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Background:DHX37 is an autosomal gene responsible for encoding a helicase from the DExD/H-box family that plays an essential role in ribosome biogenesis. Variants in this gene were previously reported in two different phenotypes: neurodevelopmental disorders and disorders/differences of sex development (DSD). Particularly for the DSD group, variants were mainly reported associated with gonadal dysgenesis and testicular regression syndrome. Summary: Focusing specifically in the DSD group, we revised the 21 DHX37 variants described across a total of 55 cases published in the literature so far. We summarized the most important clinical and molecular features of all cases, trying to have a better comprehensiveness about this gene in the sexual development. Key Messages: The trick question regarding DHX37 is how a helicase involved in basic cell function could have a specific role in testis development. Little is known about the impact of DHX37 variants in DSD individuals. Nevertheless, current research strongly suggests that DHX37 is involved in the male sex development pathway, particularly in testis determination and maintenance. This is evidenced by the predominant assignment of affected individuals as males and the presence of Wolffian structures in most of the cases. Advancements in molecular techniques, such as the generation of induced pluripotent stem cells and the digenic inheritance for DHX37 cases, are also addressed in this paper. This represents the first comprehensive review of all DHX37 variants published in the literature to date. [ABSTRACT FROM AUTHOR]

Introduction: Individuals with differences of sex development (DSD) experience complex, often competing, medical and psychosocial challenges surrounding fertility. The study aimed to characterize how “success” in fertility-related care is conceptualized and attained among individuals with a DSD, their parents or caregivers, healthcare providers, and other stakeholders. Methods: As part of a larger study, DSD stakeholders (n = 110) participated in semi-structured interviews covering the clinical care of patients with DSD. Primary questions included “What is a successful outcome in DSD care?” and “How do you achieve it?” with fertility as either a spontaneous or suggested topic of discussion. Transcripts were analyzed utilizing a phenomenological approach. This analysis focuses on the extracted themes related to fertility. Results: Fertility was discussed by 19/24 individuals with DSD, 12/19 parents or caregivers, 35/37 healthcare providers, and 19/30 other stakeholders. Components of successful fertility-related care included (1) specific discussions surrounding the relationship between DSD and fertility potential, options for fertility preservation, and options for non-biologic parenthood; (2) early and repeated introduction of these topics; and (3) consideration of age, developmental maturity, and cultural context on decisions around fertility. Challenges included the lack of fertility outcome data in this population and the irreversibility of gonadectomy. Trade-offs identified included anatomic typicality versus function, fertility preservation versus cancer risk reduction, and balancing the different priorities of stakeholders. Discussion/Conclusions: A wide range of DSD stakeholders highlighted the importance of addressing fertility concerns in achieving favorable outcomes for individuals with DSD. These stakeholder perspectives should inform fertility-related education, shared decision-making processes, and clinical care. [ABSTRACT FROM AUTHOR]

Background: In the last 15 years, the care provided for individuals born with differences of sex development (DSD) has evolved, with a strong emphasis on interdisciplinary approaches. However, these developments have not convinced some stakeholders to embrace the current model of care. This care model has also paid insufficient attention to socio-cultural differences and global inequalities. Summary: This article is an opinion statement, resulting from in-depth discussions and reflection among clinicians, patients, and family support organizations based in the USA and Europe, where we seek areas of common ground and try to identify opportunities to further develop resources. The product of these conversations is summarized in 10 panels. The corresponding sections provide additional discussion on some of the panel items. Key Messages: Participants identified areas of agreement, gained a deeper understanding of the reasons behind disagreements on certain matters, and identified the necessary steps to foster future consensus. We offer preliminary recommendations for guiding clinical management and resource allocation. By promoting a broader consensus, we aim to enhance the quality of care and well-being for individuals of all ages who have a DSD. [ABSTRACT FROM AUTHOR]

Background: Our multidisciplinary team (MDT) is a large specialized team based in Semarang, Indonesia, that cares for a wide variety of pediatric and adult individuals with differences of sex development (DSD) from across Indonesia. Here, we describe our work over the last 17 years. Methods: We analyzed phenotypic, hormonal, and genetic findings from clinical records for all patients referred to our MDT during the period 2004–2020. Results: Among 1,184 DSD patients, 10% had sex chromosome DSD, 67% had 46,XY DSD, and 23% had 46,XX DSD. The most common sex chromosome anomaly was Turner syndrome (45,X) (55 cases). For patients with 46,XY DSD under-masculinization was the most common diagnosis (311 cases), and for 46,XX DSD, a defect of Müllerian development was most common (131 cases) followed by congenital adrenal hyperplasia (CAH) (116 cases). Sanger sequencing, MLPA, and targeted gene sequencing of 257 patients with 46,XY DSD found likely causative variants in 21% (55 cases), with 13 diagnostic genes implicated. The most affected gene codes for the androgen receptor. Molecular analysis identified a diagnosis for 69 of 116 patients with CAH, with 62 carrying variants in CYP21A2 including four novel variants, and 7 patients carrying variants in CYP11B1. In many cases, these genetic diagnoses influenced the clinical management of patients and their families. Conclusions: Our work has highlighted the occurrence of different DSDs in Indonesia. By applying sequencing technologies as part of our clinical care, we have delivered a number of genetic diagnoses and identified novel pathogenic variants in some genes, which may be clinically specific to Indonesia. Genetics can inform many aspects of DSD clinical management, and while many of our patients remain undiagnosed, we hope that future testing may provide answers for even more. [ABSTRACT FROM AUTHOR]

Introduction: People with differences of sex development (DSD) and their families need education about these conditions while receiving emotional and peer support to participate in shared decision-making, reduce social isolation, and optimize physical and psychosocial outcomes. Barriers to education and support include limited knowledge and awareness by healthcare providers, tension among patient and medical communities, varied quality of educational resources, and the sensitive nature of DSD. We aimed to create an electronic repository of vetted quality online resources about DSD. Methods: The electronic resource repository (e-RR) was a collaboration between affected individuals and advocates and healthcare providers in the DSD-Translational Research Network (DSD-TRN), an NIH-supported consortium of US teams committed to standardizing and optimizing care in DSD. The e-RR development and ongoing growth involved: (1) identification of resources by the project team (3 advocates and 1 physician), (2) evaluation and feedback by DSD-TRN clinical teams, (3) creation of the e-RR, and (4) review and revision. Twitter-like descriptions accompanied each entry; resources were categorized by target age, audience, and condition. Results: Thirty-seven web-based educational, peer and advocacy support, and clinician-oriented resources were reviewed. Eight of 10 DSD-TRN teams responded to a survey regarding resource inclusion. Awareness of individual resources varied widely. Consensus was achieved when opinions differed; 30 resources were included. The e-RR is available online and as a downloadable booklet at http://www.accordalliance.org/resource-guide/. Conclusion: The e-RR increases awareness of and access to vetted educational and support resources for those with DSD and healthcare providers. It represents important collaboration between advocates and providers. [ABSTRACT FROM AUTHOR]

