Macular hypoplasia and high myopia in 48, xxyy syndrome: a unique case of 48, xxyy syndrome that presents with high myopia and macular dysplasia.

BACKGROUND: Among sex chromosome aneuploidies, 48, XXYY syndrome is a rare variant. This condition is marked by the existence of an additional X and Y chromosome in males, leading to a diverse range of physical, neurocognitive, behavioral, and psychological manifestations. Typical characteristics include a tall stature and infertility. Other phenotypes include congenital heart defects, skeletal anomalies, tremors, obesity, as well as the potential for type 2 diabetes and/or peripheral vascular disease. CASE PRESENTATION: A 6-year-old boy, who had been experiencing progressive vision deterioration in both eyes for the past two years, presented with a history of poor vision, delayed motor skills. The patient was diagnosed with micropenis in the pediatric outpatient clinic. Sparse hair, an unusually tall stature and craniofacial dysmorphology characterized by ocular hypertelorism, depressed nasal bridge, and epicanthic folds were observed. Comprehensive ophthalmic examination revealed high myopia and grade 3 macular hypoplasia. Diagnostic investigations including karyotype analysis and whole-exome sequencing identified an anomalous male karyotype comprising two X and two Y chromosomes, confirming a diagnosis of 48, XXYY syndrome. CONCLUSIONS: This study underscores the rare association of high myopia and grade 3 macular dysplasia with 48, XXYY syndrome. To our knowledge, this case marks the first recorded instance of macular dysplasia in a patient with 48, XXYY syndrome. This novel finding enhances our understanding of this syndrome's phenotypic variability.

Mediastinal Germ-cell Tumors Relapse in a Male With Klinefelter Syndrome. Is Longer Surveillance Needed?

Germ cell tumors (GCTs) are a heterogeneous group of pediatric cancers. In up to one-third of male patients, a primary mediastinal location is associated with the presence of Klinefelter syndrome (KS). We describe a case of mediastinal GCT in a patient, with unacknowledged KS, that presented a relapse 7 years from diagnosis, that is, 2 years after the end of the follow-up program usually recommended for patients with GCT. There are no recommendations for screening for KS in patients with mediastinal GCT and there are no specific guidelines for surveillance of GCT in KS patients. Our experience suggests that KS should be suspected in patients with mediastinal GCT, and a longer follow-up plan should be implemented when GCT occurs in patients with KS.

A rare case of adult-onset spastic paraparesis associated with Klinefelter syndrome.

REPORT: The rare association of Klinefelter syndrome and the clinical presentation of a late onset chronic progressive spastic paresis. CLINICAL PRESENTATION AND GENETICS: An infertile, 61-year-old man, presented with late adult onset of gait problems, deep muscle pain, and bladder problems. He presented for the first time, years after onset with a spastic paraparesis with high arched feet. His parents had already died, but the patient described high arched feet with his mother. There is no further certain information about the parents. After thorough investigation, an additional X chromosome was found, whereafter the diagnosis of Klinefelter syndrome could be made. Other acquired and genetic causes for spastic paraparesis or hereditary motor neuropathy are excluded. CONCLUSION: This rare case, together with three other literature reports by Sasaki (Intern Med 58(3):437-440, 2019), Sajra (Med Arh 61(1):52-53, 2007) and Matsubara et al., (J Neurol Neurosurg Psychiatry 57(5):640-642, 1994). suggests that Klinefelter syndrome can be associated with spastic paraparesis, besides the other various neuropsychiatric symptoms that are more commonly described.

Mixed hypogonadism: a neglected combined form of hypogonadism.

PURPOSE: Kallmann syndrome is a rare disease characterized by delayed puberty, infertility and anosmia. We report the clinical and genetic characteristics of three patients with Kallmann syndrome who presented with Klinefelter syndrome and defined this neglected combined form of hypogonadism as mixed hypogonadism. METHODS: Clinical data and examinations were obtained, including laboratory examination and magnetic resonance imagination (MRI) of the olfactory structures. Congenital hypogonadotropic hypogonadism (CHH) related genes were screened by next generation sequencing (NGS). RESULTS: Three patients with Kallmann syndrome were included. They had co-existence with Klinefelter syndrome and showed hypogonadotropic hypogonadism. Patient 1 was complicated with germinoma. CONCLUSION: Mixed hypogonadism was defined as hypogonadotropic hypogonadism in Klinefelter syndrome or primary testicular disease. Clinicians should be alert to mixed hypogonadism when spermatogenesis induction failed in patients with CHH or gonadotropin levels decrease in patients with Klinefelter syndrome.

