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

Almost 50% of infertility cases are due to male factors, and spermatogenesis failure is one of the most severe forms of male infertility. Sertoli cell-only syndrome (SCOS) also known as germ cell aplasia is characterized by azoospermia in which the seminiferous tubules of testicular biopsy are lined only with Sertoli cells. The definitive diagnosis of SCOS is by diagnostic testicular biopsy. Although SCOS may be a result of Klinefelter syndrome, most of the SCOS men have a normal karyotype. Along with genetic aberrations, signaling pathways and endocrine processes might be major factors in the development of SCOS. Sperm retrieval and intracytoplasmic sperm injection (ICSI) are available treatments for SCOS. However, some SCOS patients do not have therapeutic options to help them having a biological child. This review aims to summarize our present knowledge about SCOS and to highlight the importance of future researches in the diagnosis and treatment of this disorder.

Introduction Male factor infertility concerns 7–10% of men and among these 40–60% remain unexplained. Sources of data This review is based on recent published literature regarding the genetic causes of male infertility. Areas of agreement Screening for karyotype abnormalities, biallelic pathogenic variants in the CFTR gene and Y-chromosomal microdeletions have been routine in andrology practice for >20 years, explaining ~10% of infertility cases. Rare specific conditions, such as congenital hypogonadotropic hypogonadism, disorders of sex development and defects of sperm morphology and motility, are caused by pathogenic variants in recurrently affected genes, which facilitate high diagnostic yield (40–60%) of targeted gene panel-based testing. Areas of controversy Progress in mapping monogenic causes of quantitative spermatogenic failure, the major form of male infertility, has been slower. No ‘recurrently’ mutated key gene has been identified and worldwide, a few hundred patients in total have been assigned a possible monogenic cause. Growing points Given the high genetic heterogeneity, an optimal approach to screen for heterogenous genetic causes of spermatogenic failure is sequencing exomes or in perspective, genomes. Clinical guidelines developed by multidisciplinary experts are needed for smooth integration of expanded molecular diagnostics in the routine management of infertile men. Areas timely for developing research Di−/oligogenic causes, structural and common variants implicated in multifactorial inheritance may explain the ‘hidden’ genetic factors. It is also critical to understand how the recently identified diverse genetic factors of infertility link to general male health concerns across lifespan and how the clinical assessment could benefit from this knowledge.

Venous leg ulcers (VLUs) are the most common causes of leg ulcers due to venous insufficiency. Most cases persist for more than 6 weeks, referred to as chronic VLUs. These chronic ulcers have been described as a manifestation of Klinefelter syndrome (KS). Platelet-rich fibrin (PRF) is a second-generation platelet concentrate, which contains growth factors required for chronic wound healing. The use of PRF in the management of VLUs in KS has not been reported, to the best of our knowledge. We report a case of chronic VLU associated with KS in a 41-year-old man treated with PRF. Dermatological examination showed a tender, shallow, irregular ulcer partly covered with hard, yellow necrotic tissue on the anterior side of the lower-left leg and hyperpigmented indurated skin on both lower legs. The diagnosis of venous ulcer was established based on clinical manifestation and supported by the result of Doppler ultrasound showed chronic venous insufficiency. Histopathological examination, which showed epidermal acanthosis, dermal fibrosis, and thickening with hemosiderin deposits consistent with the diagnosis of venous ulcer. The patient presented with eunuchoid features characterized by long extremities, gynecomastia, increased fat distribution around the hips, scanty pubic hairs, and small testes. Laboratory tests found decreased levels of testosterone, increased levels of follicle-stimulating and luteinizing hormone, and bilateral testicular atrophy was found from testicular ultrasound. These physical examinations and laboratory findings supported the diagnosis of KS. The patient was treated with PRF dressing once a week. After 7 weeks of treatment with PRF, the ulcer almost reached complete closure. PRF gives a good result in a chronic VLU with KS.

Moyamoya angiopathy, a rare cerebrovascular condition, can be primary (moyamoya disease) or secondary (moyamoya syndrome). Genetic factors, such as the ring finger protein 213 (RNF213), have been associated with moyamoya disease. However, X-linked moyamoya angiopathy/moyamoya syndrome and hypergonadotropic hypogonadism associated with moyamoya syndrome are rare. We report a case of a 14-year-old boy who presented with transient bilateral hemiparesis, recurrent seizures and cognitive decline. He previously had surgery for left-sided cryptorchidism and had been diagnosed with "epileptic attacks" or "functional movement disorders" in previous hospital admissions. Magnetic resonance angiography of the brain showed narrowing of supraclinoid portion of internal carotid arteries, as well as of middle and anterior cerebral arteries, and the presence of multiple collaterals. These findings were suggestive of moyamoya angiopathy. Laboratory investigations and karyotyping revealed a diagnosis of Klinefelter syndrome. This case presents a unique association of moyamoya angiopathy and Klinefelter syndrome in a boy from a poor socio-economic background, where the diagnosis and adequate treatment were delayed due to a lack of awareness and expertise.

OBJECTIVE To investigate the prevalence of testicular microlithiasis and its association with sperm retrieval rates and histopathology in men with non-obstructive azoospermia. METHODS A total of 120 men underwent scrotal ultrasonography prior to microsurgical testicular sperm extraction. Sperm retrieval rate, testicular histopathology, testicular size, reproductive hormones, karyotyping, Y chromosome microdeletion analyses, and presence of varicoceles and hydroceles were compared between men with and without testicular microlithiasis. RESULTS The total sperm retrieval rate was 40%. Ten men with normal spermatogenesis were excluded. The remaining 110 men with non-obstructive azoospermia were analyzed and testicular microlithiasis was detected in 16 of them (14.5%). The sperm retrieval rate in that subgroup was only 6.2% (1/16) as opposed to 39.4% (37/94) in men with non-obstructive azoospermia and no evidence of microlithiasis (P = 0.009). The mean right and left testicular diameters were significantly lower in the microlithiasis group (P = 0.04). On multivariate logistic regression analysis, the presence of mictolithiasis (odds ratio 7.4, 95% confidence interval 2.3, 12.2; P = 0.01) was the only independent predictor of unsuccessful sperm retrieval. The 15 patients with microlithiasis and without successful sperm extraction were diagnosed by histopathology as having Sertoli cells only. The 16th patient with successful sperm retrieval had a histopathology of mixed atrophy and was diagnosed with Klinefelter syndrome. CONCLUSION The presence of testicular microlithiasis is associated with low sperm retrieval rates among our cohort of men with non-obstructive azoospermia undergoing scrotal ultrasonography prior to microsurgical testicular sperm extraction. Larger, prospective studies should be conducted to confirm these findings.

