Unusual sex chromosomal DSD in a domestic Shorthair cat with a 37,X/38,XY mosaic karyotype.

BACKGROUND: Sex chromosome abnormalities associated with disorders of sexual development (DSD) are rarely described in cats, mainly due to the lack of chromossome studies that precisely reveal the condition. Genetic approaches are therefore required in order to detect sex chromossomes abnormalities as variations in the number and structure of chromosomes, or the presence of a second cell line as mosaicim or chimerism. CASE PRESENTATION: A male Shorthair cryptorchid cat was presented with clinical signs of anorexia, tenesmus and hyperthermia. Ultrasonography revealed a fluid-filled structure, with approximately 1 cm in diameter, adjacent to the descending colon. Computed tomography evidenced a tubular structure, ventral to the descending colon and caudal to the bladder, which extended cranially, through two branches. Histopathological evaluation confirmed the presence of two atrophic uterine horns and one hypoplastic testicle with epididymis at the end of one of the uterine horns. The end of the other uterine horn was attached to a structure composed by a mass of adipocytes. Cytogenetic analysis revealed a mosaic 37,X/38,XY karyotype. The two cell lines were found in 15% and 85% of the lymphocytes, respectively. Genetic analysis confirmed the presence of SRY and ZFY genes in blood and hair bulbs, and revealed a marked reduction in SRY expression in the testicle. Additionally, this case presented exceptionally rare features, such as a Leydig' cell tumour and a chronic endometritis in both uterine horns. CONCLUSIONS: Complete imaging workup, cytogenetic analysis and SRY gene expression should be systematically realized, in order to properly classify disorders of sexual development (DSD) in cats.

A multi-center analysis of individuals with a 47,XXY/46,XX karyotype.

INTRODUCTION: Klinefelter syndrome (KS), a sex chromosome aneuploidy, is associated with a 47,XXY chromosomal complement and is diagnosed in ∼1:600 live male births. Individuals with a 46,XX cell line in addition to 47,XXY are less common with a limited number of published case reports. METHODOLOGY: To better understand the implications of a 47,XXY/46,XX karyotype, we conducted a retrospective, multi-center analysis of the cytogenetic findings and associated clinical records of 34 patients diagnosed with this SCA across 14 institutions. RESULTS: Presence of the XX cell line ranged from 5-98% in patient specimens. Phenotypes also exhibited significant heterogeneity with some reporting a single reason for referral and others presenting with a constellation of symptoms, including ambiguous genitalia and ovotestes. Ovotestes were present in 12% of individuals in this cohort, who had a significantly higher percentage of XX cells. Notably, two patients were assigned female sex at birth DISCUSSION: These findings highlight the variability of the clinical phenotypes associated with this SCA as well as the challenges of clinical management for this population. Karyotype or FISH analysis, which offer single-cell resolution, rather than chromosomal microarray or molecular testing, is the ideal test strategy in these instances as mosaicism can occur at low levels.

Gilles de la Tourette syndrome as a rare co-morbidity of Klinefelter syndrome.

BACKGROUND: Klinefelter syndrome (47, XXY) is the most common sex chromosome aneuploidy. In addition to male hypergonadotropic hypogonadism, a wide range of neurodevelopmental disorders, anxiety and affective symptoms have been reported in a substantial proportion of cases. CASE DESCRIPTION: We document the rare case of a 43-year-old man diagnosed with Klinefelter syndrome and co-morbid Gilles de la Tourette syndrome. He presented with multiple motor and vocal tics since adolescence, as well as anxiety and affective symptoms as his main tic-exacerbating factors. Tic severity was rated as marked (Yale Global Tic Severity Scale score of 78/100), and recommendations for the treatment of both tics and psychiatric co-morbidities were formulated. DISCUSSION: Neurodevelopmental tics in the context of Klinefelter syndrome have been previously documented in three cases only. Gilles de la Tourette syndrome is 3-4 times more common in males than females and its etiological factors include multiple genetic components (genetic heterogeneity). Our case report widens the spectrum of neurodevelopmental disorders observed in the context of Klinefelter syndrome and contributes to genetic research on the role of the X chromosome in the pathophysiology of tic disorders.

Postural tremor and sexual chromosome aneuploidies: case report and review of literature.

