Klinefelter′S Syndrome in a Western Lowland Gorilla ( Gorilla gorilla gorilla ) and Its Management

The genetic origin of Klinefelter syndrome and its effect on spermatogenesis

Systemic Lupus Erythematosus and Klinefelter Syndrome

1. Carole Samango-Sprouse, EdD*,†,‡ 2. Sophia Q. Song, BA‡ 3. Angela E. Lin, MD§ 4. Cynthia M. Powell, MD¶ 5. Andrea L. Gropman, MD*,** 1. *George Washington University, Washington, DC 2. †Florida International University, Miami, FL 3. ‡Department of Research, The Focus Foundation, Davidsonville, MD 4. §Massachusetts General Hospital for Children, Boston, MA 5. ¶University of North Carolina at Chapel Hill, Chapel Hill, NC 6. **Children’s National Medical Center, Washington, DC Sex chromosome aneuploidy (SCA) syndromes refer to disorders with an abnormality of sex chromosome number. The most common are Klinefelter syndrome (KS), resulting from the gain of an X chromosome in males, and Turner syndrome (TS), reflecting the loss of an X chromosome or the presence of a structurally different X chromosome in females. Whereas most patients with KS have nonmosaic 47,XXY, only 40% of women with TS have 45,X; the remainder have a variety of mosaicisms. The syndromes also contrast in that males with KS are characteristically tall, whereas females with TS are typically short unless they receive hormonal treatment. Despite efforts to increase awareness, KS and TS are often underdiagnosed, leading to delayed care. Only 25% of men with KS are ever diagnosed, with fewer than 10% detected prenatally, and with a median age of 27 years for those identified later in life. For TS, the median age at diagnosis is 6.6 years. Although not exclusively, optimal neurocognitive outcomes depend on the timing of diagnosis and access to early targeted treatment, so fortunately the recent development of noninvasive prenatal screening is increasing the early identification of these disorders dramatically. Pediatricians should be aware of signs that allow for early detection, and the importance of prompt referral for testing and therapy. KS occurs in 1 in 660 live births, representing the most common SCA. Affected males have androgen deficiency, which affects endocrine, central nervous system, and neurodevelopmental function. Characteristics include increased height, clinodactyly of the fifth finger, pes planus, and hypogonadism manifesting as …

Case report Klinefelter syndrome and multiple sclerosis as the cause of psychosis

Klinefelter syndrome (KS) is the most common sex chromosomal aneuploidy in males (47,XXY karyotype in 80–90% of cases), primarily characterized by hypergonadotropic hypogonadism and infertility. It encompasses a broad phenotypic spectrum, leading to variability in neurocognitive and psychosocial outcomes among affected individuals. Despite the recognized correlation between KS and various neuropsychiatric conditions, studies investigating potential sleep disorders, particularly in pediatric subjects, are lacking. This study aimed to investigate the presence of sleep-related behaviors potentially suggestive of a sleep disorder in a cohort of pediatric patients with KS, in comparison with a group of healthy male age-matched controls. During the period from January to December 2023, a validated sleep questionnaire (Sleep Disturbance Scale for Children: SDSC) was administered to the primary caregivers of 80 children with KS: 40 of preschool age (3–5 years) and 40 of school age (6–16 years). Data were compared with a control group of 180 healthy age-matched male children: 90 of preschool age (3–5 years) and 90 of school age (6–16 years). Among preschoolers, the proportion of subjects with pathological non-restorative sleep T-scores was significantly higher in the KS group compared to controls (p = 0.03). In both KS and control groups, school-aged subjects had higher questionnaire scores compared to preschoolers. The school age KS group had significantly higher mean total T-scores and mean T-scores for disorders of initiating and maintaining sleep (DIMS), disorders of arousal (DA), and disorders of excessive somnolence (DOES) compared to controls (p < 0.01 for all). The KS group also showed significantly higher percentages of children with clinically relevant T-scores for DIMS, DA, DOES, sleep hyperhidrosis, and total T-scores.Conclusion: Our study indicates that sleep disorders are more prevalent in children with KS than in the general population, especially in the school age group. Screening for sleep issues in the clinical setting using tools like the SDSC is warranted, and should start from age 6 for children with KS. Further research is needed to better understand the origins of these disturbances, the role of comorbidities, and their long-term effects to improve diagnosis and treatment strategies for these patients.What is Known:• Neurocognitive and psychosocial disorders can be observed in individuals with KS.• Sleep disorders may be associated with various neuropsychiatric conditions; however, they have not been sufficiently explored in individuals with KS, particularly in pediatric populations.What is New:• Sleep-related problems are more common in children with KS compared to the general population, especially in the school age group with regard to DIMS, DA, and DOES factors.• Starting from 6 years of age, the SDSC might be a promising early diagnostic tool for sleep disorders in children with KS.

