Cortical gray matter structure in boys with Klinefelter syndrome.

Klinefelter syndrome (KS, 47,XXY) is a common sex chromosome aneuploidy in males that is associated with a wide range of cognitive, social and emotional characteristics. The neural bases of these symptoms, however, are unclear. Brain structure in 19 pre- or early-pubertal boys with KS (11.5 ± 1.8 years) and 22 typically developing (control) boys (8.1 ± 2.3 years) was examined using surface-based analyses of cortical gray matter volume, thickness and surface area. Boys in the KS group were treatment-naïve with respect to testosterone replacement therapy. Reduced volume in the insula and dorsomedial prefrontal cortex was observed in the KS relative to the TD group, as well as increased volume in the parietal, occipital and motor regions. Further inspection of surface-based metrics indicated that whereas KS-associated increases in volume were driven by differences in thickness, KS-associated reductions in volume were associated with decreases in surface area. Exploratory analyses additionally indicated several correlations between brain structure and behavior, providing initial support for a neural basis of cognitive and emotional symptoms of this condition. Taken together, these data add support for a neuroanatomical phenotype of KS and extend previous studies through clarifying the precise neuroanatomical structural characteristics of that give rise to volumetric alterations.

Resting-State Functional Connectivity and Psychopathology in Klinefelter Syndrome (47, XXY).

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 study to map alterations of functional brain connectivity in XXY syndrome and relate these changes to brain anatomy and psychopathology. We used resting-state functional magnetic resonance imaging data from 75 individuals with XXY and 84 healthy XY males to 1) implement a brain-wide screen for altered global resting-state functional connectivity (rsFC) in XXY versus XY males and 2) decompose these alterations through seed-based analysis. We then compared these rsFC findings with measures of regional brain anatomy, psychopathology, and cognition. XXY syndrome was characterized by increased global rsFC in the left dorsolateral prefrontal cortex (DLPFC)-reflecting DLPFC overconnectivity with diverse rsFC networks. Functional overconnectivity was partly coupled to co-occurring regional volumetric changes in XXY syndrome, and variation in DLPFC-precuneus rsFC was correlated with the severity of psychopathology. By providing the first view of altered rsFC in XXY syndrome and contextualizing observed changes relative to neuroanatomy and behavior, our study helps to advance biological understanding of XXY syndrome-both as a disorder in its own right and more broadly as a model of genetic risk for psychopathology.

Evidence of intrauterine growth restriction and growth hormone deficiency in 49,XXXXY syndrome.

49,XXXXY is an X and Y chromosome variation that occurs in 1:85,000 to 1:100,000 live male births. Previous case studies have described boys with this disorder to be shorter than average when compared with boys with only one extra chromosome and with the mean stature in a small cohort reported to range from the seventh to 33rd percentile. The origin behind the possible differences in height between boys with 47,XXY and 49,XXXXY is currently unknown, however one study hypothesized that it was due to a difference in the expression of the SHOX gene. This study reports on the anthropometric measurements of 84 boys with 49,XXXXY. Forty-five percent of children with 49,XXXXY were found to be below the third percentile in height at the time of evaluation. In addition, 7.14% of the cohort were diagnosed and given treatment for growth hormone deficiency (GHD). The analysis of this cohort demonstrates that the below average heights seen throughout childhood in this population potentially begins prenatally and suggests that boys with 49,XXXXY may be at a higher risk for intrauterine growth restriction (IUGR) and GHD. Future research is needed to investigate the etiology of the poor growth in boys with 49,XXXXY and evaluate the incidence of GHD and IUGR in this population.

Prevalence and determinants of radiological vertebral fractures in patients with Klinefelter syndrome.