The human chorionic gonadotropin (hCG) stimulation test that evaluates gonadal steroidogenesis is crucial in the assessment of patients with 46,XY disorders of sex development (DSD). This study aimed to determine a testosterone (T) cutoff level that indicates an adequate testicular function using LC-MS/MS after stimulation with recombinant human chorionic gonadotropin (rhCG) in a single dose. Nineteen prepubertal children with 46,XY DSD and normal T secretion were evaluated. T and dihydrotestosterone (DHT) levels were measured by liquid chromatography technique with tandem mass spectrometry (LC-MS/MS) before and 7 days after rhCG application at 250 µg. We suggest 0.89 ng/mL as the cutoff point for T after rhCG stimulation analyzed by LC-MS/MS. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this retrospective study was to verify the association between the time of diagnosis and initial and final sex assignment in a disorder of sex development (DSD) diagnostic group, looking at the age of the patients at first visit, severity of genital ambiguity, and karyotype. Methods: The time of diagnosis was divided into 3 groups: before 2000, between 2000 and 2006, and after 2006. Data were categorized and analyzed using the χ2 test with α < 0.05. Results: A total of 567 cases were analyzed; 307 were assigned as male, 135 as female, and 125 remained undefined at the first visit. After clinical and laboratory evaluations, 369 patients were male and 198 were female. Neither initial nor final sex assignment proportions changed over time, but there were significant differences in the age at first visit, with referral occurring at an earlier age, as well as more severe genital ambiguity presentations, a higher proportion of sex chromosome aberrations, and a lower frequency of 46,XX DSD cases. This occurred both in the sample as a whole (567 cases) and in the group of 125 patients without definitive sex assignment at the first visit. The results were similar when only 284 patients aged less than 12 months at the first visit were analyzed. Discussion/Conclusion: Over time, there were no changes in sex assignment proportions, but there was an increased awareness of the need for early referral and changes in clinical, cytogenetic, and diagnostic aspects. [ABSTRACT FROM AUTHOR]

Background: Male reproductive development in mammals can be divided into a gonadal formation phase followed by a hormone-driven differentiation phase. Failure of these processes may result in Differences in Sex Development (DSD), which may include abnormalities of the male reproductive tract, including cryptorchidism, hypospadias, infertility, and testicular germ cell cancer (TGCC). These disorders are also considered to be part of a testicular dysgenesis syndrome (TDS) in males. Whilst DSDs are considered to result primarily from genetic abnormalities, the development of TDS disorders is frequently associated with environmental factors. Summary: In this review, we will discuss the development of the male reproductive system in relation to DSD and TDS. We will also describe the experimental systems, including studies involving animals and human tissues or cells that can be used to investigate the role of environmental factors in inducing male reproductive disorders. We will discuss recent studies investigating the impact of environmental chemicals (e.g., phthalates and bisphenols), lifestyle factors (e.g., smoking) and pharmaceuticals (e.g., analgesics) on foetal testis development. Finally, we will describe the evidence, involving experimental and epidemiologic approaches, for a role of environmental factors in the development of specific male reproductive disorders, including cryptorchidism, hypospadias, and TGCC. Key Messages: Environmental exposures can impact the development and function of the male reproductive system in humans. Epidemiology studies and experimental approaches using human tissues are important to translate findings from animal studies and account for species differences in response to environmental exposures. [ABSTRACT FROM AUTHOR]

Background: The suspicion of a disorder of sex development (DSD) often arises at birth, when the newborn presents with ambiguous genitalia, or even during prenatal ultrasound assessments. Less frequently, the aspect of the external genitalia is typically female or male, and the diagnosis of DSD may be delayed until a karyotype is performed for another health issue, or until pubertal age when a girl presents with absence of thelarche and/or menarche or a boy consults for gynaecomastia and/or small testes. Summary: In this review, we provide a practical, updated approach to clinical and hormonal laboratory workup of the newborn, the child, and the adolescent with a suspected DSD. We focus on how to specifically address the diagnostic approach according to the age and presentation. Key Message: We particularly highlight the importance of a detailed anatomic description of the external and internal genitalia, adequate imaging studies or surgical exploration, the assessment of reproductive hormone levels – especially testosterone, anti-Müllerian hormone, 17-hydroxyprogesterone, and gonadotropins – and karyotyping. [ABSTRACT FROM AUTHOR]

Introduction: The variants in the zinc finger (ZF) domains 1–3 in WT1 are one of the major causes of 46,XY disorders of sex development (DSD). Recently, variants in the fourth ZF (ZF4 variants) were reported to cause 46,XX DSD. However, all the 9 patients reported were de novo, and no familial cases were identified. Case Presentation and Results: The proband (16-year-old social female) had a 46,XX karyotype with dysplastic testes and moderate virilization in genitalia. A ZF4 variant, p.Arg495Gln, in WT1 was identified in the proband, her brother, and mother. The mother did not show any virilization with normal fertility, and the 46,XY brother developed normal puberty. Conclusion: The phenotypic variations due to the ZF4 variant are extremely broad in 46,XX cases. [ABSTRACT FROM AUTHOR]

