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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]

Objective: Lipoid congenital adrenal hyperplasia (LCAH) is caused by mutations in STAR. A systematic review of phenotype–genotype correlation and data on testicular histology in LCAH patients is unavailable. We aim to describe our experience and provide phenotype–genotype correlation. Design, Patients and Measurements: Retrospective review of three genetically proven LCAH patients from our centre and per‐patient data analysis from a systematic review of 292 probands. The phenotypic subgroups of 46,XY were Group A (typical female genitalia), Group B (atypical genitalia) and Group C (typical male genitalia). Results: We report three new LCAH probands from India, all diagnosed post‐infancy with preserved gonadal function and one novel variant. The systematic review reports 46,XY to 46,XX LCAH ratio of 1.1 (155:140). Patients with 46,XY LCAH in Group A were diagnosed in infancy (116/117) and had higher mineralocorticoid involvement than Group C (96.4% vs. 75%, p = 0.035), whereas Group C had preserved gonadal function. Hyperplastic adrenals are noted in ~60% of LCAH diagnosed with primary adrenal insufficiency in infancy. There was no report of gonadal germ cell cancer and rare reports of germ cell neoplasia in situ in adolescents, especially with intraabdominal gonads. Two‐thirds of LCAH probands were East‐Asian and 11/16 regional recurrent variants were from East Asia. There was minimal overlap between variants in Groups A (n = 55), B (n = 9) and C (n = 8). All nonsense and frameshift and most of the splice‐site variants and deletion/insertions were present in Group A. Conclusions: We report three new cases of LCAH from India. We propose a phenotype‐derived genotypic classification of reported STAR variants in 46,XY LCAH. [ABSTRACT FROM AUTHOR]

This article discusses the challenges and reasons for the underdiagnosis of prenatal ambiguous or atypical genitalia. The authors highlight the impact of this condition on parents and healthcare professionals, as well as the importance of effective communication and sex assignment. They explore the definitions and prevalence of ambiguous/atypical genitalia and the associated genetic, hormonal, and developmental disorders. The article identifies three main factors contributing to the underdiagnosis: lack of knowledge, lack of strong evidence, and lack of recognition and support. The authors propose strategies to improve prenatal detection, including redefining criteria and implementing comprehensive qualitative and quantitative assessments during mid-pregnancy ultrasound examinations. [Extracted from the article]

Background: Among sex chromosome aneuploidies, 48, XXYY syndrome is a rare variant. This condition is marked by the existence of an additional X and Y chromosome in males, leading to a diverse range of physical, neurocognitive, behavioral, and psychological manifestations. Typical characteristics include a tall stature and infertility. Other phenotypes include congenital heart defects, skeletal anomalies, tremors, obesity, as well as the potential for type 2 diabetes and/or peripheral vascular disease. Case presentation: A 6-year-old boy, who had been experiencing progressive vision deterioration in both eyes for the past two years, presented with a history of poor vision, delayed motor skills. The patient was diagnosed with micropenis in the pediatric outpatient clinic. Sparse hair, an unusually tall stature and craniofacial dysmorphology characterized by ocular hypertelorism, depressed nasal bridge, and epicanthic folds were observed. Comprehensive ophthalmic examination revealed high myopia and grade 3 macular hypoplasia. Diagnostic investigations including karyotype analysis and whole-exome sequencing identified an anomalous male karyotype comprising two X and two Y chromosomes, confirming a diagnosis of 48, XXYY syndrome. Conclusions: This study underscores the rare association of high myopia and grade 3 macular dysplasia with 48, XXYY syndrome. To our knowledge, this case marks the first recorded instance of macular dysplasia in a patient with 48, XXYY syndrome. This novel finding enhances our understanding of this syndrome's phenotypic variability. [ABSTRACT FROM AUTHOR]

Differences in sex development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. Ovotesticular DSD is the rarest variant of DSD where both ovarian and testicular tissues co-exist in an individual. Ambiguous genitalia may be a glaring indicator of DSD, but multiple genital anomalies should also raise a suspicion of DSD. This is a case report of a 15-year-6-month-old boy who presented during infancy with multiple genital anomalies requiring surgery. The diagnosis of ovotesticular DSD was missed until later in adolescence when he presented with progressive bilateral breast enlargement. Work-up revealed a 46, XX karyotype and dysgenetic testes, but functional ovarian tissue. The patient wanted to consider switching to a female gender but was constrained by psychosocial factors. Maintenance of a masculine phenotype was done using testosterone injections due to the relatively high cost of testosterone patches. Conclusion. Multiple genital anomalies should raise the suspicion of DSD, and prompt referral to an endocrinologist should be done before urogenital surgery and gender assignment are carried out. [ABSTRACT FROM AUTHOR]

Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery in children. Recent studies have implicated SMARCC1 , a component of the BRG1-associated factor (BAF) chromatin remodelling complex, as a candidate congenital hydrocephalus gene. However, SMARCC1 variants have not been systematically examined in a large patient cohort or conclusively linked with a human syndrome. Moreover, congenital hydrocephalus-associated SMARCC1 variants have not been functionally validated or mechanistically studied in vivo. Here, we aimed to assess the prevalence of SMARCC1 variants in an expanded patient cohort, describe associated clinical and radiographic phenotypes, and assess the impact of Smarcc1 depletion in a novel Xenopus tropicalis model of congenital hydrocephalus. To do this, we performed a genetic association study using whole-exome sequencing from a cohort consisting of 2697 total ventriculomegalic trios, including patients with neurosurgically-treated congenital hydrocephalus, that total 8091 exomes collected over 7 years (2016–23). A comparison control cohort consisted of 1798 exomes from unaffected siblings of patients with autism spectrum disorder and their unaffected parents were sourced from the Simons Simplex Collection. Enrichment and impact on protein structure were assessed in identified variants. Effects on the human fetal brain transcriptome were examined with RNA-sequencing and Smarcc1 knockdowns were generated in Xenopus and studied using optical coherence tomography imaging, in situ hybridization and immunofluorescence. SMARCC1 surpassed genome-wide significance thresholds, yielding six rare, protein-altering de novo variants localized to highly conserved residues in key functional domains. Patients exhibited hydrocephalus with aqueductal stenosis; corpus callosum abnormalities, developmental delay, and cardiac defects were also common. Xenopus knockdowns recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1. Hydrocephalic SMARCC1-variant human fetal brain and Smarcc1-variant Xenopus brain exhibited a similarly altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2. These results suggest de novo variants in SMARCC1 cause a novel human BAFopathy we term 'SMARCC1-associated developmental dysgenesis syndrome', characterized by variable presence of cerebral ventriculomegaly, aqueductal stenosis, developmental delay and a variety of structural brain or cardiac defects. These data underscore the importance of SMARCC1 and the BAF chromatin remodelling complex for human brain morphogenesis and provide evidence for a 'neural stem cell' paradigm of congenital hydrocephalus pathogenesis. These results highlight utility of trio-based whole-exome sequencing for identifying pathogenic variants in sporadic congenital structural brain disorders and suggest whole-exome sequencing may be a valuable adjunct in clinical management of congenital hydrocephalus patients. [ABSTRACT FROM AUTHOR]

