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Adolescence is an important period for sexual development, including sexual debut. The purpose of this study was to assess first romantic and sexual experiences and debut age in individuals with differences of sex development (DSD/intersex) and compare these with age-matched and gender-matched population control values.Questionnaire data on sociodemographic characteristics, romantic and sexual milestones (e.g., masturbation, dating), satisfaction with sexual life and sexual activity at follow-up, self-esteem, and feelings of femininity or masculinity were collected from 976 participants in Europe with a DSD condition. Participants were divided into six diagnostic subgroups based on their diagnostic classification: women with Turner syndrome, congenital adrenal hyperplasia, 46XY-DSD nonvirilized, and 46XY-DSD female partially virilized conditions and men with 46XY-DSD male or Klinefelter syndrome. Age-specific and gender-specific reference values were retrieved from a Dutch population sample.Individuals with DSD were less likely to reach each of the romantic and sexual milestones compared to their peers without these conditions and they were significantly older when reaching these milestones. Between clinical subgroups, individuals with Klinefelter were significantly older when reaching milestones and in the female groups and individuals with Turner were the least likely to reach milestones. Furthermore, a higher age when reaching several romantic and sexual milestones was correlated with lower self-esteem, lower satisfaction with sexual life, and lower sexual frequency at follow-up.Due to a difference in biopsychosocial context, individuals with DSD often experience a different and/or delayed sexual development during adolescence. Healthcare providers should be aware of these differences in adolescents with DSD and their sexual development to optimize affirmative counseling.

Infants with genital development considered atypical for assigned female sex may undergo feminizing genitoplasty (clitoroplasty and/or vaginoplasty) in early life. We sought to identify factors associated with parent/caregiver decisions regarding genitoplasty for their children with genital virilization.Longitudinal, observational study SETTING: Twelve pediatric centers in the United States with multidisciplinary differences/disorders of sex development clinics, 2015-2020 PARTICIPANTS: Children under 2 years old with genital appearance atypical for female sex of rearing and their parents/caregivers INTERVENTIONS/OUTCOME MEASURES: Data on the child's diagnosis and anatomic characteristics before surgery were extracted from the medical record. Parents/caregivers completed questionnaires on psychosocial distress, experience of uncertainty, cosmetic appearance of their child's genitalia, and demographic characteristics. Urologists rated cosmetic appearance. For 58 patients from the study cohort with genital virilization being raised as girls or gender-neutral, we compared these data across 3 groups based on the child's subsequent surgical intervention: (i) no surgery (n = 5), (ii) vaginoplasty without clitoroplasty (V-only) (n = 15), and (iii) vaginoplasty and clitoroplasty (V+C) (n = 38).Fathers' and urologists' ratings of genital appearance were more favorable in the no-surgery group than in the V-only and V+C groups. Clitorophallic length was greater in the V+C group compared with the V-only group, with substantial overlap between groups. Mothers' depressive and anxious symptoms were lower in the no-surgery group compared with the V-only and V+C groups.Surgical decisions were associated with fathers' and urologists' ratings of genital appearance, the child's anatomic characteristics, and mothers' depressive and anxious symptoms. Further research on surgical decision-making is needed to inform counseling practices.

Defined as congenital conditions in which development of chromosomal, gonadal, or anatomic sex is atypical, differences or disorders of sex development (DSDs) comprise many discrete diagnoses ranging from those associated with few phenotypic differences between affected and unaffected individuals to those where questions arise regarding gender of rearing, gonadal tumor risk, genital surgery, and fertility. Controversies exist in numerous areas including how DSDs are conceptualized, how to refer to the set of conditions and those affected by them, and aspects of clinical management that extend from social media to legislative bodies, courts of law, medicine, clinical practice, and scholarly research in psychology and sociology. In addition to these aspects, this review covers biological and social influences on psychosocial development and adjustment, the psychosocial and psychosexual adaptation of people born with DSDs, and roles for clinical psychologists in the clinical management of DSDs.

To facilitate the identification of related genes and candidate biomarkers for disorders of sex development (DSD), we present disorders of sex development atlas (http://dsd.geneworks.cn). Disorders of sex development are a spectrum of endocrine diseases with distinct mutations of genes or chromosomes, but several issues regarding their pathogenesis remain elusive. High-throughput methods have allowed genomic and transcriptomic analyses of DSD; however, these data are deposited in various repositories owing to a lack of integrated online resources.A descriptive study of a specialized gene discovery platform designed for DSD.Publicly available DSD omics datasets and self-produced datasets.None.None.The gene ranking result, with detailed information based on DSD terms in a gene-disease association knowledge base, and results of differential gene expression and mutation analyses from omics datasets.The disorders of sex development atlas maintains both a knowledgebase for ranking DSD candidate genes and a database for DSD-related omics data analysis and visualization. We included 4 dominant classes of DSD in the knowledgebase: 15 subclasses and 44 specific disease names. Construction of the knowledgebase was centered upon Phenolyzer, with add-on seed gene databases customized by DSD-related genes collected from MalaCards, GeneCards, and DisGeNET. For the database, 25 experimental datasets related to DSD were integrated, including 24 public datasets from Gene Expression Omnibus and Sequence Read Archive and 1 self-generated dataset. A total of 474 samples from 240 DSD samples were collected for the database.This platform provides a friendly interface that integrates flexible and comprehensive analysis tools for differential expression and gene mutations between the DSD groups and controls.