Objective: Klinefelter syndrome (KS) (47,XXY and variants, KS) is the most common sex chromosome disorder in humans. However, little is known about the onset and progression of puberty in patients with KS. In this study, we describe the onset and progression of puberty in a large series of boys with KS in a single tertiary centre. Design and Patients: Retrospective data (Tanner stages, testicular length, testosterone supplementation, levels of luteinizing hormone [LH] and testosterone) before possible testosterone treatment on 72 KS patients with 47,XXY karyotype were reviewed, and G (n = 59 patients) and P (n = 56 patients) stages were plotted on puberty nomograms. Measurements and Results: One boy had a delayed onset of puberty, as he was at the G1 stage at the age of 13.8 years (-2.2 SDs). No observations of delay were made of boys at Stage G2. The progression of G stages was within normal limits in the majority of patients; only few boys were late at G3 (4.1%; 1 out of 24) and G4 (7.4%; 2 out of 27). Testosterone supplementation was started at the average age of 15.5 years to 35 boys (47%), 2 of whom were over 18 years old. LH level was on average 18.2 IU/L (SD: 6.3 IU/L) and testosterone 9.1 nmol/L (SD: 3.1 nmol/L) when testosterone supplementation was started. Conclusions: Our results suggest that puberty starts within the normal age limits in boys with KS, and testosterone supplementation is not needed for the initial pubertal progression in the majority of patients.

BACKGROUND Human male infertility has a notable genetic component, including well-established diagnoses such as Klinefelter syndrome, Y-chromosome microdeletions and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a majority (60–70%) remain without a clear diagnosis and are classified as unexplained. This is likely in large part due to a delay in the field adopting next-generation sequencing (NGS) technologies, and the absence of clear statements from field leaders as to what constitutes a validated cause of human male infertility (the current paper aims to address this). Fortunately, there has been a significant increase in the number of male infertility NGS studies. These have revealed a considerable number of novel gene–disease relationships (GDRs), which each require stringent assessment to validate the strength of genotype–phenotype associations. To definitively assess which of these GDRs are clinically relevant, the International Male Infertility Genomics Consortium (IMIGC) has identified the need for a systematic review and a comprehensive overview of known male infertility genes and an assessment of the evidence for reported GDRs. OBJECTIVE AND RATIONALE In 2019, the first standardised clinical validity assessment of monogenic causes of male infertility was published. Here, we provide a comprehensive update of the subsequent 1.5 years, employing the joint expertise of the IMIGC to systematically evaluate all available evidence (as of 1 July 2020) for monogenic causes of isolated or syndromic male infertility, endocrine disorders or reproductive system abnormalities affecting the male sex organs. In addition, we systematically assessed the evidence for all previously reported possible monogenic causes of male infertility, using a framework designed for a more appropriate clinical interpretation of disease genes. SEARCH METHODS We performed a literature search according to the PRISMA guidelines up until 1 July 2020 for publications in English, using search terms related to ‘male infertility’ in combination with the word ‘genetics’ in PubMed. Next, the quality and the extent of all evidence supporting selected genes were assessed using an established and standardised scoring method. We assessed the experimental quality, patient phenotype assessment and functional evidence based on gene expression, mutant in-vitro cell and in-vivo animal model phenotypes. A final score was used to determine the clinical validity of each GDR, across the following five categories: no evidence, limited, moderate, strong or definitive. Variants were also reclassified according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines and were recorded in spreadsheets for each GDR, which are available at imigc.org. OUTCOMES The primary outcome of this review was an overview of all known GDRs for monogenic causes of human male infertility and their clinical validity. We identified a total of 120 genes that were moderately, strongly or definitively linked to 104 infertility phenotypes. WIDER IMPLICATIONS Our systematic review curates all currently available evidence to reveal the strength of GDRs in male infertility. The existing guidelines for genetic testing in male infertility cases are based on studies published 25 years ago, and an update is far overdue. The identification of 104 high-probability ‘human male infertility genes’ is a 33% increase from the number identified in 2019. The insights generated in the current review will provide the impetus for an update of existing guidelines, will inform novel evidence-based genetic testing strategies used in clinics, and will identify gaps in our knowledge of male infertility genetics. We discuss the relevant international guidelines regarding research related to gene discovery and provide specific recommendations to the field of male infertility. Based on our findings, the IMIGC consortium recommend several updates to the genetic testing standards currently employed in the field of human male infertility, most important being the adoption of exome sequencing, or at least sequencing of the genes validated in this study, and expanding the patient groups for which genetic testing is recommended.

The aim of present study was to assess the karyotypes of amniotic fluid cells and find the frequency of chromosomal abnormalities and their significance in clinical setting. A total of 15,401 pregnant women were assessed from March 2016 to May 2019, and 14,968 amniotic fluid samples were successfully cultured. These fetuses were grouped according to different indications including advanced maternal age, abnormal nuchal translucency (NT) values, positive first/second trimester screening results, high risk NIPT results, very low PAPP-A and free β-hCG multiples of the normal median (MoM) results, abnormal ultrasound findings or previous history of chromosomal abnormalities. Results indicated the presence of normal karyotype in 90.2% (13,497/14,968) of fetuses. Totally, 46.4% (6945/14,968) of fetuses were 46,XX and 43.8% (6552/14,968) had 46,XY chromosome pattern. A total of 1077 abnormal karyotypes were found among 14,968 fetuses, thus the rate of abnormal fetuses was calculated to be 7.2% (1072/14,968). Meanwhile, a total of 394 cases (2.8%) had a normal polymorphism in their karyotype. In other words, abnormal karyotypes were detected in one of 13.9 cases of patients underwent amniocentesis. Down syndrome, Edward’s syndrome, abnormal mosaicisms and Patau’s syndrome were detected in 4.4% (659/14,968), 0.57% (85/14,968), 0.49% (74/14,968) and 0.24% (36/14,968) of cases, respectively. Sex chromosomal abnormalities including Klinefelter syndrome, Turner syndrome and 47,XXX karyotype were detected in 64 cases (0.43%). In this article, the rates of chromosomal abnormalities are compared between different groups of patients based on the advanced maternal age, abnormal NT values, very low PAPP-A and free β-hCG MoMs results, and positive FTS results. The current investigation provides insight into the most appropriate indications for amniocentesis in Iran.