Introduction: Although it was common in the 1970s–1990s to assign female gender of rearing to 46,XY infants with limited virilization of varying etiologies, including those with partial androgen insensitivity syndrome (PAIS), long-term data on outcomes for these individuals are sparse. Therefore, our goal was to use the power of an international registry to evaluate clinical features, surgical management, and pubertal data in patients with a molecularly confirmed diagnosis of PAIS who were born before 2008 and were raised as girls. Methods: The current study interrogated the International Disorders of Sex Development Registry for available data on management and pubertal outcomes in individuals with genetically confirmed PAIS who were raised as girls. Results: Among the 11 individuals who fulfilled the key criteria for inclusion, the external masculinization score (EMS) at presentation ranged from 2 to 6 (median 5); 7 girls underwent gonadectomy before the age of 9 years, whereas 4 underwent gonadectomy in the teenage years (≥ age 13). Clitoral enlargement at puberty was reported for 3 girls (27%) who presented initially at the time of puberty with intact gonads. In the 9 individuals (82%) for whom gonadal pathology data were provided, there was no evidence of germ cell tumor at median age of 8.1 years. All girls received estrogen replacement, and 8/11 had attained Tanner stage 4–5 breast development at the last assessment. Conclusion: In general, although it appears that female assignment in PAIS is becoming uncommon, our data provide no evidence to support the practice of prophylactic prepubertal gonadectomy with respect to the risk of a germ cell tumor. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: People with differences of sex development (DSD) and their families need education about these conditions while receiving emotional and peer support to participate in shared decision-making, reduce social isolation, and optimize physical and psychosocial outcomes. Barriers to education and support include limited knowledge and awareness by healthcare providers, tension among patient and medical communities, varied quality of educational resources, and the sensitive nature of DSD. We aimed to create an electronic repository of vetted quality online resources about DSD. Methods: The electronic resource repository (e-RR) was a collaboration between affected individuals and advocates and healthcare providers in the DSD-Translational Research Network (DSD-TRN), an NIH-supported consortium of US teams committed to standardizing and optimizing care in DSD. The e-RR development and ongoing growth involved: (1) identification of resources by the project team (3 advocates and 1 physician), (2) evaluation and feedback by DSD-TRN clinical teams, (3) creation of the e-RR, and (4) review and revision. Twitter-like descriptions accompanied each entry; resources were categorized by target age, audience, and condition. Results: Thirty-seven web-based educational, peer and advocacy support, and clinician-oriented resources were reviewed. Eight of 10 DSD-TRN teams responded to a survey regarding resource inclusion. Awareness of individual resources varied widely. Consensus was achieved when opinions differed; 30 resources were included. The e-RR is available online and as a downloadable booklet at http://www.accordalliance.org/resource-guide/. Conclusion: The e-RR increases awareness of and access to vetted educational and support resources for those with DSD and healthcare providers. It represents important collaboration between advocates and providers. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this retrospective study was to verify the association between the time of diagnosis and initial and final sex assignment in a disorder of sex development (DSD) diagnostic group, looking at the age of the patients at first visit, severity of genital ambiguity, and karyotype. Methods: The time of diagnosis was divided into 3 groups: before 2000, between 2000 and 2006, and after 2006. Data were categorized and analyzed using the χ2 test with α < 0.05. Results: A total of 567 cases were analyzed; 307 were assigned as male, 135 as female, and 125 remained undefined at the first visit. After clinical and laboratory evaluations, 369 patients were male and 198 were female. Neither initial nor final sex assignment proportions changed over time, but there were significant differences in the age at first visit, with referral occurring at an earlier age, as well as more severe genital ambiguity presentations, a higher proportion of sex chromosome aberrations, and a lower frequency of 46,XX DSD cases. This occurred both in the sample as a whole (567 cases) and in the group of 125 patients without definitive sex assignment at the first visit. The results were similar when only 284 patients aged less than 12 months at the first visit were analyzed. Discussion/Conclusion: Over time, there were no changes in sex assignment proportions, but there was an increased awareness of the need for early referral and changes in clinical, cytogenetic, and diagnostic aspects. [ABSTRACT FROM AUTHOR]

The human chorionic gonadotropin (hCG) stimulation test that evaluates gonadal steroidogenesis is crucial in the assessment of patients with 46,XY disorders of sex development (DSD). This study aimed to determine a testosterone (T) cutoff level that indicates an adequate testicular function using LC-MS/MS after stimulation with recombinant human chorionic gonadotropin (rhCG) in a single dose. Nineteen prepubertal children with 46,XY DSD and normal T secretion were evaluated. T and dihydrotestosterone (DHT) levels were measured by liquid chromatography technique with tandem mass spectrometry (LC-MS/MS) before and 7 days after rhCG application at 250 µg. We suggest 0.89 ng/mL as the cutoff point for T after rhCG stimulation analyzed by LC-MS/MS. [ABSTRACT FROM AUTHOR]

Mixed gonadal dysgenesis is the most common chromosomal abnormality with ambiguous genitalia, defined as a 45,X/46,XY mosaicism. It can present with a normal male phenotype, ambiguous genitalia, or features of Turner syndrome. A 14-year-old patient was referred to the genetics clinic due to hypospadia, cryptorchidism, and aortic coarctation. During the physical examination, short stature, webbed neck, and Blashko lines on his back were noted. He had a previous karyotype reported as normal. However, due to an inadequate evolution and a low resolution on the previous test, a higher resolution karyotype was performed, identifying a mosaicism 45,X/46,XY. A multidisciplinary board examined the case, and follow-up with tumor markers was carried out to evaluate the presence of gonadoblastoma, one of the main complications in these patients. Treatment should be transdisciplinary and focused on the particular characteristics of each case. Other treatment alternatives include corrective surgery and hormonal therapy. [ABSTRACT FROM AUTHOR]

SOX genesare master regulatory genes controlling development and are fundamental to the establishment of sex determination in a multitude of organisms. The discovery of the master sex-determining gene SRY in 1990 was pivotal for the understanding of how testis development is initiated in mammals. With this discovery, an entire family of SOX factors were uncovered that play crucial roles in cell fate decisions during development. The importance of SOX genes in human reproductive development is evident from the various disorders of sex development (DSD) upon loss or overexpression of SOX gene function. Here, we review the roles that SOX genes play in gonad development and their involvement in DSD. We start with an overview of sex determination and differentiation, DSDs, and the SOX gene family and function. We then provide detailed information and discussion on SOX genes that have been implicated in DSDs, both at the gene and regulatory level. These include SRY, SOX9, SOX3, SOX8, and SOX10. This review provides insights on the crucial balance of SOX gene expression levels needed for gonad development and maintenance and how changes in these levels can lead to DSDs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In recent years, intersex advocates, medical ethicists, and lawmakers have increasingly demanded a delay of genital surgery that is not acutely medically necessary in patients with somatic intersexuality to the age of consent. This study provides a review of published surveys of affected patients' own opinions on this issue. In part with search of PubMed 2000–2021, 10 pertinent surveys of patients were identified: 3 from the USA; 4 from European countries; and one each from Brazil, China, and Malaysia. All were based on samples of clinic patients, most of whom had previously undergone genital surgery. The majority of both XX and XY patients with somatic intersexuality favored early surgery, with somewhat more syndrome-specific variability in XY patients. The available survey data clearly indicate that a mandatory delay of genital surgery in all patients with somatic intersexuality to the age of consent would disregard the wishes of the majority of surveyed patients. A syndrome- and syndrome severity-specific individualized approach to surgery decisions appears more appropriate. [ABSTRACT FROM AUTHOR]