Individuals with 46,XX/XY chimerism can display a wide range of characteristics, varying from hermaphroditism to complete male or female, and can display sex chromosome chimerism in multiple tissues, including the gonads. The gonadal tissues of females contain both granulosa and germ cells. However, the specific sex chromosome composition of the granulosa and germ cells in 46,XX/XY chimeric female is currently unknown. Here, we reported a 30-year-old woman with secondary infertility who displayed a 46,XX/46,XY chimerism in the peripheral blood. FISH testing revealed varying degrees of XX/XY chimerism in multiple tissues of the female patient. Subsequently, the patient underwent preimplantation genetic testing (PGT) treatment, and 26 oocytes were retrieved. From the twenty-four biopsied mature oocytes, a total of 23 first polar bodies (PBs) and 10 second PBs were obtained. These PBs and two immature metaphase I (MI) oocytes only displayed X chromosome signals with no presence of the Y, suggesting that all oocytes in this chimeric female were of XX germ cell origin. On the other hand, granulosa cells obtained from individual follicles exhibited varied proportions of XX/XY cell types, and six follicles possessed 100% XX or XY granulosa cells. A total of 24 oocytes were successfully fertilized, and 12 developed into blastocysts, where 5 being XY and 5 were XX. Two blastocysts were transferred with one originating from an oocyte aspirated from a follicle containing 100% XY granulosa cells. This resulted in a twin pregnancy. Subsequent prenatal diagnosis confirmed normal male and female karyotypes. Ultimately, healthy boy–girl twins were delivered at full term. In summary, this 46,XX/XY chimerism with XX germ cells presented complete female, suggesting that germ cells may exert a significant influence on the sexual determination of an individual, which provide valuable insights into the intricate processes associated with sexual development and reproduction. [ABSTRACT FROM AUTHOR]

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Background: Some medical conditions, including polycystic ovarian syndrome (PCOs), may lead to infertility. In PCOs, hormonal imbalance is significant. Antioxidants such as natural antioxidants have many health benefits, including positive effects on hormone production. Objective: Since herbal medicines are more acceptable to people, the present study was designed to evaluate the effect of an aqueous extract of orchid (SA), with antioxidative effects, on the structure of the ovary and the hypothalamic-pituitarygonadal axis hormones and free testosterone in PCOs rats. Materials and Methods: In this experimental study, 64 healthy female Wistar rats (180-200 gr) were randomly divided into 60 and 89 day control groups, PCOs, and 4 PCOs + SA groups that received 40, 80, 160, and 320 mg/kg of SA. Serum levels of gonadotropin-releasing hormone, estrogen, progesterone, testosterone, follicle-stimulating hormone, and luteinizing hormone were measured. In addition, the ovaries were extracted and examined histologically. Results: The amount of primordial, primary, secondary, and Graafian follicles and serum levels of follicle-stimulating hormone and progesterone hormones decreased in PCOs groups, while atretic follicles and the serum levels of gonadotropin-releasing hormone, luteinizing hormone, estrogen, and free testosterone were increased. SA at different doses regulated hormonal and histological imbalances caused by PCOs, and 320 mg/kg was the most effective. Conclusion: The aqueous extract of orchids root can have a positive effect on the improvement of polycystic ovary syndrome. This effect can be achieved by regulating the level of sex hormones and correcting follicular abnormalities in the ovarian tissue. [ABSTRACT FROM AUTHOR]

Hypogonadism is a highly prevalent complication of chronic opioid use associated with a constellation of affective, algesic, and cognitive symptoms as well as decreased quality of life. Given that the mainstays of pharmacologic opioid use disorder (OUD) treatment – methadone and buprenorphine – are themselves agonists or partial agonists at the mu opioid receptor, opioid-induced hypogonadism (OIH) remains an underappreciated clinical concern throughout the course of OUD treatment. Prominent theoretical frameworks for OUD emphasize the importance of negative reinforcement and hyperkatifeia, defined as the heightened salience of negative emotional and motivational states brought on by chronic opioid use. In this perspective article, we highlight the striking parallels between the symptom domains of hyperfakifeia and hypogonadism in males, who comprise the vast majority of existing clinical research on OIH. By extension we propose that future research and ultimately clinical care should focus on the identification and treatment of OIH in OUD patients to help address the longstanding paradox of poor treatment retention despite efficacious therapies, particularly in the setting of the current opioid overdose epidemic driven by high potency synthetic opioids such as fentanyl. We then review evidence from chronic pain patients that testosterone replacement provides clinically significant benefits to men with OIH. Finally, using this framework, we compare extant OUD therapeutics and discuss critical gaps in the clinical literature—including the relative dearth of data regarding hypothalamic-pituitary-gonadal function in females who use opioids—where future study should be focused. [ABSTRACT FROM AUTHOR]

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder, resulting from impaired production, secretion, or action of gonadotropin-releasing hormone (GnRH). Variants of the KISS1R gene can result in CHH. Herein we describe a Chinese boy with CHH, caused by a novel, compound heterozygous variant in KISS1R. A male infant presented to the pediatric urological surgeon at three months of age for micropenis. Laboratory investigations done at this time revealed low levels of serum gonadotropins and testosterone, suggesting a lack of minipuberty. Topical application of dihydrotestosterone gel was recommended, but the parents refused treatment. The child was brought to our hospital at 3.3 years of age for the same complaint. A diagnosis of CHH was considered, and next generation sequencing revealed a compound heterozygous variant including a novel c.182C>A (p.S61*) and a c.418C>T (p.R140C) in KISS1R. We describe a novel compound heterozygous variant in the KISS1R in a boy with CHH, born to non-consanguineous Chinese parents. This report adds to the spectrum of variants in KISS1R seen in children with CHH. [ABSTRACT FROM AUTHOR]