Метою роботи було навести огляд даних літератури щодо етіології і патогенезу синдрому Клайнфельтера (СК). Нами проведений огляд наукової літератури щодо СК за ключовими словами «синдром Клайнфельтера — Klinefelter syndrome», «синдром Клайнфельтера — Рейфенштейна — Олбрайта — Klinefelter-Reifenstein-Albright syndrome», «пубертатне недорозвинення сім’явивідних канальців — pubertal underdevelopment of seminiferous tubules», «синдром 47, XXY — syndrome 47, XXY» з використанням PubMed як пошукової системи. Статистичні дані щодо СК неоднозначні. Окремими авторами частота народження осіб із СК визначена як 1 випадок на 500–1000 живонароджених хлопчиків, надалі зростає до 3–4 % серед безплідних чоловіків, у пацієнтів із азооспермією діагностується у 10–12 % випадків. Приблизно 10 % випадків СК виявляються шляхом пренатальної діагностики. Фенотипова мінливість може залежати від ступеня вираженості генетичних дефектів, дефіциту андрогенів, чутливості андрогенних рецепторів (CAG-поліморфізм) або від випадкової інактивації додаткового матеріалу X-хромосоми. Педіатри повинні знати про фенотипову мінливість синдрому Клайнфельтера, зокрема звертати увагу на психологічні та вербальні порушення. Необхідно також проводити комплексне молекулярно-генетичне дослідження з медико-генетичним консультуванням усіх дітей із неоднозначними статевими органами. Вчасно призначена терапія зможе мінімізувати не тільки комплекс фенотипових проявів синдрому, але й, можливо, відстрочити швидку втрату клітин сперматогенезу, що дозволить допомогти цим пацієнтам у реалізації їх репродуктивної функції.

AIM: To study sex differences in attention-deficit/hyperactivity disorder (ADHD) symptoms, we explored whether X chromosome absence or excess is independently associated with deficits in attention and hyperactivity, executive function, and processing speed. METHOD: We assessed 116 children (ages 3y 10mo–11y 11mo, mean 8y 5mo, SD 1y 11mo) with a variable number of sex chromosomes: 36 females with Turner syndrome (45, X0), 20 males with Klinefelter syndrome (47, XXY), 37 typically developing females (XX), and 23 typically developing males (XY). RESULTS: X chromosome absence was associated with increased attention problems, hyperactivity, and deficits in inhibitory control, compared with female children with XX (all p0.4), while X excess affected in-laboratory as well as parent-reported working memory (all r>0.4). INTERPRETATION: Our observations provide compelling evidence that the absence or excess of an X chromosome distinctly affects cognition and behaviors associated with ADHD.

Introduction: In many cases of drug allergy, it is necessary to do in vitro test, for several reasons. BAT (basophil activation test) is a very useful weapon in these cases. In many iv. or im. depot preparations, the culprit of the allergic reaction is an excipient, and not the main component. Case report: A 37-year-old male, suffering from a Klinefelter syndrome needed treatment with a preparation of undecanoate of testosterone (Reandron). With the last administered dose, he suffered an anaphylactic shock with Kounis syndrome. The patient declined any in vivo studies, so we thought of BAT as a possibility for the diagnosis. The results were remarkable, showing a very high positivity to castor oil. Conclusions: This is the second case in the world of anaphylaxis to a preparation of Testosterone, and the first one with the castor oil (also called Cremophor or Kolliphor) as responsible. El BAT was essential for the diagnosis and ulterior treatment of this patient. This is the first time, that this study with BAT, has been done with a Testosterone preparation.

Background This study aims to analyze the fertility preservation decision-making and the sperm retrieval rate (SRR) in older adolescents (age 15-19 years) with non-mosaic Klinefelter syndrome (KS) and azoospermia in a male reproductive clinic, and to determine the accumulated SRR in older adolescents by literature review. Methods Older adolescents with non-mosaic KS and azoospermia referred for hypogonadism and fertility concerns were enrolled. Reproductive counseling and fertility preservation options were offered to patients/parents. The acceptability and the reasons affecting the reproductive decision-making were analyzed. Patients/parents who agreed on fertility preservation received microdissection testicular sperm extraction (mTESE) and cryopreservation. A comprehensive literature review regarding the SRRs in older adolescents with KS was conducted. Results A total of eight older adolescents were enrolled. After fertility preservation counseling, three patients/parents (37.5%) agreed to receive mTESE, and spermatozoa were successfully retrieved in two. "Lack of interest" and "inconsistent sperm retrieval result" were the main reasons for refusal. A total of 89 older adolescents from nine articles, and ours were collected for SRR analysis. Most of the reports had a limited number of cases, and none of them described the acceptance rate of sperm retrieval in adolescents. Forty-three out of 89 older adolescents (48.3%) had successful sperm retrieval, and there was no significant difference in the SRR between the mTESE and conventional TESE. Conclusion Successful testicular sperm retrieval in older adolescents with KS is not superior to those reported in adults. Adolescents and their parents should undergo a detailed reproductive consultation process and shared decision-making discussion before considering testicular sperm retrieval.

Introduction: Lipedema is an abnormal deposit of subcutaneous fat most often involving the lower limbs symmetrically. The physiopathology is poorly understood, but its peak of the almost exclusivel...