Primary amenorrhea may be a feature or a presenting sign of a difference of sex development, most often due to a congenital anatomic difference or hypergonadotropic hypogonadism. History and physical exam are very important, including whether any variation in external genitalia was present at birth as well as a careful review of pubertal development. Further evaluation includes hormone measurement, imaging, and genetic evaluation. Those with a disorder of sexual development diagnosis should receive care through a multidisciplinary team with psychosocial support.

Testes were associated with maleness from antiquity, and ancient societies had fanciful myths about the origins of the sexes and about fetal sexual development. 17th century anatomists developed the concept that mammals developed from eggs and discovered sperm in semen; in 1878, Hertwig observed sperm entering eggs (of sea urchins), establishing the cellular basis of sex development. Individuals with atypical genitalia were known clinically in the 17th century, with much debate about their origins, but by the late 19th century it was generally accepted that gonads determined sex, and that sex determined gender role. Testosterone was isolated in 1935, and Alfred Jost showed that both circulating testosterone and diffusible anti-Mullerian hormone were needed for male development. Patients with apparent androgen insensitivity were reported in 1937 and shown to be unresponsive to exogenous androgen by Lawson Wilkins in 1957; androgen receptor mutations were reported in 1989. Steroidogenic errors were associated with differences in sex development (DSDs) starting in the 1940s, and finding mutations in the responsible enzymes explained many forms of hyper- and hypo-androgenism in both sexes. Sex chromosomes were identified in the early 20th century; Y was associated with maleness, and the responsible SRY gene was identified in 1991. Early efforts to manage patients with DSDs were confounded by philosophical perspectives on the relative roles of prenatal biology versus postnatal environment. Approaches to natal sex assignment evolved in the later 20th century and now emphasize a team approach based on data, not guessing, parental involvement, cultural considerations, and the acknowledgement of uncertainty.

Background Previous studies have suggested that sexual function may be compromised in women born with differences of sex development (DSD) or early loss of gonadal function. Aim To describe sexual function and sexual wellbeing in women with complete androgen insensitivity syndrome (CAIS), complete gonadal dysgenesis (GD) and premature ovarian insufficiency (POI) in relation to gynecological measures and in comparison with unaffected women. Methods A cross sectional study including 20 women with CAIS, 8 women with 46,XY GD, 8 women with 46,XX GD, 21 women with POI, and 62 population-derived controls. Study participants underwent gynecological examination for anatomical measurements and evaluation of tactile sensitivity. They responded to the validated Sexual Activity Log (SAL), Profile of Female Sexual Function (PFSF), and the Personal Distress Scale (PDS). Results The women with CAIS, XY GD, XX GD and POI showed overall satisfying sexual function in comparison to unaffected age-matched population female controls with a median of 1 to 2 satisfying sexual episodes per week among both the patients and the controls depending on available partner. Women with CAIS had shorter vagina and smaller clitoris and women with XY GD had a significantly shallower vagina in comparison to controls. Clitoral width was also significantly smaller among women with XX GD compared to controls. However, results showed overall good genital touch sensitivity with no significant differences between groups. Clinical Implications Women with DSD or POI can be informed on overall satisfactory sexual function and normal genital touch sensitivity. Strengths & Limitations The strength is the use of age-matched population-based controls to these rare conditions of DSD and POI. Limitations are the nonresponder rate of recruited controls, as well as the small groups of women with DSD. Conclusion Women with differences of sex development or early loss of gonadal function show overall good sexual well-being, however clinicians have to make efforts to optimize caretaking and treatment to ensure good sexual quality of life for all patients.

Partial androgen resistance syndrome (PAIS) is the most difficult form of disorders/differences of sex development 46,XY (DSD 46,XY) for choosing of patient management. To date, there are no clear biochemical criteria, especially before puberty, that allow differentiating PAIS from other PAIS-like forms of DSD 46, XY, and genetic verification of the partial form of AIS plays an important role. Meanwhile, according to the literature, mutations in the coding region of AR gene have not been identified in more than 50% of patients with suspected AIS. We performed an extensive analysis of the AR gene in a patient with clinical and laboratory signs of AIS and found a deep intron mutation in the AR gene (p. 2450–42G>A). This variant creates an alternative splice acceptor site resulted a disturbance of the AR function. These findings indicate the need for extensive genetic analysis in a cohort of patients with suspected CPA in the absence of mutations in the AR gene using standard methods of genetic diagnosis.