Klinefelter syndrome is the most frequent chromosomal aneuploidy with a prevalence of 1 in 700. Klinefelter syndrome has been widely associated with cognitive impairment and language problems. No previous studies have systematically investigated the association of Klinefelter syndrome with psychiatric disorders in children and adolescents. To our knowledge, the only data available are from psychiatric inventories of adults with Klinefelter syndrome. To explore the extent of psychiatric morbidity in children with Klinefelter syndrome. Fifty-one subjects with Klinefelter syndrome aged 6 to 19 years were included through the Dutch Klinefelter association and 2 university medical centers. The sample was screened by using structured and standardized assessment procedures covering the full range of psychiatric problems and disorders. In addition, all boys were formally evaluated for the presence of a language disorder. RESULTS. A wide range of classifications could be applied, with language disorder (65% [33 of 51]) as the most prevalent disorder, followed by attention-deficit disorders (63% [32 of 51]) and autism spectrum disorder (27% [14 of 51]). Behavioral impairment was most evident among cases classified as autism spectrum disorder and psychotic disorder (12% [6 of 51]). Children with Klinefelter syndrome seem to be at risk for problems in social and language development, as well as for problems in regulation of emotion and behavior. This is reflected in the broad spectrum of psychiatric classifications applicable in the present selected sample. Health care professionals should be aware of an increased a priori possibility of psychiatric problems when confronted with a child with Klinefelter syndrome.

Klinefelter syndrome (KS)(47,XXY and variants, KS) is the most common sex chromosome disorder in humans. However, little is known about the onset and progression of puberty in patients with KS. In this study, we describe the onset and progression of puberty in a large series of boys with KS in a single tertiary centre. Retrospective data (Tanner stages, testicular length, testosterone supplementation, levels of luteinizing hormone [LH] and testosterone) before possible testosterone treatment on 72 KS patients with 47,XXY karyotype were reviewed, and G (n = 59 patients) and P (n = 56 patients) stages were plotted on puberty nomograms. One boy had a delayed onset of puberty, as he was at the G1 stage at the age of 13.8 years (-2.2 SDs). No observations of delay were made of boys at Stage G2. The progression of G stages was within normal limits in the majority of patients; only few boys were late at G3 (4.1%; 1 out of 24) and G4 (7.4%; 2 out of 27). Testosterone supplementation was started at the average age of 15.5 years to 35 boys (47%), 2 of whom were over 18 years old. LH level was on average 18.2 IU/L (SD: 6.3 IU/L) and testosterone 9.1 nmol/L (SD: 3.1 nmol/L) when testosterone supplementation was started. Our results suggest that puberty starts within the normal age limits in boys with KS, and testosterone supplementation is not needed for the initial pubertal progression in the majority of patients.

Objectives: Klinefelter syndrome (KS) is one of the most common sex-chromosome disorders as it affects up to 1 in every 600-1000 newborn males. Men with KS carry one extra X chromosome and they usually present a 47,XXY karyotype, but less frequent variants have also been reported in literature. KS typical symptoms include tall stature, gynecomastia, broad hips, hypogonadism and absent spermatogenesis. The syndrome is also related to a wide range of cognitive deficits, among which language-based learning disabilities and verbal cognition impairment are frequently diagnosed. The present study was carried out to investigate the role of mitochondrial subunits in KS, since the molecular mechanisms underlying KS pathogenesis are not fully understood.Methods: The study was performed by the next generation sequencing analysis and qRT-PCR assay.Results: We were able to identify a significant down-expression of mitochondrial encoded NADH: ubiquinone oxidoreductase core subunit 6 (MT-ND6) in men with KS.Conclusion: It is known that defects of the mtDNA encoding mitochondrial subunits are responsible for the malfunction of Complex I, which will eventually lead to the Complex I deficiency, the most common respiratory chain defect in human disorders. Since it has been shown that decreased Complex I protein levels could induce apoptosis, wehypothesizethat the above-mentioned MT-ND6 down-expression contributes to the wide range of phenotypes observed in men with KS.

