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Frontiers in Endocrinology 2024The term 'differences of sex development' (DSD) refers to a group of congenital conditions that are associated with atypical development of chromosomal, gonadal, and/or... (Review)
Review
46,XX Differences of Sex Development outside congenital adrenal hyperplasia: pathogenesis, clinical aspects, puberty, sex hormone replacement therapy and fertility outcomes.
The term 'differences of sex development' (DSD) refers to a group of congenital conditions that are associated with atypical development of chromosomal, gonadal, and/or anatomical sex. DSD in individuals with a 46,XX karyotype can occur due to fetal or postnatal exposure to elevated amount of androgens or maldevelopment of internal genitalia. Clinical phenotype could be quite variable and for this reason these conditions could be diagnosed at birth, in newborns with atypical genitalia, but also even later in life, due to progressive virilization during adolescence, or pubertal delay. Understand the physiological development and the molecular bases of gonadal and adrenal structures is crucial to determine the diagnosis and best management and treatment for these patients. The most common cause of DSD in 46,XX newborns is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, determining primary adrenal insufficiency and androgen excess. In this review we will focus on the other rare causes of 46,XX DSD, outside CAH, summarizing the most relevant data on genetic, clinical aspects, puberty and fertility outcomes of these rare diseases.
Topics: Humans; Adrenal Hyperplasia, Congenital; Puberty; Hormone Replacement Therapy; Fertility; Female; Male; Disorders of Sex Development; Sexual Development
PubMed: 38841305
DOI: 10.3389/fendo.2024.1402579 -
Journal of Neuroinflammation Jun 2024Mounting evidence links glucose intolerance and diabetes as aspects of metabolic dysregulation that are associated with an increased risk of developing dementia....
BACKGROUND
Mounting evidence links glucose intolerance and diabetes as aspects of metabolic dysregulation that are associated with an increased risk of developing dementia. Inflammation and inflammasome activation have emerged as a potential link between these disparate pathologies. As diet is a key factor in both the development of metabolic disorders and inflammation, we hypothesize that long term changes in dietary factors can influence nervous system function by regulating inflammasome activity and that this phenotype would be sex-dependent, as sex hormones are known to regulate metabolism and immune processes.
METHODS
5-week-old male and female transgenic mice expressing a caspase-1 bioluminescent reporter underwent cranial window surgeries and were fed control (65% complex carbohydrates, 15% fat), high glycemic index (65% carbohydrates from sucrose, 15% fat), or ketogenic (1% complex carbohydrates, 79% fat) diet from 6 to 26 weeks of age. Glucose regulation was assessed with a glucose tolerance test following a 4-h morning fast. Bioluminescence in the brain was quantified using IVIS in vivo imaging. Blood cytokine levels were measured using cytokine bead array. 16S ribosomal RNA gene amplicon sequencing of mouse feces was performed to assess alterations in the gut microbiome. Behavior associated with these dietary changes was also evaluated.
RESULTS
The ketogenic diet caused weight gain and glucose intolerance in both male and female mice. In male mice, the high glycemic diet led to increased caspase-1 biosensor activation over the course of the study, while in females the ketogenic diet drove an increase in biosensor activation compared to their respective controls. These changes correlated with an increase in inflammatory cytokines present in the serum of test mice and the emergence of anxiety-like behavior. The microbiome composition differed significantly between diets; however no significant link between diet, glucose tolerance, or caspase-1 signal was established.
CONCLUSIONS
Our findings suggest that diet composition, specifically the source and quantity of carbohydrates, has sex-specific effects on inflammasome activation in the central nervous system and behavior. This phenotype manifested as increased anxiety in male mice, and future studies are needed to determine if this phenotype is linked to alterations in microbiome composition.
