Materiały źródłowe

• #1 Klinefelter Syndrome: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/945649-overview

  In 1942, Klinefelter et al published a report describing nine men with a constellation of features: testicular dysgenesis, microorchidism, eunuchoidism, gynecomastia, elevated urinary gonadotropins, and azoospermia. The etiology was thought to be due to an endocrine disorder of unknown cause, until 1959, when Jacobs et al recognized that Klinefelter syndrome was a chromosomal disorder in which there is an extra X chromosome, resulting in the karyotype 47,XXY. […] Today, the term Klinefelter syndrome (KS) refers to a group of chromosomal disorders in which the normal male karyotype, 46,XY, has at least one extra X chromosome. XXY aneuploidy, the most common human sex chromosome disorder, has a prevalence of 1 in 500 males. It is also the most common chromosomal disorder associated with male hypogonadism and infertility.

• #2 Klinefelter Syndrome: Understanding The Genetic Etiology, Pathogenesis Diagnosis, Developmental Impact, And Therapeutic Approaches

  https://www.ijpsjournal.com/article/Klinefelter+Syndrome+Understanding+The+Genetic+Etiology+Pathogenesis+Diagnosis+Developmental+Impact+And+Therapeutic+Approaches

  One of the most prevalent chromosomal diseases, Klinefelter syndrome (KS), affects between 1 in 500 and 1 in 1,000 male infants. […] This article explores the pathophysiology and genetic etiology of Klinefelter syndrome, emphasizing the role of chromosomal abnormalities in disrupting normal male development. […] The most frequent cause of Klinefelter syndrome is one extra copy of the X chromosome in each cell (XXY). […] There seems to be a correlation between the amount of extra X chromosomal material present and the overall severity of the condition. […] Post-zygotic or meiotic nondisjunction typically brings about the acquisition of the additional X chromosome randomly. […] 47,XXY is the most prevalent KS karyotype (more than 90%). […] Klinefelter syndrome, estimated to occur in 1 in 5001 in 1000 live births, is the most prevalent numerical chromosomal anomaly among men.

• #3 Clinical features, diagnosis, and management of Klinefelter syndrome – UpToDate

  https://www.uptodate.com/contents/clinical-features-diagnosis-and-management-of-klinefelter-syndrome

  Klinefelter syndrome results from supernumerary X chromosomes in an XY male (X1+nY). Approximately 80 to 90 percent of males with Klinefelter syndrome are 47,XXY (47 chromosomes with an extra X). The extra X chromosome is due to maternal or paternal meiotic nondisjunction of the X chromosome during gametogenesis (ova or sperm production). Maternal and paternal nondisjunction occurs equally in Klinefelter syndrome.

• #4 Klinefelter’s syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Klinefelter%27s_syndrome_pathophysiology

  The extra X chromosome is retained because of a nondisjunction event during meiosis I (gametogenesis). Nondisjunction occurs when homologous chromosomes, in this case the X and Y sex chromosomes, fail to separate, producing a sperm with an X and a Y chromosome. Fertilizing a normal (X) egg produces an XXY offspring. The XXY chromosome arrangement is one of the most common genetic variations from the XY karyotype, occurring in about 1 in 500 live male births. […] Another mechanism for retaining the extra X chromosome is through a nondisjunction event during meiosis II in the female. Nondisjunction will occur when sister chromatids on the sex chromosome, in this case an X and an X, fail to separate. An XX egg is produced which, when fertilized with a Y sperm, yields XXY offspring. […] In mammals with more than one X chromosome, the genes on all but one X chromosome are not expressed; this is known as X inactivation. This happens in XXY males as well as normal XX females. A few genes located in the pseudoautosomal regions, however, have corresponding genes on the Y chromosome and are capable of being expressed. These triploid genes in XXY males may be responsible for symptoms associated with Klinefelter’s syndrome.

• #5 Klinefelter Syndrome | GLOWM

  https://www.glowm.com/section-view/heading/Klinefelter%20Syndrome/item/360

  The most frequent chromosomal complement associated with Klinefelter syndrome is 47,XXY, which may result from a nondisjunction during (1) meiosis I or meiosis II of oogenesis, or (2) meiosis I of spermatogenesis. […] Using polymorphic DNA markers, several investigators have found that the extra X chromosome is of paternal origin in 50% to 60% of cases and of maternal origin in the remaining 40% to 50% of cases. […] Among the maternal cases, nondisjunction is due to an error in meiosis I division in 70% of cases, an error in meiosis II division in 20% of cases, and a postzygotic mitotic error in 10%. […] Increased maternal age has been demonstrated in approximately 75% of cases due to maternal meiosis I nondisjunction. […] In the paternally derived 47,XXY cases, the X-Y nondisjunction must always occur in the first meiotic division.

• #6 Klinefelter Syndrome | GLOWM

  https://www.glowm.com/section-view/heading/Klinefelter%20Syndrome/item/360

  The most frequent chromosomal complement associated with Klinefelter syndrome is 47,XXY, which may result from a nondisjunction during (1) meiosis I or meiosis II of oogenesis, or (2) meiosis I of spermatogenesis. […] Using polymorphic DNA markers, several investigators have found that the extra X chromosome is of paternal origin in 50% to 60% of cases and of maternal origin in the remaining 40% to 50% of cases. […] Among the maternal cases, nondisjunction is due to an error in meiosis I division in 70% of cases, an error in meiosis II division in 20% of cases, and a postzygotic mitotic error in 10%. […] Increased maternal age has been demonstrated in approximately 75% of cases due to maternal meiosis I nondisjunction. […] In the paternally derived 47,XXY cases, the X-Y nondisjunction must always occur in the first meiotic division.

