Effects of single or combined exposure to tralopyril and ocean acidification on energy metabolism response and sex development in Pacific oysters (Crassostrea gigas).

The combined effects of the novel antifouling biocide tralopyril (TP) nitrile and ocean acidification (OA) on marine organisms are still not well understood, despite the increasing attention given to the toxic effects of emerging pollutants and OA on marine organisms in recent years. In this study, Crassostrea gigas (C. gigas) was exposed to TP, OA, and a combination of TP and OA for 21 days with a 14-day depuration. This study investigated the inter-tissue variability in energy metabolism responses and the impacts on gonadal development in C. gigas under both single and combined exposures to TP and OA. The results indicate that TP exposure and OA resulted in up-regulation of energy metabolism genes in the C. gigas, with tissues exhibiting enhanced aerobic metabolism. Furthermore, OA influences the sex determination of C. gigas, promoting the development of female individuals. Moreover, following depuration, C. gigas is able to restore normal energy metabolism and sexual development through the accumulation of suitable energy reserves. This study provides a valuable reference for the environmental and ecological risk assessment of TP, addressing the research gap in understanding the combined toxicity of TP and OA on aquatic organisms.

Through the eyes of the parents: a transdiagnostic psychiatric perspective for children with differences of sexual development.

PURPOSE: Existing literature lacks data on a subgroup exhibiting psychiatric symptoms below the DSM-5 diagnostic threshold within DSD cases. Our study aims to assess parental knowledge, attitudes toward DSD, and parental perceptions of emotional and behavioral states through a transdiagnostic perspective. METHODS: The study was conducted with a total of 35 parents of children with DSD. Two groups were established via k-means clustering, based on psychiatric symptomatology levels, derived from The Strength and Difficulties Questionnaire - Parent Form and The Revised Children's Anxiety and Depression Scale - Parent Form: with one group exhibiting lower reported psychiatric symptoms (LPS=27) and the other demonstrating higher psychiatric symptoms (HPS=8) by parents. RESULTS: Our study found that many parents were hesitant to disclose DSD diagnoses to their children, believing them to be too young to comprehend the information (42.9 %) and that they were unaware of the available support that could be provided by the medical team in disclosing the diagnosis (25.7 %). Our study found no differences in DSM-5 diagnoses between HPS and LPS groups (p>0.05), with ADHD being the most prevalent diagnosis (21.7 %) and a significant overrepresentation of children with a discrepancy between assigned gender at birth and gender upbringing in the HPS group compared to the LPS group (p<0.001). CONCLUSIONS: Our study emphasizes the necessity of a transdiagnostic approach in psychiatry to move beyond binary conceptualizations and better understand the complexities of individuals with DSD.

A Case Report on 46,XX Male Difference of Sex Development.

The 46,XX male syndrome is a very rare disorder/difference of sex development (DSD). Characterized by a 46,XX karyotype with a male phenotype and various abnormalities, including virilized external genitalia, small testes, hypergonadotropic hypogonadism, and azoospermia. Primarily described in small population studies and clinical reports, much remains to be understood about the prevalence of clinical manifestations, treatment outcomes, and long-term follow-up in this disorder. Here we describe a 24-year-old male who sought medical attention due to a history of erectile dysfunction, associated with a loss of libido, impaired concentration, difficulty sleeping, and bilateral gynecomastia. He and his family had no relevant medical history. On physical examination, the patient had a normal development of secondary sexual characteristics but presented with bilateral testicular atrophy with a volume of 6 ml per testis. A testicular and abdominal ultrasound were performed confirming testicular atrophy and finding no other abnormalities. Laboratory analysis revealed a hypergonadotropic hypogonadism with normal prolactin, thyroid stimulating hormone, hemoglobin, hematocrit, and kidney and liver function. The spermiogram, performed twice, revealed azoospermia. A bone densitometry was also performed, reporting osteopenia in the lumbar spine and left hip. A karyotype test was performed revealing a 46,XX (SRY-positive) DSD. The patient started on therapeutic supplementation with testosterone showing marked improvement of his libido, erectile dysfunction, and return of testosterone to levels within range. The patient and his partner were referred to infertility outpatient care and subsequently opted for in vitro fertilization using a sperm donor. This case report highlights the need for clinical practical awareness of this rare disorder and its wide phenotypical spectrum while also focusing on important aspects of the current literature regarding its approach and treatment. The limited data on long-term management suggest that there is a need for specialized multicenter follow-up not only to ensure a better understanding of this disorder but also to provide a better care on the quality of life and healthy well-being of this patients.

