior turbinate hypertrophy, birthweight, failure to thrive, and older age at the last clinic visit were all associated with increased odds for oSDB. CONCLUSION: Young children with TS have a high prevalence of oSDB and thus should be screened for oSDB. Polysomnography should be performed in those with associated risk factors and symptoms oSDB. Treatment of oSDB is imperative as individuals with TS are already at increased risk of behavioral problems, neurocognitive deficits, and growth impairment that may be worsened with oSDB.

Multicenter Analysis of Cardiometabolic-Related Diagnoses in Youth with Congenital Adrenal Hyperplasia: a PEDSnet study.

CONTEXT: Small cohorts of youth with congenital adrenal hyperplasia (CAH) demonstrate increased risk of obesity and poor cardiometabolic health. OBJECTIVE: To determine the odds of cardiometabolic-related diagnoses in youth with CAH compared to matched controls in a cross-sectional analysis in a large, multisite database (PEDSnet). DESIGN: Electronic health record data (2009-2019) were used to determine odds of cardiometabolic-related outcomes based on diagnosis, anthropometric and laboratory data using logistic regression among youth with CAH vs. controls. SETTING: Six PEDSnet sites. PATIENTS OR OTHER PARTICIPANTS: Youth with CAH and >1 outpatient visit in PEDSnet (n=1,647) were propensity-score matched on 8 variables to controls (n=6,588). A subset of youth with classic CAH (n=547, with glucocorticoid and mineralocorticoid prescriptions) were matched to controls (n=2,188). INTERVENTION(S): N/A. MAIN OUTCOME MEASURE(S): Odds of having cardiometabolic-related diagnoses among youth over 2 years with CAH compared to matched controls. RESULTS: Outcomes were calculated for all individuals with CAH (median age at last visit 12.9 years [7.3, 17.6]) and a subset with classic CAH (median age at last visit 11.6 years [4.7, 17.5]) compared to their matched controls. All patients with CAH had higher odds of overweight/obesity (odds ratio [95% confidence interval] 3.63 [3.24,4.07]), hypertension (3.07 [2.60,3.64]), dysglycemia (1.95 [1.35,2.82], dyslipidemia (2.28 [1.79,2.91]) and liver dysfunction (2.30 [1.91,2.76]) compared to matched controls. Patients with classic CAH had higher odds of overweight/obesity (3.21 [2.61,3.93]), hypertension (8.22 [6.71,10.08]), and liver dysfunction (2.11 [1.55,2.89]) compared to matched controls. CONCLUSIONS: Overall, youth with CAH are at increased risk of diagnoses related to worse cardiometabolic health.

Prevalence, Morbidity, and Mortality of Men With Sex Chromosome Aneuploidy in the Million Veteran Program Cohort.

Importance: The reported phenotypes of men with 47,XXY and 47,XYY syndromes include tall stature, multisystem comorbidities, and poor health-related quality of life (HRQOL). However, knowledge about these sex chromosome aneuploidy (SCA) conditions has been derived from studies in the less than 15% of patients who are clinically diagnosed and also lack diversity in age and genetic ancestry. Objectives: To determine the prevalence of clinically diagnosed and undiagnosed X or Y chromosome aneuploidy among men enrolled in the Million Veteran Program (MVP); to describe military service metrics of men with SCAs; and to compare morbidity and mortality outcomes between men with SCA with and without a clinical diagnosis vs matched controls. Design, Setting, and Participants: This cross-sectional study used a case-control recruitment design to select biological males enrolled in the MVP biobank in the US Veterans Administration health care system from 2011 to 2022. Cases were participants with 47,XXY syndrome or 47,XYY syndrome, matched 1:5 with controls based on sex, age, and genetic ancestry. Data were analyzed from January 2022 to December 2023. Exposure: Genomic identification of an additional X or Y chromosome. Main Outcomes and Measures: Outcomes of interest included prevalence of men with SCAs from genomic analysis; clinical SCA diagnosis; Charlson Comorbidity Index; rates of outpatient, inpatient, and emergency encounters per year; self-reported health outcomes; and standardized mortality ratio. Results: Of 595 612 genotyped males in the MVP, 862 had an additional X chromosome (47,XXY) and 747 had an extra Y chromosome (47,XYY), with the highest prevalence among men with East Asian (47,XXY: 10 of 7313 participants; 47,XYY: 14 of 7313 participants) and European (47,XXY: 725 of 427 143 participants; 47,XYY: 625 of 427 143 participants) ancestry. Mean (SD) age at assessment was 61 (12) years, at which point 636 veterans (74.X%) with 47,XXY and 745 veterans (99%) with 47,XYY remained undiagnosed. Individuals with 47,XXY and 47,XYY had similar military service history, all-cause standardized mortality ratio, and age of death compared with matched controls. Individuals with SCA, compared with controls, had higher Charlson Comorbidity Index scores (47,XXY: mean [SD], 4.30 [2.72] vs controls: mean [SD], 3.90 [2.47]; 47,XYY: mean [SD], 4.45 [2.90] vs controls: mean [SD], 3.82 [2.50]) and health care utilization (eg, median [IQR] outpatient encounters per year: 47,XXY, 22.6 [11.8-37.8] vs controls, 16.8 [9.4-28]; 47,XYY: 21.4 [12.4-33.8] vs controls: 17.0 [9.4-28.2]), while several measures of HRQOL were lower (eg, mean [SD] self-reported physical function: 47,XXY: 34.2 [12] vs control mean [SD] 37.8 [12.8]; 47,XYY: 36.3 [11.6] vs control 37.9 [12.8]). Men with a clinical diagnosis of 47,XXY, compared with individuals without a clinical diagnosis, had higher health care utilization (eg, median [IQR] encounters per year: 26.6 [14.9-43.2] vs 22.2 [11.3-36.0]) but lower Charlson Comorbidity Index scores (mean [SD]: 3.7 [2.7] vs 4.5 [4.1]). Conclusion and Relevance: In this case-control study of men with 47,XXY and 47,XYY syndromes, prevalence of SCA was comparable with estimates in the general population. While these men had successfully served in the military, they had higher morbidity and reported poorer HRQOL with aging. Longer longitudinal follow-up of this sample will be informative for clinical and patient-reported outcomes, the role of ancestry, and mortality statistics.

The human Y and inactive X chromosomes similarly modulate autosomal gene expression.

Somatic cells of human males and females have 45 chromosomes in common, including the "active" X chromosome. In males the 46th chromosome is a Y; in females it is an "inactive" X (Xi). Through linear modeling of autosomal gene expression in cells from individuals with zero to three Xi and zero to four Y chromosomes, we found that Xi and Y impact autosomal expression broadly and with remarkably similar effects. Studying sex chromosome structural anomalies, promoters of Xi- and Y-responsive genes, and CRISPR inhibition, we traced part of this shared effect to homologous transcription factors-ZFX and ZFY-encoded by Chr X and Y. This demonstrates sex-shared mechanisms by which Xi and Y modulate autosomal expression. Combined with earlier analyses of sex-linked gene expression, our studies show that 21% of all genes expressed in lymphoblastoid cells or fibroblasts change expression significantly in response to Xi or Y chromosomes.