A multicenter analysis of individuals with a 47,XXY/46,XX karyotype.

PURPOSE: Klinefelter syndrome, a sex chromosome aneuploidy (SCA), 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, multicenter 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% to 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, 2 patients were assigned female sex at birth. CONCLUSION: 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 fluorescence in situ hybridization 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.

Age, Sperm Retrieval, and Testicular Histology in Klinefelter Syndrome.

PURPOSE: We sought to examine sperm retrieval and testicular histology in males of different ages with Klinefelter syndrome. MATERIALS AND METHODS: We identified all males with Klinefelter syndrome who underwent microdissection testicular sperm extraction at our institution from 1995 to 2020. Patients were divided into adolescent (<20 years) and adult (≥20 years) cohorts. Histology and sperm retrieval were compared using chi-square statistics. Multivariable logistic regression models were used to examine factors associated with successful sperm retrieval. RESULTS: We identified 217 males with Klinefelter syndrome, of whom 59 were adolescents and 158 were adults. Adults were stratified into 10-year groupings (20-29 years, n = 62; 30-39 years, n = 88; ≥40 years, n = 8). Approximately 17% of adolescents had testis histology containing germ cells compared with 15% of the 20 to 29-year cohort, 14% of the 30 to 39-year cohort, and 0% over 40 years. In comparison to adolescents (53%), the sperm retrieval rate was significantly higher in the 20 to 29-year cohort (71%, P = .04) and lower in the ≥40-year cohort (13%, P = .03). In multivariable analysis, the presence of hypospermatogenesis on testis biopsy (OR 5.8, P = .03) was associated with higher odds of successful sperm retrieval. CONCLUSIONS: Younger males more frequently had germ cell-containing testis histology, however this finding was not associated with a higher odds of sperm retrieval. Reproductive urologists should counsel azoospermic males with Klinefelter syndrome that sperm retrieval during adolescence for fertility preservation is not required and can be performed in young adulthood.

[Clinicopathological characteristics of Klinefelter syndrome: a testicular biopsy analysis of 87 cases].

Objective: To investigate the clinicopathological characteristics of testicular biopsies from Klinefelter syndrome (KS) patients. Methods: The testicular biopsy specimens of 87 patients with KS (a total of 107 biopsy specimens) were collected from the Department of Pathology, Peking University Third Hospital, Beijing, China from January 2017 to July 2022. All patients were diagnosed as KS by peripheral blood karyotyping analysis. The testicular histopathologic features, testicular volume and hormone levels were evaluated retrospectively. The histopathologic analysis was used to assess the quantity and morphology of Leydig cells, the spermatogenic state of seminiferous tubules, the thickening of the basement membrane of seminiferous tubules and the changes of stroma. Results: Leydig cell proliferative nodules were seen in 95.3% (102/107) of KS testicular biopsy tissues. The eosinophilic inclusion bodies and lipofuscin in Leydig cells were found in 52.3% (56/107) and 57.9% (62/107) of specimens, respectively. The Sertoli cell only seminiferous tubules and the hyalinized tubules were found in 66.4% (71/107) and 76.6% (82/107) of the examined tissues, respectively. The tubules with complete spermatogenic arrest were found in 15.9% (17/107) of specimens, and 5.6% (6/107) of the specimens showed low spermatogenesis or incomplete spermatogenic arrest. In 85.0% (91/107) of the specimens, increased thick-walled small vessels with hyaline degeneration were identified. Conclusions: The most common features of KS testicular specimens are Leydig cell proliferative nodules, hyaline degeneration of seminiferous tubules and proliferation of thick-walled blood vessels. Testicular biopsy specimens of KS are rare. The pathologists can make a tentative diagnosis of KS based on the histological findings, combined with the ultrasound and laboratory results, which is helpful for further diagnosis and treatment of KS.

Testicular biopsy for fertility preservation in early-diagnosed Klinefelter patients: patient characteristics and long-term follow-up.