Complete Androgen Insensitivity Syndrome in a Young Girl with Primary Amenorrhea and Suspected Delayed Puberty: A Case-Based Review of Clinical Management, Surgical Follow-Up, and Oncological Risk.

Background: Complete androgen insensitivity syndrome (CAIS) is a rare disorder of sex development characterized by 46,XY karyotype and testes, yet presenting with a complete female phenotype, which is related to mutations in the androgen receptor (AR) gene. Case presentation: We herein present the case of a 14-year-old adolescent with primary amenorrhea and suspected delayed puberty whose diagnostic journey led to the identification of CAIS through the demonstration of a novel AR variant (c.159_207del). Case-based review: Our report encompasses the complexity of CAIS management, focusing on the risk of malignancy, surveillance options, hormone replacement therapy, timing of an eventual gonadectomy, and the psychosocial impact of such a diagnosis. An algorithm has been formulated for the management of CAIS starting in adolescence, highlighting the conservative approach for those patients unwilling to undergo gonadectomy. Conclusions: Primary amenorrhea and delay in puberty development may provide clues, ultimately leading to a diagnosis of CAIS. This review emphasizes the cruciality of a multidisciplinary approach in managing patients with CAIS, needing for an individualized care to optimize the overall outcome.

Single-Center Experience in Patients with Mixed Gonadal Dysgenesis.

Mixed gonadal dysgenesis (MGD) is an uncommon chromosomal Disorder of Sexual Development (DSD). There is insufficient information regarding clinical findings and growth patterns. This study aimed to provide more information about mixed gonadal dysgenesis, which has not yet been sufficiently defined. Data from 10 patients diagnosed with mixed gonadal dysgenesis were retrospectively reviewed. Clinical presentations, complaints at admission, imaging, genetic results, and treatments received by the patients were examined. Gonadal status and the gender of the patients were reared and evaluated by a multidisciplinary council decision. If received, growth hormone treatment doses and height gains were examined. The patients' ages at admission range from 6 months to 17.5 years. The median height SDS of the patients was -0.75 (2.73), the mean body weight SDS was -0.49 (±1.46), and the mean body mass index (BMI) SDS was 0.26 (±0.97). The complaints at admission varied, including ambiguous genitalia, short stature, and absence of menstruation. Some patients are completely in the female phenotype, while some are inadequately virilized male phenotype. External Masculinization Score (EMS) ranges from 1 to 6.5. The decision to raise 6 patients as female and 4 patients as male was made by a multidisciplinary council. Growth hormone treatment was administered to patients raised as female and diagnosed with short stature. The height SDS gain in treated patients was 0.42 (±0.49). Due to its rarity and varied clinical presentation, our knowledge about mixed gonadal dysgenesis is limited. Therefore, early diagnosis and individualized treatment plans are crucial for this patient group.

Sexual education and development after early childhood sexual abuse: A qualitative study of experiences of parents and children.

