Klinefelter Syndrome Patients Research Articles

The Klinefelter syndrome is associated with high recurrence of copy number variations on the X chromosome with a potential role in the clinical phenotype.

The Klinefelter syndrome (KS) is the most frequent sex chromosomal disorder in males, characterized by at least one supernumerary X chromosome (most frequent karyotype 47,XXY). This syndrome presents with a broad range of phenotypes. The common characteristics include small testes and infertility, but KS subjects are at increased risk of hypogonadism, cognitive dysfunction, obesity, diabetes, metabolic syndrome, osteoporosis, and autoimmune disorders, which are present in variable proportion. Although part of the clinical variability might be linked to a different degree of testicular function observed in KS patients, genetic mechanisms of the supernumerary X chromosome might contribute. Gene-dosage effects and parental origin of the supernumerary X chromosome have been suggested to this regard. No study has been performed analyzing the genetic constitution of the X chromosome in terms of copy number variations (CNVs) and their possible involvement in phenotype of KS. To this aim, we performed a SNP arrays analysis on 94 KS and 85 controls. We found that KS subjects have more frequently than controls X-linked CNVs (39/94, [41.5%] with respect to 12/42, [28.6%] of females, and 8/43, [18.6%] of males, p < 0.01). The number of X-linked CNVs in KS patients was 4.58 ± 1.92 CNVs/subject, significantly higher with respect to that found in control females (1.50 ± 1.29 CNVs/subject) and males (1.14 ± 0.37 CNVs/subject). Importantly, 94.4% X-linked CNVs in KS subjects were duplications, higher with respect to control males (50.0%, p < 0.001) and females (83.3%, p = 0.1). Half of the X-linked CNVs fell within regions encompassing genes and most of them (90%) included genes escaping X-inactivation in the regions of X-Y homology, particularly in the pseudoautosomal region 1 (PAR1) and Xq21.31. This study described for the first time the genetic properties of the X chromosome in KS and suggests that X-linked CNVs (especially duplications) might contribute to the clinical phenotype.

Testicular lactate content is compromised in men with Klinefelter Syndrome

Klinefelter syndrome (KS) is the most common genetic cause of human infertility, but the mechanism(s) responsible for its phenotype remain largely unknown. KS is associated with alterations in body composition and with a higher risk of developing metabolic diseases. We therefore hypothesized that KS men seeking fertility treatment possess an altered testicular metabolism profile that may hamper the nutritional support of spermatogenesis. Testicular biopsies from control (46, XY) (n = 6) and KS (47, XXY) (n = 6) individuals were collected and analyzed by proton high-resolution magic-angle spinning nuclear magnetic resonance spectroscopy. The mRNA and protein expression of crucial glycolysis-associated enzymes and transporters were evaluated in parallel by quantitative PCR and Western blot, respectively. Our data revealed altered regulation of glucose transporters (GLUT1 and GLUT3); phosphofructokinase 1, liver isoform (PFKL); and lactate dehydrogenase A (LDHA) expression in the testis of KS patients. Moreover, we detected a severe reduction in lactate and creatine accumulation within testicular tissue from KS men. The aberrant levels of the biomarkers detected in testicular biopsies of KS men may therefore be associated with the infertility phenotypes presented by these men. Mol. Reprod. Dev. 83: 208-216, 2016. © 2015 Wiley Periodicals, Inc.