Topics: Animals; Female; Male; Mice; Caspase 1; Mice, Transgenic; Sex Characteristics; Diet, Ketogenic; Dietary Carbohydrates; Central Nervous System; Gastrointestinal Microbiome; Mice, Inbred C57BL
PubMed: 38840215
DOI: 10.1186/s12974-024-03140-5 -
Nature Genetics Jun 2024Restless legs syndrome (RLS) affects up to 10% of older adults. Their healthcare is impeded by delayed diagnosis and insufficient treatment. To advance disease... (Meta-Analysis)
Meta-Analysis
Restless legs syndrome (RLS) affects up to 10% of older adults. Their healthcare is impeded by delayed diagnosis and insufficient treatment. To advance disease prediction and find new entry points for therapy, we performed meta-analyses of genome-wide association studies in 116,647 individuals with RLS (cases) and 1,546,466 controls of European ancestry. The pooled analysis increased the number of risk loci eightfold to 164, including three on chromosome X. Sex-specific meta-analyses revealed largely overlapping genetic predispositions of the sexes (r = 0.96). Locus annotation prioritized druggable genes such as glutamate receptors 1 and 4, and Mendelian randomization indicated RLS as a causal risk factor for diabetes. Machine learning approaches combining genetic and nongenetic information performed best in risk prediction (area under the curve (AUC) = 0.82-0.91). In summary, we identified targets for drug development and repurposing, prioritized potential causal relationships between RLS and relevant comorbidities and risk factors for follow-up and provided evidence that nonlinear interactions are likely relevant to RLS risk prediction.
Topics: Restless Legs Syndrome; Humans; Genome-Wide Association Study; Genetic Predisposition to Disease; Risk Factors; Female; Male; Polymorphism, Single Nucleotide; Mendelian Randomization Analysis; Machine Learning
PubMed: 38839884
DOI: 10.1038/s41588-024-01763-1 -
Scientific Data Jun 2024Sex bias is known in the prevalence/pathology of neurodevelopmental disorders. Sex-dependent differences of the certain brain areas are known to emerge perinatally...
Sex bias is known in the prevalence/pathology of neurodevelopmental disorders. Sex-dependent differences of the certain brain areas are known to emerge perinatally through the exposure to sex hormones, while gene expression patterns in the rodent embryonic brain does not seem to be completely the same between male and female. To investigate potential sex differences in gene expression and cortical organization during the embryonic period in mice, we conducted a comprehensive analysis of gene expression for the telencephalon at embryonic day (E) 11.5 (a peak of neural stem cell expansion) and E14.5 (a peak of neurogenesis) using bulk RNA-seq data. As a result, our data showed the existence of notable sex differences in gene expression patterns not obviously at E11.5, but clearly at E14.5 when neurogenesis has become its peak. These data can be useful for exploring potential contribution of genes exhibiting sex differences to the divergence in brain development. Additionally, our data underscore the significance of studying the embryonic period to gain a deeper understanding of sex differences in brain development.
Topics: Animals; Telencephalon; Mice; Female; Male; Transcriptome; Neurogenesis; Sex Characteristics
PubMed: 38839806
DOI: 10.1038/s41597-024-03421-x -
Cell Death & Disease Jun 2024Klinefelter syndrome (47,XXY) causes infertility with a testicular histology comprising two types of Sertoli cell-only tubules, representing mature and immature-like...
Klinefelter syndrome (47,XXY) causes infertility with a testicular histology comprising two types of Sertoli cell-only tubules, representing mature and immature-like Sertoli cells, and occasionally focal spermatogenesis. Here, we show that the immature-like Sertoli cells highly expressed XIST and had two X-chromosomes, while the mature Sertoli cells lacked XIST expression and had only one X-chromosome. Sertoli cells supporting focal spermatogenesis also lacked XIST expression and the additional X-chromosome, while the spermatogonia expressed XIST despite having only one X-chromosome. XIST was expressed in Sertoli cells until puberty, where a gradual loss was observed. Our results suggest that a micro-mosaic loss of the additional X-chromosome is needed for Sertoli cells to mature and to allow focal spermatogenesis.
Topics: Klinefelter Syndrome; Male; Sertoli Cells; Spermatogenesis; Animals; Humans; Mice; RNA, Long Noncoding; Chromosomes, Human, X; X Chromosome
PubMed: 38839795
DOI: 10.1038/s41419-024-06792-6 -
BMC Psychiatry Jun 2024Psychotic depression (PD) is characterized by the co-occurrence of emotional dysfunction and psychotic symptoms such as delusions and hallucinations with poor clinical...
Non-linear relationship between TSH and psychotic symptoms on first episode and drug naïve major depressive disorder patients: a large sample sized cross-sectional study in China.
