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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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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. [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]

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]

Background: Abnormal sex chromosome numbers in humans are observed in Turner (45,X) and Klinefelter (47,XXY) syndromes. Both syndromes are associated with several clinical phenotypes, whose molecular mechanisms are obscure, and show a range of inter-individual penetrance. In order to understand the effect of abnormal numbers of X chromosome on the methylome and its correlation to the variable clinical phenotype, we performed a genome-wide methylation analysis using MeDIP and Illumina's Infinium assay on individuals with four karyotypes: 45,X, 46,XY, 46,XX, and 47,XXY. Results: DNA methylation changes were widespread on all autosomal chromosomes in 45,X and in 47,XXY individuals, with Turner individuals presenting five times more affected loci. Differentially methylated CpGs, in most cases, have intermediate methylation levels and tend to occur outside CpG islands, especially in individuals with Turner syndrome. The X inactivation process appears to be less effective in Klinefelter syndrome as methylation on the X was decreased compared to normal female samples. In a large number of individuals, we verified several loci by pyrosequencing and observed only weak inter-loci correlations between the verified regions. This suggests a certain stochastic/random contribution to the methylation changes at each locus. Interestingly, methylation patterns on some PAR2 loci differ between male and Turner syndrome individuals and between female and Klinefelter syndrome individuals, which possibly contributed to this distinguished and unique autosomal methylation patterns in Turner and Klinefelter syndrome individuals. Conclusions: The presented data clearly show that gain or loss of an X chromosome results in different epigenetic effects, which are not necessary opposite. [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]

Boys and men with an extra X chromosome (47,XXY, Klinefelter syndrome) are at risk for problems in social functioning and have an increased vulnerability for autism spectrum disorders (ASD). In the search for underlying mechanisms driving this increased risk, this study focused on social attention, that is, spontaneous orientation toward facial expressions. Seventeen adults with 47,XXY and 20 non-clinical controls participated in this study. Social attention was measured using an eyetracking method that quantifies the visual scanning patterns of faces expressing different types of emotions (happy, fearful, angry, neutral) and their varying intensity levels (25%, 50%, 75%, 100%). Overall, the group with Klinefelter syndrome fixated less on the eye region of faces when compared to controls (Cohen’s d 1.4), and did not show the typical tendency, as was found in the control group, to first fixate on the eyes when presented with a face (Cohen’s d 1.0). There was no significant effect of type or intensity of emotion. Shorter looking times toward eyes showed a borderline significant correlation with self-reports of poorer social functioning, with 29% explained variance. These findings suggest a reduced tendency to rapidly and automatically attend to the eyes of others in individuals with 47,XXY. This may have impact on more complex social-cognitive abilities that build upon this. In addition to studies of behaviorally defined disorders such as ASD, studying individuals with Klinefelter syndrome provide insight into mechanisms underlying various “at risk” pathways of social dysfunction and the factors that mediate this risk. (JINS, 2015, 21, 364–372) [ABSTRACT FROM PUBLISHER]

We report a case of discordant phenotypic sex in monozygotic twins mosaic 47,XXY/46,XX: monozygotic heterokaryotypic twins. The twins presented with cognitive and comprehension delay, behavioural and language disorders, all symptoms frequently reported in Klinefelter syndrome. Molecular zygosity analysis with several markers confirmed that the twins are in effect monozygotic (MZ). Array comparative genomic hybridization found no evidence for the implication of copy number variation in the phenotypes. Ultrasound scans of the reproductive organs revealed no abnormalities. Endocrine tests showed a low testosterone level in Twin 1 (male phenotype) and a low gonadotrophin level in Twin 2 (female phenotype) which, combined with the results from ultrasound examination, provided useful information for potentially predicting the future fertility potential of the twins. Blood karyotypes revealed the presence of a normal 46,XX cell line and an aneuploïd 47,XXY cell line in both patients. Examination of the chromosome constitutions of various tissues such as blood, buccal smear and urinary sediment not surprisingly showed different proportions for the 46,XX and 47,XXY cell lines, which most likely explains the discordant phenotypic sex and mild Klinefelter features. The most plausible underlying biological mechanism is a post-zygotic loss of the Y chromosome in an initially 47,XXY zygote. This would result in an embryo with both 46,XX and 47,XXY cells lines which could subsequently divide into two monozygotic embryos through a twinning process. The two cell lines would then be distributed differently between tissues which could result in phenotypic discordances in the twins. These observations emphasize the importance of regular paediatric evaluations to determine the optimal timing for fertility preservation measures and to detect new Klinefelter features which could appear throughout childhood in the two subjects. [ABSTRACT FROM AUTHOR]