BACKGROUND: Klinefelter syndrome (KS) may induce skeletal fragility, but the studies so far published on this topic were mainly focused on the evaluation of bone mineral density (BMD) and bone microstructure, whereas data on fracture risk are still lacking. OBJECTIVE: To evaluate the prevalence and determinants of vertebral fractures (VFs), that is, the hallmark of osteoporosis, in subjects with KS. MATERIALS AND METHODS: Eighty-seven patients with KS (median age 41 years, range 18-64) were consecutively evaluated for radiological VFs (by quantitative morphometry) and lumbar spine and femoral neck BMD (by DXA). Fifty-five patients with KS were also evaluated by the fracture risk assessment (FRAX) tool. RESULTS: Low BMD was found in 22/87 (25.3%) patients [12 with osteopenia, three with osteoporosis and seven with "low BMD per age" (subject < 50 years with Z-score ≤-2.0 SD)] and VFs in 13/87 (14.9%) patients. In patients with VFs, the median spine deformity index was 2 (range 1-9). Prevalence of VFs was similar between healthy and low-BMD patients (15.9% vs 13.6%; P = .80). Noteworthy, patients with VFs had significantly higher age at diagnosis of KS as compared to patients who did not fracture (P = .039), without significant differences in age at the time of observation (P = .162), body mass index (P = .234), testosterone replacement therapy (P = .432), duration of testosterone therapy (P = .409), vitamin D therapy (P = 681), and serum testosterone levels (P = .338). Moreover, patients with VFs were more likely to complain back pain in comparison with those without VFs (33.3% vs 7.4%; P = .047). In 55 cases evaluated by the FRAX® tool, no significant differences in 10-year risk of major fracture (P = .270) and hip fracture (P = .860) were found between fractured and non-fractured patients. CONCLUSIONS: This study provides first evidence that KS may be associated with risk of VFs in close relationship with delay in disease diagnosis but independently of BMD values and serum testosterone levels or testosterone therapy.

Psychological functioning, brain morphology, and functional neuroimaging in Klinefelter syndrome.

Klinefelter syndrome (KS; 47,XXY) impacts neurodevelopment and is associated with an increased risk of cognitive, psychological and social impairments, although significant heterogeneity in the neurodevelopmental profile is seen. KS is characterized by a specific cognitive profile with predominantly verbal deficits, preserved function in non-verbal and visuo-spatial domains, executive dysfunction and social impairments, and by an increased vulnerability toward psychiatric disorders. The neurobiological underpinnings of the observed neuropsychological profile have not been established. A distinct pattern of both global and regional brain volumetric differences has been demonstrated in addition to preliminary findings of functional brain alterations related to auditory, motor, language and social processing. When present, the combination of cognitive, psychological and social challenges has the potential to negatively affect quality of life. This review intends to provide information and insight to the neuropsychological outcome and brain correlates of KS. Possible clinical intervention and future directions of research will be discussed.

Specific learning disorders in sex chromosome aneuploidies: Neural circuits of literacy and mathematics.

Sex chromosome aneuploidies (SCA) are associated with an increased risk for specific learning disorders (SLD). Individuals with Klinefelter Syndrome (KS) show an increased incidence of developmental dyslexia and individuals with Turner Syndrome (TS) are often affected by developmental dyscalculia. Accordingly, KS frequently coincides with verbal deficits, and TS with visual-spatial impairments. Though neurocognitive profiles of KS and TS are well-established, little is known about the neurobiology underling learning in SCA. This review summarizes current structural and functional magnetic resonance imaging (MRI) studies in KS and TS related to literacy and mathematical skills. It includes studies that focus on correlates between brain anatomy and cognition in SCA and on functional brain responses during learning-related tasks and at rest. We highlight important neural circuits that are related to domain-specific skills of literacy and mathematics. We discuss how identifying neuroendophenotypes of learning in SCA might contribute to developing a novel framework for SLD that accounts for potential genetic effects on learning, and from the X and Y chromosomes specifically. Future research directions are considered to establish clear brain-behavior relationships that might ultimately improve the treatment of SLD in SCA across development.

Congenital pulmonary airway malformation associated with mosaic Klinefelter syndrome.

A 26-year-old female, G4 P2012 presented for an anatomy scan at 18 weeks. Multiple macrocysts were seen in the left fetal lung, which lead to a diagnosis of congenital pulmonary airway malformation (CPAM) type II. A fetal MRI examination performed at 24 weeks of gestation confirmed the diagnosis of CPAM type II. A genetic amniocentesis was done to rule out a fetal chromosomal abnormality and the fetus was found to have mosaic Klinefelter syndrome. Fetal CPAM is not usually associated with chromosomal abnormalities unless there are other fetal malformations present. This is the first known case where a fetus with CPAM and no other malformation was found to have mosaic Klinefelter syndrome. Therefore, we believe it is prudent to offer prenatal diagnostic testing whenever a fetus with CPAM is identified with ultrasound.

