UNASSIGNED: Evaluation of the participant satisfaction with a newly developed interdisciplinary, modular education program for children, adolescents, and young adults with differences of sex development (DSD) and their parents.
UNASSIGNED: The two-day program including tailored medical information, peer consultation and psychological support aimed to improve diagnosis-specific knowledge and empowerment. Post-training satisfaction was measured using an adapted ZUF-8 questionnaire, scoring from 5 (worst) to a maximum of 26 (best) for persons aged 6-17 and from 10 to 40 points for adults, including 2 open-ended questions.
UNASSIGNED: The questionnaire, completed by 89 children (6-13 years), 92 adolescents (14-17 years), 47 young adults (18-24 years), and 345 parents, revealed consistent high satisfaction with the program regardless of age or diagnosis (children 24.4 ± 2.1, adolescents 23.5 ± 2.7; young adults 36.0 ± 4.0, parents 36.6 ± 3.4). Neither sociodemographic factors nor diagnosis burden, shame, or informedness showed relevant associations with satisfaction levels. Participants highlighted exchange and open atmosphere as key satisfaction elements.
UNASSIGNED: Satisfaction with the new education program was high in all examined groups. Implementing it in routine care requires further analysis to determine the program\'s long-term effects on well-being and knowledge.
UNASSIGNED: The first educational program for young people with DSD addressing their specific challenges through inclusive language, an open approach to sex and gender and the inclusion of self-help groups.

UNASSIGNED: Joubert syndrome a rare genetic disorder, is characterized by abnormalities in the development of the central nervous system with \"molar signs\" on magnetic resonance imaging of the brain and accompanied by cerebellar vermis hypoplasia, ataxia, hypotonia, and developmental delay. Keratoconus (KC) is a kind of genetically predisposed eye disease that causes blindness characterized by a dilated thinning of the central or paracentral cornea conically projected forward, highly irregular astigmatism, and severe visual impairment. Klinefelter syndrome is caused by an extra X chromosome in the cells of male patients, and the main phenotype is tall stature and dysplasia with secondary sex characteristics. This study was intended to identify the genetic etiology and determine the clinical diagnosis of one Han Chinese family with specific clinical manifestations of keratoconus and multiorgan involvement.
UNASSIGNED: A comprehensive ocular and related general examination was performed on one patient and his asymptomatic parents and brother. Pathogenic genes were tested by exome sequencing. CNV-seq was used to verify the copy number variation, and peripheral blood was cultured for karyotype analysis. The pathogenicity of the identified variant was determined subject to ACMG guidelines. The Gene Expression Omnibus (GEO) dataset of keratoconus-related genes in the NCBI database was obtained to analyze the differentially expressed genes in corneal tissues of the keratoconus group and the normal control group, and analysis of protein-protein interaction networks (PPI) was performed.
UNASSIGNED: Proband, a 25-year-old male, had sudden loss of vision in the left eye for 1 week. Best corrected visual acuity (BCVA): 0.5 (-1.00DS/-5.00DC*29°) in the right eye, counting fingers/40 cm in the left eye. Slit-lamp microscopy of the right eye showed mild anterior protrusion of the cornea and thinning of the cone-topped cornea. The left eye showed marked thinning of the central region of the cornea, rounded edema in the form of a cone-like bulge, epithelial bullae, edema and turbidity of the stroma, and bulging of the Descemet\'s membrane. Cranial magnetic resonance imaging (MRI) revealed changes in the midbrain and cerebellum, with a \"molar sign\" and a \"bat-winged\" ventriculus quartus cerebri. General check-up: 168 cm in height, decreased muscle tone in all four limbs, knee jerk elicited, negative Babinski sign, abdominal reflexes elicited, finger-to-nose test positive, intentional tremor evident in both hands, positive Romberg\'s sign, instability of gait, level I intellectual disability, poor adaptive behavior, communication disorders, teeth all dentures, a peculiar face with blepharophimosis, wide inner canthus distance, mild ptosis, severe positive epicanthus, high palatal arches, exotropia, hypotrichosis of beard and face, inconspicuous prominentia laryngea, and short upper and lower limbs. Exome sequencing detected compound heterozygous frameshift variants M1:c.9279dup:p.His3094Thrfs*18 and M2:c.6515_6522del:p.Lys2172Thrfs*37 in the patient\'s CPLANE1 gene and the presence of duplication-type CNV on the X chromosome. Sanger sequencing showed that the mother and father carried the M1 and M2 variants, respectively, and the younger brother carried the M2 variant, which was a novel variant. CNV-seq analysis showed the presence of a duplication-type CNV Xp22.33-Xq28 (2757837-156030895) of approximately 155 Mb on the X chromosome of the proband, which was a de novo variant and carried by neither of the parents. The two heterozygous frameshift variants and duplication-type CNV were pathogenic according to the ACMG guidelines. Differential expression analysis of keratoconus-related genes showed that CPLANE1 was upregulated in the corneal tissues of keratoconus patients compared with normal controls, and such a difference was statistically significant (p = 0.000515, <0.05). PPI analysis showed that the CPLANE1-NPHP3 complex protein acted as a bridge between cilia and extracellular matrix tissue. According to the genetic test results and clinical phenotype analysis, the family was finally diagnosed with Joubert syndrome combined with Keratoconus and Klinefelter syndrome.
UNASSIGNED: In this study, we report a proband in a Han Chinese family with both Joubert syndrome and X-linked Klinefelter syndrome as well as keratoconus, and the phenotype spectrum of CPLANE1-Joubert syndrome may be expanded accordingly. Meanwhile, the significance of exome sequencing was emphasized in aiding the clinical diagnosis of complex cases, which is difficult to make.