STUDY QUESTION Should women with X chromosome abnormalities (XCAs) be recommended to have embryos selected by both morphological and cytogenetic assessment through preimplantation genetic testing (PGT) rather than morphological assessment only in conventional IVF/ICSI treatment? SUMMARY ANSWER PGT is not a preferred recommendation for women with XCAs in the absence of other PGT indications. WHAT IS KNOWN ALREADY XCAs are the most frequent sort of chromosomal aberrations in infertile women. Patients with a complete or partial absence of one X chromosome, diagnosed as Turner Syndrome (TS), demonstrate low spontaneous pregnancy rates (5–7%) and high miscarriage rates (22.8–30.8%), as well as high chances of birth defects (20%). PGT is known to improve pregnancy rates and decrease the incidence of miscarriage in couples with chromosomal aberrations such as Robertsonian and reciprocal translocations and Klinefelter Syndrome. STUDY DESIGN, SIZE, DURATION A retrospective cohort study was conducted with 394 women with XCAs and undergoing their first oocyte retrieval and first embryo transfer cycle from June 2011 to August 2019 in the Reproductive Hospital Affiliated to Shandong University. PARTICIPANTS/MATERIALS, SETTING, METHODS Pregnancy outcomes were compared between the conventional IVF/ICSI group (n = 284) and the PGT group (n = 110) in the first fresh or frozen embryo transfer cycle for each woman with XCAs. Three platforms were applied in PGT: fluorescence in situ hybridisation (FISH, n = 34), array comparative genomic hybridisation (aCGH, n = 24) and next-generation sequencing (NGS, n = 51). The embryo aneuploidy rate and distribution of embryonic chromosomal aberrations revealed by aCGH or NGS were analysed and stratified by maternal age and type of XCAs to assess the effect of maternal XCAs on embryo karyotypes. MAIN RESULT AND THE ROLE OF CHANCE The live birth rate (LBR) per embryo transfer was similar between the PGT group and IVF/ICSI group both in the first cycle of fresh or frozen embryo transfer respectively (39.13% in PGTFISH vs 42.58% in IVF/ICSI, Padj=0.558; 66.67% in PGTFISH vs 52.08% in PGTaCGH/NGS vs 53.06% in IVF/ICSI, Padj=0.756), as was the clinical pregnancy rate (60.87% in PGTFISH vs 50.97% in IVF/ICSI, Padj =0.672; 88.89% in PGTFISH vs 58.33% in PGTaCGH/NGS vs 69.39% in IVF/ICSI, Padj =0.480) and the pregnancy loss rate (35.71% in PGTFISH vs 16.46% in IVF/ICSI, Padj =0.136; 12.50% in PGTFISH vs 10.71% in PGTaCGH/NGS vs 23.53% in IVF/ICSI, Padj =0.352). The rates of maternal and neonatal complications were also comparable between the PGT and IVF/ICSI groups with fresh and frozen transfers respectively (10.00% vs 8.85%, P = 1.000; 21.74% vs 14.55%, P = 0.272). Intriguingly, the distribution of embryonic chromosome abnormalities was more frequent on autosomes 22 (20.39%), 21 (18.45%) and 16 (17.47%), compared with the X chromosome (8.73%). LIMITATIONS, REASONS FOR CAUTION Selection bias is an inherent drawback of a retrospective study. First, our participants hosted 4.84% X chromosome mosaicism with few typical somatic anomalies of TS. Second, the incidences of history of recurrent miscarriage and abnormal offspring in the PGT group were higher than in IVF/ICSI group although binary logistic regression analysis was performed to attenuate the modifying effect of confounding factors. Third, FISH performed in this study only used X/Y probes and lacked the reference of autosome, which might have resulted in misdiagnosis and bias. Finally, intrinsic disadvantages could not be totally avoided due to the retrospective nature of this study. WIDER IMPLICATION OF THE FINDINGS In the current study, comparable pregnancy outcomes were revealed among a large cohort of women with XCAs undergoing their first cycles of PGT or conventional IVF/ICSI treatment. Moreover, the X chromosome abnormality was illustrated to cause no higher frequency of aberrations in embryos. Our data provided perspectives for genetic and reproductive counselling to XCAs individuals and their families. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by National Research and Development Plan (2016YFC1000604 and 2017YFC1001100), the National Natural Science Foundation of China (81701406), Shandong Science Fund for Distinguished Young Scholars (JQ201720), Taishan Scholars Program for Young Experts of Shandong Province (tsqn20161069) and Projects of Medical and Health Technology Development Program in Shandong Province (202005010520, 202005010523 and 2016WS0368). There is no conflict of interest to declare. TRIAL REGISTRATION NUMBER N/A.

Introduction: Increased depression and anxiety incidence in infertile individuals treated with assisted reproductive techniques have been shown in studies. Postoperative pain perception after testicular sperm extraction (TESE) is thought to be related to preoperative anxiety in non-obstructive azoospermia (NOA). Materials and methods: Twenty patients with Klinefelter syndrome (KS) and twenty male patients with normal karyotype NOA planned for TESE under local anaesthesia due to azoospermia were included in the study. Spielberger State-Trait Anxiety Inventory (STAI-T and STAI-S) inventory was given to all patients 1 h before surgery. Postoperative pain evaluation was performed at 0, 30, 60 and 120 min with visual analogue scale (VAS). STAI-T inventory was given to the patients again 2 h after the procedure. Results: Preoperative STAI-S and STAI-T scores and postoperative STAI-T scores of patients in the KS group were higher than those in the NOA group, and there was a significant difference in the statistical analysis between the two groups ( p Conclusion: The contribution of anxiety to pain perception should be kept in mind in azoospermic male patients before TESE, and additional measures should be taken considering that this may be experienced at a higher level in KS patients.