INTRODUCTION
Psychotic depression (PD) is characterized by the co-occurrence of emotional dysfunction and psychotic symptoms such as delusions and hallucinations with poor clinical outcomes. TSH may involve in the development of PD. This study aims to explore relationship between TSH and PD.
METHODS
A total of 1718 outpatients diagnosed as FEDN MDD were recruited in this study. The relationship between PD and TSH was evaluated using multivariable binary logistic regression analysis. To assess the presence of non-linear associations, a two-piecewise linear regression model was employed. Furthermore, interaction and stratified analyses were conducted with respect to sex, education, marital status, comorbid anxiety, and suicide attempt.
RESULTS
Multivariable logistic regression analysis revealed that TSH was positively associated with the risk of PD after adjusting for confounders (OR = 1.26, 95% CI: 1.11 to 1.43; p < 0.05). Smoothing plots showed a nonlinear relationship between TSH and PD, with the inflection point of TSH being 4.94 mIU/L. On the right of the inflection point, for each unit increase in serum TSH level on the right side of the inflection point, the probability of PD increased substantially by 47% (OR = 1.47, 95% CI: 1.25 to 1.73, p < 0.001), while no significant association was observed on the left side of the inflection point (OR = 0.87, 95% CI: 0.67 to 1.14, p = 0.32).
CONCLUSION
Our investigation showed a nonlinear TSH-PD relationship in FEDN MDD patients, thus contributing to effective intervention strategies for psychotic symptoms in depression patients.
Topics: Humans; Male; Female; Cross-Sectional Studies; Adult; Thyrotropin; China; Depressive Disorder, Major; Psychotic Disorders; Middle Aged; Young Adult
PubMed: 38834989
DOI: 10.1186/s12888-024-05860-7 -
Disease Models & Mechanisms May 2024Recent progress in human disease genetics is leading to rapid advances in understanding pathobiological mechanisms. However, the sheer number of risk-conveying genetic... (Review)
Review
Recent progress in human disease genetics is leading to rapid advances in understanding pathobiological mechanisms. However, the sheer number of risk-conveying genetic variants being identified demands in vivo model systems that are amenable to functional analyses at scale. Here we provide a practical guide for using the diploid frog species Xenopus tropicalis to study many genes and variants to uncover conserved mechanisms of pathobiology relevant to human disease. We discuss key considerations in modelling human genetic disorders: genetic architecture, conservation, phenotyping strategy and rigour, as well as more complex topics, such as penetrance, expressivity, sex differences and current challenges in the field. As the patient-driven gene discovery field expands significantly, the cost-effective, rapid and higher throughput nature of Xenopus make it an essential member of the model organism armamentarium for understanding gene function in development and in relation to disease.
Topics: Animals; Xenopus; Humans; Disease Models, Animal; Genetic Diseases, Inborn; Phenotype
PubMed: 38832520
DOI: 10.1242/dmm.050754 -
European Journal of Medical Genetics Jun 2024Newborn screening (NBS) for congenital adrenal hyperplasia (CAH) based on hormonal testing is successfully implemented in many countries. However, this method cannot...
Newborn screening (NBS) for congenital adrenal hyperplasia (CAH) based on hormonal testing is successfully implemented in many countries. However, this method cannot detect non-classic CAH and has high false positive rates. We have developed a novel MALDI-TOF MS assay that can identify common variants and deletions of CYP21A2 in the Chinese population. Thirty-seven clinical patients with CAH confirmed by Sanger sequencing and MLPA analysis were detected by MALDI-TOF MS assay. Two CYP21A2 variants were detected in 30 patients and one CYP21A2 variant was detected in 7 patients. The MALDI-TOF MS assay detected 67 mutant alleles in 37 patients with a detection rate of 90.5%. Sanger sequencing revealed that three variants in seven patients were not included in the designed panel. Eleven distinct CYP21A2 variants were identified, including five missense variants, two nonsense variants, two large gene deletions, one splice variant, and one frameshift variant. The most frequent variant was c.293-13C > G (37.84%), followed by c.518T > A (21.62%) and exon 1-7 deletion (17.57%). The high-throughput MALDI-TOF MS assay that can simultaneously detect common variants and deletions of CYP21A2. This assay can be used for population-based genetic screening and rapid detection of suspected patients, and is expected to be a valuable complement to biochemical-based testing for the detection of CAH.