Increasing survival rates of children following cancer treatment have resulted in a significant population of adult survivors with the common side effect of infertility. Additionally, the availability of genetic testing has identified Klinefelter syndrome (classic 47,XXY) as the cause of future male infertility for a significant number of prepubertal patients. This study explores new spermatogonia stem cell (SSC)-based fertility therapies to meet the needs of these patients. Testicular cells were isolated from cryopreserved human testes tissue stored from XY and XXY prepubertal patients and propagated in a two-dimensional culture. Cells were then incorporated into a 3D human testicular organoid (HTO) system. During a 3-week culture period, HTOs maintained their structure, viability, and metabolic activity. Cell-specific PCR and flow cytometry markers identified undifferentiated spermatogonia, Sertoli, Leydig, and peritubular cells within the HTOs. Testosterone was produced by the HTOs both with and without hCG stimulation. Upregulation of postmeiotic germ cell markers was detected after 23 days in culture. Fluorescence in situ hybridization (FISH) of chromosomes X, Y, and 18 identified haploid cells in the in vitro differentiated HTOs. Thus, 3D HTOs were successfully generated from isolated immature human testicular cells from both euploid (XY) and Klinefelter (XXY) patients, supporting androgen production and germ cell differentiation in vitro.

People with Klinefelter syndrome (KS/XXY) may be at higher risk of gender dysphoria than the general population and gender diversity needs greater recognition and consideration in services for people affected. This study aimed to give systematic insights into experiences of gender diversity among people with KS/XXY, which could inform more person-centered care for people with KS/XXY and contribute to practical guidance for healthcare professionals. We conducted individual, semi-structured interviews with 11 adults with diagnosed KS/XXY. The verbatim interview transcripts were analyzed using experiential reflexive thematic analysis, which identified four themes: (1) Experience of gender, which described participants\' experiences of exploring and negotiating their gender identity; (2) Navigating expectations, which described how participants\' gender uncertainty was associated with confusion, isolation, and shame, and how fears about other people\'s reactions caused participants to keep their gender identity secret; (3) Testosterone assumptions, which described how participants needed more discussion and counseling before testosterone replacement therapy (TRT), and how some benefited from treatment with alternative hormones to testosterone; and (4) A different approach, which described participants\' experiences of care at gender identity clinics. The findings give new insights into the gender identity journeys of people with KS/XXY, from early attempts to understand and make sense of gender, through dealing with social pressures, the development of gender identities more congruent with feelings, and experiences with hormone replacement therapy. The practice implications include that there should be improved consideration of gender identity in care for KS/XXY, better psychological support for those affected by gender diversity, and more consideration given to alternatives to testosterone-based therapies. Future research could explore the experiences of gender identity among different groups of people with KS/XXY, the development of gender identity over time, the effects of TRT on gender identity, and healthcare providers\' knowledge and attitudes about gender identity and KS/XXY.

BACKGROUND: Klinefelter syndrome (KS), a sex chromosome aneuploidy, is associated with a 47,XXY chromosomal complement and is diagnosed in ∼1:600 live male births. Individuals with a 46,XX cell line in addition to 47,XXY are less common with a limited number of published case reports.
METHODS: To better understand the implications of a 47,XXY/46,XX karyotype, we conducted a retrospective, multi-center analysis of the cytogenetic findings and associated clinical records of 34 patients diagnosed with this SCA across 14 institutions.
RESULTS: Presence of the XX cell line ranged from 5-98% in patient specimens. Phenotypes also exhibited significant heterogeneity with some reporting a single reason for referral and others presenting with a constellation of symptoms, including ambiguous genitalia and ovotestes. Ovotestes were present in 12% of individuals in this cohort, who had a significantly higher percentage of XX cells. Notably, two patients were assigned female sex at birth DISCUSSION: These findings highlight the variability of the clinical phenotypes associated with this SCA as well as the challenges of clinical management for this population. Karyotype or FISH analysis, which offer single-cell resolution, rather than chromosomal microarray or molecular testing, is the ideal test strategy in these instances as mosaicism can occur at low levels.

