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Objective: The hypothalamic‐pituitary‐testicular axis is characterised by the existence of major functional changes from its establishment in fetal life until the end of puberty. The assessment of serum testosterone and gonadotrophins and semen analysis, typically used in the adult male, is not applicable during most of infancy and childhood. On the other hand, the disorders of gonadal axis have different clinical consequences depending on the developmental stage at which the dysfunction is established. This review addresses the approaches to evaluate the hypothalamic‐pituitary‐testicular axis in the newborn, during childhood and at pubertal age. Design: We focused on the hormonal laboratory and genetic studies as well as on the clinical signs and imaging studies that guide the aetiological diagnosis and the functional status of the gonads. Results: Serum gonadotrophin and testosterone determination is useful in the first 3–6 months after birth and at pubertal age, whereas AMH and inhibin B are useful biomarkers of testis function from birth until the end of puberty. Clinical and imaging signs are helpful to appraise testicular hormone actions during fetal and postnatal life. Conclusions: The interpretation of results derived from the assessment of hypothalamic‐pituitary‐testicular in paediatric patients requires a comprehensive knowledge of the developmental physiology of the axis to understand its pathophysiology and reach an accurate diagnosis of its disorders. [ABSTRACT FROM AUTHOR]

3β-Hydroxysteroid dehydrogenases (3β-HSDs) catalyze the oxidative conversion of delta (5)-ene-3-beta-hydroxy steroids and ketosteroids. Human 3b-HSD type 2 (HSD3B2) is predominantly expressed in gonadal and adrenal steroidogenic cells for producing all classes of active steroid hormones. Mutations in HSD3B2 gene cause a rare form of congenital adrenal hyperplasia with varying degree of salt wasting and incomplete masculinization, resulting from reduced production of corticoids and androgens. Therefore, evaluation of the HSD3B2 enzymatic activity in both pathways for each steroid hormone production is important for accurately understanding and diagnosing this disorder. Using progesterone receptor (PR)- and androgen receptor (AR)-mediated transactivation, we adapted a method that easily evaluates enzymatic activity of HSD3B2 by quantifying the conversion from substrates [pregnenolone (P5) and dehydroepiandrosterone (DHEA)] to (progesterone and androstenedione). HEK293 cells were transduced to express human HSD3B2, and incubated medium containing P5 or DHEA. Depending on the incubation time with HSD3B2-expressing cells, the culture media progressively increased luciferase activities in CV-1 cells, transfected with the PR/AR expression vector and progesterone-/androgen-responsive reporter. Culture media from human and other mammalian HSD3B1-expressing cells also increased the luciferase activities. HEK293 cells expressing various missense mutations in the HSD3B2 gene revealed the potential of this system to evaluate the relationship between the enzymatic activities of mutant proteins and patient phenotype. [ABSTRACT FROM AUTHOR]

To provide an overview of the I‐CAH Registry. Following the successful roll‐out of the I‐DSD Registry in the 2000s, it was felt that there was a need for a registry for congenital adrenal hyperplasia (CAH) and this was launched in 2014 as a dedicated module within the original registry. In addition to supporting and promoting research, the I‐CAH Registry acts as an international tool for benchmarking of clinical care and it does this through the collection of standardised data for specific projects. Surveillance of novel therapies in the field of CAH can also be achieved via global collaborations. Its robust governance ensures adherence to the international standards for rare disease registries. Rare disease registries such as the I‐CAH Registry are important tools for all stakeholders involved in the care of people with CAH. [ABSTRACT FROM AUTHOR]

Endometriosis typically presents in postmenarchal patients with cyclic and acyclic pelvic pain. However, there are reports of endometriosis in premenarchal patients. We report a 10-year-old individual with 46,XY difference of sex development who was found to have endometriosis at the time of laparoscopic gonadectomy for gonadoblastoma. Although rare, endometriosis can occur in 46,XY individuals prior to puberty, highlighting the complex origin of the disease. [ABSTRACT FROM AUTHOR]

The decision regarding sex rearing in patients with Disorders of Sex Development (DSD) is heavily connected to the shared decision-making model within multidisciplinary team. Some of these patients might develop gender dysphoria, when they become adults. We have aimed to evaluate the long-term outcomes of patients with XY DSD who underwent female gender assignment at our center. We have conducted a retrospective study of all 46, XY DSD patients who underwent female assignment in our institution over the last 30 years. we have found 25 46, XY patients who were raised as a female after birth. After excluding the Androgen insensitivity syndrome (AIS) patients we have identified 15 patients who have matched study criteria. The decision on gender rearing was made by the parents in 11(74%) and by the surgical team 2(13%) during hernia repair/inguinal exploration. In 2(13%) cases, the patients opted to continue identifying as women after learning about the pathology during adolescence. Nine (60%) out of 15 patients (age17.9 ± 4.7 years (mean ± SD)) agreed to answer questionnaires regarding sexual function and satisfaction from gender assignment. Mean follow up was 11.1 ± 8.2 years (mean ± SD). only one participant consented to respond to a questionnaire regarding sexual intercourse (homosexual). The overall FSFI score was 24 which included the scores 4, 4, 3, 4, 3, 2 in the categories desire, arousal, lubrication, orgasm, satisfaction, and pain respectively. Two patients regretted the decision of female gender assignment. The first with 5α-reductase deficiency, he made the decision for assignment himself as an adult and the other (3β-hydroxysteroid dehydrogenase) who underwent gonadectomy during inguinal exploration as a child. The rest of the patients were satisfied with the choice of gender, 2 need psychological support on the daily basis. In the study group, relationship and cohabitation were significantly later in life compared to the general population. Despite the sensitivity of the subject and cultural differences, most patients (78%) were satisfied with the decision to undergo female gender assignment. Over the years, patients require meticulous follow-up in order to consider additional interventions, and mental support if it is necessary. The two cases of later regret highlight the importance of proper education of patients, their families and medical providers upon decision on gender assignment. [ABSTRACT FROM AUTHOR]