Klinefelter syndrome (KS) is a genetic syndrome characterized by the presence of an extra X chromosome that appears to increase the risk of psychopathology, such as autism symptoms. This study used functional magnetic resonance imaging to determine underlying mechanisms related to this risk, with the aim of gaining insight into neural mechanisms behind social-cognitive dysfunction in KS and autism, and understanding similarities and differences in social information processing deficits. Fourteen boys with KS, seventeen boys with autism spectrum disorders (ASD) and nineteen non-clinical male controls aged 10–18 years were scanned while matching and labeling facial expressions (i.e. face processing and affect labeling, respectively). No group differences in neural activation were found during face processing. However, during affect labeling, the ASD group showed increased activation in the amygdala compared with controls, while the KS group showed increased activation in frontal areas compared with both controls and the ASD group. No group differences in task performance were found. Although behavioral symptoms of social dysfunction appear similar both in boys with KS and ASD, this is the first study to demonstrate different underlying etiologies. These results may aid in identifying different pathways to autism symptoms, which may help understanding variability within the ASD spectrum. [ABSTRACT FROM AUTHOR]

Individuals with an extra X chromosome are at increased risk for autism symptoms. This study is the first to assess theory of mind and facial affect labeling in children with an extra X chromosome. Forty-six children with an extra X chromosome (29 boys with Klinefelter syndrome and 17 girls with Trisomy X), 56 children with autism spectrum disorder (ASD) and 88 non-clinical controls, aged 9-18 years, were included. Similar to children with ASD, children with an extra X chromosome showed significant impairments in social cognition. Regression analyses showed that different cognitive functions predicted social cognitive skills in the extra X and ASD groups. The social cognitive deficits were similar for boys and girls with an extra X chromosome, and not specific for a subgroup with high Autism Diagnostic Interview Revised autism scores. Thus, children with an extra X chromosome show social cognitive deficits, which may contribute to social dysfunction, not only in children showing a developmental pattern that is 'typical' for autism but also in those showing mild or late presenting autism symptoms.Our findingsmay also help explain variance in type of social deficit: children may show similar social difficulties, but these may arise as a consequence of different underlying information processing deficits. [ABSTRACT FROM AUTHOR]

The present study aimed to gain more insight in the social behavioral phenotype, and related autistic symptomatology, of children with an extra X chromosome in comparison to children with ASD. Participants included 60 children with an extra X chromosome (34 boys with Klinefelter syndrome and 26 girls with Trisomy X), 58 children with ASD and 106 controls, aged 9 to 18 years. We used the Autism Diagnostic Interview, Social Responsiveness Scale, Social Anxiety Scale and Social Skills Rating System. In the extra X group, levels of social dysfunction and autism symptoms were increased, being in between controls and ASD. In contrast to the ASD group, the extra X group showed increased social anxiety. The effects were similar for boys and girls with an extra X chromosome. [ABSTRACT FROM AUTHOR]

Abstract: Background: Several epidemiological studies have demonstrated an increased mortality from cardiovascular causes in patients with Klinefelter Syndrome (KS). Little information is available about the nature of the underlying cardiovascular abnormalities. Aim of the study was to investigate exercise performance, left ventricular architecture and function, vascular reactivity, and carotid intima-media thickness in a group of patients with KS. Materials and methods: Sixty-nine patients with KS and 48 age-matched controls participated in our population-controlled study. Forty-eight Klinefelter subjects were on testosterone treatment at the time of the investigation while 21 were naive and underwent a complete Doppler echocardiographic examination, a cardiopulmonary exercise test as well as a vascular study including measures of carotid intima-media thickness and endothelial function with flow-mediated dilation of the brachial artery. Patients with KS on testosterone therapy (n=48) were also matched against a population of men with treated secondary hypogonadism (n=21). Results: Patients with KS exhibited a wide array of cardiovascular abnormalities including left ventricular diastolic dysfunction, reduced maximal oxygen consumption (p<0.01), increased intima-media thickness (p<0.05) (−34% and +42% vs. controls, respectively) and a high prevalence of chronotropic incompetence (55% of patients, p<0.01). No significant difference was found between treated and untreated KS in variance with men treated for secondary hypogonadism. Conclusion: Left ventricular diastolic dysfunction, impaired cardiopulmonary performance, chronotropic incompetence, and increased intima-media thickness suggest that cardiovascular abnormalities are a common finding in KS that is not reversed by testosterone replacement therapy and may represent the pathophysiological underpinnings of the increased risk of dying from heart disease. [Copyright &y& Elsevier]