Differences/Disorders of sex development (DSDs) are conditions in which the development of chromosomal, gonadal, and anatomical sexes is atypical. DSDs are relatively rare, but their incidence is becoming alarmingly common in sub-Saharan Africa (SSA). Their etiologies and mechanisms are poorly understood. Therefore, we have investigated cytogenetic profiles, including telomere dysfunction, in a retrospective cohort of Senegalese DSD patients. Materials and methods: Peripheral blood lymphocytes were sampled from 35 DSD patients (mean age: 3.3 years; range 0–18 years) admitted to two hospital centers in Dakar. Peripheral blood lymphocytes from 150 healthy donors were used as a control. Conventional cytogenetics, telomere, and centromere staining followed by multiplex FISH, as well as FISH with SRY-specific probes, were employed. Results: Cytogenetic analysis identified 19 male and 13 female patients with apparently normal karyotypes, two patients with Turner syndrome, and one patient with Klinefelter syndrome. Additional structural chromosome aberrations were detected in 22% of the patients (8/35). Telomere analysis revealed a reduction in mean telomere lengths of DSD patients compared to those of healthy donors of similar age. This reduction in telomere length was associated with an increased rate of telomere aberrations (telomere loss and the formation of telomere doublets) and the presence of additional chromosomal aberrations. Conclusions: To the best of our knowledge, this study is the first to demonstrate a correlation between telomere dysfunction and DSDs. Further studies may reveal the link between telomere dysfunction and possible mechanisms involved in the disease itself, such as DNA repair deficiency or specific gene mutations. The present study demonstrates the relevance of implementing telomere analysis in prenatal tests as well as in diagnosed genetic DSD disorders. [ABSTRACT FROM AUTHOR]

Key Clinical Message A comprehensive diagnostic approach is crucial for patients with primary amenorrhea and short stature. Karyotyping and imaging studies help to detect hidden chromosomal abnormalities and anatomical differences, emphasizing their value in this context. Abstract A 16‐year‐old girl with absent menstruation and short stature. Further examination revealed constitutional stunting and primary amenorrhea. Karyotyping revealed a 46, XY chromosomal abnormality, whereas pelvic ultrasonography showed uterine hypoplasia and a unicornuate uterus with a rudimentary horn. After 11 months of therapy, she experienced menarche and improved secondary sexual characteristics.

Turner syndrome (TS) is the most common sex chromosome disorder affecting females and is usually diagnosed within the first 3 decades of life. It can present with primary amenorrhea or infertility and often has a typical phenotype, with associated medical conditions that require lifelong surveillance. We report the case of a 76-year-old female with a history of osteoporosis and vertebral fractures who presented to our specialist osteoporosis clinic following a neck of femur fracture. She revealed a history of short stature and primary amenorrhea as a young woman, with limited investigation and treatment. Her other medical history included coeliac disease, hypertension, and hearing and vision abnormalities. Given her phenotype, the patient was referred for a karyotype at age 76, which was consistent with mosaic TS (45, X in 78% of cells and 46, X, r(Y) in the remaining cells). We review reports of other cases of marked delay in TS diagnosis and discuss the consequences of a late diagnosis. [ABSTRACT FROM AUTHOR]

This article discusses a previously undescribed clinical hair appearance at birth in patients with trichothiodystrophy (TTD) due to ERCC2/XPD mutations. TTD is a rare genetic disorder characterized by hair abnormalities and a wide range of skin and extracutaneous manifestations. The article presents three cases of newborns with TTD who exhibited sparse, spongy, and brittle hair braided in tufts at birth. This unique hair pattern may serve as an early indicator of TTD in newborns with ichthyosis. Further studies are needed to confirm the specificity of this finding. [Extracted from the article]

Background: MECP2 duplication syndrome (MDS) is a rare X-linked genomic disorder that primarily affects males. It is characterized by delayed or absent speech development, severe motor and cognitive impairment, and recurrent respiratory infections. MDS is caused by the duplication of a chromosomal region located on chromosome Xq28, which contains the methyl CpG binding protein-2 (MECP2) gene. MECP2 functions as a transcriptional repressor or activator, regulating genes associated with nervous system development. The objective of this study is to provide a clinical description of MDS, including imaging changes observed from the fetal period to the neonatal period. Methods: Conventional G-banding was employed to analyze the chromosome karyotypes of all pedigrees under investigation. Subsequently, whole exome sequencing (WES), advanced biological information analysis, and pedigree validation were conducted, which were further confirmed by copy number variation sequencing (CNV-seq). Results: Chromosome karyotype analysis revealed that a male patient had a chromosome karyotype of 46,Y,dup(X)(q27.2q28). Whole-exon duplication in the MECP2 gene was revealed through WES results. CNV-seq validation confirmed the presence of Xq27.1q28 duplicates spanning 14.45 Mb, which was inherited from a mild phenotype mother. Neither the father nor the mother's younger brother carried this duplication. Conclusion: In this study, we examined a male child in a family who exhibited developmental delay and recurrent respiratory tract infections as the main symptoms. We conducted thorough family investigations and genetic testing to determine the underlying causes of the disease. Our findings will aid in early diagnosis, genetic counseling for male patients in this family, as well as providing prenatal diagnosis and reproductive guidance for female carriers. [ABSTRACT FROM AUTHOR]

Background: Copy number variation (CNV) of X chromosome can lead to a variety of neonatal abnormalities, especially for male fetuses. In recent years, due to the high sensitivity and high specificity of NIPS, its application has gradually expanded from chromosome aneuploidy to CNV. Few prenatal cases involving the detection of Xq duplication and deletion by NIPS have been reported, but it is of great significance for genetic counseling. Case presentation: A 36-year-old woman was referred for prenatal diagnosis and genetic counseling at 17 weeks of gestation because of abnormal result of noninvasive prenatal screening (NIPS). Multiple congenital malformations, hydrocephalus, and enlarged gallbladder were observed by prenatal ultrasound. Amniocentesis revealed the karyotype of the fetus as 46, XN, add(X) (p22.2) and the result of chromosomal microarray analysis was arr[hg19] Xq27.1q28(138,506,454–154896094) × 2 and arr[hg19] Xp22.33p22.32(168,551–5,616,964) × 1. CNV-seq showed that the mother shares a 16.42 Mb duplication in the Xq27.1-q28 region and a 2.97 Mb deletion in the Xp22.33-p22.32 region. After genetic counseling, the couple chose to terminate the pregnancy. Conclusion: The combination of NIPS and CMA would be of values in detection of subchromosomal duplications and/or deletions at fetal stage. The detection of X chromosome aberration in a male fetus should give suspicion of the possibility of maternal inheritance. [ABSTRACT FROM AUTHOR]