To summarize recent important studies on neuropsychology and epidemiology of Klinefelter syndrome. PubMed was searched for 'Klinefelter', 'Klinefelter's' and 'XXY' in titles and abstracts. Relevant studies were obtained and reviewed, as well as other articles selected by the authors. Klinefelter syndrome is the most common sex-chromosome disorder in humans, affecting one in 660 men. The key findings in Klinefelter syndrome are small testes, hypergonadotropic hypogonadism and cognitive impairment. Klinefelter syndrome scores significantly below education matched controls on a range of cognitive tests with verbal skills displaying the largest effects. Boys with Klinefelter syndrome are often in the need of speech therapy and many suffer from learning disability and may benefit from special education. New studies are elucidating aspects of cognitive functioning and suggesting that neuropsychological treatment may be of value. The socioeconomic status and educational level of Klinefelter syndrome is severely affected with many struggling to achieve any or only shorter education, resulting in low-income levels and early retirement. In addition, few become fathers and fewer live with a partner compared with controls. Medical treatment is mainly testosterone replacement therapy in order to alleviate acute and long-term consequences of hypogonadism, as well as, treating or preventing the frequent comorbidity. The neurocognitive phenotype of Klinefelter syndrome is being unraveled and the need for psychological and cognitive treatment in many cases is evident. The neurocognitive deficits no doubt influence the socioeconomic status of many Klinefelter syndrome patients, which is clearly inferior to age-matched controls.

Executive dysfunction is a well-recognized component of the cognitive phenotype of Klinefelter syndrome (KS), yet the neural basis of KS-associated cognitive weaknesses, and their association with testicular failure is unknown. We investigated executive function, brain activation, and pubertal development in adolescents with and without KS. Forty-three adolescents with KS (mean age 12.3 ± 2.3 years) and 41 typically developing boys (mean age 11.9 ± 1.8 years) underwent pubertal evaluation, behavioral assessment, and completed functional magnetic resonance imaging (fMRI) as they performed an executive function task, the go/no-go task. Group differences in activation were examined. Associations among activation, executive function, and pubertal development measures were tested in secondary analyses. Boys with KS exhibited reduced executive function, as well as lower activation in brain regions subserving executive function, including the inferior frontal gyrus, anterior insula, dorsal anterior cingulate cortex, and caudate nucleus. Secondary analyses indicated that the magnitude of activation differences in boys with KS was associated with severity of pubertal developmental delay, as indexed by lower testosterone (t(36) = 2.285; P = .028) and lower testes volume (t(36) = 2.238; P = .031). Greater parent-reported attention difficulties were additionally associated with lower testicular volume (t(36) = -2.028; P = .050). These findings indicate a neural basis for executive dysfunction in KS and suggest alterations in pubertal development may contribute to increased severity of this cognitive weakness. Future studies that examine whether these patterns change with testosterone replacement therapy are warranted.

Knowledge about Klinefelter syndrome (KS) has increased substantially since its first description almost 80years ago. A variety of treatment options concerning the spectrum of symptoms associated with KS exists, also regarding aspects beyond testicular dysfunction. Nevertheless, the diagnostic rate is still low in relation to prevalence and no international guidelines are available for KS. To create the first European Academy of Andrology (EAA) guidelines on KS. An expert group of academicians appointed by the EAA generated a consensus guideline according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. Clinical features are highly variable among patients with KS, although common characteristics are severely attenuated spermatogenesis and Leydig cell impairment, resulting in azoospermia and hypergonadotropic hypogonadism. In addition, various manifestations of neurocognitive and psychosocial phenotypes have been described as well as an increased prevalence of adverse cardiovascular, metabolic and bone-related conditions which might explain the increased morbidity/mortality in KS. Moreover, compared to the general male population, a higher prevalence of dental, coagulation and autoimmune disorders is likely to exist in patients with KS. Both genetic and epigenetic effects due to the supernumerary X chromosome as well as testosterone deficiency contribute to this pathological pattern. The majority of patients with KS is diagnosed during adulthood, but symptoms can already become obvious during infancy, childhood or adolescence. The paediatric and juvenile patients with KS require specific attention regarding their development and fertility. These guidelines provide recommendations and suggestions to care for patients with KS in various developmental stages ranging from childhood and adolescence to adulthood. This advice is based on recent research data and respective evaluations as well as validations performed by a group of experts.