BACKGROUND: In the Amsterdam Sexual Abuse Case (ASAC), infants and toddlers experienced childhood sexual abuse (CSA). The perpetrator was convicted, and psychosocial care was offered to children and families. A research project was established to investigate the impact of CSA at an early age, with this study specifically focusing on sexual education and development. OBJECTIVE: To investigate parents' and children's experiences with sexual education and development following CSA. PARTICIPANTS AND SETTING: We conducted interviews with 18 parents of 20 children, and with 6 children themselves. On average, the children were 16 months old at the time of the CSA and 16 years old during the interviews. METHODS: Qualitative open interviews using an interview guide, followed by thematic analysis. RESULTS: In general, parents and children reported common experiences with sexual education and development. However, some distinctive concerns related to past CSA were mentioned by parents such as added weight to talking about sex, being more cautious, and additional conversations about boundaries and possible influence on sexual experiences. Also, both parents and children expressed uncertainty about the impact of the past sexual abuse on sexual development. CONCLUSIONS: Our findings generally align with existing literature on sexual education in a non-abused population. Impact on sexual development as perceived by parents and children was mostly absent, indicating resilience. Nonetheless, distinctive concerns and uncertainties about the impact of early CSA persist. Future research should delve deeper into the long-term consequences of early CSA and the factors contributing to resilience over time.

Alternative isoforms and phase separation of Ref1 repress morphogenesis in Cryptococcus.

Cryptococcus neoformans, the causative agent of cryptococcosis and a representative of the Basidiomycota phylum of Fungi, is a valuable model for our understanding of eukaryotic/fungal biology. Negative feedback is a well-documented mechanism across Eukarya to regulate developmental transitions. Here, we describe a repressor of the yeast-to-hypha transition, Ref1, which completes a negative feedback loop driven by the master regulator of hyphal morphogenesis, Znf2, during sexual development. Alternative transcription of Ref1, driven by Znf2, produces a functionally distinct Ref1 isoform. Isoform-specific capacity for phase separation imparts this functional distinction, making Ref1 a stronger repressor and more vulnerable to proteolytic degradation. The multimodal nature of Ref1 provides versatility that allows cells to fine-tune Ref1 activity to suit developmental context. This work reveals a mechanism by which phase separation allows a transcriptional program to tailor its own repression to guide an organism through morphological transition.

Ovotesticular Disorders of sexual development (DSD): A rare case of peritoneal carcinomatosis in an elderly DSD male patient.

Disorders of sexual development (DSDs) represent a spectrum of conditions characterized by atypical gonadal and/or genital development. The incidence is 1 in 5,000 live births. Patients with DSD may be at increased risk for developing gonadal and reproductive tract tumors. This report summarizes the current knowledge on the risks of gonadal tumors in patients with DSD. Specifically, we focus on ovotesticular DSD (OT-DSD), which accounts for 5% of DSD cases and is defined by the presence of both ovarian and testicular tissues in the same individual. We present a rare case of a phenotypically male XY patient with OT-DSD who was diagnosed with aggressive peritoneal cancer at the age of 71.

5α Reductase Deficiency-a Rare Cause of Ambiguous Genitalia and Gender Dysphoria.

We present a case of pseudovaginal perineoscrotal hypospadias, secondary to 5α-reductase deficiency presenting as gender dysphoria. This particular enzyme deficiency accounts for only a small number of disorders of sexual development cases worldwide. A feature of this disorder is the presence of ambiguous genitalia at birth followed by the development of male secondary sexual characteristics during puberty when testicular production of testosterone can compensate for previous low circulating levels of 5-dihydrotestosterone (DHT). Our described patient, raised female, presented with gender dysphoria with no male secondary sexual features given a bilateral orchidectomy in infancy. Initial testing showed biochemical primary hypogonadism and whole-genomic sequencing demonstrated pathogenic compound heterozygous variants in the SRD5A2 gene. Treatment was commenced with injectable testosterone undecanoate leading to development of desired male secondary sexual characteristics.

Identification of subtelomeric cluster-genes associated to sexual stage in Toxoplasma gondii.