PURPOSE: To examine the link between tremor and sex chromosome abnormalities, emphasizing the necessity of comprehensive physical examination. CASE DESCRIPTION: An 18-year-old man exhibited an isolated action tremor in both hands. Despite having no familial history of tremors and no identifiable secondary causes, his tall stature and learning difficulties suggested a genetic origin. His karyotype confirmed the diagnosis of Jacob's syndrome (XYY syndrome). Therapies with primidone and propranolol were ineffective for his tremor. CONCLUSIONS: Tremor can be caused by various conditions, and aneuploidies might often be overlooked as a cause. They should be considered in young patients with concrete phenotypes and negative familiar history of tremors. Karyotyping is a cost-effective diagnostic tool crucial for genetic counselling. Common treatments for tremors often yield unsatisfactory results in these cases.

From Klinefelter Syndrome to High Grade Aneuploidies: Expanding the Gene-dosage Effect of Supernumerary X Chromosomes.

OBJECTIVE: High-grade aneuploidies of X and Y sex chromosomes (HGAs) are exceedingly rare and complex conditions. We aimed to investigate the effect of supernumerary X chromosomes (extra-Xs) on the clinical, hormonal, metabolic, and echocardiographic features of patients with HGAs. DESIGN AND METHODS: In a cross-sectional study, we compared 23 subjects with HGAs and 46 age-matched subjects with 47,XXY Klinefelter syndrome (KS), according to the number of extra-Xs: two (47,XXY and 48,XXYY), three (48,XXXY and 49,XXXYY), or four supernumerary Xs (49,XXXXY). A second cohort consisting of 46 pubertal stage-matched KS subjects was employed for validation. Clinical, hormonal, metabolic and ultrasonographic parameters were collected and analyzed. RESULTS: The increase in the number of extra-Xs was associated with a progressive adverse effect on height, pubertal development, testicular volume and function, adrenal steroidogenesis, and thyroid function. A progressive linear increase in ACTH and a decrease in cortisol/ACTH ratios were found. Weight and body mass index, Sertoli cell function, lipid profile, and glucose tolerance post-oral glucose tolerance test were all worse in the HGA cohort compared to KS. Cardiac evaluation revealed a linear association with reduced left and right end-diastolic diameters and reduced ejection fraction. CONCLUSION: The increase in the number of extra-Xs is associated with a "dose-dependent" progressive impairment in steroid producing glands, thyroid function, cardiac structure, and performance.

Case Report: A new case of YARS1-associated autosomal recessive disorder with compound heterozygous and concurrent 47, XXY.

Aminoacyl-tRNA synthetases play a pivotal role in catalyzing the precise coupling of amino acids with their corresponding tRNAs. Among them, Tyrosyl tRNA synthetase, encoded by the YARS1 gene, facilitates the aminoacylation of tyrosine to its designated tRNA. Heterozygous variants in the YARS1 gene have been linked to autosomal dominant Charcot-Marie-Tooth type C, while recent findings have unveiled biallelic YARS1 variants leading to an autosomal recessive multisystemic disorder in several cases. In this report, we present a novel case characterized by dysmorphic facies, and multisystemic symptoms, prominently encompassing neurological issues and a microarray conducted shortly after birth revealed 47, XXY. Utilizing whole exome sequencing, we uncovered a paternally inherited likely pathogenic variant (c.1099C > T, p.Arg367Trp), previously reported, coinciding with the father's history of hearing loss and neurological symptoms. Additionally, a maternally inherited variant of uncertain significance (c.782T > G, p.Leu261Arg), previously unreported, was identified within the YARS1 gene. The observed phenotypes and the presence of compound heterozygous results align with the diagnosis of an autosomal recessive disorder associated with YARS1. Through our cases, the boundaries of this emerging clinical entity are broadened. This instance underscores the significance of comprehensive genetic testing in patients exhibiting intricate phenotypes.

Subjective versus objective sleep in men with Klinefelter syndrome.