Epicardial fat: the role of testosterone and lipid metabolism in a cohort of patients with Klinefelter syndrome.

CONTEXT: Klinefelter syndrome (KS), in which subjects have additional copies of X chromosomes, is the most common male sex chromosome abnormality, with a prevalence of 1 in 660 and an incidence of about 1 in 500-700 newborns. Its sign and symptoms include infertility, generally low testosterone levels, and an increased prevalence of obesity and metabolic syndrome. Epicardial fat thickness (EFT) reflects visceral adiposity rather than general obesity. OBJECTIVE: The aim of this study was to analyze echocardiographic EFT in a cohort of patients with KS in comparison with non-obese and obese euploid controls, and to evaluate its correlation with biochemical parameters. DESIGN, SETTING AND PARTICIPANTS: Two hundred and twenty-one KS patients referred to our Rare Endocrine Diseases clinic and 77 age-matched controls underwent Doppler echocardiography and a full investigation of anthropometric and body composition, Serum levels of total testosterone (T), estradiol (E2), sex hormone binding globulin (SHBG), fasting plasma glucose, insulin, cholesterol and triglycerides were obtained. All participants underwent dual energy X-ray absorptiometry (DEXA) scan to assess truncal body fat (TrBF). MAIN OUTCOME MEASURE: EFT, body composition and metabolic parameters in KS patients and how they are affected by genotype. RESULTS: EFT was greater in KS patients than in healthy non-obese (NOb) controls, but lower than in obese (OB) controls. When KS patients were divided into groups (hypogonadal; eugonadal; receiving testosterone replacement therapy [TRT]), EFT was greater in hypogonadal patients than in NOb controls and eugonadal patients, but showed no difference from the OB controls or TRT patients. Hypogonadal patients showed increased TrBF in comparison with NOb controls and eugonadal and TRT patients, and similar TrBF to OB controls. As expected, there was a strong correlation between BMI and EFT in both KS patients and controls (P < 0.0001). In contrast, there was a strong inverse correlation between testosterone and EFT in the control group, but not in KS patients. EFT was significantly correlated with TrBF in both populations (P < 0.0001). Multivariate analyses showed that the major determinants of both EFT and TrBF were BMI and the presence of KS itself. Testosterone and triglycerides were not included as variables in the models. CONCLUSION: EFT in hypogonadal KS subjects was similar to that of the obese eugonadal controls. Even though there was a direct correlation between BMI and EFT in both populations, the influence of TrBF on EFT was stronger. The presence of the supernumerary X chromosome appeared to be one of the strongest determinants of EFT and TrBF, independent of testosterone levels.

Hemorragia masiva en gestación de 16 semanas con diagnóstico de placenta ácreta / Severe bleeding after in 16 weeks of gestation, whith placenta acreta diagnosis

Presentamos el caso de una paciente de 37 años, G2P1. Consultó de urgencia por hemorragia severa tras Interrupción Legal de Embarazo en centro externo (tras el diagnóstico de feto afecto de Sd. Klinefelter). Se realizó una laparotomía urgente por hemorragia incoercible mediante medidas conservadoras, y se practicó una histerectomía hemostática. La placenta ácreta es una patología infrecuente. El diagnóstico es difícil, especialmente durante el primer y segundo trimestre de embarazo. El objetivo del artículo es sospechar en esta patología cuando nos encontremos con una hemorragia severa tras un aborto en el segundo trimestre

We report the case of a 37-year-old patient, G2P1. She consulted as a matter of emergency for severe bleeding after legal interruption of pregnancy in 16 weeks of gestation (after diagnosis of Klinefelter syndrome fetus). A laparotomy was performed DUE to a incoercible bleeding with conservative measures and the treatment consisted in a hemostasis hysterectomy. The placenta acreta is a rare pathology. The diagnosis is difficult to do, especially during the first and second trimester of the pregnancy. The focus of this article is suspect this pathology when we find a severe bleeding after an abortion in the second trimester

Application of Neural Networks for classification of Patau, Edwards, Down, Turner and Klinefelter Syndrome based on first trimester maternal serum screening data, ultrasonographic findings and patient demographics.