• #7 Klinefelter Syndrome Clinical Presentation: History, Physical, Causes

  https://emedicine.medscape.com/article/945649-clinical

  In 1959, Klinefelter syndrome was found to be caused by a supernumerary X chromosome in a male. […] The 47,XXY karyotype of Klinefelter syndrome spontaneously arises when paired X chromosomes fail to separate (nondisjunction in stage I or II of meiosis, during oogenesis or spermatogenesis). […] Maternal and paternal meiotic nondisjunction each account for approximately 50% of Klinefelter syndrome cases. […] Increased paternal age has been linked to a possible increased risk of Klinefelter syndrome. […] Postfertilization nondisjunction is responsible for mosaicism, which is seen in approximately 10% of Klinefelter syndrome patients. […] The androgen receptor (AR) gene encodes the androgen receptor, which is located on the X chromosome. […] In individuals with Klinefelter syndrome, the X chromosome with the shortest AR CAG repeat has been demonstrated to be preferentially inactivated; this process is called skewed or nonrandom X-chromosome inactivation.

• #8 Klinefelter Syndrome | GLOWM

  https://www.glowm.com/section-view/heading/Klinefelter%20Syndrome/item/360

  The most frequent chromosomal complement associated with Klinefelter syndrome is 47,XXY, which may result from a nondisjunction during (1) meiosis I or meiosis II of oogenesis, or (2) meiosis I of spermatogenesis. […] Using polymorphic DNA markers, several investigators have found that the extra X chromosome is of paternal origin in 50% to 60% of cases and of maternal origin in the remaining 40% to 50% of cases. […] Among the maternal cases, nondisjunction is due to an error in meiosis I division in 70% of cases, an error in meiosis II division in 20% of cases, and a postzygotic mitotic error in 10%. […] Increased maternal age has been demonstrated in approximately 75% of cases due to maternal meiosis I nondisjunction. […] In the paternally derived 47,XXY cases, the X-Y nondisjunction must always occur in the first meiotic division.

• #9 Klinefelter syndrome and other sex chromosomal aneuploidies | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-1-42

  The extra X chromosome in 47,XXY results sporadically from either meiotic nondisjunction where a chromosome fails to separate during the first or second division of gametogenesis or from mitotic nondisjunction in the developing zygote. The likelihood of X chromosome nondisjunction increases with advancing maternal age. […] The effects on physical and mental development increase with the number of extra Xs, and each extra X is associated with an IQ decrease of approximately 1516 points, with language most affected, particularly expressive skills.

• #10

  https://link.springer.com/article/10.1007/s40618-016-0541-6

  Klinefelter Syndrome (KS) is characterized by an extreme heterogeneity in its clinical and genetic presentation. […] The aim of this review is to discuss KS clinical features according with the genetic and hormonal (low testosterone) factors involved in their pathogenesis. […] Clinical features depend on both the supernumerary X chromosome and the effects of hypogonadism. […] The genetic background for the KS is based on sex chromosome non-disjunction, which leads to the presence of extra X chromosome/s. […] The occurrence of the maternal or paternal meiotic non-disjunction appears equally distributed in the KS patients (nearly 50 % each). […] An advanced maternal, and possibly paternal, age has been reported as a risk factor for KS. […] Mosaicism (mainly 46,XY/47,XXY) is present in around 10-20 % of the KS patients and arises from either non-disjunction in an early mitotic division of the developing 46,XY zygote, or from loss of one of the X chromosome of a 47,XXY conception due to anaphase lagging.

• #11 Klinefelter Syndrome Clinical Presentation: History, Physical, Causes

  https://emedicine.medscape.com/article/945649-clinical

  In 1959, Klinefelter syndrome was found to be caused by a supernumerary X chromosome in a male. […] The 47,XXY karyotype of Klinefelter syndrome spontaneously arises when paired X chromosomes fail to separate (nondisjunction in stage I or II of meiosis, during oogenesis or spermatogenesis). […] Maternal and paternal meiotic nondisjunction each account for approximately 50% of Klinefelter syndrome cases. […] Increased paternal age has been linked to a possible increased risk of Klinefelter syndrome. […] Postfertilization nondisjunction is responsible for mosaicism, which is seen in approximately 10% of Klinefelter syndrome patients. […] The androgen receptor (AR) gene encodes the androgen receptor, which is located on the X chromosome. […] In individuals with Klinefelter syndrome, the X chromosome with the shortest AR CAG repeat has been demonstrated to be preferentially inactivated; this process is called skewed or nonrandom X-chromosome inactivation.

• #12 Klinefelter Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482314/

  Klinefelter syndrome is a genetic condition characterized by the presence of 2 or more X chromosomes in a phenotypic male. […] The underlying genetic etiology supernumerary X chromosomes was identified in 1959. Additional X chromosomes contribute to testicular hyalinization, fibrosis, and hypofunction, often leading to hypogonadism, genital abnormalities, and infertility. […] The molecular mechanisms underlying primary testicular failure and the phenotypic heterogeneity of physical and neurocognitive features in Klinefelter syndrome remain poorly characterized. Ongoing studies attempt to determine the influence of genetic polymorphisms, skewed X-inactivation, the parental origin of the extra X chromosome, and gene dosage. […] Additional X chromosome material contributes to testicular hyalinization and fibrosis, leading to primary gonadal failure that often progresses through adolescence and young adulthood. The prevalence of hypogonadism in adult males with Klinefelter syndrome ranges from 65% to 85%. […] The additional gene dosage of the SHOX gene in the pseudoautosomal region of the X chromosome contributes to tall stature, long limbs, and a reduced upper-lower segment ratio. The pathophysiology of neuropsychological differences observed in Klinefelter syndrome remains poorly understood.

