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STUDY QUESTION Are Sertoli cells (SCs) from adult Klinefelter men (47,XXY) capable of proliferating in vitro and maintaining their main phenotypical and functional characteristics as do SCs from adult 46,XY patients? SUMMARY ANSWER Isolated SCs from patients with Klinefelter syndrome (KS) can be expanded in vitro while maintaining their characteristics and a stable karyotype, similar to SCs from 46,XY patients. WHAT IS KNOWN ALREADY The mechanism leading to testicular tissue degeneration in KS is still unknown. A few recent studies highlight the main role played by SCs in the physiopathology of the disease, but new study models based on co-culture or testicular organoids are needed to further understand the SC's involvement in the mechanism of testicular degeneration and fibrosis, and to find therapeutical targets. KS SC expansion could be the first step towards developing such in vitro study models. SCs have been isolated from 46,XY men and expanded in vitro while maintaining the expression of phenotypical and functional markers, but propagation of SCs from KS men has not been achieved yet. STUDY DESIGN, SIZE, DURATION Testicular tissue was obtained during a testicular sperm extraction procedure for infertility treatment between 2019 and 2021 from three azoospermic adult KS (47,XXY) men (33±3.6 years old) and from three control patients (46,XY) (36±2 years old) presenting with obstructive azoospermia. SCs isolated from frozen-thawed tissue of KS and 46,XY patients were cultured for 60 days and compared. All patients signed an informed consent according to the ethical board approval of the study protocol. PARTICIPANTS/MATERIALS, SETTING, METHODS Testicular biopsies obtained from KS (n = 3) and 46,XY (n = 3) adult patients were slow-frozen. After tissue thawing SCs were isolated using a double-step enzymatic digestion and differential plating, and cultured for 60 days in DMEM medium containing FBS. Analyses were performed at different culture times (passages 5 (P5) and 10 (P10)). Quantification of cells using immunofluorescence (IF) for cell type-specific markers (Sox9, GATA4, ACTA2, INSL3, MAGEA4), SCs characterization using both IF and quantitative real-time PCR for GDNF, BMP4, AR and CLDN11 and cells karyotyping were performed. MAIN RESULTS AND THE ROLE OF CHANCE We demonstrate for the first time that a small population of human SCs isolated from frozen-thawed testis of adult KS patients can be expanded in vitro while retaining expression of characteristic markers of SCs and the 47,XXY karyotype, and exhibiting cell-specific functional proteins and gene expression (GDNF, BMP4, AR, and CLDN11) after 60 days in culture. At P10, 83.39 ± 4.2% of cultured cells from KS men and 85.34 ± 4.1% from 46,XY men expressed Sox9, and 88.8 ± 3.9% of KS cells versus 82.9 ± 3.2% of the control cells were positive for GATA4 without any differences between two groups; both Sox9 and GATA4 are typical SC markers. No differences were found between KS and 46,XY SCs in vitro in terms of cells expansion (exponential growth between P1 and P10 with an average cell count of 2.8±1.5×107 versus 3.8±1.2×107 respectively for the KS and control groups at P10). There was no significant statistical difference for functional proteins and genes expressions (GDNF, BMP4, AR, and CLDN11) neither between KS SCs and control SCs nor between P5 and P10. LIMITATIONS, REASONS FOR CAUTION The small number of donor samples is a limitation but it is due to limited availability of tissue for research in KS populations. Although no differences were observed in SCs function in the culture of isolated SCs after 60 days, the possibility of a SCs dysfunction needs to be investigated in more complex 3-dimensional models allowing the establishment of a proper cell organization and further analyses of cell functions and interactions during longer culture periods. WIDER IMPLICATIONS OF THE FINDINGS The demonstration of the possibility to propagate KS SCs in vitro could be useful to build new in vitro models for deciphering testicular cell interactions, determining deficient signalling pathways involved in impaired spermatogenesis, and identifying targets for infertility treatment in KS. As the cell numbers achieved in this study are higher than cell numbers used to develop testicular organoids, we may expect to be able to understand the behaviour and physiopathology of SCs in the disease during the long-term culture of these organoids. Such models could be further applied to understand other causes of deficiencies in seminiferous tubules. STUDY FUNDING/COMPETING INTEREST(S) M.G.G is funded by a grant from the Cliniques Universitaires Saint-Luc (FRC) for the research project on Klinefelter Syndrome Physiopathology. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER NCT05997706. [ABSTRACT FROM AUTHOR]

Background: This study aimed to evaluate the predicting factors affecting sperm retrieval. We prospectively assessedthe relationship between sonographic and microdissection testicular sperm extraction (mTESE) findings in Klinefeltersyndrome (KS).Materials and Methods: In this prospective study, 44 azoospermic men with 47, XXY karyotypes participated in thisstudy. In order to evaluate the amount of blood supply in different parts of testicular tissue, a doppler ultra-sonographicwas performed. Also, for the detection of sperm in this group mTESE technique was performed.Results: The age average of positive mTESE and negative mTESE groups was 29.4 and 33.6 years, respectively. Bycomparing the testicle volume (based on the data obtained from the clinical examinations conducted by the urologist)it was determined that there is no significant difference between mTESE positive and negative groups. Folliclestimulatinghormone (FSH) levels in men with negative mTESE (P=0.03) and testosterone levels in men with positivemTESE significantly increased (P=0.017). The overall rate of testis vascularity was significantly higher in the positivemTESE group than in the negative mTESE group. The clinical pregnancy rate in positive mTESE men was 9% percycle, 16.6% per embryos were transferred (ET), and 12.5% per cycle.Conclusion: Totally, our observation indicated that there is not a significant relationship between sonographic and mTESEresults in KS patients. However, more investigations with bigger sample Size can be useful to validate our results.