Disorders of sex development, Intersex, Informed consent, Sex diversity Keywords: Disorders of sex development; Intersex; Informed consent; Sex diversity EN Disorders of sex development Intersex Informed consent Sex diversity 21 24 4 05/16/22 20220101 NES 220101 The medical management of people born with atypical genitalia has been in the focus of ethical and societal debates for several decades. (4) How the public sphere (including discourses in art, movies, literature, and the politico-legal context) and the publicly visible performance of sex and gender (including social practices) influence the development of an individual's views and needs with regard to sexual identity and adjustment. This can be addressed by serious inquiries into the multiple processes of discrimination on the basis of sex and gender diversity and development of strategies for inclusion that meet the needs and views of those who are to be included. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

This paper reviews the current knowledge on the environmental effects on penile development in humans. The specific focus is on endocrine-disrupting chemicals (EDCs), a heterogeneous group of natural or manmade substances that interfere with endocrine function, and whether they can induce hypospadias and micropenis in male neonates. Epidemiological data and animal observations first raised suspicions about environmental effects, leading to the testis dysgenesis syndrome (TDS) hypothesis. More recent research has provided stronger indications that TDS may indeed be the result of the direct or indirect effects of EDCs. Drawing on epidemiological and toxicological studies, we also report on the effects of maternal diet and substances like pesticides, phthalates, bisphenol A, and polychlorinated biphenyls. Proximity to contamination hazards and occupational exposure are also suspected to contribute to the occurrence of hypospadias and micropenis. Lastly, the cumulative effects of EDCs and the possibility of transgenerational effects, with the penile development of subsequent generations being affected, raise concerns for long-term public health. [ABSTRACT FROM AUTHOR]

A GATA4 haploinsufficiency has been well described in patients with congenital heart defects (CHDs), whilst only a few studies have reported mutations related to a 46,XY disorder of sex development (DSD) phenotype. This study investigated the clinical phenotypes and molecular characteristics of two 46,XY DSD patients harboring GATA4 variants. Mutation analysis was performed using a targeted gene panel or whole-exome sequencing. The transactivation activity of each variant protein was examined by in vitro luciferase reporter assay using the AMH and SRY promoters. Subject 1 presented with a micropenis and hypospadias. Subject 2 showed complete female external genitalia with a 46,XY karyotype. Both patients were responsive to hCG stimulation tests and did not manifest CHD. A novel heterozygous variant, c.643A>G (p.R215G), in GATA4 was identified in Subject 1, whereas Subject 2 harbored a previously reported variant, c.1220C>A (p.P407Q), in GATA4 and a previously known pathogenic mutation, i.e., c.226C>T (p.Q76*) in the AR gene. The reporter assays using the SRY and AMH promoters revealed decreased transcriptional activity of both p.P407Q and p.R215G. However, the GATA4 p.P407Q variant was classified as likely benign. In conclusion, it is essential to integrate clinical features and endocrine findings when interpreting sequence variants. [ABSTRACT FROM AUTHOR]

Introduction: Infertility is common for individuals with differences of sex development (DSD) and is a significant concern to these individuals. Fertility potential in many DSD conditions is poorly understood. Gonadal tissue cryopreservation (GTC) for fertility preservation (FP) is offered to children with cancer undergoing gonadotoxic therapy. Our team sought to expand the field of FP by offering and evaluating the success of GTC for individuals with DSD. Materials and Methods: GTC was offered to patients with DSD undergoing prophylactic gonadectomy, after extensive multidisciplinary counseling. For those who elected to attempt GTC, data were retrospectively abstracted, including: DSD diagnosis, age at gonadectomy, indication for gonadectomy, pathology results, and final decision about long-term gonadal tissue storage. Results: Ten patients were enrolled to attempt GTC, with a mean age of 11.5 years (range 1–18). Five of the 10 patients had germ cells (GCs) present. Diagnoses (age at gonadectomy) for patients with GCs included ovotesticular DSD (13 months), mixed gonadal dysgenesis (17 months), partial gonadal dysgenesis (3 years), partial androgen insensitivity syndrome (11 years), and mixed gonadal dysgenesis (12 years). Four of the 5 subjects with GCs elected for GTC. One opted against GTC, citing immature gametes that did not match gender identity. Conclusion: GTC at the time of gonadectomy for patients with DSD is feasible. In many patients, GCs are present. While questions remain about the timing of gonadectomy, quality of GCs, and future success for use of the tissue based on technological advancement, GTC represents a novel approach to experimental FP for individuals with DSD. [ABSTRACT FROM AUTHOR]

Historically, the terms partial (PGD) and mixed gonadal dysgenesis (MGD) have been used to describe incomplete testicular differentiation in individuals with 46,XY or 45,X/46,XY karyotypes, respectively. However, it is currently unclear to what extent clinical features actually differ between these individuals. The aim of this study was to compare clinical, laboratory, and histological findings in these 2 groups. Patients with testicular dysgenesis seen in our service between 1989 and 2013 were selected. Sixty-one patients met the inclusion criteria. Individuals with 46,XY and 45,X/46,XY karyotypes were compared regarding genital features, gonadal histology and function, growth, and associated conditions. Twenty-five had mosaicism with a 45,X cell line (MGD), while a 46,XY karyotype (PGD) was found in 36 cases belonging to 32 families. Mutations in NR5A1, WT1, and SRY genes associated with testicular dysgenesis were found in 12 families. There were no significant differences regarding parental consanguinity, degree of external androgenization, gonadal location, histology, and function, and associated conditions. However, in the MGD group, the presence of a uterus, lower birth weight and length, and short stature were more often observed. Therefore, the use of histological features to classify PDG and MGD should be abandoned and replaced by classification based on karyotype. [ABSTRACT FROM AUTHOR]