Introduction: The aim of the current work was to review the clinical profile, aetiological classification, as well as the management of Egyptian paediatric patients with disorders of sex development (DSD) presenting at a tertiary centre in Cairo. Material and methods: The study was a cross-sectional observational study that included Egyptian patients who attended the Endocrinology clinic during a period of one year from January to December 2019. All patients with overt genital ambiguity aged from 0 to 18 years were recruited in the study. Diagnosis of DSD was based on clinical features and hormonal profile. Results: Out of 100 patients, 71% had 46XY DSD, 24% had 46XX DSD, while sex chromosome DSD was identified in 5%. The median age of presentation was 12 months with 19% presented during infancy. The most common cause of 46XY DSD was due to either defect in androgen synthesis or action (40%) with the majority due to androgen insensitivity syndrome (28%). Most of the 46XX DSD (21/24) patients were diagnosed as classic congenital adrenal hyperplasia secondary to deficiency of 21 hydroxylase enzyme, with 90% being salt wasters. Conclusion: Our series revealed that 46XY DSD was the most frequent DSD aetiological diagnosis, with androgen insensitivity syndrome representing the commonest cause. CAH with classic salt wasting type was the second most common disorder. Management of children with DSD is challenging especially with lack of adequate resources. The crucial issues that stand against proper diagnosis and management are late presentation combined with economic constrains, and social and cultural issues.

Purpose of review The aim of this study was to provide a basic overview on human sex development with a focus on involved genes and pathways, and also to discuss recent advances in the molecular diagnostic approaches applied to clinical workup of individuals with a difference/disorder of sex development (DSD). Recent findings Rapid developments in genetic technologies and bioinformatics analyses have helped to identify novel genes and genomic pathways associated with sex development, and have improved diagnostic algorithms to integrate clinical, hormonal and genetic data. Recently, massive parallel sequencing approaches revealed that the phenotype of some DSDs might be only explained by oligogenic inheritance. Summary Typical sex development relies on very complex biological events, which involve specific interactions of a large number of genes and pathways in a defined spatiotemporal sequence. Any perturbation in these genetic and hormonal processes may result in atypical sex development leading to a wide range of DSDs in humans. Despite the huge progress in the understanding of molecular mechanisms underlying DSDs in recent years, in less than 50% of DSD individuals, the genetic cause is currently solved at the molecular level.

Anti-müllerian hormone (AMH) is 1 of the 2 testicular hormones involved in male development of the genitalia during fetal life. When the testes differentiate, AMH is secreted by Sertoli cells and binds to its specific receptor type II (AMHR2) on the müllerian ducts, inducing their regression. In the female fetus, the lack of AMH allows the müllerian ducts to form the fallopian tubes, the uterus, and the upper part of the vagina. The human AMH gene maps to 19p13.3 and consists of 5 exons and 4 introns spanning 2,764 bp. The AMHR2 gene maps to 12q13.13, consists of 11 exons, and is 7,817 bp long. Defects in the AMH pathway are the underlying etiology of a subgroup of disorders of sex development (DSD) in 46,XY patients. The condition is known as the persistent müllerian duct syndrome (PMDS), characterized by the existence of a uterus and fallopian tubes in a boy with normally virilized external genitalia. Approximately 200 cases of patients with PMDS have been reported to date with clinical, biochemical, and molecular genetic characterization. An updated review is provided in this paper. With highly sensitive techniques, AMH and AMHR2 expression has also been detected in other tissues, and massive sequencing technologies have unveiled variants in AMH and AMHR2 genes in hitherto unsuspected conditions.

Wilms’ tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Heterozygous germline pathogenic allelic variants of WT1 have been classically associated with Denys–Drash syndrome (DDS) and Frasier syndrome (FS). Usually, exonic pathogenic missense variants in the zinc finger region are the cause of DDS, whereas pathogenic variants affecting the canonic donor lysine-threonine-serine splice site in intron 9 cause FS. Phenotypic overlap between WT1 disorders has been frequently observed. New WT1 variant-associated phenotypes, such as 46,XX testicular/ovarian-testicular disorders of sex development (DSD) and primary ovarian insufficiency, have been reported. In this report, we describe the phenotypes and genotypes of 7 Brazilian patients with pathogenic WT1 variants. The molecular study involved Sanger sequencing and massively parallel targeted sequencing using a DSD-associated gene panel. Six patients (5 with a 46,XY karyotype and 1 with a 46,XX karyotype) were initially evaluated for atypical genitalia, and a 46,XY patient with normal female genitalia sought medical attention for primary amenorrhea. Germ cell tumors were identified in 2 patients, both with variants affecting alternative splicing of WT1 between exons 9 and 10. Two pathogenic missense WT1 variants were identified in two 46,XY individuals with Wilms’ tumors; both patients were WT1 variant, c.1453_1456 (p.Arg485Glyfs*14), was identified in a 46,XX patient with testicular DSD. Nephrotic proteinuria was diagnosed in all patients, including 3 who underwent renal transplantation after progressing to end-stage kidney disease. The expanding phenotypic spectrum associated with WT1 variants in XY and XX individuals confirms their pivotal role in gonadal and renal development as well as in tumorigenesis, emphasizing the clinical implications of these variants in genetic diagnosis.