RESEARCH QUESTION: Which early-diagnosed Klinefelter syndrome patients have been offered cryopreservation of testicular tissue as part of fertility preservation before spermatogonial stem cell (SSC) loss? Do these Klinefelter syndrome patients present with behavioural, cognitive and/or psychological problems? Does a testicular biopsy procedure have long-term effects on the gonadal development of Klinefelter syndrome patients? DESIGN: Early-diagnosed Klinefelter syndrome patients followed between 2009 and 2020 and offered testicular tissue banking in an experimental context at the Universitair Ziekenhuis Brussel were included. The prevalence of behavioural, cognitive and/or psychological problems was determined. Changes in testicular volume and in gonadal function (LH, FSH, testosterone and inhibin B [INHB]) were studied. RESULTS: Of the 48 Klinefelter syndrome patients included, 22 had testicular tissue removed (biopsy group) and 26 had no surgical intervention (control group). The need for specialized education was significantly higher in prenatally (P = 0.0159) and prepubertally (P = 0.0002) diagnosed Klinefelter syndrome patients. Psychological problems were significantly more prevalent in Klinefelter syndrome patients who did not opt for fertility preservation (P = 0.0447). In the first 4.2 (1.9-9.1) years after testicular biopsy, no difference in testicular volume was observed between the biopsied and the contralateral non-biopsied testes (P > 0.9999). After pubertal onset, no differences in LH, FSH, testosterone and INHB were found between the biopsy and the control groups (P = 0.1324 for LH, P > 0.9999 for FSH, P = 0.5433 for testosterone, P > 0.9999 for INHB). CONCLUSION: Early-diagnosed Klinefelter syndrome patients presented with behavioural, cognitive and/or psychological problems. Only psychological problems seemed to influence the decision towards fertility preservation. Follow-up data confirm that harvesting testicular tissue does not have a long-term impact on the gonadal development of Klinefelter syndrome patients.

Intratesticular xenografting of Klinefelter pre-pubertal testis tissue as potential model to study testicular fibrosis.

RESEARCH QUESTION: Is intratesticular xenotransplantation a potential ex-vivo model for studying testicular fibrosis related to Klinefelter syndrome? STUDY DESIGN: First, a feasibility study of an ex-vivo model to study testicular fibrosis in patients with Klinefelter syndrome was performed. Testis tissue from boys with pre-pubertal Klinefelter syndrome (n = 3) and controls (n = 2) (<18 years) was grafted to the mouse testis (n = 12) and recovered after 2, 4, 6 and 8 weeks. Part two of this study consisted of a validation of this model, evaluating the effects of the mast cell blocker ketotifen on the histology of the grafts of Klinefelter syndrome (n = 5) and controls (n = 3), transplanted to mice (n = 10), after 4 weeks of ketotifen or saline treatment. Immunohistochemistry determined the histology of the grafts and the presence of mast cells and spermatogonia. RESULTS: The feasibility study showed that 4 weeks after transplantation, all Klinefelter syndrome grafts could be recovered. Later, degeneration was observed. Most recovered grafts showed an intact histology, with 67 ± 12% intact tubules for the Klinefelter syndrome grafts and 65 ± 15% of intact tubules for the control grafts. In the few remaining Klinefelter syndrome grafts, treatment with ketotifen improved testicular histology compared with non-treated grafts. Graft survival was patient dependent. No germ cell loss was observed after transplantation. CONCLUSION: Xenografting could become a model for the longitudinal study of the fibrotic process related to Klinefelter syndrome; however, the current model has a limited survival period and patient-specific differences in histology.

Central hypogonadism in Klinefelter syndrome: report of two cases and review of the literature.