OBJECTIVES: To investigate sleep among men with Klinefelter syndrome (KS). METHOD: We compared the sleep domains latency, disturbance, and efficiency in 30 men with KS (M age = 36.7 years, SD = 10.6) to 21 age-matched non-KS controls (M age = 36.8 years, SD = 14.4). Actigraphs were used to objectively measure sleep across 7 days and nights. Participants also completed a sleep diary over the same period, and the Pittsburgh Sleep Quality Index (PSQI). RESULTS: The mean correlation between the objective and subjective sleep measures was lower for the KS sample (M r = .15) than for controls (M r = .34). Sleep disturbance was significantly larger in the KS sample, as measured by actigraphy (p = .022, d = 0.71) and the PSQI (p = .037, d = 0.61). In regression models predicting sleep domains from KS status, age, educational level, vocational status, IQ, and mental health, KS status was not a significant predictor. Higher age was associated with more actigraphy-measured sleep disturbance. Higher educational level and being employed were associated with better sleep efficiency. CONCLUSIONS: Sleep disturbance may be a particular problem for men with KS and should be measured with complimentary methods.

Clinical characterization of epilepsy in children with chromosomal aberration 47, XXY.

OBJECTIVE: The phenotype of the chromosomal aberration 47, XXY exhibits considerable heterogenicity. In addition, epilepsy is extremely uncommon in individuals with this chromosomal disorder. As a result, the clinical characteristics of epilepsy in these patients remain poorly understood. METHODS: Clinical data and the evolution of epilepsy in a boy diagnosed with chromosomal aberration 47, XXY were collected and analyzed. Furthermore, a systematic literature review was conducted to examine the relationship between chromosomal aberration 47, XXY and epilepsy in children. RESULTS: We identified a novel phenotype associated with the chromosomal anomaly 47, XXY in a 2-year-2-month-old boy who presented with self-limited epilepsy with autonomic seizures at onset, followed by developmental and/or epileptic encephalopathy with spike-wave activation in sleep (D/EE-SWAS), which was responsive to corticosteroid treatment. Including the present case, we analyzed 21 cases of children diagnosed with epilepsy due to the presence of the 47, XXY chromosomal anomaly. The most common types of epilepsy were focal combined generalized epilepsy (n = 9), epileptic spasms (n = 6), and generalized epilepsy (n = 4). There were six cases of infantile epileptic spasm syndrome (IESS) (n = 5) and developmental and epileptic encephalopathy (n = 1), one case of Lennox-Gastaut syndrome, and one case of D/EE-SWAS. Apart from corticosteroids in IESS, 15 antiseizure medications (ASMs) were prescribed to eight children in this cohort, with valproate (n = 5) being the most frequently used. CONCLUSIONS: The epilepsy types and syndromes associated with the chromosomal anomaly 47, XXY demonstrated considerable heterogeneity. Among the observed phenotypes, IESS and focal epilepsy, which displayed partial responsiveness to multiple ASMs, were the most prevalent.

The Effect of Hormonal Therapy on the Behavioral Outcomes in 47,XXY (Klinefelter Syndrome) between 7 and 12 Years of Age.

47,XXY, also known as Klinefelter syndrome, is the most commonly occurring sex chromosomal aneuploidy (SCA). Hormonal replacement therapy (HRT) has been associated with improved neurodevelopmental capabilities in boys with 47,XXY, although studies investigating HRT's possible positive effect on behavioral outcomes are scarce. This study explores the association between behavioral outcomes and HRT in boys ages 7-12. Patients were divided into 4 groups based on HRT status: untreated, early hormonal treatment (EHT), hormonal booster therapy (HBT), and both EHT and HBT. Analysis of Variance (ANOVA) and Kruskal-Wallis tests were conducted to determine group differences on the Child Behavior Checklist (CBCL) and the Behavior Rating Inventory of Executive Function (BRIEF). The treated groups were found to have better scores in emotional control, initiative, organization of materials, behavioral rating index, metacognition index, and global executive composite than the untreated group on the BRIEF. On the CBCL, the treated groups presented better scores for somatic complaints, social problems, thought problems, attention problems, aggressive behavior, internalizing problems, total problems, affective problems, somatic problems, ADHD problems, oppositional defiant problems, and sluggish problems in comparison to the untreated group. These results offer evidence that HRT, specifically the combination of both EHT and HBT, may be successful in mitigating some undesirable behavioral outcomes. Further research is necessary to determine the efficacy of the combination of EHT and HBT regarding dosage, specific ages, and long-term benefits.

Sex chromosome aneuploidies and fertility: 47,XXY, 47,XYY, 47,XXX and 45,X/47,XXX.

