Klinefelter Syndrome Research Articles

Global Practice Patterns and Variations in the Medical and Surgical Management of Non-Obstructive Azoospermia: Results of a World-Wide Survey, Guidelines and Expert Recommendations.

Non-obstructive azoospermia (NOA) is a common, but complex problem, with multiple therapeutic options and a lack of clear guidelines. Hence, there is considerable controversy and marked variation in the management of NOA. This survey evaluates contemporary global practices related to medical and surgical management for patients with NOA. A 56-question online survey covering various aspects of the evaluation and management of NOA was sent to specialists around the globe. This paper analyzes the results of the second half of the survey dealing with the management of NOA. Results have been compared to current guidelines, and expert recommendations have been provided using a Delphi process. Participants from 49 countries submitted 336 valid responses. Hormonal therapy for 3 to 6 months was suggested before surgical sperm retrieval (SSR) by 29.6% and 23.6% of participants for normogonadotropic hypogonadism and hypergonadotropic hypogonadism respectively. The SSR rate was reported as 50.0% by 26.0% to 50.0% of participants. Interestingly, 46.0% reported successful SSR in <10% of men with Klinefelter syndrome and 41.3% routinely recommended preimplantation genetic testing. Varicocele repair prior to SSR is recommended by 57.7%. Half of the respondents (57.4%) reported using ultrasound to identify the most vascularized areas in the testis for SSR. One-third proceed directly to microdissection testicular sperm extraction (mTESE) in every case of NOA while others use a staged approach. After a failed conventional TESE, 23.8% wait for 3 months, while 33.1% wait for 6 months before proceeding to mTESE. The cut-off of follicle-stimulating hormone for positive SSR was reported to be 12-19 IU/mL by 22.5% of participants and 20-40 IU/mL by 27.8%, while 31.8% reported no upper limit. This is the largest survey to date on the real-world medical and surgical management of NOA by reproductive experts. It demonstrates a diverse practice pattern and highlights the need for evidence-based international consensus guidelines.

Giftedness and atypical sexual differentiation: enhanced perceptual functioning through estrogen deficiency instead of androgen excess.

Syndromic autism spectrum conditions (ASC), such as Klinefelter syndrome, also manifest hypogonadism. Compared to the popular Extreme Male Brain theory, the Enhanced Perceptual Functioning model explains the connection between ASC, savant traits, and giftedness more seamlessly, and their co-emergence with atypical sexual differentiation. Overexcitability of primary sensory inputs generates a relative enhancement of local to global processing of stimuli, hindering the abstraction of communication signals, in contrast to the extraordinary local information processing skills in some individuals. Weaker inhibitory function through gamma-aminobutyric acid type A (GABAA) receptors and the atypicality of synapse formation lead to this difference, and the formation of unique neural circuits that process external information. Additionally, deficiency in monitoring inner sensory information leads to alexithymia (inability to distinguish one's own emotions), which can be caused by hypoactivity of estrogen and oxytocin in the interoceptive neural circuits, comprising the anterior insular and cingulate gyri. These areas are also part of the Salience Network, which switches between the Central Executive Network for external tasks and the Default Mode Network for self-referential mind wandering. Exploring the possibility that estrogen deficiency since early development interrupts GABA shift, causing sensory processing atypicality, it helps to evaluate the co-occurrence of ASC with attention deficit hyperactivity disorder, dyslexia, and schizophrenia based on phenotypic and physiological bases. It also provides clues for understanding the common underpinnings of these neurodevelopmental disorders and gifted populations.

Changes in Testosterone Levels Following Surgical Sperm Retrieval in Men with Non-Obstructive Azoospermia: Systematic Review and Meta-Analysis.