For years, physicians have debated how best to care for children with differences in sex development (DSD, also termed intersex). Stories of suffering of adults who underwent early surgical intervention for DSD have led many health organizations to call for deferral of unnecessary procedures. While some have instituted full deferral of cosmetic procedures, standard of care remains an interdisciplinary team approach informed by parents' wishes. As the medical community hesitates to institute full deferral, citing absence of long-term data, legislation restricting early procedures is mounting. This article highlights recent data from the DSD-LIFE Study and considers whether and to what extent they support deferral.

Background Puberty is characterized by significant physical, hormonal, and psychological changes, which may be especially challenging for individuals with autism spectrum disorder (ASD). Although the etiology of ASD remains uncertain, studies suggest imbalances in hormones, such as testosterone, may modulate the autism phenotype. While differences in fetal and postnatal testosterone have been reported, there is limited literature regarding testosterone variations during adolescence in ASD. We investigated morning salivary testosterone levels in youth with ASD and typical development (TD) to explore hypothesized differences, expecting elevated hormonal levels in ASD compared to TD. Methods Youth with ASD (n = 140) and TD (n = 104), ages 10 to 13 years, were enrolled as part of a longitudinal study on pubertal development. Pubertal stage was determined by gold standard physical examination, and salivary testosterone was collected in the morning immediately upon waking and 30 min after waking and averaged across 3 days. Diagnostic (ASD/TD) and sex (male/female) differences, as well as interactions with age and puberty, were examined using robust linear mixed effect models. Results Youth with ASD showed significantly elevated testosterone concentrations compared to same-age TD peers. After the inclusion of natural cubic splines to account for nonlinearity in age, a significant age-by-sex interaction emerged with distinct developmental slopes for males and females. At younger ages, females had higher testosterone, until about 11.5 years of age, when levels began to plateau, while male testosterone concentrations continued to rapidly increase and surpass females. As expected, more advanced pubertal development was associated with elevated testosterone. In contrast, no significant effect of parent-reported social communication symptoms was observed. Limitations Limitations include an unequal sex distribution, non-representative sample (e.g., cognition and race/ethnicity), and inability to examine afternoon/evening testosterone due to detection limits. Conclusions Testosterone may play a unique role in the presentation of ASD, especially during periods of dynamic hormonal changes including puberty. Inherent developmental (age, puberty) and sex-based (male, female) factors play a more prominent role in changes in testosterone levels during adolescence. Even so, future research is warranted to determine the differential expression and impact of exposure to excess testosterone during the pubertal transition for youth with ASD.

Early exposure to mercury has been related to endocrine disruption. Steroid hormones play a crucial role in neural cell migration, differentiation, etc., as well as protecting against several neurotoxic compounds. We investigate the relation between mercury exposure and children's sexual development, and we evaluate the possible influence of different brain-derived neurotrophic factor (BDNF) polymorphisms on this association. Our study sample comprised 412 9-year-old children participating in the INMA cohort (2004-2015). Mercury concentrations were measured at birth (cord blood) and at 4 and 9 years of age (hair). Sexual development was assessed by levels of sex steroid hormones (estradiol and testosterone) in saliva and the Tanner stages of sex development at 9 years (categorized as 1: prepuberty and1: pubertal onset). Covariates and confounders were collected through questionnaires during pregnancy and childhood. Polymorphisms in the BDNF gene were genotyped in cord blood DNA. Multivariate linear regression analyses were performed between mercury levels and children's sexual development by sex. Effect modification by genetic polymorphisms and fish intake was assessed. We found marginally significant inverse associations between postnatal exposure to mercury (at 9 years) and testosterone levels (β[95%CI] = -0.16[-0.33,0.001], and -0.20[-0.42,0.03], for boys and girls, respectively). Additionally, we found that prenatal mercury was negatively associated with Tanner stage1 in boys. Finally, we found significant genetic interactions for some single nucleotide polymorphisms in the BDNF gene. In conclusion, pre and postnatal exposure to mercury seems to affect children's sexual development and BDNF may play a role in this association, but further research would be needed.