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OBJECTIVE: Klinefelter syndrome (KS) is the most common sex-chromosome aneuploidy (47,XXY), affecting 1 in 500 male participants. The phenotype of male participants with KS includes both physical features, such as tall stature and testicular insufficiency, and behavioral alterations, including difficulties in social functioning, anxiety, and depression. Studies examining underlying neural alterations associated with the behavioral phenotype, however, are sparse. We aimed to address this gap in knowledge using functional magnetic resonance imaging in conjunction with an emotion processing paradigm.
METHODS: Functional magnetic resonance imaging was conducted on 38 children and adolescents with KS ( Mage = 12.85, SD = 2.45) and 47 typical developing (control) boys ( Mage = 12.04, SD = 1.82) as they completed a facial emotion processing task. Group differences in activation occurring during the processing of angry versus neutral faces were examined while controlling for age.
RESULTS: The results indicated that relative to typically developing boys, boys with KS exhibited anomalous increases in activation of frontal, temporal, and occipital cortices. Within the KS group, secondary analyses indicated that greater activation in these regions was associated with more internalizing symptoms (e.g., anxiety, depression, withdrawn behaviors) and greater social impairments (e.g., social cognition, social communication, social motivation, social communication and interaction, functional communication).
CONCLUSIONS: The findings from this study indicate a possible neural correlation for difficulties in social and emotional function in KS and add to a growing body of research aimed at increasing our understanding of neural biomarkers in this condition. Future studies that examine the influence of testosterone-replacement therapy on these differences are warranted.

Klinefelter syndrome (KS), also known as 47,XXY, is a genetic disorder characterized by the presence of an extra X chromosome. Despite the prevalence of verbal learning disabilities, memory impairments, and executive function deficits in individuals with KS, comprehensive research on the neuropsychological profiles of affected children and adolescents remains limited. Additionally, KS has been associated with comorbid conditions such as depression, anxiety, schizophrenia, attention-deficit hyperactivity disorder (ADHD), and autism spectrum disorders (ASDs). However, systematic investigations into the neuropsychological manifestations of KS in pediatric populations are scarce. Therefore, the primary objectives of this review are to provide an overview of key studies examining the neuropsychological profiles of children and adolescents with KS and to delineate the limitations and implications of existing research findings. By synthesizing available literature, this review aims to bridge the gap in understanding the cognitive and behavioral characteristics of children and adolescents with KS, shedding light on potential avenues for future research and clinical interventions. Ultimately, this review serves as a valuable resource for clinicians, researchers, policymakers, parents, and educators involved in the assessment and management of the neuropsychological aspects of Klinefelter syndrome in pediatric populations.

BACKGROUND: Klinefelter syndrome (KS), also referred to as XXY syndrome, is a significant but inadequately studied risk factor for neuropsychiatric disability. Whether alterations in functional brain connectivity or pubertal delays are associated with aberrant cognitive-behavioral outcomes in individuals with KS is largely unknown. In this observational study, we investigated KS-related alterations in the resting-state brain network, testosterone level, and cognitive-behavioral impairment in adolescents with Klinefelter syndrome.
METHODS: We recruited 46 boys with KS, ages 8 to 17 years, and 51 age-matched typically developing (TD) boys. All participants underwent resting-state functional magnetic resonance imaging scans, pubertal, and cognitive-behavioral assessments. Resting-state functional connectivity and regional brain activity of the participants were assessed.
RESULTS: We found widespread alterations in global functional connectivity among the inferior frontal gyrus, temporal-parietal area, and hippocampus in boys with KS. Aberrant regional activities, including enhanced fALFF in the motor area and reduced ReHo in the caudate, were also found in the KS group compared to the TD children. Further, using machine learning methods, brain network alterations in these regions accurately differentiated boys with KS from TD controls. Finally, we showed that the alterations of brain network properties not only effectively predict cognitive-behavioral impairment in boys with KS, but also appear to mediate the association between total testosterone level and language ability, a cognitive domain at particular risk for dysfunction in this condition.
CONCLUSIONS: Our results offer an informatic neurobiological foundation for understanding cognitive-behavioral impairments in individuals with KS and contribute to our understanding of the interplay between pubertal status, brain function, and cognitive-behavioral outcome in this population.

BACKGROUND: Klinefelter syndrome is a common sex chromosome abnormality in males, characterized by an extra X chromosome compared to normal males. Glucose-6-phosphate dehydrogenase deficiency (G6PD) is an X-linked incomplete dominant defect disorder. In this study, we reported the unexpected detection of Klinefelter syndrome in a patient with G6PD.
METHODS: G6PD enzyme activity was measured by immunoenzyme assay, and genetic analysis was performed using a fluorescent PCR melting curve method (PCR-melting curve). Sex chromosome number abnormalities were detected by multiplex ligation-dependent probe amplification (MLPA). The patient also underwent peripheral blood chromosome karyotype analysis.
RESULTS: The patient\'s G6PD and 6PGD enzyme activities were 21.34 U/L and 22.85 U/L, respectively, and their ratio was below the reference range (0.93). The PCR-melting curve displayed a c.1388 heterozygous mutation in this boy, and the Sanger sequencing provided the same results. MLPA results suggested the presence of approxi-mately two copies of the X-chromosome in the boy. Finally, chromosome karyotype analysis confirmed that the boy had Klinefelter syndrome with a karyotype of 47, XXY.
CONCLUSIONS: Klinefelter syndrome was accidentally detected during G6PD genetic analysis in a male. X-chromosomes can interfere with the results of G6PD genetic analysis and should be noted.