Bone Mineral Status in Children and Adolescents with Klinefelter Syndrome

Objective. Klinefelter syndrome (KS) has long-term consequences on bone health. However, studies regarding bone status and metabolism during childhood and adolescence are very rare. Patients. This cross-sectional study involved 40 (mean age: 13.7 ± 3.8 years) KS children and adolescents and 80 age-matched healthy subjects. For both patient and control groups, we evaluated serum levels of ionised and total calcium, phosphate, total testosterone, luteinising hormone, follicle stimulating hormone, parathyroid hormone (PTH), 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D, osteocalcin, bone alkaline phosphatase, and urinary deoxypyridinoline concentrations. We also calculated the z-scores of the phalangeal amplitude-dependent speed of sound (AD-SoS) and the bone transmission time (BTT). Results. KS children and adolescents showed significantly reduced AD-SoS (p < 0.005) and BTT (p < 0.0005) z-scores compared to the controls. However, KS patients presented significantly higher PTH (p < 0.0001) and significantly lower 25(OH)D (p < 0.0001), osteocalcin (p < 0.05), and bone alkaline phosphatase levels (p < 0.005). Interestingly, these metabolic bone disorders were already present in the prepubertal subjects. Conclusions. KS children and adolescents exhibited impaired bone mineral status and metabolism with higher PTH levels and a significant reduction of 25-OH-D and bone formation markers. Interestingly, this impairment was already evident in prepubertal KS patients. Follow-ups should be scheduled with KS patients to investigate and ameliorate bone mineral status and metabolism until the prepubertal ages.

Early onset of puberty in an obese boy with Klinefelter syndrome.

Klinefelter syndrome (KS) is one of the most common disease entities characterized by X-chromosomal aberration causing the primary hypogonadism in adult men. Patients with KS seem to be typically characterized by tall, slender bodies with delayed puberty and hypergonadotropic hypogonadism. However, it has been known that they have a broad spectrum of phenotype ranging from almost normal external appearances to typical phenotype. Only 25% KS Patients are ever diagnosed because KS remains unrecognized. Also, boys with KS have an onset of pubertal development within the normal range, not delayed onset of puberty. Adolescents with KS are generally diagnosed as having the lack of pubertal progress. Early detection of KS can be difficult without awareness. We report an unusual case of early onset of puberty in obese boy with KS who presented with a unilateral non-hormone secreting testicular teratoma.

Attitudes of parents of Klinefelter boys and pediatricians towards neonatal screening and fertility preservation techniques in Klinefelter syndrome.

To evaluate the attitude of parents of Klinefelter syndrome (KS) boys and pediatricians with regard to early detection of KS and fertility preservation, a specific questionnaire investigating the acceptability towards neonatal screening for KS and the use of testicular biopsy and sperm collection was designed. The responses of 49 pediatricians and 18 parents were evaluated. All parents and 67% of the pediatricians consider neonatal screening for KS to be a good option. A total of 83.3% of the parents agree on performing a testicular biopsy in their pubertal KS boy, 72.2% are in favor of banking spermatozoa after masturbation while 77.7% agree on spermatozoa banking after penile vibro-stimulation or rectal electro-stimulation under general anesthesia. Sixty-nine percent of pediatricians would counsel parents and KS adolescents in favor of early detection and cryopreservation of spermatozoa after masturbation, and 71.2% agrees on testicular biopsy to detect spermatozoa or eventually spermatogonial stem cells (SSCs) for cryopreservation in minor KS patients. The majority of KS parents and pediatricians, completing a specific designed questionnaire on fertility preservation modalities, were in favor of neonatal screening of KS. Both sperm collection and SSC collection are highly appreciated by parents and pediatricians, despite the currently experimental character of these fertility preservation strategies.

The effects of transverse and longitudinal incision of tunica albuginea in microdissection testicular sperm extraction

The effects of transverse and longitudinal incision of tunica albuginea in microdissection testicular sperm extraction

The capacity to induce generation of premeiotic and meiotic cells from biopsies without sperm from nonobstructive azoospermic and klinefelter syndrome patients were different under in vitro culture conditions

To induce spermatogenesis in vitro using cells from testicular biopsies, of nonobstructive azoospermic and Klinefelter syndrome patients, in which mature sperm cells were not found after thorough search.

Age and markers of Leydig cell function, but not of Sertoli cell function predict the success of sperm retrieval in adolescents and adults with Klinefelter's syndrome.