Testicular sperm extraction (TESE) is the method of choice for recovering spermatozoa in patients with azoospermia. However, the lack of reliable biomarkers makes it impossible to predict sperm retrieval outcomes at TESE. To date, little attention has been given to anti-Müllerian hormone (AMH) serum levels in adult men with altered spermatogenesis. In this study we aimed to investigate whether serum concentrations of AMH and the AMH to total testosterone ratio (AMH/T) might be predictive factors for sperm retrieval outcomes during TESE in a cohort of 155 adult Caucasian men with azoospermia.AMH serum levels were significantly lower in nonobstructive azoospermia (NOA) that was unexplained, cryptorchidism-related, cytotoxic and genetic (medians [pmol/l] = 30.1; 21.8; 26.7; 7.3; and p = 0.02; 0.001; 0.04;0.0001, respectively]) compared with obstructive azoospermia (OA) (median = 44.8 pmol/l). Lowest values were observed in cases of genetic NOA (p 0.0001, compared with unexplained NOA) and especially in individuals with non-mosaic Klinefelter syndrome (median = 2.3 pmol/l, p 0.0001). Medians of AMH/T values were significantly lower in genetic NOA compared to unexplained, cryptorchidism-related NOA as well as OA. Only serum concentrations of AMH differed significantly between positive and negative groups in men with non-mosaic Klinefelter syndrome. The optimal cut-off of serum AMH was set at 2.5 pmol/l. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of this cut-off to predict negative outcomes of SR were 100 %, 76.9 %, 66.6 %, 100 and 84.2 %, respectively.Serum AMH levels, but not AMH/T values, are a good marker for Sertoli and germ cell population dysfunction in adult Caucasian men with non-mosaic Klinefelter syndrome and could help us to predict negative outcomes of SR at TESE with 100 % sensitivity when serum levels of AMH are below 2.5 pmol/l.RéSUMé: INTRODUCTION: L’extraction chirurgicale de spermatozoïdes testiculaires (ECST) est la méthode qui permet d’offrir aux hommes ayant une azoospermie des chances de paternité via l’assistance médicale à la procréation. Cependant, le manque de biomarqueurs fiables rend impossible de prédire les résultats de l’ECST. À ce jour, peu d’attention a été accordée aux valeurs sériques d’hormone anti-müllérienne (AMH) chez les hommes adultes ayant une spermatogenèse altérée. Dans cette étude, nous avons cherché à déterminer si les concentrations sériques d’AMH et le rapport AMH sur testostérone totale (AMH/T) pouvaient être des facteurs prédictifs des résultats de l’ECST dans une cohorte de 155 hommes adultes caucasiens ayant une azoospermie. RéSULTATS: Les concentrations sériques d’AMH étaient significativement plus faibles dans l’azoospermie non-obstructive (ANO) non inexpliquée, ANO associée à un antécédent de cryptorchidie, ANO d’origine cytotoxique et génétique (médianes [pmol/l] = 30,1; 21,8; 26,7; 7,3; et p = 0,02; 0,001; 0,04;0,0001, respectivement) comparativement au groupe contrôle d’azoospermie obstructive (AO) (médiane = 44,8 pmol/l). Les plus faibles valeurs ont été observées dans le groupe d’ANO d’origine génétique (p = 0,0001, par rapport à l’ANO non inexpliquée) et particulièrement chez les individus avec un syndrome de Klinefelter (médiane = 2,3 pmol/l, p 0,0001). Seules les concentrations sériques d’AMH différaient significativement entre les individus avec résultats positifs et négatifs d’extraction de spermatozoïdes chez les hommes atteints d’un syndrome de Klinefelter non mosaïque. Un seuil optimal du taux sérique d’AMH a été fixé à 2,5 pmol/l. La sensibilité, la spécificité, la valeur prédictive positive, la valeur prédictive négative et l’exactitude de ce seuil pour prédire un résultat négatif étaient de 100 %, 76,9 %, 66,6 %, 100 % et 84,2 %, respectivement. CONCLUSIONS: Seules les concentrations sérique d’AMH, et non pas le rapport AMH/T, sont un bon marqueur du dysfonctionnement des cellules de Sertoli ainsi que des cellules germinales chez les hommes adultes caucasiens atteints du syndrome de Klinefelter non mosaïque. Elles peuvent prédire un résultat négatif du prélèvement de spermatozoïdes lors de l’ECST avec une sensibilité de 100 % lorsque les niveaux sériques sont inférieurs à 2,5 pmol/l.

Klinefelter syndrome (KS) is an uncommon chromosomal disorder in males that has a variable clinical appearance. Classic KS involves an extra X chromosome, (47, XXY), although other variations may exist, including a milder mosaic form as well as multiple extra sex chromosomes with more dramatic phenotypes. KS is underdiagnosed, especially pre-pubertally, owing to a paucity of concrete clinical signs; however, diagnostic rates increase during and after puberty, as the consequences of hypergonadotropic hypogonadism begin to manifest. Testicular failure causing decreased circulating testosterone (T) and germ cell depletion, a hallmark feature in KS, commonly begins shortly after the onset of puberty and leads to the most commonly recognized KS traits: small testes, azoospermia, gynecomastia, decreased facial and pubic hair. While many KS men maintain adequate T levels leading up to young adulthood, some may have lower T levels at an earlier age leading to varied levels of androgenization and clinical KS features. At certain critical time points, absent or decreased T may alter the development of normal male reproductive organs, external genitalia, development of secondary sexual characteristics and spermatogenesis. Testicular failure in utero may lead to ambiguous genitalia, cryptorchidism and/or hypospadias, all of which depend on fetal T production. In the neonatal period and childhood, decreased T levels during the mini-puberty of infancy may negatively impact germ cell differentiation and male neuropsychological development. Finally, decreased T during pubertal and young adulthood can lead to decreased virilization during puberty, eunuchoid skeleton and decreased spermatogenesis. Depending on the timing of the testicular failure, a reproductive window of sperm production may exist to achieve paternity for KS men. The presence or absence of clinical characteristics reflecting decreased androgenization provides an insight to the relative testicular function during these developmental time points for those with KS and contributes to variability within the syndrome.