Gynecomastia in adolescence is a benign condition that mostly disappears spontaneously within approximately two years from onset. When it is associated with hypogonadism, it may suggest a disorder of sexual differentiation. We report the case of a young man (18 years old) with gynecomastia associated with azoospermia, small testes, hyperestrogenism and hypergonadotropic hypogonadism. A karyotype 46,XX was found, and searching for SRY (sex-determining region Y) by fluorescence in situ hybridization (FISH) highlighted the presence of the gene on the terminal region of the short arm, with breakpoints likely in Xp22.3 and Yp11.3. Implications of testosterone replacement therapy with respect to sex differentiation disorder and to physical performance are discussed. [ABSTRACT FROM AUTHOR]

Early psychosocial support for parents/legal guardians who have children with variations of sex characteristics (VSCs) is crucial in helping avoid potentially harmful medical procedures. Psychosocial support, including peer support, can help parents/legal guardians choose the best care path for their child, and it remains important throughout childhood. However, there is a lack of data on the provision of psychosocial support for families with a child who has VSCs. We sought knowledge about the timing and types of psychosocial support, and the level of implementation of psychosocial support amongst health and psychosocial care professionals and peer supporters. A survey was conducted using a purposive sample of healthcare professionals and members of peer support groups across Europe. A total of 301 responses were received and analysed using descriptive and inferential methods. The survey results showed that psychosocial support primarily addresses diagnostic procedures, medical treatment, and medical interventions. Whilst the majority of healthcare professionals aspired to have psychosocial support provided at the point where a diagnosis of VSCs was suspected, this was only reported as current practice by a minority of respondents. Overall, the survey indicates that there is a need for greater implementation of psychosocial support, and more collaboration between healthcare professionals and peer support groups in caring for children with VSCs and their families. [ABSTRACT FROM AUTHOR]

Background/Objectives: In recent years, changing paradigms, both culturally and scientifically, have fundamentally altered the approach to the treatment of children with Disorders of Sexual Development (DSD) prior to reaching the age of legal consent. In Germany, the situation changed with the introduction of legislation that includes a partial ban on DSD surgery in children in 2021. This study aims to analyze the impact of this legislation on clinical practice. Methods: From 2014 to 2024, all patients with DSD in our institution were included. The study group comprised all patients operated on after the legislation. All patients operated on before the legislation served as the control group. Karyotype, phenotype, resulting type of DSD, age at presentation and age at operation were recorded. Results: A total of 35 patients were included in this study, with 15 in the study group and 20 in the control group. The operation was authorized by the family court for all patients in the study group. A total of 46,XY patients with severe hypospadias and clinical aspect of intersexual outer genitalia were the largest proportion (25 patients, 71.4%). Nine patients (25.7%) were 46,XX girls with classical congenital adrenal hyperplasia (CAH) type. One patient (2.9%) showed a mixed gonadal dysgenesis. The mean age of the patients at first presentation in our institution was 10.7 months in the control group and 11.0 months in the study group. The mean age at operation was significantly higher in the study group (20.1 months) compared to the control group (15.1 months; p = 0.032, unpaired t-test). Conclusions: The introduction of the legislation with a partial ban of genital surgery in DSD children in Germany has led to a significant delay in surgery. Since the majority of the patients comprise severe hypospadias and 46,XX CAH patients, further amendments of the law are proposed to minimize potential harm. [ABSTRACT FROM AUTHOR]

Gynecomastia in adolescence is a benign condition that mostly disappears spontaneously within approximately two years from onset. When it is associated with hypogonadism, it may suggest a disorder of sexual differentiation. We report the case of a young man (18 years old) with gynecomastia associated with azoospermia, small testes, hyperestrogenism and hypergonadotropic hypogonadism. A karyotype 46,XX was found, and searching for SRY (sex-determining region Y) by fluorescence in situ hybridization (FISH) highlighted the presence of the gene on the terminal region of the short arm, with breakpoints likely in Xp22.3 and Yp11.3. Implications of testosterone replacement therapy with respect to sex differentiation disorder and to physical performance are discussed.

Background: The Cut Homeobox 1 (CUX1) gene has been implicated in a number of developmental processes and has recently emerged as an important cause of developmental delay and impaired intellectual development. Individuals with variants in CUX1 have been described with a variety of co-morbidities including variations in sex development (VSD) although these features have not been closely documented. Case presentation: The proband is a 14-year-old male who presented with congenital complex hypospadias, neurodevelopmental differences, and subtle dysmorphism. A family history of neurodevelopmental differences and VSD was noted. Microarray testing and whole exome sequencing found the 46,XY proband had a large heterozygous in-frame deletion of exons 4–10 of the CUX1 gene. Conclusions: Our review of the literature has revealed that variants in CUX1 are associated with a range of VSD and suggest this gene should be considered in cases where a VSD is noted at birth, especially if there is a familial history of VSD and/or neurodevelopmental differences. Further work is required to fully investigate the role and regulation of CUX1 in sex development. [ABSTRACT FROM AUTHOR]

Noonan syndrome is a congenital disorder characterized by distinctive facial appearance, congenital heart defects, short stature, and skeletal dysplasia. Although boys with Noonan syndrome frequently exhibit cryptorchidism, a mild form of 46,XY disorders of sex development (DSD), they barely manifest more severe genital abnormalities. Here, we report a boy with ambiguous genitalia, short stature, and non-specific dysmorphic features. He had no cardiac abnormalities or skeletal dysplasia. His score in the Noonan syndrome diagnostic criteria (36 of 157 points, 23%) was lower than the cutoff for diagnosis (50%). Whole-exome sequencing identified a de novo heterozygous variant (c.922A>G: p.Asn308Asp) in PTPN11 and a maternally inherited hemizygous variant (c.1439C>T: p.Pro480Leu) in FLNA. The PTPN11 variant was a known causative mutation for Noonan syndrome. FLNA is a causative gene for neurodevelopmental and skeletal abnormalities and has also been implicated in 46,XY DSD. The p.Pro480Leu variant of FLNA was assessed as deleterious by in silico analyses. These results provide evidence that whole-exome sequencing is a powerful tool for diagnosing patients with atypical disease manifestations. Furthermore, our data suggest a possible role of digenic mutations as phenotypic modifiers of Noonan syndrome. [ABSTRACT FROM AUTHOR]