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.

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

STUDY QUESTION: 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? SUMMARY ANSWER: 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. WHAT IS KNOWN ALREADY: 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. STUDY DESIGN, SIZE, DURATION: 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. PARTICIPANTS/MATERIALS, SETTING, METHODS: 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. MAIN RESULTS AND THE ROLE OF CHANCE: 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. LIMITATIONS, REASONS FOR CAUTION: 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. WIDER IMPLICATIONS OF THE FINDINGS: 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. STUDY FUNDING/COMPETING INTEREST(S): 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. TRIAL REGISTRATION NUMBER: N/A.

Klinefelter syndrome presenting as metastatic bilateral breast cancer: missed diagnostic opportunities.

Klinefelter syndrome (KS) is the most common cause of primary hypogonadism in male patients; however, the diagnosis of KS is frequently delayed or missed. This delay can lead to undesirable outcomes for patients, especially considering that individuals with KS have a higher risk of developing specific malignancies, including breast cancer, non-Hodgkin's lymphoma and mediastinal germ cell tumours. We present a case of a male patient in his 60s, where the established diagnosis of metastatic bilateral breast cancer prompted us to investigate and subsequently confirm a diagnosis of KS. This case highlights the diagnostic challenges of KS and emphasises the unfavourable consequences of a delayed diagnosis. We aim to raise awareness and enhance physicians' understanding of KS and its non-reproductive manifestations, with a view to promote early recognition and improve patient outcomes.

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.

Background: 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. Objective: To explore the trend of fertility changes in KS patients at different ages and identify potential therapeutic targets. Methods: 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. Results: 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. Conclusion: Abnormal metabolism of Leydig cells led to imbalanced expression of INSL3 and androgen receptors, which might be a potential target for spermatogenesis in KS.

The First Case Report of 47,XXY/46,XX/46,XY Mosaic Klinefelter Syndrome Patient With Mixed Connective Tissue Disorder.

Klinefelter syndrome (KS) mosaicism 47,XXY/46,XX/46,XY is an extremely rare disorder. Mixed connective tissue disorder (MCTD) is a systemic rheumatological disease with overlapping characteristic features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis (PM)/dermatomyositis (DM), and rheumatoid arthritis (RA). It contains a higher titer level of U1-RNP and anti-RNP antibodies. A 50-year-old man was referred to our clinic with gynecomastia, lower extremity rash, persistent fever, arthralgia, muscle weakness, dry eye and mouth, Raynaud's phenomenon abnormal, and hormone levels. He was a follow-up patient for MCTD. Chromosome analysis of the patient revealed an abnormal karyotype of mos47,XXY/46,XX/46,XY. Fluorescence in situ hybridization (FISH) analysis indicated ish(SRYx1),(DZYx1)(DZX1x2)/ish (SRYx0),(DYZ1x0)(DZX1x2)/ish(SRYx1), (DZYx1)(DZX1x1). Although the prevalence of autoimmune diseases in Klinefelter syndrome is unknown, it is thought that the estimated frequency is higher than men, close levels to that of women. This might be explained by several genes that regulate the function of the immune system located on the X chromosome and the gene dosage mechanism that is the escape of X-inactivation in early embryogenesis for KS development. To the best of our knowledge, this is the first case to report a 47,XXY/46,XX/46,XY Klinefelter syndrome patient with MCTD.

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

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

The risk of hypogonadism after testicular sperm extraction in men with various types of azoospermia: a prospective cohort study.