Toxoplasma gondii is an obligate intracellular parasite with sexual reproduction in the intestinal epithelium of felines. The depletion of two gene repressors, AP2XI-2 and AP2XII-1, induces merozoite formation and gene expression towards sexual commitment. Based on RNA-seq datasets of AP2XI-2 and AP2XII-1 knock downs we identified subtelomeric (ST) TgB12 and hypothetical (HP) genes upregulated. Some of the differentially expressed genes (DEGs) are arranged in ST clusters. These DEG products are characterized by high isoelectric points (pI) and may encode small proteins. The potential roles of these clusters of DEG ST genes in environmental resistance or parasite sexual development of T. gondii is discussed.

Neonatal Hydrocolpos in Bardet-Biedl Syndrome due to a Novel Frameshift Indel in the BBS10 Gene.

INTRODUCTION: Hydrocolpos, a rare condition characterized by cystic dilatation of the vagina, can arise from various etiologies, including isolated imperforate hymen and vaginal atresia. Genetic conditions, such as Bardet-Biedl syndrome (BBS), may also manifest with hydrocolpos as part of urogenital malformations. METHODS: We present a case of neonatal hydrocolpos associated with BBS. Sequencing of 19 BBS genes was performed to elucidate the genetic basis of the syndrome. RESULTS: Genetic analysis revealed a novel frameshift indel variant (c.1543_1546dup p.Thr516Argfs*7) in the BBS10 gene. This finding expands the spectrum of BBS mutations and underscores the importance of genetic evaluation in patients with hydrocolpos, particularly when associated with additional clinical features suggestive of syndromic etiology. CONCLUSION: Pediatric urologists should maintain a high index of suspicion for underlying genetic conditions, including BBS, in neonates presenting with hydrocolpos, given the potential for more severe associated complications such as renal and retinal diseases, obesity, and polydactyly.

VE-1 regulation of MAPK signaling controls sexual development in Neurospora crassa.

Sexual reproduction in fungi allows genetic recombination and increases genetic diversity, allowing adaptation and survival. The velvet complex is a fungal-specific protein assembly that regulates development, pathogenesis, and secondary metabolism in response to environmental cues, such as light. In Neurospora crassa, this complex comprises VE-1, VE-2, and LAE-1. Deletion of ve-1 or ve-2, but not lae-1, leads to increased conidiation (asexual spore formation) and reduced sexual development. Mutants lacking ve-1 and/or ve-2 are female sterile and male fertile, indicating that a VE-1/VE-2 complex regulates the development of female structures. During sexual development, we observed differential regulation of 2,117 genes in dark and 4,364 genes in light between the wild type and the ∆ve-1 strain. The pheromone response and cell wall integrity pathways were downregulated in the ∆ve-1 mutant, especially in light. Additionally, we found reduced levels of both total and phosphorylated MAK-1 and MAK-2 kinases. In vitro experiments demonstrated the binding of VE-1 and VE-2 to the promoters of mak-1 and mak-2, suggesting a direct regulatory role of VE-1/VE-2 in the transcriptional control of MAPK genes to regulate sexual development. Deletion of the photosensor gene white-collar 1 prevented the light-dependent inhibition of sexual development in the ∆ve-1 mutant by increasing transcription of the pheromone response and cell wall integrity pathway genes to the levels in the dark. Our results support the proposal that the regulation of the MAP kinase pathways by the VE-1/VE-2 complex is a key element in transcriptional regulation that occurs during sexual development. IMPORTANCE: Sexual reproduction generates new gene combinations and novel phenotypic traits and facilitates evolution. Induction of sexual development in fungi is often regulated by environmental conditions, such as the presence of light and nutrients. The velvet protein complex coordinates internal cues and environmental signals to regulate development. We have found that VE-1, a component of the velvet complex, regulates transcription during sexual development in the fungus Neurospora crassa. VE-1 regulates the transcription of many genes, including those involved in mitogen-activated protein kinase (MAPK) signaling pathways that are essential in the regulation of sexual development, and regulates the activity of the MAPK pathway. Our findings provide valuable insights into how fungi respond to environmental signals and integrate them into their reproductive processes.