Ambiguous genitalia affect 1 in 5,000 live births. Diagnostic procedures can be time-consuming, and often the etiology cannot be established in this group of individuals with differences/disorders of sex development (DSD). We aimed to evaluate the clinical presentation, sex assignment, and diagnostic workup in these patients. In this retrospective observational study, we included infants who presented with ambiguous genitalia from 2006 to 2016 at the Radboudumc (Radboud University Medical Center) DSD expert center. Relevant data were collected from patient records. Sixty-two 46,XY and fourteen 46,XX individuals were included. Sex was assigned in the first days of life and based on the combination of presence or absence of a uterus on ultrasound, AMH level, palpable gonads, and the karyotype (corresponded in 96% of the patients). In 86% of the 46,XX DSD subjects, a diagnosis was made, whereas in only 15/62 (24%) of the 46,XY DSD individuals, etiology was determined. In 52 individuals, genetic testing was performed resulting in a diagnosis in 24 patients (46%). AMH, hCG-stimulated testosterone, and dihydrotestosterone levels contributed to determining etiology, whilst basal testosterone and basal dihydrotestosterone did not. Establishing a diagnosis in infants with ambiguous genitalia is complex and challenging; this study aids to enhance this process and improve current practice. [ABSTRACT FROM AUTHOR]

Fertility remains a challenge for men with 5α-reductase-2 deficiency. Such a diagnosis was made in 2 adult brothers who are compound heterozygous for the 5α-reductase type 2 gene (SRD5A2; c.308G>C; c.689A>C). They were born with ambiguous genitalia and the male sex was assigned. Both brothers underwent reconstructive genital surgery during pediatric age and had spontaneous virilization at puberty. The older brother experienced natural conception, while the younger had a son by assisted reproductive technology. Other family members were demonstrated to be compound heterozygous or heterozygous for the same genetic variants. The older brother is the third man with 5α-reductase-2 deficiency and spontaneous paternity. The little series of men with 5α-reductase-2 deficiency and documented spontaneous or assisted paternity is reviewed. In conclusion, the possibility of fatherhood is a main indication for male sex assignment in patients with 5α-reductase-2 deficiency. [ABSTRACT FROM AUTHOR]

>bold<>italic/italic<>/bold< Utilization of a psychosocial screener to identify families affected by a disorder/difference of sex development (DSD) and at risk for adjustment challenges may facilitate efficient use of team resources to optimize care. The Psychosocial Assessment Tool (PAT) has been used in other pediatric conditions. The current study explored the reliability and validity of the PAT (modified for use within the DSD population; PAT-DSD). >bold<>italic/italic<>/bold< Participants were 197 families enrolled in the DSD-Translational Research Network (DSD-TRN) who completed a PAT-DSD during a DSD clinic visit. Psychosocial data were extracted from the DSD-TRN clinical registry. Internal reliability of the PAT-DSD was tested using the Kuder-Richardson-20 coefficient. Validity was examined by exploring the correlation of the PAT-DSD with other measures of caregiver distress and child emotional-behavioral functioning. >bold<>italic/italic<>/bold< One-third of families demonstrated psychosocial risk (27.9% "Targeted" and 6.1% "Clinical" level of risk). Internal reliability of the PAT-DSD Total score was high (α = 0.86); 4 of 8 subscales met acceptable internal reliability. A priori predicted relationships between the PAT-DSD and other psychosocial measures were supported. The PAT-DSD Total score related to measures of caregiver distress (>italic/italic< = 0.40, >italic/italic< < 0.001) and to both caregiver-reported and patient self-reported behavioral problems (>italic/italic< = 0.61, >italic/italic< < 0.00; >italic/italic< = 0.37, >italic/italic< < 0.05). >bold<>italic/italic<>/bold< This study provides evidence for the reliability and validity of the PAT-DSD. Given variability in the internal reliability across subscales, this measure is best used to screen for overall family risk, rather than to assess specific psychosocial concerns. [ABSTRACT FROM AUTHOR]

Background/Aims: Parents of children born with disorders of sex development (DSD) often experience anxiety, but risk factors, including parental perception of the severity of their child's DSD, have not been examined. We hypothesized that severity of illness (SOI) ratings would relate to parental anxiety, and would be higher for parents of children with a potentially life-threatening DSD (e.g., 21-hydroxylase deficiency). Methods: Eighty-nine parents (Mage = 33.0, 56.2% mothers) of 51 children (Mage in months = 8.7) with a DSD including ambiguous genitalia were recruited from 12 specialized DSD clinics. Parents completed questionnaires prior to genitoplasty, 6 months post-genitoplasty, and 12 months post-genitoplasty (if completed). Data were analyzed with linear mixed modeling. Results: Parental anxiety decreased over time, χ2(1) = 10.14, p < 0.01. A positive relationship between SOI and anxiety was found, with SOI being a strong predictor of anxiety (b = 0.53, p < 0.01; χ2[1] = 5.33, p < 0.05). An SOI by time interaction indicated SOI had an increasing effect on anxiety over time, b = 0.06, p < 0.05; χ2(1) = 6.30, p < 0.05. There was no diagnosis by SOI interaction. Conclusion: Parental anxiety decreased over time, but those with higher SOI ratings reported greater initial anxiety followed by slower resolution over time. Underlying etiology of DSD had no effect on the relationship between SOI and anxiety. [ABSTRACT FROM AUTHOR]

A retrospective cross-sectional study was performed in a DSD clinic at a tertiary service (University Hospital) to estimate the frequency of disorders of sex development (DSD) among men who seek medical care because of infertility. The sample included 84 men >20 years of age referred from 2010-2017 due to oligozoospermia or nonobstructive azoospermia of unknown etiology. Twelve cases (14%) were diagnosed as DSD, including Klinefelter Syndrome, 46,XX testicular DSD, and mild androgen insensitivity syndrome. Y chromosome microdeletions were detected in 2 patients. Among the remaining 70 cases there were patients with chromosome abnormalities which are not included in the DSD classification as well as rare NR5A1 variants of uncertain significance and hypergonadotropic hypogonadism and microorchidism in 46,XY subjects. In conclusion, the frequency of DSD in this study was 14%, consisting mainly of sex chromosome abnormalities but also 46,XX and 46,XY DSD. However, this figure may increase as further investigations are conducted in idiopathic cases with signs of primary testicular failure, which may present partial gonadal dysgenesis. [ABSTRACT FROM AUTHOR]

The level of connection between health care professionals and people who experience a condition that affects sex development is variable. These people and associated support groups need to be included in discussions about research and healthcare delivery. The aim of this study was to understand the experiences of individuals with disorders of sexual development (DSD), their parents, health care providers, and support groups. Workshop planning, preparation, delivery, and evaluation involved members of working groups from the COST Action DSDnet. A coordinator, in collaboration with a support group representative, led the workshop design and delivery. Our successful, facilitated workshop involved 33 attendees from 8 EU countries. The workshop provided individuals with DSD, parents, advisory groups, and professionals with an opportunity for shared learning. Outputs focused on 7 key areas, including diagnosis, childhood, and transition to adult care as well as fostering discussion around registries, future research topics, consent processes, and information needs across the life course. The importance of trustworthy and knowledgeable providers, time to understand such rare conditions, and the place support groups have in a life course approach were valuable learning points for all attendees. In conclusion, workshops can be designed and delivered in meaningful ways for all those involved in care of individuals with rare conditions. [ABSTRACT FROM AUTHOR]