Background: Klinefelter syndrome (KS), caused by XXY karyotype, is characterized by low testosterone, infertility, cognitive deficits, and increased prevalence of health problems including obesity and diabetes. It has been difficult to separate direct genetic effects from hormonal effects in human studies or in mouse models of KS because low testosterone levels are confounded with sex chromosome complement. Methods: In this study, we present the Sex Chromosome Trisomy (SCT) mouse model that produces XXY, XYY, XY, and XX mice in the same litters, each genotype with either testes or ovaries. The independence of sex chromosome complement and gonadal type allows for improved recognition of sex chromosome effects that are not dependent on levels of gonadal hormones. All mice were gonadectomized and treated with testosterone for 3 weeks. Body weight, body composition, and motor function were measured. Results: Before hormonal manipulation, XXY mice of both sexes had significantly greater body weight and relative fat mass compared to XY mice. After gonadectomy and testosterone replacement, XXY mice (both sexes) still had significantly greater body weight and relative fat mass, but less relative lean mass compared to XY mice. Liver, gonadal fat pad, and inguinal fat pad weights were also higher in XXY mice, independent of gonadal sex. In several of these measures, XX mice also differed from XY mice, and gonadal males and females differed significantly on almost every metabolic measure. The sex chromosome effects (except for testis size) were also seen in gonadally female mice before and after ovariectomy and testosterone treatment, indicating that they do not reflect group differences in levels of testicular secretions. XYY mice were similar to XY mice on body weight and metabolic variables but performed worse on motor tasks compared to other groups. Conclusions: We find that the new SCT mouse model for XXY and XYY recapitulates features found in humans with these aneuploidies. We illustrate that this model has significant promise for unveiling the role of genetic effects compared to hormonal effects in these syndromes, because many phenotypes are different in XXY vs. XY gonadal female mice which have never been exposed to testicular secretions [ABSTRACT FROM AUTHOR]

Male-factor infertility is the cause of reproductive issues in many couples. For approximately 15% of these men, the origin of the infertility is genetic. These causes include both chromosomal and single-gene disorders frequently impacting spermatogenesis. By identifying the genetic mechanism behind the infertility, we determine the ability of the couple to use assisted reproduction technologies. Use of these methods has ignited a new spectrum of concerns for the genetic competence of the offspring. By knowing what specific genetic risks exist for the offspring of men with these particular disorders, we are able to use preimplantation genetic diagnosis to detect these problems. [ABSTRACT FROM AUTHOR]

Klinefelter syndrome (KS) is a chromosomal condition (47, XXY) that may help us to unravel gene–brain behavior pathways to psychopathology. The phenotype includes social cognitive impairments and increased risk for autism traits. We used functional MRI to study neural mechanisms underlying social information processing. Eighteen nonclinical controls and thirteen men with XXY were scanned during judgments of faces with regard to trustworthiness and age. While judging faces as untrustworthy in comparison to trustworthy, men with XXY displayed less activation than controls in (i) the amygdala, which plays a key role in screening information for socio-emotional significance, (ii) the insula, which plays a role in subjective emotional experience, as well as (iii) the fusiform gyrus and (iv) the superior temporal sulcus, which are both involved in the perceptual processing of faces and which were also less involved during age judgments in men with XXY. This is the first study showing that KS can be associated with reduced involvement of the neural network subserving social cognition. Studying KS may increase our understanding of the genetic and hormonal basis of neural dysfunctions contributing to abnormalities in social cognition and behavior, which are considered core abnormalities in psychiatric disorders such as autism and schizophrenia. [ABSTRACT FROM AUTHOR]

Backgrounds: While XXY aneuploidy is the most common disorder of sex chromosomes in men, complex chromosomal rearrangements (CCRs) are rare in humans. Case description: Here we describe clinical and cytogenetic findings in a male referred to our cytogenetic laboratory by an infertility clinic. The patient's age was 35 at the time of referral. Total azoospermia was confirmed on semen analysis. Results: The karyotype of peripheral blood showed 47,XXY,t(1;3;5)(p22;q29;q22). The mother had the same CCRs. Discussion: To our best of our knowledge this is the first case of 47,XXY with CCRs. We think it is important to report such a unique chromosomal occurrence. [ABSTRACT FROM AUTHOR]