Purpose 47,XXY is associated with variable neurodevelopmental outcomes including deficits in expressive and receptive language development. Early hormonal treatment (EHT) has been associated with mitigating some deficiencies in boys with 47,XXY. This study investigates these language capabilities of 47,XXY boys in the first five years of life and the associated effects of EHT on these capabilities. Methods One hundred and seventy-five boys with 47,XXY between the ages of 0 and 5 years, 11 months completed neurodevelopmental assessments specific to age examining their expressive and receptive language capabilities. Subjects were grouped by treatment (EHT and No-T) and differences were analyzed. Results In the age groups of under 12 months, 24–35 months, 36–47 months, and 60–71 months, the EHT group scored significantly higher on expressive language assessments than the No-T group (p = 0.09, p = 0.0002, p = 0.009, and p = 0.02, respectively). In the age groups of under 12 months and 24–35 months, the EHT group scored significantly better on the auditory comprehension domain of the PLS-4/5 (p = 0.02 and p = 0.05, respectively) than the No-T group. Conclusion Study data suggest EHT may be essential in optimizing receptive and expressive language development in 47,XXY boys during early childhood, which is critical in fostering reading skills and later academic success.

Male infertility is a multifactorial pathological condition that affects half of infertile couples. The majority of cases are categorized as idiopathic, especially in cases of nonobstructive azoospermia (NOA). An increasing number of genetic abnormalities have been shown to cause spermatogenic impairment with the development of microarray technologies and next-generation sequencing (NGS), moving beyond classical karyotype and polymerase chain reaction analyses of targeted genes. However, the majority of gene mutations, such as Klinefelter syndrome, azoospermia factor microdeletion, or congenital bilateral absence of the vas deferens, fail to function in a one gene-one phenotype manner. Single-cell transcriptome analysis performed using human testicular samples has begun to be published, which has brought about a more comprehensive understanding of testicular pathology. NGS also enables omics approaches, which provide more powerful tools to interrogate the genome, epigenome, transcriptome, and proteome. Simultaneously, the involvement of environmental factors and comorbidities, which may potentially regulate epigenetic factors, has been shown, resulting in a more complex understanding of the pathophysiology of spermatic disorders, especially NOA. The combination of phenotypic data and large amounts of bioinformatical data obtained by NGS may provide a more comprehensive understanding of the pathophysiology of male infertility, which will contribute not only to a diagnosis but also to the proper selection of infertility treatment and the development of new treatment modalities for male infertility.

Klinefelter syndrome (47, XXY; Henceforth: XXY syndrome) is a high impact but poorly understood genetic risk factor for neuropsychiatric impairment. Here, we provide the first neuroimaging study to map resting-state functional connectivity (rsFC) changes in XXY syndrome and ask how these might relate to brain anatomy and psychopathology. We collected resting state functional magnetic resonance imaging data from 75 individuals with XXY and 84 healthy XY males. We implemented a brain-wide screen to identify regions with altered global rsFC in XXY vs. XY males, and then used seed-based analysis to decompose these alterations. We further compared rsFC changes with regional changes in brain volume from voxel-based morphometry and tested for correlations between rsFC and symptom variation within XXY syndrome. We found that XXY syndrome was characterized by increased global rsFC in the left dorsolateral prefrontal cortex (DLPFC), associated with overconnectivity with diverse rsFC networks. Regional rsFC changes were partly coupled to regional volumetric changes in XXY syndrome. Within the precuneus, variation in DLPFC rsFC within XXY syndrome was correlated with the severity of psychopathology in XXY individuals. Our findings provide the first view of altered functional brain connectivity in XXY syndrome and delineate links between these alterations and those relating to both brain anatomy and psychopathology. Taken together, these insights advance biological understanding of XXY syndrome as a disorder in its own right, and as a model of genetic risk for psychopathology more broadly.

The aim was to define the true incidence of gynaecomastia in adolescent boys with Klinefelter syndrome (KS) and to observe testosterone treatment effects on its duration by examination of the prospectively collected data from a specialist referral clinic for boys with KS, with comparison being made with KS boys identified by a historical newborn chromosome screening programme, together with chromosomally normal controls. Fifty-nine boys over age 13 years were referred to a specialist KS clinic; 21 developed gynaecomastia. The comparator was 14 KS boys identified at birth and 94 chromosomally normal control boys. Testosterone was routinely started at the onset of puberty if gynaecomastia, a manifestation of clinical hypogonadism, was present. Oral or transdermal testosterone was administered in the morning, in a reverse physiological rhythm, and doses were increased according to standard pubertal regimens. The incidence of gynaecomastia was not increased in both the KS cohorts compared with controls. The incidence and age of onset of gynaecomastia was 35.6%, at 12.3 (1.8) years in the KS clinic group; 36.0%, at 13.7 (0.6) years in the newborn survey group; and 34.0%, at 13.6 (0.8) years in the controls. Full resolution of the gynaecomastia occurred in the 12/14 KS clinic boys on testosterone treatment who had completed puberty and as long as adherence was maintained.Conclusion: The incidence of gynaecomastia in KS boys (overall 35.6%) is not increased over typically developing boys. Commencing testosterone when gynaecomastia develops with physiological dose escalation and full adherence can result in the resolution of the gynaecomastia. What is Known: • Gynaecomastia is a common feature in Klinefelter syndrome men. • Hypogonadism occurs from mid-puberty onwards with the absence of the usual rise in testosterone levels. What is New: • The incidence of pubertal gynaecomastia in Klinefelter syndrome is not different from typically developing boys. • Early and prompt starting of testosterone gel treatment and increasing the dose physiologically may help to resolve the gynaecomastia without the need for surgery.