To analyze the clinical and genetic characteristics of a 46,XX case of testicular disease with prostate germ cell tumor and explore its pathogenesis.The clinical features and pathological examination of the patient were reviewed, and the genetic basis was analyzed by chromosome karyotyping analysis and fluorescence in situ hybridization.The patient had slightly short stature, small testicles and large breast. Serum alpha fetoprotein was significantly increased, along with increased follicle stimulating hormone, luteinizing hormone and prolactine, and lower level of testosterone. The karyotype was 46,XX. Fluorescence in situ hybridization has identified the presence of SRY gene at the end of short arm of one X chromosome. The pathological diagnosis was primary germ cell tumor of prostate, mainly of yolk sac tumor type.A rare case of 46,XX testicular disorder of sex development combined with germ cell tumor of the prostate was diagnosed, which has enriched the phenotype spectrum of the disease and provided clues for the treatment of the disease.

PurposeThe ‘DSD Pathways’ study was initiated to assess health status and patterns of care among people enrolled in large integrated healthcare systems and diagnosed with conditions comprising the broad category of disorders (differences) of sex development (DSD). The objectives of this communication are to describe methods of cohort ascertainment for two specific DSD conditions—classic congenital adrenal hyperplasia with 46,XX karyotype (46,XX CAH) and complete androgen insensitivity syndrome (CAIS).ParticipantsUsing electronic health records we developed an algorithm that combined diagnostic codes, clinical notes, laboratory data and pharmacy records to assign each cohort candidate a ‘strength-of-evidence’ score supporting the diagnosis of interest. A sample of cohort candidates underwent a review of the full medical record to determine the score cutoffs for final cohort validation.Findings to dateAmong 5404 classic 46,XX CAH cohort candidates the strength-of-evidence scores ranged between 0 and 10. Based on sample validation, the eligibility cut-off for full review was set at the strength-of-evidence score of ≥7 among children under the age of 8 years and ≥8 among older cohort candidates. The final validation of all cohort candidates who met the cut-off criteria identified 115 persons with classic 46,XX CAH. The strength-of-evidence scores among 648 CAIS cohort candidates ranged from 2 to 10. There were no confirmed CAIS cases among cohort candidates with scores Future plansAs the first cohort of this type, the DSD Pathways study is well-positioned to fill existing knowledge gaps related to management and outcomes in this heterogeneous population. Analyses will examine diagnostic and referral patterns, adherence to care recommendations and physical and mental health morbidities examined through comparisons of DSD and reference populations and analyses of health status across DSD categories.

To report on the diagnosis and treatment process and clinical characteristics of a child with disorder of sex development (DSD) and to conduct pathological, imaging and genetic analysis for the patient.Clinical data of the patient were collected. Genetic testing including chromosomal karyotyping, fluorescence in situ hybridization (FISH), copy number variations (CNVs) analysis, SRY gene detection and multiple ligation-dependent probe amplification (MLPA) were carried out.The patient had a social gender of male, with a history of hypospadia and breast development. Sex hormone tests showed slightly raised prolactin. Imaging results showed bilateral breast hyperplasia, abnormal seminal vesicle glands, rudimentary uterus, and underdeveloped right testis. Intraoperative examination revealed that the child had an ovary on the left and a testis on the right. The pathological results showed fibroadenomatoid changes in the breast. The patient had a karyotype of 46,XX. FISH results showed 46,XX.ish(DXZ1x2, SRYx0). Molecular testing showed that NR0B1, PHEX, CXORF21, GJB1, PQBP1, and COL4A5 genes are duplicated. There was a presence of SRY gene and absence of UYT gene.DSD should be considered in patients with genital abnormality and male breast development. Ultrasound, sex hormone test and genetic testing should be performed to confirm the diagnosis of DSD, and molecular testing should be performed if necessary. Individualized treatment of DSD patient requires cooperation of multiple clinical disciplines.

Background Dozens of genes are involved in 46, XY differences in sex development (DSD). Notably, about 3/4 of patients cannot make a clear etiology diagnosis and single gene variant identified cannot fully explain the clinical heterogeneity of 46, XY DSD. Materials and methods We conducted a systematic clinical analysis of a 46, XY DSD patient, and applied whole-exome sequencing for the genetic analysis of this pedigree. The identified variants were analyzed by bioinformatic analysis and in vitro studies were performed in human embryonic kidney 293T (HEK-293T) cells which were transiently transfected with wild type or variant NR5A1 and MAP3K1 plasmid. Furthermore, protein production of SRY-box transcription factor 9 (SOX9) was analyzed in cell lysates. Results A novel NR5A1 variant (c.929A > C, p. His310Pro) and a rare MAP3K1 variant (c.2282T > C, p. Ile761Thr) were identified in the proband, whereas the proband's mother and sister who only carry rare MAP3K1 variant have remained phenotypically healthy to the present. These two variants were predicted to be pathogenic by bioinformatic analysis. In vitro, NR5A1 variant decreased the SOX9 production by 82.11% compared to wild type NR5A1, while MAP3K1 variant had little effect on the SOX9 production compared to wild type MAP3K1. Compared to wild type NR5A1 transfection, the SOX9 production of cells transfected with both wild type plasmids decreased by about 17.40%. Compared to variant NR5A1 transfection, the SOX9 production of cells transfected with both variant plasmids increased by the 36.64%. Conclusions Our findings suggested the novel compound variants of NR5A1 and MAP3K1 can alter the expression of SOX9 and ultimately lead to abnormality of sex development.