Objective Illness intrusiveness refers to the subjective cognitive appraisal of a chronic health condition interfering in daily, valued activities and may be highly relevant for parents of children with atypical genital appearance due to differences of sex development (DSD). However, a measure of illness intrusiveness has not been validated for this population. The current study aimed to evaluate the factor structure of the Illness Intrusiveness Scale for Parents (IIS-P) and examine convergent validity. Methods Participants included 102 parents (M age = 33.39 years, SD  =   6.48; 58% mothers) of 65 children (<2 years old) diagnosed with DSD participating in a larger, longitudinal study. Parents completed the IIS-P as well as self-report measures of stigma, and anxious and depressive symptoms. An exploratory factor analysis (EFA) was conducted. Results EFA results supported a 1-factor intrusiveness solution (α  =  .93), as well as a 2-factor solution measuring intrusiveness on daily living (α  =  .92) and community connectedness (α  =  .85). The 1-factor solution and both factors of the 2-factor solution demonstrated significant convergent validity with stigma as well as anxious and depressive symptoms. Conclusions Support emerged for both 1- and 2-factor solutions of the IIS-P in parents of children with DSD. The decision to evaluate illness intrusiveness as a total score or to examine the subscales of daily living and community connectedness should be tailored to the unique aims of researchers and clinicians. Future research should conduct a confirmatory factor analysis with both 1- and 2-factor models with larger, more diverse samples of caregivers. [ABSTRACT FROM AUTHOR]

Objectives and background: Congenital malformations of the kidney and urinary tract (CAKUT) have a prevalence of 4–60 in 10,000 livebirths and constitute for 40–50% of all end stage pediatric kidney disease. CAKUT can have a genetic background due to monogenetic inherited disease, such as PKD or ciliopathies. They can also be found in combination with extra-renal findings as part of a syndrome. Upon detection of genitourinary malformations during the fetal anomaly scan the question arises if further genetic testing is required. The purpose of this study was to determine the phenotypic presentation of CAKUT cases and the results of exome analysis (WES). Methods: This is a retrospective analysis of 63 fetal cases with a diagnosis of CAKUT or DSD at a single center between August 2018 and December 2022. Results: A total of 63 cases (5.6%) out of 1123 matched CAKUT phenotypes including renal parenchyma malformations. In 15 out of 63 WES analysis a pathogenic variant was detected (23.8%). In fetuses with isolated CAKUT the rate of detecting a pathogenic variant on exome sequencing was five out of 44 (11.4%). Ten out of 19 fetuses (52.6%) that displayed extra-renal findings in combination with CAKUT were diagnosed with a pathogenic variant. Conclusions: WES provides an increase in diagnosing pathogenic variants in cases of prenatally detected CAKUT. Especially in fetuses with extra-renal malformations, WES facilitates a gain in information on the fetal genotype to enhance prenatal counselling and management. [ABSTRACT FROM AUTHOR]

The management of Differences of Sex Development (DSD) has evolved considerably in recent years. The questioning of systematic early childhood treatment of DSD requires a better understanding of the outcomes of such treatments and long-term studies are therefore essential to better evaluate the prognosis of DSD. Unfortunately, limitations are numerous including the limited size of the series, the absence of standardized methodology, the evaluation of managements that no longer take place today and the absence of prospective and comparative studies. Despite these difficulties, the purpose of this paper is to present the current data on the long-term follow-up of patients with DSD from the urological, sexual and fertility points of view. Even if it remains difficult at present to establish precise recommendations, we recapitulate the most important points that should drive follow-up of these patients especially the constitution of a multidisciplinary team with a holistic approach, the organization of the transition between adolescence and adulthood, a particular attention to psychological care, a careful communication with the patients and his/her family and the use of standardized data collection systems. [ABSTRACT FROM AUTHOR]

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

Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by exposure to exogenous androgens. The most common cause of 46,XX disorders/differences in sex development (DSD) is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, comprising >90% of 46,XX DSD cases. Deficiencies of 11b-hydroxylase, 3b-hydroxysteroid dehydrogenase, and P450-oxidoreductase (POR) are rare types of CAH, resulting in 46,XX DSD. In all CAH forms, patients have normal ovarian development. The molecular genetic causes of 46,XX DSD, besides CAH, are uncommon. These etiologies include primary glucocorticoid resistance (PGCR) and aromatase deficiency with normal ovarian development. Additionally, 46,XX gonads can differentiate into testes, causing 46,XX testicular (T) DSD or a coexistence of ovarian and testicular tissue, defined as 46,XX ovotesticular (OT)-DSD. PGCR is caused by inactivating variants in NR3C1, resulting in glucocorticoid insensitivity and the signs of mineralocorticoid and androgen excess. Pathogenic variants in the CYP19A1 gene lead to aromatase deficiency, causing androgen excess. Many genes are involved in the mechanisms of gonadal development, and genes associated with 46,XX T/OT-DSD include translocations of the SRY; copy number variants in NR2F2, NR0B1, SOX3, SOX9, SOX10, and FGF9, and sequence variants in NR5A1, NR2F2, RSPO1, SOX9, WNT2B, WNT4, and WT1. Progress in cytogenetic and molecular genetic techniques has significantly improved our understanding of the etiology of non-CAH 46,XX DSD. Nonetheless, uncertainties about gonadal function and gender outcomes may make the management of these conditions challenging. This review explores the intricate landscape of diagnosing and managing these conditions, shedding light on the unique aspects that distinguish them from other types of DSD. [ABSTRACT FROM AUTHOR]