Context. 49,XXXXY syndrome is an aneuploidy that affects males and is commonly referred to as a variant of Klinefelter Syndrome. It presents a frequency of 1:85,000 to 100,000 births and an etiology related to non-disjunction of homologous chromosomes. Findings include skeletal abnormalities, hypogonadism, and cognitive impairment. Turner syndrome is also an aneuploidy of the sex chromosomes, which affects women, and has a prevalence of 1:2000 to 2500 births and a phenotype characterized by short stature and sexual infantilism. Objective. The objective of this article was to study the literature, investigate the family members and report the case. Subjects and Methods. Data collection was based on medical records, family history, karyotype analysis, and FISH analysis. Results. The karyotype of the proband revealed mos 49, XXXXY[45]/46, XY[5]. The patient's mother is affected by mosaic Turner Syndrome low level and the maternal grandmother by inversion of chromosome 9. The father, the younger brother, and the paternal grandmother present variations in the normality of their chromosomes. Conclusions. It is important to highlight that the early diagnosis of the syndrome and the initiation of therapy reduce biopsychosocial impairment. Investigation of other family members makes genetic counseling more effective. [ABSTRACT FROM AUTHOR]

Reviewed here is a case of Klinefelter Syndrome (KS) diagnosed by a primary care physician after recognition of key features of KS, confirmed by karyotype, along with a discussion of factors associated with this patient's diagnosis and care. Recognition of the key features of this syndrome is important in order to provide proper screening, risk mitigation and treatment to these patients.

Low bone mass is common in men with Klinefelter syndrome (KS), with a prevalence of 6–15% of osteoporosis and of 25–48% of osteopenia. Reduced bone mass has been described since adolescence and it might be related to both reduced bone formation and higher bone resorption. Although reduced testosterone levels are clearly involved in the pathogenesis, this relation is not always evident. Importantly, fracture risk is increased independently from bone mineral density (BMD) and testosterone levels. Here we discuss the pathogenesis of osteoporosis in patients with KS, with a particular focus on the role of testosterone and testis function. In fact, other hormonal mechanisms, such as global Leydig cell dysfunction, causing reduced insulin-like factor 3 and 25-OH vitamin D levels, and high follicle-stimulating hormone and estradiol levels, might be involved. Furthermore, genetic aspects related to the supernumerary X chromosome might be involved, as well as androgen receptor expression and function. Notably, body composition, skeletal mass and strength, and age at diagnosis are other important aspects. Although dual-energy x-ray absorptiometry is recommended in the clinical workflow for patie nts with KS to measure BMD, recent evidence suggests that alterations in the microarchitecture of the bones and vertebral fractures might be present even in subjects with normal BMD. Therefore, analysis of trabecular bone score, high-resolution peripheral quantitative computed tomography and vertebral morphometry seem promising tools to better estimate the fracture risk of patients with KS. This review also summarizes the evidence on the best available treatments for osteoporosis in men with KS, with or without hypogonadism.

Deficits in several cognitive domains are prevalent in men with Klinefelter Syndrome (KS). Verbal deficits are among the most characteristic cognitive impairments of KS, yet other cognitive domains also exhibit deficits. Executive functions, especially working memory capacity and inhibitory control, are frequently affected as well. A common limitation of previous studies addressing potential deficits in inhibitory control is their potential conflation with language-related capabilities, as for example is the case with the Stroop task. Importantly, none of the prior studies utilized the best-accepted approach to study inhibition, namely the Stop Signal Task (SST). This study therefore tested for deficits in inhibitory control in individuals with KS and controls (HC) using a version of the SST with non-semantic auditory stimuli. In addition to the classic behavioral performance measures (e.g., the go reaction time, stopping accuracy, or stop signal reaction time), we also derived parameters of inhibition and attention from electromyography (EMG), electroencephalography (EEG), and Bayesian modeling. Men with KS exhibited prolonged stopping latencies (i.e., stop signal reaction times) and reduced stopping accuracies. Yet, whereas these model-based indices were indicative of attenuated inhibitory control, neither event-related brain potentials nor an EMG-measure of the stopping latency confirmed such deficits. Behavioral and EEG indices, however, provided evidence for deficits in motor response preparation and generation, as well as the early processing of auditory stimuli. In sum, the overall pattern of results does not support the existence of inhibitory deficits in KS per se, but rather suggests that behavioral indices of impaired inhibition may result from early low-level deficits in the auditory and motor domains, as well as a differential weighting in the processing of different aspects of the task.

Background: This study aimed to evaluate the predicting factors affecting sperm retrieval. We prospectively assessed the relationship between sonographic and microdissection testicular sperm extraction (mTESE) findings in Klinefelter syndrome (KS). Materials and Methods: In this prospective study, 44 azoospermic men with 47, XXY karyotypes participated in this study. In order to evaluate the amount of blood supply in different parts of testicular tissue, a doppler ultra-sonographic was performed. Also, for the detection of sperm in this group mTESE technique was performed. Results: The age average of positive mTESE and negative mTESE groups was 29.4 and 33.6 years, respectively. By comparing the testicle volume (based on the data obtained from the clinical examinations conducted by the urologist) it was determined that there is no significant difference between mTESE positive and negative groups. Follicle-stimulating hormone (FSH) levels in men with negative mTESE (P=0.03) and testosterone levels in men with positive mTESE significantly increased (P=0.017). The overall rate of testis vascularity was significantly higher in the positive mTESE group than in the negative mTESE group. The clinical pregnancy rate in positive mTESE men was 9% per cycle, 16.6% per embryos were transferred (ET), and 12.5% per cycle. Conclusion: Totally, our observation indicated that there is not a significant relationship between sonographic and mTESE results in KS patients. However, more investigations with bigger sample Size can be useful to validate our results. [ABSTRACT FROM AUTHOR]