Subjects with Klinefelter syndrome (KS) develop several metabolic abnormalities more frequently than normal males, with a higher prevalence of obesity, type 2 diabetes (T2D), dyslipidemia, and metabolic syndrome. The etiology factors causing the increased prevalence of metabolic disorders have not been completely clarified and may involve several mechanisms, rather than simply the direct consequence of hypogonadism alone. While reduced levels of testosterone cause an unfavorable change in body composition, with higher fraction of body fat in KS compared to 46-XY peers, testosterone replacement therapy in hypogonadal KS subjects, even if associated with an improvement of body composition, is not totally effective in ameliorating lipid and glycemic abnormalities. Moreover, changes in body composition develop before puberty in KS subjects, suggesting a role of non-hormonal factors. Most genes on the redundant X chromosome(s) are subject to X inactivation, but there is a pseudo-autosomal region containing multiple genes that escape inactivation. The association of more severe karyotypes with higher prevalence of T2D suggests a role of the supernumerary X chromosomes in the onset of T2D in KS. Nevertheless, KS is associated with DNA methylation changes across the entire genome, which might be important in this context since the genetic basis of complex traits such as T2D is thought to be much related with subtle changes in the epigenome and transcriptome. Further research is needed to address this.

Klinefelter syndrome (KS) is the most prevalent sex chromosome disorder in man; it affects approximately one in 660 men and is a common cause of hypogonadism and infertility. Our current knowledge of morbidity in KS is based on observational studies and case reports and therefore is limited. We used Danish registers to obtain dates of hospital admissions and discharge diagnoses in a cohort of all males diagnosed with KS in Denmark and a randomly selected, age-matched control group. Our cohort consisted of 832 KS subjects and 4033 control subjects, contributing with a total of approximately 100,000 person years. We used stratified Cox regression analysis on main groups of diagnoses. Where significant results were found, subsequent analyses were performed on subgroups of diagnoses. We found a significantly increased risk of being hospitalized among the KS subjects [hazard ratio (HR), 1.69; 95% confidence interval, 1.54-1.86]. The increased admission risk was present in all but one of the main diagnosis groups, with the highest HRs for congenital malformations (HR, 10.7), psychiatric disorders (HR, 3.7), and endocrine and metabolic disorders (HR, 3.2). We compared hospitalization rates before and after the diagnosis of KS and found that the increased rate was present even before the diagnosis of KS. Males suffering from KS experienced an increased hospitalization rate from a variety of disorders. Some are likely to be caused by hypogonadism, and some may be linked to the syndrome per se, whereas others are not readily explained. However, other factors, e.g. socioeconomic, may be involved.

Disorders of Sex Development and Hypogonadism: Genetics, Mechanism, and Therapies

Introduction: Klinefelter syndrome (KS) is the most common sex chromosomal anomaly with hypogonadism being a common feature in this syndrome. The ejaculate volume is about normal to low in men with this syndrome. In the present report, we describe the successful treatment of a lifelong anejaculation in a man with KS. This represents the first report of successful treatment of anejaculation in KS. Case presentation: A 24-year-old Caucasian man presented with a lifelong history of failure of ejaculation. A diagnostic work-up revealed the existence of KS and administration of human chorionic gonadotrophin restored the ejaculation. Conclusion: This case report confirms further the increased prevalence of ejaculatory disorders among men with KS in whom associated hypogonadism should be considered a cause of anejaculation. Diagnosis of KS is often delayed. Early diagnosis of the syndrome before puberty is highly recommended and desirable to maintain quality of life.