Transcriptome analysis reveals miRNA expression profiles in hypothalamus tissues during the sexual development of Jining grey goats.

BACKGROUND: Exploring the physiological and molecular mechanisms underlying goat sexual maturation can enhance breeding practices and optimize reproductive efficiency and is therefore substantially important for practical breeding purposes. As an essential neuroendocrine organ in animals, the hypothalamus is involved in sexual development and other reproductive processes in female animals. Although microRNAs (miRNAs) have been identified as significant regulators of goat reproduction, there is a lack of research on the molecular regulatory mechanisms of hypothalamic miRNAs that are involved in the sexual development of goats. Therefore, we examined the dynamic changes in serum hormone profiles and hypothalamic miRNA expression profiles at four developmental stages (1 day (neonatal, D1, n = 5), 2 months (prepubertal, M2, n = 5), 4 months (sexual maturity, M4, n = 5), and 6 months (breeding period, M6, n = 5)) during sexual development in Jining grey goats. RESULTS: Transcriptome analysis revealed 95 differentially expressed miRNAs (DEMs) in the hypothalamus of goats across the four developmental stages. The target genes of these miRNAs were significantly enriched in the GnRH signalling pathway, the PI3K-Akt signalling pathway, and the Ras signalling pathway (P < 0.05). Additionally, 16 DEMs are common among the M2 vs. D1, M4 vs. D1, and M6 vs. D1 comparisons, indicating that the transition from D1 to M2 represents a potentially critical period for sexual development in Jining grey goats. The bioinformatics analysis results indicate that miR-193a/miR-193b-3p-Annexin A7 (ANXA7), miR-324-5p-Adhesion G protein-coupled receptor A1 (ADGRA1), miR-324-3p-Erbb2 receptor tyrosine kinase 2 (ERBB2), and miR-324-3p-Rap guanine nucleotide exchange factor 3 (RAPGEF3) are potentially involved in biological processes such as hormone secretion, energy metabolism, and signal transduction. In addition, we further confirmed that miR-324-3p targets the regulatory gene RAPGEF3. CONCLUSION: These results further enrich the expression profile of hypothalamic miRNAs in goats and provide important insights for studying the regulatory effects of hypothalamic miRNAs on the sexual development of goats after birth.

Short-Term Impact of Newly Imposed Legal Restriction on DSD Surgery in Children in Germany.

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.

No sex-dependent mortality in an amphibian upon infection with the chytrid fungus, Batrachochytrium dendrobatidis.

One of the major factors driving the currently ongoing biodiversity crisis is the anthropogenic spread of infectious diseases. Diseases can have conspicuous consequences, such as mass mortality events, but may also exert covert but similarly severe effects, such as sex ratio distortion via sex-biased mortality. Chytridiomycosis, caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd) is among the most important threats to amphibian biodiversity. Yet, whether Bd infection can skew sex ratios in amphibians is currently unknown, although such a hidden effect may cause the already dwindling amphibian populations to collapse. To investigate this possibility, we collected common toad (Bufo bufo) tadpoles from a natural habitat in Hungary and continuously treated them until metamorphosis with sterile Bd culture medium (control), or a liquid culture of a Hungarian or a Spanish Bd isolate. Bd prevalence was high in animals that died during the experiment but was almost zero in individuals that survived until the end of the experiment. Both Bd treatments significantly reduced survival after metamorphosis, but we did not observe sex-dependent mortality in either treatment. However, a small number of genotypically female individuals developed male phenotype (testes) in the Spanish Bd isolate treatment. Therefore, future research is needed to ascertain if larval Bd infection can affect sex ratio in common toads through female-to-male sex reversal.

Genomic testing for differences of sex development: Practices and perceptions of clinicians.