A rare sex chromosome aneuploidy syndrome, 49,XXXXY syndrome is characterized by mental retardation with severe learning difficulties, craniofacial and skeletal abnormalities, hypogonadism, and congenital heart disease. The authors describe a 30-month-old boy with 49,XXXXY syndrome, global developmental delay and white matter changes in the brain magnetic resonance imaging. They reviewed the literature to delineate a specific magnetic resonance imaging pattern of 49,XXXXY syndrome. [ABSTRACT FROM PUBLISHER]

Objective: In this study, the effects of testicular sperm extraction (TESE) outcome on Y microdeletion, caryotype analysis, and pathology results in azoospermic infertile male patients were investigated. Materials and methods: A total of 165 azoospermic infertile male patients who underwent TESE between January 2008-December 2009 in Ege University Faculty of Medicine, Urology Department have been evaluated for medical history, physical examination, spermiogram, caryotype analysis, Y chromosome microdeletion, FSH level, and TESE outcome regarding sperm availability. Results: Mean age of patients was 34±5.42 years, mean time of infertility was 73±57.7 months, and infertility type was primary in 98.8% of cases. Mean testicular volume was 12.3 cc, and varicocele was detected in 32 patients. Mean FSH level was 17 IU/mL. In 10 of the cases AZFc deletion, in 1 case AZFb deletion and in 1 case both deletions were identified. Number of patients underwent microTESE and conventional TESE were 109 and 56, respectively. Regarding the pathological outcomes, 91 (55.2%) cases were germinal cell aplasia, 32 (19.4%) cases were maturation arrest, 23 (13.9%) cases were normal spermatogenesis, 10 (6.1%) cases were tubulary sclerosis, 9 (5.5%) cases were hipospermatogenesis. The cases in which Y microdeletion was present, pathological outcome was 75% germinal cell aplasia and 25% maturation arrest. Sperm avaliability was present in 37.5% of all cases, and this ratio was 27.2% in the cases with AZFc mutation. Conclusion: TESE operation is a method that can be applied successfully in the treatment of azospermia. Detection of the AZF gene mutations is useful to predict a negative TESE outcome. [ABSTRACT FROM AUTHOR]

To compare our recent findings in a cohort of 77 nonmosaic XXY infants <2 years of age with clinical and biological features already reported. The majority of reported XXY neonates had normal external genitalia. Only undescended testes and/or micropenis were identified reasons for referral. Delayed ambulation and speech skills were also indications for postnatally karyotyping. All subjects from our cohort (73 prenatally detected subjects, five postnatal diagnoses) had height and weight within the normal range, and were not dysmorphic. Insulin-like-peptide-3 and testosterone secretion by Leydig cells appeared normally sensitive to luteinizing hormone. In reported studies, inhibin B levels were within normal range, anti-Mullerian hormone levels were normal or high and follicle-stimulating hormone (FSH) levels were significantly higher than control values, data consistent with a relative resistance to FSH. Early detection of Klinefelter syndrome is desirable for prospectively monitoring the apparition of developmental problems and the progressive decline in the tubular function of the testis, with the hope of designing future conservative interventions before germ cell degeneration is completed. [ABSTRACT FROM AUTHOR]