Although a very small group of adolescents adjudicated for sexual offending (ASO) will persist into adulthood, the use of official records of sexual recidivism after long-term follow-up periods underrates the repetition of sexually coercive behaviors during adolescence. Additionally, limited research has considered sexual reoffending as a criterion to classify this heterogeneous population. The aims of this study were to determine the prevalence of ASO who engaged in repetitive sexual offending before their adjudication, and to use it as a classification criterion to examine the differential characteristics associated with each group. A sample of 73 adjudicated ASO in Spain was examined. They were divided into sexual reoffenders (SR) ( n = 34) and sexual nonreoffenders (SNR) ( n = 39). An ex post facto research design was carried out. Assessments included reviews of official files, interviews with professionals in charge, and interviews with the ASO in which the Interpersonal Reactivity Index (IRI) was administered. Descriptive analyses were conducted for all variables and Odds Ratio ( OR) was used to compare intergroup differences. Results showed that SR had 12.95 times the odds of sexual victimization, 6.91 times the odds of having lived in a sexualized family environment, and 3 times the odds of bullying victimization. Deviant sexual fantasies were exclusively present among SR (44%). Significant differences between groups were also found in some sexual crime variables but not on the empathy scale. These results have implications for the distinction between ASO who have repeatedly engaged in sexually coercive behavior and those who engaged in a single event of sexual offending. The identification of specific risk factors and criminogenic needs for each group would benefit court decisions and more tailored interventions.

After 20 years of debate on intersex care, there has been a slight movement away from the paradigm of 'optimal gender' including early genital modification to conform to predicted gender identity towards a paradigm of 'full consent' including the provision of full information about the risks, benefits and alternatives to interventions and the postponement of irreversible interventions on minors too young to give informed consent. However, controversy continues. Against this background, the aim of this study was to analyse core aspects of current debates in intersex care. Focus was placed on controversies about surgery on external genitalia; gonadectomies; the expressed wishes of patients under the age of consent; and how to deal with intersex within the family. Eight guideline-based interviews were conducted with two people with intersex/diverse sex development conditions who had been subjected to surgery, two parents of children with an intersex/dsd condition, two medical doctors, and two psychologists. Data were analysed thematically. Findings indicate that while 'full consent' influenced actions and debate, the persons involved held differing opinions about how this policy can or should be achieved. In addition, the data illustrated how concepts such as normalcy, identity and sexuality are relevant when dealing with intersex issues.

From different sides, there is a call for better psychosocial care and counselling in the field of diverse sex development (dsd). However, studies on the specific demands, deficits and needed improvements regarding those services are rare. This exploratory online study aimed at investigating counselling experiences and the ideas that different groups of participants have concerning the localisation of counselling structures and improving care. Quantitative and qualitative data (N = 630) were analysed within a mixed methods framework. The participants included experts of experience resp. patients with different intersex/dsd conditions (n = 40), parents of children with dsd (n = 27), professional psychosocial counsellors (n = 321) and experts in the field including medical practitioners, psychologists, natural and social scientists as well as others involved, e.g., students or relatives (n = 56). The results show a gap between receiving psychosocial and medical care in the group of adult lived-experience experts, who had received less psychosocial care than medical interventions. The findings also reveal important tasks of psychosocial care. A focus was set on parental experiences. Helpful aspects reported were talking with other parents of children with intersex/dsd, aspects missed were assistance in supporting the individual development of their children. The majority of all participants (58%) held the view that, apart from multidisciplinary competence centres, there also have to be easily accessible counselling services which offer support in everyday life. The participants named increasing quality and quantity as necessary improvements in counselling structures for children and adults with intersex/dsd and their families. Implications are drawn for the specific tasks and target groups of psychosocial care and needed research in intersex healthcare over life span.

Disorders of sexual development (DSD) have been documented throughout human history with fascination. Healers of all cultures have struggled to explain, and later correct with surgery, the physical manifestations of DSD. DSD was portrayed in the mythology, legends, and art of the ancient Greeks, Romans, Sumerians, Babylonians, and Egyptians. Techniques of feminizing genitoplasties date to the time of Celsus in the time of Christ. Acceptable operative therapy for feminine phenotypes of DSD came in the 19th and 20th centuries. Masculinizing procedures, inherently more complex than feminizing genitoplasties, initially were variations of procedures for severe forms of hypospadias. Today most total penile reconstruction procedures use reconstructive and microvascular techniques invented in 20th century.