BACKGROUND: The usage of Artificial Neural Networks (ANNs) for genome-enabled classifications and establishing genome-phenotype correlations have been investigated more extensively over the past few years. The reason for this is that ANNs are good approximates of complex functions, so classification can be performed without the need for explicitly defined input-output model. This engineering tool can be applied for optimization of existing methods for disease/syndrome classification. Cytogenetic and molecular analyses are the most frequent tests used in prenatal diagnostic for the early detection of Turner, Klinefelter, Patau, Edwards and Down syndrome. These procedures can be lengthy, repetitive; and often employ invasive techniques so a robust automated method for classifying and reporting prenatal diagnostics would greatly help the clinicians with their routine work. METHODS: The database consisted of data collected from 2500 pregnant woman that came to the Institute of Gynecology, Infertility and Perinatology "Mehmedbasic" for routine antenatal care between January 2000 and December 2016. During first trimester all women were subject to screening test where values of maternal serum pregnancy-associated plasma protein A (PAPP-A) and free beta human chorionic gonadotropin (ß-hCG) were measured. Also, fetal nuchal translucency thickness and the presence or absence of the nasal bone was observed using ultrasound. RESULTS: The architectures of linear feedforward and feedback neural networks were investigated for various training data distributions and number of neurons in hidden layer. Feedback neural network architecture out performed feedforward neural network architecture in predictive ability for all five aneuploidy prenatal syndrome classes. Feedforward neural network with 15 neurons in hidden layer achieved classification sensitivity of 92.00%. Classification sensitivity of feedback (Elman's) neural network was 99.00%. Average accuracy of feedforward neural network was 89.6% and for feedback was 98.8%. CONCLUSION: The results presented in this paper prove that an expert diagnostic system based on neural networks can be efficiently used for classification of five aneuploidy syndromes, covered with this study, based on first trimester maternal serum screening data, ultrasonographic findings and patient demographics. Developed Expert System proved to be simple, robust, and powerful in properly classifying prenatal aneuploidy syndromes.

Three cases of Klinefelter's syndrome with unilateral absence of vas deferens.

Genital abnormalities such as congenital uni/bilateral absence of the vas deferens are very rare in Klinefelter's syndrome. Here, we report three cases of Klinefelter's syndrome with unilateral absence of the vas deferens. All cases had small testicles, and unilateral vas deferentia were not palpable. Hormonal evaluations revealed hypergonadotropism. One case had elevated prolactin level, and pituitary adenoma was detected by magnetic resonance imaging. All cases were diagnosed as Klinefelter's syndrome (one of them had mosaicism) cytogenetically, and some CFTR gene mutations were detected. To our knowledge, this is the first case series of both conditions existing simultaneously.

First case of osteopathia striata with cranial sclerosis in an adult male with Klinefelter syndrome.

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.

Testis ultrasound in Klinefelter syndrome infertile men: making the diagnosis and avoiding inappropriate management.

OBJECTIVE: To compare the testicular Color Doppler ultrasound (US), hormone levels, and histological results from 67 infertile men with Klinefelter syndrome (KS), vs. 66 non-KS non-obstructive azoospermic men. METHODS: Scrotal US images were collected from 67 infertile KS and 66 non-obstructive, non-KS azoospermic men. The testis volume, echotexture, vascularity, and microliths were evaluated and graded. We defined the following echo pattern alteration groups: normal, striated, coarse, and measurable nodules. The vascularization was classified as low, normal, moderate, or strong. Testosterone, follicle-stimulating hormone, luteinizing hormone, and inhibin B levels were determined. Large testicular nodules were removed. A testicular biopsy and sperm extraction was performed in 18 of the KS, and all of the 66 non-KS men. RESULTS: The mean testis volume was low in the KS, compared to the non-KS patients: i.e., 2 vs. 8 mL (P < 0.0001). The distributions in the echotexture groups differed markedly, with coarse or nodular patterns in the KS men, and normal/striated patterns in the control patients (P < 0.0001). The vascularization and microlithiasis grades were higher in the KS patients than the control men (P < 0.0001 and P < 0.001, respectively). All of the nodules removed from the KS patients were benign Leydig cell tumors, and all of the biopsies showed marked Leydig cell hyperplasia, with spermatogenesis in only two patients. The non-KS biopsies were predominantly Sertoli cell-only syndrome. CONCLUSIONS: Small testes, with a coarse or nodular echotexture, hypervascularization, and microlithiasis are associated with KS. The KS nodules were benign Leydig cell tumors/hyperplasias.