A complete gonadal dysgenesis (CGD) with 46,XY karyotype is known as the Swyer syndrome and belongs to the group of 46,XY differences of sex development (DSD). The main problem in patients with Swyer syndrome is the delayed puberty and primary amenorrhea. Moreover, intrabdominal dysgenetic gonads in the patient with genetic material of a Y chromosome may conduce to the development of gonadal tumors, such as gonadoblastoma or germinoma. The management of such patients is based on preventive excision of dysgenetic gonads and long-term hormonal replacement therapy. Sporadic cases are considered more common than familial cases. This paper presents two siblings with Swyer syndrome in whom gonadoblastoma was found. A thorough review of familial CGD with 46,XY DSD in the literature from the last 15 years suggests that the risk of gonadal tumors could be increased in familial compared to sporadic cases (66.6% vs. 15–45%, respectively). [ABSTRACT FROM AUTHOR]

Laparoscopic cystectomy for mature teratomas is associated with a high incidence of intraperitoneal spillage and tumor spread; however, extragonadal recurrence of this benign tumor is rare. We hereby present an additional case of extragonadal mature teratoma that recurred in the pouch of Douglas after ovarian cystectomy. A 43‐year‐old Japanese woman presented with atypical genital bleeding. A 7 cm mature teratoma was detected using transvaginal ultrasonography and magnetic resonance imaging. At 26 years old, she underwent bilateral cystectomy for bilateral mature teratoma of the ovary. During laparoscopic surgery, a cystic tumor appeared in the pouch of Douglas and was firmly adhered to the surrounding tissues. Both ovaries were normal. The resected tumor was diagnosed as extragonadal, benign, mature teratoma. To avoid the extragonadal recurrence of mature teratoma, removal of tumor contents from intraperitoneal spillage by lavage should be performed at the end of surgery. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) affects more women than men, with women throughout the menopausal transition potentially being the most under researched and at-risk group. Sleep disruptions, which are an established risk factor for AD, increase in prevalence with normal aging and are exacerbated in women during menopause. Sex differences showing more disrupted sleep patterns and increased AD pathology in women and female animal models have been established in literature, with much emphasis placed on loss of circulating gonadal hormones with age. Interestingly, increases in gonadotropins such as follicle stimulating hormone are emerging to be a major contributor to AD pathogenesis and may also play a role in sleep disruption, perhaps in combination with other lesser studied hormones. Several sleep influencing regions of the brain appear to be affected early in AD progression and some may exhibit sexual dimorphisms that may contribute to increased sleep disruptions in women with age. Additionally, some of the most common sleep disorders, as well as multiple health conditions that impair sleep quality, are more prevalent and more severe in women. These conditions are often comorbid with AD and have bi-directional relationships that contribute synergistically to cognitive decline and neuropathology. The association during aging of increased sleep disruption and sleep disorders, dramatic hormonal changes during and after menopause, and increased AD pathology may be interacting and contributing factors that lead to the increased number of women living with AD. [ABSTRACT FROM AUTHOR]

Introduction Turner syndrome (TS) affects ∼ 1 in 2,500 live births. The presence of hearing alterations is one of the comorbidities found in this syndrome. Objective The present study aimed to evaluate the central auditory abilities in TS and to associate the alterations found with the cytogenetic pattern of the syndrome. Methods We included children and adults aged 9 to 39 years old, diagnosed with TS, with numerical or structural alterations of sex chromosomes in their karyotype. A battery of behavioral tests of central auditory processing (CAP) was performed, including a test within the modalities: monoaural low-redundancy, dichotic listening, binaural interaction, and temporal processing (resolution and ordering). We studied auditory skills in the total sample and in the sample stratified by age, divided into groups: G1 (9 to 13 years old), G2 (14 to 19 years old), and G3 (20 to 31 years old). For the association of the cytogenetic pattern, the division was T1 (chromosome monosomy X), and T2 (other TS cytogenetic patterns). Statistical analysis presented data expressed as median and interquartile range for numerical data and as frequency and percentage for categorical data. Results We found alterations in four auditory skills in the three age groups, but there was a statistically significant difference between the age groups only in the Gaps in Noise Test (GIN) (p -value = 0.009). Regarding karyotype, a greater number of alterations in the T1 cytogenetic pattern (chromosome monosomy X) was observed in four auditory skills, but without a statistically significant difference. Conclusion The alterations found point to an impairment in CAP in TS. [ABSTRACT FROM AUTHOR]

Introduction and Objective: Prenatal suspicion of disorders/differences of sex development (DSDs) is a relatively new phenomenon. The aim of this study was to review the prenatal findings of DSD cases postnatally diagnosed in our tertiary referral center. Methods: We evaluated 57 DSD cases with sex ambiguity who had undergone prenatal ultrasound with phenotypic sex assessment and/or cell-free fetal DNA (cffDNA) for genotypic sex assessment. Results: Prenatal cffDNA had been performed in 32 cases, being positive (suggestive of male genotypic sex) in 26 and negative (suggestive of female genotypic sex) in 6. Five with cffDNA negative had a prenatal ultrasound indicating female external genitalia, in turn, in those with cffDNA positive, only two had a prenatal ultrasound indicating male external genitalia. Our postnatal data showed that when external genitalia were female or poorly virilized, prenatal ultrasound indicated female sex, but in cases of higher degree of virilization, ultrasound showed similar rates of male, female, or undetermined sex. Regarding the karyotype, our data showed those with XY karyotype had positive cffDNA, those with XX karyotype had negative cffDNA, and all five with sex chromosome anomalies had positive cffDNA because they were 45,X/46,XY. We suggested an algorithm to investigate these cases during gestation, including evaluation of uterus, fetal growth, and malformations. Conclusion: We suggest that the parents should be counseled prenatally by a dedicated multidisciplinary team with experience in DSD management and evaluated as soon as possible after birth. [ABSTRACT FROM AUTHOR]

Background: The purpose of the current study was to report a case with 45,X/46,XY/46,X,idic(Yp) mosaicism showing the male phenotype with mixed gonadal dysgenesis. Case Presentation: A 27 year-old individual, phenotypically male, presented with azoospermia and a micropenis. Both testes were not visualized in the scrotal sac. Due to the presence of a small-sized uterus, the individual was referred to the KSHEMA Center for Genetic Services for chromosomal analysis. Karyotyping revealed a mosaic karyotype of 45,X[44]/46,XY[5]/46,X,idic(Yp)[1]. This finding was further confirmed through fluorescent in situ hybridization (FISH) analysis. The individual's mosaic karyotype consisted of three cell lines, with a higher proportion of the 45,X cell line and lower proportions of the idic(Yp) and 46,XY cell lines. It is worth noting that this mosaic condition in postnatal peripheral blood has not been reported in the literature thus far. Conclusion: The case report demonstrated the importance of performing karyotype and FISH analysis in understanding genetic defects including mosaicism and other chromosomal aberrations, which can influence not only growth and puberty but also sexual development and maturation. Hence, performing cytogenetic and molecular cytogenetic analysis will help clinicians to take a further step in understanding and managing the condition. [ABSTRACT FROM AUTHOR]