• #13 Klinefelter Syndrome | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/23907

  Klinefelter syndrome typically arises from a de novo nondisjunction event rather than being inherited, though inherited cases have been reported. […] The molecular mechanisms underlying primary testicular failure and the phenotypic heterogeneity of physical and neurocognitive features in Klinefelter syndrome remain poorly characterized. […] Additional X chromosome material contributes to testicular hyalinization and fibrosis, leading to primary gonadal failure that often progresses through adolescence and young adulthood. […] The prevalence of hypogonadism in adult males with Klinefelter syndrome ranges from 65% to 85%. […] The additional gene dosage of the SHOX gene in the pseudoautosomal region of the X chromosome contributes to tall stature, long limbs, and a reduced upper-lower segment ratio. […] The pathophysiology of neuropsychological differences observed in Klinefelter syndrome remains poorly understood.

• #14 Klinefelter syndrome: Expanding the phenotype and identifying new research directions | Genetics in Medicine

  https://www.nature.com/articles/gim2003375

  In Klinefelter syndrome, testicular histology is normal or near normal in early infancy, only to show progressive loss of germ cells throughout childhood. […] Given the above, the pivotal questions can be enumerated: (1) Is germ cell failure due to an XXY Sertoli cell or to an XXY germ cell? (2) What gene(s) existing on the X chromosome in increased dose (i.e., not inactivated) cause germ cell failure in XXY? […] The precise reproductive and hormonal sequelae of these findings are not known. […] It has been proposed that administering testosterone in the first two to three months of life or treatment of preadolescent KS boys might result in the KS phenotype becoming more normalized, thus enhancing male gender social interaction. […] Testosterone may constitute therapy for some autoimmune disease, diminishing the body composition abnormalities seen in Type II diabetes. […] The analogy might be increased leukemia in Down syndrome and increased neoplasia in other sex chromosomal abnormalities.

• #15 Pathogenesis of testicular dysfunction in Klinefelter syndrome | ESPE2023 | 61st Annual ESPE (ESPE 2023) | ESPE Abstracts

  https://abstracts.eurospe.org/hrp/0097/hrp0097s1.3

  Pathogenesis of testicular dysfunction in Klinefelter syndrome. The most common genetic abnormality found among men is the presence of an additional X-chromosome which causes Klinefelter syndrome (KS). The additional X chromosome arises due to a non-disjunction during paternal or maternal meiosis and is thought to be subjected to dosage compensation by X-inactivation and expression of the long non-coding RNA, XIST. In adult men with KS, the testes appear degenerated and typically only contain Sertoli cell-only (SCO) tubules without germ cells, degenerated ghost tubules, and Leydig cell hyperplasia. […] With the emergence of bulk RNA- and later single-cell RNA-sequencing, several studies have indicated that the Sertoli cells play a central role in testicular degeneration. […] The additional X-chromosome hence seems incompatible with the maturation of Sertoli cells and spermatogenesis, while focal rescue of spermatogenesis can occur in conjunction with a micro-mosaic loss of the additional X-chromosome both in Sertoli cells and spermatogonia.

• #16 Klinefelter syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Klinefelter_syndrome

  The term „hypogonadism” in XXY symptoms is often misinterpreted to mean „small testicles”, when it instead means decreased testicular hormone/endocrine function. Because of (primary) hypogonadism, individuals often have a low serum testosterone level, but high serum follicle-stimulating hormone and luteinizing hormone levels, hypergonadotropic hypogonadism. Despite this misunderstanding of the term, testicular growth is arrested. […] Destruction and hyalinization of the seminiferous tubules cause a reduction in the function of Sertoli cells and Leydig cells, leading to decreased production of FSH and testosterone. This results in impaired spermatogenesis and further endocrine dysfunction.

• #17 Klinefelter syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Klinefelter_syndrome

  The term „hypogonadism” in XXY symptoms is often misinterpreted to mean „small testicles”, when it instead means decreased testicular hormone/endocrine function. Because of (primary) hypogonadism, individuals often have a low serum testosterone level, but high serum follicle-stimulating hormone and luteinizing hormone levels, hypergonadotropic hypogonadism. Despite this misunderstanding of the term, testicular growth is arrested. […] Destruction and hyalinization of the seminiferous tubules cause a reduction in the function of Sertoli cells and Leydig cells, leading to decreased production of FSH and testosterone. This results in impaired spermatogenesis and further endocrine dysfunction.

• #18 The Klinefelter Syndrome and Testicular Sperm Retrieval Outcomes

  https://www.mdpi.com/2073-4425/14/3/647

  Klinefelter syndrome (KS), caused by the presence of an extra X chromosome, is the most prevalent chromosomal sexual anomaly, with an estimated incidence of 1:500/1000 per male live birth (karyotype 47,XXY). […] In KS, hypogonadism is caused by a primary testicular disease. Hypergonadotropic hypogonadism is derived from structural and functional dysfunction of testicular Leydig cells (LCs) and Sertoli cells (SCs), and the hypothalamic–pituitary–gonad (HPG) axis. […] Low androgen levels are responsible for the observed androgen insufficiency (hypogonadism) in KS, with clinical features also dependent on other effects caused by an extra X chromosome. […] KS has multisystemic consequences, with higher morbidity and mortality than the general population, especially if not diagnosed and treated with T as early as possible.