White matter microstructure in a genetically defined group at increased risk of autism symptoms, and a comparison with idiopathic autism: an exploratory study.

Klinefelter syndrome (47,XXY) is associated with physical, behavioral, and cognitive consequences. Deviations in brain structure and function have been reported, but structural characteristics of white matter have barely been assessed. This exploratory diffusion tensor imaging study assessed white matter microstructure in boys with 47,XXY compared with non-clinical, male controls. Additionally, both similarities and differences between 47,XXY and autism spectrum disorders (ASD) have been reported in cognition, behavior and neural architecture. To further investigate these brain-behavior pathways, white matter microstructure in boys with 47,XXY was compared to that of boys with ASD. Fractional anisotropy (FA), radial diffusivity (Dr), axial diffusivity (Da), and mean diffusivity (MD) were assessed in 47,XXY (n = 9), ASD (n = 18), and controls (n = 14), using tract-based spatial statistics. Compared with controls, boys with 47,XXY have reduced FA, coupled with reduced Da, in the corpus callosum. Boys with 47,XXY also have reduced Dr. in the left anterior corona radiata and sagittal striatum compared with controls. Compared with boys with ASD, boys with 47,XXY show reduced Da in the right inferior fronto-occipital fasciculus. Although this study is preliminary considering the small sample size, reduced white matter integrity in the corpus callosum may be a contributing factor in the cognitive and behavioral problems associated with 47,XXY. In addition, the differences in white matter microstructure between 47,XXY and ASD may be important for our understanding of the mechanisms that are fundamental to behavioral outcome in social dysfunction, and may be targeted through intervention.

Mild Deficits of Cortical Bone in Young Adults With Klinefelter Syndrome or Anorchia Treated With Testosterone.

CONTEXT: There are currently no data evaluating volumetric bone mineral density (BMD), bone geometry, and body composition in adults with Klinefelter syndrome (KS) or anorchia who have been treated with T from adolescence. OBJECTIVE: To determine volumetric BMD, bone geometry using peripheral quantitative computed tomography (pQCT), and body composition using dual-energy x-ray absorptiometry (DXA) in men with classical KS or anorchia treated with T from adolescence (age, <16 y), compared with matched controls. METHODS: Twenty subjects (12 KS, eight anorchia) and 20 controls underwent a pQCT (66% tibia, 4% radius) and total body DXA. RESULTS: Using adjusted regression models, there was reduced tibial cortical area (95% confidence interval [CI], -88.8 to -4.4 mm(2); P = .03) and thickness (95% CI, -0.98 to -0.10 mm; P = .02) in subjects. All other bone parameters were similar between groups. Subjects had significantly higher fat mass (95% CI, 1.6 to 14.9 kg; P = .02), trunk:leg fat ratio (95% CI, 0.09 to 0.60; P = .01), and visceral adipose mass (95% CI, 0.057 to 0.283 kg; P = .004). Lean mass was similar in both groups. Lean mass was positively associated with tibial cortical area and radial total, trabecular, and volumetric density (P < .05). CONCLUSION: This first report using pQCT and DXA in men with KS or anorchia treated from adolescence showed normal volumetric BMD but reduction in cortical area and thickness, only at the 66% tibia site. Our study also demonstrated for the first time that men with KS or anorchia have increased visceral adiposity despite T treatment.

Testicular microlithiasis imaging and follow-up: guidelines of the ESUR scrotal imaging subcommittee.