45,X/46,XY chromosomal mosaic is a relatively rare disease in clinical. Patients with this type of chromosomal mosaic manifest either male or female external characteristics, with clinical features resembling Turner syndrome but milder in severity. We report a case of male phenotype patient who sought medical attention for infertility. Through G-banding chromosome karyotype analysis and whole-genome copy number variation (CNV) analysis of peripheral blood DNA, the patient was diagnosed with 45,X/46,XY chromosomal mosaic. A total of 50 chromosome karyotypes from peripheral blood lymphocytes were analyzed, revealing a karyotype diagnosis of 45,X [27]/46,XY[23]. Whole-genome CNV analysis detected a mosaic pattern with partial loss of the Y chromosome (64%), while Y chromosome microdeletion analysis did not show any noticeable abnormalities. The cases of 45,X/46,XY chromosomal mosaic with male phenotype are relatively uncommon. In this specific case, the patient exhibited a short stature and genital deformity, representing a milder clinical phenotype. [ABSTRACT FROM AUTHOR]

The lysine(K)-specific methyltransferase 2A gene (KMT2A), previously known as mixed lineage leukemia (MLL), frequently rearranged in acute leukemia, belongs to one of the most promiscuous genes and has been found fused to more than 80 different partners. KMT2A::SEPTIN6 fusion is a relatively uncommon rearrangement observed in pediatric acute myeloid leukemia (AML) patients, some of which may harbor other mutations. We herein report a case of AML-M4-infant with KMT2A::SEPTIN6 fusion and DIS3 variant. The 8-month-old girl presented with leukocytosis, anemia and thrombocytopenia. A bone marrow smear disclosed that 64% of the total nucleated cells were blasts. Karyotype analysis showed 46,X,t(X;11)(q24;q23)[10]/46,XX[10]. Fluorescence in situ hybridization analysis suggested a possible break in the KMT2A gene. After whole transcriptome sequencing, Exon 9 of KMT2A was fused in-frame with Exon 2 of SEPTIN6. This is a typical type of chromosomal rearrangement leading to the KMT2A::SEPTIN6 fusion. Meanwhile, DIS3 variant [c.2065C>T, p.R689X, variant allele frequency (VAF): 39.8%] was identified. KMT2A::SEPTIN6 fusion has been associated with the pathogenesis of AML, whereas DIS3 variants are relatively rare genetic events in pediatric AML. Regrettably, the relatives disagreed with the combination chemotherapy, and the patient eventually died of progressive disease. In conclusion, our findings provide a foundation for a better understanding of the genotypic profile of KMT2A::SEPTIN6 associated AML, and the co-existence of KMT2A::SEPTIN6 and DIS3 variant might contribute to the disease progression and transformation of AML. [ABSTRACT FROM AUTHOR]

Cathepsin S (CTSS) is a member of the cysteine protease family closely related to reproductive regulation in goats. However, its effect on litter size in goats remains unclear. In this study, the relationship between CTSS gene polymorphisms and litter size was revealed by analyzing the DNA sequence and mRNA expression of CTSS in the gonadal axis of Qianbei Ma goats. In addition, bioinformatics methods were used to evaluate the effect of non-synonymous mutations on CTSS protein structure and function. CTSS was expressed in all parts of the gonadal axis of Qianbei Ma goats, with the highest expression in the uterus in the multi-lamb group and in the fallopian tube in the single-lamb group. The sequencing results showed that four SNPs in CTSS, including g.7413C → T, g.8816A → T, g.9191 T → G and g.10193G → A, were significantly correlated with litter size (p < 0.05). All four analyzed mutation sites were in strong linkage disequilibrium (r2 > 0.33, D′ > 0.70). Additionally, the haplotype Hap1/2 had a significantly higher frequency than the other haplotypes (p < 0.05). g.7413C → T and g.8816A → T were non-synonymous mutations. The g.7413C → T mutation resulted in the substitution of serine 161 of the CTSS protein with phenylalanine (p.S161F), and the g.8816A → T mutation resulted in the substitution of aspartate 219 with tyrosine (p.N219Y). p.S161F was highly conserved across 13 species and that p.N219Y was relatively conserved in cloven-hoofed species. Mutations at two sites changed the local conformation of the CTSS protein, reduced its stability, and affected its function and goat breed evolution. These findings confirm that CTSS affects the lambing traits of goats and provide a theoretical basis for the regulatory mechanism of CTSS in affecting litter size. [ABSTRACT FROM AUTHOR]

Drug-induced liver injury (DILI) is an unwarranted problem and has been a scourge in the treatment of tuberculosis (TB) infection in general and children in particular. Usually, when the Antituberculosis treatment (ATT) regime is temporarily interrupted and modified, DILI subsides, and the whole treatment can be completed under supervision. We report a case of ATT-induced DILI not improving despite modification in the ATT regime, which ultimately led to the revealing of a yet unreported constellation of syndromes that included Wilson Disease, 46 XX gonadal dysgenesis, and Mayer Rokitansky Kuster Hauser (MRKH) Syndrome. [ABSTRACT FROM AUTHOR]

Objective: This study is a retrospective analysis of the prenatal genetic diagnosis results of 1408 foetuses at high risk of DMD/BMD to provide information for clinical genetic counselling. Background: Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder characterized by skeletal and cardiac muscle weakness. With the deepening of disease research, some treatments have been applied in clinics. Therefore, early and accurate prenatal diagnosis can inform pregnancy choices for high-risk families. Methods: A total of 1316 unrelated DMD/BMD families with confirmed genetic diagnoses were recruited from the Genetic and Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University. Prenatal diagnosis of 1408 high-risk foetuses was performed by MLPA and Sanger sequencing combined with STR linkage analysis for all families. Results: Among the 1316 families, large deletions, duplications, and small variants of the DMD gene accounted for 70.4% (927/1316), 8.2% (108/1316), and 21.4% (281/1316), respectively. Among 1316 mothers, 863 (65.6%) were carriers, and 453 (34.4%) were not carriers. The rate of de novo variants was 34.4% (453/1316) in our study. In addition, gonadal mosaicism was observed in 11 pregnant females. Prenatal diagnosis was provided for 1408 high-risk foetuses; 282 foetuses were identified as male patients, 219 foetuses were female carriers, and the remainder had normal genetics. The results of prenatal diagnosis were consistent with the results of follow-up. Conclusions: Accurate and rapid prenatal diagnosis can be achieved using MLPA, Sanger sequencing, and STR linkage analysis. Furthermore, germline mosaicism in DMD should not be ignored; considering this, a prenatal diagnosis for all pregnant women with a family history of DMD/BMD regardless of whether they carried disease-causing variants is proposed. Genetic counselling and targeted prenatal diagnosis will continue to be a cornerstone of DMD/BMD family management in the future. [ABSTRACT FROM AUTHOR]