Reviewed here is a case of Klinefelter Syndrome (KS) diagnosed by a primary care physician after recognition of key features of KS, confirmed by karyotype, along with a discussion of factors associated with this patient's diagnosis and care. Recognition of the key features of this syndrome is important in order to provide proper screening, risk mitigation and treatment to these patients. [ABSTRACT FROM AUTHOR]

Background: Men with Klinefelter Syndrome develop some degree of seminiferous tubule degeneration, hyalinization, and fibrosis by adulthood. However, the pathophysiology surrounding testicular fibrosis in Klinefelter Syndrome patients remains incompletely understood. Objectives: To perform a systematic review of literature studying the mechanisms of fibrosis initiation or propagation in Klinefelter Syndrome testes. Materials/methods: PubMed was searched systematically for articles specific to Klinefelter Syndrome and the process of fibrosis. Articles that did not contain original data or specifically addressed the target material were excluded. Additional references were extracted when pertinent from the reference lists of included studies. Results: Primary search yielded 139 articles for abstract review, which was narrowed to 16 for full‐text review. Following full‐text review, eight contained original data and met topic criteria, with one paper added from reference review for a total of nine papers. Discussion: The date range for included papers was 1992–2022. The proposed mechanisms of fibrosis mainly were centered around the impact of altered Sertoli cells on germ cells, the hormonal impact on Leydig cells, the inflammation mediated by mast cells, or the fibrous extracellular matrix deposition by peritubular myoid cells. Additionally, discussions of the role of the altered microvasculature and the specific proteins involved in the blood‐testis barrier or the seminiferous tubule architecture are reviewed. Recent papers have incorporated advanced sequencing and offer future directions for targeted gene expression analysis. Still, much of the published data consists solely of immunohistological assessment by age range, creating difficulties in extrapolating causality. Conclusion: The specific initiating factors of fibrosis of the seminiferous tubules and the propagation mechanisms unique to Klinefelter Syndrome remain incompletely understood with a relative paucity of data. Nonetheless, academic interest is increasing in this field as it may further elucidate the pathophysiology behind Klinefelter syndrome. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives: 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 (β = −0.44, p = 0.001) and TyG index (β = 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.

The amount of single-cell RNA-sequencing (scRNA-seq) data produced in the field of human male reproduction has steadily increased. Transcriptional profiles of thousands of testicular cells have been generated covering the human neonatal, prepubertal, pubertal and adult period as well as different types of male infertility; the latter include non-obstructive azoospermia, cryptozoospermia, Klinefelter syndrome and azoospermia factor deletions. In this review, we provide an overview of transcriptional changes in different testicular subpopulations during postnatal development and in cases of male infertility. Moreover, we review novel concepts regarding the existence of spermatogonial and somatic cell subtypes as well as their crosstalk and provide corresponding marker genes to facilitate their identification. We discuss the potential clinical implications of scRNA-seq findings, the need for spatial information and the necessity to corroborate findings by exploring other levels of regulation, including at the epigenetic or protein level. [ABSTRACT FROM AUTHOR]

Historically, it was thought that the number of X chromosomes plays little role in causing sex differences in traits. Recently, selected mouse models have been used increasingly to compare mice with the same type of gonad but with one versus two copies of the X chromosome. Study of these models demonstrates that mice with one X chromosome can be strikingly different from those with two X chromosomes, when the differences are not attributable to confounding group differences in gonadal hormones. The number of X chromosomes affects adiposity and metabolic disease, cardiovascular ischaemia/reperfusion injury and behaviour. The effects of X chromosome number are likely the result of inherent differences in expression of X genes that escape inactivation, and are therefore expressed from both X chromosomes in XX mice, resulting in a higher level of expression when two X chromosomes are present. The effects of X chromosome number contribute to sex differences in disease phenotypes, and may explain some features of X chromosome aneuploidies such as in Turner and Klinefelter syndromes.

Objective: Double aneuploidy cases involving autosomal and sex chromosomes are very rare. Therefore, it is difficult to determine the clinical features and prognosis of these cases. In this case, a fetus with 48,XYY,+18 karyotype is presented. Case: Cystic hygroma, cleft lip and palate, and clubbed foot were detected in the prenatal ultrasonographic evaluation of a 31-year-old pregnant woman at 13 weeks of gestation. Chorionic villus sampling revealed double aneuploidy including Klinefelter and Edwards syndromes. The molecular result was consistent with the occurrence of nondisjunction error involving chromosome 18 in maternal meiosis I (mat MI) but the finding of the extra X chromosome could not be fully explained. Post-abortion fetal pathology specimen confirmed prenatal diagnosis. Conclusion: Double aneuploidy cases may rarely present with structural anomalies due to maternal meiosis error, without advanced maternal age, as in this case. [ABSTRACT FROM AUTHOR]