PURPOSE: Klinefelter syndrome (KS) is characterized by late adolescence/young adulthood onset of primary hypogonadism. Hypogonadotropic hypogonadism (HH), when congenital, is usually associated with absent/incomplete puberty and low/normal gonadotropins. We report the clinical and genetic features of two subjects with KS and an unexpected HH hormone profile. METHODS: Magnetic resonance imaging (MRI) of hypothalamus-pituitary region and next generation sequencing (NGS) of congenital HH-associated genes were obtained. A narrative review of the literature was conducted. RESULTS: Patients were diagnosed with Klinefelter syndrome following karyotype analysis. Nevertheless, they showed unusual features: both had incomplete puberty, low gonadotropins and testosterone levels, and the first one was anosmic. Sellar lesions were excluded by MRI, and NGS was negative in both subjects. Our data add to those of the only 14 similar cases reported so far. Unexplained HH rarely occurs in KS and is variably associated with anosmia, other pituitary hormones deficiencies and heterogeneous karyotypes. However, most cases show an early, pre-pubertal onset of hypogonadism. If the causes behind this gonadotropins defect are largely unknown, hereby we provide the first review of the literature on this topic and propose some pathogenetic hypotheses, including the coexistence of KS and congenital HH as suggested by overlapping clinical features in some of these patients. CONCLUSION: HH is an exceptional occurrence in Klinefelter syndrome and is associated with heterogeneous phenotypes and, probably, aetiologies. Moreover, KS could underlie HH nonresponsive to gonadotropins. An exhaustive diagnostic workup and a tailored clinical management are advisable in these rare forms.

Meiotic Behavior of Extra Sex Chromosomes in Patients with the 47,XXY and 47,XYY Karyotype and Its Ultimate Consequences for Spermatogenesis.

Infertility is one of the most important and burning issues in present times, as a marked increase in the frequency of infertile cases has been observed all over the world. Chromosomal aneuploidy is among the known factors associated with infertility, and among sex chromosome aneuploidies, 47,XXY and 47,XYY constitute the most common class of chromosome abnormality in human live births. Considerable attention has been given to the somatic abnormalities associated with these conditions, but less is known about their meiotic progression; that is, how sex chromosome imbalance influences the meiotic process. It has been documented that men with the same underlying genetic cause of infertility do not present with uniform pathology, so it is informative to find out how meiotic progression differs in patients with similar chromosomal aneuploidy having different phenotypes. The importance of studying meiotic progression in patients with sex chromosome abnormalities has increased many fold with the introduction of assisted reproductive technologies that have made it possible for infertile men to become biological parents. Hence, exploring the possible consequences of sex chromosome aneuploidy for meiotic chromosome segregation is worthwhile. The objective of this review, in the context of current knowledge, is to discuss problems associated with fertility and progression of meiosis in two relatively common sex chromosome aneuploidies, 47,XXY and 47,XYY, reported in humans.

41,XXY * male mice: An animal model for Klinefelter syndrome.

Klinefelter syndrome (KS, 47,XXY) is the most frequent male chromosomal aneuploidy resulting in a highly heterogeneous clinical phenotype associated with hormonal dysbalance, increased rate of co-morbidities, and reduced lifespan. Two hallmarks of KS-affecting testicular functions are consistently observed: Hypergonadotropic hypogonadism and germ cell (GC) loss resulting in infertility. Although KS is being studied for decades, the underlying mechanisms for the observed pathophysiology are still unclear. Due to ethical restrictions, studies in humans are limited, and consequently, suitable animal models are needed to address the consequences of a supernumerary X chromosome. Mouse strains with comparable aneuploidies have been generated and yielded highly relevant insights into KS. We briefly describe the establishment of the KS mouse models, summarize the knowledge gained by their use, compare findings from the mouse models to those obtained in clinical studies, and also reflect on limitations of the currently used models derived from the B6Ei.Lt-Y* mouse strain, in which the Y chromosome is altered and its centromere position changed into a more distal location provoking meiotic non-disjunction. Breeding such as XY* males to XX females, the target 41,XXY *, and 41,XXY males are generated. Here, we summarize features of both models but report in particular findings from our 41,XXY * mice including some novel data on Sertoli cell characteristics.