Purpose: Differences of sex development (DSD) are congenital conditions that involve variations in individuals' sex chromosomes, genes, external and/or internal genitalia, hormones, and/or secondary sex characteristics. This study sought to elucidate the experiences of adolescents and young adults living with DSD by focusing on their experiences of intimacy and sexual health. Methods: An interpretative phenomenological research design was adopted. Semi-structured qualitative interviews were conducted with 11 Norwegian adolescents and young adults aged 16--26 years who had five different DSD conditions. The interview findings were analysed by means of a reflexive thematic analysis. Results: The participants reported feeling different, both in terms of how their body functioned and how their body looked. Lack of knowledge increased this feeling of differentness. Moreover, lack of everyday language with which to talk about intimacy and sexual concerns resulted in the participants feeling stigma. Anticipating stigmatization and lacking everyday language complicated the participants' communication regarding their DSD and sexual health. Conclusions: The sexual experiences of adolescents and young adults with DSD are diverse. Fear of stigmatization and lack of everyday language complicate communication with healthcare professionals and others. Understanding their unique needs is crucial to helping individuals achieve good sexual health. [ABSTRACT FROM AUTHOR]

45,X/46,XY mosaicism is a sex development disorder with an estimated incidence of less than 1 in 15,000 live births. Various studies have shown there is an increased risk of germ cell tumours forming in Mosaic Turner syndrome. This includes gonadoblastoma, a clinically benign mixed germ-stromal cell tumour. However, this can later develop into one or several malignant germ cell neoplasms, for which early prophylactic gonadectomy is often recommended in patients with 45,X/46,XY mosaicism. The study presents the case of an 11-year-old patient diagnosed with a Mosaic Turner syndrome karyotype, who underwent prophylactic bilateral gonadectomy. [ABSTRACT FROM AUTHOR]

Background: A mismatch between chromosomal, gonadal, and phenotypic sexes in individuals with androgen insensitivity syndrome (AIS) creates problems in sex assignment and psychosexual identification. Objective: To identify psychosexual and sex assignment peculiarities of individuals with different forms of AIS. Materials and Methods: In this qualitative study, 41 individuals with AIS aged between 15 and 31 yr who referred to the Universe Center for Reproductive Medicine Tbilisi, Georgia between 2016 and 2021 were studied. All individuals underwent clinical, genealogical, hormonal, ultrasonographic, and cytogenetic examinations. In-depth interviews and medical records assessed psychosexual profiles and sex assignment histories. Results: 32 cases were diagnosed with the complete form of AIS (CAIS), 8 individuals with the partial form (PAIS), and one with a mild form (MAIS). Individuals with CAIS and PAIS were assessed at birth and raised as girls. Individuals with CAIS and female psychosexual disposition were referred to us due to amenorrhea. Adolescent individuals with PAIS assessed as girls referred to us due to masculinization detected in puberty. An individual with MAIS was assessed at birth and raised as a boy with male genitalia. All individuals with AIS had typical hormonal data and sex chromosome complex for men. 20 sexually active individuals with CAIS had penile-vaginal contact with the man. None of the individuals with CAIS and PAIS thought about gender reassignment after being diagnosed, only the individual with MAIS aimed for male-to-female transition. Conclusion: Psychosexual identification remains a significant challenge in AIS management. Detection of female psychosexual disposition in one participant that is unusual to MAIS may be associated with somatic mosaicism of the androgen receptor gene. [ABSTRACT FROM AUTHOR]

The term ‘differences of sex development’ (DSD) refers to a group of congenital conditions that are associated with atypical development of chromosomal, gonadal, and/or anatomical sex. DSD in individuals with a 46,XX karyotype can occur due to fetal or postnatal exposure to elevated amount of androgens or maldevelopment of internal genitalia. Clinical phenotype could be quite variable and for this reason these conditions could be diagnosed at birth, in newborns with atypical genitalia, but also even later in life, due to progressive virilization during adolescence, or pubertal delay. Understand the physiological development and the molecular bases of gonadal and adrenal structures is crucial to determine the diagnosis and best management and treatment for these patients. The most common cause of DSD in 46,XX newborns is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, determining primary adrenal insufficiency and androgen excess. In this review we will focus on the other rare causes of 46,XX DSD, outside CAH, summarizing the most relevant data on genetic, clinical aspects, puberty and fertility outcomes of these rare diseases.

Swyer syndrome—a rare syndrome associated with complete gonadal dysgenesis—is seen in phenotypically female patients with 46-XY karyotype. They usually present with primary amenorrhea or delayed puberty. The dysgenetic gonad, which is nonfunctional, is prone to undergo malignant transformation such as dysgerminoma, gonadoblastoma, etc. Timely diagnosis helps in deciding appropriate management strategies for the patient such as hormone replacement therapy and gonadectomy. Thirty-year-old patient with a female external phenotype presented to us with complaints of primary amenorrhea. There was no similar family history of infertility, amenorrhea, abnormal external genitalia development, or cryptorchidism. On physical examination, the breast development of the patient was within normal limits for her age (Tanner stage 5), however; the axillary and pubic hair were underdeveloped (Tanner stage 2). Pelvic and inguinal ultrasound of the patient showed a hypoplastic uterus along with a cystic structure in left pelvis with no evidence of any testes like structure in inguinal region, pelvis, or abdomen. The patient was further evaluated with MRI of pelvis which confirmed the ultrasound findings of a hypoplastic uterus along with a dysplastic cystic left gonad with no evidence of any ovary or ovary-like structure/testes/testes-like structure in abdomen. Possibility of complete gonadal dysgenesis was given which was further confirmed by the hormonal assay that showed hypergonadotropic-hypogonadism with raised serum follicular stimulating hormone (FSH) and serum luteinizing hormone (LH) levels and a low estradiol, low testosterone, and low anti-Mullerian hormone (AMH) levels. Serum prolactin (PRL), serum thyroid stimulating hormone (TSH), and serum beta human chorionic gonadotropin (beta hCG) levels were within normal range. The cytogenetic report of the patient showed a 46-XY karyotype confirming our diagnosis. The patient was advised to undergo prophylactic gonadectomy for the left gonad. Swyer syndrome is a rare disorder of sexual development which needs vigorous clinical, laboratory, and radiological evaluation. Ultrasound is the primary investigation of choice whereas MRI is used as a problem-solving tool in localizing the streak gonads. Early diagnosis is crucial in these patients since prophylactic gonadectomy reduces the risk of developing germ cell tumor.