• #19 The Klinefelter Syndrome and Testicular Sperm Retrieval Outcomes

  https://www.mdpi.com/2073-4425/14/3/647

  Despite LC hyperplasia, LCs are dysfunctional, not responding to LH, which leads to a decrease in the synthesis and secretion of T and INSL3. […] The inadequate testicular environment favors the loss of SCs and germ cells, resulting in a reduction in spermatozoa production. […] Several mechanisms have been proposed for the increasing depletion of germ cells, including insufficient extra X chromosome inactivation, LC deficiency, disrupted apoptosis control, and imprinting aberrations. […] The existence of focal spermatogenesis in KS patients also has allowed for successful spermatozoa recovery (SSR) from the seminiferous tubules. […] The spermatozoa retrieval rate (SRR) in adolescents (15–19 y) and young adults (20–24 y) was 52%, 40–66% in adults and 30% in cases of cryptorchidism. […] The goal of T replacement therapy in young boys (early-to-mid-puberty) with KS is to promote linear growth, increase muscle mass, preserve bone density, and allow for the development of secondary sexual characteristics. […] The mTESE is a very promising TESE procedure, presenting high rates of SSR (47–69%) in KS patients. […] The current research demonstrates that, as only two children (0.63%) were afflicted in 315 children, the risk of Klinefelter karyotype transmission is low.

• #20 The Klinefelter Syndrome and Testicular Sperm Retrieval Outcomes

  https://www.mdpi.com/2073-4425/14/3/647

  Despite LC hyperplasia, LCs are dysfunctional, not responding to LH, which leads to a decrease in the synthesis and secretion of T and INSL3. […] The inadequate testicular environment favors the loss of SCs and germ cells, resulting in a reduction in spermatozoa production. […] Several mechanisms have been proposed for the increasing depletion of germ cells, including insufficient extra X chromosome inactivation, LC deficiency, disrupted apoptosis control, and imprinting aberrations. […] The existence of focal spermatogenesis in KS patients also has allowed for successful spermatozoa recovery (SSR) from the seminiferous tubules. […] The spermatozoa retrieval rate (SRR) in adolescents (15–19 y) and young adults (20–24 y) was 52%, 40–66% in adults and 30% in cases of cryptorchidism. […] The goal of T replacement therapy in young boys (early-to-mid-puberty) with KS is to promote linear growth, increase muscle mass, preserve bone density, and allow for the development of secondary sexual characteristics. […] The mTESE is a very promising TESE procedure, presenting high rates of SSR (47–69%) in KS patients. […] The current research demonstrates that, as only two children (0.63%) were afflicted in 315 children, the risk of Klinefelter karyotype transmission is low.

• #21 Klinefelter Syndrome: Practice Essentials, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/945649-overview

  However, research also indicates that by interfering with blood flow, microvascular dysfunction in the testes of patients with Klinefelter syndrome reduces circulating levels of testosterone. A study by Johannsen et al may provide insight into this process, with evidence found that excessively disorganized microvasculature formation in the testes of individuals with Klinefelter syndrome leaves the vessels immature and their vascular integrity compromised. […] The testes ability to release testosterone into the blood may consequently be decreased.

• #22 Klinefelter Syndrome (17.05.2013)

  https://di.aerzteblatt.de/int/archive/article/138490

  Although primordial germ cells (stem cells) are present in the testes of patients with Klinefelter syndrome, they degenerate unusually quickly, with the result that by puberty there are few or no remaining germ cells and very few remaining seminiferous tubules with complete spermatogenesis. The hyperplastic Leydig cells are unable to produce sufficient testosterone. This leads to testosterone deficiency, which can be modified by androgen receptor polymorphism and the severity of which varies between individual patients. […] Ultimately almost all organ systems are associated with an elevated risk of morbidity and mortality in Klinefelter syndrome. […] Whether testosterone deficiency alone is responsible for this increased morbidity and mortality is doubtful, as a historical analysis of singers castrated before puberty, i.e. men with extremely low testosterone levels, showed the same life expectancy as for eugonadal singers. One risk factor may be the usually reduced arterial diameter of patients with Klinefelter syndrome, which leads to reduced perfusion of organ systems.

• #23 Klinefelter’s syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Klinefelter%27s_syndrome_pathophysiology

  The extra X chromosome is retained because of a nondisjunction event during meiosis I (gametogenesis). Nondisjunction occurs when homologous chromosomes, in this case the X and Y sex chromosomes, fail to separate, producing a sperm with an X and a Y chromosome. Fertilizing a normal (X) egg produces an XXY offspring. The XXY chromosome arrangement is one of the most common genetic variations from the XY karyotype, occurring in about 1 in 500 live male births. […] Another mechanism for retaining the extra X chromosome is through a nondisjunction event during meiosis II in the female. Nondisjunction will occur when sister chromatids on the sex chromosome, in this case an X and an X, fail to separate. An XX egg is produced which, when fertilized with a Y sperm, yields XXY offspring. […] In mammals with more than one X chromosome, the genes on all but one X chromosome are not expressed; this is known as X inactivation. This happens in XXY males as well as normal XX females. A few genes located in the pseudoautosomal regions, however, have corresponding genes on the Y chromosome and are capable of being expressed. These triploid genes in XXY males may be responsible for symptoms associated with Klinefelter’s syndrome.