Epigenetics and genomics in Klinefelter syndrome.

Since the first description of Klinefelter syndrome (KS) was published in 1942 in The Journal of Clinical Endocrinology, large inter-individual variability in the phenotypic presentation has been demonstrated. However, our understanding of the global impact of the additional X chromosome on the genome remains an enigma. Evidence from the existing literature of KS indicates that not just one single genetic mechanism can explain the phenotype and the variable expressivity, but several mechanisms may be at play concurrently. In this review, we describe different genetic mechanisms and recent advances in the understanding of the genome, epigenome, and transcriptome of KS and the link to the phenotype and clinical heterogeneity. Future studies are needed to unite clinical data, genomic data, and basic research attempting to understand the genetics behind KS. Unraveling the genetics of KS will be of clinical relevance as it may enable the use of polygenic risk scores to predict future disease susceptibility and enable clinical risk stratification of KS patients in the future.

Rare sex chromosome variation 48,XXYY: An integrative review.

While the most common Sex Chromosome Aneuploidy (SCA) is 47,XXY, other variations, such as 48,XXYY, are less studied, perhaps due to its rarity. 48,XXYY occurs with an estimated prevalence of 1:18,000-40,000 male births. This SCA is associated with a variety of complex physical, psychological, and neuroanatomical findings. The purpose of this integrative review is to summarize the available evidence related to 48,XXYY and identify gaps in the literature. This study utilized integrative review and PRISMA-guided methodology to search six databases for information pertaining to 48,XXYY. There were no exclusion criteria related to design methodology, given the paucity of available research. Among 397 articles reviewed for potential inclusion, 30 articles remained after inclusion and exclusion criteria were applied. Seven of these articles concentrated solely on participants with 48,XXYY. Literature was summarized into categories of physical phenotype, psychosocial, behavioral, neurocognitive, and brain function. Clinical description of 48,XXYY has evolved over time to develop a deeper understanding of this complex disorder. Large gaps remain, especially a lack of experimental studies, clinical guidelines, and treatments. Additionally, few studies explore methodologies such as interviews or self-report surveys in this population. 48,XXYY presents with a wide spectrum of physical, psychological, and neurocognitive symptoms, and frequently requires complex interdisciplinary care. In order to better understand this disorder and to appropriately treat the individuals affected by it, future research should focus on experimental studies and research that utilizes a variety of methods, including participant interviews and patient-report surveys.

Genes that escape from X-chromosome inactivation: Potential contributors to Klinefelter syndrome.

One of the two X chromosomes in females is epigenetically inactivated, thereby compensating for the dosage difference in X-linked genes between XX females and XY males. Not all X-linked genes are completely inactivated, however, with 12% of genes escaping X chromosome inactivation and another 15% of genes varying in their X chromosome inactivation status across individuals, tissues or cells. Expression of these genes from the second and otherwise inactive X chromosome may underlie sex differences between males and females, and feature in many of the symptoms of XXY Klinefelter males, who have both an inactive X and a Y chromosome. We review the approaches used to identify genes that escape from X-chromosome inactivation and discuss the nature of their sex-biased expression. These genes are enriched on the short arm of the X chromosome, and, in addition to genes in the pseudoautosomal regions, include genes with and without Y-chromosomal counterparts. We highlight candidate escape genes for some of the features of Klinefelter syndrome and discuss our current understanding of the mechanisms underlying silencing and escape on the X chromosome as well as additional differences between the X in males and females that may contribute to Klinefelter syndrome.

Gonadal dysfunction and beyond: Clinical challenges in children, adolescents, and adults with 47,XXY Klinefelter syndrome.