Disorders of sex development (DSD) are conditions with an abnormal development of chromosomal, gonadal, or anatomical sex. Sex chromosome DSD involve conditions associated with either numerical or structural abnormalities of the sex chromosomes. This study included patients comprising a wide spectrum of presenting features suggestive of DSD and aimed at studying the frequency of sex chromosome abnormalities among 108 Egyptian DSD patients who presented to the Clinical Genetics and Endocrinology Clinics, National Research Centre (NRC) over the 2-year period of 2013 and 2014. The age of the studied patients ranged from 2 months to 39 years. The patients exhibited various presentations, including ambiguous genitalia, undescended testis, hypogonadism, short stature with Turner manifestations, primary or secondary amenorrhea, primary infertility, edema of the dorsum of the hands and feet, and dysmorphic features. The patients were subjected to detailed clinical examination, pubertal staging, and cytogenetic analysis. Our study reported a wide karyotypic diversity and a high frequency of sex chromosome DSD, reaching 44.44% (48/108). In conclusion, we showed a high incidence of sex chromosome DSD among Egyptian DSD patients with wide karyotype/phenotype diversity. The most frequent sex chromosome DSD detected among patients of the present study was Turner syndrome and variants (52.08%; 25/48) followed by Klinefelter syndrome and variants (43.75%; 21/48). Further long term studies are necessary for accurate detection of frequencies of different types of sex chromosomal anomalies and associated phenotypes. [ABSTRACT FROM AUTHOR]

Fanconi anemia (FA) is a pleiotropic condition with 2 characteristic phenotypic markers of hematological and cytogenetic changes. The phenotype of patients with FA is very heterogeneous, associated with an array of congenital malformations affecting the skeletal, renal, genital, and/or central nervous systems. Here, we report on a 46,XY female who presented with gonadal dysgenesis and microcephaly. Exome sequencing showed that she was homozygous for a rare variant in the FANCA gene (c.4232C>T, p.P1411L, rs201494304). Both parents were heterozygous for the mutation. The FA mutation was associated with an atypical clinical presentation, and thus exome sequencing provided essential data that otherwise would have been overlooked in the diagnosis of this patient. [ABSTRACT FROM AUTHOR]

Mutations of the androgen receptor (AR) gene are the most frequent cause of 46,XY disorders of sex development. They are associated with a variety of phenotypes, ranging from phenotypic women (complete androgen insensitivity syndrome, CAIS) to milder degrees of undervirilization (partial forms) or men with only infertility (mild form). We identified a new W752G AR mutation responsible for a familial case of CAIS and performed an in vitro study and structural analysis of this mutation and the only other reported substitution affecting the same amino acid (W752R). Although sex assignment is not discussed in cases of CAIS, we show how the phenotype-genotype correlation can be refined by in vitro and structural studies according to the nature of the amino acid substitution, which in turn may have interesting impacts on the follow-up of these patients. [ABSTRACT FROM AUTHOR]

Various disorders of sex development (DSD) result in an abnormal development of genitalia that may be recognized at prenatal ultrasonography, immediately after birth, or later in life. Because of the complex nature of DSD, the participation of a multidisciplinary team, including imaging or radiology technologists, is required to address the patient's medical needs. The first steps in the management of DSD are sex evaluation, which is based on factors such as the genotype, the presence, location, and appearance of reproductive organs, the potential for fertility, and the cultural background and beliefs of the patient's family. It is also important to ensure the detection of comorbidity (as in syndromes) and to define the etiology of DSD in order to offer the best prognosis. Ultrasonography is the primary modality for demonstrating internal organs, genitography is used to assess the urethra, vagina, and any fistulas, and magnetic resonance imaging is used as an additional modality to assess internal gonads and genitalia. This review presents the advantages and disadvantages and the sensitivity and specificity for each type of radiological imaging to help in the evaluation of DSD cases before and after birth. [ABSTRACT FROM AUTHOR]

In clinical practice, it is fundamental to compare the results of hormonal examinations obtained in the laboratory with reliable reference values. This is particularly difficult when faced with rare conditions, such as disorders of sex development, where not routinely assayed peptide hormones as well as intermediate steroid metabolites are often needed and local reliable reference values are not available. There are considerable differences among techniques and assays used in clinical and research laboratories. In fact, laboratory hormonology is undergoing a critical transition between techniques for quantitative determination: established immunoassays and mass spectrometry. Harmonizing results from different laboratories is a major challenge along the path leading to the establishment of consensus reference intervals for steroid hormones. Most of the efforts are being concentrated on testosterone, with very encouraging results being provided by the harmonization of liquid chromatography-tandem mass spectrometry results. However, this goal is still far from being achieved for the other steroid and small-molecule hormones, and a much more challenging perspective is foreseeable for protein hormones. In addition to technical issues, the importance of the definition and of the characterization of the reference population as well as sampling and processing methodology should not be underestimated, as these aspects may impact on hormonal axis and compound stability. The aim of the present review is to provide a comprehensive overview of the circulating reference values in basal condition of the hormones and proteins involved in sex development reported to date in the peer-reviewed literature. We present a series of tables where we have collected the reference intervals for each specific hormone and protein. [ABSTRACT FROM AUTHOR]

Scientific knowledge to understand the biological basis of sex development was prompted by the observation of variants different from the 2 most frequent body types, and this became one of the fields first studied by modern pediatric endocrinology. The clinical observation was supported by professionals working in different areas of laboratory sciences which led to the description of adrenal and gonadal steroidogenesis, the enzymes involved, and the different deficiencies. Steroid hormone measurements evolved from colorimetry to radioimmunoassay (RIA) and automated immunoassays, although gas and liquid chromatography coupled to mass spectrometry are now the gold standard techniques for steroid measurements. Peptide hormones and growth factors were purified, and their measurement evolved from RIA to automated immunoassays. Hormone action mechanisms were described, and their specific receptors were characterized and assayed in experimental materials and in patient tissues and cell cultures. The discovery of the genetic basis for variant sex developments began with the description of the sex chromosomes. Molecular technology allowed cloning of genes coding for the different proteins involved in sex determination and development. Experimental animal models aided in verifying the roles of proteins and also suggested new genes to be investigated. New candidate genes continue to be described based on experimental models and on next-generation sequencing of patient DNAs. [ABSTRACT FROM AUTHOR]