Background: Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency (21HD) can affect the in utero development of the genital anatomy of people with the 46XX karyotype. Health professionals engage parents in decision-making regarding managing genitals with this difference, including genital surgery options and patient communication. Aim: We sought to investigate parental communication with their daughters regarding clitoral size variation related to neonatal CAH. Methods: Semistructured in-person interviews of 24 parents of chromosomal XX children with clitoral size variation attributable to a neonatal CAH diagnosis comprised 3 management categories: (1) clitoral reduction surgery (RS) (7 parents, 9 children), (2) clitoral concealment surgery (CS) (8 parents, 8 children), and no surgery on or around the clitoris (NS) (9 parents, 7 children). Outcomes: Four representative themes, Obvious Choice, Still Different, Parental Burden, and Ignorance Is Bliss, were common across all 3 treatment groups. Results: For most parents, none of the 3 options of genital appearance alteration via clitoral reduction, clitoral concealment surgery, or avoidance of clitoral surgery ameliorated concerns, with most parents expressing an aversion to educating their child on the topic of genital differences, past treatment, or future function. Clinical Implications: Reliance on surgical treatment pathways to manage this psychosocial concern is ineffective in alleviating parental uncertainty without the application of psychosocial interventions. Strengths and Limitations: This was a qualitative study but was limited to parents of children with a specific genital difference, without direct exploration of parental values regarding the clitoris or the application of adequate psychosocial care. Conclusion: Healthcare services must have an impact on parental ability to engage in essential communication with their children in cases such as clitoral size variation related to neonatal CAH. Improved communication skills allow parents to engage in more genuine decision-making and adapt to enduring genital reality, including possible future sexual challenges for their adult child, without resorting to burdensome strategies focused on attempts to perpetuate a benevolent ignorance. [ABSTRACT FROM AUTHOR]

Purpose: Disorders/differences of sex development (DSD) result from variants in many different human genes but, frequently, have no detectable molecular cause. Methods: Detailed clinical and genetic phenotyping was conducted on a family with three children. A Sec31a animal model and functional studies were used to investigate the significance of the findings. Results: By trio whole-exome DNA sequencing we detected a heterozygous de novo nonsense SEC31A variant, in three children of healthy non-consanguineous parents. The children had different combinations of disorders that included complete gonadal dysgenesis and multiple pituitary hormone deficiency. SEC31A encodes a component of the COPII coat protein complex, necessary for intracellular anterograde vesicle-mediated transport between the endoplasmic reticulum (ER) and Golgi. CRISPR-Cas9 targeted knockout of the orthologous Sec31a gene region resulted in early embryonic lethality in homozygous mice. mRNA expression of ER-stress genes ATF4 and CHOP was increased in the children, suggesting defective protein transport. The pLI score of the gene, from gnomAD data, is 0.02. Conclusions: SEC31A might underlie a previously unrecognised clinical syndrome comprising gonadal dysgenesis, multiple pituitary hormone deficiencies, dysmorphic features and developmental delay. However, a variant that remains undetected, in a different gene, may alternatively be causal in this family. [ABSTRACT FROM AUTHOR]

Joss-Waldvogel Disdrometer (JWD) measurements at the High-Altitude Cloud Physics Laboratory (HACPL: 17.56°N, 73.4°E, above 1373 m MSL), Mahabaleshwar were investigated for determining the diurnality of the drop size distribution (DSD) associated with the precipitation characteristics over the Western Ghats of India. The JWD data for the period from 2015 to 2019 were collected and examined during the Indian Summer Monsoon (ISM) season. The number concentration of rain droplets of various diameters is considerably varying with the rain rate (R) and type of precipitating cloud. With increasing the value of R, rain droplets having larger diameter concentration significantly increases, and the distribution tail moves towards the biggest droplets. The average value of reflectivity (Z), R, liquid water content (LWC), mass-weighted mean diameter (Dm), and normalized intercept parameter (log10Nw) was found to be higher for the heavy rainfall (Rhigh =10 mm h-1) as compared to the low rainfall (Rlow < 10 mm h-1) during the entire study period. The gamma distribution of DSD shows significant differences during the low and heavy precipitation on different time periods (e.g., 00-06, 06-12, 12-18, 18-23 LST). The number of rain events contributing to the total accumulated rain varies with time. The maximum number of rain events occurred during 12-18 LST, with 23.6 % rain events of low rainfall and 4.9% of heavy rainfall. The bimodality is observed in the diurnal variation of Dm, R, and Z, with the largest peak recorded in the late afternoon hour (13-16 LST) and the second crest in the early morning hour (05 LST). At the same time, the log10Nw value drops down, indicating the lowest concentration of rain droplets. [ABSTRACT FROM AUTHOR]

This report describes the bone reduction guide which was digitally obtained to improve diagnosis, treatment outcome and follow-up. Treatment of gingival smiles due to altered passive eruption should include interdisciplinary planning and smile design to facilitate the prediction of treatment outcome. Crown lengthening surgery can be supported by digital tools to improve surgical planning and follow-up. A 30-year-old female patient was referred to a private dental clinic seeking solutions for her gingival smile. Based on the anatomical crown length, a smile design was created, and the patient was presented with a simulated smile before treatment. In the surgical phase, a full-thickness flap was raised in the upper jaw to achieve the desired outcome. Using cone-beam computed tomography to determine cementoenamel junction for smile design and treatment planning brings many benefits. Patients and clinicians can foresee treatment results. From there, appropriate changes can be made. The bone reduction guide is designed to rest on the bone to help the clinician cut the bone accurately and thoroughly follow the established plan. [ABSTRACT FROM AUTHOR]