• #24

  https://link.springer.com/article/10.1007/s40618-016-0541-6

  The androgen receptor (AR) gene, which mapped to Xq11.2-12, is of physiological importance in the testis and may play a particular role in differences of the KS phenotype. […] The situation in the germ cells seems to be different and more complex since the X inactivation in these cells follows a distinct pathway. […] Other than gene dosage effects and parental origin of the supernumerary X chromosome, recent evidence suggested that additional features of the X chromosome might have a role in phenotypic differences among KS subjects. […] Hypogonadism remains silent until pubertal onset. […] Testosterone replacement therapy is effective in improving symptoms related to androgen deficiency, but not all other features related to the genetic abnormality. […] Clinical and genetic phenotype of KS as well as their relationship are still not completely understood and need to be fully elucidated in order to improve also the clinical management of this disease.

• #25 DNA hypermethylation and differential gene expression associated with Klinefelter syndrome | Scientific Reports

  https://www.nature.com/articles/s41598-018-31780-0

  Thus, the alterations in gene expression of these pseudoautosomal genes, may indicate that KS is associated with disturbances in basic biological pathways related to cell growth and in mRNA splicing as well as an increased susceptibility to develop tic disorders. […] Our data showed that expression values of XIST in KS were equal to that seen in females, which is in agreement with earlier studies, reporting the same degree of XIST methylation in KS and females. […] This indicates that the inactivation of the supernumerary X chromosome in KS could be comparable to that seen in women. […] However, our data also revealed several genes annotated as inactivated, which are differentially expressed between KS and females which may indicate that the X inactivation is not equal to that seen in females, but is modified towards an expression pattern similar to that seen in males.

• #26 New hope for male infertility: Researchers discover key mechanism in Klinefelter syndrome

  https://medicalxpress.com/news/2024-11-male-infertility-key-mechanism-klinefelter.html

  How does an extra X chromosome lead to infertility in men? Professor Qiao Jie and her team at Peking University Third Hospital revealed why Klinefelter syndrome, a common genetic condition affecting one in every 600 men, often leads to infertility—and they’ve identified a potential way to treat it. […] Their research, titled „How the extra X chromosome impairs the development of male fetal germ cells,” published in Nature provides new insights into the molecular mechanisms at play and even offers potential treatment avenues. […] The team studied fetal germ cells (FGCs) from Klinefelter patients, which develop early in life before disappearing. They found that the presence of the extra X chromosome causes both X chromosomes to remain active in fetal germ cells, causing an overload of certain genes. This gene surge disrupts important biological pathways and prevents the cells from maturing properly.

• #27 New hope for male infertility: PKU researchers discover key mechanism in Klinefelter syndrome

  https://newsen.pku.edu.cn/news_events/news/research/14552.html

  Abnormal development of fetal germ cells in Klinefleter patients […] How does an extra X chromosome lead to infertility in men? […] Their research, titled How the extra X chromosome impairs the development of male fetal germ cells, published in Nature Cells (DOI: 10.1038/s41586-024-08104-6) provides new insights into the molecular mechanisms at play and even offers potential treatment avenues. […] The team studied fetal germ cells (FGCs) from Klinefelter patients, which develop early in life before disappearing. They found that the presence of the extra X chromosome causes both X chromosomes to remain active in fetal germ cells, causing an overload of certain genes. This gene surge disrupts important biological pathways and prevents the cells from maturing properly. […] Additionally, these cells could not move to the right location in the testes, which is necessary for them to grow into mature, sperm-producing cells. With abnormal gene activity and disrupted movement, these cells are lost early, well before they can develop into functional sperm. […] The team found that using TGF- inhibitors could help these fetal germ cells mature normally, pointing to possible treatments for infertility in men with Klinefelter syndrome.

• #28 New hope for male infertility: Researchers discover key mechanism in Klinefelter syndrome

  https://medicalxpress.com/news/2024-11-male-infertility-key-mechanism-klinefelter.html

  Additionally, these cells could not move to the right location in the testes, which is necessary for them to grow into mature, sperm-producing cells. With abnormal gene activity and disrupted movement, these cells are lost early, well before they can develop into functional sperm. […] The team found that using TGF-β inhibitors could help these fetal germ cells mature normally, pointing to possible treatments for infertility in men with Klinefelter syndrome.

• #29 Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5269463/

  A recent study demonstrated that the over expression in the mouse germ-cell-derived GC-1 and GC-2 cells of the gene Testis-expressed 11 (TEX11), an X chromosome-encoded germ-cell-specific protein that is expressed most abundantly in spermatogonia and early spermatocytes in the testes, results in a suppression of the cell proliferation. […] These results suggest that increased expression of TEX11 in the germ cells of KS patients, following the X inactivation escape, may partially contribute to the germ cell death and make TEX11 a potential candidate gene responsible for the KS spermatogenetic failure.

• #30 Klinefelter syndrome (KS): genetics, clinical phenotype and hypogonadism

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5269463/

  A recent study demonstrated that the over expression in the mouse germ-cell-derived GC-1 and GC-2 cells of the gene Testis-expressed 11 (TEX11), an X chromosome-encoded germ-cell-specific protein that is expressed most abundantly in spermatogonia and early spermatocytes in the testes, results in a suppression of the cell proliferation. […] These results suggest that increased expression of TEX11 in the germ cells of KS patients, following the X inactivation escape, may partially contribute to the germ cell death and make TEX11 a potential candidate gene responsible for the KS spermatogenetic failure.