Surgical sperm retrieval (SSR) is used to extract spermatozoa for use with intracytoplasmic sperm injection in men with obstructive and non-obstructive azoospermia (NOA). The procedure may lead to segmental devascularization, postoperative fibrosis, and atrophy with a subsequent decrease in testosterone. The aim of the study is to investigate the impact of SSR on serum levels of total testosterone (TT), follicle-stimulating hormone (FSH), luteinizing hormone (LH) testicular volume, and sexual function in infertile azoospermic men. In this systematic review and meta-analysis (SRMA), we searched articles in "PubMed" and "Scopus" exploring the impact of SSR on TT, FSH, LH, and testicular volume. The full-text articles were screened to assess eligibility before data extraction, quality assessment, and meta-analysis. Seventeen studies meeting the inclusion criteria were finally analyzed and included 1,685 infertile, azoospermic men. Patients underwent SSR and were followed in the postoperative period (one week to 32 months). The analysis showed a significant reduction in TT (mean difference [MD] 3.81 nmol/L, 95% confidence interval [CI] 0.55:7.06; p=0.02) compared to pre-SSR values. We also observed insignificant differences in serum FSH (MD 5.08 IU/L, 95% CI -5.6:15.8; p=0.35), LH (MD -2.96 IU/L, 95% CI -6.31:0.39; p=0.08), and no change in testicular volume (MD 0.07 mL, 95% CI -1.92:2.07; p=0.94) after SSR. Sexual dysfunction was associated with hypogonadism, depression, and anxiety, especially in men with unsuccessful SSR and Klinefelter syndrome. The results of this SRMA indicate a significant reduction in TT after SSR. Sexual dysfunction after testicular sperm extraction and the potential negative impact of future SSR repeat should be considered during preoperative counseling.

An integrative prediction model of successful sperm retrieval for men with non-obstructive azoospermia.

Microdissection testicular sperm extraction (micro-TESE) is an efficient method for obtaining spermatozoa from patients with non-obstructive azoospermia, but the overall success rate of this surgery is only approximately one-third. This study aimed to construct an integrative prediction model for andrologists to assess the preoperative success retrieval rate. A total of 217 patients diagnosed with non-obstructive azoospermia at the First Affiliated Hospital of Nanjing Medical University were included, in whom sperm was successfully retrieved in 71 patients. We retrospectively analyzed their clinical characteristics and pathological features. Single factor analysis and logistic regression analysis were utilized to validate the predictive performance, and the area under the curve (AUC) analysis was conducted to further assess the clinical diagnostic value of the model. The results showed that a history of Klinefelter syndrome or cryptorchidism, FSH (Follicle Stimulating Hormone) levels, and testicular pathology contributed differently to the nomogram prediction model. Relatively normal FSH levels, a history of Klinefelter syndrome or cryptorchidism, and favorable testicular pathological types were assigned higher scores, with higher scores often accompanying a preferable success rate of sperm retrieval. The integrated model showed good prediction performance, with an AUC (Area Under the Curve) of 0.781 (95% CI (confidence interval) 0.713-0.849). Overall, our integrative model demonstrates excellent prediction performance and may assist andrologists in balancing the benefits of surgery preoperatively.

Klinefelter: Which Sexuality?

Klinefelter syndrome (KS) was described by Klinefelter, Reifenstein, and Albright in 1942, who described 9 adult males with gynecomastia, small and firm testes, azoospermia, and increased serum FSH with functional Leydig cells. In 1959, using cytogenetics, Jacobs and Strong described the existence of an extra X chromosome in a male with Klinefelter syndrome The International Consensus Conference organized by the Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology in 2006 included KS in disorders of sexual development. Klinefelter syndrome is also characterized by a genetic dysfunction of the entire gonad that affects germ cells from early fetal life and Sertoli and Leydig cells from mid-puberty. Today we know much more. In this article, we have delved into the social, relational, and sexual quality of life of patients with KS, going beyond fertility studies.