Microsurgical testicular sperm extraction (mTESE), combined with intracytoplasmic sperm injection (ICSI) represents a chance for azoospermic men with Klinefelter's syndrome (KS) to father children. The objective of this study was to identify predictive factors for the success of mTESE from adolescents and adults with KS. The clinical data of 50 late pubertal adolescents (13-19years) and 85 adult patients (20-61years) with non-mosaic KS, who underwent mTESE, were analysed with respect to factors, potentially predictive of active spermatogenesis; specifically a history of cryptorchidism, age, testicular volumes, serum levels of LH, FSH, testosterone (T) and estradiol at the time of surgery. Inhibin B, AMH and INSL3 were additionally analysed in the adolescents. A younger age and a near-compensated Leydig cell function were associated with higher success of sperm retrieval via mTESE: In adolescents ≥15-19years, spermatozoa were retrieved in 45%, compared to 31% in adults; in adolescents aged 13-14years, spermatozoa were collected in only 10%. Adolescents with an LH ≤17.5U/L, along with a T level ≥7.5nmol/L had the best success rate (54%), which fell to 44% with higher LH, whereas those with low T (<7.5nmol/L), irrespective of LH had no sperm retrieval. In adults with T levels above and LH below these thresholds, the success rate was 51%, falling to 19%, if LH was higher. When T was lower than threshold, the rate was 17%. No association between testicular volumes, serum levels of FSH, Inhibin B, AMH, estradiol and mTESE success was found. A history of cryptorchidism was associated with lower retrieval rates. A window of opportunity for an approximate 50% chance to retrieve spermatozoa via mTESE exists for young, late pubertal KS patients between age 15 and young adulthood, when Leydig cell function is at its best. In these cases, referral to a centre of expertise should be considered.

Increased platelet reactivity in Klinefelter men: something new to consider.

Patients with Klinefelter syndrome (KS) exhibit an increased cardiovascular risk, but underlying mechanisms are largely unknown. The present cross-sectional study has been conducted to evaluate platelet reactivity and the expression of platelet activation markers (8-iso-prostaglandin F2α[8-iso-PGF2α] and 11-dehydro-thromboxane-B₂[11-dehydro-TXB2]) in KS patients and healthy controls. Twenty-three consecutive KS patients under testosterone replacement therapy have been included as case group and 46 age-matched healthy males recruited among hospital staff served as controls. Light transmission aggregometry was performed in both cases and controls and maximal platelet aggregation (max-A%) was defined as maximal light transmittance reached within 5min after the addition of 0.2 or 0.4mm arachidonic acid (AA). A≥50% irreversible light transmittance (LT-50%) following platelet stimulation defined an adequate platelet aggregation and AC-50% was defined as the minimal agonist concentration needed to achieve LT-50%. The AC-50% was 0.26mm AA for KS and 0.36mm for controls (p<0.001). Whereas AA (0.2mm) induced LT-50% in 69.6% of KS and in 15.2% of controls (p<0.001), the stimulation with AA (0.4mm) determined LT-50% in all cases and controls. However, max-A% was higher in KS than in controls both after AA (0.2mm) (65.61% vs. 46.30%, p=0.002,) and after AA (0.4mm) (96.43% vs. 81.04%, p<0.001). 8-iso-PGF2α and 11-dehydro-TXB2 were higher in KS than in controls (446.54pg/mg creatinine vs. 230.00pg/mg creatinine, p<0.001 and 1278.36pg/mg creatinine vs. 595.08pg/mg creatinine, p=0.001, respectively) and AC-50% inversely correlated with 8-iso-PGF2α (ρ=-0.548, p<0.001) and with 11-dehydro-TXB2 (ρ=-0.523, p<0.001). In a linear regression model, KS independently predicted a lower AC-50% (β=-0.597, p<0.001) and higher levels of 8-iso-PGF2α (β=0.709, p<0.001) and 11-dehydro-TXB2 (β=0.605, p<0.001). In contrast, no correlation has been found between max-A%, testosterone and estradiol levels in KS. We observed increased platelet reactivity in KS. This might, at least in part, explain the increased thrombotic risk associated with this disease.