RESEARCH QUESTION: What is the risk of hypogonadism in men with obstructive azoospermia, non-obstructive azoospermia (NOA) or Klinefelter syndrome after testicular sperm extraction (TESE)? DESIGN: This prospective longitudinal cohort study was carried out between 2007 and 2015. RESULTS: Around 36% of men with Klinefelter syndrome, 4% of men with obstructive azoospermia and 3% of men with NOA needed testosterone replacement therapy (TRT). Klinefelter syndrome was strongly associated with TRT while no association was found between obstructive azoospermia or NOA and TRT. Irrespective of the pre-operative diagnosis, a higher testosterone concentration before TESE was associated with a lower chance of needing TRT. CONCLUSIONS: Men with obstructive azoospermia or NOA have a similar moderate risk of clinical hypogonadism after TESE, while this risk is much larger for men with Klinefelter syndrome. The risk of clinical hypogonadism is lower when testosterone concentrations are high before TESE.

Triglyceride-glucose index levels in patients with Klinefelter syndrome and its relationship with endothelial dysfunction and insulin resistance: a cross-sectional observational study.

Objective: This study aimed to investigate the triglyceride-glucose (TyG) index, which is a simple surrogate marker of insulin resistance that is associated with various cardiometabolic diseases, in patients with Klinefelter syndrome (KS). Subjects and methods: A total of 30 patients with KS (mean age: 21.53 ± 1.66 years) and 32 healthy controls (mean age: 22.07 ± 1.01 years) were included in the study. The clinical and laboratory parameters, TyG index, asymmetric dimethylarginine (ADMA) level, homeostatic model assessment of insulin resistance (HOMA-IR) score, and high-sensitivity C-reactive protein level were measured in patients with KS and healthy subjects. Results: Patients with KS had higher HOMA-IR score (p = 0.043), ADMA levels (p < 0.001), and TyG index (p = 0.031) and lower high-density lipoprotein cholesterol levels (p < 0.001) than healthy subjects. TyG index was positively correlated with plasma ADMA (r = 0.48, p < 0.001) and HOMA-IR (r = 0.36, p = 0.011). Multivariate analyses showed that total testosterone level (ß = -0.44, p = 0.001) and TyG index (ß = 0.29, p = 0.045) were independent determinants of plasma ADMA levels. Conclusion: Patients with KS had higher TyG indices than healthy subjects. Moreover, TyG index was independently associated with endothelial dysfunction in patients. TyG index may be a practical and useful measure to show the increased endothelial dysfunction in patients with KS.

Klinefelter's Syndrome with Tremors, Ataxia and Parkinsonism.

Klinefelter's syndrome (KS) is the most common cause of hypogonadism in men. Essential tremor (ET) and parkinsonism have been reported in KS, but ataxia, which has been commonly reported with other causes of hypogonadism, is very rare in KS. Orthostatic tremor has not been reported. We present a case with multiple movement disorders, including gait ataxia, essential-type tremor, rest tremor, orthostatic tremor and parkinsonism.

Combined Alport syndrome, Klinefelter syndrome and Fanconi syndrome in a Chinese boy.

Alport syndrome (AS) is a progressive renal disease characterized by hematuria and progressive renal failure. X-linked dominant (XLAS) is the major inheritance form, accounting for almost 80% of the cases, caused by mutations in COL4A5 genes. Klinefelter syndrome (KS) is the most common genetic cause of human male gonadal dysgenesis. AS and KS are both rare disease, there are only three cases of combined AS and KS in the literatures. Fanconi syndrome (FS) caused by AS is also very rare. We report here the first case combined AS, KS and FS in a Chinese boy. We suggest that the severe renal phenotype and FS might be due to the two homozygous COL4A5 variants in our boy, and cases of AS combined KS will be good research objects for X chromosome inactivation.

The effect of testosterone treatment on bone mineral density in Klinefelter syndrome: A retrospective cohort study.