Background/Aims: Disorders of sex development (DSD) are a heterogeneous group of rare conditions. Evidence-based treatment is challenged by a lack of clinical longitudinal outcome studies. We sought to investigate the quality of life of children with DSD other than congenital adrenal hyperplasia. Methods: The participants (aged 6-18 years) were 23 patients raised as males and 7 patients raised as females. Control data were obtained from representatives of the patients' siblings matched for age and gender. The Pediatric Quality of Life InventoryTM Version 4.0 (PedsQL) Generic Core Scales were used as the study tool. Results: In comparison with the reference data, the patient group had significantly lower overall PedsQL (p < 0.01) and school functioning (p < 0.01) scores. Also, the total PedsQL score was significantly lower in patients with DSD who were of female social sex as compared to the controls who were females. Family income, surgical procedures, degree of virilization, and mode of puberty did not influence the PedsQL scores. Conclusion: This study revealed a poorer quality of life for patients with DSD as compared compared to the age-matched control group. This highlights the need for a skilled multidisciplinary team to manage this group of patients. [ABSTRACT FROM AUTHOR]

Prophylactic gonadectomy has been recommended in complete androgen insensitivity syndrome (CAIS) because of an increased risk for the development of malignant germ cell tumors in the intra-abdominal gonads. No reliable screening parameters are available to detect early (pre-)malignant changes. Because the tumor risk before puberty is very low, the timing of gonadectomy has been postponed to allow spontaneous puberty and involvement of the patients in important decisions affecting their body and health. Gonadectomy after puberty is still discussed controversially. There are difficulties in determining the absolute malignancy risk for individuals with CAIS, difficulties with hormone therapy, and lack of studies supporting different protocols. In contrast, endogenous hormone profiles show very specific features that influence bone health, psychosocial well-being, and many other aspects which still have to be investigated. For women with CAIS who wish to keep their gonads, we propose a biannual screening program which has to be evaluated in a prospective multi-center trial. [ABSTRACT FROM AUTHOR]

Background: Information sharing in chronic conditions such as disorders of/differences in sex development (DSD) is essential for a comprehensive understanding by parents and patients. We report on a qualitative analysis of communication skills of fellows undergoing training in paediatric endocrinology. Guidelines are created for the assessment of communication between health professionals and individuals with DSD and their parents. Methods: Paediatric endocrinology fellows worldwide were invited to study two interactive online cases (www.espe-elearning.org) and to describe a best practice communication with (i) the parents of a newborn with congenital adrenal hyperplasia and (ii) a young woman with 46,XY gonadal dysgenesis. The replies were analysed regarding completeness, quality, and evidence of empathy. Guidelines for structured assessment of responses were developed by 22 senior paediatric endocrinologists worldwide who assessed 10 selected replies. Consensus of assessors was established and the evaluation guidelines were created. Results: The replies of the fellows showed considerable variation in completeness, quality of wording, and evidence of empathy. Many relevant aspects of competent clinical communication were not mentioned; 15% (case 1) and 17% (case 2) of the replies were considered poor/insufficient. There was also marked variation between 17 senior experts in the application of the guidelines to assess communication skills. The guidelines were then adjusted to a 3-level assessment with empathy as a separate key item to better reflect the qualitative differences in the replies and for simplicity of use by evaluators. Conclusions: E-learning can play an important role in assessing communication skills. A practical tool is provided to assess how information is shared with patients with DSD and their families and should be refined by all stakeholders, notably interdisciplinary health professionals and patient representatives. [ABSTRACT FROM AUTHOR]

Objective: To describe the clinical characteristics, biochemistry, histopathology, and long-term outcomes in subjects with ovotesticular (OT) disorder of sex development (DSD). Study Design: This is a retrospective subset analysis of 64 cases of histologically confirmed OT DSD. Results: All subjects were South African; 97% (n = 62) were African and 92% (n = 59) were of Zulu ethnicity. The most common karyotype was 46,XX (88%; n = 56), followed by 46,XY (8%), 46,XY/45,X (3%), and 46,XX/46,XY (1%). The median age at presentation was 7 months (0.5 months to 5.1 years). Sixty-one of the subjects (95%) presented with DSD. The ovotestis was the most frequent gonad (56%), followed by the ovary (23%) and the testis (16%). Testes were more commonly located on the right and ovaries on the left (p < 0.0001). The male gender was the predominant sex of rearing in two-thirds of the subjects. Gender dysphoria was noted in 8 subjects (11%) at a median of 6.4 (4.3–9.3) years. Long-term follow-up (n = 14) revealed spontaneous puberty in 5 subjects, gender dysphoria in 2 subjects, and neuropsychiatric disorders in 4 subjects. Conclusion: OT DSD is an important differential diagnosis in Black South Africans with 46,XX DSD. [ABSTRACT FROM AUTHOR]

Background: Undervirilized 46,XY males with bifid scrotum often pose a diagnostic challenge, and the majority of cases typically do not receive a genetic diagnosis. NR5A1 mutations can be seen in 10-20% of the cases and are a relatively common cause of undervirilization. Methods: Whole-exome sequencing was utilized to study 10 undervirilized 46,XY subjects with bifid scrotum. Results: Exome sequencing identified novel NR5A1 variants, both affecting exon 7, in 2 of the 10 subjects with bifid scrotum. Subject 1 had a heterozygous frameshift variant, c.1150delC, p.Leu384fsTer1, within the ligand-binding domain inherited from his unaffected father. Subject 2 had a novel splice-site variant c.1139-2T>C, affecting the canonical splice acceptor site for exon 7 and also disrupting the ligand-binding domain. Both subjects had serum testosterone levels within the normal range as infants. Conclusions: We describe two novel NR5A1 variants,demonstrating mutations in this gene as a common cause of milder cases of 46,XY undervirilization. Whole-exome sequencing results yielded the diagnosis in 2 out of 10 cases without a previous diagnosis, supporting the value of this approach. Significant genotype-phenotype variability was also noted with Subject 1's paternal inheritance from his unaffected father. [ABSTRACT FROM AUTHOR]