Derivation of integration‐free iPSCs from a Klinefelter syndrome patient

PurposeKlinefelter syndrome (KS) (47, XXY) is the most common sex chromosome abnormality in humans. KS is characterized by gynecomastia, tall stature, small testes, low testosterone levels, learning disabilities, and behavioral problems. KS is also associated with infertility due to non‐obstructive azoospermia (NOA). The mechanism underlying NOA is still poorly understood, and although there is no current treatment, the use of microdissection testicular sperm extraction (micro‐TESE) followed by in vitro fertilization can result in successful conception. The generation of induced pluripotent stem (iPS) cells derived from KS patients may be useful for studying the disease mechanism and identifying novel therapies.MethodsCells from a KS patient were transduced with Sendai viral vectors encoding four transcription factors, OCT4, SOX2, KLF4, and C‐MYC, and the transduced cells were analyzed for in vitro and in vivo pluripotency.ResultsKS patient‐derived iPS cells were successfully generated and shown to produce teratomas in the testes of SCID mice. In vitro differentiation of the iPS cells into cardiomyocyte‐like cells was confirmed by the presence of clusters of beating cells.ConclusionsKS patient‐derived iPS cells that could differentiate into cardiomyocyte‐like cells were established.

Ploidy of spermatogenic cells of men with non-mosaic Klinefelter's syndrome as measured by a computerized cell scanning system.

This study aims to characterize the origin of testicular post-meiotic cells in non-mosaic Klinefelter's syndrome (KS). The study included testicular tissue specimens from 11 non-mosaic KS patients, with (6 positive) and without (5 negative) spermatozoa presence. The obtained testicular cells were affixed and stained for morphology followed by fluorescence in situ hybridization (FISH) for centromeric probes X, Y, and 18. We used a computerized automated cell scanning system that enables simultaneous viewing of morphology and FISH in the same cell. A total of 12,387 cells from the positive cases, 11,991 cells from the negative cases, and 1,711 cells from the controls were analyzed. The majority of spermatogonia were 47, XXY in both the positive and negative KS cases (88.9 ± 4.76 % and 90.6 ± 4.58 %) as were primary spermatocytes (76.8 ± 8.14 % and 79.6 ± 7.30 %). The respective rates of secondary spermatocytes and post-meiotic cells (round, elongating spermatids and sperm cells) were 1.1 ± 1.39 % in the positive cases, 2.9 ± 3.33 % in the negative cases, compared to 67.6 ± 6.22 % in the controls (P < 0.02). Pairing of both 18 and XY homologous chromosomes in 46,XY primary spermatocytes was 2.5 ± 2.31 % and 3.4 ± 2.39 %, respectively, compared to 19.8 ± 8.95 % in the control group (P < 0.02) and in 47,XXY primary spermatocytes in 2.4 ± 3.8 % in the positive group and 3.2 ± 2.26 % in the negative group. This study presents data to indicate that the majority of primary spermatocytes in the testes of non-mosaic KS patients are 47,XXY and could possibly develop into post-meiotic cells.

Neuropsychology and socioeconomic aspects of Klinefelter syndrome

To summarize recent important studies on neuropsychology and epidemiology of Klinefelter syndrome. PubMed was searched for 'Klinefelter', 'Klinefelter's' and 'XXY' in titles and abstracts. Relevant studies were obtained and reviewed, as well as other articles selected by the authors. Klinefelter syndrome is the most common sex-chromosome disorder in humans, affecting one in 660 men. The key findings in Klinefelter syndrome are small testes, hypergonadotropic hypogonadism and cognitive impairment. Klinefelter syndrome scores significantly below education matched controls on a range of cognitive tests with verbal skills displaying the largest effects. Boys with Klinefelter syndrome are often in the need of speech therapy and many suffer from learning disability and may benefit from special education. New studies are elucidating aspects of cognitive functioning and suggesting that neuropsychological treatment may be of value. The socioeconomic status and educational level of Klinefelter syndrome is severely affected with many struggling to achieve any or only shorter education, resulting in low-income levels and early retirement. In addition, few become fathers and fewer live with a partner compared with controls. Medical treatment is mainly testosterone replacement therapy in order to alleviate acute and long-term consequences of hypogonadism, as well as, treating or preventing the frequent comorbidity. The neurocognitive phenotype of Klinefelter syndrome is being unraveled and the need for psychological and cognitive treatment in many cases is evident. The neurocognitive deficits no doubt influence the socioeconomic status of many Klinefelter syndrome patients, which is clearly inferior to age-matched controls.