Résumé Introduction Une puberté précoce centrale idiopathique (PPCI) est. extrêmement rare chez le garçon. Sa prévalence chez les garçons présentant un syndrome de Klinefelter (SK) est méconnue. Nous décrivons un cas rare de PPCI chez un garçon présentant un SK (47,XXY). De plus, nous surlignons les différences observées entre les taux de gonadotrophines en cas de PPCI chez les patients avec caryotype normal ou présentant un syndrome de Klinefelter. Cas clinique Un garçon de 8 ans avec des antécédents de cryptorchidie a été pris en charge pour une puberté précoce (PP) (Stade de Tanner: P2/G3). Les diamètres des testicules étaient élevés pour son âge (25x35mm pour chaque côté). Le bilan hormonal a confirmé une PP avec des concentrations sanguines de testostérone, LH et FSH élevées à 4.3 ng/ml, 3.5 UI/l et 7.7 UI/l respectivement. Un test à la LHRH a révélé une réserve très élevée de LH (24 UI/l) et de FSH (14 UI/l). Aucune lésion tumorale n’a été mise en évidence par l’IRM. La recherche de mutation du gène MKRN3 n’a révélé aucune anomalie. Le garçon a été suivi et pris en charge pour une PPCI durant 2 ans. A la fin de la puberté, un hypogonadisme périphérique a permis d’évoquer le diagnostic de SK (47,XXY). L’analyse chromosomique par PCR en utilisant des marqueurs de chromosome X a confirmé l’origine maternelle des deux chromosomes X. Discussion À ce jour, 7 cas de PPCI ont été décrits chez des garçons avec un SK. Nous avons analysé les données de ces patients et comparé aux données de patients avec une PPCI mais avec un caryotype normal. Nous mettons en exergue un taux significativement élevé de la LH et de la FSH lors du diagnostic de la PPCI chez les patients avec un SK en comparaison avec un caryotype normal (LH: 9.4 ± 12 vs 1.1 ± 0.6 UI/l; FSH: 23.1 ± 38.5 vs 2.7 ± 1.5 UI/l). De plus, les taux de la LH et FSH après une stimulation par la GnRH étaient également très élevés (LH: 58 ± 48 vs 15.5 ± 0.8 UI/l; FSH: 49.1 ± 62.1 vs 5.7 ± 3.9 UI/l). Conclusions Une PPCI est. extrêmement rare chez le garçon. La description de 8 cas de PPCI dans la littérature indique un surrisque de cette pathologie chez les garçons souffrant d’un SK. La physiopathologie reste méconnue. L’origine maternelle du chromosome surnuméraire et la destruction précoce du testicule en lien avec l’anomalie chromosomique pourraient favoriser une puberté précoce. Ainsi, une analyse du caryotype pourrait être proposée chez un garçon souffrant d’une PPCI.

Klinefelter syndrome is a sex chromosomal aneuploidies with at least one extra X chromosome than normal male karyotype. The classic form of the 47 / XXY karyotype, the incidence of this syndrome is one in 500-1000 live male births. The incidence of 48 / XXYY male individuals with many phenotypic features of Klinefelter syndrome is extremely rare and occurs in 1: 18000 -1: 100.000 men. However, they differ from Klinefelter syndrome with serious behavioral problems, mental reterdation and susceptibility to psychiatric diseases [1 ]. A 38-year-old man, referred to our Medical Biology and Genetics laboratory for karyotype analysis with primary infertility. He had undergone varicocele surgery and had high levels of FSH, low levels of testosterone and high levels of LH. Semen analysis demonstrated azoospermia In the psychiatric examination of the patient, whose IQ level was 90, language, learning and behavior disorder were diagnosed. The patient with deep vein thrombosis was recommended angiography because of right heart failure. Karyotype analysis revealed with 48,XXYY. This rare case shows the importance of karyotype analysis in diagnosis. In this study, the clinical and laboratory findings of the case are presented with the literature.

Abstract Background The purpose of this study is to evaluate the prognostic factors for sperm retrieval and determine if Y chromosome deletion is associated with deleterious effects on spermatogenesis in non-mosaic Klinefelter patients. Whether Y chromosome deletion determines the sperm retrieval rate in non-mosaic Klinefelter patients has not yet been addressed. Methods We retrospectively collected medical records of azoospermic patients from Sep 2009 to Dec 2018, and enrolled 66 non-mosaic 47, XXY patients who were receiving mTESE. The predictive values of patients age, serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, prolactin, estradiol and Y chromosome deletion were assessed for successful sperm recovery. Results Testicular sperm recovery was successful in 24 (36.4%) of 66 men. The mean age (36.0 vs. 36.6 years), and levels of FSH (30.0 vs 36.9 IU/L), LH (17.7 vs 21.9 IU/L), testosterone (2.4 vs. 2.1 ng/ml), prolactin (9.1 vs. 8.8 ng/ml), and estradiol (19.4 vs. 22.3 pg/ml) did not show any significant difference when comparing patients with and without successful sperm retrieval. Partial deletion of azoospermic factor c (AZFc) was noted in 5 (20.8%) of 24 patients with successful sperm retrieval, including three b2/b3 and two gr/gr deletion cases, whereas 4 (9.5%) of 42 patients with unsuccessful sperm retrieval were noted to have AZFc partial deletion (one b2/b3, one sY1206 and two gr/gr deletion), though the difference was not statistically significant (p = 0.27). Conclusion According to present results, age and AZFc partial deletion status should not be a deterrent for azoospermic males with non-mosaic Klinefelter syndrome to undergo mTESE.

Klinefelter syndrome is the most common sex chromosome disorder, with a prevalence of 1 in every 660 males, and despite being so prevalent, less than 30% of cases do ever get diagnosed. This is due to the very heterogeneous phenotypic presentations of the patients; failure in early identification of these patients can have dire consequences on those individuals' overall health and life quality as it is a major cause of primary hypogonadism and subsequent infertility, in addition to the increased risk of neoplasms and a plethora of other systemic conditions. Our objective was to look into the literature concerning Klinefelter's: clinical features and management in the pediatric population. PubMed database was used for articles selection, from where the papers were obtained and reviewed. The clinical presentation of Klinefelter syndrome patients can vary dramatically based on the age and severity of the disease. Most cases have near-normal phenotypes during infancy except for extreme phenotypes that could present with micro-pen undescended testis. As the child grows and reaches puberty detection rate increases as signs of normal puberty such as virilization and increase in muscle mass are usually deficient or incomplete. Most cases only picked up during adulthood who presents complaining of infertility. The treatment approach consists of testosterone therapy, assisted fertility, and early detection and treatment of associated complications. [ABSTRACT FROM AUTHOR]