Objective We present prenatal diagnosis of mosaicism for double aneuploidy of 47, XXY and trisomy 7 (48,XXY,+7) at amniocentesis in a pregnancy with a favorable outcome. Case report A 33-year-old woman underwent amniocentesis at 17 weeks of gestation because of an increased risk for Down syndrome in maternal serum screening. Amniocentesis revealed a karyotype of 48,XXY,+7[8]/46,XY[16]. Simultaneous array comparative genomic hybridization (aCGH) analysis on uncultured amniocytes revealed the result of arr [GRCh37] (7) × 3 [0.54], (X) × 2 [0.52], (Y) × 1, compatible with trisomy 7 mosaicism and Klinefelter syndrome mosaicism. The parental karyotypes and prenatal ultrasound findings were normal. Repeat amniocentesis performed at 23 weeks of gestation revealed a karyotype of 48,XXY,+7[13]/46,XY[7]. Simultaneous molecular cytogenetic analyses on uncultured amniocytes revealed 30% mosaicism for 48,XXY,+7 by aCGH and 37% (37/100 cells) mosaicism for trisomy 7 and disomy X by interphase fluorescence in situ hybridization (FISH) analysis. Polymorphic DNA marker analysis excluded uniparental disomy (UPD) 7 and indicated a maternal origin of the chromosome aberration. The pregnancy was continued to 39 weeks of gestation, and a 3070-g healthy male baby was delivered. The cord blood had a karyotype of 46,XY, the umbilical cord had a karyotype of 48,XXY,+7[3]/46,XY[37], and the placenta had a karyotype of 48,XXY,+7. At age one month, the neonate was phenotypically normal, and interphase FISH analysis revealed 4.8% (5/105 cells) mosaicism on buccal mucosal cells and 8.9% (8/90 cells) mosaicism on urinary cells for trisomy 7 and disomy X, compared with 2% in normal control. Interphase FISH analysis on buccal mucosal cells at age two months revealed normal findings in 100/100 cells. Conclusion Mosaic 48,XXY,+7 at amniocentesis without UPD 7 can be associated with a favorable fetal outcome. Cytogenetic discrepancy between cultured amniocytes and uncultured amniocytes may occur in mosaic 48,XXY,+7 at amniocentesis.

Klinefelter syndrome (KS) is the most common chromosome aneuploidy and a common cause of infertility in males. KS patients have at least one extra X chromosome, and about 80% of patients have the karyotype 47,XXY. Twenty percent of KS patients have higher-grade aneuploidies (48,XXXY, 48,XXYY, 49,XXXXY) and exert some clinical manifestation different from those with 47,XXY. Here we report the case of a young man who initially presented with diabetic ketosis and foot ulcer and was later diagnosed as having an extremely rare mosaic variant of KS (47,XXY/48,XXXY/49,XXXXY). Clinical and laboratory features are summarized. The patient developed a severe foot ulcer with an 18-month history of diabetes. Learning disability was noted since early childhood. The patient had typical manifestations of KS, including increased height, sparse beard and body hair, and small penis. He also had some characteristic features of patients with additional sex chromosomes, including epicanthal folds, narrow palpebral fissures, prominent elbows, and undescended testicles. Severe myopia and myopic macular degeneration was also found. Lab tests revealed low testosterone and elevated FSH but normal LH levels. Chromosome analysis on lymphocytes revealed an aberration of 47,XXY/48,XXXY/49,XXXXY. This case provides information on KS patients with the extremely rare karyotype 47,XXY/48,XXXY/49,XXXXY, and also emphasizes the importance of considering KS in the differential diagnosis of a sterile male with diabetes.

Background Male factor is the major contributor in roughly half of infertility cases. Genetic factors account for 10–15% of male infertility. Microdeletions of azoospermia factors (AZF) on the Yq region are the second most frequent spermatogenesis disorder among infertile men after Klinefelter syndrome. We detected in our previous study a frequency of 37.5% AZF microdeletions which investigated mainly the AZFb and AZFc. We attempted in this study for the first time to evaluate the frequencies of all AZF sub-regions microdeletions and to analyze reproductive hormonal profiles in idiopathic cases of azoospermic and oligozoospermic men from Sudan. Methods A group of 51 medically fit infertile men were subjected to semen analysis. Four couples have participated in this study as a control group. Semen analysis was performed according to WHO criteria by professionals at Elsir Abu-Elhassan Fertility Centre where samples have been collected. We detected 12 STSs markers of Y chromosome AZF microdeletions using a multiplex polymerase chain reaction. Analysis of reproductive hormone levels including Follicle Stimulating, Luteinizing, and Prolactin hormones was performed using ELISA. Comparisons between outcome groups were performed using Student’s t-test Chi-square test or Fisher’s exact test. Results AZF microdeletion was identified in 16 out of 25 Azoospermic and 14 out of 26 of the Oligozoospermic. Microdeletion in the AZFa region was the most frequent among the 30 patients (N = 11) followed by AZFc, AZFd (N = 4 for each) and AZFb (N = 3). Among the Oligozoospermic participants, the most frequent deletions detected were in the AZFa region (N = 10 out of 14) and was significantly associated with Oligozoospermic phenotype, Fisher's Exact Test (2-sided) p = 0.009. Among the Azoospermic patients, the deletion of the AZFc region was the most frequent (N = 9 out of 16) and was significantly associated with Azoospermia phenotype Fisher's Exact Test p = 0.026. There was a significant difference in Y chromosome microdeletion frequency between the two groups. The hormonal analysis showed that the mean levels of PRL, LH, and FSH in Azoospermic patients were slightly higher than those in oligozoospermic. A weak negative correlation between prolactin higher level and Azoospermic patients was detected. (AZFa r = 0.665 and 0.602, p = 0.000 and 0.0004, AZFb r = 0.636 and 0.409, p = 0.000 and 0.025, and AZFd r = 0.398 and 0.442, p = 0.029 and 0.015). The correlation was positive for AZFa and negative for AZFb and AZFd. Conclusions We concluded in this study that the incidences of microdeletions of the Y chromosome confined to AZF a, b, c and d regions is 58.8% in infertile subjects with 31.4% were Azoospermic and 27.5% were Oligozoospermic. This might provide a piece of evidence that these specified regions of the Y chromosome are essential for controlling spermatogenesis. These findings will be useful for genetic counseling within infertility clinics in Sudan and to adopt appropriate methods for assisted reproduction.

The study investigates the experience of the parents of 48 children who have prenatally diagnosed with Klinefelter syndrome [KS] using a specifically developed questionnaire. Fifty percent of the participants were satisfied with the disclosure process, particularly those who received the diagnosis by an experienced geneticist. One of the aims of genetic and psychological counseling should be showing the advantages of a gradual and early disclosure with their child and underlining the possible advantages and disadvantages of spreading the diagnosis with other people to optimize support and minimize stigmatization.