Infertility is a significant health problem that affects many couples in the reproductive age range globally. While only the male factor is responsible for 20%-30% of cases of infertility, contributing to a further 20%. We aimed to describe a rare cause of male infertility, a male patient with 45,X/46,XY mosaic chromosome structure. The patient presented to our endocrinology department due to infertility. Phenotypically, the patient appeared as a normal male with normal development of the penis and secondary sex characteristics. Both testicles were small in the scrotum. Azoospermia was detected in the spectrogram. The patient underwent testicular sperm extraction using microdissection, but spermatozoa were not found in either of the testicles. In the cytogenetic and molecular cytogenetic examination of the patient’s peripheral blood, the chromosome structure was reported as a 45,X[22]/46,XY[8] mosaic karyotype, and Y microdeletion. 45,X/46,XY, sometimes called mixed gonadal dysgenesis, affects hormonal balance, gonadal development, growth, and fertility, and presents a wide range of clinical manifestations. Similar to our case, these patients may have an entirely male phenotype. Even when the patient exhibits phenotypical normal male characteristics, karyotype anomalies should always be considered when evaluating the infertility associated with azoospermia. [ABSTRACT FROM AUTHOR]

Swyer syndrome is a condition where individuals with a 46XY karyotype, typically associated with males, display complete gonadal dysgenesis and lack testicular differentiation. This results from a mutation in the SRY gene, which is essential for testis development. As a consequence, affected individuals who appear phenotypically female have male chromosomes but do not develop functional testes. As a result, there is an absence of testosterone that leads to lack of masculinization and the presence of female genitalia. This article describes a 20-year-old female from Pakistan who exhibited primary amenorrhea. On examination, she possessed a typical female physique but lacked breast growth and axillary hair. She had scant pubic hair with female-type external genitalia. The pelvic imaging showed a underdeveloped uterus, along with small ovaries and fallopian tubes. Her karyotype came out to be 46XY. The examination and radiological results indicated Swyer syndrome. During laparoscopy, the patient's uterus was found to be infantile, while the fallopian tubes were healthy. Streak gonads were also present, and due to the risk of gonadoblastoma, they were surgically removed. Hormone replacement therapy was started to induce pubertal development and optimize bone mineral accumulation. [ABSTRACT FROM AUTHOR]

Purpose: Yolk sac tumors (YST) are a rare and aggressive germ cell tumor. We aimed to conduct a population-based cohort study and develop a nomogram to predict overall survival (OS) in pediatric patients with YST. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify all pediatric patients with YST diagnosed between 2000 and 2018. The log-rank test was used to compare survival curves. To examine the impact of each factor on overall survival, a multivariate Cox proportional hazards model was created. Based on the results of the Cox regression model, a nomogram was constructed. Results: A total of 520 YST patients were identified. Overall survival rates for all patients were 92.2% at 3-year and 90.3% at 5-year, respectively. The outcome of Cox proportional hazard regression revealed that age, gender, primary sites, and treatment regimens were important independent predictors in this model. Based on the Cox regression model, we created a nomogram for predicting OS in pediatric YST patients. The chance of death increased with age in patients. Furthermore, patients with extra-gonadal YST have a lower survival rate than those with gonadal YST. Conclusions: Our study revealed that age, gender, and primary site were found to be the most important predictors of the overall survival of pediatric YST, providing crucial epidemiological information for clinical management. [ABSTRACT FROM AUTHOR]

Objective To investigate the clinical phenotypes, genetic characteristics, and pathological features of children with disorders of sex development (DSD). Methods A retrospective analysis was conducted on epidemiological, clinical phenotype, chromosomal karyotype, gonadal pathology, and genotype data of 165 hospitalized children with DSD at Children's Hospital of Hebei Province and Tangshan Maternal and Child Health Hospital from August 2008 to December 2022. Results Among the 165 children with DSD, common presenting symptoms were short stature (62/165, 37.6%), clitoromegaly (33/165, 20.0%), cryptorchidism (28/165, 17.0%), hypospadias (24/165, 14.5%), and skin pigmentation abnormalities/exteriorized pigmented labia majora (19/165, 11.5%). Chromosomal karyotype analysis was performed on 127 cases, revealing 36 cases (28.3%) of 46, XX DSD, 34 cases (26.8%) of 46, XY DSD, and 57 cases (44.9%) of sex chromosome abnormalities. Among the sex chromosome abnormal karyotypes, the 45, X karyotype (11/57, 19%) and 45, X/other karyotype mosaicism (36/57, 63%) were more common. Sixteen children underwent histopathological biopsy of gonadal tissues, resulting in retrieval of 25 gonadal tissues. The gonadal tissue biopsies revealed 3 cases of testes, 3 cases of dysplastic testes, 6 cases of ovaries, 11 cases of ovotestes, and 1 case each of streak gonad and agenesis of gonads. Genetic testing identified pathogenic/likely pathogenic variants in 23 cases (23/36, 64%), including 12 cases of 21-hydroxylase deficiency congenital adrenal hyperplasia caused by CYP21A2 pathogenic variants. Conclusions Short stature, clitoromegaly, cryptorchidism, hypospadias, and skin pigmentation abnormalities arc common phenotypes in children with DSD. 45, X/other karyotype mosaicism and CYP21A2 compound heterozygous variants are major etiological factors in children with DSD. The most commonly observed gonadal histopathology in children with DSD includes ovotestes, ovaries, and testes/dysgenetic testes. [ABSTRACT FROM AUTHOR]

Introduction: : Ovotestis is a rare cause of sexual ambiguity characterized by the presence in a patient of both testicular and ovarian tissue, leading to the development of both male and female structures. We report a case of ovotestis diagnosed in an adolescent, with a review of the literature. Case Report: A 15-year-old patient presented with a right scrotal swelling associated with gynecomastia. Histology showed a juxtaposition of ovarian stroma with ovarian follicle and seminiferous tubules. Karyotype revealed a male subject (XY). We have therefore retained the diagnosis of ovotesticular disorders of sex development. Conclusion: Ovotestis is a rare finding, heterogeneous in its genetic etiology and clinical presentation. While many patients are diagnosed during infancy or childhood, we presented a case diagnosed in a 15-year-old adolescent. [ABSTRACT FROM AUTHOR]