Analysis of the Detection Status of Non-Invasive Prenatal Testing in Sex Chromosome Abnormalities

Objective: To analyze the detection efficiency of non-invasive prenatal tests (NIPT) in single fetus sex chromosome abnormalities and explore the application value of NIPT in sex chromosome diseases. Method: A total of 47,770 singleton pregnant women received free NIPT at Dongguan Maternity and Infant Clinic. Pregnant women with NIPT results indicating sex chromosome abnormalities provided informed consent for amniocentesis and subsequent karyotype analysis and/or multiplex ligation probe amplification (MLPA) technology. The study also involved telephone follow-ups on test results and pregnancy outcomes, along with a retrospective analysis of the positive detection rate of sex chromosome abnormalities by NIPT. Results: Among the 47,770 pregnant women, NIPT identified sex chromosome abnormalities in 158 cases, resulting in a detection rate of 0.33%. Of these cases, 113 pregnant women opted for amniocentesis, while 36 declined. One newborn, whose parents refused puncture, was later diagnosed with cryptorchidism. 8 cases failed to follow up. Among the 113 cases undergoing amniocentesis, 55 were diagnosed with sex chromosome abnormalities. These included 7 cases of X monosomy, 24 cases of sex chromosome trisomy (14 cases of Klinefelter syndrome; 5 cases of Jacobs syndrome; 5 cases of trisomy X), and 24 cases with sex chromosome microdeletions and microduplications. Meanwhile, 58 cases had no abnormalities. The overall positive predictive value (PPV) of NIPT testing for sex chromosome abnormalities was 48.67%, with specific PPVs for monosomy X, Klinefelter syndrome, Jacobs syndrome, trisomy X, and sex chromosome microdeletions and microduplications being 6.19%, 12.39%, 4.42%, 4.42%, and 21.24% respectively. Conclusion: NIPT demonstrates high detection efficiency in sex chromosome diseases. However, the efficiency varies significantly across different chromosomal abnormalities. Pregnant women with NIPT results indicating sex chromosome abnormalities should undergo amniocentesis for karyotype analysis and MLPA.

Effectiveness of social management training on executive functions in males with Klinefelter syndrome (47, XXY)

Men with an extra X chromosome are at risk for social difficulties in which executive functions are known to play an important role. The aim of this study was to examine the potential efficacy of a novel neurocognitive-behavioral treatment program tailored to the specific vulnerabilities of Klinefelter syndrome (47, XXY). Social Management Training (SMT) aimed to increase the ability of individuals to regulate their thoughts, emotions and behaviors in ways that are socially adaptive. 16 Adolescents and men with Klinefelter Syndrome participated in SMT. This novel group treatment program consists of 10 sessions and includes psychoeducation, cognitive-behavioral skills training, home-assignments, and relaxation exercises. There were pre- and posttest cognitive assessments (five months apart) of executive functioning including sustained attention, inhibition, cognitive flexibility and working memory, as well as self-evaluation of executive functioning in daily life. Significant pre- to posttest improvements in inhibitory control (performance test) and metacognition skills (self-report) were found, with effects sizes of 1.3 and 0.5, respectively. No effects of intervention were found on sustained attention, cognitive flexibility and working memory. These findings suggest that SMT, with a key focus on executive dysfunction and tailored to the behavioral and cognitive profile of males with Klinefelter syndrome, may be a promising and potentially efficacious treatment approach for improving self-control and social adaptation, although larger and randomized controlled studies are warranted.

The Urgency of Karyotyping Examination in Male Infertility Patients with Primary Hypogonadism

Infertility is a failure to get pregnant after one year of sexual intercourse without using contraception. The causes of infertility, especially in men, are very complex, including the aging process, hormonal disorders, lifestyle, environment, metabolic disease, and genetic problems. One of the most difficult causes in male infertility is genetic problems. In this case, a 35 year old man was reported with primary infertility and often experienced premature ejaculation and even anejaculation. Previously, the patient had repeatedly consulted about his condition at other fertility service centers. The conclusion obtained was that the patient had azoospermia with bilateral varicoceles and had been given hormone therapy but had not yet found a final diagnosis so the patient was still confused about what had happened to him. At the first visit the patient underwent a sperm analysis and the results were azoospermia. Then, based on the results of the history and physical examination, which indicated hypogonadism, a Y chromosome microdeletion examination was carried out, and a deletion was found in the AZFc region, which is a marker of infertility that causes spermatogenic failure. The examination was continued with karyotyping, the result was 47.XXY, consistent with the condition of Klinefelter syndrome. Conclusion: Carry out a karyotyping examination if you find signs and symptoms that suggest primary hypogonadism in male infertility. This can be done to streamline the diagnostic approach time in patients with primary hypogonadism, especially those with infertility.