Background: A variant in steroidogenic factor-1 (SF-1, encoded by the gene NR5A1), p.Arg92Trp, has recently been reported in multiple families with 46,XX ovotesticular or testicular disorders of sex development (DSD). This amino acidchange impacts the DNA-binding domain and perturbs gonadal differentiation pathways. Methods: Whole-exome sequencing was performed on a 46,XX subject with ovotesticular DSD. Results: Exome results identified a heterozygous NR5A1 variant, p.Arg92Gln, in the 46,XX ovotesticular DSD proband. This arginine-to-glutamine change has been previously reported in the homozygous state in a 46,XY patient with gonadal and adrenal dysgenesis, though 46,XY and 46,XX heterozygous carriers of this variant have not been previously reported to have any clinical phenotype. Conclusions: The NR5A1 p.Arg92Gln variant, which has thus far only been seen in a family with 46,XY DSD, most likely contributes to the ovotesticular DSD in this case. In light of the recent reports of unrelated 46,XX subjects with testicular or ovotesticular DSD with the NR5A1 variant p.Arg92Trp, it appears that other mutations in the DNA binding domain have the potential to impact the factors determining testicular and ovarian differentiation. This case demonstrates the variability of phenotypes with the same genotype and broadens our understanding of the role of SF-1 in gonadal differentiation. [ABSTRACT FROM AUTHOR]

The phenotypic spectrum of patients carrying NR5A1 mutations ranges from 46,XY gonadal dysgenesis to male infertility. Phenotypic variability could be due to digenic or oligogenic inheritance of pathogenic variants in other testis-determining genes. Here, exome sequencing identified 2 pathogenic de novo NR5A1 mutations in 2 patients with 46,XY gonadal dysgenesis, p.Q206Tfs * 20 and p.Arg313Cys. The latter patient also carried a missense mutation in MAP3K1 . Our data extend the number of NR5A1 gene mutations associated with gonadal dysgenesis. The combination of an NR5A1 mutation with a MAP3K1 variant may explain the phenotypic variability associated with NR5A1 mutations. [ABSTRACT FROM AUTHOR]

Despite recent advances in our understanding, most cases of disorders of sex development (DSD) cannot be explained by mutations in known genes. In genome-wide screens of DSD patients, we and others detected duplications or deletions of potential regulatory regions of known or suspected DSD genes. It is therefore likely that a significant proportion of DSD cases may be explained by disrupted transcriptional regulation of gonad genes. Despite many recent technological advances, limited availability of relevant tissues - especially human embryonic material - can make the identification of long-range regulatory elements extremely difficult. In an attempt to overcome this limitation, we evaluated the usefulness of publicly available DNaseI hypersensitivity data from the Roadmap Epigenomics Project. For this feasibility study we used the 'gene desert' around the SOX9 gene and a genomic locus downstream of GATA4. Over 60% of our selected candidate regions had significant enhancer activity in luciferase assays. We show that this approach facilitates the detection of strong enhancer candidates worthy of further analysis. [ABSTRACT FROM AUTHOR]

This is the first molecular characterization of a female XY patient with an Xp duplication due to an X;22 translocation. Array CGH detected a copy number gain of ~ 36 Mb in the Xp22.33p21.1 region involving 150 genes. Clinical and molecular studies described in the literature have suggested DAX1 duplication as the major cause responsible for a sex reversal phenotype. Additionally, the interaction between genes and their possible role in clinical features are presented to support the discussion on genotype-phenotype correlation in cases of syndromic XY gonadal dysgenesis. [ABSTRACT FROM AUTHOR]

Congenital heart diseases (CHDs) are the most common cause of all birth defects and account for nearly 25% of all major congenital anomalies leading to mortality in the first year of life. Extracardiac anomalies including urogenital aberrations are present in ~ 30% of all cases. Here, we present a rare case of a 46,XY patient with CHD associated with ambiguous genitalia consisting of a clitoris-like phallus and a bifid scrotum. Exome sequencing revealed novel homozygous mutations in the FGFR1 and STARD3 genes that may be associated with the phenotype. [ABSTRACT FROM AUTHOR]

Virilisation of the XX foetus is the result of androgen excess, resulting most frequently from congenital adrenal hyperplasia in individuals with typical ovarian differentiation. In rare cases, 46,XX gonads may differentiate into testes, a condition known as 46,XX testicular disorders of sex development (DSD), or give rise to the coexistence of ovarian and testicular tissue, a condition known as 46,XX ovotesticular DSD. Testicular tissue differentiation may be due to the translocation of SRY to the X chromosome or an autosome. In the absence of SRY, overexpression of other pro-testis genes, e.g. SOX family genes, or failure of pro-ovarian/anti-testis genes, such as WNT4 and RSPO1, may underlie the development of testicular tissue. Recent experimental and clinical evidence giving insight into SRY -negative 46,XX testicular or ovotesticular DSD is discussed. [ABSTRACT FROM AUTHOR]

An overview of the Pediatric Endocrine Society's Ethics Symposium held in April 2015 at the annual meeting of the Pediatric Academic Societies is provided by the panel moderators with a summary of efforts by international athletic governing bodies over several decades to 'verify' the eligibility of athletes to compete in female only events, culminating in the hyperandrogenism policies that were the focus of the panel debate. This history was extensively reviewed in the symposium's opening presentation by Alan Rogol, in collaboration with Lindsay Pieper. Two sharply divergent views were then conveyed. David Allen's, in support, is provided in his article which follows. The opposing case, provided by Katrina Karkazis, is extensively summarized herein and reflected in her Science essay with Rebecca Jordan-Young which appeared shortly after the meeting.The subsequent ruling by the international Court of Arbitration for Sport to suspend the hyperandrogenism rule is noted with some speculation regarding the implications if it is upheld. [ABSTRACT FROM AUTHOR]

The goal of this update regarding the diagnosis and care of persons with disorders of sex development (DSDs) is to address changes in the clinical approach since the 2005 Consensus Conference, since knowledge and viewpoints change. An effort was made to include representatives from a broad perspective including support and advocacy groups. The goal of patient care is focused upon the best possible quality of life (QoL). The field of DSD is continuously developing. An update on the clinical evaluation of infants and older individuals with ambiguous genitalia including perceptions regarding male or female assignment is discussed. Topics include biochemical and genetic assessment, the risk of germ cell tumor development, approaches to psychosocial and psychosexual well-being and an update on support groups. Open and on-going communication with patients and parents must involve full disclosure, with the recognition that, while DSD conditions are life-long, enhancement of the best possible outcome improves QoL. The evolution of diagnosis and care continues, while it is still impossible to predict gender development in an individual case with certainty. Such decisions and decisions regarding surgery during infancy that alters external genital anatomy or removes germ cells continue to carry risk. [ABSTRACT FROM AUTHOR]