OBJECTIVES: To investigate the approach taken by clinicians involved in the diagnosis and management of individuals with Differences of Sex Development (DSD), particularly with regard to genomic testing, and identify perceived gaps/strengths/barriers in current practice. DESIGN AND METHODS: An anonymous online survey was developed, with questions exploring demographics, perceptions of genomic testing, availability of genetics services and opinions on the role and utility of genomic testing in DSD. All responses were anonymous. Clinicians involved in the diagnosis and management of individuals with DSD were recruited from relevant societies and departments across Australia and New Zealand. RESULTS: 79 eligible clinicians commenced the survey, with 63 completing it and 16 providing a partial response. The perceived benefit of having a genetic diagnosis for DSD was almost unanimous (97%). Almost half (48%) of respondents reported barriers in genomic testing. 81% of respondents reported they order genomic tests currently. Approaches to genomic testing when faced with four different clinical scenarios varied across respondents. Clinicians perceived genomic testing to be underutilised (median 36 on sliding scale from 0 to 100). CONCLUSIONS: Despite 97% of respondents reporting benefit of a genetic diagnosis for individuals with DSD, this was not reflected throughout the survey with regard to clinical implementation. When faced with clinical scenarios, the recommendations for genomic testing from respondents was much lower, indicating the discrepancy between perception and clinical practice. Genomic testing in the context of DSD is seen as both beneficial and desired, yet there are multiple barriers impacting its integration into standard clinical care.

Faculty Training on Navigating Gender and Sex in Medical Education.

Introduction: Language that assumes gender and sex are binary and aligned is pervasive in medicine and is often used when teaching on physiology and pathology. Information presented through this lens oversimplifies disease mechanisms and poorly addresses the health of gender and sexually diverse (GSD) individuals. We developed a training session to help faculty reference gender and sex in a manner that would be accurate and inclusive of GSD health. Methods: The 1-hour session for undergraduate and graduate medical educators highlighted cisgender and binary biases in medical teachings and introduced a getting-to-the-root mindset that prioritized teaching the processes underlying differences in disease profiles among gender and sex subpopulations. The training consisted of 30 minutes of didactic teaching and 20 minutes of small-group discussion. Medical education faculty attended and self-reported knowledge and awareness before and after the training. Results were compared using paired t tests. Expenses included fees for consultation and catering. Results: Forty faculty participated (pretraining survey n = 36, posttraining survey n = 21). After the training, there was a significant increase in self-reported awareness of the difference between gender and sex (p = .002), perceived relevance of gender to teachings (p = .04), and readiness to discuss physiological drivers of sex-linked disease (p = .005). Discussion: Participants reported increased understanding and consideration of gender and sex in medical education; feedback emphasized a desire for continued guidance. This easily adaptable session can provide an introduction to a series of medical teachings on gender and sex.

"Sexual Development": Timing Puberty in German Enlightenment Medicine (1778-99).

From the mid-eighteenth century onward, French vitalists started to re-theorize the bodily clock of maturation. Archaic notions of precocity as an ill omen and ancient constructions of sexual timing as ethnic markers now acquired an increasingly physiological profile. Regulatory conceptions of sexual and psychosexual "development" widely animated German literature in the closing decades of the century. Here is evidence of new interdisciplinary problematizations of pubescence (Mannbarkeit) as the coordination in time of the mental apparatus (Seele, Character) and the sex drive (Geschlechtstrieb). New developmental-physiological frames for sexual maturity and psychosexuality readily extended to the fate of Nationalcharacter, sponsoring various roundtables concerning etiological questions.