OBJECTIVES: The subcommittee on scrotal imaging, appointed by the board of the European Society of Urogenital Radiology (ESUR), have produced guidelines on imaging and follow-up in testicular microlithiasis (TML). METHODS: The authors and a superintendent university librarian independently performed a computer-assisted literature search of medical databases: MEDLINE and EMBASE. A further parallel literature search was made for the genetic conditions Klinefelter's syndrome and McCune-Albright syndrome. RESULTS: Proposed guidelines are: follow-up is not advised in patients with isolated TML in the absence of risk factors (see Key Points below); annual ultrasound (US) is advised for patients with risk factors, up to the age of 55; if TML is found with a testicular mass, urgent referral to a specialist centre is advised. CONCLUSION: Consensus opinion of the scrotal subcommittee of the ESUR is that the presence of TML alone in the absence of other risk factors is not an indication for regular scrotal US, further US screening or biopsy. US is recommended in the follow-up of patients at risk, where risk factors other than microlithiasis are present. Risk factors are discussed and the literature and recommended guidelines are presented in this article. KEY POINTS: • Follow up advised only in patients with TML and additional risk factors. • Annual US advised for patients with risk factors up to age 55. • If TML is found with testicular mass, urgent specialist referral advised. • Risk factors - personal/ family history of GCT, maldescent, orchidopexy, testicular atrophy.

Comorbidity between Klinefelter syndrome and diaphragmatic hernia. A case report.

CONTEXT: Intrathoracic cystic lesions have been diagnosed in a wide variety of age groups, and the increasing use of prenatal imaging studies has allowed detection of these defects even in utero. CASE REPORT: A 17-year-old pregnant woman in her second gestation, at 23 weeks of pregnancy, presented an ultrasound with evidence of a cystic anechoic image in the fet al left hemithorax. A morphological ultrasound examination performed at the hospital found that this cystic image measured 3.7 cm x 2.1 cm x 1.6 cm. Polyhydramnios was also present. At this time, the hypothesis of cystic adenomatoid malformation was raised. Fet al echocardiography showed only a dextroposed heart. Fet al magnetic resonance imaging produced an image compatible with a left diaphragmatic hernia containing the stomach and at least the first and second portions of the duodenum, left lobe of the liver, spleen, small intestine segments and portions of the colon. The stomach was greatly distended and the heart was shifted to the right. There was severe volume reduction of the left lung. Fet al karyotyping showed the chromosomal constitution of 47,XXY, compatible with Klinefelter syndrome. In our review of the literature, we found only one case of association between Klinefelter syndrome and diaphragmatic hernia. CONCLUSIONS: We believe that the association observed in this case was merely coincidental, since both conditions are relatively common. The chance of both events occurring simultaneously is estimated to be 1 in 1.5 million births.

48, XXYY syndrome associated tremor.

48, XXYY syndrome is a form of sex chromosome aneuploidy that affects between 1 in 18 000 to 1 in 40 000 males. It is not inherited and is diagnosed by karyotyping. It has similarities to 47, XXY Klinefelter's syndrome, with tall stature, micro-orchidism, hypergonadotropic hypogonadism and infertility in males. However, patients with 48, XXYY syndrome also commonly have dental problems, tremor, attention deficit disorder, learning difficulties, allergies and asthma. The tremor is typically reported as an intention tremor (in 71% of patients XXYY aged >20 years with 48), which becomes more common with age and worsens over time.

Prenatal ultrasound diagnosis of a 48,XXYY syndrome.

The 48,XXYY syndrome is a rare uncommon gonosome aneuploidy and its incidence is estimated to be 1:18,000-1:40,000. The phenotype associated with this syndrome, classically described as Klinefelter variant, is extremely variable but developmental abnormalities are always present. Ultrasound signs during pregnancy are inconsistent, and only three prenatal cases have been described in the literature. Here, we report a case of 48,XXYY syndrome identified in prenatal period because of the presence of polyhydramnios and bilateral clubfeet on second trimester ultrasound. This observation shows the importance of chromosomal prenatal diagnosis in cases with bilateral clubfeet on morphologic ultrasound. This diagnosis is essential for further characterization of the prenatal phenotype and to improving genetic counselling.