BACKGROUND: Although Klinefelter syndrome (KS) is the most frequent sex-hormone disorder, there is ongoing uncertainty about the often associated sex-hormone deficiency, its impact on common comorbidities, and therefore about prevention and treatment. In this study, we focus on bone loss, reported to occur in over 40% of KS patients, and the impact of testosterone replacement therapy (TRT) on this comorbidity. OBJECTIVES: This single-center retrospective cohort study in a tertiary hospital compared the effect of treatment with TRT to no TRT on evolution of bone mineral density (BMD) in KS patients. METHODS: After a medical chart review, a total of 52 KS subjects were included in this study. BMD was measured by dual-energy X-ray absorptiometry (DXA) and expressed as T-scores. RESULTS: The subjects were divided into three groups, according to TRT. In the subgroup that only started TRT after baseline measurements (mean age 31 years), we observed significant gain in BMD T-score at the lumbar spine (0.58 ± 0.60, p = 0.003; mean gain of 0.62% areal BMD per year) and total femur T-score (0.24 ± 0.39, p = 0.041; mean gain of 0.25% areal BMD per year) after a mean follow-up period of 7.5 years. Compared to untreated subjects, a significant difference in evolution was demonstrated at the lumbar level (+0.58 ± 0.60 vs. -0.14 ± 0.42, p = 0.007). In untreated subjects with normal testosterone levels, a loss of BMD (-0.27 ± 0.37, p = 0.029; mean loss of 0.49% areal BMD per year) at the femoral neck was measured. This decline was equal to the predicted loss seen in the general male population. CONCLUSION: TRT results in BMD gain in patients with KS with testosterone deficiency, mainly at the lumbar spine. However, this effect is limited (0.62% per year). Patients who were not treated with TRT because of sufficient endogenous testosterone levels, showed only the predicted age-related bone loss during follow-up. The need for TRT in maintaining bone health in KS should be evaluated on an individual basis according to the degree of sex steroid deficiency.

A dual-center study of predictive factors for sperm retrieval through microdissection testicular sperm extraction and intracytoplasmic sperm injection outcomes in men with non-mosaic Klinefelter syndrome.

PURPOSE: This study evaluated the predictors of sperm retrieval (SR) in non-mosaic Klinefelter syndrome (KS) patients undergoing microsurgical testicular sperm extraction (mTESE). The cutoff values of the predictors of SR and overall pregnancy rates after intracytoplasmic sperm injection (ICSI) were analyzed for the positive SR (PSR) cases. MATERIALS AND METHODS: The study was a dual-center retrospective study. Overall 118 patients with KS underwent mTESE between January 2011 and July 2021. Clinicopathological factors including comorbidities, endocrine profiles, and testicular volumes were analyzed. RESULTS: A total of 58 patients showed PSR (49.2%) and 60 patients (50.8%) had negative SR (NSR). The mean overall age of the patients was 32.5 years. The NSR patients had a significantly greater prevalence of obesity, diabetes mellitus, and cerebrovascular disease. The PSR group had a significantly higher left testis mean volume (p=0.039). The differences between the two study groups regarding follicular-stimulating hormone, luteinizing hormone, and testosterone variations at 1 and 3 months after mTESE were insignificant. Preoperative mean neutrophil-to-lymphocyte ratio was significantly greater in the NSR group (p=0.011), but the platelet-to-lymphocyte ratio showed no significant difference between the two study groups. A live child birth was achieved in 53.4% of the PSR patients. Multivariate logistic analysis showed that total testicular volume >3.93 mL, left testis volume >1.79 mL, and neutrophil-to-lymphocyte ratio ≤1.82 were significantly associated with PSR. CONCLUSIONS: mTESE-ICSI is a feasible method for KS patients to have a child, and total testicular volume, left testis volume, and neutrophil-to-lymphocyte ratio might be predictors of successful SR.

Oncological diseases in Klinefelter Syndrome: an overview.

Epidemiological studies have highlighted a higher incidence of morbidity and mortality among individuals with Klinefelter's Syndrome (KS), however, the relative impact of oncological diseases on KS subjects is still uncertain. While some malignancies (e.g., hematological and lung cancers) may show an increased prevalence in the KS population, only a few rare tumors (i.e., extragonadal germ cell tumors [GCTs] and male breast cancer [MBC]) seem to follow this trend. Additionally, hormonal and genetic determinants may be involved in the pathogenesis of neoplasia in KS, even if subjects affected by this syndrome generally show lower incidence of prostate cancer along with lower disease-specific mortality despite testosterone replacement therapy (TRT). This review deals with the pathophysiological and clinical aspects of neoplastic diseases occurring in KS.