Background: Supernumerary sex chromosome aneuploidies (SCA) are common genetic conditions characterized by additional X or Y chromosome, affecting ~1/500 individuals, with the most frequent karyotypes of 47,XXY (Klinefelter syndrome), 47,XXX (Trisomy X), and 47,XYY (Jacob syndrome). Although there is considerable phenotypic variation among these diagnoses, these conditions are characterized by the presence of overlapping physical, medical, developmental, and psychological features. Our interdisciplinary clinic's experience anecdotally supports previous published findings of atopic conditions, feeding difficulties, and gastroesophageal reflux to be more prevalent in SCAs (Bardsley et al., Journal of Pediatrics, 2013, 163, 1085; Samango‐Sprouse et al., The Application of Clinical Genetics, 2019, 12, 191; Tartaglia et al., Acta Paediatrica, 2008, 100, 851). Furthermore, we observed that many of these patients have also been diagnosed with eosinophilic esophagitis (EoE), an association not currently reported in the literature. Methods: We conducted a retrospective chart review of all 667 patients with SCA seen at a large tertiary care center to investigate the prevalence and presenting features of EoE. Results: Four percent of children with SCAs had a biopsy‐confirmed diagnosis of EoE, which represents an odds ratio of 32 (95% CI 6–185) when compared to the prevalence rates reported in the general population. Conclusion: Routine screening for EoE symptoms may be warranted for individuals with SCA and atopic conditions. [ABSTRACT FROM AUTHOR]

Abstract Patients with Klinefelter syndrome face many challenges in oral treatment and bone mineralization due to multiple systemic dysfunctions. This case report follows the geometrical treatment with immediate implant loading of an adult male patient with Klinefelter syndrome. Satisfactory results were demonstrated in clinical follow‐up.

Patients with Klinefelter syndrome face many challenges in oral treatment and bone mineralization due to multiple systemic dysfunctions. This case report follows the geometrical treatment with immediate implant loading of an adult male patient with Klinefelter syndrome. Satisfactory results were demonstrated in clinical follow-up. [ABSTRACT FROM AUTHOR]

Abstract Background The simultaneous occurrence of Klinefelter Syndrome (KS) and Congenital Adrenal Hyperplasia (CAH) is an exceptional event: there are just three case reports (two children and a 51 years old man) describing males affected by both KS and 21OHD (21-hydroxylase deficiency) CAH, the first causing androgen deficiency, the latter leading to androgen excess. Case report We report the 4th case of association of KS and CAH in a young man with CAH with good androgen control and with normal secondary sex characteristics, whose Klinefelter syndrome was diagnosed because of reduced testicular volume. He was the first reported case of association of KS and CAH who started androgen replacement therapy in the pubertal age and whose pubertal development was described and followed up step by step. Conclusion In a boy with CAH and small testicular volume, it’s important to consider that hypogonadism may be masked by the adrenal androgens excess and a karyotype should be performed once testicular adrenal rests have been ruled out.

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49, XXXXY syndrome is one of the rarest sexual chromosome disorders, with an incidence of 1:85000–100000 males. It is caused by nondisjunction of the X chromosomes in both meiosis I and II. Early intervention is vital to improve behavioural, neural and sexual well‐being. Information about sexual and developmental aspects is extremely limited in previous literature. We present a case of a 26‐month‐old male child presenting with hypotonia, micropenis and bilateral cryptorchidism. Karyotype study was done in Jordan at the age of 16 months and revealed 49, XXXXY syndrome. Global developmental delay, hypotonia and weak truncal muscles were noted on examination. Growth parameters were within normal limits. Kidney ultrasound revealed findings suggestive of Vesicoureteral reflux. Laboratory investigations revealed hypoandrogenism with normal 17‐OHP levels. This study reviews current knowledge about sexual and developmental characteristics of 49, XXXXY syndrome. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study is to evaluate the prognostic factors for sperm retrieval and determine if Y chromosome deletion is associated with deleterious effects on spermatogenesis in non-mosaic Klinefelter patients. Whether Y chromosome deletion determines the sperm retrieval rate in non-mosaic Klinefelter patients has not yet been addressed.Methods: We retrospectively collected medical records of azoospermic patients from Sep 2009 to Dec 2018, and enrolled 66 non-mosaic 47, XXY patients who were receiving mTESE. The predictive values of patients age, serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, prolactin, estradiol and Y chromosome deletion were assessed for successful sperm recovery.Results: Testicular sperm recovery was successful in 24 (36.4%) of 66 men. The mean age (36.0 vs. 36.6 years), and levels of FSH (30.0 vs 36.9 IU/L), LH (17.7 vs 21.9 IU/L), testosterone (2.4 vs. 2.1 ng/ml), prolactin (9.1 vs. 8.8 ng/ml), and estradiol (19.4 vs. 22.3 pg/ml) did not show any significant difference when comparing patients with and without successful sperm retrieval. Partial deletion of azoospermic factor c (AZFc) was noted in 5 (20.8%) of 24 patients with successful sperm retrieval, including three b2/b3 and two gr/gr deletion cases, whereas 4 (9.5%) of 42 patients with unsuccessful sperm retrieval were noted to have AZFc partial deletion (one b2/b3, one sY1206 and two gr/gr deletion), though the difference was not statistically significant (p = 0.27).Conclusion: According to present results, age and AZFc partial deletion status should not be a deterrent for azoospermic males with non-mosaic Klinefelter syndrome to undergo mTESE. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether a second or even a third surgery is required for sperm retrieval in non-mosaic Klinefelter syndrome patients who underwent a successful/failed micro-testicular sperm extraction (m-TESE). Material and Methods: The patients underwent physical examination, genetic analyses, pathological screening between 2008 and 2018. In the patients, sperm retrieval rates, pregnancy after intracytoplasmic sperm injection (ICSI) and baby take-home rates were examined. Results: M-TESE was repeated for the second time in thirty-five patients in total, with twenty of that underwent their first m-TESE with a negative result and fifteen with a positive result. In =6/20 patients (30%) who had a negative result with the first m-TESE and in n=9/15 patients (60%) who had a positive result with the first m-TESE, sperm was detected the second time. Pregnancy was achieved in n=2/6 patients (33%) who were negative the first time and positive the second time. Baby take-home was achieved in one patient (16.6%). Conclusion: In addition to patients from whom sperm could be retrieved previously, sperm could be detected especially in the second and even third redo m-TESE in patients from whom sperm could not be retrieved. Pregnancy occurred and baby take-home was achieved. Despite the presence of a very limited testicular tissue, it is recommended for this procedure to be performed by expert practitioners upon discussing very openly the complications and achievements, to decide accordingly and repeat m-TESE in these patients where possible. [ABSTRACT FROM AUTHOR]