The overall incidence of sex chromosome aneuploidies is approximately 1 per 500 live-born infants, but far more common at conception. I shall review the fertility aspects of the sex chromosome trisomies, XXY, XYY, and XXX, with special reference to the karyotype 45,X/47,XXX. Each has a 'specific' (but variable) phenotype but may be modified by mosaicism. Although the alterations in the hypothalamic-pituitary-gonadal axis are important (and discussed), the emphasis here is on potential fertility and if one might predict that at various epochs within an individual's life span: fetal, 'mini'-puberty, childhood, puberty, and adulthood. The reproductive axis is often affected in females with the 47,XXX karyotype with diminished ovarian reserve and accelerated loss of ovarian function. Fewer than 5% of females with Turner syndrome have the 45,X/47,XXX karyotype. They have taller stature and less severe fertility issues compared to females with the 45,X or other forms of Turner syndrome mosaicism. For the 47,XXY karyotype, non-obstructive azoospermia is almost universal with sperm retrieval by micro-testicular sperm extraction possible in slightly fewer than half of the men. Men with the 47,XYY karyotype have normal to large testes and much less testicular dysfunction than those with the 47,XXY karyotype. They do have a slight increase in infertility compared to the reference population but not nearly as severe as those with the 47,XXY karyotype. Assisted reproductive technology, especially micro-testicular sperm extraction, has an important role, especially for those with 47,XXY; however, more recent data show promising techniques for the in vitro maturation of spermatogonial stem cells and 3D organoids in culture. Assisted reproductive technology is more complex for the female, but vitrification of oocytes has shown promising advances.

Increased prevalence of nodular thyroid disease in patients with Klinefelter syndrome.

PURPOSE: Thyroid dysfunction in patients with Klinefelter syndrome (KS) remains an unresolved issue. Although low free thyroxine (FT4) levels within the normal range and normal thyroid stimulating hormone (TSH) levels have been reported, there is currently no data on nodular thyroid disease in this population. This study aims to evaluate the results of thyroid ultrasound (US) examinations in KS patients compared with healthy controls. METHODS: A cohort of 122 KS and 85 age-matched healthy male controls underwent thyroid US screening and thyroid hormone analysis. According to US risk-stratification systems, nodules ≥1 cm were examined by fine needle aspiration (FNA). RESULTS: Thyroid US detected nodular thyroid disease in 31% of KS compared to 13% of controls. No statistical differences in the maximum diameter of the largest nodules and in moderate and highly suspicious nodules were found between patients and the control group. Six KS patients and two controls with nodules underwent FNA and were confirmed as cytologically benign. In line with published data, FT4 levels were found significantly near the lower limit of the normal range compared to controls, with no differences in TSH values between the two groups. Hashimoto's thyroiditis was diagnosed in 9% of patients with KS. CONCLUSIONS: We observed a significantly higher prevalence of nodular thyroid disease in KS compared to the control group. The increase in nodular thyroid disease is likely linked to low levels of FT4, inappropriate TSH secretion, and/or genetic instability.

Reading skills in males with 47,XXY: Risk factors and the influence of hormonal replacement therapy (HRT).

PURPOSE: 47,XXY is often associated with reduced expressive language and literacy skills. This retrospective cross-sectional study investigated risk factors (hormone replacement deficiency, pre-or postnatal diagnosis, and history of family learning disabilities [FLDs]) associated with reading skills in 152 males. METHODS: We analyzed Woodcock Reading Mastery Test scores among 7 prenatally diagnosed male hormone replacement therapy (HRT) groups using analysis of variance along with analysis of variance and 2 postnatally diagnosed male HRT groups (No-T and T) using t tests. Treated prenatally diagnosed males with FLDs were compared with an identically treated prenatal HRT group with no history of FLDs using a t test. RESULTS: In prenatally diagnosed males, significant treatment differences were observed on several reading scales (eg, total reading: χ2 = 17.96, P = .006), in which the highest modality HRT group (mean [M] =119.87) outperformed the untreated group (M = 99.88). In the postnatal analysis, we observed a significant effect of treatment on basic skills (P = .01). Despite equal HRT status, males with FLDs (M = 105.79) exhibited reduced total reading skills compared with those in the no FLD group (P = 0.0006). CONCLUSION: Our findings in this pilot study reveal that the most optimal reading trajectory is associated with a prenatal diagnosis, absence of FLDs, and the highest modality HRT.

Incidence of sex chromosome aneuploidy in a prenatal population: 27-year longitudinal study in Northern Italy.

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.

Cardiorespiratory fitness in adolescents and young adults with Klinefelter syndrome - a pilot study.