Closing the sex/gender gap in dementia: homing in on the vasculature (in vitro/iPSCs)

AbstractInduced pluripotent stem cell (iPSC) models are increasingly being used to model the blood brain barrier (BBB) and to examine the contributions of genetic risk factors to neurovascular disease. While clinical and rodent studies clearly demonstrate the importance of sex in vascular‐related neurodegeneration, only a handful of published studies have thus far begun to employ iPSC modeling to examine the biology that underlies these sex‐related differences. Early reports suggested that female iPSC‐derived brain microvascular endothelial cells (BMECs) exhibit increased transendothelial electrical resistance (TEER) and thus decreased permeability than male BMEC counterparts. Conversely, male pluripotent cells were found to differentiate more readily into BMECs. However, these initial studies were often underpowered and failed to account for the considerable variability inherent between iPSC lines. More recently, consortiums have begun to generate and examine BMECs and glia from a large number of subjects with various neurodegenerative diseases. While much of this work is currently unpublished, these large‐scale datasets further support the concept that sex alters the transcriptome and function of BMECs and vascular‐associated glia. The development and use of ‘isogenic’ male and female iPSC lines derived from Klinefelter syndrome subjects is providing another powerful new approach to study sex‐dependent effects on cellular function. Both the complexity and utility of in vitro iPSC‐modeling of brain vasculature continues to improve and now includes both bioengineered vascular networks and vascularized organoids. In addition, recent progress with xenotransplantation models is providing further avenues to study the interactions between human glial, blood brain barrier function, and cerebral amyloid angiopathy. Nevertheless, there remains a pressing need to further examine and understand both the intrinsic and extrinsic effects of sex on BBB function and vascular‐related neurodegenerative disease, a topic that will be extensively discussed during this AAIC perspectives panel.

Cortical bone assessment and determinants in children and adolescents with Klinefelter syndrome

Cortical bone assessment and determinants in children and adolescents with Klinefelter syndrome

Testosterone Replacement Therapy in Klinefelter Syndrome-Follow-up Study Associating Hemostasis and RNA Expression.

Men with Klinefelter syndrome (KS) develop hypergonadotropic hypogonadism, are in need of testosterone replacement therapy (TRT), and present with a more than 4-fold increased risk of thrombosis. TRT in KS has the potential to modify thrombotic risk, but data are scarce. To assess effects of 18 months of TRT on hemostasis in KS and identify genes associated with the prothrombotic phenotype. Untreated and TRT-treated men with KS were included at baseline and matched to healthy controls. TRT was initiated in untreated KS and all groups were reassessed after 18 months of follow-up. Thrombin generation was evaluated with or without thrombomodulin, and fibrin clot lysis was evaluated by turbidity measurements. RNA expression was assessed in blood, fat, and muscle tissue of patients with TRT-treated KS and controls. Thrombin generation with thrombomodulin was slightly increased in untreated KS, but overall KS was not associated with a hypercoagulable state. KS presented with fibrinolytic impairment associated with higher body fat and higher levels of fibrinogen. Eighteen months of TRT in KS was associated with a reduction in body fat and fibrinogen, attenuating the prothrombotic profile. The expression of ENPP4 was higher in men with KS and served as a key player among a group of genes associated with impaired fibrinolysis. KS is associated with a specific expression profile contributing to fibrinolytic impairment and increased thrombotic risk in the patients. TRT in patients with KS has the potential for alleviating the prothrombotic phenotype, in particular by reducing body fat and fibrinogen.