Congenital anosmia, isolated or as a symptom of Kallmann or Klinefelter syndrome, is a rare condition found in young patients and children. Anosmia is detected during childhood, being reported by the patient or by his/her family. Besides the clinical examination and olfactometric evaluation, imaging is mandatory for the olfactory pathways investigation. Multidisciplinary approach is needed for these patients in order to determine the etiology of the smell loss. In the current paper, we are presenting the case of an 11-year-old child diagnosed in our ENT Department with congenital anosmia. [ABSTRACT FROM AUTHOR]

Introduction Thousands of genes are implicated in spermatogenesis, testicular development and endocrine regulation of testicular function. The genetic contribution to male infertility is therefore considerable, and basic and clinical research in the last years found a number of genes that could potentially be used in clinical practice. Research has also been pushed by new technologies for genetic analysis. However, genetic analyses currently recommended in standard clinical practice are still relatively few. Areas covered We review the genetic causes of male infertility, distinguishing those already approved for routine clinical application from those that are still not supported by adequate clinical studies or those responsible for very rare cause of male infertility. Genetic causes of male infertility vary from chromosomal abnormalities to copy number variations (CNVs), to single-gene mutations. Expert opinion Clinically, the most important aspect is related to the correct identification of subjects to be tested and the right application of genetic tests based on clear clinical data. A correct application of available genetic tests in the different forms of male infertility allows receiving a better and defined diagnosis, has an important role in clinical decision (treatment, prognosis), and allows appropriate genetic counseling especially in cases that should undergo assisted reproduction techniques. [ABSTRACT FROM AUTHOR]

Introduction: Klinefelter syndrome (KS), also known as 47, XXY, shows increased mortality when compared with mortality rates among the general population. Cardiovascular, hemostatic, metabolic diseases are implicated. Moreover, cardiac congenital anomalies in KS can contribute to the increase in mortality. Areas covered: In this study, we have systematically reviewed the relationships between KS and the cardiovascular system and the management of cardiovascular complication. In summary, patients with KS display increased cardiovascular risk profile, characterized by increased prevalence of metabolic alterations including dyslipidemia, diabetes mellitus (DM), and abnormalities in biomarkers of cardiovascular disease. KS subjects are characterized by subclinical abnormalities in endothelial function and in left ventricular (LV) systolic and diastolic function, which - when associated with chronotropic incompetence - may negatively influence cardiopulmonary performance. Moreover, KS patients appear to be at a higher risk for cardiovascular disease, due to thromboembolic events with high prevalence of recurrent venous ulcers, venous insufficiency, recurrent venous and arterial thromboembolism leading to deep venous thrombosis or pulmonary embolism. Expert opinion: Considering the unequivocal finding of increased mortality of KS patients, we suggest a periodic cardiovascular follow up in specialized centers with multidisciplinary care teams that comprise endocrinologists and cardiologists dedicated to KS syndrome. [ABSTRACT FROM AUTHOR]

Résumé Introduction Nous présentons un cas rare de trouble de l'identité de genre (homme vers femme) révélant un syndrome de Klinefelter, ainsi que son évolution intéressante et très atypique à court terme sous testostérone. Cas M. G. est un homme de 48 ans qui est venu consulter pour dysphorie de genre, en demandant de traitements hormonal et chirurgical. L'endocrinologue spécialisée de l'équipe de genre a retrouvé initialement un volume testiculaire de 3 mL, une infertilité partiellement explorée par le passé et des troubles de la libido avec dysfonction érectile. Les examens paracliniques montrent une testostérone biodisponible à 2574 pg. Enfin, le caryotype a révélé un diagnostic du syndrome de Klinefelter : génotype 47 XXY. En raison de la demande fluctuante du patient, 1/4 ampoule d'enanthate de testostérone toutes les 3 semaines a été introduite pour son syndrome de Klinefelter. Contrairement aux craintes des psychiatres, ce traitement n'a pas entraîné d'aggravation de la souffrance liée à la dysphorie de genre. Ainsi, alors que la gynécomastie se résorbait, sa souffrance psychologique s'est même paradoxalement améliorée suite à la récupération de sa libido : la modification corporelle liée à la testostérone a amélioré la dysphorie de genre de M. G. Discussion Tout d'abord, il est intéressant de constater que les modifications corporelles, en particulier sa gynécomastie, représentaient initialement pour M. G., un bénéfice esthétique avec un aménagement partiel de son Klinefelter, ce qui a également retardé son diagnostic. Ensuite, ce cas suggère que le pourcentage de patients souffrants de syndrome de Klinefelter parmi les patients dysphoriques de genre (1,5 %), reste à pondérer par ce manque d'imprégnation en testostérone. Cette observation atypique pourrait être davantage recherchée par caryotype, notamment chez les patients présentant une dysphorie fluctuante. Enfin, ce cas clinique incite à une approche pluridisciplinaire chez ces patients qui, rappelons-le, ne souffrent pas d'une pathologie psychiatrique. Summary Introduction We present a rare case of sex identity disorder (male to female) revealing a Klinefelter syndrome, as well as its very atypical and interesting evolution in the short term under hormonotherapy with testosterone. Case Mr G. is a 48-year-old who requested sex reassignment with hormonal therapy and surgical treatment at a specialist sex dysphoria clinic. The psychiatric assessment found a gender dysphoria according to DSM-5 criteria. The patient had many atypical criteria, such as infertility or learning disorders and upon examination, the specialized endocrinologist found a testicular volume of 3 mL, normal axillary and pubic hair as well as disorders of the libido with erectile dysfunction. Moreover, endocrinologist found a bioavailable testosterone at 2574 pg. Finally, the karyotype revealed the diagnosis of Klinefelter syndrome with a genotype: 47 XXY. Because of the patient's fluctuant ask, treatment with quarter ampoule of enanthate of testosterone every three weeks was introduced for his Klinefelter's syndrome. This treatment did not lead to aggravation of the suffering related to gender dysphoria. The patient's psychological suffering diminished and the modification of his body image modification following testosterone treatment improved Mr G.'s gender dysphoria. Discussion Mr G.'s body, particularly through moderate gynecomastia, has enabled him to find an aesthetic benefit with partial accommodation of his Klinefelter, which has also deliberately delayed his diagnosis. This report also highlights the fact that the percentage of patients with dysphoria, which is much higher among the Klinefelter syndromes in the literature, might be due to the lack of testosterone treatment. This atypical and uncommon observation could be sought at larger scales in patients with fluctuating dysphoria. Finally and more broadly, it also recalls the importance of researching the total testosterone levels of patients suffering from dysphoria, which do not suffer from a psychiatric pathology. [ABSTRACT FROM AUTHOR]