Klinefelter syndrome (KS) is the most frequent sex chromosomal aneuploidy. The karyotype 47,XXY originates from either paternal or maternal meiotic nondisjunction during gametogenesis. KS males are very likely to exhibit marked gonadal dysfunctions, presenting both in severely attenuated spermatogenesis as well as hypergonadotropic hypogonadism. In addition, neurocognitive and psychosocial impairments, as well as cardiovascular, metabolic and bone disorders are often found in KS and might explain for an increased morbidity/mortality. All conditions in KS are likely to be induced by both gene overdosage effects resulting from supernumerary X-chromosomal genes as well as testosterone deficiency. Notwithstanding, the clinical features are highly variable between KS men. Symptoms can become obvious at infancy, childhood, or adolescence. However, the majority of KS subjects is diagnosed during adulthood. KS adolescents require specific attention regarding pubertal development, in order to exploit their remaining fertility potential and allow for timely and tailored testosterone replacement. The chances for sperm retrieval might decline with age and could be hampered by testosterone replacement; therefore, cryostorage of spermatozoa is an option during adolescence, before the decompensation of endocrine and exocrine testicular functions becomes more overt. Sperm from semen or surgically retrieved, in combination with intracytoplasmic sperm injection enables KS males to become biological fathers of healthy children. The aim of this article is to present the current knowledge on KS, to guide clinical care and to highlight research needs.

Germ cell loss in Klinefelter syndrome: When and why?

Klinefelter syndrome (KS) is a quite common disorder with an incidence of 1-2 in 1,000 new-born males. Most patients are diagnosed in the light of a clinical checkup when consulting a fertility clinic with an unfulfilled child wish. Infertility in KS patients is caused by a massive germ cell loss, leading to azoospermia in more than 90% of the adult patients. Most seminiferous tubules in the adult KS testis are degenerated or hyalinized and testicular fibrosis can be observed, starting from puberty. However, focal spermatogenesis can be found in the testis of some patients. This offers the opportunity to extract spermatozoa from the testis by testicular sperm extraction (TESE). Nevertheless, TESE is only successful in about half of the KS adults seeking to father children. The reason for the germ cell loss remains unclear. To date, it is still debated whether the testicular tissue changes and the germ cell loss seen in KS is directly caused by an altered X-linked gene expression, the altered somatic environment, or a deficiency in the germ cells. In this review, we provide an overview of the current knowledge about the germ cell loss in KS patients.

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.

Copy number variation burden does not predict severity of neurodevelopmental phenotype in children with a sex chromosome trisomy.

Sex chromosome trisomies (SCTs) (XXX, XXY, and XYY karyotypes) are associated with an elevated risk of neurodevelopmental disorders. The range of severity of the phenotype is substantial. We considered whether this variable outcome was related to the presence of copy number variants (CNVs)-stretches of duplicated or deleted DNA. A sample of 125 children with an SCT were compared with 181 children of normal karyotype who had been given the same assessments. First, we compared the groups on measures of overall CNV burden: number of CNVs, total span of CNVs, and likely functional impact (probability of loss-of-function intolerance, pLI, summed over CNVs). Differences between groups were small relative to within-group variance and not statistically significant on overall test. Next, we considered whether a measure of general neurodevelopmental impairment was predicted by pLI summed score, SCT versus comparison group, or the interaction between them. There was a substantial effect of SCT/comparison status but the pLI score was not predictive of outcomes in either group. We conclude that variable presence of CNVs is not a likely explanation for the wide phenotypic variation in children with SCTs. We discuss methodological challenges of testing whether CNVs are implicated in causing neurodevelopmental problems.

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.

Integration and reanalysis of transcriptomics and methylomics data derived from blood and testis tissue of men with 47,XXY Klinefelter syndrome indicates the primary involvement of Sertoli cells in the testicular pathogenesis.