Role of vitamin D levels and vitamin D supplementation on bone mineral density in Klinefelter syndrome.

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. 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. 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. 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. 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.

Screening of endocrine organ-specific humoral autoimmunity in 47,XXY Klinefelter's syndrome reveals a significant increase in diabetes-specific immunoreactivity in comparison with healthy control men.

The aim of this study was to evaluate the frequency of humoral endocrine organ-specific autoimmunity in 47,XXY Klinefelter's syndrome (KS) by investigating the autoantibody profile specific to type 1 diabetes (T1DM), Addison's disease (AD), Hashimoto thyroiditis (HT), and autoimmune chronic atrophic gastritis (AG). Sixty-one adult Caucasian 47,XXY KS patients were tested for autoantibodies specific to T1DM (Insulin Abs, GAD Abs, IA-2 Abs, Znt8 Abs), HT (TPO Abs), AD (21-OH Abs), and AG (APC Abs). Thirty-five of these patients were not undergoing testosterone replacement therapy TRT (Group 1) and the remaining 26 patients started TRT before the beginning of the study (Group 2). KS autoantibody frequencies were compared to those found in 122 control men. Six of 61 KS patients (9.8 %) were positive for at least one endocrine autoantibody, compared to 6.5 % of controls. Interestingly, KS endocrine immunoreactivity was directed primarily against diabetes-specific autoantigens (8.2 %), with a significantly higher frequency than in controls (p = 0.016). Two KS patients (3.3 %) were TPO Ab positive, whereas no patients were positive for AD- and AG-related autoantigens. The autoantibody endocrine profile of untreated and treated KS patients was not significantly different. Our findings demonstrate for the first time that endocrine humoral immunoreactivity is not rare in KS patients and that it is more frequently directed against type 1 diabetes-related autoantigens, thus suggesting the importance of screening for organ-specific autoimmunity in clinical practice. Follow-up studies are needed to establish if autoantibody-positive KS patients will develop clinical T1DM.

MP76-09 DIFFERENTIATING KLINEFELTER SYNDROME FROM OTHER ETIOLOGIES OF AZOOSPERMIA USING MICRORNA

INTRODUCTION AND OBJECTIVES: The diagnosis of Klinefelter Syndrome (KS) is made using peripheral blood, which may not reflect genetic aberrations in the gonads. Thus far, exome sequencing has not been successful in the diagnosis of male infertility. MicroRNAs (miRs) are short RNAs that are often differentially expressed in different tissues and disease states. Our objective was to profile miR expression in testicular tissue from patients undergoing microdissection testicular sperm extraction (microTESE) or testis biopsy in order to characterize expression patterns across different karyotypes and stages of spermatogenesis and to develop new testing modalities for male infertility. METHODS: RNA was extracted from testicular tissue from five patients with KS and nonobstructive azoospermia (NOA) as well as from patients with normal male karyotypes, including four patients with obstructive azoospermia and normal testis histology, five patients with NOA and Sertoli cell only syndrome (SCO), and four patients with NOA and early maturation arrest (eMA). MiR profiling was performed using a custom panel (Exiqon) of 22 testis-specific miRs to compare expression across karyotypes. Quantitative polymerase chain reaction was used to generate miR profiles; data analysis was performed using MultiD GenEx software. RESULTS: MicroRNA profile analysis using the 22 miR panel reliably differentiated KS patients from those with normal karyotype. The panel also differentiated patients with normal testis histology from those with SCO, but patients with eMA clustered both with patients with normal histology and SCO patients (dendrogram). CONCLUSIONS: Profiling the pattern of testicular miR expression in patients with NOA is a novel method for diagnosing KS, and may also provide information about likelihood of spermatogenesis. The differential expression of the miRs in this panel shows a strong correlation with testicular histology and further work may reveal the role of miRs as novel regulatory factors of mRNA.