• #31 Klinefelter Syndrome Clinical Presentation: History, Physical, Causes

  https://emedicine.medscape.com/article/945649-clinical

  In 1959, Klinefelter syndrome was found to be caused by a supernumerary X chromosome in a male. […] The 47,XXY karyotype of Klinefelter syndrome spontaneously arises when paired X chromosomes fail to separate (nondisjunction in stage I or II of meiosis, during oogenesis or spermatogenesis). […] Maternal and paternal meiotic nondisjunction each account for approximately 50% of Klinefelter syndrome cases. […] Increased paternal age has been linked to a possible increased risk of Klinefelter syndrome. […] Postfertilization nondisjunction is responsible for mosaicism, which is seen in approximately 10% of Klinefelter syndrome patients. […] The androgen receptor (AR) gene encodes the androgen receptor, which is located on the X chromosome. […] In individuals with Klinefelter syndrome, the X chromosome with the shortest AR CAG repeat has been demonstrated to be preferentially inactivated; this process is called skewed or nonrandom X-chromosome inactivation.

• #32 Klinefelter Syndrome Clinical Presentation: History, Physical, Causes

  https://emedicine.medscape.com/article/945649-clinical

  Nonrandom X-chromosome inactivation, which preferentially leaves the allele with the longest AR CAG repeat active, may actually contribute to the hypogonadal phenotype found in Klinefelter syndrome and may also explain some of the diverse physical appearances observed in affected individuals. […] In boys with Klinefelter syndrome, the paternal origin of the supernumerary X chromosome is associated with later onset of puberty and longer CAG repeats of the androgen receptor, with later pubertal reactivation of the pituitary-testicular axis.

• #33 Klinefelter Syndrome Clinical Presentation: History, Physical, Causes

  https://emedicine.medscape.com/article/945649-clinical

  Nonrandom X-chromosome inactivation, which preferentially leaves the allele with the longest AR CAG repeat active, may actually contribute to the hypogonadal phenotype found in Klinefelter syndrome and may also explain some of the diverse physical appearances observed in affected individuals. […] In boys with Klinefelter syndrome, the paternal origin of the supernumerary X chromosome is associated with later onset of puberty and longer CAG repeats of the androgen receptor, with later pubertal reactivation of the pituitary-testicular axis.

• #34 Klinefelter Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482314/

  Klinefelter syndrome is a genetic condition characterized by the presence of 2 or more X chromosomes in a phenotypic male. […] The underlying genetic etiology supernumerary X chromosomes was identified in 1959. Additional X chromosomes contribute to testicular hyalinization, fibrosis, and hypofunction, often leading to hypogonadism, genital abnormalities, and infertility. […] The molecular mechanisms underlying primary testicular failure and the phenotypic heterogeneity of physical and neurocognitive features in Klinefelter syndrome remain poorly characterized. Ongoing studies attempt to determine the influence of genetic polymorphisms, skewed X-inactivation, the parental origin of the extra X chromosome, and gene dosage. […] Additional X chromosome material contributes to testicular hyalinization and fibrosis, leading to primary gonadal failure that often progresses through adolescence and young adulthood. The prevalence of hypogonadism in adult males with Klinefelter syndrome ranges from 65% to 85%. […] The additional gene dosage of the SHOX gene in the pseudoautosomal region of the X chromosome contributes to tall stature, long limbs, and a reduced upper-lower segment ratio. The pathophysiology of neuropsychological differences observed in Klinefelter syndrome remains poorly understood.

• #35 Klinefelter Syndrome | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/23907

  Klinefelter syndrome typically arises from a de novo nondisjunction event rather than being inherited, though inherited cases have been reported. […] The molecular mechanisms underlying primary testicular failure and the phenotypic heterogeneity of physical and neurocognitive features in Klinefelter syndrome remain poorly characterized. […] Additional X chromosome material contributes to testicular hyalinization and fibrosis, leading to primary gonadal failure that often progresses through adolescence and young adulthood. […] The prevalence of hypogonadism in adult males with Klinefelter syndrome ranges from 65% to 85%. […] The additional gene dosage of the SHOX gene in the pseudoautosomal region of the X chromosome contributes to tall stature, long limbs, and a reduced upper-lower segment ratio. […] The pathophysiology of neuropsychological differences observed in Klinefelter syndrome remains poorly understood.

• #36 DNA hypermethylation and differential gene expression associated with Klinefelter syndrome | Scientific Reports

  https://www.nature.com/articles/s41598-018-31780-0

  Klinefelter syndrome (KS) has a prevalence ranging from 85 to 250 per 100.000 newborn boys making it the most frequent sex chromosome aneuploidy in the general population. […] The molecular basis for the phenotypic traits and morbidity in KS are not clarified. […] Characterization of the methylome as well as the transcriptome of both coding and non-coding genes identified a unique epigenetic and genetic landscape of both autosomal chromosomes as well as the X chromosome in KS. […] Recently, a few studies have provided evidence that KS may be associated with widespread changes in the methylome of both blood and brain tissue. […] These genome-wide alterations in DNA methylation may play a role in the biological mechanisms underlying the clinical KS phenotype by affecting chromatin structure and gene expression and thereby potentially be responsible for the development of phenotypical traits and diseases.