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As part of creating a beautiful smile, aesthetic dental rehabilitation plays an important role. Regarding aesthetic analy-sis in the context of oral rehabilitation and treatment predictability, Digital Smile Design (DSD), mainly through plat-forms like SmileCloud®, provides invaluable resources. Our prospective study aimed to examine the relationship be-tween the clinical experience of dental practitioners and their proficiency in using DSD (SmileCloud). Additionally, the study assessed the association between previsualization scores and the category of respondents in terms of their connec-tion to the field of dentistry (laypeople, dental students, and dentists). The study included 11 subjects for whom three different dental practitioners (a 2nd and a 6th-year dental student and a 2nd-year resident doctor in Prosthodontics) created a DSD using SmileCloud. The DSDs were evaluated in an online survey regarding tooth colour, shape, and over-all smile appearance. A number of 220 responses have been collected from 48 dentists, 86 dental students and 86 lay-people. The DSD created by the 2nd year resident doctor in Prosthodontics has received significantly higher scores for tooth shape and overall smile appearance (p<0.05), as well as for the design (p<0.05) and design*respondent (p<0.05) variables. The practitioner's clinical experience considerably impacted aesthetic dental rehabilitation tools, which means there is always a learning curve involved. [ABSTRACT FROM AUTHOR]

In 2015, Malta introduced ground-breaking legal reform designed to protect the bodily integrity of intersex infants in Malta. Drawing on semi-structured interviews with healthcare professionals, lawyers, policy-makers and advocates, this article considers the extent to which this reform has improved the cultural visibility and recognition of intersex people in Malta. Engaging with literature on epistemic injustice, this article provides new evidence for a cultural silence around intersex bodies that operates not only at a level of public knowledge but also at the individual and institutional levels. Our findings relate to three categories of visibility: political, cultural and medical. While the political visibility of intersex was an important factor in the introduction and shape of law reform in Malta, our respondents felt that the legislation had had very little effect on public understandings and familiarity with intersex issues. Moreover, respondents felt that many intersex people would be unlikely to know that they were intersex due to the limited conceptual and critical resources available to them: issues such as stigma and shame further encourage the epistemic silencing of intersex issues. The lack of cultural and medical visibility has significantly limited both the intended and hoped-for effect of the legislation. The article considers the broader implications of these results beyond Malta for those seeking to use the law to improve the lived experiences of intersex people. [ABSTRACT FROM AUTHOR]

Early psychosocial support for parents/legal guardians who have children with variations of sex characteristics (VSCs) is crucial in helping avoid potentially harmful medical procedures. Psychosocial support, including peer support, can help parents/legal guardians choose the best care path for their child, and it remains important throughout childhood. However, there is a lack of data on the provision of psychosocial support for families with a child who has VSCs. We sought knowledge about the timing and types of psychosocial support, and the level of implementation of psychosocial support amongst health and psychosocial care professionals and peer supporters. A survey was conducted using a purposive sample of healthcare professionals and members of peer support groups across Europe. A total of 301 responses were received and analysed using descriptive and inferential methods. The survey results showed that psychosocial support primarily addresses diagnostic procedures, medical treatment, and medical interventions. Whilst the majority of healthcare professionals aspired to have psychosocial support provided at the point where a diagnosis of VSCs was suspected, this was only reported as current practice by a minority of respondents. Overall, the survey indicates that there is a need for greater implementation of psychosocial support, and more collaboration between healthcare professionals and peer support groups in caring for children with VSCs and their families.

Background/Objectives: In recent years, changing paradigms, both culturally and scientifically, have fundamentally altered the approach to the treatment of children with Disorders of Sexual Development (DSD) prior to reaching the age of legal consent. In Germany, the situation changed with the introduction of legislation that includes a partial ban on DSD surgery in children in 2021. This study aims to analyze the impact of this legislation on clinical practice. Methods: From 2014 to 2024, all patients with DSD in our institution were included. The study group comprised all patients operated on after the legislation. All patients operated on before the legislation served as the control group. Karyotype, phenotype, resulting type of DSD, age at presentation and age at operation were recorded. Results: A total of 35 patients were included in this study, with 15 in the study group and 20 in the control group. The operation was authorized by the family court for all patients in the study group. A total of 46,XY patients with severe hypospadias and clinical aspect of intersexual outer genitalia were the largest proportion (25 patients, 71.4%). Nine patients (25.7%) were 46,XX girls with classical congenital adrenal hyperplasia (CAH) type. One patient (2.9%) showed a mixed gonadal dysgenesis. The mean age of the patients at first presentation in our institution was 10.7 months in the control group and 11.0 months in the study group. The mean age at operation was significantly higher in the study group (20.1 months) compared to the control group (15.1 months; p = 0.032, unpaired t-test). Conclusions: The introduction of the legislation with a partial ban of genital surgery in DSD children in Germany has led to a significant delay in surgery. Since the majority of the patients comprise severe hypospadias and 46,XX CAH patients, further amendments of the law are proposed to minimize potential harm.

SOX9 is a key transcription factor for testis determination and development. Mutations in and around the SOX9 gene contribute to Differences/Disorders of Sex Development (DSD). However, a substantial proportion of DSD patients lack a definitive genetic diagnosis. SOX9 target genes are potentially DSD-causative genes, yet only a limited subset of these genes has been investigated during testis development. We hypothesize that SOX9 target genes play an integral role in testis development and could potentially be causative genes in DSD. In this study, we describe a novel testicular target gene of SOX9, Trpc3. Trpc3 exhibits high expression levels in the SOX9-expressing male Sertoli cells compared to female granulosa cells in mouse fetal gonads between embryonic day 11.5 (E11.5) and E13.5. In XY Sox9 knockout gonads, Trpc3 expression is markedly downregulated. Moreover, culture of E11.5 XY mouse gonads with TRPC3 inhibitor Pyr3 resulted in decreased germ cell numbers caused by reduced germ cell proliferation. Trpc3 is also expressed in endothelial cells and Pyr3-treated E11.5 XY mouse gonads showed a loss of the coelomic blood vessel due to increased apoptosis of endothelial cells. In the human testicular cell line NT2/D1, TRPC3 promotes cell proliferation and controls cell morphology, as observed by xCELLigence and HoloMonitor real-time analysis. In summary, our study suggests that SOX9 positively regulates Trpc3 in mouse testes and TRPC3 may mediate SOX9 function during Sertoli, germ and endothelial cell development. [ABSTRACT FROM AUTHOR]