Disorders of sex development (DSD) are a complex group of conditions with highly variable clinical phenotypes, most often caused by failure of gonadal development. DSD are estimated to occur in around 1.7% of all live births. Whilst the understanding of genes involved in gonad development has increased exponentially, approximately 50% of patients with a DSD remain without a genetic diagnosis, possibly implicating non-coding genomic regions instead. Here, we review how variants in the non-coding genome of DSD patients can be identified using techniques such as array comparative genomic hybridization (CGH) to detect copy number variants (CNVs), and more recently, whole genome sequencing (WGS). Once a CNV in a patient’s non-coding genome is identified, putative regulatory elements such as enhancers need to be determined within these vast genomic regions. We will review the available online tools and databases that can be used to refine regions with potential enhancer activity based on chromosomal accessibility, histone modifications, transcription factor binding site analysis, chromatin conformation, and disease association. We will also review the current in vitro and in vivo techniques available to demonstrate the functionality of the identified enhancers. The review concludes with a clinical update on the enhancers linked to DSD.

The 17-beta-hydroxysteroid dehydrogenase type 3 (17-β-HSD3) enzyme converts androstenedione to testosterone and is encoded by the

Cryptococcus neoformans isolates are of two mating types: MAT α strains, which are predominant, and MAT a strains, isolated from the sub-Saharan African region, where cryptococcosis is most abundant and severe. Here, we demonstrated the function of the CCAAT -binding HAP complex (Hap2/3/5/X) as a transcriptional repressor of Cpk1 pathway-related genes in cells of both mating types.

With the emergence of resistance to front-line antimalarials, there is an urgent need to develop new medicines, including those targeting sexual development. This study aimed to assess the activity of a panel of phosphatase inhibitors against the sexual development of Plasmodium berghei and evaluate their potential as transmission-blocking agents.Twenty-five compounds were screened for transmission-blocking activity in vitro using the P. berghei ookinete culture assay. The inhibitory effects on male gametogenesis, gamete-ookinete, and zygote-ookinete formation were evaluated. The transmission-blocking activity of two compounds was evaluated using an in vivo mosquito feeding assay. Their cytotoxic effects were assessed on the human cell line HepG2.Twelve compounds inhibited P. berghei ookinete formation with an ICSome phosphatase inhibitors effectively inhibited Plasmodium sexual development and exhibited evident transmission-blocking activity, suggesting that phosphatases are valid targets for antimalarial development.

Differences or disorders of sex development (DSD) include various congenital conditions in which chromosomal, gonadal, or anatomical sex development is atypical. The incidence varies according to the category of DSD but the total incidence is high if hypospadias and undescended testes are included. Fertility prospects may be a concern for DSD patients and their parents. With the development of modern medical technologies and treatment opportunities, fertility diagnostics, information, and treatment have changed. Assisted reproductive technology has developed during the past decades and has become more available with an improving success rate. Intracytoplasmic sperm injection and testicular sperm retrieval, have further improved the possibilities for men with DSD to become biological parents. Some studies have determined the presence of germ cells in the gonads of patients with DSD suggesting that the potential for fertility may be higher than previously thought. However, fertility outcomes among individuals with DSD have not been fully investigated. Moreover, previous study showed that information on fertility problems and treatment possibilities given to patients with DSD needs to be improved. The use of registries to study fertility outcomes is essential for a better knowledge of fertility in patients with these rare conditions.

Background Secreted R-spondin (RSPO) proteins play a key role in reproductive organ development, epithelial stem cell renewal and cancer induction by reinforcing canonical Wnt signaling. We have previously reported that palmoplantar keratoderma (PPK), predisposition to cutaneous squamous cell carcinoma (SCC) development and sex reversal segregate as autosomal recessive trait in patients carrying RSPO1-mutations. Although our previous findings suggested that RSPO1 secreted from fibroblasts regulates keratinocyte growth or differentiation, the role of this protein in the epidermis remains largely unexplored. Our study was aimed at expanding the phenotypic, molecular and functional characterization of RSPO1-mutated skin and keratinocytes. Results Cultured primary keratinocytes from PPK skin of a RSPO1-mutated XX-sex reversed patient displayed highly impaired differentiation and epithelial-mesenchymal transition (EMT)-like phenotype. Interestingly, RSPO1-mutated PPK skin expressed markers of increased proliferation, dedifferentiation and altered cell–cell adhesion. Furthermore, all these signs were more evident in SCC specimens of the patient. Cultured PPK patient’s keratinocytes exhibited increased expression of cell‒matrix adhesion proteins and extracellular matrix remodeling enzymes. Moreover, they showed invasiveness properties in an organotypic skin model in presence of PPK fibroblasts, which behave like cancer-associated fibroblasts. However, the co-culture with normal fibroblasts or treatment with the recombinant RSPO1 protein did not revert or reduce the EMT-like phenotype and invasion capability of PPK keratinocytes. Notably, RSPO1-mutated PPK fibroblasts induced a hyperproliferative and dedifferentiated phenotype of age-matched normal control plantar keratinocytes. Wnt signaling has a key role in both PPK promotion and SCC development. Accordingly, Wnt mediators were differentially expressed in both PPK keratinocytes and skin specimens of RSPO1-mutated patient compared to control. Conclusions Altogether our data indicate that the absence of RSPO1 in patients with 46XX disorder of sexual development affects the skin microenvironment and epidermal integrity, thus contributing to the risk of SCC tumorigenesis in palmoplantar regions exposed to major frictional stresses.