Chromosome Karyotyping and Aneuploidy Detection using Deep Learning Networks

Chromosome karyotype analysis is a vital role in the diagnosis of congenital disease, chromosomal aneuploidies. Karyotyping is defined as the process of categorizing chromosomes into one of 24 kinds. Chromosomal aneuploidies can be classified as structural and numerical. Numerical anomalies such as Down syndrome, Williams’s syndrome Pattu syndrome, Turner syndrome, klinefelter syndrome and certain kind of cancers detected with the help of karyotyping. It necessitates rigorous attention to detail and well-trained people. With these objectives in mind, in this work, we automated karyotyping and identified common numerical aneuploidies using deep learning on a dataset of 5474 distinct grayscale metaphase chromosomal impressions from the Bioimage chromosome categorization dataset (BioImLab), which is freely available online. Three stages are included in the proposed classification model. The first stage entails segmenting and individual chromosome identification using bounding box detection and modified binary mask methods. At this point, achieved individual chromosome detection accuracy is 99%. The second stage involves classifying chromosomes using a 144 deep and 1000 FC layer GLNet (GoogleNet) classifier, which has an accuracy rate of 96.33%. The last step is to accurately identify aneuploidies with a 98% detection rate. A robust automatic classification system has been developed. Many scholars have proposed various karyotyping approaches. This research compares and contrasts the outcomes of several approaches with greater accuracy.

In search of zebras: Critical analysis of the rarity of perineural breast cancer spread to the brachial plexus in men

BackgroundPerineural spread (PNS) of breast cancer to the brachial plexus is rare with reports limited to cases only in female patients. The purpose of this study was to determine the incidence of PNS in male as compared to female patients. MethodsAdult breast cancer patients referred to a single institution between 1994 – 2022 were retrospectively reviewed for imaging or biopsy confirmed cases of PNS to the brachial plexus. A systematic review of the literature was performed by two independent reviewers for articles published in any language between 1990 – 2022 in PubMed, Scopus, Embase, and Google Scholar. ResultsOf the 10,466 patients with breast cancer (10,355 female, 111 male) referred to a single institution, there were 42 female patients with PNS to the brachial plexus for an estimated incidence of 0.4%. In the same time period, there were 111 male patients treated for breast cancer, including 88 patients with Klinefelter’s syndrome (KS); however, there were no cases of male patients with PNS. A systematic review of the world’s literature also did not identify any male patients with PNS to the brachial plexus. ConclusionsThere is a lack of any reported cases of PNS of breast cancer to the brachial plexus in men or patients with KS, who have a much higher incidence of breast cancer. This may reflect either the compounding rarity of these two events or point towards a distinct hormonally-driven link between breast cancer and PNS, highlighted by the disparity in PNS incidence in men and women.

Leydig cell metabolic disorder act as a new mechanism affecting for focal spermatogenesis in Klinefelter syndrome patients: a real world cross-sectional study base on the age.

Klinefelter's syndrome (KS) was once considered infertile due to congenital chromosomal abnormalities, but the presence of focal spermatozoa changed this. The key to predict and promote spermatogenesis is to find targets that regulate focal spermatogenesis. To explore the trend of fertility changes in KS patients at different ages and identify potential therapeutic targets. Bibliometric analysis was used to collect clinical research data on KS from the Web of Science Core Collection (WoSCC) from 1992 to 2022.A cross-sectional study was conducted on 75 KS patients who underwent microscopic testicular sperm extraction (mTESE) from 2017 to 2022 in the real world. The reproductive hormones, testicular histopathology, androgen receptors, insulin-like factor 3 (INSL3) receptors and sperm recovery rate (SRR) were analyzed. Male infertility, dysplasia, Sertoli cells, Leydig cells, testosterone and spermatogenesis were the research focuses related to KS. Luteinizing hormone (LH), testosterone, and INSL3 were evaluation indicators of Leydig cell function that fluctuate with age. Testosterone and LH peaked at ages 13-19 and 30-45, while INSL3 only peaked at ages 13-19. 27 patients (27/75) recovered sperm through mTESE and experienced SRR peaks at the ages of 20, 28, 34, and 37. The SRR of fibrosis patients was 46.15%, fatty degeneration was 7.14%, and melanosis was 40.00%. The INSL3 and androgen receptors were highly expressed and roughly balanced in focal spermatogenesis. Abnormal metabolism of Leydig cells led to imbalanced expression of INSL3 and androgen receptors, which might be a potential target for spermatogenesis in KS.