Intersex people suffer human rights abuses and harms because of non-consensual early medical interventions. They have historically been rendered outside of welfare regimes and equality, diversity and inclusion policies, or forcibly subsumed within sex-binaried institutions. This article draws on critical intersex studies to interrogate the policy silences and collusions that have taken place regarding intersex people's suffering. Using Ireland and England as case studies, we show that current formations of equality and diversity policies are inadequate in relation to intersex issues. Analysis of policy documents from Ireland and the UK using Bacchi's method reveals the erasure and/or marginalisation of intersex people, despite some stated commitments to gender and sexual equality. We conclude that there is a pressing need for social policy work around intersex issues and for reform to support intersex people's equality, diversity and inclusion. [ABSTRACT FROM AUTHOR]

Establishing an early and accurate genetic diagnosis among patients with differences of sex development (DSD) is crucial in guiding the complex medical and psychosocial care they require. Genetic testing routinely utilized in clinical practice for this population is predicated upon physical exam findings and biochemical and endocrine profiling. This approach, however, is inefficient and unstandardized. Many patients with DSD, particularly those with 46,XY DSD, never receive a molecular genetic diagnosis. Rapid genome sequencing (rGS) is gaining momentum as a first‐tier diagnostic instrument in the evaluation of patients with DSD given its ability to provide greater diagnostic yield and timely results. We present the case of a patient with nonbinary genitalia and systemic findings for whom rGS identified a novel variant of the WT1 gene and resulted in a molecular diagnosis within two weeks of life. This timeframe of diagnosis for syndromic DSD is largely unprecedented at our institution. Rapid GS expedited mobilization of a multidisciplinary medical team; enabled early understanding of clinical trajectory; informed planning of medical and surgical interventions; and guided individualized psychosocial support provided to the family. This case highlights the potential of early rGS in transforming the evaluation and care of patients with DSD. [ABSTRACT FROM AUTHOR]

Objective NR5A1 is a key regulator of sex differentiation and has been implicated in spleen development through transcription activation of TLX1. Concerns exist about hypo- or asplenism in individuals who have a difference of sex development (DSD) due to an NR5A1 disease-causing variant. We aimed to assess spleen anatomy and function in a clinical cohort of such individuals and in their asymptomatic family member carriers. Design Cross-sectional assessment in 22 patients with a DSD or primary ovarian insufficiency and 5 asymptomatic carriers from 18 families, harboring 14 different NR5A1 variants. Methods Spleen anatomy was assessed by ultrasound, spleen function by peripheral blood cell count, white blood cell differentiation, percentage of nonswitched memory B cells, specific pneumococcal antibody response, % pitted red blood cells, and Howell–Jolly bodies. Results Patients and asymptomatic heterozygous individuals had significantly decreased nonswitched memory B cells compared to healthy controls, but higher than asplenic patients. Thrombocytosis and spleen hypoplasia were present in 50% of heterozygous individuals. Four out of 5 individuals homozygous for the previously described p.(Arg103Gln) variant had asplenia. Conclusions Individuals harboring a heterozygous NR5A1 variant that may cause DSD have a considerable risk for functional hyposplenism, irrespective of their gonadal phenotype. Splenic function should be assessed in these individuals, and if affected or unknown, prophylaxis is recommended to prevent invasive encapsulated bacterial infections. The splenic phenotype associated with NR5A1 variants is more severe in homozygous individuals and is, at least for the p.(Arg103Gln) variant, associated with asplenism. [ABSTRACT FROM AUTHOR]

Prenatal-onset androgen excess leads to abnormal sexual development in 46,XX individuals. This androgen excess can be caused endogenously by the adrenals or gonads or by exposure to exogenous androgens. The most common cause of 46,XX disorders/differences in sex development (DSD) is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, comprising >90% of 46,XX DSD cases. Deficiencies of 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase, and P450-oxidoreductase (POR) are rare types of CAH, resulting in 46,XX DSD. In all CAH forms, patients have normal ovarian development. The molecular genetic causes of 46,XX DSD, besides CAH, are uncommon. These etiologies include primary glucocorticoid resistance (PGCR) and aromatase deficiency with normal ovarian development. Additionally, 46,XX gonads can differentiate into testes, causing 46,XX testicular (T) DSD or a coexistence of ovarian and testicular tissue, defined as 46,XX ovotesticular (OT)-DSD. PGCR is caused by inactivating variants in NR3C1, resulting in glucocorticoid insensitivity and the signs of mineralocorticoid and androgen excess. Pathogenic variants in the CYP19A1 gene lead to aromatase deficiency, causing androgen excess. Many genes are involved in the mechanisms of gonadal development, and genes associated with 46,XX T/OT-DSD include translocations of the SRY; copy number variants in NR2F2, NR0B1, SOX3, SOX9, SOX10, and FGF9, and sequence variants in NR5A1, NR2F2, RSPO1, SOX9, WNT2B, WNT4, and WT1. Progress in cytogenetic and molecular genetic techniques has significantly improved our understanding of the etiology of non-CAH 46,XX DSD. Nonetheless, uncertainties about gonadal function and gender outcomes may make the management of these conditions challenging. This review explores the intricate landscape of diagnosing and managing these conditions, shedding light on the unique aspects that distinguish them from other types of DSD.