Topics: Humans; Steroid 21-Hydroxylase; Adrenal Hyperplasia, Congenital; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Female; Male; Infant, Newborn; Neonatal Screening; Infant; Genetic Testing; Gene Deletion
PubMed: 38830573
DOI: 10.1016/j.ejmg.2024.104950 -
Hong Kong Medical Journal = Xianggang... Jun 2024
Topics: Humans; Female; Adrenal Hyperplasia, Congenital; Hypertension; Steroid 17-alpha-Hydroxylase; Hypokalemia; Adolescent
PubMed: 38825729
DOI: 10.12809/hkmj2210635 -
JMIR Research Protocols May 2024Screening, brief intervention, and referral to treatment for adolescents (SBIRT-A) is widely recommended to promote detection and early intervention for alcohol and... (Randomized Controlled Trial)
Randomized Controlled Trial
Standard Versus Family-Based Screening, Brief Intervention, and Referral to Treatment for Adolescent Substance Use in Primary Care: Protocol for a Multisite Randomized Effectiveness Trial.
BACKGROUND
Screening, brief intervention, and referral to treatment for adolescents (SBIRT-A) is widely recommended to promote detection and early intervention for alcohol and other drug (AOD) use in pediatric primary care. Existing SBIRT-A procedures rely almost exclusively on adolescents alone, despite the recognition of caregivers as critical protective factors in adolescent development and AOD use. Moreover, controlled SBIRT-A studies conducted in primary care have yielded inconsistent findings about implementation feasibility and effects on AOD outcomes and overall developmental functioning. There is urgent need to investigate the value of systematically incorporating caregivers in SBIRT-A procedures.
OBJECTIVE
This randomized effectiveness trial will advance research and scope on SBIRT-A in primary care by conducting a head-to-head test of 2 conceptually grounded, evidence-informed approaches: a standard adolescent-only approach (SBIRT-A-Standard) versus a more expansive family-based approach (SBIRT-A-Family). The SBIRT-A-Family approach enhances the procedures of the SBIRT-A-Standard approach by screening for AOD risk with both adolescents and caregivers; leveraging multidomain, multireporter AOD risk and protection data to inform case identification and risk categorization; and directly involving caregivers in brief intervention and referral to treatment activities.
METHODS
The study will include 2300 adolescents (aged 12-17 y) and their caregivers attending 1 of 3 hospital-affiliated pediatric settings serving diverse patient populations in major urban areas. Study recruitment, screening, randomization, and all SBIRT-A activities will occur during a single pediatric visit. SBIRT-A procedures will be delivered digitally on handheld tablets using patient-facing and provider-facing programming. Primary outcomes (AOD use, co-occurring behavior problems, and parent-adolescent communication about AOD use) and secondary outcomes (adolescent quality of life, adolescent risk factors, and therapy attendance) will be assessed at screening and initial assessment and 3-, 6-, 9-, and 12-month follow-ups. The study is well powered to conduct all planned main and moderator (age, sex, race, ethnicity, and youth AOD risk status) analyses.
RESULTS
This study will be conducted over a 5-year period. Provider training was initiated in year 1 (December 2023). Participant recruitment and follow-up data collection began in year 2 (March 2024). We expect the results from this study to be published in early 2027.
CONCLUSIONS
SBIRT-A is widely endorsed but currently underused in pediatric primary care settings, and questions remain about optimal approaches and overall effectiveness. In particular, referral to treatment procedures in primary care remains virtually untested among youth. In addition, whereas research strongly supports involving families in interventions for adolescent AOD, SBIRT-A effectiveness trial testing approaches that actively engage family members in primary care are absent. This trial is designed to help fill these research gaps to inform the critical health decision of whether and how to include caregivers in SBIRT-A activities conducted in pediatric primary care.
TRIAL REGISTRATION
ClinicalTrials.gov NCT05964010; https://www.clinicaltrials.gov/study/NCT05964010.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)
PRR1-10.2196/54486.
Topics: Humans; Adolescent; Substance-Related Disorders; Referral and Consultation; Primary Health Care; Male; Female; Mass Screening; Child
PubMed: 38819923
DOI: 10.2196/54486