Venous thromboembolism in Klinefelter syndrome: a clot in the knowledge?

As few as 1 in 4 people with Klinefelter syndrome are correctly diagnosed. The disease is primarily characterised by hypogonadism and infertility, but a number of other conditions are associated with the syndrome, notably venous thromboembolism. The syndrome therefore has significant implications for health outcomes and quality of life that could be prevented with improved education and prophylactic measures.

A survey of current clinical care of children and young people with Klinefelter Syndrome in United Kingdom

A survey of current clinical care of children and young people with Klinefelter Syndrome in United Kingdom

A retrospective analysis of clinical characteristics, testosterone therapy, and comorbidity screening for klinefelter syndrome: Insights from a UK tertiary centre over the last two decades

A retrospective analysis of clinical characteristics, testosterone therapy, and comorbidity screening for klinefelter syndrome: Insights from a UK tertiary centre over the last two decades

Multidisciplinary team management in an andrology service for Klinefelter Syndrome: A review of current practice

Multidisciplinary team management in an andrology service for Klinefelter Syndrome: A review of current practice

The testicular microvasculature in Klinefelter syndrome is immature with compromised integrity and characterized by excessive inflammatory cross-talk.

Does Klinefelter syndrome (KS) lead to a distinct gene expression pattern at single-cell level in the testes that could provide insight into the reported microvascular dysfunction in the testes? A distinct gene expression pattern within microvascular-associated cells of males with KS suggests excessive endothelial cell (EC) activation, disorganized vessel formation, and the presence of immature vessels with compromised integrity. Recent studies show that males with KS exhibit microvascular dysfunction in their testes, which affects blood flow and is associated with lower circulating levels of testosterone. A comparative cross-sectional study of males with KS (n = 6), non-obstructive azoospermia (NOA) (n = 5), cryptozoospermia (n = 3), and controls (n = 15) was carried out. We analyzed publicly available single-cell RNA sequencing data of testicular cells from males with KS, males with NOA, males with cryptozoospermia, and controls. The integration of these datasets allowed us to analyze gene expression profiles and communication patterns among the cell types within the testis and to identify capillary ECs to investigate changes at the microvascular level. Rooted in changes at the single-cell level, our study demonstrates a shift in gene expression forming the foundation for altered cellular communication, microvascular remodeling, and pro-inflammatory responses within the testes of males with KS. We identified genes that were dysregulated in capillary ECs from males with KS (Padj < 0.05). Specifically, the unique microvascular gene expression in males with KS indicated enhanced capillary EC activation and increased inflammatory cross-talk, leading to impaired vessel maturation and increased EC barrier permeability. Our study is constrained by an unbalanced design, with varying sample sizes and number of cells within each group. We acknowledge the restricted access to clinical information. In addition, our findings were deduced from changes in gene expression, which limits us to infer potential biological consequences arising from these alterations. Furthermore, the absence of a pre-pubertal age group limits the generalizability of our findings and warrants further investigation. This study offers novel insights into the testicular pathophysiology in KS and underscores the potential contribution of microvascular dysfunction to the hypogonadism and infertility observed in males with KS. While this study aims to better understand the microvascular dysfunction in KS, the precise connections to testosterone deficiency and testicular atrophy remain to be fully elucidated. A.S. was supported by the Independent Research Fund Denmark (0134-00130B). C.H.G. was supported by Novo Nordisk Foundation (NNF15OC0016474, NNF20OC0060610), 'Fonden til lægevidenskabens fremme', the Familien Hede Nielsen foundation and the Independent Research Fund Denmark (0134-00406A). E.B.J. was supported by Aarhus University and E.B.J. and C.H.G by the Independent Research Fund Denmark (2096-00165A). J.M.K. was supported by Lundbeckfonden (R307-2018-3667), Carlsberg Fonden (CF19-0687), Novo Nordisk Fonden (0073440) and Steno Diabetes Center Aarhus (SDCA). The authors declare no conflicts of interest. N/A.

Klinefelter syndrome in a resource-challenged setting: A case report

Klinefelter syndrome in a resource-challenged setting: A case report