Klinefelter syndrome (KS) is a common disorder and almost every clinician in almost every sub-specialty of medicine will knowingly or unwittingly treat boys or men with a 47,XXY chromosomal constitution. Although there are numerous aspects of KS worthy of discussion, this contribution will focus specifically on the controversial, and as yet unresolved, issue of whether it is advantageous to harvest testis tissue from peri-pubertal or adolescent boys with KS in a heroic effort to preserve that child's chances of reproduction in his future adult life. What would be the rationale for that, how does the biology of spermatogenesis in the Klinefelter testis impact that decision, and what does the data show? The answer, assembled from a selection of seemingly disparate sources and directions, appears to be "No". We do not have to advocate for an aggressive approach, we do not have to preemptively preserve future fertility. We can justifiably wait until adulthood with equivalent chances of success.

Objective The presence of primary hyperparathyroidism (PHPT) and Klinefelter syndrome (KS) is rare, and its association with KS mosaicism is even rarer. We report an unusual combination of these entities with a mild phenotype of KS. Methods The patient was a 44-year-old male with a history of PHPT who had recurrent urolithiasis despite being treated with a successful parathyroidectomy. On examination, he had axillary hair growth, bilateral gynecomastia, a large port-wine stain at the right hemithorax and upper right limb, and genitalia and pubic hair corresponding to Tanner IV classification with small, normal consistency testicles. Results Laboratory findings were unremarkable except for a slightly elevated luteinizing hormone, which was normal on repeat testing. Because of the picture of unexplained gynecomastia, laboratory findings, and low-volume testis, a diagnosis of KS was considered. Chromosomal analysis revealed a rare 45,X/46,XY/47,XXY/48,XXYY/48,XXXY KS mosaic. Conclusions KS phenotypes are largely variable, and their association with PHPT remains to be elucidated.

Infertility affects approximately 15% of couples. With infertility such a common problem in a generally healthy age group, complete evaluation is needed of both men and women. Infertility work up for men includes a semen analysis, the results of which suggest various supplemental studies, including karyotype. Karyotype is indicated when a patient has findings on history or physical exam concerning for chromosomal abnormalities, azoospermia, or severe oligospermia (count

Introduction: Fanconi Aplastic Anemia is a genetically mostly autosomal recessive disease characterized by various congenital malformations, progressive pancytopenia and a predisposition to hematological malignancies. Congenital anomalies vary from patient to patient and can affect any of the major organ systems, primarily skeletal malformations. Klinefelter syndrome is the most common genetic form of male hypogonadism and the most common karyotype is 47, XXY.Case Report: In the physical examination of a 9-year-old male patient who applied with complaints of weakness and pallor, his weight, height and head circumference measurements were below 3%, microphthalmic in appearance, and other system examinations were normal. However, it was noticed that the testicular volumes were small for their age. The patient, who was diagnosed with 47, XXY Klinefelter Syndrome as a result of chromosomal examinations, was also diagnosed with Fanconi Aplastic Anemia by bone marrow examination and DEB test, and the treatment process was initiated.Conclusion: When the examinations were evaluated, the association of Klinefelter Syndrome and Fanconi Aplastic Anemia, which is very rare, was detected.Keywords: Klinefelter Syndrome, Fanconi Aplastic Anemia, Bone Marrow, ÖZETGiriş: Fankoni Aplastik Anemisi, çeşitli konjenital malformasyonlar, progresif pansitopeni ve genellikle hematolojik malignitelere yatkınlık ile karakterize genetik olarak çoğunlukla otozomal resesif olarak geçen bir hastalıktır. Konjenital anomaliler hastadan hastaya değişir ve başta iskelet malformasyonlarının yanı sıra ana organ sistemlerinden herhangi birini etkileyebilir. Klinefelter sendromu erkek hipogonadizminin en yaygın genetik formudur ve en sık görülen karyotip 47, XXY'dir. Vaka Sunumu: Halsizlik ve solukluk şikayetleri ile başvuran 9 yaşında erkek hastanın fizik muayenesinde kilo, boy ve baş çevresi ölçümleri %3’ün altında, mikroftalmik görünümde idi, diğer sistem muayeneleri normaldi. Ancak, testis volümlerinin yaşına göre küçük olduğu fark edildi. Kromozomal incelemeler sonucunda 47, XXY Klinefelter Sendromu tanısı koyulan hastaya, aynı zamanda kemik iliği incelemesi ve DEB testi ile Fankoni Aplastik Anemisi tanısı da konularak tedavi süreci başlatılmıştır. Sonuç: Yapılan tetkikler değerlendirildiğinde, oldukça nadir olarak görülen Klinefelter Sendromu ve Fankoni Aplastik Anemisi birlikteliği saptanmıştır. Anahtar Kelimeler: Klinefelter Sendromu; Fankoni Aplastik Anemisi; Kemik İliği

Insulin-like factor 3 (INSL3) is an emerging testicular marker, yet larger studies elucidating the clinical role of INSL3 in patients with hypogonadism are lacking. The aim was to describe serum INSL3 concentrations analyzed by LC–MS/MS methodology in males with hypogonadotropic hypogonadism (HH) and Klinefelter syndrome (KS). This was a combined study from two tertiary centers in Denmark and France analyzing INSL3 concentrations by LC–MS/MS. In total, 103 patients with HH and 82 patients with KS were grouped into treated (HH: n = 96; KS: n = 71) or untreated (HH: n = 7; KS: n = 11). Treatment modalities included testosterone and hCG. Serum concentrations and standard deviation (SD) scores of INSL3, total testosterone, and LH according to age and treatment were evaluated. In both HH and KS, INSL3 concentrations were low. In HH, INSL3 was low regardless of treatment, except for some hCG-treated patients with normal concentrations. In untreated HH, testosterone was low, while normal to high in most testosterone- and hCG-treated patients. In untreated KS, INSL3 and testosterone concentrations were low to normal, while in testosterone-treated KS, serum INSL3 was low in most patients. INSL3 SD scores were significantly lower in untreated HH than in untreated KS (p = 0.01). The dichotomy between lower INSL3 and higher testosterone concentrations, particularly observed in hCG-treated patients with HH, confirms that INSL3 is a different marker of Leydig cell function than testosterone. However, the clinical application of INSL3 in males with hypogonadism remains unclear.