• #37 DNA hypermethylation and differential gene expression associated with Klinefelter syndrome | Scientific Reports

  https://www.nature.com/articles/s41598-018-31780-0

  Klinefelter syndrome (KS) has a prevalence ranging from 85 to 250 per 100.000 newborn boys making it the most frequent sex chromosome aneuploidy in the general population. […] The molecular basis for the phenotypic traits and morbidity in KS are not clarified. […] Characterization of the methylome as well as the transcriptome of both coding and non-coding genes identified a unique epigenetic and genetic landscape of both autosomal chromosomes as well as the X chromosome in KS. […] Recently, a few studies have provided evidence that KS may be associated with widespread changes in the methylome of both blood and brain tissue. […] These genome-wide alterations in DNA methylation may play a role in the biological mechanisms underlying the clinical KS phenotype by affecting chromatin structure and gene expression and thereby potentially be responsible for the development of phenotypical traits and diseases.

• #38 DNA hypermethylation and differential gene expression associated with Klinefelter syndrome | Scientific Reports

  https://www.nature.com/articles/s41598-018-31780-0

  Our aim was to assess the functional impact of epigenetic alterations on the transcriptome in KS, to enhance the understanding of molecular mechanism behind the observed phenotype and the increased risk of comorbidities in addition to describe the methylome and transcriptome of KS. […] Based on our data, we point towards several candidate genes, which may be implicated in the phenotype of KS and further point towards ncRNAs, which may be involved in X chromosome inactivation in KS and in the regulation of escape genes. […] Our finding that KS was mainly associated with hypermethylation and to a lesser extent hypomethylation, are in agreement with earlier studies. […] Interestingly, this predominant hypermethylation is diametrically opposite to our recent observations for Turner syndrome.

• #39 DNA hypermethylation and differential gene expression associated with Klinefelter syndrome | Scientific Reports

  https://www.nature.com/articles/s41598-018-31780-0

  These results could imply that a gain or loss of an X chromosome in humans cause epigenetic instability or alterations, which may be implicated in the phenotype seen in sex chromosome aneuploidies, through an effect on transcriptional or translational regulation. […] In support of this hypothesis, previous studies on cell lines found evidence that the presence of aberrant chromosome material may cause epigenomic instability by changing the regulation of transcription. […] Gene set enrichment analysis suggest that KS may be associated with a deregulation of the immune system, Wnt-signaling pathway and neuron development. […] Aberrant expression of escape genes has been suggested to be associated with and likely causative for the phenotype in KS. […] The other pseudoautosomal genes found to be upregulated in KS compared to male controls in our study, had an expression level similar to female controls.

• #40 DNA hypermethylation and differential gene expression associated with Klinefelter syndrome | Scientific Reports

  https://www.nature.com/articles/s41598-018-31780-0

  These results could imply that a gain or loss of an X chromosome in humans cause epigenetic instability or alterations, which may be implicated in the phenotype seen in sex chromosome aneuploidies, through an effect on transcriptional or translational regulation. […] In support of this hypothesis, previous studies on cell lines found evidence that the presence of aberrant chromosome material may cause epigenomic instability by changing the regulation of transcription. […] Gene set enrichment analysis suggest that KS may be associated with a deregulation of the immune system, Wnt-signaling pathway and neuron development. […] Aberrant expression of escape genes has been suggested to be associated with and likely causative for the phenotype in KS. […] The other pseudoautosomal genes found to be upregulated in KS compared to male controls in our study, had an expression level similar to female controls.

• #41 New hope for male infertility: Researchers discover key mechanism in Klinefelter syndrome

  https://medicalxpress.com/news/2024-11-male-infertility-key-mechanism-klinefelter.html

  Additionally, these cells could not move to the right location in the testes, which is necessary for them to grow into mature, sperm-producing cells. With abnormal gene activity and disrupted movement, these cells are lost early, well before they can develop into functional sperm. […] The team found that using TGF-β inhibitors could help these fetal germ cells mature normally, pointing to possible treatments for infertility in men with Klinefelter syndrome.

• #42 New hope for male infertility: PKU researchers discover key mechanism in Klinefelter syndrome

  https://newsen.pku.edu.cn/news_events/news/research/14552.html

  Abnormal development of fetal germ cells in Klinefleter patients […] How does an extra X chromosome lead to infertility in men? […] Their research, titled How the extra X chromosome impairs the development of male fetal germ cells, published in Nature Cells (DOI: 10.1038/s41586-024-08104-6) provides new insights into the molecular mechanisms at play and even offers potential treatment avenues. […] The team studied fetal germ cells (FGCs) from Klinefelter patients, which develop early in life before disappearing. They found that the presence of the extra X chromosome causes both X chromosomes to remain active in fetal germ cells, causing an overload of certain genes. This gene surge disrupts important biological pathways and prevents the cells from maturing properly. […] Additionally, these cells could not move to the right location in the testes, which is necessary for them to grow into mature, sperm-producing cells. With abnormal gene activity and disrupted movement, these cells are lost early, well before they can develop into functional sperm. […] The team found that using TGF- inhibitors could help these fetal germ cells mature normally, pointing to possible treatments for infertility in men with Klinefelter syndrome.

• #43 The Klinefelter Syndrome and Testicular Sperm Retrieval Outcomes

  https://www.mdpi.com/2073-4425/14/3/647

  Klinefelter syndrome (KS), caused by the presence of an extra X chromosome, is the most prevalent chromosomal sexual anomaly, with an estimated incidence of 1:500/1000 per male live birth (karyotype 47,XXY). […] In KS, hypogonadism is caused by a primary testicular disease. Hypergonadotropic hypogonadism is derived from structural and functional dysfunction of testicular Leydig cells (LCs) and Sertoli cells (SCs), and the hypothalamic–pituitary–gonad (HPG) axis. […] Low androgen levels are responsible for the observed androgen insufficiency (hypogonadism) in KS, with clinical features also dependent on other effects caused by an extra X chromosome. […] KS has multisystemic consequences, with higher morbidity and mortality than the general population, especially if not diagnosed and treated with T as early as possible.