Klinefelter's syndrome (KS) is the most common sex chromosome abnormality identified in human males. This syndrome is generally associated with infertility. Men with KS may have a 47,XXY or a 46,XY/47,XXY karyotype. Studies carried out in humans and mice suggest that only XY cells are able to enter and complete meiosis. These cells could originate from the XY cells present in mosaic patients or from XXY cells that have lost one X chromosome. In pig, only 3 cases of pure 39,XXY have been reported until now, and no meiotic analysis was carried out. For the first time in pig species we report the analysis of a 38,XY/39,XXY boar and describe the origin of the supplementary X chromosome and the chromosomal constitutions of the germ and Sertoli cells. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Several genetic mechanisms have been proposed for the variability of the Klinefelter syndrome (KS) phenotype such as the parent-of-origin of the extra X chromosome. Parent-of-origin effects on behavior in KS can possibly provide insights into X-linked imprinting effects on psychopathology that may be extrapolated to other populations. Here, we investigated whether the parent-of-origin of the supernumerary X chromosome influences autistic and schizotypal symptom profiles in KS. Methods: Parent-of-origin of the X chromosome was determined through analysis of the polymorphic CAG tandem repeat of the androgen receptor gene. Autistic traits (Autism Diagnostic Interview—Revised) were measured in a younger KS sample (n = 33) with KS and schizotypal traits (Schizotypal Personality Questionnaire) were assessed in an older KS sample (n = 43). Scale scores on these questionnaires were entered in statistical analyses to test parent-of-origin effects. Results: The results show that parent-of-origin of the X chromosome is reflected in autistic and schizotypal symptomatology. Differences were shown in the degree of both schizotypal and autistic symptoms between the parent-of-origin groups. Furthermore, the parent-of-origin could be correctly discriminated in more than 90% of subjects through Autism Diagnostic Interview-Revised scales and in around 80% of subjects through Schizotypal Personality Questionnaire scales. Conclusions: These findings point to parent-of-origin effects on psychopathology in KS and indicate that imprinted X chromosomal genes may have differential effects on autistic and schizotypal traits. Further exploration of imprinting effects on psychopathology in KS is needed to confirm and expand on our findings. [ABSTRACT FROM AUTHOR]

This section presents abstracts of papers featured at the 2009 International Research Symposium of the Society for the Study of Behavioural Phenotypes (SSBP) including deletions of neurexin-I predispose to a wide spectrum of developmental disorders and brain stimulation for self-injury and aggression in Lesch-Nyhan Syndrome.

Abstract: Because of the risk for development of psychopathology such as psychotic symptoms, it has been suggested that studying men with the XXY karyotype may help in the search for underlying cognitive, neural and genetic mechanisms. The aim of this study was to identify cognitive mechanisms that may contribute to disorganization of thought in XXY men. A group of 24 XXY men and two non-clinical control groups (N =20, N =18) participated in the study. The level of disorganization of thought was measured using the Schizotypal Personality Questionnaire. We assessed IQ, lateralization of verbal information processing and executive functions including inhibition and mental flexibility. XXY men with high levels of disorganization showed more severe impairments in mental flexibility and inhibition as compared to non-clinical controls and other XXY men. This subgroup also showed a stronger reduction in lateralization of verbal information processing. IQ measures did not differentiate XXY men with high versus low levels of disorganization. These findings indicate that executive impairments in the domains of inhibition and mental flexibility might play a role in the increased vulnerability for disorganized thought in the XXY group. Reduced lateralization of verbal information processing points to non-optimal cerebral specialization in the XXY group, especially in XXY men with high levels of disorganization. This fits with deficits in brain functions most vulnerable to such maturational disruptions, i.e. executive dysfunctions. Our findings are in line with those reported for schizophrenia patients with thought disorder. We speculate that the underlying mechanisms of thought disorder probably are deficit specific rather than disorder specific. [Copyright &y& Elsevier]

Although tremor is deemed to be the commonest movement disorder, in adults the differential diagnosis usually boils down to whether the patient has Essential Tremor or Parkinson's Disease, which has likely led to an overdiagnosis of these conditions; yet, many important rare syndromes should be considered in the differential diagnosis of patients with tremor. The aim of this review is to focus on rare forms of tremor, also in view of the new tremor classification, as well as on tremor occurring in other neurological disorders to aid their recognition. Some of the conditions reviewed here are treatable and therefore should not be missed. This review includes orthostatic tremor, focal and task-specific tremors, Holmes tremor, palatal and oculopalatal tremor, cortical tremor, some genetic forms of tremor including fragile X-associated tremor/ataxia syndrome as well as tremor associated with neuromuscular disorders, multiple sclerosis and Wilson's disease, providing an array of demonstrative videos. The recognition of these disorders should aid the physician to make a correct diagnosis and guide a prompt intervention. This article is part of the Special Issue "Tremor" edited by Daniel D. Truong, Mark Hallett, and Aasef Shaikh. • In adults the differential diagnosis of tremor usually boils down to whether the patient has ET or PD • The new tremor classification has revised the nosology of tremor syndromes • Recognition of rare tremors is crucial because some of them are treatable disorders. • Newly identified disorders have widened the list of the genetic causes of tremor. [ABSTRACT FROM AUTHOR]