Youth with an extra X chromosome (47, XXY & 47, XXX) display higher levels of schizotypal symptoms and social anxiety as compared to typically developing youth. It is likely that the extra X chromosome group is at-risk for clinical levels of schizotypy and social anxiety. Hence, this study investigated how schizotypal and social anxiety symptoms are related and mechanisms that may explain their association in a group of 38 children and adolescents with an extra X chromosome and a comparison group of 109 typically developing peers (8-19 years). Three cognitive coping strategies were investigated as potential mediators, rumination, catastrophizing, and other-blame. Moderated mediation analyses revealed that the relationship between schizotypal symptoms and social anxiety was mediated by catastrophizing coping in the extra X chromosome group but not in the comparison group. The results suggest that youth with an extra X chromosome with schizotypal symptoms could benefit from an intervention to weaken the tendency to catastrophize life events as a way of reducing the likelihood of social anxiety symptoms. [ABSTRACT FROM AUTHOR]

Résumé L’ostéopathie striée avec sclérose de la base du crâne est une pathologie rare liée au chromosome X. Il s’agit d’une pathologie fréquemment symptomatique chez les sujets féminins et fréquemment létale chez les sujets de sexe masculin et donc considérée comme dominante liée à l’X. Nous décrivons ici le cas d’un patient masculin adulte, présentant des signes cliniques et radiologiques similaires à ceux habituellement décrits chez les patients de sexe féminin. Le diagnostic a été confirmé par l’identification d’une mutation dans le gène AMER1 . La présence d’os longs striés et le phénotype particulier du patient a également conduit au diagnostic de syndrome de Klinefelter homogène, expliquant probablement le phénotype non létal et plutôt modéré comparé aux rares patients masculins déjà rapportés. [ABSTRACT FROM AUTHOR]

Osteopathia striata with cranial sclerosis is a rare X-linked disorder. It is often lethal in male patients, and is considered X-linked dominant since affected females exhibit clinical signs, although milder than males. We describe here an adult male patient, with clinical and radiological signs similar to those described in female patients. Diagnosis was confirmed by the identification of an AMER1 mutation. The presence of long bones striation and the clinical phenotype of the patient also led to the diagnosis of non-mosaic Klinefelter syndrome, probably explaining the non-lethal and even rather minor phenotype compared to the rare affected males already described. [ABSTRACT FROM AUTHOR]

In about one-half of adult Klinefelter syndrome (KS) patients, spermatozoa can be retrieved by means of testicular biopsy (TESE). Given the expected increase in the number of diagnosed KS patients owing to the use of noninvasive prenatal testing, the probable questions of young KS patients and their parents regarding future fertility, and the fact that widespread apoptosis of spermatogonia occurs at onset of puberty, an attempt to increase the retrieval rates at TESE above those found in adult KS men by undertaking preservation techniques peripubertally has been initiated. To date, however, only a limited number of KS adolescents have been examined, demonstrating no increases in the chances of finding sperm. Furthermore, spermatogonial stem cell and testicular tissue freezing techniques, as well as in vitro maturation strategies, require further validation. Given these controversies, banking testicular tissue from prepubertal KS boys should be performed only in a research framework. [ABSTRACT FROM AUTHOR]

Gynecomastia is a common occurrence in pubertal age group, and is physiological in up to 65 percent of cases. When occurs in the family it should be investigated in order not to miss on a treatable etiology. Two brothers within the same family, presenting with bilateral gynecomastia of different causes and requiring different treatment are presented.