• #44 The Klinefelter Syndrome and Testicular Sperm Retrieval Outcomes

  https://www.mdpi.com/2073-4425/14/3/647

  Several metabolic disturbances are related to KS hypogonadism. […] The extra X chromosome originates from nondisjunction errors of the sex chromosomes, being 50% of paternal origin and 50% of maternal origin. […] The presence of an extra X chromosome, androgen deficiency, and mosaicism are thought to influence the KS phenotype. […] KS is the most frequent chromosomal abnormality in infertile individuals (3–4%) and represents 8–12% of patients with secretory azoospermia. […] Because KS patients are not a homogeneous group, the peripheral karyotype may not predict testicular cell chromosomal constitution or the presence or absence of spermatogenesis. […] The testis is a gland with two major functions: spermatogenesis and hormone synthesis. […] The integrity of the testicular cells and of the HPG axis is required for proper testicular function.

• #45 Klinefelter’s Syndrome: Causes, Symptoms, and Treatment

  https://patient.info/mens-health/klinefelters-syndrome-leaflet

  Mosaic Klinefelter’s syndrome also occurs randomly and is not 'inherited’. During early development in the womb (uterus), there is a problem with cell division. This means that some of the body’s cells have one X chromosome and one Y chromosome (46, XY), and other cells have an extra copy of the X chromosome (47, XXY). […] The main treatment for KS is with testosterone to boost the low levels. Ideally, testosterone replacement should begin at puberty and is needed lifelong. […] However, testosterone treatment does not have any effect on your fertility. […] Males with KS may have an increased risk of certain conditions affecting other body systems, including cardiovascular disease – this is due to increased cholesterol levels which may occur and the risk can be reduced with testosterone treatment.

• #46 Klinefelter’s Syndrome: Causes, Symptoms, and Treatment

  https://patient.info/mens-health/klinefelters-syndrome-leaflet

  ’Thinning’ of the bones (osteoporosis) – low levels of testosterone increase the risk of developing osteoporosis. If you have KS you should have regular bone density screening tests. […] In itself, KS does not shorten lifespan. However, life expectancy may be reduced if one of the conditions above develops (such as diabetes and/or cardiovascular disease), as these can reduce lifespan.

• #47 Logo for Cambridge Core from Cambridge University Press. Click to return to homepage.

  https://www.cambridge.org/core/journals/the-british-journal-of-psychiatry/article/klinefelters-syndrome-karyotype-47-xxy-and-schizophreniaspectrum-pathology/CF656998585479659B602A4CD4EAEDD1

  The prevalence of Klinefelter’s syndrome in the general population is 0.10.2%, but two studies indicate that the prevalence among people with schizophrenia may be much higher, lending further support to a link between X chromosomal abnormalities and liability to schizophrenia. Also, our findings are consistent with a report of auditory hallucinations in 4 out of 11 men with Klinefelter’s syndrome. Research in Klinefelter’s syndrome may reveal specific genotype-phenotype associations. Endophenotypes in schizophrenia that are shared by Klinefelter’s syndrome and schizophrenia may be the result of an X chromosomal abnormality.

• #48 Klinefelter Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482314/

  Klinefelter syndrome is a genetic condition characterized by the presence of 2 or more X chromosomes in a phenotypic male. […] The underlying genetic etiology supernumerary X chromosomes was identified in 1959. Additional X chromosomes contribute to testicular hyalinization, fibrosis, and hypofunction, often leading to hypogonadism, genital abnormalities, and infertility. […] The molecular mechanisms underlying primary testicular failure and the phenotypic heterogeneity of physical and neurocognitive features in Klinefelter syndrome remain poorly characterized. Ongoing studies attempt to determine the influence of genetic polymorphisms, skewed X-inactivation, the parental origin of the extra X chromosome, and gene dosage. […] Additional X chromosome material contributes to testicular hyalinization and fibrosis, leading to primary gonadal failure that often progresses through adolescence and young adulthood. The prevalence of hypogonadism in adult males with Klinefelter syndrome ranges from 65% to 85%. […] The additional gene dosage of the SHOX gene in the pseudoautosomal region of the X chromosome contributes to tall stature, long limbs, and a reduced upper-lower segment ratio. The pathophysiology of neuropsychological differences observed in Klinefelter syndrome remains poorly understood.

• #49 Klinefelter Syndrome | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/23907

  Klinefelter syndrome typically arises from a de novo nondisjunction event rather than being inherited, though inherited cases have been reported. […] The molecular mechanisms underlying primary testicular failure and the phenotypic heterogeneity of physical and neurocognitive features in Klinefelter syndrome remain poorly characterized. […] Additional X chromosome material contributes to testicular hyalinization and fibrosis, leading to primary gonadal failure that often progresses through adolescence and young adulthood. […] The prevalence of hypogonadism in adult males with Klinefelter syndrome ranges from 65% to 85%. […] The additional gene dosage of the SHOX gene in the pseudoautosomal region of the X chromosome contributes to tall stature, long limbs, and a reduced upper-lower segment ratio. […] The pathophysiology of neuropsychological differences observed in Klinefelter syndrome remains poorly understood.

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