Abstract: In man, the incidence of reproductive failures is high and chromosomal abnormalities remains the major cause of pregnancy wastage. The advent of molecular cytogenetic techniques and assisted reproduction technology have brought forth new approaches for the chromosomal analysis of human oocytes and spermatozoa. The oocyte analyses have evidenced the high rate of chromosomal abnormalities in women and identified premature separation of sister chromatid as a major mechanism in aneuploidy occurrence. High frequencies of aneuploidy have been found in various groups of women, such as patients over 35 or 38 years old, patients with recurrent implantation failures or recurrent miscarriages. The polar body analysis has confirmed the major contribution of premature separation of sister chromatids in aneuploidies and the effect of maternal ageing on its occurrence. In spermatozoa, the efficient adaptation of in situ chromosomal detection techniques has facilitated the segregation analysis of chromosomal abnormalities. Despites the consensus observed in sperm studies of robertsonnian translocations and inversions, new data are required for accurate estimates of imbalances in various types of structural rearrangements. For infertile patients with normal karyotypes, there is significant increase in aneuploidy frequencies, which can be extremely elevated in some groups of subjects, such as patients with large headed spermatozoa syndrome. [Copyright &y& Elsevier]

Background/Aims: Klinefelter’s syndrome is characterized by progressive testicular failure causing aspermatogenesis and androgen deficiency. Klinefelter patients classically have complete male sex differentiation, and genital anomalies are generally not recognized as associated features of the syndrome. Methods: We reviewed the cases of Klinefelter’s syndrome with genitalia abnormalities from the Cambridge Disorders of Sex Development Database, and also reviewed previous case reports of genital anomalies associated with Klinefelter’s syndrome and its variants. Results: We present seven Klinefelter patients with abnormalities of the genitalia, ranging from mild anomalies (chordee) to moderate undervirilisation (bifid scrotum and perineal hypospadias). Two cases were true hermaphrodites with karyotypes 47,XXY and 47,XXY/46,XX respectively. Though androgen insensitivity has been postulated previously as a possible pathogenic mechanism, we demonstrated normal androgen binding in 3 cases in which this was studied. Review of other case reports revealed a range of mild-to-severe abnormalities as well as cases reported as sex reversal, testicular feminization, and true hermaphroditism. Conclusion: Genital anomalies are not commonly observed in Klinefelter’s syndrome. However, it is important to acknowledge the association, and recognize Klinefelter’s syndrome as one of the causes of abnormal genitalia at birth. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: The presence of an additional X-chromosome in Klinefelter patients provides an opportunity to study the influence of this chromosome on psychiatric disorders. Previous studies have reported an excess of Klinefelter patients in psychiatric patient groups. We report an increased prevalence of psychiatric disorders including psychotic disorders in a sample of Klinefelter patients but could not find evidence of an effect of the parental origin of the extra X-chromosome on the psychiatric phenotype. Nevertheless, these findings provide further support for the role of the X-chromosome in the susceptibility to psychiatric disorders in general and psychotic disorders in particular. [Copyright &y& Elsevier]

Male infertility represents one of the clearest examples of a complex disease with a substantial genetic basis. Numerous male mouse models, mutation screening and association studies reported over the last few years reveal the high prevalence of genetic causes of spermatogenic impairment, accounting for 10-15% of severe male infertility, including chromosomal aberrations and single gene mutations. Natural selection prevents the transmission of mutations causing infertility, but this protective mechanism may be overcome by assisted reproduction techniques. Consequently, the identification of genetic factors is important for appropriate management of the infertile couple. However, a large proportion of infertile males are diagnosed as idiopathic, reflecting poor understanding of the basic mechanisms regulating spermatogenesis and sperm function. Furthermore, the molecular mechanisms underlying spermatogenic damage in cases of genetic infertility (for example Yq microdeletions) are not known. These problems can be addressed only by large scale association studies and testicular or spermatozoal expression studies in well-defined alterations of spermatogenesis. It is conceivable that these studies will have important diagnostic and therapeutic implications in the future. This review discusses the genetic causes of male infertility known to date, the genetic polymorphisms possibly associated with male infertility, and reports novel results of global gene expression profiling of normal human testis by microarray technology. [ABSTRACT FROM AUTHOR]