Youth and adolescence are times when young men negotiate their identity in relation to social and cultural expectations of being a man, with enduring implications for sexual health and wellbeing. This study explored how boys aged 10-14 years living in Korogocho slum in Nairobi, Kenya conceptualised masculinity, their perceptions of how masculinities are performed, and the linkage between conceptualisations of masculinity and sexual development. Three bases of gender socialisation were identified: (1) verbal messaging (mainly from parents and teachers); (2) observing the behaviours of older men in the community; and (3) information received from mainstream and social media. Masculinity conceptualisations focussed on financial stability, family life and responsibility, physical attributes, character and religion. Two contrasting portrayals of masculinity emerged in the form of idealised and dominant masculinities. A close linkage was found between masculinity conceptualisations and sexual development. Findings are important for programmes that aim to transform harmful gender norms and signal the need for longitudinal research exploring how gender beliefs may change over time.

A multidisciplinary DSD clinic offers the opportunity for different specialties to learn from each other, as each provides their own perspective and expertise to the management of these complex patients, leading to collaborative care. For the patient, a multi-disciplinary clinic can improve access to care and decrease stress, as patients see all of the specialists on one day. For urologists seeing patients with DSD within a multi-disciplinary DSD clinic as well as independently, understanding what other specialists provide can help facilitate care and referral. Medical genetics is part of a multi-disciplinary DSD clinic. Given the recent advances in genetic diagnostics, many of the offered tests may be less familiar to the pediatric urologist. Therefore, this conversation reviews the clinical presentations and genetic testing options including chromosomal microarray, genetic testing panel, whole exome sequencing, and whole genome sequencing and how these can be helpful in the diagnosis and management of patients with DSD conditions.

This paper aims to bring a novel approach to the discussion of unfair advantages in sport by looking for a local criterion of fairness instead of a universal criterion. A local criterion of fairness would not solve the general dispute over what counts as an unfair advantage, but it would be beneficial in evaluating specific cases and could guide further discussion about them. We seek a local criterion of fairness by comparing the specific property advantages of Caster Semenya and Eero Mäntyranta. South African Semenya is a middle-distance runner whose right to compete in the female category has been challenged owing to her assumed difference of sex development and related high level of testosterone. Finnish Mäntyranta was a cross-country skier with an exceptionally high haematocrit level. We examine whether there is a relevant difference between their advantages that would justify treating the athletes differently. We propose that the criterion 'not attainable by other athletes in the same category' could stand as a local criterion of fairness under certain conditions. However, its proper application requires further discussion on how to justify categories in sport.

The focus of this article is to review the complex determinants of gender assignment in a child with a disorder of sex development using four different clinical cases. While the care of patients with DSD may be shared across several specialties and opinions regarding their management may vary, this may be further complicated by psychosocial, cultural and economic factors. In this regard, access to behavioral health specialists with experience and specialization in the treatment of patients with DSD should be a foundational component of the standard of care and can greatly assist in the complex decision-making regarding gender assignment. We recommend an individualized approach by a multidisciplinary team utilizing a range of evolving strategies, including outcome data (or lack thereof) to support families during the decision-making process.

Summary Introduction/background Many parents of infants born with a DSD describe the process of initial sex assignment at birth as highly stressful. Parents of children with a DSD also note high distress when their children engage in behaviors that are not considered typical for their gender. Objective The goal of this article is to provide members of the health care team a brief overview of psychosocial facets of gender and gender identity particularly relevant to DSD for the purposes of enhancing shared decision-making and optimizing support for individuals with a DSD and their families. Discussion Gender identity is a multidimensional construct involving related but distinct concepts such as gender typicality, gender contentedness and felt pressure for gender differentiation, and can be assessed via standardized measures. Gender dysphoria is associated with poor psychological adjustment, and is mitigated by family and peer support. Family influences on gender identity include parental modeling of gender behavior and family composition (e.g., same-sex children vs both sons and daughters in a family). Cultural factors that may influence sex assignment include societal views on gender, and gender-related differential resource allocation within a society. In addition, religious beliefs and the presence of a “third-sex” category within a culture may also influence parental gender ideology. Clinical application Health care providers who work with patients with a DSD must have a strong grasp on the construct of gender identity, and must be able to clearly and consistently communicate with patients and families about gender beliefs in order to optimize family support and gender-related decisions.