Background: Klinefelter syndrome (KS) may be associated with a wide spectrum of phenotypic changes including endocrine, metabolic, cognitive, psychiatric and cardiorespiratory pathologies in adults. However, in adolescence the clinical phenotype of KS is not well described, especially regarding physical fitness. The present study reports on cardiorespiratory function in adolescents and young adults with KS. Methods: Adolescents and young adults with KS were recruited in a cross-sectional pilot study. Biochemical parameters of fitness including hormonal status, a body impedance analysis, the grip strength, the amount of physical activity at home for 5 days via trackbands and anamnestic parameters were assessed. In addition, participants underwent an incremental symptom-limited cardiopulmonary exercise test (CPET) on a bicycle ergometer. Results: Nineteen participants with KS aged 15.90 ± 4.12 years (range: 9.00 - 25.00) participated in the study. Pubertal status was Tanner 1 (n = 2), Tanner 2 - 4 (n = 7) and Tanner 5 (n = 10). Seven participants received testosterone replacement therapy. Mean BMI z-score was 0.45 ± 1.36 and mean fat mass was 22.93% ± 9.09. Grip strength was age-appropriate or above normal. 18 participants underwent CPET with subnormal results for maximum heart rate (z-score -2.84 ± 2.04); maximum workload (Wattmax; z score -1.28 ± 1.15) and maximum oxygen uptake per minute (z- score -2.25 ± 2.46). Eight participants (42.1%) met the criteria for chronotropic insufficiency (CI). Data from track-bands showed sedentary behavior for 81.15% ± 6.72 of the wear time. Conclusion: A substantial impairment of cardiopulmonary function can be detected in this group of boys to young adults with KS, including chronotropic insufficiency in 40%. The track-band data suggest a predominantly sedentary lifestyle, despite normal muscular strength as assessed via grip strength. Future studies need to investigate the cardiorespiratory system and its adaption to physical stress in a larger cohort and in more detail. It is feasible that the observed impairments contribute to the avoidance of sports in individuals with KS and may contribute to the development of obesity and the unfavorable metabolic phenotype.

A Morphing Point-to-Point Displacement Control Based on Long Short-Term Memory for a Coplanar XXY Stage.

In this study, visual recognition with a charge-coupled device (CCD) image feedback control system was used to record the movement of a coplanar XXY stage. The position of the stage is fedback through the image positioning method, and the positioning compensation of the stage is performed by the image compensation control parameter. The image resolution was constrained and resulted in an average positioning error of the optimized control parameter of 6.712 µm, with the root mean square error being 2.802 µm, and the settling time being approximately 7 s. The merit of a long short-term memory (LSTM) deep learning model is that it can identify long-term dependencies and sequential state data to determine the next control signal. As for improving the positioning performance, LSTM was used to develop a training model for stage motion with an additional dial indicator with an accuracy of 1 µm being used to record the XXY position information. After removing the assisting dial indicator, a new LSTM-based XXY feedback control system was subsequently constructed to reduce the positioning error. In other words, the morphing control signals are dependent not only on time, but also on the iterations of the LSTM learning process. Point-to-point commanded forward, backward and repeated back-and-forth repetitive motions were conducted. Experimental results revealed that the average positioning error achieved after using the LSTM model was 2.085 µm, with the root mean square error being 2.681 µm, and a settling time of 2.02 s. With the assistance of LSTM, the stage exhibited a higher control accuracy and less settling time than did the CCD imaging system according to three positioning indices.

Klinefelter syndrome in primary care: A case and review.

Reviewed here is a case of Klinefelter Syndrome (KS) diagnosed by a primary care physician after recognition of key features of KS, confirmed by karyotype, along with a discussion of factors associated with this patient's diagnosis and care. Recognition of the key features of this syndrome is important in order to provide proper screening, risk mitigation and treatment to these patients.

Rare Double Aneuploidy (Down-Klinefelter Syndrome): A Case Report.

Double aneuploidies, such as Down syndrome and sex chromosome aneuploidies, are relatively rare. One rare form of double aneuploidy, Down-Klinefelter syndrome, is described here. The phenotypic characteristics of a three-year-old child showed the presence of features typical of Down syndrome. He had a global developmental delay, small testes, and diabetes mellitus by 18 months of age. Regardless of the presenting clinical features, karyotyping should be performed in all patients with suspected Down syndrome. In Down-Klinefelter syndrome, anticipatory phenotype goes beyond the sum of individual syndromic characteristics.