Abstract: Genetic causes account for 10–15% of severe male infertility, including chromosomal aberrations and single gene mutations. Natural selection prevents the transmission of mutations causing infertility, while this protective mechanism may be overcome by assisted reproduction techniques. Consequently the identification of genetic factors has become good practice for appropriate management of the infertile couple. Furthermore, patients affected by some forms of genetic alterations produce a higher frequency of sperm with aneuploidies. Sperm aneuploidies are the direct result of the constitutional genetic abnormality or are caused by meiotic errors induced by the altered testicular environment that these men present. In this review we will report and discuss the genetic causes of male infertility known up to date and we will analyse genetic polymorphisms possibly associated with male infertility. [Copyright &y& Elsevier]

Abstract: Studying Klinefelter syndrome (47,XXY), a genetically defined disorder characterized by the presence of an additional X chromosome, can reveal insights into genotype–phenotype associations. Increased vulnerability to psychiatric disorders characterized by difficulties in social interactions, such as schizophrenia and autism, has been reported for this population. The reported social difficulties in 47,XXY men may arise as a consequence of impairments in the processing of social and emotional information. The present study is the first investigation of social–emotional information processing in this X chromosomal disorder. 32 Klinefelter men and 26 men from the general population, with the groups matched for age, educational level and I.Q., participated in the study. Several tasks were included, reflecting aspects of social–emotional information processing on levels of perception, experience and expression: labeling of facial expressions of emotion, emotion–cognition interactions in decision making and emotion regulation, that refers to subjective experience and identification of emotional arousal as well as verbal expression of emotions. A discrepancy between cognitive appraisal of emotions and emotional arousal was observed in Klinefelter syndrome. Taken together, Klinefelter men seem less accurate in perception of socio-emotional cues such as angry facial expressions, they are less able to identify and verbalize their emotions, but experience increased levels of emotional arousal, in comparison to the general population. Besides describing the social–emotional phenotype of this X chromosomal disorder, the present data may prove to be an important contribution to the development of more general models describing pathways to neuropsychiatric disorders characterized by social cognitive disturbances. [Copyright &y& Elsevier]

BACKGROUND: Contradictory results are available regarding prediction of testicular sperm extraction in 47,XXY patients. This study, therefore, aimed at assessing the availability of testicular sperm and evaluates clinical parameters predicting successful sperm retrieval in azoospermic 47,XXY Klinefelter’s syndrome patients. METHODS: Sperm recovery procedures were performed in 50 non‐mosaic azoospermic Klinefelter patients. The facial hair pattern and the presence of gynaecomastia in men with successful and unsuccessful sperm recovery were compared using Fisher’s exact test. The predictive value of clinical parameters such as age, testicular volume, FSH, FSH:LH ratio, testosterone and androgen sensitivity index (LH×testosterone) for successful testicular sperm retrieval was evaluated using the receiver operating characteristics (ROC) curve analysis. RESULTS: In 24 patients (48%) testicular sperm were recovered. Ninety‐four per cent of the men in whom sperm was found had a normal facial hair pattern compared to 93% in whom no sperm was recovered (not significant, NS). Seventeen percent of the men with successful testicular sperm extraction had gynaecomastia compared to 31% of the men with failed testicular sperm extraction (NS). The mean testicular volume of the largest testis in patients with sperm found was 4.2 ml compared to 3.6 ml in patients with no sperm found (NS). The mean FSH and testosterone values in patients with sperm recovered were 31.2 IU/l and 3.1 ng/ml versus 40.4 IU/l (P = 0.04) and 3.2 ng/ml (NS) in patients without sperm recovered. All examined clinical and biological parameters failed to predict the outcome of the testicular sperm extraction using ROC curve analysis. CONCLUSION: As in the general population of men with non‐obstructive azoospermia, there are currently no clinical parameters predicting successful sperm retrieval in the subpopulation of patients with non‐mosaic Klinefelter syndrome. [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. [ABSTRACT FROM AUTHOR]

Abstract: Several uncontrolled reports in the literature dating from decades ago suggest a link between Klinefelter syndrome (KS) and essential tremor (ET). Aiming to determine whether this association truly exists, we designed a controlled survey to ascertain the prevalence of reported tremor in KS. We identified subjects with KS through our hospital database and recruited controls among men who were accompanying patients to our Neurology Clinic. The presence of tremor and other variables were recorded employing a previously validated questionnaire. Whereas our control population was slightly older and more frequently reported a family history of tremor, the frequency of reported tremor was significantly higher in subjects with KS than controls with onset at a younger age. In addition, a high proportion of subjects with KS indicated gait imbalance. In summary, our study supports the previously reported association of an ET-like syndrome and KS. [Copyright &y& Elsevier]