Disorders of sex development (DSD) with mild external genital abnormalities may be diagnosed after puberty. Here, we report a case of 46,XY complete gonadal dysgenesis with a novel missense variant in sex-determining region Y (SRY), diagnosed after primary amenorrhea. A 15-yr-old patient presented to our gynecology department with a chief complaint of amenorrhea. The patient was diagnosed with a 46,XY karyotype, and SRY gene positivity. Gonadotropin levels were high, whereas testosterone levels were low. A pelvic magnetic resonance imaging (MRI) revealed a hypoplastic uterus; however, no gonads could be identified. Laparoscopy revealed bilateral streak gonads, fallopian tube-like structures, and the uterus. The gonads were removed based on the risk of gonadal malignancy. Comprehensive genetic analysis of DSD revealed a previously unreported SRY variant, c.271A>T, p.Ser91Cys, and in silico analysis predicted the variant to be pathogenic. The patient was diagnosed with 46,XY complete gonadal dysgenesis with a novel missense variant in SRY. The patient continued female hormone replacement therapy and experienced breast enlargement and cyclic menstruation. Determining the etiology of DSD can be difficult, causing anxiety in patients and their families. In addition to surgical scrutiny, genetic analysis is important to aid in diagnosis and reassure patients and their families. [ABSTRACT FROM AUTHOR]

Purpose: Report on the diagnosis of prenatally detected fetal kidneys with bilateral polycystic appearance in a single center between 1999 and 2020 with special focus on renal morphology and biometry, amniotic fluid and extrarenal findings and proposal for an diagnostic algorithm. Methods: Retrospective observational study including pregnancies with prenatally detected kidneys with bilateral polycystic appearance (n = 98). Cases and outcomes were compared according to prenatal findings with special focus on renal morphology, amount of amniotic fluid, and presence of extrarenal abnormalities. Results: Most frequent diagnoses were autosomal recessive polycystic kidney disease (ARPKD, 53.1%), Meckel–Gruber syndrome (MKS, 17.3%) and autosomal dominant polycystic kidney disease (ADPKD, 8.2%). Other diagnoses included: Joubert-, Jeune-, McKusick–Kaufman- and Bardet–Biedl syndrome, overgrowth syndromes, Mainzer–Saldino syndrome and renal tubular dysgenesis. Renal abnormalities most frequently observed were hyperechogenic parenchyma, kidney enlargement, changes of corticomedullary differentiation and cystic changes of various degree. Oligo- and anhydramnios were mainly seen in ARPKD, RTD and second-trimester MKS. Extrarenal findings included skeletal (35.7%) and cardiac (34.7%) abnormalities as well as abnormalities of the central nervous system (27.6%). Conclusion: Gestational age at manifestation, kidney size, visibility of cysts, echogenicity, amniotic fluid volume, and the presence of associated extrarenal malformations allow to differentiate between the most frequent underlying diseases presenting with bilateral polycystic kidneys on prenatal ultrasound by following a diagnostic algorithm. [ABSTRACT FROM AUTHOR]

Context. Children having gonadal tumors and disorder of sex differentiation (DSD) are rare. Objective. To investigate the presentation of DSD children with malignant gonadal tumors. Methods. A retrospective study from 2010-2020, that evaluated 17 children with DSD, including 13 females, eight months to 16 years, with congenital adrenal hyperplasia, 5-alpha reductase deficiency, androgen insensitivity syndrome, Turner, Sywer, and Klinefelter syndromes. Results. Ten children had malignant gonadal tumor; nine had germ cell tumors and one person granulosa cell tumors, while seven children with non-malignant tumor had gonadoblastoma, cystadenoma (five children), and cysts. Systemic malformations, obesity, elevated tumor markers, and psychosocial issues were observed in 90%, 90%, 70%, and 50% of children with malignancy unlike 28.6%, 42.9%, 14.35%, and 57.1% children without malignancy respectively. Most (9/10) children >12 years, had psychosocial issues, unlike 0/7 children =12 years. From 8/17 children presenting with symptoms suggestive of tumor, 75% had malignancy, while from 9/17 children with DSD presentation, 44% had malignant tumors. Malignancy was observed in 3/10 children between eight months to age six, while 7/10 children had stage 1-2 tumors. We reported a child, identified as female, aged 13 years, with partial androgen insensivity syndrome (PAIS) 46,XY, and testicular papillary serous cystadenoma with genomic variant AR NM_000044.4:c.2750del. p.(F917Sfs*27) chromosome Xq12, never published in people with PAIS nor population databases (GnomAD). Conclusion. DSD diagnosis raises numerous challenges. People with DSD have increased risk of malignancy, especially when obesity and, systemic malformations are present; also, psychosocial issues in these children are associated with postpubertal age. [ABSTRACT FROM AUTHOR]

Background: Gonadal dysgenesis with minifascicular neuropathy (GDMN) is a rare autosomal recessive condition associated with biallelic DHH pathogenic variants. In 46, XY individuals, this disorder is characterized by an association of minifascicular neuropathy (MFN) and gonadal dysgenesis, while in 46, XX subjects only the neuropathic phenotype is present. Very few patients with GDMN have been reported so far. We describe four patients with MFN due to a novel DHH likely pathogenic homozygous variant and the results of nerve ultrasound assessment. Methods: This retrospective observational study included 4 individuals from 2 unrelated Brazilian families evaluated for severe peripheral neuropathy. Genetic diagnosis was performed with a peripheral neuropathy next-generation sequencing (NGS) panel based on whole exome sequencing focused analysis that included a control SRY probe to confirm genetic sex. Clinical characterization, nerve conduction velocity studies, and high-resolution ultrasound nerve evaluation were performed in all subjects. Results: Molecular analysis disclosed in all subjects the homozygous DHH variant p.(Leu335Pro). Patients had a striking phenotype, with marked trophic changes of extremities, sensory ataxia, and distal anesthesia due to a sensory-motor demyelinating polyneuropathy. One 46, XY phenotypically female individual had gonadal dysgenesis. High-resolution nerve ultrasound showed typical minifascicular formation and increased nerve area in at least one of the nerves assessed in all patients. Conclusion: Gonadal dysgenesis with minifascicular neuropathy is a severe autosomal recessive neuropathy characterized by trophic alterations in limbs, sensory ataxia, and distal anesthesia. Nerve ultrasound studies are very suggestive of this condition and may help to avoid invasive nerve biopsies. [ABSTRACT FROM AUTHOR]