Contrast enhanced ultrasound confirms testicular circulation to be hampered by disturbed vascularization in 41, XXY* mice, a model for Klinefelter syndrome

Testosterone deficiency in Klinefelter syndrome (KS) was thought to result from disturbed Leydig cell (LC) function. However, in a KS mouse model (41,XXY*), LCs were found to be hyperplastic and hyper-reactive. Furthermore, intratesticular testosterone (ITT) concentrations were comparable to controls with a normal karyotype. We confirmed this in a cohort of patients, excluding insufficient ITT levels as the cause of hypogonadism. It was reported that arteries in KS patients are altered and circulation impaired. Changes in testicular vascularization were also found previously in the 41,XXY* mouse model. We hypothesize disturbed testicular blood supply might be involved in the endocrine phenotype. We therefore performed a study in which an enhanced ultrasound based analysis of the testicular blood flow rate in 41,XXY* mice was conducted. Adult male 41,XXY* (n = 5) and littermate mice (n = 6) underwent ultrasound analyses with the Non-Targeted Contrast Agent Vevo MicroMarker. The agent containing gas filled micro-bubbles was administered intravenously for lower body perfusion. After initial perfusion, micro-bubbles were destroyed by high ultrasound pressure and the reperfusion period was documented and analysed. In parallel, electrocardiograms (ECGs) were taken. Afterwards mice were sacrificed and testes removed for histological analysis of the vascularization. Whilst ECGs did not reveal differences in heart function between the groups, the reperfusion time for testes was significantly increased in 41,XXY* mice (XXY* 28.8 ± 1.69 s; XY* 19.9 ± 2.8 s) Testes of 41,XXY* mice (XXY* 4.6 ± 0.10 mm2; XY* 11.1 ± 0.34 mm2) and the area covered by blood vessels (XXY* 0.025 ± 0.003 mm2; XY* 0.040 ± 0.002 mm2) were significantly smaller as revealed by histology. Conclusively, our data indicate an impaired blood flow in testes of males with a supernumerary X chromosome, which might contribute to the endocrine phenotype of KS.

Clinical characteristics of men with non-mosaic Klinefelter syndrome in northeastern China: implications for genetic counseling.

Klinefelter syndrome (KS) is the most common genetic cause of male infertility. Widespread development in assisted reproductive technology has provided non-mosaic KS patients with the opportunity of having biological children. Testosterone replacement therapy and micro-dissection testicular sperm extraction are effective sperm retrieval techniques for KS patients. Despite the success of sperm retrieval and intracytoplasmic sperm injection (ICSI), some areas of early aggressive hormonal spermatogenesis and appropriate management of KS remain controversial. Androgenotherapy, a common treatment for KS, carries a risk of decreasing focal spermatogenesis by lowering the gonadotropin content. Inadequately treated hypogonadism increases psychosocial morbidity in KS patients. Preventive care must be provided from the time of diagnosis, preferentially through a multidisciplinary approach. This indicates the need for improved genetic counseling of KS patients. The aim of this study was to report the prevalence of non-mosaic KS in a Chinese infertile male population. The rate of early diagnosis was lower in KS patients; most of these were diagnosed after rising concerns of reproductive capacity. The mean age of patients with sperm or germ cells was significantly lower, while the semen volume of these patients was significantly higher. However, the semen volume was negatively correlated with the age and ratio of luteinizing hormone/testosterone content in KS patients. Therefore, genetic counseling of KS patients should focus on early diagnosis and timely treatment, in addition to improving the quality of life of all KS patients. The use of testosterone replacement therapy and/ or micro-dissection testicular sperm extraction should be preferentially considered for fertility preservation.