Study Question: Is the protein expression window during testicular development affected in prepubertal patients at risk for stem cell loss?Summary Answer: Nuclear ubiquitin carboxyl-terminal esterase L1 (UCHL1) expression in Sertoli cells and interstitial expression of inhibin α (INHA), sex-determining region Y-box 9 (SOX9) and steroidogenic acute regulatory protein (STAR) was affected in patients with Klinefelter syndrome.What Is Known Already: Some patients undergoing testicular tissue banking have already been treated before the testis biopsy is taken. These treatments include chemotherapy or hydroxyurea, which can have an influence on the stem cell number and function. A germinal loss occurs in Klinefelter patients, but its cause is currently unknown.Study Design, Size, Duration: Parrafin-embedded testicular tissue from 5 fetuses, 25 prepubertal patients and 5 adults was used to characterize the spatial and temporal distribution of different testicular marker proteins during testicular development. Expression of the markers was evaluated in germ cells, Sertoli cell and interstitial cells. The integrity of this time window was analyzed in patients at risk for germ cell loss: patients treated with hydroxyurea (n = 7), patients treated with chemotherapy (n = 6) and patients affected by Klinefelter syndrome (n = 5).Participants/materials, Setting, Methods: Immunohistochemistry was performed in normal fetal, prepubertal and adult testicular tissue to set up a timeline for the expression of melanoma antigen family A4 (MAGE-A4), ubiquitin carboxyl-terminal esterase L1 (UCHL1), octamer-binding transcription factor 4 (OCT4), stage-specific embryonic antigen-4 (SSEA4), homeobox protein NANOG, INHA, anti-Müllerian hormone, androgen receptor (AR), SOX9 and STAR. The established timeline was used to evaluate whether the expression of these markers was altered in patients at risk for germ cell loss (patients treated for sickle cell disease (hydroxyurea) or cancer (chemotherapy) and patients with Klinefelter syndrome).Main Results and the Role Of Chance: A protein expression timeline was created using different markers expressed in different testicular cell types. Less positive tubules and less positive cells per tubule were observed for MAGE-A4 and UCHL1 expression in the KS compared with the non-treated group (P < 0.01). Higher nuclear UCHL1 Sertoli cell expression was observed in the KS group compared with the non-treated group (P < 0.05). Higher interstitial expression of INHA (P < 0.05), SOX9 (P < 0.01) and STAR (P < 0.05) was observed in KS compared with the non-treated group.Limitations, Reasons For Caution: Important age variations exist in the prepubertal groups. Therefore, data were represented in three age groups. However, owing to the limited access to prepubertal tissue, no statistical comparison was possible between these groups. For the Klinefelter group, tissue was only available from patients older than 12 years.Wider Implications Of the Findings: The expression timeline can add knowledge to the process of spermatogenesis and be used to evaluate altered protein patterns in patients undergoing potentially gonadotoxic treatments, to monitor spermatogenesis established in vitro and to unravel causes of germ cell loss in Klinefelter patients. [ABSTRACT FROM AUTHOR]

Summary: This manuscript describes the role of low vitamin D in bone metabolism of Klinefelter subjects. Low vitamin D is frequent in this condition and seems to be more important than testosterone in inducing low bone mineral density (BMD) and osteoporosis. Supplementation with vitamin D restores BMD after 2 years of treatment, whereas testosterone alone seems to be ineffective. Introduction: Decreased bone mineral density (BMD) in Klinefelter syndrome (KS) is frequent, and it has been traditionally related to low testosterone (T) levels. However, low BMD can be observed also in patients with normal T levels and T replacement therapy does not necessarily increase bone mass in these patients. Nothing is known about vitamin D levels and supplementation in KS. In this study, we determine vitamin D status and bone mass in KS subjects and compare the efficacy of T therapy and vitamin D supplementation on BMD. Methods: A total of 127 non-mosaic KS patients and 60 age-matched male controls were evaluated with reproductive hormones, 25-hydroxyvitamin D, PTH, and bone densitometry by dual-energy X-ray absorptiometry (DEXA). Patients with hypogonadism and/or 25-hydroxyvitamin D deficiency were treated with T-gel 2 % and/or calcifediol and re-evaluated after 24 months of treatment. Results: 25-hydroxyvitamin D levels were significantly lower in KS patients with respect to controls, and they had significantly lower lumbar and femoral BMD. The percentage of osteopenia/osteoporosis in subjects with 25-hydroxyvitamin D deficiency was higher with respect to subjects with normal 25-hydroxyvitamin D and was not related to the presence/absence of low T levels. Subjects treated with calcifediol or T + calcifediol had a significant increase in lumbar BMD after treatment. No difference was found in T-treated group. Conclusions: These data highlight that low 25-hydroxyvitamin D levels seem to have a more critical role than low T levels in inducing low BMD in KS subjects. Furthermore, vitamin D supplementation seems to be more effective than T replacement therapy alone in increasing BMD. [ABSTRACT FROM AUTHOR]

49,XXXXY pentasomy or Fraccaro's syndrome is the most severe variant of Klinefelter's syndrome (KS) affecting about 1/85000 male births. The classical presentation is the triad: mental retardation, hypergonadotropic hypogonadism and radio ulnar synostosis. Indeed, the reproductive function of Fraccaro's syndrome is distinguished from KS. Besides, Leydig cell tumors are described in cases of KS, but never documented in the Klinefelter variants. We describe a young adult of 22 years old who presented with hyper gonadotropic hypogonadism, delayed puberty and bilateral micro-cryptorchidism. Chromosomal pentasomy was confirmed since infancy. Bilateral orchidectomy revealed a unilateral well-circumscribed Leydig cell tumor associated with bilateral Leydig cell hyperplasia. Inspired from reporting the first case of Leydig cell tumor in a 49,XXXXY patient, we summarize the particularities of testicular function in 49,XXXXY from one side, and the risk and mechanisms of Leydig cell tumorigenesis in Klinefelter variants on the other side. The histological destructions in 49,XXXXY testes and hypogonadism are more profound than in Klinefelter patients, with early Sertoli, Leydig and germ cell destruction. Furthermore, the risk of Leydigioma development in KS and its variants remains a dilemma. We believe that the risk of Leydigioma is much higher in KS than the general population. By contrast, the risk could be lower in the Klinefelter variants with more than 3 supplementary X chromosomes, owing to an earlier and more profound destruction of Leydig cells rendering them irresponsive to chronic Luteinizing hormone (LH) stimulation. [ABSTRACT FROM AUTHOR]