Ability to characterise droplet size distribution (DSD) of emulsions in real-time is essential for on-demand production of customised emulsions. In this work, for the first time, we demonstrate a possibility of estimating full DSD of oil in water emulsions from turbidity measurements using a single wavelength light source. We used recently published data of DSD and turbidity measurements of rapeseed oil in water emulsions (oil volume fractions of 0.15, 0.3 and 0.45) produced with vortex based hydrodynamic cavitation device. Measured DSDs are represented by weighted sum of three log-normal distributions. We developed an approach and a methodology based on artificial neural network (ANN) to estimate DSD from a single measurement of turbidity. A mathematical model is developed to simulate measured turbidity profiles using the known DSDs. The validated model was then used to generate simulated data of turbidity and oil volume fraction pairs (105 pairs). This synthetic data was used to train ANN which used turbidity and volume fraction as input and eight parameters of DSD as output. The developed ANN was able to capture the experimentally measured characteristic diameters and DSDs very well for three oil volume fractions and four different number of passes. The presented methodology and results will be useful for developing an in-line soft sensor based on turbidity measurements for real time estimation of full DSDs of emulsions.

Urethrocutaneous fistula (UCF) after hypospadias repair remain a frustrating Problem for all the practicing urologists. Furthermore, with the improvement in suture materials and surgical techniques, complications if they may arise also present with litigations for the urologist. We present a case of a 18 year old boy with 46 XY mixed gonadal dysgenesis who had undergone proximal hypospadias repair with Duckett’s tube urethroplasty with resultant complication of subcoronal urethrocutaneous fistula which failed first attempt at repair and resulted in two urethrocutaneous fistulas which was successfully managed by two stage Johanson’s urethroplasty.

Purpose: To study the prevalence, subtypes, and risk markers for the development of gonadal germ cell tumors (GCT's) among disorders of sexual differentiation (DSD) patients with the Y chromosome. Materials and Method: Design: A retrospective review of the patient's case records from 2010 to 2020 in Government Medical College, Thiruvananthapuram, India was studied. The study participants included 54 subjects with DSD containing the Y chromosome. Demographic data, external masculinization scoring, associated congenital anomalies, karyotyping, intraoperative findings such as gonadal location and internal genital ducts, histopathology of the resected gonads, and its immunohistochemistry were collected. The prevalence of gonadal GCT's was estimated from paraffin-embedded gonadectomy samples (S = 82). Results: The median age of occurrence of gonadal GCT's was 18 years. The prevalence of malignant gonadal GCT's was highest among the PAIS group (19.2%) followed by gonadal dysgenesis (15.8% each in MGD and CGD) and least among CAIS (7.7%) (p < 0.01). The most common type of malignant gonadal GCT's in the descending order of frequency was dysgerminoma, seminoma, mixed GCT, and yolk sac tumor. Multivariance logistic analysis showed post-puberty and the presence of congenital anomalies were associated with the occurrence of gonadal GCT's (P < 0.01). Conclusion: The overall prevalence of gonadal GCT's (malignant and premalignant) among DSD with Y chromosomes is nearly 25%. Dysgerminoma is the most common malignant gonadal GCT's. Age at or above 18 years and the presence of congenital anomalies like renal agenesis, retroperitoneal vascular defects, and congenital diaphragmatic hernia were independent risk markers for the development of gonadal GCT's. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic in 2020/2021/2022 and the resulting lockdowns forced many companies to switch to working from home, swiftly, on a large scale, and without preparation. This situation created unique challenges for software development, where individual software professionals had to shift instantly from working together at a physical venue to working remotely from home. Our research questions focus on the challenges of software professionals who work from home due to the COVID-19 pandemic, which we studied empirically at a German bank. We conducted a case study employing a mixed methods approach. We aimed to cover both the breadth of challenges via a quantitative survey, as well as a deeper understanding of these challenges via the follow-up qualitative analysis of 15 semi-structured interviews. In this article, we present the key impediments employees faced during the crisis, as well as their similarities and differences to the known challenges in distributed software development (DSD). We also analyze the employees' job satisfaction and how the identified challenges impact job satisfaction. In our study, we focus on challenges in communication, collaboration, tooling, and management. The findings of the study provide insights into this emerging topic of high industry relevance. At the same time, the study contributes to the existing academic research on work from home and on the COVID-19 pandemic aftermath. [ABSTRACT FROM AUTHOR]

Disorders of Sex Development (DSD) associated with adrenal dysfunction occur due to different defects in the proteins involved in gonadal and adrenal steroidogenesis. The deficiencies in 21-hydroxylase and 11β-hydroxylase lead to DSD in 46,XX patients, defects in StAR, P450scc, 17α-hydroxylase and 17,20-lyase lead to 46,XY DSD, and 3β-HSD2 and POR deficiencies cause both 46,XX and 46,XY DSD. Challenges in diagnosis arise from the low prevalence and the variability in serum steroid profiles. Replacement therapy with hydrocortisone and fludrocortisone helps to minimize life-threatening adrenal crises; however, availability is still an unresolved problem in many countries. Adverse health outcomes, due to the disease or its treatment, are common and include adult short stature, hypertension, osteoporosis, obesity, cardiometabolic risk, and reproductive health issues. Potential biomarkers to improve monitoring and novel treatment options that have been developed with the primary aim to decrease adrenal androgen production are promising tools to help improve the health and quality of life of these patients. Steroid profiling by mass spectrometry and next-generation sequencing technologies represent useful tools for establishing an etiologic diagnosis and drive personalized management. Nonetheless, access to health care still remains an issue requiring urgent solutions in many resource-limited settings. [ABSTRACT FROM AUTHOR]