Klinefelter syndrome (KS; 47,XXY) is the most common sex chromosomal anomaly and causes a multitude of symptoms. Often the most noticeable symptom is infertility caused by azoospermia with testicular histology showing hyalinization of tubules, germ cells loss, and Leydig cell hyperplasia. The germ cell loss begins early in life leading to partial hyalinization of the testis at puberty, but the mechanistic drivers behind this remain poorly understood. In this systematic review, we summarize the current knowledge on developmental changes in the cellularity of KS gonads supplemented by a comparative analysis of the fetal and adult gonadal transcriptome, and blood transcriptome and methylome of men with KS. We identified a high fraction of upregulated genes that escape X-chromosome inactivation, thus supporting previous hypotheses that these are the main drivers of the testicular phenotype in KS. Enrichment analysis showed overrepresentation of genes from the X- and Y-chromosome and testicular transcription factors. Furthermore, by re-evaluation of recent single cell RNA-sequencing data originating from adult KS testis, we found novel evidence that the Sertoli cell is the most affected cell type. Our results are consistent with disturbed cross-talk between somatic and germ cells in the KS testis, and with X-escapee genes acting as mediators.

The epidemiology of sex chromosome abnormalities.

Sex chromosome abnormalities (SCAs) are characterized by gain or loss of entire sex chromosomes or parts of sex chromosomes with the best-known syndromes being Turner syndrome, Klinefelter syndrome, 47,XXX syndrome, and 47,XYY syndrome. Since these syndromes were first described more than 60 years ago, several papers have reported on diseases and health related problems, neurocognitive deficits, and social challenges among affected persons. However, the generally increased comorbidity burden with specific comorbidity patterns within and across syndromes as well as early death of affected persons was not recognized until the last couple of decades, where population-based epidemiological studies were undertaken. Moreover, these epidemiological studies provided knowledge of an association between SCAs and a negatively reduced socioeconomic status in terms of education, income, retirement, cohabitation with a partner and parenthood. This review is on the aspects of epidemiology in Turner, Klinefelter, 47,XXX and 47,XYY syndrome.

Congenital heart defects associated with aneuploidy syndromes: New insights into familiar associations.

The frequent occurrence of congenital heart defects (CHDs) in chromosome abnormality syndromes is well-known, and among aneuploidy syndromes, distinctive patterns have been delineated. We update the type and frequency of CHDs in the aneuploidy syndromes involving trisomy 13, 18, 21, and 22, and in several sex chromosome abnormalities (Turner syndrome, trisomy X, Klinefelter syndrome, 47,XYY, and 48,XXYY). We also discuss the impact of noninvasive prenatal screening (mainly, cell-free DNA analysis), critical CHD screening, and the growth of parental advocacy on their surgical management and natural history. We encourage clinicians to view the cardiac diagnosis as a "phenotype" which supplements the external dysmorphology examination. When detected prenatally, severe CHDs may influence decision-making, and postnatally, they are often the major determinants of survival. This review should be useful to geneticists, cardiologists, neonatologists, perinatal specialists, other pediatric specialists, and general pediatricians. As patients survive (and thrive) into adulthood, internists and related adult specialists will also need to be informed about their natural history and management.

Metabolic and cardiovascular risk factors in Klinefelter syndrome.

Klinefelter syndrome (KS), which normally presents with a 47,XXY karyotype, is the most common sex chromosome disorder in males. It is also the most common genetic cause of male infertility. KS subjects are typically tall, with small and firm testes, gynecomastia, broad hips, and sparse body hair, although a less evident presentation is also possible. KS is also characterized by a high prevalence of hypogonadism, metabolic syndrome (MetS) and cardiovascular disease. The aim of this article is to systematically review metabolic and the cardiovascular risk factors in KS patients. Hypogonadism has an important role in the pathogenesis of the changes in body composition (particularly visceral obesity) and hence of insulin resistance and MetS, but the association between KS and MetS may go beyond hypogonadism alone. From childhood, KS patients may show an increase in visceral fat with a reduction in lean body mass and an increase in glucose and impaired fat metabolism. Their increased incidence of congenital anomalies, epicardial adipose tissue, and thromboembolic disease suggests they have a higher risk of cardiovascular disease. There is conflicting evidence on the effects of testosterone therapy on body composition and metabolism.