An Adolescent Boy with Klinefelter Syndrome and 47,XXY/46,XX Mosaicism: Case Report and Review of Literature.

Klinefelter syndrome is the most commonly reported sex chromosome abnormality. It is heavily underdiagnosed due to the substantial variability of clinical presentations but is generally characterized by small, firm testes, hypergonadotropic hypogonadism, and the absence of spermatogenesis. Most patients with Klinefelter syndrome have a 47,XXY genotype. If they present with mosaicism, two different cell lines are usually identified, an aneuploid 47,XXY cell line and a normal male 46,XY cell line. There are very few cases of 47,XXY mosaicism with the additional female cell line 46,XX described in the literature. We report a case of an adolescent with the male phenotype and a rare variant mosaic 47,XXY/46,XX karyotype who presented with painless bilateral gynaecomastia. 47,XXY and 46,XX mosaic cell lines were identified with GTG-banding and further characterized using fluorescent in situ hybridization. We summarized the available clinical presentations of reported male patients with 47,XXY/46,XX mosaicism. To improve the clinical management and quality of life in individuals with rare and cryptic genomic imbalances, the genetic diagnosis would need to be extended to atypical cases.

Clinical features and prevalence of Klinefelter syndrome in transgender individuals: A systematic review.

OBJECTIVE: Previous studies have suggested a higher prevalence of Klinefelter syndrome amongst transgender individuals. We undertook a systematic review to determine the prevalence of Klinefelter syndrome amongst transgender individuals presumed male at birth and summarize the clinical features and potential treatment implications for individuals with Klinefelter syndrome commencing gender-affirming hormone therapy. DESIGN: Using preferred reporting items for systematic review and meta-analysis guidelines, we searched EMBASE, MEDLINE and the Cochrane Central Register of Controlled Trials (CENTRAL) up to 31 December 2021. All studies reporting on the prevalence or clinical features of transgender individuals with Klinefelter syndrome were included. This study is registered with the International Prospective Register of Systematic Reviews, number CRD42021227916. RESULTS: Our search strategy retrieved 11 cohort studies comprising 1376 transgender individuals. In all, 14 of 1376 (1.02%) individuals were diagnosed with Klinefelter syndrome. Based on the seven studies in which karyotype was undertaken in all individuals, the prevalence is 9/1013 (0.88%; 95% CI, 0.41%-1.68%). Case reports highlight unique treatment considerations in this population, including azoospermia, venous thromboembolism, and monitoring of breast cancer and bone health. CONCLUSIONS: Compared to the general population, observational studies document a higher prevalence of Klinefelter syndrome amongst transgender individuals, though underdiagnosis in the general population limits conclusions. Routine karyotype in transgender people initiating gender-affirming hormone therapy is not supported unless clinical features of Klinefelter syndrome, such as small testicular volume, or hypergonadotropic hypogonadism are present. Transgender individuals with Klinefelter syndrome need to manage a unique risk profile if they desire feminizing gender-affirming hormone therapy.

A longitudinal perspective of hormone replacement therapies (HRTs) on neuromotor capabilities in males with 47,XXY (Klinefelter syndrome).

PURPOSE: The purpose of this study was to delineate the effects of variable hormone replacement therapies on neuromotor function in a large cohort of males with 47,XXY from birth to adulthood. METHODS: A total of 270 participants aged 16 days to 17 years 11 months prenatally diagnosed with 47,XXY were assessed by their pediatric endocrinologist and were administered hormone replacement therapies accordingly. Infants and school-aged children with 47,XXY were administered neuromotor assessments during routine neurodevelopmental evaluations. For statistical analysis, participants were segregated on the basis of treatment status. Two-tailed t tests, 1-way analysis of variance, and post hoc analysis determined significant group differences on each assessment. RESULTS: In infants, the early hormonal treatment (EHT) group performed significantly better than the untreated group on fine motor and motor composite domains. In school-aged children, we observed significantly improved scores on fine motor control, coordination, agility, and strength domains among males treated with EHT (or any combination thereof) compared with those who did not receive early treatment. CONCLUSION: The highest treated combination group was associated with the highest neuromotor function, although the EHT group also often performed better than the other groups. This suggests EHT may be essential in promoting long-term optimal neuromotor outcome in males with an additional X.