Abstract Background Although differentiated service delivery (DSD) for HIV treatment was endorsed by the WHO in its landmark 2016 guidelines to lessen patients’ need to frequently visit clinics and hence to reduce unnecessary burdens on health systems, uptake has been uneven globally. This paper is prompted by the HIV Policy Lab’s annual report of 2022 which reveals substantial variations in programmatic uptake of differentiated HIV treatment services across the globe. We use Uganda as a case study of an ‘early adopter’ to explore the drivers of programmatic uptake of novel differentiated HIV treatment services. Methods We conducted a qualitative case-study in Uganda. In-depth interviews were held with national-level HIV program managers (n = 18), district health team members (n = 24), HIV clinic managers (n = 36) and five focus groups with recipients of HIV care (60 participants) supplemented with documentary reviews. Our thematic analysis of the qualitative data was guided by the Consolidated Framework for Implementation Research (CFIR)’s five domains (inner context, outer setting, individuals, process of implementation). Results Our analysis reveals that drivers of Uganda’s ‘early adoption’ of DSD include: having a decades-old HIV treatment intervention implementation history; receiving substantial external donor support in policy uptake; the imperatives of having a high HIV burden; accelerated uptake of select DSD models owing to Covid-19 ‘lockdown’ restrictions; and Uganda’s participation in clinical trials underpinning WHO guidance on DSD. The identified processes of implementation entailed policy adoption of DSD (such as the role of local Technical Working Groups in domesticating global guidelines, disseminating national DSD implementation guidelines) and implementation strategies (high-level health ministry buy-in, protracted patient engagement to enhance model uptake, devising metrics for measuring DSD uptake progress) for promoting programmatic adoption. Conclusion Our analysis suggests early adoption derives from Uganda’s decades-old HIV intervention implementation experience, the imperative of having a high HIV burden which prompted innovations in HIV treatment delivery as well as outer context factors such as receiving substantial external assistance in policy uptake. Our case study of Uganda offers implementation research lessons on pragmatic strategies for promoting programmatic uptake of differentiated treatment HIV services in other countries with a high HIV burden.

As part of creating a beautiful smile, aesthetic dental rehabilitation plays an important role. Re-garding aesthetic analy-sis in the context of oral rehabilitation and treatment predictability, Dig-ital Smile Design (DSD), mainly through plat-forms like SmileCloud®, provides invaluable re-sources. Our prospective study aimed to examine the relationship be-tween the clinical experi-ence of dental practitioners and their proficiency in using DSD (SmileCloud). Additionally, the study assessed the association between previsualization scores and the category of respondents in terms of their connec-tion to the field of dentistry (laypeople, dental students, and dentists). The study included 11 subjects for whom three different dental practitioners (a 2nd and a 6th-year dental student and a 2nd-year resident doctor in Prosthodontics) created a DSD using SmileCloud. The DSDs were evaluated in an online survey regarding tooth colour, shape, and over-all smile appearance. A number of 220 responses have been collected from 48 dentists, 86 dental students and 86 lay-people. The DSD created by the 2nd year resident doctor in Prostho-dontics has received significantly higher scores for tooth shape and overall smile appearance (p

In 2015, Malta introduced ground-breaking legal reform designed to protect the bodily integrity of intersex infants in Malta. Drawing on semi-structured interviews with healthcare professionals, lawyers, policy-makers and advocates, this article considers the extent to which this reform has improved the cultural visibility and recognition of intersex people in Malta. Engaging with literature on epistemic injustice, this article provides new evidence for a cultural silence around intersex bodies that operates not only at a level of public knowledge but also at the individual and institutional levels. Our findings relate to three categories of visibility: political, cultural and medical. While the political visibility of intersex was an important factor in the introduction and shape of law reform in Malta, our respondents felt that the legislation had had very little effect on public understandings and familiarity with intersex issues. Moreover, respondents felt that many intersex people would be unlikely to know that they were intersex due to the limited conceptual and critical resources available to them: issues such as stigma and shame further encourage the epistemic silencing of intersex issues. The lack of cultural and medical visibility has significantly limited both the intended and hoped-for effect of the legislation. The article considers the broader implications of these results beyond Malta for those seeking to use the law to improve the lived experiences of intersex people.

Introduction: NR5A1 is an essential transcription factor that regulates several target genes involved in reproduction and endocrine function. Pathogenic variants in this gene are responsible for a wide spectrum of disorders/differences of sex development (DSD). Methods: The molecular study involved Sanger sequencing, in vitro assays, and whole exome sequencing (WES). Results: Four variants were identified within the NR5A1 non-coding region in 3 patients with 46,XY DSD. In vitro analyses showed that promoter activity was affected in all cases. WES revealed variants in SRA1, WWOX, and WDR11 genes. Discussion/Conclusion: Evaluation of clinical and phenotypic significance of variants located in a non-coding region of a gene can be complex, and little is known regarding their association with DSD. Nevertheless, based on the important region for interaction with cofactors essential to promote appropriated sex development and on our in vitro results, it is feasible to say that an impact on gene expression can be expected and that this may be correlated with the DSD pathophysiology presented in our patients. Considering the number of cases that remain elusive after screening for the well-known DSD related genes, we emphasize the importance of a careful molecular analysis of NR5A1 non-coding region which is commonly neglected and might explain some idiopathic DSD cases. [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 ratio between luteinizing hormone (LH) and follicle-stimulating hormone (FSH) has previously been described as an excellent marker of sex in healthy infants. However, LH/ FSH remains not fully described in patients with differences of sex development (DSD). The aim was therefore to describe LH/FSH in infants with DSD. This was a retrospective study of DSD patients, all aged 0–1.2 years. In total, 87 infants with DSD and at least one serum sample per infant were included. Longitudinal samples from single patients were included whenever possible. Serum LH/FSH ratios in these patients were plotted against recently published age-related and sex-dimorphic cutoffs. Overall, LH/FSH sometimes corresponded to assigned sex without any obvious pattern in terms of diagnoses. LH/FSH corresponded to the biological sex in all patients with Turner or Klinefelter syndrome. In patients with 46,XX or 46,XY DSD (except congenital adrenal hyperplasia (CAH)), the ratios did not correspond to the assigned sex in all cases and were interchangeably within the male and female range. In patients with CAH, the ratio corresponded to biological sex (based on sex chromosomes) in some cases but also ranged across the cutoffs. In the 15 patients with 45,X/46,XY mosaicism, the LH/FSH ratios corresponded to the assigned sex in all cases (12 were raised as males, 3 as females) and at all time points in cases with multiple sampling. While this study describes LH/FSH in infants with DSD, the exact clinical role of the ratio in the management of these patients remains to be further elucidated.