Global transcriptome analysis of peripheral blood identifies the most significantly down‐regulated genes associated with metabolism regulation in Klinefelter syndrome

The molecular pathogenesis of Klinefelter Syndrome (KS) is not fully understood. The aim of this study was to determine differences in gene expression patterns between KS patients and control individuals to help identify disease-related genes and biological pathways. Gene expression profiles of five KS patients and five healthy men were determined by microarray; 21 differentially expressed genes with a fold-change >1.5 and q-value <0.05 were identified between the groups. Genes associated with metabolism regulation and encoding liver fatty acid-binding protein (FABP1), aldehyde dehydrogenase 1 family member L1 (ALDH1L1), and vitronectin (VTN) were the most-significantly down-regulated in KS, as confirmed by quantitative reverse transcription PCR. Notably, none of these differentially expressed genes are normally found on the X chromosome. Thus, our results indicate that aberrant metabolism is involved in the pathogenesis of KS. Further elucidation of the how aberrant expression of metabolism-related genes affect the pathogenesis of KS may lead to the development of novel preventative and therapeutic strategies.

Gene expression patterns in relation to the clinical phenotype in Klinefelter syndrome.

Klinefelter syndrome (KS) is the most common chromosome disorder in men (47,XXY), exhibiting a phenotype with marked variation and increased morbidity. The pathophysiological link between the supernumerary X chromosome and the clinical phenotype remains unknown. To elucidate whether differential gene expression patterns can be detected in KS patients and whether these are related to inherent clinical features. EXAKT (Epigenetics, X-chromosomal Features and Clinical Applications in Klinefelter Syndrome Trial) is a Münster-based prospective project involving 132 Klinefelter men and their parents. A range of cardiovascular, inflammatory, and metabolic factors, in comparison to age-matched male (n = 50)/female controls (n = 50) and in relation to genetic features, is assessed. Our predefined hypothesis was that differential gene expression patterns in blood cells exist in KS patients vs male controls and are related to the clinical phenotype. Differential expression of 36 X-chromosomal and autosomal genes put KS patients into a unique genetic setting vs male and female controls. The KS cohort exhibited increased insulin resistance, enhanced inflammatory and procoagulatory status, higher waist circumference, dyslipidemia, and a markedly shorter 12-lead electrocardiogram QTc interval (partly located within the pathological range) vs male controls (all P < .001). Clinical dyshomeostasis was associated with expression patterns of dysregulated genes (all P < .01). Parental origin of the supernumerary X chromosome was a confounder regarding insulin resistance and cardiac phenotype (P < .05). Results are considered preliminary because gene expression was measured in blood cells. The supernumerary X chromosome contributes to a number of pathologies in KS. The pattern of gene expression is altered in KS, and the degree of differential gene expression is associated with the clinical phenotype.

Referential Choice in the Narratives of Italian Speakers with Klinefelter Syndrome

Klinefelter Syndrome (KS) is a genetic disorder characterized by an uneven neuro-linguistic profile. Whereas cognitive abilities appear to be within the normal range, KS patients often show poor linguistic abilities and language-based learning disorders. Although it has been proposed that KS can be considered a genetic model of language impairment, it is not yet well established whether speakers with KS are impaired in specific psycholinguistics aspects, such as reference production. The choice of an adequate referential expression (whether a full noun phrase, a null or overt pronoun, etc.) involves the use of memory mechanisms to represent the characters and actions involved, but also the ability to judge the attention and the knowledge of the hearer. The present work focuses on KS speakers’ ability to report a story based on a Sylvester and Tweety cartoon (Arnold et al ., 2009). We examine the ability to choose an appropriate referent (overt pronouns vs . null pronoun vs . full noun phrase) made during a narrative by Italian adolescents and young adults with KS (n = 8) and age-matched typically developing controls. In addition, we administered to each participant a full battery of cognitive and linguistic tests. Overall our results indicate that the correct use of referential expressions did not appear to be significantly predicted by the cognitive level of the speakers. Therefore the ability to choose an appropriate referential expression is preserved in KS whereas receptive vocabulary and comprehension skills are significantly lower as compared to controls.