À partir du milieu du XVIIIe siècle, les vitalistes français ont commencé à théoriser à nouveau l'horloge corporelle de la maturation. Les représentations archaïques de la précocité, considérée comme un mauvais présage, et les anciennes constructions du calendrier sexuel, perçues sous l'angle des marqueurs ethniques, ont acquis un profil de plus en plus physiologique. De fait, les conceptions réglementaires du « développement ¼ sexuel et psychosexuel ont largement animé la littérature allemande au cours des dernières décennies du XVIIIe siècle. On y trouve des preuves de nouvelles problématisations interdisciplinaires de la puberté (Mannbarkeit) en tant que coordination dans le temps de l'appareil mental (Seele, Character) et de la libido (Geschlechtstrieb). Les nouveaux cadres développementaux et physiologiques de la maturité sexuelle et de la psychosexualité ont également influencé le Nationalcharacter, qui a parrainé diverses tables rondes sur les questions étiologiques.

Familial 46, XY Disorder of Sexual Development identified in a Ph+BCR::ABL1P210+ Acute Lymphoblastic Leukemia septuagenarian female with RCBTB2::LPAR6 fusion gene: a case report.

Background: Familial 46, XY Disorder of Sexual Development (DSD) was discovered in a Ph+, BCR::ABL1P210+ Acute Lymphoblastic Leukemia (ALL) female with RCBTB2::LPAR6 fusion gene. Siblings developing 46, XY DSD are extremely rare. Patients with 46, XY DSD have much higher rates of gonadal cancers. Nevertheless, the incidence of hematologic malignancies in patients with DSDs has received little attention. RCBTB2::LPAR6 is a rarely reported fusion gene in ALL. Case presentation: Herein, we report a rare case of a newly diagnosed Ph+, BCR::ABL1P210+ ALL patient who was 77 years old and female by social sex. Whole Exome Sequencing (WES) and RNA sequencing revealed TET2 and NF1 mutations in addition to a rarely reported RCBTB2::LPAR6 fusion gene and 17 other genes with uncertain clinical significance. The patient was surprisingly found to have a male karyotype. On ultrasound, neither the uterus nor the ovaries were discernible. A detailed family and marital history revealed that the patient had undergone surgery at an early age for an unexplained inguinal mass. She had slow pubertal development, scanty menstruation, and few overtly feminine characteristics. She had three marriages, but none succeeded in getting pregnant. The patient had never sought therapy for infertility due to the inaccessibility of medical treatment and a lack of medical knowledge. Her sister, 73 years old and female by social sex, who had amenorrhea in adolescence and was unable to conceive, had the same experience. To our surprise, she also had a male karyotype. Conclusions: Due to the absence of long-term social attention and follow-up, studies on the incidence of hematologic malignancies in patients with 46, XY DSD are incredibly uncommon. Siblings developing 46, XY DSD is extremely rare. We report the oldest patient diagnosed with 46, XY DSD. There have not yet been any reports of familial 46, XY DSD with a concurrent diagnosis of Ph+BCR::ABL1P210+ ALL with a rarely reported RCBTB2::LPAR6 fusion gene.

A Very Early Diagnosis of Complete Androgen Insensitivity Syndrome Due to a Novel Variant in the AR Gene: A Neonatal Case Study.

Androgen insensitivity syndrome (AIS) is one of the most common Disorders of Sexual Differentiation (DSDs). AIS is characterized by an X-linked recessive inheritance pattern associated with variants in the androgen receptor (AR) gene that affects the masculinization process in individuals with XY karyotype. Here, we report a neonatal case of a very early diagnosis of complete AIS due to a novel variant in the AR gene. In the present case, after the clinical evaluation, the infant has undergone the following tests: biochemical analyses, including newborn screening workflow, karyotype analysis, and Next-Generation Sequencing (NGS) panel of 50 genes involved in DSDs. The NGS analysis identified a missense variant, c.2108C>A, in the AR gene. According to a cytogenetic analysis, the patient presented a 46, XY karyotype, thus the resulting hemizygote for the AR gene variant. The variant is not currently described in the literature nor in the ClinVar database. However, according to computational models, the variant could have a pathogenetic effect. This clinical case reveals a novel variant of the AR gene with a possible pathogenetic effect associated with AIS and highlights the importance of a multidisciplinary approach for the timely diagnosis and appropriate follow-up of the patient.